Arch Rheumatol 2014;29(3):194-202 doi: 10.5606/ArchRheumatol.2014.3855 ORIGINAL ARTICLE

The Off-Label Use of 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

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 erythematosus. Autoimmune , antiphospholipid syndrome, Sjögren's syndrome, Wegener’s granulomatosis, autoimmune hemolytic anemia, dermatomyositis, and 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. Key words: ; biologic therapy; inflammatory disorder; off-label; rituximab.

Biologists have been extensively investigating used as an off-label treatment in a number of a promising therapy in the management of inflammatory and systemic autoimmune diseases. multiple inflammatory and autoimmune diseases. Off-label use dictates the prescription of a registered Rituximab is a chimeric (murine/human) medicine for a use that is not included in the monoclonal , which targets a cluster of product information. It is considered appropriate 20 different antigens (CD20) found on the surface when there is high-quality evidence, or where of B-lymphocytes. the use is within the context of a formal research Rituximab is approved by the Food and proposal, or in exceptional cases, justified by Drug Administration (FDA) for the treatment of clinical situations.3 Rituximab has been tried as an , non-Hodgkin’s lymphoma1 off-label treatment for many conditions including and recently of anti-neutrophilic cytoplasmic systemic lupus erythematosus (SLE), Sjögren's antibody (ANCA)-associated (AAV).2 In syndrome, idiopathic thrombocytopenic purpura addition to these indications, rituximab is being (ITP), systemic vasculitides, bullous dermatologic

Received: July 12, 2013 Accepted: December 28, 2013 Correspondence: Imad Uthman, M.D., MPH, FRCP. Division of Rheumatology, Department of Internal Medicine, American University of Beirut Medical Center, 1107 2020 Riad El-Solh, Beirut, Lebanon. Tel: +961 (3) 379098 e-mail: [email protected] ©2014 Turkish League Against Rheumatism. All rights reserved. Off-label Use of Rituximab 195 diseases, and others.4 Rituximab use in a number , ITP, and thrombotic of dermatological diseases has also been reported.5 thrombocytopenic purpura. Diagnosis of these diseases was based on clinical manifestations and Several reports have acknowledged the serological markers. positive outcomes and efficacy of rituximab in the aforementioned diseases. In 2009, Ramos- Medical records were reviewed and general Casals et al.6 reported a review of the literature information regarding race, sex, and age at regarding the off-label use of rituximab in resistant onset of disease, as well as disease chronicity SLE patients, revealing a 91% positive response. and manifestations as per system review were One year later, Murray and Perry7 conducted collected. Current medications and previous a systematic review about the off-label use of treatment received were recorded along with rituximab in SLE, and found that it induced thoroughly explored comorbidities. The total dose B-cell depletion in 95% of patients, and induced of rituximab, protocol of drug administration, and significant reduction in disease activity with a side effects were documented. good safety profile. Since applicability of these The responsible treating physician identified the results to our study population remains to be patient’s response to rituximab in dermatologic and elucidated due to the current limited reports rheumatologic diseases according to symptoms and on rituximab use among this patient, we were signs. Response rate was categorized as: (i) complete enthusiastic to investigate our experience at the response without relapse meaning that the patient American University of Beirut Medical Center, attained remission by regression of symptoms and with rituximab off-label use in a variety of signs without the appearance of other signs and inflammatory rheumatologic, dermatologic, and symptoms, (ii) complete response with relapse, hematologic conditions, addressing efficacy in (iii) partial response meaning improvement in clinical response and side effects. The results of one or more of the symptoms and signs, and this study contribute to the worldwide experience (iv) no response. Improvement in cell counts and in the off-label use of this drug. remission was documented for ITP and thrombotic thrombocytopenic purpura patients. Patients were evaluated for a follow-up period of two years. Data PATIENTS AND METHODS analysis was performed using the PASW Statistics version 18.0 for Windows software program In this retrospective study, pharmacy records at (SPSS Inc., Chicago, IL, USA). On the other the American University of Beirut Medical Center hand, frequencies were extracted using descriptive were evaluated for rituximab use over the past statistics, while means were compared using the 4.5 years (January, 2006 - May, 2010). A total paired sample T test. A P-value less than or equal to of 44 patients received rituximab for off-label 0.05 was considered statistically significant. conditions during the period were evaluated. All patients were of Caucasian origin (34 females versus 10 males), and were enrolled depending RESULTS on whether there was treatment failure after conventional regimens and/or treatment side The mean age at diagnosis was 36.4±19.8 effects. Patients whose medical charts were noted years, and the mean age at study enrollment was in the pharmacy database and were reviewed 44.5±19.1 years. The mean chronicity of the in the medical records of the hospital (in- and disease is 7.4±6.4 years. Seventeen patients had out- patient) and the department, SLE. Patients with other inflammatory diseases and those who received rituximab as an off- were also reported in decreasing frequency label use for an inflammatory disorder, were as follows: ITP (n=8), APS (n=5), Sjögren's then enrolled in the study. The disorders include syndrome (n=5), polymyositis (n=4), Wegener’s SLE, antiphospholipid syndrome (APS), Sjögren's granulomatosis (n=3), autoimmune hemolytic syndrome, systemic sclerosis (SSc), Still’s disease, anemia (AIHA) (n=2), (n=2), Still’s AAV, Behçet’s disease, , disease (n=1), dermatomyositis (n=1), pemphigus poly/dermato-myositis, scleroderma, as well vulgaris (n=1), bullous (n=1), as pemphigus vulgaris, , ankylosing spondylitis (n=1), polyarteritis nodosa 196 Arch Rheumatol Steroid steroid, Steroid, NSAIDs azathioprin, Antimalarials Antimalarials Antimalarials Methotrexate Methotrexate Azathioprine, Antimalarials, Antimalarials, Antimalarials, Antimalarials, aspirin, steroid Medications used Steroid, NSAIDs Steroid, NSAIDs steroid, infliximab, steroid, Azathioprine, steroid Steroid, methotrexate Antimalarials, steroid, Antimalarials, NSAIDs NSAIDs, methotrexate mycophenolate mofetil mycophenolate Mycophenolate mofetil Mycophenolate Mycophenolate mofetil

– ANA ANA ANA Scl70 markers Anti-SSA Anti-DNA (IgG, IgM) anti-smith, 2GP1, Anti-RNP2GP1, ANA, Scl70 RF, c-ANCARF, b anticardiolipin Anticardiolipin Anticardiolipin anticardiolipin, ANA, Anti-SSA ANA, Anti-DNA ANA, Anti-DNA ANA, Anti-DNA, ANA, Anti-DNA, Positive laboratory ANA, Anti-SSA, RF Anti- lupus anticoagulant, RF Anticardiolipin (IgG, IgM)

Arthralgia splenomegaly myalgia, AIHA leucopenia, anemia Malar rash, epilepsy, small vessel vasculitis Clinical manifestations Skin ulcer, telangiectasia diarrhea, ascites, sinusitis eye dryness, loss of vision nephritic syndrome, anemia muscle weakness, Raynauld’s weakness, muscle Telegiectasia, cardiomyopathy, Headache, interstitial lung disease, microangiopathic hemolytic, anemia pleural effusion, nephritic syndrome, eye dryness, Raynaud’s phenomenon, CVA, swelling, xerostomia, arthralgia, Livedo reticularis, malar rash, swelling, Alopecia, swelling, pericardial effusion, myositis, myalgia, osteoporosis, raynauld’s pericarditis, muscle weakness, osteopenia, renal failure, arthralgia, thrombocytopenia, Sclerodactyly, telangiectasia, skin thickness, muscle weakness, morning stiffness, vertigo, Malar rash, headache, arthralgia, polyarthritis, arthralgia, myalgia, morning stiffness, anemia, Swelling, arthralgia, myalgia, muscle weakness Malar rash, psychotic disorder, cardiomyopathy, Photosensitivity, malar rash, swelling, headache, nephritic syndrome, arthralgia, thrombocytopenia, Xerostomia, Parotid swelling, Myalgia, Eye dryness Photosensitivity, alopecia, malar rash, skin dryness, discoid rash, headache, arthralgia, muscle weakness,

SLe SLE SLE SLE SLE Diagnosis SLE, APS SLE, APS SLE, APS Polymyositis Polymyositis Sjögren's syndrome Sjögren's syndrome Polymyositis, scleroderma Polymyositis, scleroderma Wegener’s granulomatosisWegener’s

F F F F F F F F F F F F F M M Sex

- - - 14 10 76 13 21 15 24 26 55 46 34 34 Age at diagnosis

- - - 17 14 19 18 57 39 26 29 35 80 56 40 Age at protocol Summary diagnosis, patient’s of clinical manifestations, pertinent laboratory markers, and previous medications used 1 2 3 4 5 6 7 8 9 14 11 10 13 15 12 able 1. Patient number T NSAIDs Off-label Use of Rituximab 197 IVIG, steroid, steroid, Steroid, Steroid, steroid, steroid, steroid, NSAIDs NSAIDs NSAIDs NSAIDs NSAIDs NSAIDs, steroids, NSAIDs, NSAIDs, infliximab, infliximab, Infliximab, azathioprin, azathioprine, Methotrexate sulfasalazine Antimalarials, Antimalarials, methotrexate, methotrexate, Antimalarials, azathioprine, azathioprine, azathioprine, methotrexate Antimalarials, Antimalarials, Antimalarials, Antimalarials, cyclophosphide, Medications used cyclophosphamide, cyclophosphamide, mycophenolate mofetil mycophenolate mycophenolate mofetil mycophenolate

– RF ANA ANA, ANA, markers Anti-SSA anti-RNP Anti-DNA ANA, RF anti-SSA, anti-SSA, anti-smith anti-DNA, anti-smith, ANA, c-ANCA ANA, p-ANCA ANA, anti-DNA, Positive laboratory lupus anticoagulant, anticardiolopin (IgM)

eye dryness muscle weakness Clinical manifestations anemia, splenomegaly arthralgia, polyarthritis, arthralgia, Arthralgia, Morning stiffness Rheumatoid nodules, xerostomia, Malar rash, discoid rash, pleuritis, Demyelinated syndrome, arrhythmia, arthralgia, myalgia, morning stiffness, arthralgia, Raynauld’s phenomenon Alopecia, headache, cerebral venous gastrointestinal hypomotility, arthralgia, arthralgia, hypomotility, gastrointestinal Sinusitis, saddle nose deformity, anemia Photosensitivity, malar rash, headache, Photosensitivity, alopecia, discoid rash, gastrointestinal bleed, muscle weakness, Alopecia, malar rash, urticaria, skin dryness, leucopenia, anemia, phenomenon Raynauld’s steroid induced diabetes mellitus, arthralgia, Rheumatoid nodule, ulnar deviation, arthralgia, morning stiffness, myalgia, leukopenia, DVT muscle weakness, morning stiffness, osteopenia, TMJ involvement, osteoporosis, keratitis, anemia osteoporosis, TMJ involvement, morning stiffness, myalgia, thrombocytopenia, interstitial lung disease, arthralgia, polyarthritis, Cerebral vasculitis, nephritic syndrome, polyarthritis, polyarthritis, morning stiffness, osteoporosis, anemia osteoporosis, stiffness, morning polyarthritis, subdural hematoma, valvular heart disease, migraine, migraine, disease, heart valvular hematoma, subdural pleural effusion, nephritic syndrome, renal failure, arryhthmia, nephritic syndrome, oral , arthralgia, sinus thrombosis, cognitive disorder, pericardial effusion,

SLE SLE SLE SLE SLE SLE, Diagnosis SLE, APS Still’s disease Sjögren's syndrome Bullous pemphigoid Ankylosing spondylitis Wegner’s GranulomatosisWegner’s

F F F F F F F F F M M Sex

– 41 49 69 69 39 36 19 19 18 25 33 Age at diagnosis

– 42 53 46 84 44 26 30 38 40 48 Age at protocol Continued 17 16 19 18 21 20 22 24 26 23 25 able 1. Patient number T 198 Arch Rheumatol IVIG Steroid Steroid Steroid Steroid Steroid Steroid, Steroid, NSAIDs cyclosporin, Steroid, IVIG Steroid, IVIG plasmapheresis, steroid, NSAIDs Medications used Steroid, NSAIDs Anti-coagulation, Steroids, NSAIDs cyclophosphamide, Steroid, leflunomide Azathioprine, steroid aspirin, azathioprine, Azathioprine, steroid, Antimalarials, steroid, Steroids, azathioprine, methotrexate, NSAIDs Mycophenolate mofetil

– – – – – – – – – – ANA ANA ANA ANA, markers (IgG, IgM) (IgG, anti-DNA, Anti-B2GP1 ANA, Anti-SSA Positive laboratory lupus anticoagulantlupus anticardiolipin (IgG, IgM) (IgG, anticardiolipin Anticardiolipin (IgG, IgM)

Epistaxis Arthralgia Osteoporosis anemia, DVT Leukemia, anemia Thrombocytopenia Thrombocytopenia Thrombocytopenia AIHA, splenomegaly Clinical manifestations thrombocytopenia, splenomegaly Osteoporosis, thrombocytopenia, lower extremity arterial thrombosis arthralgia, muscle weakness, eye dryness epistaxis, thrombocytopenia, leukopenia, thrombocytopenia, epistaxis, Photosensitivity, myocarditis, arrhythmia, CVA, headache, epilepsy, diffuse alveolar Oral candidiasis, arthralgia, splenomegaly hemorrhage, pleuralhemorrhage, effusion, hemoptysis, Headache, hemoptysis, arthralgia, myalgia, Osteoporosis, epistaxis, thrombocytopenia, Epistaxis, thrombocytopenia, splenomegaly Morning stiffness, osteoporosis, eye dryness anemia, splenomegaly, Raynauld’s phenomenon microangiopathic hemolytic anemia, splenomegaly Malar rash, nephritic syndrome, arthralgia, anemia Skin ulcer, livedo reticularis, mononeuritis multiplex, TMJ involvement, myalgia, osteoporosis, eye dryness, Headache, acute ischemic encephalopathy, xerostomia, carpel tunnel syndrome, arthralgia, Raynauld’s phenomenon, Steroid induced DM, dysphagia, arthralgia, muscle weakness,

ITP ITP ITP ITP ITP ITP ITP ITP SLE AIHA AIHA Diagnosis SLE, APS Dermatomyositis Sickle cell disease Sjögren's syndrome Sjögren's syndrome Polyarteritis nodosa Wegener’s granulomatosisWegener’s

F F F F F F F F F F F F M M M M M M Sex

– 7 51 74 67 15 79 39 26 29 29 20 25 63 35 46 34 64 Age at diagnosis

2 glycoprotein1;Anti-RNP: Anti-ribonucleoprotein antibody;SLE: Systemic lupus erythematosus; APS:Antiphospholipid syndrome; AIHA: Autoimmune hemolytic anemia; p-ANCA: Peripheral – b 75 49 21 69 69 37 37 32 32 39 55 43 35 35 68 86 40 Age at protocol 2GP1: Anti- 2GP1: Continued b 41 31 37 42 32 39 27 29 43 28 33 35 30 38 44 able 1. Patient number T 34 36 40 ANA: Antinuclear ; Scl70: Anti-topoisomerase I; NSAIDs: Non-steroidal Anti- anti-inflammatoryfactor; drugs; CVA: Cerebrovascular accident; c-ANCA: Cytoplasmic antineutrophilantineutrophil cytoplasmic cytoplasmic antibodies; antibodies; RF: Rheumatoid TMJ: Temporomandibular joint; IVIG: Intravenous immunoglobulin; Deep DVT: vein thrombosis; ITP: Idiopathic thrombocytopenic purpura. Off-label Use of Rituximab 199

(n=1), and sickle cell disease (n=1). The diagnoses, complete remission, 12 patients required only clinical manifestations, previous treatments and 1 cycle of the drug, while 14 patients required outcome are summarized in Table 1. Previous a second or a third cycle for maintenance of treatment modalities were documented; and the remission every six to eight months. Figure 2 most widely used drugs were shows the number of cycles required to achieve in 39 patients, non-steroidal anti-inflammatory remission. Patients receiving steroids as initial drugs (NSAIDs) in 23 patients, anti-malarial drugs treatment for autoimmune and inflammatory (n=17), azathioprine (n=15) and methotrexate processes were followed-up clinically and the dose (n=14). Other regimens such as mycophenolate of steroid was tapered over 8 to 12 weeks. Table 2 (n=7), cyclophosphamide (n=6), cyclosporine, provides a summary of the response to rituximab infliximab (n=5), and IVIG (n=5) were also used, for each disease reported, while Figure 3 shows but to a lesser extent. the response rate in selected diseases. The most The use of rituximab in the above reported common autoimmune disease for which rituximab cases was off-label, thus there was no consensus was used in this series was SLE. Of the 17 patients as to the dosing and number of cycles needed to with SLE included in this study, 13 patients had attain a cure. The most commonly used protocol complete response without relapse, two patients was either a 500 mg weekly dose for four weeks had partial response whereas one patient had no or two doses only of 1000 mg for every other response. Of these patients, only one patient died week. The number of cycles administered was during follow-up. decided by the treating physician depending on The efficacy of rituximab use as an off-label the clinical and laboratory response to treatment treatment of hematologic diseases was separately by the patients. Twenty-two patients received studied. The number of patients receiving 1 cycle, 10 patients received 2 cycles, whereas rituximab for hematologic causes was 11, eight eight patients received a third cycle. of whom were diagnosed with ITP. It was crucial The efficacy of rituximab was retrospectively to compare the level of platelet count before and assessed according to improvement of clinical after rituximab therapy among patients with ITP, signs and symptoms of patients. Of all the patients in order to check for treatment response. The found to be treated with rituximab, 38 patients data revealed that the mean change in platelet documented response to treatment. The degree count among the eight patients was significantly of response was divided into complete response important with an increase from 46 thousands without relapse, complete response with relapse, before rituximab treatment to 184 thousands partial response or no response. Twenty-nine after rituximab treatment, and a p-value of patients had complete response without relapse, 0.012. The apparently significant increase in three patients had relapse, while four patients platelet count indicates response to therapy and had partial response (Figure 1). Out of 44 cases, a possibly disease remission. The remission rate only two patients had no response. To achieve in ITP was 67% (four out of six patients).

80 45 76 70 40 41 60 35 50 30 28 % 40 25 30 % 20 21 20 15 10 11 10 5 8 0 5 7 No response Complete response with relapse 3 0 Partial response Complete response without relapse 1 Cycle 2 Cycle 3 Cycle 4 Cycle 6 Cycle Figure 1. Summary of rate of response Figure 2. Number of cycles to achieve remission. 200 Arch Rheumatol

Table 2. Number of cycles used with corresponding level of response

Number of patients Degree of response No response Partial response Complete response with relapse Complete response without relapse Number of cycles 1 2 2 1 12 2 0 1 1 8 3 0 1 1 6 4 0 0 0 2 6 0 0 0 1 Total number of patients 2 4 3 29

Skin infusion reactions were the most common of observational studies and case reports. The side effects reported, which were observed in almost total lack of randomized clinical trials may six out of 44 patients. The other patients did be explained by the low prevalence of systemic not have any reportable side effects of the autoimmune diseases, their diverse clinical medication. No serious hematological, renal, or presentation, and the absence of consensual hepatic toxicities were documented in our treated endpoints to be evaluated in each disease. This cohort. poses multiple questions on when and how to use these agents, since there are no current recommendations or guidelines on their use in DISCUSSION such circumstances.8 In the past decades, therapeutic approaches to B cells play important roles in the pathogenesis systemic autoimmune and inflammatory diseases of autoimmune diseases such as rheumatoid have been based on the use of glucocorticosteroids arthritis, SLE, and Sjögren's syndrome. They and immunosuppressive agents. Available data exert their pathogenic effect by producing on the use of biological agents in patients with autoantibodies which target self antigens and these conditions rely mainly on a large number 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 14 follicular B-helper T cells, among many other

12 functions. It is important to note that all these effects are independent of antibody secretion, 10 but are mediated instead through antigen- presentation, co-stimulation and production of 8 proinflammatory cytokines. Hence, one would expect that the elimination of B cells by blocking 6 CD20, the molecular target of rituximab, should be of therapeutic benefit in SLE.9 Number of patients 4 There was a predominance of females 2 over males in the population studied, which is expected, given the fact that a large number 0 of autoimmune diseases are more prevalent in ITP SLE Sjögren’s Polymyositis 10 syndrome women. Moreover, studies have shown that the No response Complete response with relapse more frequent the autoimmune disease and the Partial response Complete response without relapse later it appears, the more women are affected.11 Figure 3. Degree of response for selected diseases. ITP: Idiopathic thrombocytopenic purpura; SLE: Systemic lupus In this study, the indication for starting erythematosus. rituximab therapy was either treatment failure Off-label Use of Rituximab 201 after conventional regimens or treatment side activity. The British Isles Lupus Assessment effects. As expected, the preceding therapy for Group (BILAG) index score is a transitional index almost all patients with the diseases included in developed for the intention-to-treat analysis, and this study consisted of glucocorticosteroids (88%), may not be perfect for use in regular clinical NSAIDs (51%), and immunosuppressants (67%). practice. Since no solid guidelines and recommendations The statistically significant increase in platelet are available for the rituximab dosing protocol, the count in patients with ITP after receiving rituximab number of cycles administered was decided by the therapy also emphasizes its therapeutic efficacy in treating physician depending on the clinical and hematological diseases. Similar results were found laboratory response to treatment by the patients. in a study conducted by Dierickx et al.14 in 2009. The most commonly used protocol was either They showed that the overall response rates were repeated cycles of a 500 mg weekly dose for four 79.2% in AIHA and 70% in ITP, with a median weeks or 1000 mg every two weeks whereby each cycle consisted of two doses. It was considerably follow-up since the first rituximab administration promising that 84% of the patients showed was 15 month in AIHA and 11 months in ITP. clinical improvement after receiving rituximab, Progression-free survival at one and two years with 67% showing complete remission and 29% were respectively 72% and 56% in AIHA, and requiring only 1 cycle. 70% and 44% in ITP. Systemic lupus erythematosus was the Concerning the safety profile of rituximab, this autoimmune disease with the highest reported use study showed no statistically significant change in of rituximab in this study (17/44 patients, 38.6%). liver, kidney or bone marrow laboratory markers Although Merrill et al.12 showed no difference before and after treatment. The most common in primary or secondary end points between side effects observed were benign and consisted placebo and rituximab treatment over 52 weeks of mainly of infusion reactions. This safety profile treatment in patients with moderate-to severe SLE has been highlighted in many other studies. in the EXPLORER trial, other studies have shown Ceccarelli’s safety study on SLE found adverse more promising results. Ramos-Casals et al.8 in event rates comparable to the placebo, with 2008 showed that the best results were observed the only differences being leukopenia (12.3% in the use of rituximab for Sjögren's syndrome, vs. 4.2%), neutropenia (5.5% vs. 1.4%) and SLE, and cryoglobulinemia. A recent review hypotension (11% vs. 4.2%).15 Medeot et al.,16 on suggested that rituximab induces B-cell depletion the other hand, ascertained a rituximab safety in 95% of patients, and a significant reduction in profile in patients with refractory ITP. They found disease activity is achieved with a relatively good that rituximab administration was associated with safety profile in patients with SLE7 However, two episodes of short-term toxicity, namely a there is always a difficulty in assessing the status mild infusion reaction and a case of serum of SLE patients and response rate in any research, sickness syndrome, which improved rapidly with given the heterogeneity of the disease. Hence, steroids; no infectious or other significant long- grouping patients according to types of organ term complications were documented. systems affected in SLE shows that some have To conclude based on our study results, the better response rates to rituximab than others, for off-label use of rituximab carries a promising example, cutaneous lesions/discoid lupus shows cure for debilitating and relapsing autoimmune less improvement than neuropsychiatric or renal, and inflammatory disorders with a relatively good and multi-system diseases are more responsive safety profile. However, the fact that we still have 13 than single organ diseases. conflicting results from various observational However, the encouraging results contrast studies, reviews and case reports, dictates the with the poor outcome reported from the two necessity for large randomized control trials on randomized clinical trials (the Explorer and the the efficacy and safety of rituximab therapy in Lunar) which tested the efficacy of rituximab in various autoimmune and inflammatory diseases. SLE. The contradictory findings can be attributed This is crucial to set forth solid and reliable to several reasons including patient selection. The guidelines and recommendations for the dosing of next issue is the method used to assess clinical rituximab and its prescription protocol. 202 Arch Rheumatol

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