Arthralgias, fatigue, paresthesias and visceral pain: can joint hypermobility solve the puzzle? A case report

Background: Joint hypermobility syndrome describes a disorder in which musculoskeletal pain occurs in a generalized joint hypermobility substrate. The clinical picture comprises variable manifestations which involve mainly but not exclusively the musculoskeletal system, and evolve over the person's lifetime. Case presentation: Describing the case of a 20-year-old female with generalized arthro-myalgias, persistent fatigue and troublesome visceral pain, we illustrate how a frequently ignored clinical sign such as joint hypermobility can be the keystone to clarify different simultaneous symptoms. All of the patient's physical complaints had been investigated separately during her previous medical examinations, and several tests repeatedly gave negative results. The patient received different diagnoses that describe only part of her problems, such as irritable bowel syndrome for visceral pain, fibromyalgia for arthralgias or depression for fatigue. These approaches gave rise to pharmacological or physical treatments which did not improve her quality of life in any way and in some instances worsened the situation. Pronounced joint hypermobility which led the patient to flex her joints excessively, causing subluxations in several districts, was the only sign overlooked. Conclusion: Exploring the patient's articular features in her clinical context led us to diagnose joint hypermobility syndrome, a complex and often ignored condition. The case highlights the utility of a multidisciplinary approach and coordinated interventions to define and manage this clinical entity

Correlation between serum ANCA and cancer: a decade-long retrospective analysis of an Italian cohort

BackgroundSerum antineutrophil cytoplasmic antibodies (ANCA) are autoantibodies primarily linked with ANCA-associated vasculitides (AAV) but associated diseases include also other autoimmune diseases, infections, and malignancies. However, the association of ANCA with cancer risk remains undefined, especially in patients without AAV.ObjectiveThe aim of this study was to identify the incidence of malignancies in a large cohort during a 10-year period and to compare the incidence in ANCA-positive versus ANCA-negative subjects.MethodsA retrospective cohort study involving 6285 subjects who underwent ANCA testing was performed at Humanitas Research Hospital (ICH) (Rozzano, Italy) from 2007 to 2017, regardless of the clinical indication for ANCA testing. After retrieving comorbidity data from electronic health records, we classified chronic conditions into six major categories and generated a propensity score including age, gender, time of blood draw, and comorbidities. A 1:2 matching was performed, yielding a final cohort of 214 ANCA-positive and 319 ANCA-negative subjects. The ICH Cancer Diagnosis Registry was used to assess cancer incidence. Competing risk regression was performed using the Fine & Gray model to estimate cancer risk associated with pANCA positivity. The cANCA-positive group (n = 44) was excluded from regression analysis due to the absence of cancer events.ResultsDuring a mean follow-up of 3.9 years, 43 patients had a diagnosis of cancer (9/214 ANCA-positive patients, and 34/319 ANCA-negative patients; Chi-square p 0.007). In the pANCA-positive subgroup, no significant difference in cancer incidence was observed compared to ANCA-negative subjects. ANCA-negative subjects did not have significantly longer survival after cancer diagnosis compared with pANCA-positive patients (median survival: 203 days [IQR 120-309] vs. 266 days [IQR 124-580]). In competing risk regression analysis, no association was found between positive pANCA and cancer risk (HR 0.50; CI 95% 0.240–1.043; p 0.065).The results were consistent even when AAV cases were excluded (HR 0.53; 95% CI 0.24–1.16).ConclusionIsolated ANCA positivity is not associated with a higher incidence of malignancy. There was no significant difference in post-cancer survival between ANCA-negative and pANCA-positive subjects. The absence of malignancies in the cANCA subgroup should be interpreted with caution given the small sample size. These observations should be confirmed by prospective studies, which also should ascertain the possible underlying mechanisms

Mepolizumab for Eosinophilic Granulomatosis With Polyangiitis: A European Multicenter Observational Study.

OBJECTIVE: Mepolizumab proved to be an efficacious treatment for eosinophilic granulomatosis with polyangiitis (EGPA) at a dose of 300 mg every 4 weeks in the randomized, controlled MIRRA trial. In a few recently reported studies, successful real-life experiences with the approved dose for treating severe eosinophilic asthma (100 mg every 4 weeks) were observed. We undertook this study to assess the effectiveness and safety of mepolizumab 100 mg every 4 weeks and 300 mg every 4 weeks in a large European EGPA cohort. METHODS: We included all patients with EGPA treated with mepolizumab at the recruiting centers in 2015-2020. Treatment response was evaluated from 3 months to 24 months after initiation of mepolizumab. Complete response to treatment was defined as no disease activity (Birmingham Vasculitis Activity Score [BVAS] = 0) and a prednisolone or prednisone dose (or equivalent) of ≤4 mg/day. Respiratory outcomes included asthma and ear, nose, and throat (ENT) exacerbations. RESULTS: Two hundred three patients, of whom 191 received a stable dose of mepolizumab (158 received 100 mg every 4 weeks and 33 received 300 mg every 4 weeks) were included. Twenty-five patients (12.3%) had a complete response to treatment at 3 months. Complete response rates increased to 30.4% and 35.7% at 12 months and 24 months, respectively, and rates were comparable between mepolizumab 100 mg every 4 weeks and 300 mg every 4 weeks. Mepolizumab led to a significant reduction in BVAS score, prednisone dose, and eosinophil counts from 3 months to 24 months, with no significant differences observed between 100 mg every 4 weeks and 300 mg every 4 weeks. Eighty-two patients (40.4%) experienced asthma exacerbations (57 of 158 [36%] who received 100 mg every 4 weeks; 17 of 33 [52%] who received 300 mg every 4 weeks), and 31 patients (15.3%) experienced ENT exacerbations. Forty-four patients (21.7%) experienced adverse events (AEs), most of which were nonserious AEs (38 of 44). CONCLUSION: Mepolizumab at both 100 mg every 4 weeks and 300 mg every 4 weeks is effective for the treatment of EGPA. The 2 doses should be compared in the setting of a controlled trial

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Cutting Edge: Biomarkers for Chronic Spontaneous Urticaria

Chronic spontaneous urticaria (CSU) is defined by the appearance of wheals and a variable presence of angioedema which persists for at least 6 weeks. It represents the most common subtype of chronic urticaria and is gaining importance in civil society because of its association with impaired quality of life. Moreover, CSU has a growing impact on national health systems representing a great burden due to its variable rate of response to the approved therapies. In this scenario, the identification of clinical and molecular biomarkers is of pivotal importance. Some groups are trying to detect molecules which would be able to help clinicians in reaching a proper diagnosis; additionally, the opportunity to describe disease severity which leads to cluster patients in different groups could fill the gap in the numerous unmet clinical needs. Several biomarkers are currently being studied with the purpose to predict the response to a defined therapy; unfortunately, none of them are ready to be translated from bench to bedside

ANCA-Associated Vasculitides and Hematologic Malignancies: Lessons from the Past and Future Perspectives

The purpose of this paper is to collect and summarize all evidences relating to an association between ANCA-associated vasculitides (AAVs) and hematologic malignancies, in the form of either a paraneoplastic vasculitis or leukemias and lymphomas developing on a preexisting vasculitis. Additionally, the role of cyclophosphamide in vasculitis treatment has been assessed and compared to rituximab. Paraneoplastic AAV seems to be an uncommon presentation of hemopathies. Hematologic malignancy risk in AAV is more likely to be increased by cyclophosphamide, although not yet definitely proven. Furthermore, the pathogenesis of ANCA-associated vasculitis has been reviewed with particular emphasis on the role of proteinase 3 (PR3) in fuelling granulomatosis with polyangiitis (GPA) inflammation. PR3 is a bactericidal protein expressed by neutrophilic granules and on their plasma membrane. Derangements in its expression and function have been linked to leukemias and GPA alike. PR3-derived PR1 peptide is being studied as an immunotherapy target in leukemia and multiple myeloma. This study is aimed at bringing together various evidences from the field of immunological and hematological research, at exposing contradictions, and at revealing novel insights on the association between ANCA-associated vasculitis and hematologic malignancies