Table of Contents  
CASE REPORT
Year : 2017  |  Volume : 10  |  Issue : 1  |  Page : 85-88  

Four cases of recalcitrant pemphigus vulgaris salvaged with rituximab


Department of Dermatology, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India

Date of Web Publication9-Jan-2017

Correspondence Address:
Dr. Samyak Ganjre
Department of Dermatology, Dr. D. Y. Patil Medical College and Hospital, OPD No: 14, Sant Tukaram Nagar, Pimpri, Pune - 411 018, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-2870.197895

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  Abstract 

Although the long-term use of immunosuppressives – supplemented with more aggressive treatments such as immunoadsorption, intravenous immunoglobulins, or plasmapheresis in recalcitrant cases has dramatically improved the prognosis of pemphigus vulgaris, opportunistic infections secondary to immunosuppression continue to cause significant mortality. We report four cases– three old ones, who had accumulated significant morbidities over their disease duration ranging from 5 to 10 years, and the fourth, a teenage female intolerant to corticosteroids and idiosyncratic to methotrexate– who achieved complete remission on administration of rituximab by the lymphoma protocol. One of the old cases who had recalcitrant mucositis experienced its complete subsidence without any adjuvant whatsoever. All continue to remain asymptomatic for 11–20 months. None had infusion reactions or any delayed side effects.

Keywords: Immunosuppressives, pemphigus vulgaris, recalcitrant, rituximab


How to cite this article:
Ganjre S, Sharma YK, Gupta A, Deo K. Four cases of recalcitrant pemphigus vulgaris salvaged with rituximab. Med J DY Patil Univ 2017;10:85-8

How to cite this URL:
Ganjre S, Sharma YK, Gupta A, Deo K. Four cases of recalcitrant pemphigus vulgaris salvaged with rituximab. Med J DY Patil Univ [serial online] 2017 [cited 2019 Nov 19];10:85-8. Available from: http://www.mjdrdypu.org/text.asp?2017/10/1/85/197895


  Introduction Top


Pemphigus vulgaris is a potentially fatal immunobullous dermatosis characterized by flaccid vesicles clinically, suprabasilar clefts with acantholysis histopathologically, fishnet pattern on direct immunofluorescence and circulating immunoglobulin G autoantibodies against transmembranous adhesion glycoproteins, desmoglein 1 and desmoglein 3, detectable serologically as well as on indirect immunofluorescence.[1]

Although the conventional first-line treatment of pemphigus (daily high-dose, long-term systemic corticosteroids, with or without immunosuppressives or as pulse therapy) has dramatically improved prognosis, significant mortality persists due to opportunistic infections secondary to immunosuppression.[2] Many cases become corticoresistant; some even to the combination therapy with more aggressive treatments such as plasmapheresis, intravenous immunoglobulins, or immunoadsorption.[3] Despite lack of clear consensus, rituximab has become a widely used off-label adjuvant therapy of paraneoplastic pemphigus, recalcitrant cases of pemphigus vulgaris or pemphigus foliaceous, and even as first-line therapy for newly diagnosed cases of pemphigus, especially in the affluent. Administered either in the lymphoma (375 mg/m2 body surface area weekly, for 4 weeks) or the rheumatoid arthritis (1000 mg twice, 15 days apart) protocol, still lower doses have also been found effective (500 mg twice, 15 days apart).[4] We herein report four cases— three, known since 5-10 years and one, newly diagnosed— of pemphigus vulgaris fulfilling clinical, histopathological and direct immunofluorescence criteria; three (cases 1, 2 and 4) administered rituximab as per the lymphoma protocol and case 3; two, 500 mg, weekly doses followed 12 weeks later by third 500 mg dose of rituximab. All except case 2, received adjuvant therapy for 6-12 weeks.


  Case Reports Top


Case 1

A 62-year-old female [Figure 1]a managed [Table 1] with high-dose daily corticosteroids as a case of frequently relapsing pemphigus vulgaris since 10 years, fractured her lumbar vertebrae (4th and 5th) in a fall, underwent laminectomy and reported to us with a relapse during her postoperative period. Her depressed mood, osteoporosis, diabetes mellitus, cushingoid habitus, and increased likelihood of infections in view of recent surgery precluded use of corticosteroids and motivated us to vigorously counsel the reluctant caretakers regarding the inescapable requirement of rituximab infusion. Fortunately, she revealed gratifying remission and could be taken completely off systemic steroids. She remains asymptomatic since 18 months [Figure 2]a.
Figure 1: Before rituximab, (a) erosions and postlaminectomy scar, case 1. (b) Encrusted lip, case 2. (c) Erosions, some with active bleeding, case 3. (d) Flaccid bullae, erosions, and crusts, case 4

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Table 1: Clinicoepidemiological and follow-up details of cases

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Figure 2: After rituximab, healing with postinflammatory hyperpigmentation in case 1 (a), case 2 (b), case 3 (c), and case 4 (d)

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Case 2

A 41-year-old female [Figure 1]b managed since 5 years for predominantly mucosal pemphigus with pulse therapy – dexamethasone cyclophosphamide and dexamethasone methotrexate – had persisting mucositis, and developed cushingoid habitus and posterior subcapsular cataract. Exhibition of monotherapy with rituximab led to complete remission, including of the encrustations over the lips, for the first time. She remains asymptomatic since 20 months [Figure 2]b.

Case 3

A 19-year-old female [Figure 1]c, presenting with extensive mucocutaneous pemphigus vulgaris for 2 months, was exhibited daily steroids but went into cardiopulmonary decompensation due to acute fluid retention with steroids. She developed neutropenia with methotrexate necessitating blood transfusion and antibiotic cover. Difficulty in procurement led to delayed administration of the third infusion of rituximab by 12 weeks. Rituximab therapy along with low-dose corticosteroids (tapered within 6 weeks) led to remission which has since continued over 11 months [Figure 2]c.

Case 4

A 59-year-old male [Figure 1]d, managed since 5 years as a case of pemphigus vulgaris, presented with a severe relapse, recurrent infections, and had raised transaminases. He could be motivated to procure rituximab, was additionally given cyclophosphamide [Table 1], and continues to be asymptomatic for 12 months [Figure 2]d.


  Discussion Top


All of our old patients (cases 1, 2, and 4), managed with systemic corticosteroids and immunosuppressives on and off over approximately 6 years, had developed severe side effects. The only newly diagnosed case, a teenage female, was ineligible for cyclophosphamide, intolerant to systemic steroids, idiosyncratic (neutropenia) to methotrexate, and the administration of her third dose of rituximab got delayed by 12 weeks due to financial constraints. All received premedication – paracetamol, hydrocortisone, and pheniramine –30 min before rituximab infusion in normal saline, initiated at 8 drops/min, escalated in multiples of 8 every 30 min, up to 32 drops/min. Blood pressure, temperature, and pulse were monitored intensively during the first 30 min and half hourly thereafter.[4] No infusion-related, severe, or delayed side effects were observed. Case 2, experienced first ever remission of mucositis with rituximab monotherapy. Adjuvant therapy in the remaining three cases – corticosteroids, in cases 1 and 3, and cyclophosphamide, in case 4 – could be successfully tapered within 6–12 weeks. Control of disease activity [5] (or beginning of consolidation phase), i.e. the time interval from baseline to the time at which new lesions cease to form and established lesions begin to heal, took 6 weeks in the first two cases and 4 weeks in the last two. At the end of the consolidation phase,[5] the time at which no new lesions developed for a minimum of 2 weeks and the majority (approximately 80%) of established lesions had healed, took another 2–4 weeks, and complete remission off therapy [5] was achieved at an interval of 11–16 weeks. All patients have remained free of lesions and any infection during the further follow-up period ranging from 48 to 87 weeks [Table 1].

Rituximab – a chimeric, murine-human monoclonal antibody targetted against CD20+ B-cell surface antigen – has been approved since 1997 by the US Food and Drug Administration for the treatment of CD20 + B-cell lymphoma, non-Hodgkin lymphoma, and rheumatoid arthritis. In dermatology, its off-label use in various bullous dermatoses, particularly after its first use for paraneoplastic pemphigus in follicular non-Hodgkin lymphoma in 2001[6] and in recalcitrant pemphigus since 2002,[7] is being increasingly resorted to, either after failure of or unsuitability to the conventional first-line therapy. Binding of rituximab to transmembrane, CD20, located on pre-B and mature B lymphocytes induces their depletion in peripheral blood within a few hours thereby rendering the patients more susceptible to infections for up to an year.[8] Human antichimeric antibodies are reported to occur in <1% of cases;[9] incidence of cytopenias and malignancies lacks sufficient body of evidence.

Notwithstanding the salutary experience of our above cases, consensus guidelines regarding the evolution of specific protocols for management of vesiculobullous dermatoses and the prevalence of long-term adverse effects need larger randomized controlled trials with longer follow-up.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Williams DM. Vesiculobullous mucocutaneous disease: Pemphigus vulgaris. J Oral Pathol Med 1989;18:544-53.  Back to cited text no. 1
    
2.
Ahmed AR, Moy R. Death in pemphigus. J Am Acad Dermatol 1982;7:221-8.  Back to cited text no. 2
    
3.
Yeh SW, Sami N, Ahmed RA. Treatment of pemphigus vulgaris: Current and emerging options. Am J Clin Dermatol 2005;6:327-42.  Back to cited text no. 3
    
4.
Kanwar AJ, Vinay K. Rituximab in pemphigus. Indian J Dermatol Venereol Leprol 2012;78:671-6.  Back to cited text no. 4
[PUBMED]  Medknow Journal  
5.
Murrell DF, Dick S, Ahmed AR, Amagai M, Barnadas MA, Borradori L, et al. Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus. J Am Acad Dermatol 2008;58:1043-6.  Back to cited text no. 5
    
6.
Heizmann M, Itin P, Wernli M, Borradori L, Bargetzi MJ. Successful treatment of paraneoplastic pemphigus in follicular NHL with rituximab: Report of a case and review of treatment for paraneoplastic pemphigus in NHL and CLL. Am J Hematol 2001;66:142-4.  Back to cited text no. 6
    
7.
Salopek TG, Logsetty S, Tredget EE. Anti-CD20 chimeric monoclonal antibody (rituximab) for the treatment of recalcitrant, life-threatening pemphigus vulgaris with implications in the pathogenesis of the disorder. J Am Acad Dermatol 2002;47:785-8.  Back to cited text no. 7
    
8.
Nagel A, Hertl M, Eming R. B-cell-directed therapy for inflammatory skin diseases. J Invest Dermatol 2009;129:289-301.  Back to cited text no. 8
    
9.
McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 1998;16:2825-33.  Back to cited text no. 9
    


    Figures

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