J.-F. Besancenot

Efficacy of Tocilizumab in Two Patients with anti-TNF-alpha Refractory Uveitis

Purpose: To report on two patients with refractory uveitis treated with tocilizumab; a new humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Design: Retrospective interventional case series. Methods: Both patients received a monthly infusion of tocilizumab 8 mg/kg; associated with corticosteroids. Outcome measures were visual acuity and central retinal thickness evaluated with optical coherence tomography. Results: An improvement in visual acuity and a decrease in macular edema were observed in these two patients. Conclusions: Tocilizumab seems to be a promising treatment in refractory uveitis. A prospective study is needed to evaluate the role of this new agent in the management of refractory uveitis.

Efficacy of tocilizumab in refractory giant cell arteritis

Giant cell arteritis is the most frequent form of vasculitis characterized by a high risk of vascular thrombosis. Major complications are blindness and other vascular ischemia but bowel ischemic involvement is rare. Treatment is based on long-term steroid therapy with numerous side effects. The efficacy of immunosuppressive drugs like azathioprine methotrexate or anti-tumor necrosis factor antibodies appears to be too low to reduce the use of steroids. Th17 lymphocytes and interleukin-6 play an important role in pathogenesis of giant cell arteritis. We report here a case of effective interleukin-6 blocker in the treatment of refractory giant cell arteritis with ileitis and high-dose steroid dependence despite 2 years of treatment with steroids and methotrexate. After infusions of tocilizumab, no relapse at 6 months was found despite the decrease in corticosteroids.

Stroke associated with giant cell arteritis: a population-based study

Background Giant cell arteritis (GCA) is the most common vasculitis in people ≥50 years and can be associated with stroke. We aimed to evaluate the epidemiology and characteristics of stroke in patients with GCA. Methods All patients with a biopsy-proven diagnosis of GCA were identified among residents of the city of Dijon, France (152 000 inhabitants), between 2001 and 2012 using a prospective database. Among these, patients who suffered from stroke were retrieved by crossing data from the population-based Dijon Stroke Registry. Demographics and clinical features were recorded. We considered that the stroke was GCA-related if the stroke revealed GCA or occurred between the onset of symptoms and 4 weeks after the start of treatment. Results Among the 57 biopsy-proven patients with GCA (incidence rate 10.9/100 000/year in individuals ≥50 years), 4 (7.0%) experienced a GCA-related stroke. Three were men and all had ≥2 vascular risk factors and were ≥80 years. The stroke was vertebrobasilar for 3/4 patients and undetermined for the remaining one. The incidence rate of GCA-related stroke in patients ≥50 years was 0.76/100 000/year (95% CI 0 to 2.47), 1.36/100 000/year in men (95% CI 0 to 3.63) and 0.33/100 000/year (95% CI 0 to 1.45) in women. Conclusions This population-based study demonstrated that GCA-related stroke essentially affects the vertebrobasilar territory and mainly occurs in old men with associated vascular risk factors. Although rare, GCA symptoms must be searched for in elderly patients with stroke, and optimal vascular prevention must be conducted carefully in patients with GCA with a high vascular risk before initiating GCA treatment.

Sclérodermie systémique et cancers: 21 observations et revue de la littérature

Twenty one cases of the association systemic scleroderma and cancer are reported. Neoplasic localisations were the following: pulmonary five cases; breast two cases; esophageal cancer one case; stomach one case; colon one case; uterus four cases; ovarian cancer one case; prostatic cancer one case; renal cancer one case; malignant hemopathies six cases. In the literature, more than three hundred cases of such an association have been reported since 1886, essentially lung cancers (more than 100). Recent epidemiological studies allow to conclude to a higher frequency of lung and breast cancers. We suggest that systemic scleroderma patients should be examined attentively and carefully for these risks.

Heart involvement in Churg–Strauss syndrome: Retrospective study in French Burgundy population in past 10 years

INTRODUCTION Heart manifestations of Churg-Strauss syndrome (CSS) are varied. In the early stages of the disease, it is difficult to distinguish between lesions that are specific to CSS and those of other etiologies. The aim of our work was to compare the characteristics of patients with heart manifestations linked or not to Churg-Strauss syndrome. MATERIAL AND METHODS We recorded all clinical symptoms of patients with CSS hospitalized between 1998 and 2008 in Burgundy, France, and determined the possible relationships between heart symptoms and CSS. RESULTS From a cohort of 31 patients, we found 20 with heart lesions. When heart lesions were present, we noted fewer initial symptoms of digestive disorders (p<0.05), lower levels of lung infiltrates and fewer anti-MPO pANCA (p<0.05). Heart lesions were linked to CSS in 75% of cases. Their patients were thus younger than those in the other cardiac patients (p<0.05), were more likely to have clinical manifestations of heart involvement at diagnosis, were less likely to have lung infiltrates on the X-ray at diagnosis and during flare-ups and less likely to have lung abnormalities on X-rays during flare-ups (p<0.05) and higher level of leucocytes and eosinophils at diagnosis. CONCLUSION Heart lesions directly attributable to CSS are frequent, severe and probably underestimated. A specific physiopathology that is not mediated by ANCA seems to be involved in the genesis of CSS-related heart lesions.

Clinical Spectrum, Treatment, and Outcome of Patients with Type II Mixed Cryoglobulinemia without Evidence of Hepatitis C Infection

Objective. The clinical spectrum, etiologies, and best therapeutic approaches of type II mixed cryoglobulinemia (MC) not associated with hepatitis C virus (HCV) infection have been poorly described to date. We studied the clinical presentation and outcome of patients with type II MC with no evidence of HCV. Methods. This was a multicenter retrospective study on the clinical presentation and outcome of patients with type II MC without evidence of HCV infection. Only patients with symptomatic MC were included. Results. Thirty-three patients were included (median followup 67.2 mo). Extensive investigations for associated diseases were performed at presentation. MC was related to an autoimmune disease in 14 patients, to a lymphoid malignancy in 4 patients, and to an infectious disease in 2 patients, while MC was classified as essential (primary) in 13. Essential MC tended to be more severe than secondary disease with, in particular, more frequent renal and peripheral nerve involvement. Most patients were treated with steroid with or without immunosuppressive agents, mainly cyclophosphamide. These treatments were unable to induce sustained remission. One patient was successfully treated with lenalidomide. Seven patients with nonmalignant MC were treated with rituximab; 2 had a sustained complete remission, 3 improved greatly but relapsed within 5 months, and 2 experienced a disease flare. Conclusion. An important proportion of non HCV-related type II MC remains essential. Efforts should be made to find other etiologies than HCV, because treatments with steroid and immunosuppressants are not satisfactory, especially in severe forms. In these situations anti-CD20 therapy may present the best option but should be used with caution. New agents such as lenalidomide remain to be evaluated.

Involvement and prognosis value of CD8(+) T cells in giant cell arteritis.

CD8(+) T cells participate in the pathogenesis of some vasculitides. However, little is known about their role in Giant Cell Arteritis (GCA). This study was conducted to investigate CD8(+) T cell involvement in the pathogenesis of GCA. Analyses were performed at diagnosis and after 3 months of glucocorticoid treatment in 34 GCA patients and 26 age-matched healthy volunteers. Percentages of CD8(+) T-cell subsets, spectratype analysis of the TCR Vβ families of CD8(+) T cells, levels of cytokines and chemokines and immunohistochemistry of temporal artery biopsies (TAB) were assessed. Among total CD8(+) T cells, percentages of circulating cytotoxic CD8 T lymphocytes (CTL, CD3(+)CD8(+)perforin(+)granzymeB(+)), Tc17 (CD3(+)CD8(+)IL-17(+)), CD63(+)CD8(+) T cells and levels of soluble granzymes A and B were higher in patients than in controls, whereas the percentage of Tc1 cells (CD3(+)CD8(+)IFN-γ(+)) was similar. Moreover, CD8(+) T cells displayed a restricted TCR repertoire in GCA patients. Percentages of circulating CTL, Tc17 and soluble levels of granzymes A and B decreased after treatment. CXCR3 expression on CD8(+) T cells and its serum ligands (CXCL9, -10, -11) were higher in patients. Analyses of TAB revealed high expression of CXCL9 and -10 associated with infiltration by CXCR3(+)CD8(+) T cells expressing granzyme B and TiA1. The intensity of the CD8 T-cell infiltrate in TAB was predictive of the severity of the disease. This study demonstrates the implication and the prognostic value of CD8(+) T-cells in GCA and suggests that CD8(+) T-cells are recruited within the vascular wall through an interaction between CXCR3 and its ligands.

Clinicopathologic characteristics, treatment, and outcomes of tubulointerstitial nephritis and uveitis syndrome in adults: A national retrospective strobe-compliant study.

AbstractTubulointerstitial nephritis and uveitis (TINU) syndrome is a rare disease, defined by the association of idiopathic acute TINU. The aim of our work was to determine the characteristics of adult TINU syndrome in France, and to assess factors (including treatment) influencing medium-term prognosis.We conducted a nationwide study including 20 French hospitals. Clinical, laboratory, and renal histopathologic data of 41 biopsy-proven TINU syndromes were retrospectively collected. The patients were diagnosed between January 1, 1999 and December 1, 2015.Twenty-five females and 16 males were included (F/M ratio: 1.6:1). The median age at disease onset was 46.8 years (range 16.8–77.4) with a median serum creatinine level at 207 &mgr;mol/L (range 100–1687) and a median estimated glomerular filtration rate (eGFR) at 27 mL/min per 1.73 m2 (range 2–73). Twenty-nine patients (71%) had a bilateral anterior uveitis and 24 (59%) had deterioration in general health at presentation. Moderate proteinuria was found in 32 patients (78%) (median proteinuria 0.52 g/24 h; range 0.10–2.10), aseptic leukocyturia in 25/36 patients (70%). The evaluation of renal biopsies revealed 41 patients (100%) with an acute tubulointerstitial nephritis, 19/39 patients (49%) with light to moderate fibrosis and 5 patients (12%) with an acute tubular necrosis. Thirty-six patients (88%) were treated with oral corticosteroids. After 1 year of follow-up, the median eGFR was 76 mL/min per 1.73 m2 (range 17–119) and 32% of the patients suffered from moderate to severe chronic kidney disease. Serum creatinine (P < 0.001, r = −0.54), serum bicarbonate and phosphate levels (respectively, P = 0.01, r = 0.53; and P = 0.04, r = 0.46), and age (P = 0.03, r = −0.37) at the 1st symptoms were associated with eGFR after 1 year. During the 1st year 40% of patients had uveitis relapses. The use of oral corticosteroids was not associated with a better kidney function but was associated with fewer uveitis relapses (P = 0.44 and 0.02, respectively).In our study, 32% of patients were suffering from moderate to severe chronic kidney disease after 1 year of follow-up, and 40% had uveitis relapses during this follow-up. This work also suggests that oral corticosteroids are effective for the treatment of TINU syndromes uveitis.

Should mild hypogammaglobulinemia be managed as severe hypogammaglobulinemia? A study of 389 patients with secondary hypogammaglobulinemia

BACKGROUND Although secondary hypogammaglobulinemia is more frequent than primary hypogammaglobulinemia, its etiology and management are poorly described, particularly for mild hypogammaglobulinemia. METHODS This retrospective observational study included all adult patients with a gammaglobulin level <6.4g/L on serum electrophoresis identified at Dijon teaching hospital between April and September 2012. Clinico-biological features, etiologies and infectious complications were collected at inclusion and compared between group 1 (gammaglobulin <5g/L, severe hypogammaglobulinemia), and group 2 (gammaglobulin <6.4 and ≥5g/L, mild hypogammaglobulinemia). RESULTS Among the 4011 serum electrophoreses, 570 samples from 389 patients had gammaglobulin levels below 6.4g/L: 156 (40%) in group 1 and 233 (60%) in group 2. Mean age±SD was 67 (15) years, and sex ratio was 1.04 (M/F) with no difference between the two groups. An etiology was identified in 79% and 58% of patients in groups 1 and 2, respectively (p<0.0001). The main etiologies were similar in both groups and included malignant hemopathy treated with cytostatic agents (n=129, 33%), smoldering or newly-diagnosed hemopathy without treatment (n=49, 13%) and immunosuppressive treatment (n=91, 23%). The incidence of hypogammaglobulinemia-related infections was 22/100/year, with no significant difference between the two groups (p=0.17). Vaccination coverage against pneumococcus was 33%, and higher in group 1 (46% vs. 24%; p<0.0001). When no cause was known at inclusion, an etiology was discovered in 22/130 patients (17%), 11 in each group. CONCLUSIONS Though mild hypogammaglobulinemia does not meet the classical criteria for hypogammaglobulinemia (<5g/L), the etiology and infectious risk are similar. It therefore requires investigation and vaccination.

Amiodarone-Related Acute Respiratory Distress Syndrome following Sudden Withdrawal of Steroids

Acute lung toxicity is a rare but classical complication of amiodarone therapy. We report the case of a patient who developed an optic neuropathy after 15 years of amiodarone administration, and who was treated for 2 weeks with steroids. Following withdrawal of steroids, the patient rapidly developed an acute respiratory distress syndrome. Postmortem lung histologic examination was consistent with amiodarone-induced pneumonitis. Since this complication is thought to be of immunological origin, we speculate that the sudden withdrawal of steroids was implicated in the development of the acute lung injury.