Interferon for Chronic Demyelinating Motor Neuropathy
Interferon for Chronic Demyelinating Motor Neuropathy
abstract & commentary
Source: Martina ISJ, et al. Chronic motor neuropathies: response to interferon-ß1a after failure of conventional therapies. J Neurol Neurosurg Psychiatry 1999;66:197-201.
In this prospective, open-label, preliminary study, interferon beta-1a (INF-beta-1a) was administered to three patients with multifocal motor neuropathy (MMN) and one with chronic inflammatory demyelinating polyneuropathy (CIDP). All had been previously unresponsive, over the course of 7-9 years, to conventional therapy including prednisone, plasma exchange, intravenous immunoglobulin, or cyclophosphamide. Patients were treated with interferon beta-1a subcutaneously three times weekly at a dose of 6 million IU for six months, with an option to continue for another six months if clinical improvement occurred. Primary end points included the nine-hole peg test, 10 meters walking test, and the modified Rankin scale, while the secondary end point was a modified Medical Research Council (MRC) sumscore. Statistical analysis included conventional linear and linear spline regression.
MRC subscore and time required to perform the nine-hole peg test improved significantly in all patients, and time to walk 10 meters was significantly reduced in all patients by three months. These changes, however, did not necessarily reflect clinically significant improvement, as the modified Rankin score improved in only two patients at six months. Improvement of conduction block on nerve conduction studies was demonstrated only in the CIDP patient, and anti-GM1 titres, present in three patients at entry, remained unchanged. INF-beta-1a was well tolerated with flu-like symptoms, fever, sweats, and injection site erythema disappearing by two months. INF-beta-1a may be somewhat beneficial for acquired, chronic, refractory, demyelinating forms of neuropathy. Controlled double-blind studies are the appropriate next step.
Commentary
At least 12 functional forms of interferon a (IFN-alpha) exist in humans, synthesized predominantly by lymphocytes. This compares to only one antigenically distinct IFN-beta, synthesized by fibroblasts. Both IFN-alpha and IFN-beta, however, operate through a common pathway involving two IFN receptor subunits, two Janus tyrosine kinases (JAK), two signal transducers and activators of transcription (STAT), and the interferon regulatory family (IRF) transcription factor p48 (Stark GR, et al. Annu Rev Biochem 1998;67;227-264). As a first step in the signaling pathway, IFN receptors are dimerized by IFN at the cell membrane, resulting in initiation of the intracellular tyrosine phosphorylation cascade and phosphorylation of STATs. These STATS, in turn, dimerize and become activated for transport into the nucleus where they stimulate transcription by binding to specific DNA sequences. Other pathways also appear to be activated by IFN-alpha and IFN-beta but their physiological roles remain unclear.
Antiviral, antiproliferative, and immunomodulatory functions are induced by interferons. Antiviral mechanisms of IFN action include the dsRNA-dependent protein kinase pathway (affects transcription and translation), the 2-5A synthetase system (cleaves single-stranded RNA), and the Mx protein pathway of IFN-inducible GTPases, which interferes with viral replication at the level of viral transcription (Meurs E, et al. Cell 1990;62:379-390; Carroll SS, et al. J Biol Chem 1996;271:4988-4992). Cancer suppression is affected by IFN through its inhibition of cell growth, which varies with cell type, and through its control of apoptosis. Immunomodulation is predominantly stimulated by IFNg with IFN-alpha and IFN-beta playing more restricted roles, directed largely at resistance to viral infection. All IFNs regulate the expression of major histocompatability complex (MHC) proteins, particularly class I proteins which promote CD8+ T-cell responses, whereas IFNg is unique in its ability to induce MHC class II proteins, thereby enhancing CD4+ T-cell responses. Macrophage activation is another IFNg-unique activity, not provided by IFN-alpha and IFN-beta. All IFNs may regulate humoral immunity directly at the B-cell level, including B-cell development and proliferation, immunoglobulin (Ig) secretion, and Ig heavy-chain switching.
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