Is the risk of progressive multifocal leukoencephalopathy the real reason for natalizumab discontinuation in patients with multiple sclerosis?

<div><p>Background</p><p>Progressive multifocal leukoencephalopathy (PML) is one of the major risks of natalizumab therapy. Despite introduction of the currently employed PML risk stratification algorithm, the incidence of natalizumab-associated PML cases is not decreasing.</p><p>Objectives</p><p>We addressed the following questions: How do natalizumab-treated multiple sclerosis patients and their treating physicians assess and deal with PML risk? Is PML risk the real reason for natalizumab discontinuation?</p><p>Methods</p><p>699 natalizumab-treated multiple sclerosis patients and 99 physicians were included in this prospective observational study. Questionnaires were completed at 5 different time points. Patients were stratified into 5 subgroups according to the presence of PML risk factors (prior immunosuppression, anti-JCV antibody status, treatment duration). Patients with prior immunosuppression (n = 30, treated by n = 7 physicians) were excluded from analyses, because patient numbers were too small. Patients’ anti-JCV antibody index was not considered because data recruitment ended in 2014. Using Bayesian network and regression analysis, we examined the relationship between different patient- and physician-related factors and patients’ discontinuation of natalizumab.</p><p>Results</p><p>Patients of all subgroups and physicians assessed the PML risk as low. Overall patient adherence to natalizumab was high (87%). Only 13% of patients discontinued therapy. Natalizumab treatment cessation was associated with different patient- and physician-related factors (physicians’ assessment of general PML risk, number of treated patients per year, natalizumab treatment duration, relapses during the course of study) upon which only physicians’ judgment on treatment continuation, patients’ perception of personal PML risk, and JCV seroconversion showed significant relationships.</p><p>C<i>onclusion</i></p><p>According to the currently employed risk stratification algorithm, the <i>objective</i> PML risk probably doesn’t play a dominant role in a patients’ decision to continue or stop natalizumab treatment. The decision-making process is rather guided by <i>subjective</i> views and experiences of patients and treating neurologists. Treating physicians should consider this discrepancy in their advice to improve the risk-benefit-ratio for the individual patient.</p></div

Significant relationship between physicians’ last statement on continuation or discontinuation of natalizumab and the proportion of patients continuing or stopping therapy.

<p>Physicians’ last judgment on continuation of therapy on a visual analog scale from 0 to 25 points (1 = ‘rather continue natalizumab’, 25 = ‘rather discontinue natalizumab’) had an influence on the proportion of patients continuing/discontinuing natalizumab.</p

Assessment of personal PML risk at visit 1 to 5 for patients continuing and discontinuing natalizumab (NTZ).

<p>Patients discontinuing NTZ (green) assessed the personal PML risk higher on a visual analog scale from 0 to 25 points (0 = ‘low’, 25 = ‘high’) in all visits than patients continuing NTZ (blue) (*p < 0.01; **p < 0.0002; ns = not significant).</p

Relationship between patients’ assessment of personal PML risk and the proportion of patients stopping therapy.

<p>Patients’ assessment of personal PML risk on a visual analog scale from 0 to 25 points (0 = ‘low’, 25 = ‘high’) did not correlate with the proportion of patients stopping therapy in JCV Ab–patients (left side) and correlated only weakly in JCV Ab + patients (right side).</p

Bayesian network learned from the information of patients of the subgroups A-C and associated neurologists with the bnlearn R package.

<p>All patient-related factors are colored in green and all physician-related factors are colored in blue. JCV seroconversion during observation period, physicians’ opinion on continuation/discontinuation of NTZ in the individual patient, assessment of PML risk in general, number of treated patients per year and patients’ perception of personal PML risk, duration of NTZ treatment and relapses during the course of the study were directly associated with patients’ discontinuation of NTZ therapy (those factors are pictured as completely colour-filled boxes). For all other examined factors we found no relationship with NTZ treatment cessation (those factors are pictured as white boxes).</p

Disease-related data of patients of the groups A-E at baseline.

<p>ARR = annualized relapse rate; EDSS = Expanded Disability Status Scale; IMS + /- = prior / no prior use of immunosuppressants; JCV Ab + /- = positive / negative serostatus for anti-JCV antibodies; NTZ > / ≤ 24 months = natalizumab treatment longer / less than 24 months.</p

Descriptive demographic and professional details of participating neurologists at baseline.

<p>N describes the number of neurologists with fully completed questionnaires at baseline.</p

Additional file 1: of ALAIN01—Alemtuzumab in autoimmune inflammatory neurodegeneration: mechanisms of action and neuroprotective potential

Assessment Schedule. (DOCX 42 kb

Inhibition of the NKG2D-signaling pathway ameliorates the disease course of experimental autoimmune encephalomyelitis (EAE).

<p>(<b>A</b>) EAE disease course was reduced in NKG2D-blocking-antibody-treated C57BL/6 mice (black arrows, days of injection, clone CX5) compared with mice treated with an isotype control (two independent experiments, <i>n</i> = 8 each). Myelin oligodendrocyte protein (MOG) recall assays and flow cytometry were performed at disease onset (gray arrow). (<b>B</b>) ELISAs for IFN-γ production and the splenocyte stimulation index indicative of cell proliferation showed no significant differences for splenocytes of antibody- and isotype-treated mice at disease onset (<i>n</i> = 5 mice per group). (<b>C</b>) Flow cytometric quantification of NKG2D⁺ CD4⁺ and CD8⁺ lymphocytes invading the brain at disease onset of EAE (<i>n</i> = 5 mice per group, clone 7 used for staining). (<b>D</b>) Representative immunohistochemical staining of spinal cord samples from isotype- or anti-NKG2D-treated mice (<i>n</i> = 10 per mouse; <i>n</i> = 5 mice per group) at the disease maximum of EAE and quantification of the area of infiltrating cells (hematoxylin and eosin [H&E] staining, highlighted area) and area of demyelination (luxol fast blue [LFB] staining, highlighted area). (<b>E</b>) In vivo blockade of NKG2D by soluble NKG2D (sNKG2D) delayed the onset of EAE when administered before disease onset (left panel). In contrast, the administration of sNKG2D after disease onset had no significant effects (right panel). (<i>n</i> = 6 mice per group). *P < 0.05. ns, not significant. </p

CD4⁺NKG2D⁺ T Cells Exhibit Enhanced Migratory and Encephalitogenic Properties in Neuroinflammation

<div><p>Migration of encephalitogenic CD4⁺ T lymphocytes across the blood-brain barrier is an essential step in the pathogenesis of multiple sclerosis (MS). We here demonstrate that expression of the co-stimulatory receptor NKG2D defines a subpopulation of CD4⁺ T cells with elevated levels of markers for migration, activation, and cytolytic capacity especially when derived from MS patients. Furthermore, CD4⁺NKG2D⁺ cells produce high levels of proinflammatory IFN-γ and IL-17 upon stimulation. NKG2D promotes the capacity of CD4⁺NKG2D⁺ cells to migrate across endothelial cells in an in vitro model of the blood-brain barrier. CD4⁺NKG2D⁺ T cells are enriched in the cerebrospinal fluid of MS patients, and a significant number of CD4⁺ T cells in MS lesions coexpress NKG2D. We further elucidated the role of CD4⁺NKG2D⁺ T cells in the mouse system. NKG2D blockade restricted central nervous system migration of T lymphocytes in vivo, leading to a significant decrease in the clinical and pathologic severity of experimental autoimmune encephalomyelitis, an animal model of MS. Blockade of NKG2D reduced killing of cultivated mouse oligodendrocytes by activated CD4⁺ T cells. Taken together, we identify CD4⁺NKG2D⁺ cells as a subpopulation of T helper cells with enhanced migratory, encephalitogenic and cytotoxic properties involved in inflammatory CNS lesion development.</p> </div