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Tumour necrosis factor α (TNFα) has emerged as a potent proinflammatory mediator in the inflammatory arthritides. Studies on synovial tissue from patients with rheumatoid arthritis have shown not only the presence of large amounts of TNFα but also demonstrated its regulatory effect on the whole network of proinflammatory cytokines present in inflamed joints.1,2 Consequently, TNFα antagonists given systemically have proved to be efficient in the treatment of chronic arthritides.3,4
Here we report our experience of an attempt to ameliorate arthritis locally by intra-articular administration of TNFα antagonists. Six patients attending the department of rheumatology at Sahlgrenska University Hospital in Göteborg, who had persistent effusions in the knee joints which were non-responsive to intra-articular steroids, received a local injection of infliximab.
METHODS AND RESULTS
Table 1 presents the diagnosis and clinical characteristics of the patients. Both the diagnosis and duration of the inflammatory joint disease were variable. All these patients had a low general activity of joint disease as assessed by the arthritis index, Health Assessment Questionnaire, low levels of acute phase reactants (erythrocyte sedimentation rate (ESR), C reactive protein), and the small numbers of white blood cells in the blood and synovial fluid. Persistent synovitis of a knee joint was the main clinical feature of their disease. A decision to inject TNFα antagonists locally was made after the persistent inflammation in the knee joint did not respond to two or more arthrocenteses with concomitant corticosteroid infusions during a period of six months. Patients gave their informed consent to intra-articular injection of the TNFα antagonists.
Clinical and serological characteristics of the patients included in the study
Infliximab (Remicade, 100 mg) was mixed with 10 ml sterile water according to the instructions for intravenous infusion, and the prepared solution was injected into the knee joint as a single dose. Synovial fluid (25–85 ml) was removed before the infliximab injection. The treatment was tolerated well by all the patients and no adverse reactions occurred locally in the injected knee or systemically during the follow up.
The effect of the infliximab injection was determined by clinical examination and by telephoning the patients. Five patients had a relapse of the synovitis in the injected knee within two weeks and the sixth patient within 6–7 weeks after the infliximab injection.
DISCUSSION
These results indicate that the effect of intra-articular treatment with TNFα antagonists was no better than the local injection of corticosteroids. Several reasons for this are possible:
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The degree of infusion of the antibodies is insufficient to bind the large amount of TNFα present in the synovial cavity. Continuous local production and release of TNFα overcomes the neutralising capacity of the antibodies introduced.
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Antibodies injected into the joint neutralise only TNFα released into the synovial fluid, but do not penetrate into the synovial tissue or act on intracellular pools of TNFα.
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Complexes of anti-TNFα antibodies with TNFα can still reach receptors on the surface of target cells. A high local concentration of the immune complexes (anti-TNFα antibodies/TNFα) within the joint itself induces inflammation.5
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Local processes supporting inflammation within the joints are obviously not restricted to TNFα. The contribution of TNFα in local inflammation is less than its systemic effect. Anti-TNFα antibodies do not interrupt other mechanisms supporting inflammation within the joints.
The results of our uncontrolled study do not support the use of intra-articular TNFα inhibitors for the treatment of acute joint inflammation.