Over the last decade rheumatologists have been extremely fortunate in that a variety of very effective medications have become available for rheumatoid arthritis (RA). These so-called biologic disease modifying anti-rheumatic medications (DMARDs) differ from the traditional DMARDs, such as methotrexate, in that they target specific molecules which are responsible for the inflammation occurring in the joints and other tissues in RA. The currently available anti-TNF biologic DMARDs include infliximab (Remicade), etanercept (Enbrel) and adalimumab (Humira) and these have proved their worth in RA. A need remains for further therapies however as not everyone gains benefit from these medications and side-effects may preclude long-term treatment.
What is rituximab?
Rituximab, (also known as Mabthera or Rituxan) is an antibody which is directed against B-cells, specifically a marker on certain types of B-cells called CD-20. B-cells are required for the normal functioning of the immune system but are also intimately involved in the inflammatory process in RA. Rituximab was initially approved for the treatment of non-Hodgkin’s B cell lymphoma (a cancer of the lymph nodes) however it was subsequently found to be very effective in the treatment of RA and in a variety of other conditions in which B cells play a role, such as systemic lupus erythematosus (SLE).
Evidence of benefit.
Convincing evidence of efficacy initially came from a trial in RA in which rituximab was used either alone or in combination with methotrexate or cyclophosphamide. Subsequently the DANCER trial, involving 645 patients, confirmed the benefit of rituximab plus methotrexate and that the benefit was independent of the use of steroids. A further trial, the REFLEX study, involving patients with an inadequate response to anti-TNF a therapy showed a marked clinical improvement with rituximab therapy. The efficacy was similar to that of the TNF a inhibitors. More recent studies have shown the potential benefits of rituximab in halting radiological damage which occurs in RA. Unlike anti-TNF drugs, which can work more quickly, the full effect of rituximab may not be seen for 16-24 weeks.
Current licence for rituximab
In 2006 the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) approved rituximab for the treatment of RA in patients who have had an inadequate response to anti-TNFα therapy. The National Institute for Health and Clinical Excellence (NICE) have also issued guidance on the use of rituximab in patients with active RA who have not responded well to anti-TNF drugs.
How is rituximab given?
Rituximab is currently administered as an infusion of 1 gram given twice (two weeks apart) on a background of methotrexate. The infusions last between 3-5 hours and are given in special infusion centres in the hospital setting. A small dose of corticosteroid, anti-histamine and paracetamol are also administered at the time of the injection to reduce the risk of an infusion reaction. Although the safest and most effective timing for repeat treatment with rituximab has yet to be determined, preliminary data suggest that the interval will likely be every 6 to 12 months.
Occasionally rituximab is given as a first line biologic agent prior to anti-TNF, with or without background MTX. Although outside the licence your doctor may feel this is the best way to give the medication.
Potential side-effects and complications of rituximab
Despite being a powerful medication the side-effect profile of rituximab is favourable. The main trouble to date has been infusion reactions which most commonly occur during the first infusion. Patients may experience nausea, rash, itchiness, hot flushes, and either an elevation or reduction in blood pressure. It is very unusual for patients to stop the infusion due to this side-effect and infusion reactions become much less severe following the first infusion of rituximab. Interestingly in the longer term there does not appear to be a great increase in infections or other major side-effects.
As the drug is used for lymphoma this is not really a concern as a potential side-effect. There is also reassuring data from the over 750,000 patients who have been treated with rituximab for lymphoma, in that the drug has been well tolerated and there has not been a great increase in significant side-effects.
Very rarely (4 in 100,000 patients) a condition called progressive multifocal leukoencephalopathy (PML), which can damage the brain and spinal cord has been reported in patients taking rituximab for RA. If you experience any of the following you should see your doctor immediately: pins and needles, weakness, shaky movements, unsteadiness, loss of vision, speech problems, changes in your behaviour or mood, difficulty with moving your face, arms or legs. Of note, the incidence of this in patients with RA is extremely rare and those who have developed the condition have usually been receiving significant immunosuppressive drugs apart from rituximab.
Rituximab is not recommended in those who wish to become pregnant or those breast feeding.
Immunisation and rituximab
Where vaccination is indicated, it should ideally be given prior to rituximab treatment and avoided immediately after rituximab with a delay of several months.
This may not always be practical for vaccines with seasonal availability (such as those to influenza) and it must be recognised that responses to vaccination do not necessarily correlate with the risk of infection. In general, the timing of rituximab administration must be determined by the specialist according to clinical need without having to delay until after supplies of a seasonally variable vaccine become available and the patient has been immunised.
Live vaccines are not recommended, including the new shingles vaccine.
Many RA patients do not respond adequately to the currently available biologic DMARDs and this area of unmet need is filled to a significant degree by rituximab. However, as with all DMARDs, rituximab cannot repair joints that have already been damaged, though it can prevent further damage from occurring. Future studies will address how best to introduce rituximab into the treatment paradigm of RA to maximise the benefit for patients. We live in truly exciting times.
References available on request
Dr Andrew J K Ostor, Consultant Rheumatologist & Associate Lecturer, School of Clinical Medicine, University of Cambridge, Director, Rheumatology Research Unit
Original article: 05/12/2006
Next review due: 27/12/2016