Arthritis during interferon beta-1b treatment in multiple sclerosis

Interferon beta (IFN-beta) is the most widely prescribed disease-modifying drug for multiple sclerosis (MS). Therapy with IFN-beta may be associated with a number of adverse reactions The development or exacerbation of other autoimmune diseases is a rare but reported side effect of IFN-beta therapy. In this case report, we present clinical and laboratory findings of two MS patients who developed arthritis during IFN-beta1b treatment, probably of autoimmune origin.     

Immunomodulatory effects of interferon beta-1a in multiple sclerosis

Several studies have established a role for interferon beta (IFNbeta) as a treatment for relapsing-remitting multiple sclerosis (MS). IFNbeta has been reported to decrease the relapse rate, relapse severity, progression of disability and development of new brain lesions. Its mechanisms of action, however, remain unclear. We hypothesize that immunomodulatory effects of IFNbeta may underlie its clinical efficacy. We used intracellular cytokine flow cytometry to analyze the effects of IFNbeta-1a on expression of the anti-inflammatory cytokine, IL-10, and its effects on major co-stimulatory molecules in MS patients. We found that peripheral blood mononuclear cells (PBMC) produced more IL-10 following in vitro or in vivo treatment with IFNbeta-1a. The primary cellular sources of IL-10 were monocytes and CD4(+) T lymphocytes. IL-10 production in response to IFNbeta-1a was increased in unseparated PBMC compared to purified lymphocyte cultures, indicating that interaction between monocytes and lymphocytes may influence IL-10 production in response to IFNbeta-1a. Using flow cytometry, we monitored the ex vivo expression of two major co-stimulatory pairs-B7/CD28 and CD40/CD40L-before and after intramuscular IFNbeta-1a treatment of MS patients. IFNbeta-1a lowered the expression of B7.1 on circulating B cells and increased B7.2 expression on monocytes. CD40 expression on B cells was down-regulated, but CD40 on monocytes was up-regulated by IFNbeta-1a treatment. These data suggest that co-stimulatory molecules are modulated by IFNbeta, providing a possible mechanism for its in vivo immune regulatory effects.     

Autoimmune events during interferon beta-1b treatment for multiple sclerosis

Autoimmune events, although rarely reported during interferon beta-1b (IFNB) treatment of relapsing-remitting (RR) multiple sclerosis (MS), may be more frequent than expected due to the many immunologic abnormalities associated with this disease. We report the prospective two-year follow-up of autoimmune events in 40 RR MS patients treated with IFNB and in 21 untreated MS controls. Thyroid and liver function and serum level of 12 autoantibodies (autoAbs) against organ- (thyroid, gastric, pancreatic) and non-organ-specific antigens were serially monitored. In contrast to control patients, autoAbs (anti-nuclear, -smooth muscle or -thyroid antigens) were detected in 13 IFNB-treated patients, and these were associated with thyroid or liver function alteration in many cases. Persistent autoimmune thyroid dysfunction occurred in three IFNB-treated patients, all of whom were women with a familial history of thyroid disease or baseline anti-thyroid autoAb positivity. For improvement of the MS relapse rate, thyroid dysfunction was adequately treated without stopping IFNB. Liver function alteration (17 IFNB-treated patients, associated with non-organ-specific autoAbs in four) was transient and did not require IFNB treatment to be stopped, with the exception of one patient who was already suffering from a drug-induced hepatopathy at baseline. During the IFNB treatment of MS, several autoimmune events may occur, indicating that thyroid and liver function and autoAbs must be carefully monitored.     

Response to interferon beta-1a treatment in African American multiple sclerosis patients

BACKGROUND: African Americans (AAs) with multiple sclerosis (MS) seem to have a more severe disease course than white Americans (WAs). To our knowledge, it is not known to what extent treatment with interferon beta-1a will effect the MS disease course within the AA population. OBJECTIVE: To compare the response to treatment with interferon beta-1a between AA and WA MS patients. DESIGN: This is an exploratory post hoc analysis of the Evidence of Interferon Dose-Response: European North American Comparative Efficacy (EVIDENCE) study. SETTING: The EVIDENCE study is a randomized controlled trial that compared the efficacy of once weekly, intramuscular, 30-microg interferon beta-1a treatment with thrice weekly, subcutaneous, 44-microg interferon beta-1a therapy in treatment-na?ve MS subjects. PARTICIPANTS: Thirty-six AA subjects were compared with 616 WA subjects. MAIN OUTCOME MEASURES: The number of MS exacerbations, the proportion of exacerbation-free subjects, and the number of new MS lesions present on brain magnetic resonance imaging were compared between AA and WA subjects at 24 and 48 weeks after initiating treatment with interferon beta-1a. RESULTS: The AA subjects experienced more exacerbations and were less likely to remain exacerbation free (statistical trends). The AA subjects developed more new MS lesions on T2-weighted brain magnetic resonance imaging at 48 weeks (P = .04). CONCLUSIONS: Despite the small sample size, AA subjects appeared less responsive to treatment than WA subjects on outcome measures, reaching significance only for T2-weighted lesion count at 48 weeks. However, it is difficult to base these differences solely on response to treatment given the potential differing in MS disease course in AA patients.     

Down-regulation of survivin expression in T lymphocytes after interferon beta-1a treatment in patients with multiple sclerosis

BACKGROUND: Treatment with interferon beta reduces clinical exacerbations in multiple sclerosis (MS) through several immunomodulatory mechanisms that involve the augmentation of programmed cell death (apoptosis) of peripheral T lymphocytes. The expression of survivin, a cell cycle-regulated antiapoptosis protein, is up-regulated in mitogen-stimulated T lymphocytes from patients with MS, and this expression correlates with MS disease activity. OBJECTIVE: To evaluate the effect of interferon beta on the expression of survivin and other apoptosis regulatory molecules in peripheral T lymphocytes from patients with MS. PATIENTS AND METHODS: In a prospective, combined clinical and immunologic study, we evaluated the expression of survivin, Bcl-2 protein, and the death receptor Fas in mitogen-stimulated T lymphocytes from 26 patients with MS, before and serially after treatment with interferon beta-1a. We also investigated the long-term effects of interferon beta-1a on cellular expression of these proteins and T-lymphocyte apoptosis in a cross-sectional study of 19 patients with MS receiving long-term interferon beta-1a therapy. RESULTS: Treatment with interferon beta-1a reduced the expression of survivin in in vitro stimulated T lymphocytes. This reduced expression correlated with augmented T-cell susceptibility to apoptosis and with clinical response to treatment. In contrast, interferon beta-1a therapy did not significantly alter cellular expression of Bcl-2 protein or Fas. This down-regulatory effect of interferon beta-1a on cellular expression of survivin was maintained after long-term therapy. CONCLUSIONS: Our observations suggest that interferon beta exerts a regulatory effect on peripheral T lymphocytes through an antiapoptosis mechanism that involves the down-regulation of cellular survivin expression.     

Treatment of early onset multiple sclerosis with subcutaneous interferon beta-1a

The authors studied the tolerability of subcutaneous interferon beta-1a (IFNbeta-1a) in 51 patients with early-onset multiple sclerosis. The most frequent systemic adverse effects were flu-like symptoms in 65%. Laboratory abnormalities included asymptomatic leukopenia (27%) and elevated hepatic transaminases (35%). Treatment with IFNbeta-1a was safe and well tolerated in the majority of children and adolescents.     

Course of depression during the initiation of interferon beta-1a treatment for multiple sclerosis.

OBJECTIVE: To examine the hypothesis that increases in depression after initiation of treatment with interferon beta-1a for multiple sclerosis can be explained as representing a return to pretreatment levels of depression. DESIGN: Level of depression in patients with multiple sclerosis was assessed at 3 time points: 2 weeks before initiation of interferon beta-la treatment, at initiation of treatment, and at 2-month follow-up. SETTING: A health maintenance organization. PATIENTS: Fifty-six patients with confirmed relapsing forms of multiple sclerosis. MAIN OUTCOME MEASURE: The depression-dejection scale of the Profile of Mood States. RESULTS: Patients who scored high on the depression measure 2 weeks before the initiation of interferon beta-1a treatment showed significant reduction in depression at the initiation of treatment. However, depression returned nearly to initial levels within 2 months. CONCLUSIONS: These findings suggest that increases in depression after initiation of interferon beta-1a treatment are related to level of depression 2 weeks before initiation of treatment. Physicians should assess history of depression for all patients in whom interferon beta-1a treatment is initiated. Patients with a recent history of depression are at risk for increased depression within 2 months after starting interferon beta-1a treatment, even though they may not be depressed at the time of treatment initiation.     

Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis

The accepted standard treatment of relapsing multiple sclerosis consists of medications for disease symptoms, including treatment for acute exacerbations. However, currently there is no therapy that alters the progression of physical disability associated with this disease. The purpose of this study was to determine whether interferon beta-1a could slow the progressive, irreversible, neurological disability of relapsing multiple sclerosis. Three hundred one patients with relapsing multiple sclerosis were randomized into a double-blinded, placebo-controlled, multicenter phase I11 trial of interferon beta-la. Interferon beta-la, 6.0 million units (30 μg), was administered by intramuscular injection weekly. The primary outcome variable was time to sustained disability progression of at least 1.0 point on the Kurtzke Expanded Disability Status Scale (EDSS). Interferon beta-la treatment produced a significant delay in time to sustained EDSS progression (p equals; 0.02). The Kaplan-Meier estimate of the proportion of patients progressing by the end of 104 weeks was 34.9% in the placebo group and 21.9% in the interferon beta-la-treated group. Patients treated with interferon beta-la also had significantly fewer exacerbations (p = 0.03) and a significantly lower number and volume of gadolinium-enhanced brain lesions on magnetic resonance images (pvalues ranging between 0.02 and 0.05). Over 2 years, the annual exacerbation rate was 0.90 in placebo-treated patients versus 0.61 in interferon beta-la-treated patients. There were no major adverse events related to treatment. Interferon beta- la had a significant beneficial impact in relapsing multiple sclerosis patients by reducing the accumulation of permanent physical disability, exacerbation frequency, and disease activity measured by gadolinium-enhanced lesions on brain magnetic resonance images. This treatment may alter the hndamen- tal course of relapsing multiple sclerosis.     

Widespread maculopapular rash due to intramuscular interferon beta-1a during the treatment of multiple sclerosis

We describe a 41-year-old woman with multiple sclerosis, who presented erythematous maculopapular rash on the trunk and extremities after the second injection of interferon beta-1a. Histopathologic examination of the lesion revealed lymphocytic exocytosis and perivascular lymphocytic infiltrate in the dermis. Oral antihistamine and topical corticosteroid was started. After improvement of the lesions, the third injection was performed. However, the same reaction occurred. A prick test, which was performed 6 weeks after the eruption, also revealed positive reaction. Although injection-site reactions have been observed with interferon beta-1a, to our knowledge there have been no previous reports of interferon beta-1a-induced widespread cutaneous reaction.     

Eight-year immunogenicity and safety of interferon beta-1a-Avonex treatment in patients with multiple sclerosis

An open-label extension study of the phase III trial of intramuscular interferon beta-1a (IFNbeta-1a-Avonex) was conducted to evaluate the immunogenicity and safety of IFNbeta-1a-Avonex over six years in patients with relapsing multiple sclerosis (MS). Patients who participated in the pivotal phase III study were offered enrolment; entry was also open to patients who had not participated. All patients received IFNbeta-1a-Avonex 30 microg intramuscularly once weekly for six years, for a treatment duration of up to eight years in patients who received IFNbeta-1a-Avonex in the phase III trial. Serum levels of IFNbeta antibodies were measured every six months using a screening enzyme-linked immunosorbent assay (ELISA) followed by an antiviral cytopathic effect assay to detect neutralizing antibodies (NAbs) in serum samples positive on ELISA. The incidence of adverse events and laboratory test results assessed safety. Of 382 total patients, 218 had participated in the phase III study (103 placebo, 115 IFNbeta-1a-Avonex) and 164 had not participated; 24 of the 164 were IFNbeta-na?ve. At baseline, 281 patients were negative for IFNbeta antibodies (NAb-). NAbs (titre > or = 20) developed at any time over six years in 5% of these patients. Of 140 patients who had been on IFNbeta-1b-Betaseron, 49 were positive for NAbs (NAb+) at baseline; 11 of 115 who had been on IFNbeta-1a-Avonex were NAb+ at baseline. Thirty-nine of 49 patients who had been on Betaseron and were NAb+ had titres < 100; 36 of these 39 seroconverted to NAb- while on IFNbeta-1a-Avonex, with a median time of approximately six months. Ten patients who had been on Betaseron had NAb titres > or = 100; five remained NAb+ during six years on IFNbeta-1a-Avonex and five seroconverted to NAb-, but only after at least two years. Five patients who had been on IFNbeta-1a-Avonex during the clinical trial were NAb+ with titres < 100 at baseline; four seroconverted to NAb-, with a median time of two to three years. Six patients who had been on IFNbeta-1a-Avonex had NAb titres > or = 100; five of these remained NAb+ at six years. No patient with a NAb titre > 1000 seroconverted to NAb-, whether initially treated with IFNbeta-1a-Avonex or -Betaseron. Adverse events were similar to those observed in the pivotal phase III trial. Results from this trial indicated that IFNbeta-1a-Avonex was associated with a low incidence of NAbs and was well tolerated for up to eight years. Further, the results indicate that persistence of NAbs is dependent on titre and IFNbeta product.