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  1. A. Fehr1,
  2. F. El Noby2,
  3. N. Fathi3,
  4. R. Lotfy2
  1. 1Faculty of Medicine, Helwan University, Rheumatology & Physical Medicine Department, Helwan, Egypt
  2. 2Faculty of Medicine, Aswan University, Rheumatology Department, Aswan, Egypt
  3. 3Assuit Faculty of Medicine, Assuit, Egypt


Background: Rheumatoid arthritis is one of common form of chronic inflammatory arthritis. Methotrexate has remained anchor treatment because of its potent efficacy1. Intolerance to Methotrexate is a common cause of non-compliance2&3.

Objectives: To investigate the effect of adding caffeine orally as Methylxanthines (Caffeine), act as adenosine receptor antagonists4 to reduce symptoms of moderate to severe methotrexate intolerance in patients with Rheumatoid Arthritis5.

Methods: A prospective, randomized controlled study conducted at Aswan University Hospital, Egypt from Jan 2018 till may 2019. Sixty patients with Rheumatoid arthritis who have had experienced moderate to severe methotrexate intolerance was enrolled in the study. The methotrexate intolerance severity score (MISS)6was evaluated at base line before initiation of study then at the next three months consecutively. Patients were randomly assigned by closed envelope method into 2 groups each containing 30 patients: Group (A); 30 patients was prescribed caffeine (coffee or dark chocolate) as an antidote to methotrexate intolerance7. Group (B); 30 matched patients acted as control group that included who will continue methotrexate regimen without addition of any extra caffeine.

Results: Twenty four patients (80%) at time three follow up visit showed full improvement of symptoms of methotrexate-intolerance compared to ten patients (33.3%) at 2nd month follow up visit and seven patients (23%) at 1st month follow up visit with statistically significant difference all over the study period (P=0.005). half of study group patients discontinued anti-emetic and other drugs while none in control group did.

Conclusion: Adding caffeine to management regimen can reduce the symptoms of severe methotrexate-intolerance in Rheumatoid Arthritis patients.

References: [1]Friedman, B., & Cronstein, B. (2019). Methotrexate Mechanism in Treatment of Rheumatoid Arthritis. Joint Bone Spine, 86(3):301-307

[2]Wang, W., Zhou, H., & Liu, L. (2018). Side effects of methotrexate therapy for rheumatoid arthritis: a systematic review. European journal of medicinal chemistry. Volume 158, 502-516

[3]Bulatović, M., Heijstek, M. W., Verkaaik, M., van Dijkhuizen, E. P., Armbrust, W., Hoppenreijs, E. P., ... & Rademaker, C. M. (2011). High prevalence of methotrexate intolerance in juvenile idiopathic arthritis: development and validation of a methotrexate intolerance severity score. Arthritis & Rheumatism, 63(7), 2007-2013.

[4]Malaviya, A., Baghel, S., Verma, S., Thakran, R., & Messi, C. (2019). Use of coffee for alleviating methotrexate intolerance in rheumatic diseases. Indian Journal of Rheumatology, 14(1), 79-79.

[5]Ribeiro, J. A., & Sebastiao, A. M. (2010). Caffeine and adenosine. Journal of Alzheimer’s Disease, 20(s1), S3-S15.

[6]Fatimah, N., Salim, B., Nasim, A., Hussain, K., Gul, H., & Niazi, S. (2016). Frequency of methotrexate intolerance in rheumatoid arthritis patients using methotrexate intolerance severity score (MISS questionnaire). Clinical rheumatology, 35(5), 1341-1345.

[7]Malaviya, A. N. (2017). Methotrexate intolerance in the treatment of rheumatoid arthritis (RA): effect of adding caffeine to the management regimen. Clinical rheumatology, 36(2), 279-285.

Disclosure of Interests: None declared

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