Degenerative inter-vertebral disc disease osteochondrosis intervertebralis in Europe: prevalence, geographic variation and radiological correlates in men and women aged 50 and over.

Objectives: To assess the prevalences across Europe of radiological indices of degenerative inter-vertebral disc disease (DDD); and to quantify their associations with, age, sex, physical anthropometry, areal BMD (aBMD) and change in aBMD with time. Methods: In the population-based European Prospective Osteoporosis Study, 27 age-stratified samples of men and women from across the continent aged 50+ years had standardized lateral radiographs of the lumbar and thoracic spine to evaluate the severity of DDD, using the Kellgren-Lawrence (KL) scale. Measurements of anterior, mid-body and posterior vertebral heights on all assessed vertebrae from T4 to L4 were used to generate indices of end-plate curvature. Results: Images from 10 132 participants (56% female, mean age 63.9 years) passed quality checks. Overall, 47% of men and women had DDD grade 3 or more in the lumbar spine and 36% in both thoracic and lumbar spine. Risk ratios for DDD grades 3 and 4, adjusted for age and anthropometric determinants, varied across a three-fold range between centres, yet prevalences were highly correlated in men and women. DDD was associated with flattened, non-ovoid inter-vertebral disc spaces. KL grade 4 and loss of inter-vertebral disc space were associated with higher spine aBMD. Conclusion: KL grades 3 and 4 are often used clinically to categorize radiological DDD. Highly variable European prevalences of radiologically defined DDD grades 3+ along with the large effects of age may have growing and geographically unequal health and economic impacts as the population ages. These data encourage further studies of potential genetic and environmental causes.

Association of the X-chromosomal genes TIMP1 and IL9R with rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is an inflammatory joint disease with features of an autoimmune disease with female predominance. Candidate genes located on the X-chromosome were selected for a family trio-based association study. METHODS: A total of 1452 individuals belonging to 3 different sample sets were genotyped for 16 single-nucleotide polymorphisms (SNP) in 7 genes. The first 2 sets consisted of 100 family trios, each of French Caucasian origin, and the third of 284 additional family trios of European Caucasian origin. Subgroups were analyzed according to sex of patient and presence of anti-cyclic citrullinated peptide (anti-CCP) autoantibodies. RESULTS: Four SNP were associated with RA in the first sample set and were genotyped in the second set. In combined analysis of sets 1 and 2, evidence remained for association of 3 SNP in the genes UBA1, TIMP1, and IL9R. These were again genotyped in the third sample set. Two SNP were associated with RA in the joint analysis of all samples: rs6520278 (TIMP1) was associated with RA in general (p = 0.035) and rs3093457 (IL9R) with anti-CCP-positive RA patients (p = 0.037) and male RA patients (p = 0.010). A comparison of the results with data from whole-genome association studies further supports an association of RA with TIMPL The sex-specific association of rs3093457 (IL9R) was supported by the observation that men homozygous for rs3093457-CC are at a significantly higher risk to develop RA than women (risk ratio male/female = 2.98; p = 0.048). CONCLUSION: We provide evidence for an association of at least 2 X-chromosomal genes with RA: TIMP1 (rs6520278) and IL9R (rs3093457).

Testing for the association of the KIAA1109/Tenr/IL2/IL21 gene region with rheumatoid arthritis in a European family-based study.

INTRODUCTION: A candidate gene approach, in a large case-control association study in the Dutch population, has shown that a 480 kb block on chromosome 4q27 encompassing KIAA1109/Tenr/IL2/IL21 genes is associated with rheumatoid arthritis. Compared with case-control association studies, family-based studies have the added advantage of controlling potential differences in population structure. Therefore, our aim was to test this association in populations of European origin by using a family-based approach. METHODS: A total of 1,302 West European white individuals from 434 trio families were genotyped for the rs4505848, rs11732095, rs6822844, rs4492018 and rs1398553 polymorphisms using the TaqMan Allelic discrimination assay (Applied Biosystems). The genetic association analyses for each SNP and haplotype were performed using the Transmission Disequilibrium Test and the genotype relative risk. RESULTS: We observed evidence for association of the heterozygous rs4505848-AG genotype with rheumatoid arthritis (P = 0.04); however, no significance was found after Bonferroni correction. In concordance with previous findings in the Dutch population, we observed a trend of undertransmission for the rs6822844-T allele and rs6822844-GT genotype to rheumatoid arthritis patients. We further investigated the five SNP haplotypes of the KIAA1109/Tenr/IL2/IL21 gene region. We observed, as described in the Dutch population, a nonsignificant undertransmission of the AATGG haplotype to rheumatoid arthritis patients. CONCLUSIONS: Using a family-based study, we have provided a trend for the association of the KIAA1109/Tenr/IL2/IL21 gene region with rheumatoid arthritis in populations of European descent. Nevertheless, we failed to replicate a significant association of this region in our rheumatoid arthritis family sample. Further investigation of this region, including detection and testing of all variants, is required to confirm rheumatoid arthritis association.

The ITGAV rs3738919-C allele is associated with rheumatoid arthritis in the European Caucasian population: a family-based study.

The integrin alpha(v)beta3, whose alpha(v) subunit is encoded by the ITGAV gene, plays a key role in angiogenesis. Hyperangiogenesis is involved in rheumatoid arthritis (RA) and the ITGAV gene is located in 2q31, one of the suggested RA susceptibility loci. Our aim was to test the ITGAV gene for association and linkage to RA in a family-based study from the European Caucasian population. Two single nucleotide polymorphisms were genotyped by PCR-restriction fragment length polymorphism in 100 French Caucasian RA trio families (one RA patient and both parents), 100 other French families and 265 European families available for replication. The genetic analyses for association and linkage were performed using the comparison of allelic frequencies (affected family-based controls), the transmission disequilibrium test, and the genotype relative risk.We observed a significant RA association for the C allele of rs3738919 in the first sample (affected family-based controls, RA index cases 66.5% versus controls 56.7%; P = 0.04). The second sample showed the same trend, and the third sample again showed a significant RA association. When all sets were combined, the association was confirmed (affected family-based controls, RA index cases 64.6% versus controls 58.1%; P = 0.005). The rs3738919-C allele was also linked to RA (transmission disequilibrium test, 56.5% versus 50% of transmission; P = 0.009) and the C-allele-containing genotype was more frequent in RA index cases than in controls (RA index cases 372 versus controls 339; P = 0.002, odds ratio = 1.94, 95% confidence interval = 1.3-2.9). The rs3738919-C allele of the ITGAV gene is associated with RA in the European Caucasian population, suggesting ITGAV as a new minor RA susceptibility gene.

Linkage proof for PTPN22, a rheumatoid arthritis susceptibility gene and a human autoimmunity gene.

The tyrosine phosphatase PTPN22 allele 1858T has been associated with rheumatoid arthritis (RA) and other autoimmune diseases. RA is the most frequent of those multifactorial diseases. The RA association was usually restricted to serum rheumatoid factor positive disease (RF+). No interaction was shown with HLA-DRB1, the first RA gene. Many case-control studies replicated the RA association, showing an allele frequency increase of approximately 5% on average and large variations of population allele frequencies (2.1-15.5%). In multifactorial diseases, the final proof for a new susceptibility allele is provided by departure from Mendel's law (50% transmission from heterozygous parents). For PTPN22-1858T allele, convincing linkage proof was available only for type 1 diabetes. We aimed at providing this proof for RA. We analyzed 1,395 West European Caucasian individuals from 465 "trio" families. We replicated evidence for linkage, demonstrating departure from Mendel's law in this subset of early RA onset patients. We estimated the overtransmission of the 1858T allele in RF+ families: T = 63%, P < 0.0007. The 1858T allele frequency increased from 11.0% in controls to 17.4% in RF+ RA for the French Caucasian population and the susceptibility genotype (1858T/T or T/C) from 20.2% to 31.6% [odds ratio (OR) = 1.8 (1.2-2.8)]. In conclusion, we provided the linkage proof for the PTPN22-1858T allele and RF+ RA. With diabetes and RA, PTPN22 is therefore a "linkage-proven" autoimmunity gene. PTPN22 accounting for approximately 1% of the RA familial aggregation, many new genes could be expected that are as many leads to definitive therapy for autoimmune diseases.

Xanthelasma and lipoma in Leonardo da Vinci's Mona Lisa.

The painting Mona Lisa in the Louvre, Paris, by Leonardo da Vinci (1503-1506), shows skin alterations at the inner end of the left upper eyelid similar to xanthelasma, and a swelling of the dorsum of the right hand suggestive of a subcutaneous lipoma. These findings in a 25-30 year old woman, who died at the age of 37, may be indicative of essential hyperlipidemia, a strong risk factor for ischemic heart disease in middle age. As far as is known, this portrait of Mona Lisa painted in 1506 is the first evidence that xanthelasma and lipoma were prevalent in the sixteenth century, long before the first description by Addison and Gall in 1851.

Influence of participation in high-impact sports during adolescence and adulthood on bone mineral density in middle-aged men: a 27-year follow-up study.

This study examined whether participation in high-impact sports during adolescence and adulthood contributes to bone health in males aged 40 years. Data were analyzed on 154 Belgian men aged 13 years at study onset in 1969 and aged 40 years at the end of the 27-year follow-up. In a second analysis, subjects were divided into three groups according to their sports participation history: participation during adolescence and adulthood in high-impact sports (HH; n=18), participation during adolescence in high-impact sports and during adulthood in nonimpact sports or no sports (HN; n=15), and participation during adolescence and adulthood in nonimpact sports or no sports (NN; n=14). Body mass and impact loading during adulthood were significant predictors of total body bone mineral density (BMD) and lumbar spine BMD. Analysis of variance revealed significant differences for lumbar spine BMD between the HH (1.12 g/cm2) group and the HN (1.01 g/cm2) and NN (0.99 g/cm2) groups (F=5.07, p=0.01). Total body BMD was also higher in the HH group at age 40 years, but not significantly (F=3.17, p=0.0515). Covariance analyses for total body BMD and lumbar spine BMD, with body mass and time spent participating in sports as covariates, confirmed these results. Continued participation in impact sports is beneficial for the skeletal health of males aged 40 years.

Musculoskeletal manifestations of benign and malignant tumors of bone.

Benign and malignant tumors of bone often have common musculoskeletal manifestations mimicking rheumatic disorders. The detection and resolution of mimicking symptoms require knowledge, skills, and a problem-solving attitude for musculoskeletal disorders. Before engaging in an extensive investigation, a careful history and full physical examination must be done. This review addresses the recent literature from June 2001 to May 2002 on musculoskeletal manifestations of benign and malignant tumors of bone using "red flag" rubrics: nonspecific pain pattern, atypical soft-tissue or bony swellings, pathologic fracture, spinal paresis, osteolytic x-ray findings, and unexpected results of laboratory tests. Early diagnosis (appropriate use of imaging techniques) and multidisciplinary management have improved considerably the survival of patients with primary malignant bone disease (eg, osteosarcoma). For some benign bone tumors (eg, osteoid osteoma), interstitial laser photocoagulation is now the treatment of choice with a success rate comparable with that of other treatments.

Osteoarthritis and osteoporosis: clinical and research evidence of inverse relationship.

The etiology of osteoporosis (OP) and osteoarthritis (OA) is multifactorial: both constitutional and environmental factors, ranging from genetic susceptibility, endocrine and metabolic status, to mechanical and traumatic injury, are thought to be involved. When interpreting research data, one must bear in mind that pathophysiologic factors, especially in disorders associated with aging, must be regarded as either primary or secondary. Therefore, findings in end-stage pathology are not necessarily the evidence or explanation of the primary cause or event in the diseased tissue. Both aspects of research are important for potentially curative or preventive measures. These considerations, in the case of our topic--the inverse relationship of OP and OA--are of particular importance. Although the inverse relationship between two frequent diseases associated with aging, OA and OP, has been observed and studied for more than 30 years, the topic remains controversial for some and stimulating for many. The anthropometric differences of patients suffering from OA compared with OP are well established. OA cases have stronger body build and are more obese. There is overwhelming evidence that OA cases have increased BMD or BMC at all sites. This increased BMD is related to high peak bone mass, as shown in mother-daughter and twin studies. With aging, the bone loss in OA is lower, except when measured near an affected joint (hand, hip, knee). The lower degree of bone loss with aging is explained by lower bone turnover as measured by bone resorption-formation parameters. OA cases not only have higher apparent and real bone density, but also wider geometrical measures of the skeleton, diameters of long bones and trabeculae, both contributing positively to better strength and fewer fragility fractures. Not only is bone quantity in OA different but also bone quality, compared with controls and OP cases, with increased content of growth factors such as IGF and TGFbeta, factors required for bone repair. Furthermore, in vitro studies of osteoblasts recruited from OA bone have different differentiation patterns and phenotypes. These general bone characteristics of OA bone may explain the inverse relationship OA-OP and why OA cases have fewer fragility fractures. The role of bone, in particular subchondral bone, in the pathophysiology, initiation and progression of OA is not fully elucidated and is still controversial. In 1970, it was hypothesized that an increased number of microfractures lead to an increase in subchondral bone stiffness, which impairs its ability to act as a shock absorber, so that cartilage suffers more. Although subchondral bone is slightly hypomineralized because of local increased turnover, the increase in trabecular number and volume compensates for this, resulting in a stiffer structure. There is also some experimental evidence that osteoblasts themselves release factors such as metalloproteinases directly or indirectly from the matrix, which predispose cartilage to deterioration. Instead, the osteoblast regenerative capacity of bone in OP is compromised compared with OA, as suggested by early cell adhesion differences. The proposition that drugs which suppress bone turnover in OP, such as bisphosphonates, may be beneficial for OA is speculative. Although bone turnover in the subchondral region of established OA is increased, the general bone turnover is reduced. Further reduction of bone turnover, however, may lead to overmineralized (aged) osteons and loss of bone quality, resulting in increased fragility.