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The treatment of rheumatoid arthritis (RA) has greatly improved with the use of biological TNF inhibitors (TNFi). These biopharmaceuticals target the inflammatory cytokine TNF, and hereby decrease the autoimmune inflammation, which may otherwise lead to permanent joint damage in the afflicted patients. Although TNFi decrease clinical disease activity in the majority of the treated patients, they are not always effective. Some patients have a partial response, some lose their initial response to treatment, and others never experience effect at all. The concentration of TNFi in the patients' bloodstreams, or the generation of antibodies directed towards the TNF inhibitor (anti-TNFi Abs), are known to have an impact on treatment efficacy. Furthermore, in patients with a good treatment response, strategies for how to tamper or discontinue treatment are lacking. In this PhD thesis, ways to improve treatment with TNFi are explored in three studies. The first study describe current knowledge on the effect of intensifying treatment with TNFi as a way to increase treatment efficacy. The results from this literature review do not convincingly support that intensified treatment increase efficacy in patients with RA in general, although an effect may be seen in patients treated with infliximab. The diverging results on the efficacy of infliximab intensification may be explained by effects on subgroups of patients being masked in mixed cohorts. We suspect that if patients are sub-grouped according to factors such as blood concentration of TNFi or presence of anti-TNFi Abs, an effect of treatment intensification on clinical outcome may bee more convincing. The second study assesses the frequency of anti-TNFi Ab formation in patients with RA in remission in an effort to identify patients for whom continued treatment is superfluous. If anti-TNFi Ab and low drug concentrations in patients in remission are predictors of TNFi-free remission, the impact on treatment and economic costs may be considerable. The finding that 10% of the patients in remission have developed anti-TNFi Abs shows that the potential is substantial. The third study investigates if baseline values of various biomarkers and other variables can predict development of anti-TNFi Abs or the emergence of sub-therapeutic drug levels. From the results, it seems that baseline inflammatory activity, judged from the level of interleukin-6 and possibly C-reactive protein, predicts low drug levels after six months of treatment. This may lead to early identification of patients at risk of treatment failure owing to inadequate drug levels, with the opportunity to take measures to prevent this.

Objectives: With the present study we wanted to explore the impact of treatment with a tumor necrosis factor-α -inhibitor (TNFi) on levels of soluble biomarkers in rheumatoid arthritis (RA) patients and to identify predictors of impaired drug levels and development of anti-TNFi antibodies (anti-TNFi Abs)., Methods: Blood samples from 26 patients with established RA were taken at baseline and following 6 months of treatment with adalimumab or infliximab. Samples were analyzed for levels of TNFi, interleukin (IL)-6, and soluble TNF-receptors 1 and -2 (sTNF-R1 and -2) and for presence of anti-TNFi Abs. Clinical and demographic data were recorded as well., Results: During the initial 6 months treatment, DAS28(CRP) (Disease activity score in 28 joints using C-reactive protein) and levels of IL-6 and sTNF-R2 decreased significantly in patients without anti-TNFi Abs and in patients retaining detectable drug levels. The levels of other tested cytokines (TNF-α, TNF-β, IL-1ra, IL-1b, IL-8, IL-10, IL-12(p70), IL-13, IL-17A, IL-17F, and IL-33) were generally below detection limits. Higher baseline levels of IL-6 associated with undetectable levels of TNFi at follow-up. Anti-TNFi Abs were associated with decreased drug levels, but no predictors for anti-TNFi Ab development could be found., Conclusion: The effect of treatment with TNFi on RA disease activity depends on levels of active drug, and by presence of anti-TNFi Abs. In patients who retain detectable drug levels, and in the absence of anti-TNFi Abs, clinical outcome is improved during treatment, and circulating levels of IL-6 and sTNF-R2 decrease. Baseline levels of IL-6 may predict depletion of TNFi and may identify patients at risk of treatment failure., Competing Interests: Dr. Eng has served as a speaker for Pfizer. Dr. Bendtzen has served as a speaker for Pfizer and Hospira, and owns stocks in Novo-Nordisk and Eurodiagnostica. Dr. Bliddal has received consulting fees, honoraria, research or institutional support, educational grants, equipment, services or expenses from: Abbott, Abbvie, Amgen, AstraZeneca, Aventis, Axellus, Bristol Myers Squibb, Cambridge Nutritional Foods, Dansk Droge, Eurovita, Ferrosan, GlaxoSmithKline, Hoechst, LEO, Lundbeck, MSD, Mundipharma, Norpharma, NOVO, NutriCare, Nycomed, Pfizer, Pharmacia, Pierre-Fabre, Proctor & Gamble, Rhone-Poulenc, Roche, Roussel, Schering-Plough, Searle, Serono, UCB, Wyeth. Dr. Bliddal is not employed by and holds no shares in any of these companies. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Objective. To investigate if antibodies towards biological TNF-α inhibitors (anti-TNFi Abs) are present in patients with rheumatoid arthritis (RA) in clinical remission and to relate any anti-TNFi Abs to circulating level of TNF-α inhibitor (TNFi). Methods. Patients with RA, treated with infliximab or adalimumab, and in clinical remission (DAS28(CRP) < 2.6) were included from 6 out-patient clinics. In blood samples, presence of anti-TNFi Abs was determined by radioimmunoassay, and concentration of bioactive TNFi was measured by a cell-based reporter gene assay. Results. Anti-TNFi Abs were present in 8/44 patients (18%) treated with infliximab and 1/49 patients (2%) treated with adalimumab (p = 0.012). In the former group, anti-TNFi Abs corresponded with low levels of TNFi (p = 0.048). Anti-TNFi Ab-positive patients had shorter disease duration at initiation of TNFi therapy (p = 0.023) but were similar for the rest of the compared parameters. Conclusions. In RA patients in clinical remission, anti-TNFi Abs occur frequently in patients treated with infliximab, while they occur rarely in patients treated with adalimumab. Presence of anti-infliximab Abs is accompanied by low or undetectable levels of infliximab. These data suggest that continued infliximab treatment may be redundant in a proportion of RA patients treated with infliximab and in clinical remission.