Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial.

BACKGROUND: Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept. METHODS: The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited. Exclusion criteria included previous episodes of clinical synovitis and previous use of corticosteroids or disease-modifying antirheumatic drugs. Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation (block sizes of 2 and 4) stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months. Masking was achieved by providing four kits (identical in appearance and packaging) with pre-filled syringes with coded labels of abatacept or placebo every 3 months. The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021. All participants meeting the intention-to-treat principle were included in the analysis. This trial was registered with EudraCT (2013-003413-18). FINDINGS: Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were evaluated for eligibility and, of 213 participants, 110 were randomly assigned to abatacept and 103 to placebo. During the treatment period, seven (6%) of 110 participants in the abatacept group and 30 (29%) of 103 participants in the placebo group met the primary endpoint. At 24 months, 27 (25%) of 110 participants in the abatacept group had progressed to rheumatoid arthritis, compared with 38 (37%) of 103 in the placebo group. The estimated proportion of participants remaining arthritis-free at 12 months was 92·8% (SE 2·6) in the abatacept group and 69·2% (4·7) in the placebo group. Kaplan-Meier arthritis-free survival plots over 24 months favoured abatacept (log-rank test p=0·044). The difference in restricted mean survival time between groups was 53 days (95% CI 28-78; p<0·0001) at 12 months and 99 days (95% CI 38-161; p=0·0016) at 24 months in favour of abatacept. During treatment, abatacept was associated with improvements in pain scores, functional wellbeing, and quality-of-life measurements, as well as low scores of subclinical synovitis by ultrasonography, compared with placebo. However, the effects were not sustained at 24 months. Seven serious adverse events occurred in the abatacept group and 11 in the placebo group, including one death in each group deemed unrelated to treatment. INTERPRETATION: Therapeutic intervention during the at-risk phase of rheumatoid arthritis is feasible, with acceptable safety profiles. T-cell co-stimulation modulation with abatacept for 12 months reduces progression to rheumatoid arthritis, with evidence of sustained efficacy beyond the treatment period, and with no new safety signals. FUNDING: Bristol Myers Squibb.

Abatacept inhibits inflammation and onset of rheumatoid arthritis in individuals at high risk (ARIAA): a randomised, international, multicentre, double-blind, placebo-controlled trial.

BACKGROUND: Individuals with anti-citrullinated protein antibodies (ACPAs) and subclinical inflammatory changes in joints are at high risk of developing rheumatoid arthritis. Treatment strategies to intercept this pre-stage clinical disease remain to be developed. We aimed to assess whether 6-month treatment with abatacept improves inflammation in preclinical rheumatoid arthritis. METHODS: The abatacept reversing subclinical inflammation as measured by MRI in ACPA positive arthralgia (ARIAA) study is a randomised, international, multicentre, double-blind, placebo-controlled trial done in 14 hospitals and community centres across Europe (11 in Germany, two in Spain, and one in the Czech Republic). Adults (aged ≥18 years) with ACPA positivity, joint pain (but no swelling), and signs of osteitis, synovitis, or tenosynovitis in hand MRI were randomly assigned (1:1) to weekly subcutaneous abatacept 125 mg or placebo for 6 months followed by a double-blind, drug-free, observation phase for 12 months. The primary outcome was the proportion of participants with any reduction in inflammatory MRI lesions at 6 months. The primary efficacy analysis was done in the modified intention-to-treat population, which included participants who were randomly assigned and received study medication. Safety analyses were conducted in participants who received the study medication and had at least one post-baseline observation. The study was registered with the EUDRA-CT (2014-000555-93). FINDINGS: Between Nov 6, 2014, and June 15, 2021, 139 participants were screened. Of 100 participants, 50 were randomly assigned to abatacept 125 mg and 50 to placebo. Two participants (one from each group) were excluded due to administration failure or refusing treatment; thus, 98 were included in the modified intention-to-treat population. 70 (71%) of 98 participants were female and 28 (29%) of 98 were male. At 6 months, 28 (57%) of 49 participants in the abatacept group and 15 (31%) of 49 participants in the placebo group showed improvement in MRI subclinical inflammation (absolute difference 26·5%, 95% CI 5·9-45·6; p=0·014). Four (8%) of 49 participants in the abatacept group and 17 (35%) of 49 participants in the placebo group developed rheumatoid arthritis (hazard ratio [HR] 0·14 [0·04-0·47]; p=0·0016). Improvement of MRI inflammation (25 [51%] of 49 participants in the abatacept group, 12 [24%] of 49 in the placebo group; p=0·012) and progression to rheumatoid arthritis (17 [35%] of 49, 28 [57%] of 49; HR 0·14 [0·04-0·47]; p=0·018) remained significantly different between the two groups after 18 months, 12 months after the end of the intervention. There were 12 serious adverse events in 11 participants (four [8%] of 48 in the abatacept group and 7 [14%] of 49 in the placebo group). No deaths occurred during the study. INTERPRETATION: 6-month treatment with abatacept decreases MRI inflammation, clinical symptoms, and risk of rheumatoid arthritis development in participants at high risk. The effects of the intervention persist through a 1-year drug-free observation phase. FUNDING: Innovative Medicine Initiative.

"Deficiency in ELF4, X-Linked": a Monogenic Disease Entity Resembling Behçet's Syndrome and Inflammatory Bowel Disease.

Defining monogenic drivers of autoinflammatory syndromes elucidates mechanisms of disease in patients with these inborn errors of immunity and can facilitate targeted therapeutic interventions. Here, we describe a cohort of patients with a Behçet's- and inflammatory bowel disease (IBD)-like disorder termed "deficiency in ELF4, X-linked" (DEX) affecting males with loss-of-function variants in the ELF4 transcription factor gene located on the X chromosome. An international cohort of fourteen DEX patients was assessed to identify unifying clinical manifestations and diagnostic criteria as well as collate findings informing therapeutic responses. DEX patients exhibit a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum. Patients have been predominantly treated with anti-inflammatory agents, with the majority of DEX patients treated with biologics targeting TNFα.

Randomized placebo-controlled, double-blind clinical trial of nanoemulsion curcumin in women with aromatase inhibitor-induced arthropathy: an Alliance/NCORP pilot trial.

PURPOSE: Aromatase inhibitor (AI) therapy reduces risk of recurrence and death for postmenopausal women with breast cancer (BC); however, AI-induced arthralgia (AIIA) can lead to discontinuation of treatment. Curcumin, a bioactive polyphenolic substance, may help ameliorate inflammation-related conditions including osteoarthritis and pain. METHODS: We conducted a multisite randomized placebo-controlled, double-blind pilot trial (Alliance A22_Pilot9) to evaluate the effects of nanoemulsion curcumin (NEC, 200 mg/day) in postmenopausal women experiencing AIIA for ≥ 3 months. The primary objective was to determine the feasibility of using Functional Assessment of Cancer Treatment-Endocrine Symptoms (FACT-ES) to detect changes from 0 (T0) to 3 months (T3) of NEC treatment in AI-induced symptoms and well-being; secondary objectives included evaluation of changes in Disabilities of the Shoulder, Arm, and Hand (DASH), Brief Pain Inventory-short form (BPI-SF), grip strength, and biomarkers at T0 and T3. RESULTS: Forty-two patients were randomized to NEC or placebo; 34 women completed the 3-month study. Patient-reported outcome measures (PROMs: FACT-ES, DASH, BPI-SF) and biospecimens were collected at T0-T3 in > 80% of participants. Adherence was ≥ 90% for both arms. PROMs and grip strength did not differ significantly by treatment arm. Plasma curcumin was detected only in NEC arm participants. Serum estradiol and estrone levels were below detection or low on study agent. Gastrointestinal adverse effects were commonly reported in both arms. CONCLUSION: NEC versus placebo in a multisite randomized trial is feasible and well-tolerated. Additional studies with larger sample size are needed to further evaluate the efficacy and safety of NEC in treatment of AIIA. CLINICALTRIALS: gov Identifier: NCT03865992, first posted March 7, 2019.

Case 326.

HISTORY: A 15-year-old boy presented with a 3-week history of inner left thigh pain provoked by activity and experienced occasionally at rest. He denied nighttime pain, fever, or chills. Laboratory investigation revealed the following normal values: hemoglobin level of 15.6 g/dL (normal range, 13-16 g/dL), platelet count of 240 × 103/µL (normal range, 140-440 × 103/µL), and total leukocyte count of 7100 cells/µL (normal range, 4500-11 000 cells/µL). The percentage of neutrophils was considered low at 44% (normal range, 54%-62%), and the percentage of eosinophils was slightly high at 3.7% (normal range, 0%-3%). An anteroposterior radiograph of the left hip is shown (Fig 1). Physical therapy was initiated, with no improvement after 2 weeks of therapy. The patient was referred to an orthopedist for further evaluation. On physical examination, the patient endorsed marked left hip pain with hip flexion to 90°, limited internal and external rotation (5° and 15°, respectively), and antalgic gait favoring the left leg. Hip MRI (Fig 2) and further serologic analysis were requested for further evaluation. Although the serologic testing was performed at an outside laboratory, the physician reported positive immunoglobulin-G Lyme titers, normal C-reactive protein level, and normal erythrocyte sedimentation rate. Pelvic CT was requested (Fig 3). The patient was prescribed a course of doxycycline (100 mg twice daily for 28 days), with reported resolution of symptoms 2 weeks after initiation of treatment. Three weeks later, he presented to our department with recurrent left hip pain, which was similar in severity compared with initial presentation. A second MRI of the left hip was performed 4 months after initial presentation (Fig 4).

Serious infections in patients with VEXAS syndrome: data from the French VEXAS registry.

INTRODUCTION: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an acquired autoinflammatory monogenic disease with a poor prognosis whose determinants are not well understood. We aimed to describe serious infectious complications and their potential risk factors. METHODS: Retrospective multicentre study including patients with VEXAS syndrome from the French VEXAS Registry. Episodes of serious infections were described, and their risk factors were analysed using multivariable Cox proportional hazards models. RESULTS: Seventy-four patients with 133 serious infections were included. The most common sites of infection were lung (59%), skin (10%) and urinary tract (9%). Microbiological confirmation was obtained in 76%: 52% bacterial, 30% viral, 15% fungal and 3% mycobacterial. Among the pulmonary infections, the main pathogens were SARS-CoV-2 (28%), Legionella pneumophila (21%) and Pneumocystis jirovecii (19%). Sixteen per cent of severe infections occurred without any immunosuppressive treatment and with a daily glucocorticoid dose ≤10 mg. In multivariate analysis, age >75 years (HR (95% CI) 1.81 (1.02 to 3.24)), p.Met41Val mutation (2.29 (1.10 to 5.10)) and arthralgia (2.14 (1.18 to 3.52)) were associated with the risk of serious infections. JAK inhibitors were most associated with serious infections (3.84 (1.89 to 7.81)) compared with biologics and azacitidine. After a median follow-up of 4.4 (2.5-7.7) years, 27 (36%) patients died, including 15 (56%) due to serious infections. CONCLUSION: VEXAS syndrome is associated with a high incidence of serious infections, especially in older patients carrying the p.Met41Val mutation and treated with JAK inhibitors. The high frequency of atypical infections, especially in patients without treatment, may indicate an intrinsic immunodeficiency.

Excess Growth Hormone Triggers Inflammation-Associated Arthropathy, Subchondral Bone Loss, and Arthralgia.

Growth hormone (GH) is a key mediator of skeletal growth. In humans, excess GH secretion due to pituitary adenoma, seen in patients with acromegaly, results in severe arthropathies. This study investigated the effects of long-term excess GH on the knee joint tissues. One year-old wild-type (WT) and bovine GH (bGH) transgenic mice were used as a model for excess GH. bGH mice showed increased sensitivity to mechanical and thermal stimuli, compared with WT mice. Micro-computed tomography analyses of the distal femur subchondral bone revealed significant reductions in trabecular thickness and significantly reduced bone mineral density of the tibial subchondral bone-plate associated with increased osteoclast activity in both male and female bGH compared with WT mice. bGH mice showed severe loss of matrix from the articular cartilage, osteophytosis, synovitis, and ectopic chondrogenesis. Articular cartilage loss in the bGH mice was associated with elevated markers of inflammation and chondrocyte hypertrophy. Finally, hyperplasia of synovial cells was associated with increased expression of Ki-67 and diminished p53 levels in the synovium of bGH mice. Unlike the low-grade inflammation seen in primary osteoarthritis, arthropathy caused by excess GH affects all joint tissues and triggers severe inflammatory response. Data from this study suggest that treatment of acromegalic arthropathy should involve inhibition of ectopic chondrogenesis and chondrocyte hypertrophy.

Two- and 3-year outcomes in convalescent individuals with COVID-19: A prospective cohort study.

As the long-term consequences of coronavirus disease 2019 (COVID-19) have not been defined, it is necessary to explore persistent symptoms, long-term respiratory impairment, and impact on quality of life over time in COVID-19 survivors. In this prospective cohort study, convalescent individuals diagnosed with COVID-19 were followed-up 2 and 3 years after discharge from hospital. Participants completed an in-person interview to assess persistent symptoms and underwent blood tests, pulmonary function tests, chest high-resolution computed tomography, and the 6-min walking test. There were 762 patients at the 2-year follow-up and 613 patients at the 3-year follow-up. The mean age was 60 years and 415 (54.5%) were men. At 3 years, 39.80% of the participants had at least one symptom; most frequently, fatigue, difficulty sleeping, joint pain, shortness of breath, muscle aches, and cough. The participants experienced different degrees of pulmonary function impairment, with decreased carbon monoxide diffusion capacity being the main feature; results remained relatively stable over the 2-3 years. Multiple logistic regression analysis demonstrated that female sex and smoking were independently associated with impaired diffusion capacity. A subgroup analysis based on disease severity was performed, indicating that there was no difference in other parameters of lung function except forced vital capacity at 3-year follow-up. Persistent radiographic abnormalities, most commonly fibrotic-like changes, were observed at both timepoints. At 3 years, patients had a significantly improved Mental Component Score compared with that at 2 years, with a lower percentage with anxiety. Our study indicated that symptoms and pulmonary abnormalities persisted in COVID-19 survivors at 3 years. Further studies are warranted to explore the long-term effects of COVID-19 and develop appropriate rehabilitation strategies.

Exercise for knee osteoarthritis pain: Association or causation?

Exercise is universally recommended as a primary strategy for the management of knee osteoarthritis (OA) pain. The recommendations are based on results from more than 100 randomized controlled trials (RCTs) that compare exercise to no-attention control groups. However, due to the inherent difficulties with adequate placebo control, participant blinding and the use of patient-reported outcomes, the existing RCT evidence is imperfect. To better understand the evidence used to support a causal relationship between exercise and knee OA pain relief, we examined the existing evidence through the Bradford Hill considerations for causation. The Bradford Hill considerations, first proposed in 1965 by Sir Austin Bradford Hill, provide a framework for assessment of possible causal relationships. There are 9 considerations by which the evidence is reviewed: Strength of association, Consistency, Specificity, Temporality, Biological Gradient (Dose-Response), Plausibility, Coherence, Experiment, and Analogy. Viewing the evidence from these 9 viewpoints did neither bring forward indisputable evidence for nor against the causal relationship between exercise and improved knee OA pain. Rather, we conclude that the current evidence is not sufficient to support claims about (lack of) causality. With our review, we hope to advance the continued global conversation about how to improve the evidence-based management of patients with knee OA.

Serum levels of hydroxylated metabolites of arachidonic acid cross-sectionally and longitudinally predict knee pain progression: an observational cohort study.

OBJECTIVE: To examine associations between serum oxylipins, which regulate tissue repair and pain signalling, and knee pain/radiographic osteoarthritis (OA) at baseline and knee pain at 3 year follow-up. METHOD: Baseline, and 3 year follow-up, knee pain phenotypes were assessed from 154 participants in the Knee Pain in the Community (KPIC) cohort study. Serum and radiographic Kellgren and Lawrence (KL) and Nottingham line drawing atlas OA scores were collected at baseline. Oxylipin levels were quantified using liquid chromatography coupled with mass spectrometry. Associations were measured by linear regression and receiver operating characteristics (ROC). RESULTS: Serum levels of 8,9-epoxyeicosatrienoic acid (EET) (ß(95% confidence intervals (CI)) = 1.809 (-0.71 to 2.91)), 14,15-dihydroxyeicosatrienoic acid (DHET) (ß(95%CI) = 0.827 (0.34-1.31)), and 12-hydroxyeicosatetraenoic acid (HETE) (ß(95%CI) = 4.090 (1.92-6.26)) and anandamide (ß(95%CI) = 3.060 (1.35-4.77)) were cross-sectionally associated with current self-reported knee pain scores (numerical rating scale (NRS) item 3, average pain). Serum levels of 9- (ß(95%CI) = 0.467 (0.18-0.75)) and 15-HETE (ß(95%CI) = 0.759 (0.29-1.22)), 14-hydroxydocosahexaenoic acid (ß(95%CI) = 0.483(0.24-0.73)), and the ratio of 8,9-EET:DHET (ß(95%CI) = 0.510(0.19-0.82)) were cross-sectionally associated with KL scores. Baseline serum concentrations of 8,9-EET (ß(95%CI) = 2.166 (0.89-3.44)), 5,6-DHET (ß(95%CI) = 152.179 (69.39-234.97)), and 5-HETE (ß(95%CI) = 1.724 (0.677-2.77) showed positive longitudinal associations with follow-up knee pain scores (NRS item 3, average pain). Combined serum 8,9-EET and 5-HETE concentration showed the strongest longitudinal association (ß(95%CI) = 1.156 (0.54-1.77) with pain scores at 3 years, and ROC curves distinguished between participants with no pain and high pain scores at follow-up (area under curve (95%CI) = 0.71 (0.61-0.82)). CONCLUSIONS: Serum levels of a combination of hydroxylated metabolites of arachidonic acid may have prognostic utility for knee pain, providing a potential novel approach to identify people who are more likely to have debilitating pain in the future.

Relationships between diagnostic imaging of first carpometacarpal osteoarthritis and pain, functional status, and disease progression: A systematic review.

OBJECTIVE: To systematically review the association of pain, function, and progression in first carpometacarpal (CMC) osteoarthritis (OA) with imaging biomarkers and radiography-based staging. DESIGN: Database searches in PubMed, Embase, and the Cochrane Library, along with citation searching were conducted in accordance with published guidance. Data on the association of imaging with pain, functional status, and disease progression were extracted and synthesized, along with key information on study methodology such as sample sizes, use of control subjects, study design, number of image raters, and blinding. Methodological quality was assessed using National Heart, Lung, and Blood Institute tools. RESULTS: After duplicate removal, a total of 1969 records were screened. Forty-six articles are included in this review, covering a total of 28,202 study participants, 7263 with first CMC OA. Osteophytes were found to be one of the strongest biomarkers for pain across imaging modalities. Radiographic findings alone showed conflicting relationships with pain. However, Kellgren-Lawrence staging showed consistent associations with pain in various studies. Radiographic, sonographic, and MRI findings and staging showed little association to tools evaluating functional status across imaging modalities. The same imaging methods showed limited ability to predict progression of first CMC OA. A major limitation was the heterogeneity in the study base, limiting synthesis of results. CONCLUSION: Imaging findings and radiography-based staging systems generally showed strong associations with pain, but not with functional status or disease progression. More research and improved imaging techniques are needed to help physicians better manage patients with first CMC OA.

Hand osteoarthritis phenotypes based on a biopsychosocial approach, and their associations with cross-sectional and longitudinal pain.

OBJECTIVE: Hand osteoarthritis (OA) pain is characterized as heterogeneous and multifactorial. Differences in pain may be explained by underlying phenotypes, which have not been previously explored DESIGN: Latent class analysis determined classes of participants with hand OA from the Nor-Hand study baseline examination (2016-17) based on a biopsychosocial framework. Outcomes were hand and overall bodily pain intensity (Numeric Rating Scale, 0-10) at baseline and follow-up (2019-21), The relations of the classes to pain outcomes at baseline, follow-up, and change over time were analysed in separate models by linear regression, using the overall healthiest class as reference. RESULTS: Five classes differing in radiographic hand OA burden and OA burden in the lower extremities by ultrasound, demographic factors, psychosocial burden and pain sensitization was identified. Persons with the least severe OA but higher burden of biopsychosocial factors reported the most hand pain (beta 3.65, 95% CI 2.53, 4.75). Pain was less pronounced in persons with the most severe hand OA but low burden of biopsychosocial factors (beta 1.03, 95% CI 0.41, 1.65). Results were similar for overall bodily pain and at follow-up. Changes in pain were small, but the association between a separate class defined by higher levels of biopsychosocial burden and pain changes was significant. CONCLUSION: The five hand OA phenotypes were associated with pain at baseline and 3.5 years later. The phenotype with the least OA severity, but higher burden of biopsychosocial factors reported more pain than the phenotype with the most severe OA, reflecting the symptom-structure discordance of the hand OA pain experience.

Associations of pain sensitivity and conditioned pain modulation with physical activity: findings from the Multicenter Osteoarthritis Study (MOST).

OBJECTIVE: Individuals with chronic pain due to knee osteoarthritis (OA) are insufficiently physically active, and alterations of facilitatory and inhibitory nociceptive signaling are common in this population. Our objective was to examine the association of these alterations in nociceptive signaling with objective accelerometer-based measures of physical activity in a large observational cohort. DESIGN: We used data from the Multicenter Osteoarthritis Study. Measures of peripheral and central pain sensitivity included pressure pain threshold at the knee and mechanical temporal summation at the wrist, respectively. The presence of descending pain inhibition was assessed by conditioned pain modulation (CPM). Physical activity was quantitatively assessed over 7 days using a lower back-worn activity monitor. Summary metrics included steps/day, activity intensity, and sedentary time. Linear regression analyses were used to evaluate the association of pain sensitivity and the presence of descending pain inhibition with physical activity measures. RESULTS: Data from 1873 participants was analyzed (55.9% female, age = 62.8 ± 10.0 years). People having greater peripheral and central sensitivity showed lower step counts. CPM was not significantly related to any of the physical activity measures, and none of the exposures were significantly related to sedentary time. CONCLUSIONS: In this cohort, greater peripheral and central sensitivity were associated with reduced levels of objectively-assessed daily step counts. Further research may investigate ways to modify or treat heightened pain sensitivity as a means to increase physical activity in older adults with knee OA.

Association between hip muscle strength/function and hip cartilage defects in sub-elite football players with hip/groin pain.

OBJECTIVE: To explore associations between hip muscle strength and cartilage defects (presence and severity) on magnetic resonance imaging (MRI) in young adults with hip/groin pain participating in sub-elite football. DESIGN: Sub-elite football players with hip/groin pain (>6 months) completed assessments of isometric hip strength and functional task performance. Hip cartilage defects were assessed using the Scoring Hip Osteoarthritis with MRI tool. This exploratory, cross-sectional study used logistic and negative binomial models to assess the relationships between hip muscle strength or functional task performance and hip cartilage defects, controlling for body mass index, age, testing site and cam morphology, incorporating sex-specific interaction terms. RESULTS: One hundred and eighty-two (37 women) sub-elite (soccer or Australian football) players with hip/groin pain (age 26 ± 7 years) were included. Greater hip extension strength was associated with higher cartilage total score (adjusted incidence rate ratio [aIRR] 1.01, 95%CI: 1.0 to 1.02, p = 0.013) and superolateral cartilage score (adjusted odds ratio (aOR) 1.03, 95% confidence interval (CI): 1.01 to 1.06, p < 0.01). In female sub-elite football players, greater hip external rotation strength was associated with lateral cartilage defects (aOR 1.61, 95%CI: 1.05 to 2.48, p = 0.03) and higher cartilage total score (aIRR 1.25, 95%CI: 1.01 to 1.66, p = 0.042). A one-repetition increase in one-leg rise performance was related to lower odds of superomedial cartilage defects (aOR 0.96, 95%CI: 0.94 to 0.99, p < 0.01). CONCLUSIONS: Overall, there were few associations between peak isometric hip muscle strength and overall hip cartilage defects. It is possible that other factors may have relevance in sub-elite football players. Additional studies are needed to support or refute our findings that higher one leg rise performance was associated with reduced superomedial cartilage defect severity and greater hip extension strength was related to higher cartilage defect severity scores.

Joint involvement in sarcoidosis: systematic review and meta-analysis of prevalence, clinical pattern and outcome.

OBJECTIVES: To characterize joint involvement (JI) in sarcoidosis, a systematic search of MEDLINE, EMBASE and Cochrane Library was conducted from inception to July 2022 for publications reporting its prevalence, pattern, treatment and outcome. METHODS: The pooled prevalence estimates (PPE) with 95% CI were calculated using binomial distribution and random effects. Meta-regression method was used to examine factors affecting heterogeneity between studies. RESULTS: Forty-nine articles were identified comprising a total of 8574 sarcoidosis patients, where 12% presented with JI (95% CI 10, 14; I2 = 0%). The PPE for sarcoid arthritis (SA) was 19% (95% CI 14, 24; I2 = 95%), and 32% (95% CI 13, 51; I2 = 99%) for arthralgia. Heterogeneity was due to higher JI prevalence reported in Western Asia and the Middle East, in rheumatology clinics and via surveys. Sample size of SA varied from 12 to 117 cases. Ankles were most frequently affected (PPE 80%) followed by knees and wrists. Monoarthritis was uncommon (PPE 1%; 95% CI 0, 2; I2 = 55%). Acute SA prevailed (PPE 79%; 95% CI 72, 88; I2 = 69%) with an equal proportion of oligo and polyarthritis and was frequently accompanied by erythema nodosum (PPE 62%; 95% CI 52, 71; I2 = 16%). Chronic SA was predominantly polyarticular with a higher frequency of the upper extremity joints affected. Most common non-articular manifestations with SA included fever (52%), erythema nodosum (41%), hilar adenopathy (86%) and interstitial lung disease (23%) of which one-third required corticosteroids and/or immunosuppressants. CONCLUSION: SA occurred early in the disease with a PPE of 19% and most frequent pattern of acute oligo- or polyarthritis predominantly affecting the lower extremity large joints.

The course of cytokine and chemokine gene expression in clinically suspect arthralgia patients during progression to inflammatory arthritis.

OBJECTIVES: Autoantibody responses increase years before the onset of inflammatory arthritis (IA) and are stable during transitioning from clinically suspect arthralgia (CSA) to IA. Cytokine and chemokine levels also increase years before IA onset. However, the course in the at-risk stage of CSA during progression to disease or non-progression is unknown. To increase the understanding of processes mediating disease development, we studied the course of cytokine, chemokine and related receptors gene expression in CSA patients during progression to IA and in CSA patients who ultimately did not develop IA. METHODS: Whole-blood RNA expression of 37 inflammatory cytokines, chemokines and related receptors was determined by dual-colour reverse transcription multiplex ligation-dependent probe amplification in paired samples of CSA patients at CSA onset and either at IA development or after 24 months without IA development. ACPA-positive and ACPA-negative CSA patients developing IA were compared at CSA onset and during progression to IA. Generalised estimating equations tested changes over time. A false discovery rate approach was applied. RESULTS: None of the cytokine/chemokine genes significantly changed in expression between CSA onset and IA development. In CSA patients without IA development, G-CSF expression decreased (P = 0.001), whereas CCR6 and TNIP1 expression increased (P < 0.001 and P = 0.002, respectively) over a 2 year period. Expression levels in ACPA-positive and ACPA-negative CSA patients who developed IA were similar. CONCLUSION: Whole-blood gene expression of assessed cytokines, chemokines and related receptors did not change significantly from CSA to IA development. This suggests that changes in expression of these molecules may not be related to the final process of developing chronicity and may have occurred preceding CSA onset. Changes in gene expression in CSA patients without IA development may provide clues for processes related to resolution.

Joint tenderness at 3 months follow-up better predicts long-term pain than baseline characteristics in early rheumatoid arthritis patients.

OBJECTIVE: To investigate pain course over time and to identify baseline and 3-month predictors of unacceptable pain with or without low inflammation in early RA. METHODS: A cohort of 275 patients with early RA, recruited in 2012-2016, was investigated and followed for 2 years. Pain was assessed using a visual analogue scale (VAS; 0-100 mm). Unacceptable pain was defined as VAS pain >40, and low inflammation as CRP <10 mg/l. Baseline and 3-month predictors of unacceptable pain were evaluated using logistic regression analysis. RESULTS: After 2 years, 32% of patients reported unacceptable pain. Among those, 81% had low inflammation. Unacceptable pain, and unacceptable pain with low inflammation, at 1 and 2 years was significantly associated with several factors at 3 months, but not at baseline. Three-month predictors of these pain states at 1 and 2 years were higher scores for pain, patient global assessment, and the health assessment questionnaire, and more extensive joint tenderness compared with the number of swollen joints. No significant associations were found for objective inflammatory measures. CONCLUSION: A substantial proportion of patients had unacceptable pain with low inflammation after 2 years. Three months after diagnosis seems to be a good time-point for assessing the risk of long-term pain. The associations between patient reported outcomes and pain, and the lack of association with objective inflammatory measures, supports the uncoupling between pain and inflammation in RA. Having many tender joints, but more limited synovitis, may be predictive of long-term pain despite low inflammation in early RA.

Musculoskeletal involvement in systemic lupus erythematosus: a contrast-enhanced magnetic resonance imaging study in 107 subjects.

OBJECTIVE: Joint involvement in SLE is the most frequent manifestation and shows a wide heterogeneity. It has not a valid classification and it is often underestimated. Subclinical inflammatory musculoskeletal involvement is not well known. We aim to describe the prevalence of joint and tendon involvement in hand and wrist of SLE patients, either with clinical arthritis, arthralgia or asymptomatic and compare it with healthy subjects using contrasted MRI. METHODS: SLE patients fulfilling SLICC criteria were recruited and classified as follows: group (G) 1: hand/wrist arthritis, G2: hand/wrist arthralgia, G3: no hand/wrist symptoms. Jaccoud arthropathy, CCPa and RF positivity, hand OA or surgery were excluded. Healthy subjects (HS) were recruited as controls: G4. Contrasted MRI of non-dominant hand/wrist was performed. Images were evaluated following RAMRIS criteria extended to PIP, Tenosynovitis score for RA and peritendonitis from PsAMRIS. Groups were statistically compared. RESULTS: A total of 107 subjects were recruited (G1: 31, G2:31, G3:21, G4:24). Any lesion: SLE patients 74.7%, HS 41.67%; P 0.002. Synovitis: G1: 64.52%, G2: 51.61%, G3: 45%, G4: 20.83%; P 0.013. Erosions: G1: 29.03%; G2: 54.84%, G3: 47.62%; G4: 25%; P 0.066. Bone marrow oedema: G1: 29.03%, G2: 22.58%, G3: 19.05%, G4: 0.0%; P 0.046. Tenosynovitis: G1: 38.71%; G2: 25.81%, G3: 14.29%, G4: 0.0%; P 0.005. Peritendonitis: G1: 12.90%; G2: 3.23%, G3: 0.0%, G4: 0.0%; P 0.07. CONCLUSION: SLE patients have a high prevalence of inflammatory musculoskeletal alterations confirmed by contrasted MRI, even if asymptomatic. Not only tenosynovitis but peritendonitis is also present.

µ-Opioid Receptor Activation at the Dorsal Reticular Nucleus Shifts Diffuse Noxious Inhibitory Controls to Hyperalgesia in Chronic Joint Pain in Male Rats.

BACKGROUND: The dorsal reticular nucleus is a pain facilitatory area involved in diffuse noxious inhibitory control (DNIC) through opioidergic mechanisms that are poorly understood. The hypothesis was that signaling of µ-opioid receptors is altered in this area with prolonged chronic inflammatory pain and that this accounts for the loss of DNICs occurring in this condition. METHODS: Monoarthritis was induced in male Wistar rats (n = 5 to 9/group) by tibiotarsal injection of complete Freund's adjuvant. The immunolabeling of µ-opioid receptors and the phosphorylated forms of µ-opioid receptors and cAMP response element binding protein was quantified. Pharmacologic manipulation of µ-opioid receptors at the dorsal reticular nucleus was assessed in DNIC using the Randall-Selitto test. RESULTS: At 42 days of monoarthritis, µ-opioid receptor labeling decreased at the dorsal reticular nucleus, while its phosphorylated form and the phosphorylated cAMP response element binding protein increased. [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin acetate (DAMGO) enhanced DNIC analgesia in normal animals (means ± SD: pre-DNIC: 126.9 ± 7.0 g; DNIC - DAMGO: 147.5 ± 8.0 g vs. DNIC + DAMGO: 198.1 ± 19.3 g; P < 0.001), whereas it produced hyperalgesia in monoarthritis (pre-DNIC: 67.8 ± 7.5 g; DNIC - DAMGO: 70.6 ± 7.7 g vs. DNIC + DAMGO: 32.2 ± 2.6 g; P < 0.001). An ultra-low dose of naloxone, which prevents the excitatory signaling of the µ-opioid receptor, restored DNIC analgesia in monoarthritis (DNIC - naloxone: 60.0 ± 6.1 g vs. DNIC + naloxone: 98.0 ± 13.5 g; P < 0.001), compared to saline (DNIC - saline: 62.5 ± 5.2 g vs. DNIC + saline: 64.2 ± 3.8 g). When injected before DAMGO, it restored DNIC analgesia and decreased the phosphorylated cAMP response element binding protein in monoarthritis. CONCLUSIONS: The dorsal reticular nucleus is likely involved in a facilitatory pathway responsible for DNIC hyperalgesia. The shift of µ-opioid receptor signaling to excitatory in this pathway likely accounts for the loss of DNIC analgesia in monoarthritis.

Is hip capsule morphology associated with hip pain in patients without another structural correlate?

OBJECTIVE: The goals of this study were (i) to assess the association between hip capsule morphology and pain in patients without any other MRI abnormalities that would correlate with pain and (ii) to investigate whether hip capsule morphology in hip pain patients is different from that of controls. METHODS: In this study, 76 adults with hip pain who did not show any structural abnormalities on MRI and 46 asymptomatic volunteers were included. Manual segmentation of the anterior and posterior hip capsules was performed. Total and mean anterior hip capsule area, posterior capsule area, anterior-to-posterior capsule area ratio, and medial-to-lateral area ratio in the anterior capsule were quantified. Differences between the pain and control groups were evaluated using logistic regression models. RESULTS: Patients with hip pain showed a significantly lower anterior-to-posterior area ratio as compared with the control group (p = 0.002). The pain group's posterior hip capsule area was significantly larger than that of controls (p = 0.001). Additionally, the ratio between the medial and lateral sections of the anterior capsule was significantly lower in the pain group (p = 0.004). CONCLUSIONS: Patients with hip pain are more likely to have thicker posterior capsules and a lower ratio of the anterior-to-posterior capsule area and thinner medial anterior capsules with a lower ratio of the medial-to-lateral anterior hip capsule compartment, compared with controls. CLINICAL RELEVANCE STATEMENT: During MRI evaluations of patients with hip pain, morphology of the hip capsule should be assessed. This study aims to be a foundation for future analyses to identify thresholds distinguishing normal from abnormal hip capsule measurements. KEY POINTS: • Even with modern image modalities such as MRI, one of the biggest challenges in handling hip pain patients is finding a structural link for their pain. • Hip capsule morphologies that correlated with hip pain showed a larger posterior hip capsule area and a lower anterior-to-posterior capsule area ratio, as well as a smaller medial anterior capsule area with a lower medial-to-lateral anterior hip capsule ratio. • The hip capsule morphology is correlated with hip pain in patients who do not show other morphology abnormalities in MRI and should get more attention in clinical practice.