LIVER FUNCTION CHANGES IN PATIENTS WITH SPONDYLOARTHRITIS TAKING NONSTEROIDAL ANTI-INFLAMMATORY DRUGS OVER A LONG PERIOD: RESULTS OF A 10-YEAR PROGRESS PROSPECTIVE STUDY

Objective: to assess liver function changes in patients with spondyloarthritis (SpA) taking NSAIDs regularly over a long period.

Patients and methods. The data obtained during a 10-year PROGRESS prospective single-center cohort study of functional status, activity, and comorbidity (including gastrointestinal tract diseases) in patients with SpA were analyzed. The data of 363 SpA patients receiving NSAIDs regularly over a long period and followed up for 10 years were also explored. The changes that had occurred over a decade in the liver enzyme levels, the number of discontinued NSAID treatments because of a persistent increase in liver enzyme levels, and the number of prescriptions of hepatoprotective agents were analyzed.

Results. For 10 years, 18 patients with SpA discontinued their NSAID intake due to elevated liver enzyme levels (≥3 times greater than the reference value); during that time, the same increase in enzyme levels was observed in 2 healthy individuals (χ2 =1.39; p=0.2). In the patients with SpA as compared to the healthy individuals, the relative risk of abnormal liver function was 1.19 (95% CI, 1.009–1.405); odds ratio was 2.9 (95% CI, 0.65–12.95). There was no increased risk for discontinuation of some NSAIDs, including nimesulide (χ2 =0.03, p=0.85), the frequency of using hepatoprotective drugs was proved to be highest for diclofenac sodium, ibuprofen, nimesulide, and ketoprofen.

Conclusion. The regular long-term (as long as 10 years) use of NSAIDs to treat SpA is associated with treatment discontinuation because of elevated enzyme levels in every 10 patients. The maximum rate of discontinuation of NSAIDs due to a persistent increase in liver enzyme levels is observed 6–8 years after their regular use, so long-term NSAID therapy requires continuous monitoring of hepatic safety. The longterm intake of nimesulide, as compared with other NSAIDs, is shown to be unassociated with the higher rate of its discontinuation because of worse liver function. Hepatoprotectors are less frequently prescribed to patients taking nimesulide than to those receiving diclofenac sodium or ibuprofen and more frequently to patients using meloxicam. In most cases, prescribing hepatoprotective agents to patients receiving NSAIDs does not require discontinuation of anti-inflammatory therapy. 

1. Smolen JS, Braun J, Dougados M, et al. Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of an international task force. Ann Rheum Dis. 2014 Jan;73(1): 6-16. doi:10.1136/annrheumdis-2013-203419. Epub 2013 Jun 8.

2. Каратеев АЕ, Эрдес ШФ. Применение нестероидных противовоспалительных препаратов при анкилозирующем спондилите: долго и упорно! Терапевтический архив. 2014;86(11):123-7. [Karateev AE, Erdes ShF. The use of nonsteroidal antiinflammatory drugs in ankylosing spondylitis: long and hard! Terapevticheskii arkhiv. 2014; 86(11):123-7. (In Russ.)].

3. Гайдукова ИЗ, Ребров АП, Оттева ЭН и др. Применение нестероидных противовоспалительных препаратов для лечения аксиальных спондилоартритов, включая анкилозирующий спондилит, мониторинг эффективности и безопасности (проект рекомендации группы экспертов по диагностике и лечению спондилоартритов). Научно-практическая ревматология. 2016;54(Прил. 1):67-74. [Gaidukova IZ, Rebrov AP, Otteva EN, et al. Use of nonsteroidal anti-inflammatory drugs for the treatment of axial spondyloarthritis, including ankylosing spondylitis, monitoring their efficacy and safety (draft guidelines of the expert spondyloarthritis diagnosis and treatment group). Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2016;54(S1):67-74. (In Russ.)]. DOI:10.14412/1995-4484-2016-1S-67-74

4. Donati M, Conforti A, Lenti MC, et al. Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug-induced liver injury case-control study in Italy. Br J Clin Pharmacol. 2016 Jul;82(1):238-48. doi:10.1111/bcp.12938. Epub 2016 Apr 27.

5. Абдулганиева ДИ. Особенности ведения больных с НПВП-индуцированной гастропатией. Клинические перспективы гастроэнтерологии, гепатологии. 2011;(6):23-9. [Abdulganieva DI. Features of patients with NSAIDs-induced gastropathy. Klinicheskie perspektivy gastroenterologii, gepatologii. 2011;(6):23-9. (In Russ.)]

6. Bessone F. Non-steroidal anti-inflammatory drugs: What is the actual risk of liver damage? World J Gastroenterol. 2010 Dec 7;16(45): 5651-61.

7. Van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 1984 Apr;27(4):361-8.

8. Taylor W, Gladman D, Helliwell P, et al. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum. 2006 Aug;54(8):2665-73.

9. Lukas C, Landewe R, Sieper J, et al. Development of an ASAS-endorsed disease activity score (ASDAS) in patients with ankylosing spondylitis. Ann Rheum Dis. 2009 Jan;68(1):18-24. doi:10.1136/ard.2008.094870. Epub 2008 Jul 14.

10. Garrett S, Jenkinson T, Kennedy LG, et al. New approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol. 1994 Dec;21(12):2286-91.

11. Wells G, Becker JC, Teng J, et al. Validation of the 28-joint Disease Activity Score (DAS28) and European League Against Rheumatism response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis. 2009 Jun;68(6):954-60. doi:10.1136/ard.2007.084459. Epub 2008 May 19.

12. Реброва ОЮ. Статистический анализ медицинских данных. Москва: Медиасфера; 2002. [Rebrova OYu. Statisticheskii analiz meditsinskikh dannykh [Statistical analysis of medical data]. Moscow: Mediasfera; 2002.]

13. Ребров АП, Гайдукова ИЗ, Полянская ОГ, Спицина МЮ. Длительное применение нимесулида в реальной клинической практике: вопросы безопасности. Русский медицинский журнал. 2013;21(9):433-7. [Rebrov AP, Gaidukova IZ, Polyanskaya OG, Spitsina MYu. Prolonged use of nimesulide in real clinical practice: security issues. Russkii meditsinskii zhurnal. 2013;21(9):433-7. (In Russ.)].

14. Jessurun N, van Puijenbroek E. Relationship between structural alerts in NSAIDs and idiosyncratic hepatotoxicity: an analysis of spontaneous report data from the WHO database. Drug Saf. 2015 May;38(5): 511-5. doi:10.1007/s40264-015-0282-z.

15. Tujios S, Fontana RJ. Mechanisms of drug-induced liver injury: from bedside to bench. Nat Rev Gastroenterol Hepatol. 2011 Apr;8(4):202-11. doi:10.1038/nrgastro.2011.22. Epub 2011 Mar 8.

16. Agundez JA, Lucena MI, Martinez C, et al. Assessment of nonsteroidal anti-inflammatory drug-induced hepatotoxicity. Expert Opin Drug Metab Toxicol. 2011 Jul;7(7): 817-28. doi:10.1517/17425255.2011.574613. Epub 2011 Apr 8.

17. Bessone F, Hernandez N, Roma MG, et al. Hepatotoxicity induced by coxibs: how concerned should we be? Expert Opin Drug Saf. 2016 Nov;15(11):1463-1475. Epub 2016 Aug 26.

18. Каратеев АЕ. Модификация традиционных НПВП как метод повышения их безопасности и удобства применения. Русский медицинский журнал. 2015;23(7):392-6. [Karateev AE. Modification of traditional NSAIDs as a method to increase their safety and ease of use. Russkii meditsinskii zhurnal. 2015;23(7):392-6. (In Russ.)].

19. Jaeschke H, Williams CD, McGill MR. Caveats of using acetaminophen hepatotoxicity models for natural product testing. Toxicol Lett. 2012 Nov 23;215(1):40-1. doi:10.1016/j.toxlet.2012.09.023. Epub 2012 Oct 4.