Background/Purpose: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized debilitating joint destruction, if not treated aggressively in the patient in most need of treatment.  Personalized health care is needed in RA, as response rates are low compared to the potential side effects and cost of treatment. Anti-IL6 and anti-TNF treatments are approved for treatment of RA patients, however with varying response rates. A unique class of serological biomarkers, which are measures of extracellular matrix turnover, also called protein fingerprint, may describe specific disease mode of actions. We investigated whether early measurement after treatment initiation could identify patients that would respond to either anti-IL6 or anti-TNF treatment. 

Methods: Following tissue-specific biomarkers were measured in 800 RA patients treated with either methotrexate, tocilizumab, infliximab, entercept or adalimumab; VICM (citrullinated and MMP-degraded vimentin), C1M (MMP-degraded type I collagen), C3M (MMP-degraded type III collagen), CRPM (MMP-degraded CRP), C2M (MMP-degraded type II collagen), CTx (cathepsin K degraded type I collagen), osteocalcin (bone formation), and CRP (acute phase reactant). The baseline levels and changes in the biomarkers were investigated was investigated for each of the treatment groups. Logistic regression and classification and regression tree analysis were used to assess whether the markers alone or together could predict treatment response evaluated by DAS28 changes. Data was corrected for multiplicity.

Results: Methothraxate had a small effect on CRP, but not on any of the other markers. Tocilizumab significantly suppressed (p<0.0001) the level the connective tissue markers MMP3, VICM, C1M, C2M, C3M, CRPM and significantly increased (p<0.05) the level of the bone markers CTx and ostoecalcin. In contrast, cartilage degradation measured by C2M, was not inhibited anti-TNF treatment. A simple combination of the biomarkers (C1M, C3M, C2M, osteocalcin and CRPM) was able to double the DAS28 response rate of tocilizumab 27 to 54%. When including the change from baseline to 4 or 16 weeks in cartilage degradation or bone formation the rate was increased to 64%. Similar segregation could be reached for the anti-TNF group, however with a different set of markers; C1M, C3M, VICM and CRPM.

Conclusion: Distinct mode of action profiles were identified for each of the different treatment groups by measurement of the unique protein fingerprint markers. This may assist in identification of the patients, in any inflammatory disease, who respond most optimally to given interventions, with fewer AEs, and thus provide a stronger risk/benefit/cost value proposition to patients and payers.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/serological-biomarkers-of-specific-mode-of-action-for-early-identification-of-rheumatoid-arthritis-patients-who-respond-to-anti-il6-or-anti-tnf-treatment/