Fibromyalgia: one year in review 2024.

Fibromyalgia (FM) remains a condition with a pathogenesis that is not completely understood, affecting a significant portion of the global population. This article summarises the main advances in FM during the last year. Even in 2023, research on FM was notably active. From a clinimetric perspective, studies have been conducted to evaluate the possibilities of interchanging the primary indices of disease severity, primarily for studies with substantial case numbers. Regarding FM pathogenesis, ongoing research focuses on small fiber neuropathy: some studies have documented its association with central sensitisation, while others have revealed distinct sensory profiles in patients with FM and small fiber neuropathy compared to those solely with small fiber neuropathy. Dorsal root ganglia seem to play a crucial role in the pathogenesis of FM as they host satellite glial cells, which are targeted by pain-driving immunoglobulin G. These antibodies have been identified in a subset of patients exhibiting high symptom severity. An important study conducted on animal models confirmed the role of neuroinflammation at the level of dorsal root ganglia, in this case mediated by polymorphonuclear neutrophils. Mounting evidence underscores the link between COVID-19 and the persistence of FM symptoms after recovery. In identifying potential biomarkers aiding FM diagnosis, research has also concentrated on studying the expression of specific circulating microRNAs. Recent discoveries have unveiled novel therapeutic strategies for FM, especially focused in non-pharmacological interventions. This includes a focus on non-invasive brain stimulation and exercise programs, all directed towards relieving symptoms and improving functionality in individuals affected by the condition.

Environmental factors and fibromyalgia syndrome: a narrative review.

This in-depth review of fibromyalgia (FM), which is a complex condition characterised by chronic pain, fatigue, sleep disturbances, and a spectrum of diagnostically and therapeutically challenging symptoms, underlines the need for a comprehensive and integrated approach that also takes into account the psychological factors affecting patient responses. We focus on the substantial impact that environmental factors (climatic variations, air pollution, electromagnetic field exposure, physical and emotional traumas, dietary patterns, and infections) have on the manifestation and intensity of symptoms, and advocate personalised, holistic treatment of patients' psychological and environmental sensitivities by suggesting the benefits of tailored dietary and stress management. We also call for further research into the complex interplay of environmental, biological and psychological factors influencing FM in order to develop more effective individualised treatments that are capable of enhancing patient care and outcomes.

Tailored exercise programmes for fibromyalgia: a clinical practical guide.

OBJECTIVES: To evaluate the role of exercise in the management of fibromyalgia syndrome (FM) by addressing its complex pathogenesis involving central sensitisation, autonomic dysfunction, inflammation, and neurological irregularities, and examining how exercise impacts symptom exacerbation caused by external stressors and comorbid conditions. METHODS: This review synthesises evidence from current literature focusing on the benefits of structured and personalised exercise programmes in FM management. It discusses the importance of specifying exercise type, intensity, frequency, duration, and progression tailored to individual patient needs and clinical objectives. RESULTS: Regular physical activity effectively mitigates core aetiopathogenetic mechanisms of FM and improves associated conditions such as stress and obesity. It also provides benefits for preventing other chronic diseases, enhancing well-being, and promoting healthy ageing. Structured and personalised exercise programmes that start with a low-demand protocol and gradually increase exercise volume are most beneficial, by improving patient compliance and reducing the risk of adverse effects. CONCLUSIONS: Effective management of FM requires a patient-centred approach integrating both pharmacological and non-pharmacological treatments, with exercise playing a pivotal role. Personalised exercise prescriptions that consider FM patients' specific needs and limitations are crucial for optimising treatment outcomes and enhancing quality of life.

Significant nailfold capillary loss and late capillaroscopic pattern are associated with pulmonary arterial hypertension in systemic sclerosis.

OBJECTIVES: To evaluate differences in nailfold videocapillaroscopy (NVC) findings between systemic sclerosis-SSc patients with and without a diagnosis of pulmonary arterial hypertension (PAH). METHODS: 110 SSc patients were enrolled in this cross-sectional, case-control, multi-centre study. Patients were divided into cases (SSc-PAH confirmed by right hearth catheterization-RHC) and controls (SSc-nonPAH with low probability of PAH). NVC patterns (early, active, and late) and morphological parameters (microvascular density, non-specific abnormalities, giant capillaries, micro-haemorrhages, avascular areas) were considered using a semiquantitative scoring system. RESULTS: SSc-PAH patients showed higher frequencies of late pattern (p < 0.01), non-specific abnormalities (p < 0.01), lower capillary density (p < 0.01), higher avascular areas (p < 0.01), and a higher mean NVC score (p < 0.01). Contrarily, the early/active pattern (p < 0.01) and a higher rate of micro-haemorrhages (p = 0.04) were more frequent in non-PAH patients. By the multivariate analysis, SSc-PAH patients, compared to non-PAH, had more non-specific abnormalities (27/55, 49.1% vs 10/55, 18.2%, adjusted OR: 16.89, 95%CI: 3.06-93.16), a lower capillary density (grade 3, 20/55, 36.4% vs 5/55, 9.1%, adjusted OR: 38.33, 95%CI: 2.34-367.80), and avascular areas (18/55, 32.7% vs 10/55, 18.2%, adjusted OR: 16.90, 95%CI: 2.64-44.35). A correlation was found between the mean pulmonary arterial pressure-mPAP and avascular areas (p < 0.01), capillary density (p < 0.01), and non-specific abnormalities (p < 0.01). A clinical model including the NVC variables may be able to predict the diagnosis of PAH. CONCLUSIONS: Our results indicate that the distinctive peripheral microcirculatory injury of SSc, i.e capillary loss and morphological abnormalities, appear more severe and pronounced in patients with SSc-PAH.

Lung ultrasound compared to computed tomography detection and automated quantification of systemic sclerosis-associated interstitial lung disease: preliminary study.

Lung ultrasound (LUS) is a promising tool for detecting systemic sclerosis-associated interstitial lung disease (SSc-ILD). Currently, consensus on the best LUS findings and execution technique is lacking. OBJECTIVES: To compare qualitative and quantitative assessment of B-lines and pleural line (PL) alterations in SSc-ILD with chest computed tomography (CT) analysis. METHODS: During 2021-2022, consecutive SSc patients according to 2013 ACR/EULAR classification criteria underwent pulmonary functional tests (PFTs). On the same day, if a CT was performed over a ± 6 months period, LUS was performed by two certified blinded operators using a 14-scans method. The ≥10 B-lines cut-off proposed by Tardella and the Fairchild's PL criteria fulfilment were selected as qualitative findings. As quantitative assessment, total B-lines number and the quantitative PL score adapted from the semi-quantitative Pinal-Fernandez score were collected. CT scans were evaluated by two thoracic radiologists for ILD presence, with further processing by automated texture analysis software (qCT). RESULTS: 29 SSc patients were enrolled. Both qualitative LUS scores were significantly associated to ILD presence on CT, with Fairchild's PL criteria resulting in slightly more accuracy. Results were confirmed on multivariate analysis. All qualitative and quantitative LUS findings were found to be significantly associated with qCT ILD extension and radiological abnormalities. Mid and basal PL quantitative score correlated with mid and basal qCT ILD extents. Both B-lines and PL alterations differently correlated with PFTs and clinical variables. CONCLUSION: This preliminary study suggests the utility of a comprehensive LUS assessment for SSc-ILD detection compared with CT and qCT.

Fibromyalgia: one year in review 2023.

Fibromyalgia (FM) is a chronic syndrome characterised by widespread pain that affects millions of people worldwide. This article discusses various aspects of FM described in scientific papers published in 2022 and indexed in the PubMed database, including the most recent diagnostic acquisitions (especially in relation to the juvenile form of FM), risk factors, co-morbidities and objective measures. Emphasis is placed on the importance of identifying FM early and improving diagnostic methods (e.g. physical measurements, including walking test performance, hand grip force, and autonomic tests). The article also considers hypotheses concerning the pathophysiology of FM, including the role of inflammation, gut dysbiosis, and neuroinflammation, and possible treatment options, including medications such as antioxidants and kinin antagonists, neurostimulation, and mind-body interventions. Although ketamine, vitamin D, and hormone therapy have shown promise in reducing FM symptoms, further research is needed to optimise their use. Neurostimulation techniques, such as transcutaneous electrical nerve stimulation, transcranial direct-current stimulation and transcranial magnetic stimulation, have been investigated in terms of their efficacy in reducing pain and improving the quality of life. Finally, the role of nutrition is discussed as study findings suggest that weight control, modified high-antioxidant diets, and nutritional supplementation can help to alleviate the symptoms of FM.

Lack of cross-reactivity between rheumatoid factor IgM and anti-S1 receptor binding domain of SARS-CoV-2 IgM: a case-control study.

OBJECTIVES: Since the onset of the COVID-19 outbreak, concern has been raised about reliability of SARS-CoV-2 serological tests in people with serum positivity for rheumatoid factor (RF), due to its ability to interfere during tests carried out with immunoassay techniques, leading to false positive results. The aim of this study was to analyse, on sera from RF seropositive rheumatoid arthritis (RA) patients, the interference between RF IgM and anti-S1 RBD IgM. METHODS: The study was conducted on consecutive patients affected by RF seropositive RA and, as control group, COVID-19 patients with SARS-CoV-2 pneumonia hospitalised at Sapienza University of Rome from April 2020 and April 2021. Serum samples from COVID-19 patients during their hospitalisation were collected, while RA subjects' samples were harvested prior to the onset of the COVID-19 pandemic. All samples were tested for RF IgM using nephelometry and ELIA, and for anti-S1 RBD IgM by ELISA. RESULTS: Forty RF seropositive RA and 42 COVID-19 patients were enrolled. In all RA patients, both nephelometric assay and ELIA showed RF IgM positivity, while only one patient of the control group tested positive for RF IgM by nephelometric assay and ELIA. IgM directed to S1 RBD were not detected in sera of RA patients, while all COVID-19 patients presented anti-S1 RBD IgM (median anti-S1 RBD IgM COVID-19 vs. RA: 368.5 IU/mL, IQR 654 IU/mL vs. 18.45 IU/mL, IQR 20 IU/mL; p<0.0001). CONCLUSIONS: This study confirmed the lack of cross-reactivity between RF and anti-S1 RBD IgM, offering to clinicians a valuable tool for a better management of RA patients undergoing SARSCoV-2 serological tests.

Helicobacter pylori and Upper Endoscopy in Systemic Sclerosis: A Cross-sectional Study in the Real World.

BACKGROUND/AIMS: A role for Helicobacter pylori in triggering systemic sclerosis (SSc) has been proposed, but data are conflicting. In previous studies, infection has been generally searched for by using serology. We designed this study to assess H. pylori prevalence in SSc patients with histology of gastric mucosa, considered the criterion standard for infection diagnosis. METHODS: This cross-sectional study enrolled 30 SSc patients who complained of upper gastrointestinal symptoms. All underwent upper endoscopy with gastric biopsies. Endoscopic alterations were recorded, and gastric mucosa biopsies were used for both histological examination and searching for H. pylori. The role for proton-pump inhibitor (PPI) therapy was considered. Fisher exact test was used for statistical analysis. RESULTS: Data of 28 SSc patients were available, 14 with ongoing PPI therapy. Helicobacter pylori infection at histology was detected in 14.3% patients, and it equally occurred in patients with or without PPI therapy. Erosive esophagitis/Barrett esophagus was detected in 26.6% of cases. Among patients with PPI therapy, 30% received half dose only. The prevalence of intestinal metaplasia was low (14.3%). Endoscopic esophageal alterations were significantly more frequent in those patients showing anti-Scl70 antibody positivity. CONCLUSIONS: This study showed that prevalence of H. pylori is very low in SSc patients, so that it seems not having a role in triggering SSc. Management of gastroesophageal diseases in SSc patients needs to be improved, and looking to the autoimmune profile may be of help. Thus, collaboration between rheumatologist and gastroenterologist is highly recommended.

Systemic sclerosis Progression INvestiGation (SPRING) Italian registry: demographic and clinico-serological features of the scleroderma spectrum.

OBJECTIVES: Systemic sclerosis (SSc) is a severe multiple-organ disease characterised by unpredictable clinical course, inadequate response to treatment, and poor prognosis. National SSc registries may provide large and representative patients cohorts required for descriptive and prognostic studies. Therefore, the Italian Society for Rheumatology promoted the registry SPRING (Systemic sclerosis Progression INvestiGation). METHODS: The SPRING is a multi-centre rheumatological cohort study encompassing the wide scleroderma spectrum, namely the primary Raynaud's phenomenon (pRP), suspected secondary RP, Very Early Diagnosis of Systemic Sclerosis (VEDOSS), and definite SSc. Here we describe the demographic and clinical characteristics of a population of 2,028 Italian patients at the initial phase of enrolment, mainly focusing on the cohort of 1,538 patients with definite SSc. RESULTS: Definite SSc showed a significantly higher prevalence of digital ulcers, capillaroscopic 'late' pattern, oesophageal and cardio-pulmonary involvement compared to VEDOSS, as expected on the basis of the followed classification criteria. The in-depth analysis of definite SSc revealed that male gender, diffuse cutaneous subset, and anti-Scl70 seropositivity were significantly associated with increased prevalence of the most harmful disease manifestations. Similarly, patients with very short RP duration (≤1 year) at SSc diagnosis showed a statistically increased prevalence of unfavourable clinico-serological features. CONCLUSIONS: Nationwide registries with suitable subsetting of patients and follow-up studies since the prodromal phase of the disease may give us valuable insights into the SSc natural history and main prognostic factors.

Is fibromyalgia an autoimmune disorder?

Fibromyalgia (FM) is a multifactorial syndrome which includes not only widespread pain and stiffness, now recognized as major symptoms, but also numerous other somatic, emotional, and neuropsychic manifestation. The lack of specific validated biological and instrumental biomarkers has made FM a condition of unexplained medical significance, and its pathophysiology remains controversial and subject to debate. The current hypothesis regarding the pathogenesis of FM proposes that its development is influenced by various mechanism, including genetic predisposition, stressful life events, inflammatory processes, and cognitive-emotional factors. However, despite the extensive research conducted to date, the available data do not provide a clear understanding of the pathogenesis of FM. In this article, we report the opposing viewpoints of two leading experts who debate the question of whether FM is an autoimmune disease, based on scientific data regarding this condition. Both perspectives are discussed and the latest evidence on the pathophysiology of FM is reported to provide a comprehensive understanding of this complex syndrome.

Pharmacotherapeutic advances in fibromyalgia: what's new on the horizon?

INTRODUCTION: This review delves into Fibromyalgia Syndrome (FMS), a chronic pain condition demanding thorough understanding for precise diagnosis and treatment. Yet, a definitive pharmacological solution for FMS remains elusive. AREAS COVERED: In this article, we systematically analyze various pharmacotherapeutic prospects for FMS treatment, organized into sections based on the stage of drug development and approval. We begin with an overview of FDA-approved drugs, discussing their efficacy in FMS treatment. Next, we delve into other medications currently used for FMS but still undergoing further study, including opioids and muscle relaxants. Further, we evaluate the evidence behind medications that are currently under study, such as cannabinoids and naltrexone. Lastly, we explore new drugs that are in phase II trials. Our research involved a thorough search on PUBMED, Google Scholar, and clinicaltrials.gov. We also discuss the action mechanisms of these drugs and their potential use in specific patient groups. EXPERT OPINION: A focus on symptom-driven, combination therapy is crucial in managing FMS. There is also a need for ongoing research into drugs that target neuroinflammation, immunomodulation, and the endocannabinoid system. Bridging the gap between benchside research and clinical application is challenging, but it holds potential for more targeted and effective treatment strategies.

Practice pattern for the use of intravenous iloprost for the treatment of peripheral vasculopathy in systemic sclerosis: A case-control study from the Italian national multicenter "SPRING" (Systemic Sclerosis Progression InvestiGation) Registry.

Background: Intravenous iloprost has been widely used for the treatment of systemic sclerosis peripheral vasculopathy. No agreement has been found on the regimen and the dosage of intravenous iloprost in different scleroderma subset conditions. This study aimed to evaluate the modalities of intravenous iloprost administration within a large cohort of systemic sclerosis patients from the SPRING Registry and to identify any associated clinical-demographic, instrumental or therapeutic data. Patients and Methods: Data of systemic sclerosis patients treated with intravenous iloprost for at least 1 year (case group) were retrospectively analyzed, including different timing and duration of intravenous iloprost session, and compared with those of untreated patients (control group). Results: Out of 1895 analyzed patients, 937 (49%) received intravenous iloprost treatment, while 958 (51%) were assigned to the control group. Among cases, about 70% were treated every 4 weeks, 24% with an interval of more than 4 weeks, and only 6% of less than 4 weeks. Most patients receiving the treatment every 4 weeks, or less, underwent infusion cycle for 1 day only, while if it was scheduled with an interval of more than 4 weeks, a total number of 5 consecutive days of infusions was the preferred regimen. The comparison between the two groups revealed that patients treated with intravenous iloprost had a higher frequency of DUs (p < 0.001), pitting scars (p < 0.001), diffuse cutaneous involvement (p < 0.001), interstitial lung disease (p < 0.002), as well as higher rates of anti-topoisomerase I, "late" scleroderma pattern at nailfold videocapillaroscopy. These findings were confirmed by multivariate analysis. Conclusion: Our data provide a picture on the Italian use of intravenous iloprost among systemic sclerosis patients and showed that it was usually employed in patients with a more aggressive spectrum of the disease. The disparity of intravenous iloprost treatment strategies in the different centers suggests the need of a rational therapeutical approach based on the clinical characteristics of different patients' subsets.

Impact of COVID-19 and vaccination campaign on 1,755 systemic sclerosis patients during first three years of pandemic. Possible risks for individuals with impaired immunoreactivity to vaccine, ongoing immunomodulating treatments, and disease-related lung involvement during the next pandemic phase.

Introduction: The impact of COVID-19 pandemic represents a serious challenge for 'frail' patients' populations with inflammatory autoimmune systemic diseases such as systemic sclerosis (SSc). We investigated the prevalence and severity of COVID-19, as well the effects of COVID-19 vaccination campaign in a large series of SSc patients followed for the entire period (first 38 months) of pandemic. Patients and method: This prospective survey study included 1755 unselected SSc patients (186 M, 1,569F; mean age 58.7 ± 13.4SD years, mean disease duration 8.8 ± 7.3SD years) recruited in part by telephone survey at 37 referral centers from February 2020 to April 2023. The following parameters were carefully evaluated: i. demographic, clinical, serological, and therapeutical features; ii. prevalence and severity of COVID-19; and iii. safety, immunogenicity, and efficacy of COVID-19 vaccines. Results: The prevalence of COVID-19 recorded during the whole pandemic was significantly higher compared to Italian general population (47.3 % vs 43.3 %, p < 0.000), as well the COVID-19-related mortality (1.91 % vs 0.72 %, p < 0.001). As regards the putative prognostic factors of worse outcome, COVID-19 positive patients with SSc-related interstitial lung involvement showed significantly higher percentage of COVID-19-related hospitalization compared to those without (5.85 % vs 1.73 %; p < 0.0001), as well as of mortality rate (2.01 % vs 0.4 %; p = 0.002). Over half of patients (56.3 %) received the first two plus one booster dose of vaccine; while a fourth dose was administered to 35.6 %, and only few of them (1.99 %) had five or more doses of vaccine. Of note, an impaired seroconversion was recorded in 25.6 % of individuals after the first 2 doses of vaccine, and in 8.4 % of patients also after the booster dose. Furthermore, the absence of T-cell immunoreactivity was observed in 3/7 patients tested by QuantiFERON® SARSCoV-2 Starter Set (Qiagen). The efficacy of vaccines, evaluated by comparing the COVID-19-related death rate recorded during pre- and post-vaccination pandemic periods, revealed a quite stable outcome in SSc patients (death rate from 2.54 % to 1.76 %; p = ns), despite the significant drop of mortality observed in the Italian general population (from 2.95 % to 0.29 %; p < 0.0001). Conclusions: An increased COVID-19 prevalence and mortality rate was recorded in SSc patients; moreover, the efficacy of vaccines in term of improved outcomes was less evident in SSc compared to Italian general population. This discrepancy might be explained by concomitant adverse prognostic factors: increased rate of non-responders to vaccine in SSc series, low percentage of individuals with four or more doses of vaccine, ongoing immunomodulating treatments, disease-related interstitial lung disease, and/or reduced preventive measures in the second half of pandemic. A careful monitoring of response to COVID-19 vaccines together with adequate preventive/therapeutical strategies are highly recommendable in the near course of pandemic in this frail patients' population.

Psychological Fragility in an Italian Cohort of Systemic Sclerosis Patients During COVID-19 Pandemic Category: Short Communication.

Objective: This work aims to evaluate the prevalence of anxiety and COVID-19-related fear in systemic sclerosis (SSc) patients during the second and third waves of the SARS-CoV-2 pandemic in Italy and their possible associated factors. Methods: A cohort study was carried out on 114 SSc patients referred to our Scleroderma Clinic, matched for sex and age. Twenty-eight of them had missed scheduled examinations during the October 2020-March 2021 period and 86 has attended regular outpatient visits during the same period. Both groups were administered (by telephone for cases and in-person for controls) the Generalized Anxiety Disorder Scale-7 (GAD-7) questionnaire and the validated on SSc patients COVID-19 Fears Questionnaire for Chronic Medical Conditions (COVID-19 Fears). Concurrent factors related to higher scores were investigated in patients who did not have an outpatient follow-up. Results: The missing group had significantly more patients scoring ≥8 on the GAD-7 questionnaire [22 (78.6%) vs 16 (18.6%), p < 0.0001] and significantly higher scores on the COVID-19 Fears questionnaire (median [quartiles] 31.5 [26.25;37.25] vs 20 [13.75;28], p < 0.0001) than the attending group. Multivariate analysis performed on the missing patients group showed a significant association of the lack of work and ongoing therapy for anxiety/depression with GAD-7 (p = 0.0275 and p = 0.0188) and COVID-19 Fears score (p = 0.0016 and p = 0.0099). Conclusion: Anxiety disorder and COVID-19-related fear were greater in SSc patients who missed regular follow-ups and are associated with a lack of work activity. These findings aim to identify a subgroup deserving attention regarding risk factors for missed periodic controls.

Peripheral Microangiopathy Changes in Pulmonary Arterial Hypertension Related to Systemic Sclerosis: Data From a Multicenter Observational Study.

Systemic sclerosis (SSc) is a connective tissue disease characterized by immune-system alterations, fibrosis involving the skin and internal organs and diffuse microangiopathy. Pulmonary arterial hypertension (PAH) is a severe complication of SSc affecting about 10-15% of the patients and it is a leading cause of mortality. Due to the devastating nature of SSc-PAH, there is a clear need to systematically adopt appropriate screening programs. Nail fold videocapillaroscopy (NVC) studies have shown a more severe peripheral microvascular dysfunction in SSc patients with PAH suggesting that abnormalities in peripheral microcirculation may correlate with pulmonary microangiopathy. This is a cross-sectional study involving four tertiary University Rheumatology Units in the Center-North of Italy. Seventy patients, 35 adults with SSc and PAH confirmed by RHC (F/M 34/1; median age 65.2 ± 8.9 SD yrs), and 35 SSc patients without PAH were enrolled (F/M 3471; median age 63.3 ± 10.3 SD yrs). Clinical, laboratoristic and instrumental data were collected and NVC was performed in all patient. Specific NVC parameters were evaluated and a semi-quantitative rating scale was adopted to score these changes. Finally, patients were distributed into the suitable NVC pattern belonging to the scleroderma pattern. Our aim was to compare the peripheral microangiopathy changes in SSc patients with and without PAH, and to investigate the relationship between NVC findings and the main hemodynamic parameters of pulmonary vasculopathy. Patients with SSc-PAH+ showed a significant higher frequency of interstitial lung disease (ILD). No significant differences regarding clinical and laboratoristic parameters were observed. NVC abnormalities, avascular areas were more frequent in SSc patients with PAH, respect to those without (p = 0.03), and capillary density was significantly lower when considering grade 3 (p = 0.02). A higher NVC semiquantitative mean was found in SSc-PAH+ patients and a greater rate of the "late" pattern was detected in SSc-PAH+ subjects in respect to PAH- (57.1% vs. 25.7%) (p = 0.03). A significant correlations between pulmonary pressure values (sPAP by TTE and mPAP by RHC) and the capillary density (Spearman's rho 0.35, p = 0.04 for both). Our findings provide additional evidence to the literature data, confirming that a higher degree of peripheral nailfold microangiopathy is more common in SSc-PAH patients, and further strengthening the concept that NVC changes may run parallel with similar abnormalities inside pulmonary microcirculation.

Autophagy Hijacking in PBMC From COVID-19 Patients Results in Lymphopenia.

Autophagy is a homeostatic process responsible for the self-digestion of intracellular components and antimicrobial defense by inducing the degradation of pathogens into autophagolysosomes. Recent findings suggest an involvement of this process in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the role of autophagy in the immunological mechanisms of coronavirus disease 2019 (COVID-19) pathogenesis remains largely unexplored. This study reveals the presence of autophagy defects in peripheral immune cells from COVID-19 patients. The impairment of the autophagy process resulted in a higher percentage of lymphocytes undergoing apoptosis in COVID-19 patients. Moreover, the inverse correlation between autophagy markers levels and peripheral lymphocyte counts in COVID-19 patients confirms how a defect in autophagy might contribute to lymphopenia, causing a reduction in the activation of viral defense. These results provided intriguing data that could help in understanding the cellular underlying mechanisms in COVID-19 infection, especially in severe forms.

Prevalence and Death Rate of COVID-19 in Autoimmune Systemic Diseases in the First Three Pandemic Waves. Relationship with Disease Subgroups and Ongoing Therapies.

OBJECTIVE: Autoimmune systemic diseases (ASD) represent a predisposing condition to COVID-19. Our prospective, observational multicenter telephone survey study aimed to investigate the prevalence, prognostic factors, and outcomes of COVID-19 in Italian ASD patients. METHODS: The study included 3,918 ASD pts (815 M, 3103 F; mean age 59±12SD years) consecutively recruited between March 2020 and May 2021 at the 36 referral centers of COVID-19 and ASD Italian Study Group. The possible development of COVID-19 was recorded by means of a telephone survey using a standardized symptom assessment questionnaire. RESULTS: ASD patients showed a significantly higher prevalence of COVID-19 (8.37% vs. 6.49%; p<0.0001) but a death rate statistically comparable to the Italian general population (3.65% vs. 2.95%). Among the 328 ASD patients developing COVID-19, 17% needed hospitalization, while mild-moderate manifestations were observed in 83% of cases. Moreover, 12/57 hospitalized patients died due to severe interstitial pneumonia and/or cardiovascular events; systemic sclerosis (SSc) patients showed a significantly higher COVID-19-related death rate compared to the general population (6.29% vs. 2.95%; p=0.018). Major adverse prognostic factors to develop COVID-19 were: older age, male gender, SSc, pre-existing ASD-related interstitial lung involvement, and long-term steroid treatment. Of note, patients treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) showed a significantly lower prevalence of COVID-19 compared to those without (3.58% vs. 46.99%; p=0.000), as well as the SSc patients treated with low dose aspirin (with 5.57% vs. without 27.84%; p=0.000). CONCLUSION: During the first three pandemic waves, ASD patients showed a death rate comparable to the general population despite the significantly higher prevalence of COVID-19. A significantly increased COVID-19- related mortality was recorded in only SSc patients' subgroup, possibly favored by preexisting lung fibrosis. Moreover, ongoing long-term treatment with csDMARDs in ASD might usefully contribute to the generally positive outcomes of this frail patients' population.

Sex-related Differences in Systemic Sclerosis: A Multicenter Cross-sectional Study From the National Registry of the Italian Society for Rheumatology.

OBJECTIVE: There is still a great deal to learn about the influence of sex in systemic sclerosis (SSc). In this respect, national registries provide large and homogeneous patient cohorts for analytical studies. We therefore investigated a wide-ranging and well-characterized SSc series with the aim of identifying sex differences in disease expression, with a special focus on demographic, clinical, and serological characteristics. METHODS: A multicenter SSc cohort of 2281 patients, including 247 men, was recruited in the Italian Systemic sclerosis PRogression INvestiGation (SPRING) registry. Demographic data, disease manifestations, serological profile, and internal organ involvement were compared. RESULTS: The overall female/male ratio was 8.2:1. Female/male ratios for limited cutaneous SSc, diffuse cutaneous SSc, and SSc sine scleroderma subsets were 8.7:1, 4.9:1, and 10.7:1, respectively. A shorter time from onset of Raynaud phenomenon to SSc diagnosis, an increased prevalence of the diffuse cutaneous subset, renal crisis, and digital ulcers were found in males, whereas a significantly higher percentage of sicca syndrome, serum antinuclear antibodies, antiextractable nuclear antigens, anti-La/SSB, and anticentromere protein B was detected in the female group. Males exhibited lower left ventricular ejection fraction, as well as higher prevalence of conduction blocks, arrhythmias, ground glass, and honeycombing. Moreover, forced vital capacity and total lung capacity were medially lower in men than in women. Finally, males were more frequently treated with immunosuppressive drugs. CONCLUSION: Our study further supports the presence of several sex-related differences in patients with SSc. These differences were pronounced in the severity of cutaneous, peripheral vascular, and cardiopulmonary involvement for male patients, whereas an increased prevalence of sicca syndrome and a specific autoantibody profile characterized the female sex.