Abstract
Objective This work aims to evaluate the long-term safety of rituximab (RTX) in primary Sjögren syndrome (pSS) and to determine the safety and the efficacy of long-term treatment with B cell depleting therapy in pSS patients with active systemic disease.
Methods A historical cohort study, enrolling 35 patients with pSS treated with RTX between 2008 and 2019 in a single rheumatologic unit, was performed. When patients experienced adverse events, the treatment was suspended and patients’ data were recorded.
Results The included patients were mainly female (91%), with a mean age of 54 years. During the time of observation, 13 patients (37.1%) suspended RTX treatment (10 cases per 100 patient-years, 95% CI 0.06–0.17). Baseline demographics, disease characteristics, European Alliance of Associations for Rheumatology (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI) values, and treatment were comparable across RTX-suspended and nonsuspended groups. Patients exposed to RTX had been followed for 35.82 ± 32.56 months, and the time of observation varied from 6 to 96 months. All the patients except one experienced a significant and persisting meaningful improvement of their ESSDAI (≥ 3 points) during the long-term follow-up. For the duration of the follow-up, 13 (37%) patients discontinued RTX treatment. Four out of 13 (30.8%) discontinued the treatment after the first administration due to infusion-related reactions. During subsequent RTX courses, the main cause of withdrawal was hypogammaglobulinemia onset (7 patients). In 2 patients, hypogammaglobulinemia was associated with severe infections.
Conclusion Long-term RTX administration was shown to be a safe, well tolerated, and effective treatment in patients with active systemic disease, significantly reducing ESSDAI and controlling disease activity.
Primary Sjögren syndrome (pSS) is an autoimmune disorder characterized by sicca syndrome and extraglandular clinical features caused by lymphoplasmacytic infiltration of the exocrine glands (predominantly salivary and lacrimal glands). pSS affects mainly middle-aged women, and its incidence ranges between 3–11 per 100,000 individuals per year.1,2 More than half of the affected patients develop systemic involvement.3,4 In patients with severe disease, the excess mortality is related primarily to the development of B cell lymphoma and visceral involvement such as interstitial lung disease, renal failure, hypokalemic paralysis, and severe cryoglobulinemic vasculitis.5
Over the last 2 decades, off-label B cell targeted therapy with the anti-CD20 monoclonal antibody rituximab (RTX) has been used for the management of patients with severe pSS after the failure of conventional treatment, and has been prescribed based on the results of observational studies and randomized controlled trials.6 Further, the use of RTX in pSS patients with severe and refractory systemic disease is supported by the European Alliance of Associations for Rheumatology (EULAR) guidelines.7
The rationale for B cell depletion therapy relies upon the well-established pivotal role of B cell hyperactivity in pSS immunopathogenesis, as confirmed by the presence of autoantibodies, hypergammaglobulinemia, elevated rheumatoid factor levels, and the increased risk of non-Hodgkin B cell lymphoma.8
Despite the experience in SS treatment during the last decades, to date the right schedule of RTX administration is unclear and there are no guidelines regarding the treat-to-target approach in pSS. As far as safety is concerned, data on repeated peripheral B cell depletion with RTX and long-term therapy are missing. Thus, the incidences of hypogammaglobulinemia, associated risk factors, and adverse events (AEs) following long-term administration of RTX in routine clinical practice are mostly unexplored.
This work aims to evaluate the safety of long-term RTX treatment in pSS and to determine the consequences of repeated treatment with peripheral B cell depleting therapy over 8 years in patients with severe pSS.
METHODS
Study design and participants. A historical cohort study, enrolling 35 patients with pSS treated with RTX between 2008–2019 in the Rheumatologic Unit of San Salvatore Hospital, L’Aquila, was performed. All patients were aged ≥ 18 years, fulfilled the American-European Consensus Criteria for pSS,9 and received at least 1 RTX infusion. Disease activity assessment was performed at baseline and during follow-up using the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI).7 Systemic disease was defined as a disease that “affects or has affected any of the organs/systems included in the clinESSDAI [clinical ESSDAI] score,” and active systemic disease was defined as patients with a clinESSDAI score ≥ 1.7 Severe systemic disease was defined as “patients with ESSDAI score > 14 or high activity in any of the ESSDAI domains with a definition of high activity.”7 Patients were selected to be treated with RTX if they had moderate (5 ≤ ESSDAI ≤ 13) or high activity (ESSDAI ≥ 14)7,10, or if they had enlarged parotid glands or arthritis for at least 3 months and were unresponsive to glucocorticoids and immunosuppressive agents.7 Patients received an infusion of 1000 mg RTX on Day 1 and Day 15 to complete a single course of therapy. RTX administration was repeated every 24 weeks. Treatment was considered effective if patients experienced a clinically meaningful improvement, defined as a decrease in ESSDAI of ≥ 3 points, and/or if parotid gland enlargement and arthritis improved.7,10 When patients experienced side effects or lack of efficacy, the treatment was discontinued according to clinical judgment, and the data were recorded. Hypogammaglobulinemia was defined as IgG < 500 mg/dL.11 Patients’ files were analyzed to collect demographic characteristics, disease-specific features, and concomitant treatment. Patients with missing data were excluded from the study. The local ethics committees approved this study (Ethical Committee Azienda Sanitaria Locale 1 Avezzano/Sulmona/L’Aquila, L’Aquila, Italy; protocol number 17660/19). This study was performed according to the Good Clinical Practice guidelines, and written informed consent was obtained from all patients according to the Declaration of Helsinki. However, because of the retrospective nature of the study, after having made every reasonable effort to contact those patients who were lost to follow-up or who died during assessment, we used the fully anonymized clinical data according to Italian Law on privacy for research purposes only (Italian Data Protection Act, Authorization n. 9/2016, General authorization for the processing of personal data for scientific research purposes, 15 December 2016 [5805552]).
Statistical analysis. The statistical analysis provided descriptive statistics. Normally distributed continuous variables were expressed as mean ± SD. Data distribution was tested by using the Shapiro-Wilk test. To compare the clinical characteristics of RTX-suspended and RTX-nonsuspended, parametric or nonparametric t tests were used for all the continuous variables, and chi-square test or McNemar test with Yates correction was used for the categorical variables, as appropriate.
RESULTS
Baseline demographics, disease characteristics, and duration of exposure. The patients included in our cohort were mainly female (91%), with a mean age of 54 (SD 11.23) years. During the time of observation, 13 patients (37.1%) discontinued RTX treatment (10 cases per 100 patient-years, 95% CI 0.06–0.17). Baseline demographics, disease characteristics, ESSDAI values, and concomitant treatment were comparable across the included populations (Table 1). As of October 2020, 35 patients with pSS had been treated with up to 16 courses of RTX for up to 8 years. Patients treated with RTX had been followed for 35.82 ± 32.56 months, and the time of observation varied from 6 to 96 months. In detail, 6 patients (17.1%) received 16 RTX courses, 2 (5.7%) received 11 RTX courses, 1 (2.8%) received 10 RTX courses, 1 (2.8%) received 8 RTX courses, 1 (2.8%) received 7 RTX courses, 2 (5.7%) received 6 RTX courses, 1 (2.8%) received 5 RTX courses, 3 (8.6%) received 4 RTX courses, 4 (11.4%) received 3 RTX courses, and 6 (17.1%) received 2 RTX courses. Finally, 8 (22.8%) patients received 1 RTX infusion. At baseline, mean ESSDAI was 5.56 (SD 5.38), and there was no significant difference between the RTX-suspended and RTX-nonsuspended groups (Table 1). All the patients, except one, experienced a significantly meaningful improvement in ESSDAI (≥ 3 points) after RTX during long-term follow-up (Figure 1). In the RTX-nonsuspended group, the long-term treatment significantly reduced the number of patients with pSS who showed constitutional, glandular, pulmonary, and nervous manifestations (Supplementary Table 1, available with the online version of this article).
Treatment withdrawal. During follow-up, 13 (37%) patients suspended RTX treatment. Four out of 13 (30.8%) discontinued the treatment after the first administration due to infusion-related reactions. During subsequent courses, the main cause of withdrawal was hypogammaglobulinemia onset. This AE occurred in 7 (53.9%) patients and was associated with severe infections in 2 patients. One (7.7%) discontinued the treatment after 4 RTX courses due to the patient’s decision, and 1 (7.7%) patient discontinued because after 4 courses of treatment, there was no improvement and insufficient therapeutic response. These data are summarized in Table 2.
Hypogammaglobulinemia-related withdrawal. Among the 7 patients who discontinued RTX treatment due to hypogammaglobulinemia, the time from first RTX administration to withdrawal was 35.86 ± 28.79 months, with an average of 7 treatment courses. Two of the 7 patients had concomitant severe infection: 1 patient developed pyelonephritis and the other developed an ocular infection caused by Cytomegalovirus. There was no significant difference in age, age at pSS diagnosis, age at pSS onset, delay in diagnosis, ESSDAI, and focus score (FS) for the patients with vs without hypogammaglobulinemia.
DISCUSSION
To our knowledge, this is the first study to summarize the safety and efficacy of prolonged RTX treatment (6–96 months) in pSS. In our cohort, the RTX long-term administration was found to be a safe and well-tolerated treatment in patients with active systemic disease. Further, treatment with RTX improved disease management, significantly reducing ESSDAI, during the long-term observation. In fact, in our cohort, all the treated patients, except for one, achieved clinically meaningful improvement and maintained this result during the long-term follow-up. As far as safety is concerned, infusion-related reactions and hypogammaglobulinemia were the most common AEs observed. Four (11.4%) RTX-nonsuspended patients with pSS developed infusion-related reactions during the first administration, with mild symptoms shortly after the beginning of the first infusion that usually regressed with corticosteroids and antihistamine drugs after RTX withdrawal. The treatment was discontinued in these 4 patients while all the others did not experience any infusion-related reactions after the first course. The incidence of this AE in our cohort did not differ from what has been reported previously. In fact, Mejier et al described infusion-related reactions in 20% of treated patients and, among them, 1 patient developed mild serum sickness–like disease.12 Devauchelle-Pensec et al reported a lower rate of infusion-related reactions (8%), and no serum sickness–like disease cases were reported.13 During long-term follow-up, the most common AE reported was the insurgence of hypogammaglobulinemia, observed in 7 RTX-nonsuspended patients (14.2%), with an average insurgence time of 36 months.13 Hypogammaglobulinemia is reported to be one of the most common side effects of RTX administration in nonmalignant hematological disorders.14 Of interest, the rate of hypogammaglobulinemia in our cohort was lower when compared to the incidence of hypogammaglobulinemia during long-term follow-up of RTX-nonsuspended patients with rheumatoid arthritis (RA), which has been established to be up to 40%.15 No difference in the demographic baseline features was outlined between RTX-suspended and RTX-nonsuspended groups. Further, pSS baseline features such as disease presentation, FS, autoantibodies, and concomitant therapies did not influence the development of hypogammaglobulinemia, mirroring what was already reported in RA.16
In our cohort, only 2 patients (5.7%) developed severe infection related to hypogammaglobulinemia induced by RTX treatment, confirming the RTX safety profile during long-term use.15,16,17,18 The data observed in our cohort are similar to the results observed during long-term follow-up in RTX-nonsuspended patients with RA, in which severe infections varied from 5% to 10%, mainly associated with hypogammaglobulinemia.15,16,17,18 As suggested, monitoring Ig levels before RTX and throughout treatment courses with B cell depleting agents is recommended.16 None of our patients developed lymphoma during the long-term follow-up.
We are aware of some limitations of this study. Its retrospective nature, together with the relatively small number of included patients, limits the study power. However, our study is the first work, to our knowledge, analyzing the effect in a large pSS cohort of patients undergoing long-term RTX treatment and confirming its efficacy and safety in patients with systemic manifestations, thus endorsing its use in moderate to severely active disease, more than to treat sicca-related symptoms. The main reason for RTX discontinuation is hypogammaglobulinemia, although severe infections seem to be an uncommon AE in RTX-nonsuspended patients with pSS, even during long-term follow-up. Finally, pSS characteristics, disease presentations, and concomitant therapies do not influence RTX suspension rate. Prospective long-term studies enrolling a larger number of patients would confirm and better clarify what we observed about RTX efficacy and safety during long-term treatment in pSS. Due to the lack of specific disease-modifying drugs for patients with pSS and the conflicting results between trials using RTX in pSS, which failed to reach the primary outcome, and the large number of observational studies showing clinical benefits in pSS patients after RTX treatment, mirroring what has already been observed for RTX treatment in systemic lupus erythematous. These efforts are required to understand if RTX could be helpful in patients with pSS with severe disease, systemic manifestations, and higher risk for lymphoma development.6 Further, due to the improvement of the ESSDAI, which evaluates several domains concerning different organs, our data may suggest new perspectives in order to treat specific organ manifestations that are unresponsive to conventional drugs, as well as a possible treat-to-target approach in pSS. In fact, it has been already suggested that improvement of ESSDAI values may be helpful to assess the efficacy of specific pSS treatments, preidentifying possible targets in clinical trials and thus opening a new avenue for therapy of this disease.
ACKNOWLEDGMENT
The authors thank Mrs. Federica Sensini for her technical assistance.
Footnotes
HarmonicSS project (HORIZON H2020) supported this research.
V. Pavlich and I. Di Cola contributed equally to this work. P. Cipriani and R. Giacomelli are co–senior authors.
The authors declare no conflicts of interest relevant to this article.
- Accepted for publication October 4, 2021.
- © 2022 by the Journal of Rheumatology
REFERENCES
DATA AVAILABILITY
The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.