Ultrasound Enthesitis Response in Psoriatic Arthritis
Condition: Psoriatic Arthritis; Psoriasis; Enthesitis
MeSH terms: Arthritis; Arthritis, Psoriatic; Enthesopathy; Psoriasis
Study type: Observational

Summary: 
      The aim of this observational study will be to recruit 100 Psoriatic Arthritis (PsA) patients
      beginning on their biologic therapy and asses, both clinically and with the use of ultrasound
      (US), how enthesitis responds to biologic treatment.

      The decision to start treatment with a biologic therapy will be made by the patients' usual
      clinical rheumatology team, as part of their standard clinical care. This is independent of
      the study. Patients in whom treatment with these drugs for their PsA has been recommended
      will then be invited to participate in this study.They will then be commenced on biologic
      therapy at doses in line with the Summary of Product characteristics (SPC) for the product
      and followed up in the hospital outpatient clinic.

      Patients will have a full history taken and clinical exam performed prior to commencing on
      their prescribed biologic. The patient's history, Health Assessment Questionnaire scores and
      biobanking samples will be taken by the co-investigator. They will also calculate the
      patients tender and swollen joint score, dactylitis score, skin score, nail score and
      clinical enthesitis score.They will then have their tender entheseal points scanned as well
      as those as per the MASEI (Madrid Sonographic Enthesitis Index ) protocol by a single
      rheumatologist. The rheumatologist will be trained in ultrasound and will perform the scans
      blinded to this information both at initial consultation and at subsequent reviews.

      The patient will then commence their biologic treatment as planned at a separate review as
      per usual practise with their clinical team.

      Follow-up and final assessment at 4 months (±2 weeks) after starting biologic will include
      the clinical and ultrasound assessments as per the initial review and outlined in the
      schedule of assessments. They will also have a final blood sample taken at this point.
    

Detailed description: 
      Objective: This study will aim to clarify, in a cohort of active PsA patients, what is the
      prevalence of US confirmed enthesitis, what happens to these scores after biologic treatment,
      does this correlate with clinical scores and can enthesitis then serve as a prognostic tool
      in predicting response in patients receiving their biologic therapy.

      Aims and objectives:

      Primary outcome:

      -The change in MASEI score at 4 months from baseline assessment.

      Study design:

      A prospective,assessor-blinded, cohort observational study of biologic-naive patients with
      PsA receiving biologic treatment as part of standard clinical care.

      An observational trial was deemed appropriate to answer the study question and provide real
      life data to form the basis of future randomised controlled trials.

      Duration Participants will be in the study for a maximum of 6 months, with most participants
      completing the study within 4 months after starting the biologic. The end of the trial will
      be at the 4 month assessment for the final patient with the locking of the study database.

      Study setting The study will be carried out on one site in Musgrave Park Hospital, Belfast.
      This is an NHS (National Health Service) teaching hospital, part of the Belfast Health and
      Social Care Trust.

      Inclusion and exclusion criteria Inclusion criteria for PsA patients

      Patients with PsA will be included if they meet all of the following criteria:

        1. Aged ≥ 18 years

        2. Fulfil the Classification criteria for PSA (CASPAR criteria)

        3. Have not previously had biologic disease modifying treatment for their PsA

        4. Are due to commence on subcutaneous TNF (Tumour necrosis Factor) inhibitor or
           secukinumab as part of their standard clinical care, in line with the product SPC

        5. Are able and willing to give informed consent and comply with the requirements of the
           study protocol NOTE: DMARD therapy will be permitted and used as per standard clinical
           practice (will be captured in CRF)

      Exclusion criteria:

      Patients will not be eligible if they meet any of the following criteria:

      1. History of or current autoimmune rheumatic disease other than PsA 2. Previously received a
      biologic therapy for PsA 3. Receiving infliximab (IV TNF inhibitor) 4. Haemoglobin ≤9 g/dl 5.
      Known Human immunodeficiency Virus (HIV), hepatitis C or B infection 6. Current oral steroids
      7. Intramuscular steroids within 6 weeks of baseline (IA steroid injection will be allowed)
      8. Pregnancy or breast feeding in line with current prescribing recommendations 9. Prisoners
      or subjects who are involuntarily incarcerated. 10.Subjects who are compulsorily detained for
      treatment of either a psychiatric or physical (e.g., infectious disease) illness.

      Study procedures:

      Initial Patient Approach and consent

      The decision to start treatment with subcutaneous biologic therapy will be made by the
      patients' usual clinical rheumatology team, as part of their standard clinical care. This is
      independent of the study. Patients in whom treatment with these drugs for their PsA has been
      recommended will then be invited to participate in this study. The initial approach to
      potential participants will be by their usual clinical team.

      Written informed consent will be obtained from each subject prior to any study-related
      procedures being performed. Consenting participants will have their baseline study assessment
      performed whilst on the NHS biologic waiting list. They will then be commenced on biologic
      therapy, as prescribed and followed up in the hospital outpatient clinic as usual at the 4
      months mark.

      Initial consultation and blinding

      Each group will have a full history taken and clinical exam performed as noted below. They
      will then have their tender entheseal point scanned as well as those as per the MASEI
      protocol. The patient's history, HAQ (Health Assessment Questionnaire) scores and biobanking
      samples will be taken by the co-investigator. The co investigator will be a rheumatology
      registrar and will then assess skin, joints, nails and enthesitis points and calculate the
      scores below, all of which are routine tools used in clinical practise. A single
      rheumatologist trained in US will perform the scans blinded to this information both at
      initial consultation and at the 4 month review. The co-investigator and participants will not
      be blinded to the treatment or results, although within the first consultation neither
      patient or assessor will know what medication the consultant team will ultimately decide to
      commence the participant on.

      Biologic treatment will then be administered as planned by the patient's consultant
      rheumatologist.

      Baseline visit (up to 2 weeks prior to starting biologic):

        1. Demographic data and confirmation of inclusion and exclusion criteria

        2. Duration of PsA and psoriasis

        3. Calculate BMI

        4. Social History: Smoking status and alcohol use

        5. Family History: Of joint or skin disease

        6. Drug history

        7. Full clinical exam with height and weight

        8. Calculate MDA (Tender joint score 66 Swollen joint score 68 LEI- C or N BSA (Body
           Surface Area)/ PASI (Psoriasis Area and Severity Index) measurement Patient pain VAS
           Patient global disease activity VAS HAQ-See attached sheet)

        9. Calculate their Spondyloarthritis research consortium of Canada (SPARCC) enthesitis
           score

       10. Calculate their Leeds Enthesitis Score (LEI)

       11. Calculate Bath AS disease activity index (BASDAI)

       12. Calculate their (Dermatology Life Index score) DLQI score

       13. Calculate their Nail Severity Psoriasis Index (NAPSI) score.

       14. Calculate their Dactylitis score

       15. Calculate their Physician global assessment score

       16. Calculate their DAS (Disease Activity Score)-28 score

       17. Blood investigations: FBC (Full Blood Count), renal profile, eGFR, inflammatory markers
           (CRP, ESR) and liver profile will have been taken as part of routine care (Results will
           be noted)

       18. Blood samples for biobanking

       19. Imaging Ultrasound Scan entheseal points as per the MASEI score These will include- Six
           bilateral enthesis locations in each patient, including the proximal plantar fascia,
           distal Achilles tendon, distal and proximal patellar ligament, distal quadriceps and
           brachial triceps tendons Modalities to be documented i. Enthesophyte ii. Power Doppler
           signal iii. Entheseal calcification iv. Erosions v. Entheseal thickness

      Ultrasound scan any other entheseal points that are symptomatic, this includes if there is
      nail changes. Choose one nail bed to US scan to assess for changes.

      Sample collection for biobanking At each time point 20ml of additional blood will be
      collected from each participant each, comprising whole blood (RNA), PBMC (DNA), serum and
      plasma (for future immunoassays, metabolomics) .This will be placed on ice and transferred
      securely to Queen University Belfast and spun down and the plasma will be stored at Dr
      Rooney's Laboratory. All samples will be labelled with a unique patient study participant
      code and this will be recorded in the database. They will be stored in a freezer at a
      temperature of at least -20oC. The samples will be anonymised with their unique code and will
      only be able to be identified by the principal investigator. Analysis will include a targeted
      or unbiased protein assessment strategy in the form of a mass spectrometry based proteomics
      platform. Analysis may also include that of genetic variation markers, related to the target
      pathway of the biologic therapies. This may involve whole genome sequencing.

      Patient will then go onto their biologic treatment as planned at a separate appointment with
      their clinical team where a plan will be put in place for review to assess response to drug
      as usual at 4 months

      Interventions

      The decision to commence a patient on a biologic therapy will be made independent of the
      study protocol by the patient's rheumatology consultant. All study participants will be
      retained in the trial whenever possible to enable follow-up data collection and prevent
      missing data.

      If a patient has not been able to take their biologic therapy for a period of more than or
      equal to 6 weeks during the study they will be deemed to not have completed the treatment and
      will not be included in the final comparative analysis. Each of the biologic medications
      being used in this study has a marketing authorisation in the UK and is being used in its
      marketed presentation and packaging bearing the MA number. All medications will be sourced
      locally by the research site pharmacy in Musgrave Park Hospital at market price as per
      standard procedure independent of the study and stored and distributed as per usual
      practices.

      Biologic treatment routinely used at Musgrave Park Hospital for PsA are as follows:

        1. Etanercept

        2. Adalimumab

        3. Certolizumab pegol

        4. Golimumab

        5. Secukinumab

      Follow-up and final assessment (4 months ±2 week after starting biologic) Clinical and
      ultrasound assessments as per the initial review will be carried out without the need to go
      over exclusion/inclusion criteria, past medical history or family history. An additional
      PsARC calculation based on response will be made at this point.

      A further bio banking sample will be taken at the 4 months mark.

      Time plan and Study Centres:

      Recruitment will take place during the first 6 months of the study and the study will end 4
      months after the recruitment of the last patient. Once the first participant is referred by
      their consultant they will be put on the biologic waiting list to commence their new
      medication. This process usually takes 3 months from referral to commencing on their biologic
      medication. We will assess the participant two weeks prior to this review and then their next
      review will be at the 4 months mark prior to their second consultant review. The participant
      involvement will end then.

      Sample size Sample size calculation. On reviewing the literature in relation to the MASEI
      score, the initial paper to highlight its validity as a scanning tool in those with
      spondyloarthropathy compared with controls was able to demonstrate this with only 25
      patients.

      In this study 84% of patients demonstrated active disease as defined by a cut off score of 18
      and therefore we would expect in a cohort of active PsA patients that the vast majority will
      demonstrate active disease to allow comparison after biologic treatment. Based then on
      available data on PsA patients prescribed biologic therapy within the Belfast trust, a sample
      size of 100 patients was deemed achievable and would allow the primary outcome to be
      answered.

      Assuming 100 patients are recruited split 50/50 between IL (Interleukin)-17 and TNF. Then the
      study will have 85% power to determine a difference between groups as statistically
      significant if the difference in MASEI change scores at three months between the two groups
      is equal to 0.6 standard devia- tions of the change score. This calculation assumes equal
      variation in the change score in both groups, a significance level of 0.05 and is based on a
      two-sided hypothesis

      Recruitment Patients will first be approached by one of the seven rheumatology consultants,
      based in Musgrave Park Hospital.If patients are agreeable to hear more information on the
      research they will be referred to the research team who are based in the Belfast Trust.
      Initially an email with patient details will be sent to the research team who will telephone
      the potential participant to discuss the study and verbally explain what the study entails.
      If the patient is interested in participating in the study they will have an information
      sheet posted out to their home address. The patient will then attend for their initial
      consultation and at this point, if they are still happy to proceed with participation, they
      will be consented for inclusion in the study. Hospital numbers and personal details will be
      communicated by Trust computers and each patient will be given a unique identifier number
      once enrolled. During the study the medication the patient is then prescribed by their
      consultant team will be noted by the co-investigator and/or nurse specialist. The aim will be
      to recruit at least 2 patients a week with the expected time line to be 12 months to complete
      recruitment and 18 months at a maximum to complete the final patient assessment.

      Data Management Each patient will have a unique study code participant number to make
      information anonymised. The study will be conducted on NHS property by researchers from the
      Belfast Health and Social Care Trust and any personal information will be held securely on
      Trust property and handled in accordance with the provisions of the Data Protection Act 2018.
      Blood samples will be labelled with the unique study code for each participant prior to
      storage. These codes will be contained within a master file and will be kept under secure
      conditions within a locked fill-in cabinet on Belfast Trust property.

      Statistical analysis Analysis of MASEI scores will be by independent samples t-tests and
      Analysis of covariance. Differences between patient groups will be examined by calculating
      propensity scores, obtained from running a logistic regression analysis with grouping
      variable as outcome and patient demographic and medical history variables as explanatory. If
      the propensity analysis is statistically significant the propensity scores will be included
      in all subsequent analysis of MASEI. Secondary variables will be treated in a similar manner.
      Firstly the researchers will look as to whether the MDA (5/7) or PsARC (Yes/No) score is
      achieved at the 4 months assessment. The researchers will also compare the LEI, Dactylitis,
      66/68 Tender and swollen score change from baseline to 4 months. Finally the research team
      will look at the relationship between MASEI score and clinical scores at the 4 months mark to
      see if there is correlation. The change in US findings at the nail bed will be a descriptive
      result of any changes noted.

      The research team do not envisage any urgent safety measures that will be required a part of
      this project.

      The CI or in exceptional cases the PI will report the urgent safety measure to the Trust
      Research Office immediately by telephone or within 3 days in written form.

      Consent PI (Ashley Elliott) will be taking the written consent of the patient. Once they have
      been approached to participate by their consultant the participants will receive an
      information sheet explaining the study. Written consent will be gained at the first
      consultation.

      Declaration of interests There is no financial or other competing interests for the principal
      investigators for the trial.
    

Intervention name(s): adalimumab; Certolizumab; Etanercept; Golimumab; Secukinumab
Intervention type(s): Biological; Biological; Biological; Biological; Biological
Intervention description(s): Subcutaneous injection; Subcutaneous injection; Subcutaneous injection; Subcutaneous injection; Subcutaneous injection
Other intervention name(s): Humira; Cimzia; Enbrel; Simponi; Cosentyx
Intervention MeSH terms: Adalimumab; Golimumab; Certolizumab Pegol; Etanercept
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Psoriatic Arthritis patients with active disease who are naive to biologic therapy
      
Biospecimen description: 
      Bloods samples with whole blood/serum/plasma storage for future biomarker analysis