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© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/., The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.

Background:Pain is a common, difficult to manage symptom in hand osteoarthritis (OA). Multiple pain mechanisms may play a role in hand OA.Objectives:To investigate presence of neuropathic pain symptoms in patients with inflammatory hand OA, characteristics of those patients, their impact on health related quality of life (HR-QoL), and the influence of anti-inflammatory treatment on neuropathic pain symptoms.Methods:Data from a randomised, double-blind, placebo-controlled trial of prednisolone including 92 patients with hand OA fulfilling ACR criteria were used. At baseline patients had signs of synovial inflammation, a VAS finger pain of ≥30 mm and who flared ≥20 mm upon NSAID washout. The primary endpoint was VAS finger pain (0-100) at week 6.Neuropathic pain symptoms were measured at baseline and week 6 using the validated painDETECT questionnaire, consisting of questions on pain quality, pain intensity over time and radiating pain. Scores range -1 to 38 and patients are classified as having unlikely (18) neuropathic pain. HR-QoL was measured with physical component scale (PCS) of Short-Form 36 (SF36; 0-100), comorbidities with the Self-administered Comorbidities Questionnaire (SCQ; 0-45), radiographic severity with Kellgren-Lawrence (KL) sum score (0-120), and treatment response with OMERACT-OARSI responder criteria.Association of patient characteristics with neuropathic pain symptoms was analysed with univariate and multivariate ordinal logistic regression, with painDETECT as dependent variable. Association of neuropathic pain symptoms with HR-QoL was analysed with multivariate linear regression, adjusted for age, sex, BMI, VAS finger pain, SCQ score and KL sum score, with PCS as dependent variable. Response of neuropathic pain symptoms and VAS pain to prednisolone was analysed with generalised estimating equations. Association of neuropathic pain symptoms at baseline with response to treatment was analysed using χ2-tests and GEE.Results:91 patients had complete painDETECT data at baseline (mean painDETECT score 12.8 [SD 5.9]). Scores were 18 in 16%. Higher painDETECT score categories were associated with less radiographic damage, more comorbidities, female sex and higher VAS finger pain in multivariate analysis. (table 1)Table 1.Ordinal logistic regression with painDETECT categories as dependent variableVariablesMean (SD) N=91 (100%)Odds ratio (95% CI)Age64 (9)0.96 (0.90 to 1.02)Female sex; N (%)72 (79%)3.84 (1.19 to 12.39)*BMI; median (SD)27 (24 to 29)0.97 (0.89 to 1.06)SCQ score; median (SD)2 (1 to 5)1.04 (1.04 to 1.36)*VAS finger pain53.8 (2.1)1.02 (1.00 to 1.04)*KL sum score37 (16)0.96 (0.93 to 1.00)**pPatients with painDETECT scores >18 had a lower HR-QoL (PCS -6.5 [95%CI -10.4 to -2.6]) than those with painDETECT scores PainDETECT scores remained unchanged throughout the trial in both prednisolone-treated and placebo-treated patients, and there was no between-group difference at week 6. VAS pain improved more in the prednisolone group than in the placebo group (mean between-group difference -16.5 [95%CI -26.1 to -6.9]) (figure 1). No association between the presence of neuropathic pain symptoms at baseline and OMERACT-OARSI response to treatment was found.Conclusion:Patients with inflammatory hand OA and additional neuropathic pain symptoms are more often female and have more comorbidities, and report a lower QoL, than those without. Neuropathic pain symptoms seem unresponsive to anti-inflammatory therapy. Clinicians should be aware of neuropathic pain symptoms in their patients as they might benefit from additional, specific treatment.Acknowledgements:The authors thank all patients for their participation in the HOPE study, and participating rheumatologists for inclusion of patients in the HOPE study. We also thank research nurses B.A.M.J. van Schie-Geyer and S. Wongsodihardjo, and technicians J.C. Kwekkeboom and E.I.H. van der Voort, for their contributions.Disclosure of Interests:Coen van der Meulen: None declared, Lotte van de Stadt: None declared, Féline Kroon: None declared, Marion Kortekaas: None declared, Annelies Boonen Speakers bureau: Lecture for UCB; paid to department., Consultant of: Yes. Advisory board meetings at Galapagos, Eli Lilly and Abvvie; paid to department., Grant/research support from: Yes. Grants by Celgene and Abbvie; paid to department., Stefan Böhringer: None declared, Marieke Niesters: None declared, Monique Reijnierse: None declared, Frits Rosendaal: None declared, Naghmeh Riyazi: None declared, M. Starmans: None declared, Franktien Turkstra: None declared, Jende van Zeben: None declared, Cornelia Allaart: None declared, Margreet Kloppenburg Consultant of: For Abbvie, Pfizer, Levicept, GlaxoSmithKline, Merck-Serono, Kiniksa, Flexìon, Galapagos, Jansen, CHDR and local investigator of industry-driven trial (Abbvie). All fees were paid to the institution., Grant/research support from: Grant by the Dutch Arthritis Society

Background Seropositive arthralgia patients are at risk of developing rheumatoid arthritis (RA). Ultrasound (US) might be used to further predict which seropositive individuals will progress to RA. However, the value of US in the prediction of RA is still a point of debate, mainly due to the use of different scoring systems and compositions of joints in US protocols in literature. Objectives To investigate which joints are most discriminative in predicting arthritis development in seropositive arthralgia patients. Methods We included 174 seropositive patients with arthralgia, but without clinical arthritis. US was performed at baseline in 16 joints: bilateral metacarpal phalangeal (MCP) 2 and 3, proximal interphalangeal (PIP) 2 and 3, wrist and metatarsal phalangeal (MTP) joints 2, 3 and 5. Images were scored for grey-scale (GS) synovitis and Power Doppler (PD) on a scale of 0–3. Grades≥2 for GS synovitis and grades≥1 for PD were regarded as abnormal. Clinical arthritis development was assessed in any of 44 joints during yearly follow-up or during an unscheduled visit in case of progression of symptoms. Patients were followed until clinical arthritis development or for a maximum of 5 years. Results In a total of 2784 joints that were imaged, 112 showed GS synovitis and 14 PD. The majority of GS synovitis was present in MTP2 and MTP3 joints (56 (50%) and 32 (29%), respectively), followed by wrists (15 (13%)), MCP3 (4 (4%)), MTP5 (3 (3%)), MCP2 (2 (2%)) and none in PIPs. Out of 14 joints with PD, 7 were wrists, 3 MTP5, 2 MCP2 and 2 PIP3. Fifty-one (29%) of the patients developed clinical arthritis in at least one joint after a median follow-up of 12 (interquartile range 6–23) months. For GS synovitis, the wrist, MCP2 and MTP5 were most discriminative in predicting clinical arthritis development (12/15 (80%) of patients with GS synovitis in wrist developed clinical arthritis, 3/3 (100%) in MTP5 and 2/2 (100%) in MCP2). MTP2 and 3 were least discriminative ( Conclusions Wrist, MCP2 and MTP5 joints (although numbers were small) showed the highest predictive value for development of clinical arthritis in any of 44 joints. Although most GS synovitis was observed in MTP2 and 3, predictive value of MTP2 and 3 joints for development of clinical arthritis was low. These results indicate that the choice of joints in the US protocol may influence the predictive value of ultrasound in predicting clinical arthritis development in seropositive arthralgia patients. Disclosure of Interest None declared

Background The value of joint ultrasonography (US) in the prediction of clinical arthritis in individuals at risk of developing rheumatoid arthritis (RA) is still a point of debate, due to varying scanning protocols and different populations. We investigated whether US abnormalities assessed with a standard joint protocol can predict development of arthritis in seropositive patients with arthralgia. Methods Anti-citrullinated protein antibodies and/or rheumatoid factor positive patients with arthralgia, but without clinical arthritis were included. US was performed at baseline in 16 joints: bilateral metacarpophalangeal 2–3, proximal interphalangeal 2–3, wrist and metatarsophalangeal (MTP) joints 2–3 and 5. Images were scored semi-quantitatively for synovial thickening and for positive signs on power Doppler (PD). Association between US abnormalities and arthritis development at the joint and at the patient level was evaluated. Also, we investigated the added value of US over clinical parameters. Results Out of 163 patients who underwent US examination, 51 (31%) developed clinical arthritis after a median follow-up time of 12 (interquartile range 5–24) months, of which 44 (86%) satisfied the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA. US revealed synovial thickening and PD in at least one joint in 49 patients (30%) and 7 patients (4%), respectively. Synovial thickening was associated with both development and timing of clinical arthritis in any joint (patient level) when MTP joints were excluded from the US assessment (odds ratio 6.6, confidence interval (CI) 1.9–22), and hazard ratio 3.4, CI 1.6–6.8, respectively, with a mean time to arthritis of 23 versus 45 months when synovial thickening was present versus not present). There was no association between US and arthritis development at the joint level. Predictive capacity was highest in the groups with an intermediate and high risk of developing arthritis based on a prediction rule with clinical parameters. Conclusions Synovial thickening on US predicted clinical arthritis development at the patient level in seropositive patients with arthralgia when MTPs were excluded from the US assessment. Positive PD signs were infrequently seen in these at-risk individuals and was not predictive. In patients at intermediate risk of RA, US may help to identify those at higher risk of developing arthritis. Electronic supplementary material The online version of this article (10.1186/s13075-018-1767-9) contains supplementary material, which is available to authorized users.

Objective.To determine whether macrophage targeting by (R)-11C-PK11195 positron emission tomography (PET) can visualize subclinical joint inflammation in patients with rheumatoid arthritis (RA) without clinical arthritis during or after treatment, with flare as clinical outcome measure.Methods.(R)-11C-PK11195 PET and contrast-enhanced magnetic resonance imaging (MRI) of hands/wrists were performed in 29 patients with RA without clinical arthritis. (R)-11C-PK11195 PET uptake (semiquantitative score 0–3) in metacarpophalangeal, proximal interphalangeal, and wrist joints (i.e., 22 joints per patient) was scored and summed to obtain a cumulative PET score (range 0–66). Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) was performed on similar joints. Synovitis and bone marrow edema scores (> 1) were summed to obtain a cumulative MRI score (range 0–288). Occurrence of flare was determined during 3-year followup.Results.Flare was observed in 17/29 patients (59%). (R)-11C-PK11195 PET showed enhanced tracer uptake in 16/29 patients (55%), of which 11 (69%) developed a flare. Highest cumulative PET scores (> 6, n = 3) corresponded with highest cumulative MRI scores (> 39) and were related to development of flare in hands/wrists within 6 months. Cumulative PET scores of patients developing a flare were higher than those of patients without a flare [median (interquartile range) 2 (0–4.5) vs 0 (0–1), p < 0.05]. In contrast, no significant differences were found between cumulative MRI scores of patients with and without a flare.Conclusion.(R)-11C-PK11195 PET showed enhanced uptake, pointing to presence of subclinical synovitis in over half of patients without clinical arthritis. (R)-11C-PK11195 PET may be of value for prediction of exacerbation of RA, since cumulative PET scores > 1 were associated with development of flare within 3 years.

Introduction: Ultrasonography (US) has better sensitivity than clinical evaluation for the detection of synovitis in early rheumatoid arthritis (RA). Patients presenting with arthralgia and a positive anti-citrullinated protein antibodies (ACPA) and/or Rheumatoid Factor (IgM-RF) status are at risk for developing RA. In the present study, US utility and predictive properties in arthralgia patients at risk for the development of arthritis were studied. Methods: 192 arthralgia patients with ACPA and/or IgM-RF were included. Absence of clinical arthritis was confirmed by two physicians. US was performed by one of two trained radiologists of any painful joint, and of adjacent and contralateral joints. Joint effusion, synovitis and power Doppler (PD) signal in the synovial membrane of the joints and tenosynovitis adjacent to the joint were evaluated and classified on a 4-grade semi-quantitative scale. Grade 2-3 joint effusion, synovitis, tenosynovitis and grade 1-3 Power Doppler signal were classified as abnormal. Results: Forty-five patients (23%) developed arthritis after a mean of 11 months. Inter-observer reliability for synovitis and PD was moderate (kappa 0.46, and 0.56, respectively) and for joint effusion low (kappa 0.23). The prevalence of tenosynovitis was too low to calculate representative kappa values. At joint level, a significant association was found between US abnormalities and arthritis development in that joint for joint effusion, synovitis and PD. At patient level, a trend was seen towards more arthritis development in patients who had US abnormalities for joint effusion, synovitis, PD and tenosynovitis. Conclusions: US abnormalities were associated with arthritis development at joint level, although this association did not reach statistical significance at patient level. US could potentially be used as a diagnostic tool for subclinical arthritis in seropositive arthralgia patients. However, further research is necessary to improve test characteristics.