Acquired Hemophilia A (AHA) is a rare bleeding disorder that stems from neutralizing autoantibodies against coagulation factor VIII.4 In 2020, Tiede and colleagues published an international recommendations guideline that proposed three suggestions for using Rituximab to treat acquired hemophilia conditions.5
One recommendation suggested combining corticosteroids with Rituximab or a cytotoxic agent for first-line therapy in patients with FVIII <1 IU/dL or inhibitor titer >20 BU with a grade of 2B. This recommendation was based on the GTH-AH study, a prospective observational study with 102 patients included for analyses and a two-year UKHCDO observational study of 172 patients conducted by the United Kingdom Haemophilia Centre Doctors’ Organization to identify and characterize the presenting features and outcome of patients with acquired hemophilia A.6 The GTH-AH study established the primary endpoint as the time to achieve a partial remission (PR), defined as FVIII activity restored to .50 IU/dL and no active bleeding after stopping any hemostatic drug for 24 hours. Secondary endpoints were time to complete remission (CR), defined as PR plus negative inhibitor test, prednisolone tapered to 15 mg/day, and any other immunosuppressive treatment stopped. Overall survival, adverse events, and causes of death were also considered. Partial remission was achieved by 83% of patients after a median of 31 days (range 7-362). Patients with baseline FVIII <1 IU/dL achieved PR less often and later (77%, 43 days) than patients with ‡1 IU/dL (89%, 24 days). After adjusting other baseline characteristics, low FVIII remained associated with a lower rate of PR (hazard ratio 0.52, 95% confidence interval 0.33-0.81, P < .01). In contrast, PR achieved on steroids alone within 21 days was associated with patients with FVIII ‡1 IU/dL and inhibitor concentration <20 BU/mL (odds ratio 11.2, P < .0001). Low FVIII was also associated with a lower rate of complete remission and decreased survival.7
Tiede and associates' second recommendation included a second-line therapy with Rituximab or a cytotoxic agent, whichever was not used during first-line therapy with a grade of 1B, also based on the GTH-AH study.
A third recommendation of Rituximab at a dose of 375 mg/m2 weekly for a maximum of four cycles with a grade of 2B, which was based on one literature review, four case reports, a multicenter phase II trial, and a randomized phase III trial. A source was also referenced from the European Medicines Agency, which was no longer available for review.
In a 2017 review, the authors recommended a first line immunosuppression combination of corticosteroids and Rituximab8 derived from observations made in the UKHCDO surveillance study (n=40),6 the EACH2 registry (n=142),9 and the GTH-AH registry (n=102).7
A 2018 review of the evidence recommended Rituximab as a second line treatment. The authors report that the first-line of treatment remains corticosteroids alone or in combination with cyclophosphamide.10
For refractory disease, a 2014 systematic literature review comprised of 46 case reports and case series identified cyclophosphamide and Rituximab as the most frequently used agent for the treatment of inhibitory antibodies seen in hemophilia. In all cases exposed to cyclophosphamide, Rituximab, and other immunosuppressive agents, a success rate defined as a complete response was 40–44%, 40–63%, and 33–56%, respectively. The authors expressed the need for randomized trials and acknowledged the study's limitations and inconsistency among the reports.11
Immune thrombocytopenia (refractory)
Addressed in Immune Thrombocytopenia therapy policy L38268
Thrombotic thrombocytopenic purpura (TTP)
Primary or acquired TTP is a potentially life-threatening condition. There is a familial link, and it also has been associated with the development of autoantibodies to the ADAMTS13 enzyme. The primary treatment is plasma exchange therapy and glucocorticoids. Rituximab has been explored in the treatment of TTP, but there are no randomized trials.
A systematic review evaluating Rrituximab's efficacy for treating acute refractory or chronic relapsing nonfamilial acquired TTP identified individual data of 100 patients from 15 case series and 16 case reports. Rituximab induced complete remission (platelet recovery lasting more than 30 days) in 98% of patients, with a 9% relapse rate. For patients with complete remission, the median follow-up was 13 months. Median platelet recovery from the first dose of Rituximab was 14 days in ADAMTS13 deficiency, and autoantibody positivity were both highly predictive of response to Rituximab; each had a positive predictive value of 99% for predicting complete response, implying that these can be useful markers in predicting response to Rituximab in acute refractory or chronic relapsing idiopathic TTP.12,13 A phase 2, non-randomized, multicenter trial with forty patients to evaluate safety and efficacy of Rituximab with plasma exchange therapy and glucocorticoids did not show a difference between the Rituximab and control groups for the median number of plasma exchange treatments until remission (16.5 vs. 18; P = 0.5)., but on subgroup analysis, there was a trend for white patients to achieve higher remission rate with Rituximab than non-white.14
Investigation of Rituximab for TTP's initial management is limited to small observational studies and suggests a reduced relapse rate when used as initial TTP therapy. The STAR trial was stopped early for accrual futility after the third and final enrolled patient's death following the initial Rituximab infusion.15
Cerebral ataxia is an acquired or genetic degenerative disease of the nervous system that causes cerebellar degeneration. In some cases, a treatable cause can be identified, but there are no effective therapies in many cases. Rituximab has been proposed as a possible therapy due to clinical improvements seen in antibody-depleting treats such as plasma exchange and Rituximab response in other similar conditions. A cohort study of 118 adult patients with ataxia compared outcomes of various treatments did not report an improvement on the three patients who received Rituximab.16 There are case reports of ataxia improvement with Rituximab, but most are improvement in ataxia related to other neurological conditions.17
Autoimmune hemolytic anemia
Autoimmune hemolytic anemias (AIHAs) are rare, heterogeneous disorders characterized by the destruction of red blood cells through warm or cold antibodies. Glucocorticoids are considered the first-line agent for warm AIHA.18 Investigations into Rituximab have demonstrated a role for this agent in AIHA.
Multiple retrospective and small observational studies support the use of Rituximab for the refractory treatment of AIHA. This data is compiled in a 2015 meta-analysis of 21 observational studies with 409 patients supporting Rituximab's use in AIHA management. This analysis reported that Rituximab seems to be a safe and effective therapy for AIHA. The authors suggest that it could be used at an earlier point in therapy, before more toxic immunosuppressive drugs, or in place of splenectomy in some cases. The meta-analysis was limited as the existing evidence consisted of observational studies with data from a small prospective multicenter study support the use of low-dose Rituximab (in combination with prednisone) in patients with newly diagnosed or refractory AIHA.19 A 2013 RCT assigned 64 patients with newly diagnosed patients with warm AIHA to glucocorticoids with or without Rituximab weekly for four weeks. The authors reported a better response rate at 12 months (36 versus 75%), with responses continuing to occur over the first six months even after completing therapy. At 36 months, the remission rates remained higher in the combination group (45 versus 70%) and improved relapse-free survival in the combined therapy group (hazard ratio [HR] 0.33; 95% CI 0.12-0.88). Adverse events were similar in both groups. A 2017 trial with 32 adults with warm AIHA found similar results with response rates at 12 months of 31 versus 75 percent and 24 months of 63 versus 19 percent. A small sample size limits these trials, but larger trials are difficult as the condition is rare.
Cold AIHA may be treated by avoidance of cold triggers, but cases may be severe. Cold AIHA is not responsive to glucocorticoids or other treatment options. Several case reports followed by larger, prospective, but uncontrolled trials have shown that approximately 60% of patients respond to Rituximab.20 A retrospective study of 232 patients reported rituximab plus bendamustine therapy resulted in responses in 35 (78%) of 45 patients; 24 (53%) achieved complete response. In patients responding to Rituximab-bendamustine estimated 5-year sustained remission was 77%.21
In 2020 the First International Consensus Group met to develop recommendations and algorithms for AIHA management.18 They reviewed available evidence acknowledging the lack of clinical trials or consensus on best practices and recommend the following:
- Corticosteroids remain first-line therapy for warm-AIHA, while the addition of Rituximab should be considered early in severe cases and if no prompt response to steroids is achieved.
- Rituximab with or without bendamustine should be used in the first line for patients with cold agglutinin disease requiring therapy.
Evans syndrome is a rare autoimmune condition most often in children presents with two or more cytopenia’s, commonly AIHA and ITP with or without neutropenia. It also may occur as a secondary condition associated with other underlying diseases. First-line treatment is usually glucocorticoids and, in some cases, intravenous immunoglobulin. In refractory cases or steroid-dependent cases, Rituximab has been used.22,23 In combination with steroids, response rates of up to 76% have been reported in a case series of 17 pediatric cases. Literature is limited to one small prospective study (n=15), retrospective case series (n=68 adults and n=17 pediatrics), and case reports.23
Multiple Sclerosis (MS)
Multiple sclerosis is the most common immune-mediated inflammatory demyelinating disease of the central nervous system. First-line treatment is typically initiated with ocrelizumab, which is FDA approved to treat primary progressive multiple sclerosis.24 Rituximab has been used as an alternative for the relapsing or remitting disease.
A 2009 phase II double-blinded trial randomized 104 patients with relapsing or remitting multiple sclerosis, with 69 receiving Rituximab and thirty-five receiving placebo. They determined a single course of Rituximab reduced inflammatory brain lesions and clinical relapse for forty-eight weeks.25 In a 2009 trial called the OLYMPUS trial, 429 PPMS patients were randomized to two 1,000mg intravenous Rituximab or placebo infusions every twenty-four weeks for a total of ninety-six weeks. They evaluated the time to confirmed disease progression and did not find a statistical difference between the Rituximab versus placebo.26
The National Institute for Health and Care Excellence (NICE): Clinical guideline on multiple sclerosis in adults – Management (2014, updated 2019) does not mention Rituximab.27
A 2016 retrospective cohort study in Sweden reported switching from natalizumab (another alternative agent) to Rituximab resulted in a reduced risk of relapse compared to switching to fingoimod (1.8% vs. 17.6%; HR=0.10, 95% CI: 0.02–0.43) and a lower proportion of participants with contrast-enhancing lesions (1.4% vs. 24.2%; OR=0.05, 95% CI: 0.0–0.22). The authors concluded improved effectiveness and tolerability of Rituximab when a switch in medication is indicated.28 The 2018 European Committee of Treatment of Research in Multiple Sclerosis (ECTRIMS)/European Academy of Neurology (EAN): Guideline on the pharmacological treatment of people with multiple sclerosis (2018) rated this evidence with a moderate risk of bias using GRADE methodology.29
2018 Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology published a systematic review on disease-modifying therapies for adults with multiple sclerosis30 reports:
- They report that Rituximab is possibly no more effective than placebo in reducing the risk of disability progression in people with progressive MS (low confidence).
- Rituximab and teriflunomide are probably more effective than placebo in reducing volume or number of MRI detected T2 lesions (moderate confidence).
A 2020 report evaluating disease-modifying therapies for multiple sclerosis reported on a nationwide registry- in Sweden followed a cohort of 6421 patients, of which 3260 were taking Rituximab over six years, plus a comparator cohort of 42,645 individuals. They evaluated severe infections resulting in hospitalization. They reported that patients with MS are generally at increased risk of infection was most significant in the off-label use of Rituximab group with an incident rate of 19.7 [95% CI, 16.4-23.5] per 1000 person-years and higher than the other therapies evaluated.31 In 2018 American Academy of Neurology recommendations on disease-modifying therapies for adults with multiple sclerosis recommended a discussion about the risk of progressive multifocal leukoencephalopathy (PML) reported in case reports in patients with MS on Rituximab.32
Bullous pemphigoid (BP) is a rare autoimmune disease characterized by cutaneous blistering at the epithelial basement membrane zone. First-line therapy may consist of topical or systemic corticosteroids. Additional immunomodulatory therapies may be added to minimize the adverse effects of chronic corticosteroid therapy. A case report and two small case series suggest Rituximab may be effective for refractory bullous pemphigoid to conventional therapies.33-35 A 2015 study provides a comparison and shows that first-line combination therapy has similar or even lower rates of infection and mortality than conventional treatment.36 In 2019 the Japanese Dermatological Association published a guideline for the management of pemphigoid. They report in severe cases (including treatment-resistant cases), steroid pulse therapy, various immunosuppressants as azathioprine, plasma exchange therapy, and intravenous immunoglobulin (IVIG) therapy used in combination. The authors report that Rituximab is effective, but future clinical studies are necessary to confirm this finding.37 A 2019 consensus on the treatment of autoimmune bullous dermatoses was composed by the Brazilian Society of Dermatology.38 In cases of treatment resistance, anti-CD20 immunotherapy (rituximab) may be prescribed. New compounds are being proposed based on the immunopathogenesis of BP.39-41 A guideline on the management of bullous pemphigoid by the European Dermatology Forum and European Academy of Dermatology and Venerology (EADV) was constructed and did not mention the use of Rituximab.42 The 2012 British Association of Dermatologists' guidelines for managing bullous pemphigoid makes no mention of Rituximab.43
Idiopathic Inflammatory Myopathy
Idiopathic inflammatory myopathies (IIMs) encompass a heterogeneous group of rare autoimmune diseases characterized by muscle weakness and inflammation, but in anti-synthetase syndrome, arthritis and interstitial lung disease are more frequent and often inaugurate the disease.
Clinical practice guidelines recommend Rituximab as a treatment option for IIMs with extra muscular (lung) involvement from a large multi-disciplinary workgroup.44 However, this is based on expert opinion, without supporting evidence.45
Encephalitis is a viral infection of the central nervous system resulting in clinical syndromes of aseptic meningitis or encephalitis. Rituximab, combined with steroids and IVIG or plasma exchange therapy, is considered an alternative approach for severe cases. Titulaer and colleges reported that the use of Rituximab with second-line immunotherapy significantly improved the outcome of patients who failed to respond to first-line therapy and experienced decreased frequency of relapses.46 The 2012 Association of British Neurologists and British Infection Association National Guidelines reports some success using Rituximab in patients who fail to respond to first-line therapy.47 The 2007 NICE guideline on Chronic fatigue syndrome/ myalgic encephalomyelitis (or encephalopathy): diagnosis and management made no mention of Rituximab.48
Inflammatory myopathies are a group of disorders characterized by the common feature of immune-mediated muscle injury. Distinctions in clinical and histopathologic conditions suggest that different pathogenic processes may cause each of the inflammatory myopathies. The most common of these disorders include Dermatomyositis (DM), Polymyositis (PM), Antisynthetase syndrome, Immune-mediated necrotizing myopathy (IMNM), Inclusion body myositis (IBM), and Nonspecific myositis. Many patients with inflammatory myopathies cannot be assigned to any category and may be classified as having nonspecific myositis. In most cases, the precise mechanisms leading to tissue injury in the inflammatory myopathies are incompletely defined.49
Zhang and colleagues reported that three out of three elderly patients with refractory HMGCR-antibody-related immune-mediated necrotizing myositis achieved complete remission after treatment with Rituximab.50 So and colleagues reported four out of four patients with refractory rapidly progressive interstitial lung disease related to anti-MDA5 antibody-positive amyopathic dermatomyositis responded to Rituximab. Daily prednisolone dose usage dropped from 20 to 6.25 mg post-treatment. Two patients developed a chest infection and one wound infection within six months after the RTX infusion.51
Oddis et al. reported results from the RIM trial, with 200 randomized patients (76 with PM, 76 with DM, and 48 with juvenile DM), 195 showed no difference in the time to achieve the definition of improvement (DOI) [defined as >20% improvement in 3 of any 6 CSMs, with no more than two worsening by >25%]. Between the Rituximab late (n = 102) and Rituximab early (n = 93) groups, there was a median time to achieve a DOI of 20.2 weeks and 20.0 weeks, respectively. There was no significant difference between the two treatment groups in terms of the secondary endpoints. However, 83% of the randomized patients met the DOI, and individual CSMs improved in both groups throughout the 44-week trial.52
Levine conducted a pilot study and reported six of six patients with refractory dermatomyositis responded to Rituximab with muscle strength increasing over baseline by 36–113%. Four patients had symptoms recur in conjunction with the recurrence of CD19+ B cells. There were no treatment-related severe or serious adverse events during this study.53 Unger and colleagues reported a real-life retrospective analysis of refractory myositis patients treated with Rituximab, in which 14 of 19 patients responded as measured by CK, pulmonary function, and daily prednisone dosage. One patient died from aspiration pneumonia three weeks after the first RTX infusion.54 A retrospective cohort study included 43 refractory patients who experienced a 75% clinical response and reduction of average prednisone from 18 to 6 mg in 42% of patients. Five patients were excluded for side effects at the first Rituximab application.55 Barsotti et al. conducted a single center study with 26 patients with refractory myositis and obtained a favorable P<0.001 response rate.56 Ahn et al. performed a retrospective cohort study that included 16 patients with refractory immune-mediated myopathy and achieved a 75% response rate.57 Mahler and associates conducted a study to assess the efficacy of Rituximab in patients with inflammatory myopathies refractory to conventional immunotherapy. The study included 13 patients with refractory myositis treated with Rituximab. Patients experienced a median reduction in CK 93%.58 Valiyil and colleagues conducted a case series, which resulted in six of eight patients with refractory SRP antibody (+) myositis responded to Rituximab.59 Fasano and associates conducted a review of all available trials as of 2015; 48 studies found 458 myositis patients treated with Rituximab, with an overall response rate of 78.3%.60
IgG4 related systemic disease
Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that can affect multiple organs. The involved organs share several core pathologic features and striking clinical and serologic similarities. Elevated serum concentrations of IgG4 are common. Before its recognition as a unified disease in the early 2000s, the seemingly dissimilar manifestations had been presumed to be unrelated, single-organ disorders.61
In a French retrospective cohort, 29 of 31 (93.5%) patients with IgG4 disease exhibited a clinical response to Rituximab, with 51.5% able to withdraw steroids.62 Khosroshahi conducted a review resulting in nine of ten patients treated with Rituximab had a favorable clinical response, 10/10 were able to discontinue steroid, and DMAR.63 Omar and colleagues conducted a network meta-analysis of IgG4 treatments consisting of 15 studies with 1169 patients and showing Rituximab had lowest OR of relapse (0.10) amongst treatment studied.64 A 2020 Systemic review consisting of 27 articles and 264 patients resulted in 90.7% of patients using Rituximab as second-line therapy responded, 100% of the 10% of patients using it as first-line therapy responded.65 Carruthers et al. conducted an open-label prospective trial of 30 patients who received RTX, 97% had a clinical response, and 77% met primary outcome. The primary outcome, measured at six months, was defined as (1) decline of the IgG4-RD RI >=2 points compared with baseline; (2) no disease flares before month 6; and (3) no GC use between months 2 and 6. Complete remission was defined as an IgG4-RD RI score of 0 with no GC use.66 Wallwork conducted a study resulting in 22 (88%) patients with retroperitoneal fibrosis (73% of whom were due to IgG4 disease) had a favorable radiologic response to Rituximab. Nineteen of 19 patients had improvement in pain if present. Three patients (12%) patients experienced severe infections.67 A 2015 International consensus panel guideline for evaluation and management of IgG4 related disease, which included data supporting the use of Rituximab in some urgent cases, if glucocorticoid treatment is contraindicated.68
Myasthenia gravis (MG) is an autoimmune disorder of the postsynaptic neuromuscular junction characterized by fluctuating weakness involving variable combinations of ocular, bulbar, limb, and respiratory muscles. First-line treatment includes acetylcholinesterase inhibition, immunosuppressive agents, immunomodulating agents, and thymectomy. Approximately 10-15% of patients with generalized MG have difficulty controlling the disease referred to as treatment-refractory MG. Drug resistance has been defined as a failure of at least three second-line agents. In these refractory or resistant patients, treatment is individualized, and Rituximab is a proposed treatment option.69,70 Rituximab's potential benefits have been investigated and reported in several case reports and small (<20 patients) retrospective series in refractory MG with favorable results. A phase II randomized trial of Rituximab with generalized MG did not show a significant steroid-sparing effect at one year than placebo; however, the results were presented but then never followed with full-text publication.71 A 2017 systematic review including a total of 169 patients with myasthenia gravis treated with Rituximab and 57 patients who were Mu-Sk positive found that the Mu-SK-positive patients were more likely to achieve minimal disease manifestations (72 versus 30%) and improved rates of pharmacological or complete sustained remission (47 versus 16 percent).72 A 2020 systematic review of the literature on Rituximab's use for autoantibody against acetylcholine receptor (AChR) subtype of MG reported heterogeneous data and lack of RCTs. They found that treatment with rituximab appears to work in some. However, not all patients with the AChR subtype of MG were reported, and additional research to determine the subtype of patients who may benefit is needed.73 There is an active RCT trial to investigate further rituximab's role in refractory MG.70 Preliminary retrospective data suggest rituximab's potential role in first-line treatment for myasthenia gravis; however, data is limited.74
2020 International Consensus guidance on the management of myasthenia gravis (updated from 2016 guidelines) provides the following recommendations:
- Rituximab should be considered as an early therapeutic option in patients with MuSKAb+ MG who have an unsatisfactory response to initial immunotherapy. (Median 9, range 4-9) with 7-9 being considered appropriate.
- The efficacy of Rituximab in refractory AChR-Ab+ MG is uncertain. It is an option if patients fail or do not tolerate other IS agents. (Median 8, range 4-9)75
Neuromyelitis Optica spectrum disorders (NMOSD, previously known as Devic disease or neuromyelitis optica [NMO]) are inflammatory disorders of the central nervous system characterized by severe, immune-mediated demyelination and axonal damage predominantly targeting optic nerves and spinal cord.76,77 Rituximab has been proposed as a potential agent for attack prevention. An open-label RCT 68 patients with NMODS with or without AQP4 antibodies were randomized to Rituximab (n=33) or azathioprine(AZA) (n=35). They found a decrease in relapse rate in both groups, but more significant in the Rituximab group with AZA group decreased from 1 (0.38) to 0.51 (0.55) (P-value <0.001) and in the RIT group decreased from 1.30 (0.68) to 0.21 (0.42) (P-value <0.001). Nineteen patients (54.3%) in AZA group and 26 patients (78.8%) in RIT group became relapse-free after intervention (P-value = 0.033).78 A 2016 systematic review reported on forty-six studies that reported Rituximab's use in the treatment of NMOSD. This included small case series and case reports with a total of 438 patients. they reported a mean reduction in the annualized relapse rate ratio of 0.79 (0.15) (95%CI, −1.08 to −0.49) And a reduction in the mean expanded disability status scale score of 0.64 (0.27) (95%CI, −1.18 to −0.10). However, adverse effects were reported in 26% of patients treated with Rituximab, including infusion-related adverse effects, infection, leukopenia, and two patients with posterior reversible encephalography and seven deaths. They conclude that Rituximab therapy reduces the frequency of NMOSD relapses and neurological disability but cautions use as first-line therapy due to safety concerns.79
A 2020 multi-center, double-blinded RCT reported on 38 participants randomized to Rituximab or placebo for NMOSD. Rituximab was administered every week for four weeks, and then every six months, and patients were monitored for signs of relapse. Seven (37%) relapses occurred in patients allocated placebo, and none were recorded in patients assigned Rituximab (group difference 36·8%, 95% CI 12·3-65·5; log-rank p=0·0058). This study demonstrates the potential that rituximab may prevent relapsing disease; however, there was a 16% drop out rate and was limited by a small sample size.80
Patients with the autoimmune condition systemic lupus erythematosus may develop diffuse or focal proliferative lupus nephritis. The definition of a complete response to initial immunosuppressive therapy is variable; however, a patient who fails to achieve a complete or partial response to initial treatment has a worse overall prognosis, so investigations on therapy for resistant or refractory lupus nephritis is ongoing. Typically, patients need to be treated for a minimum of six to twelve months before a complete response may be seen with initial therapy.81 Patients who fail to respond after six months of treatment with glucocorticoids plus cyclophosphamide (CYC) or mycophenolate mofetil (MMF).82 This is based on data from cohort studies, including 43 patients with both membranous and proliferative lupus nephritis treated with Rituximab with positive results.83 A prospective study of 136 patients with lupus nephritis reported improvement in patients receiving Rituximab and reporting a response in 91% of relapse patients after re-treatment with Rituximab, an acceptable safety profile.84 This contrasted with two randomized control trials evaluating Rituximab's potential benefit that does not show benefit compared to placebo.85 A 2019 meta-analysis evaluated 24 studies with a total of 940 patients with lupus nephritis investigating the benefit of Rituximab in patients with lupus nephritis. This meta-analysis did not include a systematic review or assessment of the risk of bias, so interpretation is limited. The authors reported that complete and total remission rates were higher in patients who received Rituximab in the case series trials. In the randomized control trials, they reported that the complete response was higher in the rituximab group. However, there was no statistically significant difference between the two groups (OR =1.98, 95% CI: 0.90–4.39, P=0.05). The authors report promising results for Rituximab treatment in this population and call for further studies. Long term efficacy and toxicity of rituximab have not been fully defined.81
Minimal Change Disease
Glucocorticoid therapy is the treatment of choice in minimal change disease (MCD), leading to a complete remission of proteinuria in over 85 to 90 percent of cases. MCD is more common in children than adults and accounts for 10-25 percent of adults' nephrotic syndrome cases. Rituximab has shown in observational studies to have potential benefit in adults with frequently relapsing or glucocorticoid dependent MCD. These reports suggest that patients who have failed to obtain a durable remission with cyclophosphamide or calcineurin inhibitors may benefit from Rituximab. However, it does not appear to be effective in adults with glucocorticoid resistant MCD.86
KDOQI US commentary on the 2012 KDIGO Clinical Practice Guidelines for Idiopathic Membranous Nephropathy (2013) reports that Rituximab should be reserved for patients with frequent relapses despite optimal combinations of prednisone and corticosteroid-sparing therapy or intolerance to therapy. They also state that randomized control trials are needed to evaluate secondary agents' comparative effectiveness, including Rituximab, and recommend use in clinical trials. Optimal dosing regimen, safety, and efficacy have not been clearly established as existing data consists of case series, small trials, and retrospective analysis with 25 patients or fewer in the reports.87
In children, the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for Idiopathic Membranous Nephropathy suggest that Rituximab be considered only in children with steroid dependent, steroid-sensitive nephrotic syndrome who have continuing frequent relapses despite optimal combinations of prednisone and corticosteroid-sparing agents, and/or who have serious adverse effects of therapy with a grade of 2C. There is very low–quality evidence to support the efficacy of Rituximab.87 A small RCT with 54 children with idiopathic nephrotic syndrome dependent on prednisone and calcineurin inhibitors for >12 months were randomized. Three-month proteinuria was 70% lower in the Rituximab arm (95% confidence interval 35% to 86%) than the standard therapy arm (intention-to-treat). Additional relapse rates were 18.5% (intervention) and 48.1% (standard arm) (P = 0.029) and probabilities of being drug-free at 3 months were 62.9% and 3.7%, respectively (P < 0.001). 50% of Rituximab cases were in stable remission without drugs after nine months.88
Membranous Nephropathy (IMN)
Nephropathy membranous nephropathy is a form of nephrotic syndrome in diabetic adults. The histological changes include golem annular basement membrane thickening with little or no cellular proliferation or infiltration. 75 to 80% of cases are caused by circulating autoantibodies against podocyte antigens, while the remaining 20 to 25% are associated with various disorders.89 Their risk classifies patients for progressive disease due to MN as high risk being two or more of the following:89
- Serum creatinine ≥1.5 mg/dL [≥133 micromol/L]
- Progressive decline in kidney function (e.g., decrease in estimated glomerular filtration rate [eGFR] ≥25 percent from baseline over the prior two years)
- Severe, disabling, or life-threatening nephrotic syndrome (defined by the presence of a serum albumin <2.5 g/dL [if measured by bromocresol green methods] or <2.0 g/dL [if measured by bromocresol purple methods] and refractory edema, or a thromboembolic event)
Immunotherapy is recommended for high risk patients or patients who have shown signs of rapid disease progression. Glucocorticoids are not effective in high risk patients. In the membranous nephropathy trial of Rituximab (MENTOR), 130 patients with proton area ≥ 5g/day and 24- creatinine clearance ≥40 mL/min/1.73 m2 were randomized to receive two infusions of 1 gram administered 14 days apart of Rituximab or six months of oral cyclosporin. They found Rituximab was more effective than cyclosporin in maintaining complete or partial remission of proteinuria at 24 months. At 12 months, rates of complete or partial remission were similar between the groups, but at 24 months, Rituximab had a higher rate of complete or partial remission as compared to the cyclosporin group. Creatinine clearance was higher, anti-PLA2 antibody levels or decreased, and serious adverse events were lower in the Rituximab group as compared to cyclosporin. They concluded Rituximab was more effective at preventing further loss of kidney function and end stage renal disease than cyclosporin with supportive therapy. They did find patients with high anti -PLA2R antibody titers at baseline may be less responsive to Rituximab.90 This contrasts with the idiopathic membranous nephropathy trial (GEMRITUX), where 75 patients were assigned Rituximab or no Rituximab and did not show improvements in proteinuria at six months.91 However, this may be attributed to the short duration of follow-up as the improvement was not seen until greater than 12 months. UpToDate recommends patients classified as high risk or very high risk with stable kidney function being treated with Rituximab rather than cytotoxic therapy with a grade 2C recommendation.92 Rituximab has been shown to have potential in relapsing and remitting disease where using an immunosuppressive agent that they have not seen previously is recommended Based on observation and retrospective studies.
Antibody-mediated rejection (AMR)
Antibody-mediated rejection is caused by human leukocyte antigen (HLA) antibodies resulting in an immune attack on the transplant organ. Immune suppression to prevent this response and early graft rejection is an ongoing aspect of transplanted research. Rituximab has been used to treat AMR in lung, kidney, liver, and heart transplant patients. It has been explored as both a desensitization strategy before transplant in high-risk individuals and AMR treatment. There is a lack of high of high-quality evidence from randomized controlled trials regarding optimal therapy for ARM.
Some of the evidence's challenges were highlighted in a 2011 report from an international consensus conference on antibody-mediated rejection in heart transplantation. The panel concluded it is difficult to recommend evidence-based guidelines for AMR treatment because the criteria for diagnosis have not been well established and have been used variably in different clinical series, and the use of a multiplicity of therapeutic agents hampering the ability to evaluate the efficacy of the single agent. They stated Rituximab is beginning to be used for desensitization in highly sensitized patients awaiting heart transplantation. They recommend it as a secondary therapy for the treatment of AMR when first-line agents failed. Evidence is limited to case reports and series.93 In a 2015 scientific statement from the American Heart Association and endorsed by the International Society for Heart and Lung Transplantation, they state:
- It is reasonable for primary therapy for AMR to include IVIg, plasmapheresis, anti-lymphocyte antibodies, and
High-dose corticosteroids (Class IIa; Level of Evidence B).
- It is reasonable for secondary therapy for AMR to include Rituximab, bortezomib, and anti-complement antibodies
(Class IIa; Level of Evidence C).94
A systematic review of five RCTs and seven non-randomized controlled trials evaluating the effects of different treatments on graph survival in kidney transplant recipients suggested a potential benefit from treatment with Rituximab, plasmapheresis, and bortezomib; however, because some studies used a combination of therapies, the personal effects could not be distinguished.95 A phase III, multicenter randomized placebo-controlled trial evaluating Rituximab's effects in 38 kidney transplant recipients with biopsy-proven AMR also showed a trend in favor of Rituximab without a clinically significant difference between the groups.96 An observational study evaluating the combination of plasmapheresis, IVIG, and Rituximab versus high dose IVIG alone in the AMR treatment showed graph survival at 36 months with 92% in the combination group compared to 50% in the IVIG alone.97,98
AMR is rare in lung transplant patients. Case series of acute lung transplant patients with AMR suggests a benefit of Rituximab in treatment.99
Rituximab has also been explored in the prevention of AMR. HLA desensitization protocols are aimed at reducing the risk of progression to AMR. Rituximab has been investigated as an agent in these protocols. There is no high-quality data in the form of randomized controlled trials comparing the existing desensitization protocols. Approaches and optimal therapy have not been defined. The use of these desensitization protocols has allowed patients in need of a transplant to shorten the time to transplantation and permit transplant in approximately 75 to 80% of patients. Most of these protocols include a high dose of IVIG and Rituximab.100
A case series of twenty highly sensitized patients were enrolled and received treatment with intravenous immune globulin and Rituximab and followed for evidence of rejection. This combination was effective for desensitization for patients awaiting a transplant.101 A subsequent study included seventy-six HLA sensitized patients who met strict sensitization criteria who underwent this IVIG and Rituximab protocol. They reported significant reductions in time on the waitlist, which for deceased donor recipients was reduced from 95+/-46 months to 4.2+/-4.5 months after desensitization treatment.102 In another series of 108 patients treated with the IVIG and Rituximab protocol, 74% of the highly sensitive patients could undergo transplant after treatment.103
Graft vs. Host Disease (chronic, steroid-refractory)
Chronic graft-versus-host disease (GVHD) is a common complication of allogeneic hematopoietic cell transplant (HCT). GVHD occurs when immune cells transplanted from a non-identical donor (the graft) recognize the transplant recipient (the host) as foreign, thereby initiating an immune reaction that causes disease in the transplant recipient.104
GVHD has divided into acute and chronic variants based on the time of onset, traditionally using 100 days as a cutoff. Signs of acute and chronic GVHD have challenged the division between acute and chronic variants outside of the selected periods. The National Institutes of Health (NIH) consensus criteria for GVHD's diagnosis and standardized features of chronic GVHD and acute GVHD appear together and are widely accepted.105 Reports of Rituximab's use in patients with chronic refractory GVHD suggests the potential use of agents directed at B cells. Rituximab is currently being evaluated for chronic GVHD prophylaxis, in which Rituximab 375 mg/m2 is administered weekly for a total of four weeks. If a partial response is reported, up to two more four-week courses may be administered.
Five studies have suggested favorable response rates among patients with skin or musculoskeletal involvement. In a phase II trial consisting of thirty-seven patients with steroid-refractory chronic GVHD, clinical responses were seen in thirty-two patients (86%)106, and responses were maintained at one year. This resulted in corticosteroid dose reductions in twenty-one patients. Clinical responses were positively produced in the skin, oral cavity, and musculoskeletal system. In another study of twenty-one patients with steroid-refractory chronic GVHD, positive responses were seen in 70% of participants.107 Responses were seen in cutaneous and musculoskeletal cases for one year of therapy. A retrospective analysis consisted of eighteen patients with steroid-refractory chronic GVHD. Favorable clinical responses were seen in eleven patients (55%). One patient achieved a complete response while ten successfully reduced or discontinued corticosteroid therapy.108 A phase II randomized study evaluated agents for sclerotic chronic GVHD. Successful clinical improvements were seen in skin sclerosis or joint range of motion in ten of thirty-seven (27%) of those treated with rituximab and nine of thirty-five (36%) of patients randomized to imatinib.104,109 NCCN suggested Rituximab as a systemic agent for chronic steroid-refractory GVHD.110
Behcet’s syndrome is an auto-inflammatory disorder in which ulceration of mucous membranes and inflammation of the skin, eyes, and nervous system occurs. There are case reports on the use of Rituximab for Bechet’s treatment. The European League Against Rheumatism (EULAR) Standing Committee for Clinical Affairs multi-disciplinary task force, the Consensus Conference on Treatment of Skin and Mucosal Lesions Committee of Guideline for the Diagnosis and Treatment of Mucocutaneous Lesions of Behcet’s disease, and the evidence-based diagnosis and clinical practice guidelines for intestinal Behçet’s disease 2020 edited by Intractable Diseases, the Health and Labour Sciences Research Grants do not mention Rituximab in their guidelines).111,112
Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that predominantly affects medium-sized muscular arteries and often involves small muscular arteries. Rituximab has been used as an alternative agent for a resistant disease, defined as patients with a persistent severe or worsening disease that does respond adequately to glucocorticoids or cyclophosphamide treatment within two to three months. Evidence for the use of Rituximab in this setting is limited to case reports.113 The 2009 European League Against Rheumatism (EULAR) recommendations for the management of primary small and medium vessel vasculitis recommends patients who do not achieve remission or relapse on a maximal dose of standard therapy be referred to an expert Center for further management enrolled in clinical trials (level of evidence 3, great of recommendation C).114
Sjögren’s syndrome (pSS)
Rituximab has been evaluated for its use in pSS. The cohort studies and early small RCTs show significant improvement compared to baseline. a 2014 randomized control trial randomized 122 pSS patients to receive Rituximab (n=63) or placebo (n-57). They found no significant improvement.115 Another randomized control trial of 133 pSS patients was randomized to rituximab (n=67) or placebo (n=66) and also found no significant results in the primary outcome.116 Two recent meta-analyses, including the four randomized controlled trials, confirmed the lack of significance between group differences in mean improvement between baseline and week 24 values for fatigue, oral dryness, salivary flow rate, and Schirmer test.117,118 2019 European League Against Rheumatism recommendations concluded low quality evidence using GRADE methodology supporting the efficacy and safety Is low level evidence from therapeutic studies and underscores the need for larger trials to determine safety and efficacy. They report limited data from prospective studies suggesting a lack of efficacy in systemic disease, especially in cryoglobulinemic vasculitis.119