In this uncontrolled study, 104 patients with generalized myasthenia gravis treated with azathioprine for a median period of 29 months (range, 1 month to 12 years) were surveyed for possible adverse reactions. These occurred in 36 patients (35%) in the following order of frequency: hematologic (18%), gastrointestinal (13%), infectious diseases (13%), and elevation of liver enzymes (6%). No allergic skin reactions were observed. Azathioprine had to be discontinued temporarily in a total of 11 patients (11%) because of possible side effects. The cause of death in the nine patients who died during the period of observation (up to 12 years) was related to myasthenic crisis in two patients. In five patients, a malignant tumor was diagnosed (two carcinoma of the prostate, one ovarian carcinoma, one bronchial carcinoma, and one renal lymphoma) after 2.5 years, 6 months, 3 months, 5 years, and 6 years of treatment, respectively. A causal relationship seems unlikely in the first four cases, but cannot be excluded in the one case of late lymphoma.
Zusammenfassung Das Guillain-Barré-Syndrom (GBS), die chronische Polyneuritis (inflammatorische demyelinisierende Polyneuropathie [CIDP]), die multifokale motorische Neuropathie (MMN) und die paraproteinämischen Polyneuropathien sind behandelbare immunvermittelte Neuropathien. Beim GBS sind Plasmapherese und intravenöse Immunglobuline (IVIG) in der Akutphase in gleichem Maße wirksam. Patienten mit CIDP und MMN benötigen ne ben der Akuttherapie längerfristige Behandlungsmaßnahmen. Im Gegensatz zur CIDP, die sowohl auf polyvalente intravenöse Immunglobuline (IVIG) als auch auf Kortikosteroide gut anspricht, sind bei der MMN IVIG das Mittel der ersten Wahl. Für die Langzeittherapie sind immunsuppressive Therapien von Bedeutung, wobei jedoch kontrollierte Studien zum Einsatz dieser Medikamente bei immunvermittelten Neuropathien weitgehend fehlen. Für die paraproteinämischen Neropathien gelten ähnliche Behandlungsstrategien wie für die CIDP, wobei allerdings die Polyneuropathie mit Antikörpern gegen Myelinassoziiertes Glykoprotein (MAG) eine Sonderstellung einnimmt. Hier sind starke Immunsuppressiva nötig. Neuere Strategien wie der Einsatz von Antikörpern gegen CD20 sind hier Erfolg versprechend.
The neuropeptide Substance P (SP) has been recognized to modulate functional activities of inflammatory cells. We have previously shown that it mediates macrophage activation. In this study we examined binding characteristics of SP and searched for additional evidence of heightened metabolic activity of guinea pig peritoneal macrophages upon challenge with this peptide. Radioligand studies indicated the existence of a homogeneous class of specific binding sites with high affinity for SP on macrophages. Scatchard analysis yielded an apparent KD of 1.9 +/- 0.4 X 10(-8) M (range: 1.4 to 2.4 X 10(-8) M), which was confirmed by kinetic studies. Binding was dose related, saturable, reversible, and could be inhibited by the SP antagonist (D-Pro2,D-Phe7,D-Trp9)-SP. Examination of peptide structural requirements revealed that both the COOH- and NH2-terminus contribute to receptor-ligand interaction. Other members of the tachykinin group of peptides were devoid of stimulatory action on macrophages. Cellular responses after engagement of the receptor sites by SP included downregulation of the membrane-associated enzyme 5'-nucleotidase and stimulation of synthesis and release of arachidonic acid metabolites, as well as of the lysosomal enzyme ADGase. These actions were specific as evidenced by immunoabsorption experiments. Our findings demonstrate that macrophage activation afforded by SP is effected through a receptor-mediated mechanism. Liberation of proinflammatory and immunomodulating substances in response to SP may be relevant to the pathogenesis of neuroinflammatory disease.
Autoimmune helper T lymphocytes were selected from the blood of two myasthenic patients of different HLA-DR type, using acetylcholine receptor (AChR) from Torpedo californica. These polyclonal T cell lines were tested for reactivity with three synthetic peptides corresponding to the NH2-terminal region of the human AChR alpha subunit. This segment is a good candidate for T cell epitopes since it has a propensity to form an amphipathic alpha helix. The peptides elicited 10-30% of the response induced by native Torpedo AChR. Different peptides were recognized by the autoreactive T cells of the two patients. These results suggest that the NH2-terminal region of the AChR alpha chain contains T cell-stimulating epitopes, and that the T cell autoimmune response in myasthenia gravis, like the B cell response, is heterogeneous.
