PIM Kinases as Potential Biomarkers and Therapeutic Targets in Inflammatory Arthritides.

The Proviral Integration site for the Moloney murine leukemia virus (PIM)-1 kinase and its family members (PIM-2 and PIM-3) regulate several cellular functions including survival, proliferation, and apoptosis. Recent studies showed their involvement in the pathogenesis of rheumatoid arthritis RA, while no studies are available on psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). The main objective of this study is to assess the expression of PIM kinases in inflammatory arthritides, their correlation with proinflammatory cytokines, and their variation after treatment with biologic disease-modifying anti-rheumatic drugs or JAK inhibitors. We evaluated PIM-1, -2, and -3 expression at the gene and protein level, respectively, in the peripheral blood mononuclear cells and serum of patients with RA, PsA, axSpA, and healthy individuals (CTR). All the samples showed expression of PIM-1, -2, and -3 kinases both at the gene and protein level. PIM-1 was the most expressed protein, PIM-3 the least. PIM kinase levels differed between controls and disease groups, with reduced PIM-1 protein and increased PIM-3 protein in all disease samples compared to controls. No difference was found in the expression of these molecules between the three different pathologies. PIM levels were not modified after 6 months of therapy. In conclusion, our preliminary data suggest a deregulation of the PIM pathway in inflammatory arthritides. In-depth studies on the role of PIM kinases in this field are warranted.

Identification of Epigenetic Biomarkers of Adolescent Idiopathic Scoliosis Progression: A Workflow to Assess Local Gene Expression.

Adolescent idiopathic scoliosis (AIS) is a three-dimensional structural deformity of the spine that affects 2-3% of adolescents under the age of 16. AIS etiopathogenesis is not completely understood; however, the disease phenotype is correlated to multiple genetic loci and results from genetic-environmental interactions. One of the primary, still unresolved issues is the implementation of reliable diagnostic and prognostic markers. For clinical management improvement, predictors of curve progression are particularly needed. Recently, an epigenetic contribution to AIS development and progression was proposed; nevertheless, validation of data obtained in peripheral tissues and identification of the specific mechanisms and genes under epigenetic control remain limited. In this study, we propose a methodological approach for the identification of epigenetic markers of AIS progression through an original workflow based on the preliminary characterization of local expression of candidate genes in tissues directly involved in the pathology. The feasibility of the proposed methodological protocol has been originally tested here in terms of identification of the putative epigenetic markers of AIS progression, collection of the different tissues, retrieval of an appropriate amount and quality of RNA and DNA, and identification of suitable reference genes.

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.

Improvement of microangiopathy after haematopoietic stem cell transplantation in systemic sclerosis.

OBJECTIVES: Haematopoietic stem cell transplantation (HSCT) is a treatment option for patients with severe systemic sclerosis (SSc), but the efficacy of the procedure in remodelling the nailfold microvascular array is largely unknown. Therefore, this study aimed to evaluate the effect of HSCT on microangiopathy assessed through nailfold capillaroscopy (NC) and to compare the results with findings in patients receiving conventional immunosuppression. METHODS: We included SSc patients with severe SSc and whose pre- and post-treatment NC images were available. Findings in patients treated with HSCT were compared with patients not treated with HSCT. Images were scored by two independent observers blinded for clinical data and treatment history. Capillary pattern was determined and semiquantitative scores from 0 (no changes) to 3 (>66% alterations per millimetre) were used to quantify the degree of specific microvascular characteristics. Changes in severity of microangiopathy between baseline and post-treatment were compared between groups. RESULTS: Images of 18 HSCT patients and 21 controls were scored. From baseline to follow-up, 33% of HSCT patients showed improvement from scleroderma pattern to normal NC, compared to 6% of controls (p=0.15). Pre- to post-treatment differences in semiquantitative scores showed significant improvement in HSCT patients compared to controls regarding capillary loss (-0.5 vs. 0.0, p<0.05) and disorganisation (-0.8 vs. 0.0, p<0.05). CONCLUSIONS: The degree of microangiopathy improved significantly in severe SSc patients treated with HSCT compared with patients receiving conventional immunosuppressive therapy.

Prevalence and characteristics of diffuse idiopathic skeletal hyperostosis (DISH) in Italy.

PURPOSE: Diffuse idiopathic skeletal hyperostosis (DISH) is a benign condition characterized by ossification of the spine and prominent enthesopathies. Highly heterogeneous epidemiological figures have been reported in the literature, while in Italy the largest study has been conducted in 1992. The aim of our research is to contribute updated information about prevalence of DISH in Italy and to describe the clinical and radiographic characteristics associated with the disorder. MATERIAL AND METHODS: A retrospective review of lumbosacral spine, thoracic spine and pelvis radiographs was performed. Consecutive patients visiting the emergency department of our Institution over 3 years were enrolled. Presence of DISH was evaluated applying the Resnick and Niwayama criteria. Clinical and radiological features were also assessed. RESULTS: We included 1012 individuals (60.6% women), and DISH was present in 130 cases. The overall prevalence of DISH was 12.8% (95% CI 10.8-15.1), with higher figures in the male sample (16.8%) than in females (10.3%). In binary logistic regression adjusted for age, BMI (OR 1.50, p < 0.001) diabetes (OR 1.85, p = 0.003), hypertension (OR 2.04, p = 0.007) ischiopubic enthesopathy (OR 7.08, p < 0.001), iliac crest enthesopathy (OR 4.63, p < 0.001) and greater trochanter enthesopathy (OR 3.51, p < 0.001), were significantly associated with the condition. CONCLUSION: The prevalence of DISH observed in our study is consistent with previous literature, and we confirm that the disorder is more frequently retrieved in men and that it is associated with the presence of metabolic disorders and pelvic enthesopathy. Knowledge about the epidemiology and characteristics of DISH is needed to properly identify the condition.

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.

Prevalence and Characteristics of Fibromyalgia in Patients with Foot and Ankle Pain: The Experience of an Academic Podiatry Clinic.

Background and Objectives: Research about the prevalence of fibromyalgia in podiatric patients is limited, with data suggesting potentially higher estimates and greater foot impairment in patients with fibromyalgia compared to healthy individuals. The aim of our study is to assess the prevalence of fibromyalgia in the podiatric healthcare setting and to research the characteristics of fibromyalgia patients with foot or ankle disorders. Materials and Methods: Consecutive patients visiting the academic podiatry clinic at the University of Bologna IRCCS Rizzoli Orthopaedic Institute between 11 January and 31 March 2021 were enrolled. Results: Of the 151 patients included, 21 met the fibromyalgia survey diagnostic criteria, accounting for a prevalence of 13.9% (95% CI 8.8-20.5). As part of the podiatric assessment, the Foot Function Index (FFI) was used to calculate the impact of foot and ankle problems. Moreover, patients with fibromyalgia were asked to complete the fibromyalgia impact questionnaire (FIQ). Fibromyalgia patients had significantly worse total FFI scores (63.4 ± 23.0% vs. 53.2 ± 20.3%, p = 0.038) and there was a significant linear correlation between the FFI and the FIQ (r = 0.72, p < 0.001). Conclusions: The prevalence of fibromyalgia in the academic podiatry clinic being 13.9% confirms that, in the healthcare setting, the disease can be more frequent than in the general population. Furthermore, our findings suggest a strong correlation between foot impairment and the impact of fibromyalgia.

Health-related quality of life in patients with systemic sclerosis: evolution over time and main determinants.

OBJECTIVES: In SSc patients, disease specific determinants that influence health-related quality of life (HRQoL) over time have not been described. We aim to, in patients with SSc, (i) evaluate if and how HRQoL changes over time, and (ii) assess how different SSc domains and functional impairments contribute to changes in HRQoL over time. METHODS: All SSc patients from the Leiden SSc cohort were included; patients with disease duration <24 months were classified as incident cases. HRQoL was assessed prospectively on an annual basis using the EQ-5D and the SF36. To assess baseline associations between clinical characteristics and HRQoL, linear regressions were performed. To identify possible associations between SSc characteristics and HRQoL change over time, linear mixed models were performed in both incident and prevalent cases. RESULTS: In total, 492 SSc patients were included (n = 202 incident cases), with a median follow-up duration of 3.4 years. At baseline, presence of organ involvement was independently associated with a worse SF36 physical component score and lower EQ-5D score. Over time, gastrointestinal symptoms, Raynaud and digital ulcers were independently associated with deterioration of HRQoL in both incident and prevalent cases. In prevalent cases, pulmonary arterial hypertension (PAH) was associated with a decrease in HRQoL over time. Worse functioning as measured by six-min walking distance, mouth-opening, finger-to-palm distance and grip-strength contributed significantly to deterioration of HRQoL over time. CONCLUSION: In SSc, key clinical burdens that contribute to worsening of HRQoL over time include digital ulcers, Raynaud and gastrointestinal involvement. In addition, PAH is a significant burden in prevalent disease.

Incidence, prevalence and mortality of systemic sclerosis in Italy: a nationwide population-based study using administrative health data.

To study incidence, prevalence and mortality of systemic sclerosis (SSc) in Italy, assessing epidemiological differences between men and women and in distinct age groups. We performed a nationwide population-based study using administrative health data from regional co-payment exemption registries. Patients entitled with SSc-specific co-payment exemption were included. Fourteen of the 20 Italian regions contributed data covering a population of over 45 million individuals. Crude annual incidence rate, annual prevalence, crude annual mortality rate and standardised mortality ratio (SMR) were calculated. In 2016, the overall crude incidence rate of SSc was 18.5 (95% CI 16.9-20.2) per million per year. Incidence rate was 31.0 (95% CI 28.1-34.1) per million in women, and 4.3 (95% CI 3.2-5.6) per million in men. Peak incidence was observed in the age range 55-69 years. Overall annual prevalence was 306.1 (95% CI 301.1-311.2) per million. Prevalence was 530.8 (95% CI 521.5-540.2) per million in women and 67.8 (95% CI 64.4-71.3) per million in men, with a female to male ratio of 7.8:1. Highest prevalence was observed in the range 70-84 years. Crude annual mortality rate was 27.9 (95% CI 24.9-31.1) per 1000 patients. Overall SMR in patients with SSc was 2.8 (95% CI 1.9-3.8). SMR was 3.8 (95% CI 2.9-5.1) in men and 2.6 (95% CI 1.8-3.6) in women. We provided updated estimates on epidemiology of SSc in Italy. Our findings on incidence, prevalence and mortality of SSc are consistent with previously published literature.

Nailfold capillaroscopy in common non-rheumatic conditions: A systematic review and applications for clinical practice.

OBJECTIVE: The role of nailfold capillaroscopy (NC) in common non-rheumatic conditions has not been systematically reported. The aim of this review is to outline NC features observed in frequent non-rheumatic conditions, providing a practical tool to support rheumatologists for the interpretation of capillaroscopic abnormalities in patients with no established connective tissue disease (CTD). METHODS: We undertook a systematic search in PubMed and Web of Science databases. Studies reporting adults or children with common non-rheumatic diseases or conditions in which quantitative and/or qualitative assessment of morphological nailbed capillary findings was obtained, were included. The presence of a control group composed by subjects not affected by the studied condition and direct comparison of findings between groups were needed. RESULTS: We included 25 articles. Diabetes mellitus (11 studies), glaucoma (7 studies) and essential hypertension (3 studies) were the most represented diseases. Reduced capillary density, tortuosity, dilated capillaries, microhaemorrhages, ramified capillaries and avascular areas can be observed in diabetic patients. Association was reported between poor glycaemic control or longer duration of diabetes, or presence of microvascular complications as retinopathy and neuropathy, and more severe capillaroscopic abnormalities. Decreased capillary density, tortuosity, microhaemorrhages, dilated capillaries, avascular areas and ramifications might also be present in glaucoma, while in essential hypertension a reduced capillary density might be expected. CONCLUSION: Abnormal capillaroscopic findings are not uncommon even in individuals with no CTD. Therefore, presence of comorbidities known to potentially affect the microvascular array should always be investigated in patients undergoing NC and the interpretation of findings might be weighted accordingly.

Smoking and systemic sclerosis: influence on microangiopathy and expression of anti-topoisomerase I antibodies in a monocentric cohort.

OBJECTIVES: To investigate whether systemic sclerosis (SSc) patients exposed to active tobacco smoke exhibit a different autoantibody profile or are at higher risk for severe microangiopathy compared to never-smokers, and to assess differences between men and women. METHODS: We performed an exploratory observational study in a cohort of SSc patients fulfilling the 2013 ACR/EULAR classification criteria. According to the smoking habit, patients were categorised as ever-smokers or never-smokers. Microvascular damage was assessed at baseline using nailfold videocapillaroscopy. The presence of SSc-specific autoantibodies was investigated. RESULTS: The studied population was composed of 361 patients (279 women, 82 men). Of these, 208 (58%) were ever-smokers and 153 (42%) were never-smokers. Anti-centromere, anti-topoisomerase I (ATA) and anti-RNA polymerase III antibodies were found, respectively, in 90 (43%), 41 (20%), and 11 (5%) ever-smokers, and in 66 (43%), 40 (26%) and 5 (3%) never-smokers (all p>0.05). Scleroderma patterns early, active and late were present respectively in 12%, 44% and 21% of ever-smokers, and in 9%, 48%, and 29% of never-smokers (all p>0.05). In multivariable logistic regression, being a never-smoker was significantly associated with ATA positivity (OR 1.77, 95% CI 1.04-2.99, p= 0.034). In the gender-based sub-cohorts, 36 (27%) female patients who never smoked were ATA positive, compared to 16 (11%) ever-smoking women (p<0.001). CONCLUSIONS: We observed a significant association between smoking history and positivity of ATA and we outlined the idea of a different effect of smoking on autoantibody expression between men and women.

Mortality in tocilizumab-treated patients with COVID-19: a systematic review and meta-analysis.

OBJECTIVES: People who are exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could develop a potentially fatal disease with lung involvement and severe cytokine storm syndrome (CSS) - coronavirus disease 2019 (hereafter, COVID-19). Tocilizumab (TCZ) was administered to these subjects, despite the lack of randomised clinical trial data. Hence, summarising data on the mortality rate and related risks factors may help physicians to correctly administer TCZ. METHODS: We performed a systematic review and meta-analysis on mortality rate in TCZ- treated patients with COVID-19 according to the PRISMA guidelines. The pooled mortality rate in TCZ-treated persons was calculated and meta-regressions were done to investigate associated factors. RESULTS: We included 22 studies and 1520 TCZ-treated patients (mean age: 61 years, 95% CI: 59-64; male: 71%, 95% CI: 64-78%). The mortality estimated pooled prevalence was 19% (95% CI: 13-25, I2=100%, p<0.00001) and improvement estimated pooled prevalence was 71% (95% CI: 62-81). Factors associated with the mortality are the number of patients in intensive care unit, the number of patients requiring invasive ventilation and the sera C-reactive protein value before TCZ administration. We observed a reduction in the odds of mortality in TCZ-treated patients when compared to those treated with other therapies (OR=0.47, 95% CI: 0.22-0.98, p=0.004). CONCLUSIONS: This study showed that the mortality pooled prevalence in TCZ-treated patients is lower than the overall mortality reported in patients with severe COVID-19.

Cumulative endogenous estrogen exposure is not associated with severity of peripheral microangiopathy in patients with systemic sclerosis.

OBJECTIVES: To determine whether cumulative endogenous estrogen exposure (CEEE) is associated with severity of microvascular damage or with presence of clinical characteristics in women with systemic sclerosis (SSc). METHODS: The population was composed of female SSc patients from the Leiden CCISS (combined care in SSc) cohort. Reproductive life history was investigated through structured questionnaires and CEEE was calculated with a mathematical equation. Demographic, laboratory and clinical characteristics were available for all patients. The most recent nailfold videocapillaroscopy (NVC) was used to semiquantitatively score microangiopathy parameters. RESULTS: We included 97 patients, with a mean age of 59.6±14 years and a mean CEEE of 9±5.5 years. Ordinal logistic regression using CEEE as independent variable failed to demonstrate an association with loss (OR 1.05, 95% CI 0.97-1.14), dilated capillaries (OR 1.05, 95% CI 0.96-1.14), giants (OR 1.03, 95% CI 0.95-1.12) and ramifications (OR 0.99, 95% CI 0.92-1.07). Binary logistic regression did not show an effect of CEEE on presence of scleroderma pattern vs. non-scleroderma pattern, (OR 0.99, 95% CI 0.89-1.1) or of late scleroderma pattern vs. non-late patterns (OR 0.96, 95% CI 0.88-1.05) at NVC. Furthermore, no association was found between CEEE and presence of interstitial lung involvement (OR 0.98, 95% CI 0.88-1.08) but a trend for occurrence of digital ulcers (OR 1.09, 95% CI 0.99-1.19) was observed. CONCLUSIONS: In SSc patients, CEEE is not associated with the extent of microvascular derangement. No associations between CEEE and organ involvement were found.