From natalizumab to fingolimod in eight weeks - Immunological, clinical, and radiological data in quest of the optimal switch.

Natalizumab (NZB) discontinuation during a treatment change is associated with recurrence of disease activity in a significant proportion of multiple sclerosis (MS) patients. The immunological basis why disease reactivation occurs in selected patients is unresolved. In search of a prognostic biomarker for a safe and effective transition from NZB to fingolimod, we monitored five parameters related to pharmacokinetic and pharmacodynamic effects of the two drugs in 12 MS patients until six months on fingolimod. Clearance of free and cell-bound NZB, re-expression of alpha-4, and fingolimod-mediated changes on CD8+ and CD4+ T cell subsets showed pronounced interindividual variability. Higher frequencies of memory CD8+ T cells after six months on fingolimod were the sole association with disease reactivation. None of the investigated parameters thus had potential as prognostic biomarker for the outcome of the switch. Our findings rather support the thesis of broad interindividual differences in the immunopathogenesis of MS.

Adaptive Immune Responses in a Multiple Sclerosis Patient with Acute Varicella-Zoster Virus Reactivation during Treatment with Fingolimod.

Fingolimod, an oral sphingosine 1-phosphate (S1P) receptor modulator, is approved for the treatment of relapsing forms of multiple sclerosis (MS). The interference with S1P signaling leads to retention particularly of chemokine receptor-7 (CCR7) expressing T cells in lymph nodes. The immunological basis of varicella zoster virus (VZV) infections during fingolimod treatment is unclear. Here, we studied the dynamics of systemic and intrathecal immune responses associated with symptomatic VZV reactivation including cessation of fingolimod and initiation of antiviral therapy. Key features in peripheral blood were an about two-fold increase of VZV-specific IgG at diagnosis of VZV reactivation as compared to the previous months, a relative enrichment of effector CD4+ T cells (36% versus mean 12% in controls), and an accelerated reconstitution of absolute lymphocytes counts including a normalized CD4+/CD8+ ratio and reappearance of CCR7+ T cells. In cerebrospinal fluid (CSF) the lymphocytic pleocytosis and CD4+/CD8+ ratios at diagnosis of reactivation and after nine days of fingolimod discontinuation remained unchanged. During this time CCR7+ T cells were not observed in CSF. Further research into fingolimod-associated VZV reactivation and immune reconstitution is mandatory to prevent morbidity and mortality associated with this potentially life-threatening condition.

Conversion and reversion of anti-John Cunningham virus antibody serostatus: A prospective study.

INTRODUCTION: Determination of antibodies against the John Cunningham virus (JCV) is an important tool for risk stratification in Natalizumab-treated multiple sclerosis (MS) patients. Six-monthly testing has been suggested for anti-JCV antibody negative patients and patients with low antibody index in order to detect changes of serostatus. We conducted a prospective study with predefined testing intervals in order to investigate the predictability of anti-JCV antibody status and the intervals for repetitive testing. METHODS: Our study included 109 patients at the MS Clinic of the Departments of Neurology, Medical Universities of Innsbruck and Salzburg. Blood withdrawals were performed at five time points: baseline, month 1, 3, 6, and 12. Patients' sera were sent to Unilabs, Copenhagen, Denmark, where anti-JCV antibodies were tested by a two-step enzyme-linked immunosorbent assay. Qualitative (negative/positive) and quantitative results (anti-JCV antibody index) were used for statistical analyses. RESULTS: In our cohort, 52.3% of the patients were positive for anti-JCV antibodies at baseline, with a significant correlation with age, but no association with sex or prior disease-modifying therapy. Seven patients converted and reverted from negative to positive status and vice versa around the cut-off index of 0.4, but no patient showed a permanent seroconversion from negative to highly positive anti-JCV antibody status. CONCLUSION: Long-term anti-JCV antibody status, including seroconverters/-reverters around the cut-off index, is highly predictable by testing three times within short intervals, however, we cannot suggest clearly defined intervals for repetitive testing. The rate of real seroconverters, i.e., new infections with JCV, per year seems lower than previously described.

Tumefactive MS lesions under fingolimod: a case report and literature review.

OBJECTIVE: To report about a possible association between fingolimod treatment and tumefactive demyelinating lesions (TDL) as seen in a patient developing repeated TDL on continued fingolimod therapy. METHODS: We performed serial clinical and radiologic assessments and immunophenotyping of blood and CSF immune cells. We also present a literature review about recent similar cases. RESULTS: Clinical course and radiologic findings were consistent with diagnosis of TDL. Immune cell phenotyping showed pronounced shifts in the immune cell composition related to fingolimod treatment. In addition, we observed a subset of highly differentiated effector cells (CD45R0negCCR7neg) within the CD8+ T-cell population, which was about 2-fold enriched in the CSF compared to the peripheral blood. CONCLUSION: Our observations add further evidence for the development of atypical demyelinating lesions in some patients receiving fingolimod. These might be related to a treatment-associated shift in the immunopathology of specifically susceptible individuals.

Lymphocyte subsets show different response patterns to in vivo bound natalizumab--a flow cytometric study on patients with multiple sclerosis.

Natalizumab is an effective monoclonal antibody therapy for the treatment of relapsing-remitting multiple sclerosis (RRMS) and interferes with immune cell migration into the central nervous system by blocking the α(4) subunit of very-late activation antigen-4 (VLA-4). Although well tolerated and very effective, some patients still suffer from relapses in spite of natalizumab therapy or from unwanted side effects like progressive multifocal leukoencephalopathy (PML). In search of a routine-qualified biomarker on the effectiveness of natalizumab therapy we applied flow cytometry and analyzed natalizumab binding to α(4) and α(4) integrin surface levels on T-cells, B-cells, natural killer (NK) cells, and NKT cells from 26 RRMS patients under up to 72 weeks of therapy. Four-weekly infusions of natalizumab resulted in a significant and sustained increase of lymphocyte-bound natalizumab (p<0.001) which was paralleled by a significant decrease in detectability of the α(4) integrin subunit on all lymphocyte subsets (p<0.001). We observed pronounced natalizumab accumulations on T and B cells at single measurements in all patients who reported clinical disease activity (n = 4). The natalizumab binding capacity of in vitro saturated lymphocytes collected during therapy was strongly diminished compared to treatment-naive cells indicating a therapy-induced reduction of α(4). Summing up, this pilot study shows that flow cytometry is a useful method to monitor natalizumab binding to lymphocytes from RRMS patients under therapy. Investigating natalizumab binding provides an opportunity to evaluate the molecular level of effectiveness of natalizumab therapy in individual patients. In combination with natalizumab saturation experiments, it possibly even provides a means of studying the feasability of patient-tailored infusion intervals. A routine-qualified biomarker on the basis of individual natalizumab saturation on lymphocyte subsets might be an effective tool to improve treatment safety.

Recent developments in approved and oral multiple sclerosis treatment and an update on future treatment options.

Multiple sclerosis (MS) is the most common chronic neurological disease in young adults in the western world. There was no specific treatment available for this serious disorder until the introduction of the immunomodulatory drug interferon-ß in the mid-1990s. Since then, the number of agents and treatment strategies for MS has increased rapidly. Deeper knowledge on the heterogeneous nature of MS cleared the way for several more specific, more effective and more comfortable therapies. Here, because of the exciting recent developments concerning oral treatment forms for MS, we summarize the current state of approved and future therapy options. In particular, we highlight oral treatment options in MS.

Natalizumab therapy decreases surface expression of both VLA-heterodimer subunits on peripheral blood mononuclear cells.

Natalizumab interferes with immune cell migration into the central nervous system via blocking the alpha-4 subunit of very-late activation antigen-4 (VLA-4). Occurrence of rare but serious progressive multifocal leukoencephalopathy during prolonged natalizumab therapy of multiple sclerosis (MS) calls for a more detailed understanding of potential coeffects. We longitudinally studied alpha-4 and beta-1 surface levels on blood cells from 18 MS patients by flow cytometry. Expectedly, detectability of natalizumab-blocked alpha-4 was diminished on all investigated cell subsets. In addition, we report a concurrent and significant decrease of beta-1 surface levels on T-cells, B-cells, natural killer cells, and natural killer T cells, but not on monocytes. Uncovering secondary effects of natalizumab is mandatory to increase safety in MS therapy.