-
[show abstract]
[hide abstract]
ABSTRACT: Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). However, despite its efficacy and affordability, additional DMARDs or biologic agents are often required in order to achieve the recommended goals of low disease activity or remission. Although well tolerated by most, some patients develop important side effects such as cytopenias, gastrointestinal adverse events (stomatitis, nausea), or abnormal liver function tests, which may limit its use and may result in additional health care costs. Given the clinical implications of widespread use of MTX in RA, various studies have evaluated the role of potential biomarkers in predicting treatment effectiveness of MTX. These biomarkers include RBC MTX polyglutamate (PG) levels; genetic variation in genes from relevant biological and metabolic pathways; gene expression profiles; serum proteins. This paper provides an update on the current data regarding biomarkers of treatment response to MTX.
International Journal of Rheumatology 01/2012; 2012:978396.
-
[show abstract]
[hide abstract]
ABSTRACT: Methotrexate (MTX) is one of the most commonly prescribed and most effective drugs for the treatment of rheumatoid arthritis (RA). Given the partial response of many patients and the side effect profile of the drug, there is considerable interest in identifying biomarkers to guide MTX therapy in RA. Upon entering cells, MTX is polyglutamated. Measuring MTX polyglutamate (MTX PG) levels in circulating red blood cells has been proposed as an objective measure to help optimize MTX therapy in RA. Data are conflicting with regard to the clinical utility of MTX PG measurements as a predictor of the efficacy or toxicity of low-dose MTX effects in RA. Should large, randomized clinical trials of this assay show consistent, reproducible, long-term correlations between MTX PG levels and efficacy or toxicity, this test could become a prominent tool for clinicians to optimize the use of MTX in treating RA.
Current Rheumatology Reports 10/2010; 12(5):342-7.
-
Paula I Burgos,
Zenoria L Causey,
Ashutosh Tamhane,
James M Kelley,
Elizabeth E Brown,
Laura B Hughes, Maria I Danila,
Amalia van Everdingen,
Doyt L Conn,
Beth L Jonas,
Leigh F Callahan,
Edwin A Smith,
Richard D Brasington,
Larry W Moreland,
Désirée M van der Heijde,
Graciela S Alarcón,
S Louis Bridges
[show abstract]
[hide abstract]
ABSTRACT: To determine whether IL4R single-nucleotide polymorphisms (SNPs) rs1805010 (I50V) and rs1801275 (Q551R), which have been associated with disease severity in rheumatoid arthritis (RA) patients of European ancestry, relate to the presence of rheumatoid nodules and radiographic erosions in African Americans.
Two IL4R SNPs, rs1805010 and rs1801275, were genotyped in 749 patients from the Consortium for Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis (CLEAR) registries. End points were rheumatoid nodules defined as present either by physical examination or by chest radiography and radiographic erosions (radiographs of hands/wrists and feet were scored using the modified Sharp/van der Heijde system). Statistical analyses were performed by using logistic regression modeling adjusted for confounding factors.
Of the 749 patients with RA, 156 (20.8%) had rheumatoid nodules, with a mean age of 47.0 years, 84.6% female gender, and median disease duration of 1.9 years. Of the 461 patients with available radiographic data, 185 (40.1%) had erosions (score>0); their mean age was 46.7 years; 83.3% were women; and median disease duration was 1.5 years. Patients positive for HLA-DRB1 shared epitope (SE) and autoantibodies (rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP)) had a higher risk of developing rheumatoid nodules in the presence of the AA and AG alleles of rs1801275 (odds ratio (OR)adj=8.08 (95% confidence interval (CI): 1.60-40.89), P=0.01 and ORadj=2.97 (95% CI, 1.08 to 8.17), P=0.04, respectively). Likewise, patients positive for the HLA-DRB1 SE and RF alone had a higher risk of developing rheumatoid nodules in presence of the AA and AG alleles of rs1801275 (ORadj=8.45 (95% CI, 1.57 to 45.44), P=0.01, and ORadj=3.57 (95% CI, 1.18 to 10.76), P=0.02, respectively) and in the presence of AA allele of rs1805010 (ORadj=4.52 (95% CI, 1.20 to 17.03), P=0.03). No significant association was found between IL4R and radiographic erosions or disease susceptibility, although our statistical power was limited by relatively small numbers of cases and controls.
We found that IL4R SNPs, rs1801275 and rs1805010, are associated with rheumatoid nodules in autoantibody-positive African-American RA patients with at least one HLA-DRB1 allele encoding the SE. These findings highlight the need for analysis of genetic factors associated with clinical RA phenotypes in different racial/ethnic populations.
Arthritis research & therapy 05/2010; 12(3):R75. · 4.27 Impact Factor
-
S Louis Bridges,
Zenoria L Causey,
Paula I Burgos,
B Quynh N Huynh,
Laura B Hughes, Maria I Danila,
Amalia van Everdingen,
Stephanie Ledbetter,
Doyt L Conn,
Ashutosh Tamhane,
Andrew O Westfall,
Beth L Jonas,
Leigh F Callahan,
Edwin A Smith,
Richard Brasington,
Larry W Moreland,
Graciela S Alarcón,
Désirée M van der Heijde
[show abstract]
[hide abstract]
ABSTRACT: To describe radiographic changes in African Americans with rheumatoid arthritis (RA) from the Consortium for the Longitudinal Evaluations of African Americans with Early Rheumatoid Arthritis (CLEAR) Registry, a multicenter observational study.
Self-declared African American patients were enrolled in CLEAR I, a longitudinal cohort of early RA (disease duration of <2 years) from 2000 to 2005, or in CLEAR II, a cross-sectional cohort (any disease duration) from 2006 to the present. Demographic and clinical data were obtained, and sets of hand/wrist and foot radiographs were scored using the modified Sharp/van der Heijde scoring system.
A total of 357 and 418 patients were enrolled in CLEAR I and CLEAR II, respectively. We report here an interim analysis of radiographic severity in these patients. For the CLEAR I cohort, 294 patients had a mean radiographic score of 2.89 at the baseline visit; 32.0% showed either erosions (25.9%) or joint space narrowing (JSN; 19.4%). At the 36-month visit, the mean score was 5.65; 44.2% had erosions, 41.5% had JSN, and 54.4% had either. Among those patients without radiographic damage at baseline, 18.9% had progressed at the 36-month visit, compared with 57.1% of those with baseline damage (P < 0.0001). For the CLEAR II cohort, of 167 patients with RA of any duration, 65.3% exhibited joint erosions, 65.3% exhibited JSN, and 74.8% exhibited either. The mean radiographic score was 33.42.
To our knowledge, this is the largest radiographic study of African American RA patients. Damage occurs early in the disease and is associated with radiographic progression at 3 years of disease duration. The CLEAR Registry will provide a valuable resource for future analyses of genetic, clinical, and environmental factors associated with radiographic severity of RA in African Americans.
Arthritis care & research. 05/2010; 62(5):624-31.
-
James M Kelley,
Laura B Hughes,
Ashima Malik, Maria I Danila,
Yuanqing Edberg,
Graciela S Alarcón,
Doyt L Conn,
Beth L Jonas,
Leigh F Callahan,
Edwin A Smith,
Richard D Brasington,
Jeffrey C Edberg,
Robert P Kimberly,
Larry W Moreland,
S Louis Bridges
Annals of the rheumatic diseases 04/2010; 69(4):625-6. · 8.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This paper reports the case history of a patient who had bisphosphonate-associated osteonecrosis of the jaw (ONJ) in which adjunctive treatment with teriparatide was used. The patient was treated for 5 years with alendronate for osteoporosis and developed ONJ after extraction of maxillary teeth. An implant was placed at the site of the extracted teeth. The pathology report confirmed the clinical diagnosis of ONJ; treatment was changed from alendronate to teriparatide and the ONJ resolved. To our knowledge, this is the third case history reported in the literature in which teriparatide was successfully used as adjunct therapy in ONJ because it has an anabolic effect and presumed role in accelerating bone healing. ONJ is a serious but infrequent condition that has been recently associated with nitrogen-containing bisphosphonate therapy. Teriparatide may be a useful adjunctive therapy when ONJ develops.
Special Care in Dentistry 03/2010; 30(2):77-82.
-
James M Kelley,
Laura B Hughes,
Jeffrey D Faggard, Maria I Danila,
Monica H Crawford,
Yuanqing Edberg,
Miguel A Padilla,
Hemant K Tiwari,
Andrew O Westfall,
Graciela S Alarcón,
Doyt L Conn,
Beth L Jonas,
Leigh F Callahan,
Edwin A Smith,
Richard D Brasington,
David B Allison,
Robert P Kimberly,
Larry W Moreland,
Jeffrey C Edberg,
S Louis Bridges
PLoS Genetics 12/2009; 5(12). · 8.69 Impact Factor
-
Arthritis & Rheumatism 11/2009; 61(11):1615-6. · 7.87 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To assess whether hydroxychloroquine can delay renal damage development in lupus nephritis patients.
Lupus nephritis patients (n = 256) from the LUpus in MInorities, NAture versus nurture study (n = 635), a multiethnic cohort of African Americans, Hispanics, and Caucasians, age > or =16 years with disease duration < or =5 years at baseline (T0) were studied. Renal damage was defined using the Systemic Lupus International Collaborating Clinics Damage Index (> or =1 of the following lasting at least 6 months: estimated/measured glomerular filtration rate <50%, 24-hour proteinuria > or =3.5 gm and/or end-stage renal disease, regardless of dialysis or transplantation). Patients with renal damage before T0 were excluded (n = 53). The association between hydroxychloroquine use and renal damage (as defined, or omitting proteinuria) was estimated using Cox proportional regression analyses adjusting for potential confounders. Kaplan-Meier survival curves based on hydroxychloroquine intake or the World Health Organization (WHO) class glomerulonephritis were also derived.
Sixty-three (31.0%) of the 203 patients included developed renal damage over a mean +/- SD disease duration of 5.2 +/- 3.5 years. The most frequent renal damage domain item was proteinuria. Patients who received hydroxychloroquine (79.3%) exhibited a lower frequency of WHO class IV glomerulonephritis, had lower disease activity, and received lower glucocorticoid doses than those who did not take hydroxychloroquine. After adjusting for confounders, hydroxychloroquine was protective of renal damage occurrence in full (hazard ratio [HR] 0.12, 95% confidence interval [95% CI] 0.02-0.97, P = 0.0464) and reduced (HR 0.29, 95% CI 0.13-0.68, P = 0.0043) models. Omitting proteinuria provided comparable results. The cumulative probability of renal damage occurrence was higher in those who did not take hydroxychloroquine and those classified as WHO class IV glomerulonephritis (P < 0.0001).
After adjusting for possible confounding factors, the protective effect of hydroxychloroquine in retarding renal damage occurrence in systemic lupus erythematosus is still evident.
Arthritis & Rheumatism 06/2009; 61(6):830-9. · 7.87 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Personalized medicine refers to the utilization of technologies at the molecular level to understand disease processes and improve health outcomes. In rheumatoid arthritis (RA) some factors associated with disease outcome have been identified. These factors have not yet been integrated into a clinically useful tool to predict disease outcome in individual patients. Developments in pharmacogenomics are moving the field forward quite rapidly. Genetic variants, which may have a role in drug metabolism mediating either drug response or toxicity, have been identified for both traditional disease modifying antirheumatic drugs and biologic agents. Choosing a medication based on a patient's characteristics (sociodemographic, clinical, genetic) will result in better utilization of resources and better clinical outcomes. The ethical, political, and legal implications of personalized medicine need to be considered as well.
Therapeutic advances in musculoskeletal disease 04/2009; 1(2):97-105.
-
James M Kelley,
Laura B Hughes,
Jeffrey D Faggard, Maria I Danila,
Monica H Crawford,
Yuanqing Edberg,
Miguel A Padilla,
Hemant K Tiwari,
Andrew O Westfall,
Graciela S Alarcón,
Doyt L Conn,
Beth L Jonas,
Leigh F Callahan,
Edwin A Smith,
Richard D Brasington,
David B Allison,
Robert P Kimberly,
Larry W Moreland,
Jeffrey C Edberg,
S Louis Bridges
[show abstract]
[hide abstract]
ABSTRACT: Cytotoxic T-lymphocyte associated protein 4 (CTLA4) is a negative regulator of T-cell proliferation. Polymorphisms in CTLA4 have been inconsistently associated with susceptibility to rheumatoid arthritis (RA) in populations of European ancestry but have not been examined in African Americans. The prevalence of RA in most populations of European and Asian ancestry is approximately 1.0%; RA is purportedly less common in black Africans, with little known about its prevalence in African Americans. We sought to determine if CTLA4 polymorphisms are associated with RA in African Americans. We performed a 2-stage analysis of 12 haplotype tagging single nucleotide polymorphisms (SNPs) across CTLA4 in a total of 505 African American RA patients and 712 African American controls using Illumina and TaqMan platforms. The minor allele (G) of the rs231778 SNP was 0.054 in RA patients, compared to 0.209 in controls (4.462 x 10(-26), Fisher's exact). The presence of the G allele was associated with a substantially reduced odds ratio (OR) of having RA (AG+GG genotypes vs. AA genotype, OR 0.19, 95% CI: 0.13-0.26, p = 2.4 x 10(-28), Fisher's exact), suggesting a protective effect. This SNP is polymorphic in the African population (minor allele frequency [MAF] 0.09 in the Yoruba population), but is very rare in other groups (MAF = 0.002 in 530 Caucasians genotyped for this study). Markers associated with RA in populations of European ancestry (rs3087243 [+60C/T] and rs231775 [+49A/G]) were not replicated in African Americans. We found no confounding of association for rs231778 after stratifying for the HLA-DRB1 shared epitope, presence of anti-cyclic citrullinated peptide antibody, or degree of admixture from the European population. An African ancestry-specific genetic variant of CTLA4 appears to be associated with protection from RA in African Americans. This finding may explain, in part, the relatively low prevalence of RA in black African populations.
PLoS Genetics 04/2009; 5(3):e1000424. · 8.69 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Damage accrual in SLE has been previously shown to be an independent predictor of mortality. We sought to discern which SLICC Damage Index (SDI) domains are the most important predictors of survival in SLE.
SLE patients (ACR criteria), age > or =16 years, disease duration < or =5 years at enrolment, of African-American, Hispanic or Caucasian ethnicity were studied. Disease activity was assessed using the SLAM-Revised (SLAM-R) at diagnosis. Damage was ascertained using the SDI at the last visit. The SDI domains associated with time to death (and interaction terms) were examined by univariable and multivariable Cox proportional hazards regression analyses; those significant in the multivariable analyses were added to the final two models (with and without poverty) that included other variables known to be associated with shorter survival.
A total of 635 SLE patients were studied of whom 97 (15.3%) have died over a mean (s.d.) total disease duration of 5.7 (3.7) years. Patients were predominantly women [570 (89.8%)]; their mean (s.d.) age was 36.5 (12.6) years; 126 (19.8%) had developed renal damage, 62 (9.3%) cardiovascular, 48 (7.8%) pulmonary and 34 (5.4%) peripheral vascular damage. When excluding poverty from the multivariable model, the renal domain of the SDI was independently associated with a shorter time to death (hazard ratio = 1.65; 95% CI 1.03, 2.66).
The renal domain of the damage index is associated with a shorter time to death when poverty, a strong predictor of this outcome, is removed from the model. Preventing renal damage in lupus patients has long-term prognostic implications.
Rheumatology (Oxford, England) 03/2009; 48(5):542-5. · 4.24 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The human genome has been extensively annotated with Gene Ontology for biological functions, but minimally computationally annotated for diseases.
We used the Unified Medical Language System (UMLS) MetaMap Transfer tool (MMTx) to discover gene-disease relationships from the GeneRIF database. We utilized a comprehensive subset of UMLS, which is disease-focused and structured as a directed acyclic graph (the Disease Ontology), to filter and interpret results from MMTx. The results were validated against the Homayouni gene collection using recall and precision measurements. We compared our results with the widely used Online Mendelian Inheritance in Man (OMIM) annotations.
The validation data set suggests a 91% recall rate and 97% precision rate of disease annotation using GeneRIF, in contrast with a 22% recall and 98% precision using OMIM. Our thesaurus-based approach allows for comparisons to be made between disease containing databases and allows for increased accuracy in disease identification through synonym matching. The much higher recall rate of our approach demonstrates that annotating human genome with Disease Ontology and GeneRIF for diseases dramatically increases the coverage of the disease annotation of human genome.
BMC Genomics 02/2009; 10 Suppl 1:S6. · 4.07 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Systemic necrotizing vasculitis is rare but can have serious sequelae. Despite recent advances in cellular and molecular immunology and genetics, the causes of vasculitic syndromes remain largely undefined. Although mechanisms of blood vessel damage in systemic necrotizing vasculitis are complex, recent studies have provided significant insights.
Current Rheumatology Reports 01/2009; 10(6):430-5.
-
[show abstract]
[hide abstract]
ABSTRACT: Etanercept is one of several TNF inhibitors approved for rheumatoid arthritis (RA) and a variety of other immune-mediated inflammatory conditions. Given the plethora of drugs approved for RA, and the wide variations in cost and treatment response, markers of efficacy would be very useful. Several candidate genes, including HLA-DRB1 alleles and those encoding TNF, TNF receptors and Fc receptors, have been examined for a role in the response to treatment with etanercept. In this review, we discuss pharmacogenetic studies of etanercept in RA and other diseases, and comment on the future of such analyses to advance the goal of personalized medicine in RA.
Pharmacogenomics 09/2008; 9(8):1011-5. · 3.97 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To summarize the recent literature concerning the role of TNF-alpha in heart failure, epidemiology of heart failure in rheumatoid arthritis and risk of heart failure associated with biologic disease-modifying antirheumatic drugs in rheumatoid arthritis.
TNF-alpha has been implicated in the pathogenesis of heart failure. It has direct deleterious effects on the myocardium in the setting of acute injury or chronic heart failure. In animal models, TNF-alpha is important in cardiac remodeling, leading to cardiac dysfunction following acute injury. Both incident and worsening heart failure have been reported in patients with rheumatoid arthritis who are treated with anti-TNF-alpha therapy. Recent cohort studies, however, have shown no increased risk and, in some, a protective effect on the risk of heart failure. Certain traditional cardiovascular risk factors have a relatively lesser contribution to cardiovascular morbidity and mortality in patients with rheumatoid arthritis, suggesting that disease-related perturbations of the cytokine network may contribute to the excess risk of heart failure in these patients.
Overall mortality in rheumatoid arthritis has remained stagnant despite advances in rheumatoid arthritis and heart failure management and improved cardiovascular mortality in the general population. Heart failure prevalence is increased in patients with rheumatoid arthritis and leads to greater mortality. Despite current expert consensus contraindicating the use of anti-TNF-alpha agents in patients with moderate to severe heart failure, epidemiological studies in rheumatoid arthritis have not consistently substantiated this association.
Current Opinion in Rheumatology 06/2008; 20(3):327-33. · 4.31 Impact Factor
-
JCR Journal of Clinical Rheumatology 03/2007; 13(1):49. · 1.36 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Ectromelia virus is the causative agent of mousepox, an acute exanthematous disease of mouse colonies in Europe, Japan, China, and the U.S. The Moscow, Hampstead, and NIH79 strains are the most thoroughly studied with the Moscow strain being the most infectious and virulent for the mouse. In the late 1940s mousepox was proposed as a model for the study of the pathogenesis of smallpox and generalized vaccinia in humans. Studies in the last five decades from a succession of investigators have resulted in a detailed description of the virologic and pathologic disease course in genetically susceptible and resistant inbred and out-bred mice. We report the DNA sequence of the left-hand end, the predicted right-hand terminal repeat, and central regions of the genome of the Moscow strain of ectromelia virus (approximately 177,500 bp), which together with the previously sequenced right-hand end, yields a genome of 209,771 bp. We identified 175 potential genes specifying proteins of between 53 and 1924 amino acids, and 29 regions containing sequences related to genes predicted in other poxviruses, but unlikely to encode for functional proteins in ectromelia virus. The translated protein sequences were compared with the protein database for structure/function relationships, and these analyses were used to investigate poxvirus evolution and to attempt to explain at the cellular and molecular level the well-characterized features of the ectromelia virus natural life cycle.
Virology 01/2004; 317(1):165-86. · 3.35 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Ectromelia virus is the causative agent of mousepox, an acute exanthematous disease of mouse colonies in Europe, Japan, China, and the U.S. The Moscow, Hampstead, and NIH79 strains are the most thoroughly studied with the Moscow strain being the most infectious and virulent for the mouse. In the late 1940s mousepox was proposed as a model for the study of the pathogenesis of smallpox and generalized vaccinia in humans. Studies in the last five decades from a succession of investigators have resulted in a detailed description of the virologic and pathologic disease course in genetically susceptible and resistant inbred and out-bred mice. We report the DNA sequence of the left-hand end, the predicted right-hand terminal repeat, and central regions of the genome of the Moscow strain of ectromelia virus (approximately 177,500 bp), which together with the previously sequenced right-hand end, yields a genome of 209,771 bp. We identified 175 potential genes specifying proteins of between 53 and 1924 amino acids, and 29 regions containing sequences related to genes predicted in other poxviruses, but unlikely to encode for functional proteins in ectromelia virus. The translated protein sequences were compared with the protein database for structure/function relationships, and these analyses were used to investigate poxvirus evolution and to attempt to explain at the cellular and molecular level the well-characterized features of the ectromelia virus natural life cycle.
Virology.
