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 rituximab (8) 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).
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 rituximab'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).
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 (16). 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 (17). 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 (18).
The National Institute for Health and Care Excellence (NICE): Clinical guideline on multiple sclerosis in adults – Management (2014, updated 2019) does not mention rituximab (19).
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 (20). 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 (21).
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 sclerosis (22) 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 (23). 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 (24).
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 (25). However, this is based on expert opinion, without supporting evidence (26).
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 (27).
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 (28). 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 (29).
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 (30).
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 (31). 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 (32). 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 (33). Barsotti et al. conducted a single center study with 26 patients with refractory myositis and obtained a favorable P<0.001 response rate (34). Ahn et al. performed a retrospective cohort study that included 16 patients with refractory immune-mediated myopathy and achieved a 75% response rate (35). 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% (36). Valiyil and colleagues conducted a case series, which resulted in six of eight patients with refractory SRP antibody (+) myositis responded to rituximab (37). 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% (38).
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 (39).
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 (40). 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 (41). 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 (42). 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 (43). 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 (44). 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 (45). 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 (46).
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 (47).
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 (48).
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 (48). 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 (49).
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 AMR.
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 (50). 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) (51).
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 (52). 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 (53). 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 (54,55).
AMR is rare in lung transplant patients. Case series of acute lung transplant patients with AMR suggests a benefit of Rituximab in treatment (56).
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 (57).
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 (58). 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 (59). In another series of 108 patients treated with the IVIG and rituximab protocol, 74% of the highly sensitive patients could undergo transplant after treatment (60).
Immune thrombocytopenic purpura (ITP)
Rituximab is a chimeric monoclonal antibody directed against the B cell surface protein CD20 and has been used off-label for the treatment of ITP. The initial response to rituximab is approximately 60%, and a long term remission is reported in 15-30% of patients in prospective and retrospective cohort studies, systematic reviews and meta-analysis in both splenectomized and non-splenectomized patients (Grade 2C) (61-64). There are multiple systematic reviews and meta-analysis in the literature; however, most studies were not randomized control trails and did not offer a control arm limiting the data sets. A systematic review of patients who failed first-line therapies (19 studies, 313 adult patients half who had splenectomy) reported a complete response in 44% and a response in 63% with a median duration of 11 months (65). A meta-analysis of non-splenectomized patients (5 RT/463 patients) reported a complete response in 47% and response in 58%, which was comparable to a prior meta-analysis that also included observational studies (62,63). A multi-centered, randomized, double-blinded, placebo controlled trial with the longest duration comparing rituximab or placebo after initial corticosteroids demonstrated only a modest response at 1.5 years (66), however also reported a small benefit with rituximab could not be ruled out based on longer duration of response, numerically higher responses, and late responders (65). Factors predictive of a response have not been clearly established, but older age and longer disease duration (>10 years) seem to reduced response (67,68). There is a lack of long term safety data with reports of rare risk of progressive multifocal leucoencephalopathy and hypogammaglobulinaemia (62,69). There is an FDA black box warning for the potential to cause reactivation of hepatitis B necessitating testing for hepatitis B before use. Rituximab is included as second-line therapy in the 2018 ASH guidelines as it offers the potential for a treatment-free remission without surgical intervention (70).
Chronic inflammatory demyelinating polyneuropathy (CIDP)
Tracy and Dyck (2010) examined the data for treatment of inflammatory demyelinating peripheral neuropathies, particularly chronic inflammatory demyelinating polyneuropathy (CIDP). A large clinical trial showed short and long-term efficacy of IVIG for the treatment of CIDP and the U.S. Food and Drug Administration approved the use of IVIG (Gamunex) as a treatment for CIDP. Recent trials for other agents for CIDP treatment have not proved as promising, with a large study of methotrexate failing to show significant benefit. There are recent cases of monoclonal antibodies (e.g., rituximab, alemtuzumab) showing benefit in patients with CIDP, but the side effect profiles can be worrisome. Clinical history, neurological examination, spinal fluid examination, and electrophysiological evaluation remain mainstays for the diagnosis of demyelinating inflammatory polyradiculoneuropathy. Genetic testing and nerve biopsy are important diagnostic tools in some patients. Potential treatments for immune-mediated demyelinating polyradiculoneuropathies are varied, with the authors generally favoring IVIG and/or corticosteroids as first-line agents. Plasma exchange can be helpful in selected patients. Data for efficacy of other oral immunomodulatory agents are based primarily on case reports and case series, and have not been uniformly positive. The use of monoclonal antibodies (particularly rituximab) may have promise, but further research needs to be done, and the risks need to be carefully considered (71).
Nobile-Orazio et al (2010) stated that chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) usually respond to immune therapies including steroids and plasma exchange for CIDP and high-dose IVIGs for both diseases. Other immune therapies have been used to reduce the costs or the side-effects of these therapies, but their efficacy was only recently assessed in randomized controlled trials (RCTs). The prolonged efficacy of IVIG in CIDP has been confirmed in a 48-week RCT. Two other RCTs showed that oral methotrexate or intramuscular interferon beta were not more effective than placebo in improving the efficacy or reducing the dose of IVIG or steroids. In MMN, a RCT showed that oral mycophenolate mofetil was not more effective than placebo in increasing the efficacy or reducing the dose of IVIG. Other immune therapies were assessed in open trials in both diseases, but their efficacy remains unclear, even if in some patients a possible efficacy of rituximab was reported. Some preliminary studies suggest that subcutaneous immunoglobulin may be as effective as IVIG in the maintenance therapy of CIDP and MMN. The authors concluded that after several years of anecdotal reports, a number of RCT have now appeared in CIDP and MMN, but their results are still insufficient to support the use of new therapies in these diseases (72).
In a retrospective, observational and multi-center study, Benedetti et al (2011) analyzed the efficacy of rituximab in a large chronic inflammatory demyelinating polyneuropathy (CIDP) cohort. Thirteen CIDP patients were treated with rituximab after the partial or complete lack of efficacy of conventional therapies. Eight patients had co-occurring hematological diseases. Patients who improved by at least 2 points in standard clinical scales, or who reduced or discontinued the pre-rituximab therapies, were considered as responders. Nine patients (7 with hematological diseases) responded to rituximab: 6 of them, who were non-responders to conventional therapies, improved clinically, and the other 3 maintained the improvement that they usually achieved with IVIG or plasma exchange. Significantly associated with shorter disease duration, rituximab responses started after a median period of 2.0 months (range of 1 to 6) and lasted for a median period of 1 year (range of 1 to 5). The authors concluded that rituximab seems to be a promising therapeutic choice when it targets both CIDP and co-occurring hematological diseases (74).
In a Cochrane review, Mahdi-Rogers (2010) systematically reviewed the evidence from RCTs of cytotoxic drugs and interferons other than corticosteroids, immunoglobulin and plasma exchange for chronic inflammatory demyelinating polyneuropathy (CIDP). These researchers sought RCTs and quasi-randomized trials of all immunosuppressive agents such as azathioprine, cyclophosphamide, methotrexate, cyclosporin A, mycophenolate mofetil, and rituximab and all immunomodulatory agents such as interferon alfa and interferon beta in participants fulfilling standard diagnostic criteria for CIDP. Two authors independently selected trials, judged their methodological quality and extracted data. They wanted to measure the change in disability after 1 year as the primary outcome. Secondary outcomes were change in disability after 4 or more weeks (from randomization), change in impairment after at least 1 year, change in maximum motor nerve conduction velocity and compound muscle action potential amplitude after 1 year and for those participants who were receiving corticosteroids or IVIG, the amount of this medication given during at least 1 year after randomization. Participants with one or more serious adverse events during the first year was also a secondary outcome. Four trials fulfilled the selection criteria, one of azathioprine (27 participants), two of interferon beta-1a (77 participants in total) and 1 of methotrexate (60 participants). None of these trials showed significant benefit in the primary outcome or secondary outcomes selected for this review. The evidence from RCTs does not show significant benefit from azathioprine, interferon beta-1a or methotrexate but none of the trials was large enough to rule out small or moderate benefit. The evidence from observational studies is insufficient to avoid the need for RCTs to discover whether these drugs are beneficial. Future trials should have improved designs, more sensitive outcome measures and longer durations (73).
Sjögren's and systemic sclerosis
Primary Sjögren's syndrome (pSS) is an autoimmune disorder affecting exocrine glands; however, a subgroup of pSS patients experience systemic extra-glandular involvement leading to a worsening of disease prognosis (Carubbi, et al., 2013). Current therapeutic options are mainly empiric and often translated by other autoimmune diseases. In the last few years growing evidence suggests that B-cell depletion by rituximab (RTX) is effective also in pSS. Patients with early active disease appear to be those who could benefit the most from RTX (75).
A systematic evidence review concluded that further clinical trials are necessary to establish the efficacy of rituximab in primary Sjögren syndrome. Ramos-Casals, et al (2010) searched MEDLINE and EMBASE for articles on drug therapy for primary Sjögren syndrome published between January 1, 1986, and April 30, 2010. Controlled trials of topical and systemic drugs including adult patients with primary Sjögren syndrome were selected as the primary information source. The search strategy yielded 37 trials. The authors reported that a placebo-controlled trial found significant improvement in the Schirmer and corneal staining scores, blurred vision, and artificial tear use in patients treated with topical ocular 0.05% cyclosporine. Three placebo-controlled trials found that pilocarpine was associated with improvements in dry mouth (61%-70% vs 24%-31% in the placebo group) and dry eye (42%-53% vs 26%). Two placebo-controlled trials found that cevimeline was associated with improvement in dry mouth (66%-76% vs 35%-37% in the placebo group) and dry eye (39%-72% vs 24%-30%). Small trials (<20 patients) found no significant improvement in sicca outcomes for oral prednisone or hydroxychloroquine and limited benefits for immunosuppressive agents (azathioprine and cyclosporine). A large trial found limited benefits for oral interferon alfa-2a. Two placebo-controlled trials of infliximab and etanercept did not achieve the primary outcome (a composite visual analog scale measuring joint pain, fatigue, and dryness); neither did two small trials (<30 patients) testing rituximab, although significant results were observed in some secondary outcomes and improvement compared with baseline. The authors concluded that, in primary Sjögren syndrome, evidence from controlled trials suggests benefits for pilocarpine and cevimeline for sicca features and topical cyclosporine for moderate or severe dry eye. Anti-tumor necrosis factor agents have not shown clinical efficacy, and larger controlled trials are needed to establish the efficacy of rituximab (76). An accompanying editorial by Vissink, et al. (2010) stated that "larger trials are needed before the role of rituximab in the treatment of primary Sjögren syndrome can be settled, not only with respect to its effect on salivary flow rate and xerostomia but also with regard to the effect of rituximab treatment on general symptoms, extraglandular involvement, and life-threatening situations in primary Sjögren syndrome (77).
Carubbi et al (2013) conducted a study to investigate the efficacy and safety of RTX in comparison to disease modifying anti-rheumatic drugs (DMARDs) in early active pSS patients. Forty-one patients with early pSS and active disease (EULAR Sjögren's syndrome disease activity index, ESSDAI ≥ 6) were enrolled in the study. Patients were treated with either RTX or DMARDs in two different rheumatology centers and followed up for 120 weeks. Clinical assessment was performed by ESSDAI every 12 weeks up to week 120 and by self-reported global disease activity pain, sicca symptoms and fatigue on visual analogic scales, unstimulated saliva flow and Schirmer's I test at week 12, 24, 48, 72, 96, and 120. Laboratory assessment was performed every 12 weeks to week 120. Two labial minor salivary gland (MSG) biopsies were obtained from all patients at the time of inclusion in the study and at week 120. The investigators concluded that their study demonstrated that RTX treatment results in a faster and more pronounced decrease of ESSDAI and other clinical parameters compared to DMARDs treatment. No adverse events were reported in the two groups. The investigators also observed that RTX is able to reduce glandular infiltrate, interfere with B/T compartmentalization and consequently with the formation of ectopic lymphoid structures and germinal center-like structures in pSS-MSGs. The investigators reported that this is the first study performed in a large cohort of early active pSS patients for a period of 120 weeks. The investigators stated that the study showed that RTX is a safe and effective agent to be employed in pSS patients with systemic, extra-glandular involvement. Furthermore, they noted that their data on pSS-MSGs provide additional biological basis to employ RTX in this disease (78).
In a double-blind, randomized, placebo-controlled trial, Meijer et al (2010) examined the safety and effectiveness of rituximab in patients with primary Sjögren's syndrome (pSS). Patients with active pSS, as determined by the revised American-European Consensus Group criteria, and a rate of stimulated whole saliva secretion of greater than or equal to 0.15 ml/min were treated with either rituximab (1,000 mg) or placebo infusions on days 1 and 15. Patients were assigned randomly to a treatment group in a ratio of 2:1 (rituximab:placebo). Follow-up was conducted at 5, 12, 24, 36, and 48 weeks. The primary end point was the stimulated whole saliva flow rate, while secondary end points included functional, laboratory, and subjective variables. A total of 30 patients with pSS (29 females) were randomly allocated to a treatment group. The mean +/- SD age of the patients receiving rituximab was 43 +/- 11 years and the disease duration was 63 +/- 50 months, while patients in the placebo group were age 43 +/- 17 years and had a disease duration of 67 +/- 63 months. In the rituximab group, significant improvements, in terms of the mean change from baseline compared with that in the placebo group, were found for the primary end point of the stimulated whole saliva flow rate (p = 0.038 versus placebo) and also for various laboratory parameters (B cell and rheumatoid factor [RF] levels), subjective parameters (Multidimensional Fatigue Inventory [MFI] scores and visual analog scale [VAS] scores for sicca symptoms), and extra-glandular manifestations. Moreover, in comparison with baseline values, rituximab treatment significantly improved the stimulated whole saliva flow rate (p = 0.004) and several other variables (e.g., B cell and RF levels, unstimulated whole saliva flow rate, lacrimal gland function on the lissamine green test, MFI scores, Short-Form 36 health survey scores, and VAS scores for sicca symptoms). One patient in the rituximab group developed mild serum sickness-like disease. The authors concluded that these results indicated that rituximab is an effective and safe treatment strategy for patients with pSS (79).
Mekinian et al (2012) evaluated RTX in pSS with peripheral nervous system (PNS) involvement. Patients with pSS and PNS involvement who were included in the French AIR registry were analyzed. A total of 17 patients (aged 60 years (44 to 78 years); 14 were female) were included in this analysis. Neurological improvement was noted in 11 patients (65 %) at 3 months. Rankin scale decreased from 3 (1 to 5) to 2 (1 to 5), 2 (1 to 5) and 2 (1 to 6) after 3, 6 and 9 months (p = 0.02). European Sjögren's Syndrome Disease Activity Index (ESSDAI) decreased from 18 (10 to 44) to 11 (5 to 20), 11 (5 to 29) and 12 (5 to 30) after 3, 6 and 9 months (p < 0.05). Rituximab was effective in neurological involvement in 9/10 patients with vasculitis or cryoglobulinemia (90 %) (group 1) at 3 months and in 2/7 cases (29 %) without cryoglobulinemia and vasculitis (p = 0.03). Rankin and European Sjögren's Syndrome Disease Activity Index scales decreased significantly in group 1. The authors concluded that RTX seems effective in cryoglobulinemia or vasculitis-related PNS involvement in pSS (80).
Gottenberg et al (2013) evaluated the safety and effectiveness of rituximab in patients with progressive systemic sclerosis (pSS). The AutoImmune and Rituximab registry has included 86 patients with pSS treated with rituximab, prospectively followed-up every 6 months for 5 years. A total of 78 patients with pSS (11 men, 67 women), who already had at least 1 follow-up visit, were analyzed. Median age was 59.8 years (29 to 83), median duration of disease was 11.9 years (3 to 32). Indications for treatment were systemic involvement for 74 patients and only severe glandular involvement in 4 patients. The median ESSDAI was 11 (2 to 31); 17 patients were concomitantly treated with another immunosuppressant agent. Median follow-up was 34.9 months (6 to 81.4) (226 patient-years). Overall efficacy according to the treating physician was observed in 47 patients (60 %) after the first cycle of rituximab. Median ESSDAI decreased from 11 (2 to 31) to 7.5 (0 to 26) (p < 0.0001). Median dosage of corticosteroid decreased from 17.6 mg/day (3 to 60) to 10.8 mg/day (p = 0.1). A total of 41 patients were retreated with rituximab; 4 infusion reactions and 1 delayed serum sickness-like disease resulted in rituximab discontinuation. Three serious infections (1.3/100 patient-years) and 2 cancer-related deaths occurred. The authors concluded that in common practice, the use of rituximab in pSS is mostly restricted to patients with systemic involvement. This prospective study showed good efficacy and tolerance of rituximab in patients with pSS and systemic involvement (81).
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 (82,83).
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 (84). There are case reports of ataxia improvement with rituximab, but most are improvement in ataxia related to other neurological conditions (85).
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 (86). 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) (87).