Gloria Luque

IFNAR1 and IFNAR2 polymorphisms confer susceptibility to multiple sclerosis but not to interferon-beta treatment response.

We investigated the role of three polymorphisms in the IFNAR1 (SNPs 18417 and -408) and IFNAR2 (SNP 11876) genes in multiple sclerosis (MS) susceptibility and in the IFNbeta treatment response in a group of 147 patients and 210 controls undergoing interferon therapy during the last 2 years. Only the 18417 and the 11876 SNPs showed an association with disease susceptibility (p=0.001 and 0.035, respectively) although no differential genotype distribution were observed between interferon responders and non-responder MS patients. No alteration of the expression level of IFNAR-1 was observed with respect to the -408 genotypes or to interferon treatment response. These data suggest a role for the IFNAR pathway in susceptibility to MS.

DQB1*0602 allele shows a strong association with multiple sclerosis in patients in Malaga, Spain

Abstract.Background:The human leukocyte antigen (HLA) class II DR2 haplotype (DRB1*1501, DQA1*0102, DQB1*0602) has been associated with multiple sclerosis (MS) in all ethnic groups and very strongly in Caucasians.Aim:To investigate the possible HLA class II (DRB1, DQA1 and DQB1) associations with MS in Malaga, southern Spain.Methods:We analysed the HLA class II sub-regions DRB1, DQA1 and DQB1 by polymerase chain reaction (PCR) and sequence-specific oligonucleotide probe hybridization (PCR/SSO) for DRB1 and DQB1 and with sequence-specific primers (PCR/SSP) for DRB1 subtypes and DQA1. Possible HLA class II associations with clinical MS characteristics were investigated in 149 subjects with and 160 without MS.Results:Associations were detected between MS and the HLA class II alleles DRB1*1501 (45.6 % vs. 21.3%, p = 0.001), DQA1*0102 (44% vs. 29.4%, p = 0.001) and DQB1*0602 (45% vs. 20.6%, p = 0.001). The DR2 haplotype (DRB1*1501, DQA1*0102, DQB1*0602) was associated with MS (43.6 % vs. 20%, p = 0.002). DQB1*0602 was the only allele that maintained an association with MS in a logistic regression model. No HLA class II alleles or genotypes were significantly associated with any clinical characteristics of MS.Conclusions:Our results confirm the positive association of the DR2 haplotype with MS, particularly the allele DQB1*0602, in the population studied. DR4 was not associated with the disease in Malaga. HLA class II alleles or haplotypes were not associated with clinical or demographic characteristics, or clinical form or severity of MS.

Combination therapy with interferon Beta-1b and azathioprine in secondary progressive multiple sclerosis

Abstract Combination therapy may benefit the subgroup of patients with secondary progressive multiple sclerosis (SPMS) who do not respond to interferon beta (IFNB). We performed a two-year study of azathioprine (AZA) combined with IFNB-1b in SPMS patients who had not responded well to IFNB-1b alone. Patients with SPMS were eligible for this non-controlled prospective study if they had two or more relapses requiring corticosteroid treatment or deteriorated by at least 0.5 points on the Expanded Disability Status Scale (EDSS) while on IFNB-1b in the year preceeding the study. Patients were to continue treatment with IFNB-1b (8 MIU qod, subcutaneous) and received AZA (50 mg tid, oral). Safety was assessed in terms of adverse reactions and laboratory measures graded according to the WHO toxicity scale. Efficacy was explored by changes in relapse rate, EDSS, 9-hole peg test (9-HPT), neuropsychological scores, and magnetic resonance imaging (MRI) results. Neutralizing antibodies (NAB) were measured. Ten SPMS patients (6 females) with a median EDSS score of 4.5 were enrolled. One patient withdrew because of gastrointestinal complaints, one was withdrawn owing to poor compliance, and 8 patients completed therapy. The only frequent side effect was lymphopenia, reported at least once in all patients. Annual relapse rate was reduced by approximately 50 % in the second year. There was a significant trend for EDSS increase. Total lesion load measured by MRI decreased at 12 and 24 months; only one patient had active lesions. No changes were seen in the 9-HPT. There was a significant improvement in neuropsychological tests after 24 months (p = 0.045). One patient tested positive for NAB throughout the study, and transient NAB were detected in 4 patients. In conclusion, combination therapy with IFNB-1b and AZA was safe and generally well tolerated in patients with SPMS. Strict clinical and laboratory monitoring is recommended during this combination therapy.

Multiple sclerosis prevalence in Malaga, Southern Spain estimated by the capture–recapture method

Background: Although not definitively proven, there is commonly accepted to be a latitudinal gradient in the distribution of multiple sclerosis (MS), which is more frequent in temperate zones. The European Mediterranean countries are situated in a zone of median frequency, although ever increasing figures have been noted in the last decades. Objective: The objective of this study was to assess the current prevalence rate of MS in the province of Malaga, Southern Spain. Methods: The capture–recapture method (CRM) uses independent sources of data and permits the number of non-registered cases of a given disease to be estimated, and by doing so, to avoid ascertainment bias. Results: Use of this method showed the estimated prevalence rate of MS in the province of Malaga, Southern Spain, to be 125/105 (95% confidence interval: 102/105–169/105), higher than the figures published previously. Conclusions: Although we recognize that these data need to be confirmed in further studies and in other areas of the country using a similar method, we believe this study is the first to find such high figure of prevalence, being very similar to the figures reported in recent years in other southern European countries.

HLA class II and response to interferon-beta in multiple sclerosis

Objective –  To study the relationship between human leucocyte antigen (HLA) genotype and clinical response to interferon‐beta (IFN‐β).

Study of binding and neutralising antibodies to interferon-β in two groups of relapsing-remitting multiple sclerosis patients

Abstract Interferon (IFN)-β is generally considered an effective treatment for multiple sclerosis (MS); however, some patients do not respond to this therapy, possibly due to the production of neutralising antibodies (NAB) which can prevent the biological effect of IFN-β. We compared the two types of IFN-β, the glycosylated IFN-β1a and the non-glycosylated IFN-β1b, as their chemical differences may entail differing immunogenic capacities. We studied 22 relapsing-remitting MS patients treated with IFN-β1a and 31 treated with IFN-β1b for 1 year, using the same assay and criteria, to compare the two types of IFN-β in their ability to induce binding and neutralising antibodies and examined the correlation of the findings with the clinical data. Binding antibodies to IFN-β1a and IFN-β1b were determined by enzyme-linked immunosorbent assay. A bioassay was used to detect and quantify the NABs to IFN-β, measuring the capacity of NABs to block the antiviral resistance induced by IFNs. Binding antibodies were found in 32 % of those treated with IFN-β1a and in 52 % of those treated with IFN-β1b; NABs were found in 14 % and 24 %, respectively. Both groups showed a significant decrease in relapse rate during the first year of treatment. These results demonstrate that the IFN-β1b molecule is more immunogenic than the IFN-β1a molecule. This may be due to the non-glycosylated, chemical structure of the former, which can produce aggregates and enhance antibody production. No association was found between the presence of NABs and the clinical status of the patients.

Quality of life in multiple sclerosis patients in Spain

Objective: The cross-sectional study evaluated the psychometric properties of the Functional Assessment of Multiple Sclerosis (FAMS) Spanish version and its use in measuring quality of life (QOL) of multiple sclerosis (MS) patients in Spain. Methods: The FAMS is a factorially derived self-report scale designed to assess six primary aspects of QOL of patients with MS: Mobility, Symptoms, Emotional Well-Being, General Contentment, Thinking and Fatigue, and Family/Social Well-Being. Its Spanish translated version was used to assess QOL of 625 MS patients recruited in an outpatient clinic setting from 58 hospitals in Spain. Internal consistency of the Spanish FAMS was evaluated. Multiple regression analyses were performed to identify significant predictors from demographic, clinical and treatment characteristics, and Kurtzke Expanded Disability Status Scale (EDSS) scores in predicting FAMS scale scores. Results: Most of the patients are females (66%), and 74% were of the relapsing-remitting (RR) clinical subtype. Cronbach’s alpha coefficients were high (range=0.78-0.96), indicating subscale homogeneity comparable to that of the original English version. Linear multivariate regression analyses revealed that the EDSS is a dominant variable in predicting all the FAMS subscales, especially mobility (R2=0.51) and the total scores. Conclusions: The Spanish FAMS is a psychometrically valid instrument that allows clinicians and clinical researchers the ability to measure the QOL concerns of MS patients in Spain.

Kinetics and incidence of anti-natalizumab antibodies in multiple sclerosis patients on treatment for 18 months

Natalizumab is a monoclonal antibody shown to be highly effective in the treatment of relapsing–remitting multiple sclerosis (RRMS). Patients treated with natalizumab can develop antibodies directed against this agent that may affect the efficacy and safety of the drug. In this observational study, the kinetics of the appearance and the incidence of anti-natalizumab antibodies were followed prospectively for 18 months in a cohort of 64 consecutive patients treated with natalizumab for relapsing MS. Blood samples were drawn immediately before starting natalizumab therapy and each month afterwards. The presence of antibodies against natalizumab was assessed by enzyme-linked immunosorbent assay (ELISA) in all patients. Anti-natalizumab antibodies were detected in nine (14.1%) natalizumab-treated patients, three (4.68%) of whom were transiently positive while six (9.37%) were persistently positive (these patients discontinued natalizumab). All positive titres were observed during the first 4 months of treatment. One patient with a hypersensitivity reaction also had persistent antibodies. We conclude that antibodies against natalizumab develop early, within the first 6 months of therapy with natalizumab. Although no antibodies were detected after 4 months of therapy in this particular study, this does not rule out their development later on in exceptional cases.

Clinical benefits of interferon beta-1a in relapsing–remitting MS: a phase IV study

Objective – To evaluate the efficacy and safety of IFNβ‐1a (Avonex®, Biogen, Inc., Cambridge, MA, USA) in patients with relapsing–remitting multiple sclerosis (MS). Methods– In this multicenter, open‐label, prospective clinical trial, 96 patients with relapsing–remitting MS received IFNβ‐1a 30 mcg intramuscularly once weekly for 2 years. Outcome variables included: change from baseline in mean number of exacerbations, proportion of exacerbation‐free patients, and mean Expanded Disability Status Scale (EDSS) scores at Years 1 and 2. Results– IFNβ‐1a significantly (P < 0.0001) reduced exacerbation rate at Years 1 and 2 of treatment. The percentage of exacerbation‐free patients was 53% during Year 1 and 33% during Year 2. Mean EDSS scores were 2.96 ± 1.26 at baseline, 2.89 ± 1.42 at Year 1, and 3.00 ± 1.62 at Year 2 (P = 0.116). EDSS scores improved in 35.4%, remained stable in 28.1%, and worsened in 36.5% of patients. IFNβ‐1a treatment was well tolerated. Conclusion– This study confirms and extends the beneficial clinical profile for IFNβ‐1a in relapsing MS.

Multiple sclerosis in Gypsies from southern Spain: prevalence, mitochondrial DNA haplogroups and HLA class II association

Occasional reports have mentioned the prevalence of multiple sclerosis (MS) among Gypsies, and no studies have examined to date the prevalence of MS or human leukocyte antigen (HLA) genetics associations in the Spanish Gypsy population. We decided to study the prevalence, mitochondrial DNA (mtDNA) haplogroups and HLA class II distribution among gypsies with MS in southern Spain. We searched for Gypsy MS patients and studied HLA class II alleles by polymerase chain reaction with sequence-specific oligonucleotide (PCR/SSO) probe hybridization or sequence-specific primers amplification. An additional study of the mtDNA haplogroups by sequencing of the hypervariable segments of the control region was also performed to provide details of their ethnic origin. Estimated prevalence of MS in the Gypsy population in Malaga was 52/100,000. No significant differences were found in mtDNA between Gypsy MS patients and Gypsy controls. DRB1*1501, DQB1*0602 and DQB1*0608 alleles were the only positive HLA association with MS. The Gypsies in our series have the same anthropological origin as other European gypsy groups, as shown by mtDNA haplogroups. Although interpreted with great caution because of the small sample size, we found that the prevalence of MS in Gypsies in Malaga is not as low as that in Central Europe, although it is significantly less than that found in Caucasians from Spain (75-79/100,000). DQB1*0602 was the strongest positive association found with Gypsy MS patients, and DRB1*1501-DQB1*0602 was the most frequent haplotype in this group.