Mental health and well-being during the COVID-19 pandemic: stress vulnerability, resilience and mood disturbances in fibromyalgia and rheumatoid arthritis.

OBJECTIVES: The COVID-19 pandemic severely increased the stress levels in the population. The aim of present study was to investigate the impact of the lockdown measures on emotional well-being and disease activity in patients with fibromyalgia (FM) and rheumatoid arthritis (RA) through a telemedicine approach. METHODS: An on-line survey, including demographic characteristics, disease-activity and psychometric scales (Stress-related Vulnerability Scale, Resiliency scale), Zung Anxiety and Depression Self-assessment Scale), was anonymously administered to FM, RA and healthy controls (HC). Disease activities were compared to the pre-lockdown cohort referring to our centre. RESULTS: Levels of anxiety and depression worthy of psychiatric attention were documented in 36.7% of FM, 14.6% of RA, 12.5% of HC and in 50% of FM, 17.1% of RA, 15% of HC, respectively. HC featured the highest stress scores, followed FM and then RA. RA showed higher resiliency than FM. Both anxiety and depression scores were significantly higher in FM than RA and HC. Disease severity was higher in RA patients and lower in FM patients when compared to the respective historical cohorts. CONCLUSIONS: Lockdown significantly affected emotional well-being and disease activity of patients suffering from rheumatic diseases. While HC showed a higher vulnerability to stress, RA patients showed a greater resilience compared to both HC and to FM patients, especially. Emotional disturbances are greater in patients with RDs and in particular with FM. The use of a telemedicine approach to screen for severe symptoms represents a useful addition to the overall management of rheumatic patients.

Perceived Disease Activity in Rheumatoid Arthritis: When the Physician's Gender Matters.

BACKGROUND: In rheumatoid arthritis (RA), females usually have a worse prognosis. To date, the influence of physician gender in the evaluation of RA activity is still largely unknown. OBJECTIVES: To investigate the discrepancy in RA disease activity assessment between male and female physicians and to compare patient and evaluator perception of disease activity and global health (GH) status. METHODS: One female and one male rheumatologist evaluated 154 RA patients recording tender and swollen joint count, GH, evaluator global assessment (EGA), and patient global assessment (PGA) disease activity. A third rheumatologist calculated DAS28, CDAI, and SDAI. Difference was evaluated by Wilcoxon test. Physician-patient agreement was assessed by intraclass correlation coefficient. RESULTS: GH, PGA, and DAS28 were higher when recorded by the female examiner. Male EGA was higher than female. Among male patients, PGA was higher when collected by the female examiner. The probability of being judged as having an active disease did not rely on physician gender. The agreement with the physician's evaluation of disease activity was high. PGA values were higher than EGA in both examiners. The physician-patient agreement was moderate for the male examiner and good for the female. The female physician had a higher agreement with both genders. CONCLUSIONS: Subjective measure of disease activity differs between female and male rheumatologists, contributing to a different evaluation of disease activity. Patients have a higher perception of disease activity compared to physicians. The stronger agreement between female physicians and patients may be related to a more emphatic setting established by the female physician.

Identification of Subclinical Lung Involvement in ACPA-Positive Subjects through Functional Assessment and Serum Biomarkers.

Lung involvement is related to the natural history of anti-citrullinated proteins antibodies (ACPA)-positive rheumatoid arthritis (RA), both during the pathogenesis of the disease and as a site of disease-related injury. Increasing evidence suggests that there is a subclinical, early lung involvement during the course of the disease, even before the onset of articular manifestations, which can potentially progress to a symptomatic interstitial lung disease. To date, reliable, non-invasive markers of subclinical lung involvement are still lacking in clinical practice. The aim of this study is to evaluate the diagnostic potential of functional assessment and serum biomarkers in the identification of subclinical lung involvement in ACPA-positive subjects. Fifty ACPA-positive subjects with or without confirmed diagnosis of RA (2010 ARC-EULAR criteria) were consecutively enrolled. Each subject underwent clinical evaluation, pulmonary function testing (PFT) with assessment of diffusion lung capacity for carbon monoxide (DLCO), cardiopulmonary exercise testing (CPET), surfactant protein D (SPD) serum levels dosage and high-resolution computed tomography (HRCT) of the chest. The cohort was composed of 21 ACPA-positive subjects without arthritis (ND), 10 early (disease duration < 6 months, treatment-naïve) RA (ERA) and 17 long-standing (disease duration < 36 months, on treatment) RA (LSRA). LSRA patients had a significantly higher frequency of overall HRCT abnormalities compared to the other groups (p = 0.001). SPD serum levels were significantly higher in ACPA-positive subjects compared with healthy controls (158.5 ± 132.3 ng/mL vs 61.27 ± 34.11 ng/mL; p < 0.0001) and showed an increasing trend from ND subjects to LSRD patients (p = 0.004). Patients with HRCT abnormalities showed significantly lower values of DLCO (74.19 ± 13.2% pred. vs 131.7 ± 93% pred.; p = 0.009), evidence of ventilatory inefficiency at CPET and significantly higher SPD serum levels compared with subjects with no HRCT abnormalities (213.5 ± 157.2 ng/mL vs 117.7 ± 157.3 ng/mL; p = 0.018). Abnormal CPET responses and higher SPD levels were also associated with specific radiological findings. Impaired DLCO and increased SPD serum levels were independently associated with the presence of HRCT abnormalities. Subclinical lung abnormalities occur early in RA-associated autoimmunity. The presence of subclinical HRCT abnormalities is associated with several functional abnormalities and increased SPD serum levels of SPD. Functional evaluation through PFT and CPET, together with SPD assessment, may have a diagnostic potential in ACPA-positive subjects, contributing to the identification of those patients to be referred to HRCT scan.

Reactive arthritis: current treatment challenges and future perspectives.

Reactive arthritis is a group of inflammatory joint diseases triggered by a previous infection, often associated with extra-articular features. The clinical course and consequently the treatment are complicated by the variability of the disease evolution in the single patient. In some patients, the disease assumes a chronic and destructing course, requiring the introduction of therapy. However, the role of antibiotic treatment of the triggering infection as well as the role of the currently available disease-modifying anti-rheumatic drugs is still unclear. The better understanding of the infectious agents-host interaction in reactive arthritis pathogenesis opens the possibility of new therapeutic strategies for the disease management. The purpose of this review is to illustrate the recent discoveries about the induction of joint inflammation by the infectious agents, the prognostic factors to better identify patients at risk of chronicity, the current available therapeutic strategies and lastly, the future possibilities of therapeutic approaches to reactive arthritis.

One year in review 2019: fibromyalgia.

Fibromyalgia is characterised by chronic pain, fatigue and functional symptoms. Its aetiopathogenesis is still a matter of debate, but various pharmacological and non-pharmacological therapies are currently available for its treatment. We review the literature concerning the most recent findings related to the aetiopathogenesis, diagnosis, clinical aspects and treatment of FM published between January 2018 and January 2019.

Asymmetric Dimethyl Arginine as a Biomarker of Atherosclerosis in Rheumatoid Arthritis.

Cardiovascular disease is the main cause of morbidity and mortality in rheumatoid arthritis (RA). Despite the advent on new drugs targeting the articular manifestations, the burden of cardiovascular disease is still an unmet need in the management of RA. The pathophysiology of accelerated atherosclerosis associated to RA is not yet fully understood, and reliable and specific markers of early cardiovascular involvement are still lacking. Asymmetric dimethylarginine is gaining attention for its implication in the pathogenesis of endothelial dysfunction and as biomarkers of subclinical atherosclerosis. Moreover, the metabolic pathway of methylarginines offers possible targets for therapeutic interventions to decrease the cardiovascular risk. The purpose of this review is to describe the main causes of increased methylarginine levels in RA, their implication in accelerated atherosclerosis, the possible role as biomarkers of cardiovascular risk, and finally the available data on current pharmacological treatment.

Lung Infections in Systemic Rheumatic Disease: Focus on Opportunistic Infections.

Systemic rheumatic diseases have significant morbidity and mortality, due in large part to concurrent infections. The lung has been reported among the most frequent sites of infection in patients with rheumatic disease, who are susceptible to developing pneumonia sustained both by common pathogens and by opportunistic microorganisms. Patients with rheumatic disease show a peculiar vulnerability to infectious complications. This is due in part to intrinsic disease-related immune dysregulation and in part to the immunosuppressive treatments. Several therapeutic agents have been associated to a wide spectrum of infections, complicating the management of rheumatic diseases. This review discusses the most frequent pulmonary infections encountered in rheumatic diseases, focusing on opportunistic agents, consequent diagnostic challenges and appropriate therapeutic strategies.

Gender influence on clinical manifestations, depressive symptoms and brain-derived neurotrophic factor (BDNF) serum levels in patients affected by fibromyalgia.

INTRODUCTION: OBJECTIVES: Fibromyalgia (FM) is a common rheumatic disorder characterized by chronic, widespread pain associated with several not painful symptoms. The contribution of gender to the manifestation of the disease may influence the higher prevalence of FM among women. In spite of this, how patients' gender influences the clinical manifestation of FM is still not well understood. The frequent association with neuropsychiatric symptoms raised the attention on the role of neurotrophins, including the brain-derived neurotrophic factor (BDNF) as potential biomarkers of the condition. Aims of the study were to evaluate the influence of gender on clinical manifestations and to investigate BDNF serum levels as a potential biomarker of FM. METHODS: We consecutively enrolled 201 adult patients of both sexes diagnosed with FM. For each patient, we collected clinical and clinimetric data and, in a subgroup of 40 patients, we measured serum BDNF levels. BDNF levels have been measured also in 40 matched healthy controls (HC). RESULTS: Several symptoms were significantly higher in women compared with men, including pain, fatigue, memory problems, tenderness, balance problems and sensitivity to environmental stimuli. On the contrary, men reported a significant higher frequency of coexisting depressive symptoms. BDNF levels were significantly lower in FM patients compared with HC, discriminating with good accuracy the condition. CONCLUSION: Gender influences FM clinical manifestations, with a higher prevalence of pain, fatigue and other common FM symptoms among women while higher frequency of neuropsychiatric symptoms among men. BDNF offers promises as a potential biomarker of the disease. Key Points • Gender-related differences in the clinical manifestations of FM may contribute to the higher prevalence of FM among females. Indeed, women show higher levels of pain and symptoms traditionally associated to FM, which are evaluated to establish the diagnosis according to the clinical criteria. • The new insights into the pathogenesis of the disease raised the attention on the role of brain mediators in FM. Among these, BNDF shows potential as a diagnostic biomarker.

Gut Microbiota Structure and Metabolites, Before and After Treatment in Early Rheumatoid Arthritis Patients: A Pilot Study.

Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disease. Modifications of gut microbiota seem to be associated with the disease, but the impact of gut microbiota on therapies' outcome remains unclear. A role of T cells in RA pathogenesis has been addressed, particularly on the Th17/Treg cells balance. Our study aimed to evaluate in early RA (ERA) patients compared to a control group, fecal gut microbiota composition, short-chain fatty acids concentrations, and the levels of circulating Th17/Treg and their own cytokines, before and after 3 months of standard treatment (Methotrexate (MTX) plus glucocorticoids). Fecal microbiota characterization was carried out on 19 ERA patients and 20 controls matched for sex and age. Significant decreased biodiversity levels, and a partition on the base of the microbiota composition, between the ERA patients at baseline compared to controls, were observed. The co-occurrent analysis of interactions revealed a characteristic clustered structure of the microbial network in controls that is lost in ERA patients where an altered connection between microbes and clinical parameters/metabolites has been reported. Microbial markers such as Acetanaerobacterium elongatum, Cristiansella massiliensis, and Gracilibacter thermotolerans resulted significantly enriched in control group while the species Blautia gnavus emerged to be more abundant in ERA patients. Our results showed an alteration in Th17/Treg balance with higher Th17 levels and lower Treg levels in ERA group respect to control at baseline, those data improved after therapy. Treatment administration and the achievement of a low disease activity/remission appear to exert a positive pressure on the structure of intestinal microbiota with the consequent restoration of biodiversity, of the structure of microbial network, and of the abundance of taxa that became closer to those presented by the subject without the disease. We also found an association between Blautia gnavus and ERA patients characterized by a significant reduction of propionic acid level. Furthermore significant differences highlighted at baseline among controls and ERA patients are no more evident after treatment. These data corroborate the role played by gut microbiota in the disease and suggest that therapy aimed to restore gut microbiota would improve treatment outcome.

Dietary Habits and Nutrition in Rheumatoid Arthritis: Can Diet Influence Disease Development and Clinical Manifestations?

Rheumatoid arthritis (RA) is a systemic, autoimmune disease characterized by joint involvement, with progressive cartilage and bone destruction. Genetic and environmental factors determine RA susceptibility. In recent years, an increasing number of studies suggested that diet has a central role in disease risk and progression. Several nutrients, such as polyunsaturated fatty acids, present anti-inflammatory and antioxidant properties, featuring a protective role for RA development, while others such as red meat and salt have a harmful effect. Gut microbiota alteration and body composition modifications are indirect mechanisms of how diet influences RA onset and progression. Possible protective effects of some dietary patterns and supplements, such as the Mediterranean Diet (MD), vitamin D and probiotics, could be a possible future adjunctive therapy to standard RA treatment. Therefore, a healthy lifestyle and nutrition have to be encouraged in patients with RA.

Small-fibre pathology has no impact on somatosensory system function in patients with fibromyalgia.

We aimed to investigate whether small-fibre pathology, a common skin biopsy finding in patients with fibromyalgia, implies clinically important abnormalities of somatosensory system function and verify whether it is associated with voltage-gated sodium channel variants. In 57 consecutively enrolled patients with fibromyalgia, we used skin biopsy to distinguish patients with and without small-fibre pathology. In all patients, we assessed somatosensory system function using quantitative sensory testing (QST) and laser-evoked potentials and investigated voltage-gated sodium channel genotyping. We then compared these variables in patients with and without small-fibre pathology. We found that clinical measures, QST, and laser-evoked potential variables did not differ between patients with and without small-fibre pathology. In most patients with small-fibre pathology, QST and laser-evoked potential variables fell within normative ranges commonly used in clinical practice. Of the 57 patients, one patient without small-fibre pathology and 2 patients with small-fibre pathology had rare variants of voltage-gated sodium channels, namely SCN11A, SCN9A, and SCN1A variants. The SCN9A variant, found in a patient with small-fibre pathology, was an already profiled gain-of-function mutation, previously reported in small-fibre neuropathy. Our findings suggest that small-fibre pathology has a negligible impact on somatosensory system function in fibromyalgia. The genetic analysis suggests that patients with rare small-fibre neuropathy due to voltage-gated sodium channel variants may be misdiagnosed as patients with fibromyalgia.

Mucosa-Environment Interactions in the Pathogenesis of Rheumatoid Arthritis.

Mucosal surfaces play a central role in the pathogenesis of rheumatoid arthritis (RA). Several risk factors, such as cigarette smoking, environmental pollution, and periodontitis interact with the host at the mucosal level, triggering immune system activation. Moreover, the alteration of microbiota homeostasis is gaining increased attention for its involvement in the disease pathogenesis, modulating the immune cell response at a local and subsequently at a systemic level. Currently, the onset of the clinical manifest arthritis is thought to be the last step of a series of pathogenic events lasting years. The positivity for anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF), in absence of symptoms, characterizes a preclinical phase of RA-namely systemic autoimmune phase- which is at high risk for disease progression. Several immune abnormalities, such as local ACPA production, increased T cell polarization towards a pro-inflammatory phenotype, and innate immune cell activation can be documented in at-risk subjects. Many of these abnormalities are direct consequences of the interaction between the environment and the host, which takes place at the mucosal level. The purpose of this review is to describe the humoral and cellular immune abnormalities detected in subjects at risk of RA, highlighting their origin from the mucosa-environment interaction.

Mavrilimumab: an evidence based review of its potential in the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) management has greatly improved with the development of biologic disease modifying antirheumatic drugs, but a proportion of patients do not improve despite the biologic drugs currently available. We need new biologic agents with novel mechanisms of action for the treatment of refractory patients. Recent evidence has shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) is involved in the pathogenesis of RA. GM-CSF can exacerbate RA and elevated levels of this cytokine have been observed in synovial fluid from RA patients. Antagonism of GM-CSF can strikingly reduce established disease in mouse models of arthritis. Mavrilimumab, a human monoclonal antibody to GM-CSF receptor α, is a competitive antagonist of GM-CSF signaling. Phase I and II studies have shown good clinical response with a good safety profile in patients with mild to moderate RA, suggesting encouraging effects of mavrilimumab for the treatment of RA. This paper reviews the preclinical and clinical data evaluating the safety, tolerability, and efficacy of mavrilimumab in the treatment of RA.