Treatment of arthritis with tumour necrosis factor antagonists. Clinical, immunological and biochemical aspects

Abstract: Abstract The treatment of arthritis has undergone a dramatic change since biological agents targeting specific mediators of the disease process have been introduced. Tumour necrosis factor (TNF) antagonists have been shown to reduce signs and symptoms of disease and to retard the development of tissue damage in the majority of patients.

This thesis focuses on clinical, immunological and biochemical aspects of treatment with TNF antagonists in patients with arthritis. In particular, the studies examine: (i) the feasibility of a structured protocol with central data handling for the prospective monitoring treatment efficacy and tolerability of new treatments in clinical practice, (ii) whether serum levels of cartilage oligomeric matrix protein (COMP) change during treatment with TNF antagonists in a way that corroborates a tissue protective effects of these agents in rheumatoid arthritis (RA), (iii) how different anti-rheumatic treatments modulate the immune response induced by polysaccharide or polypeptide vaccines in patients with RA and (iv) potential predictors of infusion reactions during treatment with infliximab. All the patients who participated in the studies were monitored according to a standardised clinical protocol of the South Swedish Arthritis Treatment Group (SSATG) developed at the Department of Rheumatology in Lund. We found that such a protocol could be used for monitoring newly introduced anti-rheumatic treatments both at a university department and at other rheumatology units. The performance of TNF antagonists regarding efficacy and safety complied with results of previously published clinical trials.

Serum levels of COMP were measured in RA patients treated with infliximab and etanercept during the initial 6 months of treatment. Serum COMP levels decreased in patients with and without a clinical response, suggesting a damage retarding effect of TNF antagonist treatment. Altogether, 149 patients with RA participated in studies of the immune response to pneumococcal or influenza vaccination. Patients treated with TNF antagonists and controls showed similar responses to pneumococcal vaccine, whereas methotrexate treated patients showed reduced response to this vaccine regardless of concomitant treatment with TNF antagonists. In contrast, RA patients treated with methotrexate without TNF antagonists had significantly better immune response to influenza vaccination than those receiving TNF antagonists alone or in combination with methotrexate and/or other disease modifying antirheumatic drugs. Possible predictors of infliximab related infusion reactions were studied in a cohort of 213 patients with RA and 76 patients with spondylarthropaties. Infliximab without methotrexate and positive baseline ANA (antinuclear antibodies) were independent risk factors for developing infusion reactions in RA but not in spondylarthropaties. In conclusion, a structured protocol with central data handling is feasible in clinical practice for documenting the efficacy of and adverse events associated with drugs used for the treatment of arthritis. Serum COMP has the potential to be a useful marker for evaluating tissue effects of novel treatment modalities in RA. Methotrexate treatment in RA reduces antibody response to pneumococcal vaccine, suggesting that RA patients should be vaccinated before the initiation of his treatment. The immune response to influenza vaccination is sufficiently good to warrant vaccination of all RA patients, regardless of treatment. Positive ANA at initiation of infliximab treatment and the use of infliximab as monotherapy is associated with increased risk of infusion reactions in RA.