Proton Pump Inhibitor Use and Bone Health in Patients With Rheumatic Diseases: A Cross-Sectional Study.

OBJECTIVE: To assess the effect of proton pump inhibitor (PPI) use on bone mineral density (BMD) and bone microarchitecture as measured by the trabecular bone score (TBS) in patients with inflammatory rheumatic and musculoskeletal diseases (iRMDs). METHODS: Cross-sectional data from a prospective single-center cohort (2015 to 2022) of patients with iRMDs were used to evaluate 3 co-primary outcomes: BMD of the left femoral neck and the lumbar spine (as T-scores) and the TBS. Inverse probability weighting adjusted for numerous confounders including age, sex, body mass index, current and cumulative glucocorticoid (GC) dose, C-reactive protein levels, disability, and others. Analyses were based on general linear models, following a prespecified statistical analysis plan. RESULTS: The study included 1495 patients (75% women; mean age, 62.6±13.1 years; 49% and 63% with regular PPI and GC use, respectively). The PPI users had lower BMD at both spine (adjusted contrast -0.25; 95% CI, -0.47 to -0.04; P=.02) and femoral neck (-0.17 [-0.35 to 0.01]; P=.07). Differences between PPI users and nonusers were statistically significant only in patients concurrently using GCs at more than 7.5 mg/d prednisone equivalent. The TBS was similar in PPI users and nonusers (adjusted contrast, 0.00 [-0.04 to 0.04]; P=.97). CONCLUSION: Our results suggest that PPIs lead to a loss of BMD rather than an impairment of bone microarchitecture in patients with iRMDs. The negative association between PPI use and BMD appears to be dependent on concurrent GC use. Clinicians should carefully review the indication for PPI use in patients with iRMDs, especially in those receiving higher dose GCs.

VEXAS and Myelodysplastic Syndrome: An Interdisciplinary Challenge.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently recognized systemic autoinflammatory disease caused by somatic mutations in hematopoietic progenitor cells. This case series of four patients with VEXAS syndrome and comorbid myelodysplastic syndrome (MDS) aims to describe clinical, imaging, and hematologic disease presentations as well as response to therapy. Four patients with VEXAS syndrome and MDS are described. A detailed analysis of imaging features, hemato-oncological presentation including bone marrow microscopy and clinical-rheumatological disease features and treatment outcomes is given. All patients were male; ages ranged between 64 and 81 years; all were diagnosed with MDS. CT imaging was available for three patients, all of whom exhibited pulmonary infiltrates of varying severity, resembling COVID-19 or hypersensitivity pneumonitis without traces of scarring. Bone marrow microscopy showed maturation-disordered erythropoiesis and pathognomonic vacuolation. Somatic mutation in the UBA1 codon 41 were found in all patients by next-generation sequencing. Therapy regimes included glucocorticoids, JAK1/2-inhibitors, nucleoside analogues, as well as IL-1 and IL-6 receptor antagonists. No fatalities occurred (observation period from symptom onset: 18-68 months). Given the potential underreporting of VEXAS syndrome, we highly recommend contemporary screening for UBA1 mutations in patients presenting with ambiguous signs of systemic autoinflammatory symptoms which persist over 18 months despite treatment. The emergence of cytopenia, especially macrocytic hyperchromic anemia, should prompt early testing for UBA1 mutations. Notably conspicuous, pulmonary alterations in CT imaging of patients with therapy-resistant systemic autoinflammatory symptoms should be discussed in interdisciplinary medical teams (Rheumatology, Hematology, Radiology and further specialist departments) to facilitate timely diagnosis during the clinical course of the disease.

Continuing versus tapering low-dose glucocorticoids in patients with rheumatoid arthritis and systemic lupus erythematosus in states of low disease activity or remission: A systematic review and meta-analysis of randomised trials.

OBJECTIVES: To study the benefit and harm associated with continuing versus tapering low-dose glucocorticoids (GCs) in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) who have achieved low disease activity/remission. METHODS: A protocolised (PROSPEROCRD42022325175) systematic review and meta-analysis of randomised trials was performed. Trials compared, in patients with low disease activity/remission and GCs at baseline, continued low-dose GCs (≤7.5 mg/d prednisone equivalent) with a taper. Co-primary outcomes were time to flare and adverse events (AEs), accompanied by secondary benefit and harm outcomes. We performed meta-analyses and evaluated risk of bias and quality of evidence (QoE). Subgroup analyses were conducted for patients with RA. RESULTS: Four trials (three: RA; one: SLE; study duration 24-104 weeks) with 472 participants were included. Tapering GCs resulted in a shorter time to flare (hazard ratio 3.41 [95 %-CI 1.96-5.93]; p<0.01; very low QoE). The risks of AEs, serious AEs, and withdrawal due to AEs were similar in both groups (very low to low QoE). There were more withdrawals due to lack of efficacy with tapered GCs (risk ratio 3.02 [1.56-5.87]; low QoE). In RA, the disease activity score-28 was lower with continued GCs (mean difference 0.49 [0.07-0.91]; low QoE). One of 238 patients in the tapering groups experienced adrenal insufficiency. Subgroup analyses yielded consistent results. CONCLUSION: In RA and SLE with low disease activity, continuing low-dose GCs may provide better sustained disease control, but QoE is insufficient. Adrenal insufficiency is very rare when tapering low-dose GCs. Longer-term safety concerns for GCs remain.

The Effect of Low-Dose Glucocorticoids Over Two Years on Weight and Blood Pressure in Rheumatoid Arthritis: Individual Patient Data From Five Randomized Trials.

BACKGROUND: Weight gain and hypertension are well known adverse effects of treatment with high-dose glucocorticoids. OBJECTIVE: To evaluate the effects of 2 years of low-dose glucocorticoid treatment in rheumatoid arthritis (RA). DESIGN: Pooled analysis of 5 randomized controlled trials with 2-year interventions allowing concomitant treatment with disease-modifying antirheumatic drugs. SETTING: 12 countries in Europe. PATIENTS: Early and established RA. INTERVENTION: Glucocorticoids at 7.5 mg or less prednisone equivalent per day. MEASUREMENTS: Coprimary end points were differences in change from baseline in body weight and mean arterial pressure after 2 years in intention-to-treat analyses. Difference in the change of number of antihypertensive drugs after 2 years was a secondary end point. Subgroup and sensitivity analyses were done to assess the robustness of primary findings. RESULTS: A total of 1112 participants were included (mean age, 61.4 years [SD, 14.5]; 68% women). Both groups gained weight in 2 years, but glucocorticoids led, on average, to 1.1 kg (95% CI, 0.4 to 1.8 kg; P < 0.001) more weight gain than the control treatment. Mean arterial pressure increased by about 2 mm Hg in both groups, with a between-group difference of -0.4 mm Hg (CI, -3.0 to 2.2 mm Hg; P = 0.187). These results were consistent in sensitivity and subgroup analyses. Most patients did not change the number of antihypertensive drugs, and there was no evidence of differences between groups. LIMITATION: Body composition was not assessed, and generalizability to non-European regions may be limited. CONCLUSION: This study provides robust evidence that low-dose glucocorticoids, received over 2 years for the treatment of RA, increase weight by about 1 kg but do not increase blood pressure. PRIMARY FUNDING SOURCE: None.

[Trabecular bone score in rheumatology : Are there benefits in comparison to bone densitometry alone?] / Trabecular Bone Score in der Rheumatologie : Gibt es einen Nutzen im Vergleich zur alleinigen Osteodensitometrie?

Patients with inflammatory rheumatic diseases have an increased risk of fractures due to the inflammatory potential of the disease and also because of the treatment with glucocorticoids that is often necessary. According to the current guidelines of the Governing Body on Osteology (DVO), the fracture risk can be assessed using dual energy X­ray absorptiometry and can also be supplemented by measuring the trabecular bone score (TBS). The assessment of the TBS offers additional advantages, for example in glucocorticoid-induced osteoporosis and in patients with osteoproliferative changes of the spine (spondylarthritis) and thus optimizes the fracture risk assessment in the rheumatological patient population.

Sex and age do not modify the association between glucocorticoids and bone mineral density in patients with rheumatoid arthritis: a cross-sectional study.

BACKGROUND: It is unclear whether sex or age modify the association of glucocorticoid (GC) use with reduced bone mineral density (BMD) in patients with rheumatoid arthritis (RA). METHODS: We studied cross-sectional data of RA patients with current or previous GC treatment in a single center cohort study (Rh-GIOP cohort). Our primary outcome was the minimum T-score (measured by DXA) of either lumbar spine, total femur, or femoral neck. Current GC dose was the main exposure; cumulative GC dose and cumulative duration of GC use were also assessed. Following a predefined statistical analysis plan, linear regression analyses with adjustment for confounders assessed whether the association of GC use with BMD was modified by sex (men versus women) or age (≥ 65 versus < 65 years). RESULTS: Four hundred eighty-three patients with RA (mean age 64 ± 12 years, 80% women) were included. 33% were not currently taking GCs, 32% were treated with a dose of 5 mg/d prednisone equivalent and 11% with more than 7.5 mg/d. 23% of patients had osteoporosis by DXA (minimum T-score ≤ -2.5). The slope, i.e., the association between changes in minimum T-scores with 1 mg/d change in current GC dose, was similar in men and women (-0.07 and -0.04, respectively; difference -0.03 [-0.11 to 0.04]; p for interaction = 0.41). Slopes were also similar for elderly and non-elderly patients (-0.03 and -0.04, respectively; difference -0.01 [-0.06 to 0.05]; p for interaction = 0.77). Using cumulative dose and duration of use as exposures did not lead to substantial changes of these results. CONCLUSIONS: In our sample, the association of GC use with reduced BMD in RA was not modified by sex or age.

How to treat VEXAS syndrome: a systematic review on effectiveness and safety of current treatment strategies.

OBJECTIVES: To evaluate the effectiveness and safety of current treatment strategies for the vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. METHODS: A protocolized systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was performed. Three databases were searched for reports on treatment strategies for VEXAS. Data from the included publications was extracted and a narrative synthesis was performed. Treatment response was recorded as complete (CR), partial (PR) or none (NR) depending on changes in clinical symptoms and laboratory parameters. Patient characteristics, safety data and previous treatments were analysed. RESULTS: We identified 36 publications with a total of 116 patients; 113 (98.3%) were male. The identified reports included azacytidine (CR 9/36, 25%; PR 14/36, 38.9%), Janus kinase inhibitors (JAKi) (CR 11/33, 33%; PR 9/33, 27.3%), tocilizumab (CR 3/15, 20%; PR 6/15, 40%), allogeneic stem cell transplantation (CR 6/7, 85.7%; one patient died), anakinra (CR 4/5, 80%; NR 1/5, 20%), canakinumab (CR 1/2, 50%; PR 1/2, 50%) and glucocorticoid monotherapy (CR 1/6, 16.7%; PR 4/6, 66.7%). Individual reports were available for TNF inhibitors, rituximab and MTX. Data on adverse events were available for 67 patients (67/116, 57.8%) and included: pneumonia (12/67, 17.9%), other infections (9/67, 13.4%), venous thromboembolisms (6/67, 8.9%), cytopenias (4/67, 5.9%), and acute (4/67, 5.9%) and chronic graft-vs-host-disease (2/67, 2.9%). CONCLUSION: Current data on VEXAS treatment are limited and inhomogeneous. Treatment decisions should be individualized. For the devolvement of treatment algorithms clinical trials are needed. Adverse events remain a challenge, especially an elevated risk for venous thromboembolism associated to JAKi treatment should be carefully considered.

Safety and efficacy associated with long-term low-dose glucocorticoids in rheumatoid arthritis: a systematic review and meta-analysis.

OBJECTIVES: The aim of this study was to assess the safety and efficacy of long-term low-dose glucocorticoids (GCs) in RA. METHODS: A protocolised systematic review and meta-analysis (PROSPERO No. CRD42021252528) of double-blind, placebo-controlled randomised trials (RCTs) comparing a low dose of GCs (≤ 7.5mg/day prednisone) to placebo over at least 2 years was performed. The primary outcome investigated was adverse events (AEs). We performed random-effects meta-analyses and used the Cochrane RoB tool and GRADE to assess risk of bias and quality of evidence (QoE). RESULTS: Six trials with 1078 participants were included. There was no evidence of an increased risk of AEs (incidence rate ratio 1.08; 95% CI 0.86, 1.34; P = 0.52); however, the QoE was low. The risks of death, serious AEs, withdrawals due to AEs, and AEs of special interest did not differ from placebo (very low to moderate QoE). Infections occurred more frequently with GCs (risk ratio 1.4; 1.19-1.65; moderate QoE). Concerning benefit, we found moderate to high quality evidence of improvement in disease activity (DAS28: -0.23; -0.43 to -0.03), function (HAQ -0.09; -0.18 to 0.00), and Larsen scores (-4.61; -7.52 to -1.69). In other efficacy outcomes, including Sharp van der Heijde scores, there was no evidence of benefits with GCs. CONCLUSION: There is very low to moderate QoE for no harm with long-term low dose GCs in RA, except for an increased risk of infections in GC users. The benefit-risk ratio might be reasonable forusing low-dose long-term GCs considering the moderate to high quality evidence for disease-modifying properties.

No association between methotrexate and impaired bone mineral density in a cohort of patients with polymyalgia rheumatica, giant cell arteritis, granulomatosis with polyangiitis and other vasculitides-a cross-sectional analysis with dose-response analyses.

OBJECTIVE: To investigate whether methotrexate (MTX) use is associated with bone mineral density (BMD) in patients with polymyalgia rheumatica (PMR) and various forms of vasculitis. METHODS: Rh-GIOP is a cohort study designed to evaluate bone health in patients with inflammatory rheumatic diseases. This cross-sectional analysis assessed the baseline visits of all patients with PMR or any kind of vasculitis. Following univariable analysis, multivariable linear regression analysis was performed. The lowest T-score of either the lumbar spine or the femur was chosen as the dependent variable to examine the relationship between MTX use and BMD. These analyses were adjusted for a variety of potential confounders, including age, sex, and glucocorticoid (GC) intake. RESULTS: Of 198 patients with PMR or vasculitis, 10 patients were excluded for very high GC dose (n = 6) or short disease duration (n = 4). The remaining 188 patients had the following diseases: PMR 37.2%, giant cell arteritis 25.0%, granulomatosis with polyangiitis 16.5%, followed by rarer diseases. The mean age was 68.0 ± 11.1 years, mean disease duration was 5.58 ± 6.39 years, and 19.7% had osteoporosis by dual x-ray absorptiometry (T-score ≤ -2.5). 23.4% were taking MTX at baseline with a mean dose of 13.2 mg/week (median: 15 mg/week). 38.6% of those used a subcutaneous preparation. MTX users had similar BMD compared to non-users (minimum T-scores -1.70 (± 0.86) versus -1.75 (± 0.91), respectively; p = 0.75). There was no statistically significant dose-response relationship: neither current nor cumulative dose were associated with BMD in unadjusted or adjusted models (current dose: slope -0.02; -0.14 to 0.09; p = 0.69; cumulative dose: slope -0.12; -0.28 to 0.05; p = 0.15). CONCLUSION: In the Rh-GIOP cohort, MTX is used in about a quarter of patients with PMR or vasculitis. It is not associated with BMD levels.

Effectiveness and Safety of JAK Inhibitors in Autoinflammatory Diseases: A Systematic Review.

Introduction: Autoinflammatory diseases (AID) are rare diseases presenting with episodes of sterile inflammation. These involve multiple organs and can cause both acute organ damage and serious long-term effects, like amyloidosis. Disease-specific anti-inflammatory therapeutic strategies are established for some AID. However, their clinical course frequently includes relapsing, uncontrolled conditions. Therefore, new therapeutic approaches are needed. Janus Kinase inhibitors (JAKi) block key cytokines of AID pathogenesis and can be a potential option. Methods: A systematic review of the literature in accordance with the PRISMA guidelines was conducted. Three databases (MEDLINE, Embase and Cochrane Central Register of Controlled Trials) were searched for publications regarding the use of JAKi for AID. Data from the included publications was extracted and a narrative synthesis was performed. Criteria for defining treatment response were defined and applied. Results: We report data from 38 publications with a total of 101 patients describing the effects of JAKi in AID. Data on Type I Interferonopathies, Adult-Onset Still's Disease (AOSD), Systemic Juvenile Idiopathic Arthritis (sJIA), Familial Mediterranean Fever (FMF), and Behçet's Syndrome (BS) was identified. From a total of 52 patients with type I interferonopathies, in seven patients (7/52, 13.5%) a complete response was achieved, most (35/52, 67.3%) showed a partial response and a minority (10/52, 19.2%) showed no treatment response. For AOSD, a complete or a partial response was achieved by eleven (11/26, 42.3%) patients each. Two sJIA patients achieved complete response (2/4, 50%) and in two cases (2/4, 50%) a partial response was reported. Half of FMF patients showed a complete response and the other half had a partial one (3/6, 50.0%). Amongst BS patients most achieved a partial response (8/13, 61.5%). Five patients showed no response to therapy (5/13, 38.5%). Overall, the most frequent AEs were upper respiratory tract infections (17), pneumonia (10), BK virus viremia (10) and viruria (4), herpes zoster infection (5), viral gastroenteritis (2) and other infections (4). Conclusion: The results from this systematic review show that JAKi can be beneficial in certain AID. The risk of AEs, especially viral infections, should be considered. To accurately assess the risk benefit ratio of JAKi for AID, clinical trials should be conducted.