Pentoxifylline as Adjuvant Therapy to Etanercept in Patients with Moderately to Highly Active Rheumatoid Arthritis

Samer I. Mohammed^1, , Faiq I. Gorial² and Ibrahim A. Majeed¹

¹Department of Clinical Pharmacy, College of Pharmacy, University of Baghdad, Baghdad, Iraq

²Department of Medicine, College of Pharmacy, University of Baghdad, Baghdad, Iraq

Cite this paper:
Samer I. Mohammed, Faiq I. Gorial and Ibrahim A. Majeed. Pentoxifylline as Adjuvant Therapy to Etanercept in Patients with Moderately to Highly Active Rheumatoid Arthritis. American Journal of Pharmacological Sciences. 2013; 1(4):61-66. doi: 10.12691/ajps-1-4-4

Abstract

Objective: Rheumatoid arthritis (RA) is a common inflammatory disease associated with many extra-articular features. The aim of the study was to evaluate the effects of pentoxifylline (PTX) as adjuvant therapy to etanercept in moderately to highly active RA. Methods: A single center randomized double-blind placebo-controlled trial of 8 weeks duration was performed. Disease activity was measured via calculating the disease activity score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR) and by simplified disease activity score in 28 joints using hsCRP (SDAI-CRP). 40 Patients who were using etanercept (ETN) were randomly allocated to receive each day either pentoxifylline 400mg tablet twice daily or capsules prefilled with glucose as placebo also twice daily and were evaluated at baseline and at week 8 for clinical and hematological parameters. Results: Tumor necrosis factor (TNF), high sensitive C-reactive protein (hsCRP), duration of morning stiffness, and cardiovascular risk were significantly more reduced in pentoxifylline group than placebo group after 8weeks. Non significant changes were observed in clinical parameter like swelling joints counts (SJC),tender joints counts(TJC),visual analogue scale(VAS),evaluator global assessment (EGA),DAS28-ESR, SDAI-CRP and hematological parameter like hemoglobin (Hb) amount, erythrocyte sedimentation rate (ESR) and white blood cells (WBC) count between groups. Conclusion: PTX significantly decreased pro-inflammatory markers (TNF, hsCRP), duration of morning stiffness and cardiovascular risk. This suggests that pentoxifylline may be a promising and useful strategy to reduce the systemic inflammation and cardiovascular morbidity and mortality observed in RA patients.

Keywords:
rheumatoid arthritis pentoxifylline disease activity

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References:

[1]	Christopher VT, Joan MB. Rheumatoid arthritis. In: Klippel JH, Stone JH, Crofford LJ, White PH, eds., Primer on rheumatic diseases, 13th ed., New York, USA, Springer science and business media 2008; 114-42.
[2]	Nurmohamed MT. Cardiovascular risk in rheumatoid arthritis. Autoimmun Rev 2009;8:663-7.
[3]	Avina-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, et al. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 2008; 59:1690-7.
[4]	Bradley JR. TNF-mediated inflammatory disease. J Pathol 2008; 214(2):149-60.
[5]	“P” Monographs; Pentoxifylline (Systemic). In: Group UDE, ed. USP DIR Drug Information for the Health Care Professional, 26th ed. Taunton, MA: Micromedex, 2006.
[6]	Bayat M, Chelcheraghi F, Piryaei A, RakhshanMet al. The effect of 30-day pretreatment with Pentoxyphylline on the survival of a random skin flap in the rat: an ultrastructural and biomechanical evaluation. Med SciMonit 6 (2006). 12(6): 201-207
[7]	Romy Beatriz, Christmann de Souza, André Regis Macedo ,Kátia Akemi Kuruma. Pentoxyphylline in association with vitamin E reduces cutaneous fibrosis in systemic sclerosis ClinRheumatol (2009) 28:1207-1212.
[8]	Maksymowych WP, Avina-Zubieta A, Luong MH, Russell AS. An open study of pentoxifylline in the treatment of severe refractory rheumatoid arthritis. J Rheumatol. 1995 Apr; 22(4):625-9.
[9]	Huizinga TW, Dijkmans BA, van der Velde EA, An open study of pentoxifyllineand thalidomide as adjuvant therapy in the treatment of rheumatoid arthritis. Annals of the Rheumatic Diseases, 1996; 55(11):833-836.
[10]	Ishii O, Yamada H, Ohya S, Moriuchi E, et al. Remission induction after pentoxifylline treatment in a patient with rheumatoid arthritis. Ryumachi, 1997 Dec; 37(6):810-5.
[11]	RaghdanZeki Al-Saad, SaadAbdulrahmanHussain and Intesar Tariq Numan. Dose-response Relationship of the Anti-inflammatory Activity of pentoxifylline.
[12]	Stojanov S, Kastner DL. Familial auto inflammatory diseases: genetics, pathogenesis and treatment. CurrOpinRheumatol 2005;17: 586-599.
[13]	Robert Landewe. Barriers to Effective Disease Activity Monitoring in Rheumatoid Arthritis – Clinical Practice and Implications for Treat-to-target Guidelines. European Musculoskeletal Review, 2011;6(2):88-93.
[14]	Mitra B, Panja M. High sensitive C-reactive protein: a novel biochemical markers and its role in coronary artery disease, J Assoc physicians India .2005 Jan; 53:25-32
[15]	So T, Lee SW, Croft M. Tumor necrosis factor/ tumor necrosis receptor family members that positively regulate immunity. Int J Hematol.2006; 83(1):1-11.
[16]	Soubrier M, Zerkak D, Gossec L, et al. Which variables best predict change in rheumatoid arthritis therapy in daily clinical practice? J Rheumatol 2006; 33(7):1243-6.
[17]	Usha P R, Naidu M U R, Datla R. Clinical Efficacy and Tolerability Evaluation of pentoxifylline in Rheumatoid Arthritis: A Double-Blind, Randomised, Placebo-Controlled Study. Clinical Drug Investigation, 2002; 22(5): 329-339.
[18]	Terence Starz. Tender Points in Rheumatoid Arthritis - How Do They Help Us? J Rheumatol 2012; 39(1):1-3.
[19]	Maksymowych WP, Avina-Zubieta A, Luong MH, Russell AS. An open study of pentoxifylline in the treatment of severe refractory rheumatoid arthritis. The Journal of Rheumatology .1995; 22(4):625-629.
[20]	Richard Charles John Campbell, Michael Batley , et al. The impact of disease activity, pain, disability and treatments on fatigue in established rheumatoid arthritis. April 2012, Volume 31, Issue 4, pp 717-722.
[21]	Steven M. Cohen. Pentoxifylline in the Treatment of Distal Diabetic Neuropathy. Angiology September 1991 vol. 42 no. 9 741-746.
[22]	Rohekar G, Pope J. Test-retest reliability of patient global assessment and physician global assessment in rheumatoid arthritis. J Rheumatol. 2009; 36(10):2178-82. Epub 2009 Sep 15.
[23]	Amos RS, Constable TJ, Crockson RA, et al. Rheumatoid arthritis: relation of serum C-reactive protein and erythrocyte sedimentation rates to radiographic changes. Br Med J. 1977; 1(6055): 195-7.
[24]	Yildirim K, Karatay S, Melikoglu MA, et al. Associations between Acute Phase Reactant Levels and Disease Activity Score (DAS28) in Patients with Rheumatoid Arthritis. Ann Clin Lab Sci. 2004;34(4):423-6.
[25]	Fernandes JL, de Oliveirab R T, R L Mamoni R L, et al. Pentoxifylline reduces pro-inflammatory and increases anti-inflammatory activity in patients with coronary artery disease—A randomized placebo-controlled study. Atherosclerosis. January 2008; 196 (1): 434-42.
[26]	Maiti R, Agrawal NK, Dash D, Pandey BL. Effect of pentoxifylline on inflammatory burden, oxidative stress and platelet aggregability in hypertensive type 2 diabetes mellitus patients .VasculPharmacol. 2007 Aug-Sep;47(2-3):118-24.
[27]	González-Espinoza L, Rojas-Campos E, Medina-Pérez M, et al. pentoxifylline decreases serum levels of tumor necrosis factor alpha, interleukin 6 and C-reactive protein in hemodialysis patients: results of a randomized double-blind, controlled clinical trial. Nephrol Dial Transplant. 2012 May; 27(5):2023-8.
[28]	Huizinga TW, Dijkmans BA, van der VeldeEA ,et al. An open study of pentoxifylline and thalidomide as adjuvant therapy in the treatment of rheumatoid arthritis .Ann Rheum Dis 1996; 55: 833-6.
[29]	Fiehn C, Kessler S, Müller K. Morning stiffness of the joints is the sole predictor of short-term response to glucocorticoid treatment in active rheumatoid arthritis (RA). Rheumatol Int. 2012 Dec; 32(12):4069-70.
[30]	Manole C, Cojocaru I M, Isabela S, CameliaDoinaVrabie, et al. Extra-articular manifestations in Rheumatoid Arthritis. Maedica (Buchar) 2010; 5(4):286-291.
[31]	Cimmino MA, Salvarani C, Macchioni P, Montecucco C, et al. Extra-articular manifestations in 587 Italian patients with rheumatoid arthritis. RheumatolInt 2000; 19(6):213-7.
[32]	Mendes JB, Campos PP, Rocha MA, Andrade SP. Cilostazol and pentoxifylline decrease angiogenesis, inflammation, and fibrosis in sponge-induced intraperitoneal adhesion in mice. Life Sci. 2009 Apr 10; 84(15-16):537-43.
[33]	Pasupathi P, Deepa M, Rani P, Sankar RR. Circulating lipid peroxidation, plasma and erythrocyte antioxidant status in patients with rheumatoid arthritis. Bangladesh Med Res Counc Bull. 2009 Aug; 35(2):57-62.
[34]	Ford ES. The metabolic syndrome and C-reactive protein, fibrinogen, and leukocyte count: findings from the Third National Health and Nutrition Examination Survey. Atherosclerosis 2003; 168(2):351-8.
[35]	Mohammadzadeh A, Heidari M, SoltanghoraeeH,et al. Evaluation of the effect of pentoxifylline on white blood cell count in serum and peritoneal fluid in female rats with endometriosis. J ObstetGynaecol Res. 2008 Jun; 34(3):307-13.
[36]	Lukasz Kozera, Jacqueline Andrews, Ann W Morgan. Differentiating True Soluble Biomarkers of Cardiovascular Risk From Surrogate Measures of Inflammation Rheumatol 2011; 50(11):1944-1954.
[37]	Fernandes JL, de Oliveirab R T, R L Mamoni R L, et al. pentoxifylline reduces pro-inflammatory and increases anti-inflammatory activity in patients with coronary artery disease-A randomized placebo-controlled study. Atherosclerosis. January 2008; 196 (1): 434-42.