Integrating an evidence-based assessment of benefit and risk in disease-modifying treatment of multiple sclerosis.

BACKGROUND: As results from an increasing number of clinical trials with disease-modifying drugs (DMDs) in multiple sclerosis (MS) become available, the challenge for the treating neurologist is how to decide on the appropriate therapy for an individual patient. OBJECTIVE: An International Working Group for Treatment Optimization in MS met to consider how the principles of evidence-based medicine (EBM) should be used to assess the current best evidence regarding the treatment of MS. This report summarizes the outcome from the workshop at which this topic was addressed. RESULTS: Class I evidence from head-to-head studies provides the best tool for direct comparisons of DMDs. However, other EBM approaches to data analysis from placebo-controlled trials can be used to help determine the benefits and risks of a particular DMD relative to placebo by calculating the number needed to treat to achieve a positive outcome, such as avoiding a relapse, and the number needed to harm to produce an additional adverse event, such as having a therapy-related dropout. This provides a structured basis for comparisons between DMDs. CONCLUSION: While such comparisons have their limitations, particularly when drugs with substantially different side-effect profiles are to be compared, they can provide useful information to guide treatment decisions.

Three allele combinations associated with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated disease of polygenic etiology. Dissection of its genetic background is a complex problem, because of the combinatorial possibilities of gene-gene interactions. As genotyping methods improve throughput, approaches that can explore multigene interactions appropriately should lead to improved understanding of MS. METHODS: 286 unrelated patients with definite MS and 362 unrelated healthy controls of Russian descent were genotyped at polymorphic loci (including SNPs, repeat polymorphisms, and an insertion/deletion) of the DRB1, TNF, LT, TGFbeta1, CCR5 and CTLA4 genes and TNFa and TNFb microsatellites. Each allele carriership in patients and controls was compared by Fisher's exact test, and disease-associated combinations of alleles in the data set were sought using a Bayesian Markov chain Monte Carlo-based method recently developed by our group. RESULTS: We identified two previously unknown MS-associated tri-allelic combinations:-509TGFbeta1*C, DRB1*18(3), CTLA4*G and -238TNF*B1,-308TNF*A2, CTLA4*G, which perfectly separate MS cases from controls, at least in the present sample. The previously described DRB1*15(2) allele, the microsatellite TNFa9 allele and the biallelic combination CCR5Delta32, DRB1*04 were also reidentified as MS-associated. CONCLUSION: These results represent an independent validation of MS association with DRB1*15(2) and TNFa9 in Russians and are the first to find the interplay of three loci in conferring susceptibility to MS. They demonstrate the efficacy of our approach for the identification of complex-disease-associated combinations of alleles.

Metal-dependent hydrolysis of myelin basic protein by IgGs from the sera of patients with multiple sclerosis.

Homogeneous IgG fractions were obtained by chromatography of the sera of patients with multiple sclerosis (MS) on Protein G-Sepharose under conditions that remove non-specifically bound proteins. These IgGs contained several chelated metals, the relative amount of which decreases in the order: Fe>or=Ca>Cu>or=Zn>or=Mg>or=Mn>or=Pb>or=Co>or=Ni. In contrast to homogeneous IgGs of healthy individuals, Abs of MS patients effectively hydrolyzed human myelin basic protein (MBP). A minor metal-dependent fraction was obtained by chromatography of highly purified IgGs from MS patient on Chelex-100. This IgG fraction did not hydrolyze human MBP in the absence of Me(2+) ions but was activated after addition of Me(2+) ions: Mg(2+)>Mn(2+)>Cu(2+)>Ca(2+). Proteolytic activities of IgGs from other MS patients were also activated by other metal ions (Ni(2+), Fe(2+), Co(2+), Zn(2+), Pb(2+), and Co(2+)) and especially Ni(2+). Ni(2+)-activated IgGs were separated into distinct MBP-hydrolyzing fractions by chromatography on HiTraptrade mark Chelating Sepharose charged with Ni(2+). Detection of Mg(2+)-dependent proteolytic activity in the SDS-PAGE area corresponding only to IgG provided direct evidence that IgG from sera of MS patients possesses metal-dependent human MBP-hydrolyzing activity. Observed properties of MS abzymes distinguish them from other known mammalian metalloproteases and demonstrate their pronounced catalytic diversity. Metal-dependent IgGs from MS patients represent the first example of abzymes with metal-dependent proteolytic activity.

Hydrolysis of myelin basic protein by IgM and IgA antibodies from the sera of patients with multiple sclerosis.

BACKGROUND: The presence of abzymes (Abzs) in human sera is a specific feature of different autoimmune pathologies. We have shown that IgGs of patients with multiple sclerosis (MS) specifically hydrolyze human myelin basic protein (hMBP). However, the presence of hMBP-hydrolyzing MS IgMs and IgAs in patients with MS has not been studied. MATERIAL/METHODS: Homogeneous IgM and IgA fractions were isolated from human sera by affinity chromatography on different adsorbents. The Ab-dependent hydrolysis of hMBP was analyzed using SDS-PAGE. RESULTS: We present evidence showing that MS IgMs and IgAs (but not Abs from the sera of healthy individuals) catalyze the hydrolysis of hMBP. Specific enzymatic activities of IgMs and sIgAs from sera of any single patient were usually significantly higher than those of IgGs. Specific inhibitors of acidic and thiol proteases demonstrated a weak effect on proteolytic activity of IgGs and IgMs. However, specific inhibitors of serine proteases (AEBSF, PMSF, and benzamidine) significantly inhibited proteolytic activity. IgMs and IgAs hydrolyze specifically both human and pig MBP but not many other tested proteins. Although the biological function of this proteolytic activity is not known, it is clear that MBP-hydrolyzing Abs may play an important role in MS pathogenesis. CONCLUSIONS: The findings display the generation by the immune systems of individual MS patients of a variety of polyclonal IgGs, IgMs, and IgAs with different proteolytic properties, which hydrolyze MBP, the major protein component of the myelin-proteolipid shell of axons and a well-known MS autoantigen.

Hydrolysis of myelin basic protein by polyclonal catalytic IgGs from the sera of patients with multiple sclerosis.

Various catalytic antibodies or abzymes have been detected recently in the sera of patients with several autoimmune pathologies, where their presence is most probably associated with autoimmunization. Recently we have shown that DNase, RNase, and polysaccharide-hydrolyzing activities are associated with IgGs from the sera of patients with multiple sclerosis (MS). Here we present evidence demonstrating that highly purified MS IgGs (but not Igs from the sera of healthy individuals) catalyze specifically hydrolysis of human myelin basic protein (hMBP). In contrast to many known proteases, IgGs do not hydrolyze many other different proteins. Specific inhibitors of acidic and thiol proteases have no remarkable effect on proteolytic activity of IgGs. However, specific inhibitor of serine (PMSF, AEBSF, and benzamidin) and metal-dependent (EDTA) proteases significantly inhibit activity of proteolytic abzymes. Interestingly, the ratio of serine-like and metal-dependent activities of MS IgGs varied very much from patient to patient. The findings speak in favor of the generation by the immune systems of individual MS patients of a variety of polyclonal anti-MBP IgGs with different catalytic properties.

Recruitment of dendritic cells to the cerebrospinal fluid in bacterial neuroinfections.

Dendritic cells (DC) accumulate in the CNS during inflammation and may contribute to local immune responses. Two DC subsets present in human cerebrospinal fluid (CSF) are probably recruited from myeloid (CD11c(+)CD123(dim)) and plasmacytoid (CD11c(-)CD123(high)) blood DC. In bacterial meningitis and especially in Lyme meningoencephalitis, numbers of myeloid and plasmacytoid DC in CSF were increased, compared to non-inflammatory neurological diseases, and correlated with chemotactic activity of CSF for immature monocyte-derived DC (moDC). Multiple DC chemoattractants, including macrophage inflammatory protein (MIP)-1beta, monocyte chemotactic protein (MCP)-1, MCP-3, RANTES and stromal cell-derived factor (SDF)-1alpha were elevated in CSF in these two neuroinfections. Chemotaxis of immature moDC induced by these CSFs could be partially inhibited by mAbs against CXCR4, the receptor for SDF-1alpha, and CD88, the receptor for C5a. SDF-1alpha present in CSF also chemoattracted mature moDC, which in vivo could correspond to a diminished migration of antigen-bearing DC from the CSF to secondary lymphoid organs. Regulation of DC trafficking to and from the CSF may represent a mechanism of controlling the CNS inflammation.