Cryoglobulinemic vasculitis: a 2023 update.

PURPOSE OF REVIEW: Cryoglobulinemic vasculitis (CV) is an immune complex mediated small vessel vasculitis characterized by the presence of cryoglobulins in serum, often associated with hepatitis C infection, systemic autoimmune diseases or hematological conditions. The focus of this review is to provide an update on new insights into pathogenesis, epidemiology and therapies of infectious and noninfectious type II and type III CV. RECENT FINDINGS: The introduction of new antiviral drugs for treatment of hepatitis C infection implied major changes in HCV-related CV, allowing to shed new lights on CV pathogenesis and mechanisms of relapse and, therefore, to increase the relevance of autoimmune diseases in CV epidemiology. Specific B-cell clones are involved in the production of pathogenic immune complexes that leads to small-vessel vasculitis. Therefore, both antiviral treatments [direct-acting antivirals (DAAs) and oral nucleot(s)ide analogues] and targeted anti-CD20 therapies (rituximab) prove to be safe and effective options, leading to a better prognosis. Association of Sjögren syndrome and CV defines a specific phenotype of patients, characterized by severe manifestations and poor outcome. SUMMARY: Removing viral stimulation on B-cells through direct-acting antivirals and blocking B-cells proliferation and differentiation with rituximab are the goals of treatment of CV. However, further research is needed to identify prognostic factors of refractory and relapsing disease.

Exploring relief for Behçet's disease refractory oral ulcers: a comparison of TNF inhibitors versus apremilast.

OBJECTIVES: Oral and genital ulcers are the hallmark manifestation of Behçet's disease (BD), significantly impacting patients' quality of life. Our study focuses on comparing the effectiveness and safety of TNF inhibitors (TNFis) and apremilast in controlling oral ulcers of BD, aiming to provide evidence-based guidance for physicians in selecting appropriate treatment modalities. METHODS: A retrospective analysis was performed on BD patients treated between December 2016 and December 2021 with TNFis or apremilast for refractory oral ulcers. The study assessed treatment response by the absence of oral ulcers at 3 and 6 months, with additional evaluations for genital ulcers and articular involvement. RESULTS: The study included 78 patients, equally allocated between TNFis and apremilast treatments. Both groups showed significant oral ulcer reduction at 3 (p< 0.001) and 6 months (p= 0.01) with no significant difference between the treatments. Apremilast had a notable corticosteroid-sparing effect by the 3-month follow-up, persisting through 6 months. Both treatments were equally effective in reducing genital ulcers, with TNFis showing greater effectiveness in addressing articular involvement. Apremilast had a higher discontinuation rate due to gastrointestinal side effects. CONCLUSION: TNFis and apremilast are both effective for treating BD refractory oral ulcers. While TNFis may offer broader benefits for other disease manifestations, apremilast is distinguished by its corticosteroid-sparing effect, especially for patients with a milder disease phenotype. Treatment selection should consider individual disease severity and clinical features to ensure a personalized and effective management strategy.

The role of tobacco smoking in anti-neutrophil cytoplasmic antibody-associated vasculitis: a systematic review.

OBJECTIVES: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of systemic pauci-immune necrotising vasculitides involving small vessels, characterised by the presence of specific ANCA autoantibodies directed to leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA) and subdivided into three clinical entities: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). The aetiology of AAV is unknown and many genetic, epigenetic and environmental factors have been reported to be involved in pathogenesis. Smoking is widely recognised as a risk factor for the development of many autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. This systematic review will analyse known data about the role of smoking in the development, clinical presentation and outcome of AAV. METHODS: Articles that examined interactions between tobacco smoking and AAV (GPA, MPA, EGPA) were included. All articles selected were in English. No limitation on publication date was established. Case reports were excluded. The systematic search was performed using PubMed/Medline and Cochrane Library databases. RESULTS: The search provided a total of 131 articles. Three studies were added, obtained from the review of the reference lists of articles. 70 were removed because they were duplicated or written in languages other than English. The title and abstract of 64 articles were screened. Of these, 30 were excluded as the title and/or abstract did not meet the inclusion criteria. Thus, 34 remained for full-text review, of which 8 were excluded. 26 articles were therefore included in this review. The role of smoking in AAV development is unclear. AAV patients current smoking appear appear to be younger and more frequently males, with a lower prevalence of EGPA and MPA than GPA. Ever smokers show higher relapse rate. Smoking seems to be associated with a higher risk of cardiovascular events during follow-up. Smokers incur an increased risk of infections. Finally, many data support smoking as a risk factor for end stage renal disease and mortality in AAV patients. CONCLUSIONS: Current data support the hypothesis that smoking influences prevalence, clinical phenotype and prognosis of ANCA-associated vasculitis. However, further studies are required to fully determine its role.

The impact of environmental factors on aetiopathogenesis and clinical manifestations of Behçet's syndrome.

Behçet's syndrome (BS) is a rare multisystem vasculitis involving blood vessels of any size. BS aetiology is still unclear to date, and the heterogeneity of clinical expression among ethnics and genders make early diagnosis challenging. However, so far, considerable efforts have been made toward the understanding of BS, leading researchers to agree that the coexistence of some environmental triggers and a genetical susceptibility both underlie BS aetiopathogenesis. In particular, viral agents, oral microbial flora, and mucosal microbiota have been widely explored in this regard, but still no specific microorganism has been definitely linked to the disease aetiology. Likewise, the concept that some environmental factors may play a role in BS clinical presentation has emerged based on the growing evidence that disease severity is usually higher in male patients, and that diet and fatigue may be involved in disease recurrence, especially in mucocutaneous manifestations. Moreover, smoke cessation is acknowledged as a risk factor for oral ulcerations, although the underlying mechanism is still not clear. All those environmental factors play their effects through epigenetic mechanisms. The aim of this review is to discuss the evidence on the role of environmental factors in BS aetiopathogenesis and clinical course.

Systemic vasculitis: one year in review 2024.

Systemic vasculitides comprise a collection of rare and heterogeneous disorders capable of impacting any organ and system, posing a considerable burden of mortality and comorbidity. As with previous annual reviews of this series, this review will offer a critical overview of the latest literature on pathogenesis, biomarkers, and treatment options in both small- and large-vessel vasculitis.

Baricitinib and Pulse Steroids Combination Treatment in Hyperinflammatory COVID-19: A Rheumatological Approach in the Intensive Care Unit.

Hyperinflammatory Coronavirus disease 2019 (COVID-19) and rapidly-progressive interstitial lung diseases (RP-ILD) secondary to inflammatory myopathies (IIM) present important similarities. These data support the use of anti-rheumatic drugs for the treatment of COVID-19. The aim of this study was to compare the efficacy of combining baricitinib and pulse steroids with the Standard of Care (SoC) for the treatment of critically ill COVID-19 patients. We retrospectively enrolled consecutive patients admitted to the Intensive Care Unit (ICU) with COVID-19-pneumonia. Patients treated with SoC (dexamethasone plus remdesivir) were compared to patients treated with baricitinib plus 6-methylprednisolone pulses (Rheuma-group). We enrolled 246 patients: 104/246 in the SoC and 142/246 in the Rheuma-group. All patients presented laboratory findings suggestive of hyperinflammatory response. Sixty-four patients (26.1%) died during ICU hospitalization. The mortality rate in the Rheuma-group was significantly lower than in the SoC-group (15.5 vs. 40.4%, p < 0.001). Compared to the SoC-group, patients in the Rheuma-group presented significantly lower inflammatory biomarker levels after one week of treatment. Higher ferritin levels after one week of treatment were strongly associated with mortality (p < 0.001). In this large real-life COVID-19 cohort, baricitinib and pulse steroids led to a significant reduction in mortality, paralleled by a prompt reduction in inflammatory biomarkers. Our experience supports the similarities between hyperinflammatory COVID-19 and the IIM-associated RP-ILD.

Behçet's syndrome: one year in review 2023.

This critical review of studies on Behçet's syndrome published during 2022 includes studies on epidemiology, patients' perspective, pathogenesis, diagnosis, clinical features and management. Studies on pathogenesis included potential biomarkers mostly related to macrophages, neutrophil and cytokine balance, new GWAS and polymorphism studies, and studies on miRNAs and long non-coding RNAs. Clinical studies showed that application of pneumococcal vaccine to the prick site increased the sensitivity and specificity of the pathergy test and the prevalence of AA amyloidosis had decreased over the years. Studies on management indicated that more data are needed to understand the effect of apremilast on BS manifestations other than oral ulcers, and new BS manifestations may develop during treatment with infliximab. Other biologics and Jak inhibitors might be an option for patients who are refractory to TNF-α inhibitors. Moreover, endovascular repair of arterial aneurysms might be an alternative to open surgery.

Systemic vasculitis: one year in review 2023.

Systemic vasculitides are heterogeneous disabling diseases characterised by chronic inflammation of the blood vessels potentially leading to tissue destruction and organ failure. The recent COVID-19 pandemic has had a significant impact on the epidemiology and management of patients with systemic vasculitis. In parallel, new insights have been provided on systemic vasculitis pathogenetic mechanisms, possible new therapeutic targets, and newer glucocorticoid-sparing treatments with better safety profiles. As in the previous annual reviews of this series, in this review we will provide a critical digest of the most recent literature regarding pathophysiology, clinical manifestations, diagnostic tools and treatment options in small- and large-vessel vasculitis focusing on precision medicine in vasculitis.

ERN ReCONNET points to consider for treating patients living with autoimmune rheumatic diseases with antiviral therapies and anti-SARS-CoV-2 antibody products.

Recent studies have shown that people who are immunocompromised may inadvertently play a role in spurring the mutations of the virus that create new variants. This is because some immunocompromised individuals remain at risk of getting COVID-19 despite vaccination, experience more severe disease, are susceptible to being chronically infected and remain contagious for longer if they become infected and considering that immunocompromised individuals represent approximately 2% of the overall population, this aspect should be carefully considered. So far, some autoimmune rheumatic disease (ARD) patients with COVID-19 have been treated with antiviral therapies or anti-SARS-CoV-2 antibody products. However, there is no homogeneous approach to these treatment strategies. This issue was addressed within the European Reference Network (ERN) on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ReCONNET) in a discussion among experts and patient's representatives in the context of the rare and complex connective tissue diseases (rCTDs) covered by the Network. ERN ReCONNET is one of the 24 ERNs launched by the European Commission in 2017 with the aim of tackling low prevalence and rare diseases that require highly specialised treatment and promoting concentration of knowledge and resources through virtual networks involving healthcare providers (HCPs) across the European Union (EU). Considering the urgent need to provide guidance not only to the rCTDs community, but also to the whole ARDs community, a multidisciplinary Task Force, including expert clinicians and European Patient Advocacy Group (ePAG) Advocates, was created in the framework of ERN ReCONNET with the aim of developing overarching principles (OP) and points-to-consider (PtC) on a homogenous approach to treat immunocompromised patients with ARDs (with a particular focus on CTDs) affected by COVID-19 using antiviral therapies and anti-SARS-CoV-2 antibody products. The present work reports the final OP and PtC agreed by the Task Force.

Behçet's syndrome: one year in review 2022.

This review highlights publications on different aspects of Behçet's syndrome (BS) that appeared in 2021 and provides a critical view. These publications include works on the epidemiology of BS across different continents, newly developed instruments to assess damage in BS, studies highlighting the immunopathogenesis, genetics and epigenetic factors, histopathology of the pathergy lesion, clinical and imaging aspects of vascular involvement, and safety and efficacy of therapeutic agents including tocilizumab, apremilast and direct oral anticoagulants.

Assessing quality of life in Behçet's disease: a systematic review.

OBJECTIVES: The assessment of quality of life (QoL) in Behçet's disease (BD) patients has been a surrogate of disease outcomes, but a wider impact on the patient's lifestyle has not been considered. This systematic review aims to provide an overview of the existing tools specifically adopted to explore the QoL in BD patients. METHODS: A systematic literature review was conducted using 2 electronic databases, according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. A combination of BD and QoL-related search terms were used. All articles were screened by 3 independent reviewers for title, abstract and full text level. Studies investigating QoL in BD patients were included. RESULTS: 64 papers of 497 records were retained. Data about 7,449 patients with a BD diagnosis and QoL evaluation were collected. 47 different tools to evaluate QoL were detected. The mean number of tools adopted in each study was 2.14±1.34. General QoL and psychological and social impact were investigated in 68.75% and 54.69% respectively. The correlation with disease activity was investigated in 71.86%. CONCLUSIONS: The assessment of QoL in BD patients may provide a fundamental measurement for health to evaluate the outcome of interventions for BD patients. The adoption of a single validated QoL tool, developed including the BD patient's perspective, may provide an accurate and effective assessment, ensure the comparison within different cohorts, and set standardised values to define QoL level in BD patients.

Systemic vasculitis: one year in review 2022.

Systemic vasculitis are rare heterogeneous disorders potentially involving any organ and system with a relevant burden of mortality and comorbidity.As in the previous annual reviews of this series, in this review we will provide a critical digest of the most recent literature regarding pathophysiology, clinical manifestations, diagnostic tools and treatment options in small- and large-vessel vasculitis.

Blood biomarkers recommended for diagnosing and monitoring IgG4-related disease. Considerations from the ERN ReCONNET and collaborating partners.

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a chronic, clinically heterogenous fibroinflammatory condition, characterised by an accumulation of IgG4 secreting plasma cells in affected tissues and associated with increased serum IgG4 concentrations. Despite a growing recognition of the disease among clinicians from different specialties worldwide, its indolent nature, lack of a single diagnostic test and ability to mimic other malignant, infective and inflammatory conditions, makes the diagnosis challenging. As treatment options evolve, biomarkers correlating with disease activity, predicting prognosis and response to treatment are deemed required. A multidisciplinary panel of experts from the European Reference Network for Rare and Complex Connective tissue diseases (ERN ReCONNET) and affiliated international partners have performed a narrative literature search and reviewed the current evidence of biomarkers in IgG4-RD, including immunoglobulins, cytokines, chemokines and other soluble immune mediators, and cellular components of the immune system. The aim of this paper is to provide useful information for clinicians as to the utility of biomarkers for diagnosing and monitoring IgG4-RD in clinical routine and sets out recommendations for clinical decision making.

Sjögren's syndrome and other rare and complex connective tissue diseases: an intriguing liaison.

Sjögren's syndrome (SS) is a systemic autoimmune disease that frequently occurs concomitantly with other systemic connective tissue disorders, including rare and complex diseases such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). The presence of SS influences the clinical expression of the other autoimmune diseases, thus offering the unique opportunity to explore the similarities in genetic signatures, as well as common environmental and biologic factors modulating the expression of disease phenotypes. In this review, we will specifically discuss the possibility of defining "SS/SLE" and "SS/SSc" as distinct subsets within the context of connective tissue diseases with different clinical expression and outcomes, thus deserving an individualised assessment and personalised medical interventions.

The added value of a European Reference Network on rare and complex connective tissue and musculoskeletal diseases: insights after the first 5 years of the ERN ReCONNET.

In order to address the main challenges related to the rare diseases (RDs) the European Commission launched the European Reference Networks (ERNs), virtual networks involving healthcare providers (HCPs) across Europe. The mission of the ERNs is to tackle low prevalence and RDs that require highly specialised treatment and a concentration of knowledge and resources. In fact, ERNs offer the potential to give patients and healthcare professionals across the EU access to the best expertise and timely exchange of lifesaving knowledge, trying to make the knowledge travelling more than patients. For this reason, ERNs were established as concrete European infrastructures, and this is particularly crucial in the framework of rare and complex diseases in which no country alone has the whole knowledge and capacity to treat all types of patients.It has been five years since their kick-off launch in Vilnius in 2017. The 24 ERNs have been intensively working on different transversal areas, including patient management, education, clinical practice guidelines, patients' care pathways and many other fundamental topics. The present work is therefore aimed not only at reporting a summary of the main activities and milestones reached so far, but also at celebrating the first 5 years of the ERN on Rare and Complex Connective Tissue and Musculo-skeletal Diseases (ReCONNET), in which the members of the network built together one of the 24 infrastructures that are hopefully going to change the scenario of rare diseases across the EU.

One year in review 2021: Behçet's syndrome.

This review aims to provide a critical digest of the recent studies that enhance our understanding of Behçet's syndrome by evaluating time trends, differences in disease course between men and women, and between patients with an early and late disease onset, progress in disease assessment, novel findings on immunopathogenesis and genetics, clinical features and differential diagnosis of eye, vascular, nervous system and gastrointestinal system involvement, and new data on treatment modalities including TNF-alpha, IL-17 and IL-6 inhibitors, tofacitinib, and apremilast, as well as surgical interventions.

Adherence to treatment in Behçet's syndrome: a multi-faceted issue.

OBJECTIVES: The aim of this study is to explore the adherence to treatment in patients with Behçet's syndrome (BS), to identify the diverse adherence profiles and their correlations. METHODS: A cross-sectional study among adult BS patients was conducted administering an ad-hoc questionnaire to BS patients with the aim of investigating several dimensions related to BS management, including attitudes towards treatment. A Latent Class Analysis (LCA) was performed to identify adherence profiles and associated characteristics were identified using logistic regression analysis. RESULTS: A total of 207 patients answered the survey and 180 of them declared to take medication for BS, thus representing the study population. More than a third of the respondents have declared that they have skipped treatments before and autonomously modified (reduced or increased) the dosage of the treatment without medical consultation. LCA analysis allowed the identification of two distinct profiles, one more stick with recommended medication and the other less adherent to treatment. The less-adherent BS patient profile seems to be related with being in the third decade of life, being diagnosed with BS for more than 5 years and perceiving greater psychological impact of the disease. CONCLUSIONS: Addressing adherence in BS is not only related to measuring treatment adherence and identifying the barriers and the limitations; in fact, it should also encompass a wider approach that includes the awareness, the socio-psychological impact of the disease as well as patient education.

COVID-19: the new challenge for rheumatologists. One year later.

At the beginning of COVID-19, we underlined that this pandemic was a new challenge for rheumatologists. On the one hand, it was necessary to clarify the impact of this new viral disease on the natural history of many rheumatic diseases and, on the other hand, to define the beneficial or harmful effects of the synthetic or targeted therapies used for their treatment. In addition, we have postulated that in view of the common pathogenetic mechanisms involved, the therapeutic armamentarium currently employed in the management of viral or idiopathic systemic autoimmune rheumatic diseases could be useful to control the "cytokine storm" induced by SARS-COV-2. One year later, in the present review we have analysed the progress of the knowledge on both these aspects and updated the algorithms initially proposed for a rational use of the synthetic and targeted anti-inflammatory and immunomodulatory agents in the management of COVID-19.

One year in review 2021: systemic vasculitis.

Large- and small-vessel vasculitis are complex potentially life-threatening systemic autoimmune diseases that have recently been subjected to considerable immunologic and clinical research. Following the other reviews of this series, here we aim to summarise some of the most significant studies that have been recently published on the pathogenesis, clinical features and novel treatments of systemic vasculitis.

Long-term effectiveness and safety of secukinumab for treatment of refractory mucosal and articular Behçet's phenotype: a multicentre study.

OBJECTIVE: To evaluate the effectiveness and safety of secukinumab in patients with a mucosal and articular Behçet's phenotype resistant to conventional and biologic treatment. METHODS: A multicentre retrospective study was performed on 15 patients with a mucosal and articular phenotype of Behçet's syndrome fulfilling the International Criteria for Behçet's Disease and refractory to treatment with colchicine, disease-modifying antirheumatic drugs and at least one antitumour necrosis factor-α agent. Minimum follow-up was set at 6 months. Six patients with a polyarticular involvement were treated with secukinumab 300 mg/month, while all other cases received secukinumab 150 mg/month. Dose increase from 150 to 300 mg per month and shortening of administration frequency were allowed for poor disease control. Response evaluation was based on the number of oral ulcers in the previous 28 days and Disease Activity Score-28 for articular manifestations. RESULTS: At 3 months of follow-up, nine (66.7%) patients achieved a response (complete or partial), and this proportion further increased to 86.7% at 6 months, 76.9% at 12 months, 90.0% at 18 months and 100.0% after 24 months. Notably, all patients who started with secukinumab 300 mg/month achieved complete response by month 6. Seven (46.7%) patients could achieve a response only after switching to a higher dosage. CONCLUSIONS: Our study suggests that secukinumab at a dose of 150 and 300 mg per month is safe and effective for the long-term treatment of patients with Behçet's syndrome with a mucosal and articular phenotype refractory to previous treatments. Notably, secukinumab 300 mg/month resulted in superior complete mucosal and articular responses with no serious or dose-related adverse effects.