Cyclosporine A for CIDP

ABSTRACT & COMMENTARY

Source: Barnett MH, et al. Cyclosporine A in resistant chronic inflammatory demyelinating polyneuropathy. Muscle Nerve 1998;21:454-460.

Nineteen patients with chronic inflammatory demyelinating polyneuropathy (CIDP) unresponsive to oral corticosteroids, plasma exchange, intravenous immunoglobulin, azathioprine (n = 9), cyclophosphamide (n = 4), and total body lymphoid irradiation (n = 1), were retrospectively reviewed following treatment with Cyclosporine A (CsA). Nine men and ten women were included, with mean age at onset of 42.5 years, ranging from 19 to 68 years. Thirteen patients demonstrated a progressive course of disease, the remaining being relapsing in nature. Patients were followed with monthly neurological examinations for the first six months and then every 3-6 months. Nerve conduction studies were performed at six-month intervals. Functional status served as the primary outcome measure for the progressive CIDP group and was graded using a five-point scale: 0 = normal; 1 = symptoms or signs but not both; 2 = mild symptoms and signs; 3 = moderate symptoms and signs; 4 = requires assistance in activities of daily living; 5 = non-ambulant. Mean annual relapse incidence was the primary outcome measure for the relapsing CIDP patients. Renal function was carefully followed throughout.

Over an average follow-up of 4.9 years, CsA resulted in a mean improvement of 2.1 grades in the functional status of the 13 progressive CIDP patients, with six going from grade 4 or 5 to grade 0-2. An additional six improved one grade, and one patient required 50% fewer plasma exchanges to maintain his neurological status. Over an average follow-up of 7.3 years in the relapsing group, CsA resulted in a mean of 0.2 ± 0.4 relapses per year, compared to 1.0 ± 0.5 per year during the preceding 6.5 years, with three patients becoming relapse free and off all other CIDP treatment once CsA was begun. Clinical improvement was in all instances accompanied by physiologic improvement on nerve conduction studies.

Two patients required CsA dose reduction, and an additional two required CsA cessation due to nephrotoxicity. Hypertension developed in four, but resolved in two with discontinuation of CsA. Nausea (n = 3), edema (n = 3), and hirsutism (n = 4) did not require withdrawal of CsA. When initial dosage of CsA was compared, only 36% who began at a dose of 3-7 mg/kg/d developed side effects, compared to 89% whose beginning dose exceeded 7 mg/kg/d. With careful monitoring of renal function, CsA is a potent and relatively safe alternative for refractory CIDP.

COMMENTARY

Upwards of 30% of CIDP patients remain refractory to conventional treatments, underscoring the importance of investigating new avenues of therapy (Hahn F, et al. Brain 1996;119:1055-1066). Recently, in an open-label prospective trial, interferon- (IFN) alpha resulted in clinical improvement in nine of 16 patients (56%), as measured by mean MRC and sensory scores (Gorson KC, et al. Neurology 1998;50:84-87). Its mechanism of action in CIDP, as well as that of CsA, remains uncertain, but IFN alpha has multiple functional effects on various cell types, including reducing levels of mRNA for proinflammatory cytokines, such as tumor necrosis factor, which are elevated in CIDP (Hartung HP, et al. Ann Neurol 1991;30:48-53). Surprisingly, in the 16 study patients, IFN treatment resulted in a further increase of an already elevated level of tumor necrosis factor, suggesting that improvement resulted along other mechanistic pathways, possibly upregulation of immunosuppressive cytokine TGF-beta, upregulation of expression of adhesion molecules, or downregulation of MHC class II expression (Gutterman JU. Proc Natl Acad Sci USA 1994;91:1198-1205). Interleukin-2 (IL-2) is also involved in cytokine generation, and its production by CD4+ T-cells is blocked by CsA. Reduced IL-2 thus impedes activated T-cell subset proliferation, blocks macrophage activation, and may explain the beneficial effect of CsA in CIDP. -mr