E. Verdun

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.

Liver and thyroid function and autoimmunity during interferon-β1b treatment for MS

Background: The occurrence or recurrence of autoimmune diseases or of autoantibodies (autoAb) has been reported during type I interferon (IFN) treatment. Objective: To define the frequency of thyroid and liver dysfunction and of autoimmunity during IFN-β1b (IFNB) treatment of MS. Methods: Prospective 1-year multicenter follow-up of 156 patients with MS recruited by 18 centers was conducted. Thyroid-stimulating hormone and anti-thyroid autoAb were measured by an immunoradiometric method, thyroid hormones by chromatographic assay, and non-organ-specific autoAb by indirect immunofluorescence. Tests were repeated every 3 months. The probability of having liver, thyroid, or autoAb alterations was analyzed longitudinally with the generalized estimating equations (GEE) method. Results: Thyroid dysfunction was observed in 5.3% of cases at baseline and 8.3% de novo during IFNB treatment. GEE analysis showed that the probability of having thyroid alteration did not change significantly during treatment compared with baseline. Liver alteration was observed in 4.6% of cases at baseline and 37.5% de novo during IFNB treatment (p < 0.0001). GEE analysis showed that the probability of having liver alteration was higher (p < 0.002) at months 3 and 6 compared with baseline, returning to values similar to baseline by month 9. AutoAb were detected in 16.1% of patients at baseline and in 20% during IFNB. GEE analysis showed that the probability of having autoAb did not change significantly during treatment compared with baseline. Thyroid or liver alteration or autoAb occurring de novo during IFNB were usually transient. Conclusions: Differently from the frequency of liver function alteration (which significantly increased during the first months of IFNB treatment, suggesting a probable causal relationship with IFNB), the frequency of thyroid dysfunction or of autoimmunity showed random and insignificant changes over time, probably not related to IFNB treatment.

Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis (INCOMIN Trial) II: analysis of MRI responses to treatment and correlation with NAb

Background In RRMS, clinical exacerbations are usually associated with different types of active lesions at MRI, including: hyperintense lesions on T1-weighted post-gadolinium sequences; new hyperintense lesions or enlarging old lesions on PD/T2-weighted scans; or new hypointense lesions on T1-weighted pre-Gd sequences. Objective/methods Primary outcome was the occurrence of patients with at least one active MRI lesion of the different types indicated above during treatment with 250 mg every other day (EOD) interferon beta (IFNβ)-1b or 30 mg once weekly (OW) IFNβ-1a in outpatients with RRMS (INCOMIN Trial). Results The number of patients with at least one ‘active’ lesion, evaluated over the two-year follow-up, was significantly (P=0.014) lower in the EOD IFNβ-1b arm (13/76, 17%) then in the OW IFNβ-1a arm (25/73, 34%). NAb frequency over two-year follow-up was 22/65 (33.8%) in the EOD IFNβ-1b arm and 4/62 (6.5%) in the OW IFNβ-1a arm, significantly greater in the EOD IFNβ-1b arm. Conclusions The development of MRI active lesions is strongly reduced by EOD-IFNβ-1b compared with OW-IFNβ-1a, indicating that EOD-IFNβ-1b is more effective than OW-IFNβ-1a in reducing ongoing inflammation and demyelination in MS. Logistic regression showed that NAb status did not affect the risk of MRI activity.

High-dose, frequently administered interferon beta therapy for relapsing–remitting multiple sclerosis must be maintained over the long term: the interferon beta dose-reduction study

Long-term trials have demonstrated the continued efficacy of interferon (IFN) beta treatment in patients with relapsing-remitting (RR) multiple sclerosis (MS) during prolonged administration. The objective of the work was to evaluate the effects of reducing IFN beta administration frequency and total weekly dose in patients with RR MS who have achieved clinical and MRI disease activity stabilization during long-term IFN beta-1b treatment. Prospective 1-year follow-up of 27 RR MS patients on long-term 250 microg every other day (standard dose) IFN beta-1b treatment were randomized either to gradually reduce dose to 30 microg once-a-week IFN beta-1a (13 patients), or to continue on IFN beta-1b standard dose (14 patients). We found significant differences in the two group of patients. In the group of patients continuously treated with IFN beta-1b standard dose, 79% remained relapse free compared to 23% in the group receiving once-weekly IFN beta-1a (p=0.006). The number of patients without new PD/T2 lesions was higher in the group of patients continuously treated with IFN beta-1b standard dose (77%) compared to the once-weekly IFN beta-1a group (23%) (p=0.04). IFN beta is a long-term treatment for MS. The reduction of IFN beta-1b administration frequency and dose is not advisable even in patients free from clinical and MRI disease activity for many years.

Autoantibodies in Multiple Sclerosis Patients Before and During IFN-β1b Treatment: Are They Correlated with the Occurrence of Autoimmune Diseases?

Autoimmune side effects, namely autoantibody (autoAb) occurrence and thyroid function alteration, have been described during interferon-beta (IFN-beta) treatment for multiple sclerosis (MS). AutoAb occurrence and autoimmune thyroid diseases are also frequently detected in MS patients free of any treatment. The aim of this study was to evaluate the relationship between IFN-beta 1b treatment, autoAb occurrence, and autoimmune diseases in MS. Thyroid and liver function and serum autoAb (antithyroid, antinuclear, anti-liver, anti-kidney microsomes, anti-smooth muscle and parietal cell antigens) occurrence were evaluated in 156 relapsing-remitting MS (RRMS) patients before and every 3 months after starting IFN-beta 1b treatment (8 MIU subcutaneously [s.c.] on alternate days). The probability of having liver or thyroid function alteration or autoAb occurrence was analyzed longitudinally with the generalized estimating equations (GEE) approach. At baseline, 16.1% of patients had autoAb. During treatment, autoAb occurred de novo in 7.2% of patients. GEE analysis showed that the probability of having autoAb at any time during IFN-beta 1b treatment did not change significantly compared with baseline. AutoAb occurring de novo rarely persisted during treatment and significantly less than those already present at baseline. Positivity for autoAb at baseline or during treatment was not correlated with the development of thyroid or liver function alteration during IFN-beta 1b treatment. Our study indicates that IFN-beta treatment is a safe treatment for MS patients, free of risk of autoimmunity and of associated liver or thyroid function alteration.

Thyroid function and anti-thyroid antibodies in MS patients screened for interferon treatment. A multicenter study

Interferon beta (IFNB) treatment for multiple sclerosis (MS) has been associated with thyroid disorders (TD), in particular in patients with subclinical TD or anti-thyroid (AT) autoantibodies (autoAb) before starting treatment. TD and AT autoAb frequency was reported increased in MS. To determine whether MS patients have subclinical thyroid function abnormalities or anti-thyroid autoimmunity predisposing to develop TD, we performed a prospective multicenter screening of thyroid function and autoimmunity in 152 relapsing-remitting (RR) MS patients selected to receive IFNB treatment and in 437 healthy normothyroidal controls. Thyroid-related hormones and anti-thyroid microsomal antigen (anti-TMA) autoAb were tested with sensitive immunoradiometric or chromatographic assays. Cases were stratified for different progressively decreasing or increasing cutoff values of thyroid-stimulating hormone (TSH) (0.3, 0.2, 0.1, 3 and 5 mIU/l), and odds ratios (OR) with 95% confidence intervals (CI) calculated using logistic regression adjusted for gender, age, and anti-TMA autoAb positivity. The frequency of cases below or above the TSH cutoff values was not significantly different in MS patients and controls, and the risk to have an abnormal TSH level was not significantly increased in MS patients (OR ranging 0.37-0.84; CI, 0.05-3.01), even if anti-TMA autoAb positive (OR ranging 0.35-0.85; CI, 0.04-3.00). Frequencies of subclinical hypothyroidism and of anti-TMA autoAb positivity were, however, trending higher in MS men (ranging 5-7%) than in controls (3%). MS patients do not have an increased risk of subtle thyroid function abnormalities, subclinical TD, or anti-TMA autoAb positivity that may predispose to develop thyroid dysfunction during IFNB treatment. The positive trend for subclinical hypothyroidism and anti-TMA autoAb positivity, however, advises a longitudinal study of thyroid function and autoimmunity during IFNB treatment to see whether patients with baseline subclinical thyroid dysfunction develop clinically significant alteration during treatment.

The OPTimization of Interferon for MS Study: 375 μg interferon beta-1b in suboptimal responders

We aimed to evaluate the safety and MRI efficacy of interferon beta-1b (IFNβ-1b) 375 μg (subcutaneously [sc] every other day [eod]) in relapsing-remitting multiple sclerosis (RRMS) patients with a suboptimal response to IFNβ-1b 250 μg, i.e., with MRI activity or relapses. The OPTimization of Interferon for MS (OPTIMS) study was a prospective multicenter randomized phase 2 trial comprising a 6-month run-in phase (to identify suboptimal responders) and a 6-month randomized phase of open-label clinical and blinded MRI follow-up. During run-in all patients were treated with IFNβ-1b 250 μg sc eod; during the study phase suboptimal treatment responders were randomized either to IFNβ-1b 250 or 375 μg sc eod. Primary outcome was the proportion of patients without MRI activity during study Months 9–12 according to the intention-totreat principle. 216 RRMS patients entered the study: 83 suboptimal responders were identified and randomized, 7 refused to continue treatment, 76 were included in the analysis. More patients treated with 375 μg had no MRI activity at Months 9–12 (30/36 vs.16/40; relative risk, 0.28; 95 % confidence interval, 0.08–0.47; p = 0.0001). Sensitivity analysis (“worst case scenario”) confirmed the results. No new or unexpected adverse events were observed, but there was a trend towards more withdrawals in the 375 μg group. Increasing the dose of IFNβ-1b from 250 μg to 375 μg is a successful strategy for reducing subclinical signs of disease activity in RRMS patients. Further studies are needed to show whether this dose may also improve clinical efficacy.

Interferon-β dose and efficacy: the OPTIMS study

Abstract. Interferon beta (IFN-β) reduces exacerbation rates in patients with relapsing-remitting multiple sclerosis (MS), but some patients do not respond to treatment. Recent studies have shown a clear dose-response effect on the reduction of exacerbation rates, and on burden of disease accumulation and active lesion frequency seen on MRI. During treatment with 8 MIU IFN-β we noticed a 30% rate of treatment failure. We then treated non-responders with 12 MIU IFN-β and observed significant improvement in the clinical signs of disease activity. In order to compare the efficacy of two different doses of IFN-β-1b, a multicenter study for the optimization of interferon for MS (OPTIMS) has been organized. The design of the study is presented here.

Long term recombinant interferon alpha treatment in MS with special emphasis to side effects

Twenty relapsing-remitting (RR) clinically definite MS patients were treated with 9 MIU intramuscular recombinant interferon alpha-2a (rIFNA) (Rof eron-A, Roche) (n=12) or placebo (n=8) every other day for 6 months and followed up for a further 6 months after stopping treatment Numbers of active lesions at MRI and of patients with clinical-MRI signs of disease activity and lymphocyte interferon gamma production, which were decreased during treatment, returned to values similar to baseline and placebos after stopping treatment rIFNA chronic therapy seems therefore needed in order to maintain drug efficacy. Side effect prof ile was monitored, too, for over 1 year in the same 20 patients plus 25 additional RR MS patients. Besides the typical side effects of type 1 interferon therapy (fever, fatigue, depression, lymphopenia, hepatic enzyme elevation), occurrence of serum autoAbs was noted in 30% patients (in 60% antinuclear and in 80% antithyroid autoAbs). In two patients rIFNA treatment was stopped, in one case for antithyroid autoAbs and hypothyroidism, in the other for antinuclear autoAbs and a five-fold increase of ALT. A careful monitoring of serum autoAbs and of signs of thyroid or liver damage must always precede and accompany longterm type 1 IFN therapy.

Does high-dose interferon beta-1b improve clinical response in more severely disabled multiple sclerosis patients?

Prospective clinical open label follow-up of 52 multiple sclerosis patients treated with interferon beta-1b. After 18 months of treatment at standard 8 million international units (MIU) dose, subcutaneously on alternate days, IFNB dose was increased to 12 MIU in ten clinically non-responder patients. Eighteen months after, mean exacerbation rate, number and severity of exacerbations and number of patients with exacerbations or requiring corticosteroid treatment significantly improved, becoming similar to those of IFNB responders, always treated with 8 MIU. Baseline EDSS score of non-responders was higher than that of responders. Frequency and severity of adverse events were trending higher and dropout frequency higher in 12 MIU IFNB-treated patients.