Fanny Domont

Extrahepatic manifestations of chronic hepatitis C virus infection

During hepatitis C virus (HCV) chronic infection, extrahepatic manifestations are frequent and polymorphous. This article reports on a large cohort of patients with HCV-related autoimmune or lymphoproliferative disorders, from mixed cryoglobulinemia vasculitis to frank lymphomas. The relationship between HCV infection and such immune-related diseases has been formally demonstrated by epidemiological, clinical, immunological and pathological data, and results of therapeutic trials. More recently, other nonliver-related HCV disorders have been reported, including cardiovascular (i.e. stroke, ischemic heart disease), renal, metabolic and central nervous system diseases. For these manifestations, most evidence comes from large epidemiological studies; there is a need for mechanistic studies and therapeutic trials for confirmation. Beyond the risk of developing liver complications, that is, cirrhosis and liver cancer, patients with HCV infection have an increased risk of morbidity and mortality related to nonliver diseases. HCV chronic infection should be analyzed as a systemic disease in which extrahepatic consequences increase the weight of its pathological burden. The need for effective viral eradication measures is underlined.

Chronic hepatitis C virus infection, a new cardiovascular risk factor?

Among the large scope of extrahepatic manifestations related to hepatitis C virus (HCV) infection, many studies recently evaluated the frequency and characteristics of cardiovascular involvement. To assess the current published data on HCV infection and cardiovascular diseases. Published studies on cardiovascular disease, i.e. cerebrovascular accident and ischaemic heart disease in subjects with HCV infection were analysed from literature databases. Subjects with HCV chronic infection have an increased prevalence of carotid atherosclerosis and increased intima‐media thickness compared to healthy controls or those with hepatitis B or non‐alcoholic steatohepatitis. Active chronic HCV infection appears as an independent risk factor for ischaemic cerebrovascular accidents. Active chronic HCV infection is associated with increased risk of ischaemic heart disease. In some studies, successful interferon‐based therapy showed a beneficial impact on the cardiovascular risk. The risk of major cardiovascular events is higher in patients with HCV infection compared to controls, independent of the severity of the liver disease or the common cardiovascular risk factors. The beneficial impact of interferon‐based therapy needs to be confirmed with new direct antiviral interferon‐free agents in prospective studies with extended follow‐up

Severe infections in sarcoidosis: Incidence, predictors and long-term outcome in a cohort of 585 patients

Abstract Sarcoidosis is associated with cell-mediated immunodeficiency and treatment of symptomatic sarcoidosis usually includes systemic immunosuppressants. Data relative to incidence, prognosis factors, and outcome of infections are scarce. Retrospective cohort study of 585 patients with biopsy proven sarcoidosis in a tertiary referral specialist clinic, with a nested case-control analysis. Twenty nine patients (4.9%) with severe infections were compared to 116 controls subjects with sarcoidosis, matched according to their gender, ethnicity, age at diagnosis, and treatment with corticosteroids. After a median follow-up of 8 years [range; 1–46], 38 severe infections [mycobacterial infections (n = 14), fungal infections (n = 10), bacterial (n = 8), viral (n = 3) and parasitic (n = 1)] were observed in 30 patients. The incidence of severe infections was 0.71% persons-year (CI 95% 0.5–0.98) and 0.43% persons-year (CI 95% 0.27–0.66). Patients with severe infection were more frequently of male gender (60% vs 46%) and were more likely treated by ≥ 3 immunosuppressive agents (OR = 3.8, IC 95% [1.5–9.64], P = .005) and by cyclophosphamide (OR = 5.55, IC 95% [1.9–16.1], P = .002), and with neurological (OR = 3.36 CI 95% [1.37–8.25], P = .008), or cardiac (OR = 2.65 CI 95% [1.09–6.43], P = .031) involvement of the sarcoidosis, compared to the controls. Two patients died within the 6 months following infection, due to progressive multifocal leucoencephalopathy (n = 1), and of peritonitis (n = 1). Severe infections are observed in 5.1% of our patients with sarcoidosis after a median follow-up of 8 years. Risk factors for severe infections included neurological or cardiac involvement of sarcoidosis, the use of immunosuppressive agents and mainly cyclophosphamide.

Systemic vasculitis associated with vemurafenib treatment: Case report and literature review.

Rationale:Vemurafenib, an inhibitor of mutated B-rapidly accelerated fibrosarcoma, is frequently used in the treatment of melanoma and Erdheim–Chester disease (ECD) patients. Inflammatory adverse effects have been increasingly reported after vemurafenib treatment. Patient concerns and diagnose:We report 6 cases of vemurafenib-associated vasculitis, of whom a personal case of a 75-year-old man with history of ECD who developed purpura and rapidly progressive pauci-immune glomerulonephritis during treatment with vemurafenib. Intervention:In the 5 others cases from the literature, all patients presented skin vasculitis, and with joint involvement in 60% of them. Vemurafenib treatment was stopped (n = 3), continued at reduced doses (n = 1), or continued at the same dose (n = 2). Outcomes:Three patients (50%) received corticosteroids combined with cyclophosphamide (n = 1), and all achieved remission of vasculitis. One patient experienced vasculitis relapse after vemurafenib therapy was restarted. Lessons:Systemic vasculitis is a rare vemurafenib-associated adverse event that may be life-threatening.

Large-vessel vasculitis in human immunodeficiency virus-infected patients

Objective: The objective of this study was to describe large‐vessel vasculitis (LVV) in patients with human immunodeficiency virus (HIV) infection. It is a retrospective single‐center study conducted between 2000 and 2015 through a university hospital of 11 HIV‐infected patients with LVV. Methods: The characteristics and outcome of 11 HIV‐infected patients with LVV (7 patients fulfilled international criteria for Takayasu arteritis, 5 patients had histologic findings of vasculitis, and 5 patients had imaging features of aortitis) were analyzed and compared with those of 82 patients with LVV but without HIV infection. Results: Concerning the HIV‐infected patients with LVV (n = 11), the mean age was 40 years (range, 36‐56 years), and 55% of patients were female. At diagnosis of LLV, the mean initial CD4 cell count was 455 cells/mm3 (range, 166‐837 cells/mm3), and the median HIV viral load was 9241 copies. Vascular lesions were located in the aorta (n = 7), in supra‐aortic trunks (n = 7), and in digestive arteries (n = 3). Inflammatory aorta infiltrates showed a strong expression of interferon‐&ggr; and interleukin 6. In HIV‐negative LVV patients (n = 82), the median age was 42 years, and 88% of the patients were women. Thirty patients had an inflammatory syndrome. Seventy patients had been treated with glucocorticosteroids and 57 with immunosuppressive treatments. Compared with their negative counterparts, HIV‐positive patients with LVV were more frequently male (P = .014), had more vascular complications (ie, Ishikawa score; P = .017), and had more frequent revascularization (P = .047). After a mean follow‐up of 96 months, four relapses of vasculitis were reported, and one patient died. Regardless of the HIV virologic response, antiretroviral therapy improved LVV in only one case. Conclusions: LVV in HIV‐infected patients is a rare and severe entity.

Chapter 10 – New Antivirals for Extrahepatic Manifestations of Hepatitis C Virus: The Model of Mixed Cryoglobulinemia Vasculitis

Mixed cryoglobulinemia vasculitis (Cryovas) is a small vessel vasculitis involving mainly the skin, the joints, the peripheral nerve system, and the kidneys, mainly due to hepatitis C virus (HCV) infection. Interferon alpha–based therapy has long been the cornerstone of HCV-Cryovas treatment. In the early 2010s, use of pegylated-interferon/ribavirin and a direct antiviral agent (DAA, boceprevir or telaprevir) led to improved rates of sustained virological response and Cryovas remission, which were limited by frequent side effects. Recently, all oral, interferon-free, DAA regimens led to very high rates of Cryovas clinical remission and few toxicities. In daily practice, HCV-Cryovas patients with mild to moderate disease should be given an optimal all oral, interferon-free, DAA regimen. For patients with severe vasculitis control of disease with rituximab, with or without plasmapheresis, is required while starting optimal antiviral therapy. Other immunosuppressants should be given only in case of refractory forms of HCV-Cryovas.

Tocilizumab-Induced Drug Reaction With Eosinophilia and Systemic Symptoms Syndrome in Adult-Onset Still Disease

Background: Adult-onset Still disease is a systemic inflammatory condition characterized by spiking fevers; polyarthritis; and an evanescent, salmon-pink, maculopapular rash. Affected persons have high ferritin levels, a high leukocyte count with neutrophil predominance, and low glycosylated ferritin levels. Tocilizumab is a humanized monoclonal antibody against the interleukin-6 receptor that is used to treat refractory adult-onset Still disease. This drug can cause adverse cutaneous events, such as mild maculopapular rash, urticaria, and pruritus (1). Objective: To describe what we believe is the first reported case of severe adverse cutaneous effects from tocilizumab. Case Report: A 55-year-old woman was hospitalized for a 2-month history of spiking fevers, sore throat, arthralgia, evanescent maculopapular rash, leukocytosis (leukocyte count, 23109 cells/L with 89% neutrophils), elevated levels of C-reactive protein (485.7 nmol/L) and ferritin (38199 pmol/L), and decreased levels of glycosylated ferritin (7%). We excluded infectious diseases and lymphoma and diagnosed adult-onset Still disease. Therapy with oral corticosteroids and methotrexate was not effective and was replaced with tocilizumab monotherapy, 8 mg/kg. Ten days after the first administration, the patient developed an unusual diffuse, persistent, pruritic maculopapular rash (Figure). Laboratory studies documented a decrease in the levels of C-reactive protein (123.8 nmol/L) and ferritin (7981 pmol/L) and the leukocyte count (14109 cells/L), which suggested improvement. Skin biopsy results showed lymphocyte and eosinophil infiltration in perivascular areas, which supported a diagnosis of a drug-induced reaction. Topical corticosteroids helped alleviate the rash, but laboratory tests 10 days later revealed hypereosinophilia (eosinophil count, 2.3109 cells/L) and liver enzyme levels up to 6 times the upper limit of normal. Polymerase chain reaction testing found a human herpesvirus-6 viral load of 105 copies/mL. We excluded parasitic and blood diseases and diagnosed tocilizumab-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. The new manifestations that we attributed to this syndrome resolved 5 weeks after we discontinued tocilizumab therapy. Figure. Rash that developed 10 d after the first administration of tocilizumab. Discussion: The DRESS syndrome is a potentially life-threatening combination of severe skin eruption, fever, hypereosinophilia, and internal organ involvement (2). It typically develops 2 to 6 weeks after initiation of the culprit drug. Manifestations also usually include a morbilliform rash with facial edema, lymphadenopathy, elevated liver enzyme levels, and leukocytosis (2). An immune response to herpesvirus reactivation (human herpesvirus types 6 and 7 and EpsteinBarr virus) is associated with a more prolonged and difficult course. There are few standards for diagnosis of DRESS syndrome, which relies on a compatible history and typical clinical manifestations and laboratory results in the absence of other possible conditions. Diagnosis of this syndrome was difficult because adult-onset Still disease could have caused elevated liver enzyme levels, leukocytosis, fever, and morbilliform rash. We believe that our diagnosis is justified because the patient did not have abnormal results on liver function tests before initiation of tocilizumab therapy; her new morbilliform rash differed from the previous rash caused by adult-onset Still disease; hypereosinophilia is not a typical feature of adult-onset Still disease; and her usual manifestations of adult-onset Still disease (arthralgia, standard rash, and hyperferritinemia) had remitted when the new symptoms developed, presumably because tocilizumab therapy was successful. Tocilizumab has been proposed as the cause of other adverse cutaneous reactions, including 1 unconfirmed case of StevensJohnson syndrome (3), a few cases of psoriasiform eruptions (4), and 1 case of drug-related generalized exanthematous pustulosis (5).

Les atteintes extrahépatiques du virus de l’hépatite C : un concept revisité

L’infection chronique par le virus de l’hépatite C (VHC) est n problème majeur de santé publique avec, selon l’OMS, 150 à 70 millions de personnes infectées dans le monde. Cette infecion chronique entraîne une surmortalité liée aux complications épatiques, cirrhose puis carcinome hépatocellulaire. Toutefois ette surmortalité a été longtemps sous-estimée car elle n’intégrait as le poids des nombreuses atteintes extrahépatiques liées au