Clinical trial NCT03856840: Cytokines in Blister Fluids of Bullous Pemphigoid (BP)
Official title: Evaluation of Cytokines and Immunoglobulins in Serum and Blister Fluids Appeared Before Treatment and Subsequently Under Treatment in Bullous Pemphigoid
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Pemphigoid, Bullous
Keywords: Pemphigoid, Bullous
Bullous Pemphigoid
Blister Fluid
Eosinophil Cationic Protein
Tumor Necrosis Factor-alpha
Anti-BP180
Disease activity
Disease severity
Lead sponsor: Istanbul Medeniyet University
Sponsor class: OTHER
First posted: 2019-02-27
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: All Bullous Pemphigoid patients presented to concerning clinics who accept the terms and definitions and sign consent form.

Brief summary: This study investigates the differences of Eosinophil Cationic Protein, Tumor Necrosis Factor-alpha and Anti-BP180-NC16A IgG levels of blister fluids in Bullous Pemphigoid patients which appeared before and under treatment subsequently. These molecules will also be measured in blood serum before and under treatment. Changes of titers in serum and differences between blister fluids will be compared to observe whether correlation exists between them. These measures will also be compared between groups of responders and non-responders to the first-line treatment options to analyze correlation with treatment success.

Detailed description: Bullous Pemphigoid is an auto-immune bullous disorder in which auto-antibodies to hemidesmosomes, complement pathway, inflammatory cells and mediators play a crucial roles for disease pathogenesis.

Anti-BP180-NC16A IgG is an antibody that it primarily triggers inflammatory reactions and complement cascade in bullae development and plays major roles in disease pathogenesis. It is secreted by plasma cells which is induced by T-helper 2 cells and their cytokines in serum and lesional tissue. Anti-BP180 antibody detection in serum is very important in diagnosis and titers correlate with disease activity. Anti-BP180 antibody can also be detected in blister fluids and it may aid diagnosis.

Eosinophil cationic Protein is a cytokine and secreted by Eosinophil which is found in abundant numbers and correlated with tissue damage in Bullous Pemphigoid lesions. Serum titers of Eosinophil Cationic Protein has a correlation with disease activity and it is higher in blister fluid than serum. Tumor Necrosis Factor-alpha is an another cytokine which is secreted from inflammatory cells initially after inflammatory cascade is triggered. It is also found increased in serum blister fluids. Tumor necrosis factor-alpha is associated with clinical severity in bullous pemphigoid.

In Bullous Pemphigoid, development of bulla is required to be stopped if treatment will be considered as successful. Nevertheless smaller, more rapidly healing vesicles and bullae appear under treatment which are not regarded as findings of treatment failure. In this study we will measure Eosinophil Cationic Protein, Tumor Necrosis Factor-alpha and Anti-BP180-NC16A IgG levels with E.L.I.S.A. technique in these subsequently appeared blisters if they will appear and compare them with pretreatment blisters. We will also measure levels of these molecules in blood serum before and under treatment. We will analyze corralation between blood serum and blister fluids. Also we will compare responder patients and non-responder patients to first-line treatment options to observe correlation of changes and differences in these body fluids with treatment success.

Eligibility criteria: Inclusion Criteria:

* All patiens presented to clinics who is diagnosed with Bullous Pemphigoid by findings of clinical, histopathological, Direct Immunoflorescent evaluation.
* All relapsed/flared Bullous Pemphigoid patients.
* Patients who accept the terms and conditions and sign consent form.

Exclusion Criteria:

* Patients who are received treatment before presenting clinics where the study is conducted.
* Patients who reject to join to study and the terms and condition
* Patients who leave the study by own decision

Primary outcomes:
measure: Titers of Eosinophil Cationic Protein in blister fluid and blood serum
timeFrame: 14 Days
measure: Titers of Tumor Necrosis Factor-alpha in blister fluid and blood serum
timeFrame: 14 Days
measure: Titers of Anti-BP180-NC18A IgG in blister fluid and blood serum
timeFrame: 14 Days
Secondary outcomes:
measure: Time to control of disease activity
timeFrame: Up to 4 weeks
measure: Consolidation phase of Outcome Measures for Bullous Pemphigoid
timeFrame: 14 days
measure: Treatment Failure
timeFrame: 4 week
measure: Relapse/Flare
timeFrame: Up to one year
measure: Bullous Pemphigoid disease severity assessment
timeFrame: One day
measure: Bullous Pemphigoid Disease Area Index (B.P.D.A.I.)
timeFrame: Up to one year
measure: Bullous Pemphigoid Disease Area Index (B.P.D.A.I.)-Damage score
timeFrame: Up to one year
measure: Bullous Pemphigoid Disease Area Index (B.P.D.A.I.)-Pruritus score
timeFrame: Up to one year
Other outcomes:
Locations:
city: Istanbul
country: Turkey
facility: Istanbul Medeniyet University Goztepe Training and Research Hospital
state: Kadikoy
city: İstanbul
country: Turkey
facility: Istanbul Training and Research Hospital
state: Samatya
Study officials:
affiliation: Istanbul Medeniyet University
name: Mehmet Salih Gurel, Professor
role: STUDY_DIRECTOR
References:
citation: Bernard P, Antonicelli F. Bullous Pemphigoid: A Review of its Diagnosis, Associations and Treatment. Am J Clin Dermatol. 2017 Aug;18(4):513-528. doi: 10.1007/s40257-017-0264-2.
citation: Bagci IS, Horvath ON, Ruzicka T, Sardy M. Bullous pemphigoid. Autoimmun Rev. 2017 May;16(5):445-455. doi: 10.1016/j.autrev.2017.03.010. Epub 2017 Mar 8.
citation: Schmidt E, Zillikens D. Pemphigoid diseases. Lancet. 2013 Jan 26;381(9863):320-32. doi: 10.1016/S0140-6736(12)61140-4. Epub 2012 Dec 11.
citation: Schmidt E, della Torre R, Borradori L. Clinical features and practical diagnosis of bullous pemphigoid. Dermatol Clin. 2011 Jul;29(3):427-38, viii-ix. doi: 10.1016/j.det.2011.03.010.
citation: Marzano AV, Tedeschi A, Fanoni D, Bonanni E, Venegoni L, Berti E, Cugno M. Activation of blood coagulation in bullous pemphigoid: role of eosinophils, and local and systemic implications. Br J Dermatol. 2009 Feb;160(2):266-72. doi: 10.1111/j.1365-2133.2008.08880.x. Epub 2008 Oct 20.
citation: Engineer L, Bhol K, Kumari S, Razzaque Ahmed A. Bullous pemphigoid: interaction of interleukin 5, anti-basement membrane zone antibodies and eosinophils. A preliminary observation. Cytokine. 2001 Jan 7;13(1):32-38. doi: 10.1006/cyto.2000.0791.
citation: Provost TT, Tomasi TB Jr. Immunopathology of bullous pemphigoid. Basement membrane deposition of IgE, alternate pathway components and fibrin. Clin Exp Immunol. 1974 Oct;18(2):193-200.
citation: D'Auria L, Pimpinelli F, Ferraro C, D'Ambrogio G, Giacalone B, Bellocci M, Ameglio F. Relationship between theoretical molecular weight and blister fluid/serum ratio of cytokines and five other molecules evaluated in patients with bullous pemphigoid. J Biol Regul Homeost Agents. 1998 Jul-Sep;12(3):76-80.
citation: Giusti D, Gatouillat G, Le Jan S, Plee J, Bernard P, Antonicelli F, Pham BN. Eosinophil Cationic Protein (ECP), a predictive marker of bullous pemphigoid severity and outcome. Sci Rep. 2017 Jul 6;7(1):4833. doi: 10.1038/s41598-017-04687-5.
citation: Tedeschi A, Marzano AV, Lorini M, Balice Y, Cugno M. Eosinophil cationic protein levels parallel coagulation activation in the blister fluid of patients with bullous pemphigoid. J Eur Acad Dermatol Venereol. 2015 Apr;29(4):813-7. doi: 10.1111/jdv.12464. Epub 2014 Mar 20.
citation: D'Auria L, Pietravalle M, Mastroianni A, Ferraro C, Mussi A, Bonifati C, Giacalone B, Ameglio F. IL-5 levels in the serum and blister fluid of patients with bullous pemphigoid: correlations with eosinophil cationic protein, RANTES, IgE and disease severity. Arch Dermatol Res. 1998 Jan-Feb;290(1-2):25-7. doi: 10.1007/s004030050272. No abstract available.
citation: Dierksmeier U, Frosch PJ, Czarnetzki BM. Eosinophil chemotactic factor (ECF) in blister fluid of dermatological diseases. Br J Dermatol. 1980 Jan;102(1):43-8. doi: 10.1111/j.1365-2133.1980.tb05670.x.
citation: Ameglio F, D'Auria L, Cordiali-Fei P, Mussi A, Valenzano L, D'Agosto G, Ferraro C, Bonifati C, Giacalone B. Bullous pemphigoid and pemphigus vulgaris: correlated behaviour of serum VEGF, sE-selectin and TNF-alpha levels. J Biol Regul Homeost Agents. 1997 Oct-Dec;11(4):148-53.
citation: Murrell DF, Daniel BS, Joly P, Borradori L, Amagai M, Hashimoto T, Caux F, Marinovic B, Sinha AA, Hertl M, Bernard P, Sirois D, Cianchini G, Fairley JA, Jonkman MF, Pandya AG, Rubenstein D, Zillikens D, Payne AS, Woodley D, Zambruno G, Aoki V, Pincelli C, Diaz L, Hall RP, Meurer M, Mascaro JM Jr, Schmidt E, Shimizu H, Zone J, Swerlick R, Mimouni D, Culton D, Lipozencic J, Bince B, Grando SA, Bystryn JC, Werth VP. Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts. J Am Acad Dermatol. 2012 Mar;66(3):479-85. doi: 10.1016/j.jaad.2011.06.032. Epub 2011 Nov 5.
citation: Eming R, Sticherling M, Hofmann SC, Hunzelmann N, Kern JS, Kramer H, Pfeiffer C, Schuster V, Zillikens D, Goebeler M, Hertl M, Nast A, Orzechowski HD, Sardy M, Schmidt E, Sitaru C, Sporbeck B, Worm M. S2k guidelines for the treatment of pemphigus vulgaris/foliaceus and bullous pemphigoid. J Dtsch Dermatol Ges. 2015 Aug;13(8):833-44. doi: 10.1111/ddg.12606. No abstract available.
citation: Zhao CY, Murrell DF. Advances in understanding and managing bullous pemphigoid. F1000Res. 2015 Nov 20;4:F1000 Faculty Rev-1313. doi: 10.12688/f1000research.6896.1. eCollection 2015.
citation: Levy-Sitbon C, Barbe C, Plee J, Goeldel AL, Antonicelli F, Reguiai Z, Jolly D, Grange F, Bernard P. Assessment of bullous pemphigoid disease area index during treatment: a prospective study of 30 patients. Dermatology. 2014;229(2):116-22. doi: 10.1159/000362717. Epub 2014 Jul 5.
citation: Joly P, Roujeau JC, Benichou J, Delaporte E, D'Incan M, Dreno B, Bedane C, Sparsa A, Gorin I, Picard C, Tancrede-Bohin E, Sassolas B, Lok C, Guillaume JC, Doutre MS, Richard MA, Caux F, Prost C, Plantin P, Chosidow O, Pauwels C, Maillard H, Saiag P, Descamps V, Chevrant-Breton J, Dereure O, Hellot MF, Esteve E, Bernard P. A comparison of two regimens of topical corticosteroids in the treatment of patients with bullous pemphigoid: a multicenter randomized study. J Invest Dermatol. 2009 Jul;129(7):1681-7. doi: 10.1038/jid.2008.412. Epub 2009 Jan 29.
citation: Feliciani C, Joly P, Jonkman MF, Zambruno G, Zillikens D, Ioannides D, Kowalewski C, Jedlickova H, Karpati S, Marinovic B, Mimouni D, Uzun S, Yayli S, Hertl M, Borradori L. Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology. Br J Dermatol. 2015 Apr;172(4):867-77. doi: 10.1111/bjd.13717.