Efficacy and Safety of High-Dose Immunoglobulin-Based Regimen in Statin-Associated Autoimmune Myopathy: A Multi-Center and Multi-Disciplinary Retrospective Study

Statin-associated autoimmune myopathy is a rare muscle disorder, characterized by autoantibodies against HMGCR. The anti-HMGCR myopathy persists after statin, and often requires immunosuppressive therapy. However, there is not a standardized therapeutic approach. The purpose of this study is to report the effectiveness of the immunosuppressive treatment employed in a multi-center and multi-disciplinary cohort of patients affected by anti-HMGCR myopathy, in which an immunoglobulin (IVIG)-based treatment strategy was applied. We collected 16 consecutive patients with a diagnosis of anti-HMGCR myopathy, between 2012 and 2019, and recorded data on clinical and laboratory presentation (i.e., muscle strength, serum CK levels, and anti-HMGCR antibody titer) and treatment strategies. Our results highlight the safety and efficacy of an induction therapy combining IVIG with GCs and/or methotrexate to achieve persistent remission of the disease and steroid-free maintenance. Under IVIG-based regimens, clinical improvement and CK normalization occurred in more than two thirds of patients by six months. Relapse rate was low (3/16) and 2/3 relapses occurred after treatment suspension. Nearly 90% of the patients who successfully discontinued GCs were treated with a triple immunosuppressive regimen. In conclusion, an IVIG-based regimen, which particularly includes high-dose immunoglobulin, GCs and methotrexate, can provide a fast remission achievement with GC saving

The Local Complement Activation on Vascular Bed of Patients with Systemic Sclerosis : A Hypothesis-Generating Study

Peer reviewe

Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial

The coronavirus disease 2019 (COVID-19) pandemic is threatening billions of people worldwide. Tocilizumab has shown promising results in retrospective studies in patients with COVID-19 pneumonia with a good safety profile

The complement system in the pathogenesis of cutaneous sclerosis: comparison between Sclerodermatous GVHD and Systemic Sclerosis

La Sclerosi Sistemica (SSc) e la GVHD cronica cutanea ad espressione fibrotica (ScGVHD) sono malattie solo in minima parte comprese e che mancano di una terapia risolutiva. Sono inoltre solo apparentemente simili. Condividono l\u2019aspetto sclerotico della cute e la patogenesi a partenza immunologica, ma differiscono soprattutto sull\u2019interessamento del microcircolo. Il danno endoteliale \ue8 ritenuto essere uno dei primissimi eventi nella patogenesi della SSc ed \ue8 infatti nella SSc che i capillari sono danneggiati e quantitativamente molto ridotti, a differenza di quanto si osserva nella ScGVHD. Il sistema del complemento e la sua regolazione sono elementi fondamentali per l\u2019integrit\ue0 dell\u2019endotelio ed alcune evidenze relative al suo coinvolgimento in entrambe le malattie sono ormai state raccolte. Ci si \ue8 pertanto proposti di confrontare, nella SSc e nella ScGVHD, l\u2019espressione del complesso di attacco alla membrana (C5b-9), effettore del danno cellulare mediato dal complemento sulle cellule bersaglio e l\u2019espressione di Membrane Cofactor Protein (MCP o CD46), una delle proteine regolatrici della cascata complementare. Ci si \ue8 inoltre proposti di ricercare in tutti i pazienti arruolati la presenza di specifici polimorfismi nel gene che regola l\u2019espressione del MCP. Settantuno pazienti affetti da SSc, 5 da ScGVHD e 27 volontari sani sono stati arruolati presso l\u2019Ospedale Policlinico Universitario di Verona, Italia. Sono stati raccolti siero e DNA di tutti i pazienti e volontari. I test Elisa sono stati eseguiti su 47 pazienti sclerodermici, sui 5 affetti da ScGVHD e su 18 individui sani. Le biopsie cutanee, ottenute da 8 pazienti sclerodermici e 3 affetti da ScGVHD sono state analizzate con tecniche di immunoistochimica ed immunofluorescenza per quantificare l\u2019espressione C5b-9 e MCP sulle cellule endoteliali. Sono state confrontate con biopsie cutanee di altre malattie e di soggetti sani. L\u2019analisi statistica \ue8 stata fatta con il software STATA 10.1. I livelli sierici di C5b-9 e MCP non differivano tra i pazienti sclerodermici, quelli affetti da ScGVHD ed i soggetti sani. L\u2019analisi in immunofluorescenza delle biopsie cutanee, ha mostrato una marcata attivazione del complemento nelle pareti dei vasi nella ScGVHD ed una considerevole, ma meno spiccata attivazione anche nel microcircolo dei pazienti sclerodermici, mentre il complesso C5b-9 non \ue8 stato rilevato in nessun vaso dei campioni sani. L\u2019espressione endoteliale di MCP \ue8 risultata pi\uf9 bassa nella SSc e nella ScGVHD, sia all\u2019analisi immunoistochimica, sia allo studio con immunofluorescenza rispetto ai controlli sani. Infine, nella SSc le frequenze degli alleli meno comuni dei due polimorfismi (SNPs) appartenenti alla regione del promotore di MCP risultavano essere maggiori che nei controlli sani. Le stesse varianti polimorfiche non sono state osservate nella ScGVHD. In conclusione si conferma che il sistema del complemento \ue8 coinvolto nella patogenesi di entrambe le malattie. Soprattutto nella SSc il suo ruolo potrebbe essere in parte dovuto ad una ridotta espressione della proteina regolatrice MCP. Ulteriori ricerche in questo ambito sono auspicabili, anche in prospettiva dello sviluppo di alcuni farmaci inibitori del complemento, alcuni dei quali sono gi\ue0 in corso di sperimentazione in altre condizioni patologiche.Systemic Sclerosis (SSc) and sclerodermatous GVHD (ScGVHD) are similar diseases, poorly understood and still lacking an effective therapy. On one hand, they share clinical features and immunological mechanisms . On the other hand they differ in the microvascular damage, that is higher in SSc than in ScGVHD. Since there are some evidences that complement system could be involved in both diseases, we evaluated complement activation (by C5b-9 expression) and the expression of a regulatory protein, Membrane Cofactor Protein (MCP or CD46), in both conditions. We also investigated some genetic polymorphisms (SNPs) in complement regulation gene cluster. Seventy one patients with diagnosis of SSc, 6 with ScGVHD and 27 healthy volunteers were enrolled in the University Hospital of Verona, Italy. Serum and DNA of all patients and volunteers were collected. Elisa was performed on 47 SSc, 5 ScGVHD patients and 18 healthy volunteers. Skin biopsies, obtained from 8 SSc and 3 ScGVHD patients, underwent immunohistochemistry analysis and immunofluorescence stainings for detecting the expression of complement Membrane Attack Complex (C5b-9) and MCP on endothelial cells. Archival skin biopsies of control diseases and normal individuals were also analyzed. Statistical analysis was performed using STATA 10.1 software. Circulating levels of C5b-9 and MCP did not differ between healthy subjects, SSc and ScGVHD patients. Immunofluoresce stainings of skin biopsies showed a pronounced complement activation in ScGVHD and a little less remarkable activation in SSc vessels, if compared with healthy volunteers. MCP was lower in SSc than in ScGVHD, both in immunohistochemistry analysis and in immunofluorescence stainings and in both diseases it was lower than in healthy controls. Finally, the minor variants of two SNPs in MCP promoter region were over-expressed in SSc patients. The same uncommon alleles were not found in ScGVHD. In conclusion we confirm that complement system is involved in the pathogenesis of both diseases. Particularly in SSc its role seems to be partially related to an impaired function of regulatory protein MCP. Further researches about these topics would be useful, since some complement inhibitor drugs are on clinical trials for different diseases and others will be probably developed in future

Severe vascular complications in patients affected by systemic sclerosis cyclically treated with iloprost

The objective of this study was to evaluate the incidence of the most severe vascular complications, such as pulmonary arterial hypertension, scleroderma renal crisis, and digital necrosis requiring amputation, in a monocentric group of systemic sclerosis (SSc) patients cyclically treated with intravenous iloprost. We reviewed the record-charts of 115 patients affected by SSc (18 men and 97 women, mean age 58.9.1 \ub1 14.2 years) regularly receiving iloprost for at least 3 years; the mean duration of the treatment was 98.8 \ub1 37.5 months (a total of 946.8 years of therapy). Demographic and clinical features were recorded. None of the patients died of SSc-associated vascular complications. After iloprost administration digital gangrene requiring amputation developed in 2 patients who had concomitant peripheral arterial disease (a total of 3 episodes; annual incidence of 0.31 for 100 years of iloprost therapy). Four patients were diagnosed with pulmonary arterial hypertension during iloprost treatment (annual incidence of 0.42 for 100 years of drug therapy); in none of the cases did the complication show a progressive course. No cases of scleroderma renal crisis were observed. With the limits of an observational study and in the absence of a control group, our experience suggests that prolonged cyclic iloprost therapy may limit the incidence/progression of severe digital and visceral SSc-vasculopathy