Safety of Long-Term Combined Immunosuppression in Myasthenia Gravis

Abstract & Commentary

By Michael Rubin, MD, Professor of Clinical Neurology, NewYork-Presbyterian Hospital, Cornell Campus. Dr. Rubin is on the speaker's bureau for Athena Diagnostics, and does research for Pfizer and Merck.

Synopsis: Long-term treatment of myasthenia gravis with combined immunosuppressive therapy is generally safe and effective.

Source: Rozsa C, et al. Safety of long-term combined immunosuppressive treatment in myasthenia gravis — analysis of adverse effects of 163 patients. Eur J Neurol. 2006;13:947-952.

Prospective, open, long-term observation (mean 19 months, range 6-65 months) of 163 myasthenia gravis (MG) patients was undertaken to determine the safety of enduring combined immunosuppressive therapy. Diagnosis of MG was based on the presence of typical fluctuating muscular symptoms, combined with a decremental response on repetitive nerve stimulation testing, with or without acetylcholine receptor antibody positivity. Immunosuppressive therapy, azathioprine 1.0-2.5 mg/kg daily, combined with alternate day methylprednisolone 1-1.5 mg/kg, to a maximum of 100 mg, was administered only to generalized myasthenics who did not respond to cholinesterase inhibitors, or to those with a history of crisis. Patients were seen every 3 months, underwent clinical and laboratory assessment, and completed a detailed questionnaire. Chi-square and Mann-Whitney tests were used for statistical analysis.

Sixty-one percent of patients experienced adverse effects from medication; overall, in 52%, these were steroid-related and, in 20%, azathioprine-related. Among patients with adverse effects, 67% were due solely to steroid, 15% to azathioprine, and 18% to both. Azathioprine was discontinued in 10, due to neutropenia, hepatotoxicity, or severe joint pains (2 each), pancytopenia, vomiting, allergic skin reaction, or severe axonal polyneuropathy (one each). Steroids were discontinued in only 1 patient, due to bleeding duodenal ulcer. Osteoporosis with vertebral compression (n = 4) or hip fracture (n = 1) did not mandate medication withdrawal. Steroid induced myopathy or psychiatric complications were not observed. Cancer caused death in 3 patients (colon in 2, and endometrial in one), cardiac disease in 4, and pulmonary embolism and iliac artery thrombosis in one each. Long-term immunosuppressive therapy was deemed safe and rarely required interruption of treatment. Adverse effects appeared to correlate with disease severity at onset of treatment.

Commentary

Prolonged treatment of generalized MG for up to 2 years (88-104 weeks) with tacrolimus, 2-4.5 mg/day, also appears safe and effective (J Neurol Neurosurg Psychiatry. 2005;76;448-450). Among 12 MG patients, 3 men, 9 women, aged 4-31 years, steroid dose could be reduced in 7 (58%) and Activities of Daily Living score improved in 8 (67%). Eight patients experienced side effects, mostly minor and not requiring discontinuation of treatment. Severe headache and eye pain was seen in one, for which tacrolimus was stopped for 7 weeks and then restarted. Infection was not observed.