- Email: [email protected]
Mediators of autonomic neuropathy in rheumatoid arthritis
S18
i n d i a n j o u r n a l o f r h e u m a t o l o g y 9 ( 2 0 1 4 ) S 7 eS 6 7
Methods: 76 RA patients, randomized to receive 6 months of treatment with rosuvastatin (10 mg/day, n¼38) or placebo (n¼38) as an adjunct to existing stable antirheumatic drugs. FMD assessed by Angiodefender™. Inflammatory measures included DAS28, CRP and ESR were measured at baseline and after treatment. Estimation of serum nitrite, lipids, pro-inflammatory cytokines and adhesion molecules was done at baseline and after treatment. Results: At baseline, inflammatory measures, pro-inflammatory cytokines and adhesion molecules were elevated and FMD was impaired among both groups. FMD increased significantly (p<0.01) after treatment with rosuvastatin but did not show significant change with placebo. After treatment, DAS28, ESR, CRP, TNF-a, IL6 and lipid spectrum improved significantly on rosuvastatin as compared with placebo. Furthermore, concentrations of serum nitrite and ICAM-1 significantly lower in the rosuvastatin group compared with the placebo group. Conclusions: First study to show that rosuvastatin improves inflammatory disease activity and endothelial dysfunction in RA. Rosuvastatin lowers the proinflammatory cytokines, especially IL6 and TNF-a, which down regulates adhesion molecules and lipid level and thus the production of NO. Reduction of cytokines and CRP favorably impacts the inflammatory disease activity and vascular function.
P40. Mediators of autonomic neuropathy in rheumatoid arthritis Ashit Synglea, Nidhi Gargb, Inderjeet Vermab, Pawan Krishanb; a CardioRheuma & Healing Touch City Clinic, Fortis Multi Specialty Hospital, Mohali, India; bDepartment of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India Introduction: Cardiovascular autonomic neuropathy (CAN) is a risk predictor for sudden cardiac death in RA. RA characterized by excess cardiovascular morbidity and mortality. Elevated IL-1b levels dampen vagal activity, IL-6 influence vagal tone and anti IL6 and TNF-a improve autonomic dysfunction in RA. Aim: To identify predictors of autonomic dysfunction among patients with RA. Methods: 25 adult patients with RA and 25 age and sex matched healthy controls were enrolled in the study. Autonomic function was assessed by cardiovascular reflex tests according to Ewing and peripheral sympathetic autonomic function assessed by Sudoscan. Inflammatory measures included DAS28, ESR, CRP and pro-inflammatory cytokines were measured by ELISA method. Results: RA patients had significantly impaired CAN and sudoscan as compared to healthy controls (all p<0.05). Pro-inflammatory cytokines were significantly higher in RA as compared to healthy controls. TNF-a significantly correlated with HR response to deep breath, standing and sudomotor function, IL-6 significantly correlated with HR response to standing, ESR significantly correlated with HR response to deep breath and standing, DAS28 also significantly correlated with HR response to deep breath in RA in univariate analyses. Conclusions: This study results suggests, increased disease severity, ESR, TNF-a and IL-6 level are the significant risk predictors of autonomic dysfunction It is likely that the exposure to elevated cytokines associated with enhanced inflammatory state that characterizes RA leads to autonomic neuropathy in this disease. Treatment with anticytokine drugs especially TNF-a inhibitor and IL-6 blockade could potentially be beneficial for treatment of autonomic dysfunction and its consequences in RA.
P41. Associative role of HLA-DRB1 SNP genotypes as risk factors for susceptibility and severity of rheumatoid arthritis e A North East India population based study Somdatta Dasa, A.K. Saikiab, B.P. Dekab, Diptika Tiwaria, Tarun Kr. Basumataryc, Sujoy Boseb; aDepartments of Biological Science and bBiotechnology, Gauhati University, Guwahati, India; c Central Hospital,N.F Railway, Maligaon, Guwahati Introduction: The present study aimed to evaluate the association of HLA-DRB1 gene SNPs (rs660895 and rs6457617) with susceptibility and severity of Rheumatoid arthritis (RA) in an ethnically distinct North-East Indian population. Methods: Whole blood was collected from RA(n¼38) cases and community based age and sex matched healthy controls(n¼70) with informed consent. Genomic DNA was isolated by standard phenol-chloroform method. HLA-DRB1 SNP genotyping was performed by allele-specific PCR. Statistical analysis was performed by SPSSv13.0software. Results: The distribution of rs660895 homozygote(CC) and heterozygote(CT) variant genotypes were found to be higher in RA cases(31.6% and 34.2% respectively) compared to controls (14.3% and 25.7% respectively). For SNP rs6457617, high distribution of heterozygote(CT) genotype was found in cases(50%) compared to controls (20%); whereas the homozygote(TT) genotype was present more in controls(80%) compared to cases(31.6%). Mann-Whitney based non-parametric tests showed that distribution of DRB1rs660895 (p¼0.011) and DRB1rs6457617 (p<0.001) was significantly higher and lower respectively in RA cases compared to controls. The presence of DRB1rs660895 C-allele resulted in increased risk of susceptibility to RA{OR¼2.885(1.266-6.571) at 95% CIs, p¼0.015}.The presence of DRB1rs6457617 wild type allele(Callele) significantly resulted in an increased risk of disease predisposition {OR¼3.258(2.430-4.368) at 95%CIs, p<0.001}. Statistical corelation analysis involving RA patients showed thatDRB1rs660895, rs6457617 and combination of presence of both the mutations in individual cases resulted in more severity score of the disease state. Conclusion: The present study showed that DRB1rs660895 is associated with susceptibility to RA; whereas both the HLA-DRB1 gene SNP genotypes independently or in a combinatorial manner are associated with severity of Rheumatoid arthritis.
P42. Anti-inflammatory and immunomodulatory action of spironolactone in RA: Candidature for a novel DMARD Ashit Synglea, Inderjeet Vermab, Pawan Krishanb; aCardioRheuma& Healing Touch City Clinic, Fortis Multi Specialty Hospital, Mohali, India; b Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India Introduction: Given the cytokine inhibiting and immunomodulatory potential of spironolactone, we investigated the anti-inflammatory effects of spironolactone in RA patients. Aim: To evaluate the safety and efficacy of spironolactone in a randomized, placebo-controlled, open label study in RA patients. Methods: In this 24 week study; 70 patients (36 in Spironolactone and 34 in placebo arm) with active RA were recruited. They were randomized to oral SPIR (2 mg/kg/day) or placebo for 24 weeks as an adjunct to existing stable DMARD regimen. Outcome measures were the assessment of disease activity measures i.e. ACR response criteria, DAS28 and SDAI in RA patients at baseline and week 24. The other endpoint was change from baseline in HAQ-DI, FMD was assessed by AngioDefender™, CIMT of brachial artery and EPCs quantified by flow cytometry at week 24. Additional
i n d i a n j o u r n a l o f r h e u m a t o l o g y 9 ( 2 0 1 4 ) S 7 eS 6 7
Methods: 76 RA patients, randomized to receive 6 months of treatment with rosuvastatin (10 mg/day, n¼38) or placebo (n¼38) as an adjunct to existing stable antirheumatic drugs. FMD assessed by Angiodefender™. Inflammatory measures included DAS28, CRP and ESR were measured at baseline and after treatment. Estimation of serum nitrite, lipids, pro-inflammatory cytokines and adhesion molecules was done at baseline and after treatment. Results: At baseline, inflammatory measures, pro-inflammatory cytokines and adhesion molecules were elevated and FMD was impaired among both groups. FMD increased significantly (p<0.01) after treatment with rosuvastatin but did not show significant change with placebo. After treatment, DAS28, ESR, CRP, TNF-a, IL6 and lipid spectrum improved significantly on rosuvastatin as compared with placebo. Furthermore, concentrations of serum nitrite and ICAM-1 significantly lower in the rosuvastatin group compared with the placebo group. Conclusions: First study to show that rosuvastatin improves inflammatory disease activity and endothelial dysfunction in RA. Rosuvastatin lowers the proinflammatory cytokines, especially IL6 and TNF-a, which down regulates adhesion molecules and lipid level and thus the production of NO. Reduction of cytokines and CRP favorably impacts the inflammatory disease activity and vascular function.
P40. Mediators of autonomic neuropathy in rheumatoid arthritis Ashit Synglea, Nidhi Gargb, Inderjeet Vermab, Pawan Krishanb; a CardioRheuma & Healing Touch City Clinic, Fortis Multi Specialty Hospital, Mohali, India; bDepartment of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India Introduction: Cardiovascular autonomic neuropathy (CAN) is a risk predictor for sudden cardiac death in RA. RA characterized by excess cardiovascular morbidity and mortality. Elevated IL-1b levels dampen vagal activity, IL-6 influence vagal tone and anti IL6 and TNF-a improve autonomic dysfunction in RA. Aim: To identify predictors of autonomic dysfunction among patients with RA. Methods: 25 adult patients with RA and 25 age and sex matched healthy controls were enrolled in the study. Autonomic function was assessed by cardiovascular reflex tests according to Ewing and peripheral sympathetic autonomic function assessed by Sudoscan. Inflammatory measures included DAS28, ESR, CRP and pro-inflammatory cytokines were measured by ELISA method. Results: RA patients had significantly impaired CAN and sudoscan as compared to healthy controls (all p<0.05). Pro-inflammatory cytokines were significantly higher in RA as compared to healthy controls. TNF-a significantly correlated with HR response to deep breath, standing and sudomotor function, IL-6 significantly correlated with HR response to standing, ESR significantly correlated with HR response to deep breath and standing, DAS28 also significantly correlated with HR response to deep breath in RA in univariate analyses. Conclusions: This study results suggests, increased disease severity, ESR, TNF-a and IL-6 level are the significant risk predictors of autonomic dysfunction It is likely that the exposure to elevated cytokines associated with enhanced inflammatory state that characterizes RA leads to autonomic neuropathy in this disease. Treatment with anticytokine drugs especially TNF-a inhibitor and IL-6 blockade could potentially be beneficial for treatment of autonomic dysfunction and its consequences in RA.
P41. Associative role of HLA-DRB1 SNP genotypes as risk factors for susceptibility and severity of rheumatoid arthritis e A North East India population based study Somdatta Dasa, A.K. Saikiab, B.P. Dekab, Diptika Tiwaria, Tarun Kr. Basumataryc, Sujoy Boseb; aDepartments of Biological Science and bBiotechnology, Gauhati University, Guwahati, India; c Central Hospital,N.F Railway, Maligaon, Guwahati Introduction: The present study aimed to evaluate the association of HLA-DRB1 gene SNPs (rs660895 and rs6457617) with susceptibility and severity of Rheumatoid arthritis (RA) in an ethnically distinct North-East Indian population. Methods: Whole blood was collected from RA(n¼38) cases and community based age and sex matched healthy controls(n¼70) with informed consent. Genomic DNA was isolated by standard phenol-chloroform method. HLA-DRB1 SNP genotyping was performed by allele-specific PCR. Statistical analysis was performed by SPSSv13.0software. Results: The distribution of rs660895 homozygote(CC) and heterozygote(CT) variant genotypes were found to be higher in RA cases(31.6% and 34.2% respectively) compared to controls (14.3% and 25.7% respectively). For SNP rs6457617, high distribution of heterozygote(CT) genotype was found in cases(50%) compared to controls (20%); whereas the homozygote(TT) genotype was present more in controls(80%) compared to cases(31.6%). Mann-Whitney based non-parametric tests showed that distribution of DRB1rs660895 (p¼0.011) and DRB1rs6457617 (p<0.001) was significantly higher and lower respectively in RA cases compared to controls. The presence of DRB1rs660895 C-allele resulted in increased risk of susceptibility to RA{OR¼2.885(1.266-6.571) at 95% CIs, p¼0.015}.The presence of DRB1rs6457617 wild type allele(Callele) significantly resulted in an increased risk of disease predisposition {OR¼3.258(2.430-4.368) at 95%CIs, p<0.001}. Statistical corelation analysis involving RA patients showed thatDRB1rs660895, rs6457617 and combination of presence of both the mutations in individual cases resulted in more severity score of the disease state. Conclusion: The present study showed that DRB1rs660895 is associated with susceptibility to RA; whereas both the HLA-DRB1 gene SNP genotypes independently or in a combinatorial manner are associated with severity of Rheumatoid arthritis.
P42. Anti-inflammatory and immunomodulatory action of spironolactone in RA: Candidature for a novel DMARD Ashit Synglea, Inderjeet Vermab, Pawan Krishanb; aCardioRheuma& Healing Touch City Clinic, Fortis Multi Specialty Hospital, Mohali, India; b Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India Introduction: Given the cytokine inhibiting and immunomodulatory potential of spironolactone, we investigated the anti-inflammatory effects of spironolactone in RA patients. Aim: To evaluate the safety and efficacy of spironolactone in a randomized, placebo-controlled, open label study in RA patients. Methods: In this 24 week study; 70 patients (36 in Spironolactone and 34 in placebo arm) with active RA were recruited. They were randomized to oral SPIR (2 mg/kg/day) or placebo for 24 weeks as an adjunct to existing stable DMARD regimen. Outcome measures were the assessment of disease activity measures i.e. ACR response criteria, DAS28 and SDAI in RA patients at baseline and week 24. The other endpoint was change from baseline in HAQ-DI, FMD was assessed by AngioDefender™, CIMT of brachial artery and EPCs quantified by flow cytometry at week 24. Additional