Contributions
Abstract: P905
Type: Poster Sessions
Abstract Category: Therapy - Neuroprotection and Repair
Background: Despite the success in therapy of relapsing-remitting multiple sclerosis, progressive multiple sclerosis remains hard to treat. All-trans retinoic acid (ATRA), the active metabolite of vitamin A contributes to regulation and differentiation of the adaptive and innate immune system. In experimental autoimmune encephalomyelitis (EAE) synthetic retinoic acid inhibits Th17 cells, it may alter Th1/Th2 subsets towards Th2 and promote Treg cells. In addition, vitamin A is thought not only to reduce inflammation but also to induce remyelination and stimulate neurite outgrowth. In several EAE-experiments, retinoic acid or its metabolites ameliorated the disease course. However, except for little data on a chemical level without clinical correlation there is no evidence for use of vitamin A in human patients.
Methods: 3 patients with progressive multiple sclerosis who failed previous treatment (repetitive glucocorticoid pulse therapy) were treated with high dose ATRA. Oral ATRA was initially administered in a dose of 45 mg/m² body surface area, followed by 3 cycles of consolidation (30 day cycles with treatment during first 15 days) und multiple cycles of sustainment (3 month cycles with treatment during first 15 days). The patients were monitored clinically (EDSS, maximum walking distance, timed 25-foot walk, 9-hole peg test, PASAT 3'') and with routine safety laboratory testing. PBMC and blood serum samples were stored frozen until FACS analysis for T cell subsets.
Results: Except for mild headache ATRA was well tolerated and no pathological laboratory abnormalities were observed. After mild initial improvement, all 3 patients complained about progressive worsening of motor function, paralleled by ongoing reduction of walking ability. Taken together, there was no evidence for a therapeutic benefit of ATRA on disease progression in these 3 patients. One patient however subacutely experienced severe cognitive and motor worsening. Cerebral MRI revealed persistent gadolinium enhancing lesions, which persisted for over 3 months despite high dose steroid treatment. Flow cytometriy of peripheral blood revealed no significant alterations in T cell populations during ATRA-treatment.
Discussion: We found no evidence for clinical benefit or altered T cell populations by ATRA treatment in a small number of patients with progressive MS.
Disclosure: No source of funding; ATRA was provided free of charge by Cheplapharm;
C. Ruschil: has received travel support from Bayer, Biogen, Genzyme and Novartis, unrelated to this work; E. Dubois: nothing to disclose; M. Schittenhelm: nothing to disclose; M. Krumbholz: has received grants, travel support and personal fees from Bayer, Biogen, Genzyme, Novartis and Roche, unrelated to this work; F. Bischof: served on the scientific advisory board for Genzyme, Novartis, and Roche, received speaker honoraria and travel funding from Biogen Idec, Genzyme, and Novartis, and received research support from Novartis, all unrelated to this work
Abstract: P905
Type: Poster Sessions
Abstract Category: Therapy - Neuroprotection and Repair
Background: Despite the success in therapy of relapsing-remitting multiple sclerosis, progressive multiple sclerosis remains hard to treat. All-trans retinoic acid (ATRA), the active metabolite of vitamin A contributes to regulation and differentiation of the adaptive and innate immune system. In experimental autoimmune encephalomyelitis (EAE) synthetic retinoic acid inhibits Th17 cells, it may alter Th1/Th2 subsets towards Th2 and promote Treg cells. In addition, vitamin A is thought not only to reduce inflammation but also to induce remyelination and stimulate neurite outgrowth. In several EAE-experiments, retinoic acid or its metabolites ameliorated the disease course. However, except for little data on a chemical level without clinical correlation there is no evidence for use of vitamin A in human patients.
Methods: 3 patients with progressive multiple sclerosis who failed previous treatment (repetitive glucocorticoid pulse therapy) were treated with high dose ATRA. Oral ATRA was initially administered in a dose of 45 mg/m² body surface area, followed by 3 cycles of consolidation (30 day cycles with treatment during first 15 days) und multiple cycles of sustainment (3 month cycles with treatment during first 15 days). The patients were monitored clinically (EDSS, maximum walking distance, timed 25-foot walk, 9-hole peg test, PASAT 3'') and with routine safety laboratory testing. PBMC and blood serum samples were stored frozen until FACS analysis for T cell subsets.
Results: Except for mild headache ATRA was well tolerated and no pathological laboratory abnormalities were observed. After mild initial improvement, all 3 patients complained about progressive worsening of motor function, paralleled by ongoing reduction of walking ability. Taken together, there was no evidence for a therapeutic benefit of ATRA on disease progression in these 3 patients. One patient however subacutely experienced severe cognitive and motor worsening. Cerebral MRI revealed persistent gadolinium enhancing lesions, which persisted for over 3 months despite high dose steroid treatment. Flow cytometriy of peripheral blood revealed no significant alterations in T cell populations during ATRA-treatment.
Discussion: We found no evidence for clinical benefit or altered T cell populations by ATRA treatment in a small number of patients with progressive MS.
Disclosure: No source of funding; ATRA was provided free of charge by Cheplapharm;
C. Ruschil: has received travel support from Bayer, Biogen, Genzyme and Novartis, unrelated to this work; E. Dubois: nothing to disclose; M. Schittenhelm: nothing to disclose; M. Krumbholz: has received grants, travel support and personal fees from Bayer, Biogen, Genzyme, Novartis and Roche, unrelated to this work; F. Bischof: served on the scientific advisory board for Genzyme, Novartis, and Roche, received speaker honoraria and travel funding from Biogen Idec, Genzyme, and Novartis, and received research support from Novartis, all unrelated to this work