Conditions: Sneddon-Wilkinson Acrodermatitis Continua of Hallopeau Pustular Psoriasis Palmoplantar Pustulosis
Keywords: Anakinra Pustular Psoriasis Palmoplantar Pustulosis DITRA Subcorneal Pustular Dermatosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 18
Healthy volunteers: no

Brief summary:
Background:

* Inflammatory pustular skin diseases are a type of autoinflammatory disease in which the immune system attacks the bodys tissues. These diseases cause painful and itchy skin rashes, eye and mouth irritation, joint pain and fever. Several drugs for treating these diseases suppress the immune system. However, they can cause severe side effects when taken over a long period of time.
* Interleukin 1 (IL-1) is a small protein that may be important in causing the inflammation seen in pustular skin disease. Anakinra is a drug that works by blocking IL-1. It has been effective in treating some inflammatory conditions such as rheumatoid arthritis. However, anakinra has not been studied for use in patients with pustular skin disease. Researchers want to see whether anakinra will be effective in treating pustular skin disease.

Objectives:

\- To see if anakinra can be used to treat inflammatory pustular skin disease.

Eligibility:

\- Individuals at least 18 years of age who have inflammatory pustular skin disease.

Design:

* Participants will be screened with a physical exam and medical history. Their disease will be evaluated with blood tests, urine tests and imaging studies. Skin biopsies may also be collected.
* Participants will have an initial visit to receive the first dose of anakinra. They will be shown how to give themselves daily injections of anakinra.
* Participants will take anakinra for up to 12 weeks as long as there are no severe side effects. During this time, they will keep a study diary to record the severity of any rashes, pustules, itching, fevers, and skin or joint pain. They will bring this diary to their study visits.
* Participants will have study visits at weeks 4, 8 and 12. Treatment will be monitored at these visits with blood tests, urine tests and physical exams. Depending on the effects of the treatment, participants may have the dose of anakinra increased or decreased.
* Participants will have a final study visit 4 weeks after they stop taking anakinra.

Detailed description:
Background:

* Inflammatory disorders that present with neutrophilic pustular skin lesions, including generalized pustular psoriasis, are characterized by severe cutaneous manifestations, generalized inflammation and significant morbidity.
* Recent studies in patients with phenotypically similar pustular diseases have identified two monogenic forms of neutrophilic pustular psoriasis implicating interleukin (IL)-1 in disease pathogenesis.

  * Deficiency of the Interleukin 1 (IL-1) receptor antagonist (IL1RN, DIRA) is an autosomal recessive condition characterized by severe generalized pustular eruptions in the neonatal period, osteopenia, lytic bone lesions, joint pain, respiratory insufficiency, thrombosis, elevated acute phase reactants and significant mortality. Patients with this condition have responded rapidly to IL-1 receptor antagonist, anakinra.
  * Deficiency of IL-36 receptor antagonist (IL-36RN/IL1F5, DITRA) is an autosomal recessive condition with episodic widespread pustular skin lesions, fevers and systemic inflammation defined by marked leukocytosis and elevated c-reactive protein.
* Both IL1RN and IL36RN/IL1F5 are highly expressed in epidermal keratinocytes, suggesting a role for keratinocytes in initiating innate immunity-mediated inflammatory skin diseases, and ultimately manifesting in a pustular phenotype.
* Patients with inflammatory pustular diseases often respond poorly to conventional treatment with methotrexate, cyclosporine and anti- tumor necrosis factor (TNF) agents.
* Two recent case reports describe patients with pustular psoriasis unresponsive to TNF inhibition who responded to anti-IL-1 receptor therapy with anakinra. We hypothesize that monogenic and polygenic inflammatory pustular skin diseases share common pathogenic mechanisms mediated by IL-1.
* We propose a phase 2 study that will utilize a collaborative bench-to-bedside approach, applying targeted anti-IL-1 therapy, novel imaging modalities, and laboratory techniques including immunohistochemistry, gene expression and cytokine studies, and in vitro manipulations of skin to dissect and validate pathways in these complex diseases.

Objectives:

-To characterize the clinical efficacy, optimal dosing and safety of anakinra in patients with pustular dermatoses.

Eligibility:

* Age greater than or equal to 18 years.
* Active macroscopic noninfectious pustular skin lesions involving greater than or equal to 5% of the total body surface area, or palmoplantar involvement.
* Histopathologic confirmation of epidermal neutrophilic pustulosis.
* Patients must have maintained a stable dose of immunosuppressant therapy, retinoids or anti-neutrophil therapy for 2 weeks prior to study initiation with resultant stable or worsening skin disease.
* Use of biologic agents requires a washout period of at least 3 half-lives prior to study initiation.
* Patients must have organ and marrow function as defined below:

  * leukocytes \>3,000/mcL
  * absolute neutrophil count \>1,500/mcL
  * platelets \>100,000/mcL
  * creatinine within normal institutional limits OR creatinine clearance \>60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal.

Design:

* A 16-week, open-label phase 2 study.
* Patients will initially receive treatment with anakinra 100 mg/day by self-administered subcutaneous injection.
* Disease response will be assessed every 4 weeks, and determination of dose escalation will be made based on clinical assessment. Dose escalation can increase up to 200 mg/day, and for patients \>75 kg up to 300 mg/day at the end of week 8.
* If a response is achieved with anakinra, other immunosuppressants administered for the purpose of treatment of pustular skin disease may be tapered per physician discretion.
* Clinical assessment, and laboratory and subjective data will be collected in-person every 4 weeks to determine disease response. Telephone assessments will be performed weekly.
* Twenty-five evaluable patients will be enrolled onto this trial. The accrual ceiling for this study will be set to 30.

Arms:
arm 1: An initial dose of anakinra 100 mg/day will be administered daily via self-administered subcutaneous injection. If active disease persists at this dose, anakinra dose may be escalated up to 200 mg/day injected subcutaneously daily at week 4 and 300mg at week 8.

Interventions: intervention 1: Anakinra
Intervention descriptions: intervention 1: An initial dose of anakinra 100 mg/day will be administered daily via self-administered subcutaneous injection. If active disease persists at this dose, anakinra dose may be escalated up to 200 mg/day injected subcutaneously daily at week 4 and 300mg/day at week 8.

Protocol document:
Prot_SAP_000.pdf: 
Abbreviated Title: Anakinra in pustular dermatoses  
Version Date: December 12, 2018 
Abbreviated Title: Anakinra in pustular dermatoses  
CC Protocol #: 13-AR-0071 M 
Version Date:  December 12, 2018 
NCT#: NCT01794117 
Title: A phase 2 study of anakinra in inflammatory pustular dermatoses: Evaluation of 
therapeutic efficacy and validation of pathogenic mechanisms 
NIH Principal Investigator: 
Edward W. Cowen, M.D., M.H.Sc. 
Acting Chief, Dermatology Branch  
Senior Clinician and Head, Dermatology Consultation Service 
National Institute of Arthritis and Musculoskeletal and Skin 
Diseases (NIAMS) 
10 Center Drive, Room 12N240A 
Bethesda, MD 20892 
Phone 301-480-7196 
cowene@mail.nih.gov  
 
PARTICIPATING SITE 
Institutional PI:  
Haley Naik, M.D.  
Institution:  
University of California San Francisco 
Institution FWA#: 
FWA00000068 
Address:  
1701 Divisadero Street, Third Floor,  
 
San Francisco, CA 94143 
Phone Number:  
781-367-5876 
Email:  
Haley.Naik@ucsf.edu 
 
Commercial Agent:    Anakinra/Kineret® 


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Abbreviated Title: Anakinra in pustular dermatoses   
Version Date: December 12, 2018 
 
 
PRÉCIS 
Background: 
• Inflammatory disorders that present with neutrophilic pustular skin lesions, including 
generalized pustular psoriasis, are characterized by severe cutaneous manifestations, 
generalized inflammation and significant morbidity.  
• Recent studies in patients with phenotypically similar pustular diseases have identified 
two monogenic forms of neutrophilic pustular psoriasis implicating interleukin (IL)-1 in 
disease pathogenesis. 
o Deficiency of the IL-1 receptor antagonist (IL1RN, DIRA) is an autosomal 
recessive condition characterized by severe generalized pustular eruptions in the 
neonatal period, osteopenia, lytic bone lesions, joint pain, respiratory 
insufficiency, thrombosis, elevated acute phase reactants and significant 
mortality. Patients with this condition have responded rapidly to IL-1 receptor 
antagonist, anakinra. 
o Deficiency of IL-36 receptor antagonist (IL-36RN/IL1F5, DITRA) is an 
autosomal recessive condition with episodic widespread pustular skin lesions, 
fevers and systemic inflammation defined by marked leukocytosis and elevated c-
reactive protein.  
• Both IL1RN and IL36RN/IL1F5 are highly expressed in epidermal keratinocytes, 
suggesting a role for keratinocytes in initiating innate immunity-mediated inflammatory 
skin diseases, and ultimately manifesting in a pustular phenotype.  
• Patients with inflammatory pustular diseases often respond poorly to conventional 
treatment with methotrexate, cyclosporine and anti-TNF agents. 
• Two recent case reports describe patients with pustular psoriasis unresponsive to TNF 
inhibition who responded to anti-IL-1 receptor therapy with anakinra. 
• We hypothesize that monogenic and polygenic inflammatory pustular skin diseases share 
common pathogenic mechanisms mediated by IL-1. 
• We propose a phase 2 study that will utilize a collaborative bench-to-bedside approach, 
applying targeted anti-IL-1 therapy, novel imaging modalities, and laboratory techniques 
including immunohistochemistry, gene expression and cytokine studies, and in vitro 
manipulations of skin to dissect and validate pathways in these complex diseases. 
Objective: 
• To characterize the clinical efficacy, optimal dosing and safety of anakinra in patients 
with pustular dermatoses. 
Eligibility: 
• Age ≥ 18 years.  
• Active macroscopic noninfectious pustular skin lesions involving ≥ 5% of the total body 
surface area, or palmoplantar involvement.   
• Histopathologic confirmation of epidermal neutrophilic pustulosis. 
• Patients must have maintained a stable dose of immunosuppressant therapy, retinoids or 
anti-neutrophil therapy for 2 weeks prior to study initiation with resultant stable or 
worsening skin disease.  


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Abbreviated Title: Anakinra in pustular dermatoses   
Version Date: December 12, 2018 
 
 
• Use of biologic agents requires a washout period of at least 3 half-lives prior to study 
initiation. 
• Patients must have organ and marrow function as defined below:  
 leukocytes  
 
 
 
 
>3,000/mcL 
 absolute neutrophil count 
 
>1,500/mcL 
 platelets  
 
 
 
 
 
>100,000/mcL 
 creatinine 
 
 
 
 
 
within normal institutional limits 
 
OR 
 creatinine clearance  
 
 
>60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal. 
Design: 
• A 16-week, open-label phase 2 study. 
• Patients will initially receive treatment with anakinra 100 mg/day by self-administered 
subcutaneous injection.  
• Disease response will be assessed every 4 weeks, and determination of dose escalation 
will be made based on clinical assessment. Dose escalation can increase up to 200 
mg/day, and for patients >75 kg up to 300 mg/day at the end of week 8. 
• If a response is achieved with anakinra, other immunosuppressants administered for the 
purpose of treatment of pustular skin disease may be tapered per physician discretion.  
• Clinical assessment, and laboratory and subjective data will be collected in-person every 
4 weeks to determine disease response. Telephone assessments will be performed 
weekly. 
• Twenty-five evaluable patients will be enrolled onto this trial. The accrual ceiling for this 
study will be set to 30. 
 


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Version Date: December 12, 2018 
 
 
TABLE OF CONTENTS 
PRÉCIS ........................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 4 
1 
INTRODUCTION .................................................................................................................. 8 
1.1 
Study Objectives .............................................................................................................. 8 
1.1.1 
Primary Objective ..................................................................................................... 8 
1.1.2 
Secondary Objectives................................................................................................ 8 
1.2 
Background and Rationale ............................................................................................... 8 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 13 
2.1 
Eligibility Criteria .......................................................................................................... 13 
2.1.1 
Inclusion Criteria .................................................................................................... 13 
2.1.2 
Exclusion Criteria ................................................................................................... 14 
2.1.3 
Recruitment Strategies ............................................................................................ 15 
2.2 
Screening Evaluation...................................................................................................... 16 
2.3 
Registration Procedures.................................................................................................. 16 
2.3.1 
Registration at the Clinical Center .......................................................................... 16 
2.3.2 
For Participating Site Registration .......................................................................... 16 
2.3.3 
Treatment Assignment and Randomization/ Stratification Procedures .................. 17 
2.4 
Baseline Evaluation ........................................................................................................ 17 
3 
STUDY IMPLEMENTATION ............................................................................................ 19 
3.1 
Study Design .................................................................................................................. 19 
3.1.1 
Dose Limiting Toxicity ........................................................................................... 20 
3.1.2 
Dose Escalation ....................................................................................................... 20 
3.2 
Drug Administration ...................................................................................................... 21 
3.3 
Dose Modifications ........................................................................................................ 22 
3.4 
Quality of life tools/questionnaires ................................................................................ 24 
3.5 
Study Flowchart ............................................................................................................. 26 
3.6 
Study Calendar ............................................................................................................... 28 
3.7 
Surgical Guidelines ........................................................................................................ 32 
3.8 
Ophthalmologic Procedures ........................................................................................... 32 
3.8.1 
Ophthalmic Examination with Dilation .................................................................. 32 


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3.8.2 
Fluorescein Angiography (if clinically indicated) .................................................. 32 
3.8.3 
Optical Coherence Tomography (OCT) ................................................................. 32 
3.8.4 
Microperimetry ....................................................................................................... 32 
3.9 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 33 
3.9.1 
Criteria for removal from protocol therapy ............................................................ 33 
3.9.2 
Off-Study Criteria ................................................................................................... 33 
3.9.3 
Off Protocol Therapy and Off Study Procedure ..................................................... 33 
3.10 Basic and Clinical Science Research Plan ..................................................................... 33 
3.10.1 Characterize and dissect inflammatory pathways in participant lesional skin and 
peripheral blood mononuclear cells ...................................................................................... 33 
3.10.2 Evaluate systemic inflammation in participants with pustular dermatoses using 
imaging modalities and biomarkers of cardiometabolic disease .......................................... 34 
3.10.3 Evaluate keratinocyte responses to targeted inflammatory stimuli including 
infectious agents and danger molecules. ............................................................................... 35 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 36 
4.1 
Supportive Care .............................................................................................................. 36 
4.1.1 
NIH Patients ............................................................................................................ 36 
4.1.2 
UCSF Patients ......................................................................................................... 36 
5 
BIOSPECIMEN COLLECTION .......................................................................................... 37 
5.1 
Correlative studies for research ...................................................................................... 37 
5.1.1 
Blood (Clinical and Research Samples) ................................................................. 37 
5.1.2 
Research samples collected at UCSF ...................................................................... 37 
5.2 
Sample Storage, Tracking and Disposition .................................................................... 37 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 38 
6.1 
Data Collection ............................................................................................................... 38 
6.2 
Response Criteria ........................................................................................................... 39 
6.2.1 
Definitions............................................................................................................... 39 
6.2.2 
Disease Parameters ................................................................................................. 40 
6.2.3 
Methods for Evaluation of Measurable Disease ..................................................... 40 
6.2.4 
Response Criteria .................................................................................................... 40 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
 
41 
7.1 
Definitions ...................................................................................................................... 41 


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7.1.1 
Adverse Event ......................................................................................................... 41 
7.1.2 
Suspected adverse reaction ..................................................................................... 41 
7.1.3 
Unexpected adverse reaction .................................................................................. 41 
7.1.4 
Serious..................................................................................................................... 41 
7.1.5 
Serious Adverse Event ............................................................................................ 41 
7.1.6 
Disability ................................................................................................................. 42 
7.1.7 
Life-threatening adverse drug experience ............................................................... 42 
7.1.8 
Protocol Deviation (NIH Definition) ...................................................................... 42 
7.1.9 
Non-compliance (NIH Definition) .......................................................................... 42 
7.1.10 Unanticipated Problem............................................................................................ 42 
7.2 
NIH Intramural IRB and Clinical Director Reporting ................................................... 42 
7.2.1 
NIH Intramural IRB and NCI CD Expedited Reporting of Unanticipated Problems 
and Deaths ............................................................................................................................. 42 
7.2.2 
NIH Intramural IRB Requirements for PI Reporting at Continuing Review ......... 43 
7.3 
NCI Guidance for Reporting Expedited Adverse Events for Multi-Center Trials ......... 43 
7.4 
Data and Safety Monitoring Plan ................................................................................... 43 
7.4.1 
Principal Investigator/Research Team .................................................................... 43 
7.4.2 
Safety Monitoring Committee (SMC) .................................................................... 44 
8 
STATISTICAL CONSIDERATIONS.................................................................................. 44 
9 
COLLABORATIVE AGREEMENTS ................................................................................. 44 
9.1 
Agreement Type ............................................................................................................. 44 
9.1.1 
Clinical Trials Agreement ....................................................................................... 44 
9.1.2 
Material Transfer Agreement .................................................................................. 44 
9.2 
Multi-Institutional Guidelines ........................................................................................ 44 
9.2.1 
IRB Approvals ........................................................................................................ 44 
9.2.2 
Amendments and Consents ..................................................................................... 45 
10 HUMAN SUBJECTS PROTECTIONS ............................................................................... 45 
10.1 Rationale For Subject Selection ..................................................................................... 45 
10.2 Participation of Children ................................................................................................ 45 
10.3 Participation of NIH Subjects Unable to Give Consent ................................................. 45 
10.3.1 For Participating Sites ............................................................................................. 45 
10.4 Evaluation of Benefits and Risks/Discomforts .............................................................. 45 


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10.5 Risks/Benefits Analysis.................................................................................................. 46 
10.6 Consent Process and Documentation ............................................................................. 46 
10.6.1 Telephone Reconsent .............................................................................................. 47 
10.6.2 Informed consent of non-English speaking subjects .............................................. 47 
11 PHARMACEUTICAL INFORMATION ............................................................................. 47 
11.1 Anakinra ......................................................................................................................... 47 
11.1.1 Source: Biovitrum ................................................................................................... 48 
11.1.2 Toxicity ................................................................................................................... 48 
11.1.3 Formulation and preparation ................................................................................... 50 
11.1.4 Stability and Storage ............................................................................................... 50 
11.1.5 Administration procedures ...................................................................................... 50 
11.1.6 Incompatibilities ..................................................................................................... 51 
12 REFERENCES ..................................................................................................................... 52 
13 APPENDIX A: FORBIDDEN DRUGS ............................................................................... 56 
14 APPENDIX B: PATIENT DIARY ....................................................................................... 57 
15 APPENDIX C: PATIENT HANDOUT ............................................................................... 58 
16 APPENDIX D: DOSE MODIFICATION FLOW CHART ................................................. 59 
17 APPENDIX E: SHORT FORM  36 (ENGLISH AND SPANISH) ...................................... 60 
18 APPENDIX F: DERMATOLOGY LIFE QUALITY (ENGLISH AND SPANISH) .......... 74 
19 APPENDIX G: DERMATOLOGY LIFE QUALITY SCORING TOOL ........................... 77 
20 APPENDIX H: PUSTULAR DERMATOSIS CLINICAL ASSESSMENT SCALE .......... 79 
21 APPENDIX I: HEALTH ASSESSMENT QUESTIONNAIRE........................................... 83 
22 APPENDIX J: JOINT EXAM CLINICAL ASSESSMENT FORM .................................... 85 
23 APPENDIX K: REVIEW OF SYSTEMS ............................................................................ 86 
24 APPENDIX L: CCR PROBLEM REPORT FORM ............................................................. 88 
 


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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
• To assess the proportion of participants treated with anakinra who achieve 50% disease 
improvement by the end of week 12, as measured by total body surface area involvement 
(TBSAI50). 
1.1.2 Secondary Objectives 
Clinical Objectives 
Laboratory Objectives 
• To characterize and analyze inflammatory pathways in skin and peripheral blood 
mononuclear cells using immunohistochemistry, cytokine and gene expression studies. 
• To evaluate systemic inflammation in patients with pustular dermatoses using novel imaging 
modalities, and assess biomarkers of cardiometabolic disease using novel techniques 
including nuclear magnetic resonance spectroscopy (NMR) and HDL cholesterol efflux 
capacity. 
• To evaluate keratinocyte responses to targeted inflammatory stimuli including infectious 
agents and danger molecules. 
 
1.2 
BACKGROUND AND RATIONALE 
Inflammatory disorders that present with neutrophilic pustular skin lesions, including generalized 
pustular psoriasis, are characterized by severe cutaneous manifestations, generalized 
inflammation and significant morbidity.  Interestingly, several recent studies in patients with 
phenotypically similar pustular diseases have identified two monogenic forms of neutrophilic 
pustular psoriasis implicating interleukin (IL)-1 in disease pathogenesis (Table 1).  Whereas 
dysregulated NFkB/TNF and IL-12/23 pathways have an established role in plaque-type 
psoriasis, these recent reports of monogenic pustular diseases have suggested a role for IL-1 in 
the development of pustular skin lesions.  
 
 
 
• To assess and characterize associations between inflammatory pustular dermatoses and 
systemic manifestations from ophthalmologic, cardiovascular, gastrointestinal, 
rheumatologic and immunologic perspectives. 
• To assess the changes in quality of life and functional measures during the course of anakinra 
therapy.   
• To determine adequate dosing and safety and assess toxicity with the use of anakinra in the 
management of inflammatory pustular dermatoses. 
 


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Version Date: December 12, 2018 
 
 
Table 1: Identified monogenic pustular skin diseases 
 
Deficiency of IL-1 Receptor 
Antagonist (DIRA) 
Deficiency of IL-36 Receptor 
Antagonist (DITRA) 
Mutation 
IL1RN 
IL-36RN/IL1F5 
Inheritance 
Autosomal recessive 
Autosomal recessive 
Founder and 
type of 
mutation 
Multiple founder deletion mutations 
described in Newfoundland, Puerto 
Rico, Lebanon, Holland and Brazil 1-4. 
Single founder homozygous missense 
mutation described in 8 Tunisian 
families5.  
Two additional missense mutations 
found in 3 unrelated patients from 
England6. 
Biological 
consequence 
Loss of function of IL1RA resulting in 
unopposed IL-1 activity  
Decreased IL36RA protein resulting 
in increased inflammatory cytokines 
(ex vivo) 
Clinical 
phenotype 
Generalized pustules 
Lytic bone lesions 
Respiratory insufficiency  
Thrombosis 
Elevated acute phase reactants  
Significant mortality 
Episodic widespread pustules 
Fevers 
Elevated acute phase reactants 
Treatment 
IL-1 receptor antagonist, anakinra 
None described^ 
^Two patients with pustular psoriasis (but no mutation in IL-36RN) were successfully treated 
with IL-1 blockade7. 
 
Deficiency of the IL-1 receptor antagonist (IL1RN, DIRA) leads to a severe generalized pustular 
eruption in the neonatal period, osteopenia, lytic bone lesions, joint pain, respiratory 
insufficiency, thrombosis, elevated acute phase reactants and significant mortality 1-4.  Loss of 
function mutations in the IL-36 receptor antagonist (IL-36RN, another member of the IL-1 
cytokine family, also known as IL1F5) were recently reported.  These mutations lead to an 
autosomal recessive form of generalized pustular psoriasis called DITRA (deficiency of IL-36 
receptor antagonist), a condition characterized by episodic widespread pustular skin lesions, 
fevers and systemic inflammation defined by marked leukocytosis and elevated c-reactive 
protein5, 6.  Both DIRA and DITRA are associated with similar histologic findings including 
epidermal hyperplasia and epidermal and dermal accumulation of neutrophils, T lymphocytes 
and dendritic cells, suggesting a common underlying pathogenic pathway.  Furthermore, both 
IL1RN and IL36RN/IL1F5 are highly expressed in epidermal keratinocytes, suggesting a role for 
keratinocytes in initiating innate immunity-mediated inflammatory skin diseases8, 9, and 
ultimately manifesting in a pustular phenotype.  
The availability of biologics targeting IL-1 provides us with potent clinical tools to dissect and 
validate these pathways in inflammatory pustular skin diseases.  Patients with pustular diseases 
often respond poorly to conventional treatment with systemic retinoids, methotrexate, 


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Version Date: December 12, 2018 
 
 
cyclosporine and anti-TNF agents.  Two recent case reports, however, describe patients with 
generalized pustular psoriasis refractory to TNF inhibition who responded to anti-IL-1 receptor 
antagonist therapy with anakinra7, 10.  However, beyond these case reports, the efficacy of IL-1 
inhibition along the spectrum of neutrophilic and pustular skin conditions has not yet been 
systematically explored, and analysis of pathogenesis is lacking.  
In light of these recent case reports and the efficacy of anakinra in other neutrophilic 
inflammatory diseases such as the periodic fever syndromes, we hypothesize that monogenic and 
polygenic pustular skin diseases share common pathogenic mechanisms mediated by IL-1.  We 
aim to elucidate the shared inflammatory pathways that contribute to the development of 
neutrophilic pustular diseases.  We propose a phase 2 study that will apply targeted anti-IL-1 
therapy to dissect and validate the inflammatory pathways important in these complex diseases. 
Published data and our preliminary studies provide support for common pathogenic pathways in 
pustular psoriasis.  Keratinocyte dysregulation leads to the production of inflammatory 
chemokines and cytokines, suggesting a role for keratinocytes in the initiation of inflammatory 
skin disease11.  DIRA and DITRA are caused by a mutation in IL-1 family members, IL1RN and 
IL36RN/IL1F5, which are highly expressed in the keratinocytes of the epidermis and suggest an 
important role of the innate immune system in disease development6.  Activated keratinocytes 
recruit neutrophils into the skin, and ultimately manifest in a pustular phenotype. 
Gene expression studies and therapeutic studies support an important contribution of the adaptive 
immune system in inflammatory diseases.  Published data and preliminary data from our gene 
expression studies suggest that keratinocytes or macrophages carrying CARD14 mutations or 
lacking the IL-36 receptor antagonist produce chemokines IL-8, CCL2 and CCL206.  IL-23 
derived from activated keratinocytes 11 or newly recruited myeloid dendritic cells 12 leads to IL-
17 production.  IL-17 promotes rapid neutrophil recruitment by inducing the secretion of 
proinflammatory mediators including IL-1, IL-6, IL-8, CXC ligand 1, TNF and GM-CSF, thus 
leading to a cycle of chronic inflammation 13. 
Systemic inflammatory states are also associated with metabolic and cardiovascular risk factors. 
Psoriasis is an example of such an inflammatory state which has been shown to have an 
association with metabolic and cardiovascular disease.  Experimentally induced in vivo 
inflammation in healthy humans is associated with robust activation of TNF-α and IL-6 followed 
by a systemic insulin-resistant state, metabolic dyslipidemia and decreased HDL function 14-17.   
Additionally, acute inflammation is associated with mildly reduced HDL levels and increased 
triglycerides and small dense LDL particles 14, 18.  These lipoprotein responses may be designed 
to prevent cholesterol loss at a time of high cell turnover.  However, sustained dyslipidemia due 
to chronic inflammation may be an important pro-atherogenic feature of systemic inflammatory 
conditions.  The lipoprotein pattern observed in conditions like psoriasis (low HDL, reduced apo 
A-I) may be associated with reduction of macrophage cholesterol efflux and blunting of reverse 
cholesterol transport19, an important anti-atherosclerotic pathway in vivo, recently shown to be 
associated with subclinical atherosclerosis and angiographic coronary artery disease 20.  The 
effect of inflammation-mediated macrophage efflux defects is poorly defined in inflammatory 
pustular diseases and may provide additional information about cardiovascular and metabolic 
diseases in systemic neutrophilic inflammatory states. 
One innovative method to investigate the systemic inflammatory burden is with [18F]-
fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT).  


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Version Date: December 12, 2018 
 
 
FDG-PET/CT is a validated imaging technique that enables measurements of inflammation in 
vivo21.  FDG uptake in the arterial walls reflects metabolic activity of inflammatory cells, 
particularly macrophages, involved in atherosclerotic lesions 22.  A recent study revealed that 
psoriasis is associated not only with clinically observed inflammation in the skin, but also foci of 
subclinical inflammation within the liver, joints, tendons, and aorta that were not explained by 
traditional cardiovascular risk factors or co-morbidities23.  Importantly, vascular inflammation 
detected by PET/CT represents a stable, reproducible phenotype over time in control settings24.  
This modality can aid in detection of vascular inflammation, and has high inter-and intra-reader 
reliability24.  Since vascular inflammation on FDG-PET/CT strongly predicted future major 
vascular events and responded to interventions for traditional CV risk factors 25-29, it may also 
serve as a useful marker for evaluating vascular inflammation, disease risk and disease response 
to therapy in a range of inflammatory conditions.  
Chronic inflammatory states have also been associated with development and progression of 
malignancy.  Notably, IL-1 is found in abundance at tumor sites and thought to play a role in 
carcinogenesis and tumor growth.  IL-1 inhibition by IL-1ra may reduce tumor invasiveness, 
pointing to the potential role of IL-1 inhibition in cancer therapy30, 31.  Although monoclonal 
gammopathies have been anecdotally associated with generalized pustular dermatoses32, 33, the 
association between inflammatory pustular dermatoses and malignancy has not been 
systematically studied and this study may provide further insights into the relationship between 
innate immunity and neoplastic disease.  
In this study, we intend to apply recent insights gained from monogenic disorders to understand 
the pathogenesis of neutrophilic pustular skin disorders.  We will utilize a fully collaborative 
bench-to-bedside approach, including targeted therapeutic intervention with anakinra and 
powerful and novel clinical and laboratory techniques including immunohistochemistry, gene 
expression analysis, in vitro manipulations of skin cells, and FDG PET CT to dissect these 
complex diseases. 
Anakinra is an IL-1 receptor 1 (IL-1R1) antagonist which competitively blocks the activity of IL-
1.  This agent was initially evaluated in sepsis patients, but is currently FDA approved for 
rheumatoid arthritis (RA)34-36. It is indicated for the management of signs and symptoms of 
moderately to severely active rheumatoid arthritis in patients 18 years of age or older who have 
failed 1 or more disease modifying antirheumatic drugs (DMARDs).  Anakinra has been 
evaluated in over 1400 RA patients in four randomized, double-blind, placebo-controlled trials37-
42.  It is also effective in the management of monogenic autoinflammatory diseases including 
neonatal-onset multisystem inflammatory disease (NOMID)43-45, as well as monogenic diseases 
with a pustular phenotype including DIRA1.   
The most common adverse event associated with anakinra is injection site reaction, which occurs 
in approximately 71% of patients and generally diminishes after 4-6 weeks of daily use.  The 
most serious adverse events associated with anakinra include neutropenia, thrombocytopenia and 
infection.  In placebo-controlled trials, 0.4% of patients treated with anakinra monotherapy 
developed neutropenia.  Two percent of patients concurrently treated with anakinra and the anti-
TNF agent etanercept developed neutropenia.  Two percent of anakinra patients receiving 
anakinra alone developed a decreased platelet count (WHO toxicity grade 1) as compared with 
0% of patients treated with placebo.  In placebo-controlled trials in RA patients, the incidence of 
infection was 39% versus 37% in patients receiving anakinra versus placebo, respectively.  The 


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incidence of serious infections was 2% versus 1% in patients treated with anakinra versus 
placebo, respectively.  Serious infections consisted of bacterial cellulitis, pneumonia, and bone 
and joint infections.  In patients receiving anakinra and etanercept concurrently for up to 24 
weeks, serious infections were noted in 7% of patients, consisting primarily of bacterial 
pneumonia and cellulitis42.  Although opportunistic infections were not observed in randomized, 
double-blind, placebo-controlled clinical trials, one case each of atypical mycobacterial 
infection, histoplasmosis and esophageal candidiasis were observed in an open-label extension 
study of 1346 RA patients40.    
Among 5300 RA patients treated with anakinra in clinical trials for a mean of 15 months, 8 
lymphomas were observed46.  This rate is similar to the rate expected for the RA patient 
population in which the rate of lymphoma is at least doubled47, 48.  The most common other 
malignancies observed in clinical trials were breast, respiratory system, and digestive system 
malignancies.  Four cases of melanoma were observed in one study and its long-term open-label 
extension, but none of the cases were attributed to anakinra40.  The significance of these findings 
is unclear and the role of IL-1 antagonists in the development of malignancy is not known. 
Patients with pustular psoriasis tend to respond poorly to anti-TNF agents and are typically 
excluded from clinical studies evaluating anti-TNF agents for psoriasis.  Infectious, neoplastic 
and cardiac complications are associated with anti-TNF therapy.  In 2002, the BIOBADASER 
(Base de Datos de Productos Biologicos de la Sociedad Espanola de Reumatologia) database 
reported 17 cases of tuberculosis among 1355 patients treated with infliximab.  Eleven patients 
(65%) manifested extrapulmonary involvement and 2 deaths occurred (12% mortality rate), as 
compared with an expected 15% rate of extrapulmonary TB amongst patients with TB and 4.6% 
mortality in the general U.S. population at that time49.  Serious bacterial and fungal opportunistic 
infections have also been reported in patients treated with anti-TNF agents50.  An increased risk 
of worsening congestive heart failure (CHF) has been demonstrated with high-dose infliximab 
(all-cause mortality or CHF hospitalization: 16% at week 14, 26% at week 28)51.  Adverse 
cardiac outcomes in patients with CHF are thought to be a class effect with anti-TNF agents.  
Data from the National Databank for Rheumatic Diseases also suggests a modest increase in 
lymphoma with TNF-blockers, with an incidence ratio of 2.6 (95% CI: 1.4-4.5) in patients 
treated with infliximab, 3.8 (95% CI: 1.9-7.5) in patients treated with etanercept and 1.9 (95% 
CI: 1.3-2.7) in the patient population overall52.  Demyelinating disorders, liver toxicity and drug-
induced systemic lupus erythematosus have also been described in association with anti-TNF 
agents53, 54.   
Anakinra use for this study is exempt from an investigational new drug (IND) application 
because this investigation: 
1) Is not intended to be reported to the FDA as a well-controlled study in support of a new 
indication for use of the drug product, nor intended to be used to support any other 
significant change in the labeling for the drug; 
2) Is not intended to support a significant change in advertising to an existing lawfully marketed 
prescription drug product; 
3) Does not involve a route of administration or dosage level or use in a patient population or 
other factor that significantly increases the risks (or decreases the acceptability of the risks) 
associated with the use of the drug product; 


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4) Will be conducted in compliance with the requirements for institutional review set forth in 
FDA regulations 21 CFR 56, and requirements for informed consent as set forth in FDA 
regulations 21 CFR 50. 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Females and males, aged ≥18.   
2.1.1.2 Patients must demonstrate active noninfectious inflammatory pustular skin lesions 
resembling pustular psoriasis and involving ≥ 5% total body surface area, or 
palmoplantar involvement.  Conditions may include, but are not be limited to, pustular 
psoriasis, Sneddon-Wilkinson disease, subcorneal pustular dermatosis, reactive arthritis, 
palmoplantar pustulosis, acrodermatitis continua of Hallopeau and palmoplantar 
pustular psoriasis. 
2.1.1.3 Patients must have histopathologic confirmation of epidermal neutrophilic pustular skin 
disease. 
2.1.1.4 If taking immunosuppressants, retinoids or anti-neutrophil therapy, participants must 
maintain stable doses of these medications during the 2 weeks prior to study initiation.  
2.1.1.5 Patients must have stable topical medication regimen for 2 weeks prior to study initiation  
2.1.1.6 Patients must have normal organ and marrow function as defined below:  
 leukocytes  
 
 
 
 
>3,000/mcL 
 absolute neutrophil count 
 
>1,500/mcL 
 platelets  
 
 
 
 
 
>100,000/mcL 
 creatinine 
 
 
 
 
 
within normal institutional limits 
 
OR 
 creatinine clearance  
 
 
>60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal. 
 
2.1.1.7 Quantiferon TB Gold must be performed for screening for mycobacterium tuberculosis 
infection. However, a tuberculin skin test may be placed if the Quantiferon TB gold test 
is indeterminate (see below). Patients must have a negative Quantiferon TB Gold (or 
tuberculin skin test) or evidence of appropriate treatment prior to study entry (see 
below). 
Negative Quantiferon TB gold  
Begin study 
Indeterminate Quantiferon TB gold 
Place tuberculin skin test (TST). If 
negative, begin study.  
Positive Quantiferon TB gold or TST 
Negative CXR and ≥ 1month Tx 
prior to 1st dose of study drug 
 


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2.1.1.8 Patients must be able to understand and sign a written informed consent document and 
complete study-related procedures and questionnaires.  
2.1.2 Exclusion Criteria 
2.1.2.1 Enrollment in any other investigational treatment study or use of an investigational agent, 
or has not yet completed at least 3 half-lives since ending another investigational device 
or drug trial.  
2.1.2.2 History of treatment with canakinumab within the 12 months prior to study initiation. 
2.1.2.3 History of anakinra use. 
2.1.2.4 History of phototherapy within 2 weeks prior to study initiation. 
2.1.2.5 Patients may NOT concurrently be on biologic therapy such as etanercept, adalimumab, 
alefacept, infliximab, rituximab or rilonacept (APPENDIX A: FORBIDDEN 
DRUGS). If there is a history of use of biologic agents, there must be a washout period 
of at least 3 half-lives prior to study initiation. 
2.1.2.6 Subjects who experience a significant flare after discontinuation of a TNF inhibitor as 
part of this study that requires urgent medical management or hospitalization, or in the 
estimation of the principal investigator poses excessive risk to the patient to enter the 
study. 
2.1.2.7 Other defined dermatologic conditions which may include pustules as part of the clinical 
presentation, but which clinically and/or histologically do not resemble pustular 
psoriasis. Examples include, but are not limited to acute generalized exanthematous 
pustulosis (AGEP, a drug-induced pustular dermatosis typically caused by beta-lactam 
antibiotics, tetracyclines, oral antifungals and other drugs), bacterial or fungal 
folliculitis, cutaneous candidiasis, tinea pedis, tinea corporis, neutrophilic eccrine 
hidradenitis or eosinophilic pustular folliculitis (Ofuji syndrome). 
2.1.2.8 Known diagnosis of DIRA. 
2.1.2.9 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to anakinra or other agents used in study.  Known hypersensitivity to 
CHO-cell derived biologics or any components of anakinra.  
2.1.2.10 Treatment with a live virus vaccine during the 3 months prior to baseline visit.  No live 
vaccines will be allowed throughout the course of this study.  
2.1.2.11 Patients with active or untreated malignancy-- with the exception of cutaneous basal or 
squamous cell carcinomas, or in situ cervical carcinoma-- are ineligible because of the 
immunomodulating effects of anakinra.  The risk of recurrent malignancy secondary to 
this drug is unknown. 
2.1.2.12 Presence of active infection.  History of exposure to TB (positive PPD or Quantiferon 
TB gold) who have not been treated with a TB prophylaxis regimen for at least one 
month.  
2.1.2.13 Chest x-ray (if Quantiferon TB Gold is positive) demonstrating pleural scarring and/or 
calcified granuloma consistent with prior or current untreated TB.  
2.1.2.14 History of chronic or recurrent infection including but not limited to HIV, hepatitis B or 
hepatitis C.   


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2.1.2.15 Individuals with severe or uncontrolled recurrent cutaneous infections who are 
considered at elevated risk for serious infection on anakinra therapy will be excluded 
per physician discretion. 
2.1.2.16 Presence of other known significant autoimmune or inflammatory disease.  Examples 
include major chronic infectious/inflammatory/immunologic diseases such as systemic 
lupus erythematosus, rheumatoid arthritis, Sjogren’s syndrome and periodic fever 
syndromes.  
2.1.2.17 Other immunoregulatory or immunodeficiency diseases, such as multiple sclerosis. 
2.1.2.18 Individuals with life-threatening or disabling inflammation of the eyes, gut or joints 
requiring urgent or immediate medical attention, or at the physician’s discretion. 
2.1.2.19 Subjects for whom there is concern about compliance with the protocol procedures.  
2.1.2.20 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, uncontrolled or unmonitored psychiatric illness/social situations, or history of 
congestive heart failure, unstable angina pectoris or medically significant cardiac 
arrhythmia that would limit compliance with study requirements.  
2.1.2.21 Presence of other severe acute or chronic medical or psychiatric condition, or 
significant laboratory abnormality requiring further investigation that may cause undue 
risk for the subject’s safety, inhibit protocol participation, or interfere with 
interpretation of study results, and in the judgment of the investigator would make the 
subject enrollment inappropriate.  
2.1.2.22 The effects of anakinra on the developing human fetus are unknown.  Women of child-
bearing potential and men must agree to use adequate contraception (hormonal or 
barrier method of birth control or abstinence) prior to study entry and for the duration of 
study participation.  Should a woman become pregnant or suspect she is pregnant while 
she or her partner is participating in this study, she should inform her treating physician 
immediately.  
Females of childbearing potential must have a negative serum pregnancy test at 
screening.  Females must also have a negative serum pregnancy test at baseline and 
prior to performance of any radiologic procedure or administration of study medication 
and during each visit.  Lactating mothers will discontinue breastfeeding prior to study 
enrollment. 
2.1.2.23 Pregnant or lactating females. Women of non-childbearing potential is defined as 
women who are postmenopausal (no menses for > one year) or who have had a 
hysterectomy and will not require B-hCG testing.   
2.1.3 Recruitment Strategies 
Participants representing all ethnic groups and racial categories will be recruited for this study. 
Recruitment strategies may include a) referrals from NIH research physicians, b) referrals from 
non-NIH physicians, c) referrals from University of California, San Francisco (UCSF) and local 
area providers, d) NIH Patient Recruitment website, e) NIH Clinical Center Facebook page, f) 
print media including newspapers, specialized journals and magazines, g) advertisements posted 
on internet websites including Clinicaltrials.gov and ResearchMatch.org, local and regional 
dermatology association websites, h) interactions with patient and physician organizations in the 
local and national dermatology community including the National Psoriasis Foundation, i) 


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dissemination of IRB approved flyers at designated locations, j) dissemination of IRB-approved 
recruitment letters sent to potentially eligible participants identified by investigators via review 
of our patient database and charts.  
2.2 
SCREENING EVALUATION 
➢ Assessments to be completed prior to enrollment 
• Skin biopsy for hematoxylin and eosin staining to confirm diagnosis if prior 
confirmational biopsy has not been performed  
• Microbiologic culture of pustule confirming noninfectious etiology 
➢ Assessments to be completed within 8 weeks prior to enrollment 
• Quantiferon TB gold 
▪ Chest X-ray to ensure absence of radiographic evidence of tuberculosis only if 
Quantiferon TB gold or tuberculin skin test is positive 
• Medical history and medication review 
• CBC with differential 
• Serum B-hCG in females of childbearing potential. Not required for females who are 
status-post hysterectomy or postmenopausal (no menses for >one year).  
• Blood urea nitrogen and serum creatinine 
• Anti-HIV-1/2 screen 
• Viral Markers Hepatitis Screen (HBsAg and anti-HCV) 
2.3 
REGISTRATION PROCEDURES 
2.3.1 Registration at the Clinical Center 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to:  NCI Central Registration Office ncicentralregistration-l@mail.nih.gov.  
After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to 
advise them of the acceptance of the patient on the protocol prior to the release of any 
investigational agents.  Verification of Registration will be forwarded electronically via e-mail to 
the research team. A recorder is available during non-working hours.  
2.3.2 For Participating Site Registration 
A protocol registration form will be supplied by the NIAMS study coordinator and updates will 
be provided as needed. Subject eligibility and demographic information is required for 
registration.  Once eligibility is confirmed, complete the protocol registration form which 
contains the eligibility checklist, indicating that the patient is being registered for treatment and 
send to NIAMS study coordinator. In addition, source documents supporting the eligibility 
criteria must be sent to the NIAMS study coordinator. The NIAMS study coordinator will notify 
you either by e-mail or fax that the protocol registration form has been received which will 
include the unique patient/subject ID number. Questions about eligibility should be directed to 
the study coordinator or PI.  Questions related to registration should be directed to the study 
coordinator. 


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2.3.3 Treatment Assignment and Randomization/ Stratification Procedures 
Cohort 
Number 
Name 
Description 
1 
Cohort 1 
Subjects with pustular skin disease 
Arm 
Number 
Name 
Description 
1 
Arm 1 
An initial dose of anakinra 100 mg/day will be 
administered daily via self-administered subcutaneous 
injection. If active disease persists at this dose, anakinra 
dose may be escalated to 200 mg/day injected 
subcutaneously daily at week 4 and 300mg/day at week 
8 
 
Stratifications 
None 
Randomization and Arm Assignment 
This is an open-label non-randomized study. All subjects in cohort 1 will be directly assigned to 
arm 1. 
2.4 
BASELINE EVALUATION 
HISTORY AND PHYSICAL EXAMINATION 
• Medication review 
• Directed physical examination, including body mass index calculation 
• Detailed skin examination including: 
o Total body surface area involvement (TBSAI) 
o Physician global assessment (PGA) 
o Pustular psoriasis assessment severity index (PPASI) 
o Palmoplantar psoriasis assessment severity index (PPPASI), if appropriate 
BLOOD AND TISSUE 
• Complete blood count with differential  
• Serum creatinine and urea nitrogen 
• Serum calcium, phosphorus  
• Parathyroid hormone 
• Serum 25-OH Vitamin D 
• Hepatic panel including alkaline phosphatase 
• Serum albumin and total protein 
• Lipid Panel (total cholesterol, triglycerides, LDL, HDL) 
• Serum insulin level 


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• Serum C-peptide 
• Acute phase reactants: erythrocyte sedimentation rate, serum high-sensitivity C-reactive 
protein 
• Serum ferritin 
• Serologies: anti-nuclear antibody, anti-dsDNA antibodies, anti-ENA antibodies, 
rheumatoid factor, C3, C4, CH50.  
• Quantitative serum immunoglobulins  
• HLA class I and II typing 
• Serum protein electrophoresis 
• Anti-streptolysin O titer 
• Viral Markers Hepatitis Screen (HbsAg, Anti-HCV) 
• Skin biopsies: up to 3 (lesional x2, and non-lesional skin x1) (performed at the 
investigator’s discretion) 
• Serum, plasma and tissue cytokine levels 
• Serum beta human chorionic gonadotropin (not required if females are status post 
hysterectomy or postmenopausal) 
• Serum glucose 
• Serum storage for research 
URINE 
• Urine protein electrophoresis 
• Urinalysis 
• Urine calcium, phosphorus 
QUESTIONNAIRES/MEASUREMENTS 
• Quality of life assessments/questionnaires including DLQI, SF-36, Pruritus VAS, Pain 
VAS, and Overall Disease Severity VAS (details in Section 3.4) 
• Total body photography (performed at the investigator’s discretion) 
CONSULTATIONS 
The following consultations will be conducted at the investigator’s discretion: 
• Rheumatologic consultation including baseline joint examination with assessment by 
ACR criteria, including Health Assessment Questionnaire  
• Cardiometabolic evaluation including baseline electrocardiogram  
• Ophthalmologic examination  
• Gastrointestinal consultation when indicated  
RADIOLOGICAL 
The following procedures will be conducted at the investigator’s discretion: 
• Total body research FDG-PET CT scan  
• Joint MRI of affected joints  


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3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
This will be a phase 2, open label, prospective interventional 16-week dose titration study.  
Patients will complete a daily diary during the entire 16-week study course.  Patients will be 
instructed to score the severity of rash, pustules, itch, skin pain, joint pain and overall well-being 
into their daily diaries.  They will also document fever and doses of medications in their diaries. 
(APPENDIX B: PATIENT )   
At the baseline visit, clinical assessments, and laboratory, histopathologic and subjective data 
will be collected.  All enrolled patients will initially receive treatment with anakinra 100 mg/day 
via self-administered subcutaneous injection.  The first dose of anakinra will be administered 
under supervision in the clinic.   
At week 4, disease response will be assessed by clinical exam, laboratory markers and evaluation 
of patient diaries that are returned to clinic.  Determination for dose escalation will be made 
based on week 4 assessments. Those patients who do not achieve complete disease clearance 
with initial anakinra dosing will be increased to the next incremental dose level (see Section 
3.1.2).  
At week 8, patients will return for clinical evaluation and patients who do not achieve complete 
disease clearance on anakinra have the option of dose escalation up to the next incremental dose 
level. All patients will stop anakinra at week 12. 
Patients will return for an Off Study visit at week 16, approximately 28 days after their final dose 
is administered. Considering personal/work/travel/other obligations, a period of no more than 1 
week before or after the Week 4, 8, or 12 visits, and 2 weeks before or after the Week 16 visit 
may be permitted. 
Total body photographs will be taken at baseline, week 4, week 8, week 12 and week 16 (at the 
investigator’s discretion). 
With the patient’s consent, and at the discretion of the investigator, a skin biopsy for research 
will be taken at baseline and week 12. Skin biopsies will be taken from lesional and non-lesional 
skin. Non-lesional skin will be obtained for the purpose of comparison with lesional skin in 
immunohistochemistry, cytokine and gene expression studies, as well as in vitro keratinocytes 
studies. 
Between scheduled clinic visits, disease status will be assessed by telephone at weeks 1-3, 5-7 
and 9-11. Following discontinuation of anakinra at week 12, disease activity and adverse event 
monitoring will be assessed by telephone at weeks 13-15. A period of no more than 3 days 
before or after weeks 1-3, 5-7, 9-11, and 13-15 may be permitted. The completed patient diaries 
will be assessed upon their return to the clinic. 
Once clinical disease is deemed to be quiescent, other immunosuppressants administered for the 
purpose of treatment of pustular skin disease may be tapered per physician discretion.  Doses of 
anakinra and immunosuppressants will be recorded throughout the study period until week 12 in 
order to assess mean required dose of anakinra for maximum improvement of disease, and the 
number of participants who are able to taper other immunosuppressants while on anakinra 
therapy.   


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The primary outcome measure and all secondary outcome measures (see section 1.1.2), will be 
assessed by the multidisciplinary study team at the conclusion of week 12.  
Clinical assessment, and laboratory and subjective data will be collected monthly with the aid of 
primary care physicians during months when participants do not travel to the National Institutes 
of Health or participating site clinic.  At any time during the study time period, serious adverse 
events grade 3 or greater that are possibly, probably or definitely related to the study drug will be 
reported to the IRB.  Participants will hold therapy immediately and be evaluated emergently.  
Participants removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event. 
A total of 25 participants will be recruited for this study.  It is anticipated that 1-2 patients per 
month will enroll onto this trial.  In order to allow for a small number of unevaluable patients, 
the accrual ceiling will be set at 30 patients.  Accrual of 30 patients would be estimated to last up 
to 24 months.  If 0 of the first 9 patients fail to respond to anakinra therapy by week 12, we will 
halt further patient recruitment. 
3.1.1 Dose Limiting Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with anakinra until 
the end of study participation, regardless of inclusion in primary response evaluation. 
This study will utilize version 4.0 of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) (http://ctep.cancer.gov/reporting/ctc.html) for toxicity and adverse event reporting. 
Only those adverse events deemed possibly, probably, or definitely related to anakinra will be 
used in the definition of dose-limiting toxicity. Greater or equal to CTCAE grade 3 toxicity in 
any enrolled subject thought to be possibly, probably or definitely associated with anakinra will 
be reported to the IRB.  The adverse event will be presented to the IRB and safety monitor for 
review and consideration of protocol modification including possible trial termination.  Events 
that are considered disease-related will not be considered dose limiting or medication-induced 
adverse events. 
3.1.2 Dose Escalation 
An initial dose of anakinra 100 mg/day will be administered daily via self-administered 
subcutaneous injection. If pustule formation persists at this dose, anakinra dose may be escalated 
up to 200 mg/day injected subcutaneously daily at week 4. Participants will be re-assessed at 
week 8, and if pustule formation persists and the patient weighs ≥75kg, the dose may be 
escalated up to a maximum 300 mg/day. 
 
 
 
 
 
 
 
Dose Escalation Schedule 
Dose Level 
Dose of anakinra 
Level -1* 
50mg SC daily 
Level 1 
100 mg SC daily 
Level 2 
200 mg SC daily 
Level 3 
300 mg SC daily (patients ≥75kg only) 


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*Patients who experience an adverse event on dose level 1 that requires dose reduction may be 
reduced to dose level -1, 50mg SC daily (see Section 3.3).  Patients who require dose reduction 
due to an adverse event at any point in this study will not be eligible for dose escalation.  
 
Dose escalation will follow the rules outlined in the Table below. 
 
If a patient experiences a Grade 2 adverse event probably or definitely related to anakinra within 
7 days prior to a scheduled dose escalation, dose escalation will be postponed until resolution of 
the adverse event or a maximum of 14 days, whichever is shorter.  
3.2 
DRUG ADMINISTRATION 
Anakinra is supplied in single-use 1 ml prefilled glass syringes with 27 gauge needles as a 
sterile, clear, colorless-to-white, preservative-free solution for daily subcutaneous (SC) 
administration.  Each 1 ml prefilled glass syringe contains: 0.67 ml (100 mg) of anakinra in a 
solution (pH 6.5) containing sodium citrate (1.29 mg), sodium chloride (5.48 mg), disodium 
EDTA (0.12 mg), and polysorbate 80 (0.70 mg) in water for injection, USP.  
Patients will be instructed verbally and in writing that anakinra should be protected from light, 
stored in the refrigerator at 2oC to 8oC (36oF to 46oF) away from children, and never frozen.  
Patients will be instructed not to use any syringe if the solution appears discolored or cloudy or 
has been at room temperature ≥ 24 hours.  Patients will be instructed to avoid shaking the pre-
filled syringes, to use each syringe only once, and to inject the entire volume of solution.  
Patients will receive a diagram (APPENDIX C: PATIENT HANDOUT) of body sites where 
anakinra is to be injected, emphasizing the importance of avoiding veins, arteries and injecting 
into a new site each day.  Self-injection demonstration and technique will be provided once the 
baseline visit has concluded. 
All patients will be given a puncture-resistant container for proper disposal of syringes after use. 
Time of Assessment 
Escalation Decision Rule 
Baseline 
• Enter each patient onto study at dose level 1 
Week 4 
• If patient has achieved complete clearance of 
pustular and plaque disease, remain at dose level 1 
• If patient has not achieved complete pustule and 
plaque clearance, increase to next incremental dose 
level 
Week 8 
• If patient has achieved complete clearance of 
pustular and plaque disease, remain at current dose 
level 
• If patient has not achieved complete clearance of 
pustular and plaque disease AND patient weighs 
≥75kg, increase to next incremental dose level 


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All patients will initiate anakinra therapy with one 1ml (100 mg) prefilled syringe injected 
subcutaneously daily.  Those who achieve disease quiescence on this dose by week 4 will 
continue at this dose until week 12.  
Those who do not demonstrate disease quiescence at week 4 will increase their dose to 2-1ml 
prefilled syringes (total of 200 mg) to be injected subcutaneously daily. Those individuals who 
weight >75kg and do not demonstrate disease quiescence by week 8 on anakinra 200 mg/day 
will be instructed to increase their dose to 3-1ml prefilled syringes (total of 300mg) injected 
subcutaneously daily. 
Patients who miss a dose will be instructed to administer the dose as soon as they remember.  
However, if it is almost time to administer the next dose, the patient will be directed to skip the 
missed dose and proceed with their regularly scheduled dose.  Patients will be reminded to avoid 
double-dosing in an effort to make up the missed dose. 
If a patient misses a dose of study drug, it will be recorded in the medical record and on the CRF. 
Missed doses will not be reported to the IRB as a protocol deviation unless the patient misses >5 
doses per month. 
3.3 
DOSE MODIFICATIONS 
All dose modifications must be discussed with the PI. This study will utilize version 4.0 of the 
NCI Common Terminology Criteria for Adverse Events (CTCAE) 
(http://ctep.cancer.gov/reporting/ctc.html) for toxicity and adverse event reporting.  Expected 
pre-existing or concurrent manifestations of inflammatory pustular dermatoses include fatigue, 
malaise, pain, pruritus, arthritis, enthesitis, alopecia, pustular and papular skin lesions, 
hypopigmentation, hyperpigmentation, skin dryness, nail changes, koebnerization at sites of 
trauma or injections, uveitis, conjunctivitis, rash, hypocalcemia, hypoalbuminemia and 
leukocytosis.  Any of the above symptoms newly presenting after initiation of anakinra must be 
carefully evaluated for attribution, i.e., new skin rash may be biopsied to determine drug reaction 
versus pustular dermatosis.  See APPENDIX D: DOSE MODIFICATION FLOW CHART 
for Dose Modification Flow Chart. 
 
Adverse event 
CTCAE grade/attribution 
Protocol Action 
Any adverse event (excluding 
infection, treatment-related 
malignancy) 
Grade 2 >7 days that is probably 
or definitely related to anakinra.  
Hold study drug; *If AE 
resolves to ≤ grade 1 or 
baseline within 14 days: 
resume dose at same dose 
level. ** If AE does not 
resolve to ≤ grade 1 or 
baseline within 14 days: 
patient comes off drug.  
Any adverse event (excluding 
infection, treatment-related 
malignancy) 
Same grade 2 >7 days recurs 
that is probably or definitely 
related to anakinra.  
 
 
Hold study drug; *If AE 
resolves to ≤ grade 1 or 
baseline within 14 days: 
decrease dose by 1 dose 
level. **If AE does NOT 


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resolve to ≤ grade 1 or 
baseline within 14 days: 
patient comes off drug. 
Any adverse event (excluding 
infection, treatment-related 
malignancy) 
Same grade 2 >7 days 
recurs after dose reduction 
that is probably or definitely 
related to anakinra.  
 
Patient comes off drug.  
Any adverse event (excluding 
infection, treatment-related 
malignancy) 
Grade 3 that is probably or 
definitely related to 
anakinra.  
 
 
Hold study drug; *If AE 
resolves to ≤ grade 1 or 
baseline within 14 days: 
decrease dose by 1 dose 
level. **If AE does NOT 
resolve to ≤ grade 1 or 
baseline within 14 days: 
patient comes off drug. 
Any adverse event (excluding 
infection, treatment-related 
malignancy) 
Same grade 3 recurs after dose 
reduction that is probably or 
definitely related to anakinra. 
Patient comes off drug. 
Any adverse event (excluding 
infection, treatment-related 
malignancy) 
Grade 4 that is probably or 
definitely related to 
anakinra.  
 
 
Patient comes off drug. 
Infection 
Grade 2 that is probably or 
definitely related to anakinra 
Hold study drug until 
completion of antibiotic 
course and resolution of 
infection, then restart at same 
dose level. 
Infection 
Grade 2 recurs that is probably 
or definitely related to anakinra 
Hold study drug until 
completion of antibiotic 
course and resolution of 
infection, then decrease dose 
by 1 dose level. 
Infection 
Grade 2 recurs after dose 
reduction that is probably or 
definitely related to anakinra 
Patient comes off drug. 
Infection  
Grade 3 that is probably or 
definitely related to anakinra 
Patient comes off drug. 
Infection 
Grade 4 
Patient comes off drug. 
Treatment-related 
malignancy 
Grade 3  
Patient comes off drug. 
Treatment-related 
Grade 4  
Patient comes off drug. 


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Version Date: December 12, 2018 
 
 
malignancy 
 
Exceptions to the above treatment modifications:  
1. Alopecia any grade 
2. Grade 2 anorexia  
3. Grade 2 fever 
4. Grade 2 fatigue 
5. Grade 2 flu-like symptoms 
6. Grade 2 chills 
7. Grade 2 headache 
8. Grade 2 hypoalbuminemia 
9. Hypocalcemia toxicity grade should be assigned based on the calcium level corrected for  
degree of hypoalbuminemia according to the following formula: albumin 1 gram/dL: total 
calcium 0.2 mmol/L. Ionized calcium can also be used to assess toxicity.  
10. Grade 2 injection site reaction 
11. Grade 2 malaise 
12. Grade 2 nausea 
13. Grade 2 dry skin  
14. Grade 2 skin or soft tissue infection 
15. Grade 2 paronychia 
16. Basal cell carcinoma or squamous cell carcinoma of the skin 
 
Doses withheld while recovering from an adverse event should not be made up. 
3.4 
QUALITY OF LIFE TOOLS/QUESTIONNAIRES 
The following quality of life instruments will be administered at baseline, week 4, week 8 and 
week 12: 
1. 36-item Short Form Health Survey is a self-administered multi-purpose, short-form 
health survey with 36 questions yielding an 8-scale profile of functional health and well-
being scores as well as psychometrically-based physical and mental health summary 
measures and a preference-based health utility index.  It is a generic measure.  This scale 
has been used for the measurement of general health status quality of life.  This 
questionnaire will be administered at baseline, week 4, week 8, week 12 and week 16.  
(10-12 minutes) (APPENDIX E: SHORT FORM  36 (ENGLISH AND SPANISH)) 
2. Dermatology Life Quality Instrument (DLQI) is a 10-item questionnaire which assesses 
impact of skin disease on life quality.  It is a validated questionnaire which has been used 
in 33 different skin conditions in 32 countries and is available in 55 languages.  It is the 
most frequently used instrument in studies of randomized controlled trials in 
dermatology.  This questionnaire will be administered at baseline, week 4, week 8, week 
12 and week 16.  (2 minutes) (APPENDIX F: DERMATOLOGY LIFE QUALITY 
(ENGLISH AND SPANISH)) 


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3. Pruritus Visual Analog Scale is a self-administered psychometric response instrument 
which measures subjective characteristics or attitudes that cannot be directly measured.  
It ranges from 0-10.  This scale has been used for measurement in a variety of 
dermatologic settings. This questionnaire will be administered at baseline, week 4, week 
8, week 12 and week 16.  (1 minute) (APPENDIX H: PUSTULAR DERMATOSIS 
CLINICAL ASSESSMENT SCALE) 
4. Skin Pain Visual Analog Scale is a self-administered psychometric response instrument 
which measures subjective characteristics or attitudes that cannot be directly measured.  
It ranges from 0-10.  This scale has been used for measurement in a variety of 
dermatologic settings.  This questionnaire will be administered at baseline, week 4, week 
8, week 12 and week 16. (1 minute) (APPENDIX H: PUSTULAR DERMATOSIS 
CLINICAL ASSESSMENT SCALE)  
5. Joint Pain Visual Analog Scale is a self-administered psychometric response instrument 
which measures subjective characteristics or attitudes that cannot be directly measured.  
It ranges from 0-10.  This scale has been used for measurement in a variety of 
dermatologic settings.  This questionnaire will be administered at baseline, week 4, week 
8, week 12 and week 16.  (1 minute) (APPENDIX H: PUSTULAR DERMATOSIS 
CLINICAL ASSESSMENT SCALE) 
6. Overall Disease Severity Visual Analog Scale is a self-administered psychometric 
response instrument which measures subjective characteristics or attitudes that cannot be 
directly measured.  It ranges from 0-10.  This scale has been used for measurement in a 
variety of health settings.  This questionnaire will be administered at baseline, week 4, 
week 8, week 12 and week 16.  (1 minute) (APPENDIX H: PUSTULAR 
DERMATOSIS CLINICAL ASSESSMENT SCALE)  
7. Health Assessment Questionnaire (HAQ) is a self-administered questionnaire which aims 
to assess health-related quality of life longitudinally based on five patient-centered 
dimensions: disability, pain, medication effects, costs of care, and mortality. This 
instrument is used in the calculation of the ACR70. This questionnaire will be 
administered with each rheumatology evaluation. (5 minutes) (APPENDIX I: HEALTH 
ASSESSMENT QUESTIONNAIRE) 
 
Completed questionnaires will be maintained in the subject’s research chart until study analysis 
is completed. 
 


26 
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Version Date: December 12, 2018 
 
 
3.5 
STUDY FLOWCHART 
 
 
 
 
Baseline: clinic visit 
 
History and physical exam 
 
Safety laboratory studies (blood and urine) 
 
Research Laboratory studies (blood) 
 
Serum B-hCG (required for females of childbearing potential) 
 
Skin examination (TBSAI, PGA, PPASI, PPPASI) 
 
Skin biopsy of lesional and non-lesional skin for IHC, gene expression and cytokine studies* 
 
Joint assessment (ACR criteria, including Health Assessment Questionnaire)  
 
Ophthalmologic examination * 
 
Gastrointestinal evaluation (if history of gastrointestinal symptoms) * 
 
Cardiometabolic evaluation* 
 
FDG PET/CT scan* 
 
QOL/questionnaires  
 
Total body photographs * 
 
Teaching 
 
Dispense study drug 
Weeks 1, 2, 3 (+/- 3 days) (no clinic visit) 
 
Telephone assessment 
 
AE monitoring 
Weeks 5, 6, 7 (+/- 3 days) (no clinic visit) 
 
Telephone assessment 
 
AE monitoring 
Week 4 (+/- 1 week): clinic visit 
 
Updated history & skin examination (TBSAI, PGA, PPASI, PPPASI) 
 
Joint assessment by ACR criteria* (l if no evidence of joint disease, 
including Health Assessment Questionnaire) 
 
Follow up serum and urine laboratory studies 
 
Serum B-hCG (required for females of childbearing potential) 
 
QOL/Questionnaires  
 
Total body photographs*  
 
Dose titration to 200 mg/day as appropriate for partial and non- 
responders 
 
Teaching/reinforcement 
 
Dispense study drug 
Week 8 (+/- 1 week): clinic visit 
 
Updated history & skin examination (TBSAI, PGA, PPASI, PPPASI) 
 
Joint assessment by ACR criteria* (if no evidence of joint disease, 
including Health Assessment Questionnaire) 
 
Follow up serum and urine laboratory studies 
 
Serum B-hCG (required for females of childbearing potential) 
 
QOL/Questionnaires  
 
Total body photographs  
 
Dose titration to 300 mg/day for partial and non-responders weighing 
>75kg 
 
Teaching/reinforcement 
 
Dispense study drug 


27 
Abbreviated Title: Anakinra in pustular dermatoses   
Version Date: December 12, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Denotes procedure/consultation that is to be performed at the discretion of the investigator.  
 
 
 
Weeks 9, 10, 11 (+/- 3 days) (no clinic visit) 
 
Telephone assessment 
 
AE monitoring 
Week 12 (+/- 1 week): clinic visit 
 
Updated history & post-treatment skin examination (TBSAI, PGA, PPASI, PPPASI) 
 
Follow up serum and urine safety laboratory studies 
 
Follow up serum research laboratory studies 
 
Serum B-hCG (required for females of childbearing potential) 
 
Post-treatment skin biopsy of lesional and nonlesional skin for IHC and gene expression studies* 
 
Post-treatment joint assessment by ACR criteria (including Health Assessment Questionnaire) 
 
Post-treatment ophthalmologic examination* 
 
Post-treatment gastrointestinal evaluation (if history of gastrointestinal symptoms)* 
 
Post-treatment cardiac evaluation including electrocardiogram* 
 
Post-treatment total body FDG PET CT scan* 
 
Post-treatment QOL/questionnaires  
 
Post-treatment serum and urine laboratory studies 
 
Total body photographs* 
Week 16 (+/- 2 weeks) (clinic visit): 
 
Post-treatment skin examination (TBSAI, PGA, PPASI, PPPASI) 
 
Post-treatment joint assessment by ACR criteria* (if no evidence 
of disease, including Health Assessment Questionnaire) 
 
End-of-study labs and urines  
 
Total body photographs* 
 
QOL/questionnaires 
 
Collection of patient diaries 
 
AE monitoring 
Weeks 13, 14 15 (+/- 3 days) (no clinic visit) 
 
Telephone assessment 
 
AE monitoring 


Abbreviated Title: Anakinra in pustular dermatoses  
Version Date: December 12, 2018 
 
3.6 
STUDY CALENDAR  
 
Screening 
≤8 weeks 
prior to 
enrollment 
Baseline- 
up to 
drug 
initiation
a 
Weeks 
1, 2, 3 
(+/- 3 
days)   
Week 
4 (+/- 
1 
week) 
Weeks 
5, 6, 7 
(+/- 3 
days)   
Week 
8 (+/- 
1 
week) 
Weeks 
9, 10, 
11  
(+/- 3 
days)   
Week 
12 (+/- 1 
week):  
End of 
Treatm
ent 
Weeks 
13, 14, 
15  
(+/- 3 
days) 
Week 16  
(+/- 2 
weeks):  
Post 
Therapy 
Follow-
upa 
Eligibility 
X 
X-update 
 
Clinic 
visit 
 
Clinic 
visit 
 
Clinic 
visit 
 
 
Consent 
 
X 
 
 
 
 
 
 
 
 
H&P 
X 
X- 
update 
 
X 
 
X 
 
X 
 
X 
NIH Advanced Directives 
Formb 
 
X 
 
 
 
 
 
 
 
 
Medication review 
X 
X- 
update 
 
X 
 
X 
 
X 
 
X 
Dose titrationc 
 
 
 
X 
 
X 
 
 
 
 
Telephone surveillance 
 
 
X 
 
X 
 
X 
 
X 
 
Immunosuppressant drug 
taper (per MD discretion) 
 
 
 
 
X 
X 
X 
X 
 
 
CBC/diff, serum creatinine 
and urea nitrogen, hepatic 
panel with alk. phos, serum B-
hCG  
X 
X 
 
X 
 
X 
 
X 
 
X 


29 
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Version Date: December 12, 2018 
 
 
 
Screening 
≤8 weeks 
prior to 
enrollment 
Baseline- 
up to 
drug 
initiation
a 
Weeks 
1, 2, 3 
(+/- 3 
days)   
Week 
4 (+/- 
1 
week) 
Weeks 
5, 6, 7 
(+/- 3 
days)   
Week 
8 (+/- 
1 
week) 
Weeks 
9, 10, 
11  
(+/- 3 
days)   
Week 
12 (+/- 1 
week):  
End of 
Treatm
ent 
Weeks 
13, 14, 
15  
(+/- 3 
days) 
Week 16  
(+/- 2 
weeks):  
Post 
Therapy 
Follow-
upa 
Blood sampling: calcium, 
phosphorus, albumin, total 
protein, ESR, hs-CRP, serum 
c-peptide  
 
X 
 
X 
 
X 
 
X 
 
X 
Urine sampling: UA, calcium, 
phosphorus 
 
X 
 
X 
 
X 
 
X 
 
X 
Ferritin, lipid panel, serum 
insulin, serum glucose 
 
X 
 
 
 
 
 
 
 
 
Serum and urine protein 
electrophoresis, Parathyroid 
hormone, Serum 25-OH 
Vitamin D, anti-nuclear 
antibody, anti-dsDNA 
antibodies, anti-ENA 
antibodies, rheumatoid factor, 
C3, C4, CH50, HLA typing, 
quantitative serum 
immunoglobulins, anti-
streptolysin O titer 
 
X 
 
 
 
 
 
 
 
 
HIV screen and hepatitis 
screen 
X 
 
 
 
 
 
 
 
 
 
Total body photographs  
 
X 
 
X 
 
X 
 
X 
 
X 


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Version Date: December 12, 2018 
 
 
 
Screening 
≤8 weeks 
prior to 
enrollment 
Baseline- 
up to 
drug 
initiation
a 
Weeks 
1, 2, 3 
(+/- 3 
days)   
Week 
4 (+/- 
1 
week) 
Weeks 
5, 6, 7 
(+/- 3 
days)   
Week 
8 (+/- 
1 
week) 
Weeks 
9, 10, 
11  
(+/- 3 
days)   
Week 
12 (+/- 1 
week):  
End of 
Treatm
ent 
Weeks 
13, 14, 
15  
(+/- 3 
days) 
Week 16  
(+/- 2 
weeks):  
Post 
Therapy 
Follow-
upa 
Total body surface area 
involvement measurement 
 
X 
 
X 
 
X 
 
X 
 
X 
PGA scoring 
 
X 
 
X 
 
X 
 
X 
 
X 
Skin biopsy  
Xg 
Xh 
 
 
 
 
 
Xh 
 
 
Quantiferon T gold 
Xd 
 
 
 
 
 
 
 
 
 
Chest X-ray if positive 
Quantiferon TB Gold 
Xd 
 
 
 
 
 
 
 
 
 
Microbiologic culture of 
pustule confirming 
noninfectious etiology 
X 
 
 
 
 
 
 
 
 
 
FDG-PET CT scan  
 
X 
 
 
 
 
 
X 
 
 
Joint MRI  
 
X 
 
 
 
 
 
X 
 
 
Research blood sampling 
 
X 
 
 
 
 
 
X 
 
 
Rheumatology Consultation 
including ACR assessmente 
 
X 
 
X 
 
X 
 
X 
 
X 
Cardiometabolic evaluation 
including electrocardiogram  
 
X 
 
 
 
 
 
X 
 
 
Ophthalmologic examination  
 
X 
 
 
 
 
 
X 
 
 
Gastrointestinal consultation  
 
X 
 
 
 
 
 
X 
 
 


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Version Date: December 12, 2018 
 
 
 
Screening 
≤8 weeks 
prior to 
enrollment 
Baseline- 
up to 
drug 
initiation
a 
Weeks 
1, 2, 3 
(+/- 3 
days)   
Week 
4 (+/- 
1 
week) 
Weeks 
5, 6, 7 
(+/- 3 
days)   
Week 
8 (+/- 
1 
week) 
Weeks 
9, 10, 
11  
(+/- 3 
days)   
Week 
12 (+/- 1 
week):  
End of 
Treatm
ent 
Weeks 
13, 14, 
15  
(+/- 3 
days) 
Week 16  
(+/- 2 
weeks):  
Post 
Therapy 
Follow-
upa 
QOL/questionnairesf 
 
X 
 
X 
 
X 
 
X 
 
X 
Daily scoring diary 
 
Start Day 
0 
 
X---------------------------------------------------------------------------X 
AE Monitoring 
 
START 
X 
X 
X 
X 
X 
X 
X 
X 
 
a Additional clinical labs may be obtained as indicated at baseline and follow up visits 
b As indicated in section 10.3, all subjects at NIH will be offered the opportunity to complete an NIH advanced directives form.  This should be done preferably 
at baseline but can be done at any time during the study as long as the capacity to do so is retained.  The completion of the form is strongly recommended, but 
is not required. 
c If escalation criteria are met (see Section 3.2) 
d Within 8 weeks of enrollment 
e If the rheumatology consult is done at Week 0, the patient will be seen again at Week 12. If there is evidence of joint disease, patients will be strongly 
encouraged to have rheumatology consult during all clinic visits (Weeks 0, 4,8, 12 and 16) 
f QOL/questionnaires (see Section 3.4) 
g Skin biopsy for hematoxylin and eosin staining to confirm diagnosis if prior confirmational biopsy has not been performed 
h Performed at the investigator’s discretion for research purposes 


Abbreviated Title: Anakinra in pustular dermatoses  
Version Date: December 12, 2018 
 
3.7 
SURGICAL GUIDELINES  
Skin biopsies of lesional and nonlesional skin will be taken at baseline and week 12. Skin biopsy 
procedure will be explained to the patient and informed consent will be obtained. The risks of 
infection, scarring, nerve damage, pigment change, numbness, recurrence, bleeding, pain, and 
allergy to anesthesia will be reviewed. Sterile preparation of the proposed biopsy site will be 
performed. The biopsy site will be locally anesthetized. Size of punch biopsies will be up to 
6mm. One punch biopsy will be performed from nonlesional skin, and up to two punch biopsies 
will be performed from lesional skin. We will place sutures for hemostasis. Petrolatum and 
bandage will be applied to the wound site and wound care will be reviewed. Written wound care 
instructions will be given. We will instruct the patient regarding suture removal. 
3.8 
OPHTHALMOLOGIC PROCEDURES 
3.8.1 Ophthalmic Examination with Dilation 
Dilation of the pupils will cause temporary glare and blurring of vision. Rarely an allergic 
reaction or infection secondary to contaminated drops can occur. Dilating drops can also cause a 
sudden increase of pressure (acute glaucoma) in eyes that are already predisposed to develop this 
condition. There is little risk of glaucoma being triggered in this way, but if it is, treatment will 
be available. 
 
3.8.2 Fluorescein Angiography (if clinically indicated) 
The participant’s skin may turn yellow for several hours. The yellow color will disappear as the 
kidney filters the dye from the body. Because the dye passes through the kidneys, the urine will 
turn dark orange for up to 24 hours after the exam. Some participants may be slightly nauseous 
(upset stomach) during the exam, but their nausea usually lasts only a few seconds. If the dye 
leaks out of the vein during the injection, some of the skin around the injection site may feel 
mildly uncomfortable or become yellow. The mild discomfort usually lasts only a few minutes, 
and the yellow color goes away in a few days.  
 
Sometimes participants have an allergic reaction to the dye, but this rarely happens. Oral 
antihistamines are usually used to treat this or the antihistamines may be injected if the 
symptoms are severe. Very rarely, a participant may have a severe allergic reaction that causes 
respiratory distress and shock (“anaphylaxis”), which can be life-threatening. Trained personnel 
with drugs or, possibly, surgery would treat this immediately. 
 
3.8.3 Optical Coherence Tomography (OCT) 
There is no medical risk from OCT. 
 
3.8.4 Microperimetry  
There is no medical risk from microperimetry. 


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Version Date: December 12, 2018 
 
 
3.9 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to documenting removal from study, effort must be made to have all subjects complete a 
safety visit approximately 28 days following the last dose of study therapy. 
3.9.1 Criteria for removal from protocol therapy 
• Completion of 12-week anakinra therapy  
• Noncompliance with protocol procedures 
• Pregnancy 
• Participant requests to be withdrawn from active therapy  
• Non-allergic toxicity or observed allergic reaction to anakinra 
• Investigator discretion 
• Positive pregnancy test 
• Death 
 
3.9.2 Off-Study Criteria 
• Completion of post-treatment week 16 off-study visit 
• Participant requests to be withdrawn from study 
• Death 
3.9.3 Off Protocol Therapy and Off Study Procedure 
3.9.3.1 Clinical Center Off Protocol Therapy and Off-Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Update Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office 
ncicentralregistration-l@mail.nih.gov. 
3.9.3.2 Participating Site Off Protocol Therapy and Off-Study Procedure 
The Participant Status Update Form will be supplied by the NIAMS study coordinator. Send the 
completed form to the NIAMS study coordinator. 
3.10 BASIC AND CLINICAL SCIENCE RESEARCH PLAN 
3.10.1 Characterize and dissect inflammatory pathways in participant lesional skin and 
peripheral blood mononuclear cells  
3.10.1.1 Immunohistochemical studies 
Immunohistochemistry studies will be utilized to characterize the hematopoietic inflammatory 
infiltrate in lesional skin, including neutrophils (neutrophil elastase and CD15), myeloid 
dendritic cells (blood dendritic cell antigen [BDCA]-1, CD11c, BDCA-3), macrophages 
(CD163) and T lymphocytes (CD3).   
Two-color immunofluorescence will be performed to determine CARD14+ cells (e.g., CARD14 
versus CD11c, CARD14 versus CD163)55-57.  
 


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3.10.1.2 Global gene expression studies 
Lesional and nonlesional skin biopsies obtained before and after treatment with anakinra will be 
assayed for gene expression profiles with microarray assays.  Genes associated with immune 
dysregulation and cell differentiation will be assessed and compared between patients.  Gene 
expression will be confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) and 
quantitative RT-PCR for low-expressing cytokines.   
For patients with systemic inflammation characterized by fever, marked leukocytosis and/or 
elevated acute phase reactants, we will perform gene expression studies on peripheral blood 
mononuclear cells (PBMCs) before and after treatment with anakinra.   
These profiles will be compared with gene expression profiles from lesional skin in patients with 
known DIRA (n=2), CARD14 mutations (n=3), and familial psoriasis (n=5).  Additional analytic 
approaches will include Ingenuity Pathways Analysis (IPA), and Gene Set Enrichment Analysis 
(GSEA)55, 58, 59.   
Genomics studies will not be performed on this protocol. Genomics studies for pustular 
dermatoses will be performed on protocol 17-I-0016.  At the time of enrollment, patients will be 
offered simultaneous enrollment in protocol 17-I-0016. (Section 5.2) 
3.10.1.3 Cytokine studies 
We will perform skin and serum studies before and after anakinra therapy to assess levels of 
inflammatory cytokines including IL-1b, IL-6, IL-8, IL-17, IL-21, IL-22, IL-23, G-CSF and TNF 
using RT-PCR Luminex assay.   
3.10.2 Evaluate systemic inflammation in participants with pustular dermatoses using imaging 
modalities and biomarkers of cardiometabolic disease 
3.10.2.1 Fluoro-Deoxy-Glucose PET CT Imaging for Body Metabolism 
We will utilize a technique for quantifying the extent of atherosclerosis in the aorta by 
combining standard uptake values (SUVs) in the aortic wall obtained using FDG-PET with 
volumetric data provided by CT 60, 61.  FDG uptake will be measured in all six segments of the 
aorta by calculating the mean combining SUVs for each segment. On each axial CT image, 
region-of-interest tracings along the inner and outer wall contours of the aorta are created. The 
average SUVs are then multiplied by the wall volume to calculate the total amount of vascular 
inflammation for each segment of the aorta. This total amount of vascular inflammation of each 
aortic segment can be used as an indicator of the extent of the atherosclerotic process by 
combining the functional and structural data provided by FDG-PET and CT. 
 
Subjects will fast for six hours prior to imaging.  Blood glucose will be checked and should be in 
the 100-160 mg/dL range to ensure an optimum study.  The patient is injected with 10 mCi of 
18-Fluoro-Deoxy glucose (FDG) and then rests for 60 minutes.  The effective radiation dose of 
two 10 mCi injections of FDG is 2.6 rem.  The subject will be positioned in a 16-slice PET CT 
scanner (GE, Discovery ST).  The CT images acquired as part of the PET CT examination will 
be acquired using a low dose technique during quiet breathing.  The CT images will allow for 
attenuation correction of the PET emission data, and will aid in the accurate anatomical 


35 
Abbreviated Title: Anakinra in pustular dermatoses   
Version Date: December 12, 2018 
 
 
localization of sites of radiotracer uptake seen on PET images.  The scanning time is typically 45 
minutes. The CT and PET images are co-registered and can be viewed and interpreted.  
The presence of brown fat is inferred from the following: 
• FDG uptake in known usually symmetric distribution in the body  
• Corresponding CT appearances consistent with fat at a site of FDG uptake  
 
Whole body metabolism can be assessed by visual inspection of scout images and then 
quantified using standardized uptake volumes (SUV). 
3.10.2.2 Evaluating biomarkers of cardiometabolic disease 
We will evaluate biomarkers of cardiovascular disease by assaying pro-atherogenic lipoproteins 
via nuclear magnetic resonance spectroscopy (NMR), and high density lipoprotein (HDL) 
function via HDL cholesterol efflux capacity.  
3.10.3 Evaluate keratinocyte responses to targeted inflammatory stimuli including infectious 
agents and danger molecules. 
 
3.10.3.1 Characterize response to Toll-like receptor (TLR) stimulation  
Our preliminary data shows that keratinocytes from patients with monogenic forms of pustular 
diseases not only produce higher levels of proinflammatory cytokines and chemokines in 
response to stimulation, but also demonstrate hyper- and parakeratosis histologically, thus 
indicating abnormal differentiation and abnormal apoptosis. We will create keratinocyte cell 
lines to assess whether keratinocytes from patients with pustular lesions have abnormal 
responses to TLR stimulation.  We have made keratinocyte cell lines from skin biopsies from 
both healthy individuals and patients with monogenic pustular skin diseases (healthy controls, 
n=6; DIRA, n=2; CARD14, n=1).  We will create keratinocyte cell lines from study participants 
with genetically-undefined pustular diseases.  The keratinocyte cell lines will be immortalized as 
recently described in the presence of feeder cells and a ROCK-inhibitor.62  
Keratinocytes from healthy controls, patients with monogenic forms of pustular disease, and 
patients with genetically-undefined pustular diseases will be exposed to a panel of TLR 
stimulants.  We will use gene expression profiling to assess the impact of TLR stimulation on 
cell differentiation.   
 
3.10.3.2 Compare affected and unaffected keratinocytes and fibroblasts with those of patients 
with monogenic pustular diseases and genetically-undefined pustular diseases in an 
organotypic raft culture system  
We will study signaling pathway effects on keratinocyte proliferation and differentiation in an 
environment that closely mimics human epidermis.  The organotypic raft culture system has been 
shown to mimic the functional alterations observed in inflammatory disease63.  Immortalized 
keratinocytes (as described above) will be used to generate rafts to examine the response of these 
cells to stimuli from cytokines and TLR agonists.   


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We will evaluate inflammatory and differentiation properties in keratinocytes from study 
participants.  Immunohistochemical techniques will be applied to raft cultures to evaluate 
alterations in markers of proliferation (PCNA, Ki67) and differentiation (epidermal 
differentiation markers including loricrin, filaggrin, involucrin, keratin 1, keratin 10) between 
unaffected controls and patient samples.  Preliminary characterization by western blot analysis of 
immortalized keratinocytes from unaffected controls differentiated in culture with calcium64  
indicate that this methodology is also applicable for these samples.   
4 
CONCOMITANT MEDICATIONS/MEASURES 
No drug-drug interaction studies with anakinra in human subjects have been conducted.  
Toxicological and toxicokinetic studies in rats did not demonstrate alterations in the clearance or 
toxicological profile of either methotrexate or anakinra when the two agents were administered 
together.  In two studies of concurrent etanercept and anakinra therapy, patients were treated for 
up to 24 weeks and a 7% rate of serious infections was observed, which was higher than when 
either agent was used alone.  Two percent of patients (3/139) treated concurrently with anakinra 
and etanercept developed neutropenia (ANC < 1 x 109/L).  Patients enrolled into this study will 
be required to discontinue etanercept (Enbrel®), or other TNF-inhibitor therapy, including 
infliximab (Remicade®), golimumab (Simponi®) and adalimumab (Humira®), certolizumab 
(Cimzia®), and other TNF-inhibiting agents such as thalidomide at least three half lives prior to 
initiation of anakinra therapy because of a potential increased risk of infection (APPENDIX A: 
FORBIDDEN DRUGS).  All medication changes will be recorded in the patient daily diary.  
4.1 
SUPPORTIVE CARE 
Patients will be screened thoroughly and will be instructed by medical providers to detect and 
report early signs of side effects related to anakinra.  Patients will receive instructions on 
monitoring, recording, and reporting side effects or adverse events.  Should subjects experience 
an adverse event, they will be instructed to contact the study team immediately and to anticipate 
a clinic visit for evaluation and possible treatment. 
4.1.1 NIH Patients 
Communication and consultation with physicians and nurses is available 24 hours a day, 7 days a 
week through the nursing unit of the NIAMS Dermatology Clinic or the NIH page operator at 
(301) 496-1211.  When possible, subjects requiring supportive care will be evaluated at the NIH. 
If a subject is unable to be seen at the NIH, telephone consultation will be available, as described 
above, to assist other practitioners involved in the patient’s care.   
4.1.2 UCSF Patients 
Communication and consultation with physician and study coordinator is available 24 hours a 
day, 7 days a week through the UCSF Dermatology Clinic, the UCSF page operator or the 
confidential patient portal service, MyChart. When possible, subjects requiring supportive care 
will be evaluated at UCSF. If a subject is unable to be seen at UCSF, telephone consultation will 
be available, as described above, to assist other practitioners involved in the patient’s care.  


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5 
BIOSPECIMEN COLLECTION 
5.1 
CORRELATIVE STUDIES FOR RESEARCH   
The research nurse will be responsible for coordinating transport of biospecimen samples 
collected throughout the study. 
5.1.1 Blood (Clinical and Research Samples)  
Blood will be obtained from each patient during the initial and subsequent visits.  All blood 
volumes to be drawn will remain within the NIH Clinical Center guidelines for adult patients.  
Only clinical laboratory and/or microbiology results will be returned to the patient or their 
designated primary care provider (PCP).  In rare instances, blood drawing limit may exceed the 
expected volume as a result of loss or damage of blood samples, repeating the tests in order to 
validate unusual or erroneous results, will not exceed the limits set forth by the NIH CC MEC 
policy.  The amount of blood drawn from adults for research purposes shall not exceed 10.5 
mL/kg or 550 mL, whichever is smaller, over any eight week period.  Additionally, aliquots of 
blood may be coded and shared with other collaborating researchers/investigators, under the 
auspices of appropriate material transfer agreements. 
5.1.1.1 Clinical bloods 
Blood samples will be analyzed for standard medical evaluations as outlined in Section 2.   
5.1.1.2 Research bloods  
Research blood will be drawn to examine serologic and immunological markers, including but 
not limited to cytokines, cardiometabolic markers including fasting insulin and glucose and gene 
expression studies (see section 3.10.1.2).  
5.1.1.3 Research biopsies 
At the investigator’s discretion, research skin punch biopsies will be collected from lesional and 
nonlesional skin at baseline and week 12 to perform immunohistochemistry studies, cytokine 
studies and gene expression studies.  Keratinocyte responses to infectious and inflammatory 
stimuli will be assessed.  Keratinocytes will also be used to make cell lines which will then be 
used to study keratinocytes inflammatory and differentiation properties in vitro. 
5.1.2 Research samples collected at UCSF 
All blood (Sodium Heparin, SST, EDTA, Pax Gene tubes) and biopsy specimens in DMEM 
culture medium and biopsy specimens in RNAlater will be shipped to NIH in an ambient thermal 
container overnight to be received within 24 hours of collection. Specimens should be shipped to 
the below address: 
Yan Huang 
10 Center Dr., Room 11C-216 
Bethesda, MD 20892 
301-761-7637 
yan.huang2@nih.gov 
5.2 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Please refer to protocol 17-I-0016 for details. 


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Whole blood, blood products, tissue, and RNA from all subjects will be stored indefinitely in the 
laboratories of Dr. Goldbach-Mansky and Dr. Nehal Mehta, and coded by study date and 
number.  Patient samples will be identifiable using a database that is only accessible to the 
researchers intimately involved with the protocol.  The samples themselves will not have direct 
patient identifiers.   
Effective with amendment J, all patients will be offered simultaneous enrollment in protocol 17-
I-0016, which aims to comprehensively evaluate patients with inflammatory multi-system 
diseases clinically, genetically, immunologically, and endocrinologically, and evaluate long term 
outcomes and biomarkers.  If the patient consents to both studies, data collected on protocol 17-
I-0016 will be correlated with data collected on our protocol.   
NOTE: Prior to amendment J, subjects were offered simultaneous enrollment onto protocol 03-
AR-0173, for the purposes described above. However, data from protocol 03-AR-0173 has been 
transferred to protocol 17-I-0016. 
If the patient withdraws consent, the participant’s data will be excluded from future distributions, 
but data that have already been distributed for approved research use will not be able to be 
retrieved. 
All specimens obtained in the protocol are used as defined in the protocol.  Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described below.  
The study will remain open so long as sample or data analysis continues.  Samples from 
consenting subjects will be stored until they are no longer of scientific value or if a subject 
withdraws consent for their continued use, at which time they will be destroyed.  The PI will 
report any loss or destruction of samples to the NIH Intramural IRB as soon as he is made aware 
of such loss. 
The PI will report destroyed samples to the IRB if samples become unsalvageable because of 
environmental factors (ex. broken freezer or lack of dry ice in a shipping container) or if a patient 
withdraws consent.  Samples will also be reported as lost if they are lost in transit between 
facilities or misplaced by a researcher.  Freezer problems, lost samples or other problems 
associated with samples will also be reported to the IRB, the NCI Clinical Director, and the 
office of the CCR, NCI. 
 
Samples at NIH will be ordered in CRIS and tracked through a Clinical Trial Data Management 
system.  Should a CRIS screen not be available, the CRIS downtime procedures will be 
followed.  Samples will not be sent outside NIH without IRB notification and an executed MTA.  
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
Data will be collected by investigators during visits and recorded in the patient’s permanent 
medical record. Data will be entered into the C3D database.  Protocol-specific case report forms 
will be developed and completed by the clinical teams.  Data collection forms may include the 
clinical and laboratory information obtained from standard clinical evaluations at study entry, 


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organ-specific scales, selected research laboratory data and the follow-up outcomes that are 
necessary for determination of primary and secondary endpoints.   
Personal identifiers will not be used when collecting and storing data.  An enrollment log will be 
maintained in the regulatory binder/file which is the only location of personal identifiers with 
unique subject identification number. 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts. All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. Patients 
will be followed for adverse events for 28 days after removal from study treatment or until off-
study, whichever comes first. 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified. 
6.2 
RESPONSE CRITERIA 
6.2.1 Definitions 
For the purposes of this study, patients will be evaluated for response every 4 weeks.   
Response is defined by at least 50% reduction in TBSAI at week 12. 
Partial Response is defined by 25-49% reduction in TBSAI at week 12. 
No response to therapy is defined as stable or worsened (increase in total body surface area 
involvement) skin disease on anakinra.  


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Other parameters used to assess disease response include American College of Rheumatology 
criteria and other clinical markers. ACR20/50/70 is defined as 20%, 50% and 70% improvement 
in tender or swollen joint counts, respectively. 
6.2.2 Disease Parameters 
Measurable disease:  Total body surface area involvement of pustules and erythematous plaques 
will be measured in this study. At the time of enrollment, all study participants will have active 
disease warranting systemic therapy, as defined by macroscopic non-infective pustular and 
inflammatory skin lesions involving ≥ 5% of the total body surface area, or palmoplantar 
involvement.   
Joint involvement will also be assessed using criteria set forth by the American College of 
Rheumatology. 
6.2.3 Methods for Evaluation of Measurable Disease 
Plaque and pustular disease will be measured by Total Body Surface Area Involvement (TBSAI) 
as well as Physician Global Assessment (PGA). Additionally, Pustular Psoriasis Assessment 
Severity Index (PPASI) and Palmoplantar Psoriasis Assessment Severity Index (PPPASI) scores 
will be calculated for each patient (APPENDIX H: PUSTULAR DERMATOSIS CLINICAL 
ASSESSMENT SCALE).  All baseline evaluations will be performed as closely as possible to 
the beginning of treatment and not more than 4 weeks before the beginning of the treatment. The 
same method of assessment and the same technique should be used to characterize skin lesions at 
baseline and during follow-up.  
Clinical lesions:  Skin lesions will be documented using clinical examination and disposable 
ruler as needed, and color photography (at the investigator’s discretion). Joint lesions will be 
documented by clinical examination as delineated by ACR guidelines, and joint imaging 
modalities. Ocular involvement will be assessed through a comprehensive ophthalmic exam 
including assessment for keratoconjunctivitis. Ocular exams will occur in the eye clinic at 
baseline and at completion of the study unless otherwise medically indicated.   Specialized 
ophthalmic testing (i.e., optical coherence tomography, fluorescein angiography, fundus photos 
or visual fields) will only be performed if   medically indicated and required to establish a 
diagnosis.  
Histology:  Histologic evaluation will be used to diagnose and characterize disease at the time of 
enrollment and completion of anakinra.  
6.2.4 Response Criteria 
6.2.4.1 Evaluation of Target Lesions 
TBSAI50 is defined as 50% improvement in total body surface area involvement. 
ACR20/50/70 is defined as 20%, 50% and 70% improvement in tender or swollen joint counts 
and other clinical markers, respectively. 
 
No response to therapy is defined as stable or worsened (increase in total body surface area 
involvement) skin disease on anakinra. 


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7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
7.1 
DEFINITIONS 
7.1.1 Adverse Event 
Any untoward medical occurrence in a human subject, including any abnormal sign (for 
example, abnormal physical exam or laboratory finding), symptom, or disease, temporally 
associated with the subject’s participation in research, whether or not considered related to the 
subject’s participation in the research.  
7.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
7.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected” also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
7.1.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.1.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 


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appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
7.1.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
7.1.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death. 
7.1.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol. 
7.1.9 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects. 
7.1.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
•  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Suggests that research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
7.2 
NIH INTRAMURAL IRB AND CLINICAL DIRECTOR REPORTING  
7.2.1 NIH Intramural IRB and NCI CD Expedited Reporting of Unanticipated Problems and 
Deaths 
The Protocol PI will report in the NIH Problem Form to the NIH Intramural IRB and NCI 
Clinical Director: 
• All deaths, except deaths due to progressive disease  
• All Protocol Deviations 
• All Unanticipated Problems 
• All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 


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7.2.2 NIH Intramural IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NIH Intramural IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
• All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
• All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
• All Grade 5 events regardless of attribution;  
• All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.3 
NCI Guidance for Reporting Expedited Adverse Events for Multi-Center Trials  
The site PI must immediately report to the coordinating center PI any serious adverse event, 
whether or not considered drug related, including those listed in the protocol or investigator 
brochure and must include an assessment of whether there is a reasonable possibility that the 
drug caused the event within 24 hours of PI awareness of the event.  The Site PI must also report 
any protocol deviations to the coordinating center PI within 7 days of PI awareness using the 
problem report form (See APPENDIX L: CCR PROBLEM REPORT FORM). A copy of this 
form can also be obtained from the NIAMS study coordinator.  Participating centers must also 
submit the report to their IRB in accordance with their institutional policies. 
7.4 
DATA AND SAFETY MONITORING PLAN 
7.4.1 Principal Investigator/Research Team  
The clinical research team will meet weekly when patients are being actively treated on the trial 
to discuss each patient. Decisions about dose level enrollment and dose escalation if applicable 
will be made based on the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or 
protocol deviations will be immediately reported to the IRB using iRIS.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  


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7.4.2 Safety Monitoring Committee (SMC) 
This protocol will require oversight from the Safety Monitoring Committee (SMC).  Initial 
review will occur as soon as possible after the annual NIH Intramural IRB continuing review 
date.   Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting 
schedule permits or more frequently as may be required by the SMC.  For initial and subsequent 
reviews, protocols will not be reviewed if there is no accrual within the review period. Written 
outcome letters will be generated in response to the monitoring activities and submitted to the 
Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI. 
8 
STATISTICAL CONSIDERATIONS   
The primary objective of this one-stage phase 2 study is to obtain an estimate of the response rate 
to treatment with anakinra for pustular dermatoses. Those patients who experience at least a 50% 
improvement in TBSAI will be considered responders. With 25 evaluable patients, the maximum 
width of a two-sided 95% confidence interval will be +/-20% if the response rate is 50%, and less 
wide if the response rate is either lower or higher than 50%. An early stopping rule will be 
implemented in order to guard against undue risk to enrolled subjects. If 0 of the first 9 patients 
fail to respond to anakinra therapy, there is a 95% probability that the true response rate is 28% 
or less, which is unacceptably low, and we will halt further patient recruitment. 
All other biologic parameters will be evaluated using exploratory and descriptive methods, 
emphasizing non-parametric techniques. 
It is anticipated that 1-2 patients per month may enroll onto this trial. In order to allow for a 
small number of unevaluable patients, the accrual ceiling will be set at 30 patients. Accrual 
would be estimated to last 18-24 months in order to enroll up to 30 patients.  
9 
COLLABORATIVE AGREEMENTS  
9.1 
AGREEMENT TYPE 
9.1.1 Clinical Trials Agreement 
Clinical Trials Agreement (CTA) # 924 has been executed for the transfer of anakinra from 
Biovitrum to NCI. 
9.1.2 Material Transfer Agreement 
A Material Transfer Agreement will be executed with Hailey Naik/ University of California, San 
Francisco for the transfer of blood specimens and patient data. 
9.2 
MULTI-INSTITUTIONAL GUIDELINES 
9.2.1 IRB Approvals  
The PI will provide the NIH Intramural IRB with a copy of the participating institution’s 
approved yearly continuing review.  Registration will be halted at any participating institution in 
which a current continuing approval is not on file at the NIH Intramural IRB. 


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9.2.2 Amendments and Consents 
The NIAMS PI will provide the NIH Intramural IRB with copies of all amendments, consents 
and approvals from each participating institution. 
10 HUMAN SUBJECTS PROTECTIONS  
10.1 RATIONALE FOR SUBJECT SELECTION 
Subjects who have inflammatory pustular skin diseases will be enrolled. The gender, age and 
ethnic distribution is expected to represent the characteristics of the patients genetically 
predisposed to developing these conditions. This protocol intends to enroll an appropriately 
balanced study population consistent with the distribution of these diseases. No sex or 
racial/ethnic group will be specifically recruited or excluded for this study.  
10.2 PARTICIPATION OF CHILDREN 
Individuals under the age of 18 will not be eligible to participate in this study at this time due to 
discomfort of multiple injections and dose escalation nature of the study as well as the unknown 
safety of higher than FDA approved doses in children. 
10.3 PARTICIPATION OF NIH SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol.  However re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 10.5), all subjects will be offered the opportunity to fill in their 
wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or 
cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an 
independent assessment of whether an individual has the capacity to provide consent; assistance 
in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the 
capacity to appoint a surrogate. For those subjects that become incapacitated and do not have 
pre-determined substitute decision maker, the procedures described in MAS Policy 87-4 and 
NIH HRPP SOP 14E for appointing a surrogate decision maker for adult subjects who are (a) 
decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, 
will be followed. 
10.3.1 For Participating Sites 
Participating sites should follow local procedures regarding re-consent for subjects that become 
decisionally impaired. 
10.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
Subjects participating in this protocol may potentially benefit from an improvement in symptoms 
of neutrophilic pustular dermatosis.  Potential risks include the range of side effects listed in 


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section 11.1.2.  Subjects will be evaluated medically throughout the protocol in order to 
minimize risk.   
 
Blood Sampling 
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. 
 
Tissue Biopsy 
All care will be taken to minimize risks that may be incurred by tissue sampling.  However, there 
are procedure-related risks (such as bleeding, infection and scarring) that will be explained fully 
during informed consent.  If patients suffer any physical injury as a result of the biopsies, 
medical treatment is available at the NIH’s Clinical Center in Bethesda, Maryland or other 
participating site.  Although no compensation is available, any injury will be fully evaluated and 
treated in keeping with the benefits or care to which patients are entitled under applicable 
regulations. 
 
10.5 RISKS/BENEFITS ANALYSIS 
Inflammatory pustular dermatoses are associated with significant morbidity and mortality. 
Patients with generalized skin disease are subject to risk of infection. Many of the pustular 
dermatoses are refractory to currently-available therapies which fail to mitigate disease course 
and complications.  Randomized controlled trials have not been undertaken due to rarity of 
disease and cost of such a study.  An effective therapeutic agent for the management of this 
group of diseases would be both a significant contribution to clinical management and to our 
understanding of pathogenesis of neutrophilic and pustular disease.  Based on current scientific 
knowledge, IL-1 plays a key role in pathogenesis of neutrophilic and pustular diseases.  IL-1 
antagonist anakinra has been safely and successfully used in children with autoinflammatory 
diseases including NOMID and DIRA, and we anticipate the drug will be similarly well-tolerated 
in adults with pustular diseases.  We anticipate this study will be associated with more than 
minimal risk and offers the prospect of direct benefit due to protocol treatment for adult subjects, 
including those who are or may become unable to consent.  
10.6 CONSENT PROCESS AND DOCUMENTATION 
Patients will meet with an associate or principal investigator on the trial in the NIH Dermatology 
Clinic or participating site clinic during the initial evaluation for this study.  During that meeting, 
the investigator will inform patients of the purpose, alternatives, treatment plan, research 
objectives and follow-up of this trial.  The investigator will then provide a copy of the IRB-
approved informed consent document that is included in this protocol.  The patient will be 
allowed to take as much time as he wishes, in deciding whether or not he wishes to participate.  
If a prolonged period of time expires during the decision-making process (several weeks, as an 
example), it may be necessary to reassess the patient for protocol eligibility. Subjects will 
consent to procedures performed at the investigator’s discretion (biopsy, PET scan, CT scan, 
MRI scan) at the time of the procedure. If the subject refuses the optional procedure at that time, 
the refusal will be documented in the medical record and in the research record. The original 
signed consents go to Medical Records; and a copy of each will be placed in the research record 
(NIH policy). 


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All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before entering on the study. 
10.6.1 Telephone Reconsent 
Reconsent on this study may be obtained via telephone according to the following procedure: the 
informed consent document will be sent to the subject.  An explanation of the change (s) in the 
study will be provided over the telephone after the subject has had the opportunity to read the 
consent form.  The subject will sign and date the informed consent. A witness to the subject’s 
signature will sign and date the consent.  
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.  
A fully executed copy will be returned via mail for the subject’s records.   
The informed consent process will be documented on a progress note by the consenting 
investigator.  
10.6.2 Informed consent of non-English speaking subjects 
If there is an unexpected enrollment of a research participant for whom there is no translated 
extant IRB approved consent document, the principal investigator and/or those authorized to 
obtain informed consent will use the Short Form Oral Consent Process as described in MAS 
Policy M77-2, OHSRP SOP 12, 45 CFR 46.117 (b) (2).  The summary that will be used is the 
English version of the extant IRB approved consent document.  Signed copies of both the 
English version of the consent and the translated short form will be given to the subject or their 
legally authorized representative and the signed original will be filed in the medical record. 
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation. Preferably someone who is independent of the subject (i.e., not a 
family member) will assist in presenting information and obtaining consent. Whenever possible, 
interpreters will be provided copies of the relevant consent documents well before the consent 
conversation with the subject (24 to 48 hours if possible).  
We request prospective IRB approval of the use of the short form process for non-English 
speaking subjects and will notify the IRB at the time of continuing review of the frequency of the 
use of the Short Form. 
11 PHARMACEUTICAL INFORMATION   
11.1 ANAKINRA 
Please refer to package insert for complete information. This protocol is exempt from an IND in 
accordance with Title 21 of the Code of Federal Regulations, Part 312.2 (b) as it meets all of the 
following exemption criteria: 
1. The investigational drug is lawfully marketed in the United States. 
2. The investigation is not intended to be reported to the FDA as a well-controlled study in 
support of a new indication for use of the drug product. 


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3. The investigation is not intended to support a significant change in advertising to an 
existing lawfully marketed prescription drug product. 
4. The investigation does not involve a route of administration or dosage level or use in a 
patient population or other factor that significantly increases the risks (or decreases the 
acceptability of the risks) associated with the use of the drug product. 
5. The investigation will be conducted in compliance with the requirements for institutional 
review set forth in FDA regulations 21 CFR 56, and requirements for informed consent 
as set forth in FDA regulations 21 CFR 50. 
11.1.1 Source: Biovitrum  
Anakinra will be donated by the manufacturer. Anakinra may also be purchased directly through 
the NIH pharmacy for NIH patients. 
11.1.2 Toxicity 
The safety and efficacy of anakinrahave been evaluated in 3 randomized, double-blind, placebo-
controlled trials of 1392 patients 18 years of age with active RA42.  An additional fourth study 
was conducted to assess drug safety. 
 
Injection-site Reactions 
The most common and consistently reported treatment-related adverse event associated with 
anakinra is injection-site reaction (ISR). Seventy-one percent of patients developed an ISR, 
which was typically reported within the first 4 weeks of therapy in clinical trials.  The majority 
of ISRs were reported as mild (72.6% mild, 24.1% moderate and 3.2% severe).  The ISRs 
typically lasted for 14 to 28 days and were characterized by 1 or more of the following: 
erythema, ecchymosis, inflammation, and pain.  
Infections 
In placebo-controlled trials, the incidence of infection was 39% in the anakinra-treated patients 
and 37% in placebo-treated patients during the first 6 months of blinded treatment.  The 
incidence of serious infections in Studies 1 and 4 was 2% in anakinra-treated patients and 1% in 
patients receiving placebo over 6 months.  The incidence of serious infection over 1 year was 3% 
in anakinra-treated patients and 2% in patients receiving placebo.  These infections consisted 
primarily of bacterial events such as cellulitis, pneumonia, and bone and joint infections.  The 
majority of patients (73%) continued on study drug after the infection resolved.  No serious 
opportunistic infections were reported.  Patients with asthma appeared to be at higher risk of 
developing serious infections when treated with anakinra (8 of 177 patients, 4.5%) compared to 
placebo (0 of 50 patients, 0%). 
In open-label extension studies, the overall rate of serious infections was stable over time and 
comparable to that observed in controlled trials.  In clinical studies and post marketing 
experience, cases of opportunistic infections have been observed and included fungal, 
mycobacterial and bacterial pathogens.  Infections have been noted in all organ systems and have 
been reported in patients receiving anakinra alone or in combination with immunosuppressive 
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In patients who received both anakinra and etanercept for up to 24 weeks, the incidence of 
serious infections was 7%.  The most common infections consisted of bacterial pneumonia (4 
cases) and cellulitis (4 cases).  One patient with pulmonary fibrosis and pneumonia died due to 
respiratory failure. 
Malignancies 
Among 5300 RA patients treated with anakinra in clinical trials for a mean of 15 months 
(approximately 6400 patient years of treatment), 8 lymphomas were observed for a rate of 0.12 
cases/100 patient years.  This is 3.6 fold higher than the rate of lymphomas expected in the 
general population, based on the National Cancer Institute's Surveillance, Epidemiology and End 
Results (SEER) database.  However, reports indicate that the rate of lymphoma is doubled in the 
rheumatoid arthritis (RA) population, and may be further increased in patients with more severe 
disease activity47, 48.  Thirty-seven malignancies other than lymphoma were observed.  Of these, 
the most common were breast, respiratory system, and digestive system.  There were 4 
melanomas observed in one study and its long-term open-label extension, however these cases 
were not thought to be related to anakinra. The significance of this finding is not known.  While 
patients with RA, particularly those with highly active disease, may be at a higher risk (up to 
several-fold) for the development of lymphoma, the role of IL-1 blockers in the development of 
malignancy is not known. 
Hematologic Events 
In placebo-controlled studies with anakinra, 8% of patients receiving anakinra had a decrease in 
total white blood counts of at least one WHO toxicity grade, compared with 2% of placebo 
patients.  Nine anakinra-treated patients (0.4%) developed neutropenia (ANC < 1 x 109/L).  Nine 
percent of patients receiving anakinra had increases in eosinophil differential percentage of at 
least one WHO toxicity grade, compared with 3 % of placebo patients.  Of patients treated 
concurrently with anakinra and etanercept, 2% developed neutropenia (ANC < 1 x 109/L).  One 
neutropenic patient developed cellulitis and recovered with antibiotic therapy.  Two percent of 
patients receiving anakinra had decreased platelets, all of WHO toxicity grade one, compared to 
0% of placebo patients. 
Hypersensitivity Reactions 
Hypersensitivity reactions including anaphylactic reactions, angioedema, urticaria, rash, and 
pruritus have been reported with anakinra. 
Immunogenicity 
In placebo-controlled studies, from which data is available for up to 36 months, 49% of patients 
tested positively at one or more time points for anti-anakinra antibodies in a highly sensitive, 
anakinra-binding biosensor assay.  Of the 1615 patients with available data at Week 12 or later, 
30 (2%) were seropositive in a cell-based bioassay for antibodies capable of neutralizing the 
biologic effects of Anakinra.  Of the 13 patients with available follow-up data, 5 patients 
remained positive for neutralizing antibodies at the end of the studies.  No correlation between 
antibody development and adverse events was observed. 
Antibody assay results are highly dependent on the sensitivity and specificity of the assays.  
Additionally, the observed incidence of antibody positivity in an assay may be influenced by 
several factors, including sample handling, concomitant medications, and underlying disease.  


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For these reasons, comparison of the incidence of antibodies to anakinra with the incidence of 
antibodies to other products may be misleading. 
Other Adverse Events  
Other adverse events that occurred at similar rate to placebo included: URI, sinusitis, influenza 
like symptom, headache, nausea, diarrhea, sinusitis and abdominal pain.  
Overdosage 
There have been no cases of overdose reported with anakinra in clinical trials of rheumatoid 
arthritis.  In sepsis trials, no serious toxicities attributed to anakinra were seen when administered 
at mean calculated doses of up to 35 times those given patients with RA over a 72-hour treatment 
period. 
Experience in NOMID  
In addition to the adverse events described in the package insert, our center has considerable 
experience in treating NOMID patients with anakinra.  Our cohort of primarily pediatric patients 
has been treated with anakinra doses ranging from 1 mg/kg to 6.7 mg/kg daily.  This practice is 
consistent with that of other specialty centers where doses as high as 10 mg/kg daily were used 
to control disease in the treatment of NOMID65.  In our experience with 26 patients and 1494 
patient-years (an average of 57.5 months / patient), the most frequently observed adverse events 
were upper respiratory infections 88.5%, gastroenteritis 46.2%, otitis media 38.5%, injection site 
reactions 34.6%, urinary tract infections 23.1%, transient transaminase elevation 15.4%, 
epistaxis 15.4%, otitis externa 11.6%, cellulitis 11.6%, and pneumonia 7.7%.  One patient had an 
episode of viral meningitis, one had a catheter infection, and one had a recurrent bowel 
abscesses.  Serious adverse events during this period included an ICU admission to evaluate for a 
post lumbar puncture bleed at 1 mg/kg/day, a wound infection with surrounding cellulitis at 3 
mg/kg/day, and macrophage activation syndrome at 2 mg/kg/day.  None of the adverse events 
required discontinuation of anakinra.  In a cohort of 10 French NOMID patients treated with 
anakinra described with follow-up ranging from three months to twenty years, the only reported 
adverse events were injection site reactions65. 
11.1.3  Formulation and preparation  
Anakinra is supplied in single use prefilled glass syringes with 27 gauge needles as a sterile, 
clear, colorless-to-white, preservative free solution for daily subcutaneous (SC) administration.  
The solution may contain trace amounts of small, translucent-to-white amorphous proteinaceous 
particles.  Each prefilled glass syringe contains: 0.67 mL (100 mg) of anakinra in a solution (pH 
6.5) containing disodium EDTA (0.12 mg), sodium chloride (5.48 mg), sodium citrate (1.29 mg), 
and polysorbate 80 (0.70 mg) in Water for Injection, USP. 
11.1.4  Stability and Storage  
Anakinra should not be shaken.  Before using, the product should be checked visually for 
particles or discoloration.  If either is present, the liquid should not be used.  The medication 
should be warmed to room temperature for 60 to 90 minutes before injecting.  
11.1.5 Administration procedures  
This medication is injected subcutaneously once a day.  


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Before injecting each dose, the injection site should be cleaned with rubbing alcohol.  It is 
important to change the location of the injection site daily.  The medication should not be 
injected into an area that is tender, red, bruised, or hard or which has scars or stretch marks.   
11.1.6  Incompatibilities 
No drug-drug interaction studies in human subjects have been conducted.  Toxicologic and 
toxicokinetic studies in rats did not demonstrate any alterations in the clearance or toxicologic 
profile of either methotrexate or anakinra when the two agents were administered together. 
TNF Blocking Agents: A higher rate of serious infections has been observed in patients treated 
with concurrent anakinra and etanercept therapy than in patients treated with etanercept alone. 
Two percent of patients treated concurrently with anakinra and etanercept developed neutropenia 
(ANC< 1x109/L). Use of anakinra in combination with TNF blocking agents is not 
recommended and use of TNF blocking agents is an exclusion criterion for study entry. 


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13 APPENDIX A: FORBIDDEN DRUGS 
 
Abatacept/Orencia 
Adalimumab/Humira 
Alefacept/Amevive 
Canakinumab/Ilaris 
Certolizumab/Cimzia 
Etanercept/Enbrel 
Golimumab/Simponi 
Infliximab/Remicaide 
Rilonacept/Arcalyst 
Rituximab/Rituxan 
Phototherapy 
Live vaccines 
 
 
 
 
 


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14 APPENDIX B: PATIENT DIARY  
 
PUSTULAR DERMATOSIS DIARY
Rate the symptoms from 0-3 to best describe the severity of the symptoms listed below
0=no symptoms
1=mild symptoms
2=moderate symptoms
3=severe symptoms (worst symptom observed)
Overall-well being (0=poor, 1=fair, 2=good, 3=excellent)
Please list name of study drug: anakinra
Please list all steroid medications here: 
Please list other immunosuppressive medications here: 
Dilute bleach baths/hibiclens wash? Yes or No
Day
Date
Time 
Anakinra 
dose given
Fever
Rash
Pustules
Itching
Skin pain
Joint pain
Overall      well-
being
Dilute bleach bath/ 
hibiclens wash?
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Fever: list the actual temperature in degress farenheit
 


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15 APPENDIX C: PATIENT HANDOUT 
 
Where can I inject anakinra/Kineret®? 
Upper arm 
Abdomen 
Thigh 
 
Remember to rotate the injection site daily. 
 
 
 
 
 
 
 


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16 APPENDIX D: DOSE MODIFICATION FLOW CHART 


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17 APPENDIX E: SHORT FORM  36 (ENGLISH AND SPANISH)   
 
 
 
 
 
 


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Collection of this information is authorized under 42 USC 285. The primary use of the 
information you provide is to assess your health and quality of life. The information may be 
disclosed to clinicians and researchers for research purposes and to monitor personnel to assure 
that safety standards are maintained. Submission of this information is voluntary. 
 
 
 
 
 
 
 
 
 


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La recopilación de esta información está utorizada bajo el Código de los Estados Unidos, número 
42 USC 285. La información que usted proporcione será usada principalmente para evaluar su 
salúd y calidad de vida. Esta informatción podria ser compartida con doctores e investigadores 
para fines de investigación o con monitores para garantizar que se mantengan las normas de 
seguridad.  El proveer esta información es voluntario. 


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18 APPENDIX F: DERMATOLOGY LIFE QUALITY (ENGLISH AND SPANISH) 
 
Collection of this information is authorized under 42 USC 285. The primary use of the 
information you provide is to assess your health and quality of life. The information may be 
disclosed to clinicians and researchers for research purposes and to monitor personnel to assure 
that safety standards are maintained. Submission of this information is voluntary. 


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CUESTIONARIO SOBRE LA CALIDAD DE VIDA – DERMATOLOGÍA 
 
El objetivo de este cuestionario consiste en determinar qué efecto ha tenido su problema de la piel en su 
vida DURANTE LA ÚLTIMA SEMANA. Por favor marque con una “X” una casilla para cada pregunta. 
 
1. 
Durante la última semana, ¿ha sentido 
picazón, dolor o ardor en la piel o la ha tenido 
adolorida? 
Muchísimo 
Mucho 
Un poco 
Nada 
 
 
 
 
 
 
 
2. 
Durante la última semana, ¿se ha sentido 
avergonzado/a o cohibido/a debido a su piel? 
Muchísimo 
Mucho 
Un poco 
Nada 
 
 
 
 
 
 
 
3. 
Durante la última semana, ¿le ha molestado 
su condición de la piel para hacer las compras 
u ocuparse de la casa o el jardín? 
Muchísimo 
Mucho 
Un poco 
Nada 
 
 
 
 
 
 
 
 
Sin relación 
 
 
 
 
4. 
Durante la última semana, ¿ha influido su 
condición de la piel en la elección de la ropa 
que lleva? 
Muchísimo 
Mucho 
Un poco 
Nada 
 
 
 
 
 
 
 
 
Sin relación 
 
 
 
 
 
5. 
Durante la última semana, ¿ha influido su 
condición de la piel en alguna actividad social 
o recreativa? 
Muchísimo 
Mucho 
Un poco 
Nada 
 
 
 
 
 
 
 
 
Sin relación 
 
 
 
 
6. 
Durante la última semana, ¿ha tenido 
dificultad para practicar deportes debido a su 
condición de la piel? 
Muchísimo 
Mucho 
Un poco 
Nada 
 
 
 
 
 
 
 
 
Sin relación 
 
 
 
 
7. 
Durante la última semana, ¿le ha impedido su 
condición de la piel trabajar o estudiar? 
 
Sí 
No 
 
 
 
 
Sin relación 
 
 
 
 
Si la respuesta es "No", durante la última 
semana, ¿cuánta dificultad le ha ocasionado 
su condición de la piel en el trabajo o en sus 
estudios? 
Mucho 
Un poco 
Nada 
 
 
 
 
 
 
 
8. 
Durante la última semana, ¿su condición de 
la piel le ha ocasionado dificultades con su 
pareja, amigos íntimos o familiares? 
Muchísimo 
Mucho 
Un poco 
Nada 
 
 
 
 
 
 
 
 
Sin relación 
 
 
 
 
9. 
Durante la última semana, ¿cuánta dificultad 
le ha ocasionado su condición de la piel en 
Muchísimo 
Mucho 
 
 
 
 
 
 


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su vida sexual? 
Un poco 
Nada 
 
 
 
 
Sin relación 
 
 
 
 
10. Durante la última semana, ¿cuánta dificultad 
le ha ocasionado su tratamiento de la piel, por 
ejemplo, ocupándole tiempo o ensuciando o 
desordenando su casa? 
Muchísimo 
Mucho 
Un poco 
Nada 
 
 
 
 
 
 
 
 
Sin relación 
 
 
 
 
 
Por favor verifique que ha contestado a TODAS las preguntas. Muchas gracias. 
 
 
 
 
La recopilación de esta información está utorizada bajo el Código de los Estados Unidos, número 
42 USC 285. La información que usted proporcione será usada principalmente para evaluar su 
salúd y calidad de vida. Esta informatción podria ser compartida con doctores e investigadores 
para fines de investigación o con monitores para garantizar que se mantengan las normas de 
seguridad.  El proveer esta información es voluntario. 


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19 APPENDIX G: DERMATOLOGY LIFE QUALITY SCORING TOOL 
 
http://www.dermatology.org.uk/quality/dlqi/quality-dlqi-faqs.html  
The scoring of each answer is as follows:  
Very much 
scored 3 
A lot 
scored 2 
A little 
scored 1 
Not at all 
scored 0 
Not relevant 
scored 0 
Question unanswered 
scored 0 
Question 7: "prevented work or studying" 
scored 3 
  
The DLQI is calculated by adding the score of each question. The maximum score is 30 and the 
minimum is 0. The higher the score, the more quality of life is impaired. The DLQI can be 
expressed as a percentage of the maximum possible score of 30 but we do not recommend this 
because the "original" score is much easier to understand. 
  
Please Note: The scores associated with the different answers should not be printed on the DLQI 
itself, as this might cause bias. 
Meaning of DLQI Scores 
0-1 = no effect at all on patient's life  
2-5 = small effect on patient's life  
6-10 = moderate effect on patient's life  
11-20 = very large effect on patient's life  
21-30 = extremely large effect on patient's life 
  
Detailed analysis of the DLQI 
  
The DLQI can also be analyzed under six headings or dimensions as follows:  
• 
Symptoms and feelings 
Questions 1 and 2 Score maximum 6 
• 
Daily activities 
Questions 3 and 4 Score maximum 6 
• 
Leisure 
Questions 5 and 6 Score maximum 6 
• 
Work and School 
Question 7 
Score maximum 3 


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• 
Personal relationships 
Questions 8 and 9 Score maximum 6 
• 
Treatment 
Question 10 
Score maximum 3 
               
  
The scores for each of these sections can also be expressed as a percentage of either 6 or 3. 
Q. How do you handle missing data from DLQI? 
There is a very high success rate of accurate completion of the DLQI. However, sometimes 
subjects do make mistakes. 
  
- If one question is left unanswered this is scored 0 and the scores are summed and expressed as 
usual out of a maximum of 30. 
- If two or more questions are left unanswered the questionnaire is not scored. 
- If question 7 is answered 'yes' this is scored 3 even if in the same question one of the other 
boxes is ticked.  
- If question 7 is answered 'no' or 'not relevant' but then either 'a lot' or 'a little' is ticked this is 
then scored 2 or 1. 
- If two or more response options are ticked for one question, the response option with the 
highest score should be recorded. 
- If there is a response between two tick boxes, the lower of the two score options should be 
recorded. 
- The DLQI can be analyzed by calculating the score for each of its six sub-scales (see above). 
When using sub-scales, if the answer to one question in a sub-scale is missing, that sub-scale 
should not be scored. 
 
 
Collection of this information is authorized under 42 USC 285. The primary use of the 
information you provide is to assess your health and quality of life. The information may be 
disclosed to clinicians and researchers for research purposes and to monitor personnel to assure 
that safety standards are maintained. Submission of this information is voluntary. 


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20 APPENDIX H: PUSTULAR DERMATOSIS CLINICAL ASSESSMENT SCALE 
 
PUSTULAR PASI CALCULATION 
PSORIASIS 
CHARACTERISTIC 
RATING 
SCORE 
HEAD 
ARMS 
TRUNK  
(including 
groin) 
LEGS 
(including 
buttocks) 
Erythema/redness (E) 
Lt red, red, v red, deep red 
 
0 = None 
1 = Slight 
2 = Moderate 
3 = Severe 
4 = Very Severe 
 
 
 
 
 
Induration/thickness (I) 
0.25, 0.5, 1, 1.25mm 
 
 
 
 
 
Desquamation/scaling (D) 
Fine, coarse fine, coarse 
thick, v thick 
 
 
 
 
 
Pustules (P) 
Few, scattered, dense, 
confluent 
 
 
 
 
 
SUM: E+I+D+P  
 
 
 
 
Modifier 
x 0.1 
x 0.2 
x 0.3 
x 0.4 
Weighted plaque score 
 = sum x modifier 
 
 
 
 
% affected body surface area  
 
 
 
 
AREA SCORE 
0 = None 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
 
 
 
 
 
SUBTOTAL = Weighted plaque score x 
Area score 
 
 
 
 
PUSTULAR PASI SCORE  
 
 
Signature                                             Printed Name                                                       Date 
 


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MODIFIED PALMOPLANTAR  PASI CALCULATION 
PSORIASIS 
CHARACTERISTIC 
RATING 
SCORE 
RIGHT 
PALM 
LEFT 
PALM 
RIGHT 
SOLE 
LEFT 
SOLE 
Erythema/redness (E) 
Lt red, red, v red, deep red 
 
0 = None 
1 = Slight 
2 = Moderate 
3 = Severe 
4 = Very Severe 
 
 
 
 
 
Pustules (P) or Infiltration 
Few, scattered, dense, 
confluent 
 
 
 
 
 
Desquamation/scaling (D) 
Fine, coarse fine, coarse 
thick, v thick 
 
 
 
 
 
SUM: E+P+D  
 
 
 
 
Modifier 
x 0.2 
x 0.2 
x 0.3 
x 0.3 
Weighted plaque score 
 = sum x modifier 
 
 
 
 
% affected body surface area  
 
 
 
 
AREA SCORE 
0 = None 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
 
 
 
 
 
SUBTOTAL = Weighted plaque score x 
Area score 
 
 
 
 
PALMOPLANTAR PASI SCORE  
 
 
 
Date of 
biopsy 
Clinical 
findings 
Location of 
biopsy 
Affected/Unaffected Reason for 
biopsy 
(D, R, D/R*) 
 
 
 
 
 
 
 
 
 
 
 
 
*D- Diagnostic; R-Research, D/R- Diagnostic/Research 
 
 
Signature                                             Printed Name                                                       Date 
 


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TOTAL BODY SURFACE AREA INVOLVEMENT (TBSAI) 
 HEAD ARMS TRUNK LEGS 
 
% affected area (plaques & 
pustules) 
 
 
 
 
 
 
Body area: % affected area x 
modifier 
x 0.1 
x 0.2 
x 0.3 
x 0.4 
TOTAL 
Subtotal 
 
 
 
 
 
 
 
PHYSICIAN GLOBAL ASSESSMENT (PGA) 
PGA RATING 
SCORE 
Plaque PGA score 
Pustule PGA score 
Overall PGA score 
0 = Clear 
1 = Minimal 
2 = Mild 
3 = Moderate 
4 = Severe 
5 = Very severe 
 
 
 
 
 
 
 
 
Signature                                         Printed Name                                                       Date 
 


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PATIENT VISUAL ANALOGUE SCALES 
 
Skin pain due to skin disease: 0 (no pain) to 10 (worst imaginable pain)  
Joint pain due to skin disease: 0 (no pain) to 10 (worst imaginable pain)  
Itching: 0 (no itching) to 10 (worst imaginable itching) 
Overall disease severity: your assessment of the degree of severity of your disease 
 
 
 
 
 
 
 
 
 
SKIN PAIN 
(0-10) 
JOINT PAIN 
(0-10) 
PRURITUS 
(0-10) 
OVERALL DISEASE 
SEVERITY 
(0-10) 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of this information is authorized under 42 USC 285. The primary use of the 
information you provide is to assess your health and quality of life. The information may be 
disclosed to clinicians and researchers for research purposes and to monitor personnel to assure 
that safety standards are maintained. Submission of this information is voluntary. 
Provider Signature                                         Printed Name                                                 Date 
0 
10 
Skin Pain 
0 
10 
Pruritus 
0 
10 
 Joint Pain 
Overall  
Disease  
Severity 
0 
10 


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21 APPENDIX I: HEALTH ASSESSMENT QUESTIONNAIRE 
 


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Collection of this information is authorized under 42 USC 285. The primary use of the 
information you provide is to assess your health and quality of life. The information may be 
disclosed to clinicians and researchers for research purposes and to monitor personnel to assure 
that safety standards are maintained. Submission of this information is voluntary. 


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22 APPENDIX J: JOINT EXAM CLINICAL ASSESSMENT FORM 
 
Collection of this information is authorized under 42 USC 285. The primary use of the 
information you provide is to assess your health and quality of life. The information may be 
disclosed to clinicians and researchers for research purposes and to monitor personnel to assure 
that safety standards are maintained. Submission of this information is voluntary. 


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23 APPENDIX K: REVIEW OF SYSTEMS 
 
MEDICAL HISTORY 
 


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Collection of this information is authorized under 42 USC 285. The primary use of the 
information you provide is to assess your health and quality of life. The information may be 
disclosed to clinicians and researchers for research purposes and to monitor personnel to assure 
that safety standards are maintained. Submission of this information is voluntary. 


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Version Date: December 12, 2018 
 
 
24 APPENDIX L: CCR PROBLEM REPORT FORM 
 
CCR PROBLEM REPORT FORM 
NCI Protocol #:  
Protocol Title:  
 
 
Report version: (select one) 
____Initial Report  
____Revised Report 
____Follow-up  
Site Principal Investigator: 
 
  
Date of problem:     
Location of problem: (e.g.,  patient’s home, 
doctor’s office ) 
 
 
Who identified the problem? (provide role (not name of person): nurse, investigator, monitor, 
etc…) 
 
Brief Description of Subject (if 
applicable)  
(Do NOT include personal 
identifiers)  
Sex:  ___ Male  ___ Female 
Age:   
 ___ Not applicable (more than subject is involved) 
 
Diagnosis under study:   
Name the problem: (select all that apply)   
[  ] Adverse drug reaction   
[  ] Abnormal lab value   
[  ] Death   
[  ] Cardiac Arrest/ code  
[  ] Anaphylaxis  


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[  ] Sepsis/Infection   
[  ] Blood product reaction 
[  ] Unanticipated surgery/procedure   
[  ] Change in status (e.g. increased level of care required)    
[  ] Allergy (non-medication)  
[  ] Fall  
[  ] Injury/Accident (not fall)  
[  ] Specimen collection issue   
[  ] Informed consent issue   
[  ] Ineligible for enrollment   
[  ] Breach of PII  
[  ] Tests/procedures not performed on schedule  
[  ]  Other, brief  1-2 word description: _________________________ 
 
Detailed Description of the problem: (Include any relevant treatment, outcomes or pertinent 
history): 
 
 
*Is this problem unexpected? (see the definition of unexpected in the protocol))  __YES __NO  
Please explain: 
 
 *Is this problem related or possibly related to participation in the research?  __YES __NO  
Please explain: 
 
*Does the problem suggest the research places subjects or others at a greater risk of 
harm than was previously known or recognized?    __YES __NO      Please explain: 
 
 
Is this problem? (select all that apply) 
[  ] An Unanticipated Problem* that is:       [  ] Serious        [  ] Not Serious  


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[  ] A Protocol Deviation that is:                [  ] Serious        [  ] Not Serious 
[  ] Non-compliance 
*Note if the 3 criteria starred above are answered, “YES”, then this event is also a UP. 
Is the problem also (select one)  [  ] AE  [  ] Non-AE 
Have similar problems occurred on this protocol at your site? __YES __NO       
If “Yes”, how many? ____      Please describe: 
Describe what steps you have already taken as a result of this problem: 
 
 
In addition to the NIH Intramural IRB, this problem is also being reported to: (select all that 
apply) 
[  ] Local IRB 
[  ] Study Sponsor 
[  ] Manufacturer : ____________________  
[  ] Institutional Biosafety Committee  
[  ] Data Safety Monitoring Board 
[  ] Other: ____________________________________  
[  ] None of the above, not applicable 
INVESTIGATOR’S SIGNATURE:  
 
DATE:   
 
 

ICF_001.pdf: 
MEDICAL RECORD
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or•Parent, for Minor Patient
INSTITUTE:
National Institute of Arthritis and Musculoskeletal and Skin Diseases
STUDY NUMBER:
13-AR-0071
PRINCIPAL INVESTIGATOR: Edward Cowen, M.D. M.H.S.     
STUDY TITLE: 
A Phase 2 Study of Anakinra in Inflammatory Pustular Dermatoses: Evaluation of 
Therapeutic Efficacy and Validation of Pathogenic Mechanisms
Continuing Review Approved by the IRB on 06/10/19
Amendment Approved by the IRB on 12/26/18 (M)
Date posted to web: 06/18/19
Standard
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or
•Parent, for Minor Patient
NIH-2514-1 (07-09)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent (1)
INTRODUCTION
We invite you to take part in a research study at the National Institutes of Health (NIH).
First, we want you to know that:
Taking part in NIH research is entirely voluntary. 
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation.
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future.
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study.
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.  
Why is this study being done?
Patients with inflammatory pustular skin disease may have some of the following problems: 
painful or itchy skin rashes, irritation of the eyes, mouth sores, joint pain, fevers and fatigue. 
Medicines used to treat inflammatory pustular skin disease include acitretin, cyclosporine, 
methotrexate, adalimumab, etanercept, psoralen plus ultraviolet A (PUVA), prednisone and 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
13-AR-0071
CONTINUATION: page 2 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
colchicine. Despite these medications, patients often still have active disease. Most of the 
medicines used to treat inflammatory pustular skin disease suppress the immune system. If you 
use these medicines for a long time, you may experience bad side effects including increased risk 
for infections, liver problems, kidney problems, high blood pressure, weight gain, osteoporosis, 
endocrine problems and mood disturbances. Since the available medicines are not always helpful 
and may have side effects, we are interested in learning whether new medicines may be helpful 
with fewer side effects. 
Inflammatory pustular skin diseases fall under a category of diseases called “autoinflammatory 
diseases.” Autoinflammatory diseases are conditions with episodes of inflammation such as 
fever, rash, or joint swelling. IL-1 is a name for a small protein that is produced in the body and 
may be important in causing the inflammation seen in pustular skin disease.  Some 
autoinflammatory diseases are well-treated with medications that block the action of IL-1. IL-1 
blocking agents are very helpful as standard of care treatment for other autoinflammatory 
diseases. Anakinra is an FDA-approved medication that works by blocking IL-1 and has been 
effective in the treatment of some inflammatory conditions, such as rheumatoid arthritis. 
Anakinra has not been studied for use in patients with pustular skin disease and is, therefore, 
considered an experimental treatment in this study. We would like to study whether anakinra will 
be effective in treating your pustular disease.
Why are you being asked to participate in this study?
You have been invited to participate in this study because you have a pustular skin disease. 
How many people will take part in this study? 
Up to 30 participants will take part in this study.  The study will take place at the NIH and the 
University of California, San Francisco.
Description of Research Study
This will be a 16-week study. While on treatment, you will be evaluated at the NIH at Weeks 4, 
8, 12 and 16.  The first dose of anakinra will be administered under supervision in clinic during 
your NIH visit.  You will then start self- injecting anakinra 100 mg daily. You will be evaluated 
at the NIH at Week 4 (after one month of treatment). Depending upon your evaluation, you may 
continue injecting 100mg daily for the remainder of the study or have your dose increased to 
200mg daily. Depending on how your skin disease is responding to therapy, you may be 
evaluated at the NIH again at Week 8 (after two months of treatment). Based on the physician’s 
evaluation of you at that time, you may stay at the 200mg daily dose for the remainder of the 
study or have your dose increased to 300mg daily if you weigh more than 75 kilograms (or 165 
pounds). You will continue to take the injections for up to 12 weeks, provided that you do not 
develop side effects that would require stopping the medication, and you continue to meet the 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
13-AR-0071
CONTINUATION: page 3 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
study criteria. If you have side effects related to anakinra during the study, you will be evaluated 
by a physician and your dose of anakinra may be stopped or reduced.  
You w i l l  b e  a s k e d  to record t he  severity of rash, pustules, itching, skin pain, joint pain, 
fevers, your overall well-being, doses of medications and the side effects you are experiencing 
in a log (or diary). You will be asked to return the log to the clinical staff each time you visit the 
NIH Clinical Center.
You will also be required to have weekly telephone assessments with our research staff for the 
entire duration of the study so that we can monitor your skin disease on anakinra therapy. See the 
schedule below. 
Study time point
Event
Start of study: Day 1
NIH Clinic visit: Initiate anakinra, first dose will be administered 
under supervision in clinic
Weeks 1, 2, 3
Telephone assessment
Week 4
NIH Clinic visit: Return for follow-up evaluations
Weeks 5, 6, 7
Telephone assessment
Week 8
NIH Clinic visit: Return for follow-up evaluations 
Weeks 9, 10, 11
Telephone assessment
Week 12
NIH Clinic visit: Return for final NIH for follow-up evaluations
Weeks 13, 14, 15
Telephone assessment
Week 16
NIH Clinic visit: Complete study follow-up period, including a post-
treatment safety visit & evaluations
The maximum duration of your involvement on this trial will be up to 1 month after your last dose 
of study medication. In all treatment groups, your final study visit will occur 30 days after the 
final dose of study medication. This will take approximately two days and will be a full NIH 
study visit including a physical exam and laboratory studies. The purpose of this visit is to 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
13-AR-0071
CONTINUATION: page 4 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
determine your level of disease activity and to check for any side effects that may be related to 
the study medication. 
If your pustular disease improves with anakinra therapy during this trial and you wish to 
continue therapy, we will try to help you obtain this drug after your active treatment on the study 
ends.  However, we cannot guarantee that you will be able to obtain anakinra after your active 
treatment on the study ends.
A maximum of 30 subjects with inflammatory pustular skin disease will participate in this study. 
The maximum amount of time possible to be in the study is 4 months; however your 
participation may be shorter, depending on your response to anakinra.
Therapies that you may be taking which can compound the immunosuppressive effect of 
anakinra will be discontinued. Phototherapy must be discontinued 2 weeks prior to beginning 
anakinra. You may not be on other biologic agents while on anakinra. If you have used biologic 
agents in the past, we will advise you as to the duration of time needed between stopping that 
medication and beginning anakinra. If you have been treated with canakinumab in the past, we 
will need to wait 12 months after your last dose before we can begin anakinra. If you are taking 
any other immunosuppressants or medications for your skin disease, the doses of these 
medications must remain stable in the 2 weeks prior to study initiation and during the study.  
You are ineligible to participate in this study if you have received any live vaccines in the last 3 
months.  You may not receive any live vaccines while you are enrolled in this study.    
While you are taking anakinra, it is important that you contact the study investigators before 
beginning any new prescription medicine, over-the-counter drug, supplement and/or herbal 
medicine.
Evaluations:
Before you begin the study, we will need to confirm that you have an inflammatory pustular skin 
disease. At a minimum, this study will require the collection of blood specimens and clinical 
data, which we will describe further in this consent. The purpose of this baseline visit is to 
perform all clinical evaluations of your pustular skin disease and evaluate your eligibility for this 
trial. We will perform routine urine and blood tests. If you have not had a prior skin biopsy 
showing that you have an inflammatory pustular skin disease, we will need to perform one to 
confirm this condition. We will need to give you a chest x-ray and administer a tuberculin 
positive protein derivative (PPD) test or a blood test called the Quantiferon TB gold to make sure 
you have no evidence of tuberculosis. Once these tests have been completed and we have 
confirmed that you have an inflammatory pustular skin disease, we will begin the study. You 
will continue to have regular visits at the NIH (described below) while you remain on study. 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
13-AR-0071
CONTINUATION: page 5 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
You will be given the chance to decide whether you would like to participate in the examinations 
listed below as “optional” at the time of each procedure.
Examinations can include the following:
History and Physical Examination: 
A summary of your medical record will be requested from your physician when you are initially 
referred to the NIH.  In addition, we will review your medical history with you and you will 
have a detailed physical examination. If you have had prior biopsies done, we may also ask your 
permission to have these sent for further evaluation at the NIH.
Blood and Urine Tests: 
During your visits, blood will be drawn from a vein in your arm for autoinflammatory and 
autoimmune studies, screening for viruses and other routine tests. Also, every month additional 
blood will be drawn to monitor your progress on anakinra and for research purposes to study the 
biology of inflammatory pustular skin disease and the effects of the study medication. Routine 
urine tests and a pregnancy test for females of childbearing potential will be done.
Biopsy of the skin (optional): 
All patients with pustular skin disease must have a biopsy to confirm this diagnosis. If a biopsy 
has not been previously obtained, then a skin biopsy at the NIH will be performed. The 
biopsy will be used to confirm your diagnosis, and if possible, a portion of the biopsy 
specimen obtained will be used for research studies evaluating certain proteins that may be 
present in the skin. If a biopsy has been previously obtained, then skin biopsy at the NIH is 
optional and will be obtained for research purposes only. If a decision is made to perform a 
biopsy, the full procedure, medical reasons for doing it and all its risks and benefits will be 
explained to you by the treating physician who will perform the biopsy.
Chest X-ray:
A chest x-ray uses radiation to takes pictures of the heart, lungs, airway, blood vessels and the 
bones of the spine and chest. You may be asked to remove your clothes and wear a gown during 
this test. You will need to stand very still in order not to blur the x-ray picture and may be asked 
to hold your breath for a few seconds while the x-ray is being taken.
PET Scan (optional):
Positron emission tomography (PET) scan is a test that uses radioactive glucose (sugar) and a 
computer to create images of how organs and tissues in the body are functioning. Abnormal cells 
in the body use glucose at a different rate than normal cells and this allows the scanner to create 
a detailed picture of how your body is working.


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
13-AR-0071
CONTINUATION: page 6 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
CT Scan (optional):
A computerized tomography (CT) scan is an X-ray procedure where a high-speed computer is 
used to make multiple images or pictures of your body. You will be asked to lie still on a table 
and at time may have to hold your breath for a few seconds in order to avoid blurring the 
pictures. You may hear a slight buzzing, clicking and/or whirring sounds as the CT scanner 
moves around your body.  You will receive information on how to get ready for this procedure.
MRI Scan (optional):
This study may use magnetic resonance imaging (MRI) to look at the joints. Magnetic resonance 
imaging is a type of scan that uses magnetic fields and radio waves to make a picture of the 
joints in order to better understand the cause of any symptoms you might have in that location.  
Specialty Consultations: 
You may also be evaluated by different specialists. Their evaluations will be used in evaluating 
other signs and symptoms relating to your pustular skin disease and if there is response to 
therapy. The specialty consultations are:

Rheumatologist (Muscle and Joint Specialist)

Ophthalmologist (Eye Specialist)- optional

Cardiologist (Heart Specialist)- optional

Gastroenterologist (Specialist of the esophagus, stomach, intestines and liver)- optional
These consultants and specialists will be provided by the NIH Clinical Center. 
Questionnaires:
We also want to know about the effect that your illness has on behavior and everyday activities. 
These questionnaires are called the Quality of Life (QOL) Assessments. It will take about 60 
minutes to complete QOL assessment questions. These questionnaires will be performed at the 
time you enroll on study and at weeks 4, 8, 12 and 16. The following testing will be done:
Short Form-36 (SF-36): Self-reported questionnaire with 36 items to evaluate eight domains of 
physical and mental health. Can be completed in 10 minutes.
Dermatology Life Quality Index (DLQI): Self-reported questionnaire with 10 items to evaluate 
skin-related quality of life. Can be completed in 5 minutes.
Pruritus Visual Analog Scale: Self-reported instrument ranging from 0-10 which measures 
degree of itching. Can be completed in less than 1 minute.


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
13-AR-0071
CONTINUATION: page 7 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
Pain Visual Analog Scale:  Self-reported instrument ranging from 0-10 which measures degree 
of pain. Can be completed in less than 1 minute.
Overall Disease Severity Visual Analog Scale:  Self-reported instrument ranging from 0-10 
which measures overall disease severity. Can be completed in less than 1 minute.
Health Assessment Questionnaire: Self-reported questionnaire to evaluate ability to function in 
daily life. Can be completed in 5 minutes.
Collection of this information is authorized under 42 USC 285. The primary use of the 
information you provide is to assess your health and quality of life. The information may be 
disclosed to clinicians and researchers for research purposes and to monitor personnel to assure 
that safety standards are maintained. Submission of this information is voluntary. NIH 
Privacy 
Act Systems of Record Notice (SORN) Number: 09-25-0200.
Photographs (optional):
At your baseline visit and at weeks 4, 8, 12 and 16, your study doctor may recommend that 
pictures are taken of your face and body to document how your skin disease responds to therapy.  
Birth Control
If you are a woman who is breast-feeding or pregnant, you may not take part in the study 
because we don’t know how this medicine would affect your baby or your unborn child. If you 
are a woman who can become pregnant, or are the partner of a woman who can become 
pregnant, you will need to practice an effective form of birth control before starting study 
treatment, during study treatment, and for 1 month after you finish study treatment.  If you think 
that you or your partner is pregnant, you should tell your study doctor or nurse at once.  
Effective forms of birth control include: 
•
abstinence 

intrauterine device (IUD)
•
hormonal [birth control pills, injections, or implants]
•
tubal ligation
•
vasectomy
Risks or Discomforts of Participation
What side effects or risks can I expect from being in this study? 
You may have side effects while on the study. Everyone taking part in the study will be watched 
carefully for any side effects. However, doctors don’t know all the side effects that may occur. 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
13-AR-0071
CONTINUATION: page 8 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
Side effects may be mild or very serious. Many side effects go away soon after you stop taking 
anakinra. In some cases, side effects can be serious, or long lasting.
Anakinra:
Likely

Redness and pain at the site where the medicine is injected

Cough

Cold

Bacterial skin infections

Lung infection, pneumonia

Diarrhea

Bone and joint infections

Reaction of the immune system

Headache

Nausea

Stomach pain

Sinusitis
Less Likely

Low blood counts
Rare but Serious

Rare bacterial, fungal (a form of yeast or mold), or viral infections

Anaphylaxis (serious or life-threatening allergic reaction characterized by itchy rash, 
facial and throat swelling, and low blood pressure)
In studies using anakinra for patients with rheumatoid arthritis, patients had increased rates of 
cancers of the lymph nodes, breast, respiratory tract and digestive system as compared with the 
general population.  However, rheumatoid arthritis patients have an increased risk of cancer in 
general, and the rates of cancer seen in anakinra patients were about the same as what we expect 
to see in rheumatoid arthritis patients who are not taking anakinra.  Therefore, it is not clear what 
role anakinra plays in the development of cancer. 
Anakinra has not been systematically studied in patients with pustular skin diseases, so we do not 
know if anakinra use is associated with increased cancer risk in patients with these conditions.
Tissue biopsy:
Skin biopsy (optional): Pain at the biopsy site should be minimal and bleeding and infections are 
rare. Biopsy wounds heal with a very small, nearly unnoticeable scar, but sometimes a raised 
scar (keloid) or visible lump may result. However, the biopsy will be taken from a place on your 
body that is not easily seen. The numbing medicine is used to reduce the discomfort of the 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
13-AR-0071
CONTINUATION: page 9 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
biopsies, however, there is minimal burning discomfort caused by the injection of the numbing 
medicine and the discomfort may not be eliminated completely. You may experience discomfort 
and mild tenderness at the biopsy site for up to 1 week. You may develop a bruise around the 
biopsy site, which usually disappears in one to two weeks. In rare cases, allergic reactions to the 
numbing medication have been reported. Please contact one of the investigators if you ever have 
had an allergic reaction to any medications or anesthetic agents in the past or after this 
procedure. 
Imaging Procedures
PET/CT Scan (optional)
This research study involves exposure to radiation from up to 2 FDG PET CT scans of 10 mCi 
each.  The radiation exposure from each FDG PET CT is equivalent to the radiation from about 6 
chest x-rays.  The amount of radiation you will receive in this study is 2.6 rem which is below 
the guideline of 5 rem in adults per year allowed for research subjects by the NIH Radiation 
Safety Committee.  The average person in the United States receives a radiation exposure of 0.3 
rem per year from natural sources, such as the sun, outer space, and the earth's air and soil.  This 
radiation exposure is not required for your medical care and is for research purposes only. If you 
would like more information about radiation, please ask the investigator for a copy of the 
pamphlet, An Introduction to Radiation for NIH Research Subjects.
While there is no direct evidence that the amount of exposure received from participating in this 
study is harmful, there is indirect evidence it may not be completely safe.  There may be a very 
slight increase in the risk of cancer. 
Please tell your doctor if you have had any radiation exposure in the past year, either from other 
research studies or from medical tests or care, so we can make sure that you will not receive too 
much radiation. Radiation exposure includes x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive materials 
were injected into your body. 
If you are pregnant you will not be permitted to participate in this research study. If you are 
breast feeding and the protocol involves injection of radioactive material you will not be 
permitted to participate.  It is best to avoid radiation exposure to unborn or nursing infants since 
they are more sensitive to radiation than adults.
MRI (optional)
MRI has been used for over 20 years in hospitals around the world. There are no known long-
term risks or consequences of MRI scans. Since you may feel extra warmth from the scanner, 
please report any sensation of heat during the test. During the scan, it is possible that you may 
experience something called "peripheral nerve stimulation." This usually takes the form of a mild 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
13-AR-0071
CONTINUATION: page 10 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
sensation in the skin like a vibration. If you feel pain or a twitch in the muscle, you should report 
it to the person performing the scan. Some individuals may feel claustrophobic (confined) in the 
scanner. 
Photographs (optional)
Taking pictures of the face and body may be embarrassing to some patients. These photographs 
may be published in medical journals, without identifying the patient. 
Potential Benefits of Participation
Are there benefits to taking part in this study? 
The potential benefit of this treatment is that it might improve your pustular skin disease and 
may lead to a reduction in related symptoms. We hope that you will get personal medical 
benefit from taking part in this study, but we cannot be certain.  Because there is not much 
information about the drug’s effect on your skin disease, we do not know if you will benefit from 
taking part in this study, although the knowledge gained from this study may help others in the 
future who have a similar skin condition.  Your participation in this study will also allow us to 
learn more about pustular skin diseases.
Alternative Approaches or Treatments
What other choices do I have if I do not take part in this study? 
Instead of being in this study, you have these options:

Getting treatment or care for your skin without being in a study

Taking part in another study

Opting for no treatment
Please talk to your doctor about these and other options.
Research Subject’s Rights
What are the costs of taking part in this study? 
If you choose to take part in the study, the following will apply, in keeping with the NIH policy:

You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH. 

There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company.


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
13-AR-0071
CONTINUATION: page 11 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent

Medicines that are not part of the study treatment will not be provided or paid for by 
the Clinical Center, NIH.

Once you have completed taking part in the study, medical care will no longer be 
provided by the Clinical Center, NIH.  If your pustular disease improves with 
anakinra therapy during this trial and you wish to continue therapy, we will try to 
help you obtain this drug after your active treatment on the study ends.  However, we 
cannot guarantee that you will be able to obtain anakinra after your active treatment 
on the study ends.
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the Web 
site will include a summary of the results.  You can search this Web site at any time. 
Will your medical information be kept private?
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include:

The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

Qualified representatives from the Swedish Orphan Biovitrum, the pharmaceutical 
company who produces Anakinra.
Stopping Therapy 
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if your disease flares during treatment

if you have side effects from the treatment that your doctor thinks are too severe

if new information shows that another treatment would be better for you

you request to withdraw from therapy
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. If you leave the trial, any remaining samples of 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
13-AR-0071
CONTINUATION: page 12 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
yours that have been obtained for the study can be destroyed. However, the samples and data 
generated from the samples that have already been distributed to other researchers or placed in 
the research databases cannot be withdrawn.
Certificate of Confidentiality 
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below.
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information: 

will be used for auditing or program evaluation internally by the NIH; or 

must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA). 

is necessary for your medical treatment and you have consented to this disclosure; 

is for other research. 
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent. 
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information.
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others.
Conflict of Interest
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a Protocol Review Guide. You may ask your research team 
for a copy of the Protocol Review Guide or for more information.  Members of the research team 
who do not work for NIH are expected to follow these guidelines but they do not need to report 
their personal finances to the NIH.


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
13-AR-0071
CONTINUATION: page 13 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest. 
The Swedish Orphan Biovitrum is providing Anakinra for this study to NIH without charge, 
although it may also be purchased by the NIH pharmacy.  No NIH investigator involved in this 
study receives payments or other benefits from any company whose drug, product or device is 
being tested.  However, there are some non-NIH collaborators on this study who may receive 
payments or benefits, limited by the rules of their workplace.
Use of Specimens and Data for Future Research 
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.  
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses. These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes.  Your specimens and data will be used for research purposes only and will 
not benefit you. It is also possible that the stored specimens and data may never be used.  Results 
of research done on your specimens and data will not be available to you or your doctor.  It 
might help people who have cancer and other diseases in the future.  
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that remain will be destroyed and your data will not be used for future research. 
However, it may not be possible to withdraw or delete materials or data once they have been 
shared with other researchers.


MEDICAL RECORD
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or•Parent, for Minor Patient
STUDY NUMBER:
13-AR-0071
CONTINUATION: page 14 of 15 pages
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet)
•
Adult Patient or
•Parent, for Minor Patient
NIH-2514-1 (07-09)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
OTHER PERTINENT INFORMATION
1.
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance.
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations.
2.
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action.
3.
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines.
4.
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Edward W. Cowen, M.D., Building 10, Room 12N238, Telephone:  301-
480-7196. You may also call the Clinical Center Patient Representative at 301-496-2626. If you 
have any questions about the use of your specimens and data for future research studies, you may 
also contact the Office of the Clinical Director, Telephone:  240-760-6070. 
5. Consent Document.  Please keep a copy of this document in case you want to read it again.


MEDICAL RECORD
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or•Parent, for Minor Patient
STUDY NUMBER:
13-AR-0071
CONTINUATION: page 15 of 15 pages
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet)
•
Adult Patient or
•Parent, for Minor Patient
NIH-2514-1 (07-09)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
COMPLETE APPROPRIATE ITEM(S) BELOW:
A. Adult Patient’s Consent
B. Parent’s Permission for Minor Patient.
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study.
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.  
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.)
Signature of Adult Patient/
Legal Representative
Date
Signature of Parent(s)/ Guardian
Date
Print Name
Print Name
C. Child’s Verbal Assent (If Applicable)
The information in the above consent was described to my child and my child agrees to 
participate in the study.
Signature of Parent(s)/Guardian
Date
Print Name
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE 
FROM JUNE 10, 2019 THROUGH JUNE 24, 2020. 
Signature of Investigator
Date
Signature of Witness
Date
Print Name
Print Name