Combination therapy with interferon Beta-1b and azathioprine in secondary progressive multiple sclerosis

Abstract

Combination therapy may benefit the subgroup of patients with secondary progressive multiple sclerosis (SPMS) who do not respond to interferon beta (IFNB). We performed a two-year study of azathioprine (AZA) combined with IFNB-1b in SPMS patients who had not responded well to IFNB-1b alone. Patients with SPMS were eligible for this non-controlled prospective study if they had two or more relapses requiring corticosteroid treatment or deteriorated by at least 0.5 points on the Expanded Disability Status Scale (EDSS) while on IFNB-1b in the year preceeding the study. Patients were to continue treatment with IFNB-1b (8 MIU qod, subcutaneous) and received AZA (50 mg tid, oral). Safety was assessed in terms of adverse reactions and laboratory measures graded according to the WHO toxicity scale. Efficacy was explored by changes in relapse rate, EDSS, 9-hole peg test (9-HPT), neuropsychological scores, and magnetic resonance imaging (MRI) results. Neutralizing antibodies (NAB) were measured. Ten SPMS patients (6 females) with a median EDSS score of 4.5 were enrolled. One patient withdrew because of gastrointestinal complaints, one was withdrawn owing to poor compliance, and 8 patients completed therapy. The only frequent side effect was lymphopenia, reported at least once in all patients. Annual relapse rate was reduced by approximately 50 % in the second year. There was a significant trend for EDSS increase. Total lesion load measured by MRI decreased at 12 and 24 months; only one patient had active lesions. No changes were seen in the 9-HPT. There was a significant improvement in neuropsychological tests after 24 months ( p = 0.045). One patient tested positive for NAB throughout the study, and transient NAB were detected in 4 patients. In conclusion, combination therapy with IFNB-1b and AZA was safe and generally well tolerated in patients with SPMS. Strict clinical and laboratory monitoring is recommended during this combination therapy.

Brain Penetration of the Oral Immunomodulatory Drug FTY720 and Its Phosphorylation in the Central Nervous System during Experimental Autoimmune Encephalomyelitis: Consequences for Mode of Action in Multiple Sclerosis

“…For example, immunosuppressants like mitoxantrone and azathioprine reduce the total white blood cell count via cytotoxic mechanisms (Ferná ndez et al, 2002;Jeffery et al, 2005). Nonmitogenic anti-CD3 mAb blockade induces a profound lymphopenia via alterations in lymphocyte trafficking (Kohm et al, 2005).…”

A Multimodal Intervention for Patients with Secondary Progressive Multiple Sclerosis: Feasibility and Effect on Fatigue

“…1,2 There is increasing interest in the development of combination therapies, using immune suppressants and drugs with distinct mechanisms of action, but side-effects limit the number of pharmacologic agents that can be safely used. [3][4][5] Combinations of nonpharmaceutical treatments that are known to increase muscle strength and positively influence brain function by multiple mechanisms of action but with minimal side-effects may provide an alternative treatment. 6 Progressive muscle weakness and fatigue are the chief complaints of MS patients and lead to decreased physical activity and disability.…”

Review: Neutralizing antibodies against interferon-beta

“…reduced the frequency of patients that had developed NAbs after twelve months, but did not reduce the proportion of NAb-positive patients with titers above 100 NU/ml [Pozzilli et al 2002]. Combination of IFN-with an immunosuppressive agent have shown inconsistent results [Calabresi et al 2002;Fernandez et al 2002].…”