Background: Our understanding of osteoarthritis (OA) has evolved from a degenerative disease to one in which low-grade, chronic inflammation plays a central role. In addition, evidence suggests that OA is accompanied by both peripheral and central nervous system sensitization that can cause pain. It has been demonstrated that transcutaneous vagus nerve stimulation (tVNS) can relieve pain, inflammation, and central sensitization in other conditions including fibromyalgia, pelvic pain, and headaches. We aimed to assess the efficacy and safety of tVNS on nociceptive pain, central sensitization, and physical function in knee OA. Methods: In this 12-week study, we stimulated the auricular branch of the vagus nerve with an auricular electrode connected to a transcutaneous electrical nerve stimulation device once a day for 3 days each week for 12 weeks. A total of 68 patients with chronic knee OA were randomly assigned to the active and sham groups (34 patients in each group). We used a variety of outcome measures, including the visual analog scale (VAS), pressure pain threshold (PPT), knee injury and osteoarthritis outcome score (KOOS), PainDETECT (PD-Q) and Douleur Neuropathique 4 (DN4) questionnaires. Outcome measures were recorded at baseline, At the end of the stimulation period, and then after 4 weeks. Results: In the active group, compared to baseline, there was a significant improvement in VAS scores between the first and second follow-up visits (P < 0.001). A significant improvement in PPT was seen in the right knee, left knee, and right elbow in active tVNS, and this improvement persisted for four weeks post-intervention. Meanwhile, in the sham group, right knee PPT was improved but not maintained. There were statistically significant improvements in the PD-Q and DN4 scores in the active tVNS group (P < 0.001), whereas in the sham group, DN4 questionnaire did not show any improvement. In terms of functional outcomes, the improvement in KOOS was significant only in the active group (31.44 ± 18.49, P < 0.001). No serious adverse events were observed. Conclusion: There is preliminary evidence to support the benefits of tVNS in OA, suggesting that neuromodulation can be used as an adjunct to existing pharmacological and non-pharmacological treatments. Trial registration: The study was registered on ClinicalTrials.gov (NCT05387135) on 24/05/2022.

Background: Methotrexate (MTX) is one of the most common medications used for rheumatoid arthritis (RA) treatment. Single-nucleotide polymorphisms (SNPs) could potentially predict variability in therapeutic outcomes. Aim: This study aims to assess the impact of SNPs in genes encoding for the MTX pathway for predicting clinical and therapeutic responses to MTX in a cohort of Egyptian patients with RA. Subjects and Methods: Data from 107 Egyptian RA patients (aged 44.4 ± 11.4 years) treated with MTX monotherapy, for a duration of 3.7 ± 3.3 years, were collected. Genotypes of 10 SNPs from four different genes were analyzed using the allelic discrimination PCR technique. Results: The ATIC rs3821353 G/T (p = 0.034) and the C/T and C/C of SLC19A1 rs7279445 (p = 0.0018) were associated with a non-response to MTX, while DHFR rs10072026 C/T and C/C were associated with a good response (p < 0.001). Carriers of the ATIC rs382135 3 G (p = 0.001) and ATIC rs4673990 G (p < 0.001) alleles were more likely to develop RA, while the SLC19A1 rs11702425 T (p < 0.001) and GGH rs12681874 T (p = 0.003) allele carriers were more likely to be protected against RA. Carriers of the ATIC rs4673990 A/G genotype (p < 0.001) were at risk of developing RA, while carriers of the following genotypes were mostly protected against RA: ATIC rs3821353 T/T (p < 0.001), ATIC rs3821353 G/G (p = 0.004), SLC19A1 rs11702425 T/T (p = 0.001), SLC19A1 rs11702425 C/T (p = 0.003), GGH rs12681874 C/T (p = 0.004) and GGH rs12681874 T/T (0.002). Conclusion: The genotyping of genes involved in the MTX pathway may be helpful to predict which RA patients will/will not benefit from MTX, and thus, may help to apply a personalized medicine approach in RA.

Objectives: To determine which anatomical sites and which ultrasonographic entheseal lesions are best able to discriminate between spondyloarthritis (SpA) patients and healthy controls (HC). Methods: We included patients with psoriatic arthritis (PsA) and axial SpA (axSpA), from six Swiss hospital outpatient clinics, as well as HC. Participants completed quality of life and physical activity questionnaires and underwent a clinical examination of both joints and entheses, followed by a detailed musculoskeletal ultrasound examination including nine entheseal sites bilaterally. Entheses were scored according to the Outcome Measures in Rheumatology criteria, with an additional evaluation of bursae and power Doppler (PD) in the 2–5 mm zone. Results: Overall, 121 participants were included, including 41 with PsA (mean age in years (SD), percentage male: 54.5±11.0, 63.4%), 39 with axSpA (45.1±10.0, 51.3%) and 41 HC (43.9±10.9, 56.1%), with a total of 2178 entheses evaluated. The PsA and axSpA groups showed no significant differences regarding inflammatory markers or disease activity scores. In the univariable analysis, all ultrasonographic lesions at the enthesis showed a significant association with SpA vs HC. Only B-mode inflammatory lesions (OR=1.38, p=0.034) and active enthesitis (OR=4.45, p=0.030) retained this association in multivariable analyses. While 4/9 entheses were associated with SpA in univariable analyses, only the distal patellar ligament insertion remained significantly associated with SpA (OR=1.74, p=0.039) in multivariable analyses. Conclusion: To distinguish SpA patients from controls, the sonographic scoring system used should account not only for the presence of specific entheseal lesions (structural and inflammatory) but also for the individual site affected.

Background: Pain in osteoarthritis (OA) has been attributed traditionally to local tissue injury causing ‘nociceptive pain’. However, recent studies suggest that neuropathic and central sensitization mechanisms may contribute to the pain experience. However, the relationship between these pain mechanisms and physical function has not been thoroughly addressed. This study aimed to assess the association of central sensitization and neuropathic pain with physical function in knee OA. Results: Participants with a positive central sensitization inventory score (CSI) (≥ 40) had a decreased total Knee injury and Osteoarthritis Outcome Score (KOOS) and its subscales (p < 0.001), a longer timed up and go test time (p = 0.002) and a higher PainDETECT questionnaire (PD-Q) and visual analogue scale (p < 0.001, p = 0.026 respectively). The severity of Kellgren-Lawrence grading (KL) (p < 0.001), depressive and anxiety symptoms (p < 0.001) increased with neuropathic pain severity. In addition, participants with a high PD-Q score (≥ 19) had a longer timed up and go test time (p < 0.001) and a decreased total KOOS score (p < 0.001). Moreover, we found that CSI score, KOOS score, and KL grading were significantly predicted the PD-Q score (p = 0.046, p < 0.001, p = 0.007, respectively). Regarding the physical function predictors, multivariate linear regression analysis revealed that pressure pain threshold at right elbow and right knee (p = 0.005, p < 0.001) in addition to PD-Q (P < 0.001) were significantly associated with KOOS score, while CSI and Hospital Anxiety Depression Scale were not. Conclusion: Knee OA patients with significant central sensitization and neuropathic pain reported increased pain, more functional impairment, more anxiety and depressive symptoms than OA patients without central sensitization and neuropathic pain. Additionally, neuropathic pain and presence of central sensitization were significant predictors for functional ability.

Objectives: Development of a new ultrasound (US) synovitis score (SONography in Arthritis and Rheumatism (SONAR)-7) with evaluation of its diagnostic performance in a cohort of patients with psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), in comparison with healthy controls (HC). Methods: We included 121 participants: 41 patients with PsA and 39 patients with axSpA, from six Swiss hospitals and 41 HC. All participants underwent a clinical examination of joints (68/66 tender joint count/swollen joint count (SJC)), followed by a detailed musculoskeletal US examination of 22 joints to assess for greyscale (GS) and power Doppler (PD) synovitis in adherence with the definitions established by the Outcome Measures in Rheumatology US working group. Results: The ‘SONAR-7’ score incorporated GS and PD lesions across 14 joints, including four metacarpophalangeal joints, four distal interphalangeal joints of the hands, two metatarsophalangeal joints, knees and wrists. It demonstrated an area under the receiver operating characteristic curve of 0.831 (95% CI 0.76 to 0.90), with an excellent specificity (95.1%) and moderate sensitivity (44%), comparable to existing US scores. The inflammatory components of the SONAR-7 correlated significantly with clinical measures of inflammation and disease activity (correlation: 0.37 for SJC-28, 0.33 for Disease Activity in Psoriatic Arthritis and 0.48 for US enthesitis). New bone formation in the same joints was associated with the Health Assessment Questionnaire (p=0.035) and Bath Ankylosing Spondylitis Metrology Index (p=0.016). Conclusion: The SONAR-7 score represents a fast and effective US-based tool for the evaluation of inflammatory and structural joint involvement in patients with PsA and axSpA, with high specificity and meaningful associations with clinical and quality-of-life outcomes.