Manuela Di Franco

Background: The Mediterranean diet (MedDiet) has been associated with anti-inflammatory effects and potential benefits in several chronic conditions. However, adherence to the MedDiet and its relationship with lifestyle factors and disease severity across different rheumatological diseases remain poorly characterized. Objectives: This study aimed to evaluate differences in MedDiet adherence among patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and fibromyalgia (FM), and to explore its association with cardiovascular comorbidities, bowel habits, and disease-related outcomes. Methods: In this monocentric cross-sectional study, adherence to the MedDiet was assessed using the 14-item PREDIMED questionnaire. Self-reported data on sociodemographic characteristics, cardiovascular comorbidities, bowel habits, and dietary behaviors were collected through questionnaires. Disease activity and severity were assessed using validated disease-specific measures. Differences in MedDiet adherence across diagnostic groups were evaluated using non-parametric tests. Multivariable models were performed to examine associations between MedDiet adherence and cardiovascular comorbidities or disease outcomes, adjusting for potential confounders including age, sex, BMI, smoking status, and educational level. Results: A total of 422 participants were included (RA n = 165, PsA n = 85, FM n = 172). Significant differences in MedDiet adherence were observed across diagnostic groups (p < 0.001), with the highest adherence in RA, intermediate values in PsA, and the lowest in FM. Compared with the other groups, a higher proportion of FM participants reported food intolerances (46.5%) and restrictive diets, including lactose-free (34.9%) and gluten-free (15.1%) diets. In the FM group, high adherence to the MedDiet was significantly associated with lower FIQR scores (β = −16.9; 95% CI −32.1 to −1.7; p = 0.01) and lower PDS scores (β = −4.34; 95% CI −7.81 to −0.86; p = 0.01). Sensitivity analyses using the continuous PREDIMED score confirmed these associations. Conclusions: Adherence to the MedDiet differs across rheumatological diseases, with the lowest adherence observed in FM. Higher adherence was associated with lower disease severity and impact in FM. These findings highlight the potential relevance of nutritional counselling in rheumatological diseases and support the need for longitudinal and interventional studies evaluating the role of the MedDiet within multidisciplinary disease management.

Most fibromyalgia (FM) patients are women, with a female-to-male ratio of 3:1. While sex differences in pain perception and description have been reported, the impact of sex and gender on FM severity remains controversial. Additionally, sex-related differential item functioning (DIF) in FM assessment tools has not yet been explored. The primary aim of this study was to analyze sex- and gender-related differences in FM severity using data from a web-based FM registry. The secondary aim was to assess sex-related DIF in three commonly used questionnaires: the Polysymptomatic Distress Scale (PDS), the modified Fibromyalgia Assessment Status (ModFAS), and the revised Fibromyalgia Impact Questionnaire (FIQR). Data from 331 male and 331 female patients, matched for age and body mass index (BMI) and fulfilling ACR 2010/2011 criteria, were retrospectively collected from the Italian Fibromyalgia Registry. Multivariate analyses were conducted on the overall and sex-stratified populations. Sex-related DIF was assessed using a hybrid Ordinal Logistic Regression/Item Response Theory method. Female sex was significantly associated with greater physical impairment, despite no differences in overall disease severity. In stratified analyses, married status influenced disease impact and burden in women, whereas BMI was associated with higher disability in men. Significant sex-related DIF was detected in one item of the Symptom Severity Scale of the PDS. Women with FM experience greater physical impairment than men, despite similar disease severity. Sociodemographic factors influence FM differently across sexes. Despite minor DIF, the three FM-specific questionnaires appear valid for use in both male and female patients.

Introduction/objectives: Seasonal variation may influence musculoskeletal pain, and fibromyalgia is primarily characterized by widespread chronic pain. This study aimed to assess whether symptom severity in fibromyalgia varies by season. Methods: A retrospective, cross-sectional analysis was conducted on patients from the Italian Fibromyalgia Registry. Patients were grouped based on the season of their clinical evaluation. Disease severity was measured using disease-specific clinimetric tools: the Polysymptomatic Distress Scale (PSD), including the Widespread Pain Index (WPI) and Symptom Severity Scale (SSS), as well as the revised Fibromyalgia Impact Questionnaire (FIQR) and the modified Fibromyalgia Assessment Status (FASmod). Statistical analyses included the Kruskal–Wallis test and pairwise comparisons using the Dwass–Steel–Critchlow–Fligner test. Results: A total of 2614 patients were evaluated. Significant seasonal differences were found for both WPI ( p = 0.042) and FASmod ( p = 0.037). In female patients, these differences were more pronounced (WPI, p = 0.016; FASmod, p = 0.018), while no significant variation was observed in males. Pairwise analysis showed higher symptom severity in autumn compared to summer for both WPI ( W = −4.009; p = 0.024) and FASmod ( W = −3.800; p = 0.037). Conclusion: In fibromyalgia, widespread pain appears more severe in autumn than in summer, particularly among female patients. These findings highlight the potential role of seasonality in symptom modulation and underscore the importance of incorporating seasonal factors into patient management and education. Key Points • Seasonality influences the severity of fibromyalgia in terms of widespread chronic pain .• Findings from a large national registry (2,614 patients) demonstrate significantly higher Widespread Pain Index and modified Fibromyalgia Assessment Status scores during the autumn months compared to the summer .• The increased severity of widespread pain in autumn is specifically observed among female patients .

Introduction: Before COVID-19 pandemic, we identified the percentage of B cells expressing the Mu-opioid receptor (Mu+ B cells) as a potential marker, named Mu-Lympho-Marker (MLM), for chronic pain (CP) in patients with fibromyalgia (FM) and osteoarthritis. Objectives: Here, we demonstrate the stability of MLM over time through a comparative analysis of biological, clinical, and psychological data collected from a subgroup of patients with FM across 2 distinct research periods. Methods: This is an observational, longitudinal study. Fibromyalgia participants enrolled in the first study were called back for follow-up sampling. Clinical data were recorded. Pain score was reported using the Numerical Rating Scale. Mu+ B cells percentage of expression was analyzed by flow cytometry. Immunofluorescence analyses were performed to explore the cellular localization of Mu-opioid receptor. Pain-free subjects served as control group. All the participants filled out self-reported psychological tests. Data were statistically analyzed. Results: Mu+ B cells percentage of expression was constant in patients with FM, who consistently showed lower values than control group after 2 years (difference in the mean: 32.0 ± 4.4, t = 7.330, IC 95% [23.2–40.9], P < 0.0001). Confocal microscopy analyses revealed Mu cytoplasmic localization in patients with FM. We observed no significant changes between psychological outcomes during the 2 phases of the study, nor did we find any correlations with biological findings. Conclusion: Mu-Lympho-Marker could be a promising marker for CP, as seen in FM cohort, and could be helpful for accurate diagnosis and tailored rehabilitation strategies. Further studies are needed to study MLM in CP of different aetiologies.

Objective. Data from trials demonstrated that abatacept (ABA) has a good safety and efficacy profile in treating rheumatoid arthritis. We have studied the retention rate of ABA in a real-life cohort of patients with rheumatoid arthritis. Methods. This is a monocentric, retrospective study including patients with rheumatoid arthritis classified by the American College of Rheumatology/European League Against Rheumatism 2010 criteria who started treatment with ABA. The Kaplan-Meier method was applied to evaluate the ABA retention rate. Results. This analysis was conducted on 161 patients [male/female 21/140, median age 65 years, interquartile range (IQR) 18.7, median disease duration 169 months, IQR 144.0]. 111 patients (68.9%) received ABA subcutaneously. ABA was associated with methotrexate in 61.9% of patients and was the first biological disease-modifying antirheumatic drug in 41%. We observed a median ABA survival of 66 months [95% confidence interval (CI) 57.3-74.7], with a retention rate of 88% at 6 months and 50.9% at 5 years. Drug survival was significantly higher in patients treated with ABA subcutaneously and in male patients (p=0.039 and p=0.018, respectively). Adjusted for main confounders, female gender was the main predictor of withdrawal (hazard ratio 5.1, 95% CI 1.2-21.3). Conclusions. Our study shows that better survival is associated with subcutaneous administration and male gender, confirming ABA effectiveness.

Objective. To compare etanercept and adalimumab biosimilars (SB4 and ABP501) and respective bioriginators in terms of safety and efficacy in a real-life contest. Methods. We consequently enrolled patients affected by rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, treated with SB4, and ABP501, or with corresponding originators, belonging to the main biological prescribing centers in the Lazio region (Italy), from 2017 to 2020. Data were collected at recruitment and after 4, 8, 12, and 24 months of therapy. Results. The multicenter cohort was composed by 455 patients treated with biosimilars [SB4/ABP501 276/179; female/male 307/146; biologic disease-modifying anti-rheumatic drug (b-DMARD) naïve 56%, median age/ interquartile range 55/46-65 years] and 436 treated with originators (etanercept/adalimumab 186/259, female/ male 279/157, b-DMARD naïve 67,2%, median age/interquartile range 53/43-62 years). No differences were found about safety, but the biosimilar group presented more discontinuations due to inefficacy (pConclusions. Real-life data demonstrated a similar safety profile between biosimilars and originators, but a reduced biosimilar retention rate at 24 months. Biosimilars could be considered a valid, safe, and less expensive alternative to originators, allowing access to treatments for a wider patient population.

The human leukocyte antigen (HLA)-B*27 family of alleles is strongly associated with ankylosing spondylitis (AS), a chronic inflammatory disorder affecting the axial and peripheral joints, yet some HLA-B*27 variants not associated with AS have been shown. Since no major differences in the ligandome of associated compared to not-associated alleles have emerged, a plausible hypothesis is that the quantity rather than the quality of the presented epitopes makes the difference. In addition, the Endoplasmic Reticulum AminoPeptidases (ERAPs) 1 and 2, playing a crucial role in shaping the HLA class I epitopes, act as strong AS susceptibility factors, suggesting that an altered peptidome might be responsible for the activation of pathogenic CD8+ T cells. In this context, we have previously singled out a B*27:05-restricted CD8+ T cell response against pEBNA3A (RPPIFIRRL), an EBV peptide lacking the B*27 classic binding motif. Here, we show that a specific ERAP1/2 haplotype negatively correlates with such response in B*27:05 subjects. Moreover, we prove that the B*27:05 allele successfully presents peptides with the same suboptimal N-terminal RP motif, including the self-peptide, pDYNEIN (RPPIFGDFL). Overall, this study underscores the cooperation between the HLA-B*27 and ERAP1/2 allelic variants in defining CD8+ T cell reactivity to suboptimal viral and self-B*27 peptides and prompts further investigation of the B*27:05 peptidome composition.

Fibromyalgia is a complex and heterogeneous clinical syndrome, mainly characterized by the presence of widespread pain, possibly associated with a variety of other symptoms. Fibromyalgia can have an extremely negative impact on the psychological, physical and social lives of people affected, sometimes causing patients to experience dramatically impaired quality of life. Nowadays, the diagnosis of fibromyalgia is still clinical, thus favoring diagnostic uncertainties and making its clear identification challenging to establish, especially in primary care centers. These difficulties lead patients to undergo innumerable clinical visits, investigations and specialist consultations, thus increasing their stress, frustration and even dissatisfaction. Unfortunately, research over the last 25 years regarding a specific biomarker for the diagnosis of fibromyalgia has been fruitless. The discovery of a reliable biomarker for fibromyalgia syndrome would be a critical step towards the early identification of this condition, not only reducing patient healthcare utilization and diagnostic test execution but also providing early intervention with guideline-based treatments. This narrative article reviews different metabolite alterations proposed as possible biomarkers for fibromyalgia, focusing on their associations with clinical evidence of pain, and highlights some new, promising areas of research in this context. Nevertheless, none of the analyzed metabolites emerge as sufficiently reliable to be validated as a diagnostic biomarker. Given the complexity of this syndrome, in the future, a panel of biomarkers, including subtype-specific biomarkers, could be considered as an interesting alternative research area.

The evaluation of chronic pain is challenging because of the lack of specific biomarkers. We identified the Mu opioid receptor-positive (Mu+) B cell percentage of expression, named Mu-Lympho-Marker (MLM), as a candidate marker for chronic pain in fibromyalgia (FM) and osteoarthritis (OA) patients. Here, we investigate the role of MLM on natural killer (NK) cells in the same patients. Twenty-nine FM and twelve OA patients were analyzed, and twenty-three pain-free subjects were considered as the control group. Blood samples were collected to perform immunophenotyping and Western blot analysis. Biological and clinical data were statistically analyzed. The final results showed that the percentage of NK cells expressing Mu was statistically lower in FM and OA patients than in pain-free subjects, as already demonstrated for B cells. A Western blot analysis was performed in order to detect NK cells’ functional status. Moreover, the correlation analysis of MLM expression with pharmacological therapy did not show any significant results. In conclusion, here, we confirm the role of MLM as a suitable marker for chronic pain and underline NK cells as a new possible immune cell type involved in the “Mu opioid receptor reserve theory”.

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.