Medical Policy


Subject: Rituximab (Rituxan®) for Non-Oncologic Indications
Document #: DRUG.00041 Publish Date:    05/18/2017
Status: Revised Last Review Date:    05/04/2017


This document addresses the U.S. Food and Drug Administration (FDA) approved and off-label non-oncologic indications for use of Rituximab (Rituxan® , Genentech, Inc., South San Francisco, CA), a genetically engineered monoclonal antibody that targets a specific protein, known as CD20 found on the surface of normal and malignant B-lymphocytes. 

Note: This document does not address any FDA approved oncologic indications or off-label oncologic uses of rituximab (including conditions such as multicentric Castleman disease [MCD] and post-transplant lymphoproliferative disease [PTLD]).

Note: Please see the following related documents for additional information:

Position Statement

Medically Necessary:

  1. Rheumatoid Arthritis
    Rituximab is considered medically necessary when all of the following are met:
    1. Individual is 18 years of age or older with moderately to severely active rheumatoid arthritis; and
    2. Rituximab is given in combination with methotrexate unless intolerant of or has a medical contraindication; and
    3. Individual had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies, or has a medical contraindication to TNF antagonist therapy.
  2. Wegener's Granulomatosis and Microscopic Polyangiitis
    Rituximab, in combination with glucocorticoids, is considered medically necessary for the treatment of individuals with Wegener's granulomatosis and microscopic polyangiitis.
  3. Other Indications
    Rituximab is considered medically necessary for the treatment of any of the following conditions:
    1. Acquired inhibitors in individuals with hemophilia who fail cyclophosphamide and prednisone therapy; or
    2. Autoimmune hemolytic anemia, refractory; or
    3. Cryoglobulinemia, primary Sjögren Syndrome, or systemic lupus erythematosus refractory to standard therapy (that is, lack of response to corticosteroids and at least 2 immunosuppressive agents); or
    4. Graft-Versus-Host Disease as third-line of therapy or greater; or
    5. Hepatitis C virus infection-related cryoglobulinemic vasculitis in conjunction with intravenous methylprednisolone, and concomitant antiviral therapy for individuals with any of the following:
      1. Nephrotic proteinuria; or
      2. Evidence of rapidly progressive kidney disease; or
      3. Uncontrolled nephrotic syndrome; or
      4. Acute flare of cryoglobulinemia; or
    6. Immunoglobulin G4-related disease when any of the following are met:
      1. Failure to respond to prednisone or other corticosteroid agents; or
      2. Unable to tolerate tapering of prednisone or other corticosteroid agents; or
      3. Has a medical contraindication to prednisone or other corticosteroid agents; or
    7. Multiple sclerosis when both of the following are met:
      1. Individual has a relapsing-remitting form of multiple sclerosis; and
      2. Has had an inadequate response to, or is unable to tolerate, or has a medical contraindication to at least two alternative drug therapies indicated for the treatment of multiple sclerosis; or
    8. Neuromyelitis optica; or
    9. Pediatric nephrotic syndrome when all of the following are met:
      1. Individual 18 years of age or younger; and
      2. Has steroid-dependent, relapsing disease; and
      3. Has an inadequate response to, is intolerant of, or has a medical contraindication to corticosteroid or immunosuppressive drug therapy (such as, cyclosporine, cyclophosphamide, or mycophenolate mofetil); or
    10. Pemphigus vulgaris and other autoimmune blistering skin diseases (for example, pemphigus foliaceus, bullous pemphigoid, cicatricial pemphigoid, epidermolysis bullosa acquisita and paraneoplastic pemphigus) when refractory; or
    11. Renal transplant setting for either of the following indications:
      1. Pre-transplant to suppress panel reactive anti-human leukocyte antigens (HLA) antibodies in individuals with high panel reactive antibody (PRA) levels to HLAs; or
      2. Post-transplant in individuals with acute rejection who had received rituximab treatment pre-transplant; or
    12. Thrombocytopenic purpura, immune or idiopathic; or
    13. Thrombotic thrombocytopenic purpura (TTP), refractory or relapsing disease (that is, lack of response to plasma exchange therapy and glucocorticoids) in an individual who meets the diagnostic criteria for TTP (that is, TTP is confirmed by severely reduced baseline activity of ADAMTS 13 (less than 5%), with or without the presence of an ADAMTS 13 inhibitor in the appropriate clinical setting).

Investigational and Not Medically Necessary:

Use of rituximab is considered investigational and not medically necessary when the above criteria are not met, and for all other non-oncologic indications, including but not limited to:


Rituximab is a chimeric monoclonal antibody that targets the CD20 antigen located on the cell surface of malignant and normal B-lymphocytes. Rituximab rapidly depletes circulating and tissue-based B-cells, and demonstrates a prolonged effect on cell depletion.

Rituximab is FDA approved for the treatment of individuals with any of the following oncologic indications (Rituxan Product Information [PI] Label, 2014). Note: Use of rituximab for these oncologic indications is not addressed in this document:

FDA approved non-oncologic indications for rituximab that are addressed in this document:

Rheumatoid Arthritis

In 2006, the FDA approved the use of rituximab in combination with methotrexate in the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies. The PI label for rituximab (Rituxan, 2014) states there is limited available safety data on the use of biologic agents or disease modifying antirheumatic drugs (DMARDs) other than methotrexate following rituximab treatment in individuals with rheumatoid arthritis. A favorable risk-benefit relationship was not established to utilize rituximab in individuals with inadequate responses to non-biologic DMARDs and those who are methotrexate-naïve. Therefore, the PI label did not recommend use of rituximab if the individual with rheumatoid arthritis has not had prior inadequate response to one or more TNF antagonists.

Porter and colleagues (2016) conducted an open-label, randomised controlled, non-inferiority trial (ORBIT; NCT01021735) that directly compared the safety and effectiveness of rituximab to TNF antagonist treatment in individuals with active rheumatoid arthritis despite non-biologic DMARD treatment. A total of 295 adults (> 18 years) who met the American College of Rheumatology (ACR) classification criteria for a diagnosis of active rheumatoid arthritis (that is, disease activity score [DAS] 28 as measured by erythrocyte sedimentation rate [ESR] [DAS28-ESR] of more than 5.1) despite failure to respond to at least two non-biologic DMARDS, including methotrexate, but were not previously treated with a biologic DMARD, were randomized 1:1 to rituximab (n=144) or TNF antagonist treatment (n=151). Subjects were administered intravenous rituximab 1 gram on days 1 and 15, and after 26 weeks if they responded to treatment but had persistent disease activity (that is, DAS28-ESR > 3.2, rituximab group) or a TNF antagonist, either adalimumab (40 mg subcutaneously, every other week) or etanercept (50 mg subcutaneously, weekly) according to the subjects and rheumatologist's choice (TNF antagonist group). Subjects could switch treatment (that is, rituximab to TNF antagonist or TNF antagonist to rituximab) if they experienced drug-related toxic effects, inadequate response or loss of response. Concomitant treatment with stable doses of oral corticosteroids was allowed in addition to changes in conventional drugs and doses of nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and non-biologic DMARDs.

The primary outcome measure was change in DAS28-ESR between 0 and 12 months in the per-protocol population of subjects who were assigned to treatment and followed up for 1 year. The non-inferiority margin was specified as 0.6 DAS28-ESR units. Subject's disease activity was accessed every month for 1 year. After 6 and 12 months, there were no significant differences in the proportion of subjects achieving ACR20, ACR50, ACR70, DAS28-ESR remission, good response, moderate response, or non-response. After 12 months of treatment, the change in DAS28-ESR (in the per-protocol analysis) for rituximab-treated subjects (n=134) was -2.6 (standard deviation [SD] 1.4) and -2.4 (SD 1.5) in the TNF antagonist-treated group (n=135), with a difference within the prespecified non-inferiority margin of -0.19 (95% confidence interval [CI], -0.51-0.13; p=0.24). More subjects in the TNF antagonist-treated group switched treatment to rituximab (49 of 151, 32%) than rituximab-treated subjects who switched to TNF antagonist treatment (28 of 144, 19%) (p=0.008). The investigators reported the only notable difference between the treatment strategies was that a higher proportion of subjects continued on initial rituximab treatment without the need to switch treatment compared with subjects randomly assigned to TNF antagonist treatment (81% persistence on a TNF antagonist; p=0.008). The primary reason for switching treatments was lack of efficacy (n=45 TNF antagonist-treated subjects vs. n=25 rituximab-treated subjects).

In the final analysis, 137 of 144 (95%) rituximab-treated subjects and 143 of 151 (95%) TNF antagonist-treated subjects experienced adverse events. A total of 37 and 26 adverse events occurred in the rituximab-treated subjects compared to TNF-treated subjects, respectively. Serious adverse events were reported in 15 subjects and 12 subjects in the rituximab-treated group and TNF antagonist-treated group, respectively, and were considered "possibly, probably, or definitely" treatment-related. The most frequently occurring serious adverse event in both groups was infections (n=8, rituximab subjects vs. n=5, TNF antagonist group). No cases of progressive multifocal encephalopathy or demyelination occurred during the study. Limitations of this study include the open-label design, lack of radiographic outcomes, subjects were eligible for the study even though they were intolerant of methotrexate (rituximab is only approved for use in combination with methotrexate) and the 12-month follow-up period is insufficient to provide a comparative description of either strategy's long-term efficacy or safety. Additional comparative studies of randomized controlled design are needed to determine the long-term safety and efficacy of off-label use of rituximab in biologic DMARD-naïve individuals with rheumatoid arthritis.

Other Considerations

In 2015, the ACR updated treatment recommendations for rheumatoid arthritis (Singh, 2015) including guidance on DMARDS, biologic agents (including rituximab), tofacitinib, and glucocorticoids in established and early RA. Recommendations were issued on using a "treat-to-target approach," discontinuing and tapering medications, and the use of DMARDS and biologic agents for individuals with high-risk comorbidities such as serious infections, hepatitis, congestive heart failure, and malignancy. The ACR stated that their "treatment recommendations apply to common clinical situations, since the panel considered issues common to most patients, not exceptions." Concerning the potential use of rituximab (a non-TNF biologic) for early disease (defined as < 6 months, disease activity moderate or high despite monotherapy with a DMARD), the ACR recommends use of combination DMARDs or use of a TNF inhibitor (antagonist) or a non-TNF inhibitor biologic (all options are with or without methotrexate and given in no preference order) rather than continuing monotherapy with a DMARD (Recommendation: strong; Level of evidence: low). For established disease (defined as > 6 months), if the disease activity remains moderate or high despite monotherapy with a DMARD, the recommendation is to use combination traditional DMARDs or add a TNF inhibitor or a non-TNF inhibitor biologic (all options are with or without methotrexate and given in no preference order) rather than continuing monotherapy with a DMARD (Recommendation: strong; Level of evidence: moderate to very low).

Wegener's Granulomatosis and Microscopic Polyangiitis

Wegener's granulomatosis disorder and microscopic polyangiitis are subgroups of primary systemic small vessel vasculitis associated with ANCA (antineutrophil cytoplasmic antibodies), also known as ANCA-associated vasculitis (AAV). AAV causes blood vessels to become inflamed or swollen and as a result, blood flow is restricted. The respiratory tract and kidneys are frequently the primary targets (Keogh, 2006). In early 2011, the recommendation was made by several specialty societies to change the name of Wegener's granulomatosis to granulomatosis with polyangiitis (Falk, 2011). Wegener's granulomatosis is a rare, and rapidly progressive, immune mediated disorder that is typically treated with glucocorticosteroids and cytotoxic agents. However, relapsing disease and long-term toxicities as a result of standard therapies continue to pose challenges. Activated B-lymphocytes have been correlated with disease activity and response to therapies (Stone, 2010).

In April 2011, the FDA approved the combination of rituximab and glucocorticoids as a treatment for adults with Wegener's granulomatosis and microscopic polyangiitis. Use of concomitant immunosuppressants other than corticosteroids has not been studied in individuals with granulomatosis with polyangiitis or microscopic polyangiitis exhibiting peripheral B-cell depletion following treatment with rituximab (Rituxan PI Label, 2014).

The pivotal randomized clinical trial, Rituximab for ANCA-Associated Vasculitis (RAVE), was a double-blind, double-dummy, noninferiority trial that enrolled 197 ANCA-positive individuals with Wegener's granulomatosis or microscopic polyangiitis (Stone, 2010). For remission induction, participants received rituximab 375 mg/m2 per week for 4 weeks and placebo-cyclophosphamide in the treatment group. The control group received standard therapy with cyclophosphamide 2mg/kg per day plus placebo-rituximab infusions. Individuals in the treatment group who achieved remission between 3 and 6 months were switched from placebo-cyclophosphamide to placebo-azathioprine. Participants in the control group who had a remission between 3 and 6 months were switched from cyclophosphamide to azathioprine. Both groups received glucocorticoid treatment of 1 to 3 pulses of 1000 mg methylprednisolone followed by prednisone 1 mg/kg/day. The dose was tapered by 5 months to have glucocorticoids discontinued for individuals who were in remission. Primary endpoints were Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) of 0 and successful prednisone taper at 6 months. There were 99 individuals randomized to the rituximab group, and 98 assigned to the control group. In each group, approximately 49% of the participants were newly diagnosed. Mean BVAS/WG entry scores were 8.5 ± 3.2 in the treatment group and 8.2 ± 3.2 in the control group. Completion of 6 months of treatment without early treatment failure was achieved in 84 individuals in the rituximab group (85%) and 81 participants in the control group (83%). The primary endpoint was reached in 64% of the treatment group and 53% of the control group, which met the criterion for noninferiority (p<0.001). In a subset analysis, 34 of 51 individuals with relapsing disease at baseline and treated with rituximab had reached the primary endpoint (67%) compared to 21 of 50 participants (42%, p=0.01) in the control group. Adverse events occurred in 33 participants in the control group (33%) compared to 22 individuals in the rituximab group (22%). Stone and colleagues (2010) concluded treatment with rituximab and glucocorticoids was not inferior to the standard regimen of cyclophosphamide and glucocorticoids for remission induction in severe relapsing ANCA-associated vasculitis.

Specks and colleagues (2013) provided updated data for the RAVE trial. The primary outcome was complete remission of disease by 6 months with remission maintained at 18 months. A total of 64% of individuals treated with rituximab had achieved complete response at 6 months, with complete response maintained at 12 months and 18 months (48% and 39%, respectively). The control group had corresponding rates of complete response at 6, 12 and 18 months (53%, 39%, and 33%, respectively). There was no significant difference in mean duration of complete response between the treatment groups (p=0.76). The authors noted the criterion for noninferiority was met (p<0.001), but the criterion for superiority was not. At 18 months, there were no significant differences between the treatment groups in the number or rates of total adverse events, serious adverse events or non-disease related adverse events. There were two deaths in each group. The authors noted additional study is needed to determine "whether conventional remission-maintenance therapy or repeated B-cell depletion with rituximab is more effective in preventing relapses after initial induction of remission with rituximab."

Other Off-Label Non-Oncologic Indications for Use of Rituximab

Based on the results from published data, rituximab is used to treat other non-oncologic indications that are not currently approved by the FDA.

Acquired Inhibitors in Hemophilia

A rare condition of acquired inhibitors in individuals with hemophilia may occur and could cause life-threatening bleeding. Replacement factors are used as prophylaxis and treatment of bleeding episodes in hemophiliacs. The development of high titers of inhibitors resulting from antibodies to the replacement factor is a serious complication and decreases the efficacy of hemophilia therapy. Due to the low incidence rate of acquired inhibitors, published data consists of case reports, case series and reviews (Collins, 2009; Kruse-Jarres, 2011; Sperr, 2007; Wiestner, 2002). Treatment typically involves immune tolerance and/or depletion of inhibitors with immune suppression with prednisone and cyclophosphamide (Kruse-Jarres, 2011; Sperr, 2007). For those individuals without a sufficient reduction in inhibitors with standard immunosuppression with cyclophosphamide and prednisone, rituximab therapy has resulted in a complete response rate of inhibitor reduction of 77% (Sperr, 2007). Published data demonstrate the use of rituximab, after failure of cyclophosphamide, and prednisone immunosuppression can reduce acquired inhibitors and allow therapeutic results from factor replacement in hemophiliacs (Collins, 2009; Kruse-Jarres, 2011; Sperr, 2007; Wiestner, 2002). Additionally, specialty consensus endorses the use of rituximab to treat individuals with acquired inhibitors who have failed cyclophosphamide and prednisone treatment.

Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia is typically idiopathic or secondary to another diagnosis, and involves the production of autoantibodies and the hemolysis of red blood cells. Autoimmune hemolytic anemia is an uncommon condition with cases classified as warm autoimmune hemolytic anemia or cold agglutinin disease. Treatment of autoimmune hemolytic anemia depends on this classification and typically includes corticosteroids, immunosuppressants, immunoglobulin and splenectomy. Rituximab, as an alternative treatment for refractory autoimmune hemolytic anemia, is limited to small retrospective case series, case reports and uncontrolled trials. Further investigation is ongoing to determine whether rituximab achieves durable, effective, long-term results to improve overall health outcomes. Specialty consensus opinion recommends the use of rituximab for treatment of this condition.

Cryoglobulinemia, Primary Sjögren Syndrome, and Systemic Lupus Erythematosus

Rituximab has been increasingly used for a variety of systemic autoimmune diseases. In a systematic review of the published literature, Ramos-Casals and colleagues (2008) noted, due to the lack of randomized controlled trials and the heterogeneity in clinical features in the systemic autoimmune disease population, definitive off-label recommendations for biologic agents were difficult to make. However, based on the therapeutic response of > 80% in individuals, the authors noted rituximab should be considered a first choice biologic agent for treatment for individuals with cryoglobulinemia, primary Sjögren syndrome and systemic lupus erythematosis who are refractory to standard therapy (lack of response to corticosteroids and at least two immunosuppressive agents). Immunosuppressive agents utilized for the treatment of Sjögren syndrome include cyclosporine, methotrexate, azathioprine, corticosteroids, hydroxychloroquine, d-penicillamine, thalidomide, and nucleoside analogues (Mavragani, 2007). In addition, specialty consensus opinion suggests the use of rituximab for treatment of these systemic autoimmune diseases.

Graft-Versus-Host Disease (GVHD)

GVHD may occur in transplant recipients as a result of a T-cell mediated reaction to antigens from a donated hematopoietic stem cell graft. Symptoms include anorexia, gastrointestinal symptoms, jaundice, skin rash or blisters, a dry mouth, or dry eyes. Treatment of GVHD includes steroids, calcineurin inhibitors, immunosuppressants, T-cell depleting agents and extracorporeal photopheresis. There has been published literature regarding various treatment and prophylaxis regimens for GVHD as well as varying response rates. However, individuals that are unresponsive or are refractory to corticosteroids and standard therapies have a poor prognosis and there is no standard treatment in this setting (Teshima, 2009). The published literature consists of retrospective, case series and uncontrolled trials studying the role of rituximab as a treatment for refractory GVHD.

Investigators hypothesize B-cells and other factors may have a role in GVHD (Cutler, 2006). Low-dose (50 mg/m2 ) rituximab was used to treat 13 individuals with steroid-refractory GVHD. An overall response rate of 69%, with 23% (3 individuals) achieving complete response, 15% partial response and 30% mixed response, was reported by von Bonin (2008). Two individuals developed complications due to infection, with one death. Teshima and colleagues (2009) reported results from a phase II trial of 7 individuals with refractory chronic GVHD (cGVHD) who were treated with weekly rituximab doses of 375 mg/m2 over 4 weeks. At 1 year follow-up, the overall response rate was 43% with partial response in 3 participants, stable disease in 3 individuals and 1 participant had progressive disease. The median reduction of steroids was 67%. At a median follow-up of 30 months, 5 participants were alive and 2 deaths from infection were noted. In a retrospective study by GITMO (Gruppo Italiano Trapianto Midollo Osseo; Zaja, 2007), 38 participants with refractory GVHD were treated with rituximab. The 2-year actuarial survival was 76% and the overall response rate was 65%. Steroid therapy was reduced by 82%. There were 8 deaths during the study period with 3 cases of progressive cGVHD, 1 relapsed disease, 3 cases of sepsis and 1 sudden death.

Kharfan-Dabaja and colleagues (2009) performed a review and meta-analysis of rituximab as a treatment for steroid-refractory cGVHD. From the published literature, six studies met inclusion criteria for review, of which three studies were prospective and three were retrospective studies. There were no randomized controlled trials. There were a total of 108 individuals in the six trials. The authors were unable to analyze the heterogeneity of the responses. The data suggest rituximab is effective in treating cutaneous cGVHD; however the response was not noted in other organs. The authors concluded the:

Evidence generated through this systematic review demonstrates the gaps in the existing evidence base related to the efficacy of rituximab in treating patients with steroid-refractory cGVHD. This underscores the need for well-designed and adequately powered prospective studies to conclusively address this issue.

The off-label use of rituximab as third-line treatment or greater for refractory GVHD is based on the data from uncontrolled trials and case series which demonstrated improvement in the condition and reduction of steroid use. Based on the data for refractory GVHD, the safety and efficacy of rituximab as a prophylaxis and as first-line therapy for GVHD are being studied.

Hepatitis C Virus Infection-Related Cryoglobulinemic Vasculitis

The hepatitis C viral infection can affect the kidneys with cryoglobulinemia being the most common diagnosis. Symptoms include proteinuria, microscopic hematuria, hypertension, and mild to moderate kidney impairment (Kidney Disease Improving Global Outcomes [KDIGO, 2012]). The sustained clearance of hepatitis C virus from the serum (that is, virologic response) is the best long-term prognostic indicator of hepatitis C virus- associated renal dysfunction. Therefore, continued therapy for the underlying hepatitis C virus infection is recommended in the KDIGO clinical practice guidelines for glomerulonephritis. The guidelines also recommend the use of rituximab for individuals with "HCV infection and mixed cryoglobulinemia (IgG/IgM) with nephrotic proteinuria or evidence of progressive kidney disease or an acute flare of cryoglobulinemia, in conjunction with intravenous methylprednisolone and concomitant antiviral therapy."

Immunoglobulin G4-related Disease (IgG4-RD)

IgG4-RD is a rare systemic immune-mediated fibroinflammatory lymphoproliferative disorder of unknown origin with findings consistent with both an autoimmune disorder and an allergic disorder. The condition is comprised of various disorders that share particular pathologic, serologic, and clinical features. The commonly shared features include a dense lymphoplasmacytic infiltrate enriched in IgG4-positive plasma cells, tumor-like swelling involving one or multiple organs, and a variable degree of fibrosis that has a characteristic "storiform" pattern, occurring in a synchronous or metachronous fashion. Elevated serum concentrations of IgG4 are found in approximately 60% to 70 % of individuals with IgG4-RD. The condition usually affects individuals of middle to upper age, with an onset of 50 to 70 years; although, rare pediatric cases have been reported. Organ manifestations of IgG4-RD include Type 1 autoimmune pancreatitis and sclerosing cholangitis, salivary gland disease (such as major salivary gland enlargement or sclerosing sialadenitis), orbital disease, and retroperitoneal fibrosis. While some individuals may present with single site involvement, others may have a few or many organs affected by IgG4-RD. In addition, some organs show a distinct involvement, such as lymphadenopathy, periaortitis, or a form of tubulointerstitial nephritis (Stone, 2012).

Spontaneous remissions have occurred in IgG4-RD. Glucocorticoids are the first-line agent for remission induction in most individuals with active, untreated IgG4-RD. Glucocorticoid responsiveness within 2 to 4 weeks has been considered one diagnostic criterion for the disorder "...provided that tissue fibrosis has not supervened" (Stone, 2012); however, relapse is frequently experienced after glucocorticoids are tapered or stopped. Maintenance therapy may decrease the risk of a relapse, in particular, for IgG4-RD pancreatitis.

The off-label use of rituximab for IgG4-RD has shown efficacy in B-cell depletion in individuals who are resistant to glucocorticoids (> 40 mg/day) or unable to tolerate dose reductions (usually to below 5 mg/day of prednisone) to avoid the adverse effects of chronic, long-term glucocorticoid use. This recommendation is based on data from case reports, case series (Khosroshahi, 2010; Khosroshahi, 2012), and a prospective, single-arm, pilot trial of 30 individuals with IgG4-RD in whom 97% of participants achieved disease responses that were maintained at 6 months with use of rituximab (Carruthers, 2015). In this study, 26 (87%) of participants were treated with rituximab alone, and 77% achieved the primary outcome as defined by 3 criteria: (1) decline in the IgG4-RD Responder Index (tool) of ≥ 2 points compared with baseline; (2) no disease flares before month 6; and (3) no glucocorticoid use between months 2 and 6. Disease response was defined as an improvement of the IgG4-RD Responder Index ≥ 2 compared with baseline. A total of 97% of the participants achieved disease responses that were maintained at 6 months and were generally observed quickly, often within 2 weeks of the first infusion. Six of the 7 participants who did not achieve the primary outcome failed because of prednisone usage between months 2 and 6. At 6 months and 12 months, only 3 participants (10%) remained on glucocorticoids, 1 of whom remained on prednisone for his cold agglutinin-mediated anemia, not IgG4-RD. One participant whose clinical course was marked by diffuse lymphadenopathy and an extremely high serum IgG4 (1090 mg/dL; normal < 121 mg/dL) had recovered normal B cell concentrations by month 3 and did not maintain his response.

Multiple Sclerosis - Relapsing Forms

Relapsing-remitting multiple sclerosis (RRMS) is the most common form of MS which affects 85% to 90% of all persons at presentation. RRMS is characterized by a clinical course of clearly defined, acute relapses with full or partial recovery. No disease progression or worsening of disability develops between relapses. RRMS is characterized as having active or not active disease and as worsening (defined as increased disability confirmed over a specified time period following a relapse), or stable (defined as no evidence of increasing disability over a specified time period following a relapse).

Early studies evaluating the use of rituximab in the treatment of RRMS include a phase I study (Bar-Or, 2008), case reports, case series and nonrandomized, uncontrolled trials (Naismith, 2010).

Hauser and colleagues (2008) reported results from a phase II, double-blind 48-week trial (HERMES) of 104 individuals with RRMS who were randomized in a 2:1 ratio to rituximab (n=69 participants, 1000 mg intravenous rituximab given on days 1 and 15) and placebo infusion (n=35 participants). At baseline, a higher proportion of participants in the rituximab group had gadolinium-enhancing lesions compared to the placebo arm (36% vs. 14%, p=0.02, respectively). The primary outcome, the total number of gadolinium-enhancing lesions detected on magnetic resonance imaging (MRI) brain scans in the intention-to-treat analysis, was lower in the rituximab group (a mean of 0.5 vs. 5.5 lesions per participant; p<0.001). The volume of T2-weighted lesions at 36 weeks was also lower (-10.3 mm3 vs. +123 mm3 ; p=0.004), as was the number of new gadolinium-enhancing lesions (0.2 vs. 4.5; p<0.001). The proportion of participants with relapses was lower in the rituximab group at 24 weeks (14.5% vs. 34.3%; p=0.02) and at 48 weeks (20.3% vs. 40.0%; p=0.04). A total of 24% of individuals discontinued participation from the trial before week 48 (n=14 [40%] in the control group, n=11 [15.9%] in the treatment group). Serious adverse events were similar in both groups (13.0% vs. 14.3%) and infection-related serious adverse events were less common in the rituximab group (78% vs. 40%).

Salzer and colleagues (2016) investigated the safety and effectiveness of rituximab in a retrospective observational study of individuals with MS identified through the Swedish MS registry. Outcome data were collected from the MS registry and medical charts including adverse events grades 2-5. A total of 822 rituximab-treated individuals with MS were identified: 557 with RRMS, 198 with SPMS, and 67 with PPMS. At baseline, 26.2% had contrast-enhancing lesions (CELs). Participants were treated with 500 mg or 1000 mg intravenous rituximab every 6-12 months, during a mean 21.8 (SD 14.3) months. During treatment, a total of 59 participants experienced relapse on rituximab treatment; the annualized relapse rates were 0.044 (RRMS), 0.038 (SPMS), and 0.015 (PPMS), and 4.6% of participants displayed CELs. The median Expanded Disability Status Scale (EDSS) score remained unchanged in RRMS (p=0.42) and increased by 0.5 and 1.0 in SPMS and PPMS, respectively (p=0.10 and 0.25). Infusion-related adverse events occurred during 7.8% of infusions and most were mild. A total of 89 non-infusion-related adverse events grades ≥ 2 (n=76 infections) were recorded in 72 participants. No case of progressive multifocal leukoencephalopathy (PML) was detected. Although this study lacked a control group and was retrospective in design, it provided observational data suggesting that rituximab is safe and effective for treating RRMS for up to 2 years.

de Flon and colleagues (2016) performed an open-label multicenter phase II trial to assess the safety and efficacy in reducing inflammatory activity upon switching from first-line injectable treatments to rituximab in individuals with clinically stable RRMS. Inflammatory activity was evaluated by the presence of gadolinium-enhancing lesions measured by MRI and the development of new or enlarging T2 lesions and by CSF neurofilament light chain (CSF-NFL) levels. A total of 75 individuals with clinically stable RRMS treated with the first-line injectables interferon-β (IFN-β) and glatiramer acetate at three Swedish centers were switched to rituximab. After a run-in period of 3 months, two intravenous doses of 1000 mg rituximab were given 2 weeks apart followed by repeated clinical assessment, MRI, and CSF-NFL for 24 months. A total of 71 participants completed all clinical and radiologic assessments during the 24-month study period. The mean cumulated number of gadolinium-enhancing lesions per participant at 3 and 6 months after treatment with rituximab was reduced compared to the run-in period (0.028 vs. 0.36; p=0.029). During the first year after treatment shift, the mean number of new or enlarged T2 lesions per participant was reduced (0.01 vs. 0.28; p=0.004) and mean CSF-NFL levels were reduced by 21% (p=0.01). In this small study of individuals with RRMS, a treatment switch from IFN-β or glatiramer acetate to rituximab was associated with an equal or superior effect in reducing inflammatory activity measured by MRI and CSF-NFL during the first year after treatment shift.

Alping and colleagues (2016) compared outcomes for persons with RRMS switching from natalizumab due to John Cunningham (JC) virus antibody positivity at three Swedish MS centers with different preferential use of rituximab and fingolimod (Stockholm, n=156, fingolimod 51%; Gothenburg, n=64, fingolimod 88%; Umea, n=36, fingolimod 19%). From this registry data, a cohort of 256 individuals experienced a clinical relapse within 1.5 years of cessation of natalizumab, 1.8% (rituximab) and 17.6% (fingolimod) (hazard ratio [HR] 0.10 for rituximab; 95% CI, 0.02-0.43). The HR (favoring rituximab) for adverse events (5.3% vs. 21.1%) and treatment discontinuation (1.8% vs. 28.2%) were 0.25 (95% CI, 0.10-0.59) and 0.07 (95% CI, 0.02-0.30), respectively. Additionally, contrast-enhancing lesions were found in 1.4% (rituximab) versus 24.2% (fingolimod) of MRI examinations (odds ratio 0.05; 95% CI, 0.00-0.22). The authors stated these findings suggest an improved effectiveness and tolerability of rituximab compared with fingolimod in individuals with stable RRMS who switch from natalizumab due to JC virus antibody positivity. Although residual confounding factors such as age, sex, disability status, time on natalizumab, washout time, follow-up time, and study center cannot be ruled out, the shared reason for switching from natalizumab and the preferential use of either rituximab or fingolimod in two of the centers lessens these concerns.

Neuromyelitis Optica

Neuromyelitis optica is a rare, inflammatory, demyelinating central nervous system disease that selectively targets the optic nerve and spinal cord (Jacob, 2007). MRI spine imaging often reveals longitudinally extensive transverse myelitis defined as large, contiguous lesions over 3 or more vertebral segments. A specific serum antibody (NMO-Ig-G/aquaporin-4) has been identified in individuals with neuromyelitis optica along with perivascular immunoglobulin deposition and B-cell participation in the activated complement lytic pathway (Jacob, 2007). Glucocorticoids, plasmapheresis and immunosuppressants have been used to treat neuromyelitis optica. Cree and colleagues (2005) reported results from an open-label series of 8 consecutive individuals with neuromyelitis optica who were treated with rituximab. At an average follow-up of 12 months, 6 individuals have remained free from attacks. Five individuals received retreatment with rituximab when CD19+ cells were detectable. The authors noted the possibility that previous immunosuppression may have confounded results, or the timing of the rituximab was attributable to the natural onset of remission.

Jacob and colleagues (2008) reported retrospective, multicenter data on a series of 25 individuals with neuromyelitis optica treated with rituximab. The rituximab regimens utilized were 375 mg/m2 weekly for 4 weeks and 1000 mg infused twice, with a 2-week interval between infusions. Median follow-up of 19 months (range 6-40 months) occurred with 5 participants discontinuing treatment. In addition, 2 deaths were attributed to disease progression and sepsis. The authors reported the median annualized pretreatment relapse rate was 1.7 relapses (range 0.5–5 relapses) and the median annualized post-treatment relapse rate was 0 (range 0–3.2 relapses, p<0.001).

Because neuromyelitis optica is a rare, relapsing and debilitating disease, the off-label use of rituximab as a treatment of neuromyelitis optica is based on the data from case series which demonstrated improvements in relapse rates. Specialty consensus opinion suggests the use of rituximab as treatment for neuromyelitis optica.

Pediatric Nephrotic Syndrome

Nephrotic syndrome is a disorder of the kidneys that results from increased permeability of the glomerular filtration barrier. While the etiology of nephrotic syndrome is unclear, conditions that accompany nephrotic syndrome, such as leukemia/lymphoma and Kimura disease, suggest that the pathophysiology is immune-mediated. Nephrotic syndrome is characterized by four major clinical characteristics that are used in establishing the diagnosis: proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Nephrotic syndrome can affect children of any age, from infancy to adolescence, and is most commonly seen among school-aged children and adolescents. The prevalence worldwide is approximately 12-16 cases per 100,000 children with an incidence of 2-7 cases per 100,000 children. Males appear to be more affected than females at a ratio of 2:1 in children, but this predominance fails to persist in adolescence (Andolino and Reid-Adam, 2015).

Idiopathic nephrotic syndrome is steroid resistant in approximately 20% of cases. In addition to steroid resistance, frequent relapses and steroid dependence may result in adverse effects of chronic, long-term glucocorticoid use. Younger age, male gender, a history of atopy, longer time to first remission, a shorter time from remission to first relapse, and glucocorticoid receptor gene NR3C1 GR-9beta+TthIII-1 variants have been linked to frequent relapse and steroid dependence (Hoyer, 2015; Sureshkumar, 2014). More than 15% of steroid-resistant nephrotic syndrome will progress to end-stage renal disease.

The KDIGO clinical practice guidelines (2012) on glomerulonephritis recommend use of oral corticosteroid therapy (prednisone, prednisolone, or deflazacort dosing up to 60 mg daily for 4 to 6 weeks; followed by 40 mg/m2 or 1.5 mg/kg every other day) for at least 12 weeks, and continued for 2 to 5 months, with slow tapering. However, overtreatment with long-term steroids is not recommended. For the off-label use of rituximab in pediatric nephrotic syndrome, the KDIGO clinical practice guidelines (2012) state that rituximab should be considered only in children who have failed combination therapy of prednisone and other corticosteroid-sparing agents and have serious adverse effects of therapy.

The evidence in the peer-reviewed published medical literature suggests a treatment benefit of off-label use of rituximab in steroid-resistant, steroid-dependent pediatric nephrotic syndrome. Iijima and colleagues (2014) performed a multicenter, double-blind, randomized controlled trial evaluating the use of rituximab in the treatment of childhood-onset, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome. Participants included children and adolescents aged 2 years and older who experienced a relapse of frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome originally diagnosed as nephrotic syndrome when aged 1-18 years. Participants were randomized to receive rituximab 375 mg/m2 or placebo once weekly for 4 weeks. All participants received standard steroid treatment for relapse at screening and stopped taking immunosuppressive agents by 169 days after randomization. A total of 48 of 52 participants who were randomized received the assigned intervention (n=24, rituximab; n=24, placebo). The primary endpoint was the relapse-free period at 1 year follow-up. Treatment failure was defined as a relapse occurring by day 85, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome diagnosed between days 86 and 365, or steroid resistance. Treatment failure was reported in 10 rituximab-treated participants and 20 placebo-treated participants. The time to treatment failure was significantly longer in the rituximab group than in the placebo group (HR 0.27; 95% CI, 0.12-0.59; p=0.0005). The relapse rate was significantly lower in the rituximab group (1.54 relapses per person-year [29 relapses in 18.81 person-years]) than in the placebo group (4.17 relapses per person-year [46 relapses in 11.03 person-years]; HR 0.37; 95% CI, 0.23-0.59; p<0.0001). Only 2 participants in each group had frequent relapses in the study period. Time to relapses during reduction of steroid treatment or within 2 weeks of discontinuation of steroid treatment was significantly longer in the rituximab group than in the placebo group (HR 0.19; 95% CI, 0.07-0.54; p=0.0005). The median relapse-free period was significantly longer in the rituximab group (267 days, 95% CI, 223-374) than in the placebo group (101 days, 70-155; HR 0.27; 0.14-0.53; p<0.0001). Post-hoc analyses showed that age at disease onset and age at time of treatment did not affect the median relapse-free period in the rituximab group. At least one serious adverse event was experienced by 10 (42%) rituximab-treated participants and 6 (25%) placebo group participants; however, the difference was not significant (p=0.36).

Ravani and colleagues (2011, 2013, and 2015) evaluated the safety and efficacy of rituximab therapy in children with steroid-dependent nephrotic syndrome. In a multicenter, open-label, noninferiority, randomized controlled trial, Ravani and colleagues (2015) tested whether rituximab was noninferior to steroids in maintaining remission in juvenile steroid-dependent nephrotic syndrome. After a run-in period, participants aged 1-16 years who had developed steroid-dependent nephrotic syndrome in the previous 6  to 12 months and were maintained in remission with high prednisone doses (> 0.7 mg/kg per day) were randomly assigned to add-on therapy with rituximab 376 mg/m2 (n=15) or continued treatment with prednisone alone for 1 month (n=15). At the end of the run-in period, the average prednisone doses were 0.1 mg/kg per day lower. Prednisone was tapered in both groups after 1 month. The primary outcome (for noninferiority) was steroid withdrawal for participants on rituximab while maintaining 3-month proteinuria (mg/m2 per day) within a prespecified noninferiority margin of three times the levels among controls. Proteinuria increased at 3 months in the prednisone group (37%; 95% CI, 7% to 76%) and decreased in the rituximab group (237%; 95% CI, 220% to -51%). The 3-month proteinuria was 42% lower in the rituximab group (that is, within the noninferiority margin of three times the levels in controls). All but 1 child in the control group relapsed within 6 months. The median time to relapse in the rituximab group was 18 months (95% CI, 9-32 months). In the rituximab group, nausea and skin rash during infusion were common; transient acute arthritis occurred in one child. The investigators concluded that rituximab was noninferior to steroids for the treatment of juvenile steroid-dependent nephrotic syndrome. In addition,

The limited toxicity of rituximab and the potential benefits of maintaining disease remission while avoiding steroids and calcineurin inhibitors support the use of rituximab as a steroid-sparing agent in juvenile steroid-dependent nephrotic syndrome, but the effects of rituximab in other forms of nephrotic syndrome remain uncertain.

Sato and colleagues (2014) studied the impact of rituximab on growth and obesity in 13 children with steroid-dependent nephrotic syndrome who were refractory to treatment with multiple immunosuppressive agents. The mean follow-up was 2.3 years from the first administration of rituximab. Improvement in the height and obesity indexes was assessed from prior to the initial rituximab infusion through to the last visit. After rituximab therapy, the number of relapses were significantly decreased (2.8 before rituximab vs. 0.8/year after rituximab; p=0.0008) and the prednisolone dose (287.9 vs. 70.7 mg/kg/year, respectively; p=0.0002). A marked improvement in the height standard deviation score (SDS) was achieved by 10 of the 13 participants (77 %) (n=13; -1.6 before rituximab vs. -0.8 SDS after rituximab; p=0.03). Of note, the height SDS of 7 of 8 participants whose height was less than average at the first rituximab treatment improved from -2.6 to -1.4 SDS with rituximab therapy. At the same time, the obesity index of 12 of the 13 (92%) participants significantly improved (n=13; 16.9 vs. 3.1 %; p=0.004). The outcomes suggest that rituximab may contribute to an improvement in the growth and obesity indexes in some children with steroid-dependent nephrotic syndrome experiencing severe side effects of steroids.

Complications such as agranulocytosis have been reported as a delayed-onset complication of rituximab treatment (Kamei, 2015); however, the exact incidence and risk factors of this complication in pediatric nephrotic syndrome remain unknown. The records of 213 rituximab treatments for 114 children and adolescents with refractory nephrotic syndrome were reviewed to identify episodes of agranulocytosis (defined as an absolute neutrophil count of < 500 mm3 ). A total of 11 episodes of agranulocytosis were detected in 11 individuals. The median time of onset of agranulocytosis was 66 days (range, 54-161 days) after rituximab treatment. A total of 9 children experienced acute infections and received antibiotics; all but 1 child received granulocyte colony-stimulating factor. Agranulocytosis resolved in all cases within a median of 3 days. The incidence of agranulocytosis was 9.6% in all children and 5.2% in all treatments. The median age of the 11 children who developed agranulocytosis was 6.4 years at the first rituximab treatment, significantly younger than the median age of the 103 adolescents who did not (median, 12.5 years; p=0.0009). Five children received re-treatment with rituximab. No recurrence of agranulocytosis was observed in any child. Therefore, careful monitoring was recommended after rituximab treatment in children and adolescents with refractory nephrotic syndrome.

While rituximab treatment may maintain remission in the majority of children with steroid-dependent nephrotic syndrome, the effect may diminish over time, and some children relapse 6 to 9 months after rituximab treatment with reappearance of CD19 (a marker of B cells) (Fujinaga, 2014). Sinha and colleagues (2015) studied the efficacy and safety of intravenous rituximab administered once weekly for 2-4 doses in 193 children (mean age 10.9, range 2.2-18.7 years) with difficult-to-treat steroid dependence (n=101), calcineurin inhibitor-dependent steroid resistance (n=34) and calcineurin inhibitor-resistant nephrotic syndrome (n=58). A significant reduction in relapse rates was reported with use of rituximab (respective mean difference 2.7 relapses/year and 2.2 relapses/year, corresponding to a decrease in relapses by 81.8 and 71.0%; both p<0.0001) resulting in a significant reduction in steroid requirement (mean difference 104.5 and 113.6 mg/kg/year, respectively; both p<0.0001) and a trend to improved SDS for height (p=0.069) and body mass index (p=0.029); however, children with initial resistance and calcineurin inhibitor-dependent steroid resistance had increased risk of relapse (HR 2.66; p=0.042). Response to therapy was unsatisfactory in children with steroid- and calcineurin inhibitor-resistant nephrotic syndrome, with remission in 29.3%.

The use of rituximab was studied in a case series of 26 children with steroid-dependent nephrotic syndrome who relapsed while receiving long-term cyclosporine and subsequently switched to mycophenolate mofetil (Fujinaga, 2015). For children who required mycophenolate mofetil and high-dose prednisolone to maintain remission, a single infusion of rituximab 375 mg/m2 was added. The primary endpoint was the probability of achieving prednisolone-free remission for greater than 1 year. At a mean follow-up of 28.8 ± 9.9 months, 11 of 26 children (42 %) required rituximab treatment. A total of 22 of 26 children (85 %) achieved prednisolone-free sustained remission. The mean predose mycophenolic acid level for those who achieved prednisolone-free sustained remission were significantly higher compared with children who did not (3.1 μg/ml vs. 1.7 μg/ml; p<0.05).

The appearance of anti-rituximab antibodies may occur with repetitive rituximab treatment; therefore, if a severe infusion reaction and CD19 persists despite rituximab therapy, the presence of anti-rituximab antibodies should be considered (Ahn, 2014). To date, the use of rituximab has not been reported in the peer-reviewed published medical literature as initial treatment of pediatric nephrotic syndrome.

Pemphigus Vulgaris and Other Autoimmune Blistering Skin Diseases

Autoimmune blistering skin diseases are rare, and treatment with corticosteroids and immunosuppressive drugs may not control disease, leading to increased morbidity and mortality. Rituximab treatment for individuals with refractory pemphigus vulgaris has been studied in open label, nonrandomized, uncontrolled case series. Joly and colleagues (2007) reported on 18 (86%) out of 21 individuals who achieved complete remission of severe, refractory pemphigus with rituximab therapy. With a median follow-up of 34 months, 18 individuals were free of disease and 8 of these individuals had stopped corticosteroid therapy. In another similar study (Allen, 2007) the investigators note rituximab, "Appears to be effective in the treatment of refractory disease." Additionally, the AHFS (2016) notes rituximab is used off-label for the treatment of pemphigus vulgaris.

Renal Transplant

Renal transplantation is used for individuals with end-stage renal disease. The demand for kidney transplantation has outpaced the supply of organs, thus increasing the wait-time until transplantation. Additionally, wait-times are increased when there is difficulty in matching organs to recipients resulting from sensitization with reactive human leukocyte antigen (HLA)-specific antibodies. Vo (2010) reported "the rate of transplantation with any level of sensitization is difficult to transplant." Individuals with panel reactive antibodies 10% to 80% were transplanted 16% per year whereas panel reactive antibodies greater than 80% were transplanted less than 8% per year.

A phase I-II trial examined if a treatment protocol, consisting of intravenous immune globulin and rituximab, administered prior to kidney transplantation would improve transplantation rates by reducing anti-HLA antibody levels in highly sensitized individuals. A total of 20 individuals who were highly sensitized were treated with the combination regimen therapy. Vo and colleagues (2008) reported panel reactive antibodies were, "Significantly reduced after treatment with IVIG and rituximab (77 ± 19% before the first infusion of intravenous immune globulin (IVIG), vs. 44 ± 30% after the second infusion (p<0.001)." CD19+ cells were significantly reduced after rituximab treatment (mean percentage of total B cell lymphocytes, 6.12 ± 0.18 % prior to treatment vs. 0.90 ± 0.02% after treatment; p<0.001). A total of 16 of the 20 participants received successful transplantation (6 received a deceased donor kidney; 10 received a living donor kidney). The remaining 4 participants had panel reactive antibody levels greater than 50% and were awaiting a deceased donor kidney transplant. Mean follow-up was 22.1 ± 6 months with recipient and allograft survivals of 100% and 94%, respectively. One graft was lost due to severe rejection after a reduction of immunosuppressive therapy. Acute rejection occurred in 50% of the transplanted individuals. Acute antibody-mediated rejections occurred in 31% of the episodes and 2 individuals had late (greater than 6 months) antibody-mediated rejection episodes. Individuals with antibody-mediated rejection were treated with methylprednisolone, rabbit antithymocyte globulin and rituximab. Recipients of deceased donor kidneys had a mean waiting list time of 12 years (range, 5-27) prior to desensitization, but received transplants within 5 to 6 months after receiving combination treatment with intravenous immune globulin and rituximab.

Vo and colleagues (2010) reported on 76 HLA-sensitized individuals who were treated with intravenous immune globulin and rituximab prior to kidney transplantation. The study examined the efficacy of intravenous immune globulin and rituximab on the reduction of anti-HLA antibodies that led to kidney transplantation with incurring the risk of AMR and immediate graft loss. All participants were deemed high immunologic risks with PRA 30%-79% in 25% of individuals, and 75% of the participants had panel reactive antibodies ≥ 80%. A total of 31 individuals received living donor and 45 individuals received deceased donor kidney transplants. Data from 39 individuals show mean pretreatment class I panel reactive antibodies were 79.7% ± 35.6% versus post-treatment 67.1% ± 28.6% (p=0.0001). Recipients of deceased donor kidneys had a mean waiting list time of 95 ± 46 months prior to desensitization, but received transplants within 4 months after receiving combination treatment with intravenous immune globulin and rituximab. Acute rejection occurred in 37% of participants (8% cell mediated rejection and 29% antibody-mediated rejection). A total of 9 individuals had graft losses, with antibody-mediated rejection involved in 6 cases. Recipient and allograft survivals were 95% and 84%, respectively. The authors concluded, "IVIG and rituximab seems to offer significant benefits in reduction of anti-HLA antibodies, allowing improved rates of transplantation for highly sensitized patients, especially those awaiting deceased donor (DD), with acceptable antibody-mediated rejection and survival rates at 24 months" (Vo, 2010). Additional analysis in a randomized trial was encouraged.

Tyden and colleagues (2009) reported results from a prospective, double-blind, randomized, placebo-controlled multicenter study evaluating the efficacy and safety of rituximab as induction therapy in 140 individuals prior to renal transplantation. Participants meeting criteria, including panel reactive antibodies less than 50%, were randomized to induction therapy (tacrolimus, mycophenolate mofetil and steroids) plus rituximab versus induction therapy plus placebo. A total of 136 participants fulfilled the criteria for analysis. Treatment failure was the primary endpoint, with 10 occurrences in the rituximab group and 14 in the placebo group (p=0.348). Rejection episodes occurred 8 times in the treatment cohort versus 12 episodes in the placebo group (p=0.317). Although rejection episodes in the treatment group "tended to be less severe," survival in both groups at 6 months was 98.5% and death censored graft survival was 98%. Biopsy-proven acute rejections were not statistically significant with 11.6% in the rituximab group and 17.6% in the placebo cohort.

Thrombocytopenic Purpura, Idiopathic or Immune

Idiopathic thrombocytopenic purpura, also known as primary immune thrombocytopenic purpura, is an immune mediated hematologic disorder characterized by impaired production of platelets in the bone marrow, and destruction of the peripherally circulating platelets. These individuals typically present with low platelet counts, bleeding episodes, and platelet autoantibodies. Treatment may include maintaining hemostatic levels, administering prednisone and immune globulin and in severe cases, splenectomy.

Arnold and colleagues (2007) performed a systematic review of rituximab as a treatment of idiopathic thrombocytopenic purpura in adults. A total of 19 studies including 313 individuals were identified for evaluation of efficacy and 29 articles including 306 individuals were identified for assessment of safety. The authors noted an absence of controlled studies. In 16 of 19 studies, rituximab was given at standard weekly dosing for up to 4 weeks. Complete response, noted by a platelet count greater than 150 x 109 cells/L, was observed in 43.6% of individuals. An overall response, defined as platelet count greater than 50 x 109 cells/L, was noted in 62.5% individuals treated with rituximab. Median duration of response was 10.5 months and a median follow-up was 9.5 months. Evaluation of all deaths in rituximab-treated individuals identified 9 deaths out of 306 individuals, with 2 deaths attributed to rituximab administration. The authors concluded from the uncontrolled studies, that rituximab treatment improved platelet counts. However, prospective, randomized controlled trials are encouraged to identify the optimal timing and dose of rituximab for the treatment of idiopathic thrombocytopenic purpura.

The first report from a phase III, open-label trial of rituximab as first-line of therapy for idiopathic thrombocytopenic purpura was reported by Gudbrandsdottir (2013). Individuals with newly diagnosed idiopathic thrombocytopenic purpura and platelet counts ≤ 25 X 109 /L or ≤ 50 X 109 /L and concomitant bleeding symptoms were randomized to treatment with dexamethasone alone or in combination with rituximab. A total of 137 individuals were randomized; 4 participants did not have complete data available for analysis. The dexamethasone alone group included 71 individuals who received dexamethasone 40 mg/day for 4 days. The treatment group of 62 individuals received dexamethasone and rituximab 375 mg/m2 weekly for 4 weeks. In addition, up to 6 cycles of supplemental dexamethasone every 1 to 4 weeks was allowed. The median follow-up was 922 days. A total of 58% of participants in the rituximab plus dexamethasone group met the primary endpoint of sustained response (that is, platelets ≥ 50 X 109 /L) at 6 months follow-up compared to 37% treated with dexamethasone  alone in the control group (p=0.02). The time to relapse was defined as a decrease in platelet counts to < 50 X 109 /L following initial response to therapy. The rituximab plus dexamethasone group had a significantly longer time to relapse compared to the dexamethasone alone group (p=0.03). An increased incidence of grade 3 to 4 adverse events was observed in the rituximab plus dexamethasone group (p=0.04).

The AHFS (2016) notes that rituximab is used as an off-label treatment of idiopathic thrombocytopenic purpura.

Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura is a rare, life-threatening condition characterized by the presence of microvascular thrombosis, thrombocytopenia, and microangiopathic hemolytic anemia (MAHA) leading to end-organ ischemia and infarction (commonly brain, heart, kidneys) (Scully, 2012; Tun, 2012). Thrombotic thrombocytopenic purpura occurs due to an acquired (95% of cases) or congenital (5% of cases) deficiency of the von Willebrand factor-cleaving protease, ADAMTS 13 (A Disintegrin-like And Metalloprotease with ThromboSpondin type 1 motif 13). When ADAMTS 13 is absent or depleted, large uncleaved von Willebrand factor multimers aggregate in high shear areas of the microvasculature, leading to thrombotic microangiopathy (Scully, 2012). A diagnosis of thrombotic thrombocytopenic purpura is based on clinical history, physical examination, and blood film (blood smear). Presenting clinical features and symptoms that reflect widespread multi-organ thrombosis, include thrombocytopenia, neurological impairment (confusion, headache, paresis, aphasia, dysarthria, visual problems, encephalopathy, and coma [10%]), fever, jaundice, renal impairment, cardiac symptoms (chest pain, heart failure), and abdominal pain. ADAMTS 13 assays help to confirm the diagnosis and monitor the cause of the disease and possible need for additional treatments. "Severely reduced ADAMTS 13 activity (< 5%), ± the presence of an inhibitor or IgG antibodies, confirms the diagnosis" (Scully, 2012). ADAMTS 13 plasma concentration can be determined within < 24 hours by Elisa technique. The specificity of severe ADAMTS 13 deficiency (< 5%) in distinguishing acute thrombotic thrombocytopenic purpura from acute hemolytic uremic syndrome (aHUS) is 90% (Bianchi, 2002; Zheng, 2004). In addition, anti-ADAMTS 13 neutralizing antibodies are present in 38% to 95% of cases of idiopathic thrombotic thrombocytopenic purpura (Froissart, 2012). The primary treatment of thrombotic thrombocytopenic purpura is initiating plasma exchange and corticosteroids as soon as possible if a person presents with MAHA and thrombocytopenia in the absence of any other identifiable cause. Refractory thrombotic thrombocytopenic purpura, defined as progression of clinical symptoms during plasma exchange therapy, occurs in 10% to 20% of acquired thrombotic thrombocytopenic purpura cases (Harambat, 2011). For these individuals, increased plasma exchange, with or without the addition of cyclosporine are current treatment options (Scully, 2012).

The evidence in the peer-reviewed published medical literature for off-label use of rituximab in individuals who have relapsed or refractory thrombotic thrombocytopenic purpura includes several case series (Scully, 2007) and a nonrandomized, phase II cohort study. Scully and colleagues (2011) conducted a multicenter, nonrandomized phase II cohort trial of 47 individuals with anti-ADAMTS13 antibody-positive, new-onset (85%) or acute relapsed (15%) thrombotic thrombocytopenic purpura comparing participants with an age-, sex-, and ethnicity-matched historical control group of 40 persons. Participants were administered rituximab 375 mg/m2 weekly for 4 weeks; 3 participants died and 1 participant withdrew before receiving all 4 doses of rituximab. All participants and historical controls received plasma exchange at admission and then daily (or twice daily for new or progressive neurologic or cardiac symptoms; protocol maximum of 8 infusions) until remission, defined as sustained platelet count (> 15 X 109 /L) for 2 consecutive days; in addition, corticosteroid (typically methylprednisolone 1 g IV daily) was given for 3 days. The primary efficacy outcome was the number of plasma exchange treatments to remission. A total of 40 participants received a median of 16.5 (range, 4-34) plasma exchange treatments compared with 18 (range, 6-92) treatments in the historical control group (Mann-Whitney test; p=0.5). There was no statistical difference between groups in the number of hospital admission days, but among participants who relapsed (n=4, rituximab group; n=21, control group), the median time to relapse, defined as readmission with thrombocytopenia less than 150 X 109 /L 30 days after discharge from an acute episode, was longer in rituximab-treated participants than in historical controls (27 [range, 17-31] months vs. 18 [range, 3-60] months). Follow-up for rituximab and control groups was 12 and 49 months, respectively. The incidence of infections and serious adverse events was similar between groups.

Tun and colleagues (2012) performed a systematic review of 15 case series and 16 case reports (N=100 total cases) of immune-mediated, relapsed or refractory thrombotic thrombocytopenic purpura treated with rituximab. In all studies, rituximab was dosed at 375 mg/m2 weekly for a median of 4 doses (range, 1-8). A total of 98 (98%) participants achieved complete response, defined as platelet recovery, lack of thrombotic thrombocytopenic purpura-related symptoms, and no evidence of microangiopathic hemolytic anemia lasting more than 30 days. Only 2 participants were considered nonresponders. Nine percent of participants who achieved complete response relapsed during the median follow-up of 13 months (range, 1-97). Anti-ADAMTS13 antibody positivity and severe ADAMTS13 deficiency, that is, enzyme activity < 10%, predicted response to rituximab (positive predictive value, 99% for both). Serious rituximab-related adverse events occurred in 3 participants (3%) including abdominal abscess, acute biventricular cardiogenic shock, and sacral abscess.

Froissart and colleagues (2012) conducted a single-arm case study of 22 adults with acute (n=6) or relapsed (n=16) thrombotic thrombocytopenic purpura refractory to therapeutic plasma exchange. Rituximab was administered in 4 infusions over 15 days. Clinical outcomes were compared with a historical control group of 57 ADAMTS13-deficient individuals (from a French registry) who were treated with vincristine, with or without cyclophosphamide. Both participants and historical controls were treated using defined protocols. There was 1 (4.5%) death in the rituximab group compared with 4 (7.0%) deaths in 57 historical controls. Platelet count recovery (> 150 X 109 /L) was observed in the 21 participants (100%) versus 78% of historical controls. All rituximab-treated participants (survivors) had platelet count recovery by day 35 versus 78% of controls, with shorter time to recovery in the rituximab group. In the first year following treatment, no relapses were observed in rituximab-treated participants while 5 control group individuals experienced relapse (p=0.34). Adverse effects of rituximab were not reported during follow-up.

The outcomes of these case series and cohort study, along with specialty consensus opinion, suggest a treatment benefit of rituximab in individuals with refractory and relapsed thrombotic thrombocytopenic purpura.

Other Proposed Non-Oncologic Off-Label Uses of Rituximab

The published literature includes investigation of rituximab treatment for other non-oncologic off-label uses. However, the published literature consists of case reports, small case series, non-randomized and uncontrolled trials which preclude reliable conclusions on safety and long-term net health outcomes.

Idiopathic Inflammatory Myopathies

Idiopathic inflammatory myopathies (IIM) are a diverse group of acquired disorders characterized by chronic inflammation of striated muscle leading to primarily proximal muscle weakness. The most common subsets of IIM include adult polymyositis (PM), adult and juvenile dermatomyositis (DM), myositis in overlap with cancer or another connective tissue disease, and inclusion body myositis (IBM). IIM are frequently associated with constitutional symptoms such as fever, sweats, chills, poor appetite, vomiting, diarrhea, abdominal pain and weight loss, and commonly involve other organ systems including the skin, joints, lungs, gastrointestinal tract and heart. IIM are rare disorders with an estimated incidence of 4-10 cases per million population per year and an incidence pattern reflecting childhood onset of juvenile DM (JDM) and a later peak in adulthood, although the precise manner of development of the disease is unknown (Oddis, 2013).

The safety and effectiveness of rituximab in the treatment of IIM has been evaluated in case series and single case reports, retrospective registry data, and open-label pilot studies. Oddis and colleagues (2013) assessed the safety and efficacy of rituximab in the largest randomized, double-blind, placebo-phase trial (RIM trial) in adult and pediatric individuals with myositis. A total of 200 randomized participants (n=76 with PM, n=76 with DM, and n=8 with juvenile DM [JDM]) included adults with a diagnosis of definite or probable DM or PM and individuals 5 years of age or older with definite or probable JDM. Participants were enrolled who had muscle weakness and equal to or greater than two additional abnormal values on core set measures (CSMs) for adults. Juvenile DM participants required greater than or equal to three abnormal CSMs, with or without muscle weakness. Participants were randomized to receive either rituximab early or rituximab late, and glucocorticoid or immunosuppressive therapy was allowed at study entry. The primary endpoint compared the time to achieve the International Myositis Assessment and Clinical Studies Group preliminary definition of improvement (DOI) between the 2 groups. The secondary endpoints were the time to achieve ≥ 20% improvement in muscle strength and the proportions of participants in the early and late rituximab groups achieving the DOI at week 8. Among the randomized participants, 195 showed no difference in the time to achieve the DOI between the rituximab late (n=102) and rituximab early (n=93) groups (p=0.74 by log rank test), with a median time to achieve the DOI of 20.2 weeks and 20.0 weeks, respectively. Additionally, secondary endpoints did not significantly differ between the 2 treatment groups; however, through the 44-week trial, 161 (83%) of the randomized participants met the DOI, and individual CSMs improved in both groups. Only 1 participant withdrew early due to an adverse event in the late rituximab group. There were 67 serious adverse events in 64 participants, 26 of which were related to study drug. Infections were the most common: pneumonia (n=6), cellulitis (n=6), urosepsis (n=2), herpes zoster (n=2) and one each of septic arthritis, histoplasmosis, urinary tract infection, respiratory failure, heart failure, dysrhythmia, venous thrombosis, syncope, rash, and neurologic symptoms (without evidence of PML). As the study failed to meet the specified endpoints, in part, due to an overestimate of the rapidity of the rituximab response and an underestimate of DOI in those receiving placebo, additional well-designed studies are needed to determine the net health benefit (that is, improvement in DOI) with use of rituximab in individuals with IIM.

Membranous Nephropathy

Membranous nephropathy involves the abnormal thickening of the glomerular basement membrane and is a leading cause of nephrotic syndrome. Majority of membranous nephropathy cases occur from unknown causes and secondary membranous nephropathy may be a result of other predisposing diseases, infection or medical therapy. In most cases, conservative treatment with renin-angiotensin system blockade is provided. Immunomodulatory therapies (for example, alkylating agents, calcineurin inhibitors and corticosteroids) are used to treat individuals who are unresponsive to conservative therapy. Rituximab has been used to treat membranous nephropathy and reported in numerous case reports and series. Bomback and colleagues (2009) performed a systematic review of 21 articles involving 85 individuals with biopsy-proven membranous nephropathy treated with rituximab as primary or secondary immunosuppression. Majority of the individuals in the analysis were reported from two centers. However, there were significant variations in selection criteria, previous treatments and rituximab treatment protocols which precluded pooled data analysis. Complete remission in 15% to 20% and partial remission in 35% to 40% of individuals with refractory disease were similar to response rates for alkylating agents and calcineurin inhibitors. The authors cautioned the response rates from case series were "Not valid for direct comparisons to the randomized clinical trial-based data on alkylating agents and calcineurin inhibitors." Although positive case series have been published, Bomback (2009) concluded rituximab as a treatment for membranous nephropathy should not be provided outside of a research setting. Large, randomized controlled trials are needed to determine the optimal schedule, dose and long-term safety and efficacy.

Multiple Sclerosis - Other than Relapsing Disease

Approximately 10%-15% of persons with MS have primary-progressive MS (PPMS), which has a clinical course characterized by a steady progression of disability (that is, worsening of neurologic function) from onset without initial relapses or remissions. Forms of PPMS include having active or inactive disease with progression, meaning there is objective evidence of sustained worsening over time, or without progression. An acute relapse in an individual with progressive disease from onset is now considered to be PPMS with active disease, whereas those with progressive disease from onset without acute relapses are considered to have PPMS, active but with progression.

In an industry-sponsored Phase II/III randomized, double-blind, placebo-controlled multicenter trial (OLYMPUS), Hawker and colleagues (2009) evaluated the safety and efficacy of rituximab in the treatment of PPMS. A total of 439 participants (age range, 18-65 years) with PPMS for at least 1 year and an EDSS score ranging from 2.0 to 6.5 (median, 5.0 indicating moderate-to-severe disability with impairment of daily activities) were randomized 2:1 to receive either 2 doses of intravenous rituximab 1000 mg 2 days apart every 6 months for 4 courses (8 doses) (n=292), or placebo (n=147). The primary endpoint was time to confirmed disease progression, defined as an increase in EDSS of 1.0 point or more (≥ 0.5 points if baseline EDSS was > 5.5 points) sustained for at least 12 weeks. Follow-up was planned for 96 weeks (efficacy) and 122 weeks (safety). A total of 83% of participants completed 96 weeks and 77% completed 122 weeks of follow-up. MRI evaluations were conducted at baseline, weeks 6, 48, 96 and 122. The primary study endpoint was not met, as the time to disease progression did not differ statistically between the rituximab (30.2%) and placebo groups (38.5%) (HR=0.77; 95% CI, 0.55 to 1.09; p=0.144). At 96 weeks, the increase in T2 lesion volume on MRI brain scan (a marker of past disease activity) was less in the rituximab group than in the placebo group (p<0.001). The incidence of overall grade 3 or higher adverse events was 40% in the rituximab group and 38% in the placebo group. Serious infections occurred in 5% and in less than 1% of the rituximab and placebo groups, respectively. Incidences of infusion-associated adverse events within 24 hours of the first dose were 67% and 23% in the rituximab and placebo groups, respectively. As the trial failed to meet the primary endpoints, but suggested that rituximab may show promise in younger individuals with PPMS who have gadolinium-enhancing lesions on MRI, additional study is needed to determine the net health benefit of rituximab in a younger population with PPMS.

Myasthenia Gravis

Myasthenia gravis is a rare chronic autoimmune disorder that affects the neuromuscular junction resulting in varying degrees of muscular weakness. The normal communication of nerve impulses involves nerve endings releasing acetylcholine, a neurotransmitter at the neuromuscular junction, which normally binds with acetylcholine receptors (AChRs) which become activated and result in a muscle contraction. For individuals with myasthenia gravis, this cholinergic communication is disrupted by antibodies (Abs). According to Iorio and colleagues (2015), "…the muscle AChR is the main antigen, as AChR-Ab can be detected in up to 85% to 90% of persons with myasthenia gravis." Approximately 40% of persons with AChR-negative myasthenia gravis have serum Ab to the muscle-specific tyrosine-kinase (MuSK). MuSK-Abs induce severe functional alteration of the neuromuscular junction, although being mostly IgG4, they do not activate complement (Iorio, 2015).  

Management of myasthenia gravis is aimed at inducing and maintaining remission while avoiding unnecessary toxicity. Conventional treatment options include acetylcholinesterase inhibitors, short-term immune therapies (such as plasmapheresis or intravenous immune globulin), and long-term treatment with corticosteroids, and immunosuppressive agents, including, but not limited to, azathioprine, mycophenolate mofetil, and cyclosporine. Conventional treatments may require prolonged and life-long immunosuppression, and persons with refractory disease or frequent relapses require high doses of steroids and other immunosuppressive agents with serious side effects. For persons with non-thymomatous myasthenia gravis, thymectomy is recommended as an option to increase the probability of remission or improvement. Once thymoma is diagnosed, thymectomy is indicated irrespective of myasthenia gravis severity (Drachman, 2008; Skeie, 2010). 

Rituximab has been given a class IB recommendation (DrugPoints® , 2016) for off-label use as an effective treatment for refractory myasthenia gravis with minimal adverse effects (class I: the given test or treatment has been proven to be useful, and should be performed or administered; strength of evidence: category B, based on data derived from several small studies demonstrating that rituximab is an effective treatment for refractory myasthenia gravis with minimal side effects). In addition, an Association of British Neurologists guideline on the management of myasthenia gravis states that that rituximab may be used to manage poorly responsive myasthenia gravis when azathioprine has failed or the individual cannot tolerate it (DrugPoints, 2016; Sussman, 2015). At this time, no evidence-based guidelines or recommendation for use of rituximab in the management of myasthenia gravis are available from the American Academy of Neurology (AAN).

Several small observational studies, a prospective, open-label study, numerous case series, and a systematic review and meta-analysis suggest a treatment benefit of rituximab in the management of refractory or relapsed myasthenia gravis in individuals that have failed to respond to, or are intolerant of, conventional therapy, including azathioprine (Anderson, 2016 [n=14]; Blum, 2011 [n=14]; Collongues, 2012 [n=20]; Diaz-Manera, 2012 [n=17]; Illa, 2008 [n=6]; Iorio, 2015 [n=168]; Keung, 2013 [n=9]; Lebrun, 2009 [n=6]; Maddison, 2011 [n=10]). Improvements in Osserman scores of Myasthenia Gravis Foundation of America (MGFA) clinical classifications were observed in rituximab-treated subjects with AChR-Abs or MuSK-Abs that failed prior treatment with corticosteroids, immunosuppressants, plasma exchange, intravenous immune globulin, and/or thymectomy (DrugPoints, 2016). Rituximab was administered 375 mg/m2 weekly for 4 weeks and additional doses if necessary. Retreatment was administered as an additional dose of rituximab 375 mg/m2 at 1 month (Maddison, 2011) (given for 2 months [Diaz-Manera, 2012; Illa, 2008], 2 months [Lebrun, 2009], or 3 months after initial treatment (Collongues, 2012). Blum and colleagues (2011) administered rituximab 1 gram, divided into two doses of 500 mg and given 2 weeks apart; subjects were retreated with the same dosage if relapsed and recovery of B lymphocyte count was greater than 1%.

Anderson and colleagues (2016) reported results from a recent prospective, open-label study of 14 subjects with MuSK- and AChR-Abs in addition to seronegative subjects with myasthenia gravis who were treated with rituximab on a compassionate basis (Alberta Health Services, Canada). The mean age for all subjects was 50.9 ± 3.7 years. In total, 6 subjects had MuSK-Abs, 5 subjects had AChR-Abs, and 3 subjects had seronegative myasthenia gravis. The mean time between disease onset and initiation of rituximab was 47.1 ± 15.0 months. Rituximab was administered at a dose of 375 mg/m2 every week for 4 consecutive weeks then monthly for 2 months, or at a dose of 750 mg/m2 every 2 weeks for 1 month. The primary outcome measure was the change in the manual muscle testing (MMT) score. All 14 subjects demonstrated a marked improvement in clinical status by the end of the follow-up period (22.6 ± 2.4 months). In subjects treated with a single cycle of rituximab, MMT score was significantly reduced from a baseline of 13.1 ± 1.9 (range=5-7) to 3.5 ± 0.8 (range=0-5) at the end of the study. A total of 8 of 14 subjects taking prednisone at study initiation were able to significantly reduce the dosage by the end of the follow-up period (27.2 ± 6.0 mg to 4.7 ± 1.7 mg; p=0.02). Reductions in intermittent intravenous immune globulin infusions or plasma exchange were also significantly reduced in 11 subjects treated with a single cycle of rituximab (p=0.01 and p=0.02, respectively). Rituximab infusions were well tolerated, with only 3 subjects complaining of post-infusion headaches that resolved with standard anti-inflammatory drugs.

Collongues and colleagues (2012) reported results from the largest observational, retrospective multicenter study (n=20) to date that included the use of two different rituximab regimens to treat 13 refractory and 7 non-refractory individuals with myasthenia gravis. A total of 17 (85%) of the individuals were positive for AChR-Abs or MuSK-Abs. The mean follow-up period for the refractory myasthenia gravis cohort was 26 ± 13 months and 25 ± 13 months for the non-refractory myasthenia gravis group. After comparing a 2 year period before and after initiation of rituximab, the authors reported a statistically significant (p<0.001) decrease in the annual relapse rate for both groups. One year after rituximab therapy, there was a reduction in the use of prednisone with the mean dose decreasing from 38.5 ± 6.6 mg/day to 8.7 ± 3.7 mg/day for the refractory myasthenia gravis cohort and from 42.8 ± 8.4 mg/day to 6.4 ± 3.5 mg/day for the non-refractory myasthenia gravis cohort. The authors concluded that rituximab was "efficacious and well-tolerated" and "results should help investigators to design future therapeutic trials." The limitations of the study include the lack of a control group, retrospective design, small numbers, different rituximab dosages and schedules and the lack of long-term follow-up.

Diaz-Manera and colleagues (2012) reported retrospective results on 17 individuals with myasthenia gravis, of which 6 individuals had MuSk-Abs and 11 individuals had AChR-Abs. The entire cohort was resistant to prior prednisolone and at least three second-line immunosuppressive agents. With a mean follow-up time of 31 months (4-60 months) after therapy, all individuals with MuSK-Abs achieved remission (4 of 6) or minimal manifestations (2 of 6) status and no retreatment with rituximab was needed. A total of 10 out of 11 individuals with AChR-Abs improved at 3-month follow-up, but 6 individuals required retreatment with rituximab after a mean period of 17 months after the first dose; their status was reported again as "improved," but none of the 10 individuals with AChR-Abs reached minimal manifestation status or remission status (Kaplan-Meier, p=0.04). In addition, there were no significant changes in the second-line immunosuppressants. The authors noted that MuSK-Abs but not AChR-Abs decreased after the first dose of rituximab. The authors concluded the data suggests rituximab may be effective for individuals with myasthenia gravis and MuSK-Abs; however, the study was based on retrospective and observational data. The authors recommended a prospective double-blind randomized controlled trial should be conducted to investigate the efficacy and safety of rituximab as a first-line therapy.

Other Considerations

Iorio and colleagues (2015) performed a systematic review and meta-analysis evaluating the efficacy and safety of rituximab in the management of myasthenia gravis refractory to conventional immunosuppressive therapy. Uncontrolled observational studies were included; however, no randomized controlled trials were identified. A total of 37 studies of 168 subjects were included in the systematic review: 91 subjects had AChR-Abs, 70 subjects had MuSK-Abs, and 7 subjects were classified as "double seronegative" (dSN). The median age at onset of treatment was 43 years old (range 5-81). There was no difference in the proportion of subjects with refractory myasthenia gravis and severe disease as well as in the mean disease duration among the 3 different groups. The dose of rituximab administered was variable among the studies. Meta-analysis was performed on 15 studies after excluding case reports and studies that included less than 2 subjects. The overall response rate was 83.9%, and higher in MuSK-Ab subjects (88.8%) compared to AChR-Ab subjects (80.4%) and double seronegative subjects (85.6%); however, the differences in the response rates were not statistically significant. A total of 7 of 168 (4.2%) subjects experienced adverse effects, including infection (n=4), prolonged B-cell depletion (n=1) and heart failure after the third infusion of rituximab (n=1). The majority of subjects received a 4-dose, 375 mg/m2 rituximab regimen. The authors stated there is currently no consensus on the appropriate dose schedule for use of rituximab in the management of relapsed or refractory myasthenia gravis.

The current evidence in the peer-reviewed published medical literature consist of several retrospective, nonrandomized case series suggesting the non-FDA approved use of rituximab may improve minimal manifestation status and reduce the antibody titers in some individuals with refractory or relapsed myasthenia gravis. However, the lack of randomized controlled trials with larger sample sizes and long-term follow-up data preclude definitive conclusions regarding the appropriate individual selection criteria, effective dosing regimens and long-term safety in individuals with myasthenia gravis. There is an ongoing randomized, double-blind, phase II clinical trial (NCT02110706) currently investigating the safety and effectiveness of rituximab treatment in individuals with myasthenia gravis. The study is expected to enroll 50 subjects with an estimated primary completion date of May 2017 (final data collection date for primary outcome measure).

Solid Organ Transplant Rejection (Except Kidney)

The peer-reviewed published literature regarding off-label use of rituximab as a treatment for solid organ transplant rejection (following heart, liver, lung, or pancreas transplantation) includes case series, phase I and pilot studies. Ravichandran and colleagues (2013) reported a retrospective case review of 33 cardiac recipients who had clinical suspicion of rejection (signs or symptoms of heart failure and/or hemodynamic compromise), C4d complement staining on endomyocardial biopsy, and absence of grade 2R or greater cellular rejection. A total of 13 of the 20 individuals received rituximab. Immunosuppressive regimens varied; all individuals received steroids. All rituximab-treated individuals (100%) and 80% of controls survived at least 1 week. At year 3, survival rates were 75% and 29% in the rituximab and control groups, respectively (p=0.009). Infections and rehospitalizations occurred in 4 (31%) and 8 (65%) of 13 rituximab-treated individuals, respectively, and in 2 (10%) and 7 (35%) of 20 controls.

In a number of small case series, the use of rituximab was described in 4 individuals who developed antibody-mediated rejection after pancreas transplantation. Torrealba and colleagues (2008) reported on a case series of individuals (n=18) in which 1 individual received rituximab plus intravenous corticosteroid, intravenous immune globulin, and plasmapheresis for antibody-mediated rejection after simultaneous pancreas-kidney transplantation. This individual subsequently required chronic insulin therapy for blood glucose control. Three individuals with type 1 diabetes mellitus who underwent simultaneous pancreas-kidney transplantation and developed antibody-mediated rejection received single doses of rituximab 375 mg/m2 in combination with T-cell-directed therapies (thymoglobulin and daclizumab) (Vendrame, 2010) or intravenous immune globulin and plasmapheresis (Melcher, 2006). Two individuals in the first group remained insulin-independent for 36 months and 12 months, and 1 individual in the second group remained insulin-independent for 10 months of follow-up.

In a review of antibody-mediated rejection by Singh and colleagues (2009a), the suppression or depletion of B-cells by rituximab was noted as one treatment option to treat antibody-mediated rejection. Other treatments of antibody-mediated rejection include suppression of T-cell dependent antibody responses; removal of donor reactive antibody and blockade of the residual alloantibody; however, the authors concluded, "Rituximab deletes the naïve B-cell pool, but has no effect on plasma cells" and the efficacy of rituximab in the treatment of antibody-mediated rejection "remains poorly understood. Although all published antibody-mediated rejection (AMR) protocols report a variable rate of success, a major weakness of all current protocols is the lack of effective anti-plasma cell agents."

The International Society of Heart and Lung Transplantation (Costanzo, 2010) has published evidence-based consensus guidelines for the care of heart transplant recipients. Rituximab is recommended for:

In summary, there is insufficient evidence in the peer-reviewed published literature to draw reasonable conclusions regarding the long-term clinical effectiveness, optimal anti-rejection regimen and safety of rituximab as a treatment for solid organ transplant rejection. Prospective, randomized control trials are needed to determine the clinical effectiveness and net health outcomes of rituximab therapy on transplant grafts and OS.


Myasthenia Gravis

Myasthenia gravis is an autoimmune disease resulting in an alteration of the functioning of acetylcholine receptors in the neuromuscular junction. This disruption prevents the contraction of muscles and results in varying degrees of weakness in the voluntary muscles. Treatment typically consists of anticholinesterase agents to improve neuromuscular transmission and improve muscle strength. In some individuals, additional therapies with other drugs may be required. There are ongoing studies investigating the use of rituximab and other immunosuppressive agents to determine the effectiveness and long-term safety with these therapies (National Institutes of Health, 2016).

Rheumatoid Arthritis

Rheumatoid arthritis is a chronic inflammatory and progressive disease characterized by symmetrical joint involvement, which causes pain, swelling, stiffness, and loss of function in the joints. If left untreated, it may lead to joint destruction and progressive disability. Rheumatoid arthritis affects 2.1 million Americans usually striking people between the ages of 20 and 60, and people in their mid to late fifties are especially vulnerable. Rheumatoid arthritis is three times more common in women than in men. The traditional pharmacologic approach consists of NSAIDs to reduce pain, swelling, and inflammation, plus a DMARD such as methotrexate to slow the course of the disease and prevent joint and cartilage destruction.

Adverse Events and Warnings

Black box warnings from the FDA PI Label (Rituxan, 2014) include the following:

Additional Warnings from the FDA PI Label (2014) include:


Disease modifying anti-rheumatic drugs (DMARDs): A variety of medications (i.e., methotrexate, sulfasalazine, hydroxychloroquine) which work by altering the immune system function to halt the underlying processes that cause certain forms of inflammatory arthritis including rheumatoid arthritis.

Monoclonal Antibody: A protein developed in the laboratory that can locate and bind to specific substances in the body and on the surface of cancer cells.

Nonbiologic disease modifying antirheumatic drugs (DMARDs): A class of drugs, also referred to as synthetic DMARDs, thought to work by altering the immune system function to halt the underlying processes that cause certain forms of inflammatory conditions, although their exact mechanisms of action are unknown; includes azathioprine, hydroxychloroquine, leflunomide, methotrexate, minocycline, organic gold compounds, penicillamine, and sulfasalazine.

Refractory disease: Illness or disease that does not respond to treatment.

Relapse: After a period of improvement, the return of signs and symptoms of illness or disease.

Tumor necrosis factor (TNF) antagonists: A class of drugs (including, adalimumab, certolizumab pegol, etanercept, etanercept-szzs, golimumab, infliximab, and infliximab-dyyb) designed to neutralize inflammatory cytokines and utilized in the treatment of moderately to severely active rheumatoid arthritis.


The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.  

When services may be Medically Necessary when criteria are met for non-oncologic indications:

J9310 Injection, rituximab, 100 mg [Rituxan]
ICD-10 Diagnosis    
B17.10-B17.11 Acute hepatitis C  
B18.2 Chronic viral hepatitis C  
B19.20-B19.21 Unspecified viral hepatitis C  
D59.0-D59.1 Drug-induced, other autoimmune hemolytic anemias  
D68.311 Acquired hemophilia  
D69.3 Immune thrombocytopenic purpura (idiopathic thrombocytopenic purpura)  
D89.1 Cryoglobulinemia  
D89.810-D89.89 Other specified disorders involving the immune mechanism, not elsewhere classified [Graft-versus-host disease, ALPS]  
G35 Multiple sclerosis  
G36.0 Neuromyelitis optica [Devic]  
L10.0-L10.9 Pemphigus  
L12.0-L12.9 Pemphigoid (epidermolysis bullosa)  
M05.00-M05.9 Rheumatoid arthritis with rheumatoid factor  
M06.00-M06.09 Rheumatoid arthritis without rheumatoid factor  
M06.80-M06.9 Other specified rheumatoid arthritis and rheumatoid arthritis, unspecified  
M31.1 Thrombotic microangiopathy (thrombotic thrombocytopenic purpura)  
M31.30-M31.31 Wegener's granulomatosis  
M31.7 Microscopic polyangiitis  
M32.0-M32.9 Systemic lupus erythematosus (SLE)  
M35.00-M35.09 Sicca syndrome (Sjögren)  
M35.5 Multifocal fibrosclerosis [when specified as immunoglobulin G4-related disease]  
M35.9 Systemic involvement of connective tissue, unspecified [when specified as immunoglobulin G4-related disease]  
N01.0-N01.9 Rapidly progressive nephritic syndrome  
N04.0-N04.9 Nephrotic syndrome  
N06.0-N06.9 Isolated proteinuria with specified morphological lesion  
N08 Glomerular disorders in diseases classified elsewhere  
N18.1-N18.9 Chronic kidney disease (CKD)  
Q81.0-Q81.9 Epidermolysis bullosa  
T86.00-T86.99 Complications of transplanted organs and tissue  
Z48.22 Encounter for aftercare following kidney transplant  
Z94.0 Kidney transplant status  

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other non-oncologic or related diagnoses not listed, or when the code describes a procedure indicated in the Position Statement as investigational and not medically necessary.


Peer Reviewed Publications:

  1. Aggarwal R, Bandos A, Reed AM, et al. Predictors of clinical improvement in rituximab-treated refractory adult and juvenile dermatomyositis and adult polymyositis. Arthritis Rheumatol. 2014; 66(3):740-749.
  2. Ahn YH, Kang HG, Lee JM, et al. Development of antirituximab antibodies in children with nephrotic syndrome. Pediatr Nephrol. 2014; 29(8):1461-1464.
  3. Allen KJ, Wolverton SE. The efficacy and safety of rituximab in refractory pemphigus: a review of case reports. J Drugs Dermatol. 2007; 6(9):883-889.
  4. Alping P, Frisell T, Novakova L, et al. Rituximab versus fingolimod after natalizumab in multiple sclerosis patients. Ann Neurol. 2016; 79(6):950-958.
  5. Anderson D, Phan C, Johnston WS, Siddiqi ZA. Rituximab in refractory myasthenia gravis: a prospective, open-label study with long-term follow-up. Ann Clin Transl Neurol. 2016; 3(7):552-555.
  6. Andolino TP, Reid-Adam J. Nephrotic syndrome. Pediatr Rev. 2015; 36(3):117-125.
  7. Arnold DM, Dentali F, Crowther MA, et al. Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann Intern Med. 2007; 146(1):25-33.
  8. Bar-Or A, Calabresi AJ, Arnold D, et al. Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann Neurol. 2008; 63:395-400.
  9. Beck L, Bomback AS, Choi MJ, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis. Am J Kidney Dis. 2013; 62(3):403-441.
  10. Bianchi V, Robles R, Alberio L, et al. Von Willebrand factor-cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura. Blood. 2002; 100(2):710-713.
  11. Blum S, Gillis D, Brown H, et al. Use and monitoring of low dose rituximab in myasthenia gravis. J Neurol Neurosurg Psychiatry. 2011; 82(6):659-663.
  12. Bomback AS, Derebail VK, McGregor JG, et al. Rituximab therapy for membranous nephropathy: a systematic review. Clin J Am Soc Nephrol. 2009; 4:734-744.
  13. Carruthers MN, Topazian MD, Khosroshahi A, et al. Rituximab for IgG4-related disease: a prospective, open-label trial. Ann Rheum Dis. 2015; 74(6):1171-1177.
  14. Castillo-Trivino T, Braithwaite D, Bacchetti P, Waubant E. Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review. 2013; 8(7):e66308.
  15. Collins PW, Mathias M, Hanley J, et al. Rituximab and immune tolerance in severe hemophilia A: a consecutive national cohort. J Thromb Haemot. 2009; 7(5):787-794.
  16. Collongues N, Casez O, Lacour A, et al. Rituximab in refractory and non-refractory myasthenia: a retrospective multicenter study. Muscle Nerve. 2012; 46(5):687-691.
  17. Cree BA, Lamb S, Morgan K, et al. An open label study of the effects of rituximab in neuromyelitis optica. Neurology. 2005; 64(7):1270-1272.
  18. Cutler C, Miklos D, Kim HT, et al. Rituximab for steroid-refractory chronic graft-versus-host disease. Blood. 2006; 108:756-762.
  19. Diaz-Manera J, Martinez-Hernandez E, Querol L, et al. Long-lasting treatment effect of rituximab in MuSK myasthenia. Neurology. 2012; 78(3):189-193.
  20. de Flon P, Gunnarsson M, Laurell K, et al. Reduced inflammation in relapsing-remitting multiple sclerosis after therapy switch to rituximab. Neurology. 2016; 87(2):141-147.
  21. Donahue KE, Gartlehner G, Jonas DE, et al. Systematic review: comparative effectiveness and harms of disease-modifying medications for rheumatoid arthritis. Ann Intern Med. 2008; 148(2):124-134.
  22. Drachman DB, Adams RN, Hu R, et al. Rebooting the immune system with high-dose cyclophosphamide for treatment of refractory myasthenia gravis. Ann N Y Acad Sci. 2008; 1132:305-314.
  23. Franchini M, Mengoli C, Lippi G, et al. Immune tolerance with rituximab in congenital haemophilia with inhibitors: a systematic literature review based on individual patients' analysis. Haemophilia. 2008; 14(5):903-912.
  24. Froissart A, Buffet M, Veyradier A, et al. Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center. Crit Care Med. 2012; 40(1):104-111.
  25. Fujinaga S, Hirano D. Risk factors for early relapse during maintenance therapy after a single infusion of rituximab in children with steroid-dependent nephrotic syndrome. Pediatr Nephrol. 2014; 29:491-492.
  26. Fujinaga S, Sakuraya K, Yamada A, et al. Positive role of rituximab in switching from cyclosporine to mycophenolate mofetil for children with high-dose steroid-dependent nephrotic syndrome. Pediatr Nephrol. 2015; 30:687-691.
  27. Golbin JM, Specks U. Targeting B lymphocytes as therapy for ANCA-associated vasculitis. Rheum Dis Clin N Am. 2007; 33:741-754.
  28. Gudbrandsdottir S, Birgens HS, Frederiksen H, et al. Rituximab and dexamethasone vs dexamethasone monotherapy in newly diagnosed patients with primary immune thrombocytopenia. Blood. 2013; 121(11):1976-1981.
  29. Harambat J, Lamireau D, Delmas Y, et al. Successful treatment with rituximab for acute refractory thrombotic thrombocytopenic purpura related to acquired ADAMTS13 deficiency: a pediatric report and literature review. Pediatr Crit Care Med. 2011; 12(2):e90-e93.
  30. Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008; 358(7):676-688.
  31. Hawker K, O'Connor P, Freedman MS, et al. Rituximab in patients with primary progressive multiple sclerosis. Results of a randomized double-blind placebo-controlled multicenter trial. Annals of Neurol. 2009; 66(4):460-471.
  32. Hoyer PF. New lessons from randomized trials in steroid-sensitive nephrotic syndrome: clear evidence against long steroid therapy. Kidney Int. 2015; 87:17-19.
  33. Iijima K, Sako M, Nozu K, et al. Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2014; 384(9950):1273-1281.
  34. Illa I, Diaz-Manera J, Rojas-Garcia R, et al. Sustained response to rituximab in anti-AChR and anti-MuSK positive myasthenia gravis patients. J Neuroimmunol. 2008; 201-202:90-94.
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Government Agency, Medical Society, and Other Authoritative Publications:

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Monoclonal Antibody

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History




Revised 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Added MN statement for use of rituximab in relapsing forms of multiple sclerosis when criteria are met. Revised INV and NMN statement for multiple sclerosis, adding "other than relapsing forms (such as, primary progressive or secondary progressive)." Updated Description, Rationale, Coding, References, and Websites for Additional Information sections.
Revised 11/03/3016 MPTAC review.
Revised 11/02/2016 Hematology/Oncology Subcommittee review. Revised Subject (title) of document to: Rituximab (Rituxan® ) for Non-Oncologic Indications. Updated formatting in Position Statements. Rescoped document, removing use of rituximab for oncologic indications (FDA approved and off label uses) from the MN statements. Clarified MN statement for rheumatoid arthritis. Clarified MN statement for thrombotic thrombocytopenia purpura, adding diagnostic criteria. Combined INV and NMN statements into a single statement. Updated Description, Rationale, Background, Definitions, Coding, References and Websites for Additional Information sections.
  10/01/2016 Updated Coding section with 10/01/2016 ICD-10-CM diagnosis code changes.
Revised 05/05/2016 MPTAC review.
Revised 05/04/2016 Hematology/Oncology Subcommittee review. Format changes throughout MN and INV and NMN criteria. Clarified MN statement V. Other Indications: 1) Removed "Systemic Autoimmune Disorders" from statement for use in Cryoglobulinemia, primary Sjögren Syndrome (SS), or Systemic Lupus Erythematosus (SLE) refractory to standard therapy (that is, lack of response to corticosteroids and at least 2 immunosuppressive agents) and reordered criteria; 2) Added MN indications for IgG4-RD, pediatric nephrotic syndrome, and TTP when criteria are met. Updated Description. Rationale, Background, References, and Websites for Additional Information sections. Updated Coding section and removed ICD-9 codes.
Reviewed 08/06/2015 MPTAC review. Updated Rationale, Background, References and Websites.
Revised 11/13/2014 MPTAC review.
Revised 11/12/2014 Hematology/Oncology Subcommittee review. Added medically necessary criteria for hepatitis C virus (HCV) infection-related cryoglobulinemic vasculitis. Updated Rationale, Background, Coding, References and Websites.
Revised 11/14/2013 MPTAC review.
Revised 11/13/2013 Hematology/Oncology Subcommittee review. Removed requirement for CLL and hairy cell leukemia be CD20+. Moved medically necessary hairy cell leukemia indication to CLL section. Moved medically necessary Waldenström's macroglobulinemia indication to lymphoma section. Added maintenance therapy criteria for relapsed or refractory Hodgkin lymphoma.
Updated Rationale, Background, Coding, References and Websites.
Revised 05/09/2013 MPTAC review.
Revised 05/08/2013 Hematology/Oncology Subcommittee review. Clarification of rheumatoid arthritis criteria and addition of MTX contraindication criteria. Updated Rationale, References and Websites.
Reviewed 05/10/2012 MPTAC review.
Reviewed 05/09/2012 Hematology/Oncology Subcommittee review. Added medically necessary indication for acquired inhibitors with criteria. Updated Rationale, Coding, References and Websites.
Revised 11/17/2011 MPTAC review.
Revised 11/16/2011 Hematology/Oncology Subcommittee review. Replaced ANCA+ renal vasculitis off-label medically necessary indication with the new FDA labeled indication for Wegener's granulomatosis and microscopic polyangiitis. Clarified Multicentric Castleman's Disease. Updated Rationale, Coding, Reference and Website sections.
Revised 11/18/2010 MPTAC review.
Revised 11/17/2010 Hematology/Oncology Subcommittee review. Removed medically necessary indication for thrombotic thrombocytopenic purpura. Updated Coding section.
Revised 08/19/2010 MPTAC review. Added medically necessary criteria for ANCA-positive associated renal vasculitis; and CD20+ lymphoma associated with Castleman's Disease. Added medically necessary criteria for neuromyelitis optica, and as third line of therapy or greater for graft versus host disease. Updated Rationale, Coding, References and Web Sites.
Revised 05/13/2010 MPTAC review.
Revised 05/12/2010 Hematology/Oncology Subcommittee review. Updated FDA approved indication for CLL. Added clarification to medically necessary criteria for treatment of rheumatoid arthritis regarding intolerance or contraindication to methotrexate. Added medically necessary criteria for pre-renal transplant treatment to suppress panel reactive anti-HLA antibodies in individuals with high panel reactive antibody (PRA) levels to human leukocyte antigens (HLA).
Added medically necessary criteria for post-renal transplant use in individuals with acute rejection who had received rituximab treatment pre-transplant. Updated rationale, coding, references and websites.
Revised 08/27/2009 MPTAC review. Clarified investigational and not medically necessary statement. Updated rationale, references and websites. Updated coding to include 10/01/2009 ICD-9 changes.
Revised 05/21/2009 MPTAC review.
Revised 05/20/2009 Hematology/Oncology Subcommittee review. Added medical necessity criteria for refractory autoimmune blistering skin disease, hairy cell leukemia, specified systemic autoimmune diseases and Waldenström's macroglobulinemia. Rationale, references, websites and coding updated.
New 02/26/2009 MPTAC review. Initial document development.