Rheumatoid arthritis (RA)
Rituximab was first used in RA in 1998 (Edwards & Cambridge, 2001). Randomised, placebo-controlled trials (RCTs) have demonstrated its efficacy. Fifty-one to eighty-five percent of patients respond to therapy, depending on the criteria used, with the trial that included only patients who had failed anti-tumour necrosis factor (TNF) therapy showing lower rates of response (Edwards et al, 2004; Cohen et al, 2006). Rituximab in combination with methotrexate is licenced for the treatment of moderate to severely active RA following failure of anti-TNF therapy. Patients can take up to 3–4 months to respond (Emery et al, 2006) and seropositive patients (rheumatoid factor or antibodies to cytrullinated peptides) are much more likely to respond to treatment than seronegative patients (Tak et al, 2006). The disease almost never relapses before B cell reconstitution (Popa et al, 2007), however, patients may relapse at the start of B cell return or at a variable times afterwards. Individual patients tend to show the same pattern of relapse in relation to B cell reconstitution after repeated courses of treatment (Cambridge et al, 2006a). Patients who have an initial response to treatment usually respond to re-treatment upon relapse (Keystone et al, 2007). It was in RA that the protocol currently referred to as the ‘autoimmune protocol’ for the administration of rituximab was developed (Leandro et al, 2002a). This includes two 1000 mg infusions of rituximab given two weeks apart. It is not clear whether this is the optimal protocol and, in particular, whether a body surface area-based protocol would be more appropriate.
Rheumatoid arthritis patients are less likely to develop an infusion reaction than patients with lymphoma. Between 29% and 45% of RA patients suffer a reaction compared to 67% of lymphoma patients during the first infusion (Maloney et al, 1997; Edwards et al, 2004; Cohen et al, 2006). Following one course of therapy total immunoglobulin levels usually remain within the normal range (Edwards et al, 2004; Cohen et al, 2006). However, repeated courses of treatment may have a cumulative effect and lead to an increased frequency of hypogammaglobulinaemia (Keystone et al, 2007; Popa et al, 2007). This most commonly involves IgM but can also involve IgG. Hypogammaglobulinaemia in this setting does not appear to increase the risk of infections in all patients although individual cases have been reported (Keystone et al, 2007; Popa et al, 2007). Autoantibodies seem to be more susceptible to rituximab than anti-microbial antibodies (Cambridge et al, 2006a).
Systemic lupus erythematosus
Rituximab has been used off-label to treat patients with severe active SLE refractory or intolerant to standard therapy (Leandro et al, 2002b, 2005; Looney et al, 2004; Sfikakis et al, 2005; Risselada & Kallenberg, 2006; Smith et al, 2006; Gunnarsson et al, 2007; Tokunaga et al, 2007; Reynolds et al, 2009). However, a recent RCT in patients with non-renal SLE failed to show efficacy (Merrill et al, 2008). It is not known whether the absence of a difference between the treatment and the placebo arms is due in part to the fact that all patients were treated with high dose steroids. Trials in patients with lupus nephritis are still ongoing. Rituximab therapy in SLE has been associated with improvement in skin rashes, mouth ulcers, serositis, neurological symptoms, autoimmune cytopenias, lung involvement, vasculitis, arthralgia and arthritis (Leandro et al, 2002b, 2005; Looney et al, 2004; Sfikakis et al, 2005; Smith et al, 2006; Tokunaga et al, 2007; Reynolds et al, 2009). A good response in lupus nephritis is associated with improvement in histopathological changes on renal biopsy (Gunnarsson et al, 2007).
B cell depletion induced by rituximab seems to be more variable and less predictable in SLE than in other diseases such as RA and vasculitis. Several patients have been shown to repopulate their B cells before 5–6 months and some may not deplete with ‘full’ rituximab doses (Looney et al, 2004; Leandro et al, 2005). Potential causative factors include HACA development, different rituximab pharmacokinetics, less efficient recruitment of ADCC or complement or reduced susceptibility of B cell clones to depletion with rituximab. Patients with SLE seem to be at increased risk of developing HACAs (Looney et al, 2004). In two cases the presence of HACAs has been associated with failure of B cell depletion and lack of clinical response upon retreatment (Leandro et al, 2005; Saito et al, 2005). An FcγRIIIa genotype with higher affinity for IgG has been associated with more pronounced B cell depletion (Anolik et al, 2003), which, in itself, is associated with a better clinical response (Looney et al, 2004) but the importance of this factor when larger doses are used is not known. Some, but not all, studies have described a significant decrease in anti-double stranded (ds)DNA antibodies following rituximab and there is not always a clear correlation with clinical response (Looney et al, 2004; Leandro et al, 2005; Sfikakis et al, 2005; Smith et al, 2006; Gunnarsson et al, 2007). In some series anti-dsDNA have been shown to decrease significantly but not antibody to soluble extractable nuclear antigen (anti-ENA) or anti-microbial antibodies (Cambridge et al, 2006b; Vallerskog et al, 2007). The presence of anti-ENA antibodies and lower levels of serum C3 at baseline have been associated with a higher risk of earlier relapse (Ng et al, 2007). Usually patients who responded to an earlier course of therapy respond to re-treatment. Some patients have been treated with maintenance regimens to keep them B cell depleted and sustain the clinical response (Weide et al, 2003).
Different treatment protocols with rituximab have been used, including two infusions of 500 mg or 1000 mg 2 weeks apart, or 2–4 weekly infusions of 375 mg/m2. Some studies continued baseline immunosuppression and some gave rituximab in combination with cyclophosphamide based on a protocol first used in RA (Leandro et al, 2002b). Whether this may be associated with a higher risk of infection is not known. A small number of cases of severe infusion reactions, serum sickness-like disease and other serious side effects (including severe infections and two isolated cases of PML) have been described (Smith et al, 2006; Todd & Helfgott, 2007). PML appears to be more common in the SLE patient population than other auto-immune diseases, however, it is important to remember that PML also occurred, albeit with reduced frequency, in these patients with more traditional treatments (Nived et al, 2008). Many of the patients treated with rituximab have received other lines of immunosuppression and the relative contributions of each of the treatment modalities are frequently hard to clarify. A recent review has suggested that the risk of PML in SLE patients may not be associated with the intensity of immunosuppression (Molloy & Calabrese, 2008).
Rituximab has been used to treat primary Sjogren syndrome (pSS) and pSS with mucosa-associated lymphoid tissue lymphoma in small case series and one small RCT (Pijpe et al, 2005; Devauchelle-Pensec et al, 2007; Seror et al, 2007; Dass et al, 2008). Systemic manifestations are reported to respond to treatment including fatigue, arthralgia/arthritis, pulmonary involvement, myelitis and vasculitis with or without cryoglobulins. The response of salivary and lacrimal gland dysfunction (sicca syndrome) is more variable. If dryness results from glandular damage rather than disease activity it may explain why rituximab given in the later stages of the disease might not be able to restore glandular function. Sicca syndrome in patients with early disease (<4 years) and residual glandular function appear to respond better to treatment with rituximab (Pijpe et al, 2005) and cases of severe keratitis have been reported to respond (Zapata et al, 2007). Titres of IgM-rheumatoid factor frequently decrease following treatment (Devauchelle-Pensec et al, 2007; Seror et al, 2007), however, anti-Ro and anti-La antibodies do not change (Devauchelle-Pensec et al, 2007). In some cases associated paraprotein or cryoglobulins become undetectable (Pijpe et al, 2005; Seror et al, 2007). B cell depletion lasts for 5–8 months (Devauchelle-Pensec et al, 2007; Meijer et al, 2009) and relapse follows B cell return in some but not all patients (Seror et al, 2007; Meijer et al, 2009). Retreatment gives similar results to initial treatment (Seror et al, 2007; Meijer et al, 2009).
Up to 20% of patients with pSS develop infusion reactions and serum sickness and in some cases this is associated with the development of HACAs (Seror et al, 2007; Meijer et al, 2009). Premedication with corticosteroids and slower infusion rates have been considered to try and decrease the risk of these reactions (Pijpe et al, 2005; Devauchelle-Pensec et al, 2007). Lower total doses of rituximab and development of HACAs have been associated with decreased peripheral B cell depletion in individual cases (Pijpe et al, 2005).
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis
The ANCA-associated vasculitides (AAV) include Wegener granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome. Rituximab has been used to treat refractory cases of AAV or those in whom standard therapy is contraindicated. The majority of the data comes from case series and small prospective open-label trials (Keogh et al, 2005, 2006; Aries et al, 2006; Smith et al, 2006; Roccatello et al, 2008; Lovric et al, 2009). Most studies used four weekly 375 mg/m2 infusions in combination with high dose steroids and some continued baseline immunosuppression until clinical response. Response rates are between ninety and one hundred percent (Keogh et al, 2005, 2006; Smith et al, 2006; Roccatello et al, 2008; Lovric et al, 2009) with systemic, ENT (ear, nose and throat), lung, renal, central nervous system, skin, eye and joint manifestations reported to improve. However, in a small series of patients with severe refractory granulomatous disease, only three of the eight patients responded (Aries et al, 2006). The authors suggested that manifestations predominantly due to granulomatous lesions may be less likely to respond to B cell depletion.
B cell depletion lasts for 6–9 months. In most studies ANCA titres decrease or become negative following treatment (Keogh et al, 2005, 2006; Smith et al, 2006; Roccatello et al, 2008; Lovric et al, 2009). Patients with higher levels were less likely to become ANCA negative. Interestingly, in the study by Aries et al (2006) ANCA titres decreased in only one patient. As in RA, autoantibodies were more sensitive to treatment with rituximab than natural antibodies or antibodies to extrinsic antigens (Ferraro et al, 2008). Retreatment in patients who relapsed was effective (Keogh et al, 2005, 2006; Smith et al, 2006). A close association between B cell return, changes in ANCA titre and clinical relapse was observed in some but not in all studies and in two studies a rise in ANCA titres was treated with pre-emptive rituximab to maintain stable remission (Keogh et al, 2005, 2006).
Two deaths have been reported: one due to pneumonia and one in a patient with reactivation of hepatitis B infection who developed renal insufficiency and refused dialysis (Lovric et al, 2009). Both patients were on additional immunosuppression and whether this increases the risk of infection is unclear (Smith et al, 2006). HACAs were detectable in 18% of patients in one study and in none in another study (Keogh et al, 2006; Smith et al, 2006). HACAs were associated with incomplete depletion on retreatment with rituximab in one patient (Smith et al, 2006).
Types II and III (mixed) cryoglobulinaemia are systemic vasculitic disorders due to immune complex formation and in the case of type II most commonly associated with hepatitis C infection. Rituximab has been used in the treatment of types II, III and essential cryoglobulinaemia in individual cases, small series and open-label studies mostly for refractory disease (Sansonno et al, 2003; Zaja et al, 2003; Roccatello et al, 2004; Koukoulaki et al, 2005; Quartuccio et al, 2006, 2008; Braun et al, 2008; Saadoun et al, 2008). Major improvement in skin, joint, systemic, renal and neurological manifestations has been reported (Sansonno et al, 2003; Zaja et al, 2003; Roccatello et al, 2004; Quartuccio et al, 2006; Saadoun et al, 2008). This occurs in association with B cell depletion, a significant reduction in rheumatoid factor titre, decreased cryoglobulin levels and an increase in C4 (Sansonno et al, 2003; Zaja et al, 2003; Roccatello et al, 2004). Interestingly, in one study, cryoglobulin levels decreased following treatment but on further follow up showed fluctuations not related to repeated courses of therapy (Quartuccio et al, 2006). Disappearance of bone marrow B cell clonal expansion, a reduction in circulating clonal B cells and expansion of the T-regulatory cell pool has been documented following treatment (Quartuccio et al, 2008; Saadoun et al, 2008). Persistence of B cell clones was documented in patients who did not respond to therapy, suggesting that these clones were less susceptible to rituximab (Sansonno et al, 2003). Patients retreated upon relapse respond again to treatment (Quartuccio et al, 2006).
Most protocols used four weekly infusions of 375 mg/m2. Some gave additional doses 1 and 2 months later or maintenance therapy to prevent relapse (Roccatello et al, 2004; Quartuccio et al, 2006). A small pilot trial in six patients using a lower dose (250 mg/m2) has reported good responses in 80% of patients (Visentini et al, 2007).
A small number of cases of dose-related bradycardia have been reported. There was one case of retinal artery thrombosis following the second dose of rituximab (Zaja et al, 2003) and the authors suggest that treatment with rituximab of patients with abnormal serum proteins should be carefully monitored. In the study by Roccatello et al (2004), low dose aspirin or analogues were used to prevent thrombosis. Some studies have described increased hepatitis C virus (HCV) viraemia and reduced anti-HCV antibodies (with no detectable changes in the liver function or imaging) following treatment with rituximab, raising the question whether rituximab should be given with antiviral agents (Sansonno et al, 2003; Lake-Bakaar et al, 2007). This was not seen in other studies (Roccatello et al, 2004). An open-label trial of rituximab with antiviral therapy has been published with good results (Saadoun et al, 2008).