Rituximab, a monoclonal antibody, is not only cheaper but an equally effective treatment for rheumatoid arthritis, says ORBIT study. The findings of the head-to-head trial comparing rituximab with TNF inhibitors were published in Lancet on May 16, 2016.
Rheumatoid arthritis (RA) is a chronic inflammatory condition that can affect an individual over decades. Its treatment is expensive, particularly if it is with biologicals such as tumor necrosis factors (TNF) inhibitors i.e., £9,000-£10,000 per year. Treatment with rituximab, on the other hand, cuts down the annual cost to £4,700-£7,000. Moreover, its efficacy has been determined. Rituximab is a monoclonal antibody that fights inflammation by depleting B-lymphocytes (or B-cells — a type of white blood cells) of various pathophysiological pathways involved in the inflammatory response. However, until now, there have been no head-to-head trials comparing rituximab with TNF inhibitors.
The Optimal Management of Patients with Rheumatoid Arthritis who Require Biologic Therapy (ORBIT) study is a first of its kind. It was designed to compare the efficacy, safety, and cost-effectiveness of both drugs in patients with rheumatoid arthritis who had an active disease despite institution of the standard non-biological DMARD (NB-DMARD) therapy.
The ORBIT trial, being the first head-to-head randomized controlled trial comparing B-cell depletion with TNF inhibition in rheumatoid arthritis, has convincingly shown that rituximab is not only non-inferior but also a cheap alternative to a TNF inhibitor in biologic-naive patients with RA.
The trial involved 295 patients, all of whom were 18 years of age or older, had a seropositive RA, and a disease activity score of more than 5·1. All the patients were biological-naïve i.e., were not treated with a biologic before, and had shown a treatment failure with at least two nbDMARDS. Disease Modifying Anti-Rheumatic Drugs are the mainstay of treatment for moderate-to-severe rheumatoid arthritis.
The trial was multi-center; it included 35 rheumatology departments across the UK.
Using a web-based randomization system, the patients were randomly assigned to two groups; one receiving rituximab (IV infusion of 1 g) on day 1 and 15, the other TNF inhibitor (S/C adalimumab 40 mg; or etanercept 50 mg). The division into two groups was purely the patient’s as well as the rheumatologist’s choice. In fact, the patients could switch treatment if they encountered the drug-related side-effects or experienced a lack of efficacy.
The primary outcome of the study was a decrease in the disease activity score between 0-12 months i.e., the response was set as a decrease in DAS28-ESR by more than 1·2 good response – <3·2, and remission – <2·6.
The secondary outcomes entailed DAS28-ESR remission, and good, moderate and no response.
All the patients were followed up for one year with their disease activity assessed each month. Meanwhile, the cost as well as the effectiveness of rituximab was constantly monitored.
After 12 months, patients in the rituximab group had a change in DAS28-ESR that was -2.6; whereas for those in the TNF inhibitor group it was -2.4.
Compared to TNF inhibitor strategy, Rituximab strategy had a low health-related cost i.e., £9,405 vs £11,523 per patient.
As for adverse effects, the number was relatively, although not significantly, smaller in the rituximab group than in the TNF inhibitor group i.e., 137 vs 143. However, the incidence of serious adverse events was higher in the rituximab group i.e., 37 out of 144 patients compared to 26 out of 151 patients in the TNF inhibitors group. The side effects were deemed to be related to the monoclonal antibody treatment.
A higher proportion of patients in the rituximab group continued on initial therapy without requesting for a switch i.e., 81% vs 68% in the TNF inhibitor group.
One patient from each group died during the study.
Interpretations Regarding Rituximab
The ORBIT study persuasively shows the non-inferiority of rituximab to a TNF inhibitor in biological-naive patients with rheumatoid arthritis. Rituximab, as can be seen, also accounted for a lower treatment cost compared to the DMARD therapy (TNF inhibitors) i.e., 93% of the patients in the rituximab group required four or less infusions over a period of 12 months.
The current study can pave way for the approval of rituximab for biological-naïve patients with moderate-to-severe rheumatoid arthritis. Currently, rituximab, on account of its serious but rare side effect i.e., progressive multifocal encephalopathy, is approved only as the alternative in patients who have not responded to TNF-inhibitor. No such incidence occurred in the study; nonetheless, the ORBIT study does not preclude the possibility of the severe adverse event.
The ORBIT study, though first of its kind, had several limitations, such as:
- The study was open-label i.e., both patients and the researchers were aware of who received which drug. The open treatment allocation increased the probability of bias.
- And while the study outlined a number of primary and secondary outcome measures, it failed to capture radiological outcomes i.e., TNF inhibitors treatment produces different radiographic joint damage.
- The study enrolled patients who were seropositive for RA only. The response of rituximab is greater in patients who are seropositive disallowing extrapolation of the results from individuals who are seronegative.