Rheumatoid arthritis (RA) is a polyarticular inflammatory joint disease with a prevalence of about 1% in the adult population. The severity of the disease varies between mild self limiting illness to aggressive, drug resistant disease which causes joint destruction and deformity, and ultimately severe disability. Spondyloarthropathies (SpA) are a group of diseases composed of inflammatory conditions such as asymmetric oligoarthritis of the lower extremities. Prevalence of SpA is estimated to be around 1% in Europe. Juvenile idiopathic arthritis (JIA) represents a heterogenous group of chronic inflammatory conditions occurring in childhood or adolescence in which the cause of arthritis remains unknown. Prevalence of JIA varies between 7-400/100.000 children.

Due to its heterogeneity, the drug treatment also varies between different subtypes of JIA. In an inflamed joint, the synovium is converted into histologically differentiated pannus as a result of the influences of different inflammatory cells, cytokines and other mediators which also act together with matrix metalloproteases (MMPs) to inflict dysregulation of chondrocytes and degradation of articular cartilage. Tumor necrosis factor alpha (TNFα) and interleukin 1β (IL-1β) are key factors driving rheumatoid inflammation in the joint, eventually leading to erosions. The American College of Rheumatology (ACR) criteria are often used to define the clinical response to the treatment in RA. ACR20, ACR50 and ACR70 response criteria represent clearly defined 20%, 50% and 70% improvements in the core set of criteria, respectively. The clinical response to the drug treatment in SpA can be assessed by using BASDAI (Bath Ankylosing Spondylitis Disease Activity Index). Treatment is regarded as ineffective if the reduction of BASDAI index is lower than 50% or less than 2 cm.

According to the national guidelines in Finland, the criterion for initiating anti-TNFα therapy in RA patients is that the patient is suffering from a severe and refractory disease despite active drug treatment. Anti-TNFα therapy is usually added on to one disease modifying antirheumatic drug (DMARD) or to the combination of two or more DMARDs. The drug treatment is actively adjusted to achieve clinical remission or at least an ACR50 response. In SpA patients, anti-TNFα therapy is indicated if the patient has active disease despite treatment with DMARDs, like sulfasalazine. Anti-TNFα therapy is adjusted to achieve clinical remission or at least 50% response as assessed by BASDAI. The aim of the present study was to (1) investigate the effects of infliximab treatment on inflammatory mediator levels in patients with severe JIA, and (2) to study drug survival during anti-TNFαtherapy in patients with DMARD resistant RA or SpA. Blood samples were collected from eight JIA patients who responded favourably to infliximab treatment. Clinical effects were seen already after six weeks of treatment. Interleukin 6 (IL-6) concentrations decreased to about half and myeloperoxidase (MPO) levels by about 35% during the 12 weeks treatment period. In addition, the levels of soluble forms of adhesion molecules ICAM-1 and E-selectin became reduced in response to infliximab treatment. TNFα levels tended to increase while the levels of endogenous TNFα antagonists (soluble TNF receptors) were reduced in most of the patients during treatment.

In the second part of the study, drug survival in 104 infliximab-treated patients was evaluated after six, 12 and 24 months of treatment, and in 53 etanercept and 43 adalimumab-treated patients after 12 months. Drug survival in infliximab-treated RA and SpA patients after six, 12 and 24 months follow-up was 71%, 53% and 40%, respectively. The reasons for discontinuations were remission (7% in six months / 8% in 12 months / 7% in 24 months), adverse event (13% / 16% / 24%) and lack of efficacy (8% / 16% / 22%). Infections and hypersensitivity reactions were the main adverse events requiring discontinuation of infliximab treatment, and also two cases of drug related leukopenia and one case of elevated aminotransferases were observed. After 12 months, the continuation rate was 74% in the etanercept and 60% in the adalimumab-treated patients. Eleven patients were regarded as poor responders, seven (13%) in the etanercept group and four (9%) in the adalimumab group. Adverse even! ts (mainly infections and injection reactions) caused six (11%) discontinuations in etanercept-treated group and 11 (26%) discontinuations in adalimumab group. Etanercept was discontinued due to some other adverse event in two patients, in one patient due to adenocarcinoma of the ovary and in one patient due to drug related leukopenia. One patient treated with adalimumab developed the clinical and immunological features of systemic lupus erythematosus (SLE).

In summary, treatment with a TNFα antagonist infliximab reduced the levels of inflammatory mediators IL-6, MPO and soluble ICAM-1 and E-selectin in conjunction with a good clinical response in patients with JIA. Drug survival in RA and SpA patients with one or more DMARDs in addition to infliximab, etanercept or adalimumab treatment was good and comparable to the results obtained in previous observational studies in patients with less-severe disease. The use of concomitant DMARDs or oral glucocorticoids could be diminished. The results support the clinical view that combination of DMARDs and TNFα antagonists is an effective and relatively safe treatment of severe and DMARD-refractory RA and SpA. In the future, specifying the pathogenetic mechanism of RA, SpA and JIA as well as finding more specific biomarkers will improve the drug development and assist to design the drug treatment to meet the needs of the individual patient.