Abstract Hepatitis C virus (HCV) infected patients are known to be at risk of developing liver complications i.e. cirrhosis and liver cancer. However, the risks of morbidity and mortality are ...underestimated because they do not take into account non-liver consequences of chronic hepatitis C virus infection. Numerous extrahepatic manifestations have been reported in up to 74% of patients, from perceived to disabling conditions. The majority of data concern hepatitis C virus-related autoimmune and/or lymphoproliferative disorders, from mixed cryoglobulinaemia vasculitis to frank lymphomas. More recently, other hepatitis C virus-associated disorders have been reported including cardiovascular, renal, metabolic, and central nervous system diseases. This review aims to outline most of the extrahepatic manifestations that are currently being investigated, including some of autoimmune and/or lymphoproliferative nature, and others in which the role of immune mechanisms appears less clear. Beyond the liver, hepatitis C virus chronic infection should be analyzed as a multifaceted systemic disease leading to heavy direct and indirect costs. The accurate consideration of extrahepatic consequences of such a systemic infection significantly increases the weight of its pathological burden. The need for effective viral eradication measures is underlined.
Cryoglobulinemia Vasculitis Cacoub, Patrice, MD; Comarmond, Cloe, MD; Domont, Fanny, MD ...
The American journal of medicine,
09/2015, Volume:
128, Issue:
9
Journal Article
Peer reviewed
Open access
Abstract Cryoglobulinemic vasculitis (CryoVas) is a small-vessel vasculitis involving mainly the skin, the joints, the peripheral nervous system, and the kidneys. Type I CryoVas is single monoclonal ...immunoglobulins related to an underlying B-cell lymphoproliferative disorder. Type II and III cryoglobulins, often referred to as mixed cryoglobulinemia, consist of polyclonal immunoglobulin (Ig)G with or without monoclonal IgM with rheumatoid factor activity. Hepatitis C virus (HCV) infection represents the main cause of mixed CryoVas. The 10-year survival rates are 63%, 65%, and 87% in HCV-positive mixed CryoVas, HCV-negative mixed CryoVas, and type I CryoVas patients, respectively. In HCV-positive patients, baseline poor prognostic factors include the presence of severe liver fibrosis, and central nervous system, kidney, and heart involvement. Treatment with antivirals is associated with a good prognosis, whereas use of immunosuppressants (including corticosteroids) is associated with a poor outcome. In HCV-negative patients, pulmonary and gastrointestinal involvement, renal insufficiency, and age > 65 years are independently associated with death. Increased risk of lymphoma also should be underlined. Treatment of type I CryoVas is that of the hemopathy; specific treatment also includes plasma exchange, corticosteroids, rituximab, and ilomedine. In HCV-CryoVas with mild-to-moderate disease, an optimal antiviral treatment should be given. For HCV-CryoVas with severe vasculitis (ie, worsening of renal function, mononeuritis multiplex, extensive skin disease, intestinal ischemia…) control of disease with rituximab, with or without plasmapheresis, is required before initiation of antiviral therapy. Other immunosuppressants should be given only in case of refractory forms of CryoVas, frequently associated with underlying B-cell lymphoma.
Abstract Circulating mixed cryoglobulins are detected in 40%–60% of patients with hepatitis C virus (HCV) infection, and overt cryoglobulinemia vasculitis (CryoVas) develops in about 15% of patients. ...Remission of vasculitis has been associated with viral clearance, but few studies have reported the effectiveness of direct acting antiviral drugs in these patients. We performed open-label, prospective, multi-center study of the effectiveness and tolerance of an all-oral, interferon- and ribavirin-free regimen of sofosbuvir plus daclatasvir in patients with HCV-associated CryoVas. Forty-one consecutive patients with active HCV-associated CryoVas (median age, 56 years; 53.6% women) were recruited from hospitals in Paris, France from 2014 through 2016. They received sofosbuvir (400 mg/day) plus daclatasvir (60 mg/day) for 12 weeks (n=32) or 24 weeks (n=9) and evaluated every 4 weeks until week 24 and at week 36. Blood samples were analyzed for complete blood count, serum chemistry profile, level of alanine aminotransferase, rheumatoid factor activity, C4 fraction of complement, and cryoglobulin; peripheral blood mononuclear cells were isolated for flow cytometry analysis. Thirty-seven patients (90.2%) had a complete clinical response (defined by improvement of all the affected organs involved at baseline and no clinical relapse) after a median time of 12 weeks’ therapy; all had a sustained virologic response (no detectable serum HCV RNA 12 weeks after the end of antiviral therapy). Patients’ mean cryoglobulin level decreased from 0.56±0.18 at baseline to 0.21±0.14 g/L at week 36, and no cryoglobulin was detected in 50% of patients at this time point. After antiviral therapy, patients had increased numbers of T-regulatory cells, IgM+CD21–/low memory B cells, CD4+CXCR5+ IL21+ cells, and T-helper 17 cells, compared with before therapy. After a median follow-up period of 26 months (interquartile range, 20–30 months), no patients had a serious adverse event or relapse of vasculitis.
Objective
Oral ulcers, the hallmark lesion of Behçet's disease (BD), can be disabling and resistant to conventional treatment, and there is a need for safe and effective treatment. We undertook this ...study to investigate the long‐term safety and efficacy of ustekinumab therapy for BD‐related oral ulcers that are resistant to colchicine.
Methods
This multicenter, prospective, open‐label study included 30 patients who fulfilled the criteria of the International Study Group for BD and who were diagnosed as having active oral ulcers resistant to colchicine. Patients were treated subcutaneously with ustekinumab 90 mg at inclusion, at week 4, and then once every 12 weeks. Each patient was assessed longitudinally for the presence and number of oral ulcers, and median numbers of oral ulcers (with interquartile range IQR) were calculated. The primary efficacy end point was the proportion of patients at week 12 who experienced complete response, defined as having no oral ulcers.
Results
The median number of oral ulcers per patient during ustekinumab therapy was significantly lower at week 12 compared to baseline (0 IQR 0–1 versus 2 IQR 2–3; P < 0.0001). Complete response was achieved in 60.0% and 88.9% of patients at weeks 12 and 24, respectively. The median Behçet's Syndrome Activity Score (in which higher scores indicate more active disease) was significantly lower at weeks 12 and 24 (17.5 IQR 10–42.5 and 10 IQR 8–11, respectively) versus baseline (70 IQR 50–70; P < 0.0001). After a median follow‐up of 12 months (IQR 6–16 months), 26 patients (86.7%) were still receiving ustekinumab treatment. Reasons for ustekinumab discontinuation included BD flare (n = 3) and side effects (n = 1). Seven patients (23.3%) experienced adverse events, including headaches (n = 4) and asthenia (n = 2), with no serious side effects.
Conclusion
Ustekinumab seems to be effective in treating BD‐related oral ulcers that are resistant to treatment with colchicine.
Objective
Earlier studies of eosinophilic granulomatosis with polyangiitis (Churg‐Strauss) (EGPA), with limited patient numbers and followup durations, demonstrated that clinical presentation at ...diagnosis, but not outcome, differed according to antineutrophil cytoplasmic antibody (ANCA) status. This study was undertaken to describe the main characteristics of a larger patient cohort and their long‐term outcomes.
Methods
A retrospective study of EGPA patients in the French Vasculitis Study Group cohort who satisfied the American College of Rheumatology criteria and/or Chapel Hill definitions was conducted. Patient characteristics and outcomes were compared according to ANCA status and year of diagnosis.
Results
We identified 383 patients diagnosed between 1957 and June 2009 (128 33.4% before 1997 or earlier) and followed up for a mean ± SD of 66.8 ± 62.5 months. At diagnosis, their mean ± SD age was 50.3 ± 15.7 years, and 91.1% had asthma (duration 9.3 ± 10.8 years). Main manifestations included peripheral neuropathy (51.4%); ear, nose, and throat (ENT) signs (48.0%); skin lesions (39.7%); lung infiltrates (38.6%); and cardiomyopathy (16.4%). Among the 348 patients tested at diagnosis for ANCA, the 108 ANCA‐positive patients (31.0%) had significantly more frequent ENT manifestations, peripheral neuropathy, and/or renal involvement, but less frequent cardiac manifestations, than the ANCA‐negative patients. Vasculitis relapses occurred in 35.2% of the ANCA‐positive versus 22.5% of the ANCA‐negative patients (P = 0.01), and 5.6% versus 12.5%, respectively, died (P < 0.05). The 5‐year relapse‐free survival rate was 58.1% (95% confidence interval 95% CI 45.6–68.6) for ANCA‐positive and 67.8% (95% CI 59.8–74.5) for ANCA‐negative patients (P = 0.35). Multivariable analysis identified cardiomyopathy, older age, and diagnosis during or prior to 1996 as independent risk factors for death and lower eosinophil count at diagnosis as predictive of relapse.
Conclusion
The characteristics and long‐term outcomes of EGPA patients differ according to their ANCA status. Although EGPA relapses remain frequent, mortality has declined, at least since 1996.
To assess the efficacy of tocilizumab in patients with Takayasu arteritis (TA).
We conducted a retrospective multicenter study in 46 TA patients treated with tocilizumab. We analyzed factors ...associated with response to tocilizumab (assessed using NIH score).
Forty-six patients with TA were included, with a median age of 43 years 29–54, and 35 (76%) females. We observed a decrease in the median NIH scale (from 3 2–3 at baseline to 0 0–1 and 0 at 3 and 6 months, respectively; p < 0.0001). The daily prednisone dose also decreased from 15 mg 8–19 at baseline to 4 mg 5–21 and 5 mg 4.5–9 at 3 and 6 months, respectively (p < 0.0001) under tocilizumab. The overall tocilizumab failure free survival was 81% CI 95%; 0.7–0.95, 72% CI 95%; 0.55–0.95 and 48% CI 95%; 0.2–0.1 at 12, 24 and 48 months, respectively. The presence of constitutional symptoms (HR 5.6 CI 95%; 1.08–29, p = 0.041), and C-reactive protein level (HR 1.16 CI 95%; 1.01–1.31, P = 0.003) at the time of tocilizumab initiation were significantly associated with tocilizumab event-free survival. The event-free survival was significantly better under tocilizumab therapy in comparison to DMARDs (p = 0.02).
This large multicenter study shows that tocilizumab is efficient and may reduce the incidence of relapses in TA.
•Tocilizumab can lead patients TA to remission in 80%, have steroid sparing effect and a good safety profile.•Tocilizumab can be used in monotherapy and as first line therapy.•Tocilizumab can be used in monotherapy and is effective as first line therapy.
Abstract Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis, which affects small- and medium-sized blood vessels and is often associated with cytoplasmic ANCA. GPA occurs in ...patients between 45 and 60 years old of both genders, and is rarely observed in blacks. The prevalence of GPA increases along a south–north gradient in Europe (20 to 150/million). The main clinical characteristics involve the upper and/or lower respiratory tract and kidneys. Ear, nose and throat manifestations with recurrent sinusitis and crusting rhinorrhea are usually severe. Lung nodules are frequently seen, sometimes excavated. Renal involvement is characterized by rapidly progressive necrotizing glomerulonephritis with extracapillary crescents. Limited forms of GPA predominantly affect the upper respiratory tract, whereas generalized forms of GPA include renal manifestations and/or alveolar hemorrhage and/or vital organ involvement with an altered general condition. The combination of immunosuppressant drugs and corticosteroids has converted this typically fatal illness into one in which 80% of patients achieve remission. However, despite considerable therapeutic progress over the last decades, relapses remain frequent (50% at 5 years), and maintenance treatment is now the main therapeutic challenge.
Abstract Objective To evaluate the efficacy and safety of ustekinumab in the treatment of oral ulcers (OU) in patients with Behçet's disease (BD). Patients and methods Prospective study including 14 ...patients median age of 39 (34; 41) years, with 71% of men fulfilling criteria of the International Study Group for BD and with active OU resistant to colchicine. Patients received ustekinumab 90 mg (n = 11) or 45 mg (n = 3) subcutaneously at inclusion, at week 4, and every 12 weeks. The primary efficacy endpoint was the proportion of patients with complete response (CR), defined as no oral ulcer, at week 12. Results At week 12, 64% were in CR, 21% in partial response and 14% non-responders. The median number of OU decreased from 2 2; 4 to 1 0; 1.25 (p = 0.0005) at week 12. Mean change from baseline to week 12 of Behçet's syndrome activity score (BSAS) was 22.8 ± 0.3 (p = 0.01). The median daily corticosteroids dose decreased from 12.5 (10; 16.3) to 5 5; 10 mg/day (p = 0.02). Three patients reported headaches, leading to discontinuation of ustekinumab in one case. After a median follow-up of 7 3; 12 months, 10 (71%) patients were still receiving ustekinumab and four (28%) experienced a relapse. Decreased levels of circulating IL-17 and IL-12 median IQR; 3.9 1.6; 10.6 vs. 29.2 25.2; 42.7 pg/ml, and 29.4 23.1; 33.3 vs. 56.1 51.1; 64.4 pg/ml, p = 0.008 for both were observed under ustekinumab, respectively. Conclusion Ustekinumab seems to be efficient and safe for patient with BD and refractory OU although relapses are frequent.
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.
The goal of this work was to assess the safety and efficacy of biologics (ie, tumor necrosis factor-α antagonists and tocilizumab) in patients with Takayasu arteritis.
This was a retrospective, ...multicenter study of the characteristics and outcomes of 49 patients with Takayasu arteritis (80% female; median age, 42 years 20-55 years treated by tumor necrosis factor-α antagonists 80% or tocilizumab 20%) and fulfilling American College of Rheumatology or Ishikawa criteria. Factors associated with complete response were assessed. Eighty-eight percent of patients with Takayasu arteritis were inadequately controlled with or were intolerant to conventional immunosuppressive therapy (median number, 3 1-5). Overall response (ie, complete and partial) to biological-targeted treatments at 6 and 12 months was 75% and 83%, respectively. There were significantly lower C-reactive protein levels at the initiation of biological-targeted treatments (22 mg/L 10-46 mg/L versus 58 mg/L 26-76 mg/L; P=0.006) and a trend toward fewer immunosuppressants drugs used before biologics (P=0.054) in responders (ie, complete or partial responders) relative to nonresponders to biological-targeted treatments. C-reactive protein levels and daily prednisone dose significantly decreased after 12 months of biological-targeted treatments (30 versus 6 mg/L P<0.05 and 15 versus 7.5 mg P<0.05 at baseline and 12 months, respectively). The 3-year relapse-free survival was 90.9% (83.5%-99%) over the biological treatment period compared with 58.7% (43.3%-79.7%; P=0.0025) with disease-modifying antirheumatic drugs. No difference in efficacy was found between tumor necrosis factor-α antagonists and tocilizumab. After a median follow-up of 24 months (2-95 months), 21% of patients experienced adverse effects, with biological-targeted treatments discontinued in 6.6% of cases.
This nationwide study shows a high efficacy of biological-targeted treatments in refractory patients with Takayasu arteritis with an acceptable safety profile.
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