Although colchicine is the mainstay of familial Mediterranean fever (FMF) treatment, 5-10% of patients are considered to have colchicine resistance (CR). However, there is no globally agreed CR definition or indications for biological disease-modifying anti-rheumatic drugs (bDMARDs). A survey on 'Biologics in Monogenic Autoinflammatory Diseases', part of the 'Clinical Practice Strategies' (CLiPS) initiative, was conducted by a JIR cohort-initiated eCOST network among expert participants worldwide. Our primary aim was to provide a flowchart reflecting the different CR definitions and present data regarding bDMARD indications. The secondary aim was to determine how specific biases influence clinical approaches. We analysed the CliPS according to the experience levels of physicians, country-specific FMF prevalence, countries' gross domestic product, bDMARD availability and reimbursement policies of the countries. A total of 223 responses from 46 countries were included in the study. Almost half of the respondents (73/160, 45.6%) indicated that three to four attacks within the preceding 6 months were necessary for their CR definition. The most frequently used acute-phase reactant was C-reactive protein (157/164, 95.7%). Almost three-fourths of the respondents (74%, n=165) considered that supplementary factors, including complications of FMF, attack severity, elevated activity scores, patient-reported outcome and quality of life scales, influenced their CR definition. We present a novel flowchart describing physicians' general attitudes and unique findings regarding management strategies for colchicine-resistant FMF and shifting trends influenced by epidemiological and socioeconomic factors.

ObjectivesOral enzyme combination (OEC) therapy with bromelain, trypsin and rutoside reduces pain and improves function in patients with knee osteoarthritis (OA). Here, we investigated several potential biological mechanisms underlying the clinical effects of OEC therapy in patients with established knee OA with respect to innate immunity, systemic inflammation and cartilage turnover (EudraCT 2020-003154-80, NCT05038410).MethodsPatients (age ≥40 years, body mass index (BMI) ≤35 kg/m2) with symptomatic knee OA were randomised to either placebo or OEC, administered 2×3 tablets/day, for 8 weeks before crossing over after a 4-week washout period. Different markers exploring innate immunity, inflammation and cartilage matrix degradation have been measured in the blood using immunoassays or cytometric methods. Data from the modified intention-to-treat population (mITT) were analysed using a generalised linear mixed model. No correction for multiple comparisons was made due to the exploratory nature of the study.ResultsAltogether, 45 patients were randomised; 43 completed both treatment sequences (mITT; mean age: 63.3 years; mean BMI: 27.4 kg/m2; mean global Knee injury and Osteoarthritis Outcome Score (KOOS): 48.7). OEC significantly increased levels of α2-macroglobulin (p=0.038) and interleukin-10 (p<0.0001) while decreasing urinary carboxyl-terminal cross-linked telopeptide of type II collagen (p=0.038). Patients administered OEC exhibited significant improvements in KOOS Pain (p=0.0464) and Symptoms (p=0.026) subdomains but not globally. OEC was well tolerated, with no serious related adverse events reported in either group.ConclusionsOne of the key findings of this proof-of-mechanism study is that OEC modulates IL-10 production, suggesting an anti-inflammatory effect in patients with knee OA. This main finding contributes to explaining the effects of OEC on pain and function in these patients.Trial registration numberNCT05038410.

ObjectiveTo assess the efficacy of long-term treatment with risankizumab across the updated Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) domains and key related conditions of psoriatic arthritis (PsA).MethodsThis post hoc analysis primarily used data from the phase 3 KEEPsAKE 1 trial of adult patients with PsA, with data from KEEPsAKE 2 pooled for prespecified outcomes. Outcomes measuring risankizumab efficacy across key GRAPPA-recognised domains of PsA (peripheral arthritis, enthesitis, dactylitis, skin and nail psoriasis, axial disease) and PsA-related conditions such as inflammatory bowel disease (IBD) and uveitis were assessed over 100 weeks of treatment (~2 years). Statistical approaches included non-responder imputation (as-observed with imputation) for categorical variables and mixed-effect model for repeated measures for continuous variables including as-observed measurements at all visits. PsA-related conditions were evaluated via adverse events through 100 weeks.ResultsOverall, in KEEPsAKE 1 and KEEPsAKE 2, 412/483 (85.3%) and 181/224 (80.8%) of patients randomised to risankizumab completed treatment to week 100. Risankizumab demonstrated efficacy across all GRAPPA-defined domains through 100 weeks, including swollen and tender joint counts, enthesitis, dactylitis, skin and nail outcomes, and axial disease. In KEEPsAKE 1, 42.4% of patients had achieved a Disease Activity in Psoriatic Arthritis measurement of low disease activity and 62.9% had reached a minimal clinically important difference in pain at week 100. Rates of new onset or flare of IBD and uveitis were low.ConclusionsTreatment with risankizumab provides durable improvement in the signs and symptoms of PsA across all GRAPPA disease domains and related conditions.

ObjectiveThe common gain-of-function variant rs35705950, located in the promoter of MUC5B gene, has been strongly associated with interstitial lung diseases (ILDs) of different aetiology, such as idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-associated ILD (RA-ILD). In this study, we aimed to investigate the association of this variant and its nearby single nucleotide polymorphisms (SNPs) in the largest cohort of systemic sclerosis-associated ILD (SSc-ILD) to date.MethodsSamples were collected from blood/saliva, followed by DNA extraction and genotyping using SNP arrays. Data for rs35705950 and additional 903 variants within 100 Kb were obtained using genomic imputation. Subsequently, we tested their association in a meta-analysis to increase the consistency of the results, including 10 European ancestry cohorts comprising 2363 patients with SSc-ILD, 3526 SSc patients without ILD and 15 076 controls.ResultsMeta-analysis showed no significant association between rs35705950 and SSc-ILD, either comparing patients with SSc with and without ILD (p value: 0.588, OR: 1.05, 95% CI: 0.87 to 1.27) nor patients with SSc-ILD with controls (p value: 0.061, OR: 1.16, 95% CI: 0.99 to 1.36). Moreover, none of the additional 903 variants tested in the genomic region reached statistical significance.ConclusionDespite analysing the largest and most statistically powered SSc-ILD cohort to date, we found no evidence of association between the MUC5B promoter variant rs35705950 and its surrounding SNPs with SSc-ILD. These results suggest that the pathogenic mechanisms underlying SSc-ILD may only partially overlap with those of other similar ILDs, such as IPF or RA-ILD. This highlights the need for further studies regarding their genetic architecture.

ObjectivesThe aim of the study was to evaluate the ultrasound findings in lacrimal glands in a cohort of patients with suspected primary Sjögren’s disease (pSjD) and to assess the relationship with the diagnosis and the association with functional tests and autoantibodies.MethodsPatients with suspected pSjD, evaluated by salivary gland ultrasound (SGUS) and lacrimal gland (LGUS) as part of the diagnostic set-up were included. All had unstimulated sialometry, Schirmer’s test and laboratory test done (including autoantibodies). Ultrasound examination was performed with a GE Logiq E10 (a linear 4–20 MHz transducer for SGUS and a 6–24 MHz hockey stick transducer for LGUS). The OMERACT consensus-based greyscale scoring system (0–3) for salivary glands was applied for all glands. A score of ≥2 was considered pathological.Results30 patients were included, one was subsequently excluded due to missing data, 13 were diagnosed with pSjD according to the American College of Rheumatology/EULAR classification criteria. The sensitivity and specificity for LGUS for pSJD diagnosis were 61.5 and 87.5, respectively. The PPV and NPV values were 80.0 and 73.3, respectively—better than SGUS for the current cohort. There was no statistically significant association between LGUS and Schirmer’s test positivity (p value: 0.86), but there was a significant association between LGUS and SSA (OR: 17.4, p=0.005) as well as SSB (OR: 23.0, p=0.003).ConclusionLGUS has moderate sensitivity and high specificity for the diagnosis of pSjD. The OMERACT scoring system appears relevant for scoring pathology in the lacrimal glands using grade ≥2 as cut-off and may be a valuable supplementary tool for diagnostic evaluation in pSjD.

ObjectiveSjögren’s disease (SjD) is a chronic exocrine disorder typified by inflammation and dryness, but also profound fatigue, suggesting a pathological basis in cellular bioenergetics. In healthy states, dysfunctional mitochondria are recycled by mitophagic processes; when impaired, poorly functioning mitochondria persist and produce inflammatory reactive oxygen species. Employing a case–control study, we tested our hypothesis that mitochondrial dysregulation in T cells is associated with fatigue in SjD.MethodsWe isolated pan T cells from peripheral blood mononuclear cells of 13 SjD and 4 non-Sjögren’s sicca (NSS) subjects, who completed several fatigue questionnaires, along with 8 healthy subjects. Using Seahorse, we analysed T cells for mitochondrial oxygen consumption rate (OCR) and extracellular acidification rate, which we assessed for correlation with fatigue measures. Using public microarray data available for 190 SjD and 32 healthy subjects, we identified a mitophagic transcriptional signature that stratified SjD patients into 5 discrete clusters. Comparisons between the SjD subjects in these clusters to healthy individuals identified differentially expressed transcripts, which we subjected to bioinformatic interrogation.ResultsBasal OCR, ATP-linked respiration, maximal respiration and reserve capacity were significantly lower in SjD and NSS subjects compared with healthy individuals, with no differences in non-mitochondrial respiration, basal glycolysis or glycolytic reserve. Scores related to a sleep questionnaire and Bowman’s Profile of Fatigue and Discomfort showed correlation with altered OCR in SjD. Subgroup differential expression analysis revealed dynamic transcriptional activity between mitophagy subgroups, expanding the number of differentially expressed transcripts tenfold.ConclusionsMitochondrial dysfunction and fatigue are significant problems in SjD warranting further investigation.

ObjectivesSuperb microvascular imaging (SMI) provides a more sensitive assessment of small vessels compared with power and colour Doppler ultrasonography (PDUS and CDUS). We aimed to investigate the potential of SMI for use in research and clinical practice in Behçet syndrome (BS) and to gain a better understanding of erythema nodosum (EN) like and superficial thrombophlebitis (STM) lesions using SMI.MethodsWe studied 51 patients with BS and 31 patients with non-BS with red palpable lesions on physical examination. B-mode US, CDUS, PDUS and SMI were performed and recorded by the same radiologist and recorded images were additionally evaluated independently by another radiologist. Vessel-wall signal intensity of STM lesions by SMI was graded in four groups according to the percentages of the affected vessel-wall area (Grade 0: no signal, Grade 1: < 25%, Grade 2: 25%–50%, Grade 3: 50%–75% and Grade 4: >75%).ResultsThe lesions of 26 patients with BS and 17 patients with non-BS were diagnosed as STM with CDUS. SMI of STM lesions revealed vessel-wall signals in 21/26 patients with BS (81%), in contrast to only 3/17 (18%) patients with non-BS. While 16 of 21 patients with BS (76%) had at least grade 2 signal, only 1 of 3 non-BS had it. Lesions of 25 BS and 11 non-BS were diagnosed as EN by CDUS and SMI showed no vessel-wall signal in these patients.ConclusionsEvaluation of the vessel wall with SMI in BS may be a promising approach for showing inflammation as an inexpensive, non-invasive and reliable imaging method that does not require a contrast agent.

Relationships between patient education and long-term clinical outcomes are complex. This study used real-world data to evaluate the impact of improved pain knowledge on clinical outcomes in fibromyalgia patients. Prospectively collected registry-based observational data were analysed to emulate a randomised clinical trial. Study participants were diagnosed with fibromyalgia, had a high need to learn about pain (Numeric Rating Scale >7), had attended a 2-day therapeutic educational programme and re-rated their learning needs after the programme. A good educational outcome was defined as a re-rating score <5, while a poor outcome was ≥5. The primary endpoint at 9 months was the overall impact of fibromyalgia, measured by the Fibromyalgia Impact Questionnaire Revised (FIQR) impact subscale. The eligible cohort comprised 450 participants. The intention-to-treat from population included 121 participants (26.9%) with a good educational outcome and 329 participants (73.1%) with a poor educational outcome (comparator group). Missing outcome data were handled implicitly by the repeated measures linear mixed models, assuming data are missing at random.At the 9-month endpoint, the fully adjusted FIQR impact subscale score was lower in the good educational outcome group (8.0 (95% CI 7.3 to 8.7)) compared with the poor educational outcome group (9.6 (95% CI 9.0 to 10.2)), indicating a better clinical outcome for those with a good educational outcome. The model-estimated between-group difference was -1.6 (95% CI -2.5 to -0.7; p=0.0006) FIQR impact subscale units. This study suggests that achieving pain educational learning objectives leads to better clinical outcomes in fibromyalgia patients, supporting the integration of pain education into patient programmes.

The phase III SELECT-MONOTHERAPY trial (NCT02706951) demonstrated the safety and efficacy of upadacitinib (UPA) monotherapy through 84 weeks in patients with rheumatoid arthritis who responded inadequately to methotrexate. Here we report week 260 results. Patients were randomised to continue methotrexate or UPA 15 mg (UPA15) or 30 mg (UPA30) monotherapy for 14 weeks. From week 14, patients continuing methotrexate switched to UPA15 or UPA30 per prespecified assignment; patients randomised to UPA continued treatment. Following a protocol amendment, all cohorts switched to open-label UPA15. Safety was summarised using exposure-adjusted event and incidence rates. Efficacy was reported as observed and using non-responder imputation (NRI). Of 648 randomised patients, 598 entered the long-term extension. Of these, 249 (41.6%) discontinued study drug by week 260 primarily due to adverse events (14.5%), consent withdrawal (9.9%), lost to follow-up (3.3%), lack of efficacy (2.2%), COVID-19 (0.7%) or other reasons (11.0%). Rates of herpes zoster, non-melanoma skin cancer, hepatic disorder, neutropenia, lymphopenia and creatine kinase elevation were higher with UPA30 versus UPA15. Long-term UPA safety data were consistent with the established UPA safety profile. Based on NRI, >39% of patients treated continuously with UPA achieved low disease activity per Clinical Disease Activity Index ≤10 (UPA15, n=93/217; UPA30, n=91/215) and 28-joint Disease Activity Score using C reactive protein ≤3.2 (UPA15, n=90/217; UPA30, n=94/215) at week 260. Efficacy was similar among patients switching from methotrexate to UPA. No new safety risks were identified with long-term UPA treatment. UPA monotherapy was efficacious in treating rheumatoid arthritis through week 260. NCT02706951.

Juvenile dermatomyositis (JDM) is a multisystem autoimmune disease associated with considerable morbidity and mortality, having a significant impact on patient health. Early diagnosis and appropriate treatment play a key role in optimising outcomes. JDM management remains challenging, particularly in severe or refractory cases, due to the limited evidence regarding therapeutic options. Given these challenges, Janus kinase inhibitors, including tofacitinib, have emerged as promising alternatives, yet evidence in paediatric populations is still scarce. We present the case of a child with JDM who achieved sustained remission with tofacitinib monotherapy following the failure of previous therapies. While its use is currently restricted to refractory cases, these findings suggest its potential for earlier integration into treatment algorithms. This work aims to provide valuable insights to guide therapeutic strategies in JDM.