Earlier is better when treating rheumatoid arthritis: but can we detect a window of opportunity?

Abstract

ObjectivesThe window of opportunity (WOO) hypothesis suggests a limited time frame to stop rheumatoid arthritis (RA). We hypothesised that a WOO could either be represented by a hyperbolic (‘curved’) decline in the chance to achieve the outcome sustained drug-free remission (sDFR) over time, after which achieving sDFR is not possible anymore, or by a more gradual linear decline approaching zero chance to achieve sDFR.MethodsPatients with RA (symptom duration <2 years) were included from two randomised trials: BehandelStrategieën (BeSt), n=508 and Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED), n=479. Cox-regression was performed to assess the shape of the association between symptom duration and sDFR (Disease Activity Score<1.6, no disease-modifying anti-rheumatic drugs for ≥1 year) for patients starting slow-acting monotherapy (IMPROVED, BeSt) or fast-acting combination therapy (BeSt). Likelihood ratio tests were used to compare the fit of linear and non-linear models in both databases separately. Predictions from the best fitting models were used to assess whether the absolute risk to achieve sDFR approaches zero with increasing symptom duration.ResultsIn BeSt and IMPROVED, 54/226 and 110/421 patients achieved sDFR with fast-acting treatment, and 53/243 (BeSt) with slow-acting treatment. Non-linear models did not fit better than linear models (fast-acting treatment BeSt p=0.743, IMPROVED p=0.337; slow-acting treatment BeSt p=0.609). After slow-acting monotherapy, linear models declined steeper. None of the models approached zero chance to achieve sDFR over time.ConclusionsThe chance to achieve sDFR decreased gradually over time, and decreased fastest in patients starting slow-acting monotherapy. In both treatment groups, we found no evidence for a WOO within 2 years symptom duration.

Joint‐Specific Memory and Sustained Risk for New Joint Accumulation in Autoimmune Arthritis

“…A leading model to conceptualize the benefit of early aggressive arthritis therapy in RA is the "window of opportunity hypothesis", which postulates that effective early therapy induces a durable change in natural history by interrupting an autoimmune response that is not yet well established (19). Findings of clinical trials have suggested benefits to early intervention in terms of the prevention of structural injury and, to a much more modest extent, the achievement of drug-free remission, although a specific timeframe for intervention has proven difficult to define (20)(21)(22). Our data do not directly address whether such a window of opportunity exists, but do identify an important complementary principle that we term the joint accumulation hypothesis (Figure 5).…”

A systematic review on biological therapies in juvenile idiopathic inflammatory myopathies: an evidence gap in precision medicine

“…Therefore, the cumulative effect of such sequential treatment could contribute to determining the overall efficacy of biologic agents. On the other hand, we might speculate that earlier use of biologic agents after accurate patient selection might result in higher efficacy of such medication, following the "windows of opportunity hypothesis" elaborated for rheumatoid arthritis (48), and thus in a reduced burden of disease complication. However, in absence of higher-quality studies, we had to accept open-label studies, retrospective cohorts, and case series and outline the poor quality of evidence.…”

Cross-Tissue Transcriptomic Analysis Leveraging Machine Learning Approaches Identifies New Biomarkers for Rheumatoid Arthritis

“…While our understanding of disease pathogenesis has greatly improved and the number of available, effective therapeutics has significantly increased, there remains significant barriers to caring for patients with RA, and they continue to suffer from the morbidity and mortality associated with the disease. There is an urgent need to develop objective biomarkers for the early diagnosis and prompt initiation of disease-modifying therapy during the so-called "window of opportunity" (3)(4)(5)(6). Additionally, clinicians need tests to help accurately assess disease activity or treatment targets in order to adjust therapy appropriately.…”