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Myasthenia gravis (MG) exemplifies autoimmune disease. Most patients require immunomodulating treatment, including steroids, chemotherapy, or intravenous immunoglobulin (Ig), in addition to anticholinesterase treatment. Drachman et al1 published the beneficial effects of high dose cyclophosphamide in three patients with severe refractory myasthenia. We recount our experience of three myasthenic patients treated in a similar way.
Materials and methods
All patients participated in studies approved by the Drexel University College of Medicine and signed informed consent. These three patients with severe (class IVb) refractory MG includes all patients treated. Patients received cyclophosphamide 50 mg/kg (adjusted ideal body weight)/day over four consecutive days. Patients received antibacterial, antiviral, and antifungal prophylaxis. Haemorrhagic cystitis prophylaxis included Mesna and forced diuresis. Packed red cells and platelets were transfused to maintain haemoglobin ⩾8.5 g/dL and platelets ⩾10 × 109/L, respectively. Patients received filgrastion (G-CSF) (5 μg/kg/day) starting day 10 until their absolute neutrophil count (ANC) reached 10 × 109/L for two consecutive days.
Patient 1 was diagnosed with seronegative MG at 30 years of age by a positive tensilon test and a decremental response on repetitive stimulation. Initial treatment included pyridostigine and plasmapheresis, but worsening symptoms prompted thymectomies at 12 and 18 months later. Her thymic pathology revealed thymic hyperplasia. Additional treatment with only transient responses included low dose oral cyclophosphamide, intravenous Ig, azathioprine, methylprednisolone, and continued pyridostigine with plasmapheresis. She required 27 intubations between initial diagnosis and immunoablative treatment at 41 years of age.
Patient 2, previously reported, suffered from both seronegative MG and chronic inflammatory demyelinating polyneuropathy (CIDP).2 He presented at 47 years of age with fluctuating double vision, ptosis, dysphagia, arm weakness, and breathing difficulties. Testing revealed a decremental response on repetitive stimulation. Pyridostigine was initiated. Thymectomy revealed a 75 g lipoma. His MG resulted in two intubations. After thymectomy, to control symptoms, prednisone (25–40 mg daily) was required. At 54 years of age, CIDP was diagnosed. Despite steroids (plasmapheresis, intravenous Ig, azathioprine, and pyridostigmine) he continued with symptoms of double vision, dysphonia, and dysphasia with a continued decremental response to repetitive stimulation. At 56 years of age, he underwent high dose cyclophosphamide without stem cell rescue.
Patient 3 was diagnosed with antibody positive MG at 12 years of age, initially treated with pyridostigine. She received her first thymectomy at age 18 years and continued on pyridostigine and occasional steroids. By 36 years of age, she was steroid dependent. Between ages 38 and 41 years she required 11 intubations and only transiently responded to intravenous Ig and plasmapheresis. A second thymectomy was performed at age 39 and cyclosporine (CsA) was initiated. She continued on prednisone 25 mg qod, scheduled intravenous Ig every 3–4 weeks, and intermittent plasmapheresis. The CsA and Cellcept were maintained but poorly tolerated. At 41 years of age, she underwent high dose cyclophosphamide without stem cell rescue.
Patient 1 had 13 days of neutropenia, required three units of packed red cells and three platelet transfusions. Patient 2 had 9 days of neutropenia, required two units of packed red cells, and three platelet transfusions. Patient 3 had 11 days of neutropenia, required five units of packed red cells, and two platelet transfusions. Patients 1 and 3 experienced MG flares requiring intravenous Ig and plasmapheresis, but neither required intubation.
Neurological follow up
Patient 1, intubated 27 times before treatment, required a single intubation during 48 months of follow up. To control less severe exacerbations, during the first 40 months after immunoablative treatment, oral cyclophosphamide was necessary. She continues scheduled plasmapheresis and pyridostigmine. No other immunomodulatory medications are prescribed.
Patient 2 had myasthenic symptoms of dysphagia and diplopia. Seven months after treatment pyridostigmine was stopped and after 12 months prednisone was stopped. Twenty five months after treatment, his MG is in full remission.
Patient 3 experienced five flares at 1, 6, 11, 19, and 30 weeks following treatment. The exacerbations at 1, 6, and 11 weeks required intravenous Ig and steroids; exacerbations at 1, 19, and 30 weeks required plasmapheresis. Her last exacerbation necessitated intubation. Between exacerbations her functional ability consistently improved. She stopped steroids at 50 weeks. At 52 weeks, a slow pyridostigine taper began. Her serum AChr levels did not correlate with disease activity during the follow up periods.
The patients discussed have all suffered from severe refractory MG, which requires multiple intubations. All underwent thymectomy: patients 1 and 3 repeat thymectomies. Patient 2 had an early and sustained response to treatment. Patients 1 and 3 had multiple exacerbations. As this treatment targets IgG production, exacerbations following treatment are expected. Patient 1, who required 27 intubations before treatment and only once since, and who has in the past 6 months stopped oral cyclophosphamide, may yet to enjoy the maximum benefit of this treatment. Patient 3, one year after treatment, has an improving activity level. The intervals between exacerbations are increasing: 5, 8, and 11 weeks. It is 26 weeks since her last exacerbation.
Recently, Drachman et al1 published a single institution case series of three patients with refractory MG who were also treated with high dose cyclophosphamide. In this series, one patient had AChR antibody negative MuSK antibody positive myasthenia. Their mean disease duration was 10.3 (range: 3–15) years; one required intubation and median follow up was 24 (range: 7–40) months. In comparison, in the three patients described here, two had antibody negative myasthenia and the mean disease duration was 16.3 (range: 9–29) years. All required multiple intubations: 27, 2, and 11, and our median follow up is 25 (range: 13–48) months. During follow up, patient 3’s serum AChr levels remained detectable and did not correlate with her clinical course. Drachman et al reported a decline in antibody levels in their patients treated in a similar way, although AChr antibody titres and MuSK antibodies persisted in their patients even after 2 years.1 This suggests that long term remissions in MG may be possible even without achieving complete immunoablation. High dose cyclophosphamide has the potential to significantly reduce symptoms and increase life quality among people with MG refractory compared to conventional treatment. Long term follow up is necessary to evaluate the duration effect and time to maximum benefit. High dose cyclophosphamide treatment warrants further study as a treatment for severe refractory MG.