Table 2.

MoA of immunosuppressive therapies occasionally or historically used off-label in patients with MS^a

Drug	MoA (included in labelb)	MoA (evidence for additional mechanisms)	Safety
Azathioprine [169]	A purine analogue that is incorporated into DNA and blocks the de novo purine synthesis pathway [170]	Induces apoptosis in stimulated T cells [107]	Over 10 % of patients experience leukopenia, cancer risk increases with treatment duration and cumulative dose [171]
Cyclophosphamide [172]	Active metabolites of cyclophosphamide alkylate DNA during cell division, impairing DNA synthesis and leading to apoptosis in actively proliferating cells [173]	Inhibits the suppressive capability of Treg (at low doses) [174] Suppresses Th1/enhances Th2 T-cell responses [175]	Side effects include risk of malignancy [175]
Methotrexate [176]	Competitive inhibitor of DHFR, leading to a deficiency of nucleic acid precursors and impaired DNA synthesis [177]	Impairs lymphocyte activation and adhesion [178] Increases sensitivity to apoptosis [179]	Rare cases of severe pancytopenia [180]
Mycophenolate mofetil [181]	Reversible inhibitor of IMD type II, an enzyme mainly found in lymphocytes and responsible for de novo synthesis of the purine nucleotide guanine [182] Impairs DNA synthesis and increases apoptosis in activated T cells and impairs proliferation in B and T cells [183]	Inhibits antigen presentation by DCs [183] Impairs recruitment of lymphocytes and monocytes to sites of inflammation [183]	Risk of transitory leukopenia, digestive disorders, and benign infections [184]

MoA mechanism of action, MS multiple sclerosis, DNA deoxyribonucleic acid, Treg T regulatory cell, Th T helper, DHFR dihydrofolate reductase, IMD inosine 5’-monophosphate dehydrogenase, DC dendritic cell

^aThe MoA of these therapies is not completely understood and the listed mechanisms are hypotheses

^bIncluded in labels where drug is approved, though drug may be used off-label in treatment of MS