For autoimmune diseases, the only indication for which rituximab is approved by the Food and Drugs Administration (FDA) is active RA unresponsive to DMARDs and anti-TNF-alpha agents. Rituximab is beneficial for other off-label indications in patients with autoimmune disease (such as SLE) and Castleman's disease.
The most popular protocol for RA is IV infusion of 1000 mg/m2 on days 1 and 15 in combination with MTX. Subsequent courses may be administered every 24 weeks (based on clinical evaluation), and if necessary, may be repeated, but no sooner than every 16 weeks. For patients with RA, pre-medication with IV methylprednisolone 100 mg (or equivalent) is recommended, 30 minutes before each dose of rituximab. For granulomatosis with polyangiitis (GP) (previously Wegener's granulomatosis), the protocol is different: IV infusion with 375 mg/m2 once weekly for four doses (in combination with IV methylprednisolone for 1 to 3 days followed by daily prednisone). The protocol for microscopic polyangiitis (MPA) is similar to that of GP.
Rituximab was evaluated for chronic immune thrombocytopenic purpura (ITP) in a multi-center phase II study of 60 patients, who received an IV infusion of 375 mg/m2 once weekly for 4 doses; 40% of patients achieved a steady platelet level. A few studies also suggested that low-dose treatment with 100 mg/m2, either alone or in combination with steroids would suffice and result in fewer AEs; however, further data on this dose are lacking.
For refractory pemphigus vulgaris (PV), the recommended treatment is IV infusion of 375 mg/m2 rituximab once weekly in weeks 1, 2, and 3 of a 4-week cycle, which is repeated for one additional cycle, followed by one dose per month for 4 months (total of ten doses in 6 months). The initial infusion should be started at 50 mg/hour, and if there is no reaction, the rate should be increased by 50 mg every 30 minutes (100 mg/hour).
EFFICACY
Several studies suggest that rituximab may be beneficial for the treatment of SyS. In a study of eight patients with SyS, the B-cell infiltrate was depleted in the skin after rituximab infusion, signifying that the drug might be a possible therapy for skin fibrosis . Another study of 15 patients with SyS also showed histological improvement in the skin after rituximab therapy .
In a study of 257 patients with SLE treated with rituximab and prednisone, disease activity was not significantly improved compared with placebo. However, in a subgroup analysis of African American and Hispanic patients, there was a significant benefit for rituximab therapy. Furthermore, in open trials for long-term treatment, rituximab was found to be superior . The lack of efficacy in the overall trial could be associated with the clinical set-up of the trial, inclusion of too many subsets, or non-stratification of patients positive or negative for anti-double-stranded DNA antibodies .
A case series indicated that rituximab might be beneficial in hemolytic anemia, thrombocytopenia, and arthritis-related SLE .
In a study of 646 patients with RA who had treatment failure with anti-TNF-alpha blockers, follow-up at 6 months after therapy with rituximab resulted in a good clinical response and even remission of the disease .
In the SUNRISE (Study of Retreatment with Rituximab in Patients with Rheumatoid Arthritis Receiving Background Methotrexate) trial, 559 patients with RA with inadequate response to one or more TNF-alpha inhibitors were given two treatment cycles of rituximab to assess the efficacy and safety profile of the drug. Of the total 559 patients in the study, 475 patients received the second cycle of therapy, with a significant response compared with the placebo group, as measured by the ACR20 .
In a study of 42 patients with severe PV, rituximab was administered as monotherapy, inducing remission in 36 patients for periods of 8 to 64 months. In those patients requiring an additional dose, the safety profile remained good .
ADVERSE EFFECTS AND SAFETY
One of the AEs associated with rituximab is an infusion reaction, characterized by fever, chills, rash, swelling (of hands, feet, and face), bronchospasm, and hypotension. In most cases, the reaction is immediate (30 minutes to 2 hours), usually during the first infusion, but is less severe with subsequent infusions. Pretreatment with acetaminophen and an anti-histamine is recommended to prevent this infusion reaction. If the infusion reaction occurs, the infusion rate should be decreased or discontinued. Additional treatment with steroids may also be warranted. Rituximab treatment requires monitoring of several AEs, including infections, TB, and lymphoma. It is contraindicated in the case of pregnancy and breastfeeding, active infections, live vaccination, severe congestive heart failure, a history of demyelinating disease, and a 5-year history of non-lymphoproliferative cancer .
In a meta-analysis assessing the safety of rituximab, including long-term therapy, 123 of 2,578 patients with RA withdrew because of malignancy, infection, a severe infusion reaction, or cardiac event. Most AEs occurred during the first course of therapy. The incidence of malignancies was not increased in patients with RA treated with rituximab .
Rituximab causes a decrease in gammaglobulin concentrations, depending on the cumulative dose; however, this does not seem to lead to a higher risk for severe infection. A few cases of progressive multifocal leukoencephalopathy (PML) were reported in some patients after rituximab therapy.
OFATUMUMAB
Mechanism
Ofatumumab (trade name Arzerra) is a fully human monoclonal antibody directed against the membrane proximal epitope on the CD20 molecule.
INDICATIONS AND DOSAGE
Ofatumumab is indicated for the treatment of chronic lymphocytic leukemia. Owing to its B-cell-suppressing effect, it is also used in the USA and Europe as an off-label treatment for patients with RA who have failed MTX therapy. In a combined phase I and II study, patients received three escalating doses of ofatumumab (300, 700, and 1000 mg), with each dose given as two separate IV administrations with 2 weeks between them, over a period of 24 weeks . Prior to administration, all patients in the high-dose groups received premedication with acetaminophen, anti-histamine, and glucocorticoids.
The recommended protocol for maximum efficacy and safety is IV administration of 700 mg over 4 hours with appropriate premedication, repeated every 2 weeks.
EFFICACY
Two studies reported efficacy of ofatumumab compared with placebo or MTX in patients previously treated with DMARDs or biologic therapies; all such therapies were discontinued prior to study entry. In one study, comparing the efficacy of ofatumumab (three different dose groups) with patients treated with placebo or MTX, significantly higher rates of ACR20 were seen in the ofatumumab groups compared with the placebo group. In addition, the efficacy was dose-dependent, as assessed by the ACR20 and the circulating B-cell population.
In another multi-center double-blind RCT of biologic therapies in naive patients with RA, ofatumumab 700 mg was compared with placebo, and a significantly higher rate of improvement as measured by ACR20 was noted in the ofatumumab group. No significant differences were noted between seronegative and seropositive patients in this study .
ADVERSE EFFECTS AND SAFETY
In a study comparing the safety of ofatumumab (three different dose groups), the main AEs were related to infusion reaction, which was mild to moderate and occurred mainly with the first and second administrations. However, after 24 weeks of treatment, a significant number of AEs occurred in the highest-dose (1000 mg) group. No difference in infections was noted between the different dosage groups and the placebo. Other AEs included rash, dyspnea, rhinitis, nausea, pruritus, URT infections, headaches, fatigue, flushing, hypertension, and diarrhea.
In another double-blind multi-center study, the most common reactions were urticaria and rash on the day of the first infusion. Most of the reactions were mild to moderate, and severe AEs were infrequent . No case of PML was reported.
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