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 Table of Contents  
Year : 2019  |  Volume : 14  |  Issue : 1  |  Page : 79-80

Use of coffee for alleviating methotrexate intolerance in rheumatic diseases

Department of Rheumatology, Joint Disease Clinic, Indian Spinal Injuries Centre, Vasant Kunj, New Delhi, India

Date of Web Publication14-Mar-2019

Correspondence Address:
Prof. Anand Narayan Malaviya
Department of Rheumatology, Joint Disease Clinic, Indian Spinal Injuries Centre, Sector-C, Vasant Kunj, New Delhi - 110 070
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_144_18

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How to cite this article:
Malaviya AN, Baghel SS, Verma S, Thakran R, Messi C. Use of coffee for alleviating methotrexate intolerance in rheumatic diseases. Indian J Rheumatol 2019;14:79-80

How to cite this URL:
Malaviya AN, Baghel SS, Verma S, Thakran R, Messi C. Use of coffee for alleviating methotrexate intolerance in rheumatic diseases. Indian J Rheumatol [serial online] 2019 [cited 2021 Oct 15];14:79-80. Available from:

Dear Editor,

Nonadherence to methotrexate (MTX) treatment in patients with rheumatoid arthritis (RA) (~1/3rd patients) has been a major challenge in daily practice.[1] This may also be true with the use of MTX in other systemic immunoinflammatory rheumatic diseases. A major component of MTX-nonadherence is the so-called “MTX-intolerance.” It is a constellation of nonspecific symptoms usually classified as “associative,” “anticipatory” or “behavioural.”[2],[3],[4] The cause of MTX intolerance is not known, but it could be related to increased intra- and extra-cellular levels of adenosine the main active anti-inflammatory molecule,[5] in particular through its action on adenosine receptors in the central nervous system,[6] which is largely due to antagonism of the action of endogenous adenosine at A1-and A2a-receptors in the central nervous system.[7] Based on this, mechanism Joel Kremer had suggested the use of “a few extra cups of coffee” to offset MTX-intolerance.[8] Taking the cue from that, a small study showed that a significant proportion of patients got relief with a schedule of coffee intake synchronized with MTX.[9] On similar lines, the present communication reports the effect of coffee intake for relieving MTX intolerance in a much larger number of patients.

The present study included a total of 410 patients; 396 (96.58%) with RA, 4 (0.97%) with spondyloarthritis, and others 10 (1.21%) others (undifferentiated connective tissue diseases, systemic lupus erythematosus Sjögren's). All the patients were receiving a weekly dose of MTX (maximum 25 mg/week). To improve the MTX-adherence, the standard recommendations were followed, i.e., splitting the oral MTX dose at >15 mg/week[10],[11] or switching to subcutaneous route,[12] and folate supplementation.[13] The severity of the intolerance was measured on a standard 0–100 numeric rating scale with 21 small circles from 0 to 100, at 5 unit increments. Of the 410 patients, 212 (51.7%) had minimal MTX intolerance not requiring any intervention (<10% intolerance), 198 (48.29%) patients had moderate-severe MTX intolerance (>10%). The latter was advised to take strong coffee synchronized with the MTX-dose as follows: Two cups early in the morning on the day of MTX, another two cups 2–3 h before the dose of MTX taken late in the evening. A 3rd dose of two cups was repeated the next morning with breakfast. This schedule was repeated every week synchronized with the weekly dose of MTX. In those with severe MTX-intolerance, palonosetron 0.5 mg tablets, 1 tablet 30 min before the MTX dose, repeated after 12 h, was advised. In addition, the patients were intensely counseled, explaining the importance of MTX in the treatment of their ailment and the proven efficacy of caffeine (in the form of coffee). The results were as follows [Table 1]:
Table 1: Response to coffee intake

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A total of 103 (52.02%) patients who had relief with coffee were fond of coffee so, continued taking it for >1 year. Another 63 (31.81%) patients who had relief with coffee intake felt no need of it after 3–6 months, so stopped taking it and remained free of symptoms. Nine patients (4.54%) did not like taking coffee, gave it up immediately and managed MTX-intolerance with a variety of home remedies (including chocolates [contains small amounts of caffeine], sweet candies, anti-emetics, and avoiding a few meals). Twenty-three (11.61%) patients did not try coffee for the various reasons, and somehow managed the problem of MTX-intolerance.

Thus, the above results tend to confirm an earlier observation that caffeine (in the form of coffee) reduces the intolerance to MTX and improves the compliance rate. It would now require a properly controlled double-blind trial using natural coffee in “the intervention arm” and decaffeinated coffee in the “placebo arm” to prove or disprove the efficacy of caffeine (as a natural coffee drink) in offsetting MTX intolerance.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Alarcón GS, Tracy IC, Blackburn WD Jr. Methotrexate in rheumatoid arthritis. Toxic effects as the major factor in limiting long-term treatment. Arthritis Rheum 1989;32:671-6.  Back to cited text no. 1
Ćalasan MB, van den Bosch OF, Creemers MC, Custers M, Heurkens AH, van Woerkom JM, et al. Prevalence of methotrexate intolerance in rheumatoid arthritis and psoriatic arthritis. Arthritis Res Ther 2013;15:R217.  Back to cited text no. 2
Bulatović M, Heijstek MW, Verkaaik M, van Dijkhuizen EH, Armbrust W, Hoppenreijs EP, et al. High prevalence of methotrexate intolerance in juvenile idiopathic arthritis: Development and validation of a methotrexate intolerance severity score. Arthritis Rheum 2011;63:2007-13.  Back to cited text no. 3
Fatimah N, Salim B, Nasim A, Hussain K, Gul H, Niazi S, et al. Frequency of methotrexate intolerance in rheumatoid arthritis patients using methotrexate intolerance severity score (MISS questionnaire). Clin Rheumatol 2016;35:1341-5.  Back to cited text no. 4
Tian H, Cronstein BN. Understanding the mechanisms of action of methotrexate: Implications for the treatment of rheumatoid arthritis. Bull NYU Hosp Jt Dis 2007;65:168-73.  Back to cited text no. 5
Ribeiro JA, Sebastião AM. Caffeine and adenosine. J Alzheimers Dis 2010;20 Suppl 1:S3-15.  Back to cited text no. 6
Daly JW, Shi D, Nikodijevic O, Jacobson KA. The role of adenosine receptors in the central action of caffeine. Pharmacopsychoecologia 1994;7:201-13.  Back to cited text no. 7
Bernstein S. 2014 ACR/ARHP Annual Meeting: Weinblatt ME, Kremer J. Methotrexate Use in Patients with RA. The Rheumatologist. Available from: [Last accessed on 2018 Jul 15].  Back to cited text no. 8
Malaviya AN. Methotrexate intolerance in the treatment of rheumatoid arthritis (RA): Effect of adding caffeine to the management regimen. Clin Rheumatol 2017;36:279-85.  Back to cited text no. 9
Hoekstra M, Haagsma C, Neef C, Proost J, Knuif A, van de Laar M, et al. Splitting high-dose oral methotrexate improves bioavailability: A pharmacokinetic study in patients with rheumatoid arthritis. J Rheumatol 2006;33:481-5.  Back to cited text no. 10
Mohamedali NK, Ravindran V. Splitting dose of methotrexate in the management of rheumatoid arthritis: Making a mountain out of a molehill? Indian J Rheumatol 2017;12:114-5.  Back to cited text no. 11
  [Full text]  
Braun J. Methotrexate: Optimizing the efficacy in rheumatoid arthritis. Ther Adv Musculoskelet Dis 2011;3:151-8.  Back to cited text no. 12
Hoekstra M, van de Laar MA, Bernelot Moens HJ, Kruijsen MW, Haagsma CJ. Longterm observational study of methotrexate use in a Dutch cohort of 1022 patients with rheumatoid arthritis. J Rheumatol 2003;30:2325-9.  Back to cited text no. 13


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