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.

Validation of Qualisex questionnaire to evaluate sexual dysfunction in women affected by fibromyalgia.

OBJECTIVES: Fibromyalgia (FM) may have consequences on sexual life. The objective was to validate the Qualisex questionnaire in the assessment of sexual dysfunction in women affected by FM. METHODS: We consecutively enrolled FM women (American College of Rheumatology-ACR 2016) referring to our Fibromyalgia Clinic, from 2020 to 2022. Demographic, clinical data and evaluation of FM symptoms severity (Revised Fibromyalgia Impact Questionnaire (R-FIQ), Symptoms Severity Scale-SSS, Widespread Pain Index-WPI) were assessed. Hospital Anxiety and Depression Scale (HADS) and Qualisex questionnaire were anonymously administered. Qualisex includes 10 questions on different items of sexual life with higher scores suggestive of greater negative impact of the disease on sexuality. RESULTS: The cohort was composed by 373 FM women. Cronbach's alpha test was used to validate Qualisex questionnaire (0.878). Moreover, we observed higher values of Qualisex in married women (p<0.001), in women with lower grade of education (p=0.002) and with lower sexual feeling with partner (p<0.001). Higher values of Qualisex Total score showed a positive correlation with HADS-A/D (p<0.001 r=0.312; p<0.001 r=0.542 respectively), VAS pain, VAS fatigue, VAS dryness (p<0.001 r=0,438; p<0.001 r=0.375; p<0.001 r=0.370 respectively) and relationship duration (p<0.001 r=0.202). Multivariate analysis revealed a significant influence of relationship duration, VAS pain, fatigue, dryness, HADS-A/D, R-FIQ and all Qualisex items, on Qualisex Total score corrected for patients' age (p<0.001). CONCLUSIONS: This study validated Qualisex questionnaire as a good test for the sexual disorders' evaluation in FM women. Its use allows the assessment of different factors associated with sexual dysfunction, showing an impact of FM on sexuality. Moreover, due to demotivation feelings, sexual dysfunction contributes to worsen patients' quality of life.

Gender differences in the revised Fibromyalgia Impact Questionnaire: a pilot study.

OBJECTIVES: Fibromyalgia (FM) is a chronic syndrome characterised by widespread musculoskeletal pain associated with symptoms such as fatigue, sleep disturbances and cognitive impairment. Prevalence is higher in females but the application of the 2010/2011 and 2016 revision of the American College of Rheumatology (ACR) criteria reduced prevalence differences and the actual female:male ratio is approximately 3:1. Even if lately some studies have been conducted regarding FM gender differences, disease severity is still assessed using questionnaires, such as the Revised Fibromyalgia Impact Questionnaire (FIQR), designed and validated through a predominantly female sample. The aim of this pilot study was to compare the 21 items of the FIQR among male and female patients in order to evaluate the possible existence of a gender bias. METHODS: In this case-control study, consecutive patients with a diagnosis of FM (2016 ACR criteria) were asked to answer an online survey, including demographic characteristics, disease variables and the Italian version of the FIQR. Among the 544 patients that compiled the questionnaire, 78 patients, 39 males and 39 females, matched for age and disease duration, were consecutively enrolled in order to compare their FIQR scores. RESULTS: The univariate analysis showed that total FIQR scores and physical function domain scores were significantly higher in females and, among the 21 items of the FIQR, the female group obtained significantly higher scores in 6 of them. Our results showed that female patients obtain significantly higher scores in the FIQR total score and physical function domain score, in particular in 5 out of the 9 sub-items of the FIQR physical function domain. CONCLUSIONS: These preliminary results indicate that the use of the FIQR as a severity index in male patients probably underestimates the disease impact in this group.

Pain Biomarkers in Fibromyalgia Syndrome: Current Understanding and Future Directions.

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.

Common-sense model of self-regulation to cluster fibromyalgia patients: results from a cross-sectional study in Italy.

OBJECTIVES: Fibromyalgia is a severe and disabling chronic pain syndrome affecting millions of people worldwide. Various patients' subgroups were identified using different atheoretical measures, hardly effective to tailor treatments. Previous literature findings showed the relevance of fibromyalgia patients' illness perceptions in adjusting to the disease. The present study aims to identify clusters of fibromyalgia patients based on their illness perceptions and investigate whether they can differ across pain, mood, physical functioning, catastrophising, and pain acceptance measures. METHODS: Fifty-three newly referred fibromyalgia patients completed clinical and psychological questionnaires. Patients' subgroups were created by applying hierarchical cluster analysis to their answers to Illness Perception Questionnaire-Revised subscales. Potential differences across subgroups in outcome variables were tested. RESULTS: Cluster analysis identified two patient groups. Group A (32 patients) had a higher representation of fibromyalgia as a chronic disease with severe consequences, lower beliefs in personal and treatment control, and a higher fibromyalgia-related emotional distress than group B (21 patients). Clusters did not differ on pain intensity and duration. Group A, compared to group B, showed worse physical functioning and overall impairment due to fibromyalgia, a poorer psychological condition, a higher tendency to catastrophise, and less pain acceptance. CONCLUSIONS: Study findings reveal two fibromyalgia subgroups differing in emotional suffering and impairment despite similar pain intensity and duration. Patients' illness perceptions and attitudes towards pain, like catastrophising and acceptance, might be critical in adjusting to the disease. A detailed assessment of such risk and protective factors is critical to differentiate patients' subgroups with different needs and thus offering tailored treatments.

Adherence of Italian rheumatologists to the EULAR recommendations and outcomes in early rheumatoid arthritis patients after starting conventional DMARDs: Methotrexate in Italian patients wiTh Rheumatoid Arthritis (the MITRA study). A cohort study of the Italian Society for Rheumatology.

OBJECTIVES: The aim of this study was to assess the real-life adherence of Italian rheumatologist to the 2013 EULAR recommendations and treatment outcome in rheumatoid arthritis (RA) patients who started a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD). METHODS: The MITRA study is an Italian multicentre observational cohort focused on treatment naïve RA patients with early diagnosis recruited in an 18-month period starting from 2015. The data related to treatment with csDMARDs during the following 12 months follow-up were presented in this paper. RESULTS: Two-hundred and fifty-nine RA patients from MITRA cohort who had a follow-up visit and started a csDMARD were included in the prospective analysis. Methotrexate was started as first conventional DMARD in 224 (86.4%) patients. During the first year after starting conventional DMARDs, 175 (67.6%) RA patients reached the pre-specified target, which was DAS28 remission (<2.6) for 112 (43.2%) patients and LDA (<3.2) for 63 (24.3%) patients. Factors that negatively impacted the target achievement were fibromyalgia (HR: 0.2 [0.05-0.81]), HAQ-DI (HR: 0.72 [0.56-0.93]) and ESR (HR: 0.99 [0.99-1]). Globally, 33 (12.7%) patients started a biologic DMARD, while 61 out of 84 (72.6%) patients who had never reached the target remained on conventional DMARD. One-hundred and ninety-three adverse events (AEs) were recorded, the majority classified as mild (91 cases, 51%). CONCLUSIONS: A high proportion of RA patients achieved the target during the first-year follow-up. However, a considerable portion of RA patients did not start a biological drug although the target was never reached. AEs remain frequent with conventional DMARDs, but the majority were mild.

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.

Methotrexate in Italian patients wiTh Rheumatoid Arthritis (MITRA study): an observational study about the use of methotrexate in early RA patients and the adherence to the EULAR 2013 recommendations. A project of the Italian Society for Rheumatology.

OBJECTIVES: To assess the delay between the disease onset and the beginning of methotrexate (MTX) treatment in RA patients and to evaluate the Italian rheumatologists' adherence to the EULAR 2013 recommendations. METHODS: MITRA is an Italian multicentre observational study carried out on DMARD-naïve RA patients recruited in an 18-month period starting from 2015. The data related to the patients' characteristics at baseline will be presented. RESULTS: 332 patients from 13 Italian centres were recruited: the median delay between the onset of symptoms and the beginning of MTX was 197 days (102-431); in 20% of patients a treatment with DMARDs was started within the first 90 days from the onset of symptoms. The clinical target selected was DAS28 remission in 64.2% of cases and low disease activity in 35.8%. Among patients in DAS28 high disease activity, 92.6% received a control visit which was rescheduled within the first 3 months, similarly to those in DAS28 moderate disease activity (91.6%). A DMARD monotherapy was prescribed in 319 patients, while a combined therapy of DMARDs was preferred in 13 cases; 282 patients were treated with MTX. Glucocorticoids were prescribed in 229 patients: the median dosage was of 5 mg (IQR 5-7.5) of prednisone equivalent/day. CONCLUSIONS: Diagnostic delay in RA patients continues to be longer than expected. The choice of low disease activity as a target is still very frequent and tight control does not seem to be based on disease activity. This paper offers a realistic and detailed picture of the clinical practice among Italian rheumatologists.

Identification of MOR-Positive B Cell as Possible Innovative Biomarker (Mu Lympho-Marker) for Chronic Pain Diagnosis in Patients with Fibromyalgia and Osteoarthritis Diseases.

Fibromyalgia (FM) diagnosis follows the American College of Rheumatology (ACR) criteria, based on clinical evaluation and written questionnaires without any objective diagnostic tool. The lack of specific biomarkers is a tragic aspect for FM and chronic pain diseases in general. Interestingly, the endogenous opioid system is close to the immune one because of the expression of opioid receptors on lymphocytes membrane. Here we analyzed the role of the Mu opioid receptor on B lymphocytes as a specific biomarker for FM and osteoarthritis (OA) patients. We enrolled three groups of females: FM patients, OA patients (chronic pain control group) and healthy subjects (pain-free negative control group). We collected blood samples to apply immunophenotyping analysis. Written tests were administrated for psychological analysis. Data were statistically analyzed. Final results showed that the percentage of Mu-positive B cells were statistically lower in FM and OA patients than in pain-free subjects. A low expression of Mu-positive B cell was not associated with the psychological characteristics investigated. In conclusion, here we propose the percentage of Mu-positive B cells as a biological marker for an objective diagnosis of chronic pain suffering patients, also contributing to the legitimacy of FM as a truly painful disease.

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.

Pain modulation in patients with fibromyalgia undergoing acupuncture treatment is associated with fluctuations in serum neuropeptide Y levels.

OBJECTIVES: Neuropeptide Y (NPY) is a neurotransmitter released by sympathetic neurons, which is probably involved in pain modulation. Acupuncture is increasingly used as an alternative or complementary means of controlling pain in rheumatic diseases such as fibromyalgia (FM), a chronic widespread pain syndrome accompanied by allodynia and hyperalgesia. The aim of the present study was to assess the effects of an acupuncture cycle on serum NPY levels in patients with FM, and identify possible correlations between its serum levels and clinical and clinimetric parameters. METHODS: The study involved 30 FM patients who underwent clinical and clinimetric evaluations and blood sampling at baseline and at the end of the treatment, and 20 healthy subjects who underwent blood sampling. RESULTS: The baseline serum NPY levels of the patients were higher than those of the controls. They had significantly increased by the end of the treatment, when there was also a statistically significant reduction in pain, the number of tender points number, and the clinimetric scores. CONCLUSIONS: These findings confirm the analgesic properties of acupuncture as a complementary treatment in FM, and indicate that NPY could play a role in pain modulation.

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.

Autophagy generates citrullinated peptides in human synoviocytes: a possible trigger for anti-citrullinated peptide antibodies.

OBJECTIVES: Autophagy may represent a functional processing event that creates a substrate for autoreactivity. In particular, autophagy may play a role in the pathogenesis of RA, since autophagy is a key cellular event involved in the generation of citrullinated peptides, with consequent breakage of tolerance. Thus, in RA, autophagy may be the common feature in several situations (including smoking, joint injury and infection) that may drive the adaptive responses to citrullinated self-proteins. The aim of this study was the analysis, in vitro, of the role of autophagy in the generation of citrullinated peptides and, in vivo, of the relationship between autophagy and the production of anti-CCP antibodies (Abs). METHODS: For autophagy induction, fibroblast-like synoviocytes, primary fibroblasts and monocytes were stimulated with tunicamycin or rapamycin. Peptidyl arginine deiminase activity was tested by enzyme-linked immunosorbent assay, and protein citrullination was evaluated by western blotting. The main citrullinated RA candidate antigens, vimentin, α-enolase and filaggrin, were demonstrated by immunoprecipitation. The relationship between autophagy and anti-CCP Abs was analysed in 30 early-active RA patients. RESULTS: Our results demonstrated in vitro a role for autophagy in the citrullination process. Cells treated with tunicamycin or rapamycin showed peptidyl arginine deiminase 4 activation, with consequent protein citrullination. Immunoblotting and immunoprecipitation experiments, using specific Abs, identified the main citrullinated proteins: vimentin, α-enolase and filaggrin. In vivo, a significant association between levels of autophagy and anti-CCP Abs was observed in treatment-naïve early-active RA patients. CONCLUSION: These findings support the view that the processing of proteins in autophagy generates citrullinated peptides recognized by the immune system in RA.

Abnormal resting state functional connectivity of the periaqueductal grey in patients with fibromyalgia.

OBJECTIVES: Emerging evidence associates chronic pain syndrome, such as fibromyalgia, with endogenous pain modulatory system dysfunction, leading to an impaired descending pain inhibition. In this study, using resting-state functional magnetic resonance imaging (fMRI), we aimed at seeking possible functional connectivity changes of the periaqueductal gray (PAG), a brainstem area that belongs to the endogenous pain modulatory system, in patients with fibromyalgia. METHODS: In 20 patients with fibromyalgia and 15 healthy subjects, we investigated PAG functional connectivity using resting-state fMRI. We also analysed the correlation between clinical variables, such as pain severity, disease duration, and depressive personality traits with PAG functional connectivity. RESULTS: Compared with control subjects, we identified that patients with fibromyalgia had an increased PAG connectivity with insula, anterior cingulate cortex, and anterior prefrontal cortex. The functional connectivity between PAG and the rostral ventral medulla, however, was not concordantly increased. PAG functional connectivity correlated with pain severity, disease duration, and the depressive personality trait rating. CONCLUSIONS: Our fMRI study showing abnormal resting state functional connectivity of the PAG suggests that patients with fibromyalgia have an endogenous pain modulatory system dysfunction, possibly causing an impaired descending pain inhibition. This abnormal PAG functioning might underlay the chronic pain these patients suffer from.

Hyperexcitability in pain matrices in patients with fibromyalgia.

OBJECTIVES: Emerging evidence associates fibromyalgia (FM) with pain system dysfunction. In this study, using laser evoked potentials (LEPs) and paired laser stimuli, we tested excitability in the pain matrices and sought possible changes in patients with FM. METHODS: In 20 patients with FM and 15 healthy subjects, after recording control nociceptive system-mediated Aδ- and C-fibre-related LEPs, we measured excitability in the pain matrices by testing the Aδ-LEP conditioned by a preceding C-LEP. RESULTS: No difference was found in control LEP amplitudes for Aδ- or C-fibres between patients and healthy subjects. Conversely, the Aδ-LEP amplitude, conditioned by a preceding C-LEP, was significantly higher in patients than in healthy subjects (p<0.001). CONCLUSIONS: Objective evidence from increased conditioned Aδ-LEP amplitudes reflecting hyperexcitability in the pain matrices in FM, provides diagnostically useful information and might help in developing new therapeutic approaches.

Hypovitaminosis D in recent onset rheumatoid arthritis is predictive of reduced response to treatment and increased disease activity: a 12 month follow-up study.

BACKGROUND: Vitamin D displays immunomodulatory activities and has been proposed as a potential player in the pathogenesis of rheumatoid arthritis (RA). A negative association between serum 25(OH) vitamin D levels and RA activity was demonstrated but longitudinal studies investigating the role of vitamin D levels in predicting RA activity and response to treatment are lacking. Therefore, this study was designed to test the hypothesis of an association between serum 25(OH) vitamin D levels at RA diagnosis and disease activity evaluated by clinimetric, laboratory and ultrasound (US) parameters and to detect the prevalence of remission and response to treatment after 12 months follow-up. METHODS: This is a longitudinal, retrospective study on data obtained from thirty-seven patients with early RA treatment-naïve. Serum inflammatory markers, auto-antibodies and 25(OH) vitamin D levels were obtained at baseline. Hypovitaminosis D was diagnosed for 25(OH) vitamin D levels < 20 ng/ml. Tender joint count (TJCs), swollen joint count (SJCs), Visual Analog Scales (VAS), Disease Activity Score (DAS) 28 score were assessed at baseline and 12 months after diagnosis. Joints synovitis and power-Doppler were evaluated at baseline and 12 months later. RESULTS: At baseline mean 25(OH) vitamin D levels were 24.4 ± 11.9 ng/ml; 35% of study subjects had hypovitaminosis D which strongly associated with higher RA activity and lower prevalence of remission and response to treatment (all p-values < 0.001). The percentage of patients not presenting a reduction of the US synovitis score after 12 months from diagnosis was significantly higher among patients with hypovitaminosis D than in those with normal serum 25(OH) vitamin D at baseline. CONCLUSIONS: In patients with early RA and basal hypovitaminosis D after 12 months follow-up reduction of disease activity and percentage of remission and response to treatment were significantly lower than those observed in patients with normal vitamin D levels. These results provide further support to the immunomodulatory action of vitamin D in RA and suggest a role of basal vitamin D status in the prediction of disease evolution. Vitamin D measurement and possibly vitamin D supplementation should be considered an additional option in the management of early RA patients.

Decrease of asymmetric dimethyl arginine after anti-TNF therapy in patients with rheumatoid arthritis.

Chronic inflammatory diseases such as rheumatoid arthritis (RA) are associated with accelerated atherosclerosis and increased morbidity and mortality for cardiovascular events. Asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, contributes to the impairment of endothelial function, the earlier and reversible stage of atherosclerotic plaque formation. Since tumor necrosis factor (TNF) inhibits enzymatic degradation of ADMA, anti-TNF agents could restore its physiological level. The aim of this study was to investigate the effect of TNF inhibitors on ADMA serum levels in patients with RA. Our results suggest a possible effect of anti-TNF drugs on ADMA serum levels; longer studies would be necessary to confirm the role ADMA in assessing cardiovascular risk in RA.