Cachexia in preclinical rheumatoid arthritis: Longitudinal observational study of thigh magnetic resonance imaging from osteoarthritis initiative cohort.

BACKGROUND: Preclinical rheumatoid arthritis (Pre-RA) is defined as the early stage before the development of clinical RA. While cachexia is a well-known and potentially modifiable complication of RA, it is not known if such an association exists also in the Pre-RA stage. To investigate such issue, we aimed to compare the longitudinal alterations in the muscle composition and adiposity of participants with Pre-RA with the matched controls. METHODS: In this observational cohort study, the Osteoarthritis Initiative (OAI) participants were categorized into Pre-RA and propensity score (PS)-matched control groups. Pre-RA was retrospectively defined as the absence of RA from baseline to year-2, with progression to physician-diagnosed clinical RA between years 3-8 of the follow-up period. Using a validated deep learning algorithm, we measured MRI biomarkers of thigh muscles and adiposity at baseline and year-2 follow-ups of the cohort. The outcomes were the differences between Pre-RA and control groups in the 2-year rate of change for thigh muscle composition [cross-sectional area (CSA) and intramuscular adipose tissue (Intra-MAT)] and adiposity [intermuscular adipose tissue (Inter-MAT) and subcutaneous adipose tissue (SAT)]. Linear mixed-effect regression models were used for comparison. RESULTS: After 1:3 PS-matching of the groups for confounding variables (demographics, risk factors, co-morbidities, and knee osteoarthritis status), 408 thighs (102 Pre-RA and 306 control) of 322 participants were included (age mean ± SD: 61.7 ± 8.9 years; female/male: 1.8). Over a 2-year period, Pre-RA was associated with a larger decrease in total thigh muscle CSA [estimate, 95% confidence interval (CI): -180.13 mm2/2-year, -252.80 to -107.47, P-value < 0.001]. Further examination of thigh muscle composition showed that the association of the presence of Pre-RA with a larger decrease in muscle CSA over 2 years was noticeable in the quadriceps, flexors, and sartorius muscle groups (P-values < 0.05). Comparison of changes in total adipose tissue showed no difference between Pre-RA and control participants (estimate, 95% CI: 48.48 mm2/2-year, -213.51 to 310.47, P-value = 0.691). However, in the detailed analysis of thigh adiposity, Pre-RA presence was associated with a larger increase in Inter-MAT (estimate, 95% CI: 150.55 mm2/2-year, 95.58 to 205.51, P-value < 0.001). CONCLUSIONS: Preclinical rheumatoid arthritis is associated with a decrease in muscle cross-sectional area and an increase in intermuscular adipose tissue, similar to rheumatoid cachexia in clinical rheumatoid arthritis. These findings suggest the presence of cachexia in the preclinical phase of rheumatoid arthritis. Given that cachexia, which can exacerbate health outcomes, is potentially modifiable, this study emphasizes the importance of early identification of patients in their preclinical phase.

Immune checkpoint inhibitor therapy in patients with cancer and pre-existing systemic sclerosis.

OBJECTIVE: Immune checkpoint inhibitor (ICI) therapies have dramatically improved outcomes in multiple cancers. ICI's mechanism of action involves immune system activation to augment anti-tumor immunity. Patients with pre-existing autoimmune diseases, such as systemic sclerosis (SSc), were excluded from initial ICI clinical trials due to concern that such immune system activation could precipitate an autoimmune disease flare or new, severe immune related adverse events (irAE). In the present study, we report our experience with ICIs in patients with pre-existing SSc. METHODS: Patients with SSc who received ICI therapy for cancer were identified from the Johns Hopkins Scleroderma Center Research Registry. Through chart review and prespecified definitions, we identified whether patients experienced worsening SSc activity or new irAEs. SSc disease activity worsening was pre-defined as an increase in modified Rodnan skin score (mRSS), new scleroderma renal crisis, progression of interstitial lung disease (ILD) on CT scan, increased Raynaud's phenomenon frequency or severity, new pulmonary hypertension, or myositis flare. IrAEs also included active inflammatory arthritis and dermatitis. RESULTS: Eight patients with SSc who received ICI therapy for cancer were included. Overall, SSc symptoms remained stable during and after ICI therapy. None of the patients with long-standing sine or limited cutaneous SSc (lcSSc) had progressive skin thickening after ICI therapy. One patient, who was early in his diffuse cutaneous SSc (dcSSc) disease course, experienced worsening skin thickening and renal crisis. Three patients (38 %) experienced a total of five irAEs (grade 2: diarrhea, mucositis and dermatitis; grade 3: pneumonitis, and grade 4: nephritis). The patient with grade 4 nephritis developed scleroderma renal crisis and immune checkpoint related nephritis simultaneously. There were no deaths due to irAEs. CONCLUSION: In this study, ICI therapy was well tolerated in patients with longstanding, sine or lcSSc. IrAE were common but generally manageable. Patients with early, active SSc may be at greater risk from ICI therapy, but more research is needed.

Treatment Patterns and Effectiveness of Tofacitinib in Patients Initiating Therapy for Rheumatoid Arthritis: Results From the CorEvitas Rheumatoid Arthritis Registry.

OBJECTIVE: This real-world analysis assessed baseline demographics/characteristics and treatment patterns/effectiveness in patients with rheumatoid arthritis (RA) initiating tofacitinib (TOF) in the US CorEvitas RA Registry. METHODS: The primary analysis of this study included patients with RA initiating TOF with a 12-month follow-up visit from November 2012 to January 2021. Outcomes included baseline demographics/characteristics and TOF initiation/discontinuation reasons, treatment patterns, and effectiveness (disease activity and patient-reported outcomes [PROs] at 12 months); the primary effectiveness outcome was Clinical Disease Activity Index low disease activity (CDAI LDA). All data, analyzed descriptively, were stratified by TOF regimen (monotherapy vs combination therapy), line of therapy (second- to fourth-line), time of initiation (2012-2014, 2015-2017, or 2018-2020), and dose (5 mg twice daily vs 11 mg once daily). RESULTS: Of 2874 patients with RA who initiated TOF, 1298 had a qualifying 12-month follow-up visit; of these, 43.1% were monotherapy and 66.5% were fourth-line therapy. Overall, tumor necrosis factor inhibitors (40.8%) were the most common treatment immediately prior to TOF initiation. The most common reason for TOF initiation (among those with a reason) was lack/loss of efficacy of prior treatment (67.7%). Overall, at 12 months, 31.9% and 10.1% had achieved CDAI LDA and remission, respectively; 22.4%, 10.4%, and 5% had achieved ≥ 20%, ≥ 50%, and ≥ 70% improvement in modified American College of Rheumatology core set measures, respectively; and improvements in PROs were observed. Effectiveness was generally similar across TOF stratifications. CONCLUSION: TOF effectiveness (CDAI LDA) was observed in a US real-world setting of patients with RA regardless of TOF regimen, line of therapy, time of initiation, and dose. (ClinicalTrials.gov: NCT04721808).

Effects of Savoring Meditation on Positive Emotions and Pain-Related Brain Function: A Mechanistic Randomized Controlled Trial in People With Rheumatoid Arthritis.

Positive emotions are a promising target for intervention in chronic pain, but mixed findings across trials to date suggest that existing interventions may not be optimized to efficiently engage the target. The aim of the current pilot mechanistic randomized controlled trial was to test the effects of a positive emotion-enhancing intervention called Savoring Meditation on pain-related neural and behavioral targets in patients with rheumatoid arthritis. Participants included 44 patients with a physician-confirmed diagnosis of rheumatoid arthritis (n = 29 included in functional magnetic resonance imaging (fMRI) analyses), who were randomized to either Savoring Meditation or a Slow Breathing control. Both meditation interventions were brief (four 20-minute sessions). Self-report measures were collected pre-and post-intervention. An fMRI task was conducted at post-intervention, during which participants practiced the meditation technique on which they had been trained while exposed to non-painful and painful thermal stimuli. Savoring significantly reduced experimental pain intensity ratings relative to rest (P < .001). Savoring also increased cerebral blood flow in the ventromedial prefrontal cortex and increased connectivity between the ventromedial prefrontal cortex and caudate during noxious thermal stimulation relative to Slow Breathing (z = 2.3 voxelwise, false discovery rate cluster corrected P = .05). Participants in the Savoring condition also reported significantly increased positive emotions (ps < .05) and reduced anhedonic symptoms (P < .01) from pre- to post-intervention. These findings suggest that Savoring recruits reward-enhancing corticostriatal circuits in the face of pain, and future work should extend these findings to evaluate if these mechanisms of Savoring are associated with improved clinical pain outcomes in diverse patient populations. PERSPECTIVE: Savoring Meditation is a novel positive emotion-enhancing intervention designed for patients with chronic pain. The present findings provide preliminary evidence that Savoring Meditation is acutely analgesic, and engages neural and subjective emotional targets that are relevant to pain self-management. Future work should evaluate the clinical translation of these findings.