Cytokines in Blister Fluids of Bullous Pemphigoid (BP)

Pemphigoid, Bullous Clinical Trial

— BP  

Official title:

Evaluation of Cytokines and Immunoglobulins in Serum and Blister Fluids Appeared Before Treatment and Subsequently Under Treatment in Bullous Pemphigoid

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03856840
• Other study ID #: 2018/0181
• Status: Completed
• Start date: January 29, 2018
• Est. completion date: August 27, 2019

Study information

• Verified date: October 2019
• Source: Istanbul Medeniyet University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: August 27, 2019
• Est. primary completion date: May 23, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Blister
• Pemphigoid, Bullous

Locations

Country	Name	City	State
Turkey	Istanbul Medeniyet University Goztepe Training and Research Hospital	Istanbul	Kadikoy
Turkey	Istanbul Training and Research Hospital	Istanbul	Samatya

Sponsors (1)

Lead Sponsor	Collaborator
Mahmut Can Koska

Country where clinical trial is conducted

Turkey, 

References & Publications (19)

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. — View Citation

Bagci IS, Horváth ON, Ruzicka T, Sárdy M. Bullous pemphigoid. Autoimmun Rev. 2017 May;16(5):445-455. doi: 10.1016/j.autrev.2017.03.010. Epub 2017 Mar 8. Review. — View 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. Review. — View 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. — View 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. — View 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. — View 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, Sárdy 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. — View 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. — View Citation

Feliciani C, Joly P, Jonkman MF, Zambruno G, Zillikens D, Ioannides D, Kowalewski C, Jedlickova H, Kárpáti 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. — View Citation

Giusti D, Gatouillat G, Le Jan S, Plée 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. — View 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. — View Citation

Lévy-Sitbon C, Barbe C, Plee J, Goeldel AL, Antonicelli F, Reguiaï 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. — View 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. — View 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. — View 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. — View 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. Review. — View 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. Review. — View 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. — View Citation

Zhao CY, Murrell DF. Advances in understanding and managing bullous pemphigoid. F1000Res. 2015 Nov 20;4. pii: F1000 Faculty Rev-1313. doi: 10.12688/f1000research.6896.1. eCollection 2015. Review. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Titers of Eosinophil Cationic Protein in blister fluid and blood serum	Calculated of measurements of Eosinophil Cationic Protein (pg/ml) by ELISA technique in blister fluids and serums that obtained before treatment and under first and second weeks of treatment.	14 Days
Primary	Titers of Tumor Necrosis Factor-alpha in blister fluid and blood serum	Calculated of measurements of Tumor Necrosis Factor-alpha (pg/ml) by ELISA technique in blister fluids and serums that obtained before treatment and under first and second weeks of treatment.	14 Days
Primary	Titers of Anti-BP180-NC18A IgG in blister fluid and blood serum	Calculated of measurements of Anti-BP180-NC18A IgG (U/ml) by ELISA technique in blister fluids and serums that obtained before treatment and under first and second weeks of treatment.	14 Days
Secondary	Time to control of disease activity	Time interval between initiation of treatment and control of disease activity/beginning of consolidation phase	Up to 4 weeks
Secondary	Consolidation phase of Outcome Measures for Bullous Pemphigoid	Time interval between control of disease activity and end of consolidation phase.	14 days
Secondary	Treatment Failure	Development of nontransient lesions that heal in more than one week, continued extension of old lesions, failure of established lesions to begin to heal or continued pruritus despite of Treatment of one month.	4 week
Secondary	Relapse/Flare	Appearance of more than three lesions per month or at least one large eczematous lesion or urticarial plaques that do not heal within one week, or extension of established lesions or daily pruritus in patient who was achieved disease control	Up to one year
Secondary	Bullous Pemphigoid disease severity assessment	This assessment will depend on multiple factors according to more than one classification. Patients will be separated to mild, moderate, severe conditions according to their clinical findings.; Mild: Involvement of less than %10 of skin surface area and appearance of less than 10 bullae in each day. Both feature will be necessary to regard individual patient's disease as mild.; Moderate: Involvement of %10-30 of skin surface area and appearance of less than 10 bullae in each day. Both feature will be necessary to regard individual patient's disease as moderate.; Severe: Involvement of more than %30 of skin surface area or appearance of more than 10 bullae in each day or B.P.D.A.I. score more than 56 (without Visual analogue score of pruritus). Existence of even one of this findings will ve sufficient to regard individual patient's disease as severe.	One day
Secondary	Bullous Pemphigoid Disease Area Index (B.P.D.A.I.)	BPDAI is an index to assess disease area and severity depending on involvement of mucosa and skin region, lesion number and size. Minimum score is 0 and maximum score is 360.; This index will be calculated at before treatment, second week and fourth week of treatment. After first month it will be calculated in each follow-up visit.	Up to one year
Secondary	Bullous Pemphigoid Disease Area Index (B.P.D.A.I.)-Damage score	Scars of previous lesions are also included to this index, minimum score is 0 and maximum score is 12.; This index will be calculated at before treatment, second week and fourth week of treatment. After first month it will be calculated in each follow-up visit.	Up to one year
Secondary	Bullous Pemphigoid Disease Area Index (B.P.D.A.I.)-Pruritus score	Visual analogue score of pruritus is also part of this index. Minimum score is 0 and maximum score is 10. This score will be assessed for last 24 hours, last one week, last one month one by one; thus maximum score will be 30.; This index will be calculated at before treatment, second week and fourth week of treatment. After first month it will be calculated in each follow-up visit.	Up to one year