C. Avolio

Changes of serum sICAM-1 and MMP-9 induced by rIFNβ-1b treatment in relapsing-remitting MS

OBJECTIVEnTo correlate changes in serum levels of intercellular adhesion molecule-1 (sICAM-1) and matrix metalloproteinases (MMP) with clinical and MRI evidence of disease activity in MS patients receiving treatment with interferon-beta (rIFNbeta)-1b.nnnBACKGROUNDnrIFNbeta reduces the frequency of gadolinium-enhancing (Gd+) MRI in relapsing-remitting MS (RRMS). Its mechanism of action on improving the integrity of the blood-brain barrier remains unclear.nnnMETHODSnsICAM-1 and MMP-9 and MMP-2 serum levels were longitudinally (24 months) investigated (ELISA; zymography) in correlation with the modifications of the integrated area under the curve of Expanded Disability Status Scale scores normalized to entry baseline (deltaEDSS AUC) and of GD+ MRI scans, and with neutralizing antibodies (NAB) to rIFNbeta-1b production (MxA) in 36 RRMS patients.nnnRESULTSnDuring the first 12 months of treatment, levels of sICAM-1 increased and MMP-9 decreased significantly. After 12 months, levels returned toward baseline. Levels of sICAM-1 and MMP-9 were significantly negatively correlated. MMP-2 levels did not change significantly during the same period. During the second semester of the study, deltaEDSS AUC was significantly reduced. The percentage of patients with Gd+ MRI decreased significantly in the first (33%), second (29%), third (20%), and fourth (28%) semesters of treatment compared to baseline (62%). The NAB+ patients (14%) tended to have lower sICAM-1 levels at the ninth month; a higher MMP-9 activity at the sixth, 12th, and 18th months; and a greater deltaEDSS AUC in the third semester of treatment in comparison with the NAB- patients.nnnCONCLUSIONSnThese results show that rIFNbeta-1b therapy increases sICAM-1 serum levels and reduces serum MMP-9 activity.

Multivariate analysis of predictive factors of multiple sclerosis course with a validated method to assess clinical events.

The clinical data of 309 patients with definite multiple sclerosis were recorded in the European data base for multiple sclerosis (EDMUS) to determine the prognostic significance of several demographic and clinical variables. An interview with closed questions structured according to standardised criteria of disease phases and courses was used to assess the clinical course. The reliability was evaluated by four trained neurologists in a sample of 33 patients with multiple sclerosis. Both the within and between rater agreement on data collection was fair to high for the historical variables (K = 0.33-1). Between rater agreement was more variable for the evaluation of 12 different EDMUS event categories (K = 0.3-0.95). The predictive model for the time to reach a secondary progression showed that an age at onset older than 25 (p = 0.006) and an event at onset followed by disability > or = 3 on the Kurtzke expanded disability status scale (EDSS; p = 0.004) were the most unfavourable clinical variables in 249 patients with relapsing remitting (180) or relapsing progressive (69) courses. In the 69 patients with relapsing progressive disease, the time to reach severe disability (EDSS > or = 6) was negatively influenced by a first interval between attacks shorter than one year, a number of bouts with EDSS > 2 in the first two years of the disease, and involvement of the pyramidal system at onset (p < 0.05). In 60 patients with chronic progressive disease this outcome was negatively influenced by pyramidal, brainstem, and sensory involvement at onset (p < 0.01).

Soluble intercellular adhesion molecule-1 in serum and cerebrospinal fluid of clinically active relapsing-remitting multiple sclerosis Correlation with Gd-DTPA magnetic resonance imaging-enhancement and cerebrospinal fluid findings

We measured soluble intercellular adhesion molecule-1 (sICAM-1) in the serum and cerebrospinal fluid (CSF) of 35 clinically active relapsing-remitting (RR) multiple sclerosis (MS) patients who underwent both lumbar puncture and gadopentetate dimeglumine (Gd-DTPA)-enhanced MRI within an interval of 1 week, and of 30 neurological controls of whom 17 had noninflammatory neurologic diseases (NIND), 8 bacterial meningitis (BM), and 5 AIDS dementia complex (ADC). Thirteen of the MS patients assumed corticosteroids at the time of the study. While sICAM-1 serum levels were highest in the BM group (p < 0.005), untreated MS patients showed levels higher (p < 0.05) than treated MS and NIND, but similar to ADC. Moreover, the untreated MS group had CSF/serum sICAM-1:CSF/serum albumin (sICAM-1 index) values higher than the treated group (p < 0.01), NIND (p < 0.005), and BM (p < 0.05); high sICAM-1 index was found also in ADC. Untreated MS patients with one or more Gd-DTPA-enhancing MRI lesions (Gd-positive) had higher mean values of CSF/serum albumin ratio (QAlbumin) and CSF mononuclear cells compared to patients without such lesions (Gd-negative). In the untreated Gd-negative patients, sICAM-1 serum levels were higher (p < 0.05) than those in Gd-positive patients. In the latter group, there were positive correlations between the number of CSF mononuclear cells and both IgG (p < 0.01) and sICAM-1 indices (p < 0.05), between QAlbumin and QsICAM-1 (p < 0.005) and between Qalbumin and the Expanded Disability Status Scale score (p = 0.05). There were no significant correlations in the Gd-negative group. These results suggest that sICAM-1 index can be a better marker of intrathecal sICAM-1 synthesis than CSF levels and provide additional insights, in vivo, into the blood-brain barrier mechanisms underlying MRI Gd-enhancement in clinically active RR MS. NEUROLOGY 1996;47: 1535-1541

Soluble Intercellular Adhesion Molecule-1 (sICAM-1) in serum and cerebrospinal fluid of demyelinating diseases of the central and peripheral nervous system

Serum and cerebrospinal fluid (CSF) soluble Intercellular adhesion molecule-1 (ICAM-1) levels were evaluated (ELISA) in 22 untreated and 13 corticosteroid-treated active relapsing remitting (RR) Multiple Sclerosis (MS), in 10 untreated and 10 corticosteroid-treated Guillain-Barré syndrome (GBS) and in 17 non-inflammatory neurological diseases (NIND). Twenty-eight clinically inactive RR MS were assayed for serum sICAM-1 before and after 3 months treatment of 8 MIU rIFNb-1b taken s.c. every other day. High sICAM-1 serum levels above the NIND values were found in untreated clinically active MS and in untreated GBS (P50.05) but not in the untreated clinically inactive MS group. The active MS group showed significantly (P=0.0001) higher sICAM-1 serum levels if compared to the inactive group. Corticosteroid-treated active MS and GBS patients showed lower (P50.05) serum sICAM-1 levels than the corresponding untreated groups. Serum sICAM-1 levels after 3 months of rIFNb-1b treatment (P50.0001, paired t-test) resulted increased compared to pretreatment values in MS. The mean values of CSF/serum sICAM-1: CSF/serum Albumin ratios (sICAM-1 Index) in active untreated MS patients were higher compared to NIND (P50.005) and to corticosteroid-treated MS group (P=0.01). sICAM Index values in GBS did not differ from those in NIND. The results seem to suggest potential roles for serum sICAM-1 in downregulating the ongoing inflammatory response at the blood-brain barrier level and for CSF sICAM-1 in the maintenance of a central nervous system local immune response.

Comparison of clinical and demographic features between affected pairs of Italian Multiple Sclerosis multiplex families; relation to tumour necrosis factor genomic polymorphisms

We conducted a comparative analysis of clinical and demographic findings between pairs of relatives (36 sibling and 9 parent/child), concordant for Multiple Sclerosis (MS), from 40 MS Italian Multiplex families. A genetic TNF (alpha and beta) loci typing in 51 affected and 69 healthy relatives belonging to 25 of these families was also performed. The sib pairs resulted significantly concordant for age at onset (r=0.414, P<0.013), Progression Index (r=0.34, P<0.05) and sensory symptoms at onset (k=0.37), and significantly not concordant for sex (k=-0.37), whereas no concordance was found for year at onset and disease course. The only significant result in the small group of parent/child pairs was that parents developed MS at an age of 18.74 years significantly (P=0.020) greater than their children. Genomic analysis identified 13 variants of TNF-a alleles, 7 of TNF-b, 6 of TNF-d and 3 of TNF-e. No differences in the frequencies of the various TNF alleles were observed between affected and healthy relatives. The two-point lod-score analysis of the TNF locus showed not significant or negative results for the TNFalpha loci and slightly positive results (Zmax=0.4 at theta=0.2 cM) for the TNFbeta-b locus in the lowest penetrance dominant model. The Sib pair analysis, using combined TNFalpha and TNFbeta haplotypes, demonstrated a TNF allele sharing between affected sib-pairs which did not exceed the expected 50%. These results suggest that genetic factors may partially influence the disease onset and the progression rate in sibling pairs. A recall bias and/or an anticipation phenomenon could explain the development of MS at an older age in parents than in their children. In this small-sized cohort of MS Italian families no significant associations were confirmed between TNF polymorphism and MS.

Serum soluble ICAM-1 and gelatinase B novel markers of clinical efficacy of the RIFN-beta-1b in relapsing-remitting multiple sclerosis

5 6 3 Therapeutic and DiagnostieAppllcations of Solubilized MHC Ih Pepfide Complexes in Multiple Sclerosis E. SpaeL N. Wehner, S. Mocei, M. Zilberm an, L. Schain, D. Buekm an, J. Winldehake, M. Howard, Anergen, lnc., USA 5 6 6 S e r u m Soluble I C A M I and Gela t inase B Novd M a r k e r s of Clinical Efficacy of the R I F N b e t a l b in R d a p s i n g R c m i t t i n g

Cerebrospinal fluid and serum soluble adhesion molecules in multiple sclerosis

Multiple Sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) characterized by a multifocal inflammatory leukocyte infiltration and demyelination. It is widely accepted that an “activation” of CNS microvascular endothelial cells (EC) associated with blood-brain barrier (BBB) damage represents early event in demyelinating lesion development [1, 2]. However, the mechanisms responsible for the migration of lymphocytes through microvascular EC into the CNS have not been clearly identified. This traffic needs peripheral blood mononuclear cells (PBMC) activation, recruitment and strong adhesion to vascular ECs. Normally, vascular ECs have low adhesiveness for PBMC, but when stimulated by cytokines, such as interleukin-1, tumor necrosis factor and interferon gamma [3–5], released by inflammatory cells, they express surface adhesion proteins.

2. Intra-blood-lacrimal barrier IgG and IgA synthesis in active multiple sclerosis

Second Conference of the Italian National Group for Neuroimmunology (GNI) Rome, Italy, 6-7 April 1990

Disease Duration, Relapse rate and Clinical Course in Multiple Sclerosis: Relation to IgG Production within the Blood Brain Barrier

The interrelationships between the cerebrospinal fluid (CSF) abnormalities and the clinical course of multiple sclerosis (MS) have been investigated in several studies. Clinical variables are often difficult to define in MS, and some of them (age, disease duration, number of bouts, disability) are likely to be interdependent.2 Moreover, the lack of uniformity in the definition of clinical and temporal parameters employed in the assessment of the disease course10 hampered comparable results in different studies.