Rheumatoid Arthritis: Krishnaswami S

Kremer JM, Bloom BJ, Breedveld FC, Coombs JH, Fletcher MP, Gruben D, Krishnaswami S, Burgos-Vargas R, Wilkinson B, Zerbini CA, Zwillich SH. · Albany Medical College, Albany, New York. · Arthritis Rheum. · Pubmed #19565475 No free full text.

Abstract: OBJECTIVE: To determine the efficacy, safety, and tolerability of 3 different dosages of CP-690,550, a potent, orally active JAK inhibitor, in patients with active rheumatoid arthritis (RA) in whom methotrexate, etanercept, infliximab, or adalimumab caused an inadequate or toxic response. METHODS: Patients (n = 264) were randomized equally to receive placebo, 5 mg of CP-690,550, 15 mg of CP-690,550, or 30 mg of CP-690,550 twice daily for 6 weeks, and were followed up for an additional 6 weeks after treatment. The primary efficacy end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at 6 weeks. RESULTS: By week 6, the ACR20 response rates were 70.5%, 81.2%, and 76.8% in the 5 mg, 15 mg, and 30 mg twice daily groups, respectively, compared with 29.2% in the placebo group (P < 0.001). Improvements in disease activity in CP-690,550-treated patients compared with placebo were seen in all treatment groups as early as week 1. ACR50 and ACR70 response rates significantly improved in all treatment groups by week 4. The most common adverse events reported were headache and nausea. The infection rate in both the 15 mg twice daily group and the 30 mg twice daily group was 30.4% (versus 26.2% in the placebo group). No opportunistic infections or deaths occurred. Increases in mean low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels, and increases in mean serum creatinine level (0.04-0.06 mg/dl) were seen in all CP-690,550 treatment arms. CONCLUSION: Our findings indicate that CP-690,550 is efficacious in the treatment of RA, resulting in rapid, statistically significant, and clinically meaningful reductions in the signs and symptoms of RA. Further studies of CP-690,550 in RA are warranted.

Low CA, Cunningham AL, Kao AH, Krishnaswami S, Kuller LH, Wasko MC. · Western Psychiatric Institute and Clinic, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA 15213, USA. · Biol Psychol. · Pubmed #19428978 No free full text.

Abstract: Converging lines of evidence support an association between systemic inflammation and depressive symptoms. Neuroimmune pathways may account for the high prevalence of depression in individuals with inflammatory conditions such as rheumatoid arthritis (RA). However, this relationship is complicated by factors linked to both inflammatory disease activity and mood, such as pain and physical disability. The goal of this cross-sectional study was to examine the relationship between C-reactive protein (CRP) and depressive symptoms among 173 women with RA. Somatic symptoms of depression and circulating CRP were significantly associated in regression analyses adjusted for body mass index (beta=.19, p<.05), but this relationship was attenuated when pain and disability were included as covariates (beta=.09, p=.24). CRP was not significantly associated with negative mood symptoms of depression. Findings suggest that depression in the context of RA may result from the overlap of somatic depressive and RA symptoms rather than neuroimmune pathways.

Foeldvari I, Szer IS, Zemel LS, Lovell DJ, Giannini EH, Robbins JL, West CR, Steidle G, Krishnaswami S, Bloom BJ. · Hamburger Zentrum für Kinder- und Jugendrheumatologie, Am Klinikum Eilbek, Dehnhaide 120, 22081 Hamburg, Germany. · J Rheumatol. · Pubmed #19012356 No free full text.

Abstract: OBJECTIVE: To compare the efficacy and safety of celecoxib and naproxen in children with juvenile rheumatoid arthritis (JRA). METHODS: In this multicenter, randomized, double-blind, noninferiority study, subjects with JRA were randomized to receive a target dose of celecoxib 3 mg/kg bid or 6 mg/kg bid, or a target dose of naproxen 7.5 mg/kg bid for 12 weeks (maximum allowed dose=600 mg total daily dose). The primary efficacy measure was the percentage of responders at Week 12 attaining the American College of Rheumatology pediatric 30% improvement criterion (ACR Pediatric-30). RESULTS: Both celecoxib doses were at least as effective as naproxen at Week 12 [ACR Pediatric-30 treatment differences: celecoxib 3 mg/kg bid-naproxen=1.36% (95% CI -13.08 to 15.80); celecoxib 6 mg/kg bid-naproxen=13.02% (95% CI -0.22 to 26.25)]. Celecoxib 6 mg/kg bid had a numerically higher response rate than celecoxib 3 mg/kg bid at all postrandomization visits and a numerically higher response rate than naproxen 7.5 mg/kg bid at Weeks 4, 8, and 12. Improvement in each ACR Pediatric-30 core set measure was comparable to or numerically higher for celecoxib 6 mg/kg bid than naproxen or celecoxib 3 mg/kg bid. Adverse event rates were similar for all treatment groups, except that gastrointestinal adverse events were more common in the naproxen group, although the difference was not statistically significant. CONCLUSION: Celecoxib 3 mg/kg bid and 6 mg/kg bid were at least as effective as naproxen 7.5 mg/kg bid in treating the signs and symptoms of JRA over 12 weeks. All treatments were generally well tolerated.

Kao AH, Wasko MC, Krishnaswami S, Wagner J, Edmundowicz D, Shaw P, Cunningham AL, Danchenko N, Sutton-Tyrrell K, Tracy RP, Kuller LH, Manzi S. · Department of Medicine, Division of Rheumatology and Clinical Immunology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Am J Cardiol. · Pubmed #18774002 No free full text.

Abstract: Patients with systemic lupus erythematosus (SLE) and those with rheumatoid arthritis (RA) have increased risk for atherosclerotic cardiovascular disease. The aims of this study were to compare the presence of coronary artery calcium (CAC) in age- and race-matched women with SLE, those with RA, and healthy controls without diabetes mellitus or history of myocardial infarction, angina pectoris, or stroke and to investigate its relation with traditional risk factors, inflammation, and endothelial activation. Study subjects completed cardiovascular risk factor assessment and electron-beam computed tomography that measured CAC. The 2 patient groups had similar prevalence and extent of CAC as well as significantly increased odds of having any CAC (odds ratio 1.87, 95% confidence interval 1.09 to 3.21) and more extensive CAC (odds ratio 4.04, 95% confidence interval 1.42 to 11.56 for CAC score >100) compared with healthy controls. After controlling for differences in cardiovascular risk factors, including insulin resistance and hypertension, the results remained statistically significant. After adjustment for differences in levels of C-reactive protein and/or soluble intercellular adhesion molecule-1, however, women with chronic inflammatory diseases no longer had significantly increased odds of having any CAC or more extensive CAC compared with controls. In conclusion, asymptomatic and nondiabetic women with chronic inflammatory diseases had significantly increased odds of having CAC and more extensive CAC compared with age- and race-matched healthy controls. The increased odds for CAC may in part result from higher levels of inflammation and endothelial activation in these patients.

Hutmacher MM, Krishnaswami S, Kowalski KG. · Pharmacometrics Group, Pfizer Corporation, Ann Arbor, MI, USA. · J Pharmacokinet Pharmacodyn. · Pubmed #18058203 No free full text.

Abstract: Currently, no general methods have been developed to relate pharmacologically based models, such as indirect response models, to discrete or ordered categorical data. We propose the use of an unobservable latent variable (LV), through which indirect response models can be linked with drug exposure. The resulting indirect latent variable response model (ILVRM) is demonstrated using a case study of a JAK3 inhibitor, which was administered to patients in a rheumatoid arthritis (RA) study. The clinical endpoint for signs and symptoms in RA is the American College of Rheumatology response criterion of 20%--a binary response variable. In this case study, four exposure-response models, which have different pharmacological interpretations, were constructed and fitted using the ILVRM method. Specifically, two indirect response models, an effect compartment model, and a model which assumes instantaneous (direct) drug action were assessed and compared for their ability to predict the response data. In general, different model interpretations can influence drug inference, such as time to drug effect onset, as well as affect extrapolations of responses to untested experimental conditions, and the underlying pharmacology that operates to generate key response features does not change because the response was measured discretely. Consideration of these model interpretations can impact future study designs and ultimately provide greater insight into drug development strategies.

Kao AH, Krishnaswami S, Cunningham A, Edmundowicz D, Morel PA, Kuller LH, Wasko MC. · Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. · J Rheumatol. · Pubmed #18050383 No free full text.

Abstract: OBJECTIVE: To examine the association between disease duration of rheumatoid arthritis (RA) and the presence and extent of coronary artery calcification (CAC) in women with RA. METHODS: In this cross-sectional study, 185 women with RA duration of at least 2 years and no clinical cardiovascular disease completed electron-beam tomography (EBT) scans and risk factor assessment. Multivariable logistic regression was used to associate RA duration quartiles with subclinical CAC and extent of CAC. RESULTS: Age was similar across the quartiles of RA duration. Patients with RA > 23 years had significant increased odds (unadjusted OR 2.60, 95% CI 1.21 5.53) of having more extensive CAC compared to the referent group, those with RA for 2 7 years. This association remained significant after adjustment for traditional coronary heart disease (CHD) risk factors and RA-related covariates. Patients with intermediate RA duration (8 13 yrs) were more likely to have presence of any CAC (OR 3.03, 95% CI 1.06 8.66) compared to the referent group only after adjusting for age, race, and traditional CHD risk factors. Patients with longer RA duration were more likely to have cumulative joint damage, manifested as prior joint surgery, joint deformity, and greater functional disability. Lower body mass index also was associated with longer RA duration. CONCLUSION: Patients with longstanding RA have more extensive subclinical atherosclerosis or CAC compared to patients of the same age, independent of other CHD risk factors. RA duration may be a surrogate for factors related to the disease process or its treatment that may promote coronary atherogenesis.