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Background and Purpose: Only a small proportion of cerebral small vessel disease (cSVD), a frequent cause of stroke and cognitive or motor disability in adults, is attributable to monogenic conditions. The hereditary nature of a patient's cSVD may be masked by a mild or non-informative phenotype, as single-gene disorders have a variable mode of presentation, penetrance and disease severity., Case Description: An adult patient is here described with recurrent acute ischaemic strokes due to cSVD with no other phenotypic manifestation, in whom the pathogenic c.139G>A (p.G47R) missense variant in ADA2 (NM_001282225.2), consistent with the diagnosis of adenosine deaminase 2 deficiency syndrome, was detected by targeted next-generation sequencing., Conclusions: Clinical suspicion of adenosine deaminase 2 deficiency syndrome may be overlooked in stroke patients in whom other specific disease features are lacking. This case enlarges the mode of presentation of the syndrome and highlights the diagnostic potential of next-generation sequencing of known cSVD genes in young adults with recurrent small subcortical infarcts presenting with a lacunar syndrome., (© 2023 European Academy of Neurology.)

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., (© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Takayasu Arteritis (TAK) is a large-vessel vasculitis that preferentially involves the aorta and its primary branches. Cardiac involvement is frequent in TAK and is a major determinant of the patient's outcome. Glucocorticoids (GC) are the mainstay of therapy for TAK, with high doses of GC effective to induce remission. However, relapses are common and lead to repeated and prolonged GC treatments with high risk of related adverse events. Potential GC toxicity is a major concern, especially because patients with TAK are young and need to be treated for several years, often for the whole life. Conventional immunosuppressive drugs are used in patients with severe manifestations but present some limitations. New therapeutic approaches are needed for patients with refractory disease or contraindications to conventional therapies. Fortunately, major progress has been made in understanding TAK pathogenesis, leading to the development of targeted biotherapies. In particular, IL-6 and TNF-α pathways seems to be the most promising therapeutic targets, with emerging data on Tocilizumab and TNF inhibitors. On the other hand, new insights on JAK-Inhibitors, Rituximab, Ustekinumab and Abatacept have been explored in recent studies. This review summarizes the emerging therapies used in TAK, focusing on the most recent studies on biologics and analyzing their efficacy and safety., Competing Interests: RS has received consulting fees from GSK, Roche and Otzuka. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Regola, Uzzo, Toniati, Trezzi, Sinico and Franceschini.)

Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a rare autoimmune disease characterized by medium and small vessels inflammation. Cardiac vasculitic involvement is one of the most severe manifestations with a significant impact on patients' long-term prognosis: anyway, a specific therapeutic approach for heart involvement in EGPA has not been explored yet. Current regimen consists of a long-term therapy with high dose of glucocorticoids, causing the well-known related-adverse events; immunosuppressive drugs are used in patients with severe manifestations, with some limitations. New therapeutic approaches are needed for patients with refractory disease or contraindications to conventional therapies. The quest for the ideal therapy is going toward a more and more personalized approach: on the one hand, efforts are made to use already existing therapies in the most appropriate way; on the other hand, new insights into EGPA pathogenesis allow the discovery of new targets, as demonstrated by mepolizumab and rituximab, targeting eosinophils, and B-cell compartments. This review summarizes the emerging therapies used in EGPA, focusing on the most recent studies on biologics and analyzing their efficacy and safety., Competing Interests: RAS has received consulting fees from GSK, Roche, and Otsuka. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Uzzo, Regola, Trezzi, Toniati, Franceschini and Sinico.)

A hyperinflammatory syndrome (HIS) may cause a life-threatening acute respiratory distress syndrome (ARDS) in patients with COVID-19 pneumonia. A prospective series of 100 consecutive patients admitted to the Spedali Civili University Hospital in Brescia (Italy) between March 9th and March 20th with confirmed COVID-19 pneumonia and ARDS requiring ventilatory support was analyzed to determine whether intravenous administration of tocilizumab (TCZ), a monoclonal antibody that targets the interleukin 6 (IL-6) receptor, was associated with improved outcome. Tocilizumab was administered at a dosage of 8 mg/kg by two consecutive intravenous infusions 12 h apart. A third infusion was optional based on clinical response. The outcome measure was an improvement in acute respiratory failure assessed by means of the Brescia COVID Respiratory Severity Score (BCRSS 0 to 8, with higher scores indicating higher severity) at 24-72 h and 10 days after tocilizumab administration. Out of 100 treated patients (88 M, 12 F; median age: 62 years), 43 received TCZ in the intensive care unit (ICU), while 57 in the general ward as no ICU beds were available. Of these 57 patients, 37 (65%) improved and suspended noninvasive ventilation (NIV) (median BCRSS: 1 [IQR 0-2]), 7 (12%) patients remained stable in NIV, and 13 (23%) patients worsened (10 died, 3 were admitted to ICU). Of the 43 patients treated in the ICU, 32 (74%) improved (17 of them were taken off the ventilator and were discharged to the ward), 1 (2%) remained stable (BCRSS: 5) and 10 (24%) died (all of them had BCRSS≥7 before TCZ). Overall at 10 days, the respiratory condition was improved or stabilized in 77 (77%) patients, of whom 61 showed a significant clearing of diffuse bilateral opacities on chest x-ray and 15 were discharged from the hospital. Respiratory condition worsened in 23 (23%) patients, of whom 20 (20%) died. All the patients presented with lymphopenia and high levels of C-reactive protein (CRP), fibrinogen, ferritin and IL-6 indicating a HIS. During the 10-day follow-up, three cases of severe adverse events were recorded: two patients developed septic shock and died, one had gastrointestinal perforation requiring urgent surgery and was alive at day 10. In conclusion, our series showed that COVID-19 pneumonia with ARDS was characterized by HIS. The response to TCZ was rapid, sustained, and associated with significant clinical improvement., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: The efficacy of tocilizumab (TCZ) in GCA is supported by two randomized controlled studies, in which TCZ allowed remission to be achieved after 52 weeks of treatment. However, after discontinuation of treatment, half of the patients relapsed. The aim of this study was to analyse the efficacy and safety of long-term treatment with TCZ and the role of fluorodeoxyglucose (FDG)-PET/CT scanning in the follow-up of these patients., Methods: We collected the clinical data of a monocentric cohort of GCA patients retrospectively., Results: Thirty-two patients were treated with TCZ [25 males and 7 females; age = 74 (59-81) years]. Most of them achieved and maintained clinical remission (1 month: 69%; 3 months: 91%; 6 months: 96%; 12 months: 100%), with serological and FDG-PET/CT scan improvement and a reduction of concomitant glucocorticoid therapy. Nineteen patients were treated for >52 weeks, and in 13 of them a dose tapering was performed, whereas in 2 cases TCZ was suspended for disease remission. Only two patients relapsed: one during TCZ tapering and one after TCZ discontinuation. Ten cases of mild infections and a case of urinary sepsis were reported; in patients treated for >1 year there was no increase in the incidence of side effects compared with patients treated for <12 months., Conclusion: In our cohort of patients, we confirmed the efficacy of TCZ in the induction and maintenance of remission of GCA, demonstrating an important steroid-sparing effect and a good safety profile. Long-term treatment seems to prevent relapse of the disease, suggesting that TCZ treatment can be continued for >52 weeks with efficacy and safety., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Immunoglobulin G4-related diseases (IgG4-RD) are a group of chronic relapsing-remitting inflammatory conditions, characterised by tissue infiltration with lymphocytes and IgG4-secreting plasma cells, fibrosis and a usually favourable response to steroids. In this narrative review, we summarise the results of a systematic literature research, which was performed as part of the European Reference Network ReCONNET, aimed at evaluating existing clinical practice guidelines (CPGs) and recommendations in IgG4-RD. From 167 publications initially obtained from a systematic literature search, only one was identified as a systematic multispecialist, evidence-based, consensus guidance statement on diagnosis and treatment of IgG4-RD, which may be recommended for use as CPG in IgG4-RD. With the recognition of a limited evidence based in this increasingly recognised disease, the group discussion has identified the following unmet needs: lack of shared classification criteria, absence of formal guidelines on diagnosis, no evidence-based therapeutic recommendations and lack of activity and damage indices. Areas of unmet needs include the difficulties in diagnosis, management and monitoring and the scarcity of expert centres., Competing Interests: Competing interests: None declared.

Due to the rarity of relapsing polychondritis (RP), many unmet needs remain in the management of RP. Here, we present a systematic review of clinical practice guidelines (CPGs) published for RP, as well as a list of the most striking unmet needs for this rare disease. We carried out a systematic search in PubMed and Embase based on controlled terms (medical subject headings and Emtree) and keywords of the disease and publication type (CPGs). The systematic literature review identified 20 citations, among which no CPGs could be identified. We identified 11 main areas with unmet needs in the field of RP: the diagnosis strategy for RP; the therapeutic management of RP; the management of pregnancy in RP; the management of the disease in specific age groups (for instance in paediatric-onset RP); the evaluation of adherence to treatment; the follow-up of patients with RP, including the frequency of screening for the potential complications and the optimal imaging tools for each involved region; perioperative and anaesthetic management (due to tracheal involvement); risk of neoplasms in RP, including haematological malignancies; the prevention and management of infections; tools for assessment of disease activity and damage; and patient-reported outcomes and quality of life indicators. Patients and physicians should work together within the frame of the ReCONNET network to derive valuable evidence for obtaining literature-informed CPGs., Competing Interests: Competing interests: None declared.

Sjögren's syndrome (SS) is a systemic progressive autoimmune disease characterized by a complex pathogenesis requiring a predisposing genetic background and involving immune cell activation and autoantibody production. The immune response is directed to the exocrine glands, causing the typical 'sicca syndrome', but major organ involvement is also often seen. The etiology of the disease is unknown. Infections could play a pivotal role: compared to normal subjects, patients with SS displayed higher titers of anti-Epstein-Barr virus (EBV) early antigens, but lower titers of other infectious agent antibodies such as rubella and cytomegalovirus (CMV) suggest that some infections may have a protective role against the development of autoimmune disease. Recent findings seem to show that low vitamin D levels in patients with SS could be associated with severe complications such as lymphoma and peripheral neuropathy. This could open new insights into the disease etiology. The current treatments for SS range from symptomatic therapies to systemic immunosuppressive drugs, especially B cell-targeted drugs in cases of organ involvement. Vitamin D supplementation may be an additional tool for optimization of SS treatment.

Objective: Oral cyclophosphamide (CYC) is a promising therapy for Systemic Sclerosis (SSc)-related interstitial lung disease (ILD). The use of intravenous (i.v.) pulses has been considered as an alternative route of drug administration, possibly associated with reduced toxicity. Our objectives were to re-evaluate our experience with i.v. CYC, to review the literature, and to pool our results with those available from other groups, improving the statistical power of the analysis., Methods: 1) Retrospective analysis of our center experience on 16 patients with SSc and active alveolitis, treated with i.v. CYC 750 mg + 6-methylprednisolone 125 mg every 3 weeks. 2) Pooled analysis of papers published in peer-reviewed journals reporting detailed data on each patient treated with i.v. CYC. The end-point was modification in the results of lung function tests (LFT) after 6 months. Piecewise regression analysis was performed using a linear mixed-effects model adjusted for baseline values to evaluate the changes in LFT., Results: Retrospective analysis. In the period before therapy there was a significant deterioration in FVC (in 6 months: -4.3%; p=0.0009) and DLCO (-2.1%; p=0.018). After 6 months of treatment there was a modest improvement in the FVC (+2.7% p=0.08) and DLCO (+2.2%; p=0.08). Pooled analysis. In 53 evaluable patients, the improvement in LFT reached conventional statistical significance (FVC: +2.85%; 95% confidence intervals: +0.04, +5.66%; p=0.04. DLCO: +4.4%; 95% confidence intervals: +1.2%, +7.5%; p<0.001)., Conclusion: i.v. CYC for 6 months can achieve a small, but significant improvement of LFT in patients with SSc and active alveolitis.

Old generation H1-type antihistamines are the standard therapeutic option for acquired cold urticaria (ACU), but adverse effects are common. New antihistamines are well tolerated but efficacy is often poor. The present study aims to evaluate efficacy and safety of cinnarizine in the treatment of ACU patients intolerant to old antihistamines and resistant to new drugs. We studied 14 patients (4 males and 10 females). Mean duration of the disease was 48.9 (range 7-102) months. Cold cube test was positive in 78.6 % of patients. Cold urticaria was idiopathic in 10 (71.4 %) patients. Cryoglobulins were detected in the serum of 4 cases (28.6 %). Cinnarizine (25 mg t.i.d.) was administered for 3 months, and then it was gently tapered off and stopped within 2 months. A complete or good response was obtained in 8 (57.1 %) and 2 (14.3 %) patients, respectively. Only two patients were unresponsive (21.4 %). Tapering off or stopping cinnarizine was followed by the relapse of cold urticaria in 7 cases (50.0 %). These patients were amenable to a second treatment cycle. Six patients (42.9 %) had a persistent remission. A patient interrupted the therapy because of severe vertigo. Three patients reported mild and transitory adverse effects including epigastralgia, weight gain and drowsiness. In conclusion, cinnarizine at high doses may be considered as an effective and well-tolerated treatment for ACU.