The potential pathogenic role of gut microbiota in rheumatic diseases: a human-centred narrative review.

A growing amount of evidence suggests that gut microbiota plays an important role in human health, including a possible role in the pathogenesis of rheumatic and musculoskeletal diseases (RMD). We analysed the current evidence about the role of microbiota in rheumatoid arthritis (RA), spondyloarthritis (SpA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). In RA, we found a general consensus regarding a reduction of diversity and a specific bacterial signature, with consistent changes according to the different ethnic and geographical areas. The major pathogenetic role in RA is recognised for P. copri, L. salivarius and Collinsella, even if findings become more heterogeneous when considering established disease. In SpA, we found a relative gut abundance of Akkermansia, Coprococcus, Ruminoccocus and a relative reduction in Bacterioides and Firmicutes spp. Human and preclinical data suggest loss of mucosal barrier, increased permeability and Th1- and Th17-mediated inflammation. Additionally, HLA-B27 seems to play a role in shaping the intestinal microbiota and the consequent inflammation. In SLE, the typical gut microbiota signature was characterised by a reduction in the Firmicutes/Bacteroidetes ratio and by enrichment of Rhodococcus, Eggerthella, Klebsiella, Prevotella, Eubacterium and Flavonifractor, even if their real pathogenic impact remains unclear. In SSc, gastrointestinal dysbiosis is well documented with an increase of pro-inflammatory species (Fusobacterium, Prevotella, Ruminococcus, Akkermansia, γ-Proteobacteria, Erwinia, Trabsulsiella, Bifidobacterium, Lactobacillus, Firmicutes and Actinobacteria) and a reduction of species as Faecalibacterium, Clostridium, Bacteroidetes and Rikenella. In conclusion, seems possible to recognise a distinct gut microbiota profile for each RMD, even if significant differences in bacterial species do exist between different studies and there is a high risk of bias due to the cross-sectional nature of such studies. Therefore longitudinal studies are needed, especially on patients with preclinical and early disease, to investigate the real role of gut microbiota in the pathogenesis of RMD.

Long-term effectiveness and predictors of bisphosphonate treatment in type I complex regional pain syndrome.

OBJECTIVES: Complex regional pain syndrome (CRPS) is a painful disease that leads to chronic pain and disability. Bisphosphonates are largely used in the real-life for the treatment of CRPS, but data on long-term effectiveness and its predictors are lacking. METHODS: We conducted a longitudinal observational study on patients with type I CRPS treated with IV neridronate (100 mg on 4 occasions). Clinical and demographic characteristics were collected at baseline, after 3 months (M3) and after 12 months (M12). Multivariable logistic regression was employed to determine the factors associated with long-term response to treatment. RESULTS: 103 patients with type I CRPS treated with IV neridronate were included in the study. Mean VAS pain at baseline was 79.1 mm and decreased significantly at M3 (-45.9 mm, 95% CI 40.1 to 51.8) and M12 (-61.6 mm, 95% CI 55.3 to 67.9). Hyperalgesia and allodynia resolved in 84.3% and 88.1% of patients at M12. Loss of motion resolved in 53.5% of patients. The predictors of excellent response were gender (male better), predisposing event to CRPS (no event being better than any predisposing event), site of CRPS (lower limb being better), and early response at M3 on VAS pain (2.5 times the chance of being excellent responder every 10 mm decrease). CONCLUSIONS: In this real-life study neridronate was associated with rapid and progressive improvement of symptoms of CRPS which was maintained up to 3 years of follow-up. The predictors of excellent response were early response, lower limb localisation, absence of predisposing events and male gender.

Ultrasonographic non-radiographic erosions could predict the efficacy of belimumab in articular systemic lupus erythematosus.

The aim of this study is to characterise lupus-related arthritis and assess if the presence of ultrasound-detected erosions could be associated with belimumab in the treatment of systemic lupus erythematosus (SLE) articular manifestations. We performed a spontaneous, monocentric, retrospective, and observational study. We enrolled patients affected by SLE with articular involvement treated with belimumab. We excluded patients with positive rheumatoid factor (RF) or anti-citrullinated peptide antibody (ACPA), Jaccoud's arthropathy, and radiographic erosions. Patients were assessed at baseline, 3, and 6 months. We collected laboratory and clinical data from electronic records. Joint disease activity was assessed using disease activity score on 28 joints based on C-reactive protein (DAS28-CRP), swollen and tender joints count. All patients underwent an ultrasound examination of the wrist, metacarpophalangeal, proximal interphalangeal, and metatarsal-phalangeal joints before the initiation of treatment with belimumab. We performed Student's T-test and Mann-Whitney's U-test to assess the difference between means and Fisher's exact test to assess difference in proportions, and linear univariate regression to investigate predictors of disease activity. We enrolled 23 patients (female 82.6%, mean age of 50.65 ± 14.1 years). Seven patients (30.4%) presented bone erosions at baseline. Patients with bone erosions were generally older (61 ± 16.1 vs 46.13 ± 10.7 years, p = 0.016), more frequently male (42.8 vs 6.2%, p = 0.03), with higher baseline CRP levels (10.29 ± 11.6 vs 2.25 ± 3.1 mg/L, p = 0.015) and C4 levels (0.19 ± 0.17 vs 0.1 ± 0.04 g/L, p = 0.05). After 6 months of treatment with belimumab, patients without erosions improved their DAS28-CRP significantly (2.95 ± 0.89 vs 2.26 ± 0.48, p = 0.01), while patients with erosions did not (3.6 ± 0.79 vs 3.2 ± 0.95, p = 0.413). DAS28-CRP did not differ between the two groups at baseline, while it was significantly lower at the other two time points in patients without erosions. The majority of patients achieved remission at 6 months follow-up based on DAS28-CRP criteria (73.9%), with a significant difference between patients with and without erosions (42.8 vs 87.5%, p = 0.045). The presence of articular ultrasound-detected erosions could be predictive of a decreased efficacy of belimumab in the articular manifestations of SLE. A possible explanation is a rheumatoid-like articular phenotype, despite the lack of ACPA-positivity and radiologic erosions. However, due to the small sample population, larger cohorts are needed to assess the possible predictive role of this finding.

Bone Loss in Inflammatory Rheumatic Musculoskeletal Disease Patients Treated With Low-Dose Glucocorticoids and Prevention by Anti-Osteoporosis Medications.

OBJECTIVE: The negative effects of glucocorticoids on bone depend on dose and treatment duration. However, it is unclear whether a safe dose exists, especially for patients with inflammatory rheumatic musculoskeletal diseases (iRMDs). We undertook this study to determine the effects of glucocorticoid doses on bone health in iRMD patients. METHODS: We conducted a longitudinal cohort study on women with iRMD. Bone mineral density (BMD) and fractures were assessed prospectively and compared to a matched cohort without iRMD. Kaplan-Meier curves with log rank test were made for iRMD patients (stratified for glucocorticoid use and dose) and the matched cohort. Multivariable Cox regression survival models were also employed to analyze the effect of glucocorticoids on fracture. RESULTS: A total of 884 women with iRMD and 1,766 controls (matched for age, T score, and 10-year fracture risk) were included in the study and followed up for up to 6 years. BMD decreased significantly in all patients receiving glucocorticoids who were not receiving anti-osteoporosis treatment (-4.26% for ≥5 mg/day of prednisone equivalent, P = 0.0011; -4.23% for 2.5-5 mg/day, P = 0.0422; -2.66% for 0-2.5 mg/day, P = 0.0006). Anti-osteoporosis treatment (largely bisphosphonates) prevented bone loss only in patients receiving <5 mg/day of prednisone equivalent. Fracture incidence was higher in patients with iRMD compared to controls, but only glucocorticoid doses ≥5 mg/day were associated with significantly higher risk of fracture. CONCLUSION: Glucocorticoid doses as low as 2.5 mg/day were associated with BMD loss in iRMD patients, but this effect was preventable. BMD loss in patients receiving ≥5 mg/day was not totally prevented by anti-osteoporosis medications currently used in clinical practice, resulting in higher risk of fracture.

Tapering glucocorticoids and risk of flare in rheumatoid arthritis on biological disease-modifying antirheumatic drugs (bDMARDs).

INTRODUCTION: Glucocorticoids are still a mainstream of rheumatoid arthritis (RA) treatment. Reducing glucocorticoids should be attempted in all patients. However, choosing the right tapering strategy is challenging. The primary aim of our study is to determine the dose-response association between glucocorticoid tapering and risk of flare in RA. METHODS: We conducted a case-crossover study to determine the factors associated to higher risk of flare in patients with RA. In case-crossover studies time-varying factors are assessed before events (hazard periods) and before control periods. We defined hazard periods as the 6 months immediately preceding flares of RA. Control periods were the 6 months prior to visits without flare. Exposure of interest was the tapering of glucocorticoids to various doses. RESULTS: 508 patients with RA were included in the study and 267 (52.5%) had at least a flare and served as the case-crossover study population. 1545 visits were available for analysis and 345 (22.3%) flares were recorded. Discontinuation of glucocorticoids (ie, tapering to doses of 0 mg/day) and tapering to 0-2.5 mg/day was associated with higher risk of flare (adjusted OR (aOR) of 1.45, 95% CI: 1.13 to 2.24 and aOR of 1.37; 95% CI: 1.06 to 2.01, respectively). Tapering to doses >2.5 mg/day was not associated with significantly higher risk of flare. CONCLUSIONS: We found that tapering to doses of >2.5 mg/day was generally effective in terms of risk of flare. Flare risk was higher when glucocorticoids were tapered to doses ≤2.5 mg/day. Our study might help design new tapering strategies in patients with RA on biological disease-modifying antirheumatic drugs.

Effects on Serum Inflammatory Cytokines of Cholecalciferol Supplementation in Healthy Subjects with Vitamin D Deficiency.

The effects of different cholecalciferol supplementation regimens on serum inflammatory cytokines in healthy subjects with vitamin D deficiency are still lacking. This is a single-center, open-label, randomized, parallel group study involving healthy subjects deficient in vitamin D (baseline 25OHD < 20 ng/mL) receiving oral cholecalciferol with three different dosing regimens: Group A: 10,000 IU/day for 8 weeks followed by 1000 IU/day for 4 weeks; Group B: 50,000 IU/week for 12 weeks and Group C: 100,000 IU every other week for 12 weeks. IL-17A, IL-6, IL-8, IL-10, IL-23 and TNFα were measured at baseline and at week 4, 8, 12, and 16. 75 healthy subjects were enrolled (58.7% female), with an average age of 34.1 ± 10.2 years. No statistical differences were observed among groups at baseline for either IL-6, IL-17A, IL-23, IL-8 or IL-10 at any time point; TNFα was indetectable. Concerning the whole sample, the time trend analysis showed a statistically significant linear trend for decreasing values over the treatment period for IL-6 (p = 0.016) and IL-17A (p = 0.006), while no significant time trends were observed for the other teste cytokines. No significant differences were found in the serum concentrations of the tested cytokines between week 12 and week 16. In young healthy individuals deficient in vitamin D, cholecalciferol administration showed a decrease in the serum IL-6 and IL-17A concentrations, without marked differences using the three regimens.

Higher body mass index is associated with a lower iloprost infusion rate tolerance and higher iloprost-related adverse events in patients with systemic sclerosis.

Background: Systemic sclerosis (SSc) is an autoimmune disease characterized by vasospasm and microvascular involvement. Iloprost (ILO), a prostaglandin analogous, is used for the treatment of SSc-related Raynaud's phenomenon and digital ulcers. The suggested dose is 0.5-2 ng/kg/min for 6-8 h, and the maximum dose is decided upon the patient's tolerance. Objectives: This study aims to analyze ILO infusion tolerance and possible predictive factors in patients with SSc. Design: This is a retrospective observational study. Method: We evaluated 113 patients with SSc beginning ILO intravenous (IV) infusion treatment between 2004 and 2021. We assessed the maximum tolerated ILO IV infusion rate, the incidence of adverse events (AEs), and the need for symptomatic therapy during the dose-finding sessions. We collected relevant demographic and medical and employed generalized linear models to assess possible predictors of maximum tolerated ILO infusion rate and AEs and logistic regression to assess predictors of AEs. Results: The median ILO infusion rate at the end of the dose-finding process was 0.88 ng/kg/min [interquartile range (IQR) = 0.37]. We found a significant inverse correlation between ILO infusion rate and body mass index (BMI) at the beginning of treatment. BMI was negatively associated with ILO infusion rate (ß = -0.21, p = 0.02) after correction for relevant confounding factors. Overweight patients (BMI >26) presented a 13-fold increased risk of developing AEs during ILO titration [adjusted odds ratio = 13.979, 95% confidence interval (CI) = 2.359-82.845]. AEs during ILO titration occurred in 47.8% of patients, of whom 22.2% presented hypotension. Other AEs were headache, nausea, vomiting, diarrhea, and edema. Symptomatic therapy was needed in half of the patients at least once. Conclusion: This study showed that higher BMI was statistically associated with lower ILO infusion rate tolerance and higher AEs rate, underlying a possible BMI-dependent endothelial dysfunction. Individual ILO regimens still need to be tailored to the patient. Plain Language Summary: Introduction: Systemic sclerosis is a rare a rheumatic disease characterized by skin thickening, vasospasm, and digital ulcers (DUs), as well as other organs involvement. Iloprost, which is administered as intravenous infusion, is one of the main treatments for this disease, and it is effective in reducing vasospasm and the frequency of DUs. Even if there is a suggested dose range, the exact dose must be tailored on each patient, because the tolerance to the drug is variable. Tolerance is limited by dose-dependent unwanted effects, as headache, low blood pressure, dizziness, and sickness. This study aimed to identify possible predictors of such tolerance.Materials and Methods: We collected data from our patients with systemic sclerosis beginning the treatment with iloprost between January 2004 and November 2021 at our hospital facility in Verona, Italy, and analyzed different factors that could be associated with a better tolerance, as age, sex, disease duration, smoking habit, body mass index (a measure of body fatness), blood pressure, concomitant medications, and different patterns of the disease.Results: We found that a higher body mass index was associated with lower iloprost tolerance and higher adverse events rate in patients with systemic sclerosis, while we did not find a correlation with other factors. We believe overweight and obese patients (who have a higher body mass index) have a defect in the vasodilatation mechanism and can therefore be more susceptible to the effect of this medication.Conclusions: While preliminary, our results could provide a good starting point to develop a predictive tool to limit adverse events during this therapy.

Comparable long-term retention rates and effects on bone mineral density of denosumab treatment in patients with osteoporosis with or without autoimmune inflammatory rheumatic diseases: real-life data.

Objectives: To investigate whether concomitant autoimmune inflammatory rheumatic diseases (AIIRDs) represent a risk factor for denosumab discontinuation and to explore other possible predictors. Design: This is a real-life retrospective study conducted at our centre on consecutive patients who started treatment with denosumab from January 2014 to October 2021. Methods: Data on patients' characteristics, denosumab prescriptions and reason for discontinuation were collected from their medical electronic records. A log-rank test was run to assess differences in the denosumab retention rate between the not AIIRD and AIIRD patients. A backward stepwise logistic regression was used to identify possible predictors of denosumab discontinuation. When available, BMD data of the lumbar spine and total hip were collected. Results: Three hundred and sixty-three patients were included (265 not AIIRD and 98 AIIRD; median follow-up, 44 months). Sixty-nine patients discontinued denosumab at any time point (4 due to patient's decision, 3 due to medical decision, 62 were lost in follow-up). The log-rank test did not find a statistically significant difference for denosumab persistence between the two subgroups. In the binary logistic regression analysis, only older age at initiation and lower baseline serum 25-hydroxy vitamin D were confirmed as predictors for discontinuation. BMD significantly increased from baseline to the last prescription visit at both the lumbar spine and the total hip, without statistically significant differences in the not AIIRD and AIIRD patients. Conclusion: The present data seem to suggest that AIIRDs do not represent a risk factor for denosumab discontinuation. Furthermore, the presence of AIIRDs does not seem to impair its effectiveness in terms of BMD.

Rheumatoid arthritis and myasthenia gravis: a case-based review of the therapeutic options.

INTRODUCTION: Myasthenia gravis is an autoimmune disease affecting the neuromuscular junction, often associated with other autoimmune diseases, including rheumatoid arthritis. Patients with rheumatoid arthritis present an increased prevalence of myasthenia gravis compared to the general population. While these two diseases share some therapeutic options, such as glucocorticoids, methotrexate, and rituximab, there are no guidelines for treating concomitant disease. We aim to review the available evidence and to discuss the efficacy and safety of the therapeutic options in patients with rheumatoid arthritis associated with myasthenia gravis. METHOD: We described three patients with rheumatoid arthritis associated with myasthenia gravis and we performed a systematic review of the associated literature. RESULTS: A 48-year-old man and two women (48 and 55 years old) with concomitant diagnoses of active rheumatoid arthritis and well-controlled myasthenia gravis are described. They were treated with methotrexate, leflunomide, upadacitinib, and adalimumab. None of them experienced changes in their myasthenic symptoms. We found 9 additional cases from our literature review. Methotrexate, rituximab, upadacitinib, diphenyl sulfone, auranofin, and loxoprofen sodium did not show an impact on the seven patients with previously well-controlled myasthenia. Glucocorticoids, methotrexate, and rituximab proved effective in active myasthenia gravis and arthritis. Conflicting data emerged for Tumor-necrosis factor inhibitors. CONCLUSIONS: Although the available evidence remains scarce, we consider glucocorticoids, methotrexate, and rituximab as safe and effective options. The role of tumor-necrosis factor inhibitors remains uncertain. Eventually, Janus Kinase inhibitors are a novel interesting option for these patients. Key Points • To date, the only evidence on the treatment of patients with rheumatoid arthritis and concomitant myasthenia gravis derives from case reports. • Based on the review of the available case reports and on the cases we described, we consider glucocorticoids, methotrexate, and rituximab as safe and effective options, while the role of Tumor-necrosis factor inhibitors remains uncertain. • Based on the cases we described, Janus Kinase inhibitors are a novel interesting option for patients with concomitant rheumatoid arthritis and myasthenia gravis.