Rheumatoid Arthritis: Saag KG

Danila MI, Patkar NM, Curtis JR, Saag KG, Teng GG. · Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA. · Curr Opin Rheumatol. · Pubmed #18388526 No free full text.

Abstract: PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

Patkar NM, Teng GG, Curtis JR, Saag KG. · Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama 35294-3408, USA. · Curr Opin Rheumatol. · Pubmed #18388525 No free full text.

Abstract: PURPOSE OF REVIEW: Rheumatoid arthritis patients have higher risk for infections due to comorbidities, underlying immunosuppression and use of glucocorticoids and disease modifying antirheumatic drugs. The association between treatment with antitumor necrosis factor alpha agents and serious infections, including opportunistic infections such as tuberculosis, in rheumatoid arthritis patients remains controversial. We present recent literature on this topic with a focus on clinical applications of this new data. RECENT FINDINGS: Prospective cohort studies and population-based registries have described the incidence and risk of serious infections in large rheumatoid arthritis patient populations of antitumor necrosis factor alpha users. Although some studies have suggested a one and one-half to two-fold increased risk, especially immediately after initiating the treatment, not all have shown an elevated risk for serious bacterial infections or tuberculosis. SUMMARY: Although antitumor necrosis factor alpha agents may be independent risk factors for infections there is an absolute low rate of infection in those treated with these agents (approximately 5 per 100 patient-years). Screening for latent tuberculosis with tuberculin skin testing is effective, and compliance with the recommendations for preventing this disease in recipients of antitumor necrosis factor alpha agents has partially decreased the risk of infections. Clinical suspicion toward developing infection in those being treated with antitumor necrosis factor alpha agents, particularly earlier in the treatment course, is important for effective management of patients.

Gaffo A, Saag KG, Curtis JR. · Center for Education and Research and Therapeutics of Musculoskeletal Diseases, University of Alabama at Birmingham, Birmingham, AL, USA. · Am J Health Syst Pharm. · Pubmed #17158693 No free full text.

Abstract: PURPOSE: Current and investigational treatments of rheumatoid arthritis (RA) are described. SUMMARY: The current therapies used to treat RA include nonsteroidal antiinflammatory drugs (NSAIDs), used for the management of pain and inflammation; disease-modifying antirheumatic drugs (DMARDs), used as first-line therapy for all newly diagnosed cases of RA; and biological-response modifiers, targeted agents that selectively inhibit specific molecules of the immune system. Glucocorticoids and other antirheumatic drugs are also used to treat RA. DMARDs include methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide. NSAIDs and glucocorticoids are effective in controlling the pain, inflammation, and stiffness related to RA. Unlike NSAIDs, they slow clinical and radiographic progression of RA. The biological-response modifiers include infliximab, etanercept, and adalimumab (inhibitors of tumor necrosis factor [TNF]-alpha); anakinra, a recombinant inhibitor of interleukin-1; abatacept, the first costimulation blocker; and rituximab, a chimeric anti-CD20 monoclonal antibody. Investigational therapies for RA include anti-interleukin-6-receptor monoclonal antibodies, new TNF-alpha inhibitors (including one for oral administration), and antibodies against proteins critical for B-cell function and survival. Data accumulated in the past decade favor early aggressive therapy for patients suspected of having RA, including early referral to a rheumatologist, new diagnostic techniques, and aggressive therapy with DMARDs, glucocorticoids, and biological agents. The benefits of this approach have been demonstrated in clinical trials. CONCLUSION: Pharmacologic treatments of RA include NSAIDs, glucocorticoids, DMARDs, and biological agents. With an improved understanding of the pathophysiology of RA and the evidence from various clinical trials with the agents, early aggressive therapy with a combination of drugs or biological agents may be warranted for the effective treatment of RA.

Da Silva JA, Jacobs JW, Kirwan JR, Boers M, Saag KG, Inês LB, de Koning EJ, Buttgereit F, Cutolo M, Capell H, Rau R, Bijlsma JW. · Reumatologia, Hospitais da Universidade, 3000-075 Coimbra, Portugal. · Ann Rheum Dis. · Pubmed #16107513 links to  free full text

Abstract: Adverse effects of glucocorticoids have been abundantly reported. Published reports on low dose glucocorticoid treatment show that few of the commonly held beliefs about their incidence, prevalence, and impact are supported by clear scientific evidence. Safety data from recent randomised controlled clinical trials of low dose glucocorticoid treatment in RA suggest that adverse effects associated with this drug are modest, and often not statistically different from those of placebo.

Buttgereit F, Saag KG, Cutolo M, da Silva JA, Bijlsma JW. · Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany. · Scand J Rheumatol. · Pubmed #15903020 No free full text.

Abstract: Glucocorticoids (GCs) have powerful and potent anti-inflammatory and immunomodulatory effects in rheumatoid arthritis (RA) and many other diseases. These effects are mediated by up to four different mechanisms of action: cytosolic glucocorticoid receptor (cGCR)-mediated classical genomic and rapid non-genomic effects, membrane-bound glucocorticoid receptor (mGCR)-mediated non-genomic effects and non-specific non-genomic effects. On the basis of this detailed knowledge of mechanisms there are currently interesting approaches being considered that may lead to the development of GC drugs and GCR ligands with an improved benefit to side-effect ratio. Another interesting field of GC research is the phenomenon of GCR resistance. Several different mechanisms may mediate this phenomenon; among them are alterations in number, binding affinity, or phosphorylation status of the GCR. Other mechanisms of GC resistance being investigated are polymorphic changes and/or overexpression of (co-)chaperones, the increased expression of inflammatory transcription factors, overexpression of the GCR beta isoform, the multidrug resistance pump, and an altered mGCR expression.

Bijlsma JW, Saag KG, Buttgereit F, da Silva JA. · Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Box 85500, 3508 GA Utrecht, The Netherlands. · Rheum Dis Clin North Am. · Pubmed #15639052 No free full text.

Abstract: Recent evidence for a disease-modifying potential of low-dose glucocorticoids (GCs) in the treatment of rheumatoid arthritis has renewed the debate on the risk benefit ratio with this therapy. Two recent developments are described that might have a positive influence on these risk benefit ratios. One is the improvement in new GC compounds--designer GCs, alterations in bioactivity, and alterations in formulations. The other is a better understanding and management of the toxicity of GCs.

Townsend HB, Saag KG. · Center for Education and Research on Therapeutics of Musculoskeletal Disorders, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham 35294-3408, USA. · Clin Exp Rheumatol. · Pubmed #15552519 No free full text.

Abstract: Glucocorticoids have long been recognized to have beneficial effects in rheumatoid arthritis (RA) (1,2). Several clinical trials over the last decade have further documented the efficacy of glucocorticoids in relieving inflammation and in preventing radiographic erosions in early RA (3-5). Additionally, research has yielded new insights about the cellular mechanisms responsible for these perceived beneficial effects (6,7). Despite potential short term benefits, there is a lack of demonstrated long-term efficacy as well as concerns about short and long-term toxicity. Although these concerns have limited enthusiasm for glucocorticoids by many patients and practitioners, in the U.S. it is estimated that 44% to 75% of RA patients use glucocorticoids (8,9). Confusion and controversy may relate to the fact that toxicity reports are also limited by only modest data quality and quantity. Given growing clinical and basic science evidence supporting the efficacy of glucocorticoids for the treatment of rheumatoid arthritis, their use may further increase. In this review we will examine the latest data supporting the benefits and risks of glucocorticoid use in RA.

Saag KG. · Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, 1813 Sixth Avenue South, Birmingham, AL 35294-3296, USA. · Endocrinol Metab Clin North Am. · Pubmed #12699296 No free full text.

Abstract: Therapeutic use of glucocorticoids can lead to many well-known adverse events. Of all potential serious side effects, glucocorticoid-induced osteoporosis (GIOP) is one of the most devastating complications of protracted glucocorticoid therapy in rheumatoid arthritis. GIOP is the most common form of drug-induced osteoporosis. Although much has been written about the association of glucocorticoids with bone disease among patients with chronic inflammatory conditions, many issues remain unsettled. This article focuses on areas of continued controversies, including the epidemiology and pathogenesis of GIOP, specification of a "safe" dose, methods for diagnosis of GIOP, and an evidence-based approach for GIOP prevention.

Saag KG. · Division of Clinical Immunology and Rheumatology, Center for Education and Research on Therapeutics (CERTs) of Musculoskeletal Disorders, University of Alabama at Birmingham, MEB 625, 1813 Sixth Avenue South, Birmingham, AL 35294-3296, USA. · Curr Rheumatol Rep. · Pubmed #12010606 No free full text.

Abstract: More than 50 years after their discovery, glucocorticoids continue to be a mainstay of treatment for many patients with rheumatoid arthritis (RA). Although the short- and moderate-term efficacy of glucocorticoids in RA is seldom debated, increasing evidence favors a disease-modifying role of glucocorticoids. Despite renewed enthusiasm based on this newer long-term data, glucocorticoid use is marred substantially by the potential for many serious adverse events. Glucocorticoid-induced osteoporosis is one of the most predictable and serious complications for many chronic and some acute users. The correct identification of patients at high risk for bone complications and the institution of appropriate preventive measures may partially attenuate this adverse outcome.

Mikuls TR, Saag KG. · Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA. · Rheum Dis Clin North Am. · Pubmed #11396093 No free full text.

Abstract: It is increasingly clear that coexistent disease plays a pivotal role in RA outcome and that efforts aimed at specifically addressing these comorbidities need to be aggressively sought, investigated, and implemented once proven effective. RA-associated costs are currently increasing at twice the rate of the medical care index. Comorbidity in the setting of RA independently predicts disease-associated disability (a major cost component) and mortality, underscoring the need for a more comprehensive approach to RA, one that adequately addresses disease-specific comorbidities. At present, many primary and secondary preventative measures (Table 1) for RA-specific comorbidities remain largely unproved and require rigorous investigation in a randomized prospective fashion. Despite this ongoing need, advances are being made in our understanding of the underlying pathogenesis of these comorbid conditions and their relation with RA. This improved understanding should translate into further effective interventions. Bisphosphonates, for instance, have been shown to be effective in the prevention of GIOP and associated fractures. The past several years have seen other exciting therapeutic advances in RA. DMARD combinations have been shown to be more effective and no more toxic than MTX monotherapy. In addition to the recent release of COX-2 NSAIDs, three new disease-modifying agents (leflunomide, etanercept, and infliximab) have been added to the therapeutic armamentarium; these are options that have markedly changed the treatment landscape in RA. Although these important advances have generated much deserved optimism, the precise effect that these agents may have on RA-specific comorbidity remains to be seen. The next decade should prove to be an exciting time in RA management. Better identification, understanding, and management of RA comorbidities have great potential to improve quality of life and survival among our patients with RA.

Criswell LA, Saag KG, Sems KM, Welch V, Shea B, Wells G, Suarez-Almazor ME. · Division of Rheumatology, University of California, San Francisco, 521 Parnassus Avenue, C405, Box 0633, San Francisco, CA 94143-0633, USA. · Cochrane Database Syst Rev. · Pubmed #10796420 No free full text.

Abstract: OBJECTIVES: To perform a systematic review of low-dose corticosteroid efficacy in the moderate term for the treatment of rheumatoid arthritis (RA). SEARCH STRATEGY: We conducted a search in MEDLINE from 1966 to 1998, using the keywords "corticosteroids" and "rheumatoid arthritis". We also handsearched all issues of Arthritis and Rheumatism and the Scandinavian Journal of Rheumatology from their dates of first publication to 1994. Furthermore, we examined all Arthritis and Rheumatism abstracts over the 15 year period preceding 1994. References of all identified studies were searched for relevant trials. Authors of unpublished manuscripts were contacted. SELECTION CRITERIA: Studies were selected by two independent reviewers (LC, KS) using a set of predetermined criteria. Specifically, we required that trials be randomized or cross-over and report at least one of the following outcome measures in a quantitative manner: joint tenderness, joint swelling, grip strength, or erythrocyte sedimentation rate (ESR). We also required that trials be of at least three months duration and use prednisone (or a comparable corticosteroid preparation) at a mean dosage of less than or equal to 15 mg/day. We included studies that used either placebo or active drug controls (i.e., comparative studies). DATA COLLECTION AND ANALYSIS: We compared the effectiveness of prednisone to placebo and/or active controls using a fixed effects model for continuous data. A chi square test for homogeneity was performed, and where heterogeneity existed a random effects model was used. We reported results for all available outcomes recommended by the Outcome Measures for Rheumatology Trials (OMERACT) group. These included the number of tender and swollen joints, pain, functional status and ESR. Grip strength was also evaluated. Standardized mean differences (SMD) were used for outcomes assessing the same concept with different scales (eg. swollen joint counts). MAIN RESULTS: Very few studies directly assessed the effectiveness of corticosteroids for RA treatment and many were of poor methodologic quality. Only seven of 34 studies identified by our search met criteria for inclusion. Our results indicated that corticosteroids were significantly more effective than placebo controls for four of six outcomes assessed [standardized mean difference for tender joints = -0.37 (95%CI: -0. 59, -0.14), swollen joints = -0.41 (-0.67, -0.16), pain = -0.43 (-0. 74, -0.12), and functional status = -0.57 (-0.92, -0.22)]. The results for grip strength and ESR were not significant [GS = +0.30 (-0.19, +0.80), weighted mean difference (WMD) for ESR = -7.03 (-18. 06, +4.01)]. The single trial that compared prednisone to aspirin indicated no statistically significant difference between these groups for joint tenderness (0.10 (-0.35, +0.55) and for ESR [0.00 (-11.09, +11.09]. Overall, the four outcomes assessed in the single trial that compared prednisone to chloroquine suggested that the effectiveness of these two agents is similar [SMD for joint tenderness = +0.23 (-0.30, +0.75), swollen joints = +0.43 (-0.11, +0. 96), functional status = -0.27 (-0.80, +0.26), and WMD for ESR = -16. 00 (-30.58, -1.42)]. REVIEWER'S CONCLUSIONS: Based on the limited data available, moderate-term prednisone treatment of RA appears to be superior to placebo and comparable to treatment with aspirin or chloroquine in improving several common rheumatoid arthritis disease activity measures.

Mikuls TR, Kahn D, Utrie PC, Miller SJ, Koehnke R, Goeckeler W, Saag KG. · Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, USA. · Scand J Rheumatol. · Pubmed #11846055 No free full text.

Abstract: We examined the preliminary safety and efficacy of intravenous samarium-153-EDTMP (Sm-153) in the treatment of refractory rheumatoid arthritis (RA). In an open-label sequential group comparison of 0.5, 1.0, and 2.0 mCi/kg, Sm-153 was administered as a single intravenous infusion to 24 patients with refractory disease. Across treatment doses, the frequency of American College of Rheumatology (ACR) 20% responses was 25%, 29%, 25%, and 33% at 2, 4, 8, and 12 weeks, respectively. Expected significant declines in absolute neutrophil count, hemoglobin, and platelet counts were observed with nadirs seen between 2-4 weeks. Sm-153, at doses of 0.5 and 1.0 mCi/kg, is well tolerated but minimally effective in the treatment of refractory RA as measured using ACR response criteria.

Patkar NM, Curtis JR, Teng GG, Allison JJ, Saag M, Martin C, Saag KG. · Center for Education and Research on Therapeutics of Musculoskeletal Disorders, University of Alabama at Birmingham, Birmingham, AL 35294-3408, USA. · J Clin Epidemiol. · Pubmed #18834713 No free full text.

Abstract: OBJECTIVE: To evaluate diagnostic properties of International Classification of Diseases, Version 9 (ICD-9) diagnosis codes and infection criteria to identify bacterial infections among rheumatoid arthritis (RA) patients. STUDY DESIGN AND SETTING: We performed a cross-sectional study of RA patients with and without ICD-9 codes for bacterial infections. Sixteen bacterial infection criteria were developed. Diagnostic properties of comprehensive and restrictive sets of ICD-9 codes and the infection criteria were tested against an adjudicated review of medical records. RESULTS: Records on 162 RA patients with and 50 without purported bacterial infections were reviewed. Positive and negative predictive values of ICD-9 codes ranged from 54%-85% and 84%-100%, respectively. Positive predictive values of the medical records based criteria were 84% and 89% for "definite" and "definite or empirically treated" infections, respectively. Positive predictive value of infection criteria increased by 50% as disease prevalence increased using ICD-9 codes to enhance infection likelihood. CONCLUSION: ICD-9 codes alone may misclassify bacterial infections in hospitalized RA patients. Misclassification varies with the specificity of the codes used and strength of evidence required to confirm infections. Combining ICD-9 codes with infection criteria identified infections with greatest accuracy. Novel infection criteria may limit the requirement to review medical records.

Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, Paulus HE, Mudano A, Pisu M, Elkins-Melton M, Outman R, Allison JJ, Suarez Almazor M, Bridges SL, Chatham WW, Hochberg M, MacLean C, Mikuls T, Moreland LW, O'Dell J, Turkiewicz AM, Furst DE, Anonymous00442. · University of Alabama, Birmingham, AL, USA. · Arthritis Rheum. · Pubmed #18512708 links to  free full text

This publication has no abstract.

Curtis JR, Xi J, Patkar N, Xie A, Saag KG, Martin C. · University of Alabama at Birmingham, AL, USA. · Arthritis Rheum. · Pubmed #18050253 links to  free full text

This publication has no abstract.

Curtis JR, Kramer JM, Martin C, Saag KG, Patkar N, Shatin D, Burgess M, Xie A, Braun MM. · Center for Education and Research on Therapeutics of Musculoskeletal Disorders, The University of Alabama at Birmingham, Birmingham, AL, USA. · Rheumatology (Oxford). · Pubmed #17938138 links to  free full text

Abstract: OBJECTIVES: New onset heart failure (HF) has been associated with the use of TNF-alpha antagonists etanercept and infliximab based upon spontaneous adverse event reports. HF clinical trials of these agents were stopped early due to futility or worsening of existing HF. A potential association between etanercept and infliximab and new onset HF has been studied minimally at a population level. METHODS: Using administrative claims from a large U.S. health care organization, we identified rheumatoid arthritis (RA) and Crohn's disease (CD) patients receiving infliximab or etanercept (exposed), and comparator cohorts of RA and CD patients receiving non-biologic immunosuppressives (unexposed). We studied adults < 50 years to reduce potential confounding related to common age-related comorbidities. Based on abstracted medical records of suspected HF cases, a physician panel adjudicated cases as definite, possible or no HF. RESULTS: Among 4018 RA and CD patients with mean duration follow-up of 18 months, 9 of 33 suspected HF cases (identified using claims data) were adjudicated as definite (n = 5) or possible (n = 4) HF. The relative risk of HF among TNF-alpha antagonist-treated RA and CD patients was 4.3 and 1.2, respectively (P = NS for both). The absolute difference in cumulative incidence of HF among infliximab or etanercept-exposed compared to unexposed patients was 3.4 and 0.3 cases per 1000 persons for RA and CD (P = NS), respectively, yielding a number needed to harm of 294 for RA and 3333 for CD. CONCLUSION: We found only a small number of presumed HF cases (n = 9, or 0.2%) in a large population of relatively young RA and CD patients. Although there was an increased relative risk of incident, HF that was not statistically significant among those exposed to TNF-alpha antagonists compared to those unexposed, larger cohorts are needed to provide more precise risk estimates and permit adjustment for potential confounding.

Curtis JR, Patkar N, Xie A, Martin C, Allison JJ, Saag M, Shatin D, Saag KG. · University of Alabama at Birmingham, Center for Education and Research on Therapeutics, AL 35294, USA. · Arthritis Rheum. · Pubmed #17393394 links to  free full text

Abstract: OBJECTIVE: To evaluate the risk of serious bacterial infections associated with tumor necrosis factor alpha (TNFalpha) antagonists among rheumatoid arthritis (RA) patients. METHODS: A retrospective cohort study of US RA patients enrolled in a large health care organization identified patients who received either TNFalpha antagonists or methotrexate (MTX). Administrative data were used to identify hospitalizations with possible bacterial infections; corresponding medical records were abstracted and reviewed by infectious disease specialists for evidence of definite infections. Proportional hazards models evaluated time-dependent infection risks associated with TNFalpha antagonists. RESULTS: Hospital medical records with claims-identified suspected bacterial infections were abstracted (n=187) among RA patients who received TNFalpha antagonists (n=2,393; observation time 3,894 person-years) or MTX (n=2,933; 4,846 person-years). Over a median followup time of 17 months, the rate of hospitalization with a confirmed bacterial infection was 2.7% among the patients treated with TNFalpha antagonists compared with 2.0% among the patients treated with MTX only. The multivariable-adjusted hazard ratio (HR) of infection among the patients who received TNFalpha antagonists was 1.9 (95% confidence interval [95% CI] 1.3-2.8) compared with patients who received MTX only. The incidence of infections was highest within 6 months after initiating TNFalpha antagonist therapy (2.9 versus 1.4 infections per 100 person-years; multivariable-adjusted HR 4.2, 95% CI 2.0-8.8). CONCLUSION: The multivariable-adjusted risk of hospitalization with a physician-confirmed definite bacterial infection was approximately 2-fold higher overall and 4-fold higher in the first 6 months among patients receiving TNFalpha antagonists versus those receiving MTX alone. RA patients were at increased risk of serious infections, irrespective of the method used to define an infectious outcome. Patients and physicians should vigilantly monitor for signs of infection when using TNFalpha antagonists, particularly shortly after treatment initiation.

Curtis JR, Martin C, Saag KG, Patkar NM, Kramer J, Shatin D, Allison J, Braun MM. · University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. · Arthritis Rheum. · Pubmed #17330283 links to  free full text

This publication has no abstract.

Criswell LA, Saag KG, Mikuls TR, Cerhan JR, Merlino LA, Lum RF, Pfeiffer KA, Woehl B, Seldin MF. · Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California, San Francisco, CA, USA. · Ann Rheum Dis. · Pubmed #16887863 No free full text.

Abstract: OBJECTIVE: To determine whether the impact of tobacco exposure on rheumatoid arthritis (RA) risk is influenced by polymorphisms at the HLA-DRB1 and glutathione S-transferase M1 (GSTM1) loci. METHODS: Subjects were participants from a case-control study nested within the Iowa Women's Health Study, a population based, prospective cohort study of postmenopausal women. Incident RA cases (n = 115) were identified and medical records reviewed to confirm RA diagnosis. Controls without RA (n = 466) were matched with RA cases by age and ethnic background. HLA-DRB1 typing classified subjects according to the presence of alleles encoding the RA "shared epitope" (SE) sequence. GSTM1 was genotyped using a multiplex polymerase chain reaction assay. Conditional logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals. RESULTS: Strong positive associations of smoking (OR = 6.0, p = 0.004), SE positivity (OR = 4.6, p = 0.0006), and GSTM1 null genotype (OR = 3.4, p = 0.007) with risk of RA, and significant gene-environment interactions (smoking by SE interaction p = 0.034; smoking by GSTM1 interaction p = 0.047) were observed. Stratified analyses indicated that exposure to tobacco smoke primarily increased the risk of RA among subjects who lacked genetic risk factors for the disease (that is, SE negative or GSTM1 present). CONCLUSIONS: Although these findings require confirmation in other groups, the results support the importance of considering both genetic and environmental factors, and also their interaction, in studies of complex diseases like RA.

Hughes LB, Beasley TM, Patel H, Tiwari HK, Morgan SL, Baggott JE, Saag KG, McNicholl J, Moreland LW, Alarcón GS, Bridges SL. · Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 415 Lyons-Harrison Research Building, Birmingham, AL 35294-0007, USA. · Ann Rheum Dis. · Pubmed #16439441 No free full text.

Abstract: BACKGROUND: The anti-folate drug methotrexate (MTX) is commonly used to treat rheumatoid arthritis. OBJECTIVE: To determine the allele frequencies of five common coding single-nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene in African-Americans and Caucasians with rheumatoid arthritis and controls to assess whether there are differences in allele frequencies among these ethnic or racial groups and whether these SNPs differentially affect the efficacy or toxicity of MTX. METHODS: Allele frequencies in the 677, 1298 and 3 additional SNPs in the MTHFR coding region in 223 (193 Caucasians and 30 African-Americans) patients with rheumatoid arthritis who previously participated in one of two prospective clinical trials were characterised, and genotypes were correlated with the efficacy and toxicity of MTX. Another 308 subjects with rheumatoid arthritis who participated in observational studies, one group predominantly Caucasian and the other African-American, as well as 103 normal controls (53 African-Americans and 50 Caucasians) were used to characterise allele frequencies of these SNPs and their associated haplotypes. RESULTS: Significantly different allele frequencies were seen in three of the five SNPs and haplotype frequencies between Caucasians and African-Americans. Allele frequencies were similar between patients with rheumatoid arthritis and controls of the same racial or ethnic group. Frequencies of the rs4846051C, 677T and 1298C alleles were 0.33, 0.11 and 0.13, respectively, among African-Americans with rheumatoid arthritis. Among Caucasians with rheumatoid arthritis, these allele frequencies were 0.08 (p<0.001 compared with African-Americans with rheumatoid arthritis), 0.30 (p = 0.002) and 0.34 (p<0.001), respectively. There was no association between SNP alleles or haplotypes and response to MTX as measured by the mean change in the 28-joint Disease Activity Score from baseline values. In Caucasians, the 1298 A (major) allele was associated with a significant increase in MTX-related adverse events characteristic of a recessive genetic effect (odds ratio 15.86, 95% confidence interval 1.51 to 167.01; p = 0.021), confirming previous reports. There was an association between scores of MTX toxicity and the rs4846051 C allele, and haplotypes containing this allele, in African-Americans, but not in Caucasians. CONCLUSIONS: : These results, although preliminary, highlight racial or ethnic differences in frequencies of common MTHFR SNPs. The MTHFR 1298 A and the rs4846051 C alleles were associated with MTX-related adverse events in Caucasians and African-Americans, respectively, but these findings should be replicated in larger studies. The rs4846051 SNP, which is far more common in African-Americans than in Caucasians, can also be proved to be a useful ancestry informative marker in future studies on genetic admixture.

Mikuls TR, Saag KG, Curtis J, Bridges SL, Alarcon GS, Westfall AO, Lim SS, Smith EA, Jonas BL, Moreland LW, Anonymous00291. · Department of Medicine, University of Nebraska Medica Center and Omaha VA Medical Center, Omaha, NE 68198-3025, USA. · J Natl Med Assoc. · Pubmed #16173331 links to  free full text

Abstract: PURPOSE: To examine the prevalence of osteopenia and/or osteoporosis among African Americans with early rheumatoid arthritis (RA) and to assess the effect of using race/ethnicity-specific normative data. METHODS: Bone mineral density (BMD) of the hip and spine was assessed in African Americans with early RA. To examine the impact of using different normative data on disease classification, we calculated two sets of T scores, the first using sex-matched reference data from Caucasians and the second using data from African Americans. Osteoporosis was defined as a BMD at either site > or =2.5 SD below the young adult mean. Osteopenia was defined as a BMD > or =1 SD and <2.5 SD below this mean. RESULTS: Using Caucasian referent data, 33% (n=48) of patients had osteopenia or worse (n=48, 32.9%) and 5% (n=8) were osteoporotic. With the use of African-American normative data, 55% (n=94) were osteopenic or worse, and 16% (n=27) were osteoporotic. CONCLUSION: African Americans with RA are at risk of osteopenia and/or osteoporosis. Different diagnostic classifications may occur in this population based solely on the normative data used for assessing fracture risk. These results underscore the need for a standardized approach in defining osteopenia and osteoporosis in African Americans.

Shatin D, Rawson NS, Curtis JR, Braun MM, Martin CK, Moreland LW, Becker AF, Patkar NM, Allison JJ, Saag KG. · Center for Health Care Policy and Evaluation, Minneapolis, MN, USA. · Pharmacoepidemiol Drug Saf. · Pubmed #16136625 No free full text.

Abstract: PURPOSE: Following its licensure, tuberculosis (TB) was reported as a potential adverse effect of infliximab. Subsequently, the product circular was changed to recommend tuberculin skin testing before patients received infliximab, which was reinforced by several risk communication efforts. The aim of this study was to evaluate patterns and predictors of documented tuberculin skin testing in patients before and after manufacturer, federal, and academic risk communications. METHODS: Patients administered infliximab were identified from 11 health plans located throughout the United States, and claims data were examined to determine whether the patients had received a tuberculin skin test. Patients were divided into three cohorts depending on the timing of their first infliximab treatment in relation to the risk communication efforts. RESULTS: The overall tuberculin skin testing rate doubled from 15.4% in the first cohort to 30.9% in the last cohort, while the rate of pre-infliximab treatment testing increased from 0 to 27.7% (Chi-squared test for trend, p < 0.0001 for both). Tuberculin skin testing rates were significantly higher in women, those with a diagnosis of rheumatoid or psoriatic arthritis, and those with a rheumatologist as prescriber. After multivariable analysis, only rheumatologist remained significantly associated with tuberculin skin testing. CONCLUSIONS: Although the tuberculin skin testing rate was relatively low overall, tuberculin skin testing doubled over 30 months of ongoing risk communication efforts and under ascertainment likely occurred. We also found variation in the tuberculin skin testing rate associated with physician specialty. This study demonstrates a significant change in patient care following risk communication efforts.

Pisu M, James N, Sampsel S, Saag KG. · Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 1530 3rd Avenue North, Birmingham, AL 35294-3408, USA. · Rheumatology (Oxford). · Pubmed #15769791 links to  free full text

Abstract: OBJECTIVE: To estimate the costs of glucocorticoid associated adverse events (GAEs) in patients with rheumatoid arthritis (RA). METHODS: We conducted a literature review of studies reporting GAEs in RA patients, and developed a Markov model with the following GAEs: fractures (vertebral, hip, pelvic), hypertension, diabetes, gastrointestinal complications, pneumonia, urinary tract infection, cataract and, in an extended model, myocardial infarction (MI) and stroke. Two-year total costs were calculated using direct medical costs (2001 US dollars [USD]) and by running 10,000 Monte Carlo simulations with probability values randomly selected from the GAE literature. RESULTS: On average, glucocorticoid users spent USD 445 more than non-users, or USD 0.46 for each dollar spent on purchasing the drug. When adding MI and stroke, users spent on average USD 430 more than non-users, or USD 0.44 for each dollar spent on purchasing the drug; this incremental cost ranged from USD 193 to USD 682 if MI and stroke were excluded, respectively. In 70% of the simulations there were more deaths among users than among non-users, in both the model with and without MI and stroke. CONCLUSIONS: Although results varied depending on attributed GAEs, in general glucocorticoid users spent more than non-users on GAE treatment, and had higher mortality. Patients, providers and policy makers should consider these potential costs of GAEs when making treatment decisions.

MacLean CH, Saag KG, Solomon DH, Morton SC, Sampsel S, Klippel JH. · RAND Corporation, Santa Monica, California and University of California Los Angeles School of Medicine, USA. · Arthritis Rheum. · Pubmed #15077259 links to  free full text

Abstract: OBJECTIVE: To develop a comprehensive set of explicit process measures to assess the quality of health care for osteoarthritis, rheumatoid arthritis, and analgesics use. METHODS: Potential quality measures and a summary of existing data to support or refute the relationship between the processes of care proposed in the indicators and relevant clinical outcomes were developed through a comprehensive literature review. The proposed measures and literature summary were presented to a multidisciplinary panel of experts in arthritis and pain. Using a modification of the RAND/UCLA Appropriateness Method, the panel rated each proposed measure for its validity as a measure of health care quality. RESULTS: Among 66 proposed indicators, the expert panel rated 51 as valid measures of health care including 14 for osteoarthritis, 27 for rheumatoid arthritis, and 10 for analgesics use. CONCLUSIONS: Sufficient scientific evidence and expert consensus exist to support a comprehensive set of measures to assess the quality of heath care for osteoarthritis, rheumatoid arthritis, and analgesics use. These measures can be used to gain an understanding of the quality of care for patients with arthritis.

Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG, Anonymous00131. · College of Public Health, University of Iowa, Iowa City. · Arthritis Rheum. · Pubmed #14730601 links to  free full text

Abstract: OBJECTIVE: Vitamin D is a potent regulator of calcium homeostasis and may have immunomodulatory effects. The influence of vitamin D on human autoimmune disease has not been well defined. The purpose of this study was to evaluate the association of dietary and supplemental vitamin D intake with rheumatoid arthritis (RA) incidence. METHODS: We analyzed data from a prospective cohort study of 29,368 women of ages 55-69 years without a history of RA at study baseline in 1986. Diet was ascertained using a self-administered, 127-item validated food frequency questionnaire that included supplemental vitamin D use. Risk ratios (RRs) and 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards regression, adjusting for potential confounders. RESULTS: Through 11 years of followup, 152 cases of RA were validated against medical records. Greater intake (highest versus lowest tertile) of vitamin D was inversely associated with risk of RA (RR 0.67, 95% CI 0.44-1.00, P for trend = 0.05). Inverse associations were apparent for both dietary (RR 0.72, 95% CI 0.46-1.14, P for trend = 0.16) and supplemental (RR 0.66, 95% CI 0.43-1.00, P for trend = 0.03) vitamin D. No individual food item high in vitamin D content and/or calcium was strongly associated with RA risk, but a composite measure of milk products was suggestive of an inverse association with risk of RA (RR 0.66, 95% CI 0.42-1.01, P for trend = 0.06). CONCLUSION: Greater intake of vitamin D may be associated with a lower risk of RA in older women, although this finding is hypothesis generating.