Patients with ankylosing spondylitis have been breast fed less often than healthy controls: a case-control retrospective study.

OBJECTIVE: Ankylosing spondylitis (AS) is a chronic inflammatory disease affecting the spine and pelvis of young adults. On the HLA-B27 genetic background, the occurrence of AS is influenced by the intestinal microbiota. The goal of our study was to test whether breast feeding, which influences microbiota, can prevent the development of AS. METHODS: First, 203 patients with HLA-B27-positive AS fulfilling the modified New York criteria were recruited in the Department of Rheumatology, Ste Marguerite hospital in Marseilles. A total of 293 healthy siblings were also recruited to make up a control group within the same families. Second, 280 healthy controls, and 100 patients with rheumatoid arthritis and their siblings were recruited. The data collected were age, gender, number of brothers and sisters, age at disease onset, type and duration of feeding (breast or bottle). RESULTS: Patients with AS had been breast fed less often than healthy controls. In families where children were breast fed, the patients with AS were less often breast fed than their healthy siblings (57% vs 72%), giving an OR for AS onset of 0.53 (95% CI (0.36 to 0.77), p value=0.0009). Breast feeding reduced familial prevalence of AS. The frequency of breast feeding was similar in the AS siblings and in the 280 unrelated controls. However, patients with AS were less often breast fed compared with the 280 unrelated controls (OR 0.6, 95% CI (0.42 to 0.89), p<0.01). CONCLUSIONS: Our study suggests a breastfeeding-induced protective effect on the occurrence of AS. To our knowledge, this is the first study of breastfeeding history in patients with AS.

Transfer of the shared epitope through microchimerism in women with rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is an autoimmune disease that affects mostly women and is associated with HLA-DRB1 genes having in common a shared epitope sequence. In parallel, cells and/or DNA originating from pregnancy (microchimerism) persist for decades and could contribute to autoimmunity. The aim of this study was to examine whether microchimerism may be a source of the shared epitope among women with RA. METHODS: Women with RA and healthy women who lacked RA-associated genes such as HLA-DRB1*01 (n=33 and n=46, respectively) and/or HLA-DRB1*04 (n=48 and n=64, respectively), were tested for DRB1*01 or DRB1*04 microchimerism by HLA-specific quantitative polymerase chain reaction assays. As controls, alleles not associated with RA (DQB1*02 and DRB1*15/16) were also analyzed. RESULTS: Compared with healthy women, women (42% with RA had a higher frequency and higher levels of DRB1*04 microchimerism versus 8%; P=0.00002) as well as DRB1*01 microchimerism (30% versus 4%; P=0.0015). Moreover, no difference in microchimerism was observed for alleles not associated with RA. CONCLUSION: Women with RA had microchimerism with RA-associated HLA alleles, but not with non-RA-associated HLA alleles, more often and at higher levels compared with healthy women. These observations are the first to indicate that microchimerism can contribute to the risk of an autoimmune disease by providing HLA susceptibility alleles.

New autoantigens in rheumatoid arthritis (RA): screening 8268 protein arrays with sera from patients with RA.

OBJECTIVE: To identify new IgG autoantibodies in sera from patients with rheumatoid arthritis (RA). METHODS: We tested serum samples from 19 patients with RA with given human leukocyte antigen (HLA)-DR genotypes, from 7 patients with spondylarthropathy, 2 patients with lupus, 4 patients with systemic sclerosis and 10 healthy individuals on 8268 human protein arrays. RESULTS: We identified four antigens (peptidyl arginine deiminase 4 (PAD4), protein kinase Cbeta1 (PKCbeta1), phosphatylinositol 4 phosphate 5 kinase type II gamma (PIP4K2C) and v raf murine sarcoma viral oncogene homologue B1 catalytic domain (BRAF)) that were recognised almost uniquely by sera from patients with RA on protein arrays. Using purified proteins, we confirmed that PAD4 and BRAF are recognised almost uniquely by patients with RA. CONCLUSION: We identified PAD4 and BRAF as RA specific autoantigens.

HLA-DRB1*0404 is strongly associated with high titers of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis.

OBJECTIVE: To test whether the presence of RA associated HLA-DRB1*0101, HLA-DRB1*0401 and HLA-DRB1*0404 alleles individually influences anti-cyclic citrullinated peptide antibodies (anti-CCP) production. METHODS: The frequency of anti-CCP antibodies was calculated in the sera of 260 RA patients expressing either two (double dose genotypes SE+/SE+), one (single dose genotypes SE+/SE-) or no RA associated HLA-DR alleles (SE-/SE-). Anti-CCP antibodies titers were also determined. RESULTS: RA associated HLA-DR alleles are not mandatory for production of anti-CCP. We found that 68% of SE-/SE- patients were anti-CCP positive. There was no significant difference in anti-CCP between SE negative patient (SE-/SE-) and patients expressing at least one SE (SE+/SE+ and SE+/SE-) (p=0.140). We observed no statistical difference in anti-CCP between RA patients expressing one or two SE (82% vs. 77%, p=0.577). Among SE+/SE-patients, HLA-DRB1*0404 was associated with anti-CCP with a statistically significant difference compared with SE negative patients (90% anti-CCP positive, p=0.02). HLA-DRB1*0404 was also associated with high titers of anti CCP with a statistically significant difference compared with HLA-DRB1*0401 and HLA-DRB1*0101 patients (p=0.025). CONCLUSIONS: The RA-associated HLA-DRB1*0404 allele was the most strongly associated with the presence of anti-CCP in RA sera. Moreover, HLA-DRB1*0404 patients had higher titers of anti CCP than patients with other RA associated HLA-DR alleles.

A rigorous method for multigenic families' functional annotation: the peptidyl arginine deiminase (PADs) proteins family example.

BACKGROUND: large scale and reliable proteins' functional annotation is a major challenge in modern biology. Phylogenetic analyses have been shown to be important for such tasks. However, up to now, phylogenetic annotation did not take into account expression data (i.e. ESTs, Microarrays, SAGE, ...). Therefore, integrating such data, like ESTs in phylogenetic annotation could be a major advance in post genomic analyses. We developed an approach enabling the combination of expression data and phylogenetic analysis. To illustrate our method, we used an example protein family, the peptidyl arginine deiminases (PADs), probably implied in Rheumatoid Arthritis. RESULTS: the analysis was performed as follows: we built a phylogeny of PAD proteins from the NCBI's NR protein database. We completed the phylogenetic reconstruction of PADs using an enlarged sequence database containing translations of ESTs contigs. We then extracted all corresponding expression data contained in EST database This analysis allowed us 1/To extend the spectrum of homologs-containing species and to improve the reconstruction of genes' evolutionary history. 2/To deduce an accurate gene expression pattern for each member of this protein family. 3/To show a correlation between paralogous sequences' evolution rate and pattern of tissular expression. CONCLUSION: coupling phylogenetic reconstruction and expression data is a promising way of analysis that could be applied to all multigenic families to investigate the relationship between molecular and transcriptional evolution and to improve functional annotation.

[Hyperparathyroidism induced by lithium. A new case]. / Hyperparathyroïdie induite par le lithium. Un nouveau cas.

INTRODUCTION: Lithium salts, used for the first time in 1949, had proved to be a highly effective preventive measure in bipolar illness. The first report of lithium-induced hyperparathyroidism was suggested by Garfinkel et al. in 1973. About 40 cases have been reported since, suggesting an enhancement of occurrence of hyperparathyroidism in patients cured by lithium carbonate. We report here a new case discovered by a systematic measurement of calcemia after a surgical intervention for a hip joint prosthesis. EXEGESIS: Unusual metabolic features associated with this case of hyperparathyroidism include low urinary calcium excretion, normal cyclic AMP excretion and lack of calcic nephrolithiasis. The mechanism probably results from lithium linking with the calcium receptor on the parathyroid and then stimulating PTH secretion. In the same way it could enhance the tubular reabsorption of urinary calcium. Lithium withdrawal is often inefficient in clinical and laboratory test abnormalities and surgery is usually required. CONCLUSION: It is very important to recognise this particular secondary effect of lithium therapy because clinical symptoms of hypercalcemia can simulate a worsening of the bipolar illness.

Influence of shared epitope-negative HLA-DRB1 alleles on genetic susceptibility to rheumatoid arthritis.

OBJECTIVE: Most patients with rheumatoid arthritis (RA) express the shared epitope (SE). It is not known whether SE-negative HLA-DRB1 alleles influence the development of RA. This study examined the influence of SE-negative HLA-DR alleles (DRB1*X) on the development of RA in 3 different French populations. METHODS: HLA-DRB1 alleles were defined by polymerase chain reaction with sequence-specific oligonucleotide hybridization or sequence-specific primers. SE-negative alleles were classified according to the electric charge of their P4 pocket. HLA-DRB1 alleles *0103, *0402, *07, *08, *11 (except *1107), *12, and *13 have a neutral or negative P4 charge and are called DRB1*XP4n. HLA-DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16 have a positive P4 charge and are called DRB1*XP4p. RESULTS: Among the SE-negative subjects, DRB1 genotypes with 1 or 2 DRB1*XP4n alleles were significantly overrepresented in the control subjects compared with the RA patients, whereas DRB1*XP4p/XP4p genotypes were equally represented in the patients and controls. In single-dose SE-positive subjects, SE/XP4n genotypes were equally represented in the patients and controls. However, SE/XP4p genotypes were significantly overrepresented in the RA patients. CONCLUSION: The DRB1*X allele polymorphism influences susceptibility to RA. Alleles that have a neutral or negative electric charge in their P4 pocket (DRB1*XP4n), such as DRB1*0103, *0402, *07, *08, *11 (except *1107), *12, and *13, protect against RA. Alleles that have a positive electric charge in their P4 pocket (DRB1*XP4p), such as DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16, have no influence on the predisposition to RA.

Pubic pain in athletes: a case due to an abscess in the obturator muscle.

Pubic pain is a common symptom in soccer players. Its cause can be difficult to determine. We report a case in a 19-year-old soccer player who had an abscess in the obturator internus muscle. We are aware of only one similar report in the literature. Painful limitation of internal rotation of the hip and evidence of infection suggested the diagnosis, which was confirmed by magnetic resonance imaging. In a soccer player, a fever and groin pain do not always indicate osteitis pubis. Limitation of internal rotation of the hip should suggest a lesion in the obturator internus muscle.