Clinical Focus

  • Rheumatology
  • Lupus
  • arthritis
  • Immunology and Rheumatology
  • Gout

Academic Appointments

Administrative Appointments

  • Director and PI, Stanford ARAMIS (2013 - Present)
  • Director, Clinical Epidemiology, Division of Immunology and Rheumatology, Stanford University (2008 - Present)
  • Member, Institute for Immunity, Transplant and Immunology, Stanford University (2008 - Present)
  • Reviewer, Scientific Advisory Council (Study Section), Research and Education Foundation, American College of Rheumatology (2007 - 2009)
  • Member, Annual Meeting Abstract selection committee, Epidemiology and health outcomes Section, American College of Rheumatology (2007 - Present)
  • Faculty, RAND-University of Pittsburgh Health Institute (2007 - 2008)
  • Member Institutional Review Board, The Reading Hospital and Medical Center (2005 - 2005)

Honors & Awards

  • Runner up Gold Medal for academic proficiency, University of Kerala (1993)
  • Beverly Sackler Endowment Award, Cambridge University, UK (1994-5)
  • Annual Reseach Awards, Indian Council for Medical Research (1992,1993 & 1994)
  • Research Training Fellowship in Cancer Epidemiology, The World Health Organization (1994-95)
  • Distinguished Fellow Award, American College of Rheumatology (2002)
  • Multidisciplinary Clinical Research Scholar, NIH Roadmap Inititative/University of Pittsburgh (2005-2008)
  • T. Williams Franklin Scholar, Association of Subspecialty Professors (2009-2011)

Professional Education

  • Fellowship:Stanford University School of Medicine (2002) CA
  • Residency:The Chicago Medical School (2000) IL
  • Medical Education:Kerala University-Trivandrum Medical College (1994) India
  • MBBS (MD Equivalent), University of Kerala, Medicine (1994)
  • M. Phil, Cambridge University, Epidemiology (1995)

Community and International Work

  • Krishnan E. Gout and the risk for coronary artery disease: The MRFIT study.




    Ongoing Project


    Opportunities for Student Involvement


  • In the news

    Ongoing Project


    Opportunities for Student Involvement


Research & Scholarship

Current Research and Scholarly Interests

I am a clinical epidemiologist. My long-term goal is to develop ways and means of disease prevention in the context of rheumatic diseases. Currently, my core investigative areas are: 1) Cardiovascular impact of inflammatory arthritis 2) Healthcare utilization of populations 3) Methodological innovations for improvement of individual and population phenotyping and health outcome measurement 4)Health outcomes in extreme old age.

Clinical Trials

  • Ankylosing Spondylitis and Spondyloarthritis Evaluation Tool Study Not Recruiting

    This study aims to test whether a new instrument (questionnaire) is useful for identifying patients with ankylosing spondylitis.

    Stanford is currently not accepting patients for this trial. For more information, please contact ESWAR KRISHNAN, MD, 650-725-8004.

    View full details


2013-14 Courses

Postdoctoral Advisees


Journal Articles

  • Atherosclerotic Cardiovascular Disease in Hospitalized Patients With Systemic Sclerosis: Higher Mortality Than Patients With Lupus and Rheumatoid Arthritis ARTHRITIS CARE & RESEARCH Dave, A. J., Fiorentino, D., Lingala, B., Krishnan, E., Chung, L. 2014; 66 (2): 323-327


    Systemic sclerosis (SSc; scleroderma) patients have an increased risk for atherosclerotic cardiovascular disease (ASCVD), possibly mediated through inflammatory and fibrotic mechanisms affecting the macrovasculature and microvasculature. We utilized the US Nationwide Inpatient Sample to assess the frequency of and mortality risk associated with ASCVD among hospitalized SSc patients.We examined the frequency and mortality associated with primary diagnoses and procedures related to ASCVD among adult SSc patients using data from 1993 to 2007. Using multivariate logistic regression (controlling for age, sex, nonelective admission, and modified Charlson Comorbidity Index), we compared the odds of death among hospitalized SSc patients with ASCVD to those with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), as well as to a control group that excluded patients with connective tissue diseases.A total of 308,452 hospitalizations of SSc patients were included, of which 5.4% were associated with a primary ASCVD diagnosis or procedure. ASCVD-related SSc hospitalizations were more likely to result in death compared with non-ASCVD SSc hospitalizations (odds ratio [OR] 1.3, 95% confidence interval [95% CI] 1.1-1.4). Multivariate analyses showed that ASCVD-related SSc hospitalizations were more likely to result in death than similar hospitalizations of SLE (OR 1.5, 95% CI 1.2-1.8), RA (OR 2.3, 95% CI 1.9-2.8), and control patients (OR 1.4, 95% CI 1.2-1.8) with ASCVD.SSc patients with ASCVD have higher in-hospital mortality than comparable groups of SLE and RA patients with ASCVD. Further research to elucidate the specific mechanisms underlying ASCVD in SSc is necessary.

    View details for DOI 10.1002/acr.22152

    View details for Web of Science ID 000330266100020

    View details for PubMedID 24022876

  • Gout and the heart. Rheumatic diseases clinics of North America Bhole, V., Krishnan, E. 2014; 40 (1): 125-143


    The association between gout and cardiovascular diseases has been noted for centuries but was not subjected to rigorous epidemiologic studies until recently. The published literature is almost unanimous in the strength and consistency of this association. However, the impact of gout over and above that conferred by hyperuricemia and other risk factors of cardiovascular disease has not been well studied. Future studies are expected to shed light on the pathophysiologic basis of this association.

    View details for DOI 10.1016/j.rdc.2013.10.004

    View details for PubMedID 24268013

  • Health and Exercise-Related Medical Issues among 1,212 Ultramarathon Runners: Baseline Findings from the Ultrarunners Longitudinal TRAcking (ULTRA) Study. PloS one Hoffman, M. D., Krishnan, E. 2014; 9 (1): e83867


    Regular exercise is associated with substantial health benefits; however, little is known about the health impact of extreme levels of exercise. This study examined the prevalence of chronic diseases, health-care utilization, and risk factors for exercise-related injuries among ultramarathon runners. Retrospective, self-reported enrollment data from an ongoing longitudinal observational study of 1,212 active ultramarathon runners were analyzed. The most prevalent chronic medical conditions were allergies/hay fever (25.1%) and exercise-induced asthma (13.0%), but there was a low prevalence of serious medical issues including cancers (4.5%), coronary artery disease (0.7%), seizure disorders (0.7%), diabetes (0.7%), and human immunodeficiency virus (HIV) infection (0.2%). In the year preceding enrollment, most (64.6%) reported an exercise-related injury that resulted in lost training days (median of 14 days), but little nonattendance of work or school due to illness, injury, or exercise-related medical conditions (medians of 0 days for each). The knee was the most common area of exercise-related injury. Prior year incidence of stress fractures was 5.5% with most (44.5%) involving the foot. Ultramarathon runners who sustained exercise-related injuries were younger (p<0.001) and less experienced (p<0.01) than those without injury. Stress fractures were more common (p<0.01) among women than men. We conclude that, compared with the general population, ultramarathon runners appear healthier and report fewer missed work or school days due to illness or injury. Ultramarathon runners have a higher prevalence of asthma and allergies than the general population, and the prevalence of serious medical issues was nontrivial and should be recognized by those providing medical care to these individuals. Ultramarathon runners, compared with shorter distance runners, have a similar annual incidence of exercise-related injuries but higher proportion of stress fractures involving the foot, and it is the younger and less experienced ultramarathoners who appear most at risk for injury.

    View details for DOI 10.1371/journal.pone.0083867

    View details for PubMedID 24416176

  • Big Data and Clinicians: A Review on the State of the Science JMIR Med Inform Wang, W., Krishnan, E. 2014; 2 (1): e1

    View details for DOI 10.2196/medinform.2913

  • 1extending the floor and the ceiling for assessment of physical function. Arthritis and rheumatism Fries, J. F., Lingala, B., Siemons, L., Glas, C. A., Cella, D., Hussain, Y. N., Bruce, B., Krishnan, E. 2014


    Objective. The objective of the current study was to improve the assessment of physical function by improving the precision of assessment at the floor (extremely poor function) and at the ceiling (extremely good health) of the health continuum. Methods. Under the NIH PROMIS program, we developed new physical function floor and ceiling items to supplement the existing item bank. Using item response theory (IRT) and the standard PROMIS methodology, we developed 30 floor items and 26 ceiling items and administered them during a 12-month prospective observational study of 737 individuals at the extremes of health status. Change over time was compared across anchor instruments and across items by means of effect sizes. Using the observed changes in scores, we back-calculated sample size requirements for the new and comparison measures. Results. We studied 444 subjects with chronic illness and/or extreme age, and 293 generally fit subjects including athletes in training. IRT analyses confirmed that the new floor and ceiling items outperformed reference items (p<0.001). The estimated post-hoc sample size requirements were reduced by a factor of two to four at the floor and a factor of two at the ceiling. Conclusion. Extending the range of physical function measurement can substantially improve measurement quality, can reduce sample size requirements and improve research efficiency. The paradigm shift from Disability to Physical Function includes the entire spectrum of physical function, signals improvement in the conceptual base of outcome assessment, and may be transformative as medical goals more closely approach societal goals for health. © 2013 American College of Rheumatology.

    View details for DOI 10.1002/art.38342

    View details for PubMedID 24403003

  • Chronic Kidney Disease and the Risk of Incident Gout Among Middle-Aged Men A Seven-Year Prospective Observational Study ARTHRITIS AND RHEUMATISM Krishnan, E. 2013; 65 (12): 3271-3278


    The kidney is the major organ that facilitates excretion of urate in humans. Surprisingly, few studies have assessed whether a reduced glomerular filtration rate (GFR) and/or kidney damage is associated with a higher incidence of gout, and this study was undertaken to address this question.Data from a 7-year followup of patients enrolled in the Multiple Risk Factor Intervention Trial, a primary prevention trial for cardiovascular disease among 12,866 men ages 35-57 years, were used for the present investigation. Presence of gout was determined by the study physicians from the original trial. Chronic kidney disease was defined using criteria similar to those proposed by the National Kidney Foundation. The Cox proportional hazards regression model was used to assess the association between gout and chronic kidney disease, after accounting for the effects of potential confounders.Overall, there were 722 cases of physician- diagnosed incident gout over 76,602 person-years of followup. The standardized incidence ratio of gout among those with chronic kidney disease was 1,217 (95% confidence interval [95% CI] 1,191-1,244). The adjusted hazard ratio (HR) among those with chronic kidney disease was 1.61 (95% CI 1.60-1.61). Each standard deviation decline in the estimated GFR was associated with an HR of 1.43 (95% CI 1.35-1.51). Including the serum urate level, as well as the urate-chronic kidney disease interaction term, as variables in the second analysis did not attenuate the HR. Proteinuria and hematuria, two markers of kidney damage, were associated with an elevated risk of gout independent of the estimated GFR.Chronic kidney disease manifesting as reduced glomerular function or as presence of blood or protein in the urine increases the risk of incident gout.

    View details for DOI 10.1002/art.38171

    View details for Web of Science ID 000327692600030

    View details for PubMedID 23982888

  • Upper-Extremity and Mobility Subdomains From the Patient-Reported Outcomes Measurement Information System (PROMIS) Adult Physical Functioning Item Bank ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION Hays, R. D., Spritzer, K. L., Amtmann, D., Lai, J., DeWitt, E. M., Rothrock, N., DeWalt, D. A., Riley, W. T., Fries, J. F., Krishnan, E. 2013; 94 (11): 2291-2296


    To create upper-extremity and mobility subdomain scores from the Patient-Reported Outcomes Measurement Information System (PROMIS) physical functioning adult item bank.Expert reviews were used to identify upper-extremity and mobility items from the PROMIS item bank. Psychometric analyses were conducted to assess empirical support for scoring upper-extremity and mobility subdomains.Data were collected from the U.S. general population and multiple disease groups via self-administered surveys.The sample (N=21,773) included 21,133 English-speaking adults who participated in the PROMIS wave 1 data collection and 640 Spanish-speaking Latino adults recruited separately.Not applicable.We used English- and Spanish-language data and existing PROMIS item parameters for the physical functioning item bank to estimate upper-extremity and mobility scores. In addition, we fit graded response models to calibrate the upper-extremity items and mobility items separately, compare separate to combined calibrations, and produce subdomain scores.After eliminating items because of local dependency, 16 items remained to assess upper extremity and 17 items to assess mobility. The estimated correlation between upper extremity and mobility was .59 using existing PROMIS physical functioning item parameters (r=.60 using parameters calibrated separately for upper-extremity and mobility items).Upper-extremity and mobility subdomains shared about 35% of the variance in common, and produced comparable scores whether calibrated separately or together. The identification of the subset of items tapping these 2 aspects of physical functioning and scored using the existing PROMIS parameters provides the option of scoring these subdomains in addition to the overall physical functioning score.

    View details for DOI 10.1016/j.apmr.2013.05.014

    View details for Web of Science ID 000326852600035

    View details for PubMedID 23751290

  • Citrullination Within the Atherosclerotic Plaque: A Potential Target for the Anti-Citrullinated Protein Antibody Response in Rheumatoid Arthritis ARTHRITIS AND RHEUMATISM Sokolove, J., Brennan, M. J., Sharpe, O., Lahey, L. J., Kao, A. H., Krishnan, E., Edmundowicz, D., Lepus, C. M., Wasko, M. C., Robinson, W. H. 2013; 65 (7): 1719-1724


    BACKGROUND/PURPOSE: Patients with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease, an observation not explained by traditional cardiac risk factors and generally limited to those with RA-associated autoantibodies such as rheumatoid factor and anti-citrullinated protein antibodies (ACPA). We hypothesized that citrullinated proteins within the atherosclerotic plaque can be targeted by ACPA, forming stimulatory immune complexes which propagate the progression of atherosclerosis. METHODS AND RESULTS: Protein lysates prepared from atherosclerotic segments of human aorta were investigated for the presence of citrulline-modified proteins and specifically citrullinated fibrinogen (cFb) by immunoprecipitation and/or immunoblotting followed by mass spectrometry. Immunohistochemistry was performed in coronary artery plaques for the presence of citrullinated proteins and the PAD4 enzyme. Serum levels of anti-cyclic citrullinated peptide (CCP), anti-citrullinated vimentin (cVim), and anti-cFb antibodies were measured in 134 women with seropositive RA previously characterized for the presence of subclinical atherosclerosis by electron beam CT scan (EBCT). Western analysis of atherosclerotic plaque lysates demonstrated several citrullinated proteins and the presence of cFb was confirmed by immunoprecipitation, and mass spectrometry. Immunohistochemistry demonstrated co-localization of citrullinated proteins and the PAD4 enzyme within the coronary artery plaque. In age-adjusted regression models, antibodies targeting cFb and cit-vimentin, but not CCP2, were associated with an increased aortic plaque burden. CONCLUSION: Citrullinated proteins are prevalent within the atherosclerotic plaque, and certain ACPAs are associated with atherosclerotic burden. These observations suggest that targeting of citrullinated epitopes, specifically cFb, within the atherosclerotic plaque could provide a mechanism for accelerated atherosclerosis observed in patients with RA. © 2013 American College of Rheumatology.

    View details for DOI 10.1002/art.37961

    View details for Web of Science ID 000322155000007

  • Atherosclerotic cardiovascular disease and dermatomyositis: an analysis of the Nationwide Inpatient Sample survey. Arthritis research & therapy Linos, E., Fiorentino, D., Lingala, B., Krishnan, E., Chung, L. 2013; 15 (1): R7


    ABSTRACT: INTRODUCTION: Increased rates of cardiovascular disease are implicated in several rheumatologic diseases. Our aim was to characterize dermatomyositis hospitalizations and evaluate cardiovascular-associated mortality in this patient population. METHODS: We examined the frequency and mortality rates of several atherosclerotic cardiovascular diagnoses and procedures among hospitalized adult patients with dermatomyositis using data from the US Nationwide Inpatient Sample (NIS) from 1993 to 2007. We compared the odds of death among hospitalized dermatomyositis patients with each cardiovascular diagnosis or procedure to those without, as well as to controls with cardiovascular diagnoses, using logistic regression. RESULTS: A total of 50,322 hospitalizations of dermatomyositis patients occurred between 1993 and 2007 (mean age 58 years, and 73% female). Of all dermatomyositis hospitalizations, 20% were associated with a concurrent atherosclerotic cardiovascular diagnosis or procedure. The overall in-hospital mortality was 5.7%. Dermatomyositis patients with any associated atherosclerotic cardiovascular diagnosis or procedure were twice as likely to die during the inpatient stay compared to dermatomyositis patients who did not have atherosclerotic cardiovascular disease (OR = 2.0 95% CI 1.7-2.5, p < 0.0001). The odds ratio for death in patients with both dermatomyositis and cardiovascular disease compared to controls with cardiovascular disease alone was 1.98 (95% CI 1.57-2.48) in multivariate adjusted models. CONCLUSIONS: Approximately one fifth of dermatomyositis hospitalizations in the US were associated with an atherosclerotic cardiovascular diagnosis or procedure. These patients have double the risk of in-hospital death in comparison with controls and dermatomyositis patients without a cardiovascular diagnosis, making identification of these groups important for both prognostic purposes and clinical care.

    View details for PubMedID 23298514

  • Tophaceous gout and high level of hyperuricaemia are both associated with increased risk of mortality in patients with gout. Annals of the rheumatic diseases Perez-Ruiz, F., Martínez-Indart, L., Carmona, L., Herrero-Beites, A. M., Pijoan, J. I., Krishnan, E. 2013


    BACKGROUND: While several studies have reported a link between the presence of gout and adverse cardiovascular (CV) events in the general population, none has addressed the question of whether the mortality risk of patients with gout is influenced by disease severity. METHODS: We applied survival analysis methodology to prospectively collected data on clinical and radiographic measures of disease severity and mortality in a specialty clinic based cohort of 706 patients with gout (1992-2008). Standardised mortality ratios (SMR) were calculated to assess the magnitude of excess mortality among patients with gout compared with the underlying general population. RESULTS: Mean follow-up was 47 months. Tophaceous deposition was present in 30.5% of patients; >4 joints were involved in 34.6% of cases. Mean annual flare rate was 3.4. Arterial hypertension (41.2%), hyperlipidaemia (42.2%), diabetes mellitus (20.1%), renal function impairment (26.6%) and a previous CV event (25.3%) were recorded. 64 (9.1%) patients died, death being attributed to vascular causes in 38 (59%) patients. SMR for gout patients was 2.37 (95% CI 1.82 to 3.03), 1.57 (1.18 to 2.05) and 4.50 (2.06 to 8.54) overall, and in men and women, respectively. The presence of tophi and the highest baseline serum urate (SU) levels were independently associated with a higher risk of mortality, in addition to age, loop diuretic use and a history of a previous vascular event. In the multivariable survival regression models, with time varying covariates, the presence of tophi remained a significant mortality risk after adjustment for baseline SU levels (1.98; 1.24 to 3.20). CONCLUSIONS: High baseline SU level and the presence of subcutaneous tophi were both associated with an increased risk of mortality in patients with gout, in most cases attributed to a CV cause. This suggests a plausible pathophysiological link between greater total body urate load and CV disease.

    View details for PubMedID 23313809

  • Serum Urate and Incidence of Kidney Disease Among Veterans with Gout. The Journal of rheumatology Krishnan, E., Akhras, K. S., Sharma, H., Marynchenko, M., Wu, E., Tawk, R. H., Liu, J., Shi, L. 2013


    OBJECTIVE: To study the association between serum urate level (sUA) and the risk of incident kidney disease among US veterans with gouty arthritis. METHODS: From 2002 through 2011 adult male patients with gout who were free of kidney disease were identified in the data from the Veterans Administration VISN 16 database and were followed until incidence of kidney disease, death, or the last available observation. Accumulated hazard curves for time to kidney disease were estimated for patients with average sUA levels > 7 mg/dl (high) versus ? 7 mg/dl (low) based on Kaplan-Meier analyses; and statistical comparison was conducted using a log-rank test. A Cox proportional hazard model with time-varying covariates was used to estimate the unadjusted and adjusted hazard ratios for kidney disease. RESULTS: Eligible patients (n = 2116) were mostly white (53%), with average age 62.6 years, mean body mass index 31.2 kg/m2, and high baseline prevalence of hypertension (93%), hyperlipidemia (67%), and diabetes (20%). Mean followup time was 6.5 years. The estimated rates of all incident kidney disease in the overall low versus high sUA groups were 2% versus 4% at Year 1, 3% versus 6% at Year 2, and 5% versus 9% at Year 3, respectively (p < 0.0001). After adjustment, high sUA continued to predict a significantly higher risk of kidney disease development (HR 1.43, 95% CI 1.20-1.70). CONCLUSION: Male veterans with gout and sUA levels > 7 mg/dl had an increased incidence of kidney disease.

    View details for PubMedID 23678154

  • Relative and attributable diabetes risk associated with hyperuricemia in US veterans with gout. QJM : monthly journal of the Association of Physicians Krishnan, E., Akhras, K. S., Sharma, H., Marynchenko, M., Wu, E. Q., Tawk, R., Liu, J., Shi, L. 2013


    BACKGROUND: Hyperuricemia is known to be a risk factor for incident type 2 diabetes mellitus, but the absolute magnitude of the association is not known. We aimed to evaluate the strength of association between hyperuricemia and the risk of developing diabetes among the US veterans with gout.Methods: Patients (age ? 18 years) with ?2 clinical encounters with gout diagnoses, no history of inflammatory diseases or diabetes and two serum urate (sUA) measurements between 1 January 2002 and 1 January 2011 were selected. Diabetes was identified using International Classification of Disease-9-Clinical Modification codes, use of anti-diabetic medications or HbA1c ?6.5%. sUA levels were assessed at 6-month cycles (hyperuricemia: sUA >7 mg/dl). Accumulated hazard curves for time to first diabetes diagnosis were derived from Kaplan-Meier (KM) analysis. Risk of diabetes associated with hyperuricemia was estimated using a Cox proportional hazards model. Population attributable fraction (AF) of new-onset diabetes within 1 year was estimated using logistic regression.Results: Among 1923 patients, average age was 62.9 years, body mass index was 30.6 kg/m(2), and follow-up time was 80 months. Diabetes rates from KM were 19% for sUA ? 7 mg/dl, 23% for 7 mg/dl < sUA ? 9 mg/dl and 27% for sUA > 9 mg/dl at the end of follow-up period (P < 0.001). Hyperuricemia was associated with a significantly higher risk of developing diabetes, after adjusting for confounding factors (hazard ratio: 1.19, 95% confidence interval: [1.01-1.41]). Approximately, 8.7% of all new cases of diabetes were statistically attributed to hyperuricemia.Conclusions: Among veterans, hyperuricemia was associated with excess risk for developing diabetes. Approximately, 1 in 11 new cases of diabetes were statistically attributed to hyperuricemia.

    View details for PubMedID 23620537

  • The components of action planning and their associations with behavior and health outcomes. Chronic illness Lorig, K., Laurent, D. D., Plant, K., Krishnan, E., Ritter, P. L. 2013


    Based on the works of Kiesler and Bandura, action plans have become important tools in patient self-management programs. One such program, shown effective in randomized trials, is the Internet Chronic Disease Self-Management Program. An implementation of this program, Healthy Living Canada, included detailed information on action plans and health-related outcome measures.Action plans were coded by type, and associations between action plans, confidence in completion and completion were examined. Numbers of Action Plans attempted and competed and completion rates were calculated for participants and compared to six-month changes in outcomes using regression models.Five of seven outcome measures significantly improved at six-months. A total of 1136 action plans were posted by 254 participants in 12 workshops (mean 3.9 out of 5 possible); 59% of action plans involved exercise, 16% food, and 14% role management. Confidence of completion was associated with completion. Action plan completion measures were associated with improvements in activity limitation, aerobic exercise, and self-efficacy. Baseline self-efficacy was associated with at least partial completion of action plans.Action planning appears to be an important component of self-management interventions, with successful completion associated with improved health and self-efficacy outcomes.

    View details for PubMedID 23838837

  • Exercise Habits of Ultramarathon Runners: Baseline Findings from the ULTRA Study. Journal of strength and conditioning research / National Strength & Conditioning Association Hoffman, M. D., Krishnan, E. 2013


    Little is known about exercise habits of those who compete in foot races longer than the standard 42-km marathon distance. The purpose of this work was to describe the past-year and lifetime exercise patterns of a large cohort of ultramarathon runners. Information on exercise history was collected on 1,345 current and former ultramarathon runners as baseline data for participation in a longitudinal observational study. Median age at the first ultramarathon was 36 years, and the median number of years of regular running prior to the first ultramarathon was 7 (interquartile range 3-15). Age at first ultramarathon did not changed across the past several decades, but there was evidence of an inverse relationship (r=-0.13, p<0.0001) between number of years of regular running prior to the first ultramarathon and calendar year. The active ultramarathon runners (n=1,212) had a prior year median running distance of 3,347 km, which was minimally related to age (r=-0.068, p=0.018), but mostly related to their longest ultramarathon competition of the year (p<0.0001). Running injuries represented the most common reason for discontinuation of regular running, while work and family commitments were reported as the main reasons for not running an ultramarathon in the prior year among those who were regularly running and intending to run ultramarathons again. We conclude that runners tend to be well into adulthood and with several years of running experience before running their first ultramarathon, but 25% have only been regularly running for 3 years or less at the time of their first ultramarathon.

    View details for PubMedID 23838972

  • What have the Framingham cohorts taught us about hyperuricemia and gout? International Journal of Clinical Rheumatology Bhole V, Krishnan E 2013; 8 (2): 149-151
  • Body Mass Index and its Correlates in 1,212 Ultramarathon Runners: Baseline Findings from the ULTRA Study. Journal of physical activity & health Hoffman, M. D., Chen, L., Krishnan, E. 2013


    Little is known about the sociodemographics and lifestyle behaviors of ultramarathon runners, and the effects of these characteristics on body weight and body mass index (BMI).We cross-sectionally analyzed baseline data of 1,212 ultramarathoners on sociodemographics, lifestyle behaviors and BMI from the initial 12-month enrollment period in a longitudinal observational study.The ultramarathoners were mostly middle-aged men who were more educated, more likely to be in a stable relationship, and more likely to use over-the-counter vitamins/supplements than the general population. They appear to gain less body weight with advancing age than the general population. Factors with the greatest effect on current BMI were BMI at 25 years of age and sex which explained 48% and 3% of the variance. Negligible, but statistically significant direct relationships, with BMI were observed for age, work hours per week, television watching hours per week, and composite fat consumption frequency score. Negligible, but statistically significant inverse relationships, with BMI were observed for running distance during the prior year, and composite fruit and vegetable consumption frequency score.While lifestyle decisions were found to impact BMI within this group of ultramarathoners, BMI at age 25 was the strongest predictor of current BMI.

    View details for PubMedID 24385475

  • Responsiveness and minimally important difference for the Patient-Reported Outcomes Measurement Information System (PROMIS) 20-item physical functioning short form in a prospective observational study of rheumatoid arthritis. Annals of the rheumatic diseases Hays, R. D., Spritzer, K. L., Fries, J. F., Krishnan, E. 2013


    To estimate responsiveness (sensitivity to change) and minimally important difference (MID) for the Patient-Reported Outcomes Measurement Information System (PROMIS) 20-item physical functioning scale (PROMIS PF-20).The PROMIS PF-20, short form 36 (SF-36) physical functioning scale, and Health Assessment Questionnaire (HAQ) were administered at baseline, and 6 and 12 months later to a sample of 451 persons with rheumatoid arthritis. A retrospective change (anchor) item was administered at the 12-month follow-up. We estimated responsiveness between 12 months and baseline, and between 12 months and 6 months using one-way analysis of variance F-statistics. We estimated the MID for the PROMIS PF-20 using prospective change for people reporting getting 'a little better' or 'a little worse' on the anchor item.F-statistics for prospective change on the PROMIS PF-20, SF-36 and HAQ by the anchor item over 12 and 6 months (in parentheses) were 16.64 (14.98), 12.20 (7.92) and 10.36 (12.90), respectively. The MID for the PROMIS PF-20 was 2 points (about 0.20 of an SD).The PROMIS PF-20 is more responsive than two widely used ('legacy') measures. The MID is a small effect size. The measure can be useful for assessing physical functioning in clinical trials and observational studies.

    View details for DOI 10.1136/annrheumdis-2013-204053

    View details for PubMedID 24095937

  • Development and assessment of floor and ceiling items for the PROMIS physical function item bank. Arthritis research & therapy Bruce, B., Fries, J., Lingala, B., Hussain, Y. N., Krishnan, E. 2013; 15 (5): R144-?


    Disability and Physical Function (PF) outcome assessment has had limited ability to measure functional status at the floor (very poor functional abilities) or the ceiling (very high functional abilities). We sought to identify, develop and evaluate new floor and ceiling items to enable broader and more precise assessment of PF outcomes for the NIH Patient-Reported-Outcomes Measurement Information System (PROMIS).We conducted two cross-sectional studies using NIH PROMIS item improvement protocols with expert review, participant survey and focus group methods. In Study 1, respondents with low PF abilities evaluated new floor items, and those with high PF abilities evaluated new ceiling items for clarity, importance and relevance. In Study 2, we compared difficulty ratings of new floor items by low functioning respondents and ceiling items by high functioning respondents to reference PROMIS PF-10 items. We used frequencies, percentages, means and standard deviations to analyze the data.In Study 1, low (n = 84) and high (n = 90) functioning respondents were mostly White, women, 70 years old, with some college, and disability scores of 0.62 and 0.30. More than 90% of the 31 new floor and 31 new ceiling items were rated as clear, important and relevant, leaving 26 ceiling and 30 floor items for Study 2. Low (n = 246) and high (n = 637) functioning Study 2 respondents were mostly White, women, 70 years old, with some college, and Health Assessment Questionnaire (HAQ) scores of 1.62 and 0.003. Compared to difficulty ratings of reference items, ceiling items were rated to be 10% more to greater than 40% more difficult to do, and floor items were rated to be about 12% to nearly 90% less difficult to do.These new floor and ceiling items considerably extend the measurable range of physical function at either extreme. They will help improve instrument performance in populations with broad functional ranges and those concentrated at one or the other extreme ends of functioning. Optimal use of these new items will be assisted by computerized adaptive testing (CAT), reducing questionnaire burden and insuring item administration to appropriate individuals.

    View details for DOI 10.1186/ar4327

    View details for PubMedID 24286166

  • The Filipino Gout- A Review. Arthritis care & research Prasad, P., Krishnan, E. 2013


    The perceived high prevalence of gout and hyperuricemia in Filipinos residing in the United States has been a largely neglected area of research, in part because Filipinos are grouped with many other diverse Asian subgroups. The high population growth rate of this community in the U.S. makes such research valuable. This review summarizes epidemiologic findings on gout and hyperuricemia in Filipinos, and compares findings to Pacific Islanders, a separate category of ethnicity often confused with Filipinos. Literature shows that Filipinos residing in the U.S. have a higher prevalence of gout and hyperuricemia compared to other races in the U.S. On average, Filipinos exhibit a serum urate level approximately 1 mg/dL higher than Caucasians in the United States and Filipinos in the Philippines. Many studies have opined that Filipinos residing in the U.S. are not adapted to compensate for the high purine American diet, which leads to high renal urate load. The competing roles of comorbidities, genetics and healthcare utilization deserve further exploration. © 2013 American College of Rheumatology.

    View details for DOI 10.1002/acr.22118

    View details for PubMedID 23983155

  • Trends in physician diagnosed gout and gout therapies in the US: results from the national ambulatory health care surveys 1993 to 2009. Arthritis research & therapy Krishnan, E., Chen, L. 2013; 15 (6): R181-?


    Gouty arthritis (gout) is primarily cared for in ambulatory care settings. Although the prevalence of gout in the US is thought to be increasing, there have been few data on this as well as temporal changes in gout medication use.We analyzed annual visit and drug utilization data from national sample surveys of physician practices and hospital outpatient clinics in the US from 1993 to 2009. Gout diagnosis was recorded by individual physicians.The frequency of visits for gout increased three-fold from 1993 through 2009; most of the increases were observed from 2003 onwards. The increase was only partly explained by changes in age and gender composition of the surveys over time. A concomitant increase in prescriptions for allopurinol and colchicine and decrease in prescriptions for anti-inflammatories was observed. Aspirin use, a putative risk factor for gout and gout flares, increased substantially over this period. Probenecid use was negligible. Frequency of systemic steroid use has not changed over time.The number of ambulatory visits for gout has increased almost three-fold in the first decade of the millennium coinciding with increases in physician and patient awareness. This increase was primarily due to visits among the elderly. Uricosuric use remained negligible whereas the uses of allopurinol and colchicine have increased rapidly. Use of traditional non-steroidals has declined, possibly due to safety concerns whereas glucocorticoid use remains unchanged.

    View details for DOI 10.1186/ar4370

    View details for PubMedID 24286510

  • Reduced Glomerular Function and Prevalence of Gout: NHANES 2009-10 PLOS ONE Krishnan, E. 2012; 7 (11)


    The renal tubule is a major route of clearance of uric acid, a product of purine metabolism. The links between reduced glomerular filtration rate (GFR), hyperuricemia, and gout in the general population are not well understood. The objective of the present study was to estimate prevalence of gout and hyperuricemia among people with impaired GFR in the US general population.Cross-sectional, survey-weighted analyses of data on adults (age>20 years) in the 2009-10 cycle of the US National Health and Nutrition Examination Surveys (n = 5,589). Associations between self-reported physician diagnosis of gout and degrees of renal impairment were the primary focus of the present analyses.In the 2009-2010 period, there was an estimated 7.5 million people with gout in the US. There were 1.25 million men and 0.78 million women with moderate or severe renal impairment and gout. The age standardized prevalence of gout was 2.9% among those with normal GFR compared to 24% among those with GFR<60 ml/min/1.73 m(2).In multivariable logistic regression analyses that adjusted for age, gender, body mass index, hypertension, diabetes, hypertension medications, including diuretics, blood lead levels, and hyperlipidemia, the odds ratios of gout and hyperuricemia were 5.9 (2.2, 15.7) and 9.58 (4.3, 22.0) respectively among those with severe renal impairment compared to those with no renal impairment. Approximately 2-3 fold increase in prevalence of gout was observed for each 30 ml/min/1.73 m(2) decrease in GFR, after accounting for the above factors.Renal glomerular function is an important risk factor for gout. The prevalence of hyperuricemia and gout increases with decreasing glomerular function independent of other factors. This association is non-linear and an eGFR of 60 ml/min/1.73 m(2) appears to be a threshold for the dramatic increase in the prevalence of gout.

    View details for DOI 10.1371/journal.pone.0050046

    View details for Web of Science ID 000311885800043

    View details for PubMedID 23209642

  • Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity NATURE MEDICINE Li, G., Yu, M., Lee, W., Tsang, M., Krishnan, E., Weyand, C. M., Goronzy, J. J. 2012; 18 (10): 1518-U113


    The ability of the human immune system to respond to vaccination declines with age. We identified an age-associated defect in T cell receptor (TCR)-induced extracellular signal-regulated kinase (ERK) phosphorylation in naive CD4(+) T cells, whereas other signals, such as ? chain-associated protein kinase 70 (ZAP70) and phospholipase C-?1 phosphorylation, were not impaired. The defective ERK signaling was caused by the dual specific phosphatase 6 (DUSP6), whose protein expression increased with age due to a decline in repression by miR-181a. Reconstitution of miR-181a lowered DUSP6 expression in naive CD4(+) T cells in elderly individuals. DUSP6 repression using miR-181a or specific siRNA and DUSP6 inhibition by the allosteric inhibitor (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one improved CD4(+) T cell responses, as seen by increased expression of activation markers, improved proliferation and supported preferential T helper type 1 cell differentiation. DUSP6 is a potential intervention target for restoring T cell responses in the elderly, which may augment the effectiveness of vaccination.

    View details for DOI 10.1038/nm.2963

    View details for Web of Science ID 000309587500030

    View details for PubMedID 23023500

  • Pegloticase and the patient with treatment-failure gout. Expert review of clinical pharmacology Dave, A. J., Kelly, V. M., Krishnan, E. 2012; 5 (5): 501-508


    Gout is an inflammatory arthritis characterized by sudden, painful inflammation. Gout can affect any joint in an asymmetric distribution. Gouty attacks may be isolated or can be followed by years of recurrent flares. Over time, elevated serum urate levels and tophaceous deposits can lead to deformity and disability from underlying bony erosion. The concept of 'treatment-failure gout' describes a unique population that has been either unable to tolerate allopurinol or who have not experienced normalization of serum urate levels on allopurinol. It is estimated that approximately 1-1.5% of the estimated 3-8 million people with gout in the USA have treatment-failure gout. Pegloticase is an US FDA-approved intravenous medication that is a mammalian recombinant uricase conjugated to monomethoxy polyethylene glycol. Two recent Phase III trials have found pegloticase to be effective in the management of treatment-failure gout. These studies also highlight safety concerns regarding the drug's immunogenicity.

    View details for DOI 10.1586/ecp.12.48

    View details for PubMedID 23121270

  • Low-Level Lead Exposure and the Prevalence of Gout An Observational Study ANNALS OF INTERNAL MEDICINE Krishnan, E., Lingala, B., Bhalla, V. 2012; 157 (4): 233-?


    Blood lead levels (BLLs) less than 1.21 µmol/L (<25 µg/dL) among adults are considered acceptable by current national standards. Lead toxicity can lead to gouty arthritis (gout), but whether the low lead exposure in the contemporary general population confers risk for gout is not known.To determine whether BLLs within the range currently considered acceptable are associated with gout.Population-based cross-sectional study.The National Health and Nutrition Examination Survey for 2005 through 2008.6153 civilians aged 40 years or older with an estimated glomerular filtration rate greater than 10 mL/min per 1.73 m2.Outcome variables were self-reported physician diagnosis of gout and serum urate level. Blood lead level was the principal exposure variable. Additional data collected were anthropometric measures, blood pressure, dietary purine intake, medication use, medical history, and serum creatinine concentration.The prevalence of gout was 6.05% (95% CI, 4.49% to 7.62%) among patients in the highest BLL quartile (mean, 0.19 µmol/L [3.95 µg/dL]) compared with 1.76% (CI, 1.10% to 2.42%) among those in the lowest quartile (mean, 0.04 µmol/L [0.89 µg/dL]). Each doubling of BLL was associated with an unadjusted odds ratio of 1.74 (CI, 1.47 to 2.05) for gout and 1.25 (CI, 1.12 to 1.40) for hyperuricemia. After adjustment for renal function, diabetes, diuretic use, hypertension, race, body mass index, income, and education level, the highest BLL quartile was associated with a 3.6-fold higher risk for gout and a 1.9-fold higher risk for hyperuricemia compared with the lowest quartile.Blood lead level does not necessarily reflect the total body lead burden.Blood lead levels in the range currently considered acceptable are associated with increased prevalence of gout and hyperuricemia.

    View details for Web of Science ID 000307813200014

    View details for PubMedID 22910934

  • Hyperuricemia in Young Adults and Risk of Insulin Resistance, Prediabetes, and Diabetes: A 15-Year Follow-up Study AMERICAN JOURNAL OF EPIDEMIOLOGY Krishnan, E., Pandya, B. J., Chung, L., Hariri, A., Dabbous, O. 2012; 176 (2): 108-116


    The objective of this study was to assess the utility of hyperuricemia as a marker for diabetes and prediabetes (impaired fasting glucose) and insulin resistance in young adults. Using Cox proportional hazards regression models, the authors analyzed 15-year follow-up data on 5,012 persons in 4 US cities who were aged 18-30 years and diabetes-free at the time of enrollment. At baseline (1986), 88% of participants had a body mass index (weight (kg)/height (m)(2)) less than 30. During the follow-up period (through 2001), the incidence rates of diabetes and prediabetes (insulin resistance and impaired fasting glucose) were higher among persons with greater serum urate concentrations. In multivariable Cox regression analyses that adjusted for age, gender, race, body mass index, family history of diabetes, diastolic blood pressure, total cholesterol, smoking, and alcohol use, the hazard ratios for diabetes, insulin resistance, and prediabetes among persons with hyperuricemia (serum urate level >7 mg/dL vs. ?7.0 mg/dL) were 1.87 (95% confidence interval (CI): 1.33, 2.62), 1.36 (95% CI: 1.23, 1.51), and 1.25 (95% CI: 1.04, 1.52), respectively. This observation was generally consistent across subgroups. The authors conclude that hyperuricemia in the midtwenties is an independent marker for predicting diabetes and prediabetes among young adults in the subsequent 15 years.

    View details for DOI 10.1093/aje/kws002

    View details for Web of Science ID 000306406500005

    View details for PubMedID 22753829

  • Nature Versus Nurture in Gout: A Twin Study AMERICAN JOURNAL OF MEDICINE Krishnan, E., Lessov-Schlaggar, C. N., Krasnow, R. E., Swan, G. E. 2012; 125 (5): 499-504


    Gouty arthritis (gout) is the most common inflammatory arthritis in the United States and several other countries. Some rare forms of gout have a known genetic basis, but the relative importance of genetic factors on the risk for the lifetime prevalence of gout is not clear.We performed a heritability analysis for hyperuricemia and gout among 514 unselected, all-male twin pairs who were a part of the National Heart, Lung, and Blood Institute twin study, a prospective observational cohort study. Statistical analyses were performed using structural equation models and maximum likelihood methods. The covariates used for adjustment in the structural equation models were identified using bivariate logistic regressions.The study population included 253 monozygotic (MZ) and 261 dizygotic (DZ) twin pairs, aged 48 (±3) years at baseline and followed for a mean of 34 years. The lifetime prevalence of gout did not differ between MZ and DZ twins. The concordance of hyperuricemia was 53% in MZ and 24% in DZ twin pairs (P<.001). Models that quantified the relative contribution of genetic and environmental factors on phenotypic variance showed that individual variability in gout was substantially influenced by environmental factors shared between co-twins and not by genetic factors. In contrast, individual differences in hyperuricemia were influenced significantly by genetic factors.Hyperuricemia is a genetic trait. Outside the context of rare genetic disorders, risk for gout is determined by the environment. This has implications for prevention and treatment approaches.

    View details for DOI 10.1016/j.amjmed.2011.11.010

    View details for Web of Science ID 000302774600025

    View details for PubMedID 22365026

  • Hyperuricemia and the echocardiographic measures of myocardial dysfunction. Congestive heart failure (Greenwich, Conn.) Krishnan, E., Hariri, A., Dabbous, O., Pandya, B. J. 2012; 18 (3): 138-143


    Few studies have investigated the association between hyperuricemia and subclinical myocardial dysfunction. The authors analyzed the relationship between serum uric acid and subclinical markers of heart failure in participants in the Framingham Offspring Cohort (N=2169, mean age 57.3 years, 55.4% women). Cardiac dysfunction was assessed through echocardiographic measurements of left ventricular (LV) mass and thickness, end-diastolic LV thickness, and LV fractional shortening at the sixth visit, approximately 24 years after study onset. Participants in the highest serum uric acid quartile (? 6.2 mg/dL serum uric acid) had a significantly greater frequency of echocardiographic abnormalities compared with those in the lowest quartile (<4.3 mg/dL). Those in the highest quartile had multivariable-adjusted odds ratios of 9.013 (95% confidence interval, 2.051-39.604) for abnormal LV ejection fraction and 4.584 (95% confidence interval, 1.951-10.768) for LV systolic dysfunction compared with those in the lowest quartile. Hyperuricemia in young adults can be a marker for subsequent heart failure.

    View details for DOI 10.1111/j.1751-7133.2011.00259.x

    View details for PubMedID 22587743

  • Disability in rheumatoid arthritis in the era of biological treatments ANNALS OF THE RHEUMATIC DISEASES Krishnan, E., Lingala, B., Bruce, B., Fries, J. F. 2012; 71 (2): 213-218


    Rheumatoid arthritis (RA) is a disabling disease. The authors studied the impact of new, expensive and occasionally toxic biological treatments on disability outcomes in real-world populations of patients with RA.The authors analysed Health Assessment Questionnaire Disability Index data on 4651 adult patients with RA collected prospectively from 1983 to 2006. They studied trends in disability using multilevel mixed-effects multivariable linear regression (mixed) models that adjusted for the effects of time trends in gender, ethnicity, age, smoking behaviour and disease duration.Overall, the patients were predominantly female (76%), were predominantly white (88%), had 13 years of education and have had RA for 13 years, on average. The time period from 1983 to 2006 saw major increases in the use of disease-modifying agents and biological agents, and a decrease in smoking. After adjustments, the disability rates declined at annual rates of 1.7% (1.5-1.8%) overall and 2.7% (2.4-3.1%) among men. The annual rate of disability declines in the biological era was greater than that in the preceding period, suggesting accelerated improvement. These declines were documented in all patient subgroups such as men, women, African-Americans, obese, older age groups and early disease (p<0.001), but not among the 1401 patients (where disability remained stable) who died on follow-up.Aggressive use of traditional disease-modifying agents and introduction of biological agents were associated with substantial gains in disability outcomes. Our finding supports the prevailing notion that 'tight inflammation control' is a desirable therapeutic strategy.

    View details for DOI 10.1136/annrheumdis-2011-200354

    View details for Web of Science ID 000298681800009

    View details for PubMedID 21953343

  • Lifestyle Risk Factors Predict Disability and Death in Healthy Aging Adults AMERICAN JOURNAL OF MEDICINE Chakravarty, E. F., Hubert, H. B., Krishnan, E., Bruce, B. B., Lingala, V. B., Fries, J. F. 2012; 125 (2): 190-197


    Associations between modifiable health risk factors during middle age with disability and mortality in later life are critical to maximizing longevity while preserving function. Positive health effects of maintenance of normal weight, routine exercise, and nonsmoking are known for the short and intermediate term. We studied the effects of these risk factors into advanced age.A cohort of 2327 college alumnae aged 60 years or more was followed annually (1986-2005) by questionnaires addressing health risk factors, history, and Health Assessment Questionnaire disability. Mortality data were ascertained from the National Death Index. Low-, medium-, and high-risk groups were created on the basis of the number (0, 1, ?2) of health risk factors (overweight, smoking, inactivity) at baseline. Disability and mortality for each group were estimated from unadjusted data and regression analyses. Multivariable survival analyses estimated time to disability or death.The medium- and high-risk groups had higher disability than the low-risk group throughout the study (P<.001). Low-risk subjects had onset of moderate disability delayed 8.3 years compared with high-risk subjects. Mortality rates were higher in the high-risk group (384 vs 247 per 10,000 person-years). Multivariable survival analyses showed the number of risk factors to be associated with cumulative disability and increased mortality.Seniors with fewer behavioral risk factors during middle age have lower disability and improved survival. These data document that the associations of lifestyle risk factors on health continue into the ninth decade.

    View details for DOI 10.1016/j.amjmed.2011.08.006

    View details for Web of Science ID 000299531700023

    View details for PubMedID 22269623

  • Dutch translation and cross-cultural adaptation of the PROMIS (R) physical function item bank and cognitive pre-test in Dutch arthritis patients ARTHRITIS RESEARCH & THERAPY Voshaar, M. A., ten Klooster, P. M., Taal, E., Krishnan, E., van de Laar, M. A. 2012; 14 (2)

    View details for DOI 10.1186/ar3760

    View details for Web of Science ID 000311025900006

  • Metabolic syndrome and gout. Oxidative Stress in Advanced Basic Research and Clinical Practice. Studies on Arthritis and Joint Diseases. Springer Krishnan E 2012
  • Muscle strength, mass, and quality in older men and women with knee osteoarthritis ARTHRITIS CARE & RESEARCH Conroy, M. B., Kwoh, C. K., Krishnan, E., Nevitt, M. C., Boudreau, R., Carbone, L. D., Chen, H., Harris, T. B., Newman, A. B., Goodpaster, B. H. 2012; 64 (1): 15-21


    To examine the relationship between knee osteoarthritis (OA) and muscle parameters in a biracial cohort of older adults.Participants in the Health, Aging and Body Composition Study (n = 858) were included in this cross-sectional analysis. Computed tomography was used to measure muscle area, and quadriceps strength was measured isokinetically. Muscle quality (specific torque) was defined as strength per unit of muscle area for both the entire thigh and quadriceps. Knee OA was assessed based on radiographic features and knee pain. We compared muscle parameters between those with and without radiographic knee OA (+RKOA group and -RKOA group, respectively) and among 4 groups defined by +RKOA and -RKOA with and without pain.The mean ± SD age was 73.5 ± 2.9 years and the mean ± SD body mass index (BMI) was 27.9 ± 4.8 kg/m(2) . Fifty-eight percent of participants were women and 44% were African American. Compared to the -RKOA participants, +RKOA participants had a higher BMI (30.2 versus 26.8 kg/m(2)), larger thigh muscles (117.9 versus 108.9 cm(2)), and a greater amount of intermuscular fat (12.5 versus 9.9 cm(2) ; all P < 0.0001). In adjusted models, the +RKOA participants had significantly lower specific torque (P < 0.001), indicating poorer muscle quality, than -RKOA participants, but there was no difference between groups in quadriceps specific torque. The +RKOA without pain (P < 0.05) and the +RKOA with pain (P < 0.001) participants had lower specific torque compared to the -RKOA without pain group. There were no significant differences in quadriceps specific torque among groups.Muscle quality was significantly poorer in participants with RKOA regardless of pain status. Future studies should address how lifestyle interventions might affect muscle quality and progression of knee OA.

    View details for DOI 10.1002/acr.20588

    View details for Web of Science ID 000298536700004

    View details for PubMedID 22213722

  • Metabolic Syndrome and gout In: Alcaraz M (Ed) Oxidative Stress in Advanced Basic Research and Clinical Practice. Studies on Arthritis and Joint Diseases. Springer Krishnan E 2012
  • Hyperuricemia and untreated gout are poor prognostic markers among those with a recent acute myocardial infarction ARTHRITIS RESEARCH & THERAPY Krishnan, E., Pandya, B. J., Lingala, B., Hariri, A., Dabbous, O. 2012; 14 (1)


    Patients with a history of myocardial infarction (MI) are often at risk for complications, including subsequent MI and death. Use of prognostic markers may aid in preventing these poor outcomes. Hyperuricemia is associated with increased risk for coronary heart disease (CHD) and/or mortality; however, it is unknown if serum urate (sUA) levels predict outcomes in patients with previous MI. The purpose of this study was to assess hyperuricemia as a biomarker of CHD outcomes in such patients.These were post hoc analyses of datasets from the Aspirin Myocardial Infarction Study, a 1:1 randomized, double-blind clinical trial, conducted from 1975 to 1979, that examined mortality rates following daily aspirin administration over three years in individuals with documented MI. The primary outcome measures were all-cause death, CHD mortality, coronary incidence, and stroke by quartile of baseline sUA. A sub-analysis of all outcome measures in the presence or absence of gouty arthritis was also performed.Of 4,524 enrolled participants, data on 4,352 were analyzed here. All outcomes were greatest for patients in the fourth sUA quartile. In multivariate regression models, the hazard ratios (HR) for patients in the highest quartile were 1.88 for all-cause mortality (95% confidence interval (CI), 1.45 to 2.46), 1.99 for CHD mortality (95% CI, 1.49 to 2.66), and 1.36 for coronary incidence (95% CI, 1.08 to 1.70). Participants with untreated gout had an adjusted hazard ratio ranging from 1.5 to 2.0 (all P < 0.01) for these outcomes. Participants with gout who were receiving treatment did not exhibit this additional risk.sUA and untreated gout may be independent prognostic markers for poor all-cause and CHD mortality in patients with recent acute MI.

    View details for DOI 10.1186/ar3684

    View details for Web of Science ID 000304698800024

    View details for PubMedID 22251426

  • Epidemiology and Risk Factors In: Gout & Other Crystal Arthropathies Terkeltaub R(Ed.) Elsevier Saunders Krishnan E 2012
  • Dutch translation and cross-cultural adaptation of the PROMIS® physical function item bank and cognitive pre-test in Dutch arthritis patients. Arthritis research & therapy Oude Voshaar, M. A., ten Klooster, P. M., Taal, E., Krishnan, E., van de Laar, M. A. 2012; 14 (2): R47-?


    Patient-reported physical function is an established outcome domain in clinical studies in rheumatology. To overcome the limitations of the current generation of questionnaires, the Patient-Reported Outcomes Measurement Information System (PROMIS®) project in the USA has developed calibrated item banks for measuring several domains of health status in people with a wide range of chronic diseases. The aim of this study was to translate and cross-culturally adapt the PROMIS physical function item bank to the Dutch language and to pretest it in a sample of patients with arthritis.The items of the PROMIS physical function item bank were translated using rigorous forward-backward protocols and the translated version was subsequently cognitively pretested in a sample of Dutch patients with rheumatoid arthritis.Few issues were encountered in the forward-backward translation. Only 5 of the 124 items to be translated had to be rewritten because of culturally inappropriate content. Subsequent pretesting showed that overall, questions of the Dutch version were understood as they were intended, while only one item required rewriting.Results suggest that the translated version of the PROMIS physical function item bank is semantically and conceptually equivalent to the original. Future work will be directed at creating a Dutch-Flemish final version of the item bank to be used in research with Dutch speaking populations.

    View details for DOI 10.1186/ar3760

    View details for PubMedID 22390734

  • Hyperuricemia and carotid artery dilatation among young adults without metabolic syndrome Rheumatology Reports Krishnan E, Wildman R, Cooper J, Sutton-Tyrrell K. 2012; 10.4081: rr.2012.e7
  • Gout and the risk for incident heart failure and systolic dysfunction BMJ OPEN Krishnan, E. 2012; 2 (1)


    To test the hypothesis that gouty arthritis (gout) is a risk factor for incidence of heart failure and for echocardiographic measures signifying subclinical heart failure.Post-hoc, longitudinal and cross-sectional analyses of a prospective cohort study where data were collected in 4-year intervals since 1971.The population-based Framingham Offspring Study.4989 adults (mean age 36 years, 52% women) free of clinical heart failure at baseline.Incident heart failure, echocardiographic measures of left ventricular systolic dysfunction, dilatation and hypertrophy.Participants with gout (n=228) had two to three times higher incidence of clinical heart failure and echocardiographic measures of systolic dysfunction compared with those without. In Cox regression analyses, gout was associated with an adjusted HR of 1.74 (95% CI 1.03 to 2.93) for incident heart failure and RRs of 3.70 (95% CI 1.68 to 8.16) for abnormally low left ventricular ejection fraction and of 3.60 (95% CI 1.80 to 7.72) for global left ventricle systolic dysfunction. These risk relationships were consistently observed in all clinical subgroups. Overall, participants with gout had greater mortality than those without (adjusted HR 1.58, 95% CI 1.40 to 1.78). Mortality was elevated in subgroup of patients with gout and heart failure (adjusted HR 1.50, 95% CI 1.30 to 1.73) compared to those with heart failure but without gout.Gout is associated with increased risk for clinical heart failure, subclinical measures of systolic dysfunction and mortality.

    View details for DOI 10.1136/bmjopen-2011-000282

    View details for Web of Science ID 000315037200008

    View details for PubMedID 22337813

  • The Future of Measuring Patient-Reported Outcomes in Rheumatology ARTHRITIS CARE & RESEARCH Khanna, D., Krishnan, E., DeWitt, E. M., Khanna, P. P., Spiegel, B., Hays, R. D. 2011; 63: S486-S490

    View details for DOI 10.1002/acr.20581

    View details for Web of Science ID 000297219500037

    View details for PubMedID 22588770

  • Chronic kidney disease in gout in a managed care setting BMC NEPHROLOGY Fuldeore, M. J., Riedel, A. A., Zarotsky, V., Pandya, B. J., Dabbous, O., Krishnan, E. 2011; 12


    To study the prevalence of chronic kidney disease (CKD) and its impact on allopurinol dosing and uric acid control among patients with gout.This was a retrospective study using data from a large US health plan. Claims and laboratory data were analyzed for enrollees from the health plan database from January 2002 through December 2005. Patients with gout were identified from pharmacy and medical claims data based on the presence of codes for gout medication or gout diagnosis. Severity of CKD was determined using the estimated glomerular filtration rate (eGFR). Allopurinol titration was defined as a change in average daily dose from first prescription to last prescription of ? 50 mg.A total of 3,929 patients were identified for inclusion in this study, 39% of whom had CKD (based on having an eGFR < 90 mL/min/1.73 m2). Subjects with CKD were older (p < 0.01) and more likely to be women (p < 0.01), had a greater number of comorbid conditions (p < 0.01), and were more likely to be prescribed allopurinol (p < 0.01) compared to those with no CKD. The average starting dose of allopurinol was lower among those with CKD, and it decreased with worsening kidney function. Among the 3,122 gout patients who used allopurinol, only 25.6% without CKD and 22.2% with CKD achieved a serum uric acid concentration of < 6.0 mg/dL (p = 0.0409). Also, only 15% of allopurinol users had an upward dose titration (by ?50 mg), but the average increase in dose did not differ significantly between those with and without CKD.About two out of every five patients with gout in this population had CKD. Allopurinol doses were not adjusted in the majority of CKD patients. Serum uric acid control in gout was poor among patients without CKD and even worse among those with CKD.

    View details for DOI 10.1186/1471-2369-12-36

    View details for Web of Science ID 000304362900001

    View details for PubMedID 21812963

  • Developing a Construct to Evaluate Flares in Rheumatoid Arthritis: A Conceptual Report of the OMERACT RA Flare Definition Working Group JOURNAL OF RHEUMATOLOGY Alten, R., Pohl, C., Choy, E. H., Christensen, R., Furst, D. E., Hewlett, S. E., Leong, A., May, J. E., Sanderson, T. C., Strand, V., Woodworth, T. G., Bingham, C. O. 2011; 38 (8): 1745-1750


    Rheumatoid arthritis (RA) patients and healthcare professionals (HCP) recognize that episodic worsening disease activity, often described as a "flare," is a common feature of RA that can contribute to impaired function and disability. However, there is no standard definition to enable measurement of its intensity and impact. The conceptual framework of the Outcome Measures in Rheumatology Clinical Trials (OMERACT) RA Flare Definition Working Group includes an anchoring statement, developed at OMERACT 9 in 2008: "flare in RA" is defined as worsening of signs and symptoms of sufficient intensity and duration to lead to change in therapy. Subsequently, domains characterizing flare have been identified by comprehensive literature review, patient focus groups, and patient/HCP Delphi exercises. This led to a consensus regarding preliminary domains and a research agenda at OMERACT 10 in May 2010. The conceptual framework of flare takes into account validated approaches to measurement in RA: (1) various disease activity indices (e.g., Disease Activity Score, Clinical Disease Activity Index, Simplified Disease Activity Index); (2) use of patient-reported outcomes (PRO); and (3) characterization of minimally clinically detectable and important differences (MCDD, MCID). The measurement of RA flare is composed of data collection assessing a range of unique domains describing key features of RA worsening at the time of patient self-report of flare, and then periodically for the duration of the flare. The components envisioned are: (1) Patient self-report using a "patient global question" with well characterized and validated anchors; (2) Patient assessment using a flare questionnaire and PRO available at the time of each self-report; (3) Physician/HCP assessment of disease activity status; and (4) Physician's determination whether to change treatment. In randomized controlled trials and observational studies, such a conceptual approach is intended to lead to a valid measure of this outcome/response, thus expanding an understanding of the true impact of a therapy to limit disease activity. Clinically, this approach is intended to enhance patient-HCP communication. This article describes the conceptual framework being used by the OMERACT RA Flare Definition Working Group in developing a standardized method for description and measurement of "flare in RA" to guide individual patient treatment.

    View details for DOI 10.3899/jrheum.110440

    View details for Web of Science ID 000293315000037

    View details for PubMedID 21807796

  • Identifying Preliminary Domains to Detect and Measure Rheumatoid Arthritis Flares: Report of the OMERACT 10 RA Flare Workshop JOURNAL OF RHEUMATOLOGY Bingham, C. O., Alten, R., Bartlett, S. J., Bykerk, V. P., Brooks, P. M., Choy, E., Christensen, R., Furst, D. E., Hewlett, S. E., Leong, A., May, J. E., Montie, P., Pohl, C., Sanderson, T. C., Strand, V., Woodworth, T. G. 2011; 38 (8): 1751-1758


    While disease flares in rheumatoid arthritis (RA) are a recognized aspect of the disease process, there is limited formative research to describe them.The Outcome Measures in Rheumatology Clinical Trials (OMERACT) RA Flare Definition Working Group is conducting an international research project to understand the specific characteristics and impact of episodic disease worsening, or "flare," so that outcome measures can be developed or modified to reflect this uncommonly measured, but very real and sometimes disabling RA disease feature. Patient research partners provided critical insights into the multidimensional nature of flare. The perspectives of patients and healthcare and research professionals are being integrated to ensure that any outcome measurement to detect flares fulfills the first OMERACT criteria of Truth. Through an iterative data-driven Delphi process, a preliminary list of key domains has been identified to evaluate flare.At OMERACT 10, consensus was achieved identifying features of flare in addition to the existing core set for RA, including fatigue, stiffness, symptom persistence, systemic features, and participation. Patient self-report of flare was identified as a component of the research agenda needed to establish criterion validity for a flare definition; this can be used in prospective studies to further evaluate the Discrimination and Feasibility components of the OMERACT filter for a flare outcome measure.Our work to date has provided better understanding of key aspects of the RA disease process as episodic, potentially disabling disease worsening even when a patient is in low disease activity. It also highlights the importance of developing ways to enhance communication between patients and clinicians and improve the ability to achieve "tight control" of disease.

    View details for DOI 10.3899/jrheum.110401

    View details for Web of Science ID 000293315000038

    View details for PubMedID 21807797

  • The PROMIS of Better Outcome Assessment: Responsiveness, Floor and Ceiling Effects, and Internet Administration JOURNAL OF RHEUMATOLOGY Fries, J., Rose, M., Krishnan, E. 2011; 38 (8): 1759-1764


    Use of item response theory (IRT) and, subsequently, computerized adaptive testing (CAT), under the umbrella of the NIH-PROMIS initiative (National Institutes of Health-Patient-Reported Outcomes Measurement Information System), to bring strong new assets to the development of more sensitive, more widely applicable, and more efficiently administered patient-reported outcome (PRO) instruments. We present data on current progress in 3 crucial areas: floor and ceiling effects, responsiveness to change, and interactive computer-based administration over the Internet.We examined nearly 1000 patients with rheumatoid arthritis and related diseases in a series of studies including a one-year longitudinal examination of detection of change; compared responsiveness of the Legacy SF-36 and HAQ-DI instruments with IRT-based instruments; performed a randomized head-to-head trial of 4 modes of item administration; and simulated the effect of lack of floor and ceiling items upon statistical power and sample sizes.IRT-based PROMIS instruments are more sensitive to change, resulting in the potential to reduce sample size requirements substantially by up to a factor of 4. The modes of administration tested did not differ from each other in any instance by more than one-tenth of a standard deviation. Floor and ceiling effects greatly reduce the number of available subjects, particularly at the ceiling.Failure to adequately address floor and ceiling effects, which determine the range of an instrument, can result in suboptimal assessment of many patients. Improved items, improved instruments, and computer-based administration improve PRO assessment and represent a fundamental advance in clinical outcomes research.

    View details for DOI 10.3899/jrheum.110402

    View details for Web of Science ID 000293315000039

    View details for PubMedID 21807798

  • An Analysis of Connective Tissue Disease-associated Interstitial Lung Disease at a US Tertiary Care Center: Better Survival in Patients with Systemic Sclerosis JOURNAL OF RHEUMATOLOGY Su, R., Bennett, M., Jacobs, S., Hunter, T., Bailey, C., Krishnan, E., Rosen, G., Chung, L. 2011; 38 (4): 693-701


    To compare survival of patients with connective tissue disease-associated interstitial lung disease (CTD-ILD) versus idiopathic pulmonary fibrosis (IPF) and patients with systemic sclerosis-associated ILD (SSc-ILD) versus other CTD-ILD followed at our center.We used the Stanford ILD database, which contains prospectively collected information on patients with ILD evaluated at our tertiary care center from 2002 to 2009. Survival at last followup from time of ILD diagnosis was calculated using the Kaplan-Meier estimator. Prognostic factors for survival in the overall cohort (IPF and CTD-ILD) and in the CTD-ILD group were identified with univariate and multivariate Cox regression models.Of 427 patients with ILD, 148 (35%) had IPF and 76 (18%) had CTD-ILD at the baseline visit. The cumulative incidence of CTD was 4%. After a median followup of 4 years, 67 patients (36.4%) had died and 4 (2.2%) were lost to followup. Patients with IPF (n = 122) and CTD-ILD (n = 62) experienced similar survival rates (5-year survival about 50%). Patients with SSc-ILD (n = 24) experienced better survival than those with other CTD-ILD (n = 38), with 1-year, 3-year, and 5-year survival rates of 100%, 90%, and 77%, respectively, versus 78%, 42%, and 38% (p = 0.01). The presence of SSc in patients with CTD-ILD decreased the risk of death by > 80% even after correcting for age at ILD diagnosis, sex, and ethnicity (HR = 0.17, 95% CI 0.04-0.83).Survival in patients with SSc-ILD was better than in patients with other CTD-ILD, potentially related to routine screening for and early detection of ILD in patients with SSc at our center.

    View details for DOI 10.3899/jrheum.100675

    View details for Web of Science ID 000289333800018

    View details for PubMedID 21285162

  • Relationship between physician specialty and allopurinol prescribing patterns: a study of patients with gout in managed care settings CURRENT MEDICAL RESEARCH AND OPINION Pandya, B. J., Riedel, A. A., Swindle, J. P., Becker, L. K., Hariri, A., Dabbous, O., Krishnan, E. 2011; 27 (4): 737-744


    Allopurinol is used to lower serum uric acid (sUA) levels in gout patients. The objective of this study was to investigate the influence of physician specialty on allopurinol treatment patterns and sUA control.This was a retrospective study using claims from a managed care database of US health plan enrollees. Gout patients at least 18 years of age who received allopurinol were identified from the database between January 1, 2002 and April 30, 2007. The index date was defined as the date of the earliest allopurinol claim, and patients were required to have health plan enrollment for at least 365 days prior to and following the index date for inclusion. Physician specialty was determined using the index allopurinol claim. Dosage of allopurinol prescription(s) and number of gout flares were determined from claims data. sUA measurements were used to assess goal attainment over a period of at least one year following the index allopurinol prescription.There were 3363 patients with gout of whom 69.9% received an index allopurinol prescription from a generalist/internist, 5.7% from a rheumatologist, 2.6% from a nephrologist, and 21.8% from a physician with other specialty. Of patients receiving their index prescription from a nephrologist, 38.7% reached the sUA goal of <6?mg/dL (357??mol/L), as compared to patients prescribed by a rheumatologist, generalist/internist, or other physician (35.4%, 31.4%, and 39.4%, respectively; P?=?0.015). When controlling for patient characteristics, multivariate analysis did not reveal statistically significant different odds of sUA goal attainment based on prescribing physician specialty, though separate analyses indicated that patients prescribed by a nephrologist had fewer gout flares. Change in allopurinol dosage from initial to final dose was more frequent among patients prescribed by rheumatologists and nephrologists.There is significant heterogeneity in the specialists' management of sUA levels in patients with gout, possibly reflecting differences in case mix and treatment approaches. Limitations related to the use of claims data, such as inability to observe medications filled over-the-counter, should be considered when interpreting study results.

    View details for DOI 10.1185/03007995.2011.552570

    View details for Web of Science ID 000288380900004

    View details for PubMedID 21271794

  • Uric acid in heart disease: a new C-reactive protein? CURRENT OPINION IN RHEUMATOLOGY Krishnan, E., Sokolove, J. 2011; 23 (2): 174-177


    To review and interpret the recently published data on hyperuricemia and cardiovascular disease to present an opinion on the nature of link between serum uric acid concentration and the risk for cardiovascular outcomes, and to comment on its implications for clinical practice.Evidence has accumulated in prospective observational studies that link hyperuricemia among younger adults with the risk of subsequent hypertension. Such associations have been observed with respect to insulin resistance, diabetes, and other cardiovascular risk factors. Newer data confirm the link between hyperuricemia and cardiovascular mortality. The use of allopurinol has been shown to be associated with reduced mortality risk in longer term observational studies and with reduced blood pressure in short-term randomized controlled trials. None of these findings is confounded by traditional risk factors.The available evidence has established a link between hyperuricemia and cardiovascular disease and this may be causal. Without waiting for the resolution of causality arguments, one can start using serum uric acid concentration as an inexpensive cardiovascular risk marker.

    View details for DOI 10.1097/BOR.0b013e3283432dd3

    View details for Web of Science ID 000286879200009

    View details for PubMedID 21178630

  • OMERACT RA Flare Definition Working Group. Identifying preliminary domains to detect and measure rheumatoid arthritis flares: report of the OMERACT 10 RA Flare Workshop. J Rheumatol Bingham CO 3rd, Alten R, Bartlett SJ, Bykerk VP et al 2011; 38 (8): 1751-8
  • Patient-Reported Outcomes Measurement Information System (PROMIS®) -- The future of measuring patient reported outcomes in rheumatology. Arthritis care & research Khanna, D., Krishnan, E., Dewitt, E. M., Khanna, P. P., Spiegel, B., Hays, R. D. 2011; 63 (S11): S486-S490

    View details for PubMedID 22428088

  • Systemic sclerosis 2011. International journal of rheumatology Chung, L., Distler, O., Hummers, L., Krishnan, E., Steen, V. 2011; 2011: 308231-?

    View details for DOI 10.1155/2011/308231

    View details for PubMedID 22577388

  • Hyperuricemia and carotid artery dilatation among young adults without metabolic syndrome Rheumatology Reports Krishnan E, Wildman RP, Barinas-Mitchell, Cooper J, Sutton-Tyrrell K 2011; 4: e7
  • Hyperuricemia and the risk for subclinical coronary atherosclerosis - data from a prospective observational cohort study ARTHRITIS RESEARCH & THERAPY Krishnan, E., Pandya, B. J., Chung, L., Dabbous, O. 2011; 13 (2)


    Our purpose was to test the hypothesis that hyperuricemia is associated with coronary artery calcification (CAC) among a relatively healthy population, and that the extent of calcification is directly proportional to the serum uric acid (sUA) concentration.Data from 2,498 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study were analyzed using logistic regression models. Subjects were free of clinical heart disease, diabetes, and renal impairment. The main measure was the presence of any CAC by computerized tomography (Agatston score >0).Forty-eight percent of the study participants were male and 45% were African-American. Mean (± SD) age was 40 ± 4 years, body mass index 28 ± 6 kg/m2, Framingham risk score -0.7 ± 5%, blood pressure 113 ± 14/75 ± 11 mmHg, alcohol consumption 12 ± 27 ml/day, and sUA 297 ± 89 ?mol/L (5.0 ± 1.5 mg/dL). Prevalence of CAC increased with sUA concentration among both men and women. Adjusted for age, gender, race, lipoproteins, triglycerides, smoking, blood pressure, presence of metabolic syndrome, C-reactive protein, waist circumference, alcohol use, creatinine, and serum albumin, the highest quartile of sUA (>393 ?mol/L [6.6 mg/dL] for men and >274 ?mol/L [4.6 mg/dL] for women) was associated with an odds ratio of 1.87 (1.19-2.93) compared to the lowest quartile (<291 ?mol/L [4.9 mg/dL] for men and <196 ?mol/L [3.3 mg/dL] for women). Among those with any CAC, each unit increase in sUA was associated with a 22% increase in Agatston score (P = 0.008) after adjusting for the above covariates.Hyperuricemia is an independent risk factor for subclinical atherosclerosis in young adults.

    View details for DOI 10.1186/ar3322

    View details for Web of Science ID 000292449700031

    View details for PubMedID 21501486

  • OMERACT RA Flare Definition Working Group. Developing a construct to evaluate flares in rheumatoid arthritis: a conceptual report of the OMERACT RA Flare Definition Working Group J rheumatol Alten R, Pohl C, Choy EH, Christensen R et. al 2011; 38 (8): 1745-80
  • Epidemiology and risk factors In: Gout & Other Crystal Arthropathies. Terkeltaub R(Ed.) Elsevier Saunders Krishnan E 2011
  • Improved responsiveness and reduced sample size requirements of PROMIS physical function scales with item response theory ARTHRITIS RESEARCH & THERAPY Fries, J. F., Krishnan, E., Rose, M., Lingala, B., Bruce, B. 2011; 13 (5)


    The Health Assessment Questionnaire Disability Index (HAQ) and the SF-36 PF-10, among other instruments, yield sensitive and valid Disability (Physical Function) endpoints. Modern techniques, such as Item Response Theory (IRT), now enable development of more precise instruments using improved items. The NIH Patient Reported Outcomes Measurement Information System (PROMIS) is charged with developing improved IRT-based tools. We compared the ability to detect change in physical function using original (Legacy) instruments with Item-Improved and PROMIS IRT-based instruments.We studied two Legacy (original) Physical Function/Disability instruments (HAQ, PF-10), their item-improved derivatives (Item-Improved HAQ and PF-10), and the IRT-based PROMIS Physical Function 10- (PROMIS PF 10) and 20-item (PROMIS PF 20) instruments. We compared sensitivity to detect 12-month changes in physical function in 451 rheumatoid arthritis (RA) patients and assessed relative responsiveness using P-values, effect sizes (ES), and sample size requirements.The study sample was 81% female, 87% Caucasian, 65 years of age, had 14 years of education, and had moderate baseline disability. All instruments were sensitive to detecting change (< 0.05) in physical function over one year. The most responsive instruments in these patients were the Item-Improved HAQ and the PROMIS PF 20. IRT-improved instruments could detect a 1.2% difference with 80% power, while reference instruments could detect only a 2.3% difference (P < 0.01). The best IRT-based instruments required only one-quarter of the sample sizes of the Legacy (PF-10) comparator (95 versus 427). The HAQ outperformed the PF-10 in more impaired populations; the reverse was true in more normal populations. Considering especially the range of severity measured, the PROMIS PF 20 appears the most responsive instrument.Physical Function scales using item improved or IRT-based items can result in greater responsiveness and precision across a broader range of physical function. This can reduce sample size requirements and thus study costs.

    View details for DOI 10.1186/ar3461

    View details for Web of Science ID 000301174600007

    View details for PubMedID 21914216

  • Febuxostat for the treatment of hyperuricemia in patients with gout International Journal of Clinical Rheumatology Kelly VM, Krishnan E 2011; 6: (5;): 485-493
  • Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Postarthroplasty Mortality: A Cross-sectional Analysis from the Nationwide Inpatient Sample JOURNAL OF RHEUMATOLOGY Domsic, R. T., Lingala, B., Krishnan, E. 2010; 37 (7): 1467-1472


    Systemic lupus erythematosus (SLE) is a disease of considerable morbidity, and this may place patients at greater risk for poor in-hospital postoperative outcomes for procedures such as arthroplasty. Our aim was to test this hypothesis.We compared the in-hospital postoperative mortality risk for patients with SLE undergoing hip and knee arthroplasty to those with rheumatoid arthritis (RA) and the general population without either condition, using data from the Nationwide Inpatient Sample (1993-2006). We performed parallel, weighted, multivariable logistic regressions to calculate mortality risk stratified by joint site, type of admission, hospital type, income category, race, length of stay, surgical indication, and medical comorbidities.The unadjusted mortality rates (per 1000 procedures) for patients with SLE, patients with RA, and controls were 7.4, 3.0, and 6.5, respectively, for nonelective procedures and 2.4, 1.3, and 1.8 for elective procedures. After adjustment for potential confounders, patients with SLE had an OR of 4.0 (95% CI 1.9-8.0) for postoperative mortality with hip replacements and an OR of 1.2 (95% CI 0.2-7.5) for mortality with knee replacements. Mortality risk of patients with RA was not different from that of controls. The adjusted risk estimates for those who underwent arthroplasty before and after 2002 and those who underwent surgery for nonfracture indications were similar.Arthroplasty, especially of hips, in patients with SLE is associated with relatively higher postoperative mortality risk.

    View details for DOI 10.3899/jrheum.091371

    View details for Web of Science ID 000280217100017

    View details for PubMedID 20472923

  • Inflammation, oxidative stress and lipids: the risk triad for atherosclerosis in gout RHEUMATOLOGY Krishnan, E. 2010; 49 (7): 1229-1238


    For many years, the relationship between cardiovascular disease risk and gout, though strong and consistent, was suspected of being coincidental rather than causative. In recent years, compelling epidemiological and clinical data have increasingly favoured an aetiological connection. However, that connection is notably complex, involving a multifaceted model that includes interactions between inflammatory processes, oxidative stress and potential genetic influences, as well as cardiovascular and renal components that remain only partly explained. Urate appears to be able to activate the immune response, and in that context has a mediating role in the inflammatory process via the inflammasome. This interaction of urate and inflammation is central to the inflammatory cascade associated with gout flares. In the arena of oxidative stress, urate has both antioxidant and pro-oxidant properties, and while potentially beneficial in scavenging free radicals, it can also impair endothelial function and thereby give rise to atherosclerotic risk. Human and animal studies have revealed associations between hyperuricaemia and a host of atherosclerotic risk factors, whereas a reduction in urate levels is frequently associated with improvement or even resolution of such risk factors. The degree to which reduction of serum urate can reliably improve cardiovascular risk remains uncertain. It is hoped that the introduction of newer urate-lowering agents may help to clarify this picture and improve treatment options for both gout and atherosclerosis.

    View details for DOI 10.1093/rheumatology/keq037

    View details for Web of Science ID 000278970100004

    View details for PubMedID 20202928

  • Epidemiology of Gout in Women Fifty-two-Year Followup of a Prospective Cohort ARTHRITIS AND RHEUMATISM Bhole, V., De Vera, M., Rahman, M. M., Krishnan, E., Choi, H. 2010; 62 (4): 1069-1076


    Despite the recent doubling of the incidence of gout among women and its substantial prevalence particularly in the aging female population, the risk factors for gout among women remain unknown. We undertook this study to evaluate purported risk factors for incident gout among women and to compare them with those among men.Using prospective data from the Framingham Heart Study, we examined over a 52-year period (1950-2002) the relationship between purported risk factors and the incidence of gout in 2,476 women and 1,951 men.We documented 304 incident cases of gout, 104 of them among women. The incidence rates of gout for women per 1,000 person-years according to serum uric acid levels of <5.0, 5.0-5.9, 6.0-6.9, 7.0-7.9, and > or = 8.0 mg/dl were 0.8, 2.5, 4.2, 13.1, and 27.3, respectively (P for trend < 0.0001). The magnitude of this association was lower than that among men (P for interaction = 0.0002). Multivariate relative risks conferred by increasing age (per 5 years), obesity (body mass index > or = 30 kg/m(2)), alcohol intake (> or = 7 ounces of pure alcohol/week), hypertension, and diuretic use were 1.24, 2.74, 3.10, 1.82, and 2.39, respectively (all P < 0.05), for women.These prospective data with long-term followup provide evidence that higher levels of serum uric acid increase the risk of gout in a graded manner among women, but the rate of increase is lower than that among men. Increasing age, obesity, alcohol consumption, hypertension, and diuretic use were associated with the risk of incident gout among women.

    View details for DOI 10.1002/art.27338

    View details for Web of Science ID 000279432300018

    View details for PubMedID 20131266

  • Vascular disease in systemic sclerosis. International journal of rheumatology Chung, L., Distler, O., Hummers, L., Krishnan, E., Steen, V. 2010; 2010: 714172-?

    View details for DOI 10.1155/2010/714172

    View details for PubMedID 21048994

  • Hyperuricemia and Incident Heart Failure CIRCULATION-HEART FAILURE Krishnan, E. 2009; 2 (6): 556-562


    Hyperuricemia, a known correlate of oxidative stress, is a marker for adverse prognosis among individuals with heart failure. However, the relationship between hyperuricemia and the risk for incidence of heart failure in a community-based population has not been studied.We prospectively analyzed the relationship between serum uric acid concentration at baseline and subsequent heart failure among the participants of the Framingham Offspring cohort (n=4912; mean baseline age, 36 years; 52% women). By using Cox regressions, we calculated the risk of heart failure with increasing serum uric acid after adjusting for sex, age, smoking, body mass index, renal dysfunction, diuretics, systolic blood pressure, valvular heart disease, diabetes, alcohol, and use of antihypertensive medications. The incidence rates of heart failure were approximately 6-fold higher among those at the highest quartile of serum uric acid (>6.3 mg/dL) compared with those at the lowest quartile (<3.4 mg/dL). The adjusted hazard ratio for the highest quartile of serum uric acid compared with the lowest was 2.1 (1.04 to 4.22). The relationship between hyperuricemia and heart failure was found in participants without metabolic syndrome and other subgroups as well.Hyperuricemia is a novel, independent risk factor for heart failure in a group of young general community dwellers. This has implications for development of preventive strategies for heart failure.

    View details for DOI 10.1161/CIRCHEARTFAILURE.108.797662

    View details for Web of Science ID 000271893100006

    View details for PubMedID 19919980

  • Progress in Assessing Physical Function in Arthritis: PROMIS Short Forms and Computerized Adaptive Testing JOURNAL OF RHEUMATOLOGY Fries, J. F., Cella, D., Rose, M., Krishnan, E., Bruce, B. 2009; 36 (9): 2061-2066


    Assessing self-reported physical function/disability with the Health Assessment Questionnaire Disability Index (HAQ) and other instruments has become central in arthritis research. Item response theory (IRT) and computerized adaptive testing (CAT) techniques can increase reliability and statistical power. IRT-based instruments can improve measurement precision substantially over a wider range of disease severity. These modern methods were applied and the magnitude of improvement was estimated.A 199-item physical function/disability item bank was developed by distilling 1865 items to 124, including Legacy Health Assessment Questionnaire (HAQ) and Physical Function-10 items, and improving precision through qualitative and quantitative evaluation in over 21,000 subjects, which included about 1500 patients with rheumatoid arthritis and osteoarthritis. Four new instruments, (A) Patient-Reported Outcomes Measurement Information (PROMIS) HAQ, which evolved from the original (Legacy) HAQ; (B) "best" PROMIS 10; (C) 20-item static (short) forms; and (D) simulated PROMIS CAT, which sequentially selected the most informative item, were compared with the HAQ.Online and mailed administration modes yielded similar item and domain scores. The HAQ and PROMIS HAQ 20-item scales yielded greater information content versus other scales in patients with more severe disease. The "best" PROMIS 20-item scale outperformed the other 20-item static forms over a broad range of 4 standard deviations. The 10-item simulated PROMIS CAT outperformed all other forms.Improved items and instruments yielded better information. The PROMIS HAQ is currently available and considered validated. The new PROMIS short forms, after validation, are likely to represent further improvement. CAT-based physical function/disability assessment offers superior performance over static forms of equal length.

    View details for DOI 10.3899/jrheum.090358

    View details for Web of Science ID 000269677600039

    View details for PubMedID 19738214

  • What constitutes progress in assessing patient outcomes? JOURNAL OF CLINICAL EPIDEMIOLOGY Fries, J. F., Krishnan, E. 2009; 62 (8): 779-780


    Patient self-reported disability outcomes, measured using instruments such as the Health Assessment Questionnaire Disability Index (HAQ-DI) form a foundation for clinical studies of several conditions, notably arthritis. These instruments are "static" because the instrument is the same in all applications. Although generally performing well, they may fail at extremes of disability, the so-called floor and ceiling effects. Another limitation is the degree of measurement error, the signal-to-noise ratio. These two issues drive down the statistical power of clinical trials and increase their expense.

    View details for DOI 10.1016/j.jclinepi.2008.12.001

    View details for Web of Science ID 000268200300001

    View details for PubMedID 19282147

  • Items, Instruments, Crosswalks, and PROMIS JOURNAL OF RHEUMATOLOGY Fries, J. F., Krishnan, E., Bruce, B. 2009; 36 (6): 1093-1095

    View details for DOI 10.3899/jrheum.090320

    View details for Web of Science ID 000266891500001

    View details for PubMedID 19509084

  • Characterizing systemic sclerosis in Northern California: focus on Asian and Hispanic patients CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Schmajuk, G., Bush, T. M., Burkham, J., Krishnan, E., Chung, L. 2009; 27 (3): S22-S25
  • Characterizing systemic sclerosis in Northern California: focus on Asian and Hispanic patients. Clinical and experimental rheumatology Schmajuk, G., Bush, T. M., Burkham, J., Krishnan, E., Chung, L. 2009; 27 (3): 22-25


    Previous studies suggest that Asian and Hispanic patients with systemic sclerosis (SSc) may have more severe disease than their Caucasian counterparts. The purpose of this study is to compare the clinical features of a group of Asian, Hispanic, and Caucasian patients with SSc in Northern California.We performed a cross-sectional study of patients receiving care at Stanford University Medical Center, Palo Alto Veterans Affairs Hospital, Santa Clara Valley Medical Center and San Francisco General Hospital between 1996 and 2006. Patients included in the analyses fulfilled the American College of Rheumatology criteria for SSc and could be classified as Caucasian, Asian, or Hispanic. Analyses using Caucasians as the reference group were performed.One hundred and ninety-nine patients met the criteria for SSc, and 165 of these patients were classified as Caucasian (47%), Asian (26%), or Hispanic (27%). Disease subtype did not differ significantly among the three groups. Asian patients were less likely to have digital ulcers (26% vs. 47%, p=0.02) or anemia (26% vs. 45%, p=0.04) than Caucasians, and Hispanic patients had a lower frequency of lung disease than Caucasians (48% vs. 67%, p=0.04), but there were no other significant differences in disease manifestations.In our cohort of SSc patients living in Northern California, clinical manifestations in Asian and Hispanic patients did not differ substantially from Caucasians. Further research is necessary to confirm these results and to investigate gene-environment interactions which may affect the clinical expression of disease in different racial groups.

    View details for PubMedID 19796557

  • Frequency, Risk, and Cost of Gout-related Episodes Among the Elderly: Does Serum Uric Acid Level Matter? JOURNAL OF RHEUMATOLOGY Wu, E. Q., Patel, P. A., Mody, R. R., Yu, A. P., Cahill, K. E., Tang, J., Krishnan, E. 2009; 36 (5): 1032-1040


    We examined the association between serum uric acid (SUA) level and the frequency, risk, and cost of gout flares among the elderly.Data were extracted from the Integrated Healthcare Information Services claims database (1999-2005). Patients were included if they had gout, were aged 65 years and older and had both medical and pharmacy benefits, and electronic laboratory data. Patients with gout and gouty episodes were identified using algorithms based on ICD-9-CM codes and medications. Logistic regression and negative binomial regressions were used to study the relationship between SUA concentration and the annual frequency and one-year risk of gout episodes. Generalized linear models were used to examine the direct healthcare costs associated with gout episodes in the 30 days following each episode.Elderly patients with gout (n = 2237) with high (6-8.99 mg/dl) and very high (> 9 mg/dl) SUA concentrations were more likely to develop a flare within 12 months compared to patients with normal (< 6 mg/dl) SUA levels (OR 2.1, 95% CI 1.7-2.6; OR 3.4, 95% CI 2.6-4.4, respectively). In multivariate regressions, the average annual number of flares increased by 11.9% (p < 0.001) with each unit-increase in SUA level above 6 mg/dl (p < 0.001). Among patients with very high SUA levels, average adjusted total healthcare and gout-related costs per episode were $2,555 and $356 higher, respectively, than those of patients with normal SUA levels (both p < 0.001).Higher SUA levels are associated with increased frequency and risk of gout episode, and with higher total and gout-related direct healthcare costs per episode.

    View details for DOI 10.3899/jrheum.080487

    View details for Web of Science ID 000266066200031

    View details for PubMedID 19369467

  • Poor Outcomes After Acute Myocardial Infarction in Systemic Lupus Erythematosus JOURNAL OF RHEUMATOLOGY Shah, M. A., Shah, A. M., Krishnan, E. 2009; 36 (3): 570-575


    Systemic lupus erythematosus (SLE) is associated with higher risk for acute myocardial infarction (MI); but the post-infarction outcomes among these patients are unknown. Our objective was to compare post-acute MI outcomes in patients with SLE to those with diabetes mellitus (DM) and those with neither condition.We analyzed the risk for prolonged hospitalization and in-hospital mortality following acute MI in the 1993-2002 US Nationwide Inpatient Sample. We used logistic regression to calculate odds ratios (OR) for prolonged hospitalization and Cox proportional hazards regression to calculate hazard ratios (HR) for in-hospital mortality with and without adjustments for age, sex, race/ethnicity, socioeconomic status, and presence of congestive heart failure.For the SLE (n = 2192), DM (n = 236,016), SLE/DM (n = 474), and control (n = 667,956) groups, the in-hospital mortality rates were 8.3%, 6.2%, 5.7%, and 4.7%, respectively. In multivariable regression models, all 3 disease groups had higher adverse outcome risk compared to control. The OR for prolonged hospitalization was higher for those with SLE (OR 1.48, 95% CI 1.32-1.79) compared to those with DM (OR 1.30, 95% CI 1.28-1.32). A similar pattern was observed for hazard ratios for in-hospital mortality as well (SLE, HR 1.65, 95% CI 1.33-2.04; DM, HR 1.11, 95% CI 1.07-1.14).SLE, like DM, increases risk of poor outcomes after acute MI. These patients need to be triaged appropriately for aggressive care.

    View details for DOI 10.3899/jrheum.080373

    View details for Web of Science ID 000263940000018

    View details for PubMedID 19208594

  • Gout and the risk of type 2 diabetes among men with a high cardiovascular risk profile RHEUMATOLOGY Choi, H. K., de Vera, M. A., Krishnan, E. 2008; 47 (10): 1567-1570


    Our objective was to evaluate the independent relation between a history of gout and the future risk of type 2 diabetes among men with a high cardiovascular risk profile.We prospectively examined over a 6-yr period the relation between gout and the risk of incident type 2 diabetes in 11 351 male participants from the Multiple Risk Factor Intervention Trial (MRFIT). Incident diabetes was defined based on the American Diabetes Association (ADA) criteria for epidemiological studies. Cox proportional hazards regression was used to adjust for potential confounders.We documented 1215 new cases of type 2 diabetes. After adjusting for age, BMI, smoking, family history of type 2 diabetes, alcohol intake, dietary factors and presence of individual components of the metabolic syndrome, the multivariate relative risk (RR) for incident type 2 diabetes among men with gout at baseline, as compared with men without gout, was 1.34 (95% CI 1.09, 1.64). When we further adjusted for serum uric acid levels, the association remained significant (RR 1.26; 95% CI 1.02, 1.54). When we updated the status of gout annually during follow-up as a time-varying covariate, the association remained similar. The association also remained similar in our subgroup analyses by major covariates (P-values for interaction >0.16).These findings from men with a high cardiovascular risk profile suggest that men with gout are at a higher future risk of type 2 diabetes independent of other known risk factors. These data expand on well-established, cross-sectional associations between hyperuricaemia, gout and the metabolic syndrome, and extend the link to the future risk of type 2 diabetes.

    View details for DOI 10.1093/rheumatology/ken305

    View details for Web of Science ID 000259326600025

    View details for PubMedID 18710901

  • Hyperuricaemia - Where nephrology meets rheumatology RHEUMATOLOGY Avram, Z., Krishnan, E. 2008; 47 (7): 960-964


    Rheumatologists care for patients with gouty arthritis, a condition caused by chronic and uncontrolled hyperuricaemia. Hyperuricaemia, gout and renal dysfunction are often bedfellows, raising the possibility of the former causing the latter. We sought the answer to the question 'Among patients with normal measures of glomerular filtration, does hyperuricaemia predict future renal disease'? We identified prospective cohort studies evaluating the relationship between serum uric acid and chronic kidney function from the past 20 yrs, through MEDLINE, Cochrane Library and EMBASE searches and bibliography cross-referencing. Nine cohort studies that met the selection criteria were found. Because of the extreme heterogeneity, a statistical meta-analysis was not performed. Most (eight out of nine) studies found an independent risk factor for deterioration of kidney function. Nearly all published prospective studies support the role of hyperuricaemia as an independent risk factor for renal dysfunction. In the absence of large randomized controlled trials of uric acid reduction, it remains uncertain if this relation is causal or merely an epiphenomenon. Regardless, our review suggests that hyperuricaemia is a useful, inexpensively measured, widely available and useful early marker for chronic kidney disease.

    View details for DOI 10.1093/rheumatology/ken070

    View details for Web of Science ID 000256977100005

    View details for PubMedID 18443007

  • Gout and coronary artery disease: epidemiologic clues. Current rheumatology reports Krishnan, E. 2008; 10 (3): 249-255


    Gout is the leading cause of inflammatory arthritis, typically affecting men and characterized by intermittent, abrupt onset of intense inflammation. The association between gout, atherosclerosis, and vascular disease has been noted in medical literature since the end of the 19th century, yet it has not been well studied. This review critically appraises the few epidemiologic studies that ask if gout is a risk factor for coronary artery disease. An exhaustive literature search using search engines and cross-referencing found four major studies and several smaller studies that have evaluated gout as a risk factor for coronary artery disease. The available studies were too heterogeneous to permit formal meta-analysis. Although there are gaps in evidence pointing to a causative pathway, overall, evidence exists for a relationship between gouty arthritis and coronary artery disease independent of traditional risk factors.

    View details for PubMedID 18638434

  • Long-term cardiovascular mortality among middle-aged men with gout ARCHIVES OF INTERNAL MEDICINE Krishnan, E., Svendsen, K., Neaton, J. D., Grandits, G., Kuller, L. H. 2008; 168 (10): 1104-1110


    There are limited data available on the association of gouty arthritis (gout) in middle age with long-term cardiovascular disease (CVD) mortality.We performed a 17-year follow-up study of 9105 men, aged 41 to 63 years and at above-average risk for coronary heart disease, who were randomized to the Multiple Risk Factor Intervention Trial and who did not die or have clinical or electrocardiographic evidence of coronary artery disease during the 6-year trial. Risk of CVD death and other causes subsequent to the sixth annual examination associated with gout was assessed by means of Cox proportional hazards regressions.The unadjusted mortality rates from CVD among those with and without gout were 10.3 per 1000 person-years and 8.0 per 1000 person-years, respectively, representing an approximately 30% greater risk. After adjustment for traditional risk factors, use of diuretics and aspirin, and serum creatinine level, the hazard ratio (gout vs no gout) for coronary heart disease mortality was 1.35 (95% confidence interval [CI], 1.06-1.72). The hazard ratio for death from myocardial infarction was 1.35 (95% CI, 0.94-1.93); for death from CVD overall, 1.21 (95% CI, 0.99-1.49); and for death from any cause, 1.09 (95% CI, 1.00-1.19) (P = .04). The association between hyperuricemia and CVD was weak and did not persist when analysis was limited to men with hyperuricemia without a diagnosis of gout.Among middle-aged men, a diagnosis of gout accompanied by an elevated uric acid level imparts significant independent CVD mortality Identifier: NCT00000487.

    View details for Web of Science ID 000256057000014

    View details for PubMedID 18504339

  • Gout in ambulatory care settings in the united states JOURNAL OF RHEUMATOLOGY Krishnan, E., Lienesch, D., Kwoh, C. K. 2008; 35 (3): 498-501


    To describe the ambulatory care utilization by patients with gouty arthritis (gout) in the United States using a nationally representative sample.A cross-sectional survey design based on the ambulatory care data from the 2002 US National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey was used to examine the ambulatory care burden for gout, the characteristics of gout patients, the types of providers who see gout patients, and prescribing patterns associated with the management of gout. Weighted analyses were performed to estimate the effect of age, sex, and ethnicity on the association with gout and prescription of allopurinol.Of the 973 million ambulatory care visits in the United States, 3.9 million were for gout. The majority of visits were for men. The average age for men with gout was lower than that for women with gout (65 vs 70 years of age). Over two-thirds of these gout visits were attended to by primary care providers, whereas visits to rheumatologists constituted only a very small proportion of these visits (1.3%). There were 2.8 million prescriptions for allopurinol, 700,000 prescriptions for nonsteroidal antiinflammatory drugs, 381,000 prescriptions for colchicine, and 341,000 prescriptions for prednisone. After adjusting for age and sex, Asians were 2.7 times more likely than Caucasians to have a gout visit. Yet these patients had lower probability of receiving allopurinol (odds ratio 0.04, 95% confidence interval 0.01-0.27).The majority of patients with gout are seen by generalist physicians. Asian ethnicity is associated with higher number of visits for gout, but a lower frequency of allopurinol treatment.

    View details for Web of Science ID 000253913300025

    View details for PubMedID 18260174

  • Factors associated with patients who leave acute-care hospitals against medical advice AMERICAN JOURNAL OF PUBLIC HEALTH Ibrahim, S. A., Kwoh, C. K., Krishnan, E. 2007; 97 (12): 2204-2208


    We examined hospital- and patient-related factors associated with discharge against medical advice (termed self-discharge) after emergency admission to acute-care hospitals.We analyzed data from the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project using logistic regression models to assess the relationship between self-discharge and a set of patient and hospital characteristics.Of 3,039,050 discharges in the sample, 43 678 were against medical advice (1.44%). In multivariable modeling, predictors of self-discharge included having Medicaid insurance (adjusted odds ratio [AOR]=3.32; 95% confidence interval [CI]=3.22, 3.42), having Medicare insurance (AOR=1.64; 95% CI=1.59, 1.70), urban location (AOR=1.66; 95% CI=1.61, 1.72), medium (AOR=1.25; 95% CI=1.20, 1.29) or large (AOR=1.08, 95% CI=1.05, 1.12) hospital (defined by the number of beds), shorter hospital stay (OR=0.84; 95% CI=0.84, 0.85), and African American race (AOR=1.10; 95% CI=1.07, 1.14). Teaching hospitals had fewer self-discharges (AOR=0.90; 95% CI=0.88, 0.92). Other predictors of discharge against medical advice included age, gender, and income.Approximately 1 in 70 hospital discharges in the United States are against medical advice. Both hospital and patient characteristics were associated with these decisions.

    View details for DOI 10.2105/AJPH.2006.100164

    View details for Web of Science ID 000251395900027

    View details for PubMedID 17971552

  • Hospitalizations and mortality in systemic sclerosis: results from the Nationwide Inpatient Sample RHEUMATOLOGY Chung, L., Krishnan, E., Chakravarty, E. F. 2007; 46 (12): 1808-1813


    To study the causes of hospitalizations and predictors of subsequent adverse outcomes for contemporary cohorts of patients with systemic sclerosis (SSc) in the USA.The data source was the 2002 and 2003 Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (HCUP-NIS) databases. We identified all discharges with an International Classification of Diseases-Clinical Modification (ICD9-CM) code of 710.1 (limited and diffuse SSc), then excluded those with concomitant diagnoses for lupus or rheumatoid arthritis. We calculated hospitalization rates, in-hospital mortality rates and mean length of stay (LOS). Multivariate logistic and linear regression models for in-hospital death and LOS were performed adjusting for sociodemographic and comorbidity covariates.The overall in-hospital mortality rate was 6.3% and the mean LOS was 6.6 days. Hospitalization rates were 4.5 times higher in women than in men, but in-hospital mortality was approximately 25% lower (P = 0.005). SSc was the most common principal diagnosis for all SSc hospitalizations, with the most common secondary diagnosis (24%) being pulmonary fibrosis. After SSc, respiratory failure was the second most common principal diagnosis in patients who died. Pulmonary fibrosis increased the odds of in-hospital death by 2.63 [95% confidence interval (CI) 1.98-3.49] fold and increased LOS by 7.25% (95% CI 0.90-13.60).Women with SSc had higher rates of hospitalization but lower in-hospital mortality than men. Pulmonary fibrosis was the major predictor of poor hospitalization outcomes in SSc patients in recent years, emphasizing the importance of continuing to develop more effective therapies for this fatal complication of the disease.

    View details for DOI 10.1093/rheumatology/kem273

    View details for Web of Science ID 000251197900014

    View details for PubMedID 17986481

  • Primary knee and hip arthroplasty among nonagenarians and centenarians in the United States ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH Krishnan, E., Fries, J. F., Kwoh, C. K. 2007; 57 (6): 1038-1042


    The number of individuals ages >or=100 years in the US is expected to increase considerably in the future along with the need for arthroplasties. This report focuses on the poorly studied epidemiology and mortality outcomes of arthroplasty among these individuals.We describe the epidemiology of knee and hip arthroplasties among centenarians using data from a large hospital discharge database in the US (the Nationwide Inpatient Sample) during the period 1993 through 2002. We used nonagenarians as the comparison group with adjustment for differences in the prevalence of congestive heart failure, neurologic diseases such as dementia and stroke, renal and hepatic diseases, obesity, anemia, malignancy, coagulopathy, and depression and other psychiatric illnesses. Cox regression models were used to study the mortality outcomes following arthroplasty.Overall, there were 679 hip arthroplasties and 7 knee arthroplasties among centenarians in this database. The corresponding figures for nonagenarians were 33,975 and 2,050, respectively. A vast majority (83%) of hip arthroplasty recipients were women. Risk-adjusted mortality estimates following arthroplasty for centenarians were higher than for nonagenarians (hazard ratio 1.46, 95% confidence interval 1.10-1.95). However, this was similar to differences in overall in-hospital mortality (hazard ratio 1.36, 95% confidence interval 1.32-1.40) between these 2 age categories.In the US population, hip and knee arthroplasty are very rarely performed among centenarians. Our in-hospital mortality data suggest that arthroplasties should not be denied to centenarians solely because of short-term postoperative life expectancy estimates.

    View details for DOI 10.1002/art.22888

    View details for Web of Science ID 000248705800021

    View details for PubMedID 17665474

  • Hyperuricemia and incidence of hypertension among men without metabolic syndrome HYPERTENSION Krishnan, E., Kwoh, C. K., Schumacher, H. R., Kuller, L. 2007; 49 (2): 298-303


    The aim of this project was to study the risk of developing hypertension over a 6-year follow-up in normotensive men with baseline hyperuricemia (serum uric acid >7.0 mg/dL) but without diabetes/glucose intolerance or metabolic syndrome. We analyzed the data on men without metabolic syndrome or hypertension at baseline from the Multiple Risk Factor Intervention Trial. These men (n=3073; age: 35 to 57 years) were followed for an average of 6 years by annual examinations. Follow-up blood pressure among those with baseline was consistently higher than among those with normal serum uric acid concentration. We used Cox regression models for adjustment for the effects of serum creatinine, body mass index, age, blood pressure, proteinuria, serum cholesterol and triglycerides, alcohol and tobacco use, risk factor interventions, and use of diuretics. In these models, normotensive men with baseline hyperuricemia had an 80% excess risk for incident hypertension (hazard ratio: 1.81; 95% CI: 1.59 to 2.07) compared with those who did not. Each unit increase in serum uric acid was associated with a 9% increase in the risk for incident hypertension (hazard ratio: 1.09; 95% CI: 1.02 to 1.17). We conclude that the hyperuricemia-hypertension risk relationship is present among normotensive middle-aged men without diabetes/glucose intolerance or metabolic syndrome.

    View details for DOI 10.1161/01.HYP.0000254480.64564.b6

    View details for Web of Science ID 000243598900012

    View details for PubMedID 17190877

  • Ethics of Clinical Trials : Kartha CC, editor. Kerala fifty years and beyond. Trivandrum, India: Gautha Books Krishnan E 2007
  • Sleep-disordered breathing among women with fibromyalgia syndrome JCR-JOURNAL OF CLINICAL RHEUMATOLOGY Shah, M. A., Feinberg, S., Krishnan, E. 2006; 12 (6): 277-281


    In clinical practice, polysomnograms ("sleep studies") are seldom ordered for patients with fibromyalgia, although sleep issues dominate the symptom complex. One reason for this is the lack of understanding how information from these studies could aid clinical decisions.The authors conducted a chart review of one rheumatologist's community-based practice where polysomnograms were offered routinely to all women who met the American College of Rheumatology criteria for fibromyalgia. Interpretation of these standardized protocol-based polysomnograms was performed by a board-certified neurologist using standard criteria.Mean age of the study subjects (n = 23) was 45 (standard deviation, 7.8) years. Median body mass index was 27 kg/m2 (interquartile range 20-48). These women had poor sleep with many arousals (median arousal index 23), apnea-hypopneas (median apnea-hypopnea index 22, interquartile range 17-30). Desaturation was common with half the patients having nadir oxygen saturation less than 87%. Restless legs were detected in polysomnograms among many women who clinically denied it (mean leg movement index 5.8).A large proportion of women with fibromyalgia in a general rheumatology practice had sleep-disordered breathing, which can be detected using sleep polysomnograms. Studies are needed to examine if treatment of the commonly detected sleep apnea will have a beneficial effect on symptoms of fibromyalgia.

    View details for DOI 10.1097/01.rhu.0000249771.97221.36

    View details for Web of Science ID 000242753600004

    View details for PubMedID 17149057

  • Ethnicity and mortality from systemic lupus erythematosus in the US ANNALS OF THE RHEUMATIC DISEASES Krishnan, E., Hubert, H. B. 2006; 65 (11): 1500-1505


    To study ethnic differences in mortality from systemic lupus erythematosus (lupus) in two large, population-based datasets.We analysed the national death data (1979-98) from the National Center for Health Statistics (Hyattsville, Maryland, USA) and hospitalisation data (1993-2002) from the Nationwide Inpatient Sample (NIS), the largest hospitalisation database in the US.The overall, unadjusted, lupus mortality in the National Center for Health Statistics data was 4.6 per million, whereas the proportion of in-hospital mortality from the NIS was 2.9%. African-Americans had disproportionately higher mortality risk than Caucasians (all-cause mortality relative risk adjusted for age = 1.24 (women), 1.36 (men); lupus mortality relative risk = 3.91 (women), 2.40 (men)). Excess risk was found among in-hospital deaths (odds ratio adjusted for age = 1.4 (women), 1.3 (men)). Lupus death rates increased overall from 1979 to 98 (p<0.001). The proportional increase was greatest among African-Americans. Among Caucasian men, death rates declined significantly (p<0.001), but rates did not change substantially for African-American men. The African-American:Caucasian mortality ratio rose with time among men, but there was little change among women. In analyses of the NIS data adjusted for age, the in-hospital mortality risk decreased with time among Caucasian women (p<0.001).African-Americans with lupus have 2-3-fold higher lupus mortality risk than Caucasians. The magnitude of the risk disparity is disproportionately higher than the disparity in all-cause mortality. A lupus-specific biological factor, as opposed to socioeconomic and access-to-care factors, may be responsible for this phenomenon.

    View details for DOI 10.1136/ard.2005.040907

    View details for Web of Science ID 000241215500019

    View details for PubMedID 16627544

  • Hospitalization and mortality of patients with systemic lupus erythematosus JOURNAL OF RHEUMATOLOGY Krishnan, E. 2006; 33 (9): 1770-1774


    To describe hospitalization and mortality outcomes of patients with systemic lupus erythematosus (SLE) in the general population.Hospitalizations of patients with SLE (n = 76,961) were identified from the US Nationwide Inpatient Sample, spanning 5 years from 1998 to 2002. Correlates of mortality were analyzed using logistic regression, while those of hospitalization charges were studied using median regressions.Overall, 11% of all hospitalizations were for SLE and/or lupus flare. There were 2454 (3.1%) hospitalizations that ended in death. Half of all deaths occurred within 7 days after admission. There were 3 peaks in mortality risk after admission, the first on Day 6, the second Day 33, the third Day 57. Patients in higher income strata and those with private insurance had better mortality outcomes than the rest. Hospitalization charges were expensive, at about US $10,000 per incident. Hospital charges were driven primarily by length of stay and number of medical procedures.Hospitalizations for SLE are expensive, and 1 in 30 hospitalizations culminates in death. There appears to be a trimodal pattern in the time risk of death following admission. Patients with higher socioeconomic status and those with private insurance were less likely to die in hospital.

    View details for Web of Science ID 000240377400012

    View details for PubMedID 16832848

  • Gout and the risk of acute myocardial infarction ARTHRITIS AND RHEUMATISM Krishnan, E., Baker, J. F., Furst, D. E., Schumacher, H. R. 2006; 54 (8): 2688-2696


    To determine if hyperuricemia and gouty arthritis are independent risk factors for acute myocardial infarction (MI) and, if so, whether they are independent of renal function, diuretic use, metabolic syndrome, and other established risk factors.We performed multivariable logistic and instrumental variable probit regressions on data from the Multiple Risk Factor Intervention Trial (MRFIT).Overall, there were 12,866 men in the MRFIT who were followed up for a mean of 6.5 years. There were 118 events of acute MI in the group with gout (10.5%) and 990 events in the group without gout (8.43%; P = 0.018). Hyperuricemia was an independent risk factor for acute MI in the multivariable regression models, with an odds ratio (OR) of 1.11 (95% confidence interval [95% CI] 1.08-1.15, P < 0.001). In multivariable regressions in which the above risk factors were used as covariates, gout was found to be associated with a higher risk of acute MI (OR 1.26 [95% CI 1.14-1.40], P < 0.001). Subgroup analyses showed that a relationship between gout and the risk of acute MI was present among nonusers of alcohol, diuretics, or aspirin and among those who did not have metabolic syndrome, diabetes mellitus, or obesity. In separate analyses, a relationship between gout and the risk of acute MI was evident among those with and without those hyperuricemia.The independent risk relationship between hyperuricemia and acute MI is confirmed. Gouty arthritis is associated with an excess risk of acute MI, and this is not explained by its well-known links with renal function, metabolic syndrome, diuretic use, and traditional cardiovascular risk factors.

    View details for DOI 10.1002/art.22014

    View details for Web of Science ID 000239641400039

    View details for PubMedID 16871533

  • Obstetric hospitalizations in the United States for women with systemic lupus erythematosus and rheumatoid arthritis ARTHRITIS AND RHEUMATISM Chakravarty, E. F., Nelson, L., Krishnan, E. 2006; 54 (3): 899-907


    To estimate the national occurrence of pregnancies in women with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and to compare pregnancy outcomes in these patients with those in women with pregestational diabetes mellitus (DM) and with the general obstetric population.We studied the 2002 Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project to estimate the number of obstetric hospitalizations, deliveries, and cesarean deliveries in women with SLE, RA, pregestational DM, and the general obstetric population. Pregnancy outcomes included length of hospital stay, hypertensive disorders including preeclampsia, premature rupture of membranes, and intrauterine growth restriction.Of an estimated 4.04 million deliveries, 3,264 occurred in women with SLE, 1,425 in women with RA, and 13,574 in women with pregestational DM. Women with SLE, RA, and pregestational DM had significantly increased rates of hypertensive disorders compared with the general obstetric population (23.2%, 11.1%, 27.4%, and 7.8%, respectively), longer hospital stays, and significantly higher risk of cesarean delivery. Although women with SLE, RA, and pregestational DM were significantly older than women in the general obstetric population, disparities in the risk of adverse outcomes of pregnancy remained statistically significant after adjustment for maternal age.To our knowledge, this is the first study to examine national data on pregnancy outcomes in women with common rheumatic diseases. As with underlying pregestational DM, women with SLE and RA appear to have a higher age-adjusted risk of adverse outcomes of pregnancy and longer hospital stays than do pregnant women in the general population, and careful antenatal monitoring should be performed.

    View details for DOI 10.1002/art.21663

    View details for Web of Science ID 000236019700023

    View details for PubMedID 16508972

  • Stroke subtypes among young patients with systemic lupus erythematosus. American journal of medicine Krishnan, E. 2005; 118 (12): 1415-?


    Systemic lupus erythematosus (lupus) is a systemic inflammatory disease associated with premature atherosclerosis, vasculitis, coagulopathy, and excessive incidence of stroke, especially among young patients. Little is known about subtypes of stroke in lupus.A 20% sample of all the hospitalizations in the United States in the years 2001 and 2002 (N approximately 15 million) were analyzed to identify hospitalizations of young patients (age < or =50 years) with systemic lupus erythematosus (n=25704). Proportions of hospitalization for stroke subtypes were compared between the lupus group and the general population group. Age- and sex-adjusted odds ratios for stroke were calculated with logistic regression models.In the lupus group, there were 313 hospitalizations for stroke of which 206 hospitalizations had stroke as the primary diagnosis. Age- and sex-adjusted stroke risk was higher among the lupus group (odds ratio 1.5, 95% confidence interval 1.3-1.8). Patients with lupus had higher risk for all stroke subtypes except in subarachnoid hemorrhage in which a trend toward a lower risk was observed (odds ratio 0.57, 95% confidence interval 0.34-0.96). Although 12.3% (n=38) of stroke admissions in the lupus group resulted in in-hospital death, this case fatality rate was not statistically different from that for stroke in the general population group.Stroke is an important poor outcome in young patients with lupus. Compared with the general population, patients with lupus are more likely to be hospitalized for the risk of ischemic stroke and intracerebral hemorrhage. The risk of subarachnoid hemorrhage, however, seems to be lower in patients with lupus.

    View details for PubMedID 16378793

  • Systemic sclerosis mortality in the United States: 1979-1998 EUROPEAN JOURNAL OF EPIDEMIOLOGY Krishnan, E., Furst, D. E. 2005; 20 (10): 855-861


    The US national mortality rates from systemic sclerosis (SSc) have not been reported since 1979. We studied age, gender and race specific time trends in US national mortality rates of SSc during the period 1979-1998 using poisson regression models. Over the 4.93 billion person-years of observation during the study period, there were 18,126 deaths from SSc, representing a mortality rate of 3.9 per million. The age adjusted mortality rates for men and women were 1.9 and 5.4 per million respectively. There were relatively few deaths in the extremes of age. SSc mortality rates increased with age in both genders and in all racial groups (p<0.001). In multivariable models adjusted for two-way statistical interactions, being African-American, female and of older age were associated with higher death rates. Over the 20 years of observation, overall (age-adjusted) SSc mortality rates showed a 36% increase (p<0.001) and subgroup analyses revealed that the increases were confined to women of both races. This rise occurred during a period in which post-diagnosis survival of SSc is known to have increased, suggesting an increasing incidence of this disease.

    View details for DOI 10.1007/s10654-005-2210-5

    View details for Web of Science ID 000233240200010

    View details for PubMedID 16283476

  • Impact of age and comorbidities on the criteria for remission and response in rheumatoid arthritis ANNALS OF THE RHEUMATIC DISEASES Krishnan, E., Hakkinen, A., Sokka, T., Hannonen, P. 2005; 64 (9): 1350-1352


    To determine to what extent health status impairment in rheumatoid arthritis (RA) measured by self report of pain, global assessment, and functional disability is attributable to age and other comorbid conditions as opposed to the disease itself.Pain, global assessment, and Health Assessment Questionnaire Disability Index (HAQ-DI) were measured in a random sample of 1530 adults in the Central Finland District, Finland. Median regressions were used for multivariable analyses.The mean age was 55.4 years and 72% were women. A large majority of the population reported some pain (76%) and less than perfect general health (83%). The overall mean values of pain, HAQ-DI, and general health were 20 mm, 0.25 units, and 21 mm, respectively. The most common self reported musculoskeletal comorbidities were osteoarthritis (24%) and chronic back pain (25%). Age and number of comorbidities were the only statistically significant correlates of pain and general health in multivariable analyses.Self reported disability, pain, and poor health were widely prevalent in the general population and are related to age and comorbid conditions. This needs to be taken into account when interpreting remission and response rates using current criteria and for future development of definitions for these end points in RA and other rheumatic diseases.

    View details for DOI 10.1136/ard.2005.037903

    View details for Web of Science ID 000231208700020

    View details for PubMedID 15760927

  • Serum uric acid and cardiovascular disease: Recent developments, and where do they leave us? AMERICAN JOURNAL OF MEDICINE Baker, J. F., Krishnan, E., Chen, L., Schumacher, H. R. 2005; 118 (8): 816-826


    The relationship between serum uric acid (SUA) and cardiovascular disease has been controversial. Here we review recent literature assessing whether hyperuricemia is an independent risk factor for adverse cardiovascular outcomes. Studies from the past 6 years evaluating the association of SUA with cardiovascular disease were identified through MEDLINE, EMBASE, and Cochrane library searches, bibliography cross-referencing, and review articles. Twenty-one cohort studies in healthy and high-risk patients with cardiovascular disease were identified and reviewed. In studies of high-risk patients, in which more overall events were recorded, 10 of 11 studies were supportive of an independent association. In 10 studies of healthy patients, 6 suggested an independent association of SUA with adverse cardiovascular outcomes. Increasing SUA is likely an independent risk factor for cardiovascular disease in high-risk individuals. However, the magnitude of excess risk attributable to high SUA is likely to be small in healthy individuals. Trials of SUA-lowering therapy in hyperuricemic patients evaluating the effect on cardiovascular outcomes are justified in high-risk patients.

    View details for DOI 10.1016/j.amjmed.2005.03.043

    View details for Web of Science ID 000231037100003

    View details for PubMedID 16084170

  • Unregistered trials are unethical PLOS MEDICINE Krishnan, E. 2005; 2 (2): 169-169

    View details for DOI 10.1371/journal.pmed.0020048

    View details for Web of Science ID 000227856700024

    View details for PubMedID 15737003

  • Rheumatoid arthritis: Radiographic progression is getting milder JOURNAL OF RHEUMATOLOGY Krishnan, E., Fries, J. F. 2005; 32 (1): 195-195

    View details for Web of Science ID 000226148000037

    View details for PubMedID 15630753

  • National databases and rheumatology research II: the National Health and Nutrition Examination Surveys RHEUMATIC DISEASE CLINICS OF NORTH AMERICA Sokka, T., Krishnan, E. 2004; 30 (4): 869-?


    Three National Health and Nutrition Examination Surveys were conducted in the United States between 1971 and 1994 to provide data on the nutritional and health status of the population and on specific target conditions. This article describes features of the surveys and provides examples of research on musculoskeletal disorders that used the survey data.

    View details for DOI 10.1016/j.rdc.2004.07.009

    View details for Web of Science ID 000224910200012

    View details for PubMedID 15488698

  • Declines in mortality from acute myocardial infarction in successive incidence and birth cohorts of patients with rheumatoid arthritis CIRCULATION Krishnan, E., Lingala, V. B., Singh, G. 2004; 110 (13): 1774-1779


    Patients with rheumatoid arthritis are at high risk for acute myocardial infarction (AMI). The treatment of rheumatoid arthritis has become more intensive over the past 2 decades, resulting in tighter control of inflammation and lower levels of disability. The impact of this on atherosclerotic cardiovascular diseases is not known.Death rates from AMI in a cohort of 3862 patients with rheumatoid arthritis followed up from 1980 to 1997 were studied. Time trends in AMI mortality among successive incidence and birth cohorts were examined by use of multivariable Poisson regression models and by comparing standardized mortality ratios. The mean age was 56 years in this predominantly female cohort (76%), and median disease duration was 6.5 years. During the period of observation, the use of methotrexate increased substantially, whereas that of prednisone was relatively stable. Over the 22,209 person-years of observation, there were 157 deaths as a result of AMI, with a death rate of 7.06 per 1000 person-years. Mortality rates were higher in older age groups and in men. After adjustment for age, sex, race, and disease duration, the risk of AMI declined in successive incidence years (relative risk, 0.94; 95% CI, 0.92 to 0.96). Patients with rheumatoid arthritis incident after 1990 did not have excess AMI mortality compared with general population. Declines in mortality trends were observed in successive birth cohorts as well.Mortality as a result of AMI among patients with rheumatoid arthritis has declined over time.

    View details for DOI 10.1161/01.CIR.0000142864.83780.81

    View details for Web of Science ID 000224128400012

    View details for PubMedID 15381644

  • Attrition bias in rheumatoid arthritis databanks: A case study of 6346 patients in 11 databanks and 65,649 administrations of the health assessment questionnaire JOURNAL OF RHEUMATOLOGY Krishnan, E., Murtagh, K., Bruce, B., Cline, D., Singh, G., Fries, J. F. 2004; 31 (7): 1320-1326


    Patient dropout (attrition) can bias and threaten validity of databank-based studies. Although there are several databanks of rheumatoid arthritis (RA) in operation, this phenomenon has not been well studied.We studied the attrition patterns of patients with RA in 11 long-running databanks where patients were followed using semiannual Health Assessment Questionnaires. Attrition rates were calculated as the proportion of living patients who were in active followup at the cutoff date. Mantel-Haenszel methods and Weibull regression were used to model the relationship between attrition and age, sex, race, education, disease duration, functional disability, and other characteristics.Overall, 6346 patients with RA were recruited into the study cohorts and followed for 32,823 person-years with 65,649 observations. The crude attrition rate was 3.8% per cycle. Rates were lowest in community-based databanks. Smaller size of the centers, inner-city location, and university clinic settings were associated with worse attrition. In multivariable analyses, younger age, lower levels of education, and non-Caucasian race predicted attrition. Level of disability and disease duration were not associated with attrition. Conclusion. In terms of person-years of followup and observation-points, this may be the largest study on attrition to date. While it is possible to have very high overall retention rates, certain types of databanks (smaller, inner-city-based, and university-based) are more likely to be biased due to selective retention of older, more educated Caucasian patients.

    View details for Web of Science ID 000222481600015

    View details for PubMedID 15229950

  • Similar prediction of mortality by the health assessment questionnaire in patients with rheumatoid arthritis and the general population ANNALS OF THE RHEUMATIC DISEASES Sokka, T., Hakkinen, A., Krishnan, E., Hannonen, P. 2004; 63 (5): 494-497


    The self report health assessment questionnaire (HAQ) quantifies disability in activities of daily living (ADL). In patients with rheumatoid arthritis, the HAQ predicts mortality, work disability, and hip replacement surgery. It has been widely used in rheumatology, but population based data are rare.To determine whether the HAQ predicts mortality in patients with rheumatoid arthritis (n = 1095) and community controls (n = 1490).A mailed questionnaire including the HAQ, visual analogue scales for pain and global health, comorbidities, education level, height, weight, and smoking status was administered in June 2000. Two years later, the vital status of the subjects was ascertained from the Finnish Population Register database.There were 41 deaths (10.1%) among the 404 patients with rheumatoid arthritis who had a baseline HAQ > or =1 (indicating at least some difficulty in most ADL), and 16 (2.3%) among 691 patients with HAQ <1 (p<0.001); in the community controls the values were 20 (13.6%) among 147 with HAQ > or =1, and 14 (1.0%) among 1343 with HAQ <1 (p<0.001). A higher HAQ score was an independent predictor of mortality in patients with rheumatoid arthritis (hazard ratio 2.73 (95% confidence interval, 1.86 to 4.02); p<0.001) and in community controls (2.75 (1.61 to 4.70); p<0.001).The HAQ predicts mortality in the community population as well as in patients with rheumatoid arthritis. People with similar levels of disability appear to have a similar likelihood of mortality over two years.

    View details for DOI 10.1136/ard.2003.009530

    View details for Web of Science ID 000220813600006

    View details for PubMedID 15082478

  • Normative values for the health assessment questionnaire disability index - Benchmarking disability in the general population ARTHRITIS AND RHEUMATISM Krishnan, E., Sokka, T., Hakkinen, A., Hubert, H., Hannonen, P. 2004; 50 (3): 953-960


    The Health Assessment Questionnaire (HAQ) disability index (DI) has been commonly used in rheumatology to quantify functional disability in patient groups, but current general population values of this index are not available. This study was undertaken to establish normative values for the HAQ DI in a general population and to analyze its correlates.The HAQ DI (range of scores 0-3) was measured in a random sample of 1,530 adults in the Central Finland District. Prevalence rates of disability by strata of age, sex, education level, body mass index (BMI), and health behaviors (including smoking and exercise habits) were calculated. Pearson's product-moment correlation coefficient and ordinary least squares regression were used to analyze the data.The estimated population mean HAQ DI was 0.25 (95% confidence interval 0.22-0.28), and 32% of respondents had at least some disability. Both for men and for women, functional disability increased exponentially with age. The HAQ DI was correlated with pain (r = 0.58) and global self assessment (r = 0.61). The prevalence of disability decreased with increasing number of years of education, lower BMI, and increasing frequency of physical exercise.Almost one-third of the general population has some functional disability. Functional disability is associated in part with lifestyle choices and increases with age in a nonlinear manner. The normative values of the HAQ DI that we have presented could be used as a reference benchmark for clinical and epidemiologic studies using this measure of disability.

    View details for DOI 10.1002/art.20048

    View details for Web of Science ID 000220119200035

    View details for PubMedID 15022339

  • Patient questionnaires and formal education level as prospective predictors of mortality over 10 years in 97% of 1416 patients with rheumatoid arthritis from 15 United States private practices JOURNAL OF RHEUMATOLOGY Pincus, T., Keysor, J., Sokka, T., Krishnan, E., Callahan, L. F. 2004; 31 (2): 229-234


    To prospectively analyze patient questionnaire scores concerning functional disability as well as formal education level as potential predictors of premature mortality over 10 years in 1416 patients with rheumatoid arthritis (RA) from 15 private practice rheumatology settings in 11 diverse cities in the United States.At baseline in 1985 and periodically over 10 years, patients completed mailed self-report multidimensional health assessment questionnaires (MDHAQ) that included functional disability scores, formal education level, and other demographic and clinical data. Vital status was determined 10 years after baseline. Potential predictors of 10 year mortality were analyzed using descriptive statistics and Cox proportional hazards models.Vital status was accounted for in 1378 patients, 97.3% of the cohort. The standard mortality ratio was 1.6, similar to most reported series of patients with RA, as 401 patients died versus 251 expected over 10 years. Evidence of "dose-response" relations was seen for age, formal education level, functional disability scores, and helplessness scores as predictors of mortality. In Cox proportional hazards models, age, sex, formal education level, functional disability, and helplessness scores remained significant independent predictors of 10 year mortality.Functional disability and low formal education level are significant predictors of premature mortality in people with RA under care in US private practice settings, as in most reported cohorts of patients with RA. This study shows that it is possible to account for more than 95% of patients over 10 years using mailed questionnaires to monitor patient status.

    View details for Web of Science ID 000188735200007

    View details for PubMedID 14760789

  • Equipoise, design bias, and randomized controlled trials: the elusive ethics of new drug development ARTHRITIS RESEARCH & THERAPY Fries, J. F., Krishnan, E. 2004; 6 (3): R250-R255


    The concept of 'equipoise', or the 'uncertainty principle', has been represented as a central ethical principle, and holds that a subject may be enrolled in a randomized controlled trial (RCT) only if there is true uncertainty about which of the trial arms is most likely to benefit the patient. We sought to estimate the frequency with which equipoise conditions were met in industry-sponsored RCTs in rheumatology, to explore the reasons for any deviations from equipoise, to examine the concept of 'design bias', and to consider alternative ethical formulations that might improve subject safety and autonomy. We studied abstracts accepted for the 2001 American College of Rheumatology meetings that reported RCTs, acknowledged industry sponsorship, and had clinical end-points (n = 45), and examined the proportion of studies that favored the registration or marketing of the sponsor's drug. In every trial (45/45) results were favorable to the sponsor, indicating that results could have been predicted in advance solely by knowledge of sponsorship (P < 0.0001). Equipoise clearly was being systematically violated. Publication bias appeared to be an incomplete explanation for this dramatic result; this bias occurs after a study is completed. Rather, we hypothesize that 'design bias', in which extensive preliminary data are used to design studies with a high likelihood of being positive, is the major cause of the asymmetric results. Design 'bias' occurs before the trial is begun and is inconsistent with the equipoise principle. However, design bias increases scientific efficiency, decreases drug development costs, and limits the number of subjects required, probably reducing aggregate risks to participants. Conceptual and ethical issues were found with the equipoise principle, which encourages performance of negative studies; ignores patient values, patient autonomy, and social benefits; is applied at a conceptually inappropriate decision point (after randomization rather than before); and is in conflict with the Belmont, Nuremberg, and other sets of ethical principles, as well as with US Food and Drug Administration procedures. We propose a principle of 'positive expected outcomes', which informs the assessment that a trial is ethical, together with a restatement of the priority of personal autonomy.

    View details for DOI 10.1186/ar1170

    View details for Web of Science ID 000222512700015

    View details for PubMedID 15142271

  • Percentile benchmarks in patients with rheumatoid arthritis: Health Assessment Questionnaire as a quality indicator (QI) ARTHRITIS RESEARCH & THERAPY Krishnan, E., Tugwell, P., Fries, J. F. 2004; 6 (6): R505-R513


    Physicians are in need of a simple objective, standardized tool to compare their patients with rheumatoid arthritis, as a group and individually, with national standards. The Disability Index of the Health Assessment Questionnaire (HAQ-DI) is a simple, robust tool that can fulfill these needs. However, use of this tool as a quality indicator (QI) is hampered by the unavailability of national reference values or benchmarks based on large, multicentric, heterogenous longitudinal patient cohorts. We utilized the 20-year longitudinal prospective data from 11 data banks of Arthritis Rheumatism and Aging Medical Information to calculate reference values for HAQ-DI. Overall, 6436 patients with rheumatoid arthritis were longitudinally followed for 32,324 person-years over the 20 years from 1981 to 2000. There were 64,647 HAQ-DI measurements, with an average of 19 measurements per person. Overall, 75% of patients were women and 89% were Caucasian; the median baseline age was 58.4 years and the median baseline HAQ-DI was 1.13. Few patients were treated with biologics. The HAQ-DI values had a Gaussian distribution except for the approximately 10% of observations showing no disability. Percentile benchmarks allow disability outcomes to be compared and contrasted between different patient populations. Reference values for the HAQ-DI, presented here numerically and graphically, can be used in clinical practice as a QI measure to track functional disability outcomes and to measure response to therapy, and by arthritis patients in self-management programs.

    View details for DOI 10.1186/ar1220

    View details for Web of Science ID 000225160100008

    View details for PubMedID 15535828

  • Musculoskeletal disorders and the national health and nutrition examination surveys (NHANES) Rheumatic disease clinics of North America Sokka T, Krishnan E 2004; 30 (4): 869-878
  • Measuring effectiveness of drugs in observational databanks: promises and perils ARTHRITIS RESEARCH & THERAPY Krishnan, E., Fries, J. F. 2004; 6 (2): 41-44


    Observational databanks have inherent strengths and shortcomings. As in randomized controlled trials, poor design of these databanks can either exaggerate or reduce estimates of drug effectiveness and can limit generalizability. This commentary highlights selected aspects of study design, data collection and statistical analysis that can help overcome many of these inadequacies. An international metaRegister and a formal mechanism for standardizing and sharing drug data could help improve the utility of databanks. Medical journals have a vital role in enforcing a quality checklist that improves reporting.

    View details for DOI 10.1186/ar1151

    View details for Web of Science ID 000189035200001

    View details for PubMedID 15059263

  • A randomized, controlled trial of interferon-beta-1a (Avonex(R)) in patients with rheumatoid arthritis: a pilot study [ISRCTN03626626]. Arthritis research & therapy Genovese, M. C., Chakravarty, E. F., Krishnan, E., Moreland, L. W. 2004; 6 (1): R73-R77


    The objective of this study was to evaluate the safety and possible efficacy of IFN-beta-1a for the treatment of patients with rheumatoid arthritis (RA). Twenty-two patients with active RA were enrolled in a phase II randomized, double-blind, placebo-controlled trial of 30 microg IFN-beta-1a by weekly self-injection for 24 weeks. The primary outcome of the study was safety. Secondary outcomes included the proportion of patients achieving an American College of Rheumatology (ACR) 20 response at 24 weeks. There were no significant differences in adverse events reported in the two groups. Fewer than 20% of patients in each arm of the study achieved an ACR 20 response at 24 weeks (P = 0.71). Sixty-nine percent of patients receiving IFN-beta and 67% receiving placebo terminated the study early, most of them secondary to a perceived lack of efficacy. Overall, IFN-beta-1a had a safety profile similar to that of placebo. There were no significant differences in the proportion of patients achieving an ACR 20 response between the two groups.

    View details for PubMedID 14979940

  • Musculoskeletal disorders and the national health and nutrition examination surveys (NHANES) Rheumatic Disease Clinics of North America Sokka T, Krishnan E 2004; 30 (4): 869-874
  • Smoking, gender and rheumatoid arthritis-epidemiological clues to etiology - Results from the behavioral risk factor surveillance system JOINT BONE SPINE Krishnan, E. 2003; 70 (6): 496-502


    This study was undertaken to confirm and extend our earlier observation that gender is a biological effect modifier of smoking-rheumatoid arthritis (RA) relationship in a diverse national survey sample in the United States.Smoking history of 644 cases of RA and 1509 geographically matched general population controls were compared using weighted logistic regression.There were 644 respondents with RA (cases) and 1509 geographically matched controls. Cases were significantly younger, less educated, more likely to be single and female than controls. Among cases 57% were smokers while among controls 49% smoked. Among women, after adjusting for age, hysterectomy had an age adjusted odds ratio 1.45, (95% CI 0.99-2.10) and menopause an adjusted odds ratio 1.18 (95% CI 0.99-2.10) were associated with smoking. In univariable analysis ever-smoking was associated with increased risk of RA (odds ratio 1.34, 95% CI 1.0-1.81). Among the strata of smokers, there was an increasing gradient of risk with increasing exposure to smoking (P = 0.041). In separate multivariable models, smoking increased the risk in men (odds ratio 2.29, 95% CI 1.35-3.90) while in women the risk was not elevated (odds ratio 0.98, 95% CI 0.67-1.42). After adjusting for the statistically significant interaction both female gender (odds ratio 2.30, 95% CI 1.39-3.83) and having ever smoked (odds ratio 2.31, 95% CI 1.36-3.94) emerged as significant risk factors for RA.Gender interacts with smoking in by an unknown mechanism to lead to differential risk of RA.

    View details for DOI 10.1016/S1297-319X(03)00141-6

    View details for Web of Science ID 000188322100017

    View details for PubMedID 14667562

  • Reduction in long-term functional disability in rheumatoid arthritis from 1977 to 1998: A longitudinal study of 3035 patients AMERICAN JOURNAL OF MEDICINE Krishnan, E., Fries, J. F. 2003; 115 (5): 371-376


    If newer, more aggressive treatment strategies in rheumatoid arthritis are more effective, long-term outcomes in rheumatoid arthritis should be improving substantially. We therefore assessed trends in disability over time in a large cohort of patients with rheumatoid arthritis.We examined functional disability data from 3035 patients with rheumatoid arthritis whose disease onset was from 1977 to 1998. Disability data were collected semiannually with the Health Assessment Questionnaire disability index. We then estimated average disability for each patient. We also computed mean disability for each calendar year by averaging the values from all patients in that year. We examined the relation of successive annual cohorts and subsequent disability, adjusting for age, sex, race, education, clinical center, disease duration, follow-up, and attrition. We used two regression approaches: ordinary and generalized least squares.Average disability declined by about 2% to 3% per calendar year of disease onset (2.7% to 2.8% per year [P <0.001] in univariable models and 2.0% to 2.1% per year [P <0.001] in multivariable models). This trend was consistent by age, sex, race, disease duration, clinical center, and baseline disability.After accounting for potential confounders, average disability levels in rheumatoid arthritis have declined by approximately 40% in the 20+ years since 1977. This decline is consistent with a beneficial effect of the associated changes in treatment strategies.

    View details for DOI 10.1016/S0002-9343(03)00397-8

    View details for Web of Science ID 000185776400005

    View details for PubMedID 14553872

  • Early and extensive erosiveness in peripheral joints predicts atlantoaxial subluxations in patients with rheumatoid arthritis ARTHRITIS AND RHEUMATISM Neva, M. H., Isomaki, P., Hannonen, P., KAUPPI, M., Krishnan, E., Sokka, T. 2003; 48 (7): 1808-1813


    To study the prevalence of cervical spine subluxations and predictive factors for atlantoaxial subluxations (including anterior atlantoaxial subluxation and atlantoaxial impaction, i.e., vertical subluxation) in patients with rheumatoid arthritis (RA) who were treated early and continuously with disease-modifying antirheumatic drugs for 8-13 years.Radiographs of the cervical spine were obtained in 103 of 110 patients (the 110 surviving patients of the original 135-patient cohort) at their 8-13-year followup visits. The prevalence of cervical spine subluxations was determined. Demographic variables and the first 5-year serial data concerning disease course were analyzed in a logistic regression model to find predictive factors for atlantoaxial subluxations.Atlantoaxial subluxations were found in 14 patients (14%), and 5 patients (5%) had subaxial subluxations. Older age at baseline, greater disease activity during the first 5 years, and early erosiveness in peripheral joints predicted the development of atlantoaxial subluxations. Patients who had >or=10% of the maximum possible radiographic damage (by Larsen score) in peripheral joints at 5 years were 15.9 times more likely to develop atlantoaxial subluxations at 8-13 years than patients whose peripheral joint damage remained <10% of the maximum.Compared with historical control RA cohorts, a lower prevalence of cervical spine destruction was found in the present group of patients. Rapid erosiveness in peripheral joints was the best predictor for atlantoaxial subluxations. Extensive erosiveness in peripheral joints should alert rheumatologists to the possible development of atlantoaxial subluxations in patients with RA.

    View details for DOI 10.1002/art.11086

    View details for Web of Science ID 000184067700007

    View details for PubMedID 12847673

  • Long-term observational studies In: Smolen J, Lipsky P (Eds.) Targeted therapies in rheumatology. London: Martin Dunitz Krishnan E, Singh G, Tugwell P 2003
  • Functional disability in rheumatoid arthritis patients compared with a community population in Finland ARTHRITIS AND RHEUMATISM Sokka, T., Krishnan, E., Hakkinen, A., Hannonen, P. 2003; 48 (1): 59-63


    To compare Health Assessment Questionnaire (HAQ) scores of patients with rheumatoid arthritis (RA) with HAQ scores from a sex- and age-adjusted population.Patients with RA (n = 1,095) and control subjects (n = 1,530) completed a mailed questionnaire that comprised the HAQ, pain and global health scores, education level, and comorbidities, as well as height, weight, and lifestyle attitudes, including smoking and exercise habits.The HAQ scores increased (indicating declining function) with older age in patients and controls. The HAQ scores were above the reference values (>95th percentile of the HAQ scores of the age- and sex-matched population) in 17-45% of women with RA and in 7-32% of men with RA ages 30-79 years, while the HAQ scores of the patients > or =80 years were similar to those of the age- and sex-matched population. In a logistic regression model, the odds ratio for disability (HAQ score > or =1; at least some difficulties in most activities of daily living) was 7.7 (95% confidence interval 5.3-11.1; P < 0.001) among patients with RA compared with community controls, when adjusted for age, sex, education, smoking, exercise, body mass index, number of comorbidities, and pain.RA is associated with a >7-fold risk of disability compared with that in a general population of adults in the same community. The impact of disability due to RA appears to be greater in younger and middle-age people than in elderly patients.

    View details for DOI 10.1002/art.10731

    View details for Web of Science ID 000180418500008

    View details for PubMedID 12528104

  • Smoking-gender interaction and risk for rheumatoid arthritis ARTHRITIS RESEARCH & THERAPY Krishnan, E., Sokka, T., Hannonen, P. 2003; 5 (3): R158-R162


    The present case-control study was conducted to investigate the relationship between smoking and rheumatoid arthritis, and to investigate formally the interaction between sex, smoking, and risk for developing rheumatoid arthritis. The study was performed in the Central District of Finland. Cases were patients with rheumatoid arthritis and the control group was a random sample of the general population. Logistic regression models were used to evaluate the effect of smoking on risk for rheumatoid arthritis, after adjusting for the effects of age, education, body mass index, and indices of general health and pain. Overall, 1095 patients with rheumatoid arthritis and 1530 control individuals were included. Patients were older, less well educated, more disabled, and had poorer levels of general health as compared with control individuals (all P < 0.01). Preliminary analyses revealed the presence of substantial statistical interaction between smoking and sex (P < 0.001). In separate multivariable analyses, past history of smoking was associated with increased risk for rheumatoid arthritis overall in men (odds ratio 2.0, 95% confidence interval 1.2-3.2) but not in women. Among men, this effect was seen only for rheumatoid factor-positive rheumatoid arthritis. There were significant interactions between smoking and age among women but not among men. We conclude that sex is a biologic effect modifier in the association between smoking and rheumatoid arthritis. The role of menopause in the etiology of rheumatoid arthritis merits further research.

    View details for DOI 10.1186/ar750

    View details for Web of Science ID 000182395200004

    View details for PubMedID 12723987

  • Long-term observational studies In: Smolen J, Lipsky P (Eds.) Targeted therapies in rheumatology. London: Martin Dunitz; Krishnan E, Singh G, Tugwell P 2003
  • Epidemiology of gynaecological cancers n: Soutter (Ed) Shaw?s Textbook of Gynaecology Churchill Livingstone. Edinburgh Day NE, Krishnan E 1997
  • PLAGUE IN INDIA LANCET Krishnan, E. 1994; 344 (8932): 1298-1298

    View details for Web of Science ID A1994PP70100044

    View details for PubMedID 7968006

  • SCREENING MAMMOGRAPHY LANCET Nair, M. K., Krishnan, E., Varghese, C. 1994; 343 (8900): 793-793

    View details for Web of Science ID A1994NC35100043

    View details for PubMedID 7907750

  • Survival in multiple myeloma in Kerala. National medical journal of India Nair, M. K., Varghese, C., Krishnan, E., Sankaranarayanan, R., Nair, B. 1993; 6 (1): 7-10


    The reported incidence of multiple myeloma in India ranges from 0.5 to 1.2 per 100,000 but there have been few studies on the effect of treatment of this condition. We, therefore, analysed the clinical profile of patients in Kerala with myeloma, the treatment given and the factors affecting survival.Case records of 142 patients with multiple myeloma treated at the Regional Cancer Centre, Trivandrum, between 1984 and 1989 were reviewed and abstracted. Chemotherapy (using melphalan and prednisolone) and radiotherapy were the treatment modalities. Survival analysis was done using the Kaplan-Meier estimates and multivariate analysis of factors affecting survival was performed using Cox's proportional hazards regression model.The mean age of the patients was 61 years and 90 were males. Bone pain and pallor were the most common presenting symptoms and the median survival was 30 months. A combination of melphalan and prednisolone was found to be well tolerated and achieved a survival rate of 62% at 5 years. Hemibody irradiation was beneficial in a small group of patients. On a multivariate analysis, Bence-Jones proteinuria, melphalan and prednisolone combination chemotherapy and response to treatment at 6 months were the most significant factors affecting survival. Socioeconomic status did not seem to influence survival.Melphalan and prednisolone chemotherapy achieves prolonged survival in myeloma. Radiotherapy can relieve symptoms and in a small group of patients hemibody irradiation can achieve prolonged remission. Further studies are required to identify the subgroups in which certain treatments are most effective in improving survival.

    View details for PubMedID 8453369

  • INDEPENDENT PREDICTORS OF RESPONSE AND DISEASE-FREE SURVIVAL IN ORAL-CANCER TREATED WITH RADICAL RADIATION-THERAPY CANCER Nair, M. K., Sankaranarayanan, R., Krishnan, E., Padmanabhan, T. K., Mayadevi, S., Mathew, A. 1992; 69 (9): 2221-2226


    There have been no reports concerning the independent predictors of response and disease-free survival (DFS) in oral cancer in India, where the highest incidence is reported. The authors analyzed the outcome of radical radiation therapy of 378 patients with oral cancer and found that the complete response rate within 6 months of completion of treatment was 45% and the 5-year DFS was 34% (95% confidence interval 29% to 39%). Regional lymph node involvement (P less than 0.001), histologic type (P less than 0.01), and the intraoral site of lesion (P less than 0.025) were identified as independent predictors of response when adjusted in a forward stepwise logistic regression analysis. The Cox proportional hazards regression analysis revealed that regional lymph node involvement (P less than 0.001) and histologic type (P less than 0.05) were independent prognostic factors for DFS. Patients with fixed regional lymph node involvement demonstrated a relative risk (RR) of 2.4 compared with those with N0 disease. Patients with well-differentiated squamous carcinoma had an RR of 2, and those with other histologic types (other than verrucous carcinoma) had an RR of 1.5.

    View details for Web of Science ID A1992HP19400001

    View details for PubMedID 1562966

  • Evaluation of reply-paid postcards as a cost-effective follow-up strategy in Kerala Cancer Registry Abstract: Newsletter of the National Cancer Registry Programme-ICMR, Varchese C, Ramadas K, Krishnan E, Suma OV, Bhaskar SJ 1991; 5: 12-14
  • The case for an aggressive prevention strategy Kerala Medical Journal Krishnan E, Soman CR 1991; 33 (4): 108

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