Anti-Tumour Necrosis Factor

In ankylosing spondylitis (AS), there has been consistent benefit with the use of anti-TNF therapy, shown initially in pilot studies, open follow up studies, and, most importantly, in several randomised controlled trials. The cytokine, tumour necrosis factor-alpha (TNF-alpha) plays a key role in the pathogenesis of many chronic inflammatory and rheumatic diseases, in particular, Crohn's disease, rheumatoid arthritis (RA), AS, and psoriatic arthritis. Controlled trials have shown that the TNF inhibitors significantly reduce symptoms and signs, improve function and quality of life, and reduce radiologically evident damage in patients with rheumatoid diseases. The antitumor necrosis factor-alpha agents currently available, infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira), are approved for the treatment of RA in North America and partly in Europe.

The situation in spondyloarthritis is different from that of rheumatoid arthritis because there is an unmet medical need, especially in ankylosing spondylitis: no therapies with disease-modifying antirheumatic drugs are available for severely affected patients, especially with spinal disease. Thus, tumor necrosis factor blockers may even be considered a first-line treatment in a patient with active ankylosing spondylitis and psoriatic arthritis whose condition is not sufficiently controlled with nonsteroidal antiinflammatory drugs in the case of axial disease, and sulfasalazine or methotrexate in the case of peripheral arthritis. Results of the available clinical trials provide strong evidence of the clinical effectiveness of infliximab and etanercept, and are supported by continuation data of up to one year. Currently there is no other known disease controlling antirheumatic treatment for AS. This is in sharp contrast with RA, where many DMARDs are known to be effective.

For reasons that are not entirely clear, etanercept does not work in Crohn's disease. Infliximab was very recently approved for AS in Europe. The efficacy of etanercept was first demonstrated in psoriatic arthritis, and it is now approved for this indication. Injection site and intravenous reactions and increased risk of infection (in particular, reactivation of tuberculosis) are associated with the use of these agents. Guidelines are currently needed to ensure appropriate selection of patients suitable for anti-TNF therapy, which can lead to harm, with rare, but possible, side effects, such as increased risk of lymphoproliferative disease, the development of lupus-like syndromes and demyelination, including optic neuritis and reactivation of multiple sclerosis. The TNF inhibitors are expensive and in some patients need to be given continuously to maintain benefit, even in the presence of other immunosuppressive therapy.

There is hope that ankylosis may be preventable, but it remains to be shown whether patients benefit from long-term antitumor necrosis factor therapy and whether radiologic progression and ankylosis can be stopped. Rheumatologists consider both disease activity and severity to be determinants of starting TNF blockers. Severe adverse events have remained rare. Complicated infections including tuberculosis have been reported. These can be largely prevented by appropriate screening. There is need to identify patients with AS with active disease who are at increased risk of severe disease, with deterioration of functional capacities, and who therefore are the best candidates, as they have the most to gain from the use of anti-TNF treatment. As it stands now, the benefits of antitumor necrosis factor therapy in ankylosing spondylitis seem to outweigh these shortcomings.

The current long term experience with TNF blocker therapy in AS is now about five years. More data on long term treatment beyond two years are currently being collected. There is no evidence that the long term use of these agents must be discouraged, there is just a need for more data. Evidence for the consecutive use of different agents is limited. Therefore, successive use of different TNF blocker drugs cannot be recommended at the present time. As further data become available, these will be used to guide decision making.

The following recommendations were developed by a review of published reports in combination with expert opinion, including a Delphi exercise, and a consensus meeting of the ASsessments in AS (ASAS) Working Group

The final international consensus comprises the following requirements for the use of anti-tumour necrosis factor (anti-TNF) for treating patients with ankylosing spondylitis (AS):

1. For the initiation of anti-TNF therapy: (a) a diagnosis of definitive AS; (b) presence of active disease for at least four weeks as defined by both a sustained Bath AS Disease Activity Index (BASDAI) of at least 4 and an expert opinion based on clinical features, acute phase reactants, and imaging modalities; (c) presence of refractory disease defined by failure of at least two non-steroidal anti-inflammatory drugs during a single three month period, failure of intra-articular steroids if indicated, and failure of sulfasalazine in patients with peripheral arthritis; (d) application and implementation of the usual precautions and contraindications for biological therapy.
2. For the monitoring of anti-TNF therapy: both the BASDAI and the ASAS core set for clinical practice should be followed regularly.
3. For the discontinuation of anti-TNF therapy: in non-responders, consideration should be made after 6–12 weeks’ treatment. Response is defined as improvement of (a) at least 50% or 2 units (on a 0–10 scale) of the BASDAI, (b) expert opinion that treatment should be continued.

Infliximab

Infliximab is a monoclonal chimeric human anti-TNF antibody that binds with high affinity to TNF. It is currently licensed for the treatment of RA to reduce signs and symptoms of RA in patients with active disease, to improve the physical function of patients, and to reduce the rate of progression of joint damage. Infliximab is approved for combination therapy with methotrexate in RA in a dose of 3 mg/kg given every eight weeks after the usual initial saturation phase, where infliximab is given at weeks 0, 2, and 6. Furthermore, infliximab is approved for acute and maintenance treatment of Crohn’s disease in a dose of 5 mg/kg. Infliximab is given as an intravenous infusion usually over 1–2 hours.

Etanercept

Etanercept is a recombinant 75 kDa TNF p75 receptor fusion protein that acts competitively to inhibit the cell surface receptor binding of TNF. It is licensed for the treatment of active RA when the response to DMARDs, including methotrexate, has been inadequate. Etanercept is administered by subcutaneous injection at a dose of 25 mg twice weekly or 50 mg once a week.

Adalimumab

Adalimumab is a monoclonal, fully human, anti-TNF antibody that binds with high affinity to TNF. It is approved for the treatment of active RA in the USA. It is given by subcutaneous injection at a dose of 40 mg every two weeks or weekly.

References:

Maksymowych WP, Inman RD, Gladman D, Thomson G, Stone M, Karsh J, et al. Canadian Rheumatology Association Consensus on the use of anti-TNF--directed therapies in the treatment of spondylarthritis. J Rheumatol 2003;30:1356–63.

T Pham, D van der Heijde, A Calin, M A Khan, Sj van der Linden, N Bellamy, and M Dougados. Initiation of biological agents in patients with ankylosing spondylitis: results of a Delphi study by the ASAS Group. Ann Rheum Dis 2003 62: 812-816.

van den Bosch F, Kruithof E, Baeten D, Herssens A, de Keyser F, Mielants H, et al. Randomized double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor (infliximab) versus placebo in active spondylarthropathy. Arthritis Rheum 2002;46:755–65

van der Linden SM, Valkenburg HA, de Jongh BM, Cats A. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals. A comparison of relatives of spondylitis patients with the general population. Arthritis Rheum 1984;27:241–9

van der Linden SM, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis: a proposal for modification of the New York criteria. Arthritis Rheum 1984;27:361–8