Brentuximab vedotin for skin involvement in refractory diffuse cutaneous systemic sclerosis, an open-label trial.

OBJECTIVE: We explored the efficacy and safety of brentuximab vedotin, a chimeric anti-CD30 antibody drug conjugate, in patients with severe active diffuse cutaneous systemic sclerosis (dcSSc). METHODS: This phase II proof-of-concept, single center, open-label, single arm, investigator-initiated trial included patients ≥18 years, with dcSSc, modified Rodnan skin score (mRSS) ≥15 with <5 years since the first non-Raynaud's symptom and/or skin worsening despite immunosuppression who were treated with intravenous brentuximab vedotin 0.6 mg/Kg q3 weeks for 45 weeks. The primary end point was a decrease in mRSS of ≥ 8 points at 48 weeks. RESULTS: Eleven patients were treated with brentuximab vedotin, with 9 completing the study. The mean mRSS reduction at week 48 was 11.3 (95% CI 6.9, 15.8; p= 0.001), meeting the primary end point in the intention to treat analysis (7/11 had a decrease in mRSS ≥8). The % forced vital capacity increased by 7.8% (12.5). The Composite Response Index in dcSSc (CRISS) suggested a beneficial treatment effect (86% ≥0.6). Most adverse events were mild. No SAEs were attributed to brentuximab vedotin. CONCLUSION: In dcSSc, brentuximab vedotin improved skin and FVC; without safety concerns. A placebo-controlled trial is warranted to corroborate these initial findings.

Performance of the 2019 ACR/EULAR classification criteria for IgG4-related disease and clinical phenotypes in a Spanish multicentre registry (REERIGG4).

OBJECTIVES: Several IgG4-related disease (IgG4-RD) phenotypes have been proposed and the first set of classification criteria have been recently created. Our objectives were to assess the phenotype distribution and the performance of the classification criteria in Spanish patients as genetic and geographical differences may exist. METHODS: We performed a cross-sectional multicentre study (Registro Español de Enfermedad Relacionada con la IgG4, REERIGG4) with nine participating centres from Spain. Patients were recruited from November 2013 to December 2018. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria (AECC) were used. RESULTS: We included 105 patients; 88% had Caucasian ethnicity. On diagnosis, 86% met the international pathology consensus while 92% met the Japanese comprehensive criteria. The phenotype distribution was head and neck 25%, Mikulicz and systemic (MS) 20%, pancreato-hepato-biliary (PHB) 13%, retroperitoneal and aorta (RA) 26%. Sixteen per cent had an undefined phenotype. Seventy-seven per cent of the cases met the AECC. From the 24 patients not meeting the AECC, 33% met exclusion criteria, and 67% did not get a score ≥20 points. Incomplete pathology reports were associated to failure to meet the AECC. CONCLUSIONS: The PHB phenotype was rare among Spanish IgG4-RD patients. The MS phenotype was less frequent and the RA phenotype was more prevalent than in other, Asian patient series. An undefined phenotype should be considered as some patients do not fall into any of the categories. Three quarters of the cases met the 2019 AECC. Incomplete pathology reports were the leading causes of failure to meet the criteria.

Efficacy and safety of rituximab for IgG4-related pancreato-biliary disease: A systematic review and meta-analysis.

BACKGROUND: Type I autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-SC) belong to the IgG4-related disease (IgG4-RD) spectrum. Both entities respond to glucocorticoids, but iatrogenic toxicity associated with prolonged steroid therapy and relapse represent relevant clinical concerns in the long-term. Rituximab is increasingly used as an effective alternative strategy to induce remission but data regarding the safety and efficacy of B-cell depletion therapy for pancreato-biliary involvement of IgG4-RD are limited. We performed a systematic review and meta-analysis to estimate the rate of remission, flare, and adverse events (AEs) occurring in pancreato-biliary IgG4-RD following rituximab treatment. METHODS: The MEDLINE, SCOPUS, and EMBASE databases were searched from inception to December 2020 to identify studies reporting the outcomes of IgG4-related pancreato-biliary disease after treatment with rituximab. Studies involving ≥2 patients were selected. In case of duplicated studies, the most recent or the one with the biggest N were chosen. The study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled effects were calculated using a random-effect model and expressed in terms of pooled remission, relapse, and AEs rates. RESULTS: Seven cohort studies met inclusion criteria and 101 patients were included. Reasons for rituximab administration were new disease onset (18.5%), disease flare after glucocorticoids (63.5%), and glucocorticoids intolerance (17.9%). The median follow-up time was 19 months. The pooled rate of complete response at 6 months was 88.9% (95%CI 80.5-93.9) with no heterogeneity (I2 = 0%). The pooled estimate of relapse rate was 21% (95%CI 10.5-40.3) with moderate heterogeneity (I2 = 51%). A higher rate of relapse (35.9%, 95%CI 17.3-60.1) was reported in studies including patients with multiorgan involvement (OOI). The median time to relapse was 10 months. The pooled estimate of rituximab-related AEs was 25% (95%CI 8.8-53) with substantial heterogeneity (I2 = 73.6%). No publication bias was observed. CONCLUSION: Treatment of IgG4-related pancreato-biliary disease with rituximab is associated with high remission rate, a higher relapse rate in the presence of OOI, and limited AEs. Randomized controlled trials with adequate power are needed to confirm these findings.

Sclerosing Cholangitis Related to IgG4: Not Always a Curable Entity.

IgG4-related disease is a recently-described fibro-inflammatory condition with characteristic histopathological findings in the organs involved. The most commonly affected organs are pancreas, lymph nodes, and retroperitoneum. Liver disease usually involves bile structures and therefore IgG4-related disease is considered a cause of secondary sclerosing cholangitis. One out of three patients with IgG4 sclerosing cholangitis also presents autoimmune pancreatitis, although it can be associated with manifestations in other organs. One of the main features of IgG4-related disease is its good prognosis due to the great response to glucocorticoid therapy. However, relapse of the disease is not uncommon, especially when steroid therapy is decreased or stopped. Rituximab seems to be an effective treatment to achieve remission of the disease. We report the case of a 74 year-old man diagnosed with IgG4-related disease based on increase of serum IgG4 levels, imaging and histopathological findings, with systemic involvement including sclerosing cholangitis. Despite the absence of liver fibrosis at onset, the early use of glucocorticoids and rituximab therapy, the patient presented clinical and analytical deterioration, leading to secondary biliary cirrhosis. In conclusion, this clinical case highlights the importance of prompt diagnosis and therapeutics for sclerosing cholangitis secondary to IgG4-related disease in order to avoid progression of the disease and development of liver cirrhosis, as well as the refractory, aggressive nature of the disease in some cases as this one.

Cardiac involvement in systemic sclerosis: differences between clinical subsets and influence on survival.

Cardiac involvement (CI) is a known complication of SSc associated with increased mortality. Our objective was to describe a cohort of patients with SSc and CI and to assess the differences between cutaneous subsets regarding their presentation and survival. Three hundred and ninety-three Spanish patients from a single center, diagnosed with SSc, were retrospectively studied for evidence of CI using noninvasive and invasive tests from 1976 to 2011. Clinical, epidemiological, immunological and therapeutic features of patients with CI were compared to those without it and within the different cutaneous subsets of SSc. CI was present in 173 (44 %) patients. Mitral regurgitation (67 %), conduction alterations (45 %) and left ventricle diastolic dysfunction (40 %) were the most common findings. Pericardial involvement and heart failure were more frequent in diffuse SSc (dcSSc) than in limited or sine scleroderma SSc. CI accounted for 20 % of deaths, and it was an independent mortality risk factor (HR 2.1, P = 0.02), but once CI was established, classical dcSSc mortality risk factors determined mortality. Patients with dcSSc developed CI faster than limited (HR 1.9, P = 0.003) or sine SSc patients (HR 2.5, P = 0.002), specially during the first year after SSc onset. We found statistically significant differences between the 3 SSc subsets in the presentation of pericardial involvement and heart failure. CI increased the mortality and appeared at a higher rate, especially during the first year after SSc onset. Screening for heart involvement should be performed at diagnosis and during follow-up.

Mixed Connective Tissue Disease and Epitope Spreading: An Historical Cohort Study.

OBJECTIVES: Mixed connective tissue disease (MCTD) is characterized by the presence of anti-U1-snRNP autoantibodies and a variable set of associated clinical features. Some MCTD patients test positive over time to autoantibodies against Sm, proteins spatially related with U1-snRNP. This situation has been attributed to expanding of the autoimmune response by a phenomenon known as epitope spreading. Our aim was to study the frequency of this phenomenon in MCTD patients and the specific clinical features of those with epitope spreading. METHODS: All anti-U1-RNP-positive patients (2010-2015) were retrospectively reviewed, and those meeting the MCTD criteria were included in the study. Patients showing epitope spreading were compared with the remainder of the MCTD cohort. In addition, the clinical features of patients with epitope spreading were compared before and after the phenomenon occurred. RESULTS: Among 72 anti-U1-RNP-positive patients, 40 (37 women) were diagnosed with MCTD. Thirteen MCTD patients (43%) presented epitope spreading, mainly during the first 2 years after the diagnosis of the disease (median, 1.4 years). Patients with epitope spreading had a significantly lower prevalence of skin sclerosis (0% vs. 44%, P = 0.004) and a greater prevalence of interstitial lung disease (46% vs. 15%, P = 0.05) than those without. Arthritis (92% vs. 25%, P = 0.02) and muscle involvement (67% vs. 17%, P = 0.02) were less frequent after epitope spreading had occurred. CONCLUSION: Epitope spreading is common in MCTD, occurring early after the diagnosis. The clinical manifestations in patients with this phenomenon differ from those without, and their clinical features change after the immunological phenomenon has occurred.

[Pharyngeal-cervical-brachial variant of Guillain-Barré syndrome]. / Variante faringo-cérvico-braquial del síndrome de Guillain-Barré

Guillain-Barré syndrome is an acute inflammatory demyelinating polyneuropathy. Infrequent loco-regional variants, like the pharyngeal-cervical-brachial, have been described. We report the case of a 63-year-old male admitted to the emergency department with cervical and upper limb weakness, inability to swallow and chew, he also presented a rapidly progressive acute respiratory failure due to weakness of the respiratory muscles secondary to the pharyngeal-cervical-brachial variant of Guillain-Barré syndrome. This variant, although unusual, presents a well-defined clinical pattern and diagnostic criteria, which is important in order to start an early treatment to improve the prognosis, not always favorable, to these patients.

State-of-the-art evidence in the treatment of systemic sclerosis.

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with multi-organ involvement, fibrosis and vasculopathy. Treatment in SSc, including early diffuse cutaneous SSc (dcSSc) and the use of organ-specific therapies, has improved, as evident from randomized clinical trials. Treatments for early dcSSc include immunosuppressive agents such as mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab and tocilizumab. Patients with rapidly progressive early dcSSc might be eligible for autologous haematopoietic stem cell transplantation, which can improve survival. Morbidity from interstitial lung disease and pulmonary arterial hypertension is improving with the use of proven therapies. Mycophenolate mofetil has surpassed cyclophosphamide as the initial treatment for SSc-interstitial lung disease. Nintedanib and possibly perfinidone can be considered in SSc pulmonary fibrosis. Pulmonary arterial hypertension is frequently treated with initial combination therapy (for example, with phosphodiesterase 5 inhibitors and endothelin receptor antagonists) and, if necessary, the addition of a prostacyclin analogue. Raynaud phenomenon and digital ulcers are treated with dihydropyridine calcium channel blockers (especially nifedipine), then phosphodiesterase 5 inhibitors or intravenous iloprost. Bosentan can reduce the development of new digital ulcers. Trial data for other manifestations are mostly lacking. Research is needed to develop targeted and highly effective treatments, best practices for organ-specific screening and early intervention, and sensitive outcome measurements.

Development of an algorithm for IgG4-related disease management.

OBJECTIVES: IgG4-related disease (IgG4-RD) is a rare fibro-inflammatory condition affecting multiple organs lacking standardized management. In this article, we review the evidence available to provide European expert-based statements on the management of IgG4-RD which were integrated in a final algorithm. METHODS: A panel of nine European experts in IgG4-RD from different specialties was asked to elaborate a set of consensus statements through a Delphi exercise. Three rounds of survey were taken. Consensus was reached when ≥75% of the responders agreed with a statement. RESULTS: Thirty-one statements on induction treatment, maintenance treatment, non-pharmacological treatment, and general considerations were assessed. Patients should be treated promptly in situations when there is an immediate organ threatened, or when organ damage is anticipated. Glucocorticoids (GC) are considered the first line of treatment and should be progressively tapered. Maintenance treatment is recommended for patients with high disease activity or with risk factors for relapse. Rituximab is effective for induction and maintenance of remission, but its use can be limited by economics. Low dose GC with or without GC-sparing agents can be used for maintenance therapy. Stenting or surgery should be ancillary to pharmacological treatment. Follow up should be based on physical examination, blood works, and imaging studies. Furthermore, it should be tailored on individual patient clinical history. 18-fluorodeoxyglucose positron emission tomography/computerized tomography may provide additional information over other imaging modalities. CONCLUSIONS: These new statements and algorithm reached a high degree of agreement and may help guiding the clinical management of IgG4-RD.

Trends in diagnosis of cardiac transthyretin amyloidosis: 3-year analysis of scintigraphic studies: Prevalence of myocardial uptake and its predictor factors.

To determine the prevalence of myocardial uptake (MU) and to identify predictors of MU in patients undergoing scintigraphy. Retrospective single-center series of technetium-99 m-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scans performed from March 2017 to March 2020. All patients undergoing scintigraphy were included, except those with preexisting amyloidosis. The features of MU, patients' characteristics and comorbidities were documented. Multivariate analysis was used to find items predicting MU. A total of 3,629 99mTc-DPD scans (total 11,444) were performed in patients aged > 70. The overall prevalence of MU was 2.7% (82/3,629); 1.2% in 2017-2018, to 2% in 2018-2019, and to 3.7% in 2019-2020. The prevalence of MU in patients without suspected cardiomyopathy was 1.2%; 1.1% in 2017-2018, 1.5% in 2018-2019 and 1% in 2019-2020. There is an increase in the number of requests due to suspected cardiomyopathy from 0.2% in 2017-2018 to 1.4% in 2018-2019 and to 4.8% in 2019-2020. Age, male sex, hypertension, heart failure, atrial fibrillation, atrioventricular block, aortic stenosis, and carpal tunnel syndrome were found to be predictors of MU. In patients without heart failure, only age, atrial fibrillation, and carpal tunnel syndrome were predicted MU. The prevalence of MU in scintigraphic studies surged over time due to the incremental referrals under the indication of cardiomyopathy workup. Atrial fibrillation and carpal tunnel syndrome were predictors for MU in patients without heart failure. Identifying patients with MU and no heart failure for extended screening for ATTR can lead to an earlier diagnosis and application of novel treatments.

Radiography-based triage for COVID-19 in the Emergency Department in a Spanish cohort of patients.

Background: Strategies to determine who could be safely discharged home from the Emergency Department (ED) in COVID-19 are needed to decongestion healthcare systems. Objectives: To describe the outcomes of an ED triage system for non-severe patients with suspected COVID-19 and possible pneumonia based on chest X-ray (CXR) upon admission. Material and methods: Retrospective, single-center study performed in Barcelona (Spain) during the COVID-19 peak in March-April 2020. Patients with COVID-19 symptoms and potential pneumonia, without respiratory insufficiency, with priority class IV-V (Andorran triage model) had a CXR upon admission. This approach tried to optimize resource use and to facilitate discharges. The results after adopting this organizational approach are reported. Results: We included 834 patients, 53% were female. Most patients were white (66%) or Hispanic (27%). CXR showed pneumonia in 523 (62.7%). Compared to those without pneumonia, patients with pneumonia were older (55 vs 46.6 years old) and had a higher Charlson comorbidity index (1.9 vs 1.3). Patients with pneumonia were at a higher risk for a combined outcome of admission and/or death (91 vs 12%). Death rates tended to be numerically higher in the pneumonia group (10 vs 1). Among patients without pneumonia in the initial CXR, 10% reconsulted (40% of them with new pneumonia). Conclusion: CXR identified pneumonia in a significant number of patients. Those without pneumonia were mostly discharged. Mortality among patients with an initially negative CXR was low. CXR triage for pneumonia in non-severe COVID-19 patients in the ED can be an effective strategy to optimize resource use.

Introducción: La pandemia de COVID-19 conlleva una alta ocupación de los servicios de urgencias (SU). Se requieren nuevas estrategias para optimizar la gestión de estos recursos. Objetivos: Describir los resultados de un sistema de triaje en urgencias para pacientes no graves con sospecha de COVID-19 y posible neumonía, basado en la radiografía de tórax (RT). Material y métodos: Estudio retrospectivo, unicéntrico realizado en Barcelona (España) entre marzo y abril de 2020. Se realizó una RT al ingreso en SU de pacientes con síntomas de COVID-19 y sospecha de neumonía, sin insuficiencia respiratoria, con una prioridad clase IV-V (sistema andorrano de triaje). Esta medida pretende optimizar los recursos y facilitar las altas. Se reportan los resultados tras adoptar esta estrategia. Resultados: Se incluyeron 834 pacientes (53% mujeres, 66% caucásicos, 27% hispánicos). La RT mostró neumonía en 523 (62,7%). Comparados con los pacientes sin neumonía, los que sí la padecían eran mayores (55 vs. 46,6 años), con un índice de comorbilidad de Charlson más elevado (1,9 vs. 1,3) y con mayor riesgo de ingreso y/o muerte (91 vs. 12%). La mortalidad fue numéricamente mayor en el grupo con neumonía (10 vs. 1). El 10% de los pacientes sin neumonía en RT consultaron de nuevo al SU (40% con neumonía). Conclusión: La RT identificó neumonía en múltiples pacientes. Los que no tenían neumonía fueron mayoritariamente dados de alta. La mortalidad entre pacientes con RT negativa fue baja. La RT como triaje para neumonía en pacientes con COVID-19 no grave puede ahorrar recursos.

Radiography-based triage for COVID-19 in the Emergency Department in a Spanish cohort of patients.

BACKGROUND: Strategies to determine who could be safely discharged home from the Emergency Department (ED) in COVID-19 are needed to decongestion healthcare systems. OBJECTIVES: To describe the outcomes of an ED triage system for non-severe patients with suspected COVID-19 and possible pneumonia based on chest X-ray (CXR) upon admission. MATERIAL AND METHODS: Retrospective, single-center study performed in Barcelona (Spain) during the COVID-19 peak in March-April 2020. Patients with COVID-19 symptoms and potential pneumonia, without respiratory insufficiency, with priority class IV-V (Andorran triage model) had a CXR upon admission. This approach tried to optimize resource use and to facilitate discharges. The results after adopting this organizational approach are reported. RESULTS: We included 834 patients, 53% were female. Most patients were white (66%) or Hispanic (27%). CXR showed pneumonia in 523 (62.7%). Compared to those without pneumonia, patients with pneumonia were older (55 vs 46.6 years old) and had a higher Charlson comorbidity index (1.9 vs 1.3). Patients with pneumonia were at a higher risk for a combined outcome of admission and/or death (91 vs 12%). Death rates tended to be numerically higher in the pneumonia group (10 vs 1). Among patients without pneumonia in the initial CXR, 10% reconsulted (40% of them with new pneumonia). CONCLUSION: CXR identified pneumonia in a significant number of patients. Those without pneumonia were mostly discharged. Mortality among patients with an initially negative CXR was low. CXR triage for pneumonia in non-severe COVID-19 patients in the ED can be an effective strategy to optimize resource use.

Response to Treatment in IgG4-Related Disease Assessed by Quantitative PET/CT Scan.

OBJECTIVE: The aim of this study was to assess disease activity by different PET/CT measurements in IgG4-related disease (IgG4-RD) flares and their correlation with the IgG4-RD responder index (IgG4-RI). PATIENTS AND METHODS: Patients were retrospectively recruited from a single center in Barcelona, Spain. They all had IgG4-RD flares with an 18F-FDG PET/CT examination performed within the 2 first weeks of the flare onset and another one after at least 3 months of treatment between 2012 and 2018. Epidemiologic, clinical, laboratory, and therapeutic data were collected at baseline and at follow-up. Semiquantitative and volumetric measurements from PET/CT explorations were recorded. In addition, a 5-point visual scale was (adapted Deauville score) trialed. The IgG4-RI was used as the criterion standard to assess response before and after treatment. RESULTS: Eighteen patients with a total of 23 flares were included. The median time to second PET/CT examination was 7 months. Remission (complete and partial) according to IgG4-RI was observed in 20 flares (87%). All PET/CT measurements (SUVmax and SUVmean, total lesion glycolysis, MTV, and adapted Deauville score) were statistically significantly lower on the follow-up evaluation, except for the size of the lesion. The correlation of all these parameters with the IgG4-RI was positive except for SUVmean and the size of the lesion. CONCLUSIONS: Semiquantitative, volumetric, and visual parameters in PET/CT scans correlated with response to treatment assessed by IgG4-RI. Volumetric and visual items are less subject to variations and could be used to improve activity scores and treatment strategies.

Emerging therapy options for IgG4-related disease.

INTRODUCTION: Awareness of IgG4-related disease (IgG4-RD) is increasing worldwide and specialists are now familiar with most of its clinical manifestations and mimickers. IgG4-RD promptly responds to glucocorticoids and repeated courses are typically used to induce and maintain remission because the disease relapses in most patients. If left untreated, it can lead to organ dysfunction, organ failure and death. Advancement in our understanding of IgG4-RD pathogenesis is leading to the identification of novel therapeutic targets and emerging treatments are now setting the stage for personalized therapies for the future. AREAS COVERED: This review focuses on emerging treatment options for IgG4-RD based on our advancing understanding of disease pathophysiology. Research was performed in the English literature on Pubmed and clinicaltrials.gov databases. EXPERT OPINION: Glucocorticoids remain the first-line induction treatment for the multi-organ manifestations of IgG4-RD. Alternative immunosuppressive agents for maintaining remission are warranted in order to avoid long-term steroid toxicity, and to offer a more mechanistic and personalized therapeutic strategy. Targeting B and T-lymphocyte activation represents the most promising approach, but randomized controlled trials are eagerly awaited to confirm positive preliminary experiences reported in case series and small cohort studies.