A clinical therapeutic trial of cyclosporine in myasthenia gravis.

We randomly assigned 39 patients with steroid-dependent generalized myasthenia gravis to treatment with cyclosporine (5 mg/kg per body weight in divided doses) or placebo. Duration of treatment was 6 months. Patients were evaluated monthly. Primary measures of efficacy were quantified strength testing, antihuman acetylcholine receptor antibody titer, and dosage of corticosteroid medication. At the end of the study, patients in the cyclosporine group had significantly greater improvement in strength (p = 0.004) and a reduction in antireceptor antibody titer (p = 0.01). Percentage reduction of steroid medication was greater in the cyclosporine group, although the difference was not statistically significant (p = 0.12). There were no treatment failures, and there was one drug failure in the cyclosporine group. In the placebo group, there were three treatment failures. No significant nephrotoxicity was noted at this dosage during the first 6 months. During the subsequent 18 months of open-label therapy, continued reduction in steroid dosage occurred. Cumulative side effects, however, caused 35% of patients to discontinue the medication; 10% did so secondary to slowly progressive nephrotoxicity.

Immunointervention with cyclosporin A in autoimmune neurological disorders.

Cyclosporin A has proven a remarkably effective compound in suppressing disease activity in a number of animal models of autoimmune neurological disorders. During the last decade a number of controlled clinical trials have been carried out in human neurological disorders which are considered to be immune-mediated. The results of those trials are reviewed.

Cyclosporine-induced sympathetic activation and hypertension after heart transplantation.

BACKGROUND: Hypertension is a frequent complication of cyclosporine-induced immunosuppression, but the underlying mechanism is unknown. In anesthetized animals, the administration of cyclosporine increases sympathetic-nerve discharge, which may contribute to hypertension. METHODS: To determine whether cyclosporine-induced hypertension is accompanied by sustained sympathetic neural activation in patients, we recorded sympathetic action potentials using intraneural microelectrodes (in the peroneal nerve) in heart-transplant recipients receiving azathioprine and prednisone alone (n = 5) or in combination with cyclosporine (n = 14). We performed the same studies in eight patients with myasthenia gravis who were receiving cyclosporine and eight who were not, in five patients with essential hypertension, and in nine normal controls. RESULTS: Heart-transplant recipients receiving cyclosporine had higher mean arterial blood pressure (+/- SE) than those not receiving cyclosporine (112 +/- 3 vs. 96 +/- 4 mm Hg; P less than 0.05) and a 2.7-fold higher rate of sympathetic-nerve firing (80 +/- 3 vs. 30 +/- 4 bursts per minute; P less than 0.05). For patients with myasthenia gravis, similar doses of cyclosporine were associated with smaller elevations in mean arterial blood pressure (100 +/- 2 mm Hg, as compared with 91 +/- 4 mm Hg in those not receiving cyclosporine; P less than 0.05) and in the rate of sympathetic-nerve firing (46 +/- 3 bursts per minute, as compared with 25 +/- 4 bursts per minute; P less than 0.05). Sympathetic activity in patients with heart transplants or myasthenia gravis who were not being treated with cyclosporine was no different from that in patients with essential hypertension or in normal controls. CONCLUSIONS: Cyclosporine-induced hypertension is associated with sympathetic neural activation, which may be accentuated by the cardiac denervation that results from heart transplantation.

Humoral factors in inflammatory disorders of the central and peripheral nervous system.

The immune-mediated disorders of the central and peripheral nervous systems all involve humoral mechanisms in which immunoglobulin, complement and/or other mediators are implicated. The disorders can be characterized by pattern of disease activity, site of immunoglobulin synthesis, humoral mechanism of injury, and presence of one or more concurrent cellular mechanisms of injury. Control of the humoral responses is presumably T-cell dependent. While these disorders should be viewed as having both humoral and cellular components, the specific components of each disorder might predict the response to specific therapeutic approaches.

Comparison and standardization of measurement of anti-acetylcholine receptor antibody between laboratories.

The presence of autoantibodies to the acetylcholine receptor (anti-AChR) is useful in the diagnosis of myasthenia gravis, and their titre correlates with severity of the disease. Standardization of their measurement is therefore clinically important. Six laboratories world-wide were asked to determine anti-AChR under local conditions in coded samples and to repeat the measurement on the same samples recorded. There was a high degree of consensus over rank order of the samples but a wide systematic variation in the titres obtained. Standardization of units is an important next step in improving the comparability of anti-AChR data between laboratories.

Preliminary results of a double-blind, randomized, placebo-controlled trial of cyclosporine in myasthenia gravis.

We randomly assigned 20 patients with progressively worsening generalized myasthenia gravis of recent onset whose illness was not controlled by anticholinesterase therapy to treatment with either cyclosporine (6 mg per kilogram of body weight per day) or placebo. Patients who had been treated with thymectomy, steroids, or other immunosuppressive agents were excluded. The duration of treatment was 12 months. Disease activity was assessed by quantified strength testing and by measurements of antihuman acetylcholine-receptor antibody. Patients were assessed at 6 months and 12 months, or at the following early end points: drug failure (doubling of creatinine), treatment failure (respiratory or swallowing difficulty), or protocol violation (stopping medication for more than five days). At six months, patients in the cyclosporine group had had significantly more objective improvement in strength; one early end point had been reached (drug failure; no treatment failures). In the placebo group, three early end points had been reached (all treatment failures). The decline in titers of acetylcholine-receptor antibody was larger in the treated group, although the difference was not statistically significant. At the end of the study (after 12 months of treatment or arrival at an earlier end point), improvement in strength and reduction in titers of anti-receptor antibody continued to be greater in the cyclosporine group. Nephrotoxicity occurred in three patients receiving cyclosporine but was nonprogressive with a reduction in dosage and reversible with discontinuation of the drug. These results are preliminary and need confirmation, but we conclude that cyclosporine is probably an effective therapy in some patients with myasthenia gravis.

Assessment of therapeutic plasmapheresis in demyelinating neurologic disorders.

Considerable controversy exists with regard to therapeutic efficacy of plasmapheresis in the immune-mediated demyelinating disorders of the peripheral and central nervous system: acute inflammatory polyneuropathy (Guillain-Barré syndrome), chronic inflammatory demyelinating polyneuropathy, and multiple sclerosis. In an effort to establish specific situations where plasmapheresis was of therapeutic value, we reviewed the experience at Southwestern Medical School, University of Texas Health Science Center at Dallas, and that published in the literature. In acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome), plasmapheresis may prevent progression of the illness, and it significantly increases the rate of recovery. For patients with chronic inflammatory polyneuropathy, plasmapheresis has produced clinical improvement in 50% of corticosteroid-refractory patients. The use of plasmapheresis in patients with acute or chronic progressive multiple sclerosis still remains controversial.

Immune regulation in myasthenia gravis: evidence for an increased suppressor T-cell population.

The production of anti-acetylcholine receptor antibodies in myasthenia gravis represents a persistent and unexplained break in self-tolerance. The studies reported here demonstrate an altered regulatory T-cell population with an increase in the percentage of circulating T-suppressor cells as defined by two independently developed murine monoclonal antibody markers. Leu 2a- and OKT8a-positive cells were significantly increased within the T-cell population in myasthenia gravis (25.0 +/- 6.4% versus 20.7 +/- 2.9% and 34.9 +/- 7.0% versus 26.0 +/- 3.2%, respectively) compared to an age- and sex-equivalent group. In addition, the circulating total T-cell population was reduced in myasthenia gravis. Patients with symptomatically uncontrolled disease (with or without immunosuppression) demonstrated significantly altered ratios of helper to suppressor T-cells, while patients whose myasthenia symptoms were controlled did not differ from normal subjects.

Plasmapheresis in multiple sclerosis: prospective trial of pheresis and immunosuppression versus immunosuppression alone.

A prospective trial of plasmapheresis and azathioprine or azathioprine alone was carrier out on 20 patients with chronic progressive MS. Seven of 10 patients in each group continued therapy for 12 months. When the groups were compared by disability ratings, the combination of plasmapheresis and azathioprine was no better than azathioprine alone. Transient subjective improvement occasionally followed plasmapheresis, but no objective improvement was documented.

Sources of error in the diagnosis of Guillain-Barre syndrome.

A careful monitoring of the accuracy of diagnosis in six cases of Guillain-Barre syndrome has shown that a substantial proportion of these patients initially diagnosed as having Guillain-Barre syndrome on the basis of characteristic clinical findings and an elevated level of protein in the spinal fluid had a neuropathy caused by another etiology. The pitfalls in the laboratory and clinical diagnosis of disorders that were confused with Guillain-Barre syndrome were several: the pattern of neurological dysfunction in the Guillain-Barre syndrome was not unique to that disorder; no specific laboratory test existed to confirm the diagnosis of Guillain-Barre syndrome; and the laboratory diagnosis of other causes of similar neurological disorders (especially heavy metal intoxication) depended upon tests that are very unreliable.

Humoral immunity in myasthenia gravis: biochemical characterization of acquired antireceptor antibodies and clinical correlations.

The titer and characteristics of antiacetylcholine receptor antibody (AChR-Ab) were investigated in 184 patients with myasthenia gravis. Mean AChR-Ab titers of each clinical grade increased with the severity of the disease. AChR-Ab was always of an IgG class. IgM (5 of 92) and IgA (2 of 48) class AChR-Ab were detected, but only concurrently with IgG and in low concentrations. IgG subclass 3 was not prominent. In 3 patients with AChR-Ab titers in the normal range, blockade of bungarotoxin binding to receptor could still be demonstrated. AChR-Ab from 6 patients was heterogeneous in affinity for receptor, reactivity from human ocular and gastrocnemius muscle, and blockade ot toxin binding. AChR-Ab was oligoclonal in 4 of 6 patients, as shown by concurrent production of AChR-Ab IgG of both kappa and lambda types. Amniotic fluid and fetal cord serum did not interfere with antibody-receptor interaction. Variation in the pattern of weakness among patients was a function of both the heterogeneity of AChR antibodies and the antigenic uniqueness of receptor complexes from different human muscles.

A rapid immunoadsorbent radioimmunoassay for anti-acetylcholine receptor antibody.

Antibody to the human nicotinic acetylcholine receptor has been demonstrated in the disorder myasthenia gravis and is the pathologic factor producing the characteristic symptoms of the disorder. A rapid, quantitative and sensitive radioimmunoassay using human acetylcholine receptor, affinity labeled with iodinated alpha-bungarotoxin, and utilizing the immunoadsorbent protein A-bearing Staphylococcal aureus is described. The assay has proven as effective and more efficient than double antibody immunoprecipitation assays in diagnostic screening, evaluation of various forms of therapy, determining kinetics of receptor and antibody interaction, and the production of antireceptor antibody by peripheral blood lymphocytes in culture.

Humoral immunity in myasthenia gravis: clinical correlations of anti-receptor antibody avidity and titer.

Antibody to human acetylcholine receptor (AChR Ab) in myasthenia gravis (MG) correlates with clinical (Osserman) classification. Patients in remission R) or with ocular only (I) symptoms differed significantly from those with generalized disease (IIA, IIB, III, IV) (p less than 0.01, p less than 0.05 respectively). Patients with mild generalized disease (IIA) differed significantly from those with acute severe (III) or chronic severe (IV) disease (p less than 0.01). However, within each clinical class titers ranged over two or three orders of magnitude. This variation in AChR Ab titer for patients with similar diseases severity was not explained by differences in immunoglobulin class. All patients produced IgG AChR Ab and occasional patients produced IgM or IgA at less than 10% of their IgG titer. No IgM to IgG switch was identified. In MG patients negative for AChR Ab by immunoprecipitation assay, blockade of toxin binding to extracted human AChR could still be identified indicating antibody specificity to the toxin binding site. The avidity of AChR Ab for receptor assayed in six myasthenic patients with differing severities of disease, varied widely with T1/2 (time to half-maximal binding) ranges from 25 to 81 minutes. However, differences in AChR Ab avidity did not explain differences in severity of disease in patients with similar titers. AChR Ab was fractionated in six patients into IgG kappa and IgG lambda; in four patients AChR Ab activity could be demonstrated in both fractions. Thus, differences among MG patients as a group are due to production of several AChR Ab idiotypes, with individual patients being oligoclonal or polyclonal as well. Differences in IgG subclass (complement fixation) and site of attachment of AChR Ab to receptor subunits may resolve these differences.