Neuromyelitis optica: Contribution of therapeutic responses markers monitoring in patients given rituximab.

Neuromyelitis optica (NMO) is a central nervous system inflammatory autoimmune disease characterized by medullary and/or optical nerve damage. It is rare but life-threatening. Concerning the treatment of NMO, many drugs have been used in background therapy. Some studies have shown efficacy of rituximab (an antiCD20 monoclonal anti-body) either on the reduction of the annual number of exacerbation or the mean score EDSS. In 2013, a Korean team reported a new protocol during which they administered rituximab only when memory B lymphocytes CD27+ were detectable in the bloodstream. In our patient, institution of this protocol led to clinical benefit with a major decrease in the EDSS score over time (7 in August 2012 vs. 1 in October 2015), a reduction of the total administered dose (4g in 2013 vs. 1.375g in 2014 vs. 0g in 2015) and side effects. Compared with the rate of theoretical administration, health expenditure savings reached 1700 Euros per month over the 11-month treatment. Monitoring therapeutic response markers with memory B lymphocyte counts appear to be an efficient cost-effective way to measure clinical efficiency, reduce total doses, and limit side effects.

Optimized stepwise combination algorithms of non-invasive liver fibrosis scores including Hepascore in hepatitis C virus patients.

BACKGROUND: Non-invasive liver fibrosis scores such as Hepascore (HS) have been proposed as an alternative to liver biopsy in hepatitis C virus (HCV)-infected patients. AIM: To validate HS as an alternative to liver biopsy and Fibrotest (FT) and propose five optimized combination algorithms to improve diagnostic accuracy. METHODS: The cohort included 467 patients with HCV. There were 274/467 (59%) men, and mean age was 47 +/- 12 years. RESULTS: Hepascore area under ROC curves (AUC) for > or =F2, F3F4 and F4 diagnosis were 0.82, 0.84 and 0.90 respectively, in the same range as FT. HS and FT were concordant in 387/467 (82%) for fibrosis staging. Among these patients, 342/387 (88%) were concordant with liver biopsy. AUCs of aspartate aminotransferase (AST) to Platelets Ratio Index (APRI) and Forns for > or =F2 were 0.76 and 0.73 (0.65-0.79) respectively. The algorithm combining APRI and HS had the highest rate of avoided liver biopsies (45%) with a high diagnostic accuracy (91%). CONCLUSIONS: Hepascore is an accurate non-invasive marker for > or =F2 and F4 diagnosis in HCV patients. In a pragmatic approach, a stepwise optimized algorithm combining APRI and FT or HS considerably increases diagnostic accuracy and avoided liver biopsies.

Validation and comparison of indexes for fibrosis and cirrhosis prediction in chronic hepatitis C patients: proposal for a pragmatic approach classification without liver biopsies.

Noninvasive indexes have been developed to predict fibrosis staging. The aim of this study was to assess the diagnostic accuracy of these indexes in comparison with liver histology in hepatitis C virus (HCV)-infected patients. A total of 235 consecutive patients with HCV infection from the Fibropaca multicentre independent study were included in this paper. FibroTest (FT), aspartate aminotransferase to platelet ratio index (APRI) and Forns score were assessed in the cohort and compared with liver histology performed on the same day. The main end point was the area under characteristic curves (AUCs) for the diagnosis of significant fibrosis (F2-F4) and cirrhosis (F4) by the METAVIR classification. Mean age was 46 (+/-11) years, 55% were males, 42% (n = 99) had significant fibrosis (F2-F4) and 7% (n = 16) had cirrhosis (F4). For the diagnosis of significant fibrosis, respective AUCs of FT, APRI and Forns score were 0.81 (95% confidence interval: 0.76-0.86), 0.71 (0.67-0.79) and 0.76 (0.70-0.82); for cirrhosis prognosis, AUCs of FT and APRI were 0.82 (0.77-0.87) and 0.81 (0.76-0.86) (AUCs not significantly different). Using each index independently, all patients were classified by FT, 214 (91%) patients were classified by APRI and 129 (55%) by Forns score. There were significantly more cases of discordances between APRI and liver biopsy than between FT or Forns score and liver biopsy (P < 0.05). Performing all scores (FT, Forns and APRI) without liver biopsy allowed fibrosis to be well evaluated in 191 patients (81.3%), including patients with FT failure. Liver biopsy remained mandatory to evaluate fibrosis in 44 patients (18.7%). Our study shows that performing all the tests and liver biopsy improves the diagnostic accuracy for liver fibrosis in chronic hepatitis C patients without patent comorbidities. The combination of all tests with liver biopsy allowed 225/235 (96%) patients to be correctly classified. The combination of all tests without liver biopsy allowed 191/235 (81.3%) patients to be correctly classified; liver biopsy remained mandatory in some patients (18.7%).

Monocyte-independent T cell activation by simultaneous binding of three CD2 monoclonal antibodies (D66 + T11.1 + GT2).

Mitogenic pairs of CD2 mAb typically transduce activation/proliferation signals within T cells. However, complementary signal(s) provided by accessory cells are required to induce T cell proliferation. We show here that a particular combination of three CD2 mAb, D66 + GT2 + T11.1, leads to the proliferation of highly purified human T lymphocytes, without other complementary signal(s). The CD2 triplets was able to induce CD4+ and, to a lesser extent, CD8+ cells to proliferate. Interestingly, the so-called "naive" T cells (CD45RA+) were strongly stimulated, but more immature cells, such as thymocytes, were not. The proliferative response induced by the CD2 triplet was entirely mediated by the IL-2 autocrine pathway, as shown by the complete inhibition with anti-IL2 Ab. T cells stimulated with the CD2 triplet were also able to secrete TNF alpha. We found no evidence for an unusual secretion of cytokines that might explain the lack of requirement of complementary signal(s). As high as it was, the proliferation induced by the CD2 mAb triplet could be further increased by the addition of IL-1, and this proliferative fraction could be inhibited by antibodies against TNF alpha. The CD2 mAb triplet increased [Ca2+]i, while mitogenic CD2 mAb pairs needed the presence of a cross-linking agent. Thus, our data show that T cells can be activated to fully proliferate by this particular CD2 pathway, in the absence of accessory signal(s).

Mitogenic CD2 monoclonal antibody pairs predispose peripheral T cells to undergo apoptosis on interaction with a third CD2 monoclonal antibody.

When stimulated for a few days with the mitogenic GT2 + T11(1) CD2 mAb pair and IL-2, resting T cells were induced to proliferate but the introduction into the cultures of a third CD2 mAb resulted in apoptotic cell death of 40 to 60% of the cells. The death signal was active on T cells entered the cell cycle without causing an apparent cell cycle block and without discriminating between the G1 and S phases. Apoptosis was not prevented by cycloheximide or actinomycin D, indicating that the death program was already expressed in preactivated cells awaiting an appropriate signal. A series of Abs, directed at various cell surface molecules, were unable to trigger apoptosis (except CD3 mAb), whereas most of the CD2 mAb tested were active, provided the third CD2 mAb was recognizing an epitope different from GT2 and T11(1). Mere aggregation of CD2 molecules did not seem to be the triggering signal of apoptosis, because cross-linking cell-bound GT2 + T11(1) with an Ab to mouse IgG had no effect, suggesting that a conformational change was imposed on CD2 molecules by the third CD2 mAb. Stimulation performed in the presence of IL-2 predisposed both CD45R0+ and CD45RA+ T cells to apoptosis, whereas stimulation in the presence of IL-4 primed only CD45RA+ T cells to undergo this process. Monocytes and potent co-signals of the CD2 pathway were unable to prevent CD2-induced apoptosis. Thus, successive engagements of the CD2 molecule of mature T cells by two and three CD2 mAbs recognizing distinct epitopes can provide in short term cultures signals for proliferation and apoptosis, depending on the activation state of the cells.