Th17 cells, but not Th1 cells, from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines upon synovial fibroblast interaction, including autocrine interleukin-17A production.

OBJECTIVE: Both Th1 cells and Th17 cells have been recognized in rheumatoid arthritis (RA); however, it remains unclear whether Th1 cells and/or Th17 cells are involved in driving disease chronicity and destructiveness. The aim of this study was to identify and characterize the functional role of Th17 cells in early RA. METHODS: Flow cytometry analysis was performed on peripheral blood mononuclear cells (PBMCs) from treatment-naive patients with early RA and age-matched healthy volunteers. PBMCs from these patients, naive T cells, and primary CCR6- Th1 cells and CCR6+ Th17 cells were sorted and cultured in the absence or presence of synovial fibroblasts from patients with early RA (RASFs), and cytokine expression and gene transcription were analyzed. In addition, tumor necrosis factor α (TNFα)- and interleukin-17A (IL-17A)-blocking experiments were performed. RESULTS: In the PBMCs of treatment-naive patients with early RA, an increased fraction of IL-17A-and TNFα-producing CCR6+ Th17 cells was observed. When cocultured with RASFs, these primary Th17 cells were potent inducers of IL-6 and IL-8 and the tissue-destructive enzymes matrix metalloproteinase 1 (MMP-1) and MMP-3, whereas primary Th1 cells or naive T cells were not. Importantly, specific up-regulation of IL-17A but not TNFα or interferon-γ was observed in RASF/Th17 cell cocultures. In addition to TNFα blocking, IL-17A neutralization was required to further down-regulate Th17 activity in RASF/Th17 cell cocultures. CONCLUSION: Th17 cells, but not Th1 cells, cooperated with RASFs in a proinflammatory feedback loop, revealing a potential mechanism by which human Th17 cells drive chronic destructive disease in patients with RA. Furthermore, the neutralization of IL-17A activity is essential in current anti-TNF therapies to suppress Th17 cell activity in patients with early RA and potentially other Th17 cell-mediated disorders.

Does anti-mutated citrullinated vimentin have additional value as a serological marker in the diagnostic and prognostic investigation of patients with rheumatoid arthritis? A systematic review.

OBJECTIVE: To review the diagnostic and prognostic value of anti-mutated citrullinated vimentin (MCV) in rheumatoid arthritis, taking into account the already available serology. METHODS: Medline was searched via PubMed (1966 to May 2008) for anti-MCV and related terms, arthritis and arthropathies. Studies with anti-MCV, arthritis/arthropathy, and primary data on diagnosis and/or prognosis were included. Their methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) instrument for diagnostic studies and the modified Hayden list for prognostic studies. RESULTS: Of 14 eligible studies, 11 included diagnostic data and 3 included prognostic data. No study evaluated anti-MCV as an added diagnostic test to the already available anti-cyclic citrullinated peptide (CCP) and rheumatoid factor serology. One study included the optimal patient spectrum resulting in a sensitivity of 0.59 and specificity of 0.98. A total of 10 diagnostic case-control studies using the same anti-MCV kit showed a sensitivity of 0.64-0.84 and a specificity of 0.79-0.96. This almost equalled the performance of anti-CCP in the same studies. The prognostic evaluation of anti-MCV was limited by differences in study methodology, outcome and statistical modelling. Individual studies showed moderate associations for anti-MCV and radiological progression with the strength of the association comparable to that of anti-CCP. CONCLUSIONS: Study heterogeneity, choice of study population and methodological limitations limited overall conclusions about the true diagnostic and prognostic test performance of anti-MCV. Evidence from the diagnostic case-control studies suggests that anti-MCV may be used as an alternative for anti-CCP.

Higher serum vitamin D3 levels are associated with better cognitive test performance in patients with Alzheimer's disease.

BACKGROUND/AIMS: Recent studies suggest that vitamin D metabolites may be important for preserving cognitive function via specific neuroprotective effects. No large studies have examined the association between vitamin D status and cognition. METHODS: In this cross-sectional study, we analyzed the serum 25-hydroxyvitamin D(3) levels and Mini-Mental State Examination (MMSE) test scores of 225 older outpatients who were diagnosed as having probable Alzheimer's disease (AD). In addition to the 25-hydroxyvitamin D(3) levels, we analyzed the serum vitamin B(1), B(6) and B(12) levels. RESULTS: An association was found between MMSE test scores and serum 25-hydroxyvitamin D(3) levels, with a beta-coefficient of 0.05 (p = 0.01). Vitamin-D-sufficient patients had significantly higher MMSE scores as compared to vitamin-D-insufficient ones. No association was found with the other serum vitamin levels. CONCLUSIONS: These data support the idea that a relationship exists between vitamin D status and cognition in patients with probable AD. However, given the cross-sectional design of this study, no causality can be concluded. Further prospective studies are needed to specify the contribution of vitamin D status to the onset and course of cognitive decline and AD.

Evidence for involvement of 17beta-estradiol in intestinal calcium absorption independent of 1,25-dihydroxyvitamin D3 level in the Rat.

The sex steroid 17beta-estradiol (17beta-E2) has a broad range of actions, including effects on calcium and bone metabolism. This study with 3-month-old Brown Norway rats was designed to investigate the role of 17beta-E2 in the regulation of calcium homeostasis. Rats were divided in four groups, sham-operated, ovariectomized (OVX), and OVX supplemented with either a 0.025-mg or 0.05-mg 17beta-E2 pellet implanted subcutaneously. After 4 weeks, in none of the groups was serum calcium, phosphate, or parathyroid hormone altered compared with the sham group, while only in the OVX rats was a significant reduction in urinary calcium found. Bone mineral density and osteocalcin were modified, as can be expected after OVX and 17beta-E2 supplementation. OVX resulted in a nonsignificant increase in serum 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Supplementation with either one of the 17beta-E2 dosages resulted in an 80% reduction of 1,25(OH)2D3 and only a 20% reduction in 25-hydroxyvitamin D3 levels. OVX, as well as supplementation with 17beta-E2, did not affect serum levels of vitamin D binding protein. As a consequence, the estimated free 1,25(OH)2D3 levels were also significantly decreased in the 17beta-E2-supplemented group compared with the sham and OVX groups. Next, the consequences for intestinal calcium absorption were analyzed by the in situ intestinal loop technique. Although the 1,25(OH)2D3 serum level was increased, OVX resulted in a significant decrease in intestinal calcium absorption in the duodenum. Despite the strongly reduced 1,25(OH)2D3 levels (18. 1 +/- 2.1 and 16.4 +/- 2.2 pmol/l compared with 143.5 +/- 29 pmol/l for the OVX group), the OVX-induced decrease in calcium absorption could partially be restored by supplementation with either 0.025 mg or 0.05 mg of 17beta-E2. None of the treatments resulted in a significant change in calcium handling in the jejunum, although the trends were similar as those observed in the duodenum. 17beta-E2 did not change the VDR levels in both the intestine and the kidney. In conclusion, the present study demonstrates that 17beta-E2 is positively involved in intestinal calcium absorption, and the data strengthen the assertion that 17beta-E2 exerts this effect independent of 1,25(OH)2D3. In general, 17beta-E2 not only affects bone turnover but also calcium homeostasis via an effect on intestinal calcium absorption. (J Bone Miner Res 1999;14:57-64)

Interaction between vitamin D receptor genotype and estrogen receptor alpha genotype influences vertebral fracture risk.

In view of the interactions of vitamin D and the estrogen endocrine system, we studied the combined influence of polymorphisms in the estrogen receptor (ER) alpha gene and the vitamin D receptor (VDR) gene on the susceptibility to osteoporotic vertebral fractures in 634 women aged 55 yr and older. Three VDR haplotypes (1, 2, and 3) of the BsmI, ApaI, and TaqI restriction fragment length polymorphisms and three ERalpha haplotypes (1, 2, and 3) of the PvuII and XbaI restriction fragment length polymorphisms were identified. We captured 131 nonvertebral and 85 vertebral fracture cases during a mean follow-up period of 7 yr. ERalpha haplotype 1 was dose-dependently associated with increased vertebral fracture risk (P < 0.001) corresponding to an odds ratio of 1.9 [95% confidence interval (CI), 0.9-4.1] per copy of the risk allele. VDR haplotype 1 was overrepresented in vertebral fracture cases. There was a significant interaction (P = 0.01) between ERalpha haplotype 1 and VDR haplotype 1 in determining vertebral fracture risk. The association of ERalpha haplotype 1 with vertebral fracture risk was only present in homozygous carriers of VDR haplotype 1. The risk of fracture was 2.5 (95% CI, 0.6-9.9) for heterozygous and 10.3 (95% CI, 2.7-40) for homozygous carriers of ERalpha haplotype 1. These associations were independent of bone mineral density. In conclusion, interaction between ERalpha and VDR gene polymorphisms leads to increased risk of osteoporotic vertebral fractures in women, largely independent of bone mineral density.

1,25-dihydroxyvitamin D3 modulates Th17 polarization and interleukin-22 expression by memory T cells from patients with early rheumatoid arthritis.

OBJECTIVE: To examine the immunologic mechanism by which 1,25-dihydroxyvitamin D(3) (1,25[OH](2)D(3)) may prevent corticosteroid-induced osteoporosis in patients with early rheumatoid arthritis (RA), with a focus on T cell biology. METHODS: Peripheral blood mononuclear cells (PBMCs) and CD4+CD45RO+ (memory) and CD4+CD45RO- (non-memory) T cells separated by fluorescence-activated cell sorting (FACS) from treatment-naive patients with early RA were stimulated with anti-CD3/anti-CD28 in the absence or presence of various concentrations of 1,25(OH)(2)D(3), dexamethasone (DEX), and 1,25(OH)(2)D(3) and DEX combined. Levels of T cell cytokines were determined by enzyme-linked immunosorbent assay and flow cytometry. RESULTS: The presence of 1,25(OH)(2)D(3) reduced interleukin-17A (IL-17A) and interferon-gamma levels and increased IL-4 levels in stimulated PBMCs from treatment-naive patients with early RA. In addition, 1,25(OH)(2)D(3) had favorable effects on tumor necrosis factor alpha (TNFalpha):IL-4 and IL-17A:IL-4 ratios and prevented the unfavorable effects of DEX on these ratios. Enhanced percentages of IL-17A- and IL-22-expressing CD4+ T cells and IL-17A-expressing memory T cells were observed in PBMCs from treatment-naive patients with early RA as compared with healthy controls. Of note, we found no difference in the percentage of CD45RO+ and CD45RO- cells between these 2 groups. Interestingly, 1,25(OH)(2)D(3), in contrast to DEX, directly modulated human Th17 polarization, accompanied by suppression of IL-17A, IL-17F, TNFalpha, and IL-22 production by memory T cells sorted by FACS from patients with early RA. CONCLUSION: These data indicate that 1,25(OH)(2)D(3) may contribute its bone-sparing effects in RA patients taking corticosteroids by the modulation of Th17 polarization, inhibition of Th17 cytokines, and stimulation of IL-4.

Poncet's disease: reactive arthritis accompanying tuberculosis. Two case reports and a review of the literature.

OBJECTIVE: Reactive arthritis (ReA) in tuberculosis (TB) is known as Poncet's disease. It is a rare aseptic form of arthritis observed in patients with active TB. We present two such patients and review the literature on Poncet's disease. METHODS: Two patients who were identified with Poncet's disease at the Department of Rheumatology of Erasmus MC, Rotterdam University Hospital, during the last 5 yrs are reported. In addition, a review of the literature on Poncet's disease is given: the PubMed/MEDLINE database was studied up to December 2005 using the term 'Poncet's disease' and the terms 'arthritis', 'reactive' and 'tuberculosis'. RESULTS: After careful work-up, the polyarthritis and erythema nodosum in both presented patients with active TB could be diagnosed as Poncet's disease. Resolution of the arthritis with anti-TB drugs occurred in just a few days. Reviewing the literature, 50 case reports were found. In most reports 'Poncet's disease' was described as an aseptic polyarthritis, presumably ReA arthritis developing in the presence of active TB elsewhere. However, no uniform characterization of the term 'Poncet's disease' could be abstracted from these reports. CONCLUSION: Both presented patients and the review of the literature demonstrate that active TB may be complicated by ReA known as Poncet's disease. Early recognition of this rare complication of TB is of major importance to avoid delayed initiation of appropriate treatment.

Physiological effects of kangaroo care in very small preterm infants.

Kangaroo care for preterm infants has great benefits for the parents and for the parent-infant bonding process. A clinical observational study was conducted in which several physiological variables were collected, including among others transcutaneous oxygen pressure, heart rate, respiratory rate, occurrence of apneic attacks, breathing pattern (studied with power spectrum analysis), behavioral states and rectal temperature, during kangaroo care in small preterm infants. Kangaroo-care did not significantly affect any of these physiological variables comparing the period of 1 h before, 1 h during and 1 h after kangaroo care. We conclude that kangaroo care is a safe method, even for very small nonstabilized preterm infants.

Endosonography in the clinical staging of Klatskin tumor.

Endosonography was performed preoperatively in 46 patients with carcinoma of the common hepatic duct and its bifurcation. The results of endosonography were correlated with findings during surgery and pathological examination of the resected specimen and classified according to the new (1987) TNM classification. Overall accuracy in assessing the depth of tumor infiltration was 86.0%. Endosonography was accurate in predicting the presence of lymph nodes but not accurate in defining non-metastatic changes of lymph nodes. Staging of distant metastases was not accurate due to the low penetration depth of ultrasound.

Consequences of vitamin D receptor gene polymorphisms for growth inhibition of cultured human peripheral blood mononuclear cells by 1, 25-dihydroxyvitamin D3.

OBJECTIVE: In the vitamin D receptor (VDR) gene a BsmI restriction fragment length polymorphism (RFLP) in intron 8 and a translational start-site polymorphism, identified as a FokI RFLP, have been described. Crucial for a proper interpretation of these polymorphisms in association studies is the knowledge whether they have direct consequences for 1,25-(OH)2D3 action at cellular level. The present study was designed to assess functional significance of the FokI and BsmI VDR gene polymorphisms in peripheral blood mononuclear cells (PBMC) with a natural occurring VDR genotype for cell growth inhibition by 1,25-(OH)2D3. DESIGN: PBMC of women were isolated, VDR genotyped and in vitro inhibition by 1,25-(OH)2D3 of Phytohemagglutinin (PHA)-stimulated growth of PBMC was examined in relation to VDR genotype. RESULTS: PHA-stimulated growth and maximal growth inhibition were independent of VDR genotype. However, the FF genotype had a significant lower ED50 than the Ff genotype corresponding to an allele dose effect of 0.32 nM per f allele copy (P = 0.0036). For BsmI genotypes no differences in ED50 were observed. CONCLUSION: The present study demonstrates for the first time in cells with a natural VDR genotype a direct functional consequence of the VDR gene translational start-site polymorphism for the action of 1,25-(OH)2D3. Especially under conditions of vitamin D insufficiency these findings might have clinical implications.