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BACKGROUND: Studies have suggested that nonspecific nonsteroidal anti-inflammatory drugs may inhibit matrix biosynthesis by articular cartilage, thereby accelerating the progression of osteoarthritis (OA). OBJECTIVE: The objective of this analysis was to determine whether 1-year treatment with the cyclooxygenase-2-specific inhibitor celecoxib at up to twice the recommended and maximally effective dose for OA had any deleterious effects on OA progression by assessing radiographic changes in knee or hip joint morphology in patients with OA. METHODS: In a 12-month, multicenter, prospective, open-label trial, patients with OA of the knee or hip or rheumatoid arthritis received celecoxib at doses ranging from that recommended for the treatment of OA (200 mg/d) to twice the recommended daily dosage (400 mg/d). Available radiographs showing baseline and end-of-treatment status were analyzed using semiquantitative measures of index joint morphology in patients with mild to moderate OA. The morphologic scores were then subjected to mean change and shift-table analysis to determine the extent and rate of disease progression. RESULTS: A total of 2,327 patients (796 with OA of the knee, 1,531 with OA of the hip) were included. A subset of 344 patients (160 with OA of the knee, 184 with OA of the hip) had radiographs from both before and after 12 months' celecoxib treatment. One hundred forty-seven and 158 pairs of knee and hip radiographs, respectively, were available for analysis. These revealed that, with the exception of significant hip joint-space narrowing (P = 0.029), no evidence of disease progression with long-term celecoxib treatment could be detected. The observed increase in hip joint-space narrowing was small (0.14 units/y) (95% CI, 0.08-0.20), was observed prior to celecoxib exposure (by mean change or shift-table analysis), and was not dose related. CONCLUSION: These results are consistent with the hypothesis that long-term therapy with celecoxib does not accelerate progression of OA of the knee or hip. [ABSTRACT FROM AUTHOR]

Background: In a phase II study, etanercept (recombinant human tumor necrosis factor receptor [p75]:Fc fusion protein) safely produced rapid, dose-dependent improvement in rheumatoid arthritis over 3 months.Objective: To confirm the benefit of etanercept therapy of longer duration and simplified dosing in patients with rheumatoid arthritis.Design: Randomized, double-blind, placebo-controlled trial with blinded joint assessors.Setting: 13 North American centers.Patients: 234 patients with active rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs.Intervention: Twice-weekly subcutaneous injections of etanercept, 10 or 25 mg, or placebo for 6 months.Measurements: The primary end points were 20% and 50% improvement in disease activity according to American College of Rheumatology (ACR) responses at 3 and 6 months. Other end points were 70% ACR responses at 3 and 6 months and other measures of disease activity at 3 and 6 months.Results: Etanercept significantly reduced disease activity in a dose-related fashion. At 3 months, 62% of the patients receiving 25 mg of etanercept and 23% of the placebo recipients achieved 20% ACR response (P < 0.001). At 6 months, 59% of the 25-mg group and 11% of the placebo group achieved a 20% ACR response (P < 0.001); 40% and 5%, respectively, achieved a 50% ACR response (P < 0.01). The respective mean percentage reduction in the number of tender and swollen joints at 6 months was 56% and 47% in the 25-mg group and 6% and -7% in the placebo group (P < 0.05). Significantly more etanercept recipients achieved a 70% ACR response, minimal disease status (0 to 5 affected joints), and improved quality of life. Etanercept was well tolerated, with no dose-limiting toxic effects.Conclusions: Etanercept can safely provide rapid, significant, and sustained benefit in patients with active rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Expression of the TAM (TYRO3, AXL, MER) family of receptor tyrosine kinases (RTK) has been associated with cancer progression, metastasis, and drug resistance. In immune cells, TAM RTKs can dampen inflammation in favor of homeostatic wound-healing responses, thus potentially contributing to the evasion of cancer cells from immune surveillance. Here we characterize the small-molecule RXDX-106 as a selective and potent pan-TAM RTK inhibitor with slow dissociation kinetics and significant antitumor activity in multiple syngeneic tumor models. Expression of AXL and MER on both immune and tumor cells increased during tumor progression. Tumor growth inhibition (TGI) following treatment with RXDX-106 was observed in wild-type mice and was abrogated in immunodeficient mice, suggesting that the antitumor activity of RXDX-106 is, in part, due to the presence of immune cells. RXDX-106-mediated TGI was associated with increased tumor-infiltrating leukocytes, M1-polarized intratumoral macrophages, and activation of natural killer cells. RXDX-106 proportionally increased intratumoral CD8 + T cells and T-cell function as indicated by both IFNγ production and LCK phosphorylation (pY393). RXDX-106 exhibited its effects via direct actions on TAM RTKs expressed on intratumoral macrophages and dendritic cells, leading to indirect activation of other immune cells in the tumor. RXDX-106 also potentiated the effects of an immune checkpoint inhibitor, α-PD-1 Ab, resulting in enhanced antitumor efficacy and survival. Collectively, these results demonstrate the capacity of RXDX-106 to inhibit tumor growth and progression and suggest it may serve as an effective therapy against multiple tumor types. SIGNIFICANCE: The pan-TAM small-molecule kinase inhibitor RXDX-106 activates both innate and adaptive immunity to inhibit tumor growth and progression, indicating its clinical potential to treat a wide variety of cancers., (©2019 American Association for Cancer Research.)

Background: Compared with White Americans, Black American men are at a significant increased risk of presenting with prostate cancer (PCa) and associated mortality, suggesting a link to African-ancestry. However, PCa status within Africa is largely unknown. We address the clinical presentation of PCa within Black South African men., Methods: Over 1,000 participants with or without PCa have enrolled in the Southern African Prostate Cancer Study (SAPCS). Using genome-wide profiling we establish a unique within Africa population substructure. Adjusting for age, clinical variables were assessed, compared against Black Americans and between rural and urban localities while addressing potential socio-demographic confounders., Results: We report a significant difference in the distribution of prostate specific antigen (PSA) levels skewed towards higher PSA levels in the PCa cases (83.0% present with a PSA ≥ 20 µg/L; median PSA = 98.8 µg/L) relative to men with no detectable PCa (18.5% present with a PSA ≥ 20 µg/L; median PSA = 9.1 µg/L). Compared with Black Americans, Black South Africans presented with significantly more aggressive disease defined by Gleason score >7 (17% and 36%, respectively) and PSA ≥ 20 µg/L (17.2% and 83.2%, respectively). We report exasperated disease aggression defined by Gleason score >7 (P = 0.0042) and poorly differentiated tumor grade (P < 0.0001) within rural versus urban localities., Conclusion: Black South African men present with higher PSA levels and histopathological tumor grade compared with Black Americans, which is further escalated in men from rural localities. Our data suggests that lack of PSA testing may be contributing to an aggressive PCa disease phenotype within South African men., (© 2014 The Authors. Prostate published by Wiley Periodicals, Inc.)

Background: Although African ancestry represents a significant risk factor for prostate cancer, few studies have investigated the significance of prostate cancer and relevance of previously defined genetic and epidemiological prostate cancer risk factors within Africa. We recently established the Southern African Prostate Cancer Study (SAPCS), a resource for epidemiological and genetic analysis of prostate cancer risk and outcomes in Black men from South Africa. Biased towards highly aggressive prostate cancer disease, this is the first reported data analysis., Methods: The SAPCS is an ongoing population-based study of Black men with or without prostate cancer. Pilot analysis was performed for the first 837 participants, 522 cases and 315 controls. We investigate 46 pre-defined prostate cancer risk alleles and up to 24 epidemiological measures including demographic, lifestyle and environmental factors, for power to predict disease status and to drive on-going SAPCS recruitment, sampling procedures and research direction., Results: Preliminary results suggest that no previously defined risk alleles significantly predict prostate cancer occurrence within the SAPCS. Furthermore, genetic risk profiles did not enhance the predictive power of prostate specific antigen (PSA) testing. Our study supports several lifestyle/environmental factors contributing to prostate cancer risk including a family history of cancer, diabetes, current sexual activity and erectile dysfunction, balding pattern, frequent aspirin usage and high PSA levels., Conclusions: Despite a clear increased prostate cancer risk associated with an African ancestry, experimental data is lacking within Africa. This pilot study is therefore a significant contribution to the field. While genetic risk factors (largely European-defined) show no evidence for disease prediction in the SAPCS, several epidemiological factors were associated with prostate cancer status. We call for improved study power by building on the SAPCS resource, further validation of associated factors in independent African-based resources, and genome-wide approaches to define African-specific risk alleles.

Within-population genetic diversity is greatest within Africa, while between-population genetic diversity is directly proportional to geographic distance. The most divergent contemporary human populations include the click-speaking forager peoples of southern Africa, broadly defined as Khoesan. Both intra- (Bantu expansion) and inter-continental migration (European-driven colonization) have resulted in complex patterns of admixture between ancient geographically isolated Khoesan and more recently diverged populations. Using gender-specific analysis and almost 1 million autosomal markers, we determine the significance of estimated ancestral contributions that have shaped five contemporary southern African populations in a cohort of 103 individuals. Limited by lack of available data for homogenous Khoesan representation, we identify the Ju/'hoan (n = 19) as a distinct early diverging human lineage with little to no significant non-Khoesan contribution. In contrast to the Ju/'hoan, we identify ancient signatures of Khoesan and Bantu unions resulting in significant Khoesan- and Bantu-derived contributions to the Southern Bantu amaXhosa (n = 15) and Khoesan !Xun (n = 14), respectively. Our data further suggests that contemporary !Xun represent distinct Khoesan prehistories. Khoesan assimilation with European settlement at the most southern tip of Africa resulted in significant ancestral Khoesan contributions to the Coloured (n = 25) and Baster (n = 30) populations. The latter populations were further impacted by 170 years of East Indian slave trade and intra-continental migrations resulting in a complex pattern of genetic variation (admixture). The populations of southern Africa provide a unique opportunity to investigate the genomic variability from some of the oldest human lineages to the implications of complex admixture patterns including ancient and recently diverged human lineages., Competing Interests: The authors have declared that no competing interests exist.

Background: Inflammation has been implicated in prostate cancer (PCa) pathogenesis. Promoter DNA variants responsible for differential expression of key cytokines may therefore influence susceptibility to PCa., Methods: Two interleukin-6 (IL-6) promoter variants, -174G>C and -6331T>C, were genotyped for association with PCa risk and survival using the Risk Factors for Prostate Cancer Study (RFPCS, 825 cases and 732 controls) and the Melbourne Collaborative Cohort Study (MCCS, 818 cases and 1,745 controls). Impact of genotypes on IL-6 transcriptional activity was measured using Low Density Arrays., Results: A significant increase in IL-6 transcriptional activity in malignant compared to benign prostate tissue supports a role for IL-6 in PCa. The -174G>C variant showed no association with PCa risk, overall survival, or IL-6 transcriptional activity. The -6331 C-allele was significantly associated with an increased risk in the RFPCS (OR = 1.29, 95% CI = 1.08-1.54), but not in the MCCS. In the MCCS however, cases presenting with a CC genotype conferred a higher risk of mortality (HR = 2.27, 95% CI = 1.34-3.85), which was maintained although reduced overall in the pooled analysis with RFPCS (HR = 1.68, 95% CI = 1.10-2.54). Furthermore, we associate the minor C-allele with a significant decrease in IL-6 transcriptional activity., Conclusions: While our study refutes a role for IL-6 -174G>C, it is the first to implicate -6331T>C with PCa risk and poor survival. Our observation that -6331T>C has a significant impact on IL-6 transcriptional activity, calls for further investigations into the role of this variant as a novel PCa biomarker., (Copyright © 2012 Wiley Periodicals, Inc.)

Mutations in the SERPINA1 gene can cause deficiency in the circulating serine protease inhibitor α(1)-Antitrypsin (α(1)AT). α(1)AT deficiency is the major contributor to pulmonary emphysema and liver disease in persons of European ancestry, with a prevalence of 1 in 2500 in the USA. We present the discovery and characterization of a novel SERPINA1 mutant from an asymptomatic Middle Eastern male with circulating α(1)AT deficiency. This 49 base pair deletion mutation (T379Δ), originally mistyped by IEF, causes a frame-shift replacement of the last sixteen α(1)AT residues and adds an extra twenty-four residues. Functional analysis showed that the mutant protein is not secreted and prone to intracellular aggregation.

The Tasmanian devil (Sarcophilus harrisii) is threatened with extinction because of a contagious cancer known as Devil Facial Tumor Disease. The inability to mount an immune response and to reject these tumors might be caused by a lack of genetic diversity within a dwindling population. Here we report a whole-genome analysis of two animals originating from extreme northwest and southeast Tasmania, the maximal geographic spread, together with the genome from a tumor taken from one of them. A 3.3-Gb de novo assembly of the sequence data from two complementary next-generation sequencing platforms was used to identify 1 million polymorphic genomic positions, roughly one-quarter of the number observed between two genetically distant human genomes. Analysis of 14 complete mitochondrial genomes from current and museum specimens, as well as mitochondrial and nuclear SNP markers in 175 animals, suggests that the observed low genetic diversity in today's population preceded the Devil Facial Tumor Disease disease outbreak by at least 100 y. Using a genetically characterized breeding stock based on the genome sequence will enable preservation of the extant genetic diversity in future Tasmanian devil populations.

Although inflammation is emerging as a candidate prostate cancer risk factor, the T-helper cytokine-rich [interleukins (IL)-5, 13 and 4] chromosomal region at 5q31.1 has been implicated in prostate cancer pathogenesis. In particular, IL-4 has been associated with prostate cancer progression, whereas the IL-4 -589C>T (rs2243250) promoter variant has been associated with differential gene expression. We genotyped rs2243250 and 11 tag single-nucleotide polymorphisms (SNPs) spanning 200 kb across the 5q31.1 region on 825 cases and 732 controls from the Risk Factors for Prostate Cancer Study. The minor alleles of rs2243250 and an IL-4 tagSNP rs2227284 were associated with a small increase in prostate cancer risk. Per allele odds ratios (ORs) are 1.32 [95% confidence interval (CI) 1.08-1.61, P = 0.006] and 1.26 (95% CI 1.07-1.48, P = 0.005), respectively. Although these associations were not replicated in an analysis of the Melbourne Collaborative Cohort Study, including 810 cases and 1733 controls, no clinicopathological characteristic was implicated for this divergence. Correlating rs2243250 genotypes to IL-4 gene transcript levels and circulating IL-4 plasma levels, we observe in contrast to previous reports, a non-significant trend toward the minor T-allele decreasing the likelihood of IL-4 activity. From our observed association between a low IL-4 producing promoter T-allele and prostate cancer risk, our study suggests an antitumor role for IL-4 in prostate cancer. Although we saw no association for IL-5 or IL-13 gene variants and prostate cancer risk, our findings call for further evaluation of IL-4 as a contributor to prostate cancer susceptibility.

Prostate cancer is the most common cancer in Western society males, with incidence rates predicted to rise with global aging. Etiology of prostate cancer is however poorly understood, while current diagnostic tools can be invasive (digital rectal exam or biopsy) and/or lack specificity for the disease (prostate-specific antigen (PSA) testing). Substantial histological, epidemiological and molecular genetic evidence indicates that inflammation is important in prostate cancer pathogenesis. In this review, we summarize the current status of inflammatory genetic markers influencing susceptibility to prostate cancer. The focus will be on inflammatory cytokines regulating T-helper cell and chemokine homeostasis, together with the Toll-like receptors as key players in the host innate immune system. Although association studies indicating a genetic basis for prostate cancer are presently limited mainly due to lack of replication, larger and more ethnically and clinically defined study populations may help elucidate the true contribution of inflammatory gene variants to prostate cancer risk.

A newly described heterodimeric cytokine, interleukin-23 (IL-23) is emerging as a key player in both the innate and the adaptive T helper (Th)17 driven immune response as well as an initiator of several autoimmune diseases. The rate-limiting element of IL-23 production is believed to be driven by expression of the unique p19 subunit encoded by IL23A. We set out to perform comprehensive DNA sequencing of this previously under-studied gene in 96 individuals from two evolutionary distinct human population groups, Southern African Bantu and European. We observed a total of 33 different DNA variants within these two groups, 22 (67%) of which are currently not reported in any available database. We further demonstrate both inter-population and intra-species sequence conservation within the coding and known regulatory regions of IL23A, supporting a critical physiological role for IL-23. We conclude that IL23A may have undergone positive selection pressure directed towards conservation, suggesting that functional genetic variants within IL23A will have a significant impact on the host immune response.

Background: Chronic inflammation is considered to be implicated in the development of prostate cancer. In this study we are the first to investigate a potential association between variants in an autoimmune related region on chromosome 4q27 and prostate cancer risk. This region harbors two cytokine genes IL-2 and the recently described IL-21., Methods: We genotyped six variants previously associated with autoimmune disease (namely rs13151961, rs13119723, rs17388568, rs3136534, rs6822844 and rs6840978) and one functional IL-2 promoter variant (rs2069762) for possible association with prostate cancer risk using the Australian Risk Factors for Prostate Cancer case-control Study., Results: Overall, our results do not support an association between the seven variants at position 4q27 and prostate cancer risk. Per allele odds ratios (ORs) were not significantly different from 1 (all P-values = 0.06). However, we found suggestive evidence for a significant association between the presence of the rs13119723 variant (located in a protein of unknown function) and men with a family history of prostate cancer in first-degree relatives (P-value for interaction 0.02). The per allele OR associated with this variant was significantly higher than 1 (2.37; 95% C.I. = 1.01-5.57)., Conclusions: We suggest that genetic variation within the chromosome 4q27 locus might be associated with prostate cancer susceptibility in men with a family history of the disease. Furthermore, our study alludes to a potential role of unknown protein KIAA1109 in conferring this risk.

Background: High-throughput custom designed genotyping arrays are a valuable resource for biologically focused research studies and increasingly for validation of variation predicted by next-generation sequencing (NGS) technologies. We investigate the Illumina GoldenGate chemistry using custom designed VeraCode and sentrix array matrix (SAM) assays for each of these applications, respectively. We highlight applications for interpretation of Illumina generated genotype cluster plots to maximise data inclusion and reduce genotyping errors., Findings: We illustrate the dramatic effect of outliers in genotype calling and data interpretation, as well as suggest simple means to avoid genotyping errors. Furthermore we present this platform as a successful method for two-cluster rare or non-autosomal variant calling. The success of high-throughput technologies to accurately call rare variants will become an essential feature for future association studies. Finally, we highlight additional advantages of the Illumina GoldenGate chemistry in generating unusually segregated cluster plots that identify potential NGS generated sequencing error resulting from minimal coverage., Conclusions: We demonstrate the importance of visually inspecting genotype cluster plots generated by the Illumina software and issue warnings regarding commonly accepted quality control parameters. In addition to suggesting applications to minimise data exclusion, we propose that the Illumina cluster plots may be helpful in identifying potential in-put sequence errors, particularly important for studies to validate NGS generated variation.

The genetic structure of the indigenous hunter-gatherer peoples of southern Africa, the oldest known lineage of modern human, is important for understanding human diversity. Studies based on mitochondrial and small sets of nuclear markers have shown that these hunter-gatherers, known as Khoisan, San, or Bushmen, are genetically divergent from other humans. However, until now, fully sequenced human genomes have been limited to recently diverged populations. Here we present the complete genome sequences of an indigenous hunter-gatherer from the Kalahari Desert and a Bantu from southern Africa, as well as protein-coding regions from an additional three hunter-gatherers from disparate regions of the Kalahari. We characterize the extent of whole-genome and exome diversity among the five men, reporting 1.3 million novel DNA differences genome-wide, including 13,146 novel amino acid variants. In terms of nucleotide substitutions, the Bushmen seem to be, on average, more different from each other than, for example, a European and an Asian. Observed genomic differences between the hunter-gatherers and others may help to pinpoint genetic adaptations to an agricultural lifestyle. Adding the described variants to current databases will facilitate inclusion of southern Africans in medical research efforts, particularly when family and medical histories can be correlated with genome-wide data.

Purpose: Alternative CCND1 splicing results in cyclin D1b, which has specialized, protumorigenic functions in prostate not shared by the cyclin D1a (full length) isoform. Here, the frequency, tumor relevance, and mechanisms controlling cyclin D1b were challenged., Experimental Design: First, relative expression of both cyclin D1 isoforms was determined in prostate adenocarcinomas. Second, relevance of the androgen axis was determined. Third, minigenes were created to interrogate the role of the G/A870 polymorphism (within the splice site), and findings were validated in primary tissue. Fourth, the effect of G/A870 on cancer risk was assessed in two large case-control studies., Results: Cyclin D1b is induced in tumors, and a significant subset expressed this isoform in the absence of detectable cyclin D1a. Accordingly, the isoforms showed noncorrelated expression patterns, and hormone status did not alter splicing. Whereas G/A870 was not independently predictive of cancer risk, A870 predisposed for transcript-b production in cells and in normal prostate. The influence of A870 on overall transcript-b levels was relieved in tumors, indicating that aberrations in tumorigenesis likely alter the influence of the polymorphism., Conclusions: These studies reveal that cyclin D1b is specifically elevated in prostate tumorigenesis. Cyclin D1b expression patterns are distinct from that observed with cyclin D1a. The A870 allele predisposes for transcript-b production in a context-specific manner. Although A870 does not independently predict cancer risk, tumor cells can bypass the influence of the polymorphism. These findings have major implications for the analyses of D-cyclin function in the prostate and provide the foundation for future studies directed at identifying potential modifiers of the G/A870 polymorphism.

Mutation detection has, until recently, relied heavily on the use of gel-based methods that can be both time consuming and difficult to design. Nongel-based systems are therefore important to increase simplicity and improve turn around time without compromising assay sensitivity and accuracy, especially in the diagnostic/clinical setting. In this study, we assessed the latest of the nongel-based methods, namely high-resolution melt (HRM) curve analysis. HRM is a closed-tube method that incorporates a saturating dye during DNA amplification followed by a monitoring of the change in fluorescence as the DNA duplex is denatured by an increasing temperature. We assessed 10 amplicons derived from eight genes, namely SERPINA1, CXCR7, MBL, VDR, NKX3A, NPY, TP53, and HRAS using two platforms, the LightScanner System using LC Green PLUS DNA binding dye (Idaho Technology, Salt Lake City, UT, USA) and the LightCycler 480 using the HRM Master dye (Roche Diagnostics, Indianapolis, IN, USA). DNA variants (mutations or polymorphims) were previously identified using denaturing gradient gel electrophoresis (DGGE) a method, similarly to HRM, based upon the different melting properties of double-stranded DNA. Fragments were selected based on variant and fragment complexity. This included the presence of multiple sequence variants, variants in alternate orientations, and single or multiple variants (constitutional or somatic) in GC-rich fragments. We demonstrate current limitations of the HRM method for the analysis of complex DNA regions and call for caution when using HRM as the sole method to make a clinical diagnosis based on genetic analysis.

Analysis of SNPs for association, linkage, haplotype, and pharmacogenetic studies has led to a dramatic increase in the number and evolution of medium- to high-throughput genotyping technologies. This study introduces Plexor as a new method for medium-throughput (single SNP) genotyping. We compare this fluorescent-based chemistry for call rate, accuracy, affordability, throughput, and overall efficiency against two commonly used technologies. These include fluorescent-based TaqMan allelic discrimination for single SNP analysis (medium-throughput) and the homogenous MassEXTEND (hME) chemistry using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry for multiple SNP analysis (high-throughput). Analysis of 11 SNPs, including all six possible nucleotide substitutions, showed Plexor to be highly comparable for both call rate (94.7%) and accuracy (99.2%) to the TaqMan (94.6% and 99.8%, respectively) and hME (91.9% and 98.1%, respectively) chemistries. We demonstrate that this novel method is an efficient, cost-effective alternative to TaqMan genotyping commonly used in diagnostic settings., ((c) 2007 Wiley-Liss, Inc.)

Objective: Approximately 3% of the US population over the age of 65 years has rheumatoid arthritis (RA). We compared the safety and efficacy of etanercept (Enbrel) in patients with RA who were > or = 65 years to those < 65 years in open-label and double-blind, randomized clinical trials., Methods: Patients from 4 double-blind, randomized controlled trials and 5 open-label trials were included in this retrospective analysis. Patients were grouped by age (< 65 or > or = 65 yrs) at time of study entry. All patients received etanercept subcutaneously twice weekly. Improvement in signs and symptoms was assessed by the proportion of patients who achieved the American College of Rheumatology definition of improvement (ACR 20). The ACR 50 and ACR 70 responses were calculated in an analogous fashion. Safety was assessed at regularly scheduled visits., Results: Of 1128 patients enrolled in etanercept trials, 197 (17%) were > or = 65 years of age. Clinical response was rapid and sustained and did not differ between age groups. At one year, 69% of patients < 65 years and 66% of patients > or = 65 years met the ACR 20. Forty percent of the patients > or = 65 years met the ACR 50 and 17% met the ACR 70. Etanercept was well tolerated. Although injection site reactions, headache, and rhinitis occurred somewhat more frequently in younger patients, the overall rates and types of other adverse events were comparable in both groups., Conclusion: Etanercept is a new treatment option for older patients with RA and has substantial benefit and comparable safety regardless of patient age.

Objective: Patients with rheumatoid arthritis (RA) treated with etanercept (Enbrel) in controlled studies of 3 to 6 months' duration had rapid and sustained improvement of their disease, with minimal safety issues. In this study, we examine safety and clinical benefit after longer term treatment with etanercept., Methods: All adult patients with RA with a previously inadequate response to one or more disease modifying antirheumatic drugs, and who received at least one dose of etanercept as monotherapy in controlled or open label clinical trials were evaluated for safety and clinical benefit. Adverse event rates were compared as was evidence of continued benefit over time., Results: Etanercept continued to be safe and well tolerated in 628 adult patients treated for a median of 25 mo (maximum 43 mo; 1109 patient-years). Nine percent of patients withdrew due to lack of efficacy and 7% due to adverse events. Most adverse events were mild, and no statistically significant increases in frequency of events were seen when patients received etanercept over longer periods of time. Clinical benefit was maintained with longterm therapy. A 100% improvement in individual disease activity measures was achieved by 17% to 28% of the patients. Fifty-five percent of patients who were taking corticosteroids (mean dose at baseline 6.6 mg/day) decreased or discontinued corticosteroid therapy while maintaining control of their arthritis symptoms., Conclusion: Etanercept continued to be safe and well tolerated, and its clinical benefit was sustained for a median of 25 mo and for as long as 43 mo in patients with RA.

Objective: To study the functional status and health-related quality of life (HRQOL) of patients with rheumatoid arthritis (RA) after treatment with celecoxib, compared with placebo and naproxen., Methods: This was a prospective, randomized, double-blind, parallel group trial conducted at 79 sites in the United States and Canada over a 12-week treatment period. Patients were randomly assigned to 5 groups: placebo, 100 mg twice a day of celecoxib, 200 mg twice a day of celecoxib, 400 mg twice a day of celecoxib, and 500 mg twice a day of naproxen. The Health Assessment Questionnaire (HAQ) disability index was used to measure functional status. The Medical Outcomes Study Short Form 36 (SF-36) was used to measure general HRQOL., Results: Enrollees were 1,149 patients with diagnosed and active RA. At the end of the treatment period, patients in the 4 active treatment groups had significant improvement in both functional status and overall HRQOL in comparison with the placebo group. Patients in the twice-daily 100 mg celecoxib group significantly differed from placebo at weeks 2 and 6 on HAQ scores and at week 12 on 5 domains and both summary scores of the SF-36. Patients treated with twice-daily 200 mg celecoxib had significantly better functional status than placebo at all times of testing with the HAQ, and also had significantly better function than those treated with naproxen after 2 and 12 weeks of treatment. Patients in the twice-daily 200 mg and 400 mg celecoxib groups showed similar improvement in HRQOL as determined by the 8 domain scores and 2 summary scores of the SF-36., Conclusion: Celecoxib was better than placebo and comparable with naproxen in improving functional status and overall HRQOL among RA patients.

Objective: Gastric (GU) and duodenal ulcers (DU) are common adverse effects of nonsteroidal anti-inflammatory drugs (NSAID). Endoscopically diagnosed upper gastrointestinal (GI) ulceration occurs in about 24% of longterm NSAID users. Coadministration of misoprostol with the NSAID reduces the incidence of NSAID induced GU and DU and their complications. However, compliance is limited by the different dosing regimens of misoprostol and NSAID and GI symptoms associated with misoprostol at its recommended q.i.d. dose. We compared the efficacy, safety, and incidence of endoscopic upper GI ulceration associated with the administration of 2 combinations of diclofenac (50 or 75 mg) and misoprostol 200 microg (D50/M200 t.i.d., D75/M200 b.i.d.), diclofenac 75 mg b.i.d., and placebo in a 6 week, randomized, double blind study in patients with osteoarthritis (OA) of the knee or hip., Methods: A total of 572 patients with symptomatic OA of the knee or hip and history of GU, DU. or 10 or more erosions were randomized to receive D50/M200 t.i.d., D75/M200 b.i.d., diclofenac 75 mg b.i.d., or placebo for 6 weeks. Arthritis assessments were performed at baseline, 2, and 6 weeks, and upper GI endoscopies at baseline and end of treatment., Results: All active treatment groups were significantly better than placebo, at all visits, in improving OA symptoms. There were no significant differences in arthritis efficacy between the diclofenac/ misoprostol combinations and diclofenac. However, endoscopically diagnosed GU and/or DU were significantly less frequent in patients receiving D50/M200 t.i.d. (8%), D75/M200 b.i.d. (7%), and placebo (4%) compared to diclofenac 75 mg b.i.d. (17%). Adverse events were not different between the active treatment groups, except for higher incidences of flatulence with D75/M200 and diarrhea with D50/M200., Conclusion: Diclofenac 50 mg/misoprostol 200 microg t.i.d. and diclofenac 75 mg/misoprostol 200 microg b.i.d. are as efficacious as diclofenac 75 mg b.i.d. in the treatment of OA, but are associated with a significantly lower incidence of gastric and/or duodenal ulcers.

Background: Tumor necrosis factor (TNF) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis, and antagonism of TNF may reduce the activity of the disease. This study evaluated the safety and efficacy of a novel TNF antagonist - a recombinant fusion protein that consists of the soluble TNF receptor (p75) linked to the Fc portion of human IgG1 (TNFR:Fc)., Methods: In this multicenter, double-blind trial, we randomly assigned 180 patients with refractory rheumatoid arthritis to receive subcutaneous injections of placebo or one of three doses of TNFR:Fc (0.25, 2, or 16 mg per square meter of body-surface area) twice weekly for three months. The clinical response was measured by changes in composite symptoms of arthritis defined according to American College of Rheumatology criteria., Results: Treatment with TNFR:Fc led to significant reductions in disease activity, and the therapeutic effects of TNFR:Fc were dose-related. At three months, 75 percent of the patients in the group assigned to 16 mg of TNFR:Fc per square meter had improvement of 20 percent or more in symptoms, as compared with 14 percent in the placebo group (P<0.001). In the group assigned to 16 mg per square meter, the mean percent reduction in the number of tender or swollen joints at three months was 61 percent, as compared with 25 percent in the placebo group (P<0.001). The most common adverse events were mild injection-site reactions and mild upper respiratory tract symptoms. There were no dose-limiting toxic effects, and no antibodies to TNFR:Fc were detected in serum samples., Conclusions: In this three-month trial TNFR:Fc was safe, well tolerated, and associated with improvement in the inflammatory symptoms of rheumatoid arthritis.

Objective: To compare the effectiveness and tolerability of three misoprostol dosing regimens for the prevention of gastric and duodenal ulcers associated with long-term nonsteroidal anti-inflammatory drug (NSAID) therapy., Design: A multicenter, 12-week, randomized, double-blind, placebo-controlled, parallel, four-limb study., Patients: Eligibility criteria included upper gastrointestinal symptoms during NSAID therapy and no endoscopic evidence of gastric or duodenal ulcers. A total of 1623 patients was enrolled; 1197 of these met major accession and regimen-compliance criteria and completed the trial. These 1197 patients composed the evaluable group., Interventions: Patients were randomly assigned to one of four regimens: placebo four times daily; 200 micrograms of misoprostol twice daily and placebo twice daily; 200 micrograms of misoprostol three times daily and placebo once daily; and 200 micrograms of misoprostol four times daily., Measurements: Upper gastrointestinal endoscopic examinations for ulcers were done after 4, 8, and 12 weeks of therapy. Tolerability and safety of the regimens were assessed by adverse-event monitoring., Results: In the placebo group, the incidence of gastric ulcers was 15.7% and the incidence of duodenal ulcers was 7.5%. The incidence of gastric ulcers was significantly lower in the groups receiving misoprostol twice daily (8.1%; difference, 7.6% [95% CI, 2.7% to 12.5%]; P = 0.002), three times daily (3.9%; difference, 11.8% [CI, 7.4% to 16.3%]; P < 0.001), and four times daily (4%; difference, 11.7% [CI, 6.7% to 16.8%]; P < 0.001) compared with placebo. The gastric ulcer rate was significantly higher in patients receiving misoprostol twice daily compared with those receiving misoprostol three times daily (difference, 4.2% [95% CI, 0.7% to 7.7%]; P = 0.02). A significant (P = 0.02) misoprostol dose-response effect was noted in the prevention of gastric ulcers. The incidence of duodenal ulcers was significantly lower in the groups receiving misoprostol twice daily (2.6%; difference, 4.9% [CI, 1.5% to 8.2%]; P = 0.004), three times daily (3.3%; difference, 4.2% [CI, 0.6% to 7.7%]; P = 0.019), and four times daily (1.4%; difference, 6.1% [CI, 2.6% to 9.6%]; P = 0.007) compared with placebo. No significant difference was detected between patients receiving misoprostol twice daily and those receiving misoprostol three times daily, and no dose-response effect was noted with duodenal ulcers. The incidence of withdrawals for adverse events was significantly lower in the groups receiving misoprostol twice daily (12%) and three times daily (12%) than in the group receiving it four times daily (20%). The incidence of gastrointestinal adverse events was significantly higher in the group receiving misoprostol four times daily (74%) than in the placebo group (62%)., Conclusion: Misoprostol, 200 micrograms twice or three times daily, offers substantial protection against gastric and duodenal ulcers in patients receiving long-term NSAID therapy. These dosages were better tolerated than the currently approved regimen of 200 micrograms four times daily.

Background: This study was developed to compare the incidence of endoscopically diagnosed ulcers in elderly patients taking nabumetone, ibuprofen, or concomitant ibuprofen/misoprostol. Further research is indicated to better establish the clinical relevance of these endoscopy findings., Methods: We conducted a prospective, multicenter, randomized, endoscopist-blinded, 12-week study involving 171 patients with osteoarthritis aged 60 years and older. Patients were randomized to receive nabumetone, 1000 mg (n = 58); ibuprofen, 600 mg four times daily (n = 53); or ibuprofen, 600 mg four times daily, administered concomitantly with misoprostol, 200 micrograms four times daily (n = 60). Endoscopy was performed at baseline and at weeks 2, 6, and 12. Endoscopy results were scored on a scale of 1 to 9. Significant ulcers were defined as breaks in the mucosa greater than 5 mm with appreciable depth., Results: Of the 171 randomized patients, 148 completed the study. There was no significant difference in the incidence of significant ulcers between the nabumetone group and the ibuprofen/misoprostol group (one vs zero). There were significantly fewer significant ulcers in the nabumetone and ibuprofen/misoprostol groups than in the ibuprofen monotherapy group (one and zero vs eight; P < .01). There also was a significant difference in the time to ulcer development, with a greater risk of developing an ulcer sooner with ibuprofen treatment (P < .01) than either nabumetone or ibuprofen/misoprostol treatment. The severity of osteoarthritis, based on physicians' assessments, improved in 64% of patients in the nabumetone group, 55% of those in the ibuprofen group, and 63% of those in the ibuprofen/misoprostol group., Conclusions: Nabumetone is equivalent in ulcerogenicity to concomitant ibuprofen/misoprostol and is significantly less ulcerogenic than ibuprofen alone.

Twenty-two patients with fibrositis, selected from a general medical outpatient population by a screening questionnaire and subsequent evaluation, were compared with age-, sex-, and clinic-matched patients without fibrositis. Although there was a high prevalence of musculoskeletal complaints in both groups, the fibrositis patients had a uniform constellation of symptoms, including axial pain, severe aching and stiffness, morning fatigue, and modulation by specific factors. They also had a higher incidence of tension headache and irritable bowel syndrome. The use of a dolorimeter demonstrated that fibrositis patients had many more areas of localized tenderness than control patients, but also that fibrositis patients did not have diffusely diminished pain threshold and tolerance. Using the criteria of this study, fibrositis appears to be a common and readily definable syndrome within the spectrum of soft tissue rheumatism.

Twenty-two patients with fibrositis and 22 control patients selected from a general medical outpatient population were given 3 standardized psychological questionnaires: the Beck Depression Inventory, the Spielberger State and Trait Anxiety Inventory, and the SCL-90-R. There were no statistically significant differences between fibrositis patients and control patients on any of these tests, a finding at variance with a commonly held belief that patients with fibrositis have an underlying psychological disorder. While psychological factors may be important in some patients with fibrositis, these results indicate that the presence of a psychopathologic condition is not mandatory for the persistence of fibrositis.