No diagnostic tests to neither confirm nor exclude RA diagnosis nor its impersonating diseases in patients with difficult-to-treat rheumatoid arthritis (D2T RA) were found. Ultrasonography was the most suitable diagnostic test in D2T RA, including those with obesity or fibromyalgia.

To review the evidence regarding the diagnostic concerns in D2T RA patients for informing the EULAR recommendations for its management in these patients.

This systematic literature review (SLR) was executed concerning the optimal validation of RA diagnosis and of impersonating diseases and the evaluation of the activity of the inflammatory disease. PubMed and Embase were explored for appropriate papers and assessed.

Overall, 82 papers were chosen for detailed evaluation. An extensive outline of the existing literature concerning the diagnostic concerns in cases of D2T RA has been presented in this systematic literature review.

The recognized evidence had numerous limitations:

• there were no studies comprising D2T RA patients exactly, and only a few encompassed RA patients in whom there was clear doubt about RA diagnosis or occurrence of inflammatory activity;
• only correlations were described mostly, not directly beneficial to assess the accuracy of noticing inflammatory activity clinically;
• heterogeneous, and frequently suboptimal, reference standards were considered;
• low risk of bias was found only in limited studies

No diagnostic test with sufficient validity and precision was identified to define RA diagnosis or connected impersonating disease. To establish inflammatory activity in RA patients and in those with fibromyalgia and obesity, ultrasonography was studied most widely and was designated as the most assuring diagnostic test.

The lack of high-quality studies concerning diagnostic issues in D2T RA patients has been emphasized in this review. No diagnostic tests with satisfactory validity and precision were found to approve nor exclude RA diagnosis nor its impersonating diseases in D2T RA patients.