The Off-Label Use of Rituximab for the Management of Inflammatory Disorders: American University of Beirut Medical Center Experience
Dana HARB,2 Hiba MOUKADEM,2 Rabih NAYFE,1 Ali MEHDI,3 Abdel Fattah MASRI,2 Ziad SALEM,2 Ali TAHER,2 Imad UTHMAN2
1Department of Internal Medicine, Akron General Medical Center, Copley/OH, USA
2Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
3Department of Internal Medicine, The Cleveland Clinic Foundation, Cleveland/OH, USA
Keywords: Autoimmune disease; biologic therapy; inflammatory disorder; off-label; rituximab.
Objectives: This study aims to evaluate the efficacy of off-label use of rituximab with possible side effects.
Patients and methods: Records of the 44 American University of Beirut Medical Center pharmacies were searched for patients who used rituximab over the past 4.5 years, and data on rituximab dosage, protocol and side effects were documented. The majority of patients had systemic lupus erythematosus. Autoimmune thrombocytopenic purpura, antiphospholipid syndrome, Sjögren's syndrome, Wegener’s granulomatosis, autoimmune hemolytic anemia, dermatomyositis, and pemphigus vulgaris were also reported. Outcome measures were improvement in signs and symptoms during a follow-up period of two years.
Results: Twenty-nine out of the 44 patients had complete response without relapse. Of those, 12 patients were in remission after the first cycle. Of the systemic lupus erythematosus cases, 12 had complete response without relapse; of which, five patients had remission after the first cycle. No significant toxicities were noted.
Conclusion: The off-label use of rituximab in various inflammatory diseases showed improvement in symptoms with no significant side effects in patients who have failed previous treatment with multiple conventional regimens.
Biologists have been extensively investigating a promising therapy in the management of multiple inflammatory and autoimmune diseases. Rituximab is a chimeric (murine/ human) monoclonal antibody, which targets a cluster of 20 different antigens (CD20) found on the surface of B-lymphocytes.
Rituximab is approved by the Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis, non-Hodgkin’s lymphoma(1) and recently of anti-neutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV).(2) In addition to these indications, rituximab is being used as an off-label treatment in a number of inflammatory and systemic autoimmune diseases. Off-label use dictates the prescription of a registered medicine for a use that is not included in the product information. It is considered appropriate when there is high-quality evidence, or where the use is within the context of a formal research proposal, or in exceptional cases, justified by clinical situations.(3) Rituximab has been tried as an off-label treatment for many conditions including systemic lupus erythematosus (SLE), Sjögren's syndrome, idiopathic thrombocytopenic purpura (ITP), systemic vasculitides, bullous dermatologic diseases, and others.(4) Rituximab use in a number of dermatological diseases has also been reported.(5)
Several reports have acknowledged the positive outcomes and efficacy of rituximab in the aforementioned diseases. In 2009, Ramos- Casals et al.(6) reported a review of the literature regarding the off-label use of rituximab in resistant SLE patients, revealing a 91% positive response. One year later, Murray and Perry(7) conducted a systematic review about the off-label use of rituximab in SLE, and found that it induced B-cell depletion in 95% of patients, and induced significant reduction in disease activity with a good safety profile. Since applicability of these results to our study population remains to be elucidated due to the current limited reports on rituximab use among this patient, we were enthusiastic to investigate our experience at the American University of Beirut Medical Center, with rituximab off-label use in a variety of inflammatory rheumatologic, dermatologic, and hematologic conditions, addressing efficacy in clinical response and side effects. The results of this study contribute to the worldwide experience in the off-label use of this drug.
Patients and Methods
In this retrospective study, pharmacy records at the American University of Beirut Medical Center were evaluated for rituximab use over the past
4.5 years (January, 2006 - May, 2010). A total of 44 patients received rituximab for off-label conditions during the period were evaluated. All patients were of Caucasian origin (34 females versus 10 males), and were enrolled depending on whether there was treatment failure after conventional regimens and/or treatment side effects. Patients whose medical charts were noted in the pharmacy database and were reviewed in the medical records of the hospital (in- and out- patient) and the dermatology department, and those who received rituximab as an off- label use for an inflammatory disorder, were then enrolled in the study. The disorders include SLE, antiphospholipid syndrome (APS), Sjögren's syndrome, systemic sclerosis (SSc), Still’s disease, A AV, Behçet’s disease, cr yoglobulinemia, poly/dermato-myositis, scleroderma, as well as pemphigus vulgaris, bullous pemphigoid, epidermolysis bullosa, ITP, and thrombotic thrombocytopenic purpura. Diagnosis of these diseases was based on clinical manifestations and serological markers.
Medical records were reviewed and general information regarding race, sex, and age at onset of disease, as well as disease chronicity and manifestations as per system review were collected. Current medications and previous treatment received were recorded along with thoroughly explored comorbidities. The total dose of rituximab, protocol of drug administration, and side effects were documented.
The responsible treating physician identified the patient’s response to rituximab in dermatologic and rheumatologic diseases according to symptoms and signs. Response rate was categorized as: (i) complete response without relapse meaning that the patient attained remission by regression of symptoms and signs without the appearance of other signs and symptoms, (ii) complete response with relapse, (iii) partial response meaning improvement in one or more of the symptoms and signs, and (iv) no response. Improvement in cell counts and remission was documented for ITP and thrombotic thrombocytopenic purpura patients. Patients were evaluated for a follow-up period of two years. Data analysis was performed using the PASW Statistics version 18.0 for Windows software program (SPSS Inc., Chicago, IL, USA). On the other hand, frequencies were extracted using descriptive statistics, while means were compared using the paired sample T test. A P-value less than or equal to
0.05 was considered statistically significant.
The mean age at diagnosis was 36.4±19.8 years, and the mean age at study enrollment was 44.5±19.1 years. The mean chronicity of the disease is 7.4±6.4 years. Seventeen patients had SLE. Patients with other inflammatory diseases were also reported in decreasing frequency as follows: ITP (n=8), APS (n=5), Sjögren's syndrome (n=5), polymyositis (n=4), Wegener’s granulomatosis (n=3), autoimmune hemolytic anemia (AIHA) (n=2), scleroderma (n=2), Still’s disease (n=1), dermatomyositis (n=1), pemphigus v ulgaris (n=1), bullous pemphigoid (n=1), ankylosing spondylitis (n=1), polyarteritis nodosa (n=1), and sickle cell disease (n=1). The diagnoses, clinical manifestations, previous treatments and outcome are summarized in Table 1. Previous treatment modalities were documented; and the most widely used drugs were corticosteroids in 39 patients, non-steroidal anti-inflammatory drugs (NSAIDs) in 23 patients, anti-malarial drugs (n=17), azathioprine (n=15) and methotrexate (n=14). Other regimens such as mycophenolate (n=7), cyclophosphamide (n=6), cyclosporine, infliximab (n=5), and IVIG (n=5) were also used, but to a lesser extent.
The use of rituximab in the above reported cases was off-label, thus there was no consensus as to the dosing and number of cycles needed to attain a cure. The most commonly used protocol was either a 500 mg weekly dose for four weeks or two doses only of 1000 mg for every other week. The number of cycles administered was decided by the treating physician depending on the clinical and laboratory response to treatment by the patients. Twenty-two patients received
1 cycle, 10 patients received 2 cycles, whereas eight patients received a third cycle.
The efficacy of rituximab was retrospectively assessed according to improvement of clinical signs and symptoms of patients. Of all the patients found to be treated with rituximab, 38 patients documented response to treatment. The degree of response was divided into complete response without relapse, complete response with relapse, partial response or no response. Twenty-nine patients had complete response without relapse, three patients had relapse, while four patients had partial response (Figure 1). Out of 44 cases, only two patients had no response. To achieve complete remission, 12 patients required only 1 cycle of the drug, while 14 patients required a second or a third cycle for maintenance of remission every six to eight months. Figure 2 shows the number of cycles required to achieve remission. Patients receiving steroids as initial treatment for autoimmune and inflammatory processes were followed-up clinically and the dose of steroid was tapered over 8 to 12 weeks. Table 2 provides a summary of the response to rituximab for each disease reported, while Figure 3 shows the response rate in selected diseases. The most common autoimmune disease for which rituximab was used in this series was SLE. Of the 17 patients with SLE included in this study, 13 patients had complete response without relapse, two patients had partial response whereas one patient had no response. Of these patients, only one patient died during follow-up.
The efficacy of rituximab use as an off-label treatment of hematologic diseases was separately studied. The number of patients receiv ing rituximab for hematologic causes was 11, eight of whom were diagnosed with ITP. It was crucial to compare the level of platelet count before and after rituximab therapy among patients with ITP, in order to check for treatment response. The data revealed that the mean change in platelet count among the eight patients was significantly important with an increase from 46 thousands before rituximab treatment to 184 thousands after rituximab treatment, and a p-value of 0.012. The apparently significant increase in platelet count indicates response to therapy and a possibly disease remission. The remission rate in ITP was 67% (four out of six patients).
Skin infusion reactions were the most common side effects reported, which were observed in six out of 44 patients. The other patients did not have any reportable side effects of the medication. No serious hematological, renal, or hepatic toxicities were documented in our treated cohort.
In the past decades, therapeutic approaches to systemic autoimmune and inflammatory diseases have been based on the use of glucocorticosteroids and immunosuppressive agents. Available data on the use of biological agents in patients with these conditions rely mainly on a large number of observational studies and case reports. The almost total lack of randomized clinical trials may be explained by the low prevalence of systemic autoimmune diseases, their diverse clinical presentation, and the absence of consensual endpoints to be evaluated in each disease. This poses multiple questions on when and how to use these agents, since there are no current recommendations or guidelines on their use in such circumstances.(8)
B cells play important roles in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, SLE, and Sjögren's syndrome. They exert their pathogenic effect by producing autoantibodies which target self antigens and induce inflammation and tissue injury, disrupting T cell tolerance, activating autoreactive memory T cells, attracting and activating dendritic cells, inhibiting regulatory T cells, and recruiting follicular B-helper T cells, among many other functions. It is important to note that all these effects are independent of antibody secretion, but are mediated instead through antigen-presentation, co-stimulation and production of proinflammatory cytokines. Hence, one would expect that the elimination of B cells by blocking CD20, the molecular target of rituximab, should be of therapeutic benefit in SLE.(9)
There was a predominance of females over males in the population studied, which is expected, given the fact that a large number of autoimmune diseases are more prevalent in women.(10)
Moreover, studies have shown that the more frequent the autoimmune disease and the later it appears, the more women are affected.11In this study, the indication for starting rituximab therapy was either treatment failure after conventional regimens or treatment side effects. As expected, the preceding therapy for almost all patients with the diseases included in this study consisted of glucocorticosteroids (88%), NSAIDs (51%), and immunosuppressants (67%). Since no solid guidelines and recommendations are available for the rituximab dosing protocol, the number of cycles administered was decided by the treating physician depending on the clinical and laboratory response to treatment by the patients. The most commonly used protocol was either repeated cycles of a 500 mg weekly dose for four weeks or 1000 mg every two weeks whereby each cycle consisted of two doses. It was considerably promising that 84% of the patients showed clinical improvement after receiving rituximab, with 67% showing complete remission and 29% requiring only 1 cycle.
Systemic lupus er ythematosus was the autoimmune disease with the highest reported use of rituximab in this study (17/44 patients, 38.6%). Although Merrill et al.(12) showed no difference in primary or secondary end points between placebo and rituximab treatment over 52 weeks of treatment in patients with moderate-to severe SLE in the EXPLORER trial, other studies have shown more promising results. Ramos-Casals et al.(8) in 2008 showed that the best results were observed in the use of rituximab for Sjögren's syndrome, SLE, and cryoglobulinemia. A recent review suggested that rituximab induces B-cell depletion in 95% of patients, and a significant reduction in disease activity is achieved with a relatively good safety profile in patients with SLE7 However, there is always a difficulty in assessing the status of SLE patients and response rate in any research, given the heterogeneity of the disease. Hence, grouping patients according to types of organ systems affected in SLE shows that some have better response rates to rituximab than others, for example, cutaneous lesions/discoid lupus shows less improvement than neuropsychiatric or renal, and multi-system diseases are more responsive than single organ diseases.(13)
However, the encouraging results contrast with the poor outcome reported from the two randomized clinical trials (the Explorer and the Lunar) which tested the efficacy of rituximab in SLE. The contradictory findings can be attributed to several reasons including patient selection. The next issue is the method used to assess clinical activity. The British Isles Lupus Assessment Group (BILAG) index score is a transitional index developed for the intention-to-treat analysis, and may not be perfect for use in regular clinical practice.
The statistically significant increase in platelet count in patients with ITP after receiving rituximab therapy also emphasizes its therapeutic efficacy in hematological diseases. Similar results were found in a study conducted by Dierickx et al.(14) in 2009. They showed that the overall response rates were 79.2% in AIHA and 70% in ITP, with a median follow-up since the first rituximab administration was 15 month in AIHA and 11 months in ITP. Progression-free survival at one and two years were respectively 72% and 56% in AIHA, and 70% and 44% in ITP.
Concerning the safety profile of rituximab, this study showed no statistically significant change in liver, kidney or bone marrow laboratory markers before and after treatment. The most common side effects observed were benign and consisted mainly of infusion reactions. This safety profile has been highlighted in many other studies. Ceccarelli’s safety study on SLE found adverse event rates comparable to the placebo, with the only differences being leukopenia (12.3% vs. 4.2%), neutropenia (5.5% vs. 1.4%) and hypotension (11% vs. 4.2%).(15) Medeot et al.,(16) on the other hand, ascertained a rituximab safety profile in patients with refractory ITP. They found that rituximab administration was associated with two episodes of short-term toxicity, namely a mild infusion reaction and a case of serum sickness syndrome, which improved rapidly with steroids; no infectious or other significant long- term complications were documented.
To conclude based on our study results, the off-label use of rituximab carries a promising cure for debilitating and relapsing autoimmune and inflammatory disorders with a relatively good safety profile. However, the fact that we still have conflicting results from various observational studies, reviews and case reports, dictates the necessity for large randomized control trials on the efficacy and safety of rituximab therapy in various autoimmune and inflammatory diseases. This is crucial to set forth solid and reliable guidelines and recommendations for the dosing of rituximab and its prescription protocol.
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.
The authors received no financial support for the research and/or authorship of this article.
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