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Objectives Morning stiffness (MS) is characteristic for Rheumatoid Arthritis (RA) and associates with markers of systemic and local inflammation in RA-patients. In patients with arthralgia, MS is a cardinal symptom to recognize arthralgia at-risk for RA-development (i.e. clinically suspect arthralgia, CSA). In CSA, MS is also assumed to reflect inflammation, but this has never been studied. Therefore we aimed to study whether MS in CSA-patients is associated with systemic- and subclinical joint-inflammation. Methods 575 patients presenting with CSA underwent laboratory investigations and contrast-enhanced 1.5 T-MRI of hand and forefoot (scored according to the RAMRIS-method). Associations of MS (duration ≥60 min) with presence of subclinical joint-inflammation (synovitis, tenosynovitis and osteitis) and increased-CRP (≥ 5 mg/l) were determined with logistic regression. Additionally, the effect of MS-duration (≥30, ≥60, ≥120 min) was studied. Results 195 (34%) CSA-patients experienced MS. These patients more often had subclinical synovitis (34% vs 21%, OR 1.95 (95%CI 1.32–2.87)), subclinical tenosynovitis (36% vs 26%, OR 1.59 (1.10–2.31)) and increased-CRP (31% vs 19%, OR 1.93 (1.30–2.88)) than patients without MS. In multivariable analyses, subclinical synovitis (OR 1.77 (1.16–2.69)) and CRP (OR 1.78 (1.17–2.69)) remained independently associated with MS. In CSA-patients who later developed RA, and thus in retrospect were ‘pre-RA’ at time of CSA, MS was more strongly associated with subclinical synovitis (OR 2.56 (1.04–6.52)) and CRP (OR 3.86 (1.45–10.24)). Furthermore, associations increased with longer MS-durations. Conclusion Inflammation indeed associates with MS, already in the CSA-phase that preceded clinical arthritis. These results increase understanding of MS when assessing arthralgia in clinical practice.

BackgroundClinically suspect arthralgia (CSA) is characterised by arthralgia of small joints and considered a risk stage for development of rheumatoid arthritis (RA). However, it remains unknown if the function of the hands is already affected and what mechanisms underlie impaired hand-function in CSA.MethodsWe studied various measures of hand function in two CSA populations. CSA patients in the TREAT EARLIER-trial (n=236) were evaluated at baseline for: grip strength on a dynamometer (GS), patient-reported difficulties in the grip domain of the Health Assessment Questionnaire (HAQ) questionnaire and incomplete fist closure at physical examination. Findings were validated in an independent CSA cohort (n=600) where hand function was measured as: GS evaluated by squeezing the examiner’s fingers, grip domain of the HAQ questionnaire and fist closure. Contrast-enhanced MRI of the hands measured synovitis, tenosynovitis and bone marrow oedema (summed as subclinical inflammation) in both cohorts.ResultsGS (on a dynamometer) was reduced in 75% compared with reference values in healthy controls, 60% reported grip difficulties and 13% had incomplete fist closure. Reduced GS was associated with subclinical inflammation (−0.38 kg/point inflammation, 95% CI −0.68 to −0.08). Studying separate MRI features, GS reduction was independently associated with tenosynovitis, decreasing with −2.63 kg (95% CI −2.26 to −0.33)/point tenosynovitis (range observed tenosynovitis scores: 0–20). Similar relations with tenosynovitis were seen for patient-reported grip difficulties (OR 1.12/point, 95% CI 1.07 to 1.42) and incomplete fist closure (OR 1.36/point, 95% CI 1.03 to 1.79). In the validation cohort, 36% had decreased examiner-assessed GS, 51% reported grip difficulties and 14% incomplete fist closure: all were associated with tenosynovitis. Decreased dynamometer-measured GS was most sensitive for detecting tenosynovitis (75%), while incomplete fist closure was most specific (88%–90%).ConclusionHand function is already often affected before RA development. These limitations are related to subclinical inflammation and tenosynovitis in particular.

BackgroundRheumatoid arthritis (RA) is the most common autoimmune disease, and requires long-term treatment to suppress inflammation. Currently, methotrexate is initiated as first-line treatment when arthritis becomes clinically apparent with joint swelling. However, disease processes begin long before and become clinically recognizable when patients develop symptoms. We hypothesized that the ‘at risk phase’ of symptoms and subclinical joint-inflammation is a therapeutic window to permanently modify the disease course.ObjectivesWe studied if intervention in the pre-arthritis phase of arthralgia and subclinical joint inflammation prevents the development of clinical arthritis or reduces the burden of disease.MethodsIn this randomised, double-blind, 2-year proof-of-concept trial, adults with arthralgia clinically suspected of progressing to RA and MRI-detected subclinical joint-inflammation, recruited from all rheumatology outpatient-clinics in the southwest-Netherlands, were randomly assigned (1:1) to a single intramuscular glucocorticoid injection (120 mg) and a one-year course of oral methotrexate (up to 25 mg/week), or placebo injection and placebo tablets. Subsequently, participants were followed for another year without study medication. The primary endpoint was the development of clinically detectable arthritis (fulfilling the 2010 RA-criteria or involving ≥2 joints) that persisted for at least 2 weeks. Patient reported physical functioning, along with symptoms and workability, were key secondary endpoints and measured 4-monthly. Additionally, the course of MRI-detected inflammation was studied (the sum of tenosynovitis, synovitis, osteitis, scored with the RA-MRI Scoring (RAMRIS) method). All participants entered the intention-to-treat analysis. We performed two prespecified subgroup analyses. Firstly, analyses were restricted in participants with high risk of clinical arthritis development (PPV ≥70%). Secondly, analyses were stratified for ACPA-status. The trial is registered with the Netherlands Trials Registry (NTR4853 trial NL4599).ResultsFrom April 16th, 2015 to September 11th, 2019, we randomly assigned 236 participants to treatment (n=119) or placebo (n=117). After 24 months, arthritis free survival was similar in both groups (80% versus 82%, HR 0.81 (95%CI 0.45, 1.48)). Physical functioning improved more in the treatment-group during the first months and remained better (mean between-group difference over two-years HAQ -0·1(-0·2,-0·03;p=0·004). Similarly, pain (-9 on scale 0-100: (95%CI -12,-4; p<0·001), morning stiffness (-12 (95%CI -16,-8;p<0·001), presenteeism (-8% (95%CI -13%,-3%;p=0·001) showed sustained improvement compared to placebo. MRI-detected joint-inflammation was also persistently improved (mean difference over 2 years -1·4 points (95%CI -2·0,-0.9;p<0·001). High-risk participants in the treatment group showed a delay in clinical arthritis development: they developed the endpoint less often during treatment, but frequencies became similar at 24 months (67% in both groups). A similar delaying effect was observed in ACPA-positive participants, where 48% and 52% had developed persistent clinical arthritis at 24 months. The number of serious adverse events was equal between the groups; adverse events were as expected from methotrexate.ConclusionMethotrexate, the cornerstone treatment of RA, initiated at the pre-arthritis stage of joint symptoms and subclinical inflammation, did not prevent the development of clinical arthritis, but modified the disease course as measured by sustained improvement in MRI-detected inflammation, related symptoms and impairments. These findings of sustained disease modification may open up a new treatment landscape in a pre-arthritis phase of RA, where limitations can be just as severe as at the onset of clinical arthritis.Figure 1.AcknowledgementsWe thank Prof. dr. R. ten Cate, prof. dr. S. le Cessie and dr. A.M.J. Langers for their role in the Data Safety and Monitoring Board. We thank all participants, and all rheumatologist of the following hospitals: Albert Schweitzer Hospital, Alrijne Hospital, Erasmus Medical Center, Haven-policlinic Rotterdam, IJselland Hospital, Ikazia Hospital, Franciscus Gasthuis & Vlietland Hospital, Groene Hart Hospital, Haaglanden Medical Center (all locations), Haga Hospital, Langeland Hospital, Meander Medical Center, Maasstad, Hospital, Reinier de Graaf Gasthuis, Reumazorg Zuid-West Nederland and Spaarne Gasthuis. We acknowledge the team of treating rheumatologists and research nurses of the LUMC, in particular Dr F.J. van der Giesen. Our gratitude also goes to the PhD students who scored MRIs for trial screening, in particular dr. H.W. van Steenbergen, dr. W. Nieuwenhuis, dr. R.M. ten Brink, dr. D.M. Boeters, dr. L. Mangnus, X.M.E. Matthijssen and F. Wouters. We thank dr. M. Reijnierse, prof. dr. S.C. Cannegieter and prof. dr. D. van der Heijde for their advice, and dr. J. Schoones for his help with the systematic literature search. We acknowledge the funder of the study: NWO ZonMW grant (program ‘translationeel onderzoek’, project number 95104004).Disclosure of InterestsNone declared.

Figure 1 (A) Association of subclinical inflammation with tender MCP joints (N=226 with tenderness vs N=376 without tenderness): OR 1.84, 95% CI 1.29 to 2.63. (B) Association of subclinical inflammation with tender MCP joints in patients who developed inflammatory arthritis (N=33 with tenderness vs N=54 without tenderness): OR 1.79, 95% CI 0.74 to 4.30.

BackgroundAt time of Rheumatoid arthritis (RA) diagnosis, patients typically present with clinical arthritis of hand and foot-joints. It is unknown whether RA starts in hands or feet.ObjectivesTo investigate this, we performed functional, clinical and imaging studies during progression from clinically suspect arthralgia (CSA) to RA. We also studied whether functional disabilities of hands/feet in CSA contribute to predicting RA-development.Methods600 CSA-patients were followed for development of clinical inflammatory arthritis (IA) during a median follow-up of 25 months, of whom 99 developed IA. Functional disabilities were measured at baseline/4/12/24 months with the Health Assessment Questionnaire Disability-Index (HAQ); HAQ-items assessing hand- and foot-disabilities were selected. The course of disabilities towards IA-development (here considered as t=0) was depicted by increasing incidences and analysed using linear mixed models. To evaluate robustness of findings, tender hand/foot joints and subclinical joint-inflammation (measured with CE-1.5TMRI of hand/foot) were additionally studied. Associations between disabilities at CSA-presentation (here t=0) and future IA-development were studied using Cox-regression in the total CSA-population.ResultsDuring IA-development, hand-disabilities occurred earlier and more frequently than foot-disabilities. Despite both hand- and foot-disabilities rose significantly towards IA-development, hand-disabilities were more severe during this course (mean difference over time: 0.41 units,95%CI=0.28-0.55,p<0.001, on a range 0-3). Similar to functional disabilities, tender joints and subclinical joint-inflammation occurred earlier in the hands than feet (Figure 1). In the total CSA-population, a single HAQ-question on difficulties with dressing (hand-functioning) was independently predictive for IA-development: HR=2.2,95%CI=1.4-3.5,p=0.001.ConclusionEvaluation of functional disabilities, supported by clinical and imaging findings, revealed that joint involvement starts predominantly in the hands during RA-development. Additionally, a single question on dressing-difficulties adds value to risk stratification in CSA-patients and is easy to use in clinical practice.Figure 1.Functional disabilities (A), tender joints (B) and subclinical joint-inflammation (C) towards IA-development occur earlier and more frequently in the hands than in the feetlines depict the increasing incidence of functional disabilities (HAQ), tender joints (physical examination) and subclinical joint-inflammation (MRI-detected) in the hands and feet prior to development of inflammatory arthritis.Abbreviations: HAQ= Health Assessment Questionnaire; IA= inflammatory arthritis.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

ObjectivesIt is unknown whether rheumatoid arthritis (RA) starts in hands or feet. To investigate this, we performed functional, clinical and imaging studies during progression from clinically suspect arthralgia (CSA) to RA. Additionally, we studied whether functional disabilities of hands/feet at CSA onset contribute to predicting RA development.Methods600 patients with CSA were followed for clinical inflammatory arthritis (IA) during median follow-up of 25 months, during which 99 developed IA. Functional disabilities were measured at baseline/4/12/24 months with the Health Assessment Questionnaire Disability Index (HAQ); HAQ items assessing hand disabilities and foot disabilities were selected. The course of disabilities towards IA development (here considered as t=0) was depicted by increasing incidences and analysed using linear mixed models. To evaluate robustness of findings, tender hand/foot joints and subclinical joint inflammation (measured with CE-1.5TMRI) of hand/foot were additionally studied. Associations between disabilities at CSA presentation (here t=0) and future IA development were studied using Cox regression in the total CSA population.ResultsDuring IA development, hand disabilities occurred earlier and more frequently than foot disabilities. Despite both hand disabilities and foot disabilities rose significantly towards IA development, hand disabilities were more severe during this course (mean difference over time: 0.41 units, 95% CI 0.28 to 0.55, p<0.001, on a range 0–3). Similar to functional disabilities, tender joints and subclinical joint inflammation occurred earlier in the hands than feet. In the total CSA population, a single HAQ question on difficulties with dressing (hand functioning) was independently predictive for IA development: HR=2.2, 95% CI 1.4 to 3.5, p=0.001.ConclusionEvaluation of functional disabilities, supported by clinical and imaging findings, revealed that joint involvement starts predominantly in the hands during RA development. Additionally, a single question on dressing difficulties adds value to risk stratification in patients with CSA.