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We conducted a retrospective study of pemphigus vulgaris (n=24) and foliaceus (n=7) patients treated with adjuvant rituximab to determine efficacy and adverse events. The endpoint for efficacy was complete remission of disease on no or minimal therapy.
18 patients (58%) achieved the study endpoint. Of these, 13 patients achieved complete remission off systemic therapy. Patients achieving the study endpoint had a median disease duration prior to rituximab of 19 months, versus 86 months in those not achieving the endpoint (p=0.01). For the 18 patients achieving the endpoint, the median duration of remission was 19 +/− 2 months. Eight (44%) of these 18 patients relapsed 6–17 months after treatment. Serious adverse events attributed to rituximab (osteomyelitis, phlegmon) occurred in two patients (6%). In paired serum samples from 10 patients before and after rituximab, the percent change in serum desmoglein index value (median −80%) was unrelated to the percent change in pneumococcal antibodies (median +8%) (Spearman rank correlation coefficient r=−0.2).
Our experience suggests that patients treated with rituximab earlier in the course of disease may have better outcomes. A discussion of rituximab mechanism of action supports the rationale for early therapy. Prospective clinical studies are necessary to substantiate this observation.
Pemphigus is a group of rare but potentially fatal dermatologic conditions in which autoantibodies against epidermal adhesion proteins known as desmogleins (Dsgs) cause blisters in the mucous membranes and/or skin1. Pemphigus foliaceus (PF) is characterized by superficial skin blisters caused by autoantibodies to Dsg1. Pemphigus vulgaris (PV) demonstrates deeper blisters in the suprabasal layer of the epidermis. PV is typically associated with autoantibodies to Dsg3 in mucosal-dominant disease, and Dsg3 plus Dsg1 in mucocutaneous disease. Widespread skin and mucosal blistering can lead to fatal complications including malnutrition, dehydration, and sepsis. Current therapies aim to decrease antibody production by generally suppressing the immune system. However, chronic immune suppression also risks complications, including fatal infection and secondary cancers. The challenge in pemphigus treatment, therefore, is to balance risk of disease with risk of therapy.
Rituximab, an anti-CD20 monoclonal antibody, has shown impressive 86% and 100% efficacy in two prospective trials of 21 and 11 pemphigus patients, respectively, although one (5%) of 21 patients experienced fatal septicemia 2;3. Other prospective and retrospective analyses have reported variable efficacy and serious infections, raising debate as to the appropriate clinical use of rituximab in pemphigus4–9. To begin to form hypotheses as to what patient characteristics may lead to better clinical response, we conducted a retrospective study of all pemphigus patients seen at our medical center and treated with rituximab (n=31). Here we report the efficacy and side effects of their treatment. Our observations indicate that rituximab therapy early in the course of disease is significantly more likely to lead to complete disease remission on no or minimal systemic therapy.
We conducted a retrospective single center study of all pemphigus patients seen at the University of Pennsylvania and treated with rituximab between March 2005 and November 2010, with follow up through January 2012. All studies were approved by the Institutional Review Board. Diagnoses were confirmed by clinical presentation, histology, and immunofluorescence or ELISA assays.
The study population included 24 patients (77%) with pemphigus vulgaris and 7 (23%) with pemphigus foliaceus, with 18 (58%) women and 13 (42%) men (Table 1). The median age was 50 (range 26–86). The median disease duration prior to rituximab treatment was 41 months (range 3–234). Before rituximab, all patients were treated with systemic therapies, most commonly corticosteroids +/− mycophenolate mofetil or azathioprine. Due to lack of response, contraindications, or adverse effects with these therapies, patients were treated with adjuvant rituximab. All patients were on systemic immunosuppressive therapies at the time of first rituximab infusion, indicated by an asterisk in Table 1. Although disease severity scores were not prospectively determined, all patients had severe and/or refractory disease that prompted rituximab adjuvant therapy.
Clinical response to rituximab was assessed according to the consensus statements for pemphigus10. Outcomes were classified as complete remission (CR, absence of skin and mucosal lesions for at least 2 months) and partial remission (PR, transient new lesions that heal within one week). Outcomes could be achieved off therapy, on minimal therapy (with doses defined for each medication), or on doses greater than minimal therapy. The endpoint of the study was complete remission of disease on no or minimal therapy.
After rituximab, all 31 patients experienced clinical improvement of disease activity. Overall, 18 patients (58%) achieved complete remission of disease on no or minimal systemic therapy, with similar efficacy in PV and PF (58% and 57%, respectively) (Table 1). Of these 18 patients, 13 patients achieved complete remission off all systemic therapy. Analysis of demographic data indicates that patients achieving complete remission on no or minimal therapy had a median disease duration prior to rituximab of 19 months (interquartile range 14–41), compared to 86 months (interquartile range 55–144) in patients not achieving the study endpoint (p=0.01 by Wilcoxon rank sum test) (Figure 1). Study endpoints were not significantly associated with sex, age, or dosing regimen.
Of the 18 patients achieving the endpoint, 12 patients required a single cycle of rituximab, 3 patients required 2 cycles of rituximab, and 3 patients required 3 cycles of rituximab to attain complete remission. The individual rituximab regimens and response are further detailed in Table 2. Rituximab was administered using either an oncologic regimen consisting of 4 weekly infusions of 375 mg/m2 or a rheumatologic regimen consisting of two 1000 mg infusions separated by two weeks. Two patients did not receive full infusions, due to scheduling conflict (PV15) or hospitalization for syncope due to anemia (PV24). Patients received additional cycles of rituximab for one of two reasons: to improve outcome or to treat relapse. Responses to rituximab retreatment for the first indication were mixed. Of the 15 patients retreated to improve outcome, 8 improved, achieving complete remission on no or minimal therapy, while the other 7 were not able to taper to minimal therapy, or did taper to no or minimal therapy but disease recurred within 2 months. One patient receiving 6 cycles of rituximab achieved partial remission of disease on topical steroids but did not experience further improvement with repeated infusions.
A second reason for additional cycles of rituximab was to treat relapse. Of the 18 patients achieving the study endpoint, 10 (56%) did not relapse and have remained in complete remission, with follow up from 8–28 months after rituximab infusion. The median relapse-free remission time was 19 +/− 2 months (Figure 2). Eight (44%) of the 18 patients relapsed 6–17 months after rituximab infusion (indicated in parentheses in Table 2). Of the 8 relapsed patients, 4 patients were retreated with rituximab; two attained complete remission off therapy, one attained partial remission off therapy, and the other attained complete remission on medication doses greater than minimal therapy. Of the other 4 patients, 2 patients were recently retreated with rituximab with follow up pending; one is being treated with prednisone due to concurrent pregnancy, and the final patient is being observed in partial remission off therapy.
Although not a primary study endpoint, 5 patients achieved partial remission of disease off therapy after a single cycle of rituximab with a 21 month median duration of response (range 13–80). Partial remission is defined as the presence of transient lesions that heal within one week without use of any medication, including topical steroids. All 5 patients considered this a favorable outcome and did not desire retreatment. Two patients relapsed after 16 and 21 months and were retreated with rituximab, again achieving partial remission off therapy.
Serious adverse events were identified according to FDA definitions, including events that are fatal, life-threatening, require hospitalization, or cause disability or permanent damage. Prior to rituximab, 5 patients (16%) experienced 5 serious adverse events (SAEs) attributed to disease or its treatment, including pulmonary embolism, avascular necrosis, suicidal ideation, psychosis with suicide attempt, and severe blistering with multi-organism superinfection. These SAEs were observed during the median 41 month period between disease onset and the start of rituximab therapy. During the median 28 months of follow up after rituximab, 5 patients experienced 6 SAEs, 2 of which were attributed to rituximab. One patient (PF3) developed osteomyelitis 4 months after rituximab infusion while on 10 mg daily prednisone. The patient successfully tapered to 1 mg prednisone daily and remained in complete remission. However, the patient subsequently died of a fatal gastrointestinal bleed, attributed to higher dose corticosteroids prescribed for complications after a corneal transplant. One patient (PV20) treated with 6 cycles of rituximab, achieving partial remission on topical steroids, developed perirectal phlegmon and intrapelvic abscesses requiring surgical debridement. Other SAEs occurring after rituximab but not directly attributed to rituximab included hospitalization for syncope due to anemia, prostate cancer, and melanoma. Serum immunoglobulin levels were not available for the patients in our study.
Serum anti-desmoglein antibody levels were determined in all pemphigus patients for whom serum samples were available before and after rituximab therapy (n=10). Because desmoglein ELISA is not standard of care for diagnosis or management of pemphigus, paired serum samples were not available for all pemphigus patients. Serial dilutions of patient serum (1:100 up to 1:12800) were tested by desmoglein ELISA (MBL International) and an index value was calculated as previously described 11. Serum antibodies against pneumococcal capsular polysaccharide were measured in the same serum samples by ELISA (Binding Site).
In 10 paired serum samples from pemphigus patients before and after rituximab administration, a median change of −80% in serum desmoglein index value was observed after rituximab therapy. In the same group of patients, all of whom had received multiple courses of rituximab (range 2–6), serum Pneumococcal antibody concentration was stable with a median change of +8% (Figure 3). There was no correlation between the levels of serum anti-desmoglein and anti-Pneumococcal antibodies (Spearman rank correlation coefficient r=−0.2). One patient sample demonstrated an 81% decrease in desmoglein index value, but a 607% increase in Pneumococcal antibody concentration. This patient had developed fever, pharyngitis, and sinusitis responding to oral antibiotic therapy. Blood cultures were negative; throat and respiratory cultures were not performed.
A recent meta-analysis encompassing 153 pemphigus patients reported a complete remission rate of 65% after rituximab therapy 9. Most prior studies used complete remission of disease as the endpoint for rituximab efficacy, regardless of the dose of systemic therapy. However, complete remission on no or minimal therapy has been identified as the consensus endpoint for current pemphigus studies10. Although it is impossible to retrospectively analyze efficacy of most past studies under the consensus endpoint, complete remission off oral systemic therapy was observed in 23% of patients in the meta-analysis, 38% of 21 patients treated with a single cycle of rituximab, and 100% of 11 patients treated with rituximab and intravenous immunoglobulin2;3;9.
Our experience supports the early use of rituximab for pemphigus therapy, based on both efficacy and safety. Overall, 18 patients (58%) achieved the study endpoint, with 13 of these patients (42% of total) achieving complete remission off therapy. Seven patients (23%) achieved complete remission off therapy after a single cycle of rituximab. Achievement of the study endpoint was associated with early rituximab therapy of disease (Figure 1). There are limitations to our ability to substantiate this latter observation, including the retrospective study design, small number of patients, and potential for confounding by indication (i.e. that patients treated later in the course of disease have more refractory disease.) However, published prospective studies of pemphigus patients treated with first-line steroid sparing agents such as mycophenolate mofetil or azathioprine did not identify any cases of complete remission off therapy12–14, raising the question for future prospective studies as to whether rituximab should be a first-line steroid sparing agent in pemphigus. An increased potential for better outcome with early use of rituximab is logical based on the mechanism of CD20-targeted B cell depletion. Rituximab therapy, if 100% efficient, would deplete most of the B cell lineage, from pro-B cells in the bone marrow that have not yet formed the antibody repertoire to antigen-experienced memory B cells in the periphery. Repopulating B cells would produce new heavy and light chain combinations that ideally would not reproduce the pathogenic autoreactive clones. Antibody-secreting cells (plasma cells), which can survive for weeks to decades, are CD20 negative and hence are not directly targeted by rituximab. Data from our study and others 2;15;16 showing a selective decrease in pemphigus autoantibodies after rituximab suggest that pemphigus autoantibodies are preferentially produced by short-lived plasma cells, which are more dependent on the CD20+ memory B cell pool for replenishment. In contrast, protective antibodies against pneumococcus, tetanus, varicella zoster virus or Epstein-Barr virus are unaffected in the serum, likely due to secretion from long-lived plasma cells. Factors determining the production of short-lived versus long-lived plasma cells are uncertain, although continued autoantigen stimulation in the setting of more longstanding disease could encourage the production and/or retention of long-lived autoreactive plasma cells that would be resistant to rituximab therapy. Consequently, early intervention with rituximab could be more likely to result in modification of the disease process, with possible long-term remission of disease.
Concern over rituximab safety stems from multiple studies. Two (10%) of 21 patients in the prospective case series of rituximab in pemphigus experienced severe infections, including fatal septicemia 2. A meta-analysis of 153 pemphigus patients treated with rituximab showed that 7% developed serious infections, with 2 fatalities (1.3%) 9. In our study, two patients (6%) experienced serious adverse events attributed to rituximab, both non-fatal infections. However, serious infection, as well as other life-threatening SAEs, occurred in pemphigus patients prior to rituximab therapy. Thus, although risk of infection is an important consideration with rituximab, pemphigus patients, because of their underlying disease as well as its treatment, are susceptible to infection and other SAEs regardless of rituximab therapy.
In conclusion, our experience has shown that rituximab is an effective therapy for pemphigus, potentially more so when given early in the course of disease. Additionally, rituximab appears to be as safe as conventional immunosuppressive therapies. Current standard of care typically indicates rituximab for late therapy of pemphigus, after conventional treatments have failed 17;18. Our study suggests better clinical outcome with early rituximab treatment of pemphigus. Future prospective clinical trials would be valuable to determine the relative safety and efficacy of rituximab as a first-line steroid-sparing agent in pemphigus compared to mycophenolate mofetil or azathioprine.
This work was supported by the Department of Dermatology, University of Milan (LL), AR052672 (JRS), AR002207 (VPW), AR053505 and AR057001 (ASP), CTSA UL1-RR-024134 (KJP), and the Penn Skin Disease Research Center AR057217 (JRS and ASP).
Authorship responsibility: Study design, figures, and writing of the manuscript: LL, ASP. Data collection: KJT, NF, JRS, DET, VPW, ASP. Data analysis: LL, KJP, ASP. All authors contributed to data interpretation and critical review of the manuscript.
Financial disclosure/conflict of interest: LL, KJT, KJP, NF, JRS, and ASP declare no conflict of interest. DET has partial stock ownership of Biogen IDEC. VPW serves as a consultant for Lupus Foundation of America, Pfizer, Medimmune, Genentech, Novartis, Celgene, Stiefel, Rigel, Astion, Amgen, Infinity Pharmaceuticals, Sanofi Aventis, and UBC; has research grants from Amgen, Celgene; has partial stock ownership of UV Therapeutics; and University of Pennsylvania holds copyright for CLASI, CDASI disease activity indices.