Benefits of Switch from Oral to Subcutaneous Route on Adherence to Methotrexate in Patients with Rheumatoid Arthritis in Real Life Setting.

PURPOSE: The purpose of the APRIM study (for Adherence Polyarthrite Rhumatoïde Injection Methotrexate) was to investigate the change in treatment adherence of patients with rheumatic arthritis (RA) who switched from oral to subcutaneous methotrexate (MTX). PATIENTS AND METHODS: Prospective, observational study in RA patients treated with MTX and switching from oral to subcutaneous (SC) route in real-life conditions. Data on motivations for switch, disease activity (DAS28-CRP), quality of life (AISM-2 SF), disability (HAQ-DI), and adherence to MTX were collected at inclusion (M0) and 6 months later (M6). Adherence was assessed by the 8-item Morisky Medication Adherence Scale (MMAS-8) and defined as high (MMAS-8 = 8), medium (MMAS-8 = 6 or ≤8) or low (MMAS-8 < 6). The primary evaluation criterion was the proportion of patients who maintained strong adherence or improved adherence by at least one category (from low to medium or strong or from medium to strong) between M0 and M6. RESULTS: The analysis involved 207 patients (age 60.4±12.7 years, 75.2% females). 6.7% were in remission and 15.5% had low disease activity (LDA) at baseline. 58.5% reached the primary criterion and strong adherence rate increased from 42.0% to 50.7%. Change of route was combined with increased MTX dose in 34.8% of patients. Switch to SC route increased the proportion of patients with remission or LDA from 22.8% to 52.9% and increased quality of life even in patients with unchanged MTX dose. CONCLUSION: Overall, change from oral to SC route improved adherence to MTX, RA control and quality of life independently of change in MTX dose.

MTX optimization or adding bDMARD equally improve disease activity in rheumatoid arthritis: results from the prospective study STRATEGE.

OBJECTIVES: The STRATEGE (Therapeutic Strategy in Patients Treated With Methotrexate for Rheumatoid Arthritis) study aimed to describe treatment strategies in current practice in RA biologic DMARD (bDMARD)-naïve patients with an inadequate response to MTX therapy, and to compare clinical efficacy of the different therapeutic strategies on disease activity after 6 months. METHODS: The main inclusion criteria of this prospective, observational, multicentre study were confirmed RA diagnosis, treatment by MTX monotherapy and need for therapeutic management modification. RESULTS: The 722 patients included had a mean (s.d.) RA duration of 5.3 (6.7) years, a mean DAS28 of 4.0 (1.1); they were all receiving MTX monotherapy, 68% oral, at a mean dose of 15.0 (4.1) mg/week. Two major strategies were identified: (i) MTX monotherapy dose and/or route optimization (72%) and (ii) bDMARD initiation ± MTX (16%). MTX dosing was modified for 70% of patients, maintained (dose and route) for 28% of patients and interrupted for 2%. bDMARDs were started when the MTX mean dose was 17.4 mg/week, 56% parenterally; MTX was maintained concomitantly for 96% of patients. Six-month follow-up results adjusted by propensity score showed that both options were equally successful in improving disease activity and physical function, with 63 and 68% of good-to-moderate EULAR responses, respectively. CONCLUSION: The STRATEGE study shows the importance of initial MTX treatment optimization before initiation of a biological treatment and emphasizes the importance of treat-to-target strategy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02288520.

Efficacy of mifepristone - Prostaglandin analogue combination in medical termination of pregnancy up to and beyond 7 weeks of amenorrhea: The RYMMa study.

OBJECTIVE: To assess, in real-life conditions, the success rate of the protocol mifepristone 600 mg / prostaglandin analogue (PG) in women requesting medical termination of pregnancy (MToP) either up to or beyond 7 weeks of amenorrhea (WA). STUDY DESIGN: The study was performed between 2015 and 2016. This was a non-interventional prospective, multicentre, longitudinal study conducted in France, among a sample of public and/or private centres dealing with MToP. Characteristics of women, term of Mtop, modality of PG used were reported. The primary outcome was success of MToP, defined as complete abortion without surgical procedure. RESULTS: A total of 893 pregnant women with less than the legal term of 14 WA were included in this study: 490 (54.9 %) ≤7 WA and 403 (45.1 %) >7 WA comprising 29 > 9 WA. The mean age of women was 28.1 ± 6.8 years and the one of pregnancy was 7.0 WA ± 1.3 WA. The most frequently used PG combined to mifepristone 600 mg was misoprostol 400 µg (57.0 % ≤7 WA and 35.1 % >7 WA) or 800 µg per os (oral or oral transmucosal) (27.5 % ≤7 WA and 40.1 % >7 WA). Vaginal misoprostol (6.4 %, N = 48) and gemeprost (5.2 %, N = 39) were less used. In women ≤7 WA (N = 422) and women >7 WA (N = 354) for whom result of the MToP was collected, success rates were 94.5 % (95 %CI 91.9 %-96.5 %) and 92.4 % (95 %CI 89.1 %-94.9 %), respectively (p = 0.219). In multivariate regression analysis, three factors were significantly associated with a higher risk of MToP failure: increased number of previous pregnancies (OR = 1.233; 95 %CI 1.086-1.401 for one pregnancy), increased number of previous surgical ToPs (OR = 1.563; 95 %CI 1.036-2.359 for one ToP) and increased interval between mifepristone and PG intake (OR = 1.061; 95 %CI 1.012-1.112 for one hour). Term of pregnancy (OR = 1.497; 95 %CI 0.833-2.690 for ≤7 WA vs >7WA), administration route (OR = 1.553; 95 %CI 0.488-4.936 for oral vs oral transmucosal; and OR = 1.216; 95 %CI 0.625-2.366 for vaginal vs oral transmucosal), and dose of misoprostol (OR = 1.000; 95 %CI 0.999-1.001), were not associated with the risk of failure. Overall, tolerance was good. CONCLUSION: This study showed, in real-life settings, a high rate of success for MToP using mifepristone 600 mg, independent of the pregnancy term and the therapeutic protocol used. MToP was safe and well tolerated however only a small number of women beyond 9 WA have been included.

Use of Auto-Injector for Methotrexate Subcutaneous Self-Injections: High Satisfaction Level and Good Compliance in SELF-I Study, a Randomized, Open-Label, Parallel Group Study.

INTRODUCTION: The objective of the study was to compare compliance and acceptability of a new auto-injector (AI) versus syringe for administration of methotrexate (MTX) in patients with rheumatoid arthritis (RA). METHODS: We conducted a randomized, open-label, parallel group study comparing AI to pre-filled syringe (PFS). Adult patients with RA (ACR/EULAR 2010) receiving MTX (orally or by injection) for at least 3 months were allocated to AI or PFS for 6 months and then were allocated to AI for 6 further months. Two co-primary endpoints were defined at M6: percentage of patients with compliance at least 80%; change in functional capacity assessed by Health Assessment Questionnaire (HAQ). Secondary endpoints included quality of life (RaQoL), RA activity (DAS28), and acceptability. Local safety at injection site was assessed at each visit. RESULTS: Two-hundred and sixty-five patients were randomized. The main analysis was conducted on per protocol set (99 AI and 98 PFS). Compliance was 96.2% in AI and 98.9% in PFS. Good complier rates were 89.9% and 94.9%, thus a difference of - 5.0% (- 18.9%; 8.9%). HAQ remained stable in both groups. No difference was found on RaQoL, change in RA activity, and safety profile. Autonomy, acceptability, and patient satisfaction were better with AI, and patients having had the experience of both AI and PFS preferred AI (p < 0.001). CONCLUSIONS: Although this study did not demonstrate non-inferiority of AI versus PFS, compliance was excellent in the two groups, and AI, which was preferred by patients, is a valuable alternative to PFS for administration of MTX. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02553018. FUNDING: Nordic Pharma SAS.

Evaluation of Usability and Acceptance of a New Autoinjector Intended for Methotrexate Subcutaneous Self-Administration in the Management of Rheumatoid Arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, for which the introduction of injectable treatments has had a major impact on quality of life directly related to the disease. The purpose of this descriptive study was to evaluate the usability of a new autoinjector, intended for methotrexate self-administration, based on the device's design and instructions for use (IFU). METHODS: This multicenter trial included three user groups: a group of patients with established RA subdivided into two groups according to their hand disability, and a group of caregivers or nurses. Each subject performed three simulated injections with a water-filled device on a foam pad. The first injection was made just after reading the IFU without further instructions (first phase). The second phase consisted of two injections made after explanations provided upon request of the subject in an optimum environment and in a "worst-case" home environment. The usability of the autoinjector was assessed by a questionnaire (success: ≥75% of positive responses) and by a score card reflecting injection performances (success: execution of ≥75% of handling steps). RESULTS: Forty-two subjects were enrolled in the study. During the first phase, the great majority of subjects succeeded in the usability questionnaire (90.5%) and in the injection performance (95.2%) with no major differences between the user groups. In the Second phase, all subjects from all three user groups succeeded in the usability questionnaire and had a positive rate of device handling, regardless of the environment and of the user group. No safety concerns were raised during the study. CONCLUSIONS: This study found a very high level of usability and subject acceptance of the autoinjector, intended for methotrexate self-administration, regardless of the hand disability and environmental conditions. FUNDING: Nordic Group. TRIAL REGISTRATION: EudraCT reference number: 2014-A0141245.

A family-based genome-wide association study reveals an association of spondyloarthritis with MAPK14.

OBJECTIVE: More than 40 loci have been associated with ankylosing spondylitis (AS), but less is known about genetic associations in spondyloarthritis (SpA) as a whole. We conducted a family-based genome-wide association study (GWAS) to identify new non-major histocompatibility complex (MHC) genetic factors associated with SpA. METHODS: 906 subjects from 156 French multiplex families, including 438 with SpA, were genotyped using Affymetrix 250K microarrays. Association was tested with Unphased. The best-associated non-MHC single nucleotide polymorphisms (SNPs) were then genotyped in two independent familial cohorts (including 215 French and 294 North American patients with SpA, respectively) to replicate associations. RESULTS: 43 non-MHC SNPs yielded an association signal with SpA in the discovery cohort (p<1×10-4). In the extension studies, association was replicated at a nominal p value of p<0.05 for 16 SNPs in the second cohort and for three SNPs in the third cohort. Combined analysis identified an association close to genome-wide significance between rs7761118, an intronic SNP of MAPK14, and SpA (p=3.5×10-7). Such association appeared to be independent of HLA-B27. CONCLUSIONS: We report here for the first time a family-based GWAS study on SpA and identified an associated polymorphism near MAPK14. Further analyses are needed to better understand the functional basis of this genetic association.

Whole-genome single nucleotide polymorphism-based linkage analysis in spondyloarthritis multiplex families reveals a new susceptibility locus in 13q13.

OBJECTIVE: Spondyloarthritis (SpA) is a chronic inflammatory disorder with high heritability but with complex genetics. Apart from HLA-B27, most of the underlying genetic components remain to be identified. We conducted a whole-genome high-density non-parametric linkage analysis to identify new genetic factors of susceptibility to SpA. METHODS: 914 subjects including 462 with SpA from 143 multiplex families were genotyped using Affymetrix 250K microarrays. After quality control, 189 368 single nucleotide polymorphisms (SNPs) were kept for further analyses. Both non-parametric and parametric linkage analyses were performed using Merlin software. Association was tested with Unphased. RESULTS: Non-parametric linkage analysis identified two regions significantly linked to SpA: the major histocompatibility complex (LODmax=24.77) and a new 13q13 locus (LODmax=5.03). Additionally, eight loci achieved suggestive LOD scores, including the previously identified SPA2 locus at 9q33 (LODmax=3.51). Parametric analysis supported a codominant model in 13q13 with a maximum heterogeneity LOD, 'HLOD' score of 3.084 (α=0.28). Identification of meiotic recombination events around the 13q13 linkage peak in affected subjects from the 43 best-linked families allowed us to map the disease interval between 38.753 and 40.040 Mb. Family-based association analysis of the SNPs inside this interval in the best-linked families identified a SNP near FREM2 (rs1945502) which reached a p value close to statistical significance (corrected p=0.08). CONCLUSION: We report here for the first time a significant linkage between 13q13 and SpA. Identification of susceptibility factor inside this chromosomal region through targeted sequencing in linked families is underway.

Association between the IL-1 family gene cluster and spondyloarthritis.

OBJECTIVE: Spondyloarthritis is a group of articular disorders sharing a genetic background. Polymorphisms in the IL-1 gene cluster have previously been associated with ankylosing spondylitis (AS), a subset of spondyloarthritis. This study examined the association between several of these polymorphisms and the whole spondyloarthritis. Particular attention was devoted to genotype-phenotype correlations. METHODS: Seven single-nucleotide polymorphisms (SNP) and a variable number tandem repeat located in the IL-1 gene cluster were genotyped in 185 independent spondyloarthritis trios. Family-based association test (FBAT) was computed using the FBAT software. Analysis was carried in spondyloarthritis as a whole and also in AS. A case-control replication study was performed for four of the SNP, in an independent sample of 414 spondyloarthritis and 264 controls. A combined analysis of both studies was performed. RESULTS: The SNP rs2856836 in IL1A was significantly associated with spondyloarthritis (p=0.009) and AS (p=0.010) in the family study. The case-control study revealed an association between another IL1A variant (rs1894399) and AS (p=0.035), and between IL1F10.3 (rs3811058) and spondyloarthritis (p=0.041). By combining family and case-control studies an association between AS and IL1A was confirmed (rs1894399, p=0.024), whereas non-AS was more significantly associated with IL1F10.3 (p=0.0043). Family-based and case-control studies revealed significant association between the two most frequent haplotypes combining the four SNP of the replication study and both spondyloarthritis (p=0.0054 and p=0.038) and AS phenotypes (p=0.018 and 0.0036). CONCLUSION: This study is the first to demonstrate an association between several polymorphisms located in the IL-1 gene cluster and spondyloarthritis as a whole. The IL1A locus was strongly associated with AS phenotype, whereas IL1F10 was associated with non-AS.

Systematic candidate gene investigations in the SPA2 locus (9q32) show an association between TNFSF8 and susceptibility to spondylarthritis.

OBJECTIVE: Our group previously identified a new susceptibility region linked to spondylarthritis (SpA) on chromosome 9q31-34. Fine mapping of this SPA2 locus allowed us to refine the peak of linkage to a 1.3-Mb interval. The objective of this study was to resequence most positional candidate genes lying in that region, to identify polymorphisms, and to examine their association with SpA. METHODS: Variants screening was performed in 30 independent patients with SpA from families with a high linkage score to the SPA2 locus and 30 control subjects. The coding regions, intron-exon boundaries, and 5'- and 3'-flanking regions of ZNF618, A1L4R1_HUMAN (AF495724), AMBP, KIF12, ORM1, ORM2, C9ORF91, ENSESTG000000230601, and TNFSF8 were resequenced to identify polymorphisms. Selected variants were genotyped in an extended French cohort (442 patients and 268 control subjects overall). Replication was performed in a combined Belgian and Portuguese cohort (433 patients and 299 control subjects). RESULTS: Variants screening allowed us to identify 98 polymorphisms, 5 of which were selected for further studies, based on statistical significance. The rare intronic single-nucleotide polymorphism (SNP) rs3181357, located in TNFSF8, was significantly associated with SpA in the French and the replication cohorts (odds ratio [OR] 2.03, P = 0.009 and OR 2.26, P = 0.0014, respectively) and in the pooled analysis (OR 2.14, P = 0.0001). CONCLUSION: Positional candidate gene screening in the SPA2 locus allowed us to identify and replicate an association between a rare SNP located in TNFSF8 and SpA. This new finding appears to be independent of an association with a haplotype near TNFSF15, which we recently reported.

Comprehensive linkage and association analyses identify haplotype, near to the TNFSF15 gene, significantly associated with spondyloarthritis.

Spondyloarthritis (SpA) is a chronic inflammatory disorder with a strong genetic predisposition dominated by the role of HLA-B27. However, the contribution of other genes to the disease susceptibility has been clearly demonstrated. We previously reported significant evidence of linkage of SpA to chromosome 9q31-34. The current study aimed to characterize this locus, named SPA2. First, we performed a fine linkage mapping of SPA2 (24 cM) with 28 microsatellite markers in 149 multiplex families, which allowed us to reduce the area of investigation to an 18 cM (13 Mb) locus delimited by the markers D9S279 and D9S112. Second, we constructed a linkage disequilibrium (LD) map of this region with 1,536 tag single-nucleotide polymorphisms (SNPs) in 136 families (263 patients). The association was assessed using a transmission disequilibrium test. One tag SNP, rs4979459, yielded a significant P-value (4.9 x 10(-5)). Third, we performed an extension association study with rs4979459 and 30 surrounding SNPs in LD with it, in 287 families (668 patients), and in a sample of 139 cases and 163 controls. Strong association was observed in both familial and case/control datasets for several SNPs. In the replication study, carried with 8 SNPs in an independent sample of 232 cases and 149 controls, one SNP, rs6478105, yielded a nominal P-value<3 x 10(-2). Pooled case/control study (371 cases and 312 controls) as well as combined analysis of extension and replication data showed very significant association (P<5 x 10(-4)) for 6 of the 8 latter markers (rs7849556, rs10817669, rs10759734, rs6478105, rs10982396, and rs10733612). Finally, haplotype association investigations identified a strongly associated haplotype (P<8.8 x 10(-5)) consisting of these 6 SNPs and located in the direct vicinity of the TNFSF15 gene. In conclusion, we have identified within the SPA2 locus a haplotype strongly associated with predisposition to SpA which is located near to TNFSF15, one of the major candidate genes in this region.

Comprehensive survey of mutations in RP2 and RPGR in patients affected with distinct retinal dystrophies: genotype-phenotype correlations and impact on genetic counseling.

X-linked forms of retinitis pigmentosa (RP) (XLRP) account for 10 to 20% of families with RP and are mainly accounted for by mutations in the RP2 or RP GTPase regulator (RPGR) genes. We report the screening of these genes in a cohort of 127 French family comprising: 1) 93 familial cases of RP suggesting X-linked inheritance, including 48 out of 93 families with expression in females but no male to male transmission; 2) seven male sibships of RP; 3) 25 sporadic male cases of RP; and 4) two cone dystrophies (COD). A total of 5 out of the 93 RP families excluded linkage to the RP2 and RP3 loci and were removed form the cohort. A total of 14 RP2 mutations, 12 of which are novel, were identified in 14 out of 88 familial cases of RP and 1 out of 25 sporadic male case (4%). In 13 out of 14 of the familial cases, no expression of the disease was noted in females, while in 1 out of 14 families one woman developed RP in the third decade. A total of 42 RPGR mutations, 26 of which were novel, were identified in 80 families, including: 69 out of 88 familial cases (78.4%); 2 out of 7 male sibship (28.6%); 8 out of 25 sporadic male cases (32.0%); and 1 out of 2 COD. No expression of the disease was noted in females in 41 out of 69 familial cases (59.4%), while at least one severely affected woman was recognized in 28 out of 69 families (40.6%). The frequency of RP2 and RPGR mutations in familial cases of RP suggestive of X-linked transmission are in accordance to that reported elsewhere (RP2: 15.9% vs. 6-20%; RPGR: 78.4% vs. 55-90%). Interestingly, about 30% of male sporadic cases and 30% of male sibships of RP carried RP2 or RPGR mutations, confirming the pertinence of the genetic screening of XLRP genes in male patients affected with RP commencing in the first decade and leading to profound visual impairment before the age of 30 years.

The genetics of spondyloarthropathies.

The spondyloarthropathies constitute a group of inflammatory joint diseases linked by shared characteristics that include a strong common genetic background. Genetic factors include major histocompatibility complex (MHC) genes, among which HLA-B27 contributes 30% of the overall genetic susceptibility to spondyloarthropathies, and non-MHC genes, none of which have been identified to date. Genome screens have identified regions that may contain susceptibility genes for spondyloarthropathies. In particular, a locus on the long arm of chromosome 9 (9q31-34) was identified by two groups working independently from each other. Studies using the candidate gene approach ruled out a role for most of the tested genes, including CARD15/NOD2. However, several independent groups have reported significant associations between ankylosing spondylitis and the IL-1 gene cluster on the long arm of chromosome 2.

Molecular diagnostics of mitochondrial disorders.

The mitochondrial respiratory chain (RC) results from the expression of both mitochondrial and nuclear genes. The number of disease-causing mutations in nuclear genes is steadily growing and mitochondrial DNA (mtDNA) deletions and mutations account for no more than 15-20% of pediatric patients. Unfortunately, the disease-causing mutations have been identified for only a small number of patients. Thus, elucidating the genetic bases of RC is both essential for genetic diagnosis of patients and for fundamental knowledge of these disorders. The molecular diagnostics of mitochondrial disorders come under both genetic diagnosis and research. Indeed, identification of a new gene in a specific patient allows to perform genetic diagnosis in other families and identification of mutations in already known disease-causing genes allows to constitute a cohort of patients for further functional studies. Thus, elucidating the genetic bases of RC deficiency is an essential task that needs the use of several appropriate strategies. Fine phenotypage of patients and candidate gene screening is the first step for the constitution of a well-characterized cohort of patients. Genetic mapping has to be used in large families. This approach is greatly enhanced in the case of consanguineous families. The consanguinity of the parents should also lead to test genetic markers surrounding the gene loci rather than to directly sequence several candidate genes. However, the main problem is encountered in the cases of sporadic cases for which no genetic approaches can be developed. In these cases, functional complementation by human chromosomes or cDNA is the only presently available strategy.