Clinical Research Overview
Decrease of Asymmetric Dimethyl Arginine After Anti-TNF Therapy in Patients with Rheumatoid Arthritis
DDR
DRUG DEVELOPMENT RESEARCH 75 : S67–S69 (2014)
Francesca Romana Spinelli,1* Manuela Di Franco,1 Alessio Metere,2 Fabrizio Conti,1 Cristina Iannuccelli,1 Luciano Agati,3 and Guido Valesini1 1 Department of Internal Medicine and Medical Specialities, Rheumatology Unit, Sapienza University of Rome, 00161 Rome, Italy 2 Section of Biomarkers in Degenerative Diseases, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161 Rome, Italy 3 Department of Cardiovascular and Respiratory Sciences, Sapienza University of Rome, 00161 Rome, Italy
Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics
Preclinical Research
Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics
Clinical Development Phases I-III Regulatory, Quality, Manufacturing
Postmarketing Phase IV
ABSTRACT Chronic inflammatory diseases such as rheumatoid arthritis (RA) are associated with accelerated atherosclerosis and increased morbidity and mortality for cardiovascular events. Asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, contributes to the impairment of endothelial function, the earlier and reversible stage of atherosclerotic plaque formation. Since tumor necrosis factor (TNF) inhibits enzymatic degradation of ADMA, anti-TNF agents could restore its physiological level. The aim of this study was to investigate the effect of TNF inhibitors on ADMA serum levels in patients with RA. Our results suggest a possible effect of anti-TNF drugs on ADMA serum levels; longer studies would be necessary to confirm the role ADMA in assessing cardiovascular risk in RA. Drug Dev Res 75 : S67–S69, 2014. © 2014 Wiley Periodicals, Inc. Key words: asymmetric dimethyl arginine; rheumatoid arthritis; endothelial function; anti-tumor necrosis factor (anti-TNF)
INTRODUCTION
Chronic inflammatory diseases, such as rheumatoid arthritis (RA), are associated with accelerated atherosclerosis and increased morbidity and mortality for cardiovascular events. Asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), contributes to the impairment of endothelial function, the earlier and reversible stage of atherosclerotic plaque formation. Previous studies found elevated ADMA levels in RA patients [Surdacki et al., 2007; Turiel et al., 2010; Di Franco et al., 2012; Sandoo et al., 2012a; Sandoo et al., 2012b]. Since © 2014 Wiley Periodicals, Inc.
Funding/support information: The study was supported by “Fondazione Umberto Di Mario” ONLUS. Conflict of interest: None of the authors has any conflict of interest to declare. *Correspondence to: Francesca Romana Spinelli, Dipartimento di Medicina Interna e Specialità Mediche, Cattedra e Divisione di Reumatologia, Sapienza Università di Roma, viale del Policlinico 155, 00161 Rome, Italy. E-mail: [email protected] Published online in Wiley Online Library (wileyonlinelibrary .com). DOI: 10.1002/ddr.21200
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SPINELLI ET AL.
tumor necrosis factor (TNF) inhibits enzymatic degradation of ADMA, anti-TNF agents could restore its physiological level. The aim of this study was to investigate the effect of TNF inhibitors on ADMA serum levels in patients with RA.
P < 0.0001). We detected a positive correlation between ADMA serum levels and DAS28 scores (r = 0.23, P = 0.02) (Fig. 2).
DISCUSSION
We enrolled 33 patients (23F, 9M, mean age 48.4 + 12.2 years, mean disease duration 114 + 86.7 months). Mean baseline ADMA serum levels were 0.53 + 0.16 μmol/L. After 3 months of anti-TNF treatment with etanercept (n = 26) or adalimumab (n = 7), ADMA levels significantly decreased (0.44 ± 0.13 μmol/L, P = 0.004 vs baseline) (Fig. 1). As expected, anti-TNF treatment significantly reduced DAS28 score (from 5.3 ± 1.2 at baseline to 3.6 ± 1.3;
The results of the present study demonstrate the reduction of ADMA serum levels in RA patients treated with TNF inhibitors. As a NOS inhibitor, ADMA is involved in the endothelial dysfunction found in the pre-clinical stage of atherosclerosis. A number of studies demonstrated higher ADMA serum levels in RA patients correlating with surrogate markers of cardiovascular risk [Surdacki et al., 2007; Turiel et al., 2010; Spinelli et al., 2013]. In patients with early RA, we previously showed increased ADMA serum levels that were restored by 12 months treatment with Disease Modifying Anti-Rheumatic Drugs (DMARDs) [Di Franco et al., 2012]. Conversely, Turiel et al. did not observed any effect of methotrexate or adalimumab on ADMA serum levels in RA patients treated for 18 months [Turiel et al., 2010]. Angel et al. found a reduction in L-arginine and in the L-arginine/ADMA ratio after 12 months of treatment with anti-TNF; however, baseline ADMA levels were comparable to healthy subjects [Angel et al., 2012]. Finally, Sandoo et al. studied the short-term effect of adalimumab, etanercept and infliximab in 35 RA patients: after 2 weeks and 3 months, ADMA values were similar to baseline [Sandoo et al., 2012a]. Explanations of these contrasting results could lie in the different methods employed for ADMA determination (enzymatic vs chromatographic assays) and the heterogeneity of populations evaluated. Interestingly, in our cohort of patients, disease activity seems to parallel ADMA levels. In conclusion, we demonstrated a decrease of ADMA serum levels in RA patients treated with TNF
Fig. 1. Effect of 3 months anti-tumor necrosis factor (TNF) treatment on asymmetric dimethyl arginine (ADMA) serum levels in rheumatoid arthritis patients.
Fig. 2. Correlation between asymmetric dimethyl arginine (ADMA) serum levels and disease activity scale 28 joint (DAS28) scores.
MATERIALS AND METHODS
Patients with RA diagnosed according to 1987 American College of Rheumatology classification criteria, who were due to start anti-TNF therapy, without previously diagnosed cardiovascular disease, kidney failure, dyslipidaemia, and/or diabetes, were eligible to enter the study. All the participants signed a written informed consent and underwent a peripheral blood sample collection just before starting the therapy and after 3 months. ADMA serum levels were determined by commercial enzyme linked immunosorbent assay (ELISA; Vinci-Biochem, Firenze, Italia); each serum was tested in triplicate at baseline and after 3 months of treatment. Disease activity was assessed by the Disease Activity Score 28 (DAS28). Data for matched pairs were analysed with Wilcoxon test. Correlation between ADMA and DAS28 was evaluated with Spearman test. A P value ≤ 0.05 was considered statistically significant. RESULTS
Drug Dev. Res.
ADMA IN ANTI-TNF TREATED PATIENTS
antagonists; longer studies on larger cohort would be necessary to confirm its possible role in assessing cardiovascular risk in RA patients.
ACKNOWLEDGMENT
Editorial assistance was provided by Mary Hines on behalf of HPS—Health Publishing and Services Srl and funded by Pfizer Italia. REFERENCES Angel K, Provan SA, Mowinckel P, Seljeflot I, Kvien TK, Atar D. 2012. The L-arginine/asymmetric dimethylarginine ratio is improved by anti-tumor necrosis factor-α therapy in inflammatory arthropathies. Associations with aortic stiffness. Atherosclerosis 225:160–165. Di Franco M, Spinelli FR, Metere A, Gerardi MC, Conti V, Boccalini F, Iannuccelli C, Ciciarello F, Agati L, Valesini G. 2012. Serum levels of asymmetric dimethylarginine and apelin as potential markers of vascular endothelial dysfunction in early rheumatoid arthritis. Mediators Inflamm 2012:347268. doi: 10.1155/2012/ 347268. Sandoo A, Dimitroulas T, Toms TE, Hodson J, Veldhuijzen van Zanten JJ, Smith JP, Kitas GD. 2012a. Clinical
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remission following treatment with tumour necrosis factor-alpha antagonists is not accompanied by changes in asymmetric dimethylarginine in patients with rheumatoid arthritis. Clin Biochem 45:1399–1403. Sandoo A, Dimitroulas T, Veldhuijzen van Zanten JJ, Smith JP, Metsios GS, Nightingale P, Stavropoulos-Kalinoglou A, Kitas GD. 2012b. Lack of association between asymmetric dimethylarginine and in vivo microvascular or macrovascular endothelial function in patients with rheumatoid arthritis. Clin Exp Rheumatol 30:388–396. Spinelli FR, Metere A, Barbati C, Pierdominici M, Iannuccelli C, Lucchino B, Ciciarello F, Agati L, Valesini G, Di Franco M. 2013. Effect of therapeutic inhibition of TNF on circulating endothelial progenitor cells in patients with rheumatoid arthritis. Mediators Inflamm 2013:537539. doi: 10.1155/2013/537539. Surdacki A, Martens-Lobenhoffer J, Wloch A, Marewicz E, Rakowski T, Wieczorek-Surdacka E, Dubiel JS, Pryjma J, Bode-Böger SM. 2007. Elevated plasma asymmetric dimethyl-Larginine levels are linked to endothelial progenitor cell depletion and carotid atherosclerosis in rheumatoid arthritis. Arthritis Rheum 56:809–819. Turiel M, Tomasoni L, Sitia S, Cicala S, Gianturco L, Ricci C, Atzeni F, De Gennaro Colonna V, Longhi M, Sarzi-Puttini P. 2010. Effects of long-term disease-modifying antirheumatic drugs on endothelial function in patients with early rheumatoid arthritis. Cardiovasc Ther 28:e53–e64.
Drug Dev. Res.
Decrease of Asymmetric Dimethyl Arginine After Anti-TNF Therapy in Patients with Rheumatoid Arthritis
DDR
DRUG DEVELOPMENT RESEARCH 75 : S67–S69 (2014)
Francesca Romana Spinelli,1* Manuela Di Franco,1 Alessio Metere,2 Fabrizio Conti,1 Cristina Iannuccelli,1 Luciano Agati,3 and Guido Valesini1 1 Department of Internal Medicine and Medical Specialities, Rheumatology Unit, Sapienza University of Rome, 00161 Rome, Italy 2 Section of Biomarkers in Degenerative Diseases, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161 Rome, Italy 3 Department of Cardiovascular and Respiratory Sciences, Sapienza University of Rome, 00161 Rome, Italy
Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics
Preclinical Research
Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics
Clinical Development Phases I-III Regulatory, Quality, Manufacturing
Postmarketing Phase IV
ABSTRACT Chronic inflammatory diseases such as rheumatoid arthritis (RA) are associated with accelerated atherosclerosis and increased morbidity and mortality for cardiovascular events. Asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, contributes to the impairment of endothelial function, the earlier and reversible stage of atherosclerotic plaque formation. Since tumor necrosis factor (TNF) inhibits enzymatic degradation of ADMA, anti-TNF agents could restore its physiological level. The aim of this study was to investigate the effect of TNF inhibitors on ADMA serum levels in patients with RA. Our results suggest a possible effect of anti-TNF drugs on ADMA serum levels; longer studies would be necessary to confirm the role ADMA in assessing cardiovascular risk in RA. Drug Dev Res 75 : S67–S69, 2014. © 2014 Wiley Periodicals, Inc. Key words: asymmetric dimethyl arginine; rheumatoid arthritis; endothelial function; anti-tumor necrosis factor (anti-TNF)
INTRODUCTION
Chronic inflammatory diseases, such as rheumatoid arthritis (RA), are associated with accelerated atherosclerosis and increased morbidity and mortality for cardiovascular events. Asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), contributes to the impairment of endothelial function, the earlier and reversible stage of atherosclerotic plaque formation. Previous studies found elevated ADMA levels in RA patients [Surdacki et al., 2007; Turiel et al., 2010; Di Franco et al., 2012; Sandoo et al., 2012a; Sandoo et al., 2012b]. Since © 2014 Wiley Periodicals, Inc.
Funding/support information: The study was supported by “Fondazione Umberto Di Mario” ONLUS. Conflict of interest: None of the authors has any conflict of interest to declare. *Correspondence to: Francesca Romana Spinelli, Dipartimento di Medicina Interna e Specialità Mediche, Cattedra e Divisione di Reumatologia, Sapienza Università di Roma, viale del Policlinico 155, 00161 Rome, Italy. E-mail: [email protected] Published online in Wiley Online Library (wileyonlinelibrary .com). DOI: 10.1002/ddr.21200
S68
SPINELLI ET AL.
tumor necrosis factor (TNF) inhibits enzymatic degradation of ADMA, anti-TNF agents could restore its physiological level. The aim of this study was to investigate the effect of TNF inhibitors on ADMA serum levels in patients with RA.
P < 0.0001). We detected a positive correlation between ADMA serum levels and DAS28 scores (r = 0.23, P = 0.02) (Fig. 2).
DISCUSSION
We enrolled 33 patients (23F, 9M, mean age 48.4 + 12.2 years, mean disease duration 114 + 86.7 months). Mean baseline ADMA serum levels were 0.53 + 0.16 μmol/L. After 3 months of anti-TNF treatment with etanercept (n = 26) or adalimumab (n = 7), ADMA levels significantly decreased (0.44 ± 0.13 μmol/L, P = 0.004 vs baseline) (Fig. 1). As expected, anti-TNF treatment significantly reduced DAS28 score (from 5.3 ± 1.2 at baseline to 3.6 ± 1.3;
The results of the present study demonstrate the reduction of ADMA serum levels in RA patients treated with TNF inhibitors. As a NOS inhibitor, ADMA is involved in the endothelial dysfunction found in the pre-clinical stage of atherosclerosis. A number of studies demonstrated higher ADMA serum levels in RA patients correlating with surrogate markers of cardiovascular risk [Surdacki et al., 2007; Turiel et al., 2010; Spinelli et al., 2013]. In patients with early RA, we previously showed increased ADMA serum levels that were restored by 12 months treatment with Disease Modifying Anti-Rheumatic Drugs (DMARDs) [Di Franco et al., 2012]. Conversely, Turiel et al. did not observed any effect of methotrexate or adalimumab on ADMA serum levels in RA patients treated for 18 months [Turiel et al., 2010]. Angel et al. found a reduction in L-arginine and in the L-arginine/ADMA ratio after 12 months of treatment with anti-TNF; however, baseline ADMA levels were comparable to healthy subjects [Angel et al., 2012]. Finally, Sandoo et al. studied the short-term effect of adalimumab, etanercept and infliximab in 35 RA patients: after 2 weeks and 3 months, ADMA values were similar to baseline [Sandoo et al., 2012a]. Explanations of these contrasting results could lie in the different methods employed for ADMA determination (enzymatic vs chromatographic assays) and the heterogeneity of populations evaluated. Interestingly, in our cohort of patients, disease activity seems to parallel ADMA levels. In conclusion, we demonstrated a decrease of ADMA serum levels in RA patients treated with TNF
Fig. 1. Effect of 3 months anti-tumor necrosis factor (TNF) treatment on asymmetric dimethyl arginine (ADMA) serum levels in rheumatoid arthritis patients.
Fig. 2. Correlation between asymmetric dimethyl arginine (ADMA) serum levels and disease activity scale 28 joint (DAS28) scores.
MATERIALS AND METHODS
Patients with RA diagnosed according to 1987 American College of Rheumatology classification criteria, who were due to start anti-TNF therapy, without previously diagnosed cardiovascular disease, kidney failure, dyslipidaemia, and/or diabetes, were eligible to enter the study. All the participants signed a written informed consent and underwent a peripheral blood sample collection just before starting the therapy and after 3 months. ADMA serum levels were determined by commercial enzyme linked immunosorbent assay (ELISA; Vinci-Biochem, Firenze, Italia); each serum was tested in triplicate at baseline and after 3 months of treatment. Disease activity was assessed by the Disease Activity Score 28 (DAS28). Data for matched pairs were analysed with Wilcoxon test. Correlation between ADMA and DAS28 was evaluated with Spearman test. A P value ≤ 0.05 was considered statistically significant. RESULTS
Drug Dev. Res.
ADMA IN ANTI-TNF TREATED PATIENTS
antagonists; longer studies on larger cohort would be necessary to confirm its possible role in assessing cardiovascular risk in RA patients.
ACKNOWLEDGMENT
Editorial assistance was provided by Mary Hines on behalf of HPS—Health Publishing and Services Srl and funded by Pfizer Italia. REFERENCES Angel K, Provan SA, Mowinckel P, Seljeflot I, Kvien TK, Atar D. 2012. The L-arginine/asymmetric dimethylarginine ratio is improved by anti-tumor necrosis factor-α therapy in inflammatory arthropathies. Associations with aortic stiffness. Atherosclerosis 225:160–165. Di Franco M, Spinelli FR, Metere A, Gerardi MC, Conti V, Boccalini F, Iannuccelli C, Ciciarello F, Agati L, Valesini G. 2012. Serum levels of asymmetric dimethylarginine and apelin as potential markers of vascular endothelial dysfunction in early rheumatoid arthritis. Mediators Inflamm 2012:347268. doi: 10.1155/2012/ 347268. Sandoo A, Dimitroulas T, Toms TE, Hodson J, Veldhuijzen van Zanten JJ, Smith JP, Kitas GD. 2012a. Clinical
S69
remission following treatment with tumour necrosis factor-alpha antagonists is not accompanied by changes in asymmetric dimethylarginine in patients with rheumatoid arthritis. Clin Biochem 45:1399–1403. Sandoo A, Dimitroulas T, Veldhuijzen van Zanten JJ, Smith JP, Metsios GS, Nightingale P, Stavropoulos-Kalinoglou A, Kitas GD. 2012b. Lack of association between asymmetric dimethylarginine and in vivo microvascular or macrovascular endothelial function in patients with rheumatoid arthritis. Clin Exp Rheumatol 30:388–396. Spinelli FR, Metere A, Barbati C, Pierdominici M, Iannuccelli C, Lucchino B, Ciciarello F, Agati L, Valesini G, Di Franco M. 2013. Effect of therapeutic inhibition of TNF on circulating endothelial progenitor cells in patients with rheumatoid arthritis. Mediators Inflamm 2013:537539. doi: 10.1155/2013/537539. Surdacki A, Martens-Lobenhoffer J, Wloch A, Marewicz E, Rakowski T, Wieczorek-Surdacka E, Dubiel JS, Pryjma J, Bode-Böger SM. 2007. Elevated plasma asymmetric dimethyl-Larginine levels are linked to endothelial progenitor cell depletion and carotid atherosclerosis in rheumatoid arthritis. Arthritis Rheum 56:809–819. Turiel M, Tomasoni L, Sitia S, Cicala S, Gianturco L, Ricci C, Atzeni F, De Gennaro Colonna V, Longhi M, Sarzi-Puttini P. 2010. Effects of long-term disease-modifying antirheumatic drugs on endothelial function in patients with early rheumatoid arthritis. Cardiovasc Ther 28:e53–e64.
Drug Dev. Res.
