Clinical UM Guideline


Subject: Rituximab (Rituxan®) for Non-Oncologic Indications
Guideline #: CG-DRUG-94 Publish Date:    12/27/2018
Status: Revised Last Review Date:    09/13/2018


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:

Clinical Indications

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 Sjogren 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 either of the following are met:
      1. As first-line treatment in adults with moderate to severe pemphigus vulgaris; or
      2. Disease is treatment-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).

Not Medically Necessary:

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


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.




Injection, rituximab, 10 mg [Rituxan]



ICD-10 Diagnosis




Acute hepatitis C



Chronic viral hepatitis C



Unspecified viral hepatitis C



Drug-induced, other autoimmune hemolytic anemias



Acquired hemophilia



Immune thrombocytopenic purpura (idiopathic thrombocytopenic purpura)






Other specified disorders involving the immune mechanism, not elsewhere classified [Graft-versus-host disease, ALPS]



Multiple sclerosis



Neuromyelitis optica [Devic]






Pemphigoid (epidermolysis bullosa)



Rheumatoid arthritis with rheumatoid factor



Rheumatoid arthritis without rheumatoid factor



Other specified rheumatoid arthritis and rheumatoid arthritis, unspecified



Thrombotic microangiopathy (thrombotic thrombocytopenic purpura)



Wegener’s granulomatosis



Microscopic polyangiitis



Systemic lupus erythematosus (SLE)



Sicca syndrome (Sjögren)



Multifocal fibrosclerosis [when specified as immunoglobulin G4-related disease]



Systemic involvement of connective tissue, unspecified [when specified as immunoglobulin G4-related disease]



Rapidly progressive nephritic syndrome



Nephrotic syndrome



Isolated proteinuria with specified morphological lesion



Glomerular disorders in diseases classified elsewhere



Chronic kidney disease (CKD)



Epidermolysis bullosa



Complications of transplanted organs and tissue



Encounter for aftercare following kidney transplant



Kidney transplant status


Note: this document does not address the use of rituximab for any oncology-related diagnosis code.

Discussion/General Information

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, 2018). 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 (Rituxan PI Label, 2018):

Pemphigus Vulgaris and Other Autoimmune Pemphigoid Blistering Skin Diseases

Pemphigus Diseases

Pemphigus is a life-threatening autoimmune blistering disease affecting the skin and mucosa and is comprised of three major forms characterized by autoantibodies directed against epidermal cell junctions: pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus (PNP). Pemphigus blisters are more superficial and flaccid and often rupture. Exfoliation and blister formation with skin friction (Nikolsky sign) is positive in pemphigus vulgaris. The combination of high dose systemic corticosteroids and conventional immunosuppressive drugs, such as azathioprine and mycophenolate mofetil, are widely used in the treatment of pemphigus vulgaris. However, only 50% of persons achieve complete remission off-therapy. Many individuals relapse and require maintenance corticosteroid therapy, leading to high cumulative doses of corticosteroids and accompanying side effects. PNP is a unique autoimmune blistering condition that can affect multiple organs other than the skin. It is a life-threatening disease associated with an underlying malignancy, most commonly of lymphoproliferative origin. PNP presents most frequently between 45 and 70 years of age, but it also occurs in children and adolescents. The clinical picture may resemble pemphigus vulgaris, pemphigoid diseases, erythema multiforme, graft-versus-host disease, or lichen planus. The earliest and most consistent finding is a painful, severe, chronic and often recalcitrant stomatitis. Treatment of PNP is difficult, and the best outcomes have been reported with benign neoplasms that are surgically excised. The first-line treatment of PNP is high-dose corticosteroids with the addition of steroid-sparing agents. Treatment failures are often managed with rituximab, with or without intravenous immune globulin (IVIG). In general, the prognosis is poor, not only because of eventual progression of malignant tumors but also because treatment with aggressive immunosuppressive therapy often results in infectious complications, which is the most common cause of death in PNP (Tirado-Sanchez, 2017; Wieczoreck, 2016).

In May 2018, the FDA approved rituximab to treat moderate to severe pemphigus vulgaris in adults and has orphan drug status designation for this indication. Additionally, the AHFS (2016) states rituximab is used off-label for the treatment of refractory pemphigus vulgaris. The efficacy and safety of rituximab as first-line therapy for pemphigus vulgaris was evaluated in a prospective, multicenter, parallel-group, open-label randomized trial conducted in France (Ritux 3; NCT00784589) comparing a non-U.S. approved rituximab product in combination with short-term prednisone versus prednisone alone for the treatment of pemphigus vulgaris (Joly, 2017). Eligible subjects aged 18-80 years were newly diagnosed with pemphigus (n=74 pemphigus vulgaris; n=16 pemphigus foliaceus) and being treated for the first time (not at the time of a relapse). A total of 90 subjects were randomized to receive either daily oral prednisone with tapering over 12 or 18 months (prednisone alone group), or rituximab on days 0 and 14, and 500 mg at months 12 and 18, combined with a short-term daily prednisone regimen tapered over 3 or 6 months (rituximab plus short-term prednisone group). Subjects were followed for 3 years. The primary endpoint was the proportion of subjects who achieved complete remission off-therapy at month 24 (intention-to-treat analysis). At month 24, 41 of 46 (89%) subjects assigned to rituximab plus short-term prednisone were in complete remission off-therapy compared with 15 of 44 (34%) subjects assigned to prednisone alone (absolute difference, 55 percentage points; 95% CI, 38.4-71.7; p<0.0001). This difference corresponded to a relative risk of success of 2.61 (95% CI, 1.71-3.99, p<0.0001), corresponding to 1.82 subjects (95% CI, 1.39-2.60) who would need to be treated with rituximab plus prednisone (rather than prednisone alone) for one additional success. No subject died during the study. Severe adverse events of grade 3-4 were greater in the prednisone-alone group (53 events in 29 subjects; mean, 1.20) than in the rituximab plus prednisone group (27 events in 16 subjects; mean, 0.59; p=0.0021). The most common of these events in both groups were diabetes and endocrine disorders (11 [21%] with prednisone alone vs. 6 [22%] with rituximab plus prednisone), myopathy (10 [19%] vs. 3 [11%]), and bone disorders (5 [9%] vs. 5 [19%]).

An observational study with follow-up to 5 years (Cianchini, 2012) and small case series (Ahmed, 2016; Cho, 2014; Ingen-Housz-Oro, 2015; Joly, 2007) report a treatment benefit of rituximab, with or without corticosteroids, in terms of prolonged clinical response and remission rates as first-line treatment for pemphigus diseases. Brown and colleagues (2018) subsequently compared rates of clinical remission, serologic remission, and adverse effects of corticosteroids, IVIG, and rituximab in a retrospective review of 63 individuals with pemphigus vulgaris, pemphigus foliaceus, or PNP. Three study groups were compared: 1) individuals treated with systemic corticosteroids; 2) refractory individuals treated with IVIG; and, 3) refractory individuals treated with rituximab. The overall number of adverse effects was not significantly different between the groups but those observed in individuals treated with systemic corticosteroids were more severe. Clinical remission was less likely in the individuals treated with systemic corticosteroids than in individuals treated with IVIG or rituximab (p=0.000467). Serologic remission was more likely in individuals treated with systemic corticosteroids or rituximab than in those treated with IVIG (p=0.002118). Rituximab was significantly more likely to produce clinical remission than systemic corticosteroids therapy, suggesting its clinical utility as first-line treatment for pemphigus diseases.

Grando (2018) retrospectively analyzed long-term follow-up data on individuals with pemphigus disease to determine if rituximab was safe and effective in maintaining stable clinical remission when combined with other therapies including IVIG and immunosuppressive drugs. Clinical outcomes were summarized for 123 individuals (n=117 pemphigus vulgaris; n=6 pemphigus foliaceus) aged 6-89 years treated by the Blistering Disease Clinic at the University of California, Irvine from 2007 to 2017. All individuals had active disease on the first visit and had prior prednisone treatment with or without conventional immunosuppressive drugs. All individuals received a daily protocol of oral prednisone or methylprednisolone and minocycline (or doxycycline) and niacinamide. Prednisone dose was increased for disease progression or switched to methylprednisolone until disease control was achieved. IVIG was combined with mycophenolate mofetil, azathioprine, or cyclophosphamide to maintain complete remission of disease. Rituximab was administered to individuals who were intolerant of these immunosuppressive agents, including 8 individuals with refractory pemphigus vulgaris, 31 individuals with relapsed pemphigus vulgaris, and 2 individuals with relapsed pemphigus foliaceus. Corticosteroids were then tapered and all other medications were continued without a change for 6 months. If the individual maintained remission, the frequency of IVIG was decreased over time. The mean time to disease control was 0.2 months and time to complete remission was 1.7 months. Duration of complete remission on drugs until relapse or end of treatment was 19.3 months. The mean duration of complete remission off drugs until relapse was 15.8 months. The overall complete remission rate off all drugs was 100%, with 12% overall relapse rate. Most relapses, 8.1 versus 3.3%, occurred during the time of treatment, compared to posttreatment. No individual had more than a single relapse. The duration of the posttreatment follow-up ranged from 9 to 97 months (mean, 64.8 months). The clinical outcome in individuals that received IVIG with rituximab or another immunosuppressive drug were similar. No serious side effects or adverse reactions were observed in those treated with rituximab.

Pemphigoid Diseases

Pemphigoid diseases are a group of subepidermal, blistering, autoimmune diseases primarily affecting the skin, especially the lower abdomen, groin, and flexor surfaces of the extremities. Autoantibodies (anti-BPA-1 and anti-antibody 2) are directed against the basal layer of the epidermis and mucosa. The Nikolsky sign is negative in pemphigoid diseases. The condition tends to persist for months or years with periods of exacerbation and remission. There are two predominant types of pemphigoid diseases: bullous pemphigoid and mucous membrane pemphigoid (MMP) (also called cicatricial pemphigoid, MM-dominant epidermolysis bullosa acquisita [EBA], or MM-dominant linear IgA bullous dermatoses). Bullous pemphigoid is distinguished from other blistering skin diseases (that is, epidermolysis bullosa acquisita and MMP) by the following clinical presentations: 1) absence of atrophic scars; 2) absence of head and neck involvement; and, 3) relative absence of mucosal involvement. Initial therapy is determined by the extent and rate of progression of lesions. In MMP, the mucous membranes of the mouth and eyes are most often affected, but those of the nose, throat, genitalia, and anus may also be affected; scar formation can lead to major disability. The symptoms of MMP vary among affected individuals depending upon the specific site(s) involved and the progression of the disease. Localized variants of the condition have been reported, including pemphigoid gestationis, linear IgA disease, anti-laminin g1/anti-p200 pemphigoid, lichen planus pemphigoides, and pemphigoid with renal insufficiency. Azathioprine and mycophenolate mofetil or mycophenolate sodium are used in the treatment of pemphigoid diseases; however, mycophenolate mofetil may replace azathioprine as the first-line adjuvant of choice in the treatment of moderate to severe autoimmune bullous diseases, including epidermolysis bullosa acquisita and MMP pemphigoid, due to its safety profile. Likewise, oral cyclophosphamide provides optimal immunosuppression in the treatment of severe relapsing autoimmune bullous diseases, but it also produces the highest cumulative dose.

The off-FDA label use of rituximab has been reported in numerous single case reports, case series, and retrospective cohort studies (Ahmed, 2016; Barreiro-Capurro, 2013; Maley, 2016; Salman, 2017; Shetty and Ahmed, 2013a; Shetty and Ahmed, 2013b; You, 2017). Rituximab, in combination therapy with corticosteroids, conventional immunosuppressive drugs, with or without IVIG, has improved time to disease control or complete and sustained clinical remission with repeat rituximab treatment in children, adolescents, and adults with treatment-refractory pemphigoid diseases (including bullous pemphigoid, epidermolysis bullosa acquisita, and MPP [including ocular cicatricial/MPP pemphigoid disease]).

Lamberts and colleagues (2018) assessed the efficacy and safety of rituximab in recalcitrant pemphigoid diseases in 28 individuals with bullous pemphigoid (n=8), MMP (n=14), epidermolysis bullosa acquisita (n=5), and linear IgA disease (n=1). Early and late endpoints were disease control, partial remission, complete remission, and relapses. Treatment with 500 mg rituximab (n=6) or 1000 mg rituximab (n=22) was administered on days 1 and 15. Eight individuals received additional 500 mg rituximab at months 6 and 12. Overall, disease control was achieved in 67.9%, partial remission in 57.1%, and complete remission in 21.4% of the cases. A total of 66.7% of individuals relapsed during follow-up; repeated treatment with rituximab led to partial or complete remission in 85.7% of the retreated cases. There was no significant difference in response found between pemphigoid subtypes. Five severe adverse events and three deaths were reported; however, one death was possibly related to rituximab therapy and one death was related to disease complications.


The evidence on use of rituximab in combination with corticosteroids as first-line treatment of newly diagnosed pemphigus diseases and as treatment of refractory disease (with or without corticosteroids and other combination therapies) consists of a randomized controlled trial, case series, and retrospective cohort studies. The randomized controlled trial (Joly, 2017) found that individuals treated with rituximab and short-term corticosteroids (3 to 6 months) had significantly better outcomes than those treated with long-term corticosteroid use. Evidence on the off-label use of rituximab in pemphigoid diseases (specifically, bullous pemphigoid, epidermolysis bullosa acquisita, and MMP) in an individual refractory to first-line conventional therapy consists of case reports, case series, and retrospective comparative studies where most individuals responded to rituximab therapy. Adverse events include mild to moderate infusion-related reactions such as fever and chills/rigors. In most cases, these reactions occurred following the initiation of the first infusion and usually subsided with the slowing or interruption of the infusion as well as with symptomatic treatment. Premedication may reduce the probability of infusion-related adverse effects. Serious grade 3 or 4 adverse events associated with rituximab was described in some individuals with pemphigus vulgaris and pemphigoid diseases, including events that resulted in mortality. The current FDA label (Rituxan PI Label, 2018) includes warnings and precautions for use of rituximab in pemphigus vulgaris and other conditions.

Rheumatoid Arthritis (RA)

RA 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. RA 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. RA is three times more common in women than in men. The traditional pharmacologic approach consists of nonsteroidal anti-inflammatory drugs (NSAIDs) to reduce pain, swelling, and inflammation, plus a disease modifying antirheumatic drug (DMARD) such as methotrexate to slow the course of the disease and prevent joint and cartilage destruction.

In 2006, the FDA approved rituximab in combination with methotrexate in the treatment of adults with moderately to severely active RA who have an inadequate response to one or more TNF antagonist therapies. The PI label for rituximab (Rituxan, 2018) states there is limited available safety data on the use of biologic agents or DMARDs other than methotrexate following rituximab treatment in individuals with RA. 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-naive. Therefore, the PI label does not recommend use of rituximab if the individual with RA has not had a prior inadequate response to one or more TNF antagonists.

Porter and colleagues (2016) conducted an open-label, randomized controlled, non-inferiority trial (ORBIT; NCT01021735) that directly compared the safety and effectiveness of rituximab to TNF antagonist treatment in subjects with active RA 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 RA (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 rituximab 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 or etanercept 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 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-naive individuals with RA.

Other Considerations

In 2015, the ACR updated treatment recommendations for RA (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 (WG) and Microscopic Polyangiitis (MPA)

Granulomatosis with polyangiitis (GPA), more commonly known as WG, and MPA are subgroups of primary systemic small vessel vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA), also known as ANCA-associated vasculitis (AAV). AAV causes blood vessels to become inflamed or swollen and as a result, blood flow is restricted (Falk, 2011). The respiratory tract and kidneys are frequently the primary targets (Keogh, 2006). WG 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 WG and MPA. Use of concomitant immunosuppressants other than corticosteroids has not been studied in individuals with GPA or MPA exhibiting peripheral B-cell depletion following treatment with rituximab (Rituxan PI Label, 2018).

A double-blind, double-dummy, noninferiority, randomized controlled trial (Rituximab for ANCA-Associated Vasculitis [RAVE]) evaluated use of rituximab in 197 ANCA-positive subjects with WG or MPA (Stone, 2010). For induction of remission, subjects in the treatment group (n=99) received weekly rituximab for 4 weeks and placebo-cyclophosphamide. The control group (n=98) received standard therapy with daily cyclophosphamide plus placebo-rituximab infusions. Subjects in the treatment group who achieved remission between 3 and 6 months were switched from placebo-cyclophosphamide to placebo-azathioprine. Subjects 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 methylprednisolone followed by daily prednisone. The dose was tapered by 5 months to have glucocorticoids discontinued for subjects who were in remission. Primary endpoints were Birmingham Vasculitis Activity Score for WG (BVAS/WG) of 0 and successful prednisone taper at 6 months. 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 subjects in the rituximab group (85%) and 81 subjects 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 subjects with relapsing disease at baseline and treated with rituximab had reached the primary endpoint (67%) compared to 21 of 50 subjects (42%, p=0.01) in the control group. Adverse events occurred in 33 subjects in the control group (33%) compared to 22 subjects in the rituximab group (22%). Stone and colleagues (2010) concluded that 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 on 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 subjects treated with rituximab who achieved complete response at 6 months maintained response 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.”

Off-Label Non-Oncologic Indications for Use of Rituximab

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

Acquired Inhibitors in Hemophilia (AIH)

AIH is a rare condition that 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. Treatment of AIH typically involves immune tolerance and/or depletion of inhibitors with immunosuppression with prednisone and cyclophosphamide (Kruse-Jarres, 2011; Sperr, 2007). Due to the low incidence rate of AIH, published data demonstrating use of rituximab after failure of conventional therapy consists of case reports, case series and review articles (Collins, 2009; Kruse-Jarres, 2011; Rossi, 2016; Sperr, 2007; Wiestner, 2002). Rituximab therapy has resulted in a complete response rate of inhibitor reduction of 77% for those individuals without a sufficient reduction in inhibitors with standard immunosuppression with cyclophosphamide and prednisone (Sperr, 2007). Additionally, specialty consensus recommends the off-label use of rituximab to treat individuals with AIH who have failed cyclophosphamide and prednisone treatment.

Autoimmune Hemolytic Anemia (AHA)

AHA is an uncommon condition with cases classified as warm AHA or cold agglutinin disease. AHA is typically idiopathic or secondary to another diagnosis, and involves the production of autoantibodies and the hemolysis of red blood cells. Treatment of AHA depends on this classification and typically includes corticosteroids, immunosuppressants, immunoglobulin and splenectomy. Use of rituximab in treatment refractory AHA has been evaluated in two multicenter, randomized controlled trials (Birgens, 2013; Michel, 2017), a meta-analysis of observational studies (Reynaud, 2015), prospective and retrospective single arm studies (Ducassou, 2017; Maung, 2013), and numerous small case studies and single case reports. Specialty consensus opinion recommends the off-label use of rituximab for treatment of this condition.

Cryoglobulinemia, Primary Sjogren Syndrome, and Systemic Lupus Erythematosus (SLE)

Rituximab has been used as off-label treatment for various systemic autoimmune diseases. Ramos-Casals and colleagues (2008) systematically reviewed the published literature, stating it was difficult to make definitive off-label recommendations for use of biologic agents in the treatment of systemic autoimmune diseases due to lack of randomized controlled trials and heterogeneity in clinical features in this population. Based on the therapeutic response of > 80%, the authors noted rituximab should be considered a first choice biologic agent for treatment for individuals with cryoglobulinemia, primary Sjogren syndrome and SLE who are refractory to standard therapy (lack of response to corticosteroids and at least two immunosuppressive agents). Immunosuppressive agents utilized for the treatment of Sjogren syndrome include cyclosporine, methotrexate, azathioprine, corticosteroids, hydroxychloroquine, d-penicillamine, thalidomide, and nucleoside analogues (Mavragani, 2007). Additionally, specialty consensus opinion recommends the off-label 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 rituximab was used to treat 13 subjects with steroid-refractory GVHD. An overall response rate of 69%, with 23% (3 subjects) achieving complete response, 15% partial response and 30% mixed response, was reported by von Bonin (2008). Two subjects developed complications due to infection, with one death. Teshima and colleagues (2009) reported results from a phase II trial of 7 subjects with refractory chronic GVHD (cGVHD) who were treated with weekly rituximab for 4 weeks. At 1 year follow-up, the overall response rate was 43% with partial response in 3 subjects, stable disease in 3 subjects and 1 subject had progressive disease. The median reduction of steroids was 67%. At a median follow-up of 30 months, 5 subjects were alive and 2 deaths from infection were noted. In a retrospective study by GITMO (Gruppo Italiano Trapianto Midollo Osseo; Zaja, 2007), 38 subjects 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 subjects 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 demonstrates improvement in symptoms 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.”

Montero and colleagues (2018) evaluated randomised controlled trials and quasi-randomized controlled trials to identify the benefits and harms of currently available treatment options for hepatitis C virus-related mixed cryoglobulinemia with active manifestations of vasculitis (cutaneous or glomerulonephritis). In two studies, use of rituximab slightly improved skin vasculitis (n=78 participants; risk ratio [RR] 0.57, 95% CI, 0.28-1.16; moderate certainty evidence) and made little of no difference in kidney disease (moderate certainty evidence). Rituximab slightly increased infusion reactions compared to immunosuppressive medication (3 studies, 118 participants; RR 4.33, 95% CI, 0.76-24.75, moderate certainty evidence); however, treatment discontinuation due to adverse reactions were similar (3 studies, 118 participants: RR 0.97, 95% CI, 0.22-4.36, moderate certainty evidence). The authors concluded that use of rituximab may be beneficial to stop the immune response in hepatitis C virus-related mixed cryoglobulinemia. Likewise, for skin vasculitis, it may be appropriate to combine antiviral treatment with deletion of B-cell clonal expansions by using of rituximab.

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. Additionally, 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 subjects with IgG4-RD in whom 97% of subjects achieved disease responses that were maintained at 6 months with use of rituximab (Carruthers, 2015). In this study, 26 (87%) of subjects 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 subjects 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 subjects 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 subjects (10%) remained on glucocorticoids, 1 of whom remained on prednisone for his cold agglutinin-mediated anemia, not IgG4-RD. One subject 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 subjects with RRMS who were randomized in a 2:1 ratio to rituximab (n=69 subjects, rituximab given on days 1 and 15) and placebo infusion (n=35 subjects). At baseline, a higher proportion of subjects 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 subject; 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 subjects 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 subjects 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) evaluated the safety and effectiveness of rituximab in a retrospective observational study of subjects 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 subjects with MS were identified: 557 with RRMS, 198 with secondary progressive multiple sclerosis (SPMS), and 67 with primary progressive multiple sclerosis (PPMS). At baseline, 26.2% had contrast-enhancing lesions (CELs). Subjects were treated with 500 mg or 1000 mg rituximab every 6-12 months, during a mean 21.8 (SD 14.3) months. During treatment, a total of 59 subjects experienced relapse on rituximab treatment; the annualized relapse rates were 0.044 (RRMS), 0.038 (SPMS), and 0.015 (PPMS), and 4.6% of subjects 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 subjects. 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 subjects 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 subjects 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 doses of rituximab were given 2 weeks apart followed by repeated clinical assessment, MRI, and CSF-NFL for 24 months. A total of 71 subjects completed all clinical and radiologic assessments during the 24-month study period. The mean cumulated number of gadolinium-enhancing lesions per subject 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 subject 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 subjects 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 subjects 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.

In 2018, the American Academy of Neurology (AAN) published updated practice guideline recommendations on use of disease-modifying therapies for adults with MS (Rae-Grant, 2018). For adults with RRMS, the AAN guideline recommendations conclude:

For adults with PPMS, the AAN guideline concludes that “…rituximab is possibly no more effective than placebo in decreasing the risk of disease progression over 2 years (low confidence in the evidence, 1 Class II study).” A randomized controlled trial of rituximab in PPMS “…was promising but inconclusive (Hawker, 2009.”

Neuromyelitis Optica

Neuromyelitis optica (NMO) 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 NMO 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 NMO. Cree and colleagues (2005) reported results from an open-label series of 8 consecutive subjects with NMO who were treated with rituximab. At an average follow-up of 12 months, 6 subjects have remained free from attacks. Five subjects 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 subjects with NMO 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 subjects discontinuing treatment. Additionally, 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).

The Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (Scott, 2011) published an evidence-based guideline on the clinical evaluation and treatment of transverse myelitis due to NMO. The AAN’s Level C recommendation is based on review of two class III studies in which rituximab decreased the number of relapses in individuals with transverse myelitis due to NMO. 

Mealy and colleagues (2014) performed a retrospective, multicenter analysis of relapses in 90 individuals with NMO and NMO spectrum disorder treated with azathioprine, mycophenolate, and/or rituximab at the Mayo Clinic and the Johns Hopkins Hospital. Annualized relapse rates were analyzed from 10 years of data. In this group of individuals with NMO and NMO spectrum disorder, use of rituximab significantly reduced the relapse rate up to 88.2%.

The off-label use of rituximab in the treatment of NMO considers data from these case series which demonstrate improvements in relapse rates. Additionally, specialty consensus opinion recommends the off-label use of rituximab as treatment for NMO.

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 (ESRD).

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. Subjects 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. Subjects were randomized to receive rituximab 375 mg/m2 or placebo once weekly for 4 weeks. All subjects received standard steroid treatment for relapse at screening and stopped taking immunosuppressive agents by 169 days after randomization. A total of 48 of 52 subjects 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 subjects and 20 placebo-treated subjects. 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 subjects 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 subjects and 6 (25%) placebo group subjects; 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, subjects 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 subjects 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. Additionally,

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 subjects (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 subjects whose height was < 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%) subjects 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 subjects. 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 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 > 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.

Renal Transplantation

Renal transplantation is used for individuals with ESRD. 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 PRA 10% to 80% were transplanted 16% per year whereas PRA > 80% were transplanted < 8% per year. The available peer-reviewed published medical literature has evaluated use of rituximab in populations of subjects identified during the pre-renal transplant phase. However, use of rituximab in the post-transplant setting in subjects who did not receive rituximab treatment pre-transplant has not been studied.

A phase I-II trial examined if a treatment protocol, consisting of IVIG 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 subjects who were highly sensitized were treated with the combination regimen therapy. Vo and colleagues (2008) reported PRA were, “Significantly reduced after treatment with IVIG and rituximab (77 ± 19% before the first infusion of 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 subjects received successful transplantation (6 received a deceased donor kidney; 10 received a living donor kidney). The remaining 4 subjects had panel reactive antibody levels > 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 subjects. Acute antibody-mediated rejections (ABMR) occurred in 31% of the episodes and 2 subjects had late (> 6 months) ABMR episodes. Subjects with ABMR 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 IVIG and rituximab.

Vo and colleagues (2010) reported on 76 HLA-sensitized subjects who were treated with IVIG and rituximab prior to kidney transplantation. The study examined the efficacy of IVIG and rituximab on the reduction of anti-HLA antibodies that led to kidney transplantation with incurring the risk of ABMR and immediate graft loss. All subjects were deemed high immunologic risks with PRA 30%-79% in 25% of subjects, and 75% of the subjects had PRA ≥ 80%. A total of 31 subjects received living donor and 45 subjects received deceased donor kidney transplants. Data from 39 subjects show mean pretreatment class I PRA 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 IVIG and rituximab. Acute rejection occurred in 37% of subjects (8% cell mediated rejection and 29% ABMR). A total of 9 subjects had graft losses, with ABMR 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 ABMR 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 subjects prior to renal transplantation. Subjects meeting criteria, including PRA < 50%, were randomized to induction therapy (tacrolimus, mycophenolate mofetil and steroids) plus rituximab versus induction therapy plus placebo. A total of 136 subjects 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.

The KDIGO clinical practice guidelines (2017) on the evaluation and care of living kidney donors states that HLA-incompatible living donor transplantation remains the most difficult hurdle in achieving successful transplant outcomes. Acceptable management includes B-cell depleting treatments, including rituximab, “…but increased risk of early rejection remains, requiring additional immunosuppression and attendant risks to the recipient.” While incompatible transplantation after desensitization may offer a substantial survival benefit compared with dialysis or waiting for a deceased donor kidney, there are few high-quality studies testing this hypothesis.

Thrombocytopenic Purpura, Idiopathic or Immune

Idiopathic thrombocytopenic purpura (ITP), 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 IVIG, and splenectomy in severe cases.

Arnold and colleagues (2007) performed a systematic review of rituximab as a treatment of ITP in adults. A total of 19 studies including 313 subjects were identified for evaluation of efficacy and 29 articles including 306 subjects 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 > 150 x 109 cells/L, was observed in 43.6% of subjects. An overall response, defined as platelet count > 50 x 109 cells/L, was noted in 62.5% subjects 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 subjects identified 9 deaths out of 306 subjects, 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 ITP.

The initial report from a phase III, open-label trial of rituximab as first-line of therapy for ITP was reported by Gudbrandsdottir (2013). Subjects with newly diagnosed ITP 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 subjects were randomized; 4 subjects with incomplete data were excluded from the analysis. The dexamethasone alone group included 71 subjects who received dexamethasone 40 mg/day for 4 days. The treatment group of 62 subjects received dexamethasone and rituximab 375 mg/m2 weekly for 4 weeks. Additionally, 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 subjects 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).

Additionally, the AHFS (2016) states rituximab is used as an off-label treatment of ITP.

Thrombotic Thrombocytopenic Purpura (TTP)

TTP 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). TTP 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 TTP 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 TTP from acute hemolytic uremic syndrome (aHUS) is 90% (Bianchi, 2002; Zheng, 2004). Additionally, anti-ADAMTS 13 neutralizing antibodies are present in 38% to 95% of cases of idiopathic TTP (Froissart, 2012). The primary treatment of TTP 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 TTP, defined as progression of clinical symptoms during plasma exchange therapy, occurs in 10% to 20% of acquired TTP cases (Harambat, 2011). For these subjects, 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 subjects who have relapsed or refractory TTP 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 subjects with anti-ADAMTS13 antibody-positive, new-onset (85%) or acute relapsed (15%) TTP comparing subjects with an age-, sex-, and ethnicity-matched historical control group of 40 persons. Subjects were administered rituximab 375 mg/m2 weekly for 4 weeks; 3 subjects died and 1 subject withdrew before receiving all 4 doses of rituximab. All subjects 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; additionally, 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 subjects 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 subjects who relapsed (n=4, rituximab group; n=21, control group), the median time to relapse, defined as readmission with thrombocytopenia < 150 X 109/L 30 days after discharge from an acute episode, was longer in rituximab-treated subjects 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 TTP 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%) subjects achieved complete response, defined as platelet recovery, lack of TTP-related symptoms, and no evidence of microangiopathic hemolytic anemia lasting more than 30 days. Only 2 subjects were considered nonresponders. Nine percent of subjects 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 subjects (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) TTP 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 subjects (from a French registry) who were treated with vincristine, with or without cyclophosphamide. Both subjects 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 subjects (100%) versus 78% of historical controls. All rituximab-treated subjects (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 subjects while 5 control group subjects 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 TTP.

Other Proposed Non-Oncologic Off-Label Uses of Rituximab

The peer-reviewed published medical literature consists of case reports, small case series, non-randomized and uncontrolled trials, and systematic reviews evaluating rituximab in the treatment of other non-oncologic off-label uses. Some publications report short-term treatment outcomes for rare conditions which preclude reliable conclusions on the safety and long-term net health benefit of rituximab for these non-FDA approved uses, including, but not limited to, treatment of certain connective tissue diseases (CTDs) resulting in interstitial lung disease (Daoussis, 2017; Sharp, 2016), idiopathic inflammatory myositis (including dermatomyositis, polymyositis, and antisynthetase syndrome), and systemic sclerosis (scleroderma) (Thiebaut, 2018).

Autoimmune Encephalitis

N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune condition with prominent psychiatric symptoms which may include acute behavioral changes, psychosis, and catatonia, seizures, memory deficits, decrease of level of consciousness, dyskinesias, speech problems and central hypoventilation (autonomic and breathing dysregulation). NMDAR encephalitis resembles the phenotypes obtained with genetic and pharmacological decreases of levels and function of NMDAR. A substantial number of individuals with NMDAR encephalitis fail to respond to first-line immunotherapy, such as steroids, plasmapheresis, and IVIG and for these individuals, the treatment strategy and outcome are unknown (Titular, 2013). Additionally, studies suggest that the syndrome and response to treatment may differ between children and adults (Florance, 2009).

In a multi-institutional observational cohort study, Titular and colleagues (2013) tested for the presence of NMDAR antibodies in serum or cerebral spinal fluid (CSF) samples of individuals with encephalitis between 2007 and January 2012. A total of 577 subjects (median age, 21 years; range, 8 months to 85 years; n=211 children < 18 years) who tested positive for NMDAR antibodies were assessed at symptom onset and at months 4, 8, 12, 18, and 24, by use of the modified Rankin scale (mRS). Treatment included first-line immunotherapy (steroids, IVIG, and plasmapheresis) or tumor removal and second-line immunotherapy with rituximab and/or cyclophosphamide. There was no predefined protocol establishing the order or combination of treatments within each line of therapies. Predictors of outcome were determined by use of a generalized linear mixed model with binary distribution. A total of 125 assessable subjects who did not improve with first-line immunotherapy or tumor removal received second-line immunotherapy. Among those subjects, 84 of 125 reached an mRS 0-2 during the first 24 months, while 49 of 96 subjects who did not receive second-line immunotherapy reached an mRS 0-2 (median 10 and 15 months, respectively). Multivariable analysis identified the use of second-line immunotherapy as an additional factor for good outcome (odds ratio, 2.69, 95% CI, 1.24-5.80; p=0.012). A limitation of this study was lack of randomization to treatment resulting in selection bias. The choice of adding second-line immunotherapy was based on physician’s preference, family acceptance of potential side effects, and availability of the drugs. It was unclear how many subjects received single-agent rituximab. Another limitation includes lack of standard treatment regimens, as the frequency and duration of therapy was inconsistent for those treated with second-line immunotherapy.  

Dale and colleagues (2014) evaluated the efficacy and safety of rituximab in a multicenter retrospective study of 144 children and adolescents with pediatric autoimmune and inflammatory disorders of the central nervous system (CNS), of which 39 subjects had NMDAR encephalitis (females, n=29; median age at presentation, 8.7 years [range, 1.6-17 years); diagnostic marker: CSF NMDAR antibody [n=34], serum NMDAR antibody [n=5], and ovarian teratoma [n=3]). Prior immunotherapies in the NMDAR encephalitis subjects included steroids (n=37), IVIG (n=34), plasma exchange (n=11), cyclophosphamide (n=8), and mycophenolate mofetil or azathioprine (n=4). Rituximab was given after a median disease duration of 0.1 years (range, 0.05 to 5.1 years) in NMDAR encephalitis subjects. The investigators reported a “definite, probable, or possible benefit” of rituximab use in 16, 16, and 6 NMDAR encephalitis subjects, respectively. The change in mRS of 0 to 2 was greater in subjects given rituximab early in their disease course compared to those treated later. A total of 32 of 39 NMDAR encephalitis subjects experienced ongoing disability (including 2 deaths) following rituximab therapy. Overall, infusion adverse events were recorded in 18 of 144 (12.5%) study subjects, including anaphylaxis in 3 subjects. Eleven subjects (7.6%) experienced an infectious adverse event, including 2 subjects each with grade 5 (death) and grade 4 (disabling) infectious adverse events (median follow-up, 1.65 years [range of 0.1 to 8.5]). No subjects developed progressive multifocal leukoencephalopathy. The investigators concluded that off-label use of rituximab should be restricted to pediatric autoimmune and inflammatory CNS disorders with significant morbidity and mortality. Limitations of this study include the unblinded retrospective design, lack of a control group, and subjective assessment of treatment benefit.

The long-term risks and benefits of rituximab in the treatment of NMDAR encephalitis remains undefined. The heterogeneity of the presenting symptoms, lack of objective measures to evaluate improvement in disability, and use of other immunotherapies before and after rituximab therapy limits drawing conclusions as to the net health benefit of rituximab in the treatment of NMDAR encephalitis. Additional study is needed to determine the optimal dosing, frequency and duration of rituximab in homogenous patient populations with NMDAR encephalitis.

Limbic encephalitis represents a group of autoimmune conditions characterized by inflammation of the limbic system and other parts of the brain. The chief sign of limbic encephalitis is a severe impairment of short-term memory; however, symptoms may also include confusion, psychiatric symptoms, and seizures. Limbic encephalitis is often associated with an underlying neoplasm (paraneoplastic limbic encephalitis); however, some cases never have a neoplasm identified (non-paraneoplastic limbic encephalitis). Treatment includes removal of the neoplasm (if identified) and immunotherapy (National Institutes of Health [NIH], 2018). Lee and colleagues (2016) evaluated the efficacy and safety of rituximab as second-line immunotherapy for autoimmune limbic encephalitis to determine factors associated with functional improvement and favorable outcome following treatment. The authors reviewed a cohort of 80 subjects treated with rituximab as second-line immunotherapy for autoimmune limbic encephalitis and 81 subjects without rituximab as a control group from the Korea Autoimmune Synaptic and Paraneoplastic Encephalitis Registry. Subjects were grouped according to the detection or type of antibodies. Evaluation of clinical, laboratory, first-line immunotherapy, and rituximab treatment profiles was performed and improvements in outcomes defined as change in mRS score and a favorable mRS score (0 to 2) at the last follow-up. Functional improvement occurred more frequently in the rituximab group compared to the control group. In the rituximab group, 30 (37.5%) subjects had synaptic autoantibodies, 15 (18.8%) with paraneoplastic autoantibodies, and 35 subjects (43.8%) were antibody-negative. The effect of rituximab was the same regardless of autoantibody status. Additional monthly rituximab therapy and partial response to first-line immunotherapies were associated with mRS score improvements, as well as favorable mRS scores; mRS scores of 4 to 6 as the worst neurologic status predicted an unfavorable mRS score. There were no reported serious infusion-related or infectious adverse effects of rituximab. The authors concluded that rituximab was safe and effective as second-line immunotherapy for autoimmune limbic encephalitis, regardless of autoantibody status, suggesting that additional monthly therapy might potentiate the efficacy of rituximab. Limitations of this study include the non-randomized design, lack of standardized treatment and follow-up protocols, and absence of follow-up of serum immunoglobulin levels or autoantibody titers which may be a good indicator of response to rituximab. Additional well-designed randomized controlled studies with standardized treatment protocols are needed to establish the effectiveness of rituximab in the treatment of autoimmune limbic encephalitis.

Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)

The National Institutes of Health (NIH, 2017) describes CIDP as:

…a neurological disorder characterized by progressive weakness and impaired sensory function in the legs and arms. The disorder, which is sometimes called chronic relapsing polyneuropathy, is caused by damage to the myelin sheath (the fatty covering that wraps around and protects nerve fibers) of the peripheral nerves.

CIDP is more common in young adults, although it can occur at any age and in both genders. Presenting symptoms include numbness or tingling (beginning in the toes and fingers), weakness of the arms and legs, loss of deep tendon reflexes (areflexia), fatigue, and abnormal sensations. CIDP is closely related to Guillain-Barre syndrome and is considered the chronic counterpart of that acute disease. Treatment of CIDP includes corticosteroids (prednisone) prescribed alone or in combination with immunosuppressant drugs. Plasmapheresis/plasma exchange and IVIG therapy are considered other treatment options, with the latter used as first-line therapy.

Benedetti and colleagues (2011) retrospectively evaluated a cohort of 13 Italian subjects with CIDP treated with rituximab for partial or complete lack of response to conventional therapies; 8 of the 13 subjects had comorbid hematologic diseases. Treatment responders were those subjects who improved by at least two points in standard clinical scales, or who reduced or discontinued the pre-rituximab therapies. A total of 9 of 13 subjects (n=7 with hematologic diseases) responded to rituximab. Six of the 9 responders (who had complete lack of response to conventional therapies) improved clinically and the other 3 responders maintained improvement that they usually achieved with IVIG or plasma exchange. Responses to rituximab were significantly associated with shorter disease duration. The authors suggested that “timely post-onset administration of rituximab seems to be associated with better responses.”

Ware and colleagues (2014) reported on 10 cases of childhood CIDP managed at a single treatment center. IVIG was identified as the effective first-line therapy in most cases, with refractory cases responding to corticosteroids and rituximab.

Velardo and colleagues (2017) reported on use of rituximab in 4 subjects (1 adolescent; 3 adults) with severe, treatment-refractory CIDP. Pre-rituximab therapy included corticosteroids, IVIG, and other immunosuppressive agents. One subject had comorbid MGUS (anti-MAG negative disease). Rituximab was administered in three or four cycles. A comparison of standard nerve conduction parameters (including nerve conduction velocity) was performed between pre- and post-treatment follow-up examinations, with follow-up times varying from 18 to 36 months. The authors reported that all subjects showed marked improvement in terms of limb strength and disability. The interval between the first cycle of rituximab and the beginning of clinical recovery was very short for all subjects. One subject maintained stable disease and oral steroids were discontinued 6 months after the first rituximab infusion. Limitations of this case series include the small sample size, inconsistent reporting of assessment parameters for all subjects at all post-treatment examinations, and short-term outcomes.

In a Cochrane review, Mahdi-Rogers and colleagues (2017) evaluated the randomized and quasi-randomized trials of all immunosuppressive and immunomodulatory agents other than corticosteroids, IVIG and plasma exchange for the treatment of CIDP. Only four trials fulfilled the selection criteria, and none evaluated use of rituximab for CIDP. The authors suggest that future well-designed studies are needed of longer treatment duration with more sensitive outcome measures relevant to people with CIDP.

Idiopathic Inflammatory Myopathies (IIM)

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 subjects with myositis. A total of 200 randomized subjects (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 subjects 5 years of age or older with definite or probable JDM. Subjects were enrolled who had muscle weakness and ≥ two additional abnormal values on core set measures (CSMs) for adults. Juvenile DM subjects required ≥ to three abnormal CSMs, with or without muscle weakness. Subjects 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 subjects in the early and late rituximab groups achieving the DOI at week 8. Among the randomized subjects, 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 subjects met the DOI, and individual CSMs improved in both groups. Only 1 subject withdrew early due to an adverse event in the late rituximab group. There were 67 serious adverse events in 64 subjects, 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 subjects with biopsy-proven membranous nephropathy treated with rituximab as primary or secondary immunosuppression. Majority of the subjects 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 subjects 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 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 subjects (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 rituximab 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 subjects 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 < 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 IVIG), 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®, 2018) 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). Additionally, 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, 2018; 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 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 subjects 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, IVIG, and/or thymectomy (DrugPoints, 2018). Rituximab was administered weekly for 4 weeks and additional doses if necessary. Retreatment was administered as an additional dose 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 in two doses given 2 weeks apart; subjects were retreated with the same dosage if relapsed and recovery of B lymphocyte count was > 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 every week for 4 consecutive weeks then monthly for 2 months, or 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 IVIG 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 subjects with myasthenia gravis. A total of 17 (85%) of the subjects 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 subjects with myasthenia gravis, of which 6 subjects had MuSk-Abs and 11 subjects 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 subjects 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 subjects with AChR-Abs improved at 3-month follow-up, but 6 subjects 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 subjects with AChR-Abs reached minimal manifestation status or remission status (Kaplan-Meier, p=0.04). Additionally, 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 subjects 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 evaluate 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 < 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 studying the safety and effectiveness of rituximab treatment in subjects with myasthenia gravis. The study is expected to enroll 50 subjects with an estimated study completion date of May 2018.

Solid Organ Transplant Rejection (Except Kidney)

The evidence in the peer-reviewed published medical literature regarding off-label use of rituximab for individuals who have solid organ transplantation (that is, heart, liver, lung, or pancreatic islet transplantation) and are receiving induction immunosuppressive therapy or who have ABMR includes small case series, cohort studies and pilot studies. Ravichandran and colleagues (2013) performed 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 subjects received rituximab. Immunosuppressive regimens varied; all subjects received steroids. All rituximab-treated subjects (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 subjects, 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 subjects who developed ABMR after pancreas transplantation. Torrealba and colleagues (2008) reported on a case series of subjects (n=18) in which 1 subject received rituximab plus intravenous corticosteroid, IVIG, and plasmapheresis for ABMR after simultaneous pancreas-kidney transplantation. This subject subsequently required chronic insulin therapy for blood glucose control. Three subjects with type 1 diabetes mellitus who underwent simultaneous pancreas-kidney transplantation and developed ABMR received single doses of rituximab 375 mg/m2 in combination with T-cell-directed therapies (thymoglobulin and daclizumab) (Vendrame, 2010) or IVIG and plasmapheresis (Melcher, 2006). Two subjects in the first group remained insulin-independent for 36 months and 12 months, and 1 subject in the second group remained insulin-independent for 10 months of follow-up.

In a review of ABMR by Singh and colleagues (2009a), the suppression or depletion of B-cells by rituximab was noted as one treatment option to treat ABMR. Other treatments of ABMR 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 ABMR “remains poorly understood. Although all published ABMR 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:

The International Society of Heart and Lung Transplantation (Levine, 2016) published a set of evidence-based consensus guidelines on the care of lung transplant recipients. The guideline recognize AMR as a cause of allograft dysfunction in lung transplant recipients and unlike AMR in other solid-organ transplant recipients, there are no standardized diagnostic criteria or an agreed-upon definition. The sensitized candidate presents unique challenges in the pre-and post-transplant setting, as “waitlist protocols for desensitization have generally been based on kidney transplant candidate protocols and involve IVIg and plasmapheresis with occasional addition of bortezomib and rituximab.” The guideline notes these interventions “…may reduce mean fluorescent intensity (MFI) without changing the PRA and thus may not increase the donor pool.” As the majority of lung transplants are unscheduled, the timing of waitlist desensitization is problematic if antibody levels rebound. The guideline states that perioperative management with plasmapheresis, immunoabsorption, IVIG, or rituximab may improve outcomes in a recipient with known donor-specific antibodies (DSA); however, this consensus statement is based on observational data from renal transplant protocols (Vo, 2010).

In summary, there is insufficient evidence in the peer-reviewed published medical 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.

Stiff Person Syndrome

Stiff person syndrome, also known as Moersch-Woltman syndrome, is a rare antibody-mediated impaired γ-aminobutyric acidergic (GABAergic) syndrome with features of an autoimmune disorder. The condition is characterized by progressive muscle stiffness and repeated episodes of painful muscle spasms that occur randomly or are triggered by a variety of different events, including a sudden noise or light physical contact. The severity and progression of symptoms varies from one person to another and if left untreated, can progress to difficulty walking and may significantly impact a person's ability to perform routine daily tasks. Most individuals improve with GABA-enhancing drugs and IVIG, but some respond poorly and remain disabled. Disease prevalence is 1 to 2 persons in a million, and as a result, randomized controlled studies examining the efficacy of various treatment regimens are lacking (Rineer, 2017). The available literature evaluating use of rituximab in stiff person syndrome consists of a single double-blind, placebo-controlled study and a few anecdotal case reports.

Dalakas and colleagues (2017) reported outcomes from a double-blind, placebo-controlled study of two biweekly injections of rituximab in 24 subjects with symptomatic stiff person syndrome as confirmed by high serum anti-glutamic acid decarboxylase (GAD) antibody titers. The primary outcome was a change in stiffness scores at 6 months. Secondary outcomes were changes in heightened-sensitivity and quality of life scores. No statistically significant changes were noted at 3 or 6 months after treatment in all outcomes. Quality of life scores improved significantly (p<0.01) at 3 months in both groups, but not at 6 months, suggesting an early placebo effect. The authors suggested that rituximab's lack of efficacy could be due to a considerable placebo effect, insensitivity of scales to quantify stiffness (especially in the less severely affected persons), or drug effectiveness in only a small subset of persons. The placebo effect was prominent in this study and attributed to the subjective nature of the subjects’ symptomatology, the frequent fluctuations, and the underlying anxiety which for some subjects was pronounced and appeared to create a strong anticipatory effect. Additionally, fear and anxiety in individuals with stiff person syndrome may exhibit day-to-day variation that may aggravate stiffness and spasms and have an overall impact on assessing response to therapies.

Rineer and colleagues (2017) evaluated the peer-reviewed published medical literature on treatment outcomes in subjects with stiff person syndrome with rituximab compared to standard of care. Cases were reviewed if the individual had a clinical presentation consistent with a diagnosis of stiff person syndrome, a positive serology (anti-GAD or antiamphiphysin), or an electromyography consistent with the condition. Treatment outcomes were evaluated based on EMG changes, anti-GAD titers, and clinical mobility. A total of nine case studies reported mixed outcomes with use of rituximab in subjects’ refractory to treatment with IVIG. Of these cases, clinical improvement was reported in 7 of 9 subjects following rituximab. However, the dose and schedule of rituximab varied among these subjects, and clinical improvement reported in 6 subjects required an additional dose of rituximab because of recurrence of symptoms several months after the original dose. This small number of case reports limits drawing conclusions as to the net health benefit of rituximab in treatment-refractory stiff person syndrome.

FDA PI Label Adverse Events and Warnings for Rituximab

Black box warnings from the FDA PI Label (Rituxan, 2018) include the following:

Additional Warnings from the FDA PI Label (2018) 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 RA.

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.


Peer Reviewed Publications:

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  5. Alping P, Frisell T, Novakova L, et al. Rituximab versus fingolimod after natalizumab in multiple sclerosis patients. Ann Neurol. 2016; 79(6):950-958.
  6. 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.
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  9. Barcellini W, Zaja F, Zaninoni A, et al. Low-dose rituximab in adult patients with idiopathic autoimmune hemolytic anemia: clinical efficacy and biologic studies. Blood. 2012; 119(16):3691-3697.
  10. 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.
  11. Barreiro-Capurro A, Mascaro-Galy JM, Iranzo P. Retrospective study of the clinical, histologic, and immunologic features of epidermolysis bullosa acquisita in 9 patients. Actas Dermosifiliogr. 2013; 104(10):904-914.
  12. 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.
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  15. Birgens H, Frederiksen H, Hasselbalch HC, et al. A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia. Br J Haematol. 2013; 163(3):393-399.
  16. 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.
  17. 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.
  18. Brown AE, Motaparthi K, Hsu S. Rituximab and intravenous immunoglobulin as alternatives to long-term systemic corticosteroids in the treatment of pemphigus: a single center case series of 63 patients. Dermatol Online J. 2018; 23(12).
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  20. 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.
  21. Cho YT, Chu CY, Wang LF. First-line combination therapy with rituximab and corticosteroids provides a high complete remission rate in moderate-to-severe bullous pemphigoid. Br J Dermatol. 2015; 173(1):302-304.
  22. Cho YT, Lee FY, Chu CY, et al. First-line combination therapy with rituximab and corticosteroids is effective and safe for pemphigus. Acta Derm Venereol. 2014; 94(4):472-473.
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  30. Dale RC, Brilot F, Duffy LV, et al. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology. 2014; 83(2):142-150.
  31. Damato V, Evoli A, Iorio R. Efficacy and safety of rituximab therapy in neuromyelitis optica spectrum disorders: a systematic review and meta-analysis. JAMA Neurol. 2016; 73(11):1342-1348.
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  33. 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.
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Chimeric 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.





  12/27/2018 Updated coding section with 01/01/2019 HCPCS changes; added J9312, removed J9310 deleted 12/31/2018.



Medical Policy & Technology Assessment Committee (MPTAC) review. Revised MN statement for rituximab in autoimmune blistering skin diseases, adding criterion for use as first-line treatment in adults with moderate to severe pemphigus vulgaris. Updated Description, Discussion, References, and Websites for Additional Information sections.



MPTAC review. Initial document development. Moved content of DRUG.00041 Rituximab (Rituxan®) for Non-Oncologic Indications to a new clinical utilization management guideline with the same title. Clarified NMN statement, adding chronic inflammatory demyelinating polyradiculoneuropathy and stiff person syndrome.