The Effect of Pulse Methylprednisolone Plus Theophylline Treatment on Clinical, Pulmonary and Inflammatory Markers in Relapses of Multiple Sclerosis

Abstract

Objective: The aim of this study was to evaluate whether there was a relationship between severity of multiple sclerosis (MS) exacerbation and pulmonary function test (PFT) and to determine the effect of theophylline, which was added to intravenous methylprednisolone, on serum Tumor Necrosis Factor (TNF)-alpha levels and clinical scores in MS relapses. Study Design: Double blind randomized controlled trial. Material and Methods: The baseline Expanded Disability Status Scale (EDSS) score was determined, PFT was performed and blood was taken for analysis of TNF- alpha in patients with MS exacerbation. Patients were randomly divided into two groups; group 1 received intravenous methylprednisolone+IV theophylline and group 2 intravenous methylprednisolone+placebo for 5 days. PFT and EDSS score were repeated and blood was taken for TNF-alpha on the 5th and 30th days of the treatment. Results: Twenty-four patients (14 female, 10 male) were included in the study. Mean age was 32.6±9, duration of disease was 5.4±4.2 years, number of exacerbations was 5±2. There was a significant correlation between the number of exacerbations and EDSS score (p=0.000, r=1). Restrictive PFT findings were detected in 8 and decrease in carbon monoxide diffusing capacity (DLCO) in 3 cases. In within-group analysis, EDSS score was found to be decreased on day 5 and still low on day 30 in the theophylline group (baseline 3±1.3; 5th day 2.4±1.6; 30th day 2±1.7). There was no statistically significant difference in the EDSS score of the placebo group (3±1.6; 2.8±1.7; 2.4±1.9 respectively). While serum TNF-alpha level was not changed in the placebo group, there was a non-significant decrease on day 5 and increase on day 30 in the theophylline group. There was no correlation between the clinical parameters, PFT and TNF-alpha level. Conclusion: There was no correlation between severity of MS and PFT findings. It is suggested that theophylline might be effective in MS exacerbations since it caused decreases in clinical scores; studies with longer treatment duration are needed to clarify its possible anti-inflammatory effect. Turkish Başlık: Metilprednisolona Eklenen Teofilin Tedavisinin Multipl Skleroz Atağında Klinik, Pulmoner ve İnflamatuvar Göstergelere Etkisi Anahtar Kelimeler: Multiple sclerosis, inflammation, theophylline, TNF-alpha Amaç: Bu çalışmanın amacı, multipl skleroz (MS) ataklarının şiddeti ile fonksiyon testleri (PFT) arasında ilişki olup olmadığını araştırmak ve metilprednisolon tedavisine eklenen teofilinin serum TNF- alpha düzeyine ve MS ataklarındaki klinik skorlara etkisini araştırmaktır. Gereç ve Yöntemler: MS atağı ile başvuran hastalarda başlangıç EDSS (Expanded Disability Status Scale) skorları saptandı, solunum fonksiyon testleri yapılarak TNF-alfa düzeyleri için kanlar alındı. Hastalar randomize olarak iki gruba ayrıldı.; grup 1 intravenöz methylprednisolon+IV theofilin ve grup 2 intravenöz methylprednisolon+plasebo tedavisini 5 gün süreyle aldı.. PFT ve EDSS skorları değerlendirmesi ve TNF-alfa düzeyi için kan alımı 5. ve 30. günlerde tekrarlandı. Bulgular: Yirmidört hasta (14 kadın, 10 erkek) çalışmaya alındı. Ortalama yaş 32.6±9 yıl, ortalama hastalık süresi 5.4±4.2 yıl, ortalama atak sayısı 5±2 idi. EDSS skoru ile atak sayısı arasında anlamlı bir korelasyon saptandı (p=0.000, r=1). PFT incelemesinde 8 hastada restriktif PFT bulguları ve 3 hastada karbon monoksid diffuzyon kapasitesinde azalma (DLCO) saptandı. Grup analizinde EDSS skorunun teofilin grubunda 5. günde azalma olduğu ve 30. günde bu azalmanın devam ettiği görüldü (başlangıç 3±1.3; 5 gün 2.4±1.6; 30. gün 2±1.7). Plasebo alan gruta ise EDSS skorlarında anlamlı farklılık gözlenmedi (sırasıyla 3±1.6; 2.8±1.7; 2.4±1.9). TNF-alfa düzeyi placebo grubunda değişiklik göstermezken teofilin grubunda 5. günde anlamlı olmayan azalma, 30. günde ise artış saptandı. Klinik parametreler, PFT ve TNF- alpha düzeyleri arasında anlamlı korelasyon saptanmadı. Sonuç: Multipl sklerozda hastalık şiddeti ile PFT bulguları arasında korelasyon saptanmadı. Olası antienflamatuvar etkileri ortaya çıkarmak için daha uzun süreli çalışmalara ihtiyaç olmasına karşın klinik skorlarda oluşturduğu azalma nedeniyle teofilin MS tedavisinde yararlı olabilir.

Keywords

• Multiple sclerosis, inflammation, theophylline, TNF-alpha

The Effect of Pulse Methylprednisolone Plus Theophylline Treatment on Clinical, Pulmonary and Inflammatory Markers in Relapses of Multiple Sclerosis

Öz

Kaynakça

1. Hauser SL, Oksenberg JR. The neurobiology of multiple sclerosis:genes, inflammation, and neurodegeneration. Neuron 2006;52:61-76. [CrossRef]
2. Peterson LK, Fujinami RS. Inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of multiple sclerosis. J Neuroimmunol 2007;184:37-44. [CrossRef]
3. Nicoletti F, Di Marco R, Patti F, Zaccone P, L’Episcopo MR, Reggio E, et al. Short-term treatment of relapsing remitting multiple sclerosis patients with interferon (IFN)-beta1B transiently increases the blood levels of interleukin (IL)-6, IL-10 and IFN-gamma without significantly modifying those of IL-1beta, IL-2, IL-4 and tumour necrosis factor-alpha. Cytokine 2000;12:682-7. [CrossRef]
4. Kassiotis G, Kollias G. Uncoupling the proinflammatory from the immunosuppressive properties of tumor necrosis factor (TNF) at the p55 TNF receptor level:implications for pathogenesis and therapy of autoimmune demyelination. J Exp Med 2001;193:427-34. [CrossRef]
5. Rieckmann P, Albrecht M, Kitze B, Weber T, Tumani H, Broocks A, et al. Tumor necrosis factor—a messenger RNA expression in patients with relapsing-remitting multiple sclerosis is associated with disease activity. Ann Neurol 1995;37:82-8. [CrossRef]
6. Ozenci V, Kouwenhoven M, Huang YM, Kivisäkk P, Link H. Multiple sclerosis is associated with an imbalance between tumour necrosis factor-alpha (TNF-alpha)- and IL-10-secreting blood cells that is corrected by interferon-beta (IFN-beta) treatment. Clin Exp Immunol 2000;120:147-53. [CrossRef]
7. Yoshimura T, Nagao T, Nakao T, Watanabe S, Usami E, Kobayashi J, et al. Modulation of Th1- and Th2-like cytokine production from mitogen-stimulated human peripheral blood mononuclear cells by phosphodiesterase inhibitors. Gen Pharmacol 1998;30:175-80. [CrossRef]
8. Yoshikawa M, Suzumura A, Tamaru T, Takayanagi T, Sawada M. Effects of phosphodiesterase inhibitors on cytokine production by microglia. Mult Scler 1999;5:126-33. [CrossRef]

9. Moore CS, Earl N, Frenette R, Styhler A, Mancini JA, Nicholson DW, et al. Peripheral phosphodiesterase 4 inhibition produced by 4-[2-(3,4-Bis-difluoromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl]-3-methylpyridine1-oxide (L-826,141) prevents experimental autoimmune encephalomyelitis. J Pharmacol Exp Ther 2006;319:63-72. [CrossRef]
10. Navikas V, Matusevicius D, Söderström M, Pirskanen R, Fredrikson S, Link H. The phosphodiesterase i.v. inhibitor rolipram in vitro reduces the numbers of MBP-reactive IFN-gamma and TNFalpha mRNA expressing blood mononuclear cells in patients with multiple sclerosis. Clin Neuropharmacol 1998;21:236-44.
11. Dinter H. Phosphodiesterase type 4 inhibitors:potential in the treatment of multiple sclerosis? Biodrugs 2000;13:87-94. [CrossRef]
12. Rieckmann P, Weber F, Günther A, Martin S, Bitsch A, Broocks A, et al. Pentoxifylline, a phosphodiesterase inhibitor, induces immune deviation in patients with multiple sclerosis. J Neuroimmunol 1996;64:193-200. [CrossRef]
13. Feng J, Misu T, Fujihara K, Sakoda S, Nakatsuji Y, Fukaura H, et al. Ibudilast, a nonselective phosphodiesterase inhibitor, regulates Th1/Th2 balance and NKT cell subset in multiple sclerosis. Mult Scler 2004;10:494-8. [CrossRef]
14. Suzumura A, Nakamuro T, Tamaru T, Takayanagi T. Drop in relapse rate of MS by combination therapy of three different phosphodiesterase inhibitors. Mult Scler 2000;6:56-8. [CrossRef]
15. Boswell-Smith V, Spina D, Page CP. Phosphodiesterase inhibitors. Br J Pharmacol 2006;147:252-7. [CrossRef]
16. Anderson M. The properties of aminophylline. Emerg Nurse 2007;15:24-7.
17. Yıldırım E, Yıldız F, Özkara SK, Başyiğit I, Boyacı H, Ilgazlı A. Effects of different combined bronchodilator therapies on airway inflammation in COPD. Clin Drug Invest 2005;25:453-61. [CrossRef]
18. Barnes PJ. Theophylline:new perspectives for an old drug. Am J Respir Crit Care Med 2003;167:813-8. [CrossRef]
19. Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, et al. Diagnostic criteria for multiple sclerosis:2005 revisions to the “McDonald Criteria”. Ann Neurol 2005;58:840-6. [CrossRef]
20. Noseworthy JH. Treatment of relapses and relapsing remitting multiple sclerosis. In:McDonald WI, Noseworthy JH, (eds), Multiple sclerosis 2. Philadelphia:Butterworth-Heinemann;2003. pp.169-91. [CrossRef]
21. Sloka JS, Stefanelli M. The mechanism of action of methylprednisolone in the treatment of multiple sclerosis. Multiple Sclerosis 2005;11:425-32. [CrossRef]
22. Frohman EM, Shah A, Eggenberger E, Metz L, Zivadinov R, Stüve O. Corticosteroids for multiple sclerosis:I. Application for treating exacerbations. Neurotherapeutics 2007;4:618-26. [CrossRef]
23. Dastidar SG, Rajagopal D, Ray A. Therapeutic benefit of PDE4 inhibitors in inflammatory diseases. Curr Opin Investig Drugs 2007;8:364-72.
24. Sommer N, Martin R, McFarland HF, Quigley L, Cannella B, Raine CS, et al. Therapeutic potential of phosphodiesterase type 4 inhibition in chronic autoimmune demyelinating disease. J Neuroimmunol 1997;79:54-61. [CrossRef]
25. Rott O, Cash E, Fleischer B. Phosphodiesterase inhibitor pentoxifylline, a selective suppressor of T helper type 1- but not type 2-associated lymphokine production,prevents induction of experimental autoimmune encephalomyelitis in Lewis rats. Eur J Immunol 1993;23:1745-51. [CrossRef]
26. Altintas A, Demir T, Ikitimur HD, Yildirim N. Pulmonary function in multiple sclerosis without any respiratory complaints. Clin Neurol Neurosurg 2007;109:242-6. [CrossRef]