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Neoplasm development in Multiple Sclerosis (MS) patients treated with disease-modifying therapies (DMTs) has been widely discussed. The aim of this work is to determine neoplasm frequency, relationship with the prescription pattern of DMTs, and influence of the patients' baseline characteristics. Data from 250 MS outpatients were collected during the period 1981-2019 from the medical records of the Neurology Service of the HUPM (Hospital Universitario Puerta del Mar)-in Southern Spain-and analysed using Cox models. Neoplasm prevalence was 24%, mainly located on the skin, with cancer prevalence as expected for MS (6.8%). Latency period from MS onset to neoplasm diagnosis was 10.4 ± 6.9 years (median 9.30 [0.9-30.5]). During the observation period β-IFN (70.4% of patients), glatiramer acetate (30.4%), natalizumab (16.8%), fingolimod (24.8%), dimethyl fumarate (24.0%), alemtuzumab (6.0%), and teriflunomide (4.8%) were administered as monotherapy. Change of pattern in step therapy was significantly different in cancer patients vs unaffected individuals (p = 0.011) (29.4% did not receive DMTs [p = 0.000]). Extended Cox model: Smoking (HR = 3.938, CI 95% 1.392-11.140, p = 0.010), being female (HR = 2.006, 1.070-3.760, p = 0.030), and age at MS diagnosis (AGE-DG) (HR = 1.036, 1.012-1.061, p = 0.004) were risk factors for neoplasm development. Secondary progressive MS (SPMS) phenotype (HR = 0.179, 0.042-0.764, p = 0.020) and treatment-time with IFN (HR = 0.923, 0.873-0.977, p = 0.006) or DMF (HR = 0.725, 0.507-1.036, p = 0.077) were protective factors. Tobacco and IFN lost their negative/positive influence as survival time increased. Cox PH model: Tobacco/AGE-DG interaction was a risk factor for cancer (HR = 1.099, 1.001-1.208, p = 0.049), followed by FLM treatment-time (HR = 1.219, 0.979-1.517). In conclusion, smoking, female sex, and AGE-DG were risk factors, and SPMS and IFN treatment-time were protective factors for neoplasm development; smoking/AGE-DG interaction was the main cancer risk factor.

Objective: To find out if patients with multiple sclerosis adhere to treatment with beta interferons and glatiramer acetate, the percentage of withdrawal and its causes., Methods: Observational, longitudinal, prospective, national, multicentre study which selected multiple sclerosis patients who attended the hospital pharmacy department to collect their medication. The main variable was the adherence percentage during a year, measured as the relationship between the dose of the dispensed and necessary drug. Treatment withdrawals and their causes were then measured., Results: Over a six-month period, 543 patients from 39 pharmacy departments were included. The average time exposed to the drugs during the study period was 312 days and the average adherence in this period was 61.5% (95% CI: 59.4-63.5). Thirty-four (6.26%) of the 543 study participants withdrew treatment, which for most cases was decided by the doctor., Conclusions: Multiple sclerosis patients' treatment adherence during a period of one year has been lower than the ideal. The causes should therefore be analysed and corrective measures established., (Copyright © 2010 SEFH. Published by Elsevier Espana. All rights reserved.)

Background: Adherence to interferon β-1b (INFβ-1b) therapy is essential to maximize the beneficial effects of treatment in multiple sclerosis (MS). For that reason, the main objectives of this study are to assess adherence to INFβ-1b in patients suffering from MS in Spain, and to identify the factors responsible for adherence in routine clinical practice., Methodology/principal Findings: This was an observational, retrospective, cross-sectional study including 120 Spanish patients with MS under INFβ-1b treatment. Therapeutic adherence was assessed with Morisky-Green test and with the percentage of doses received. The proportion of adherent patients assessed by Morisky-Green test was 68.3%, being indicative of poor adherence. Nevertheless, the percentage of doses received, which was based on the number of injected medication, was 94.3%. The main reason for missing INFβ-1b injections was forgetting some of the administrations (64%). Therefore, interventions that diminish forgetfulness might have a positive effect in the proportion of adherent patients and in the percentage of doses received. In addition, age and comorbidities had a significant effect in the number of doses injected per month, and should be considered in the management of adherence in MS patients., Conclusion/significance: Among all the available methods for assessing adherence, the overall consumption of the intended dose has to be considered when addressing adherence.

Killer cell immunoglobulin-like receptors (KIRs) are regulators of cytolytic activity of natural killer and certain T cells through interactions with human leukocyte antigen (HLA) class I ligands. KIRs have been shown to contribute to the pathogenesis of several autoimmune diseases, but their role in multiple sclerosis (MS) is still unclear. Here we determined the influence of KIR genes and their HLA class I ligands on susceptibility to MS and on the response to interferon-beta treatment in a Spanish population. KIR and HLA genotyping were performed in 200 MS patients and 200 controls. Significantly higher frequencies were found for KIR2DL5 and KIR3DS1 genes in MS patients and the carriage of the KIR2DL1 gene was associated with a higher progression index. Moreover, the frequency of the HLA-Bw4 motif was significantly reduced in MS patients. The KIR2DL1 and HLA-C2 matches were more frequent in MS patients, whereas the KIR3DL1 and HLA-Bw4 matches were more frequent in healthy controls. Nevertheless, non significant associations were found between all the KIR genes and therapeutic response to interferon-beta. Our results confirm that the carriage of HLA-Bw4 is a protective factor in MS and suggest that KIR2DL5 and KIR3DS1 may have a predisposing role in the disease., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Aim: To assess the budget impact of the treatment for relapsing remitting multiple sclerosis (RRMS), interferons, and glatiramer acetate, from the National Health System perspective in Spain., Patients and Methods: A budget impact model was designed to compare the cost of RRMS treatment in different settings, using a five year time-horizon, considering different percentages of administration of each medication. A reference setting o base case using all the available first line treatments (interferons and glatiramer acetate) was compared with five alternatives scenarios excluding each one of these treatments. The cost analysis (euros, year 2010) includes direct medical resources (drugs, administration, visits, disease management, diagnostic tests). Unitary cost data was obtained from the health costs database e-Salud and drugs catalogue., Results: Considering a cohort of 22 255 patients with RRMS, the mean global budget impact per year would be 260 775 470 euros in the base case. The setting that excluded glatiramer acetate increases the budget impact in a 3.23% (372 euros per patient per year). Pharmacological costs were the key drivers of total cost (90%)., Conclusion: The use of glatiramer acetate in the first-line-treatment of RRMS patients is a cost-saving strategy, which may decrease the budget impact from the National Health System perspective in Spain.

The post-marketing international Global Adherence Project investigated adherence to disease-modifying therapy for relapsing-remitting multiple sclerosis. We report adherence data from the first 2 years in the Spanish subset of patients (n = 254 at baseline). The overall adherence rate was 85.4%. Patients taking intramuscular (IM) interferon-β (IFNβ)-1a were significantly more adherent (96.4%) compared with patients taking subcutaneous (SC) IFNβ-1a 22 μg (79.1%; p = 0.0064), SC IFNβ-1a 44 μg (79.6%; p = 0.0064) and glatiramer acetate (82.7%; p = 0.0184). At year 1 (n = 142), the overall adherence rate was 86.6%. Patients on IM IFNβ-1a were significantly more adherent than patients on SC IFNβ-1a 22 μg (93.9 vs. 66.7%; p = 0.0251). At year 2 (n = 131), the overall adherence rate was 82% (87.5% for IM IFNβ-1a, 80.0% for SC IFNβ-1a 22 μg, 77.8% for SC IFNβ-1a 44 μg, 85.2% for IFNβ-1b, and 80.0% for glatiramer acetate). In conclusion, adherence remained high among all disease-modifying therapies over the first 2 years of the study and was significantly higher for IM IFNβ-1a, at visit 1, compared with SC IFNβ-1a., (Copyright © 2011 S. Karger AG, Basel.)

Background: In this article we report adherence data from the first 2 years in a subset of patients from the Global Adherence Project (GAP; n=2,648) in Spain., Methods: A questionnaire assessing adherence to Disease-modifying therapies (DMTs), was distributed annually to patients and their treating neurologists. Non-adherence was defined as missing a DMT injection or changing a dose in the four weeks prior to completing the survey. Patients signed informed consent and Ethics Committees approved annual follow-ups, visit 1 (V1) and visit 2 (V2) in 15 out of 18 centres in Spain., Results: A total of 254 patients were enrolled in Spain. Patients had a mean age of 37.9 years and 70.4% were female, and had been on their treatment for a median time of 28 months, and the overall adherence rate was 85.4%. Patients taking intramuscular interferon beta (IFNB)-1a (Avonex®) were significantly more adherent (94.6%) compared with patients taking subcutaneous (s.c.) IFNB-1a 22.g (Rebif®22) (79.1%; p=0.0064), s.c. IFNB-1a 44.g (Rebif®44) (79.6%; p=0.0064) and glatiramer acetate (GA) (82.7%; p=0.0184). At V1 (n=142), the overall adherence rate was 86.6% and patients on Avonex® were significantly more adherent than patients on Rebif®22 (93.9% versus 66.7%; p=0.0251). At V2 (n=131), the overall adherence rate was 82.4% (Avonex®, 87.5%; Rebif®22, 80%; Rebif®44, 77.8%; Betaferon®, 85.2%, and Copaxone®, 80%) without significant differences., Conclusions: Adherence remained high over the first 2 years of the study. It was highest with Avonex®, being significant on first assessment, after 40.5 months of therapy, on average compared with other DMTs and at year 1 compared with Rebif®22.

The objective of this study was to investigate whether the presence of lipid-specific oligoclonal IgM bands (LS-OCMB) in cerebrospinal fluid (CSF) influences the response to treatment with beta-interferon in relapsing-remitting multiple sclerosis (RRMS) patients. We performed a collaborative prospective study including RRMS patients with brain MRI and LS-OCMB studies performed before starting interferon treatment. The primary endpoint was the risk of having a relapse after treatment initiation. Secondary endpoints included relapse rate, relapse-rate reduction, proportion of relapse-free patients and proportion of patients with sustained disability increase during follow-up. One-hundred and two patients were included. After a mean follow-up of 37.4 months, the risk of suffering a relapse was two-fold higher in patients with LS-OCMB (hazard ratio 2.0, 95% confidence interval 1.1-3.8). LS-OCMB+ patients showed lower reduction in relapse rate (51.8% versus 80.8%; p < 0.0001), higher relapse rate in the first year (0.8 versus 0.2; p = 0.001), lower proportion of relapse-free patients (25% versus 61.3%; p = 0.003), and higher proportion of patients with sustained 1.0 increase in the Expanded Disability Status Score (45% versus 12.9%; p = 0.0003). In conclusion, LS-OCMB can have an influence on the response to interferon treatment in RRMS patients. They could be used as a biological marker to predict high inflammatory activity after treatment.

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Interferon-beta is the most usual therapy in relapsing-remiting MS. However, approximately 50% of the treated patients do not respond adequately. Very recently, a genome-wide association study on interferon-beta pharmacogenetics has described polymorphisms at several genes that are associated with response to this treatment. Our aim is to replicate the results obtained at the two loci most strongly implicated in the response to interferon-beta treatment, HAPLN1 and GPC5., Patients and Methods: We performed a case-control study, analyzing 199 patients with MS treated with interferon-beta for at least 2 years and at least two documented relapses over the 2 years, previous to treatment onset. Responders had neither relapses nor increase in expanded disability status scale (EDSS) over the 2-year follow-up period, whereas nonresponders had at least two relapses or an increase in EDSS of at least 1 point. We studied three single-nucleotide polymorphisms (SNPs) in the GPC5 locus and three SNPs in the HAPLN1 locus by TaqMan technology. Allelic frequencies between responders and nonresponders were compared by a chi-square test., Results: An association was found between GPC5 polymorphisms and the response to interferon-beta therapy in patients with MS, in agreement with earlier data (responder vs nonresponder patients: rs10492503, P = 0.0005). The other locus studied (HAPLN1) did not show association with treatment response to interferon-beta (all SNPs P > 0.05)., Conclusions: We confirm the association of polymorphisms within GPC5 with response to interferon-beta therapy in patients with MS.

Background: Osteoporosis is a complication of multiple sclerosis (MS), especially if corticosteroid therapy is given. Little is known about the effect on bone of immunomodulatory therapy (IMT) for MS., Aim: We sought to evaluate bone mass in patients with MS on IMT., Methods: We measured bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) in 37 patients with MS who received IMT. Different IMTs were administered: interferon beta-1a in 70%, interferon beta-1b in 27% and Glatiramer in 3%. High-dose pulse corticosteroid therapy (intravenous methylprednisolone 500 mg) was given to 81% ranging from 1 to 17 courses., Results: Both mean BMD Z-score at spine of 0.53 (CI, 0.15-0.92; P = 0.0084) and mean BMD Z-score at femur of 0.72 (CI, 0.42-1.01; P < 0.0001) were significantly greater than zero., Conclusions: IMT may have a favorable effect on bone in patients with MS even in the presence of pulse steroid therapy.

Interferon-beta is a biological treatment widely used in multiple sclerosis (MS). However, not every patient responds equally well to this therapy. In this study, our aim was to evaluate the influence of a dinucleotide microsatellite located in the first intron of the interferon-gamma gene on relapse eradication in a group of interferon-beta-treated patients. Our results show a very different allelic distribution when patients with relapses were compared with relapse-free patients.

Introduction: The availability of the interferon beta in its three forms at the moment available in our country and of glatiramer acetate has marked a point of flexion in the natural history of multiple sclerosis (MS), but the high cost of these treatments cause that its use is questioned. In this work we have studied the effectiveness and efficiency of the processing with interferon beta, and the cost-utility of these treatments in MS in Spain has been also analyzed., Patients and Methods: For this work we studied 102 patients affected of RR MS, treated with the three interferons beta which we have available in our country. We used as control 330 patients who had participated in the pivotal clinical interferon trials with both interferon beta 1a. In these patients in addition to effectiveness data, we have studied the disability measured as area below curve and the quality of life (AVACs). We also calculated the economical costs, considering the relation cost-utility in our country., Results: Besides to confirm the data of effectiveness of three interferons, in this study a saving of 23 days/year is demonstrated what corresponds to 0.063 AVACs. The additional cost of interferons is greater than the avoided cost until the fifth year of treatment in which the tendency is reversed in favor of the group of treated patients, if we assume that the same effectiveness that we found in the first years is maintained in the long term., Conclusion: The use of the treatment with interferon beta is justified by its effectiveness, efficacy and efficiency. The additional cost of the treatment will be compensated in the long term if the effectiveness of the interferon beta is maintained.

Objective: To analyze the experience in daily clinical practice of interferon-beta (IFN-beta) treatment in relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS) in Galicia (Spain)., Patients and Methods: Patients with RR-MS and SP-MS treated with IFN-beta1a and 1b between 1995 and December/2000, analyzing demographic and clinical data., Results: 313 patients were included, with a mean age of 38.2 years. A total of 296 patients (94.6%) were clinically defined MS and 17 (5.4%) were laboratory supported (Poser criteria); 84.6% of the patients were RR and 15.4% were SP. The mean duration of the disease prior to treatment was 7.06 years. Betaferon was used in 52.4% patients (115 RR-MS and 47 SP-MS), Avonex in 26% and Rebif in 21.6%. Relapse rate was reduced in 68.8% for the RR-MS for Betaferon-treated patients, 73.3% for Avonex treated and 35.7% for Rebif-treated patients. Betaferon reduced relapse rate in 50% for SP-MS. The global EDSS remained stable during IFN-beta treatment. During treatment, 33% of Betaferon, 60.5% of Avonex and 54.5% of Rebif-treated patients remained relapse-free. Treatment was suspended in 12.9% of Betaferon, 6.2% of Avonex, and 3% Rebif-treated patients. The most frequent causes of treatment suspension were increase in disability and in relapse count., Conclusions: The present study supports the benefits of IFN-beta treatment in RR MS and SP MS in daily clinical practice, with reduction in relapses count and incapacity, good over-all tolerance and low incidence of serious adverse side-effects.

The HLA-DR2 haplotype (DRB1*1501, DQB1*0602) on chromosome 6p21 has consistently demonstrated both association and linkage with multiple sclerosis (MS) in case-control and family studies, particularly in Caucasians of Northern European descent. However, the role of a gene within this region in determining clinical features or response to immunotherapy remains largely unknown. A new familial MS data set from the Mediterranean Spanish Basin was collected according to rigorous ascertainment criteria. We confirm, primarily in the cohort originating from Continental Spain, that similar to other high-risk groups, there was a significant association with HLA-DR2. No other DR or DQ alleles were found to be associated with disease susceptibility nor were alleles at the class I A and B loci. Overall, the effect of HLA appears to be less substantial than that observed in a reference US population with a higher disease incidence. No effect of the HLA-DR2 haplotype on age of onset, initial clinical symptoms and disease course was observed. Similarly, no difference in the distribution of responders and nonresponders to interferon-beta (IFNB) therapy, as defined by primary and secondary end points, was observed when individuals were stratified according to HLA-DR2 status.

Objectives: To determine the prevalence and characteristics of multiple sclerosis (EM) in the Marina Alta health district., Patients and Methods: A descriptive, retrospective study localizing cases (crossed register method). Day of prevalence: 1/05/01. Registers of the area analyzed: hospital admission, Neurology Clinic, Emergency Department of the hospital and Health Centres. The criteria of Poser were used for diagnosis. We analyzed the demographic, clinical and paraclinical aspects of the episodes and treatment (interferon-beta)., Results: Male/female ratio: 2.4. Average age: 46.6 years. Prevalence of definite EM: 40.3/100,000. Prevalence of autochthonous cases of EM: 28.7/100,000. Average age at onset: 32.6 years. Average duration of illness: 12.5 years. Commonest clinical form: remitting relapsing (48.1%), followed by progressive relapsing (7%), benign (5.5%) and primary progressive (1.8%). 5.5% died, all with the progressive secondary form. EDSS disability: greater in the progressive secondary form. Magnetic resonance (MR) was the commonest investigation used (84% of the results in concordance and 13% normal). Positive BOC in 70% of cases. We studied 202 episodes. The systems most affected were: sensory and pyramidal. Worsening of EDSS after recovery from the episode: 51.7%. 29% received interferon-beta, with five cases (31%) of major side effects (one psychotic outbursts, three with neutropenia and one generalized allergic reaction)., Conclusions: In the Marina Alta the prevalence of EM adjusted for the autochthonous population is in the medium risk zone. The clinical features and course of the disease in our patients are similar to those seen in other national and foreign series. The most worthwhile tests were cranial MR and BOC CSF. Treatment with interferon-beta requires strict control in view of the high frequency of serious side effects seen.

Objective: A protocol system is being used in Spain for the prescription of innovative drugs including interferon beta-1b (IFNbeta-1b). Petitions for dispensing and reimbursement are based on the inclusion and exclusion criteria of pivotal trials, and are reviewed individually for approval by specialist committees. To estimate the performance of IFNbeta-1b in the clinical setting, data collected by the INSALUD and regional health services of Andalusia and Catalonia, together responsible for the healthcare of nearly 30 million individuals, were compiled in a common database for analysis., Methods: Data comprise demographic and disease characteristics at the time of petition and at follow-up 3 months after treatment initiation and every 6 months thereafter. Efficacy was estimated by mean number of relapses per year, proportion of relapse-free patients, and disease progression as measured by the Expanded Disability Status Scale (EDSS). Safety parameters included adverse events and laboratory analyses., Results: Between September 1995 and database cutoff in mid-1998, petitions of 1419 patients were approved for IFNbeta-1b treatment. Patients were homogenous across the three databases and in the subgroups of patients completing 1 year (n = 940) and 2 years (n = 302) of treatment. There was a marked decrease in the mean number of relapses in the first 12 months of IFNbeta-1b treatment for the 938 patients documented for 12 months, with a mean of 0.4 (+/- 0.7 SD) relapses per patient and year, and a 2-year mean of 0.9 (+/- 1.20 SD) in the 302 patients documented for 24 months. Of the 938 patients followed for > or = 12 months, 505 (53.8%) were documented as being relapse-free during 12 months of treatment, and 146 (48.3%) of the 302 patients followed for > or = 24 months, were relapse-free during 24 months of treatment. There were no differences in mean or median EDSS scores between baseline and months 12 and 24. Skin disorders were the most frequent adverse events, reported in over one-third of all patients; there were 159 injection site events, most frequently erythema (115 events). Systemic AEs pointing towards flu-like symptoms were reported in 288 of 1419 patients (20.3%). Leukopenia was the most frequently reported laboratory event. Elevations in liver transaminases were noted for 12 patients (0.8%) with SGOT increase and 7 (0.5%) with SGPT increase., Conclusion: The protocol system has helped make IFN treatment available to 8-10% of the estimated 15,000-18,000 MS patients in the regions studied. In terms of efficacy, IFNbeta-1b performed in line with the pivotal study results. The safety profile of IFNbeta-1b was consistent with the published findings and the drug labelling, and no new side effects or increased incidence of known side effects was observed.

Background: The multiple sclerosis seems to be the junction between genetics alteration and an unknown environmental factor, that they would originate an autoimmune alteration, that they would be the reason of the inflammation and demyelinization responsible of the disease. Our objective has been the determination of this possible environmental factor and to reach it, we have studied the appearance of Herpesviridae family viruses., Materials and Methods: 204 blood samples were studied: 102 from relapsing-remitting multiple sclerosis patients (43 were undergoing beta-interferon treatment), and 102 from blood donors with the same age and sex than multiple sclerosis patients. From this samples, we extracted the DNA of peripheral blood mononuclear cells (PBMCs), and we analyzed by polymerase chain reaction (PCR) to detect the appearance of herpes simplex virus, varicella zoster virus, Epstein-Barr virus, cytomegalovirus, human herpesvirus 6 (HHV-6), human herpesvirus 7 and human herpesvirus 8., Results: a) we only found significative difference (p = 0.0001) in HHV-6: 21.5% donors positive samples (22/102), opposite to 49.02% of positivity in mulytiple sclerosis patients (50/102); b) we didn't found significative differences in none of other viruses studied, between patients treated with beta-interferon and non-treated ones., Conclusions: Our results suggest us that HHV-6 can play an important role in the multiple sclerosis development. The beta-interferon treatment doesn't affect to DNA prevalence of none of studied viruses.

Introduction: Recombinant beta-1B interferon has been used in our country since the end of 1995 for treatment of remittent-recurrent multiple sclerosis (RRME). At the present time there are still gaps in the effectiveness, side-effects and management of patients on this treatment., Objective: To determine the evolution, side-effects and practical difficulties involved in the management of patients with RRME given interferon beta-1B and prospectively followed up one year after starting treatment., Material and Methods: This paper gives a prospective description of 41 treated patients with an average follow-up of 254 days., Results: The patients tolerated and followed their treatment well. Treatment was only withdrawn in two cases. We observed a 40% reduction in the annual incidence of exacerbations (with respect to previous years) and there was improvement on the amplified dysfunction scale of Kurtzke in the patients whose exacerbations were treated with megadoses of steroids. The side-effects were those we expected, apart from an increase in thyroid complications and the appearance of a depressive syndrome. Treatment did not have to be changed because of the side-effects. In two patients with serious side-effects (thyroiditis and a depressive syndrome) the symptoms disappeared when treatment was stopped., Conclusion: The results and side-effects were similar to those published. We had fewer patients who withdrew from the trial. There were no cases of patients not following the prescribed treatment.

A randomized, double-blind, placebo-controlled trial was conducted to assess interferon-beta efficacy and safety in the treatment of anogenital condylomatous lesions. One hundred patients received a daily intramuscular injection of either interferon-beta (IFN-beta) (2 MIU/day) or placebo for 10 days. Of 94 evaluable patients, the complete response rate observed 8 weeks after treatment was significantly higher in the group receiving IFN-beta, as compared to the placebo-treated group (51% vs 28.9%, P < 0.05). After one year, 24 patients (100%) out of 24 complete responders to IFN-beta who attended for follow-up remained free of lesions. Twelve of 13 patients with complete response to placebo (92.3%) remained free of lesions after one year. Side effects were mild and no significant analytical changes were observed. In conclusion, interferon-beta is an effective and safe treatment for long-term eradication of anogenital condylomatous lesions.