Structural progression rate decreases over time on serial radiography and magnetic resonance imaging of sacroiliac joints and spine in a five-year follow-up study of patients with ankylosing spondylitis treated with tumour necrosis factor inhibitor.

OBJECTIVE: To investigate temporal changes in structural progression assessed by serial conventional radiography and magnetic resonance imaging (MRI) of the sacroiliac joints (SIJs) and spine in patients with ankylosing spondylitis (AS) treated with tumour necrosis factor (TNF) inhibitor for 5 years. METHOD: Forty-two patients were included and 33 patients were followed for 5 years in a prospective investigator-initiated study. Conventional radiographs were required four times and MRI seven times. The modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS); Spondyloarthritis Research Consortium of Canada (SPARCC) MRI SIJ and Spine Inflammation, and SPARCC MRI SIJ Structural Score (SSS) for Fat, Erosion, Backfill, and Ankylosis; and the Canada-Denmark MRI scores for Spine Inflammation, Fat, Erosion, and New Bone Formation (NBF) were applied. RESULTS: Compared with baseline, MRI Inflammation had decreased significantly at week 22 (spine)/week 46 (SIJ) and thereafter. MRI SIJ Fat (from week 22), SIJ Ankylosis, Spine NBF, and mSASSS had increased significantly at week 46 and thereafter. SIJ Erosion had decreased from year 2. The annual progression rate in mSASSS was significantly higher during weeks 0-46 compared to week 46 to year 3. In multivariate regression analyses, baseline SIJ Inflammation and Backfill were independent predictors of 5 year progression in SIJ Ankylosis. Spine Erosion predicted progression in Spine NBF. Longitudinally, Ankylosing Spondylitis Disease Activity Score, Bath Ankylosing Spondylitis Disease Activity Index, MRI Spine Inflammation, Fat, and Erosion scores were significantly associated with mSASSS. SIJ Inflammation, Fat, Erosion, and Backfill scores were longitudinally associated with SIJ Ankylosis. Structural progression was not associated with body mass index, smoking, or Assessment of SpondyloArthritis international Society Non-Steroidal Anti-Inflammatory Drug Index. CONCLUSION: In a 5 year follow-up study of patients with AS treated with TNF inhibitor, structural progression decreased over time.

Recurrence of spondylarthropathy among first-degree relatives of patients: a systematic cross-sectional study.

OBJECTIVE: To examine the recurrence of manifestations belonging to the spectrum of spondylarthropathy (SpA) in first-degree relatives of patients with SpA, and to estimate the recurrence risk ratio. METHODS: Parents and siblings of consecutive SpA probands have been thoroughly investigated, including clinical data collection, pelvic x ray and human leukocyte antigen (HLA)-B27 status determination. The diagnosis of SpA was made according to European Spondylarthropathy Study Group and/or the Amor criteria. The recurrence risk ratio lambda(1), which gives an estimate of the weight of genetic factors, was calculated as the ratio of the recurrence risk of SpA in first-degree relatives compared with the population prevalence of SpA. The lambda(non-HLA) was obtained by similar calculations restricted to HLA-B27+ individuals. RESULTS: Most manifestations of SpA were more frequent among the 157 HLA-B27+ relatives of 83 probands than among their 111 HLA-B27- relatives. A diagnosis of SpA was made in 50 relatives of 31 (37%) probands. Recurrence was very similar between parents and siblings, without gender difference, resulting in overall recurrence risk of 12% in first-degree relatives and of 22.7% in HLA-B27+ relatives. The lambda(1) value was 40 and the lambda(non-HLA) value was 6.5, very close to the lambda(HLA) value of 6.25 estimated from linkage study in SpA. CONCLUSIONS: A similar recurrence risk of SpA was observed between parents and siblings, consistent with a model of inheritance with no dominance variance and without sex influence. The weight of the non-HLA genetic component was equivalent to that estimated for the HLA locus, and fitted a model of multiplicative interaction between HLA and non-HLA genetic components.

Lack of association between Tenascin-C gene and spondyloarthritis.

OBJECTIVES: We previously identified a new susceptibility region linked to SpA in 9q31-34. Tenascin-C (TNC) appears as one of the best positional and functional candidate genes lying within this SPA2 locus. The objectives of the present study were to identify TNC polymorphisms, and to examine their putative association with SpA. METHODS: We first performed variants screening in 20 independent SpA patients from families with high linkage score to the SPA2 locus, and three unrelated controls: TNCs coding regions (28 exons), intron-exon boundaries and 5'- and 3'-flank regions were fully re-sequenced to identify polymorphisms. Then we genotyped selected variants in 183 independent trios, and assessed their intrafamilial association with SpA by transmission disequilibrium test. RESULTS: Variants screening allowed us to identify 26 polymorphisms, 7 of which were selected for further study, in addition to an intronic polymorphism previously reported as associated with Achilles tendon injuries. In intrafamilial association test, none of the variants showed significant transmission disequilibrium. Results from analysis restricted to AS were not different from those obtained on the whole SpA group. CONCLUSIONS: TNC was one of the best positional and functional candidate genes within the SPA2 locus. Nevertheless, we found no association between polymorphisms in this gene and SpA. However, we cannot exclude that variants located in intronic regions or in the vicinity of TNC, which were not tested in the present study, could be implicated in the predisposition to SpA.

Increase in vertebral body size in postmenopausal women with osteoporosis.

Bone geometry plays a prominent role in bone strength. Cross-sectional studies have shown that advancing age is associated with increasing diameter of long bones, related to both periostal apposition and endosteal resorption. However, there are few data provided by prospective studies, especially concerning the changes in vertebral body dimensions. The objective of this prospective study was to measure the changes occurring in the vertebral body size of women with postmenopausal osteoporosis. Three-year data from placebo groups of the SOTI and TROPOS trials, performed in women with postmenopausal osteoporosis, were used for this study. In these trials, patients underwent lateral radiographs of the thoracic and lumbar spine at baseline and annually over 3 years, according to standardized procedures. Six-point digitization method was used: the four corner points of the vertebral body from T4 to L4 are marked, as well as an additional point in the middle of the upper and lower endplates. From these 6 points, the vertebral body perimeter, area and depth were measured at baseline and at 3 years. The analysis excluded all vertebrae with prevalent or incident fracture. A total of 2017 postmenopausal women (mean age 73.4+/-6.1 years) with a mean lumbar spine T score of -3.1+/-1.5, and a mean femoral neck T score of -3.0+/-0.7 are included in the analysis. Vertebral body dimensions increased over 3 years, by 2.1+/-5.5% (mean depth+/-SD), by 1.7+/-8.3% (mean area+/-SD) and by 1.5+/-4.9% (mean perimeter+/-SD) at the thoracic level (T4 to T12). At the lumbar level (L1 to L4), these dimensions increased as well: 1.4+/-3.6% (mean depth+/-SD), 1.4+/-5.7% (mean area+/-SD), 0.7+/-2.9% (mean perimeter+/-SD). A significant increase in vertebral body size was observed for each vertebral level from T5 to L4 for each of these parameters (p<0.01). These prospective results demonstrate that vertebral body dimensions increase over 3 years in women with postmenopausal osteoporosis.

Detection of small joint synovitis by ultrasonography: the learning curve of rheumatologists.

BACKGROUND: Ultrasonography allows assessment of soft tissue structures and has become a valued tool for diagnosing synovitis. OBJECTIVE: To assess the learning curve for ultrasonography in evaluating synovitis of the small joints in rheumatoid arthritis. METHODS: Metacarpophalangeal (MCP), metatarsophalangeal (MTP), and proximal interphalangeal (PIP) joints were evaluated using ultrasonography (Esaote AU 5 Epi, linear probe 10-13 MHz) by four rheumatologists, the first being experienced (senior), the others having no (fellows 1 and 2) or little (fellow 3) experience in ultrasonography. For each fellow, the learning curve was divided into blocks. In each block the fellow examined five consecutive patients with the senior; then, blinded to the senior's results, two further patients alone (seven patients examined per block). For each evaluation, the MCP, PIP, and MTP joints were individually tagged as having synovitis or not. The ultrasonography results were compared between fellow and senior for the two last patients of each block, using proportions of agreement and kappa statistics. RESULTS: 70 patients were evaluated (seven practice patients, followed by nine blocks). For fellows 1 and 2, the proportions of agreement were respectively 42% and 47% (kappa = 0 and 0) at the first evaluation, and rose progressively to 82% and 82% (kappa = 0.63 and 0.62) at the ninth evaluation. For fellow 3, initially good results were followed by decreased accuracy. CONCLUSIONS: Detecting synovitis of the MCP, PIP, and MTP joints using ultrasonography can be done accurately by rheumatologists initially not experienced in this technique. At least 70 examinations were necessary to develop competence.

The role of HLA genes in familial spondyloarthropathy: a comprehensive study of 70 multiplex families.

OBJECTIVES: To investigate whether HLA alleles, other than HLA-B27, influence predisposition to spondyloarthropathy (SpA) in multiplex families. METHODS: Seventy French families with at least two affected SpA members were recruited. Patients, and their first degree relatives were typed for HLA-A, B, C, and DR, and extended HLA haplotypes were determined. The distribution of HLA-A, C, and DR alleles carried on HLA-B27+ haplotypes in SpA families was compared with the distribution of these alleles among HLA-B27+ haplotypes in the French general population. Contribution to SpA susceptibility of HLA-A, B, C, and DR alleles, other than HLA-B27, was tested by transmission disequilibrium test. The contribution of HLA alleles to specific presentation features of SpA was examined. RESULTS: Frequencies of HLA-A, C, and DR alleles carried on HLA-B27+ haplotypes from SpA families were comparable with those seen in the French population, except for DR13 which was overrepresented among patients (pcorr<0.001). Most interestingly, the HLA-DR4 allele was transmitted in excess to patients with SpA, independently of linkage to HLA-B27 (pcorr=0.05), and in a direction opposite to that for HLA-B27+ unaffected siblings (pcorr=0.01). Finally, the distribution of HLA alleles was not related to the presentation feature of SpA. CONCLUSION: HLA predisposition to familial SpA appears not to be limited to HLA-B27, but some HLA-DR alleles also have a significant influence. In particular, HLA-DR4 contributes significantly to a genetic predisposition to SpA, which may have implications in our understanding of SpA pathogenesis.

Phenotypic diversity is not determined by independent genetic factors in familial spondylarthropathy.

OBJECTIVE: To analyze the segregation of manifestations belonging to the spectrum of spondylarthropathy (SpA) among patients and unaffected siblings within SpA multiplex families. METHODS: Ninety-five multiplex families have been investigated. The diagnosis of SpA was made according to European Spondylarthropathy Study Group criteria. The prevalence of SpA manifestations was determined in unaffected siblings and compared with their prevalence in patients. RESULTS: We compared 241 SpA patients with 259 unaffected siblings. The prevalence of skeletal and extraarticular features not used as diagnostic criteria, i.e., radiographic sacroiliitis, peripheral enthesitis, uveitis, psoriasis, and inflammatory bowel disease, was significantly increased in patients compared with unaffected siblings. This result was not accounted for by sex or HLA-B27 distribution differences. CONCLUSION: In familial SpA, skeletal and extraarticular manifestations tend to segregate together, implying that all subsets are predominantly determined by a shared component, and that accessory factors must be responsible for phenotype diversity.

The familial form of spondylarthropathy: a clinical study of 115 multiplex families. Groupe Français d'Etude Génétique des Spondylarthropathies.

OBJECTIVE: To investigate the interrelationships among different phenotypes, and their relationship to the HLA-Blocus, in multiplex families with spondylarthropathy (SpA). METHODS: We recruited 115 white French families, each of which had at least 2 members with SpA. Pedigrees were established. Clinical data and pelvic radiographs were collected. The HLA-B27 status of all patients was determined. Analysis was performed to determine the prevalence of SpA manifestations according to sex, disease duration, and HLA-B status, and to examine clustering of specific manifestations in subsets of families. RESULTS: We identified 329 SpA patients. Mean +/-SD age at onset was 24+/-9.4 years. The male:female ratio was 186:143, or 1.3, with few sex differences in disease expression. Axial manifestations and HLA-B27 were each present in 97% of the patients. Inflammatory bowel disease and HLA-B35 were overrepresented in the 7 families containing HLA-B27-negative patients. The frequency of radiographic sacroiliitis increased in parallel with disease duration. Peripheral enthesitis, radiographic sacroiliitis, and psoriasis were evenly distributed in the families. Clustering independent of age was only observed for peripheral arthritis, suggesting that specific factors may predispose individuals to this manifestation. CONCLUSION: Familial SpA appears to be homogeneous, based on the high frequencies of axial skeletal involvement and HLA-B27. The lack of clustering of most manifestations in families suggests that a predominant shared component, including HLA-B27, predisposes individuals to all forms of familial SpA, and that ubiquitous genetic or environmental factors contribute to phenotype diversity.