Response to “Increased awareness of hypogammaglobulinemia after B‐cell targeting therapies” by Karim MY

We thank Dr Karim, MY for his interest in and kind comments on our study (1), in which we reported a low rate (i.e. 7 out of 700; 1%) of patients who required immunoglobulin replacement therapy (IGRT) for recurrent infections despite treatment with prophylactic antibiotics and/or hypogammaglobulinemia during rituximab (RTX) therapy in our cohort. This rate was the lowest compared to other published cohorts, which predominantly comprised patients with ANCA‐associated vasculitis (AAV), ranging from 4–21% (2‐4)

Effect of rituximab or tumour necrosis factor inhibitors on lung infection and survival in rheumatoid arthritis-associated bronchiectasis

Objective To evaluate rituximab (RTX) in patients with RA-associated bronchiectasis (RA-BR) and compare 5-year respiratory survival between those treated with RTX and TNF inhibitors (TNFi). Methods A retrospective observational cohort study of RA-BR in RTX or TNFi-treated RA patients from two UK centres over 10 years. BR was assessed using number of infective exacerbation/year. Respiratory survival was measured from therapy initiation to discontinuation either due to lung exacerbation or lung-related deaths. Results Of 800 RTX-treated RA patients, 68 had RA-BR (prevalence 8.5%). Post-RTX, new BR was diagnosed in 3/735 patients (incidence 0.4%). At 12 months post-Cycle 1 RTX, 21/68 (31%) patients had fewer exacerbations than the year pre-RTX, 36/68 (53%) remained stable and 11/68 (16%) had increased exacerbations. The rates of exacerbation improved after Cycle 2 and stabilized up to 5 cycles. Of patients who received ≥2 RTX cycles (n = 60), increased exacerbations occurred in 7/60 (12%) and were associated with low IgG, aspergillosis and concurrent alpha-1-antitrypsin deficiency. Overall, 8/68 (11.8%) patients discontinued RTX while 15/46 (32.6%) discontinued TNFi due to respiratory causes. The adjusted 5-year respiratory survival was better in RTX-treated compared with TNFi-treated RA-BR patients; HR 0.40 (95% CI 0.17, 0.96); P =0.041. Conclusion The majority of RTX-treated RA-BR patients had stable/improved pulmonary symptoms in this long-term follow-up. In isolated cases, worsening of exacerbation had definable causes. Rates of discontinuation due to adverse lung outcomes were better for RTX than a matched TNFi cohort. RTX is an acceptable therapeutic choice for RA-BR if a biologic is needed

Publisher Correction: A novel two-score system for interferon status segregates autoimmune diseases and correlates with clinical features

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper

B cell tetherin: a flow‐cytometric cell‐specific assay for response to Type‐I interferon predicts clinical features and flares in SLE

Objective: Type I interferon (IFN-I) responses are broadly associated with autoimmune disease including SLE. Given the cardinal role of autoantibodies in SLE, we investigated whether a B cell-specific IFN assay might correlate with SLE activity. Methods: B cells and PBMCs were stimulated with IFN-I and IFN-II. Gene expression was scrutinized for pathway-related membrane protein expression. A flow-cytometric assay for tetherin (CD317), an IFN-induced protein ubiquitously expressed on leucocytes, was validated in vitro then clinically against SLE diagnosis, plasmablast expansion, and BILAG-2004 score in a discovery cohort (156 SLE; 30 RA; 22 healthy controls). A second longitudinal validation cohort of 80 patients was also evaluated for SLE flare prediction. Results: In vitro, a close cell-specific and dose-responsive relationship between IFN-I responsive genes and cell surface tetherin in all immune subsets existed. Tetherin expression on multiple cell subsets was selectively responsive to stimulation with IFN-I compared to IFN-II and -III. In patient samples from the discovery cohort memory B-cell tetherin was best associated with diagnosis (SLE/HC: effect size=0.11, p=0.003; SLE/RA: effect size=0.17,

Lessons for rituximab therapy in patients with rheumatoid arthritis

B-cell depletion therapy is an effective option for the treatment of rheumatoid arthritis but often does not result in complete B-cell depletion. Complete B-cell depletion after rituximab treatment is associated with clinical response, and this outcome leads to long-term maintenance of therapy. Low pretreatment plasmablast counts, concomitant treatment with disease-modifying antirheumatic drugs, no smoking exposure, the presence of anticitrullinated protein antibodies or rheumatoid factor, and a low interferon signature are all predictive of complete B-cell depletion and clinical response. Half of patients who initially show complete B-cell depletion and clinical response after rituximab treatment eventually lose responsiveness with further infusions. However three-quarters of these patients regain this outcome in their following treatment cycle, suggesting that loss of response is reversible and that patients can still benefit from rituximab retreatment. The efficacy of reduced doses of rituximab is being investigated, but preliminary results suggest that these strategies are best used for maintenance therapy, particularly in patients who suffer adverse events or who are at a high risk of infection. Infusion-related reactions are the most common adverse events associated with rituximab treatment, and monitoring of IgG concentrations is crucial, as low concentrations are correlated with an increased risk of infection

A Personalised Rituximab Retreatment Approach Based on Clinical and B-Cell Biomarkers in Anca-Associated Vasculitis

Background: Time to relapse after rituximab for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is variable, and optimal retreatment strategy has remained unclear. In AAV following rituximab induction, the study objective was to evaluate clinical and B-cell predictors of relapse in order to develop a retreatment algorithm. Methods: A retrospective observational study was conducted in 70 rituximab-treated ANCA-associated vasculitis patients followed up for over 10 years. Complete response (CR) was defined as Birmingham Vasculitis Activity Score v3.0 = 0. Retreatment was given on clinical relapse, defined as new features or worsening of persistent disease (not by biomarker status). Peripheral B-cell subsets were measured using highly sensitive flow cytometry. Predictors were tested using multivariable Cox regression. Results: Median time to retreatment for cycles 1–5 were 84, 73, 67, 60, and 73 weeks. Over 467 patient-years follow-up, 158 relapses occurred in 60 patients; 16 (in 15 patients) were major (renal = 7, neurological = 4, ENT = 3, and respiratory = 2). The major-relapse rate was 3.4/100 patient-years. In multivariable analysis, concomitant immunosuppressant [HR, 0.48 (95% CI, 0.24–0.94)], achieving CR [0.24 (0.12–0.50)], and naïve B-cell repopulation at 6 months [0.43 (0.22–0.84)] were associated with longer time to relapse. Personalized retreatment using these three predictors in this cohort would have avoided an unnecessary fixed retreatment in 24% of patients. Area under the receiver operating characteristic for prediction of time to relapse was greater if guided by naïve B-cell repopulation than if previously evaluated ANCA and/or CD19+ cells return at 6 months had been used, 0.82 and 0.53, respectively. Conclusion: Our findings suggest that all patients should be coprescribed oral immunosuppressant. Those with incomplete response or with absent naïve B cells should be retreated at 6 months. Patients with complete response and naïve repopulation should not receive fixed retreatment. This algorithm could reduce unnecessary retreatment and warrant investigation in clinical trials

Safety of rituximab for remission maintenance in relapsing anca–associated vasculitis: repeat cycles on clinical relapse are associated with low rates of hypogammaglobulinaemia.

Background: Rituximab is effective in ANCA-associated vasculitis (AAV). Since relapse often occurs after an initial response, either fixed-interval rituximab re-treatment or re-treatment-at-relapse is used to maintain long term response. Attrition of immunoglobulin levels and risk of infection are a potential concern with repeat cycles of B cell depletion with up to 67% of patients with low IgG after 36 months in one series[1]. We previously reported good long term efficacy using re-treatment-at-relapse[2]. Objectives: To evaluate immunoglobulin levels, serious adverse events and serious infections during rituximab treatment of refractory AAV based on the re-treatment-at-relapse strategy. Methods: We conducted an observational study of patients with AAV treated with at least 2 cycles of rituximab in a single centre between January 2006 and December 2012 – a total of 142 patient-years follow up. Each cycle consisted of 2x1000mg infusions repeated on clinical relapse. IgG levels were measured at baseline and 6 months after each cycle (normal range 6.0-16.0). Severe adverse events were defined as those resulting in hospitalisation which lasted more than 24 hours, flares requiring intravenous therapy, malignancies, life-threatening situations or death. Results: 30 patients (18 male and 12 female) with a median age of 58.9 years old (range 21-83) were identified. 22 patients were PR3 positive, 7 were MPO positive and 1 was ANCA negative but with a positive histology for granulomatosis with polyangiitis (GPA). Numbers of repeat cycles are shown in Table 1. Median time to re-treatment for cycles 1-4 were 82, 71, 58 and 57 weeks respectively. There were 26 serious adverse events: 1 death due to bronchopneumonia and 26 hospital admissions (median duration 6 days) were recorded in 14 patients. Of these, 9 were due to flares requiring intravenous methylprednisolone and 8 were serious infection (5.6/100 patient-years), mostly lower respiratory tract infection. 6 patients with serious infection had lower IgM at baseline and a greater reduction in IgG, although was not statistically significant. IgG data are shown in Table 1. 4 patients had low IgG before rituximab and only 1 developed low IgG during therapy. 1 patient with low IgG at baseline had two serious infections and required intravenous immunoglobulin. No other patient had to discontinue rituximab therapy due to low IgG. Conclusions: Re-treatment at relapse did not result in progressive reduction in IgG in patients with normal immunoglobulins at baseline. Serious infection rates were low. This is of particular importance since there are limited other effective agents for this relapsing disease