The "great imitator": IgG4-related disease of the oral cavity. Two case reports and scoping review.

This study aimed to review the lesser-known intraoral manifestations of immunoglobulin G4-related disease (IgG4-RD). In this paper we report an unprecedented case of oral IgG4-RD mimicking angiolymphoid hyperplasia with eosinophilia (ALHE), and another case presenting as plasma cell gingivitis. We then performed a scoping review of published cases of IgG4-RD involving the oral cavity. The following data were collected for each case: age, sex, intraoral site(s) involved, clinical appearance, imaging features, serum IgG4 values, histopathology, treatment, and follow-up duration. Fifty-one cases of oral IgG4-RD were published in literature. The hard palate and jaw bones were the two main locations reported, while the histological identification of a IgG4/IgG plasma cells ratio ≥40% was fundamental for diagnosis. Conversely, the pathological features of storiform fibrosis and obliterative phlebitis were not common. Future reports regarding oral IgG4-RD should report clear adherence to the recognized international diagnostic criteria of the disease.

Venous and arterial thromboembolic risk of Janus kinase inhibitors: a systematic review with meta-analysis.

OBJECTIVE: Preliminary data led licencing authorities to alert clinicians of an increased venous thrombotic risk associated to the use of Janus kinase (JAK) inhibitors (JAKi). We performed a systematic review to estimate the risk of venous and arterial thrombosis associated to JAKi for the treatment of immune-mediated inflammatory diseases (IMIDs). METHODS: Randomized controlled trials (RCTs) on JAKi in patients with IMIDs were identified by the MEDLINE and EMBASE databases until October 2021. Risk of bias was assessed according to Cochrane criteria. The beta-binomial model was applied to calculate pooled odds ratio (OR) and corresponding 95% CI. The PROSPERO registration number is CRD42022324143. RESULTS: We have included one phase I, 21 phase II, three phase II-III and 36 phase III RCTs for a total of 19 443 patients in the JAKi group and 6354 in the control group. Thirty-one (unweighted rate 0.16%; 95% CI: 0.10, 0.21) events were reported in the JAKi group and 20 (unweighted rate 0.22%; 95% CI: 0.12, 0.32) in the control group in a mean follow-up of 16.8 weeks. IMID patients treated with JAKi did not have an increased thromboembolic risk compared with those treated with placebo (OR 0.82; 95% CI: 0.43, 1.56). No statistically different results were seen in subanalyses for each investigated IMID, drug and dosage. CONCLUSION: JAKi do not increase thromboembolic risk compared with placebo in IMID patients enrolled in selected RCTs.

Fibromyalgia severity according to age categories: results of a cross-sectional study from a large national database.

OBJECTIVES: The role of age in influencing the severity of fibromyalgia (FM) is still controversial. The aim of this study is to define the contribution of age in the severity of FM from data from a large national database. METHODS: This cross-sectional study included adult patients with FM diagnosed according to the 2010/2011 American College of Rheumatology criteria. Disease severity was assessed with the revised Fibromyalgia Impact Questionnaire (FIQR) and the modified Fibromyalgia Assessment Status (FAS 2019mod). Patients were grouped into five age categories (between 18-40 years, between 41-50 years, between 51-60 years, between 61-70 years, and ≥71 years). Differences in disease severity between groups were assessed by one-way analysis of variance (ANOVA). RESULTS: The study included 2889 patients (199 males and 2690 females), mean age of 52.58 (±11.82) years, with a mean FIQR score of 59.22 (±22.98) and a mean FAS 2019mod of 25.50 (±8.66). Comparing the mean values of the various indices between age categories, there were no statistically significant differences between the groups for FIQR total score and FAS 2019mod. However, the 60-70 years category showed the lowest scores for both scales. The main difference emerged for the FIQR physical function subscale, where the ≥71 years category showed significantly higher scores (p<0.05) compared the 18-40 years category. CONCLUSIONS: The severity of FM has a significant level of stationarity according to age categories. Patients between 60-70 years have a lower disease burden. Physical function is the health domain with the most significant difference between the groups.

Evidence-based efficacy of methotrexate in adult Crohn's disease in different intestinal and extraintestinal indications.

Introduction: Methotrexate (MTX) is included in the therapeutic armamentarium of Crohn's disease (CD), although its positioning is currently uncertain in an era in which many effective biological drugs are available. No systematic reviews or meta-analysis have stratified the clinical outcomes of MTX according to the specific clinical scenarios of its use. Methods: Medline, PubMed and Scopus were used to extract eligible studies, from database inception to May 2021. A total of 163 studies were included. A systematic review was performed by stratifying the outcomes of MTX according to formulation, clinical indication and criteria of efficacy. Results: The use of MTX is supported by randomized clinical trials only in steroid-dependent CD, with similar outcomes to thiopurines. The use of MTX in patients with steroid-refractoriness, failure of thiopurines or in combination with biologics is not supported by high levels of evidence. Combination therapy with biologics can optimize the immunogenic profile of the biological drug, but the impact on long-term clinical outcomes is described only in small series with anti-TNFα. Other off-label uses, such as fistulizing disease, mucosal healing, postoperative prevention and extraintestinal manifestations, are described in small uncontrolled series. The best performance in most indications was shown by parenteral MTX, favouring higher doses (25 mg/week) in the induction phase. Discussion: Evidence from high-quality studies in favour of MTX is scarce and limited to the steroid-dependent disease, in which other drugs are the leading players today. Many limitations on study design have been found, such as the prevalence of retrospective underpowered studies and the lack of stratification of outcomes according to specific types of patients and formulations of MTX. Conclusion: MTX is a valid option as steroid-sparing agent in steroid-dependent CD. Numerous other clinical scenarios require well-designed clinical studies in terms of patient profile, drug formulation and dosage, and criteria of efficacy.

The association between body mass index and fibromyalgia severity: data from a cross-sectional survey of 2339 patients.

OBJECTIVE: Various studies have shown that overweight and obesity are central features of FM, but the real impact of a high BMI on clinical severity in patients with FM is still controversial. The aim of this study was to analyse the relationships between BMI categories and measures of symptom severity and functional impairment using data from a Web-based registry of patients with FM. METHODS: Adult patients with an ACR 2010/2011 diagnosis of FM underwent a complete physical examination and laboratory tests and were asked to complete a package of questionnaires covering their sociodemographic and treatment details, in addition to the following disease-specific questionnaires: the revised Fibromyalgia Impact Questionnaire (FIQR), the modified Fibromyalgia Assessment Status questionnaire (ModFAS) and the Polysymptomatic Distress Scale (PDS). RESULTS: A total of 2339 patients were recruited and divided into two weight categories, underweight/normal (U/N, n = 1127, 48.2%) and overweight/obese (O/O, n = 1212, 51.8%). The total and subscales of FIQR, ModFAS and PSD scores were significantly higher in the O/O patients, as were all the mean scores of the individual FIQR items (P < 0.001 for all). CONCLUSION: Our findings demonstrate that O/O patients with FM are significantly more impaired than U/N patients in all the symptomatological and functional domains as measured using the FIQR, ModFAS and PDS, thus suggesting that being O/O has an additional effect on symptoms and function.

JAK inhibitors and psoriatic arthritis: A systematic review and meta-analysis.

BACKGROUND: Despite the therapeutic armamentarium for the treatment of psoriatic arthritis (PsA) has considerably expanded over the last thirty years, additional drugs are needed to improve care of this disease. JAK inhibitors (JAKinhibs) are small molecules able to interfere with the JAK/STAT pathway, involved in the pathogenesis of PsA. Tofacitinib and Upadacitinib were recently approved for the treatment of PsA. Our aim was to assess the efficacy and safety of JAKinhibs for the treatment of PsA. METHODS: A systematic review of the literature was performed to identify RCTs by electronic search of MEDLINE and EMBASE database until April 2021. RCTs were considered eligible if included only patients with PsA treated with JAKinhibs. The pooled efficacy and safety outcomes were calculated by meta-analysis and expressed as odds ratio (OR) and 95% confidence intervals (95% CI). Statistical heterogeneity was assessed with the I2 statistic. RESULTS: Five RCTs for a total of 3293 PsA patients treated with different JAKinhibs or placebo were included (2 phase III studies on Tofacitinib, 1 phase II study on Filgotinib and 2 phase III studies on Upadacitinib). All the studies were judged at low risk of bias according to Cochrane criteria. JAKinhibs showed a significantly higher ACR20 response rate compared to placebo (OR 3.78, 95% CI 2.72-5.24, I^2 = 57%, random effect model).and were associated with a non-statistically significant higher risk of serious adverse events (OR 1.12, 95% CI 0.14-2.82, I^2 = 46%, random effect model). CONCLUSIONS: This is the first systematic review that performed a comprehensive evaluation of the efficacy and safety of JAKinhibs for PsA in RCTs. Our analysis suggests a statistically significant benefit of JAKinhibs that appear to be effective and safe over placebo for the treatment of PsA.

The role of IL-6 and IL-6 blockade in COVID-19.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a dysregulated hyperinflammatory response. AREAS COVERED: Authors review evidence on IL-6 and IL-6 blockade in coronavirus disease 2019 (COVID-19) and discuss the pathophysiological and prognostic roles of this cytokine and the clinical impact of pharmacological blockade of IL-6 . The material includes original articles and reviews published from March 2020 to March 2021 and searched on PubMed, medRxiv, and bioRxiv. EXPERT OPINION: IL-6 is one of the most prominent pro-inflammatory cytokines. Increased levels are recorded in COVID-19 patients, especially those with severe-to-critical disease. Evidence is accumulating on the relevance of IL-6 as a prognostic marker in COVID-19. Since IL-6 is a druggable target for several inflammatory diseases, pharmacological blockers of the IL-6 signaling pathway were repurposed to blunt the abnormal SARS-CoV-2-induced cytokine release. Data are limited to few randomized controlled trials that reported encouraging, though not conclusive, results, indicating the usefulness of IL-6 blockade early in the course of the disease in patients with hyperinflammation and no or limited organ damage. Further research is warranted to explore the role of IL-6 in different COVID-19 phenotypes and identify subgroups of patients who may mostly benefit from IL-6 pathway inhibition.

Long-term methotrexate use in rheumatoid arthritis patients: real-world data from the MARTE study.

BACKGROUND: The MARTE study investigated the demographic, clinical, and therapeutic characteristics of rheumatoid arthritis (RA) patients ongoing methotrexate (MTX) treatment for longer than 8 years. METHODS: This cross-sectional, observational study considered 587 RA patients from 67 Rheumatology Units across Italy. Data collected included demographic, clinical, and therapeutic characteristics, focusing on MTX prescription patterns (route of administration, dosing regimens, treatment duration, and discontinuation). RESULTS: As initial therapy, 90.6% of patients received one conventional synthetic Disease Modifying Anti Rheumatic Drug (csDMARD), with treatment started within the first 3 months from diagnosis in half of the patients. MTX was the first csDMARD in 46.2% of patients. The prevalent route of administration at diagnosis was the intramuscular (60.5%), while at study entry (baseline) 57.6% were receiving subcutaneous MTX. Patients who required a higher MTX dose at study entry were those who received a significantly lower starting MTX dose (P<0.001). Significantly higher MTX doses were currently required in men (P<0.001), current smokers (P=0.013), and overweight patients (P=0.028), whereas patients on oral therapy received significantly lower doses of MTX (P<0.001). CONCLUSIONS: The MARTE study confirms once again the potential of the proper use of MTX in the treatment of RA. Data from our study suggest that a higher dose of MTX should be used since the first stages in overweight patients, men, and smokers.

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.

Use of ultrasound in treatment decisions for patients with rheumatoid arthritis: an observational study in Italy.

In rheumatoid arthritis (RA), treatment response is generally assessed using standard clinical disease activity measures. However, ultrasound has become increasingly popular among rheumatologists to monitor disease activity and response. The purpose of this analysis of ECOgraphic evaluation for STaging ARthritis (ECOSTAR) study data was to determine how ultrasound affects clinicians' decisions about changing treatment in RA. ECOSTAR was an observational, cohort study conducted between March 2010 and December 2012 at nine clinical centers in Italy in RA patients being considered for treatment change. After clinical evaluation of each patient, patients underwent diagnostic ultrasound (US) investigations and each patient was given a total echography score using a combination of scores for joint effusion, synovial hypertrophy, and power Doppler. The US results were provided to the clinicians and the influence of US on the clinicians' treatment choices were recorded. Ninety-five patients screened for study inclusion had confirmed RA (mean age 53.9 years; mean disease duration 8.9 years). Therapy changes were made by clinicians according to the hand and wrist joint US scores: score 0 appeared to have no influence on clinicians' decision to modify treatment, scores >0-3 were associated with a numerically higher estimated probability of not changing therapy than changing therapy, and scores >3 had a greater influence on the clinician to modify therapy and an increased probability of the clinician changing therapy versus not changing therapy. Ultrasonography scores appear to influence treatment decisions in patients with RA, with clinicians appearing less likely to alter treatment regimens in patients with low ultrasound scores and more likely to change treatment regimens when higher scores are obtained. Further research is warranted.