A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis.

BACKGROUND: Dermatomyositis is a clinically distinct myopathy characterized by rash and a complement-mediated microangiopathy that results in the destruction of muscle fibers. In some patients the condition becomes resistant to therapy and causes severe physical disabilities. METHODS: We conducted a double-blind, placebo-controlled study of 15 patients (age, 18 to 55 years) with biopsy-proved, treatment-resistant dermatomyositis. The patients continued to receive prednisone (mean daily dose, 25 mg) and were randomly assigned to receive one infusion of immune globulin (2 g per kilogram of body weight) or placebo per month for three months, with the option of crossing over to the alternative therapy for three more months. Clinical response was gauged by assessing muscle strength, neuromuscular symptoms, and changes in the rash. Changes in immune-mediated muscle abnormalities were determined by repeated muscle biopsies. RESULTS: The eight patients assigned to immune globulin had a significant improvement in sores of muscle strength (P < 0.018) and neuromuscular symptoms (P < 0.035), whereas the seven patients assigned to placebo did not. With crossovers a total of 12 patients received immune globulin. Of these, nine with severe disabilities had a major improvement to nearly normal function. Their mean muscle-strength scores increased from 74.5 to 84.7, and their neuromuscular symptoms improved. Two of the other three patients had mild improvement, and one had no change in his condition. Of 11 placebo-treated patients, none had a major improvement, 3 had mild improvement, 3 had no change in their condition, and 5 had worsening of their condition. Repeated biopsies in five patients of muscles whose strength improved to almost normal showed an increase in muscle-fiber diameter (P < 0.04), an increase in the number and a decrease in the diameter of capillaries (P < 0.01), resolution of complement deposits on capillaries, and a reduction in the expression of intercellular adhesion molecule 1 and major-histocompatibility-complex class I antigens. CONCLUSIONS: High-dose intravenous immune globulin is a safe and effective treatment for refractory dermatomyositis.

Treatment of inclusion-body myositis with high-dose intravenous immunoglobulin.

We report the treatment of four patients with inclusion-body myositis (IBM) and severe slowly progressive weakness using high-dose intravenous immunoglobulin (IVIg). After two monthly infusions, the strength of the proximal and less atrophic muscle groups improved or normalized in three of the four patients. The improvement lasted from 2 to 4 months. Intravenous immunoglobulin is the first treatment modality to improve the strength of some muscles in patients with this disabling inflammatory myopathy. In view of the high cost of IVIg, the unexpected but encouraging results from this pilot study warrant a controlled trial.

Treatment of autoimmune neuromuscular diseases with high-dose intravenous immune globulin.

The majority of autoimmune neuromuscular diseases fall into three groups: 1) The autoimmune neuropathies, which include the acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome), the chronic inflammatory demyelinating polyneuropathy, the paraproteinemic polyneuropathies, and the anti-GM1-associated motor neuropathies with conduction block; 2) the inflammatory myopathies, which include the dermatomyositis and polymyositis complex; and 3) the autoimmune neuromuscular junction defects, which include myasthenia gravis, and the Lambert-Eaton myasthenic syndrome. Laboratory and clinical evidence suggests that circulating antibodies or sensitized lymphocytes are operating in the pathogenesis of these conditions. Current immunotherapies include treatment with plasmapheresis, high-dose steroids, or immunosuppressive drugs. Although all of these therapies are effective in a number of patients and for some period of time, they often result in serious side effects that necessitate their discontinuation. The need for safer and more effective therapies in the treatment of these conditions prompted the use of high-dose i.v. immune globulin (IVIG). A number of small trials and a few reports suggest that IVIG is safe and effective in the treatment of patients with autoimmune neuropathies, inflammatory myopathies, and myasthenia gravis unresponsive to conventional therapies. We will present current experience with IVIG in the above-mentioned autoimmune neuromuscular diseases, and we will stress the need for long-term controlled studies. The possible immunomodulatory action of IVIG in these conditions will also be discussed.

Spontaneous Kearns-Sayre/chronic external ophthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: a slip-replication model and metabolic therapy.

The muscle mitochondria of a patient with Kearns-Sayre/chronic external ophthalmoplegia plus syndrome were found to be completely deficient in respiratory complex I activity and partially deficient in complex IV and V activities. Treatment of the patient with coenzyme Q10 and succinate resulted in clinical improvement of respiratory function, consistent with the respiratory deficiencies. Restriction enzyme analysis of the muscle mtDNA revealed a 4.9-kilobase deletion in 50% of the mtDNA molecules. Polymerase chain reaction analysis demonstrated that the deletion was present in the patient's muscle but not in her lymphocytes or platelets. Furthermore, the deletion was not present in the muscle or platelets of two sisters. Hence, the mutation probably occurred in the patient's somatic cells. Direct sequencing of polymerase chain reaction-amplified DNA revealed a 4977-base-pair deletion removing four genes for subunits of complex I, one gene for complex IV, two genes for complex V, and five genes for tRNAs, which paralleled the respiratory enzymes affected in the disease. A 13-base-pair direct repeat was observed upstream from both breakpoints. Relative to the direction of heavy-strand replication, the first repeat was retained and the second repeat was deleted, suggesting a slip-replication mechanism. Sequence analysis of the human mtDNA revealed many direct repeats of 10 base pairs or greater, indicating that this mechanism could account for other reported deletions. We postulate that the prevalence of direct repeats in the mtDNA is a consequence of the guanine-cytosine bias of the heavy and light strands.

Supraspinal modulation of nociception in awake rats by stimulation of the dorsal column nuclei.

Rats with bilateral dorsal column (DC) lesions and chronic placement of stimulating electrodes on DC nuclei (DCN) and sham-operated rats were studied using the tail immersion test for phasic pain and the formalin test for tonic pain. DCN stimulation produced a clear inhibitory effect, through a supraspinal loop, in both phasic and tonic pain in awake rats.