A 10-year retrospective cohort analysis of rituximab for the treatment of pemphigus in a Chinese population

To the Editor: Rituximab plus prednisone has been reported to be more effective and safer than prednisone alone as first-line treatment for pemphigus.1Joly P. Maho-Vaillant M. Prost-Squarcioni C. et al.First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial.Lancet. 2017; 389: 2031-2040Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar However, few studies of rituximab for pemphigus have been performed in China.2Cho Y.T. Huang Y.M. Wang L.F. et al.Maintenance therapy with azathioprine prolonged duration of remission for pemphigus patients who received rituximab as first-line or add-on therapy.J Formos Med Assoc. 2020; 119: 230-237Crossref PubMed Scopus (6) Google Scholar,3Qui Y.F. Zhong S. Wang P.R. et al.Rituximab in combination with corticosteroid in the treatment of 14 patients with refactory bullous disease.J Clin Dermatol. 2011; 40 ([In Chinese]): 536-539Google Scholar We conducted an observational study of 74 Chinese pemphigus patients between 2008 and 2018 to retrospectively assess long-term effectiveness and safety of rituximab.Patients were divided into a first-line group, with rituximab as initial treatment; a second-line group, with corticosteroids or immunosuppressive therapy before initiation of rituximab; and a third-line group, with both corticosteroids and immunosuppressive agents before rituximab (Table I). The latter 2 groups comprised patients with corticosteroid-refractory, corticosteroid-dependent pemphigus, and those with severe contraindications to corticosteroids. Patients received lymphoma protocol (weekly infusions of rituximab at 375 mg/m2 for 4 weeks; n = 53) or rheumatoid arthritis protocol (2 infusions of 1000 mg on days 1 and 15; n = 21). In general, patients with mild, moderate, severe, and extensive pemphigus were systemically administered prednisone at 0.5, 0.75, 1.0, and 1.5 mg/kg at baseline, respectively. Median follow-up time was 26.1 months.Table IBaseline characteristics of patients with pemphigus treated with rituximabCharacteristicsNo. or median% or IQRAge, y39.130.2-51.3Sex Men3547.3 Women3952.7Type of pemphigus Vulgaris5675.7 Foliaceus1824.3Disease severity Mild2027.0 Moderate3547.3 Severe1114.9 Extensive810.8Body-surface area involved (%)2010-35Disease duration at baseline, mo15.46.3-47.4Line of treatment First68.1 Second1621.6 Third5270.3Rituximab protocol LP5371.6 RAP2128.4Follow-up, mo26.116.4-42.2IQR, Interquartile range; LP, lymphoma protocol; RAP, rheumatoid arthritis protocol. Open table in a new tab Sixty-seven patients (90.5%) achieved disease control4Murrell D.F. Dick S. Ahmed A.R. et al.Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus.J Am Acad Dermatol. 2008; 58: 1043-1046Abstract Full Text Full Text PDF PubMed Scopus (416) Google Scholar after a median of 1.8 months (interquartile range [IQR] 1.1-3.5 months), whereas 49 (66.2%) achieved complete remission4Murrell D.F. Dick S. Ahmed A.R. et al.Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus.J Am Acad Dermatol. 2008; 58: 1043-1046Abstract Full Text Full Text PDF PubMed Scopus (416) Google Scholar during the observation period. Complete remission rates in the first-line and non–first-line groups were 100% (6/6) and 63.2% (43/68), respectively (P = .09). One patient was excluded because of a missing complete remission date. Of the 48 remaining patients who achieved complete remission, 13 (27.1%) relapsed. Three relapsed patients added a second course of rituximab alone and regained disease control; 2 regained complete remission before the last follow-up. Median time to complete remission and relapse was 11.7 months (IQR 8.8-20.0) and 12.3 months (IQR 3.7-17.8), respectively. One- and 2-year relapse rates were 15.3% (95% confidence interval 7.2%-31.1%) and 39.1% (95% confidence interval 23.6%-59.8%), respectively.The most common severe adverse events were infections (11 infections occurred in 10 patients), with pneumonia being the most prevalent (10/74, 13.5%) (Supplemental Table I available via Mendeley at https://data.mendeley.com/datasets/kw4wzp4b4z/2). Three patients (4.1%) died during the study, all from severe pneumonia; all were young or middle-aged men with moderate to severe pemphigus vulgaris for greater than 6 months who were immunosuppressed at baseline (low B-cell or immunoglobulin M level). Although rituximab does not increase the infection rate compared with systemic corticosteroid treatment,1Joly P. Maho-Vaillant M. Prost-Squarcioni C. et al.First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial.Lancet. 2017; 389: 2031-2040Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar infection remains a common complication with rituximab and was the most prevalent severe adverse event in our study. Rituximab should be used with caution in immunosuppressed patients.Among the evaluated biomarkers (Supplemental data), low IgM level was observed in 39 of 74 patients, and was consistently lower at 2- to 6-month follow-up among patients with infections (Fig 1) (Supplemental Table II). The median time from baseline to first infection was 2.4 months (range 0.4-70.0; IQR 1.7-2.9). Moreover, the median IgM level in infected patients was consistently lower than the normal limit from month 2. These findings indicate that infections may be associated with low IgM levels. However, the validity of IgM as a predictive biomarker for infections warrants further investigation.Our data indicate that rituximab is an effective treatment for Chinese pemphigus patients. Infections, particularly pneumonia, were the most common severe adverse event and may be associated with a low level of IgM. To the Editor: Rituximab plus prednisone has been reported to be more effective and safer than prednisone alone as first-line treatment for pemphigus.1Joly P. Maho-Vaillant M. Prost-Squarcioni C. et al.First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial.Lancet. 2017; 389: 2031-2040Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar However, few studies of rituximab for pemphigus have been performed in China.2Cho Y.T. Huang Y.M. Wang L.F. et al.Maintenance therapy with azathioprine prolonged duration of remission for pemphigus patients who received rituximab as first-line or add-on therapy.J Formos Med Assoc. 2020; 119: 230-237Crossref PubMed Scopus (6) Google Scholar,3Qui Y.F. Zhong S. Wang P.R. et al.Rituximab in combination with corticosteroid in the treatment of 14 patients with refactory bullous disease.J Clin Dermatol. 2011; 40 ([In Chinese]): 536-539Google Scholar We conducted an observational study of 74 Chinese pemphigus patients between 2008 and 2018 to retrospectively assess long-term effectiveness and safety of rituximab. Patients were divided into a first-line group, with rituximab as initial treatment; a second-line group, with corticosteroids or immunosuppressive therapy before initiation of rituximab; and a third-line group, with both corticosteroids and immunosuppressive agents before rituximab (Table I). The latter 2 groups comprised patients with corticosteroid-refractory, corticosteroid-dependent pemphigus, and those with severe contraindications to corticosteroids. Patients received lymphoma protocol (weekly infusions of rituximab at 375 mg/m2 for 4 weeks; n = 53) or rheumatoid arthritis protocol (2 infusions of 1000 mg on days 1 and 15; n = 21). In general, patients with mild, moderate, severe, and extensive pemphigus were systemically administered prednisone at 0.5, 0.75, 1.0, and 1.5 mg/kg at baseline, respectively. Median follow-up time was 26.1 months. IQR, Interquartile range; LP, lymphoma protocol; RAP, rheumatoid arthritis protocol. Sixty-seven patients (90.5%) achieved disease control4Murrell D.F. Dick S. Ahmed A.R. et al.Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus.J Am Acad Dermatol. 2008; 58: 1043-1046Abstract Full Text Full Text PDF PubMed Scopus (416) Google Scholar after a median of 1.8 months (interquartile range [IQR] 1.1-3.5 months), whereas 49 (66.2%) achieved complete remission4Murrell D.F. Dick S. Ahmed A.R. et al.Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus.J Am Acad Dermatol. 2008; 58: 1043-1046Abstract Full Text Full Text PDF PubMed Scopus (416) Google Scholar during the observation period. Complete remission rates in the first-line and non–first-line groups were 100% (6/6) and 63.2% (43/68), respectively (P = .09). One patient was excluded because of a missing complete remission date. Of the 48 remaining patients who achieved complete remission, 13 (27.1%) relapsed. Three relapsed patients added a second course of rituximab alone and regained disease control; 2 regained complete remission before the last follow-up. Median time to complete remission and relapse was 11.7 months (IQR 8.8-20.0) and 12.3 months (IQR 3.7-17.8), respectively. One- and 2-year relapse rates were 15.3% (95% confidence interval 7.2%-31.1%) and 39.1% (95% confidence interval 23.6%-59.8%), respectively. The most common severe adverse events were infections (11 infections occurred in 10 patients), with pneumonia being the most prevalent (10/74, 13.5%) (Supplemental Table I available via Mendeley at https://data.mendeley.com/datasets/kw4wzp4b4z/2). Three patients (4.1%) died during the study, all from severe pneumonia; all were young or middle-aged men with moderate to severe pemphigus vulgaris for greater than 6 months who were immunosuppressed at baseline (low B-cell or immunoglobulin M level). Although rituximab does not increase the infection rate compared with systemic corticosteroid treatment,1Joly P. Maho-Vaillant M. Prost-Squarcioni C. et al.First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial.Lancet. 2017; 389: 2031-2040Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar infection remains a common complication with rituximab and was the most prevalent severe adverse event in our study. Rituximab should be used with caution in immunosuppressed patients. Among the evaluated biomarkers (Supplemental data), low IgM level was observed in 39 of 74 patients, and was consistently lower at 2- to 6-month follow-up among patients with infections (Fig 1) (Supplemental Table II). The median time from baseline to first infection was 2.4 months (range 0.4-70.0; IQR 1.7-2.9). Moreover, the median IgM level in infected patients was consistently lower than the normal limit from month 2. These findings indicate that infections may be associated with low IgM levels. However, the validity of IgM as a predictive biomarker for infections warrants further investigation. Our data indicate that rituximab is an effective treatment for Chinese pemphigus patients. Infections, particularly pneumonia, were the most common severe adverse event and may be associated with a low level of IgM. None disclosed. We thank Clare Cox, PhD, of Edanz Evidence Generation for editing a draft of this article.