Sustained DMARD-free remission in rheumatoid arthritis – about concepts and moving towards practice

Sustained DMARD-free remission (SDFR) is the best possible outcome in RA. It is characterized by sustained absence of clinical arthritis, which is accompanied by resolution of symptoms and restoration of normal physical functioning. Therefore it's the best proxy for cure in RA. The mechanisms underlying SDFR-development are yet unidentified. Hypothetically, there are two possible scenarios. The first hypothesis is based on the concept of regaining immune-tolerance, which implies that RA-patients are similar at diagnosis and that disease-processes during the disease-course shift into a favorable direction, resulting in regaining a state in which arthritis is persistently absent. This could imply that SDFR is theoretically achievable for all RA-patients. The alternative hypothesis is that RA-patients who achieve SDFR are intrinsically different from those who cannot. This would imply that DMARD-cessation could be restricted to a subgroup of RA-patients. Since the 1990s, DMARD-discontinuation and SDFR have been increasingly studied as long-term-outcome in RA. In this review, we describe hitherto results of clinical, genetic, serological, histological and imaging studies and looked for arguments for the first or second hypothesis in both auto-antibody-positive and auto-antibody-negative RA. In auto-antibody-negative RA, SDFR is presumably restricted to a subgroup of patients with high serological-markers of inflammation at diagnosis and a rapid and sustained decrease in inflammation after treatment-start. Identifying these RA-patients could be helpful in realizing personalized-medicine. In auto-antibody-positive RA, only few patients achieve SDFR and no definite conclusions can be drawn, but data could suggest that SDFR-patients might be a subgroup with relatively low inflammation from disease-presentation onwards.</p

Advances in the genetics of rheumatoid arthritis point to subclassification into distinct disease subsets

In the past few years considerable advances have been made in the genetics of susceptibility to rheumatoid arthritis (RA). For decades the HLA-DRB1 alleles were the only extensively replicated genetic factor, but more genetic risk factors have now been identified that predispose to RA. Interestingly, several of the observed genetic variants conferred risk to anticitrulline-peptide antibody (ACPA)-positive RA and two variants may be restricted to ACPA-negative RA, pointing to the need for subclassification of RA. The current manuscript reviews recently identified genetic factors predisposing to ACPA-positive RA and ACPA-negative RA. Additionally, although being scarcely explored, genetic variants affecting the severity of disease course are discussed

The earlier, the better or the worse? Towards accurate management of patients with arthralgia at risk for RA

The favourable long-term results of early treatment in patients with classified rheumatoid arthritis have resulted in an increasing interest in the diseases phases preceding clinical arthritis. The hypothesis to test is that an intervention in these early phases may better prevent or reduce disease persistence than an intervention when arthritis has become clinically manifest. While several placebo-controlled trials are still ongoing, to date there is no firm evidence that this hypothesis truly holds. Therefore, it is important to reflect on the current status of arthralgia preceding clinical arthritis. Inherent to every new field of research, attitudes are conflicting, with opinions propagating innovation (based on the fear of undertreatment) on the one hand, and critical sounds pleading for more restraint (fear of overtreatment) on the other hand. In this Viewpoint, we will examine these divergent opinions, relate them to a preferred ultimate scenario and provide considerations for future studies and daily practice

Response to: "does ACPA-negative RA consist of subgroups related to sustained DMARD-free remission and serological markers at disease presentation" by Masi and Fleischmann

Pathophysiology and treatment of rheumatic disease

Association of Interosseous Tendon Inflammation in the Hand With Different Early Arthritides in a 10-Year Magnetic Resonance Imaging Study

Objective: Inflammation around the tendons of the hand interosseous muscles (interosseous tendon inflammation [ITI]) was recently identified on magnetic resonance imaging (MRI) in a set of patients with rheumatoid arthritis (RA) and arthralgia. We conducted a large MRI study to assess the prevalence of ITI at diagnosis of RA and of other arthritides, as well as its relationship with clinical signs. Methods: A total of 1,205 patients presenting with various types of early arthritis between 2010 and 2020 underwent contrast-enhanced hand MRI as part of the prospective Leiden Early Arthritis Cohort. MRI was evaluated with blinding for clinical data, for ITI lateral of metacarpophalangeal (MCP) joints 2–5, and for synovitis/tenosynovitis/osteitis. We assessed ITI presence at baseline per diagnosis and its relationship with clinical characteristics (ie, presence of hand arthritis, increased acute phase reactants, and local joint swelling and tenderness). Logistic regression and generalized estimating equations were used with adjustment for age and established local inflammation features (synovitis/tenosynovitis/osteitis). Results: A total of 36% of patients with early RA (n = 532) had ITI; this was similar in patients with anti–citrullinated protein antibody (ACPA)-negative RA (37%) and those with ACPA-positive RA (34%; P = 0.53). ITI occurred regularly in remitting seronegative symmetrical synovitis with pitting edema (60%) and connective tissue diseases (44%) and less frequently in undifferentiated arthritis (14%), psoriatic arthritis (14%), inflammatory osteoarthritis (8%), reactive arthritis (7%), crystal arthritis (7%), and peripheral spondylarthritis (4%). ITI occurred more often in diagnoses with frequent arthritis of the hands (P &lt; 0.001) and increased acute-phase reactants (P &lt; 0.001). Within RA, ITI occurred together with local MCP joint synovitis (odds ratio [OR] 2.4, 95% confidence interval [95% CI] 1.7–3.4), tenosynovitis (OR 2.4, 95% CI 1.8–3.3), and osteitis (OR 2.2, 95% CI 1.6–3.1) on MRI. Moreover, ITI presence was associated with local MCP joint tenderness (OR 1.6, 95% CI 1.2–2.1) and swelling (OR 1.8, 95% CI 1.3–2.6), independent of age and MRI-detected synovitis/tenosynovitis/osteitis. Conclusion:ITI occurs regularly in RA and other arthritides with preferential involvement of hand joints and increased acute-phase reactants. At the MCP joint level, ITI associates independently with joint tenderness and swelling. Hence, ITI is a newly identified inflamed tissue mainly found in arthritides with particularly extensive and symptomatic inflammation.</p

To treat or not to treat? Current attitudes on treatment aimed at modifying the disease burden in clinically suspect arthralgia:a survey among participants of the TREAT EARLIER trial and healthcare professionals

Objectives While awaiting therapies accomplishing rheumatoid arthritis (RA)-prevention in individuals at-risk, recent evidence supports that a 1-year methotrexate treatment may lead to sustained reduction in disease burden and subclinical joint inflammation in patients with clinically suspect arthralgia (CSA). We aimed to study the previously unexplored attitudes of CSA patients and rheumatologists on 1-year DMARD treatment in the arthralgia phase to reduce the disease burden, while not preventing RA.Methods CSA patients who participated in the TREAT EARLIER trial, thus being expert by experience, were informed on the trial results. Thereafter they completed an anonymous questionnaire about their attitudes on treatment in the CSA phase. We used the same approach for Dutch healthcare professionals in rheumatology.Results The majority of trial participants (85%) considered the effects of the 1-year treatment as found in the TREAT EARLIER trial, beneficial in the symptomatic at-risk stage. 79% would recommend a 1-year methotrexate course to others with comparable joint complaints. Two-thirds indicated RA prevention and improving disease burden to be equally important treatment goals in the CSA phase. Most healthcare professionals (88%) were inclined to prescribe 1-year treatment to CSA patients aimed at long-term improvement of symptoms and functioning, while not preventing RA development. 59% believed the profits of a 1-year methotrexate course to outweigh disadvantages, for example, side effects.Conclusions A considerable willingness exists among CSA patients and rheumatologists to start a 1-year treatment resulting in long-term improvement of symptoms and functioning, while not preventing RA. This emphasises the need for more research optimising treatment regimens and disease monitoring in individuals at-risk to facilitate such treatment decisions in the future, while avoiding an intervention, either limited or for a prolonged period, which may have harms that outweigh benefits.Trial registration number The Netherlands Trials Registry (NTR4853-trial-NL4599). EudraCT number: NL2014-004472-35