Responsiveness of patient reported outcome measures in multiple sclerosis relapses: the REMS study.

OBJECTIVES: To assess the responsiveness of the three most used patient reported multiple sclerosis (MS) specific questionnaires: the Functional Assessment of MS (FAMS), the MS Impact Scale (MSIS-29) and the 54 item MS Quality of Life (MSQOL-54). DESIGN: Prospective multicentre longitudinal study on 104 MS patients treated with intravenous steroids for clinical exacerbation. METHODS: Patient reported data, Expanded Disability Status Scale (EDSS) score and clinical information were collected at admission and 8 weeks later. "Internal" (distribution based) responsiveness was assessed by standardised response means (SRM). "External" (anchor based) responsiveness was assessed by receiver operating characteristic (ROC) curves in relation to corresponding changes in a pre-specified reference measure (anchor). The pre-specified anchor was patients' self-reported recovery assessed on a 5 point Likert scale. RESULTS: SRM was 0.39 for FAMS, 0.58 for MSIS-29 physical scale, 0.45 for MSIS-29 psychological scale, 0.71 for MSQOL-54 physical health composite and 0.57 for MSQOL-54 mental health composite. Seventy-three patients (70%) reported they had improved; physicians agreed substantially with patient assessments (kappa statistic 0.70, 95% CI 0.54 to 0.85). Areas under ROC curves differed significantly from 0.50 only for the MSIS-29 and MSQOL-54 scales where areas ranged from 0.65 (95% CI 0.53 to 0.76) for the MSIS-29 psychological scale to 0.70 (95% CI 0.58 to 0.81) for the MSQOL-54 mental health composite. Areas under ROC curves assessed using a physician based anchor were similar to the patient based areas. CONCLUSIONS: The responsiveness of the MS specific instruments was less than ideal. The MSIS-29 and MSQOL-54 were significantly more responsive, using both distribution based and anchor based approaches, than FAMS, and should be preferred in longitudinal studies.

Cyclophosphamide for multiple sclerosis.

BACKGROUND: Multiple sclerosis is a presumed cell-mediated autoimmune disease of the central nervous system. Cyclophosphamide (CFX) is a cytotoxic and immunosuppressive agent, used in systemic autoimmune diseases. Controversial results have been reported on its efficacy in MS. We conducted a systematic review of all relevant trials, evaluating the efficacy of CFX in patients with progressive MS. OBJECTIVES: The main objective was to determine whether CFX slows the progression of MS. SEARCH STRATEGY: We searched the Cochrane MS Group Trials Register (searched June 2006), Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3 2006), MEDLINE (January 1966 to June 2006), EMBASE (January 1988 to June 2006) and reference lists of articles. We also contacted researchers in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating the clinical effect of CFX treatment in patients affected by clinically definite progressive MS.CFX had to be administered alone or in combination with adrenocorticotropic hormone (ACTH) or steroids. The comparison group had to be placebo or no treatment or the same co-intervention (ACTH or steroids) DATA COLLECTION AND ANALYSIS: Two reviewers independently decided the eligibility of the study, assessed the trial quality and extracted data. We also contacted study authors for original data. MAIN RESULTS: Of the 461 identified references, we initially selected 70: only four RCTs were included for the final analysis. Intensive immunosuppression with CFX (alone or associated with ACTH or prednisone) in patients with progressive MS compared to placebo or no treatment (152 participants) did not prevent the long-term (12, 18, 24 months) clinical disability progression as defined as evolution to a next step of Expanded Disability Status Scale (EDSS) score. However, the mean change in disability (final disability subtracted from the baseline) significantly favoured the treated group at 12 (effect size - 0.21, 95% confidence interval - 0.25 to -0.17) and 18 months (- 0.19, 95% confidence interval - 0.24 to - 0.14) but favoured the control group at 24 months (0.14, CI 0.07 to 0.21). We were unable to verify the efficacy of other schedules. Five patients died; sepsis and amenorrhea frequently occurred in treated patients (descriptive analysis). AUTHORS' CONCLUSIONS: We were unable to achieve all of the objectives specified for the review. This review shows that the overall effect of CFX (administered as intensive schedule) in the treatment of progressive MS does not support its use in clinical practice.

Depression during interferon therapy for chronic viral hepatitis: early identification of patients at risk by means of a computerized test.

OBJECTIVES: At the doses used for the treatment of chronic viral hepatitis, interferon (IFN)-related side-effects are usually modest, even though in some cases they require the interruption of therapy. Neuropsychiatric disturbances that range from modest depression and irritability to forms of manic-depressive psychosis and attempted or successful suicides are among the most important side-effects. The aim of our study was to determine whether the Minnesota Multiphasic Personality Inventory (MMPI) is a sensitive and reliable test for the early identification of patients at risk of depression before IFN therapy is commenced, and whether it could be useful for the monitoring of these patients during treatment. METHODS: We prospectively studied 67 patients with chronic active liver diseases, consecutively enrolled in open studies and treated with r-IFNalpha2. Before starting therapy and after 3 months of treatment, all patients underwent a clinical neurological evaluation and MMPI. RESULTS: At baseline, the correlation between the clinical evaluation and the score of the depression scale of the MMPI was statistically significant (P< 0.0001). Nine of 14 (64.3%) patients with a baseline score > or = 60/100 showed a depressive mood after 3 months of therapy. Five of 44 patients (11.3%) with a baseline score < 60/100 showed a depression of medium level after 3 months of treatment. This difference was highly significant (P< 0.0001). CONCLUSIONS: According to our results, the MMPI is a reliable and sensitive test for the early identification of patients at risk of depression before and during IFN therapy for chronic viral liver diseases.

Outcome of liver disease in a large cohort of histologically proven chronic hepatitis C: influence of HCV genotype.

OBJECTIVE: To assess the influence of hepatitis C virus (HCV) genotypes on the clinical outcome of liver disease, we analysed 2,307 patients. RESULTS: The most frequently represented genotypes were 1b (40%) and 2 (28.1%). Patients with these genotypes had a median age higher than patients with other genotypes (P< 0.01). The overall survival of subjects with genotype 1b was poorer than the survival of patients with other genotypes (P< 0.01). Liver cirrhosis was found in 280 patients (12.1%), and type 1b was the most represented isolate among them (P< 0.01). Sixty-two patients (22%) developed hepatocellular carcinoma (HCC) during a follow-up of 1481.8 cumulative years (estimated crude incidence rate, 4.1 cases per 100 person-years for all cirrhotics; 5.9 cases for genotype 1a; 4.5 cases for genotype 1b; and 2.8 cases for genotypes non-1). Considering the whole population of 2,307 patients, only genotype 1b was associated significantly with both cirrhosis and the development of HCC. One hundred and nineteen cirrhotic patients underwent treatment with interferon in uncontrolled studies. Interferon therapy was associated with both better survival (P< 0.01) and a lower cumulative hazard for HCC (P< 0.01). CONCLUSIONS: Genotype 1b was associated with a poorer prognosis, probably because it leads to cirrhosis and consequently to HCC development. However, our data did not confirm genotype 1b as an independent risk factor for HCC in liver cirrhosis, which plays a major role in carcinogenesis. Interferon should be considered as a useful strategy in cirrhosis for improvement of survival and reduction of HCC risk.

Cyclophosphamide for multiple sclerosis.

BACKGROUND: Multiple sclerosis is a presumed cell-mediated autoimmune disease of the central nervous system. Cyclophosphamide (CFX) is a cytotoxic and immunosuppressive agent, used in systemic autoimmune diseases. Controversial results have been reported on its efficacy in MS. We conducted a systematic review of all relevant trials, evaluating the CFX efficacy in patients with progressive MS. OBJECTIVES: The main objectives were to determine whether CFX slows the disease progression. SEARCH STRATEGY: Electronic databases (including MEDLINE, EMBASE, Cochrane Controlled Trials Register) were systematically searched. References list of retrieved studies and conference abstracts on the main meetings on Multiple Sclerosis were handsearched. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating the clinical effect of CFX treatment in patients affected by clinically definite progressive MS. CFX had to be administered alone or in combination with ACTH or steroids. The comparison group had to be placebo or no treatment or the same co intervention (ACTH or steroids) The main outcome criteria were : progression of disability (defined as an increase of 0.5 point in Kurtzke Extended Disability Status Scale (EDSS) for patients with baseline EDSS > or = 6 and 1 for EDSS < or = 5.5), differences of disability between treatment-control groups and the number of patients with side effects. DATA COLLECTION AND ANALYSIS: The identified references were reviewed by two reviewers who independently decided the eligibility of the study, extracted and summarized data and assessed the trial's quality. The statistical analysis was performed using the Cochrane RevMan software and analyzed using Cochrane MetaView. MAIN RESULTS: Of the 326 identified references, 80 were selected for full review, only four RCTs were selected for the final analysis. Intensive immunosuppression with CFX (alone or associated with ACTH or prednisone) in patients with progressive MS compared to placebo or no-treatment (152 participants) did not prevent the long -term (12-18-24 months) risk to evolution to a next step of EDSS. However, the mean change in disability (final disability subtracted from the baseline) significantly favoured the treated group at 12 (effect size - 0.21; C. I. - 0.24, - 0.17) and 18 months (- 0.19; C. I. - 0.24, - 0.14). We were not able to verify the efficacy of other schedules. Five patients died; sepsis and amenorrhea frequently occurred in treated patients (descriptive analysis). REVIEWER'S CONCLUSIONS: Only limited objectives were reached. This review shows a role of CFX in the treatment of progressive MS, but less toxic schedules must be considered, before its use in the clinical practice.

Azathioprine. Safety profile in multiple sclerosis patients.

Azathioprine (Aza) has been proposed in the treatment of multiple sclerosis (MS) since 1971 and continues to be used in MS Clinical Centres. Recent data, suggesting its efficacy in reducing MRI lesion load and in refractory IFN-treated MS patients, has renewed interest in this drug. Its therapeutic index over other immunosuppressive agents is generally considered favourable, but concerns about a possible risk of malignancy have limited its use. On the other hand, the occurrence of unexpected adverse events (AEs) in clinical trials in recent years has aroused the interest in the safety profile of the drugs. No systematic review of AEs in patients affected by MS is available. The aim of this study is to review the safety profile of the drug in patients affected by MS, in order to support a correct management of these patients in the clinical practice. The controlled and observational clinical studies published between 1971 and 2007 have been included. The AEs have been registered in ad hoc form and the frequency has been calculated. The risk of cancer and toxicity on reproductive function has been also considered. Gastrointestinal complaints and leukopenia are the most frequent AEs of Aza therapy in MS, occurring in more than 10% of the patients, while infections, allergy, anaemia, thrombocytopenia and pancytopenia are common (>1%-<10%). Pancreatitis is not common (>0.1%-<1%). Most of them are easily managed by dosage adjustment or therapy interruption. The cancer risk increases with the treatment duration and cumulative dose. No data on reproductive toxicity in MS treated with Aza are available. The safety profile of Aza is acceptable, if strategies for management of expected AEs are adopted, following dosage and treatment duration indications, and if long-term monitoring to evaluate the risk of cancer is warranted.

Interferon treatment may trigger primary headaches in multiple sclerosis patients.

Recent data have suggested that interferon-beta (IFN-beta) may aggravate headaches in multiple sclerosis (MS) patients. The aim of this study was to investigate the life-time prevalence of primary headaches in MS patients treated with interferons in comparison with patients treated with other disease-modifying agents. Attention was focused on the onset of headache and the changes in pre-existing headaches in relation to the onset of therapy. The study was open-labelled and not randomized. We studied 150 consecutive MS patients treated with IFN-beta (109 patients: 54 with 1b, 55 with 1a) and with other drugs (41 patients: 14 with glatiramer acetate, 27 with azathioprine). All patients underwent a semi-structured interview to diagnose headache type, according to the International Headache Society criteria. The frequency of primary headaches was higher in the interferon-group (72%) compared to patients in the other group (54%) (P=0.03). Worsening of pre-existing headaches or development of de novo headache occurred only in the interferon-group (41 and 48%, respectively) and not in the other group (P<0.001). These results show that headache should be considered among the side-effects of interferon in MS patients.

A post-marketing study on immunomodulating treatments for relapsing-remitting multiple sclerosis in Lombardia: preliminary results.

The preliminary results of a post-marketing study on relapsing-remitting multiple sclerosis patients treated with immunomodulating agents attending the Lombardia Region's Multiple Sclerosis Centers are presented. A total of 294 patients treated with Betaferon (67), Avonex (115), Rebif 22 (45), Rebif 44 (18) and Copaxone (49) were included. Relapse frequency consistently decreases at 1 year and continues to decrease after 5 years of treatment, without differences between therapeutic groups. Eighty-seven out of 294 patients (29.6%) discontinued treatment for different reasons. Forty-eight of them shifted to a second therapeutic agent. A different trend, to lower or higher doses of interferon or immunosuppression, according to reasons of discontinuation, was observed.

Prevalence of primary headaches in people with multiple sclerosis.

The aim was to investigate the lifetime prevalence of headache and primary headache (diagnoses according to International Headache Society criteria) in multiple sclerosis (MS). The relationships between headache and clinical features of MS and MS therapy were also investigated. We studied 137 patients with clinically definite MS; 88 reported headache, 21 of whom developed headache after the initiation of interferon. The prevalence of all headaches in the remaining 116 patients was 57.7%. Migraine was found in 25.0%, tension-type headache in 31.9%, and cluster headache in one patient. A significant correlation (P = 0.007, Fisher's exact test) between migraine and relapsing-remitting MS was found. Primary headaches are common in MS patients. Further studies are needed to clarify the mechanisms underlying this association, particularly the association between migraine and relapsing-remitting MS, and the role of interferon in the development of new headache.