Effects of one-year tofacitinib therapy on bone metabolism in rheumatoid arthritis.

Janus kinase (JAK) inhibitors are used to treat rheumatoid arthritis (RA). We assessed the effects of tofacitinib on bone density and bone markers in association with clinical and laboratory parameters in RA. Tofacitinib stabilized bone density and resulted in a positive balance of bone turnover. INTRODUCTION: Janus kinase (JAK) inhibitors emerged as new therapeutic options in rheumatoid arthritis (RA). We have little information on how it affects areal and volumetric bone mineral density (BMD) and bone turnover markers. The aim of this study was to assess the effects of 1-year tofacitinib therapy on bone metabolism in RA. METHODS: Thirty RA patients with active disease were treated with either 5 mg bid or 10 mg bid tofacitinib for 12 months. We determined DAS28, CRP, IgM rheumatoid factor (RF), and anti-cyclic citrullinated peptide (CCP) levels, as well as serum levels of sclerostin, osteocalcin (OC), P1NP, DKK-1, OPG, RANKL, and 25-hydroxy-vitamin D3. Areal and volumetric BMD were assessed by DXA and peripheral quantitative CT (QCT), respectively. RESULTS: Twenty-six patients (13 on each arm) completed the study. Tofacitinib was clinically effective by suppressing DAS28, CRP, and HAQ. This was accompanied by the attenuation of further bone loss. Tofacitinib therapy significantly increased OC, OPG, and vitamin D3, while decreased CTX levels (p < 0.05). Age and multiple bone markers (OC, CTX, P1NP, RANKL) inversely correlated with L2-4 and femoral neck BMD by DXA. CRP, DAS28, and RANKL inversely determined volumetric BMD by QCT. Age, CRP, anti-CCP, and DKK-1 influenced the effects of tofacitinib therapy on BMD changes. CONCLUSIONS: One-year tofacitinib treatment stabilized BMD in RA patients and resulted in a positive balance of bone turnover as indicated by bone biomarkers. Further studies are needed to evaluate the potential beneficial effects of JAK inhibitors on inflammatory bone loss.

Comparison of peripheral quantitative computed tomography forearm bone density versus DXA in rheumatoid arthritis patients and controls.

Rheumatoid arthritis (RA) has been associated with osteoporosis. Quantitative computed tomography (QCT) is capable of assessing bone density and composition. We found lower bone density in RA compared to controls. Age and RA duration influenced bone density. QCT may be useful to assess bone metabolism in RA. INTRODUCTION: RA is associated with generalized and periarticular osteoporosis. In addition to DXA that determines areal bone mineral density (BMD), peripheral QCT also detects volumetric BMD. QCT differentiates between total, trabecular, and cortical BMD. Here, we compared DXA and QCT in RA patients and healthy controls. METHODS: BMD of 57 female RA patients and 32 age-matched healthy female controls were assessed by DXA. QCT of the forearm ultradistal region was also performed. Densitometry data were correlated with age, disease duration, disease activity, serum CRP, and anti-CCP levels. RESULTS: Total bone density (310.4 ± 79.7 versus 354.0 ± 54.1 mg/cm3; p = 0.007) and attenuation (0.37 ± 0.05 versus 0.40 ± 0.03 1/cm; p = 0.001), trabecular density (157.6 ± 57.0 versus 193.8 ± 48.7 mg/cm3; p = 0.005) and attenuation (0.28 ± 0.03 versus 0.32 ± 0.04 1/cm; p < 0.0001), and cortical density (434.3 ± 115.8 versus 492.5 ± 64.0 mg/cm3; p = 0.006) and attenuation (0.44 ± 0.07 versus 0.47 ± 0.04 1/cm; p = 0.004) were significantly lower in RA. Both lumbar and femoral neck BMD, as well as T-scores, were significantly lower in RA versus controls (p < 0.001 in all cases). In RA, total and cortical QCT attenuation and density were associated with age, the presence of RA, and their combination. In contrast, trabecular density and attenuation were only affected by the presence of the disease but not by age. Also in RA, total trabecular and cortical density as determined by QCT significantly correlated with lumbar and/or femoral neck BMD as measured by DXA. Finally, anti-CCP seropositivity was associated with lower trabecular density and attenuation. CONCLUSIONS: Both DXA and QCT may be suitable to study bone metabolism in RA. Areal BMD determined by DXA may correlate with volumetric bone density measured by QCT. Moreover, trabecular osteoporosis may be associated by the underlying autoimmune-inflammatory disease, while cortical osteoporosis may rather be age-related.

Vitamin D status in men with psoriatic arthritis: a case-control study.

UNLABELLED: We determined hypovitaminosis D prevalence in men with psoriatic arthritis. This is a cross-sectional, analyst blinded, age- and sex-matched, case-control study. Men with psoriatic arthritis have significantly lower 25-hydroxyvitamin D levels. Men with psoriatic arthritis are at increased odds of suffering from hypovitaminosis D. INTRODUCTION: Skeletal manifestations as a result of abrupted bone metabolism may be predominant in psoriatic arthritis (PsA). Vitamin D plays a vital role in maintenance of skeletal health and is known to modulate the immune system in various autoimmune diseases including PsA. The aim of the present study was to determine the prevalence of hypovitaminosis D in a treatment naïve, de novo psoriatic arthritis male cohort in a cross-sectional, analyst blinded, age- and sex-matched, case-control study. METHODS: 25 hydroxyvitamin D (25OHD), parathyroid (PTH), osteocalcin (OC) and C-terminal telopeptides of type-I collagen (CTx) levels, and lumbar spine and femoral neck bone mineral density were compared between 53 PsA and controls. RESULTS: The prevalence of hypovitaminosis D (25 hydroxyvitamin D (25OHD) levels <75 nmol/L) was 81 and 57 % in the PsA and control groups, respectively. Compared to the healthy controls, 25OHD (67.2 (12-137) nmol/L vs. 51.9 (15-95) nmol/L; p = 0.001) was significantly lower, and osteocalcin (13.6 (5-33) µg/L vs. 18.2 (6-35) µg/L; p = 0.003) and C-terminal telopeptides of type-I collagen (0.20 (0.01-0.71) µg/L vs. 0.28 (0.06-0.69) µg/L; p = 0.008) were significantly higher in the PsA group. A significant association was found between hypovitaminosis D and PsA; the odds for patients with PsA of having hypovitaminosis D was 3.297 (95 % confidence interval 1.372 to 7.922). CONCLUSION: The results of this study suggest that men with PsA have significantly lower 25-hydroxyvitamin D levels, and furthermore, men with PsA are at statistically significant increased odds of suffering from hypovitaminosis D.

Internal initiation in Saccharomyces cerevisiae mediated by an initiator tRNA/eIF2-independent internal ribosome entry site element.

Internal initiation of translation can be mediated by specific internal ribosome entry site (IRES) elements that are located in certain mammalian and viral mRNA molecules. Thus far, these mammalian cellular and viral IRES elements have not been shown to function in the yeast Saccharomyces cerevisiae. We report here that a recently discovered IRES located in the genome of cricket paralysis virus can direct the efficient translation of a second URA3 cistron in dicistronic mRNAs in S. cerevisiae, thereby conferring uracil-independent growth. Curiously, the IRES functions poorly in wild-type yeast but functions efficiently either in the presence of constitutive expression of the eIF2 kinase GCN2 or in cells that have two initiator tRNA(met) genes disrupted. Both of these conditions have been shown to lower the amounts of ternary eIF2-GTP/initiator tRNA(met) complexes. Furthermore, tRNA(met)-independent initiation was also observed in translation-competent extracts prepared from S. cerevisiae in the presence of edeine, a compound that has been shown to interfere with start codon recognition by ribosomal subunits carrying ternary complexes. Therefore, the cricket paralysis virus IRES is likely to recruit ribosomes by internal initiation in S. cerevisiae in the absence of eIF2 and initiator tRNA(met), by the same mechanism of factor-independent ribosome recruitment used in mammalian cells. These findings will allow the use of yeast genetics to determine the mechanism of internal ribosome entry.

Dual roles of a multiprotein complex from S. cerevisiae in transcription and DNA repair.

Yeast RNA polymerase II initiation factor b, homolog of human TFIIH, is a protein kinase capable of phosphorylating the C-terminal repeat domain of the polymerase; it possesses a DNA-dependent ATPase activity as well. The 85 kd and 50 kd subunits of factor b are now identified as RAD3 and SSL1 proteins, respectively; both are known to be involved in DNA repair. Factor b interacts specifically with another DNA repair protein, SSL2. The ATPase activity of factor b may be due entirely to that associated with a helicase function of RAD3. Factor b transcriptional activity was unaffected, however, by amino acid substitution at a conserved residue in the RAD3 nucleotide-binding domain, suggesting that the ATPase/helicase function is not required for transcription. These results identify factor b as a core repairosome, which may be responsible for the preferential repair of actively transcribed genes in eukaryotes.

SSL2, a suppressor of a stem-loop mutation in the HIS4 leader encodes the yeast homolog of human ERCC-3.

Reversion of haploid, His4- yeast containing a stem-loop mutation in the 5' UTR that blocks HIS4 translation initiation identified four unlinked suppressor genes, SSL1-SSL4, which restore His4+ expression. The SSL2 gene encodes an essential 95 kd protein with ATP-dependent helicase motifs. SSL2 protein is 54% identical to the protein encoded by the human gene, ERCC-3, for which a defective form causes xeroderma pigmentosum and Cockayne's syndrome. An SSL2 allele made to resemble the defective ERCC-3 gene confers UV light hypersensitivity to yeast cells. Hence, SSL2 is the functional homolog of ERCC-3. However, the SSL2 suppressor gene does not restore HIS4 expression by removal of the stem-loop from DNA or the mRNA. We propose that SSL2 and ERCC-3 may have two functions, one defined by a UV repair defect, and a second essential function that is related to gene expression.