ToRaRI (Tofacitinib in Rheumatoid Arthritis a Real-Life experience in Italy): Effectiveness, safety profile of tofacitinib and concordance between patient-reported outcomes and physician's global assessment of disease activity in a retrospective study in Central-Italy.

INTRODUCTION: The use of Janus Kinase Inhibitors (JAK-Is) in rheumatoid arthritis (RA) has entered in daily practice. In consideration of ORAL-Surveillance trial and the new EULAR recommendations, real-world data are needed to assess Jak-Is safety and effectiveness. The multicenter study presented here aimed to evaluate effectiveness and safety of tofacitinib in a real-life cohort. METHODS: A retrospective analysis was performed from September 2021 to December 2022. Data were collected when tofacitinib was started (T0) and after 3 (T3), 6 (T6) and 12 (T12) months of treatment. The primary objective was to analyze the efficacy and safety of tofacitinib. Safety was assessed by recording adverse events (AEs) with and without discontinuation. The secondary objective was to assess the difference between Patient-Reported Outcomes (PROs) and Physician's Global Assessment of disease activity (PhGA). RESULTS: 122 patients were included in the study from the following rheumatology Centers: Pisa, Ancona, Florence (two Centers), Siena, and Sardinia. A statistically significant improvement in DAS-28-CRP, CDAI and SDAI score was observed at T3, T6, compared to baseline (p < 0.001). Improvement was confirmed in patients who reach T12. Patients naïve to bDMARDs showed a shorter remission time and higher remission rates. There was also a statistically significant improvement in PROs compared to baseline (p < 0.001). The improvement was rapid and was consistent with PhGA. The 12-month retention rate for tofacitinib was 89.35%. Reasons to stop tofacitinib were: insufficient response (7), gastrointestinal symptoms (2), infection (1), malignancy (1), Zoster (1), pruritus sine materia (1). CONCLUSIONS: Tofacitinib is safe and effective in our RA cohort. It induces higher remission rates in patients naive to bDMARDs, suggesting that there may be a benefit using it as first-line therapy. Additionally, improvement in PROs was consistent with PhGA scores, demonstrating how tofacitinib affects both the objective and subjective components of disease activity. Key Points 1. JAK inhibitors are considered at a similar level as biologic agents in terms of effectiveness. 2. After ORAL-Surveillance results, real-world data are needed to assess the benefit/risk profile of Jaki. 3. Disagreement between patients and physicians has been previously reported with biologic therapy among patients with rheumatoid arthritis, with patients rating disease activity higher than physicians. 4. Jak inhibitors could reduce this discrepancy, due to their mechanism of action.

Late-Onset Pompe Disease with Normal Creatine Kinase Levels: The Importance of Rheumatological Suspicion.

Pompe disease (PD), also defined as acid maltase deficiency, is a rare autosomal recessive disease that causes glycogen accumulation due to a deficiency of the lysosomal enzyme acid α-glucosidase. An excessive amount of undisposed glycogen causes progressive muscle weakness throughout the body. It particularly affects skeletal muscles and the nervous system, especially in the late-onset phase. Here, we present a clinical case of late-onset PD (LOPD) with normal CK (creatinine kinase) values treated after a misdiagnosis of demyelinating motor polyneuropathy and chronic inflammatory neuropathy. The suspicion of possible fibromyalgia induced the patient to seek a rheumatology consultation, and the investigations performed led to the diagnosis of PD. The patient was investigated for genetic and enzymatic studies. PD was diagnosed using the α-glucosidase assay on DBS. In LOPD, clinical manifestations, such as muscle weakness, exercise intolerance, myalgia, or even high hyperCKemia, often appear as nonspecific and may mimic a wide variety of other muscle disorders, such as limb muscle dystrophies, congenital, metabolic, or inflammatory myopathies. In our case, the patient had CK values in the normal range but with continued complaints typical of PD. An analysis of enzyme activity revealed a pathologic value, and genetic analysis identified the c.-32-13T>G mutation in homozygosis. The association of the pathological enzyme value and mutation in homozygosity with LOPD led to a familial segregation study. Our results contribute to the characterization of PD in Italy and support the importance of rheumatologic attention. This suggests further studies are needed to define the broad clinical and pathological spectrum observed in this disease.

Fibromyalgia: one year in review 2022.

Fibromyalgia syndrome (FM) is a chronic widespread pain syndrome characterised by fatigue, sleep disturbances and many idiopathic pain symptoms. The aim of this review is to describe and summarise the most recent findings concerning the diagnosis, aetiopathogenesis and treatment of fibromyalgia syndrome published between January 2021 and January 2022 and appearing on PubMed database. In particular, last year's literature focused on the impact of COVID-19 pandemic on FM patients, on new aetiopathogenetic horizons and the last conclusions about pharmacological and non-pharmacological interventions.

Rheumatoid Arthritis disease activity assessment in routine care: performance of the most widely used composite disease activity indices and patient-reported outcome measures.

BACKGROUND AND AIM: To evaluate the convergent and discriminative validity of many continuous composite disease activity indices and patient-reported outcome measures (PROMs) in rheumatoid arthritis (RA). METHODS: In consecutive RA patients in moderate or high disease activity, according to the Simplified Disease Activity Index (SDAI) definition, were computed four additional composite disease activity indices, the 28-joint Disease Activity Score - erythrocyte sedimentation rate (DAS28-ESR), the Clinical Disease Activity Index (CDAI), the Chronic Arthritis Systemic Index (CASI), and the Mean Overall Index for RA (MOI-RA), and five PROMs, the Patients' Activity Scale (PAS), the Rheumatoid Arthritis Impact of Disease (RAID), the 5-item RA Disease Activity Index (RADAI-5), the Routine Assessment of Patient Index Data (RAPID3), and the Clinical Arthritis Activity (PRO-CLARA). Spearman's rho correlation coefficients were determined to assess their convergent validity, and discriminative performance was calculated by the area under the receiver-operating curve (AUC-ROC). The patients' opinion of their symptomatic status (PASS) was used as the external criterion. RESULTS: 246 RA patients with moderate (29.3%) or high disease activity (70.7%) have been assessed. The indices all showed a significant correlation (p <0.0001 for all). Among the composite disease activity indices, the CDAI was the one that showed the best discriminating ability compared to the PASS (AUC = 0.962), while among the PROMs the RAID was the most performing (AUC = 0.879). CONCLUSIONS: CDAI as composite index of disease activity, and RAID as PROM, are the two instruments with the best performances in relation to PASS. The use of validated disease activity measures can help in clinical practice to adopt treat-to-target strategies in RA patients. (www.actabiomedica.it).

Cannabis and Autoimmunity: Possible Mechanisms of Action.

Medical cannabis (MC) describes the usually inhaled or ingested use of a cannabis plant or cannabis extract for medicinal purposes. The action of whole cannabis plants is extremely complex because their large number of active compounds not only bind to a plethora of different receptors but also interact with each other both synergistically and otherwise. Renewed interest in the medicinal properties of cannabis has led to increasing research into the practical uses of cannabis derivatives, and it has been found that the endocannabinoid system (particularly CB2 receptor activation) is a possible target for the treatment of inflammatory and the autoimmune diseases related to immune cell activation. However, in vivo findings still lack, creating difficulties in applying translational cannabinoid research to human immune functions. In this review, we summarized the main mechanisms of action of medical cannabis plant especially regarding the immune system and the endocannabinoid system, looking at preliminary clinical data in three most important autoimmune diseases of three different specialities: rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease.

Vaccination against SARS-CoV-2 in patients with rheumatic diseases: doubts and perspectives.

Since January 2020, the whole world has been facing the worst epidemic for a century. SARS-CoV- 2 infection has so far caused more than one million deaths, with the only measures capable of containing the spread of the virus being social distancing, frequent hand washing, and the wearing of masks. Vaccine development was urgently needed and there are now more than 90 candidate vaccines being developed using different technologies. The European Medicines Agency has recently approved a second mRNA-based vaccine, but the introduction of vaccines has raised some doubts about patients with rheumatic disease, who are at high risk of infection because of disease activity and the therapies used to treat it. The aim of this study was to investigate how vaccines may interact with the immune system and treatment of such patients, and how to monitor the post-vaccine antibody titres and T cell responses in order to assess their efficacy and safety.

Prevalence of COVID infections in a population of rheumatic patients from Lombardy and Marche treated with biological drugs or small molecules: A multicentre retrospective study.

OBJECTIVE: The COVID-19 pandemic has raised questions about the management of systemic immunosuppressive treatments for rheumatic conditions. It is well known that rheumatic patients are at risk of developing infections because of their immunocompromised state. Moreover, drugs such as hydroxychloroquine or tocilizumab that are widely used to treat rheumatic diseases are now being used to treat COVID-19. The aim of this multicentre retrospective study of rheumatic patients in the Italian regions of Lombardy and Marche was to determine whether patients receiving biological or small molecules treatment are more susceptible to the development of COVID-19 than the general population. METHODS: The local registry data of 10,260 rheumatic patients being treated with bDMARDs or small molecules were evaluated from 15 March to 23 April 2020. The final analysis was based on the registry data relating to 7.204, telephone contacts and/or outpatient visits. RESULTS: Forty-seven of the 7.204 patients were diagnosed with COVID-19, seven of whom died; the patients who had symptoms resembling those of COVID-19 but had negative swabs were considered negative for the disease. The overall infection rate was 0.65, and the crude case fatality risk (CFR) in the patients with COVID-19 was 14.9%. There was no difference in the mortality rate among the patients receiving the different individual biological drugs or small molecules. CONCLUSIONS: Our findings suggest that the susceptibility of rheumatic patients to COVID-19 is the same as that of the general population, but confirm that age, disease duration, and the number of co-morbidities are associated with an increased risk of a severe form of the disease. It seems that immunosuppressants drugs do not effectively represent a risk factor for COVID- 19.

The effect of novel coronavirus disease-2019 (COVID-19) on fibromyalgia syndrome.

OBJECTIVES: Fibromyalgia syndrome (FM) is a complex disease that is mainly characterised by chronic widespread pain, fatigue and sleep disturbances and may be precipitated or worsened by many stressors. The aim of this study was to observe the behaviour of FM symptoms during the course of coronavirus disease 2019 (COVID-19). METHODS: Patients who had been diagnosed as having FM for ≥3 months were recruited between February and May 2020. The collected data were age, sex, educational level and marital status; height and weight; and the scores of the revised Fibromyalgia Impact Questionnaire (FIQR), the modified Fibromyalgia Assessment Status 2019 (FASmod), and the Polysymptomatic Distress Scale (PDS). The patients were divided into those with or without concomitant COVID-19 infection. RESULTS: Eight hundred and ninety-seven (93%) of the 965 patients (881 women [91.3%] and 84 men [8.7%]) were followed up on an outpatient basis because of FM and 68 (7.0%) were either followed up as out-patients or hospitalised because of COVID-19. There was no difference in the sociodemographic data of the two groups, but there were statistically significant between-group differences in the results of the clinimetric tests. The major differences between the score of the items (those with the greatest disease impact) were the following related symptoms: sleep quality (FIQR15), fatigue/energy (FIQR13), pain (FIQR12), stiffness (FIQR14). CONCLUSIONS: The mean total and subdomain scores of all the tests were significantly higher in the patients with COVID-19, which suggests that global FM symptoms are more severe in patients with infection. Further studies of the post-COVID19 patients are being carried out in order to discover whether the worsened symptomatology continues because of their hypersensitised state.

The role of a chest computed tomography severity score in coronavirus disease 2019 pneumonia.

The chest computed tomography (CT) characteristics of coronavirus disease 2019 (COVID-19) are important for diagnostic and prognostic purposes. The aim of this study was to investigate chest CT findings in COVID-19 patients in order to determine the optimal cut-off value of a CT severity score that can be considered a potential prognostic indicator of a severe/critical outcome.The CT findings were evaluated by means of a severity score that included the extent (0-4 grading scale) and nature (0-4 grading scale) of CT abnormalities. The images were evaluated at 3 levels bilaterally. A receiver operating characteristics (ROC) curve was used to identify the optimal score (Youden's index) predicting severe/critical COVID-19.The study involved 165 COVID-19 patients (131 men [79.4%] and 34 women [20.6%] with a mean age of 61.5 ±â€Š12.5 years), of whom 30 (18.2%) had severe/critical disease and 135 (81.8%) mild/typical disease. The most frequent CT finding was bilateral predominantly subpleural and basilar airspace changes, with more extensive ground-glass opacities than consolidation. CT findings of consolidation, a crazy-paving pattern, linear opacities, air bronchogram, and extrapulmonary lesions correlated with severe/critical COVID-19. The mean CT severity score was 63.95 in the severe/critical group, and 35.62 in the mild/typical group (P < .001). ROC curve analysis showed that a CT severity score of 38 predicted the development of severe/critical symptoms.A CT severity score can help the risk stratification of COVID-19 patients.

Fibromyalgia: an update on clinical characteristics, aetiopathogenesis and treatment.

Fibromyalgia is characterized by chronic widespread pain, fatigue, sleep disturbances and functional symptoms. The etiopathogenesis, diagnostic criteria and classification criteria of fibromyalgia are still debated and, consequently, so are the strategies for treating this condition. Fibromyalgia is the third most frequent musculoskeletal condition, and its prevalence increases with age. However, although diagnosis has improved with the evolution of more accurate diagnostic criteria, a considerable proportion of physicians still fail to recognize the syndrome. Many factors contribute to the development of fibromyalgia in a unique manner: genetic predisposition, personal experiences, emotional-cognitive factors, the mind-body relationship and a biopsychological ability to cope with stress. The multiple components of the pathogenesis and maintenance of the condition necessitate a multi-modal treatment approach. Individually tailored treatment is an important consideration, with the increasing recognition that different fibromyalgia subgroups exist with different clinical characteristics. Consequently, although an evidence-based approach to fibromyalgia management is always desirable, the approach of physicians is inevitably empirical, and must have the aim of creating a strong alliance with the patient and formulating shared, realistic treatment goals.

Predictive validity of the 5-item Compliance Questionnaire for Rheumatology (CQR5) in detecting poor adherence of patients with rheumatoid arthritis to biological medication.

BACKGROUND: Adherence is a key factor for therapeutic success in patients with rheumatoid arthritis (RA). The aim of this study was to determine whether results from the 5-item Compliance Questionnaire for Rheumatology (CQR5) can predict future poor adherence to biological disease-modifying anti-rheumatic drugs (bDMARDs) in patients with RA, using medication possession ratio (MPR) as the gold standard comparator. METHODS: RA patients starting a bDMARD were prospectively followed for 12 months. At baseline, CQR5 was collected in relation to the prescribed bDMARD. Patients were dichotomised into good adherers and poor adherers, categories that were then used as the variable in a predictive function analysis of the CQR5 in order to determine the accuracy of the classification at the end of the study period in comparison with the MPR. The sensitivity, specificity, and likelihood ratio of detecting poor adherers were also determined because this is the clinically important purpose of the questionnaire. Satisfactory adherence was defined as > 80% compliance with the prescribed dose regimen. RESULTS: Of the 210 RA patients enrolled (147 women and 63 men; mean age 58.6 ± 12.8 years; mean disease duration 7.4 ± 2.5 years), at the end of the 12-month follow-up, 152 patients (72.4%) were good adherers and 58 (27.6%) were poor adherers according to MPR. Predictive analyses showed that the sensitivity and specificity of the CQR5 in detecting poor adherence were respectively 89.9% (95% CI 84.07-94.10%) and 80.8% (95% CI 67.46-90.37%). The accuracy of the CQR5 was 83.04% (95% CI 77.27-87.85%), the positive likelihood ratio (i.e. detecting ≤ 80% adherence) 4.67 (95% CI 2.58-8.18), and the area under curve 0.85 (95% CI 0.79-0.89). CONCLUSION: Higher baseline CQR5 scores significantly predict the treatment adherence of RA patients. This suggests that this instrument could be used for screening purposes in order to identify patients who are poorly adherent to bDMARDs.

Extra-intestinal manifestations of inflammatory bowel diseases.

Inflammatory bowel disease (IBDs), including the two main subtypes of Crohn's disease and ulcerative colitis, not only affects the gastrointestinal system, but also has a wide range of extra-intestinal manifestations (EIMs) that are major sources of morbidity and disability, and therefore represent what can be considered a real syndrome. The pathogenetic mechanisms underlying these EIMs are unknown, but some may share a common pathogenesis with IBD and others may be due to IBD treatment. The aim of this review is to examine our current knowledge of IBD EIMs and their treatment.

Chest CT features of coronavirus disease 2019 (COVID-19) pneumonia: key points for radiologists.

COVID-19 is an emerging infection caused by a novel coronavirus that is moving so rapidly that on 30 January 2020 the World Health Organization declared the outbreak a Public Health Emergency of International Concern and on 11 March 2020 as a pandemic. An early diagnosis of COVID-19 is crucial for disease treatment and control of the disease spread. Real-time reverse-transcription polymerase chain reaction (RT-PCR) demonstrated a low sensibility; therefore chest computed tomography (CT) plays a pivotal role not only in the early detection and diagnosis, especially for false negative RT-PCR tests, but also in monitoring the clinical course and in evaluating the disease severity. This paper reports the CT findings with some hints on the temporal changes over the course of the disease: the CT hallmarks of COVID-19 are bilateral distribution of ground glass opacities with or without consolidation in the posterior and peripheral lung, but the predominant findings in later phases include consolidations, linear opacities, "crazy-paving" pattern, "reversed halo" sign and vascular enlargement. The CT findings of COVID-19 overlap with the CT findings of other diseases, in particular the viral pneumonia including influenza viruses, parainfluenza virus, adenovirus, respiratory syncytial virus, rhinovirus, human metapneumovirus, etc. There are differences as well as similarities in the CT features of COVID-19 compared with those of the severe acute respiratory syndrome. The aim of this article is to review the typical and atypical CT findings in COVID-19 patients in order to help radiologists and clinicians to become more familiar with the disease.

COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome?

A severe outbreak of coronavirus disease 2019 (COVID-19) emerged in China in December 2019, and spread so rapidly that more than 200,000 cases have so far been reported worldwide; on January 30, 2020, the WHO declared it the sixth public health emergency of international concern. The two previously reported coronavirus epidemics (severe acute respiratory syndrome [SARS] and Middle East respiratory syndrome [MERS]) share similar pathogenetic, epidemiological and clinical features as COVID-19. As little is currently known about SARS-CoV-2, it is likely that lessons learned from these major epidemics can be applied to the new pandemic, including the use of novel immunosuppressive drugs.

Adding medical cannabis to standard analgesic treatment for fibromyalgia: a prospective observational study.

OBJECTIVES: To assess any clinical improvement attributable to the addition of medical cannabis treatment (MCT) to the stable (>3 months) standard analgesic treatment of fibromyalgia (FM) patients, the retention rate and any changes in the concomitant analgesic treatment over a period of six months. METHODS: The study involved 102 consecutive FM patients with VAS scores ≥4 despite standard analgesic treatment. Patients were prescribed two oil-diluted cannabis extracts: Bedrocan (22% THC, <1% CBD), and Bediol (6.3% THC, 8% CBD). FM severity was periodically assessed using Fibromyalgia Impact Questionnaire (FIQR), Fibromyalgia Assessment Scale (FAS), FACIT-Fatigue score, Pittsburgh Sleep Quality Index (PSQI), and Zung Depression and Anxiety Scales. During the study, patients were allowed to reduce or stop their concomitant analgesic therapy. RESULTS: The 6-month retention rate was 64%. A significant improvement in the PSQI and FIQR was observed in respectively 44% and 33% of patients. 50% showed a moderate improvement in the anxiety and depression scales. Multiple regression analysis showed a correlation between the body mass index (BMI) and FIQR improvement (p=0.017). Concomitant analgesic treatment was reduced or suspended in 47% of the patients. One-third experienced mild adverse events, which did not cause any significant treatment modifications. CONCLUSIONS: This observational study shows that adjunctive MCT offers a possible clinical advantage in FM patients, especially in those with sleep dysfunctions. The clinical improvement inversely correlated with BMI. The retention rate and changes in concomitant analgesic therapy reflect MCT efficacy of the improved quality of life of patients. Further studies are needed to confirm these data, identify MCT-responsive sub-groups of FM patients, and establish the most appropriate posology and duration of the therapy.

Exercise therapy in fibromyalgia patients: comparison of a web-based intervention with usual care.

OBJECTIVES: The aim of this study was to investigate the effectiveness of a web-based exercise intervention in improving the severity of symptoms in different health domains in patients with fibromyalgia (FM). METHODS: Consecutive FM patients insufficiently responding to drug treatment (defined as a score of >4 on a numerical rating scale of pain) were enrolled in a web-based intervention group (Fibro-Web) and underwent a 24-week daily home exercise programme. They were evaluated through the revised Fibromyalgia Impact Questionnaire (FIQR) and the Modified Fibromyalgia Assessment Status questionnaire (Mod FAS) at baseline, and then every two weeks until the end of the programme. The outcomes were compared with those of patients receiving usual care. RESULTS: The final analysis was based on 140 patients: 68 in the Fibro-Web group and 72 in the usual care group. At the end of the 24-week study period, the patients in the Fibro-Web group showed a significant improvement in overall and sub-scale scores of the FIQR (p=0.0279) and Mod FAS (p=0.0057), expressed as time-integrated values. This improvement started in the 16th week. CONCLUSIONS: The use of a web-based daily exercise programme in FM patients significantly improves disease severity indices.