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1.  Steps in the management of psoriatic arthritis: a guide for clinicians 
Psoriatic arthritis is a common systemic inflammatory disorder, which in addition to skin and nail involvement may be associated with peripheral and axial joint involvement, enthesitis, dactylitis, and important comorbidities – especially cardiovascular morbidity. Better insights into the involved pathogenic mechanisms have resulted in an improved therapeutic armamentarium, which targets key pathways in its pathogenesis. This has resulted in significant clinical responses to newer therapeutic agents, especially those directed at inhibition of tumor necrosis factor α. Biological therapy leads to significant levels of remission, improved quality of life, and retards or improves structural radiological damage.
PMCID: PMC3539260  PMID: 23342240
metabolic syndrome; psoriasis; psoriatic arthritis; rituximab; T helper 17 cells; tumor necrosis factor α blockade
2.  The Lupus Family Registry and Repository 
Rheumatology (Oxford, England)  2010;50(1):47-59.
The Lupus Family Registry and Repository (LFRR) was established with the goal of assembling and distributing materials and data from families with one or more living members diagnosed with SLE, in order to address SLE genetics. In the present article, we describe the problems and solutions of the registry design and biometric data gathering; the protocols implemented to guarantee data quality and protection of participant privacy and consent; and the establishment of a local and international network of collaborators. At the same time, we illustrate how the LFRR has enabled progress in lupus genetics research, answering old scientific questions while laying out new challenges in the elucidation of the biologic mechanisms that underlie disease pathogenesis. Trained staff ascertain SLE cases, unaffected family members and population-based controls, proceeding in compliance with the relevant laws and standards; participant consent and privacy are central to the LFRR’s effort. Data, DNA, serum, plasma, peripheral blood and transformed B-cell lines are collected and stored, and subject to strict quality control and safety measures. Coded data and materials derived from the registry are available for approved scientific users. The LFRR has contributed to the discovery of most of the 37 genetic associations now known to contribute to lupus through 104 publications. The LFRR contains 2618 lupus cases from 1954 pedigrees that are being studied by 76 approved users and their collaborators. The registry includes difficult to obtain populations, such as multiplex pedigrees, minority patients and affected males, and constitutes the largest collection of lupus pedigrees in the world. The LFRR is a useful resource for the discovery and characterization of genetic associations in SLE.
PMCID: PMC3307518  PMID: 20864496
Systemic lupus erythematosus; Registry; Repository; Autoimmune diseases; Genetics; Heritability; Genome-wide association studies; Linkage analysis; Minorities; Women
3.  Efficacy and Safety of Febuxostat in Patients with Hyperuricemia and Gout 
The past decade has witnessed an exponential increase of novel therapeutic modalities for a variety of rheumatic disorders, including gout. During the past few years two novel therapeutic agents have been approved by the US Food and Drug Administration for the treatment of hyperuricemia in patients with gout, one of them being febuxostat, a nonpurine selective inhibitor of xanthine oxidase. Review of its pharmacokinetics and pharmacodynamics, efficacy and safety profile, and use in gout patients with comorbid conditions reveals that age and gender have no clinically significant effect and dose adjustments based on age or gender are not required. In addition, febuxostat can be used in patients with mild-to-moderate renal or hepatic involvement. Its overall efficacy and safety profile is comparable and, in certain subsets such as gout patients with mild and moderate renal insufficiency, is superior to allopurinol.
PMCID: PMC3383531  PMID: 22870483
hyperuricemia; febuxostat; gout; safety profile; efficacy profile
4.  Comparative assessment of biologics in treatment of psoriasis: drug design and clinical effectiveness of ustekinumab 
The development of psoriasis and psoriatic arthritis is a multistep process that leads to chronic or recurrent inflammation. Recent studies have suggested the importance of T helper (TH)1 and TH17 cells, accessory cells, and proinflammatory cytokines in the pathogenesis of the enthesis, synovium, and skin involvement in psoriasis in the presence of susceptibility genes that remain quiescent until triggered. Biologics, such as soluble CTLA-4 immunoglobulin, tumor necrosis factor (TNF) inhibitors, and ustekinumab, inhibit T cell activation which eventually leads to further stimulation of the interleukin 12, 17, and 23 axis, TNF-α, and lymphotoxin-α. Treatment with TNF-α blockers has been effective in refractory psoriasis and psoriatic arthritis, but there is still a subgroup of patients who do not respond to TNF inhibitors and, paradoxically, when treated, may develop TNF-induced psoriasis. Ustekinumab, because of its different mechanism of action at the level of the interleukin 12, 17, and 23 pathways, is an alternative treatment for this group of patients.
PMCID: PMC3023274  PMID: 21267358
psoriasis; psoriatic arthritis; biologics; ustekinumab; tumor necrosis factor inhibitors
5.  Undifferentiated spondyloarthritis following allogeneic stem cell transplantation 
Stem cell transplant has been utilized in the treatment of malignancies and rheumatic disease. Rheumatic disease may be transferred from the donor with active disease or may be developed in a recipient de novo as a late complication of SCT.
Case Presentation
We here report the rare case of a 26-year old male patient, who has been diagnosed with undifferentiated spondyloarthropathy after unique circumstance. The patient suffered from intermittent inflammatory back pain and peripheral joint swelling for several years and did not find relief through multiple emergency room visits at different medical facilities. After a thorough history and physical exam, it was noted that our patient had developed signs of axial disease along with dactylitis and overall that he had been insidiously developing an undifferentiated spondyloarthopathy after allogeneic stem cell transplantation.
Our observation supports the hypothesis that de novo rheumatic disease can develop after stem cell transplant for a variety of reasons. Thus, larger studies and awareness of this association are needed to delineate the exact underlying mechanism(s).
PMCID: PMC2902413  PMID: 20579362
6.  The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial 
The purpose of this study was to compare urate-lowering (UL) efficacy and safety of daily febuxostat and allopurinol in subjects with gout and serum urate (sUA) ≥ 8.0 mg/dL in a six-month trial.
Subjects (n = 2,269) were randomized to febuxostat 40 mg or 80 mg, or allopurinol 300 mg (200 mg in moderate renal impairment). Endpoints included the proportion of all subjects with sUA <6.0 mg/dL and the proportion of subjects with mild/moderate renal impairment and sUA <6.0 mg/dL. Safety assessments included blinded adjudication of each cardiovascular (CV) adverse event (AE) and death.
Comorbidities included: renal impairment (65%); obesity (64%); hyperlipidemia (42%); and hypertension (53%). In febuxostat 40 mg, febuxostat 80 mg, and allopurinol groups, primary endpoint was achieved in 45%, 67%, and 42%, respectively. Febuxostat 40 mg UL was statistically non-inferior to allopurinol, but febuxostat 80 mg was superior to both (P < 0.001). Achievement of target sUA in subjects with renal impairment was also superior with febuxostat 80 mg (72%; P < 0.001) compared with febuxostat 40 mg (50%) or allopurinol (42%), but febuxostat 40 mg showed greater efficacy than allopurinol (P = 0.021). Rates of AEs did not differ across treatment groups. Adjudicated (APTC) CV event rates were 0.0% for febuxostat 40 mg and 0.4% for both febuxostat 80 mg and allopurinol. One death occurred in each febuxostat group and three in the allopurinol group.
Urate-lowering efficacy of febuxostat 80 mg exceeded that of febuxostat 40 mg and allopurinol (300/200 mg), which were comparable. In subjects with mild/moderate renal impairment, both febuxostat doses were more efficacious than allopurinol and equally safe. At the doses tested, safety of febuxostat and allopurinol was comparable.
Clinical Trial Registration
PMCID: PMC2888216  PMID: 20370912
7.  Chlamydiae as Etiologic Agents for Chronic Undifferentiated Spondyloarthritis 
Arthritis and rheumatism  2009;60(5):1311-1316.
The majority of cases of Chlamydia-Induced reactive arthritis (CiReA) do not present with the classic triad of arthritis, conjunctivitis/iritis, and urethritis. Moreover, acute chlamydial infections are often asymptomatic. The aim of the present study was to assess the prevalence of synovial C. trachomatis (Ct) and C. pneumoniae (Cpn) infections in subjects with chronic undifferentiated spondyloarthritis (uSpA).
Study subjects met the European Spondyloarthropathy Study Group (ESSG) criteria without evidence of ankylosing spondylitis, psoriasis, inflammatory bowel disease, or preceding dysentery. Symptoms were present for at least 6 months. Data collected on the day of the test included standard demographics, history and physical examination (including joint count, evaluation for dactylitis and/or enthesitis, and skin exam), HLA-B27, history of Ct or Cpn. Each subject underwent synovial biopsy; tissue and concomitantly procured PBMC were analyzed by PCR for Ct and Cpn DNA. Synovial tissue from 167 subjects with osteoarthritis (OA) served as controls.
26 subjects met entry criteria and had a synovial biopsy (25 knee, 1 wrist). 16/26 (62%) were PCR-positive for either Ct or Cpn DNA, 10/16 (63%) for Ct, 4/16 (25%) for Cpn, 2/16 (13%) for both. These patients were significantly more likely to be PCR-positive compared to patients with OA (20/167 [12%]; p < 0.0001). No specific clinical characteristics differentiated PCR-positive from PCR-negative subjects. 4/26 (15%) subjects were PCR-positive in PBMC (3 Ct; 1 Cpn), 2 of which also were PCR-positive in synovial tissue (1 Ct; 1 Cpn). No significant correlation between PCR-positivity and HLA-B27-positivity was found.
The synovial tissue PCR-positivity rate in subjects with uSpA identified here is significantly higher than that found in the synovial tissue of subjects with OA. This result suggests that chlamydial infection, often occult, may be etiologic for uSpA in many patients.
PMCID: PMC2757404  PMID: 19404948
8.  Association of the IRF5 Risk Haplotype With High Serum Interferon-α Activity in Systemic Lupus Erythematosus Patients 
Arthritis and rheumatism  2008;58(8):2481-2487.
A haplotype of the interferon regulatory factor 5 (IRF5) gene has been associated with the risk of developing systemic lupus erythematosus (SLE), and our previous studies have demonstrated that high levels of serum interferon-α (IFNα) activity are a heritable risk factor for SLE. The aim of this study was to determine whether the IRF5 SLE risk haplotype mediates the risk of SLE by predisposing patients to the development of high levels of serum IFNα activity.
IFNα levels in 199 SLE patients of European and Hispanic ancestry were measured with a sensitive functional reporter cell assay. The rs2004640, rs3807306, rs10488631, and rs2280714 single-nucleotide polymorphisms (SNPs) in IRF5 were genotyped in these patients. Haplotypes were categorized as SLE risk, neutral, or protective based on published data.
SLE patients with risk/risk and risk/neutral IRF5 genotypes had higher serum IFNα activity than did those with protective/protective and neutral/protective genotypes (P = 0.025). This differential effect of IRF5 genotype on serum IFNα levels was driven largely by SLE patients who were positive for either anti–RNA binding protein (anti-RBP) or anti–double-stranded DNA (anti-dsDNA) autoantibodies (P = 0.012 for risk/risk or risk/neutral versus protective/protective or neutral/protective). The rs3807306 genotype was independently associated with high serum IFNα in this autoantibody group. We found no difference in IFNα activity according to IRF5 genotype in patients lacking either type of autoantibody or in patients positive for both classes of autoantibody.
The IRF5 SLE risk haplotype is associated with higher serum IFNα activity in SLE patients, and this effect is most prominent in patients positive for either anti-RBP or anti-dsDNA autoantibodies. This study demonstrates the biologic relevance of the SLE risk haplotype of IRF5 at the protein level.
PMCID: PMC2621107  PMID: 18668568
9.  Osteopontin and Systemic Lupus Erythematosus Association: A Probable Gene-Gender Interaction 
PLoS ONE  2008;3(3):e1757.
Osteopontin (SPP1) is an important bone matrix mediator found to have key roles in inflammation and immunity. SPP1 genetic polymorphisms and increased osteopontin protein levels have been reported to be associated with SLE in small patient collections. The present study evaluates association between SPP1 polymorphisms and SLE in a large cohort of 1141 unrelated SLE patients [707 European-American (EA) and 434 African-American (AA)], and 2009 unrelated controls (1309 EA and 700 AA). Population-based case-control association analyses were performed. To control for potential population stratification, admixture adjusted logistic regression, genomic control (GC), structured association (STRAT), and principal components analysis (PCA) were applied. Combined analysis of 2 ethnic groups, showed the minor allele of 2 SNPs (rs1126616T and rs9138C) significantly associated with higher risk of SLE in males (P = 0.0005, OR = 1.73, 95% CI = 1.28–2.33), but not in females. Indeed, significant gene-gender interactions in the 2 SNPs, rs1126772 and rs9138, were detected (P = 0.001 and P = 0.0006, respectively). Further, haplotype analysis identified rs1126616T-rs1126772A-rs9138C which demonstrated significant association with SLE in general (P = 0.02, OR = 1.30, 95%CI 1.08–1.57), especially in males (P = 0.0003, OR = 2.42, 95%CI 1.51–3.89). Subgroup analysis with single SNPs and haplotypes also identified a similar pattern of gender-specific association in AA and EA. GC, STRAT, and PCA results within each group showed consistent associations. Our data suggest SPP1 is associated with SLE, and this association is especially stronger in males. To our knowledge, this report serves as the first association of a specific autosomal gene with human male lupus.
PMCID: PMC2258418  PMID: 18335026
10.  HLA-B27-Associated Reactive Arthritis: Pathogenetic and Clinical Considerations 
Clinical Microbiology Reviews  2004;17(2):348-369.
Current evidence supports the concept that reactive arthritis (ReA) is an immune-mediated synovitis resulting from slow bacterial infections and showing intra-articular persistence of viable, nonculturable bacteria and/or immunogenetic bacterial antigens synthesized by metabolically active bacteria residing in the joint and/or elsewhere in the body. The mechanisms that lead to the development of ReA are complex and basically involve an interaction between an arthritogenic agent and a predisposed host. The way in which a host accommodates to invasive facultative intracellular bacteria is the key to the development of ReA. The details of the molecular pathways that explain the articular and extra-articular manifestations of the disease are still under investigation. Several studies have been done to gain a better understanding of the pathogenesis of ReA; these constitute the basis for a more rational therapeutic approach to this disease.
PMCID: PMC387405  PMID: 15084505

Results 1-10 (10)