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Vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC) are potentially severe and complex disease in its management among the various allergic eye diseases. In this regard, studies clarified the etiopathogenetic mechanisms. The workup should be multidisciplinary. The treatment includes topical and systemic medications with anti-inflammatory and immunosuppressant activity. However, a definition of nationally- and internationally-shared diagnostic protocols would also be needed and validated access to therapeutic options of proven safety and efficacy to avoid the use of galenic preparations, up to now still essential in the management of moderate-severe VKC. Finally, recognizing VKC and AKC, among rare diseases, at a national and international level would be an essential step to allow the management of VKC with adequate timings and settings within the National Health System.

Introduction: Disease modifying treatments are commonly used in the treatment of multiple sclerosis. As different opportunistic infections have been reported, concerns are also raised regarding the risk of invasive fungal infections. Areas covered: Both clinical trials and observational studies on safety and efficacy of diseases modifying treatment for multiple sclerosis were reviewed and data regarding the occurrence of invasive fungal infections were reported. Papers evaluating the following drugs were reviewed: rituximab, ocrelizumab, alemtuzumab, fingolimod, natalizumab, dimethyl fumarate, interferon, glatiramer acetate, cladribine, teriflunomide. Expert opinion: Overall, the occurrence of invasive fungal infections was low, with most infective events reported among patients treated with monoclonal antibodies and fingolimod. Aspergillosis and cryptococcal meningitidis were the most representative fungal infections. Although not common, these infections may be difficult to diagnose and their fatality rate is often high. For this reason, screening protocols for fungal infections must be implemented in the clinical practice when managing patients with MS.

Innate lymphoid cells (ILC) are a family of immune cells that are emerging as potent orchestrators of immune responses. In cancer, ILCs display both pro- and antitumorigenic functions depending on the nature of the tumor and the involved ILC subset. Little is known about the ILC–tumor cross-talk in human melanoma. Here, we showed that ILC1s were enriched but functionally impaired in cytokine secretion in both peripheral blood mononuclear cells and tumor-infiltrated lymph nodes of melanoma patients. These findings were confirmed in vivo in murine cutaneous melanoma. Multiple immunosuppressive mechanisms are described in the melanoma microenvironment. Among others, adenosine and kynurenines were shown to suppress antitumor immune responses. By exposing ILCs to adenosine and kynurenines, we observed a similar shift toward the ILC1 subset distribution and impairment in proinflammatory cytokine production to that of patient samples studied ex vivo. Thus, we hypothesized that the immunosuppressive microenvironment of malignant melanoma might shape ILC subpopulations. Hence, we provide a rationale for the use of drugs targeting adenosine and kynurenine pathways in melanoma patients.

Background and ObjectivesSeveral studies have assessed risk factors associated with the severity of COVID-19 outcomes in people with multiple sclerosis (PwMS). The potential role of disease-modifying therapies (DMTs) and demographic and clinical factors on the risk of acquiring SARS-CoV-2 infection has not been evaluated so far. The objective of this study was to assess risk factors of contracting SARS-CoV-2 infection in PwMS by using data collected in the Italian MS Register (IMSR).MethodsA case-control (1:2) study was set up. Cases included PwMS with a confirmed diagnosis of COVID-19, and controls included PwMS without a confirmed diagnosis of COVID-19. Both groups were propensity score–matched by the date of COVID-19 diagnosis, the date of last visit, and the region of residence. No healthy controls were included in this study. COVID-19 risk was estimated by multivariable logistic regression models including demographic and clinical covariates. The impact of DMTs was assessed in 3 independent logistic regression models including one of the following covariates: last administered DMT, previous DMT sequences, or the place where the last treatment was administered.ResultsA total of 779 PwMS with confirmed COVID-19 (cases) were matched to 1,558 PwMS without COVID-19 (controls). In all 3 models, comorbidities, female sex, and a younger age were significantly associated (p < 0.02) with a higher risk of contracting COVID-19. Patients receiving natalizumab as last DMT (OR [95% CI]: 2.38 [1.66–3.42], p < 0.0001) and those who underwent an escalation treatment strategy (1.57 [1.16–2.13], p = 0.003) were at significantly higher COVID-19 risk. Moreover, PwMS receiving their last DMT requiring hospital access (1.65 [1.34–2.04], p < 0.0001) showed a significant higher risk than those taking self-administered DMTs at home.DiscussionThis case-control study embedded in the IMSR showed that PwMS at higher COVID-19 risk are younger, more frequently female individuals, and with comorbidities. Long-lasting escalation approach and last therapies that expose patients to the hospital environment seem to significantly increase the risk of SARS-CoV2 infection in PwMS.Classification of EvidenceThis study provides Class III evidence that among patients with MS, younger age, being female individuals, having more comorbidities, receiving natalizumab, undergoing an escalating treatment strategy, or receiving treatment at a hospital were associated with being infected with COVID-19. Among patients with MS who were infected with COVID-19, a severe course was associated with increasing age and having a progressive form of MS, whereas not being on treatment or receiving an interferon beta agent was protective.

Background: Emergency hospital admissions are common in multiple sclerosis (MS), and can highlight unmet medical needs. Objectives: To evaluate burden, predictors and outcomes of MS emergency admissions. Methods: This is a population-based study, conducted in the Campania Region (South Italy) from 2015 to 2019, using hospital discharge records, drug prescriptions and outpatients. The risk of emergency hospital admissions and the likelihood of worse outcomes were evaluated using the Cox regression and multinomial logistic regression models, respectively, in relation to age, sex, disease-modifying treatments (DMTs), comorbidities and adherence. Results: We recorded 1225 emergency admissions for 1001 patients (out of 5765 prevalent MS patients), overall costing 4,143,764.67 EUR. The risk of emergency admissions increased with age (hazard ratio (HR) = 1.02; 95% confidence interval (CI) = 1.01, 1.03; p Conclusion: With 17% people with MS requiring emergency medical care over 5 years, improved management of DMTs and comorbidities could potentially reduce their medical, social and financial burden.

[Objective] To describe the clinical characteristics and outcomes in patients with refractory myasthenia gravis (MG) and to determine the effectiveness and side effects of the drugs used for their treatment., [Methods] This observational retrospective cross-sectional multicenter study was based on data from the Spanish MG Registry (NMD-ES). Patients were considered refractory when their MG Foundation of America post-interventional status (MGFA-PIS) was unchanged or worse after corticosteroids and two or more other immunosuppressive agents. Clinical and immunologic characteristics of drug-refractory patients, efficiency and toxicity of drugs used, and outcome (MGFA-PIS) at end of follow-up were studied., [Results] We included 990 patients from 15 hospitals. Eighty-four patients (68 of 842 anti-acetylcholine receptor [AChR], 5 of 26 anti-muscle-specific tyrosine kinase [MusK], 10 of 120 seronegative, and 1 of 2 double-seropositive patients) were drug refractory. Drug-refractory patients were more frequently women (p, [Interpretation] In this study, 8.5% of MG patients were drug-refractory. New more specific drugs are needed to treat drug-refractory MG patients., This work was funded by the Instituto de Salud Carlos III through the project PI19/01774 (cofunded by the European Union ERDF), PI I. Illa and E. Gallardo. E. Cortés-Vicente was supported by a Juan Rodés grant (JR19/00037) from the Fondo de Investigación en Salud, Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF, “A way to make Europe”/“Investing in your future”), Ministry of Health (Spain). R. Álvarez-Velasco was supported by grant SLT008/18/00207 from the Health Research and Innovation Strategic Plan (PERIS). The NMD-ES Project and F. Pla-Junca (data curator) are partially funded by the Centro de Investigación Biomédica en Red de Enfsermedades Raras (CIBERER).

ObjectiveA subanalysis of the multicentre Early Lupus inception cohort was performed to investigate the real-world Glucocorticoids (GCs) Use in newly diagnosed systemic lupus erythematosus (SLE) Patients (GULP).MethodsPatients starting prednisone (PDN) ≥5 mg/day and concomitant hydroxychloroquine or immunosuppressant within 12 months of SLE classification were enrolled. Core set variables were recorded at baseline and every 6 months, including changes in PDN dose, European Consensus Lupus Activity Measurement (ECLAM) and Systemic Lupus International Collaborating Clinics damage index. Regression models analysed predictors of tapering PDNResultsThe GULP study included 127 patients with SLE; 73 (57.5%) tapered and maintained PDN ConclusionTapering PDN

Background: Fingolimod (FTY) induces sequestration of lymphocytes in secondary lymphoid organs and the average lymphocyte recovery following discontinuation takes 1–2months. It has been hypothesized that the therapeutic effects of subsequent cell-depleting agents may be compromised if initiated before lymphocyte recovery has occurred. Objective: To assess the risk of relapses following FTY discontinuation and the initiation of a B/T cell-depleting agent in relation to washout duration using data from the Italian MS Register. Methods: The risk of relapses was assessed in relation to different washout durations (< 6, 6–11, 12–17 and > / = 18weeks) in patients starting alemtuzumab, rituximab, ocrelizumab or cladribine following FTY discontinuation. Results: We included 329 patients in the analysis (226F, 103M; mean age 41 ± 10years). During the cell-depleting treatment, the incidence rate ratio for a relapse was significantly greater in patients with a washout period of 12–17 and > / = 18weeks compared to the reference period (< 6weeks). The risk of a relapse was significantly influenced by the occurrence of relapses during FTY treatment and by washout length, with hazard ratios markedly increasing with the washout duration. Conclusion: The risk of relapses increases with the washout duration when switching from FTY to lymphocyte-depleting agents.

Background/Aims: To translate the University of California, Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA SCTC GIT) 2.0 questionnaire from English to Turkish and to validate it. Materials and Methods: UCLA SCTC GIT 2.0 was translated into Turkish using the translation-retranslation method. The available Turkish GIT 2.0 and the Short Form 36 (SF-36) were administered to 97 Turkish-speaking patients with systemic sclerosis (Ssc). Internal consistency reliability and structural validity were assessed by analyzing the correlations between the UCLA SCTC GIT 2.0 and the SF-36 scales. Internal consistency was determined by calculating Cronbach’s alpha. For evaluation of reliability, the questionnaire scale was repeatedly applied to a subgroup of patients with a 2-week interval, and the intraclass correlation coefficient (ICC) was calculated. The Spearman’s correlation coefficients between the GIT and the SF-36 scores were calculated. Results: A group of 97 patients with Ssc with a mean age of 55.37±11.35 years and a female predominance (87.6%) were included in the study. The Cronbach’s alpha value for the UCLA SCTC GIT 2.0 scale was 0.894. ICC was 0.821 (p=0.000). The scale showed acceptable reliability, with the exception of the diarrhea subscale (alpha=0.356). There was a moderate correlation between the total GIT score and the Short Form 36 (SF-36) subscales. All of the items in the scale were included in the validity analysis owing to their reliability. Conclusion: The Turkish GIT 2.0 scale showed good internal consistency, high reliability, and an acceptable validity. © Copyright 2019 by The Turkish Society of Gastroenterology.

Introduction: The early suspension of Altitude trial in recent years has induced most nephrologists and cardiologists to abandon Aliskiren use. Consequently, the potential usefulness of the direct renin inhibition in IgA glomerulonephritis remained an under-investigated therapeutic option. Case Report: We report the case of a 53 years old IgA GMN patient unresponsive to all conventional anti-angiotensin-2 agents, steroids and immunosuppressants, in which the administration of Aliskiren permitted to achieve and maintain a complete proteinuria remission in the absence of any adverse event. Conclusion: Aliskiren might represent a valid and safe therapeutic option in IgA GMN, although further investigations would be needed to confirm this conclusion.

Background: IBD management has been significantly affected during the COVID-19 lockdown with potential clinical issues. Aims: The aim of this study was to analyse the impact of COVID-19 pandemic on the Italian paediatric IBD cohort. Methods: This was a multicentre, retrospective, cohort investigation including 21 different Italian IBD referral centres. An electronic data collection was performed among the participating centres including: clinical characteristics of IBD patients, number of COVID-19 cases and clinical outcomes, disease management during the lockdown and the previous 9 weeks. Results: 2291 children affected by IBD were enrolled. We experienced a significant reduction of the hospital admissions [604/2291 (26.3%) vs 1281/2291 (55.9%); p < 0.001]. More specifically, we observed a reduction of hospitalizations for new diagnosis (from n = 44 to n = 27) and endoscopic re-evaluations (from n = 46 to n = 8). Hospitalization for relapses and surgical procedures remained substantially unchanged. Biologic infusions did not significantly vary [393/2291 (17.1%) vs 368/2291 (16%); p = 0.3]. Telemedicine services for children with IBD were activated in 52.3% of the centres. In 42/2291(1.8%) children immunosuppressive therapies were adapted due to the concurrent COVID-19 pandemic. Conclusion: Due to the several limitations of the lockdown, cares for children with IBD have been kept to minimal standards, giving priorities to the urgencies and to biologics’ infusions and implementing telemedicine services.

Highlights • Lymphopenia and eosinopenia are associated with the severe form of COVID-19. • Increased levels of D-dimer, procalcitonin, and C reactive protein are prognostic biomarkers predicting coagulopathy. • Corticosteroids resulted the best therapy for the immune dysregulation in severe form of COVID-19. • Anticoagulative therapy is associated with reduced in-hospital mortality for COVID-19., Clinical symptoms of COVID-19 include fever, cough, and fatigue which may progress to acute respiratory distress syndrome (ARDS). The main hematological laboratory findings associated with the severe form of disease are represented by lymphopenia and eosinopenia which mostly occur in the elderly population characterized by cardiovascular comorbidities and immunosenescence. Besides, increased levels of D-dimer, procalcitonin, and C reactive protein (CRP) seem to be powerful prognostic biomarkers helping to predict the onset of coagulopathy. The host immune response to SARS-CoV-2 can lead to an aberrant inflammatory response or “cytokine storm” which contributes to the severity of illness. At immunological level, patients affected by a severe form of COVID-19 show poor clinical trajectories characterized by differential “immunotypes” for which T cell response seems to play a critical role in understanding pathogenic mechanisms of disease. Also, patients with mild to severe COVID-19 displayed macrophage activation syndrome (MAS), very low human leukocyte antigen D related (HLA-DR) expression with a parallel reduction of CD04+ lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. Corticosteroids resulted the best therapy for the immune dysregulation whereas repurposing of tocilizumab (IL-6 receptor antagonist) appears to have mixed results in patients with COVID-19. Besides, anticoagulative therapy was associated with reduced in-hospital mortality and need of intubation among COVID-19 patients. Furthermore, the beneficial use of intravenous immunoglobulin (IVIG) and passive immunotherapy with convalescent plasma needs to be validated in large controlled clinical trials. In this review, we summarize the main hematological parameters with a prognostic value in COVID-19 and the basis of immunological reactivity during COVID-19, with a focus on ongoing clinical trials evaluating immune targets as possible therapeutic strategies.

BACKGROUND: The C5a receptor inhibitor avacopan is being studied for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.METHODS: In this randomized, controlled trial, we assigned patients with ANCA-associated vasculitis in a 1:1 ratio to receive oral avacopan at a dose of 30 mg twice daily or oral prednisone on a tapering schedule. All the patients received either cyclophosphamide (followed by azathioprine) or rituximab. The first primary end point was remission, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 (on a scale from 0 to 63, with higher scores indicating greater disease activity) at week 26 and no glucocorticoid use in the previous 4 weeks. The second primary end point was sustained remission, defined as remission at both weeks 26 and 52. Both end points were tested for noninferiority (by a margin of 20 percentage points) and for superiority.RESULTS: A total of 331 patients underwent randomization; 166 were assigned to receive avacopan, and 165 were assigned to receive prednisone. The mean BVAS at baseline was 16 in both groups. Remission at week 26 (the first primary end point) was observed in 120 of 166 patients (72.3%) receiving avacopan and in 115 of 164 patients (70.1%) receiving prednisone (estimated common difference, 3.4 percentage points; 95% confidence interval [CI], -6.0 to 12.8; PCONCLUSIONS: In this trial involving patients with ANCA-associated vasculitis, avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52. All the patients received cyclophosphamide or rituximab. The safety and clinical effects of avacopan beyond 52 weeks were not addressed in the trial. (Funded by ChemoCentryx; ADVOCATE ClinicalTrials.gov number, NCT02994927.).

Objective. Digestive involvement (DI) has been reported in 10-30% of primary Sjögren's syndrome (pSS) patients, and few studies have systematically analysed the prevalence of DI in pSS patients. The aim of this study was to describe DI prevalence in pSS patients from the Sjögrenser Study, and to analyse its clinical associations. Methods. All patients included in the Sjögrenser study, a Spanish multicentre randomised cohort, containing demographic, clinical and histologic data, have been analysed retrospectively. Patients were classified according to the presence of DI (oesophageal, gastric, intestinal, hepatic and pancreatic), and we have performed DI clinical associations, descriptive statistics, Student t or ?2 test, and uni and multivariate logistic regression. Results. From 437 included patients, 95% were women, with a median age of 58 years, 71 (16.2%) presented DI: 21 (29.5%) chronic atrophic gastritis, 12 (16.9%) oesophageal motility dysfunction, 3 (4.2%) lymphocytic colitis, 18 (25.3%) primary biliary cholangitis, 15 (21.1%) autoimmune hepatitis, 7 (9.8%) pancreatic involvement and 5 (7%) coeliac disease. Half of them developed DI at the same time or after pSS diagnosis. Patients with DI were significantly older at pSS diagnosis (p=0.032), more frequently women (p=0.009), presented more autoimmune hypothyroidism and C3 hypocomplementaemia (p=0.040), and were treated more frequently with glucocorticoids, immunosuppressant and biologic therapies. Patients with pancreatic involvement presented more central nervous system and renal involvement, Raynaud's phenomenon, lymphoma and C3/C4 hypocomplementaemia. Conclusion. DI is frequent in Sjögrenser patients, mainly in the form of autoimmune disorders, and seem to be associated with a more severe phenotype. Our results suggest that DI should be evaluated in pSS patients, especially those with more severe disease. © 2020 Clinical and Experimental Rheumatology.

Background: Belimumab was recently approved for treatment of lupus glomerulonephritis (LN). Aim: To evaluate renal response and its predictors in LN patients receiving belimumab in real-life. Patients and methods: We considered all patients fulfilling the SLEDAI-2K renal items and/or having estimated glomerular filtration rate (eGFR)≤60 ml/min/1.73 m2, with positive anti-dsDNA and/or low C3/C4 enrolled in the multicentre Italian lupus cohort BeRLiSS (BElimumab in Real LIfe Setting Study), treated with monthly IV Belimumab 10 mg/kg over standard treatment. Primary efficacy renal response (PERR), defined as proteinuria ≤0.7 g/24 h, eGFR≥60 ml/min/1.73 m2 without rescue therapy, was considered as primary outcome. Complete renal response (CRR; proteinuria

The main aim of the study is to evaluate the efficacy and safety profile of ocrelizumab (OCR), rituximab (RTX), and cladribine (CLA), employed as natalizumab (NTZ) exit strategies in relapsing–remitting multiple sclerosis (RRMS) patients at high-risk for progressive multifocal leukoencephalopathy (PML). This is a multicentre, retrospective, real-world study on consecutive RRMS patients from eleven tertiary Italian MS centres, who switched from NTZ to OCR, RTX, and CLA from January 1st, 2019, to December 31st, 2019. The primary study outcomes were the annualized relapse rate (ARR) and magnetic resonance imaging (MRI) outcome. Treatment effects were estimated by the inverse probability treatment weighting (IPTW), based on propensity-score (PS) approach. Additional endpoint included confirmed disability progression (CDP) as measured by Expanded Disability Status Scale and adverse events (AEs). Patients satisfying predefined inclusion and exclusion criteria were 120; 64 switched to OCR, 36 to RTX, and 20 to CLA. Patients from the 3 groups did not show differences for baseline characteristics, also after post hoc analysis. The IPTW PS-adjusted models revealed that patients on OCR had a lower risk for ARR than patients on CLA (ExpBOCR0.485, CI 95% 0.264–0.893,p = 0.020). This result was confirmed also for 12-month MRI activity (ExpBOCR0.248 CI 95% 0.065–0.948,p = 0.042). No differences were found in other pairwise comparisons (OCR vs RTX and RTX vs CLA) for the investigated outcomes. AEs were similar among the 3 groups. Anti-CD20 drugs were revealed to be effective and safe options as NTZ exit strategies. All investigated DMTs showed a good safety profile.

In recent years, an autoantibody directed against the 5′-citosolic nucleotidase1A (cN1A) was identified in the sera of sporadic inclusion body myositis (s-IBM) patients with widely variable sensitivity (33%–76%) and specificity (87%–100%). We assessed the sensitivity/specificity of anti-cN1A antibodies in an Italian cohort of s-IBM patients, searching for a potential correlation with clinical data. We collected clinical data and sera from 62 consecutive s-IBM patients and 62 other inflammatory myopathies patients. Testing for anti-cN1A antibodies was performed using a commercial ELISA. Anti-cN1A antibodies were detected in 23 s-IBM patients, resulting in a sensitivity of 37.1% with a specificity of 96.8%. Positive and negative predictive values were 92.0% and 60.6%, respectively. We did not find significant difference regarding demographic variables, nor quadriceps or finger flexor weakness. Nevertheless, we found that anti-cN1A-positive patients presented significantly lower scores in IBMFRS item 1 (swallowing, p = 0.045) and more frequently reported more severe swallowing problems, expressed as an IBMFRS item 1 score ≤ 2 (p &lt, 0.001). We confirmed the low sensitivity and high specificity of anti-cN1A Ab in s-IBM patients with a high positive predictive value. The presence of anti-CN1A antibodies identified patients with a greater risk of more severe dysphagia.

Introduction and objectives: Intrapatient blood level variability (IPV) of calcineurin inhibitors has been associated with poor outcomes in solid-organ transplant, but data for heart transplant are scarce. Our purpose was to ascertain the clinical impact of IPV in a multi-institutional cohort of heart transplant recipients. Methods: We retrospectively studied patients aged = 18 years, with a first heart transplant performed between 2000 and 2014 and surviving = 1 year. IPV was assessed by the coefficient of variation of trough levels from posttransplant months 4 to 12. A composite of rejection or mortality/graft loss or rejection and all-cause mortality/graft loss between years 1 to 5 posttransplant were analyzed by Cox regression analysis. Results: The study group consisted of 1581 recipients (median age, 56 years; women, 21%). Cyclosporine immediate-release tacrolimus and prolonged-release tacrolimus were used in 790, 527 and 264 patients, respectively. On multivariable analysis, coefficient of variation > 27.8% showed a nonsignificant trend to association with 5-year rejection-free survival (HR, 1.298; 95%CI, 0.993-1.695; P =.056) and with 5-year mortality (HR, 1.387; 95%CI, 0.979-1.963; P =.065). Association with rejection became significant on analysis of only those patients without rejection episodes during the first year posttransplant (HR, 1.609; 95%CI, 1.129-2.295; P =.011). The tacrolimus-based formulation had less IPV than cyclosporine and better results with less influence of IPV. Conclusions: IPV of calcineurin inhibitors is only marginally associated with mid-term outcomes after heart transplant, particularly with the tacrolimus-based immunosuppression, although it could play a role in the most stable recipients. Full English text available from:www.revespcardiol.org/en © 2021 Sociedad Española de Cardiología

Background: In patients with Multiple Sclerosis (pwMS) disease-modifying therapies (DMTs) affects immune response to antigens. Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response. Methods: We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARS-Cov-2 vaccination with mRNA vaccines (BNT162b2, Pfizer/BioNTech,Inc or mRNA-1273, Moderna Tx,Inc). A blood collection before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche-Diagnostics). The log-transform of the antibody levels was analyzed by multivariable linear regression. Findings: 780 pwMS (76% BNT162b2 and 24% mRNA-1273) had pre- and 4-week post-vaccination blood assessments. 87 (11·2%) were untreated, 154 (19·7%) on ocrelizumab, 25 (3·2%) on rituximab, 85 (10·9%) on fingolimod, 25 (3·2%) on cladribine and 404 (51·7%) on other DMTs. 677 patients (86·8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariable analysis, the antibody levels of patients on ocrelizumab (201-fold decrease (95%CI=128–317), p < 0·001), fingolimod (26-fold decrease (95%CI=16–42), p < 0·001) and rituximab (20-fold decrease (95%CI=10–43), p < 0·001) were significantly reduced as compared to untreated patients. Vaccination with mRNA-1273 resulted in a systematically 3·25-fold higher antibody level (95%CI=2·46–4·27) than with the BNT162b2 vaccine (p < 0·001). The antibody levels on anti-CD20 therapies correlated to the time since last infusion, and rituximab had longer intervals (mean=386 days) than ocrelizumab patients (mean=129 days). Interpretation: In pwMS, anti-CD20 treatment and fingolimod led to a reduced humoral response to mRNA-based SARS-CoV-2 vaccines. As mRNA-1273 elicits 3·25-higher antibody levels than BNT162b2, this vaccine may be preferentially considered for patients under anti-CD20 treatment or fingolimod. Combining our data with those on the cellular immune response to vaccines, and including clinical follow-up, will contribute to better define the most appropriate SARS-CoV-2 vaccine strategies in the context of DMTs and MS. Funding: FISM[2021/Special-Multi/001]; Italian Ministry of Health‘Progetto Z844A 5 × 1000′.

Objective: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). Methods: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. Results: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18–4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (

Vaccination is one of the most successful medical interventions that has saved the life of millions of people. Vaccination is particularly important in patients with multiple myeloma, who have an increased risk of infections due to the disease-inherent immune suppression, and because of the immune suppressive effects of therapy. Hence, all appropriate measures should be exploited, to elicit an effective immune response to common pathogens like influenza, pneumococci, varicella zoster virus, and to those bacteria and viruses (haemophilus influenzae, meningococci, and hepatitis) that frequently may pose a significant risk to patients with multiple myeloma. Patients after autologous, and specifically after allogeneic transplantation have severely reduced antibody titers, and therefore require a broader spectrum of vaccinations. Response to vaccination in myeloma often is less vigorous than in the general population, mandating either measurement of the postvaccination antibody titers and/or repeating the vaccination. Here, we compile the existing data on vaccination in multiple myeloma and provide recommendations for clinical practice. ispartof: LEUKEMIA vol:35 issue:1 pages:31-44 ispartof: location:England status: published

To the Editor: We believe that the design of the FLIGHT trial has several methodologic flaws. First, since this was an open-label trial, the investigators would generally be more reluctant to shift medication in patients who were receiving mycophenolate mofetil than in those who were receiving glucocorticoids alone, even if the patient’s platelet count was less than 30×109 per liter ({sa2q2}the cutoff value for treatment failure), a factor that might have had an effect on the primary end point. Second, the trial lacks essential data to allow for interpretation of the results, including the number of patients who discontinued mycophenolate mofetil and the cumulative dose of glucocorticoids. Third, the results do not show whether mycophenolate mofetil had a “steroid- sparing” effect, which was the rationale for the trial. Fourth, randomization was not stratified according to the type of ITP that had been diagnosed at baseline, as indicated.1 In addition, we cannot reproduce the power calculation. Finally, we are concerned by the use of a medication that may cause miscarriage and birth defects, since women of childbearing age represent 30 to 40% of patients with newly diagnosed ITP. We strongly believe that at this stage, mycophenolate mofetil should be considered only as a potential second-line option in patients with ITP rather than as first-line therapy.

Although the use of glucocorticoids (GC) is well established, the therapeutic response to these agents often shows important interindividual differences, in particular among young patients with inflammatory bowel diseases (IBD). Currently, GC resistance or dependence cannot be predicted by clinical or laboratory findings. The aim of this study was to investigate the association of gender and age with GC efficacy and with the expression of Glucocorticoid-Induced Leucine Zipper (GILZ). One hundred thirty patients (mean age at enrolment 12.6 years, 53 Crohn’s disease, 70 males) were enrolled in this retrospective study. IBD patients with active disease despite prednisone at a daily dose of up to 2 mg/kg over a period of 4 weeks were defined as steroid resistant. Patients who initially responded but relapsed upon dose reduction were considered steroid-dependent. Total RNA was extracted from biopsies of 14 patients (9 males) and the levels of GILZ mRNA were evaluated by real-time PCR. Association between clinical response to prednisone and the considered demographic variables was evaluated using logistic regression models. After 4 weeks of treatment, 112 patients were responders to prednisone and 18 were resistant; at this time-point, resistant patients were older than responders (p=0.032). After 12 weeks, 42, 71 and 12 patients were sensitive, dependent and resistant respectively; at this time-point, females were more prone than males to develop prednisone dependence vs a good response (p=0.028) while age had no effect. Age was associated with response both at 4 and 12 weeks in the subgroups of females: resistant patients were older than sensitive ones at 4 weeks (p=0.02). Likewise, at 12 weeks of therapy, dependent patients resulted older than sensitive ones (p=0.05). No association of age with prednisone response was found in males. In a subgroup of 14 patients (5 females), GILZ mRNA expression in intestinal biopsies was higher in males (p=0.0031). Patients with unfavorable response (7) presented lower GILZ expression at disease onset in comparison to the responder group (p=0.017). Older females with IBD have a higher incidence of prednisone unfavorable response and reduced intestinal expression of the GC pharmacodynamic marker GILZ.

Animal models, human observational and genetic studies have shown that immune and inflammatory mechanisms play a key role in hypertension and its complications. We review the effects of immunomodulatory interventions on blood pressure, target organ damage and cardiovascular risk in humans. In experimental and small clinical studies both non-specific immunomodulatory approaches, such as mycophenolate mofetil and methotrexate, and medications targeting T and B lymphocytes, such as tacrolimus, cyclosporine, everolimus, rituximab, lower blood pressure and reduce organ damage. Mechanistically targeted immune interventions include isolevuglandin (isoLG) scavengers to prevent neo-antigen formation, co-stimulation blockade (abatacept, belatacept), and anti-cytokine therapies (secukinumab, tocilizumab, canakinumab, TNF-α inhibitors). In many studies, trial designs have been complicated by a lack of blood pressure related endpoints, inclusion of largely normotensive study populations, polypharmacy, and established comorbidities. Among a wide range of interventions reviewed, TNF-α inhibitors have provided the most robust evidence of blood pressure lowering. Treatment of periodontitis also appears to deliver non-pharmacological antihypertensive effects. Evidence of immunomodulatory drugs influencing hypertension-mediated organ damage are discussed. Animal model, observational studies, and trial data in humans support the therapeutic potential of immune targeted therapies in blood pressure lowering and in hypertension-mediated organ damage. Targeted studies are now needed to address their effects on blood pressure in hypertensive individuals.

IntroductionSerum uric acid levels have been reported as predictors of cardiovascular, pulmonary, neurological and renal morbidity in patients with SLE. However, their role in cumulative global damage in these patients has not yet been determined.ObjectiveTo determine whether serum uric acid levels are associated with new damage in patients with SLE.MethodsThis is a longitudinal study of patients with SLE from the Almenara Lupus Cohort, which began in 2012. At each visit, demographic and clinical characteristics were evaluated, such as activity (Systemic Lupus Erythematosus Disease Activity Index-2K or SLEDAI-2K) and cumulative damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index or SDI). Treatment (glucocorticoids, immunosuppressive drugs and antimalarials) was also recorded. Univariable and multivariable Cox regression models were used to determine the impact of serum uric acid levels on the risk of new damage.ResultsWe evaluated 237 patients, with a mean age (SD) at diagnosis of 35.9 (13.1) years; 220 patients (92.8%) were women, and the duration of the disease was 7.3 (6.6) years. The mean SLEDAI-2K and SDI scores were 5.1 (4.2) and 0.9 (1.3), respectively. Serum uric acid level was 4.5 (1.4) mg/dL. Follow-up time was 3.1 (1.3) years, and 112 (47.3%) patients accrued damage during follow-up. In univariable and multivariable analyses, serum uric acid levels were associated with new damage (HR=1.141 (95% CI 1.016 to 1.282), p=0.026; HR=1.189 (95% CI 1.025 to 1.378), p=0.022, respectively).ConclusionHigher serum uric acid levels are associated with global damage in patients with SLE.

Due to the frequent presence of interstitial lung disease and widespread use of immunosuppressive treatment, systemic sclerosis (SSc) patients may be considered at risk for a more severe disease course and higher mortality when they develop Severe Acute Respiratory Syndrome - Coronavirus - 2 (SARS-CoV-2) virus infection. Therefore, with World Scleroderma Foundation endorsement, experts from different specialties including rheumatology, virology and clinical immunology gathered virtually to answer to the main practical clinical questions regarding SARS-CoV-2 infection coming from both patients and physicians. This preliminary advice is aligned with other national and international recommendations, adapted for SSc patients.

Objectives To evaluate long-term treatment and outcomes of patients with primary central nervous system vasculitis (PCNSV). Methods In this cohort of 191 consecutive patients with PCNSV seen at Mayo Clinic, Rochester, MN, over 35 years with long-term follow-up we analyzed response to and duration of therapy, frequency of relapses, long-term remission, efficacy of maintenance therapy and initial intravenous glucocorticoid (GC) pulses, survival and degree of disability. We also compared the efficacy of initial IV and oral cyclophosphamide (CYC). Results A favorable initial response was observed in 83% of patients treated with prednisone (PDN) alone, 81% of those treated with PDN and CYC and 95% of those initially treated with PDN and an immunosuppressant other than CYC. One or more relapses were observed in 30% of patients, 35% had discontinued therapy by last follow-up, and 21.5% maintained remission for at least 12 months after discontinuing therapy. Maintenance therapy was prescribed in 19% of all patients and 34% of patients initially treated with CYC and PDN. High disability scores (Rankin 4–6) and deaths were less frequently observed in patients receiving maintenance therapy and more frequently in patients with Aβ-related angiitis. Large vessel involvement and cerebral infarction at diagnosis were associated with a poor treatment response. Aspirin use was positively associated with long-term remission and having gadolinium-enhanced cerebral lesions or meninges was negatively associated. A high disability score at last follow-up and higher mortality rate were associated with increasing age, cerebral infarction and cognitive dysfunction at diagnosis. Lymphocytic vasculitis on biopsy was associated with a more benign course with reduced disability and mortality. Patients initially treated with mycophenolate mofetil had better outcomes compared to those treated with CYC and PDN. No therapeutic advantages were observed in the patients initially treated with intravenous GC pulses. Intravenous and oral CYC were equally effective in inducing the remission. Conclusions The majority of patients with PCNSV responded to treatment. We found patient subsets with different outcomes. Mycophenolate mofetil may be an effective alternative to CYC.

In this dramatic period where the whole world is affected by the outbreak of coronavirus disease 19 (COVID‐19), scientific data relating to the causative virus SARS‐CoV‐2 as well as the subsequent therapeutic repercussions on the management of other diseases should be divulged in order to share as much information as possible among experts in a timely manner.

Atopic dermatitis (AD) is one of the most common cutaneous inflammatory diseases both in adults and in children. It is a chronic, remitting-relapsing dermatitis, primarily managed by dermatologists, but also by allergists and primary care physicians. Due to coexistence of comorbidities, often a multidisciplinary team is required. Topical calcineurin inhibitors (TCIs - i.e. tacrolimus and pimecrolimus) are a class of steroid-sparing, anti-inflammatory agents that have been shown to be efficacious for the treatment of AD acute flares and in maintenance therapy. In particular, the application of tacrolimus ointment twice daily reduces AD severity and pruritus. Moreover, maintenance therapy with an intermittent application of tacrolimus to recurrent skin sites (proactive therapy) decreases frequency and severity of relapses. Many studies have also assessed the efficacy of TCIs in disorders other than AD. Although US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) issued a "black box warning" regarding the possible cancerogenic activity of these drugs, there is currently no strong evidence of an increased rate of malignancy in treated patients, and observational data from postmarketing surveillance studies have shown no safety concerns. A panel of dermatologists have thoroughly discussed the use of tacrolimus in AD after 15-year experience. The experts focused on AD flare treatment, maintenance therapy and management of side effects. Consensus was reached on some areas of interest, namely the stages of AD in which tacrolimus is recommended, the amount of drug to be applied, how to manage side effects, and how to improve patient's compliance. Moreover, the panel of experts recommended to perform randomized clinical trials to confirm the efficacy of tacrolimus off-label use, which led to successful outcomes in other skin diseases.

INTRODUCTION: Patients with Crohn's disease experiencing endoscopic postoperative recurrence (POR) may benefit from antitumor necrosis factor (TNF) agents but scarce data on this are available. Our aim was to assess the efficacy of anti-TNF in improving mucosal lesions in patients with endoscopic POR. METHODS: Multicenter, retrospective, study of patients with Crohn's disease who underwent therapy with anti-TNF agents for endoscopic POR (Rutgeerts score > i1). Treatment outcomes were assessed by the findings in the last ileocolonoscopy performed after anti-TNF therapy was initiated. Endoscopic improvement and remission were defined as any reduction in the baseline Rutgeerts score and by a Rutgeerts score < i2, respectively. RESULTS: A total of 179 patients were included, 83 were treated with infliximab and 96 with adalimumab. Median time on anti-TNF therapy at the last endoscopic assessment was 31 months (interquartile range, 13-54). Endoscopic improvement was observed in 61%, including 42% who achieved endoscopic remission. Concomitant use of thiopurines and treatment with infliximab were associated with endoscopic improvement (odds ratio [OR] 2.15, 95% confidence interval [CI] 1.04-4.46; P = 0.03, and OR 2.34, 95% CI 1.18-4.62; P < 0.01, respectively) and endoscopic remission (OR 3.16, 95% CI 1.65-6.05; P < 0.01, and OR 2.01, 95% CI 1.05-3.88; P = 0.04, respectively) in the multivariable logistic regression analysis. These results were confirmed in a propensity-matched score analysis. DISCUSSION: In patients with endoscopic POR, anti-TNF agents improve mucosal lesions in almost two-thirds of the patients. In this setting, concomitant use of thiopurines and use of infliximab seem to be more effective in improving mucosal lesions.

Background Pregnancy after heart transplantation (HTx) may expose the recipient to hemodynamic and immunologic risks and the newborn to toxic effects of immunosuppressive therapy. Adequate preconception counseling is crucial to identify optimal timing and to modify immunosuppressive therapy to minimize risks for both the mother and the fetus. Methods We describe our experience with 12 pregnancies occurred in 11 women who had undergone HTx at our center. Results Pregnancies ran without severe complications or rejections, and none of the babies have shown major defects at birth. However, as reported in the literature, weight at birth rated in lower range in most of the newborns, probably due to in utero cyclosporine exposure. Up to now, none of the babies showed clinical signs of heart disease, although more than half of the mothers had an inherited or familial cardiomyopathy. Conclusions Despite potential mother and fetal complications, successful pregnancy and delivery are possible after HTx, provided that optimum timing, close monitoring, and therapy adjustments are guaranteed. Becoming a mother appears to be an important achievement for young women after HTx, even when there is a risk to transmit an inheritable heart disease.

Objective: To investigate the pharmacokinetics, effectiveness, and safety of subcutaneous (SC) abatacept treatment over 24 months in patients with polyarticular-course juvenile idiopathic arthritis (JIA). Methods: In this phase III, open-label, international, multicenter, single-arm study, patients with polyarticular JIA (cohort 1, ages 6–17 years and cohort 2, ages 2–5 years) in whom treatment with ≥1 disease-modifying antirheumatic drug was unsuccessful received weight-tiered SC abatacept weekly: 10 to

Background: Several studies have shown an association between 25-hydroxyvitamin D (25[OH]D) levels and multiple sclerosis (MS) susceptibility and/or level of disease activity in patients treated with first line drugs. Aims: To investigate whether baseline 25[OH]D values could influence disease activity also during treatment with the second-line drug fingolimod (FTY). Patients and methods: We enrolled 176 MS patients who started FTY at the San Raffaele Hospital (OSR) MS center with available 25[OH]D measurement at the time of treatment start. We then prospectively followed them for 2 years with periodic clinical examinations and MRI scans. Results: We found no linear correlation between baseline 25[OH]D levels and annualized relapse rate (ARR) or time to first relapse. However, we observed that patients with serum 25[OH]D ≥ 100 nmol/l showed a lower number of Gd+ and combined unique activity (CUA) lesions at baseline compared to patients with the lowest 25[OH]D levels (less than 50 nmol/l, p value < 0.05). Moreover, they showed fewer CUA lesions at 2-year follow-up also when accounting for baseline level of disease activity (p value < 0.05). Conclusions: In patients treated with FTY, those with the highest baseline 25(OH)D levels had a significantly lower number of active lesions at baseline; the same effect, even if weaker, was observed also at 2-year follow-up when adjusting for baseline disease activity. Given Vitamin D supplementation safety profile, also if a causal effect has not yet been shown, most of MS patients could probably benefit from 25[OH]D levels above those currently considered to be sufficient.

Purpose: To correlate rheumatologic with ophthalmic and laboratory findings in patients with rheumatoid arthritis (RA) to identify what effect these have on development of ocular disease. Methods: This is a cross-sectional study of 172 eyes of 86 patients with RA. Patients were examined by a group of rheumatologists. Sociodemographic, clinical, and laboratory data were collected. All patients underwent complete ophthalmologic examination including corneal topography and endothelial cell count. Results: There was no significant correlation between RA-negative prognostic indicators (NPIs) and pathologic corneal findings. Patients using disease-modifying antirheumatic drugs (DMARDs) and antimalarial drugs had greater corneal volumes (mean difference 8.51 mm3, 90% confidence interval [CI], 3.98-13.04, P = 0.004; and 2.24, 90% CI, 0.32-4.54, P = 0.048, respectively). Patients using azathioprine had lower endothelial cell counts compared with those using other drugs (mean difference 180 cells/mm2, 90% CI, 69-291, P = 0.008). Patients using biologic DMARDs had better tear osmolarity values (between 280 and 300 mOsm/L) than patients not using them (mean difference 14.3 mOsm/L, P = 0.022). There was no correlation between NPIs of RA and positive keratoconus screening indices (Spearman correlation OD -0.013, P = 0.91; OS -0.033, P = 0.76). Conclusions: There was no clear correlation between RA-NPIs and pathologic corneal findings in our study. DMARDs treatment may help maintain corneal integrity in our patients and prevented collagenolytic manifestations of RA. Other medications such as azathioprine should be used carefully, as endothelial damage may potentially occur. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

PURPOSE OF REVIEW: To report the most recent therapeutic advances of thyroid eye disease (TED) and offer general recommendations for management of TED. RECENT FINDINGS: Treatment of Graves ophthalmopathy is traditionally based on the use of high doses of corticosteroids and/or radiotherapy (RT) to decrease the activity of the disease, with the subsequent proptosis, strabismus and eyelid deformites treated with different surgical procedures. In recent years, the evidence that oxidative stress plays a relevant role in exacerbating TED severity has encouraged the use of antioxydative agents such as selenium, which has shown a capacity in limiting the disease progression. In addition, reports have shown the effectiveness of biological immunosuppressive agents in the management of TED. The main advantage of these medications seems to be the long lasting effects, which may reduce recurrence, and effectiveness in steroid-resistant cases. The reported increased accuracy of imaging techniques in evaluating fat and muscle volumes may provide useful information for surgical management. SUMMARY: The use of selenium, in mild TED, seems to limit disease progression without carrying the risk of relevant side-effects. Biological agents may provide an effective and long lasting block of the inflammatory activity of TED, with a possible lower risk of recurrence and reduction in the need for surgical intervention in moderate-to-severe disease. The accurate evaluation of fat and muscle volume, using a recently published algorithm for imaging, gives relevant information for preoperative assessment, allowing the customization of orbital decompression.

Purpose To investigate the effect of cyclosporine on corneal ultrastructure and on major signs and symptoms of patients with dry eye disease.Patients and methods In this prospective cohort study, patients with dry eye disease were treated with a drop of cyclosporine 0.05% twice daily. Clinical evaluation was carried out at baseline and at months 1, 3, and 6. All patients completed the Ocular Surface Disease Index (OSDI) questionnaire, and tear film break-up time (BUT), fluorescein and lissamine green staining, and Schirmer test were carried out. In vivo confocal microscopy was also performed and epithelial cellular density, keratocyte activation, and subbasal plexus morphology were assessed.Results A total of 40 patients completed the study. After 6 months, OSDI, BUT, and fluorescein and lissamine green staining showed a clinically significant improvement. During the 6-month follow-up, density of intermediate epithelial cells increased from 1969.5 +/- 85.4 cell/mm(2) to 4881.2 +/- 75.7 cell/mm(2) (P

none 55 si First published: 22 December 2016 Background: High-quality data on the management of autoimmune hepatitis (AIH) are scarce. Despite published guidelines, management of AIH is still expert based rather than evidence based. Aim: To survey expert hepatologists, asking each to describe their practices in the management of patients with AIH. Methods: A survey questionnaire was distributed to members of the International AIH Group. The questionnaire consisted of four clinical scenarios on different presentations of AIH. Results: Sixty surveys were sent, out of which 37 were returned. None reported budesonide as a first line induction agent for the acute presentation of AIH. Five (14%) participants reported using thiopurine S-methyltransferase measurements before commencement of thiopurine maintenance therapy. Thirteen (35%) routinely perform liver biopsy at 2 years of biochemical remission. If histological inflammatory activity is absent, four (11%) participants reduced azathioprine, whereas 10 (27%) attempted withdrawal altogether. Regarding the management of difficult-to-treat patients, mycophenolate mofetil is the most widely used second-line agent (n = ~450 in 28 centres), whereas tacrolimus (n = ~115 in 21 centres) and ciclosporin (n = ~112 in 18 centres) are less often reported. One centre reported considerable experience with infliximab, while rescue therapy with rituximab has been tried in seven centres. Conclusions: There is a wide variation in the management of patients with autoimmune hepatitis even among the most expert in the field. Although good quality evidence is lacking, there is considerable experience with second-line therapies. Future prospective studies should address these issues, so that we move from an expert- to an evidence- and personalised-based care in autoimmune hepatitis. mixed R. Liberal; Y. S. de Boer; R. J. Andrade; G. Bouma; G. N. Dalekos; A. Floreani; D. Gleeson; G. M. Hirschfield; P. Invernizzi; M. Lenzi; A. W. Lohse; G. Macedo; P. Milkiewicz; B. Terziroli; B. van Hoek; J. M. Vierling; M. A. Heneghan; on behalf of the International Autoimmune Hepatitis Group (IAIHG); A. Pares; A. J. Montano-Loza; A. Granito; A. E. Kremer; A. Floreani; A. W. Lohse; B. van Hoek; B. Terziroli; C. Schramm; C. Lammert; E. L. R. Cancado; E. Bjornsson; F. Lammert; G. N. Dalekos; G. Bouma; G. M. Hirschflield; G. Macedo; H. Hofer; I. Mackay; J. Neuberger; J. M. Vierling; J.P.H. Drenth; C.M.J. van Nieuwkerk; L. Muratori; M. Lenzi; M. Swain; M. Heneghan; M. Zeniya; O. Chazouilleres; P. Gines; P. Invernizzi; P. Milkiewicz; R. J. Andrade; R. Chapman; T. Berg; H. van Buuren; X. Ma R. Liberal; Y. S. de Boer; R. J. Andrade; G. Bouma; G. N. Dalekos; A. Floreani; D. Gleeson; G. M. Hirschfield; P. Invernizzi; M. Lenzi; A. W. Lohse; G. Macedo; P. Milkiewicz; B. Terziroli; B. van Hoek; J. M. Vierling; M. A. Heneghan; on behalf of the International Autoimmune Hepatitis Group (IAIHG); A. Pares; A. J. Montano-Loza; A. Granito; A. E. Kremer; A. Floreani; A. W. Lohse; B. van Hoek; B. Terziroli; C. Schramm; C. Lammert; E. L. R. Cancado; E. Bjornsson; F. Lammert; G. N. Dalekos; G. Bouma; G. M. Hirschflield; G. Macedo; H. Hofer; I. Mackay; J. Neuberger; J. M. Vierling; J.P.H. Drenth; C.M.J. van Nieuwkerk; L. Muratori; M. Lenzi; M. Swain; M. Heneghan; M. Zeniya; O. Chazouilleres; P. Gines; P. Invernizzi; P. Milkiewicz; R. J. Andrade; R. Chapman; T. Berg; H. van Buuren; X. Ma

Background Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) with a consistent safety profile in clinical trials. We report three cases of multiple teeth loss during teriflunomide treatment. Case reports Case 1: a 39 year-old woman started teriflunomide for RRMS, switching from interferon beta. Four months later she complained about mandibular pain followed by the sudden loss of 4 teeth, in the absence of bleeding or trauma. Suspecting a causal role, we discontinued teriflunomide and started the accelerated elimination procedure with cholestyramine. Orthopantomography and a subsequent dental CT scan showed diffuse alveolar atrophy and periapical bone loss in several residual roots. Investigating retrospectively the patient's dental history, and revising previous orthopantomographies dating from 2009, we highlighted a chronic and progressive dental pathology with several cavities and teeth loss. Case 2: A 52-year-old woman affected by multiple sclerosis (MS) since 1988, switched from interferon beta to teriflunomide treatment due to poor tolerability. One year later she experienced the sudden loss of five teeth in the absence of traumatic events. Dental assessment and orthopantomography confirmed moderate chronic periodontitis. Teriflunomide was discontinued and the accelerated elimination procedure with cholestyramine was performed. Case 3: A 56-year-old woman affected by MS for thirty years. She switched from interferon beta to teriflunomide due to injection site reactions. After eighteen months she experienced hypermobility of several teeth without gum inflammation or pain, followed by sudden loss of twelve teeth. No dental examination is available. Teriflunomide was discontinued without accelerated elimination procedure. Discussion Odontogenic infections (periodontal disease and dental caries) are common and can cause teeth loss if left untreated as in case 1. It is conceivable that local infections favoured by teriflunomide accelerated pulpitis, endodontic infections and periapical reactions followed by teeth loss in predisposed subjects. Poor oral hygiene is common in MS patients and might favour dental infections. Conclusions We underline the importance to assess concomitant teeth morbidity and to recommend accurate oral hygiene before and during teriflunomide treatment.

kiykim, ayca/0000-0001-5821-3963; Baris, Safa/0000-0002-4730-9422; AGREBI, Nourhen/0000-0001-5703-9668; Ayaz, Nuray Aktay/0000-0003-3594-7387; Cekic, Sukru/0000-0002-9574-1842; Karaca, Neslihan/0000-0002-2202-7082; Kara, Emine Manolya/0000-0001-6234-7024; /0000-0002-9065-1901; Lo, Bernice/0000-0002-1087-6845, WOS: 000495746100038, PubMed: 31238161, BACKGROUND: LPS-responsive beige-like anchor (LRBA) deficiency presents with susceptibility to infections, autoimmunity, and lymphoproliferation. the long-term efficacy of cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (abatacept) as targeted therapy for its immune dysregulatory features remains to be established. OBJECTIVE: To determine the clinical and immunologic features of LRBA deficiency and long-term efficacy of abatacept treatment in controlling the different disease manifestations. METHODS: Twenty-two LRBA-deficient patients were recruited from different immunology centers and followed prospectively. Eighteen patients on abatacept were evaluated every 3 months for long-term clinical and immunologic responses. LRBA expression, lymphocyte subpopulations, and circulating T follicular helper cells were determined by flow cytometry. RESULTS: the mean age of the patients was 13.4 +/- 7.9 years, and the follow-up period was 3.4 +/- 2.3 years. Recurrent infections (n = 19 [86.4%]), immune dysregulation (n = 18 [81.8%]), and lymphoproliferation (n = 16 [72.7%]) were common clinical features. the long-term benefits of abatacept in 16 patients were demonstrated by complete control of lymphoproliferation and chronic diarrhea followed by immune dysregulation, most notably autoimmune cytopenias. Weekly or every other week administration of abatacept gave better disease control compared with every 4 weeks. There were no serious side effects related to the abatacept therapy. Circulating T follicular helper cell frequencies were found to be a reliable biomarker of disease activity, which decreased on abatacept therapy in most subjects. However, high circulating T follicular helper cell frequencies persisted in 2 patients who had a more severe disease phenotype that was relatively resistant to abatacept therapy. CONCLUSIONS: Long-term abatacept therapy is effective in most patients with LRBA deficiency. (C) 2019 American Academy of Allergy, Asthma & Immunology, Scientific and Technological Research Council of TurkeyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [217S847]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [5R01AI085090]; NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [R01AI085090, R01AI085090, R01AI065617, R01AI065617, R01AI085090, R01AI085090, R01AI065617, R01AI065617] Funding Source: NIH RePORTER, This work was supported by grants from the Scientific and Technological Research Council of Turkey (grant no. 217S847 to S.B.) and the National Institutes of Health (grant no. 5R01AI085090 to T.A.C.).

Reactivation of hepatitis B virus (HBV) replication is characterized by increased HBV-DNA serum values of about 1 log or by HBV DNA turning positive if previously undetectable in serum, possibly associated with liver damage and seldom life-threatening. Due to HBV reactivation, hepatitis B surface antigen (HBsAg)-negative/anti-HBc-positive subjects may revert to HBsAg-positive. In patients with hemo-lymphoproliferative disease, the frequency of HBV reactivation depends on the type of lymphoproliferative disorder, the individual's HBV serological status and the potency and duration of immunosuppression. In particular, it occurs in 10%-50% of the HBsAg-positive and in 2%-25% of the HBsAg- negative/anti-HBc-positive, the highest incidences being registered in patients receiving rituximab-based therapy. HBV reactivation can be prevented by accurate screening of patients at risk and by a pharmacological prophylaxis with anti-HBV nucleo(t)sides starting 2-3 wk before the beginning of immunosuppressive treatment and covering the entire period of administration of immunosuppressive drugs and a long subsequent period, the duration of which depends substantially on the degree of immunodepression achieved. Patients with significant HBV replication before immunosuppressive therapy should receive anti-HBV nucleo(t)sides as a long-term (may be life-long) treatment. This review article is mainly directed to doctors engaged every day in the treatment of patients with onco-lymphoproliferative diseases, so that they can broaden their knowledge on HBV infection and on its reactivation induced by the drugs with high immunosuppressive potential that they use in the care of their patients.

Daclizumab, a MS treatment targeting IL2-receptor, has been recently withdrawn following reports of immune-mediated encephalitis. We report the case of a 39-years-old woman treated with daclizumab that presented a progressive decrease in the strength at her lower limbs which further worsened after the drug was stopped. Post-treatment MRI showed more than 20 new enhancing lesions. No symptoms nor signs associated with immune-mediated encephalitis were present. Our case highlights the problem of disease course after daclizumab discontinuation and urge neurologists to strictly monitor patients discontinuing the drug in order to exclude both the occurrence of immune-mediated encephalitis and disease reactivation.

Sen, Sait/0000-0002-1100-6657, WOS: 000522854900020, PubMed: 31696856, Rapidly progressive glomerulonephritis (RPGN) is rare syndrome in children, characterized by clinical features of glomerulonephritis and rapid loss of renal function, and is associated with crescentic glomerulonephritis. Primary membranous nephropathy (MN) is an immune-complex-mediated cause of the adult nephrotic syndrome but occurs less frequently in children. RPGN is rarely observed in adults with primary MN. in this article, we report a case of MN, which developed during long-term follow-up of previously treated RPGN. Our case may be the first to demonstrate primary MN and crescentic glomerulonephritis in a child. We would like to underline the importance of not dropping the long-term follow-up of cases with primary RPGN (not accompanied by other glomerulonephritis and vasculitis symptoms) who had improved with treatment.

PURPOSE: Typhlitis, also known as neutropenic colitis, is a rare inflammatory condition and a potentially life-threatening disease process that typically involves the cecum. Delay in diagnosis may lead to a fatal prognosis with a death rate of 21–48%. Ultrasound evaluation of right lower quadrant may lead to an accurate and rapid diagnosis. METHODS: We describe the case of a 59-year-old female with advanced Churg–Strauss syndrome treated with cyclophosphamide, with acute right lower quadrant pain. RESULTS: Ultrasound was the first diagnostic step in the diagnosis of typhlitis. Sonographic findings were comparable to CT imaging. CONCLUSIONS: Bowel bedside ultrasound evaluation in emergency settings may lead to a prompt and definitive diagnosis. Although CT is considered the gold standard in the diagnosis and staging of neutropenic colitis, ultrasound was able to identify the pathology accurately. Ultrasound findings of typhlitis are highly characteristic, showing circumferential wall thickening with predominant submucosa.