Rituximab as a maintenance treatment in patients with pemphigus vulgaris: When is the right time for discontinuation?

Rituximab is a monoclonal anti-CD20 antibody with a promising effect in controlling some immune-mediated disorders including pemphigus vulgaris. 1 Due to the relapsing nature of autoimmune disorders, multiple courses of rituximab might be needed to keep patients in remission. On the other hand, long-term use of B-cell depleting agents would be associated with some complications including a higher risk for developing serious infections, hypogamma-globulinemia

The scheduling, safety profile, and optimal dosing for long-term maintenance therapy with rituximab in pemphigus has yet remained to be determined.
Hence, we focused on existing data in this regard and tried to summarize the experience of rheumatologists, neurologists, and dermatologists on long-term administration of rituximab to provide a practical guide for clinicians.
After an appropriate response to induction therapy with rituximab, some experts prefer to continue a maintenance dose versus re-treatment after relapses.Although re-treatment approach is logically superior due to using lower doses of rituximab, Fowler et al revealed that maintenance therapy in patients with non-Hodgkin lymphoma for up to 2 years was associated with a significantly higher complete response rate at the end of the study versus those merely received re-treatment on relapses.Moreover, 3-year overall survival rates were the same in two groups of patients. 3nger maintenance therapies were reported by rheumatologists in rheumatoid arthritis and other disorders.Charles et al. conducted a study in 39 centers in France to evaluate the clinical effect of continuing rituximab infusions for an extra 18 months, after completion of a standard 18 months of maintenance treatment among patients with ANCA-associated vasculitis.They found a lower rate of relapse in patients receiving 36 months of treatment. 4Another study on 1246 patients with rheumatoid arthritis with over 5 years of recurrent administration of rituximab failed to show any predisposition to severe or opportunistic infections among patients. 5cohort study on 107 patients with multiple sclerosis, treatment with a mean duration of 33.2 months did not show an increased risk of adverse events. 6udies investigating the best protocol for maintenance therapy with rituximab are scarce and there is no consensus on immunologic or clinical criteria enabling clinician to decide about discontinuation of treatment.The suggested items are negative direct immunofluorescence results, persistent complete clinical remission, serum antidesmoglein 1 and 3 autoantibody levels less than 14 U/mL for at least 1 year, measures of B-cell depletion/reconstitution or markers of disease activity. 7tuximab-associated B-cell depletion is a dose-dependent effect. 8wever, it might not be a precise predictor of disease activity.There Barra et al. also reported a subgroup of patients with multiple sclerosis, experiencing clinical relapse despite CD20 counts of zero who has been considered as nonresponders, went to remission with receiving further doses of rituximab. 6ose experts supporting the re-dosing of rituximab based on B-cell return, hypothesized that higher relative percentages of peripheral regulatory B cells at the time of B-cell repopulation after rituximab may be associated with more prolonged remission. 10other suggested tool for predicting the adverse effects during long-term rituximab treatment is determining the Staphylococcus aureus (S. aureus) nasal carriage status.Besada et al. conducted a study on 29 patients suffering from granulomatosis with polyangiitis who received a cumulative dose of 9 g for remission induction and maintenance during 49 months and found that persistent S. aureus nasal carriage was not a risk factor for disease relapses, and interestingly, was associated with a lower frequency of chronic infections and higher level of total serum Ig, compared to non-Sa carriers. 11It could be due to the role of S. aureus in preventing colonization of other bacteria which led to a decrease in chronic infections and hence a better tolerance for long-term rituximab treatment in patients with S. aureus nasal carriage.However, it is not clear that this outcome is significant merely in patients with granulomatosis with polyangiitis, a disease with strong predilection for sinus and nasal mucosa, or could be seen in patients with other disorders under treatment with rituximab.
Low IgG levels before the initiation of rituximab treatment, the reduced number of T lymphocytes and age ≥ 65, have been shown to be associated with a high risk of severe infection in long-term rituximab therapy. 12In Pendergraft et al. study on 172 patients with ANCA-associated vasculitis treated with long-term rituximab, the only significant predictor of death was achieving remission at an age greater than 80 years. 13Thietart et al. compared the induction and maintenance phase of rituximab therapy in patients with 75 years and older with ANCA-associated vasculitis and revealed an increase in incidence of serious infections and death only in induction, not in the maintenance phase in old patients and concluded that clinicians need to be focused on reducing serious infections during the first months of therapy in older patients. 14

Boleto et al. conducted one of the longest longitudinal studies
of rituximab treatment in patient with rheumatoid arthritis and followed patients for up to 12 years.They noted that treatment duration as well as rituximab cumulative doses was not as important as low gamma globulin level prior to rituximab therapy as a prognostic factor for predicting the development of hypogammaglobulinemia. 15om dermatologists' point of view, rituximab is a promising option for both first-line and maintenance treatment of pemphigus. 16ly et al. published a guideline on management of pemphigus and suggested two infusions of 500 mg rituximab on 12 and 18 months after reaching to a complete remission in patients with pemphigus vulgaris. 16There is not enough data in literature regarding infusion of rituximab after this period of time in those in complete remission.
It seems that the most important factor to consider additional rituximab cycles is re-rise of anti-desmoglein antibodies in patients with pemphigus. 16Hence, evaluating of anti-desmoglein antibodies level is strongly suggested at least every 6 months.
Previous studies showed that taking rituximab as a first-line treatment in pemphigus patients could lead to a considerably lower rate of adverse effects 2 and a better clinical efficacy. 1Hence, early prescription of rituximab during the course of disease might reduce the duration of treatment and the cumulative dose of medication needed for the patients. 1reover, there are some limited reports of neoplasm development following rituximab therapy which raise some concerns regarding long-term rituximab therapy. 17Although most of studies in this regard did not find any significant impact of rituximab on developing a secondary malignancy in patients with non-Hodgkin lymphoma, 18 a study on 1028 patients with follicular lymphoma with a median follow-up time of 6 years found an increased risk of development of secondary hematological malignancies in patients receiving multiple cycles of rituximab and concluded that achievement of as long remission period as possible should be the aim of treatment. 19recent study showed an elevated BAFF (B-cell activating factor) level in sera of patients with pemphigus after 3 and 6 months of treatment with rituximab and speculated that BAFF might play an important role in repopulation of B cells after rituximab therapy.20 One can infer that prevention of this repopulation by adding an anti-BAFF medication to rituximab could result in a longer and more prompt clinical effect and a reduction in the number of rituximab cycles, needed for patients with pemphigus.
According to above mentioned data, finding the optimal timing and duration of therapy as well as correct scheduling, needs further future randomized investigations.The decision to recommend maintenance rituximab therapy should be upon a much more individually tailored approach and considering risks and benefits of long-term treatment, based on clinical, immunological, and prognostic features of each patient.
Monitoring of IgG levels before the initiation of rituximab and every 6-12 months during long-term treatment, evaluating of direct immunofluorescence results, serum anti-desmoglein 1 and 3 autoantibody levels, measurement of B-cell depletion/reconstitution, and probably monitoring of BAFF level could be used for addressing an important and challenging issue of determining who is more likely to experience the relapse and hence, benefits from long-term treatment and who is at an increased risk of toxicity and serious infections in case of long-term rituximab treatment.Moreover, it is rational to closely monitor patients receiving more rituximab cycles for secondary malignancies.Hence, we suggest to perform an oncology consultation for patients on long-term rituximab treatment in this regard.This issue should be evaluated in further studies.

FU N D I N G I N FO R M ATI O N
We received no funding for this project.
are some reports in the literature with evidence of ongoing inflammation despite of B-cell depletion.von Büdingen et al. reported a case of relapsing multiple sclerosis with CNS inflammation and presence of oligoclonal band in CSF even after nearly 7 years of anti-CD20 therapy and B-cell depletion, indicating active antibody synthesis by long-lasting plasma cells in possible ectopic lymphoid aggregates in the meninges.They suggested the oligoclonal band as a useful endpoint for rituximab therapy in patients with multiple sclerosis. 9| 407 ARYANIAN et al.