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Predictive factors of prognosis in multiple sclerosis
A y-interferon (-IFN)-activated calcium (Caz+) lymphocytes from multiple sclerosis (MS) patients immune activation during disease exacerbations sMartino,
Lucia Moiola, Massimo Filippi. Viiocio Bruno Colombo, Giancario Corni, Luigi ME. Grimaldi Neuroimmunology Unit - DEBIT, Dept. of Neurology. Raffaele Scientific Institute, Milano, Italy.
Martinelli, Umversity
influx in Tinfluences Elena
Bmmbilla,
of Milano.
San
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
Clinical and immunological evidences indicate that rlFN is crucial in modulating Tlymphocyte 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 transfrom MS patients plasmalemma y-lFN-activated Ca *+ influx In T-lymphocytes (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 2+ influx. Active MS lesions were visualized used lo detect the ylFN-activated Ca 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 1st 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
MULTIPLE SCLERDSlS AND CANCER A RRTROSPECTIVR COHORT STUDY.
COMBINED MHIBITORS OF MATRIX METALLOPROIEINASES AND TNF PROCESSING ARE EFFECTWE IN MODELS OF MULTIPLE SCLEROSIS
The mc&nce
ofvanous
IN NORWAY.
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.
caners
m multiple sclercns (MS) wa# evaluxed LII a 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-
rettmpective cohort study wmpndag
up “me was 18.4 years. A signiacant
(SIR=1
70.95%
Cl 1.05-2.60).
excess dksvl-
A non-si&a&aat
WaobEenrsd
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
-69-
Lucia Moiola, Massimo Filippi. Viiocio Bruno Colombo, Giancario Corni, Luigi ME. Grimaldi Neuroimmunology Unit - DEBIT, Dept. of Neurology. Raffaele Scientific Institute, Milano, Italy.
Martinelli, Umversity
influx in Tinfluences Elena
Bmmbilla,
of Milano.
San
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
Clinical and immunological evidences indicate that rlFN is crucial in modulating Tlymphocyte 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 transfrom MS patients plasmalemma y-lFN-activated Ca *+ influx In T-lymphocytes (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 2+ influx. Active MS lesions were visualized used lo detect the ylFN-activated Ca 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 1st 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
MULTIPLE SCLERDSlS AND CANCER A RRTROSPECTIVR COHORT STUDY.
COMBINED MHIBITORS OF MATRIX METALLOPROIEINASES AND TNF PROCESSING ARE EFFECTWE IN MODELS OF MULTIPLE SCLEROSIS
The mc&nce
ofvanous
IN NORWAY.
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.
caners
m multiple sclercns (MS) wa# evaluxed LII a 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-
rettmpective cohort study wmpndag
up “me was 18.4 years. A signiacant
(SIR=1
70.95%
Cl 1.05-2.60).
excess dksvl-
A non-si&a&aat
WaobEenrsd
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
-69-