The immune defect that could account for the multisystemic involvement that characterizes systemic lupus erythematosus (SLE) remains unknown. We hypothesized that iterative disease flares correspond to a recurrent defect in the peripheral immune suppression exerted by naturally occurring T regulatory cells (Tregs). Surprisingly, Tregs isolated from lupus patients show the same phenotypic and functional characteristics as corresponding cells found in healthy controls. A decrease in the proportion of circulating Tregs among other CD4+ T cells is nevertheless evidenced in active patients when this group is compared with healthy controls (0.57 ± 0.24%, n = 45 vs 1.29 ± 0.38%, n = 82, p < 0.0001) or with inactive patients (1.22 ± 0.67%, n = 62, p < 0.0001). In contrast, the proportion of Tregs in other systemic autoimmune diseases such as primary Sjögren syndrome and inflammatory myopathy does not significantly differ from controls’ values (1.15 ± 0.46%, n = 21, p = 0.09 and 1.16 ± 0.44%, n = 16, p = 0.43, respectively). Lupus Tregs do not accumulate in either the lymph nodes or the diseased kidneys and are not killed by a circulating soluble factor, but demonstrate in vitro a heightened sensitivity to Fas-induced apoptosis. Finally, we show that the extent of Treg depletion correlates with the clinical severity of the flare. SLE flares are therefore associated with a global Treg depletion and not with a phenomenon of tissue redistribution. In summary, we suggest that the physiopathology of SLE could be tied to a defect in the homeostatic control of the Treg subpopulation.

Sarcoidosis is characterized by extensive local inflammation (granuloma, cytokine secretion) associated with anergy (poor response to antigens in vitro and in vivo). We postulated that this paradoxical situation would correspond to a disequilibrium between effector and regulatory T lymphocytes (T reg cells). We show that CD4+CD25brightFoxP3+ cells accumulate at the periphery of sarcoid granulomas, in bronchoalveolar lavage fluid, and in peripheral blood of patients with active disease. These cells exhibited powerful antiproliferative activity, yet did not completely inhibit TNF-α production. Sarcoidosis is therefore associated with a global T reg cell subset amplification whose activity would be insufficient to control local inflammation. At the same time, peripheral T reg cells exert powerful antiproliferative activity that may account for the state of anergy. Altogether, these findings advance our conceptual understanding of immune regulation in a way that resolves the immune paradox of sarcoidosis and permit us to envisage a profound clinical impact of T reg cell manipulation on immunity.

Key Points• PIK3CA and NRAS mutations are recurrent in BRAFV600E wild-type ECD patients.• 57.5% (46/80) of ECD patients have a BRAFV600E mutation, and an additional 10.9% and 3.7% have PIK3CA and NRAS mutations, respectively.Erdheim-Chester disease (ECD) is a rare histiocytic disorder that is challenging to diagnose and treat. We performed molecular analysis of BRAF in the largest cohort of ECD patients studied to date followed by N/KRAS, PIK3CA, and AKT1 mutational analysis in BRAF wild-type patients. Forty-six of 80 (57.5%) of patients were BRAFV600E-mutant. NRAS mutations were detected in 3 of 17 ECD BRAFV600E wild-type patients. PIK3CA

Objective. Erdheim-Chester disease (ECD) is a rare, non-Langerhans form of histiocytosis of unknown origin, characterized by infiltration of tissues by spumous histiocytes. ECD features heterogeneous systemic manifestations, and the general prognosis remains poor despite various treatment options.Methods. We treated 8 patients with multisystemic ECD with subcutaneous interferon-␣ (IFN␣) at a dosage of 3-9 ؋ 10 6 units 3 times weekly, for a median duration of 23 months (range 1-46 months).Results. Treatment was generally well tolerated, and side effects remained limited to fever following injections. Treatment was discontinued in 1 patient, because of severe depression. During treatment, some manifestations of ECD disappeared (i.e., xanthelasma, exophthalmos, papilledema, and intracranial hypertension). The efficacy of IFN␣ on cardiovascular ECD was variable, however. Treatment resulted in partial regression of "coated aorta" in some cases and clear failure in others; 2 patients died. The level of C-reactive protein diminished sharply in 5 patients.

Objective. To analyze the clinical findings, treatment, outcome, and prevalence of cerebral venous thrombosis (CVT) in a large cohort of patients with Behçet's disease (BD) from a single center. Methods. We reported a series of 64 consecutive patients with CVT who fulfilled the international criteria for BD. Multivariate analysis was performed to define factors that affect prognosis.

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] >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.

A strategy is proposed for the etiologic diagnosis of uveitis. The benefit of more invasive investigations remains to be determined.

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