Rituximab use in Rheumatoid Arthritis: A Seven-Year Retrospective Study of 52 Patients at a Saudi Arabian Hospital

Introduction

Rheumatoid arthritis (RA) is a complex inflammatory disease that causes inflammation and progressive joint destruction, resulting in significant morbidity and reduced quality of life, with a global prevalence of 0.24% [1–4]. It occurs when the immune system mistakenly attacks the body’s own tissues, leading to joint inflammation. It can result in long-term joint damage and disability if not properly managed. RA diagnosis involves clinical evaluation, serological markers like rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA), and imaging such as MRI and ultrasound. Early treatment is crucial to prevent joint damage, with methotrexate as the first-line disease-modifying anti-rheumatic drug (DMARD). For patients who do not respond to traditional DMARDs, biologics like TNF inhibitors, IL-6 inhibitors, rituximab, and targeted synthetic DMARDs such as Janus kinase (JAK) inhibitors are used to control inflammation and improve long-term outcomes [1–4]. Various treatment options have been developed to manage RA symptoms and slow disease progression [5]. Knowledge of RA has evolved, particularly throughout the last decade. However, the specific processes surrounding the emergence and advancement of RA have yet to be fully explored and elucidated. Humoral immunity, pro-inflammatory cytokines, dysregulated immune responses, and autoantibody formation play major roles in RA pathogenesis and lead to the initiation of inflammation and joint damage [6].

B lymphocytes play a significant role in triggering the generation of inflammatory cytokines, such as interleukin-6 (IL-6), IL-1, and tumor necrosis factor-alpha (TNF-α). When elevated, these cytokines contribute to the attraction of other immune cells to the site of inflammation, such as the articular and extraarticular organs, and further exacerbate joint damage and increase inflammation [7]. Additionally, B lymphocytes play an important role in antigen presentation, T-lymphocyte activation, and autoantibody production, and regulatory B cells possess immunosuppressive functions and can help control inflammation [7]. Targeting cytokines, such as interleukin-1(IL-1), TNF-α, tyrosine kinase, interleukin-17(IL-17), and IL-6, plays a significant role in the effective medical management of RA [6,7].

Recent advances in understanding of the mechanisms and roles of these cytokines in RA have enabled the creation of more precise and effective therapeutic approaches. The emergence of different therapeutic and treatment regimens has resulted in substantial improvements in the treatment courses and plans for RA [5–7]. These treatments include conventional disease-modifying anti-rheumatic drugs (cDMARDs), synthetic disease-modifying anti-rheumatic drugs (DMARDs), and targeted biological drugs. Different B cell-directed therapies, such as rituximab (RTX), have shown efficacy in the treatment of RA [7]. RTX is a monoclonal antibody that targets CD20+ B cells by inhibiting their interaction with CD20, rendering them unable to respond to the ligand. This depletes these cells and suppresses various cell survival pathways and B cell maturation signals. RTX adhesion to this receptor within the membrane triggers immune cell production and antibody formation, resulting in decreased CD20+, reduced inflammation and autoantibody production, slowed disease progression, and symptom alleviation, and regular monitoring is required during therapy to ensure patient safety [1–7]. cDMARDS, like methotrexate (MTX) in conjunction with RTX, have been approved as RA treatments [8] and are considered a second-line treatment by the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) [9,10]. In certain diseases, such as lymphoproliferative conditions and interstitial lung disease (ILD), RTX can be a first-line therapy [11–15]. For hepatitis B, RTX is associated with a high risk of infection activation; therefore, patients who are at high risk of hepatitis B infection should receive antiviral prophylaxis [16].

The growing number of targeted synthetic disease-modifying anti-rheumatic drugs (tsDMARDs) and biological disease-modifying anti-rheumatic drugs (bDMARDs) has created a challenge regarding which treatment options to choose as the first-, second-, and third-line drugs. Having early treatment strategies and alternative disease-modifying anti-rheumatic drugs in case of treatment failure is crucial, as starting therapy early on in RA progression improves disease remission rates and prevents disability. The key principles of RA management are to minimize disease activity and decrease disease symptoms, morbidity, and mortality. These are achieved by adopting and emphasizing more proactive treatment methods and starting DMARDS therapy as early as possible. Prioritizing treatment regimens in RA is a multifaceted and complex process that requires a comprehensive understanding of the disease, the available treatments, and patient preferences [17].

RA management has evolved to prioritize early and aggressive treatment with personalized treatment plans using a combination of conventional and biological DMARDs. The availability of biological drugs, cost, required healthcare services, underlying comorbidities, pregnancy planning, and patient preferences are the most important factors that influence this decision [18,19]. Rituximab can be recommended for RA as a bDMARD, especially for patients not responding to csDMARDs or with poor prognostic factors or if contraindications to TNF inhibitors exist [18,19]. The key advantage of RTX is its dosage frequency (every 6 months after the initial cycle); however, its route of administration (intravenous) requires admission to a day medical unit, which increases its associated expense and means the patient/caregiver has to miss work. Furthermore, RTX has several potential adverse events and considerations. Therefore, this retrospective study aimed to present our experience of rituximab treatment at a single center in Saudi Arabia between 2015 and 2022 in 52 patients with rheumatoid arthritis.

Material and Methods

ETHICAL CONSIDERATIONS:

The study was approved by the Institutional Research Board (IRB) at King Saud University (Approval No: E-19-3677). Due to the retrospective nature of the study, patient consent was waived, in compliance with national regulations and institutional guidelines. The analysis followed the ethical standards of the Declaration of Helsinki.

STUDY DESIGN AND SETTING:

This study was a retrospective cohort analysis carried out at King Khalid University Hospital in Riyadh. The study included all patients with rheumatoid arthritis (RA) who received at least 1 dose of rituximab (RTX) between April 2015 and October 2022. The start date was chosen because this was when the hospital implemented an electronic health record (EHR) system, allowing for standardized data extraction.

STUDY POPULATION:

Patients were eligible for inclusion if they were aged 18 years or older and met the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA [20]. Patients under 18 years were excluded. Overall, 52 patients were taken into consideration in the final analysis. This study followed the guidelines outlined in the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) [21].

DATA COLLECTION:

Data were extracted from the hospital’s EHR using a standardized data collection sheet. Variables collected included patient demographics (age, sex, disease duration), clinical parameters (disease activity scores, joint involvement), laboratory values (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], autoantibodies), and treatment details (previous and current medications, including RTX, prednisolone dosage, and dose-tapering regimen). Additionally, information on comorbidities and adverse events related to RTX was obtained. To ensure objectivity, all data were collected and validated by 2 independent researchers to minimize bias.

OUTCOME MEASURES:

The primary outcome was the tapering of prednisolone, defined as a reduction in dose by at least 25% during the treatment period. Secondary outcomes included activity of the disease (measured by DAS28 scores), treatment response, and adverse events. Patients were categorized into 2 groups: those who tapered prednisolone (tapering group) and those who did not (non-tapering group).

STATISTICAL ANALYSIS:

All statistical analyses were performed using IBM SPSS Statistics for Windows version 26 (IBM Corp, Armonk, NY, USA). Descriptive statistics were used to summarize patient demographics, disease characteristics, and treatment patterns. Continuous variables (eg, age, prednisolone dose) were presented as means±standard deviations, while categorical variables (eg, sex, tapering status) are presented as frequencies and percentages. Differences between the tapering and non-tapering groups were assessed using independent t test for continuous variables and chi-square test for categorical variables. The level of statistical significance was set at P<0.05. Missing data were handled by performing sensitivity analyses, and cases with incomplete data for primary outcomes were excluded.

Results

CHARACTERISTICS OF PATIENTS WITH RA:

A total of 678 patients were screened, of whom 52 (7.7%) were recruited for this study. Among them, 44 (84.6%) were female, with a mean age of 57.1±11 years and a mean disease duration of 28±7 years. Fifty patients (96.15%) tested positive for either rheumatoid factor (RF) or anti-cyclic citrullinated peptide (ACPA), while two patients tested negative for both. The mean body mass index (BMI) was 30.4±6.41. Thirty-five patients (67.3%) lived in Riyadh, and 51 (98.1%) had never smoked. Thirty-seven patients (71.2%) had one or more comorbidities, with 17 (45.9%) having one comorbidity. Interstitial lung disease (ILD) was identified in 5.8% of the patients. Seven patients (13.5%) had latent tuberculosis (TB), and one (1.9%) had a history of active TB. Four patients (7.7%) had hepatitis B core antibodies, but no patients tested positive for hepatitis B surface antigens or hepatitis C antibodies (Table 1).

MEDICATION REGIMEN PRIORITIZATION:

Upon initiation of rituximab (RTX), 48 patients (92%) were receiving conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Methotrexate (MTX) monotherapy was prescribed to 33 patients (63.46%), and MTX-based combinations were used for 13 patients (25%). The remaining patients received alternative csDMARDs (3.85%). Prednisolone was administered to 22 patients (42.31%) at the start of RTX treatment, with a mean dose of 10.45±10.25 mg, which significantly decreased to 3.41±5.54 mg after RTX initiation (p<0.001). Ten patients (45.4%) discontinued prednisolone while on RTX (Table 2).

RTX was prioritized as the first-, second-, third-, fourth-, or fifth-line therapy in 35%, 25%, 12%, 13%, and 15% of patients, respectively (Figure 1). Among patients who failed to respond to biologic DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs) before RTX initiation, 50%, 30%, 12%, and 8% had previously been exposed to a TNF inhibitor (TNFi), tocilizumab (TOC), abatacept (ABA), and Janus kinase inhibitor (JAKi), respectively (Figure 2).

The mean number of RTX doses received was 14±4.4. RTX tapering was attempted in eight patients (15.38%). Older patients (p=0.049), those living outside Riyadh (p=0.005), and those who had used fewer bDMARDs or tsDMARDs prior to RTX (p=0.001) were more likely to taper without needing to reinstitute the full dose. Eleven patients (21%) experienced adverse events. RTX therapy was initiated due to primary failure, secondary failure, or adverse events related to previous bDMARD/tsDMARD use in 21 (40%), seven (13%), and nine patients (17%), respectively. One patient (1.9%) had concomitant ILD, and another (1.9%) had malignancy. The remaining patients received RTX either based on their preferences or for unspecified reasons in their records.

Seven patients (13.46%) discontinued RTX treatment. Discontinuation was due to adverse events in two patients (28.56%), treatment failure in three patients (42.85%), drug-free remission in one patient (14.28%), and death unrelated to the drug in one patient (14.28%) (Table 3).

Discussion

Our study provides practical insights into the positioning and tapering of rituximab (RTX) in rheumatoid arthritis (RA) treatment. We observed that patients living outside Riyadh and those who used fewer bDMARDs/tsDMARDs prior to RTX were more likely to successfully taper RTX. This highlights the influence of patient location and prior medication use on management outcomes. One of the primary challenges in managing RA in Saudi Arabia is the delay in diagnosis, which hinders early intervention and optimal management. Additionally, limited access to specialized care and expensive medications are barriers to effective treatment for some patients. Several factors in Saudi Arabia impact a rheumatologist’s decision to prescribe bDMARDs, and this decision may be influenced by individual patient characteristics, preferences, route of administration, and underlying comorbidities [19]. Omair et al [19] surveyed practicing rheumatologists in Saudi Arabia to explore RA management strategies. They found that the absence of national recommendations for Saudi Arabian patients with RA has resulted in a lack of standardized medical treatment, emphasizing the need for improvements in various aspects of rheumatology practice. Additionally, some rheumatologists stated that they do not use certain medications due to unavailability, which is a significant factor contributing to suboptimal patient care [19]. In our study, we observed that patients living outside of Riyadh and those who used fewer bDMARDs/tsDMARDs prior to RTX had successful RTX tapering, indicating that resident distance is an essential factor in patient management options and prioritization.

Comparing our findings with previous studies, Chatzidionysiou et al [22] found that RTX significantly reduced disease activity scores (DAS28) in RA patients, particularly those who were seropositive, aligning with our observation that 96% of our patients were positive for ACPA or RF. Similarly, the ORBIT study showed that RTX and TNFi-first strategies were equally effective in seropositive patients, supporting our finding that 35% of patients received RTX as first-line therapy. Additionally, 64.8% of patients were co-treated with MTX, closely matching our study, where 63.46% received MTX monotherapy and 25% received an MTX-based combination. In our cohort, 96% were positive for ACPA or RF, markers that may predict RTX treatment response. This aligns with Chatzidionysiou et al [22], who identified anti-CCP positivity, fewer previous DMARDs, no prior biological agents, and higher disease activity as factors for significant RTX response after 6 months [22]. RTX is recommended for RA patients who do not respond adequately to or experience adverse effects from other biological drugs, such as anti-TNF agents. When combined with MTX, RTX may be more effective in seropositive patients, while seronegative patients might need alternative treatments [23]. In our study, RTX was used as first-line therapy for 35% of patients. The ORBIT study by Porter et al [24] found RTX and TNFi-first strategies to be equally effective in seropositive RA patients. Our findings indicate that RTX was started in 21 patients (40%) due to primary failure of previous bDMARDs/tsDMARDs and in 7 patients (13%) due to secondary failure. Subsequent real-life data have confirmed RTX’s efficacy after other biological drugs fail [25]. Our results also mirror those of Gul et al [26], who emphasized the importance of different treatment strategies for RA remission. Despite the benefits, 13.46% of our patients discontinued RTX due to treatment failure, remission, or adverse events, with 2 patients experiencing adverse events similar to those reported in other studies. The introduction of other medications, such as TOC, ABA, and JAK inhibitors, has reduced the reliance on RTX. Manders et al [27] conducted a comparative analysis in RA patients in Belgium and the Netherlands on the therapeutic effect of biological drugs who had failed prior anti-TNFi treatments. While they found no statistically significant differences among the biological treatments based on DAS28 scores, RTX was noted to be the most cost-effective option. Various factors, including RF presence, previous medication use, and the risks of serious infections and malignancies, can influence treatment responses [27]. We noted that 15% of patients could taper RTX, influenced by factors such as older age, less prior bDMARD use, and residency outside Riyadh. Successful discontinuation of DMARD and biological therapy is predicted by factors such as shorter disease duration, absence of erosions, low baseline disease activity, specific demographic characteristics, certain medications, lower patient-reported outcome scores, and lack of synovitis. These predictors help identify patients who are more likely to achieve drug-free remission and guide treatment decisions. This is also consistent with Wientjes et al [28], who assessed the effects of RTX dosage tapering and dose frequency in 387 RA patients compared to standard low-dose RTX therapy and found that RTX tapering could significantly reduce doses indicating potential benefits of adopting tapering protocols for RA treatment. In our study, 10 patients discontinued prednisolone during RTX treatment, leading to a significant reduction in the mean prednisolone dose. Additionally, 2 patients experienced adverse events after starting RTX, underscoring the risks associated with RTX for RA. However, these events were infrequent and not severe, consistent with findings from other studies [29–31].

Biosimilars are biological drugs that are comparable to previously licensed biological products and have transformed the management of various conditions, including RA. They offer more affordable treatment options, improving access to medications, and reducing healthcare costs. Biosimilars of RTX, approved globally, demonstrate similar efficacy and safety to the original RTX [29]. The clinical response rates do not substantially differ between biosimilar RTX and the reference medication [32]. In Saudi Arabia, Rixathon® and Truxima® are 2 licensed RTX biosimilars (https://www.sfda.gov.sa/en/node/86696; https://www.sfda.gov.sa/en/node/86224; https://www.sfda.gov.sa/en/drugs-list) that have partially addressed the challenges associated with RTX availability in hospitals. However, rheumatologists and patients must remain vigilant and informed about the implications of using biosimilars for RA management.

Limitations of our study include its retrospective design, which may introduce bias, and the small sample size, which limits generalizability. Additionally, the absence of detailed disease assessments for outcome measures could affect the interpretation of our results. The study also lacked a control group to directly compare RTX outcomes with other treatment strategies. Despite these limitations, our findings contribute valuable insights into RTX tapering and its implications for RA management in Saudi Arabia.

Conclusions

This retrospective study supports the findings from other studies and current clinical guidelines that recommend rituximab in patients with rheumatoid arthritis, highlighting the importance of patient monitoring during treatment. Multicenter studies are required to determine the economic impact of tapering biological drugs.