Nowadays 1s not posslblk to know the course and prognosts after the dlagnosls of (MS) has been establIshed. From a series of 277 patients with defimte or probable MS, recorded m the European Database for MS (EDMUS), those patients with > 10 years of Qsease and non reversible dlsabdlty ( 3 on the Kurt&e adapted disability status scale (EIS) (n= 60) and those patients with EIS z 7, m any time of evolution (n= 24), have been selected. The aim of the present study is to find among cbmcal and paraclimcal features of MS ihose. that prove to mfluence in progression of MS, and so, could to show a predictive value m estabhshmg the prognosis of the disease Such variables have been analysed by stepmse method. pomhng-up seven final variables potentially predictive of the prognosis Sex, actual age, number of relapses in the long story short. the interval between first and second relapses, mono versus polysymptomatlc onset, number of relapses m the first two years of the disease and age at the onset (~28 versus c 28 years) StatIstical analysts of this seven variables by Cox’s model showed three of them having a statistical slgnifiction (p 5 0.05) as predictive factors number of relapses in the long story short, the Interval between first and second relapses and the number of relapses tn the first two years of the disease

MULTIPLE SCLERDSlS AND CANCER IN NORWAY. A RRTROSPECTIVR COHORT STUDY.

The mc&nce ofvanous caners m multiple sclercns (MS) wa# evaluxed LII a rettmpective cohort study wmpndag 1271 MS pat18nt.s. 530 men aad 741 lwwnm Longrtudinal populatia-lmed itidcna studice i&ntificd the c&or-t Computenaed linkage with tha Caace.r Regidry dNanvy -md 73 caacer cases ( standardized mci&oce ratio (SIR)= 0.86,95% Cl 0.68-1.09). Mcpn follow- up “me was 18.4 years. A signiacant excess dksvl- WaobEenrsd (SIR=1 70.95% Cl 1.05-2.60). A non-si&a&aat axcees dcanca in the urinary tract was e&en& No signi6wntly inenved tit in bmnatd@c or lympludic malignannes or malignant brain lumora was dz4arv& We m a siseifeantly reduced risk for cancer in Ihe dig&i= m (SlR=O.Jl. 9% Cl 0.24-0.93). The data mcluding all cancers indicste that a MS paKnt is not at PIy unusual risk for s.lbsequen1 cancer developme”I

A y-interferon (-IFN)-activated calcium (Caz+) influx in T- lymphocytes from multiple sclerosis (MS) patients influences immune activation during disease exacerbations

sMartino, Lucia Moiola, Massimo Filippi. Viiocio Martinelli, Elena Bmmbilla, Bruno Colombo, Giancario Corni, Luigi ME. Grimaldi Neuroimmunology Unit - DEBIT, Dept. of Neurology. Umversity of Milano. San Raffaele Scientific Institute, Milano, Italy.

Clinical and immunological evidences indicate that rlFN is crucial in modulating T- lymphocyte achvily during central nervous system demyehnation characteristic of MS. However, the intracellular mechanism by which y-IFN exerts its activity in MS is nor completely clarified. We recendy repolted the presence of a new trans- plasmalemma y-lFN-activated Ca *+ influx In T-lymphocytes from MS patients (Proc. Natl. Acad. Sci. USA 1994;91:4825-9). Pharmacological studies suggest that at least part of y-IFN contribution to MS pathogenesis is exerted through this Ca*+-dependent mechanism. To substantiate this observation we have now evaluated the clinical, magnetic resonance imaging (MI) and immunological correlates of the influx in 41 clinically active and 39 stable relapsing-remitting definite MS oatients. Three of these Datlents were also seriallv studied everv 15 days for 12’months. Controls included 32 patients with other neurological or active autormmune diseases and 21 healthy subjects. Fura- fluorimetry was used lo detect the ylFN-activated Ca 2+ influx. Active MS lesions were visualized by gadolinium-enhanced brain-MM. The ability lo proliferate in response to mitogens of influx-positive and influx-negative T-lymphocytes was investigated by microproliferation assays. The influx was detected in 61% of the active MS patients and 43% of the stable MS patients but in only 11% of the controls (p&001). Influx-posilivity increased to 77% in clinically active patients during the 1 st waak afier the onset 01 a clinical exacerbation but was detected in only 33% of the clintcally stable patients with benign MS. Gadolinium-enhancing brain lesions were more common in influx-oositive (73%) comoared to influx-neoative oatients _- _- .~ (50%) (p<O.O5). The serial &dy shdwed’that ihe clinical attack; were’always preceded by a peak increase of intracellular Ca2+ due lo the influx (from 4 to 45 days) which-was associated with MRI evidence of inflammation. Influx-positive but not -nenative T-lvmohocvtes became fullv activated in resDonse to low doses (1 ~~rnl)~ Gi”jphytoie&aggiutinin additionei with y-IFN or Ii-2 indicating a low& threshold of rmmunological excitability of these cells. Our data suggest that the y IFN-activated Ca2+ influx plays a crucial role in the early events of ceIIular immune actrvation associated with disease activity in MS by rendering T-lymphocytes more susceptible lo full activation. The hyper-responsiveness to activatory stimuli of influx-positive cells also provides a potential explanation for the common observation that viral infections (able to induce rlFN production) often precede clinical relapses MI MS. We envisage the potential value for the detection of the Influx as a clin!cal/immunological marker of disease activity in future clinical trials.

COMBINED MHIBITORS OF MATRIX METALLOPROIEINASES AND TNF PROCESSING ARE EFFECTWE IN MODELS OF MULTIPLE SCLEROSIS

There is emerging evidence for a role of matrix metalloproteinases (MMPs) in the pathology associated with neuroinflammatory diseases such as multiple sclerosis. It has been proposed that MMPs are involved in blood brain barrier breakdown, leucocyte infiltration, generation of immunogenic MBP fragments and demyelination (Opdenakker et al, Immunol. Today, 15,3:103-107 (1994)). A further role for MMP activity in MS has been provided by the recent discovery that processing of the pro-inflammatory cytokine,TNF, is dependent on an MMP-like enzyme (Gearing et al, Nature, 370:555-557 (1994)). We have produced a series of synthetic compounds (TMls) which combine inhibition of MMP activity and TNF processing. These compounds inhibit both the MMP activity and TNF release from rat glial cells and leucocytes in culture. TMIs are also effective in models relevant to multiple sclerosis, reducing clinical scores and weight loss in acute EAE and inhibiting leucocyte accumulation, blood brain barrier breakdown and demyelination in a DTH model in Lewis rats. We conclude that drugs which combine inhibition of MMP activity and TNF processing are effective against the key pathological features in models of multiple sclerosis and should he considered for clinical investigation.

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