STOP-I-SEP

Treatment tested

• DMT withdrawal
• Interferon beta-1b

  Interferon alpha/beta receptor agonist

• Azathioprine

  Amidophosphoribosyltransferase inhibitor|DNA inhibitor

• Teriflunomide

  Dihydroorotate dehydrogenase inhibitor

• Glatiramer acetate

  Unknown

• Cyclophosphamide anhydrous
• Dimethyl fumarate

  Kelch-like ECH-associated protein 1 inhibitor

• Methotrexate

  Dihydrofolate reductase inhibitor

• Mycophenolate mofetil

  Inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitor

• Ocrelizumab

  B-lymphocyte antigen CD20 binding agent

• Interferon beta-1a

  Interferon alpha/beta receptor agonist

• Peginterferon beta-1a

  Interferon alpha/beta receptor agonist

• Rituximab

  B-lymphocyte antigen CD20 binding agent

Compared with

• DMT continuation
• Interferon beta-1a

  Interferon alpha/beta receptor agonist

• Interferon beta-1b

  Interferon alpha/beta receptor agonist

• PLEDIGRY
• Glatiramer acetate

  Unknown

• Teriflunomide

  Dihydroorotate dehydrogenase inhibitor

• Dimethyl fumarate

  Kelch-like ECH-associated protein 1 inhibitor

• Fingolimod
• Natalizumab

  Integrin alpha-4/beta-1 inhibitor|Integrin alpha-4/beta-7 inhibitor

• IMUREL
• NOVATREX
• Mycophenolate mofetil

  Inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitor

• Cyclophosphamide anhydrous

Other measures (21)

Inclusion Criteria: * Patients > 50 years old; * Secondary progressive phenotype for at least 3 years; The secondary progressive phenotype will be defined as progressive deterioration of disability not due to relapse, with an increase of at least 1 EDSS point since the beginning of the progressive phase (or 0.5 EDSS point if EDSS score ≥ 5.5). * Disease modifying therapy of MS for at least 3 years (interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil, rituximab, ocrelizumab); Both patients with the same DMT or with successive DMTs during 3 years can be included. It is important to note that patients could have been treated with fingolimod or natalizumab 2 or 3 years before inclusion, but not during the year before inclusion ; * No evidence of focal inflammatory activity for at least 3 years (no clinical relapse and no gadolinium enhancement on an MRI scan); * EDSS≥3. Concomitant medications with Fampridine are allowed throughout the study, provided they have been introduced at least 1 months before inclusion. Natalizumab and fingolimod during the year before inclusion were excluded because of the risk of recurrence of inflammatory activity or even rebound of inflammatory activity after withdrawal. Both patients with the same DMT or with successive DMTs during 3 years can be included, as for example, cyclophosphamide is used for 1 or 2 years, sometimes followed by mycophenolate mofetil. For Rituximab and Ocrelizumab, inclusion in STOP-I-SEP will be at 6 months from the last infusion to take into account the mode of action of these treatments and their specific administration scheme. Exclusion Criteria: * Patients treated with mitoxantrone or alemtuzumab, during the previous 3 years before inclusion; * Patients treated with natalizumab or fingolimod during the year before inclusion; * Change of disease modifying therapy of MS for less than a year * Other neurological or systemic disease ; * Incapacity to understand or sign the consent form ; * Contraindication to MRI ; * Pregnancy or breast-feeding ; * Patient in another clinical trial * Persons referred to in Articles L. 1121-5 to L. 1121-8 and L. 1122-1-2 of the Public Health Code (eg minors, protected adults, …).

Further controlled and randomized prospective studies in Multiple sclerosis, analyzing the potential impact of treatment discontinuation on disability progression, focal disease activity and quality of life are needed. The optimum patient age and duration of inactive SPMS before treatment withdrawal and the monitoring procedures also need to be specified, the ultimate goal being to provide evidence-based recommendations for clinical practice. Following the previous retrospective experience, we decided to drive a multicenter prospective study in France based on the hypothesis that stopping disease modifying therapy will not induce an increased risk of disability progression and relapse in selected SPMS patients (older patients without lesion activity) but will improve the quality of life and may reduce treatment-related costs.