Rheumatology最新文献

Objectives: VEXAS is a recently described acquired auto-inflammatory and haematological syndrome caused by somatic mutations in UBA1. To date, VEXAS is not a recognized cause of acquired immunodeficiency.

Methods: Two of our ten VEXAS patients developed a disseminated Mycobacterium avium infection. To shed light on this observation, we retrospectively studied all patients with disseminated non-tuberculous mycobacterial infections (NTMi) seen at our institution over 13 years. Inclusion criteria were a positive blood/bone marrow culture, or two positive cultures from distinct sites, or one positive culture with two involved sites.

Results: Patient 1 presented with fever, rash, orbital cellulitis and lung infiltrates. Patient 2 presented with fever and purpura. In both cases, Mycobacterium avium was identified on bone marrow culture. Twenty cases of disseminated NTMi were reviewed. Among 11 HIV-negative patients, three had chronic immune-mediated disease; three had untreated myeloid neoplasm; two had VEXAS; one had undergone kidney transplantation; one had GATA-2 deficiency; and one had no identified aetiology. None had lymphoid neoplasia or had undergone bone marrow transplantation. HIV-negative cases had higher CD4 counts than HIV-positive patients (median CD4: 515/mm3  vs 38/mm3, P < 0.001). Monocytopenia was present in seven cases. At 2 years, six patients had died, including both VEXAS patients.

Conclusion: VEXAS patients have an intrinsic susceptibility to disseminated NTMi, which may result from monocytic dysfunction. NTMi can mimic VEXAS flare. Clinicians should maintain a high suspicion for opportunistic infections before escalating immunosuppressive therapy. Further studies are needed to confirm and better decipher the herein reported observations.

Objective: The objective of this study was to identify predictors of renal flares in patients with SLE treated for active extra-renal disease.

Methods: Data from four clinical trials of belimumab in SLE (BLISS-52, NCT00424476; BLISS-76, NCT00410384; BLISS-NEA, NCT01345253; BLISS-SC, NCT01484496) were used. Patients were assigned to belimumab or placebo on top of standard therapy. We investigated the performance of predictors of renal flares through weeks 52-76 using proportional hazards regression analysis.

Results: Of 3225 participants, 192 developed at least one renal flare during follow-up, with the first occurring after a median time of 197 days. Current/former renal involvement [hazards ratio (HR): 15.4; 95% CI: 8.3-28.2; P < 0.001], low serum albumin levels (HR 0.9; 95% CI: 0.8-0.9; P < 0.001), proteinuria (HR: 1.6; 95% CI: 1.5-1.7; P < 0.001), and low C3 levels (HR: 2.9; 95% CI: 2.1-4.1; P < 0.001) at baseline appeared robust determinants of impending renal flares. Anti-dsDNA positivity yielded an increased hazard for renal flares (HR: 2.1; 95% CI: 1.4-3.2; P < 0.001), which attenuated after adjustments. Anti-Sm positivity was associated with renal flares in the placebo (HR: 3.7; 95% CI: 2.0-6.9; P < 0.001) but not in the belimumab subgroup, whereas anti-ribosomal P positivity was associated with renal flares in the belimumab subgroup only (HR: 2.8; 95% CI: 1.5-5.0; P = 0.001).

Conclusion: A history of renal involvement, high baseline proteinuria, hypoalbuminaemia, and C3 consumption were robust determinants of impending renal flares. In addition to anti-dsDNA, anti-Sm and anti-ribosomal P protein antibody positivity may have value in surveillance of renal SLE.

Objective: To investigate predictive factors for irreversible organ damage in systemic sclerosis (SSc) and establish a nomogram model.

Methods: This retrospective study included patients with SSc who were treated at our hospital between March 2013 and March 2023. Irreversible organ damage included heart failure, respiratory failure, renal failure, and gangrene of the hands and feet. Cox and LASSO regression analyses were performed to determine the predictive factors. Based on the results, a nomogram model was developed. The model was evaluated using the C-indices, calibration plots and DCA.

Results: A total of 361 patients with systemic sclerosis were randomly divided into the development (n = 181) and validation (n = 180) groups. Multivariate Cox regression analysis showed that age ≥65 years, weight loss, digital ulcers, mRSS ≥16, elevated creatinine, elevated myoglobin, elevated C-reactive protein, renal involvement and cardiac involvement were independent risk factors. Based on the LASSO analysis, a nomogram model of irreversible organ damage was established. The C-indices of the development group at 24, 60 and 96 m were 96.7, 84.5 and 85.7, whereas those of the validation group at 24, 60 and 96 m were 86.6, 79.1 and 78.5, respectively. The results of the DCA showed that the nomogram can be used as a valuable tool to predict irreversible organ damage in patients with SSc.

Conclusion: We included commonly used clinical indicators. According to the nomogram, the probability of irreversible organ damage can be calculated and high-risk patients can be identified.

Objectives: It is well-known that long-term osteoarthritis prognosis is not improved by corticosteroid treatments. Here we investigate what could underlie this phenomenon by measuring the short term corticosteroid response of osteoarthritic joint synovial macrophages (OA-Mf).

Methods: We determined the genome-wide transcriptomic response to corticosteroids of end-stage OA-Mf. This was compared with lipopolysaccharide-tolerized and β-glucan-trained circulating blood monocyte-derived macrophage models.

Results: Upon corticosteroid stimulation, the trained and tolerized macrophages significantly altered the abundance of 201 and 257 RNA transcripts, respectively. By contrast, by the same criteria, OA-Mf had a very restricted corticosteroid response of only 12 RNA transcripts. Furthermore, while metalloproteinases 1, 2, 3 and 10 expression clearly distinguish OA-Mf from both the tolerized and trained macrophage models, OA-Mf IL-1, chemokine (CXCL) and cytokine (CCL) family member profiles resembled the tolerized macrophage model, with the exception that OA-Mf showed high levels of CCL20.

Conclusion: Terminal osteoarthritis joints harbour macrophages with an inflammatory state that closely resembles the tolerized macrophage state, and this is compounded by a weak corticosteroid response capacity that may explain the lack of positive long-term effects of corticosteroid treatment for osteoarthritis patients.

Objective: Our objective was to test the hypothesis, in a double-blind, placebo-controlled study that vipoglanstat, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1), which decreases prostaglandin E2 (PGE2) and increases prostacyclin biosynthesis, improves RP.

Methods: Patients with SSc and ≥7 RP attacks during the last screening week prior to a baseline visit were randomized to 4 weeks treatment with vipoglanstat 120 mg or placebo. A daily electronic diary captured RP attacks (duration and pain) and Raynaud's Condition Score, with change in RP attacks/week as the primary end point. Cold challenge assessments were performed at baseline and end of treatment. Exploratory end points included patients' and physicians' global impression of change, Assessment of Scleroderma-associated Raynaud's Phenomenon questionnaire, mPGES-1 activity, and urinary excretion of arachidonic acid metabolites.

Results: Sixty-nine subjects received vipoglanstat (n = 33) or placebo (n = 36). The mean weekly number of RP attacks [baseline; vipoglanstat 14.4 (S.D. 6.7), placebo 18.2 (12.6)] decreased by 3.4 (95% CI -5.8; -1.0) and 4.2 (-6.5; -2.0) attacks per week (P = 0.628), respectively. All patient-reported outcomes improved, with no difference between the groups. The mean change in recovery of peripheral blood flow after the cold challenge did not differ between the study groups. Vipoglanstat fully inhibited mPGES-1, resulting in 57% reduction of PGE2 and 50% increase of prostacyclin metabolites in the urine. Vipoglanstat was safe and well tolerated.

Conclusion: Although vipoglanstat was safe, and well tolerated in a dose achieving full inhibition of mPGES-1, it was ineffective in SSc-related RP. Further development and evaluation of vipoglanstat will therefore be in other diseases where mPGES-1 plays a pathogenetic role.

Trial registration: ClinicalTrials.gov, https://www.clinicaltrials.gov, NCT0474420.

Objectives: Reactive arthritis (ReA) provides a unique opportunity to comprehend how a mucosal infection leads to inflammatory arthritis at a distant site without the apparent invasion of the pathogen. Unfortunately, conventional stool cultures after ReA provide limited information, and there is a dearth of metagenomic studies in ReA. The objective of this study was to identify gut microbiota associated with the development of ReA.

Methods: Patients with ReA or undifferentiated peripheral spondyloarthritis (UpSpA) were included if they presented within 4 weeks of the onset of the current episode of arthritis. Metagenomic DNA was extracted from the stools of these patients and of 36 age- and sex-similar controls. Sequencing and analysis were done using a standard 16S ribosomal pipeline.

Results: Of 55 patients, there was no difference between the gut microbiota of postdiarrheal ReA (n = 20) and of upSpA (n = 35). Comparing the gut microbiota of patients vs healthy controls, the patients had significantly higher alpha and beta diversity measures. After stringency filters, Proteobacteria had high abundance while Firmicutes had lesser as compared with the controls. Six families were overexpressed in patients, while another five were overexpressed in controls. Sixteen genera and 18 species were significantly different between patients and controls. At the species level there was strong association of Staphylococcus aureus, Clostridium septicum Klebsiella pneumoniae, Escherichia coli, Empedobacter brevis, Roseburia hominis, Bacillus velezensis and Crassaminicella with ReA.

Conclusion: The microbiota of classical gut-associated ReA and upSpA is similar. Patients have higher diversities in their gut microbiota compared with healthy controls. Both known and previously unreported species associated with ReA/upSpA were identified.

Objectives: We aimed to assess whether patient-physician discordance regarding disease activity affects treat-to-target (T2T) implementation and clinical outcomes in RA.

Methods: This was an analysis of the 2-year T2T-guided trial Care in early RA (CareRA). During year 1, DMARD escalations were mandated by the protocol when DAS28-CRP was >3.2. During year 2, treatment was at the rheumatologists' discretion. At each visit we assessed T2T implementation, defined as escalating DMARDs if DAS28-CRP >3.2. Patient-physician discordance was defined by the discordance score (DS), a weighted difference between patient-reported and clinical/laboratory outcomes. Using generalized linear mixed models and multilevel mediation analysis, we studied the association between time-varying DS, T2T implementation and the odds of remission (Simplified Disease Activity Index ≤3.3), physical functioning (HAQ score) and radiographic progression at year 2.

Results: Over 2 years, 379 patients were assessed at 3129 follow-up visits. On 445 (14%) of these visits, DAS28-CRP was >3.2, and DMARDs were escalated in 217/445 (49%) of such cases. T2T implementation declined over time and was consistently lower during the second year (year 1: 57-66%; year 2: 17-52%). Higher DS over time was negatively associated with remission and physical functioning at year 2, partly mediated by a lower proportion of T2T-adherent visits. No such association was found for radiographic progression.

Conclusion: Even in a trial setting, T2T was applied on only around 50% of visits. T2T was less likely to be implemented with increasing patient-physician discordance regarding disease activity, which was in turn associated with less remission and worse functional outcome, but not with radiographic progression.