Cloé Comarmond

Extrahepatic manifestations of chronic hepatitis C virus infection

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.

Anti TNF-α in refractory Takayasu's arteritis: Cases series and review of the literature

Takayasu arteritis (TA) is a rare large vessels vasculitis. Conventional therapy consists of glucocorticoids which may be associated with other immunosuppressive drugs. However, some patients fail to achieve remission with conventional treatment. The use of anti-tumor necrosis factor-α (TNF-α) in patients with difficult to treat TA could be useful. We report here the main characteristics, treatment and outcome of 84 patients (5 personal cases and 79 patients from the literature) with refractory Takayasu arteritis treated with anti TNF-α. The mean age was 28.5years [median 26.0years, range 7-61years], with 74/83 (89%) of female. All patients, except one, were inadequately controlled with other immunosuppressive regimens before anti TNF-α therapy. First line of anti-TNF-α included infliximab (IFX) in 81% (68/84) and etanercept (ETA) in 19% (16/84). Most patients received IFX at 5mg/kg associated to methotrexate or azathioprine. Thirty one out of 84 (37%) patients achieved a complete remission, and 45 (53.5%) were partial responders. There were 8 (9.5%) non responders at all. Twenty seven out of 84 (32%) patients needed to increase the dose of anti TNF-α because of uncontrolled disease and 15 (18%) needed to change of anti TNF-α. Glucocorticoids have been tapered in 41/79 (52%) [from 20mg (13.1-60) to 2.5mg (0-10) daily, at baseline and after anti-TNF, respectively, p<0.0001] and discontinued in 31/77 (40%). After a median follow-up of 10months [range 3-82], 17 (20%) side effects were recorded leading to discontinuation of anti TNF-α in 8 cases. They included mainly infections, and hypersensitivity reactions. In conclusion, anti-TNF-α are an efficient therapy in refractory TA patients although side effects are observed in 20% of cases. Further studies are warranted to assess the long term efficacy and safety of anti-TNF in TA and to better define if they should be prescribed earlier in the course of TA.

Granulomatosis with polyangiitis (Wegener): Clinical aspects and treatment

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.

Efficacy of Biological-Targeted Treatments in Takayasu Arteritis Multicenter, Retrospective Study of 49 Patients

Background— The goal of this work was to assess the safety and efficacy of biologics (ie, tumor necrosis factor-&agr; antagonists and tocilizumab) in patients with Takayasu arteritis. Methods and Results— 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-&agr; 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-&agr; 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. Conclusion— This nationwide study shows a high efficacy of biological-targeted treatments in refractory patients with Takayasu arteritis with an acceptable safety profile.Background— 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. Methods and Results— 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. Conclusion— This nationwide study shows a high efficacy of biological-targeted treatments in refractory patients with Takayasu arteritis with an acceptable safety profile. # CLINICAL PERSPECTIVE {#article-title-34}

Pulmonary fibrosis in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis: a series of 49 patients and review of the literature.

AbstractPulmonary fibrosis (PF) is an uncommon manifestation observed in patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), particularly microscopic polyangiitis (MPA). While patients with PF associated with AAV seem to have a worse prognosis, these patients have been described only in case reports or small retrospective case series. In this retrospective multicenter study, we report the main features and long-term outcomes of patients with PF associated with AAV, fulfilling the American College of Rheumatology criteria and/or Chapel Hill definitions. Forty-nine patients (30 men [61%]; median age at diagnosis of AAV, 68 [interquartile range, 58–73] years) with PF associated with AAV were identified. Forty (81.6%) patients had MPA and 9 (18.4%) had granulomatosis with polyangiitis. The diagnosis of PF preceded the onset of vasculitis in 22 (45%) patients. Usual interstitial pneumonia was the main radiologic pattern (n = 18, 43%). ANCA were mostly of antimyeloperoxidase specificity (88%). All patients were treated with glucocorticoids as induction therapy, combined with cyclophosphamide (CYC) (n = 36, 73.5%) or rituximab (RTX) (n = 1, 2%). Factors associated with mortality included occurrence of chronic respiratory insufficiency (hazard ratio [HR], 7.44; 95% confidence interval [CI], 1.6–34.5; p = 0.003), induction therapy with glucocorticoids alone (HR, 2.94; CI, 1.05–8.33; p = 0.04), and initial weigh loss (HR, 2.83; CI, 1.05–7.65; p = 0.041). The 3-year survival rate in patients treated with glucocorticoids alone or combined with an immunosuppressant (CYC or RTX) as induction therapy was 64% (95% CI, 41–99) and 94% (95% CI, 86–100), respectively (p = 0.03). After a median follow-up of 48 months [interquartile range, 14–88 mo], 18 (37%) patients died, including 11 related to respiratory insufficiency. PF is a rare manifestation of AAV with a very poor prognosis. Induction therapy with CYC might improve the outcome.

International therapeutic guidelines for patients with HCV-related extrahepatic disorders. A multidisciplinary expert statement

Hepatitis C virus (HCV) is both hepatotrophic and lymphotropic virus that causes liver as well extrahepatic manifestations including cryoglobulinemic vasculitis, the most frequent and studied condition, lymphoma, and neurologic, cardiovascular, endocrine-metabolic or renal diseases. HCV-extrahepatic manifestations (HCV-EHMs) may severely affect the overall prognosis, while viral eradication significantly reduces non-liver related deaths. Different clinical manifestations may coexist in the same patient. Due to the variety of HCV clinical manifestations, a multidisciplinary approach along with appropriate therapeutic strategies are required. In the era of interferon-free anti-HCV treatments, international recommendations for the therapeutic management of HCV-EHMs are needed. This implies the need to define the best criteria to use antivirals and/or other therapeutic approaches. The present recommendations, based on qualified expert experience and specific literature, will focus on etiological (antiviral) therapies and/or traditional pathogenetic treatments that still maintain their therapeutic utility.

Long-Term Outcomes and Prognostic Factors of Complications in Takayasu Arteritis: A Multicenter Study of 318 Patients

Background: Because of the wide variation in the course of Takayasu arteritis (TA), predicting outcome is challenging. We assess long-term outcome and prognosis factors for vascular complications in patients with TA. Methods: A retrospective multicenter study of characteristics and outcomes of 318 patients with TA fulfilling American College of Rheumatology and Ishikawa criteria was analyzed. Factors associated with event-free survival, relapse-free survival, and incidences of vascular complications were assessed. Risk factors for vascular complications were identified in a multivariable model. Results: The median age at TA diagnosis was 36 [25–47] years, and 276 patients (86.8%) were women. After a median follow-up of 6.1 years, relapses were observed in 43%, vascular complications in 38%, and death in 5%. Progressive clinical course was observed in 45%, carotidodynia in 10%, and retinopathy in 4%. The 5- and 10-year event-free survival, relapse-free survival, and complication-free survival were 48.2% (42.2; 54.9) and 36.4% (30.3; 43.9), 58.6% (52.7; 65.1) and 47.7% (41.2; 55.1), and 69.9% (64.3; 76.0) and 53.7% (46.8; 61.7), respectively. Progressive disease course (P=0.018) and carotidynia (P=0.036) were independently associated with event-free survival. Male sex (P=0.048), elevated C-reactive protein (P=0.013), and carotidynia (P=0.003) were associated with relapse-free survival. Progressive disease course (P=0.017), thoracic aorta involvement (P=0.009), and retinopathy (P=0.002) were associated with complication-free survival. Conclusions: This nationwide study shows that 50% of patients with TA will relapse and experience a vascular complication ⩽10 years from diagnosis. We identified specific characteristics that identified those at highest risk for subsequent vascular complications.

Myocarditis in auto-immune or auto-inflammatory diseases.

Myocarditis is a major cause of heart disease in young patients and a common precursor of heart failure due to dilated cardiomyopathy. Some auto-immune and/or auto-inflammatory diseases may be accompanied by myocarditis, such as sarcoidosis, Behçets disease, eosinophilic granulomatosis with polyangiitis, myositis, and systemic lupus erythematosus. However, data concerning myocarditis in such auto-immune and/or auto-inflammatory diseases are sparse. New therapeutic strategies should better target the modulation of the immune system, depending on the phase of the disease and the type of underlying auto-immune and/or auto-inflammatory disease.

Approaches to immunosuppression in Behçet's disease

Behçets disease (BD) is a systemic large-vessel vasculitis characterized by a wide clinical spectrum including recurrent oral and genital ulcerations, uveitis, and vascular, neurological, articular, renal and gastrointestinal manifestations. Therapeutic management of BD depends on the clinical presentation and organ involved. Although colchicine, nonsteroidal anti-inflammatory agents and topical treatments with corticosteroids are often sufficient for mucocutaneous and joint involvement, a more aggressive approach with immunosuppressive agents is warranted for severe manifestations such as posterior uveitis, retinal vasculitis and vascular, neurological and gastrointestinal involvement. However, some patients still have refractory disease, relapse, sight-threatening eye disease or irreversible organ damage. Recent improvements in the understanding of the pathogenic mechanisms have led to the identification of potential targets and future therapies for BD. In contrast to current nonspecific immunosuppressive agents, the emergence of immunomodulatory drugs provides the possibility of interfering with specific pathogenic pathways. Novel targeted immunosuppressive therapies might be used in the future for BD.

Rituximab therapy for Takayasu arteritis: a seven patients experience and a review of the literature

Objectives To assess the efficacy and safety of rituximab (RTX) in patients with Takayasu arteritis (TAK). Methods We conducted a retrospective study on seven TAK patients treated with RTX. Six of the seven patients had a disease refractory to high dose glucocorticoids and conventional immunosuppressive and/or biologic agents. One newly diagnosed, treatment-naïve TAK patient refused glucocorticoids and received RTX alone. Clinical evaluation, laboratory tests and imaging modalities (CT or MR-angiography, and 18 F-fluorodeoxyglucose PET/CT) were performed at first RTX administration and every 6 months thereafter. Disease activity was assessed using the Kerr index. We also performed a literature review using PubMed, Ovid MEDLINE and Cochrane library. Results Seven patients (6 females) were included in the study. Mean ( s . d .) age was 32.4 (17.3) years. At first RTX administration, all patients had active disease according to the Kerr index (⩾2), and had also evidence of active disease at PET/CT. Despite RTX treatment, four of the seven patients had evidence of persistent disease activity and/or radiographic disease progression during follow-up. Three out of seven patients in whom RTX was employed as rescue therapy achieved complete remission. In the literature review, we identified five papers describing nine patients treated with RTX with good results in eight cases, but short follow-up. Conclusion Our data do not support a role for RTX as first line biologic therapy in TAK patients, but it may have a role in some patients as second or third line biologic therapy.