Yassine Taoufik

Cidofovir in addition to antiretroviral treatment is not effective for AIDS-associated progressive multifocal leukoencephalopathy: a multicohort analysis

Objective:To establish the effectiveness of cidofovir for AIDS-related progressive multifocal leukoencephalopathy (PML) in patients concomitantly receiving combination antiretroviral therapy. Design:Analysis of raw data pooled from one prospective and five cohort studies. Setting:Tertiary care centers for the treatment of HIV-associated complications. Patients:Three hundred seventy HIV-infected PML patients diagnosed from 1996 treated with combination antiretroviral therapy with or without cidofovir. All studies had already published their results but for four of them, additional patients and follow-up data are included in this report. Follow-up was started from the date of first abnormal neuroimaging; those treated with cidofovir were entered at risk at the date of cidofovir initiation.Main study outcomes were time to PML-related death and odds of 12-month moderately severe to severe disability (Rankin score ≥4). Results:Sixty-four percent of the PML cases were confirmed by histopathology or JC virus DNA detection in cerebrospinal fluid; 185 (50%) received cidofovir (median five cycles). During 463 person-years of follow-up, 167 PML-related deaths occurred (36.6 per 100 person-years of follow-up). Estimated 1 year survival was 0.56 (95% confidence interval, 0.50–0.61). In multivariate models stratified by cohort and adjusted for type of diagnosis and relevant prognostic confounders, cidofovir treatment was not associated with survival (hazard ratio for death 0.93, 0.66–1.32). Results were similar using time to death from any cause as the outcome. Furthermore, 12-month moderately severe to severe disability was not associated with the use of cidofovir. Conclusion:In combination antiretroviral therapy-treated PML patients, cidofovir use did not influence PML-related mortality or residual disability. New treatments for AIDS-related PML are urgently needed.

B cell activation biomarkers as predictive factors for the response to rituximab in rheumatoid arthritis: A six-month, national, multicenter, open-label study†

OBJECTIVE To examine whether serum B cell markers can predict response to rituximab, a B cell-depleting monoclonal antibody, in patients with refractory rheumatoid arthritis (RA). METHODS This rituximab re-treatment dose study (SMART [eSsai MAbthera sur la dose de Re-Traitement]) involved 208 patients with refractory RA. Serum markers of B cell activation (anti-cyclic citrullinated peptide [anti-CCP] antibodies, rheumatoid factor [RF], serum IgG, IgA, and IgM levels, serum κ and λ free light chains, and serum BAFF) were assessed before the first rituximab cycle (1,000 mg on days 1 and 15). Univariate and multivariate analyses were performed to identify factors associated with a European League Against Rheumatism (EULAR) response at 24 weeks. RESULTS There were 149 responders (72%). Two baseline factors were associated with a EULAR response at 24 weeks in multivariate analysis: the presence of anti-CCP antibodies or RF (odds ratio 3.5 [95% confidence interval 1.6-7.6]) and a serum IgG concentration above normal (odds ratio 2.11 [95% confidence interval 1.02-4.33]), with synergy between them (odds ratio 6.0 [95% confidence interval 2.2-16.2]). CONCLUSION The presence of RF or anti-CCP antibodies and elevated IgG are 2 simple biomarkers that can be used routinely before therapy to predict response to rituximab in patients with refractory RA.

Blood Memory B Cells Are Disturbed and Predict the Response to Rituximab in Patients With Rheumatoid Arthritis

OBJECTIVE To examine blood B cell subsets in patients with rheumatoid arthritis (RA) prior to B cell depletion therapy and to assess their potential as predictors of clinical response to rituximab (RTX). METHODS Blood B cell subsets were assessed by flow cytometry in 208 RA patients included in an RTX retreatment study (assessed prior to RTX treatment) and in 47 age-matched controls. Expression of BAFF receptor (BAFF-R) on B cells and serum B cell biomarkers was also measured. B cell subsets and BAFF-R expression were compared between RA patient and control populations. Univariate and multivariate analyses were performed to identify baseline factors associated with a European League Against Rheumatism response 24 weeks after 1 cycle of RTX. RESULTS Mean ± SD counts of both CD27- naive and CD27+ memory B cells were decreased in RA patients (188.6 ± 121.4/mm(3)) compared with controls (257.3 ± 154.1/mm(3)) (P = 0.001) and were partially restored in patients treated with methotrexate (MTX) plus anti-tumor necrosis factor compared with patients treated with MTX alone. Within the CD27+ memory B cells, the CD27+IgD- switched memory subtype was selectively decreased, irrespective of treatment. The frequency of CD27+ memory B cells correlated inversely with levels of several B cell activation biomarkers in RA. Serum BAFF level and BAFF-R expression was comparable in RA patients and controls. A low baseline CD27+ memory B cell frequency was associated with a greater clinical response to RTX (odds ratio 0.97 [95% confidence interval 0.95-0.99], P = 0.0015). CONCLUSION In B cell depletion therapy-naive RA patients, a low frequency of CD27+ memory B cells correlated with levels of serum B cell activation biomarkers and may predict response to RTX. These results suggest that low memory B cell frequency may be indicative of a B cell-driven RA subtype that is more sensitive to B cell depletion therapy.

Progressive contraction of the latent HIV reservoir around a core of less-differentiated CD4+ memory T Cells

In patients who are receiving prolonged antiretroviral treatment (ART), HIV can persist within a small pool of long-lived resting memory CD4+ T cells infected with integrated latent virus. This latent reservoir involves distinct memory subsets. Here we provide results that suggest a progressive reduction of the size of the blood latent reservoir around a core of less-differentiated memory subsets (central memory and stem cell-like memory (TSCM) CD4+ T cells). This process appears to be driven by the differences in initial sizes and decay rates between latently infected memory subsets. Our results also suggest an extreme stability of the TSCM sub-reservoir, the size of which is directly related to cumulative plasma virus exposure before the onset of ART, stressing the importance of early initiation of effective ART. The presence of these intrinsic dynamics within the latent reservoir may have implications for the design of optimal HIV therapeutic purging strategies.

Treatment of pediatric Erdheim‐Chester disease with interleukin‐1–targeting drugs

Erdheim-Chester disease (ECD) is a rare nonLangerhans systemic histiocytosis of unknown origin. ECD typically involves bilateral symmetric cortical osteosclerosis of the diaphyseal and metaphyseal regions in the long bones and infiltration of other organs (1). The diagnosis is based on typical histologic findings, with xanthogranulomatous infiltration of tissue by foamy CD68-positive and CD1a-negative histiocytes. Published data on therapeutic approaches, including surgery, corticosteroids, cytotoxic drugs, stem cell transplantation, and others, are limited to case reports and small series and show generally incomplete and/or transient remission and frequent toxicity (2–4). More recently, interferon(IFN ) has been suggested as a treatment option; it has demonstrated variable efficacy and sometimes limited tolerance (5–7). Herein we report on a child with ECD who was treated with anakinra, a recombinant, nonglycosylated homolog of the human interleukin-1 (IL-1) receptor antagonist, and we describe a rationale for this treatment. The patient, a 10-year-old girl, presented with recurrent fever, elevated erythrocyte sedimentation rate (ESR) and increased C-reactive protein (CRP) levels, bone pain, and failure to thrive, and was diagnosed as having ECD. Bone radiography revealed multiple osteolytic and osteosclerotic lesions in the femurs, tibia, and pelvis. Whole-body magnetic resonance imaging (MRI) showed high-intensity signal of the skeletal bone marrow on fat-suppressed T2-weighted images, retroperitoneal infiltration, and diffuse low-intensity signal in the metadiaphyses (Figure 1C). Histologic findings on bone biopsy confirmed the diagnosis of ECD (Figure 2). Treatment with subcutaneous IFN alfa-2a (3 10 units 3 times per week) resulted in normalization of clinical symptoms, ESR and CRP values, and liver and spleen volumes, significant regression of retroperitoneal infiltration, and improvement of bone marrow signal intensity within 4 months. However, after 10 months of treatment the patient experienced relapse, manifested by fever, bone pain, and increased ESR and CRP levels. Treatment with vinblastine (6 mg/m/ week) and prednisone (2 mg/kg/day) for 6 weeks showed no efficacy. The patient was then treated with PEGylated IFN alfa-2a (1.5 g/kg/week) (8), with good efficacy. However, after 12 months of treatment, another relapse occurred. To obtain a rationale for a potential alternative treatment option targeting specific cytokines, IL-1 , IL-6, and tumor necrosis factor (TNF ) levels in unstimulated and lipopolysaccharide (LPS; 1 g/ml)–stimulated peripheral blood mononuclear cells (PBMCs), which had been isolated from whole blood samples with Ficoll-Paque and cultured in RPMI, were measured by enzyme-linked immunosorbent assay. Data on the patient were compared with data from 15 healthy controls. As shown in Figure 1A, the unstimulated PBMCs from the patient displayed increased levels of IL-1 (40.3fold), IL-6 (23.9-fold), and TNF (5.6-fold). Following LPS stimulation, levels of IL-1 , IL-6, and TNF were comparable to those in controls. These findings suggested that high basal levels of IL-1 and IL-6 may participate in the pathophysiology of ECD. Serum levels of IL-1 were within the normal range. We therefore hypothesized that targeting of IL-1 might have a beneficial effect on the disease course, and consequently, treatment with anakinra (2 mg/kg/day) was instituted. Within 1 week, fever and bone pain resolved, and 1 month later, the ESR and CRP normalized (Figure 1B). During the subsequent 10 months the patient gained weight (8 kg) and height (6 cm). However, no significant changes in the bone lesions or retroperitoneal infiltration were seen on MRI 7 months after initiation of this treatment (Figure 1C). During Figure 1. A, Production of cytokines (interleukin-1 [IL-1 ], IL-6, and tumor necrosis factor [TNF ]) by peripheral blood mononuclear cells from the patient and from 15 healthy controls, with or without lipopolysaccharide (LPS) stimulation. B, Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels before and after initiation of treatment with anakinra. IFN2a interferon alfa-2a. C, Comparative magnetic resonance imaging findings before (left) and 6 months after (right) initiation of treatment with anakinra. Frontal view whole-body images (T2-weighted with fat suppression) show no evidence of change in retroperitoneal infiltration (arrows).

CCL19, a B Cell Chemokine, Is Related to the Decrease of Blood Memory B Cells and Predicts the Clinical Response to Rituximab in Patients With Rheumatoid Arthritis

OBJECTIVE Migration of B cells from peripheral blood to the synovium in patients with rheumatoid arthritis (RA) may predict clinical response to rituximab (RTX). We undertook this study to investigate whether serum levels of chemokines involved in B cell trafficking are correlated with blood levels of memory B cells or serum levels of B cell activation biomarkers before B cell depletion and whether chemokine levels predict RTX responsiveness. METHODS Blood B cell subsets were analyzed by flow cytometry (CD27, IgD), and serum B cell activation biomarkers (rheumatoid factor, anti-cyclic citrullinated peptide, free light chains, IgG, IgA, IgM, and BAFF) were measured in 208 RA patients and 70 control subjects. Serum CCL19, CXCL12, and CXCL13 chemokine levels in patients and controls were determined by enzyme-linked immunosorbent assay. The first course of RTX was administered to RA patients, and the response was evaluated at week 24 according to European League Against Rheumatism (EULAR) criteria. Results were expressed as the odds ratio (OR) and 95% confidence interval (95% CI). RESULTS Levels of all chemokines were increased in RA patients compared with controls, and levels were inversely correlated with CD27+ memory B cell frequency. CCL19 and CXCL13 levels correlated with levels of 6 serum B cell biomarkers and 4 serum B cell biomarkers, respectively. By univariate analysis, the CCL19 level was positively associated with EULAR response (OR 1.43 [95% CI 1.08-1.90], P = 0.01). By multivariate analysis, the CCL19 level was predictive of a response to RTX (OR 1.48 [95% CI 1.06-2.06], P = 0.02), but this did not persist after adjustment for autoantibody status. CONCLUSION CXCL13 and CCL19 reflect blood B cell disturbances and their levels correlate with those of other serum B cell biomarkers. CXCL13 and CCL19 are, therefore, surrogate measures for serum B cell biomarkers in RA. Serum CCL19 measurement is a new hallmark of the B cell-mediated RA subtype and may predict clinical response to RTX.

Use of Whole‐Blood Transcriptomic Profiling to Highlight Several Pathophysiologic Pathways Associated With Response to Rituximab in Patients With Rheumatoid Arthritis: Data From a Randomized, Controlled, Open‐Label Trial

To identify a molecular signature that could be predictive of the clinical response to rituximab (RTX) and elucidate the transcriptomic changes after RTX therapy in patients with rheumatoid arthritis (RA), with the use of whole‐blood transcriptomic profiling.

Interferon-alpha triggers B cell effector 1 (Be1) commitment.

B-cells can contribute to the pathogenesis of autoimmune diseases not only through auto-antibody secretion but also via cytokine production. Therapeutic depletion of B-cells influences the functions and maintenance of various T-cell subsets. The mechanisms governing the functional heterogeneity of B-cell subsets as cytokine-producing cells are poorly understood. B-cells can differentiate into two functionally polarized effectors, one (B-effector-1-cells) producing a Th-1-like cytokine pattern and the other (Be2) producing a Th-2-like pattern. IL-12 and IFN-γ play a key role in Be1 polarization, but the initial trigger of Be1 commitment is unclear. Type-I-interferons are produced early in the immune response and prime several processes involved in innate and adaptive responses. Here, we report that IFN-α triggers a signaling cascade in resting human naive B-cells, involving STAT4 and T-bet, two key IFN-γ gene imprinting factors. IFN-α primed naive B-cells for IFN-γ production and increased IFN-γ gene responsiveness to IL-12. IFN-γ continues this polarization by re-inducing T-bet and up-regulating IL-12Rβ2 expression. IFN-α and IFN-γ therefore pave the way for the action of IL-12. These results point to a coordinated action of IFN-α, IFN-γ and IL-12 in Be1 polarization of naive B-cells, and may provide new insights into the mechanisms by which type-I-interferons favor autoimmunity.

High risk features contrast with favorable outcomes in HIV-associated Hodgkin Lymphoma in the modern cART era, ANRS CO16 LYMPHOVIR cohort

BACKGROUND Human immunodeficiency virus (HIV) infection is associated with a high risk of classical Hodgkins lymphoma (cHL) in the combined antiretroviral therapy (cART) era. METHODS We analyzed the characteristics and outcome of HIV-associated cHL diagnosed in the modern cART era. The French ANRS-CO16 Lymphovir cohort enrolled 159 HIV-positive patients with lymphoma, including 68 (43%) with cHL. HIV-HL patients were compared with a series of non-HV-infected patients consecutively diagnosed with HL. RESULTS Most patients (76%) had Ann-Arbor stages III-IV and 96% of patients were treated with ABVD. At diagnosis, median CD4 T-cell count was 387/µL and 94% of patients were treated with cART. All patients received cART after diagnosis. Five patients died from early progression (n = 2), sepsis (1) or after relapse (2). Two additional patients relapsed during follow-up. Two-year overall and progression free survivals (PFS) were 94% [95% CI, 89%, 100%] and 89% [82%, 97%], respectively. The only factor associated with progression or death was age with a relative risk of 8.1 [1.0; 67.0] above 45 years. The PFS of Lymphovir patients appeared similar to PFS of HIV-negative patients, 86% [82%, 90%], but patients with HIV infection displayed higher risk features than HIV-negative patients. CONCLUSIONS Although high-risk features still predominate in HIV-HL, the prognosis of these patients, treated with cART and mainly ABVD, has markedly improved in the modern cART era and is now similar to non-HIV-infected patients.

Tissue Competence Imprinting and Tissue Residency of CD8 T Cells

T cell immunity is characterized by striking tissue specialization. Tissue-specificity imprinting starts during priming by tissue-derived migratory dendritic cells in the non-random, specialized micro-anatomical area of the draining lymph node and is influenced by constitutive and induced cues from local environment. Besides tissue-specific effectors, memory cells also exhibit a tissue-specificity. Long-lived tissue-resident memory T cells likely play a considerable role in preventing pathogen invasion. Understanding of the mechanisms of tissue specialization of T cells is of major importance for the design of optimal vaccination strategies and therapeutic interventions in tissue/organ-specific inflammatory diseases. The present review summarizes our current knowledge and hypothesis about tissue-specificity imprinting and tissue residency of T cells.