Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects

Abstract

Cyclophosphamide is an alkylating agent used to treat malignancies and immune-mediated inflammatory non-malignant processes such as lupus nephritis and immune-mediated neuropathies. It has been studied as a treatment for multiple sclerosis (MS) for the past 30 years and is used by physicians in selected cases of progressive or worsening MS. Review of published reports suggests that it is efficacious in cases of worsening MS that have an inflammatory component as evidenced by relapses and/or gadolinium (Gd)-enhancing lesions on magnetic resonance imaging (MRI) or in patients in earlier stages of disease where inflammation predominates over degenerative processes in the central nervous system (CNS). There is no evidence of efficacy in primary progressive MS or later stages of secondary progressive MS. Although a general immunosuppressant that affects both T- and B-cell function, cyclophosphamide has selective immune effects in MS by suppressing IL-12 and Th1-type responses and enhancing Th2/Th3 responses (IL-4, IL-10, TGF-beta; eosinophils in peripheral blood). Side effects include nausea, alopecia, infertility, bladder toxicity and risk of malignancy. The most commonly used regimens involve every 4- to 8-week outpatient i.v. pulse therapy given with or without corticosteroids and are usually well-tolerated by patients. Cyclophosphamide is currently used in patients whose disease is not controlled by beta-interferon or glatiramer acetate and those with rapidly worsening MS.

Therapeutic Approach to the Management of Pediatric Demyelinating Disease: Multiple Sclerosis and Acute Disseminated Encephalomyelitis

“…Cyclophosphamide is typically infused monthly (with or without induction) and works as an immunosuppressing agent affecting cytokine expression (with pronounced effects on IL-12) along with T-cell and B-cell function [95]. In adults with RRMS, cyclophosphamide appears to reduce relapse rate and the accrual of new lesions on MRI [96,97] Fig.…”

The Influence of Cyclophosphamide on Immune Function of Murine Macrophages

“…There is no evidence of efficacy in primary progressive MS or later stages of secondary progressive MS. In these high doses of CY therapy, patients show low proinflammatory cytokine secretion which activates anti-inflammatory cytokine secretion, what is suggested in an elegant review by Weiner and Cohen as one of curative effects in MS neurodegenerative disease (Weiner & Cohen 2002). That high dose treatment can express quite a different suppressor effect on the immune system mediated by B and T lymphocytes that mediate two branches of humoral and cellular immune responses.…”

Immunosuppressive Agents in Multiple Sclerosis

“…Apart from strong immunosuppression, cyclophosphamide can also exert immunomodulatory effects shifting immune responses from TH1 toward TH2 by an unknown mechanism. 65 Cyclophosphamide can cause several side effects, such as alopecia, nausea, vomiting, hemorrhagic cystitis, leukopenia, myocarditis, infertility, and pulmonary interstitial fibrosis.…”