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Use of biological agents in rheumatic disease.

In a large number of rheumatic diseases the disease process is driven by the immune system. In the past few decades, there have been great advances in our understanding of the immunopathology and pathogenesis of the rheumatic diseases. At the same time, there have been similar advances in the development of drugs, particularly in the field of biopharmaceutical drugs that can target specific components of the immune response central to these diseases. Biological drugs can be monoclonal antibodies or proteins produced by living cells that bind with receptors on various cells to block formation or action of various cytokines or cell mediators, or in other ways change cell function. (1), (2)

The area where there has been the most use of these drugs in research and later in the clinical setting has been in the treatment of inflammatory arthritis, particularly rheumatoid arthritis (RA), but also in the treatment of ankylosing spondylitis (AS), undifferentiated spondyloarthritis, reactive arthritis, psoriatic arthritis (PsA) and juvenile idiopathic arthritis (JIA). In these diseases, the biological disease-modifying anti-rheumatic drugs (DMARDs) have made a great difference to patients who have failed conventional synthetic DMARDs, not only in improvement of symptoms and function, but by inhibiting structural damage to joints. (2), (3)

The first biological DMARDs to be used in the treatment of inflammatory arthritis were the TNF-alpha blockers. There are now several different TNF-alpha blocking drugs available in South Africa. Infliximab (Revellex) is given as an intravenous infusion every 8 weeks at a dose of 3 mg/kg (5mg/kg for AS), etanercept (Enbrel) is given subcutaneously at a dose F of 25 mg twice aweek, and adalimumab (Humira) subcutaneously at a dose of 40 mg every second week. All three drugs have been shown to be equally effective in the treatment of inflammatory arthritis and are indicated for these diseases. (3)

The main safety concerns with these drugs, as with any that affect the immune system, have been the potentially increased risk of infection. Clinical trials have shown that the infection risk was comparable to placebo groups on the whole as far as most infections were concerned. The infection of concern, particularly in a high-risk country, is tuberculosis (TB). There is a risk of reactivation of latent TB infection (LTBI) as well as newly acquired infection. TNF-alpha plays a specific role in the formation of granuloma that contains the TB organism in LTBI, and inhibition can lead to breakdown of the granuloma and release of the organisms. All patients are tested for LTBI before starting a biological drug and are treated if the infection is present. The risk of TB has been reduced using this approach, but it is still something to be looked for every time a patient on a biological agent is assessed at follow-up. Other safety concerns are the risk of malignancy and lymphoma, which do not seem to be increased compared with the background population of patients with severe inflammatory arthritis. There have been a few cases of demyelinating disease and patients with any suspicion of such a disease should not receive these drugs. Another contraindication is heart failure, as it can be worsened. Safety in pregnancy has not been established, although specific abnormalities related to the drug have not been seen in babies born to patients on these drugs during pregnancy. (2)

Other biological drugs have become available, namely abatacept (Orencia), rituximab (MabThera) and tocilizumab (Actemra). Abatacept is a selective costimulation modulator that inhibits the costimulation of T cells important in the RA disease pathogenesis. It is given at a dose of 750 mg or 1 000 mg, depending on the mass of the patient, as an intravenous infusion every month. Rituximab is an anti-CD20 monoclonal antibody which depletes CD-20 positive B cells in the body. The dose for RA is two 1 000 mg intravenous infusions given 14 days apart every 6 months or when a patient again starts to show symptoms of active disease. Abatacept inhibits the cytokine IL-6 and is given with a dosing schedule of 4 or 8 mg/kg every 4 weeks as an intravenous infusion. In clinical trials, the response to all three drugs has been comparable to that seen with the TNF-alpha blockers. The safety of these drugs is similar to that of the TNF-alpha blockers, with the risk of infection remaining the main concern, although the risk of TB seems to be decreased.

The use of biologics in other connective tissue diseases has not been as widely studied.Most are anecdotal studies, as most diseases are uncommon and the clinical picture is variable, making randomised controlled trials difficult. Rituximab has shown promise in treating several connective tissue diseases where conventional therapies have failed, including systemic lupus erythematosus (SLE), various types of vasculitis, Sjogren's syndrome and possibly scleroderma.

The biological drugs have opened new horizons for the treatment of rheumatic diseases and will continue to be important drugs. Unfortunately the technology used to make these drugs is expensive, which currently severely limits their use, but it is hoped that the price will improve and that we will be able to give the benefit of another type of treatment to a greater number of our patients with rheumatic disease.


* The biological drugs have made a major impact on the way rheumatic diseases can be treated.

* They have been used mainly in the treatment of inflammatory arthritis.

* Some biologicals show promise in the treatment of other connective tissue diseases, particularly vasculitis and lupus.

* Several of these drugs block cytokines, such as the TNF-alpha blockers and IL-6 blockers, while others block activation of cells that produce cytokines or produce apoptosis in cells (e.g. abatacept and rituximab).

* Currently available drugs are in injectable form used at different time intervals.

* The main concerns in the use of biological drugs have been increased infection rate, particularly activation of tuberculosis.

* On the whole the biologics are relatively safe drugs offering real benefit in previously difficult-to-treat diseases.

References available at

ELSA VAN DUUREN, BMedSci, MB ChB, MSc (Sports Medicine), MMed (Med Phys)

Rheumatologist, Jacaranda Hospital, Pretoria

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Author:Van Duuren, Elsa
Publication:CME: Your SA Journal of CPD
Date:Aug 1, 2011
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