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Immunomodulation and immunosuppression are generally linked to an increased risk of infection. In the growing field of new and potent drugs for multiple sclerosis (MS), we review the current data concerning infections and prevention of infectious diseases. This is of importance for recently licensed and future MS treatment options, but also for long-term established therapies for MS. Some of the disease-modifying therapies (DMT) go along with threats of specific severe infections or complications, which require a more intensive long-term monitoring and multi-disciplinary surveillance. We update the existing warning notices and infectious issues which have to be considered using drugs for multiple sclerosis., (© 2013 British Society for Immunology.)

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently defined inflammatory central nervous system (CNS) disorder, prominently involving the brainstem and in particular the pons. The condition features a combination of clinical symptoms essentially referable to brainstem pathology and a characteristic magnetic resonance imaging (MRI) appearance with punctate and curvilinear gadolinium enhancement 'peppering' the pons. The radiological distribution is focused in the pons and adjacent rhombencephalic structures such as the cerebellar peduncles, cerebellum, medulla and the midbrain. While the lesion burden with a perivascular pattern is typically most dense in these pontine and peripontine regions, enhancing lesions may additionally extend into the spinal cord and supratentorial structures such as the thalamus, basal ganglia, capsula interna, corpus callosum and the cerebral white matter. Another core feature is clinical and radiological responsiveness to glucocorticosteroid (GCS)-based immunosuppression. As withdrawal of GCS treatment results commonly in disease exacerbation, long-term immunosuppressive therapy appears to be mandatory for sustained improvement. Diagnosis of CLIPPERS is challenging, and requires careful exclusion of alternative diagnoses. A specific serum or cerebrospinal fluid (CSF) biomarker for the disorder is currently not known. Pathogenesis of CLIPPERS remains poorly understood, and the nosological position of CLIPPERS has still to be established. Whether CLIPPERS represents an independent, actual new disorder or a syndrome that includes aetiologically heterogeneous diseases and/or their prestages remains a debated and not finally clarified issue. Clinicians and radiologists should be aware of this condition and its differential diagnoses, given that CLIPPERS constitutes a treatable condition and that patients may benefit from an early introduction of GCS ensued by long-term immunosuppression. Based on previous reports in literature - currently encompassing more than 50 reported cases of CLIPPERS - this review addresses clinical features, diagnostic criteria, differential diagnoses and therapeutic management of this peculiar disorder., (© 2013 British Society for Immunology.)

During the last two decades, treatment options for patients with multiple sclerosis (MS) have broadened tremendously. All agents that are currently approved for clinical use have potential side effects, and a careful risk-benefit evaluation is part of a decision algorithm to identify the optimal treatment choice for an individual patient. Whereas glatiramer acetate and interferon beta preparations have been used in MS for decades and have a proven safety record, more recently approved drugs appear to be more effective, but potential risks might be more severe. The potential complications of some novel therapies might not even have been identified to their full extent. This review is aimed at the clinical neurologist in that it offers insights into potential adverse events of each of the approved MS therapeutics: interferon beta, glatiramer acetate, mitoxantrone, natalizumab, fingolimod and teriflunomide, as well as recently approved therapeutics such as dimethyl fumarate and alemtuzumab. It also provides recommendations for monitoring the different drugs during therapy in order to avoid common side effects., (© 2013 British Society for Immunology.)

Monoclonal antibodies (mAbs) are used as therapeutics in a number of disciplines in medicine, such as oncology, rheumatology, gastroenterology, dermatology and transplant rejection prevention. Since the introduction and reintroduction of the anti-alpha4-integrin mAb natalizumab in 2004 and 2006, mAbs have gained relevance in the treatment of multiple sclerosis (MS). At present, numerous mAbs have been tested in clinical trials in relapsing-remitting MS, and in progressive forms of MS. One of the agents that might soon be approved for very active forms of relapsing-remitting MS is alemtuzumab, a humanized mAb against CD52. This review provides insights into clinical studies with the mAbs natalizumab, alemtuzumab, daclizumab, rituximab, ocrelizumab and ofatumumab., (© 2013 British Society for Immunology.)

Escalation therapy with mitoxantrone (MX) in highly active multiple sclerosis is limited by partially dose-dependent side-effects. Predictors of therapeutic response may result in individualized risk stratification and MX dosing. ATP-binding cassette-transporters ABCB1 and ABCG2 represent multi-drug resistance mechanisms involved in active cellular MX efflux. Here, we investigated the role of ABC-gene single nucleotide polymorphisms (SNPs) for clinical MX response, corroborated by experimental in vitro and in vivo data. Frequencies of ABCB1 2677G>T, 3435C>T and five ABCG2-SNPs were analysed in 832 multiple sclerosis patients (Germany, Spain) and 264 healthy donors. Using a flow-cytometry-based in vitro assay, MX efflux in leukocytes from individuals with variant alleles in both ABC-genes (designated genotype ABCB1/ABCG2-L(ow), 22.2% of patients) was 37.7% lower than from individuals homozygous for common alleles (ABCB1/ABCG2-H(igh), P < 0.05, 14.8% of patients), resulting in genotype-dependent MX accumulation and cell death. Addition of glucocorticosteroids (GCs) inhibited MX efflux in vitro. ABC-transporters were highly expressed in leukocyte subsets, glial and neuronal cells as well as myocardium, i.e. cells/tissues potentially affected by MX therapy. In vivo significance was further corroborated in experimental autoimmune encephalomyelitis in Abcg2(-/-) animals. Using a MX dose titrated to be ineffective in wild-type animals, disease course and histopathology in Abcg2(-/-) mice were strongly ameliorated. Retrospective clinical analysis in MX monotherapy patients (n = 155) used expanded disability status scale, relapse rate and multiple sclerosis functional composite as major outcome parameters. The clinical response rate [overall 121 of 155 patients (78.1%)] increased significantly with genotypes associated with decreasing ABCB1/ABCG2-function [ABCB1/ABCG2-H 15/24 (62.5%) responders, ABCB1/ABCG2-I(ntermediate) 78/98 (79.6%), ABCB1/ABCG2-L 28/33 (84.8%), exact Cochran-Armitage test P = 0.039]. The odds ratio for response was 1.9 (95% CI 1.0-3.5) with each increase in ABCB1/ABCG2 score (from ABCB1/ABCG2-H to -I-, and -I to -L). In 36 patients with severe cardiac or haematological side effects no statistically relevant difference in genotype frequency was observed. However, one patient with biopsy proven cardiomyopathy only after 24 mg/m2 MX exhibited a rare genotype with variant, partly homozygous alleles in 3 ABC-transporter genes. In conclusion, SNPs in ABC-transporter genes may serve as pharmacogenetic markers associated with clinical response to MX therapy in multiple sclerosis. Combined MX/GC-treatment warrants further investigation.

The apoptosis-inducing effects of i.v. methylprednisolone were investigated as a possible method of controlling inflammation in the CNS in adoptive transfer-experimental autoimmune encephalomyelitis (AT-EAE) in Lewis rats. Two pulses of methylprednisolone were given at the peak of mild and of severe disease. T-cell apoptosis was assessed on spinal cord cross-sections by morphology and TUNEL staining. Concentrations of methylprednisolone were measured in serum, CSF and spinal cord tissue by high-pressure liquid chromatography (HPLC). In severe EAE, 10 mg/kg methylprednisolone increased T-cell apoptosis significantly and T-cell infiltration was marginally decreased. A maximal dose of 50 mg/kg methylprednisolone was superior in both respects and, in contrast to 10 mg/kg methylprednisolone, was also effective in mild EAE. A dose of 1 mg/kg methylprednisolone did not produce notable changes compared with controls treated with phosphate-buffered saline. Serum, CSF and spinal cord concentrations of methylprednisolone measured by HPLC 2 h after a single i.v. injection of 10 or 50 mg/kg methylprednisolone revealed significantly higher methylprednisolone concentrations in severe EAE compared with mild disease. With 50 mg/kg methylprednisolone, we obtained serum and CSF concentrations in the region of 10(-5) M methylprednisolone. We also studied the expression of bcl-2, a typical anti-apoptotic regulatory protein, in T cells, and found no change after methylprednisolone treatment compared with controls. Methylprednisolone did not induce apoptosis of oligodendrocytes, which would have been an unwanted side effect in CNS cells. This study provides evidence that methylprednisolone dose-dependently augments T-cell apoptosisin situ in AT-EAE. Our results may have implications for the use of glucocorticosteroids at very high doses in the treatment of inflammatory disorders of the CNS, such as multiple sclerosis, or of other target organs.

Bacterial compounds induce the production of reactive oxygen species (ROS) in meningitis. Rifampin releases smaller quantities of proinflammatory compounds from Streptococcus pneumoniae than do beta-lactam antibiotics. Therefore, rabbits infected intracisternally with S. pneumoniae were treated intravenously either with rifampin 5 mg/kg/h or ceftriaxone 10 mg/kg/h (n=9 each). Before initiation of antibiotic treatment, a strong positive correlation between ROS production of cerebrospinal fluid (CSF) phagocyte populations and bacterial CSF titers was observed (granulocytes: rs=.90, P<.0001; monocytes: rs=.81, P<.0001). CSF leukocytes from rifampin-treated rabbits produced less ROS (monocytes at 2 h after initiation of treatment: P=.045; at 5 h: P=.014; granulocytes at 5 h: P=.036) than did leukocytes from animals receiving ceftriaxone. The CSF malondialdehyde concentrations and the density of apoptotic neurons in the dentate gyrus were lower in rifampin- than in ceftriaxone-treated animals (P=.002 and.005). The use of rifampin to reduce the release of ROS and to decrease secondary brain injury appears promising.

In many degenerative and metabolic muscle diseases cells die without a marked inflammatory response. A potential mechanism how this could be accomplished is apoptotic cell death. Since there are no data available about apoptosis in cells of myogenic origin, we examined rat skeletal myoblasts for their potential to undergo apoptosis when exposed to reactive oxygen intermediates and nitric oxide. We observed morphologic changes typical for apoptotic cell death, and DNA fragmentation was confirmed by gel electrophoresis and molecular labeling assays. With these methods we could show that both reactive oxygen intermediates and nitric oxide can induce apoptosis in myoblasts in a dose-dependent manner. These results are discussed with regard to possible implications on the pathophysiology of various muscle diseases.

Apoptosis plays a critical role in natural recovery from experimental autoimmune disorders of the nervous system. Here we investigated in experimental autoimmune neuritis (EAN) whether apoptosis is augmented by high-dose corticosteroids, the mainstay of therapeutically active compounds in this group of disorders. Adoptive transfer EAN was induced by intravenous injection of P2-specific T cell blasts. At disease onset or at the maximum of disease two pulses of steroids were given within 12 hours, and animals were sacrificed 6 hours later. Steroid therapy significantly reduced T cell infiltration in sciatic nerve. Treatment on both day 4 and day 7 caused a significant increase of T cell apoptosis (42% vs 8.4% in placebo-treated animals on day 4, p < 0.05; 22.5% vs 7.0% on day 7, p < 0.05) in sciatic nerve as assessed by molecular labeling techniques. In addition, reduction of body weight and thymus weight and augmentation of thymocyte apoptosis were observed in steroid recipients. Steroid treatment markedly reduced cellular proliferation in lymphoid organs as measured by bromodeoxyuridine incorporation. Glucocorticosteroid treatment augments T cell apoptosis in inflammatory lesions of the peripheral nervous system, and this may add to their anti-inflammatory properties mediated by downregulation of cytokine expression.