Tumour necrosis factor inhibitors

Although the triggering factors for many autoimmune diseases are not known, one of the key inflammatory mediators in the attending chronic inflammatory process is the cytokine, tumour necrosis factor-alpha (TNF-α).1 TNF-α overexpression acts as a driver for inflammation that damages cartilage, bone and bowel mucosa, and TNF-α inhibition leads to significant clinical improvements and reduction of this damage. Three TNF-α inhibitors are currently listed by the Pharmaceutical Benefits Scheme (PBS) for use in Australia, in instances of severe disease uncontrolled by other disease modifying measures. They are:

Infliximab binds to TNF-α and TNF-β and lyses TNF-producing cells to neutralise their activity.2 It is licensed for use in combination with weekly low-dose methotrexate therapy in rheumatoid arthritis, and is given by intravenous infusion at baseline, 2 weeks, 6 weeks, and thereafter 8-weekly. The dose is 3 mg per kilogram in rheumatoid arthritis and 5 mg per kilogram in ankylosing spondylitis and psoriatic arthritis (Box 1). In Crohn’s disease, it is approved for acute and maintenance therapy and the dose is 5 mg per kilogram (Box 1). The presence of murine sequences is associated with the formation of anti-chimeric antibody production, which can result in infusion reactions and a reduction in efficacy with long-term therapy, although the rate of discontinuation of treatment for this reason is less than 2%.3

Etanercept is a recombinant dimer of human TNF receptor proteins fused and bound to human IgG1 that acts competitively to inhibit the binding of TNF to its cell surface receptor. It is given by subcutaneous injection 25 mg twice weekly. Studies have shown that 50 mg given once a week has equal efficacy to twice-weekly injections in patients with rheumatoid arthritis.4 For reasons that are not entirely clear, etanercept is not effective in Crohn’s disease.

Adalimumab is a monoclonal fully human anti-TNF-α antibody that binds with high affinity to TNF-α. It is approved for treating rheumatoid arthritis both in combination with methotrexate and as monotherapy. It is given by subcutaneous injection at a dose of 40 mg every 2 weeks. By replacing murine with human elements, the production of antibodies that neutralise the adalimumab injections is reduced.

TNF inhibitors are generally well tolerated, with prompt onset of action and much earlier relief of symptoms compared with standard DMARD therapy in rheumatoid arthritis, or with standard immunosuppressive therapy in Crohn’s disease. Box 2 lists the major adverse effects. Injection site reactions or intravenous infusion reactions of mild to moderate severity occur, and are managed with antihistamines, injection of hydrocortisone or, less commonly, cessation of therapy (E2).6-10 Serious infections can occur including septic arthritis, infected prostheses and a variety of opportunist infections such as pneumocystis and tuberculosis (E2).29 In particular, susceptibility to infection and reactivation of latent tuberculosis early after commencement of anti-TNF therapy, and dissemination in a miliary fashion has been documented (E2).30 This means that patients commencing anti-TNF therapy should have a screening chest x-ray and Mantoux test. However, this guideline was developed primarily for the US and European populations. The interpretation of the Mantoux test in the Australian population, where previous BCG has been common and the prevalence of tuberculosis is low, is difficult. Induration of more than 10 mm and erythema of 15 or greater at 48–72 hours are considered appropriate to avoid clinically irrelevant positive results. Isoniazid therapy for 9 months is indicated if anti-TNF therapy is deemed necessary and the Mantoux result is significantly positive.24,31 Demyelinating disorders such as reactivation of multiple sclerosis or optic neuritis have been reported.32 The incidence of lymphoproliferative disease is increased in rheumatoid arthritis, especially in patients with high disease activity, but this also occurs in such patients on methotrexate therapy.33,34 The TNF inhibitors may increase that risk (E3). Long-term controlled and adequately powered follow-up studies are required to settle this issue. There is no evidence that TNF inhibitors increase the incidence of other malignancies or recurrence in patients with prior malignancy in the controlled clinical trial database, but further observation in controlled and adequately powered studies are required (E3).32 The development of antinuclear antibodies and dsDNA antibodies is not uncommon, but SLE (systemic lupus erythematosus)-like syndromes are much rarer and abate with drug cessation (E3-2).32 Other rare reports include pancytopenia, aplastic anaemia,32 and aggravation of congestive cardiac failure.32 Safety, apart from anecdotal reports, is unknown in patients with hepatitis B and C infection, and data are limited in pregnancy or lactation.

Box 3 describes situations in which TNF inhibitors are not appropriate.

In rheumatoid arthritis, there is Level 111 evidence for their use as subcutaneous or intravenous injections, generally in combination with methotrexate therapy.

In Crohn’s disease, there is accumulating Level 311 evidence for their use with conventional immunosuppressive agents. Prospective studies using these drugs in combination therapy are awaited. The results of these studies will be important to ensure rational use of these expensive new therapies.

Toxicity includes injection and infusion reactions, infection risk (particularly with tuberculosis reactivation), and SLE-like syndromes. Risk of lymphoproliferative and demyelinating disease are under ongoing assessment in long-term follow-up studies.

Box 4 contains important messages for patients.