MTHFR c.665C>T and c.1298A>C Polymorphisms in Tailoring Personalized Anti-TNF-α Therapy for Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease with a prevalence of 1%. Currently, RA treatment aims to achieve low disease activity or remission. Failure to achieve this goal causes disease progression with a poor prognosis. When treatment with first-line drugs fails, treatment with tumor necrosis factor-α (TNF-α) inhibitors may be prescribed to which many patients do not respond adequately, making the identification of response markers urgent. This study investigated the association of two RA-related genetic polymorphisms, c.665C>T (historically referred to as C677T) and c.1298A>C, in the MTHFR gene as response markers to an anti-TNF-α therapy. A total of 81 patients were enrolled, 60% of whom responded to the therapy. Analyses showed that both polymorphisms were associated with a response to therapy in an allele dose-dependent manner. The association for c.665C>T was significant for a rare genotype (p = 0.01). However, the observed opposite trend of association for c.1298A>C was not significant. An analysis revealed that c.1298A>C, unlike c.665C>T, was also significantly associated with the drug type (p = 0.032). Our preliminary results showed that the genetic polymorphisms in the MTHFR gene were associated with a response to anti-TNF-α therapy, with a potential significance for the anti-TNF-α drug type. This evidence suggests a role for one-carbon metabolism in anti-TNF-α drug efficacy and contributes to further personalized RA interventions.

Seropositivity-Dependent Association between LINE-1 Methylation and Response to Methotrexate Therapy in Early Rheumatoid Arthritis Patients.

BACKGROUND: Methotrexate (MTX) is considered the first choice among disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA) treatment. However, response to it varies as approximately 40% of the patients do not respond and would lose the most effective period of treatment time. Therefore, having a predictive biomarker before starting MTX treatment is of utmost importance. Methylation of long interspersed nucleotide element-1 (LINE-1) is generally considered a surrogate marker for global genomic methylation, which has been reported to associate with disease activity after MTX therapy. METHODS: We performed a prospective study on 273 naïve early RA (ERA) patients who were treated with MTX, followed up to 12 months, and classified according to their therapy response. The baseline LINE-1 methylation levels in peripheral blood mononuclear cells (PBMC) of cases were assessed by bisulfite pyrosequencing. RESULTS: Baseline LINE-1 methylation level per se turned out not to predict the response to the therapy, nor did age, sex, body mass index, or smoking status. However, if cases were stratified according to positivity to rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) or seronegativity, we observed an opposite association between baseline LINE-1 methylation levels and optimal response to MTX therapy among responders. The best response to MTX therapy was associated with hypermethylated LINE-1 among double-positive ERA cases (p-value: 0.002) and with hypomethylated LINE-1 in seronegative ERA patients (p-value: 0.01). CONCLUSION: The LINE-1 methylation level in PBMCs of naïve ERA cases associates with the degree of response to MTX therapy in an opposite way depending on the presence of RF and ACPA antibodies. Our results suggest LINE-1 methylation level as a new epigenetic biomarker for predicting the degree of response to MTX in both double-positive and seronegative ERA patients.

Preliminary study on immune cells in the synovium of end-stage osteoarthritis and rheumatoid arthritis patients: neutrophils and IgG4-secreting plasma cells as differential diagnosis candidates.

OBJECTIVE: Immune cell evaluation could be useful for clarifying etiopathogenesis, providing a support for formulating the diagnoses of clinically similar joint pathologies or guiding indications for possible therapeutic targets. To contribute to differential diagnosis in joint pathologies we performed an immunophenotypical profile analyzing different immune cells in synovial tissues from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: The Krenn and immunologic synovitis (IMSYC) scores, which include the evaluation of T lymphocytes (CD3 positive), B lymphocytes (CD20), endothelial cells (CD31), macrophages (CD68) and proliferating cells (Ki-67 positive) were used to analyze the synovial tissue samples. Moreover, to corroborate immune activation, neutrophils (CD15 positive), NK cells (CD56 positive), plasma cells (CD138 positive), IgG4 and IgG4 secreting-CD138 cells were analyzed using immunohistochemical techniques. RESULTS: We confirmed that all the samples had a high synovitis score according to both the Krenn and IMSYC scores. In both the RA and OA groups, we found similar scores for CD3 (T lymphocytes), CD20 (B lymphocytes), CD31 (endothelial cells), CD56 (NK cells), CD68 (macrophages) CD138 (plasma cells) and IgG4. In contrast, CD15 (neutrophils) was significantly higher in RA compared to OA. Interestingly, IgG4 secreting-CD138 cells were significantly higher in RA than OA, even if CD138 had the same score in both the RA and OA samples. CONCLUSIONS: This study found that the scores for different immune cells were similar in both RA and OA synovial tissue with a high synovitis score. CD15 and IgG4 secreting-CD138 were the only immune cells with a higher score in RA compared to OA, suggesting a potential use for discriminating among pathologies with a high synovitis score.

Mesenchymal stromal cells from a progressive pseudorheumatoid dysplasia patient show altered osteogenic differentiation.

BACKGROUND: Progressive pseudorheumatoid dysplasia (PPRD) is a rare autosomal recessive non-inflammatory skeletal disease with childhood onset and is characterized by a progressive chondropathy in multiple joints, and skeletal abnormalities. To date, the etiopathological relationship between biological modification occurring in PPRD and genetic mutation remains an open issue, partially due to the limited availability of biological samples obtained from PPRD patients for experimental studies. CASE PRESENTATION: We describe the clinical features of a PPRD patient and experimental results obtained from the biological characterization of PPRD mesenchymal stromal cells (MSCs) and osteoblasts (OBs) compared to normal cell populations. Phenotypic profile modifications were found in PPRD compared to normal subjects, essentially ascribed to decreased expression of CD146, osteocalcin (OC) and bone sialoprotein in PPRD MSCs and enhanced CD146, OC and collagen type I expression in PPRD OBs. Gene expression of Dickkopf-1, a master inhibitor of WNT signaling, was remarkably increased in PPRD MSCs compared to normal expression range, whereas PPRD OBs essentially exhibited higher OC gene expression levels. PPRD MSCs failed to efficiently differentiate into mature OBs, so showing a greatly impaired osteogenic potential. CONCLUSIONS: Since all regenerative processes require stem cell reservoirs, compromised functionality of MSCs may lead to an imbalance in bone homeostasis, suggesting a potential role of MSCs in the pathological mechanisms of PPRD caused by WNT1-inducible signaling pathway protein-3 (WISP3) mutations. In consideration of the lack of compounds with proven efficacy in such a rare disease, these data might contribute to better identify new specific and effective therapeutic approaches.

Prevalence of Type 2 and Type 1 Diabetes in Psoriatic Arthritis: An Italian Study.

OBJECTIVE: Psoriatic arthritis (PsA) is burdened by an increased susceptibility to cardiovascular diseases. Comorbid diabetes may represent one of the key factors contributing to this risk. The aim of our medical records review study was to investigate the prevalence of type 2 diabetes (T2D) and type 1 diabetes (T1D) in an Italian PsA cohort. METHODS: The clinical records of all patients consecutively seen at our clinic with a diagnosis of PsA during a 12-month period were reviewed to identify comorbid T2D or T1D. For comparison, a 1:1 age- and sex-matched group of individuals with noninflammatory diseases was recruited. RESULTS: The final study cohort comprised 408 patients. The prevalence of T2D was 7.8% (95% confidence interval, 5.6-10.8) in PsA and 4.4% in controls (95% confidence interval, 2.8-6.9; p = 0.04). Two cases (0.49%) of T1D were identified in the PsA cohort, whereas no cases were observed in controls. In a multivariate logistic regression model including age, disease duration, and body mass index (BMI) as covariates, increasing age (odds ratio [OR], 1.079; p = 0.006) and BMI (OR, 1.188; p = 0.011) but not PsA duration predicted being classified as having T2D. In a similar model accounting for age and BMI, average disease activity score including 28 joints and C-reactive protein showed a trend toward significance (OR, 1.639; p = 0.066). CONCLUSIONS: In conclusion, our data provide further support to the emerging evidence of an increased risk of T2D in PsA patients. Cardiometabolic comorbidity represents a significant aspect of integrated arthritis management to improve long-term cardiovascular outcomes and to provide a comprehensive treatment.

Osteitis condensans ilii: prevalence and characteristics of a neglected mimic of sacroiliitis.

OBJECTIVES: Osteitis condensans ilii (OCI) is a benign condition characterised by triangular sclerosis of the iliac bone which may mimic radiographic sacroiliitis. Prevalence is estimated between 0.9 and 2.5%, with female predominance, but the most recent article reporting original epidemiological data in the general population was published in 1971. The aim of our study is to contribute updated figures about prevalence of OCI in Italy. METHOD: A retrospective review of pelvic radiographs was conducted. Consecutive patients visiting the emergency department of our Institution between 1st January and 31st December 2020 were enrolled. Individuals with a past diagnosis of axial spondyloarthritis were excluded. Presence of OCI was evaluated by two musculoskeletal radiologists. Clinical and radiologic features such as osteoarthritis and insertional enthesopathy were also assessed. RESULTS: We included 1047 individuals (61% female) with a median age of 74 years. OCI was present in 10 cases, accounting for a prevalence in the general population of 1.0% (95% CI 0.5-1.7). All patients with OCI were women and, in the female sample, prevalence was 1.6% (95% CI 0.7-2.8). Clinical characteristics and associated radiographic features were not different between patients with OCI and women without OCI. CONCLUSIONS: The prevalence of OCI observed in our study is consistent with previous literature, and we confirm that it is more frequently retrieved in women. Longitudinal research is warranted to elucidate the evolution, while knowledge about the disorder is needed to raise the awareness of rheumatologists and radiologists and to properly identify and report the condition. Key Points • OCI may mimic sacroiliitis and is a major differential diagnosis of radiographic axial spondyloarthritis. • Prevalence of OCI in our sample is 1.0%, in line with previous literature. • OCI predominantly affects women, and our study suggests that the disorder can be incidentally identified even after childbearing age. • Increased awareness of the characteristics of OCI can facilitate identification and reporting of the disorder.

The Effect of Ketogenic Diet on Inflammatory Arthritis and Cardiovascular Health in Rheumatic Conditions: A Mini Review.

The principle of ketogenic diet (KD) is restriction of carbohydrates to a maximum of 5-10% of the total daily caloric intake, aiming at shifting body metabolism toward ketone bodies. Different studies suggested promising results of KD to help patients to lose weight, to reduce insulin requirements in diabetes, to supplement cancer protocols, to treat neurological conditions and to optimize control of metabolic and cardiovascular diseases. However, literature about the anti-inflammatory properties of KD in rheumatic diseases is still limited. The beneficial effects of weight loss in patients with inflammatory arthritis can be explained by biomechanical and biochemical factors. Obesity is associated with macrophage activation and production of pro-inflammatory cytokines including TNF-α, IL-1b, and IL-6. The clinical effect of KD may be primarily attributed to improvement of insulin sensitivity. Insulin resistance is associated with an increase of TNF-α, IL-1α, IL-1ß, IL-6, and leptin. Moreover, reduction of body's adipose tissue and weight loss account for part of the anti-inflammatory effects and for the impact of KD on cardiovascular health. In rheumatoid arthritis, fasting was shown to be effective in reducing disease symptoms, possibly through the production of ß-hydroxybutyrate (BHB), the main ketone body. BHB may exert inhibitory effects also on IL-17 and intermittent fasting improved the clinical manifestations of psoriatic arthritis. In ankylosing spondylitis, current literature doesn't allow to draw conclusion about the effects of KD. Future prospective studies will be needed to elucidate the potential beneficial effects of KD on specific domains and clinical outcomes in patients with inflammatory arthritis.

Impaired immunogenicity to COVID-19 vaccines in autoimmune systemic diseases. High prevalence of non-response in different patients' subgroups.

Autoimmune systemic diseases (ASD) may show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed to evaluate the seroconversion after the vaccination cycle and at 6-12-month follow-up, as well the safety and efficacy of vaccines in preventing COVID-19. The study included 478 unselected ASD patients (mean age 59 ± 15 years), namely 101 rheumatoid arthritis (RA), 38 systemic lupus erythematosus (SLE), 265 systemic sclerosis (SSc), 61 cryoglobulinemic vasculitis (CV), and a miscellanea of 13 systemic vasculitis. The control group included 502 individuals from the general population (mean age 59 ± 14SD years). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was evaluated by measuring serum IgG-neutralizing antibody (NAb) (SARS-CoV-2 IgG II Quant antibody test kit; Abbott Laboratories, Chicago, IL) on samples obtained within 3 weeks after vaccination cycle. The short-term results of our prospective study revealed significantly lower NAb levels in ASD series compared to controls [286 (53-1203) vs 825 (451-1542) BAU/mL, p < 0.0001], as well as between single ASD subgroups and controls. More interestingly, higher percentage of non-responders to vaccine was recorded in ASD patients compared to controls [13.2% (63/478), vs 2.8% (14/502); p < 0.0001]. Increased prevalence of non-response to vaccine was also observed in different ASD subgroups, in patients with ASD-related interstitial lung disease (p = 0.009), and in those treated with glucocorticoids (p = 0.002), mycophenolate-mofetil (p < 0.0001), or rituximab (p < 0.0001). Comparable percentages of vaccine-related adverse effects were recorded among responder and non-responder ASD patients. Patients with weak/absent seroconversion, believed to be immune to SARS-CoV-2 infection, are at high risk to develop COVID-19. Early determination of serum NAb after vaccination cycle may allow to identify three main groups of ASD patients: responders, subjects with suboptimal response, non-responders. Patients with suboptimal response should be prioritized for a booster-dose of vaccine, while a different type of vaccine could be administered to non-responder individuals.

Hyperuricemia in Psoriatic Arthritis: Epidemiology, Pathophysiology, and Clinical Implications.

Psoriatic arthritis (PsA) represents the articular component of the systemic psoriatic disease and the extra-cutaneous disorder most frequently found in patients with psoriasis. Besides the articular involvement, PsA is associated with several metabolic abnormalities such as insulin resistance, hypertension, diabetes and hyperuricemia. Uric acid is the final product of purine metabolism and the etiological substrate of gout. Accumulating evidence highlights the emerging role of hyperuricemia as a major cardiovascular risk factor. Moreover, different studies evaluated the interplay between hyperuricemia and psoriatic disease, suggesting that individuals affected by psoriasis or PsA might present higher serum levels of uric acid and that hyperuricemia might affect severity of clinical manifestations and degree of inflammation in PsA patients. In this review, we focus on the bidirectional relationship between uric acid and PsA, analyzing how uric acid may be involved in the pathogenesis of psoriasis/PsA and how clinical manifestations of PsA and inflammatory mediators are affected by uric acid concentrations. Finally, the effects of anti-rheumatic drugs on uric acid levels and the potential benefit of urate-lowering therapies on psoriasis and PsA were summarized.

Fibromyalgia: a new facet of the post-COVID-19 syndrome spectrum? Results from a web-based survey.

OBJECTIVE: Postacute COVID-19 syndrome (PACS) is an emerging entity characterised by a large array of manifestations, including musculoskeletal complaints, fatigue and cognitive or sleep disturbances. Since similar symptoms are present also in patients with fibromyalgia (FM), we decided to perform a web-based cross-sectional survey aimed at investigating the prevalence and predictors of FM in patients who recovered from COVID-19. METHODS: Data were anonymously collected between 5 and 18 April 2021. The collection form consisted of 28 questions gathering demographic information, features and duration of acute COVID-19, comorbid diseases, and other individual's attributes such as height and weight. The American College of Rheumatology (ACR) Survey Criteria and the Italian version of the Fibromyalgia Impact Questionnaire completed the survey. RESULTS: A final sample of 616 individuals (77.4% women) filled the form 6±3 months after the COVID-19 diagnosis. Of these, 189 (30.7%) satisfied the ACR survey criteria for FM (56.6% women). A multivariate logistic regression model including demographic and clinical factors showed that male gender (OR: 9.95, 95% CI 6.02 to 16.43, p<0.0001) and obesity (OR: 41.20, 95% CI 18.00 to 98.88, p<0.0001) were the strongest predictors of being classified as having post-COVID-19 FM. Hospital admission rate was significantly higher in men (15.8% vs 9.2%, p=0.001) and obese (19.2 vs 10.8%, p=0.016) respondents. CONCLUSION: Our data suggest that clinical features of FM are common in patients who recovered from COVID-19 and that obesity and male gender affect the risk of developing post-COVID-19 FM.

Higher 90-Day Mortality after Surgery for Hip Fractures in Patients with COVID-19: A Case-Control Study from a Single Center in Italy.

The mortality of hip fracture (HF) patients is increased by concomitant COVID-19; however, evidence is limited to only short follow-up. A retrospective matched case-control study was designed with the aim to report the 90-day mortality and determine the hazard ratio (HR) of concomitant HF and COVID-19 infection. Cases were patients hospitalized for HF and diagnosed with COVID-19. Controls were patients hospitalized for HF not meeting the criteria for COVID-19 diagnosis and were individually matched with each case through a case-control (1:3) matching algorithm. A total of 89 HF patients were treated during the study period, and 14 of them were diagnosed as COVID-19 positive (overall 15.7%). Patients' demographic, clinical, and surgical characteristics were similar between case and control groups. At 90 days after surgery, 5 deaths were registered among the 14 COVID-19 cases (35.7%) and 4 among the 42 HF controls (9.5%). COVID-19-positive cases had a higher risk of mortality at 30 days (HR = 4.51; p = 0.0490) and 90 days (HR = 4.50; p = 0.025) with respect to controls. Patients with concomitant HF and COVID-19 exhibit high perioperative mortality, which reaches a plateau of nearly 30-35% after 30 to 45 days and is stable up to 90 days. The mortality risk is more than four-fold higher in patients with COVID-19.

Fibromyalgia syndrome - a risk factor for poor outcomes following orthopaedic surgery: A systematic review.

BACKGROUND: Fibromyalgia (FM) is a complex syndrome incorporating many features associated with poor outcome in orthopaedic surgery. Aim of the present review was to comprehensively characterize the available evidence on the consequences of pre-existent FM on the outcomes of orthopaedic surgery. METHODS: We performed a systematic search in MedLine and Web of Science (WOS) to identify studies evaluating the effect of FM on patient-centred outcomes, opioids consumption and postoperative complications. RESULTS: The search strategy identified 519 records in PubMed and 507 in WOS. A total of 27 articles were deemed eligible for inclusion in qualitative synthesis. Based on quality assessment, 10 studies were rated as good quality, 10 as fair quality and 7 as poor quality. Studies reporting the prevalence of FM in consecutive patients undergoing orthopaedic surgery (n = 19) were included in quantitative synthesis. The pooled prevalence of FM in patients undergoing orthopaedic surgery was 4.1% (95% CI: 2.4-6.8) in those receiving hip or knee surgery, 10.1% (95% CI: 5.7-17.2) in those receiving shoulder or elbow surgery and 21.0% (95% CI: 18.5-23.7) in those receiving spinal surgery. The results of our systematic review consistently report FM as a significant risk factor for less satisfaction, higher pain, worse functional outcome, increased risk for postoperative opioids prescription and higher rate of medical and surgical complications following orthopaedic surgery. CONCLUSION: Identifying pre-existing FM in patients scheduled for elective orthopaedic surgery may help to better assess the benefit/risk ratio, improve patients' awareness and minimize any discrepancy between expectancy and results.

Insulin Signaling in Arthritis.

Inflammatory arthritis is burdened by an increased risk of metabolic disorders. Cytokines and other mediators in inflammatory diseases lead to insulin resistance, diabetes and hyperlipidemia. Accumulating evidence in the field of immunometabolism suggests that the cause-effect relationship between arthritis and metabolic abnormalities might be bidirectional. Indeed, the immune response can be modulated by various factors such as environmental agents, bacterial products and hormones. Insulin is produced by pancreatic cells and regulates glucose, fat metabolism and cell growth. The action of insulin is mediated through the insulin receptor (IR), localized on the cellular membrane of hepatocytes, myocytes and adipocytes but also on the surface of T cells, macrophages, and dendritic cells. In murine models, the absence of IR in T-cells coincided with reduced cytokine production, proliferation, and migration. In macrophages, defective insulin signaling resulted in enhanced glycolysis affecting the responses to pathogens. In this review, we focalize on the bidirectional cause-effect relationship between impaired insulin signaling and arthritis analyzing how insulin signaling may be involved in the aberrant immune response implicated in arthritis and how inflammatory mediators affect insulin signaling. Finally, the effect of glucose-lowering agents on arthritis was summarized.