Safety and effectiveness of transjugular renal biopsy for systemic lupus erythematosus and antiphospholipid antibody syndrome patients taking antithrombotics.

BACKGROUND: Renal biopsy is the cornerstone of systemic lupus erythematosus (SLE) nephritis and antiphospholipid syndrome (APS) nephropathy management. However, transcutaneous renal biopsy (TCRB) is hampered by the antithrombotic treatment frequently prescribed for those diseases. Transjugular renal biopsy (TJRB) offers an attractive alternative for patients at increased risk of bleeding. The primary objective of the study was to describe the safety profile and diagnostic performance of TJRB in SLE and APS patients. METHODS: All SLE and/or APS patients who underwent a renal biopsy in our department (between January 2004 and October 2016) were retrospectively reviewed. Major complications were death, haemostasis nephrectomy, renal artery embolization, red blood cell transfusion, sepsis and vascular thrombosis; macroscopic haematuria, symptomatic perirenal/retroperitoneal bleeding and renal arteriovenous fistula without artery embolization were considered as minor complications. RESULTS: Two hundred and fifty-six TJRBs-119 without antithrombotics (untreated), 69 under aspirin and 68 on anticoagulants and 54 TCRBs without antithrombotics-were analysed. Their major and minor complication rates, respectively, did not differ significantly for the four groups: 0 and 8% for untreated TJRBs, 1 and 6% for aspirin-treated, 6 and 10% for anticoagulant-treated and 2 and 2% for TCRBs. The number of glomeruli sampled and the biopsy contribution to establishing a histological diagnosis was similar for the four groups. CONCLUSIONS: TJRBs obtained from SLE and APS patients taking antithrombotics had diagnostic yields and safety profiles similar to those of untreated TCRBs. Thus, TJRB should be considered for SLE and APS patients at risk of bleeding.

Catastrophic antiphospholipid syndrome and pregnancy: an experience of 13 cases.

OBJECTIVE: Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening disease caused by the onset of rapidly progressive and widespread small-vessel thromboses in the presence of aPLs. The aim of this study was to examine pregnancy-related CAPS. METHODS: Retrospective series of 13 patients with pregnancy-related CAPS with special focus on the follow-up. RESULTS; Eleven patients had known APS and had been treated with low-molecular-weight heparin (n = 10), aspirin (n = 8), oral anticoagulants (n = 1), HCQ (n = 3) and/or steroids (n = 1) during pregnancy. The most frequent manifestations of CAPS were cutaneous (n = 11), hepatic (n = 11), renal (n = 10), cardiac (n = 8) and neurological (n = 5). CAPS usually followed haemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome (n = 12), which was associated with pre-eclampsia (n = 6) or with eclampsia (n = 3). No maternal death was observed. The perinatal mortality of 54% was related to prematurity with a mean gestational age of 26.6 weeks at onset of CAPS or HELLP syndrome. During a mean follow-up of 4.8 years (range 2-8 years), seven new pregnancies occurred in five patients and led to one miscarriage, four successful pregnancies and two HELLP syndrome with pre-eclampsia or eclampsia that occurred at 28 weeks gestation in both cases despite optimal treatment. No relapse of CAPS was observed. Two mothers suddenly died 2.5 and 6 years after CAPS. CONCLUSION: The occurrence of HELLP syndrome in a patient with APS should raise the suspicion of CAPS in the following days, and anticoagulation should be maintained post-partum or post-abortum. Subsequent pregnancies are at very high risk.

Interleukin-25: a cytokine linking eosinophils and adaptive immunity in Churg-Strauss syndrome.

Churg-Strauss syndrome (CSS) is characterized by systemic vasculitis and blood and tissue eosinophilia. Blood eosinophilia correlates with disease activity, and activated T cells from CSS patients are predominantly T helper 2 (Th2). Interleukin (IL)-25 has been shown to link innate and adaptive immunity by enhancing Th2 cytokine production. We sought to determine the involvement of IL-25 and its receptor IL-17RB in the pathogenesis of CSS. We found increased levels of IL-25 in the serum of active CSS patients (952 ± 697 vs 75 ± 49 pg/mL in inactive patients and 47 ± 6 pg/mL in healthy donors). IL-25 was correlated with disease activity and eosinophil level. Eosinophils were the main source of IL-25, whereas activated CD4(+) memory T cells were the IL-17RB-expressing cells in CSS. IL-25 enhanced the production of IL-4, IL-5, and IL-13 by activated peripheral blood mononuclear cells. IL-25 and IL-17RB were observed within the vasculitic lesions of patients with CSS, and IL-17RB colocalized with T cells. Increased expression of IL-17RB, tumor necrosis factor receptor-associated factor 6, and JunB in vasculitic lesions of CSS underscored the IL-25-mediated activation, whereas up-regulation of GATA3 and IL-10 supported Th2 differentiation. Our findings suggest that eosinophils, through the production of IL-25, exert a critical role in promoting Th2 responses in target tissues of CSS.

Hydroxychloroquine levels in patients with systemic lupus erythematosus: whole blood is preferable but serum levels also detect non-adherence.

BACKGROUND: Hydroxychloroquine (HCQ) levels can be measured in both serum and whole blood. No cut-off point for non-adherence has been established in serum nor have these methods ever been compared. The aims of this study were to compare these two approaches and determine if serum HCQ cut-off points can be established to identify non-adherent patients. METHODS: HCQ levels were measured in serum and whole blood from 573 patients with systemic lupus erythematosus (SLE). The risk factors for active SLE (SLEDAI score > 4) were identified by multiple logistic regression. Serum HCQ levels were measured in 68 additional patients known to be non-adherent, i.e. with whole-blood HCQ < 200 ng/mL. RESULTS: The mean (± SD) HCQ levels were 469 ± 223 ng/mL in serum and 916 ± 449 ng/mL in whole blood. The mean ratio of serum/whole-blood HCQ levels was 0.53 ± 0.15. In the multivariate analysis, low whole-blood HCQ levels (P = 0.023), but not serum HCQ levels, were independently associated with active SLE. From the mean serum/whole-blood level ratio, a serum HCQ level of 106 ng/mL was extrapolated as the corresponding cut-off to identify non-adherent patients with a sensitivity of 0.87 (95% CI 0.76-0.94) and specificity of 0.89 (95% CI 0.72-0.98). All serum HCQ levels of patients with whole-blood HCQ below the detectable level (< 20 ng/mL) were also undetectable (< 20 ng/mL). CONCLUSIONS: These data suggest that whole blood is better than serum for assessing the pharmacokinetic/pharmacodynamic relation of HCQ. Our results support the use of serum HCQ levels to assess non-adherence when whole blood is unavailable.

Monitoring Disease Activity in Systemic Lupus Erythematosus With Single-Molecule Array Digital Enzyme-Linked Immunosorbent Assay Quantification of Serum Interferon-α.

OBJECTIVE: No simple or standardized assay is available to quantify interferon-α (IFNα) in routine clinical practice. Single-molecule array (Simoa) digital enzyme-linked immunosorbent assay (ELISA) technology enables direct IFNα quantification at attomolar (femtogram per milliliter [fg/ml]) concentrations. This study was undertaken to assess IFNα digital ELISA diagnostic performances to monitor systemic lupus erythematosus (SLE) activity. METHODS: IFNα concentrations in serum samples from 150 consecutive SLE patients in a cross-sectional study were determined with digital ELISA and a functional biologic activity assay (bioassay). According to their Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) flare composite scores, patients were divided into groups with inactive SLE (SLEDAI score of <4 or clinical SLEDAI score of 0) or active SLE (SLEDAI score of ≥4 or clinical SLEDAI score of >0), and into groups with no flare or mild/moderate flare or severe flare. RESULTS: Based on serum samples from healthy blood donors, the abnormal serum IFNα level threshold value was 136 fg/ml. Next, using receiver operating characteristic curves for an SLE patient series that was widely heterogeneous in terms of disease activity and organ involvement, the threshold IFNα value associated with active disease was determined to be 266 fg/ml. The digital ELISA-assessed serum IFNα level was a better biomarker of disease activity than the Farr assay because its specificity, likelihood ratio for positive results, and positive predictive value better discerned active SLE or flare from inactive disease. The digital ELISA was more sensitive than the bioassay for detecting low-abnormal serum IFNα concentrations and identifying patients with low disease activity. CONCLUSION: Direct serum IFNα determination with a highly sensitive assay might improve monitoring of clinical SLE activity and selection of the best candidates for anti-IFNα treatment.

Arterial aneurysms in Wegener's granulomatosis: case report and literature review.

OBJECTIVE: Arterial aneurysms are characteristic of medium-size vessel vasculitis but are a very unusual feature of Wegener's granulomatosis (WG). We describe a typical WG case, complicated by arterial aneurysms and review previously reported cases. METHODS: Medline database search of cases published between January 1978 and July 2006, in English, reporting arterial aneurysms complicating WG. RESULTS: Five years after diagnosis, a 29-year-old man with typical WG developed macro- and microaneurysms located on branches of the hepatic and renal arteries during a disease relapse. The main symptoms were abdominal pain, vomiting, and altered general status. He was successfully treated by coil embolization in combination with prednisone, intravenous mycophenolate mofetil, and high-dose immunoglobulins. Twelve additional cases of WG complicated by arterial aneurysms are reported in the English literature. This represents a life-threatening complication since rupture occurred in half of the patients. CONCLUSIONS: Although small-vessel injury predominates in WG, inflammation of medium-size arteries may occur and lead to aneurysm formation. Abdominal angiography should be recommended when unexplained abdominal pain occurs during a WG flare.

[Arterial manifestations of Behçet's disease. 12 cases]. / Manifestations artérielles de la maladie de Behçet. Douze observations.

Out of 196 patients with Behçet's disease, 12 (10 men and 2 women, mean age 34 +/- 7 years) had non-coronary arterial lesions. Behçet's disease was complete in 4 patients. The arterial lesions had appeared 8.6 +/- 8 years on average (20 years at most) after the first sign of the disease. Three patients showed evidence of stenosis or occlusion involving one or several arteries. Eight patients had both stenotic and aneurysmal lesions. One patient had an arteriovenous fistula. Another developed a false aneurysm at the site of introduction of a femoral catheter. Yet another patient developed an anastomotic aneurysm one year after implantation of an abdominal aortic graft. In 2 cases histology showed fragmentation of the media associated with vasculitis of the vasa vasorum. Two patients with pulmonary aneurysm died of massive haemoptysis. In 2 patients combined corticosteroid and cyclophosphamide therapy failed to prevent the development of aneurysmal lesions. Phlebitis was associated with arterial involvement in 7 patients. Comparison between patients with or without arterial lesions showed no significant difference in time of onset of Behçet's disease, sex, main clinical features and presence of HLA B5. Aneurysmal lesions respond poorly to medical treatment, and surgery is mandatory. Since recurrence at the site of anastomosis is possible, prolonged monitoring is required.

Lower vitamin D levels are associated with higher systemic lupus erythematosus activity, but not predictive of disease flare-up.

OBJECTIVES: Growing evidence suggests that vitamin D plays a key role in the pathogenesis and progression of autoimmune diseases, including systemic lupus erythematosus (SLE). Recent studies have found an association between lower serum 25-hydroxyvitamin D (25(OH)D) levels and higher SLE activity. We studied the relationship between 25(OH)D levels and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, and we assessed for the first time the role of vitamin D in predicting SLE flare-ups. METHODS: Serum 25(OH)D levels were measured in 170 patients with SLE who were prospectively followed up for 6 months (Plaquenil LUpus Systemic study, ClinicalTrials.gov number NCT00413361). RESULTS: The mean SLEDAI score was 2.03±2.43 and 12.3% patients had active disease (SLEDAI ≥6). The mean 25(OH)D level was 20.6±9.8 ng/mL. Deficiency (25(OH)D <10 ng/mL) was observed in 27 (15.9%), insufficiency (10≤25(OH)D<30) in 112 (65.9%) and optimal vitamin D status (25(OH)D≥30) in 31 (18.2%) patients. In multivariate analysis, female gender (p=0.018), absence of defined antiphospholipid syndrome (p=0.002) and higher creatinine clearance (p=0.004) were predictive of lower 25(OH)D levels. In multivariate analysis, lower 25(OH)D levels were associated with high SLE activity (p=0.02). Relapse-free survival rate was not statistically different according to the vitamin D status during the 6-month follow-up (p=0.22). CONCLUSIONS: We found a low vitamin D status in the majority of patients with SLE, and a modest association between lower 25(OH)D levels and high disease activity. There was no association between baseline 25(OH)D levels and relapse-free survival rate.

Primary adrenal insufficiency due to bilateral adrenal hemorrhage-adrenal infarction in the antiphospholipid syndrome: long-term outcome of 16 patients.

CONTEXT: Primary adrenal insufficiency due to bilateral adrenal hemorrhage-adrenal infarction is a rare and life-threatening manifestation of the antiphospholipid syndrome (APLS). Data on the long-term outcome are scarce. OBJECTIVE: The aims of the present study were to analyze the long-term outcome related to APLS per se and to characterize the course of adrenal involvement. DESIGN: We conducted a retrospective study of patients with bilateral adrenal hemorrhage-adrenal infarction secondary to APLS seen in the Department of Internal Medicine of Pitié-Salpêtrière Hospital in Paris (France) between January 1990 and July 2010. RESULTS: Three patients died during the acute phase related to APLS manifestations. Sixteen patients (7 males; 9 females) were followed up during a median period of 3.5 years (range 0.3-28.1 years). Three episodes of recurrent thrombosis were noted. One patient died from cerebral hemorrhage 3 months after the onset of adrenal insufficiency. Repeated Synacthen tests showed complete absence of response in 8 of the 10 patients assessed; cortisol and aldosterone increased appropriately in one patient and to some extent in another one. Dehydroepiandrosterone levels and 24-hour urinary epinephrine levels remained abnormally low in all evaluated patients. Adrenal imaging performed more than 1 year after the initial event revealed completely atrophic glands in 9 of 11 patients. CONCLUSIONS: This particular subset of APLS patients who survive the acute phase has a rather favorable long-term outcome. Although adrenal dysfunction is generally irreversible, adrenocortical function may, at least partially, recover in rare cases. In this view, measurement of early morning cortisol during follow-up is indicated to detect these patients.

Pulmonary arterial hypertension is a major mortality factor in diffuse systemic sclerosis, independent of interstitial lung disease.

OBJECTIVE: To determine whether pulmonary arterial hypertension (PAH) is a prognostic factor for mortality in diffuse cutaneous systemic sclerosis (dcSSc), independent of interstitial lung disease (ILD). METHODS: ILD was diagnosed by high-resolution computed tomography and PAH (pulmonary arterial systolic pressure [PASP] > or =45 mm Hg) by echocardiography. All patients with ILD underwent testing for total lung capacity (TLC), forced vital capacity (FVC), and diffusing capacity for carbon monoxide. RESULTS: Eighty-six patients with dcSSc (mean age at diagnosis 44.5 years) were followed up for a median of 72.5 months. ILD was found in 52 patients (60%) and PAH in 18 (21%). ILD was associated with PAH in 15 patients. Seventeen patients died (19.8%), 9 of whom had PAH (P = 0.001) and 10 of whom had ILD (P = 0.99). By multivariate analysis, age at SSc diagnosis and PAH were the only independent predictors of death (hazard ratio [HR] 1.057, 95% confidence interval [95% CI] 1.009-1.109, P = 0.020 and HR 4.09, 95% CI 1.47-11.5, P = 0.007, respectively). Mean TLC and mean FVC were similar in ILD patients with and those without PAH (P = 0.71 and P = 0.40, respectively). Among ILD patients, age at SSc diagnosis and PAH were again the sole predictors of death (HR 1.073, 95% CI 1.003-1.149, P = 0.042 and HR 5.07, 95% CI 1.09-23.8, P = 0.038, respectively). Twenty ILD patients received at least 6 monthly pulses of intravenous cyclophosphamide (CYC). In CYC-treated patients with PAH (n = 8), PASP increased significantly during the CYC regimen (mean +/- SD 55 +/- 14.5 mm Hg; P = 0.015 versus baseline), while TLC remained stable during the same period. CONCLUSION: These results indicate that, independent of ILD, PAH is a major prognostic factor for survival in dcSSc.

[Ovulation induction therapy and systemic lupus erythematosus]. / Induction d'ovulation et lupus.

Improvement in the prognosis of SLE prognosis has led to considering infertility therapy. The earliest reports displayed complications such as SLE revealed by ovulation induction or thrombophlebitis. Fertility is known to be normal in women with SLE, excepting amenorrhea accompanying severe flare-ups, renal insufficiency-related hypofertility and ovarian failure secondary to cyclophosphamide therapy. Anti-phospholipid antibodies are suspected to cause defective nidation and placental ischemia. An exponential rise of serum estradiol is observed irrespective of the ovulation induction protocol used, leading to SLE flare-up and thrombosis. We have experience with 114 cycles in 21 women with SLE and/or APS. A complication (fetal loss, SLE flare-up, thrombophlebitis) revealed the underlying disease in 8 women. Eighteen pregnancies led to 9 live-births, 4 fetal deaths and 5 embryonic losses. Pregnancy rate was higher after ovulation induction using gonadotropins (25% per cycle), than clomiphene (4%). Pregnancy rate was similar after IVFETE, whether the protocol was planned or not. However, three-quarters of the pregnancies after unplanned IVFETE led to abortions. On the contrary, 6 out of 7 pregnancies after planned IVFETE led to live-births. Two women developed thrombophlebitis after gonadotropins therapy. A SLE flare-up appeared after 13 out of 62 cycles, with a flare-up rate higher after gonadotropins (27% per cycle) than clomiphene therapy (6%), and after an unplanned (30%) than a planned procedure (10%). In conclusion, ovulation induction therapy can reveal SLE or APS. Clomiphene complications are uncommon. When gonadotropin therapy is considered, a preventive anti-inflammatory therapy should be discussed in SLE patients, in conjunction with heparin and/or anti-aggregate therapy for those with asymptomatic anti-phospholipid antibodies or prior thrombotic events.

Longterm followup after treatment of polyarteritis nodosa and Churg-Strauss angiitis with comparison of steroids, plasma exchange and cyclophosphamide to steroids and plasma exchange. A prospective randomized trial of 71 patients. The Cooperative Study Group for Polyarteritis Nodosa.

We attempted to define the most effective treatment for polyarteritis nodosa and Churg-Strauss angiitis, with a prospective, randomized, multicenter trial of cyclophosphamide in conjunction with corticosteroids and plasma exchanges, compared to corticosteroids and plasma exchanges. A total of 71 patients who fulfilled clinical, histological and/or arteriographic diagnostic criteria were randomly designated to receive either prednisone and plasma exchanges (group A, n = 39) or cyclophosphamide, prednisone and plasma exchanges (group B, n = 32). The end points of the study were control of the disease (recovery and remission) and death. Upon study entry clinical and laboratory features did not differ in the 2 groups. Treatment was stopped in 19 patients because of ineffectiveness in 10 (9 in Group A) and side effects in 9 (8 in Group B). Initial control of the disease was similar in both groups. At 5 years, 27 patients had completely recovered and 14 patients were in clinical remission. The cyclophosphamide-prednisone-plasma exchange association was beneficial in preventing relapses during longterm followup. Nineteen deaths were reported during the followup period. There was no difference between the 10 year cumulative survival rates of the 2 groups (respectively, 72 and 75%). Thus, the association of cyclophosphamide with corticosteroids and plasma exchanges reduced the incidence of relapses and improved the quality of the clinical response to therapy.

Hepatitis C virus infection in systemic lupus erythematosus: a case-control study.

OBJECTIVE: Viruses might be one of the elements that trigger systemic lupus erythematosus (SLE). Steroid therapy may influence the natural history of virus infections. The most frequent extrahepatic manifestations of hepatitis C virus (HCV) including arthralgia, myalgia, sicca syndrome, and antinuclear antibodies, may mimic a connective tissue disease, particularly SLE. Reports on the association between SLE and HCV infection are scarce. We investigated the association of HCV infection and SLE. METHODS: Retrospective case-control monocentric study of 19 patients with SLE and anti-HCV antibodies versus 42 randomized SLE patients without anti-HCV antibodies, matched for age and sex, coming from our cohort of 700 patients with SLE. SLE and HCV-infection features were reviewed. RESULTS: Mode of infection was blood product transfusion, drug addiction, or unknown. Prevalence of lupus clinical manifestations, antinuclear, anti-dsDNA, anti-extractable nuclear antigen antibodies, and complement levels was not different between HCV positive and negative SLE patients. Prevalence of cryoglobulin was higher in SLE patients with anti-HCV antibodies (p < 0.04), but none had a mixed cryoglobulinemia syndrome. ALT activity was increased in 11 HCV positive patients and 13 had detectable HCV RNA. Liver biopsy showed cirrhosis in 2 and mild fibrosis and activity in 5. One patient treated with interferon-alpha had a sustained virological response without SLE flare. Steroid therapy did not seem to alter HCV course. CONCLUSION: SLE in HCV positive patients shows higher prevalence of cryoglobulin without mixed cryoglobulinemia syndrome. HCV infection has moderate signs of biochemical and liver pathological severity. SLE by itself or treated with steroids does not seem to worsen HCV infection.