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 (). 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 . Although disease severity scores were not prospectively determined, all patients had severe and/or refractory disease that prompted rituximab adjuvant therapy.
Patient characteristics prior to rituximab and response to rituximab therapy
Efficacy of rituximab therapy, including retreatment and relapse
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) (). 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) (). Study endpoints were not significantly associated with sex, age, or dosing regimen.
Figure 1 Complete remission of disease on no or minimal therapy is associated with use of rituximab earlier in the course of disease. Median disease duration prior to rituximab was 19 months (interquartile range 14–41) for patients achieving the study (more ...)
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 . 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.
Summary of rituximab regimens, retreatment, and relapse.
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 (). Eight (44%) of the 18 patients relapsed 6–17 months after rituximab infusion (indicated in parentheses in ). 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.
Figure 2 Kaplan-Meier plot of time to relapse after rituximab infusion in patients achieving complete remission (n=18). Circles indicate duration of follow up for patients remaining in complete remission (n=10). The median duration of remission was 19+/−2 (more ...)
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
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% (). 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.
Figure 3 Changes, from before to after rituximab therapy, in serum levels of desmoglein and Pneumococcal capsular polysaccharide antibodies were unrelated (n=10, Spearman rank correlation coefficient r=−0.2). A median change of −80% in desmoglein (more ...)