Methotrexate (MTX) and Caffeine

 

Recently I had written a blog post on Methotrexate (MTX) and Caffeine in German [1]. This is an offspring and not merely a translation of this article.

Klaus Krüger, a German Professor of Rheumatology based in Munich, told in an interview for BDI aktuell [a publication of the BDI, which stands for Berufsverband Deutscher Internisten - Professional Association of German Internists], that even though MTX is generally well tolerated, nausea is a common side effect. He mentioned coffee being able to alleviate this side effect.

As I've known Dr. Krüger for at least 15 years, I thought to look for the study not mentioned in BDI aktuell. He monitores, condenses and lectures on studies and won't give this kind of information without having read a study. And I've found a likely study by Dr. Anand Narayan Malaviya [2].

In his study, A.N. Malaviya examined the effect of caffeine on the symptoms of methotrexate intolerance in patients with rheumatoid arthritis. Caffeine (coffee / dark chocolate) relieved the symptoms of MTX intolerance in the majority of patients.

Let's look at some details of this study, which looked at 855 patients treated with methotrexate. 313 patiens did not have any MTX intolerance, leaving 542 patients with some degree of MTX intolerance. In 422 patients MTX intolerance did not require any intervention. 120 (14 % of the initial 855) patients had 'moderate' or 'severe' MTX intolerance. “Among these, 55 % had complete relief of symptoms and were able to continue taking the advised dose of MTX; 13.3 % had partial improvement and continued taking MTX but only with antiemetics; 7.5 % were minimally better but were somehow managing; 10 % were complete caffeine failure without any relief; 14.2 % did not like caffeine (coffee or dark chocolate) and did not want to take it.” Tea, not coffee is mostly drunk in the northern part of India.

I myself like coffee and dark chocolate, but I would have no hesitation in recommending tea drinkers to give it a try; however, precisely that was not tested. Dark chocolate and coffee contain slightly more caffeine when compared to tea. However, it is more important that the polyphenols in tea (e.g. epigallocatechin gallate) bind the caffeine and only release it in the intestine, which renders the kinetics different from those of coffee, for example. It may well be the case that the faster absorption of caffeine from coffee is more effective at preventing methotrexate nausea.

I've always been concerned about strategies to keep patients on MTX as it is very effective in itself or as a co-medication [3]. Give coffee a chance!


Links and annotations:
[1] https://rheumatologe.blogspot.com/2021/07/methotrexat-mtx-und-kaffee.html – more annotations and links to texts in German there
[2] Malaviya AN. Methotrexate intolerance in the treatment of rheumatoid arthritis (RA): effect of adding caffeine to the management regimen. Clin Rheumatol. 2017 Feb;36(2):279-285. doi: 10.1007/s10067-016-3398-3. Epub 2016 Sep 6. PMID: 27596742.  https://pubmed.ncbi.nlm.nih.gov/27596742/
[3] https://rheumatologe.blogspot.com/2015/05/methotrexate-and-hydrating.html

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CR6086 at the 2020 EULAR Online Meeting

When I've checked for novel drug candidates, I've stumpled on CR6086. Somehow the number reminded me of Intel's 8086-series and others might associate Nokia's 6086-series. But CR6086 is an EP4 [a prostanoid receptor] receptor antagonist, which “may improve the response of tumours to immuno-oncology therapies, e.g. immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 drugs” [1]. CR6086 wouldn't be the first drug that proves useful not only in oncology but also in rheumatology.

There had been a study at the 2016 ACR/ARHP Annual Meeting [2], in which the authors concluded: "CR6086 was safe up to the maximum tested dose of 300 mg."

Adis Insight [3] has data up to March 28^th 2020 (“No recent reports of development identified for phase-I development in Rheumatoid-arthritis(In volunteers) in Italy (PO)”), and mentions two dates for study NCT03163966 in the Czech Republic (3^rd November 2017) and the preliminary data presented at the 2018 ACR/ARHP Annual Meeting as CREATIVE trial data [4]. Now there is data on study NCT03163966.

K. Pavelka and colleagues presented the following study [5] at the 2020 EULAR Online Meetin: „AB0360 EFFICACY AND SAFETY OF THE PROSTAGLANDIN EP4 RECEPTOR ANTAGONIST CR6086 ADDED TO METHOTREXATE IN DMARD-NAIVE EARLY RA PATIENTS: A PHASE 2 RANDOMIZED CONTROLLED TRIAL“. The authors concluded: „There was no benefit demonstrated for CR6086 added to MTX in the study cohort as a whole. However, in a post-hoc analysis, enhanced responses were observed with CR6086 90mg bid added to MTX in patients >6 months disease duration. This generated the hypothesis that addition of CR6086 90mg bid may benefit in RA patients initiating MTX after the window of opportunity, to be tested in further studies.“ There aren't any irregularities in methods and results. Even without post-hoc analysis there's a difference for MTX with or without CR6086. But 'll show you, why I habor doubts.

I've looked at a study by G. Caselli and colleagues [6]: „Pharmacological Characterisation of CR6086, a Potent Prostaglandin E2 Receptor 4 Antagonist, as a New Potential Disease-Modifying Anti-Rheumatic Drug“. In results the authors tell us: „ In models of human immune cells in culture, CR6086 reduced key cytokine players of RA (IL-6 and VEGF expression in macrophages, IL-23 release from dendritic cells, IL-17 release from Th17 cells). In the CIA model of RA in rats and mice, CR6086 significantly improved all features of arthritis: severity, histology, inflammation and pain. In rats, CR6086 was better than the selective cyclooxygenase-2 inhibitor rofecoxib and at least as effective as the Janus kinase inhibitor tofacitinib.“ But there's no hint to what happens to MTX if combined with CR6086.

J.M. Kremer and R.A. Hamilton published in 1995 [7]: „The effects of nonsteroidal antiinflammatory drugs on methotrexate (MTX) pharmacokinetics: impairment of renal clearance of MTX at weekly maintenance doses but not at 7.5 mg“. So NSAIDs alter renal clearance of MTX at normal weekly maintenance doses. In a more recent study (2011) Yuichi Uwai and colleagues [8] showed in their meta-analysis „that NSAIDs increase blood levels of methotrexate by influencing renal excretion of the antifolate“.

Now, CR6086 isn't an NSAID, but it may (ot may not) effect the renal clearance of MTX.

K. Pavelka and colleagues stated the „hypothesis that addition of CR6086 90mg bid may benefit in RA patients initiating MTX after the window of opportunity“. I have my doubts, but I agree that this has to be tested in further studies. Hopefully, K. Pavelka and colleagues are right.

Links and References:

[1] http://www.rottapharmbiotech.com/cr6086-for-immuno-oncology/

[2] Persiani S, Manzotti C, Vitalini C, Giacovelli G, Girolami F, D'Amato M, Caselli G, Rovati LC. a First-in-Human Study of CR6086, a New Potent EP4 Prostanoid Receptor Antagonist, Demonstrates Good Safety and Tolerability at Therapeutically Relevant Exposures [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/a-first-in-human-study-of-cr6086-a-new-potent-ep4-prostanoid-receptor-antagonist-demonstrates-good-safety-and-tolerability-at-therapeutically-relevant-exposures/. Accessed July 2, 2020.

[3] https://adisinsight.springer.com/drugs/800048940

[4] Vitalini C, Barbetta B, Giacovelli G, Brambilla N, D'Amato M, Girolami F, Rovati LC. Acr Hybrid Analysis: Blinded Data from the Ongoing Phase IIb Trial with the EP4 Receptor Antagonist CR6086 in DMARD-Naïve Patients with Early Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/acr-hybrid-analysis-blinded-data-from-the-ongoing-phase-iib-trial-with-the-ep4-receptor-antagonist-cr6086-in-dmard-naive-patients-with-early-rheumatoid-arthritis/. Accessed July 3, 2020.

[5] K. Pavelka1, I. D. Delina2, M. Mazur3, M. D’amato4, G. Giacovelli4, F. Girolami4, M. Krogulec5, R. Ostgard6, A. R. Bihlet7, O. Kubassova8, L. Rovati4,9, P. C. Taylor10. AB0360 EFFICACY AND SAFETY OF THE PROSTAGLANDIN EP4 RECEPTOR ANTAGONIST CR6086 ADDED TO METHOTREXATE IN DMARD-NAIVE EARLY RA PATIENTS: A PHASE 2 RANDOMIZED CONTROLLED TRIAL. DOI: 10.1136/annrheumdis-2020-eular.5636

[6] Caselli G, Bonazzi A, Lanza M, et al. Pharmacological characterisation of CR6086, a potent prostaglandin E₂ receptor 4 antagonist, as a new potential disease-modifying anti-rheumatic drug. Arthritis Res Ther. 2018;20(1):39. Published 2018 Mar 1. doi:10.1186/s13075-018-1537-8

https://pubmed.ncbi.nlm.nih.gov/29490676/

[7] Kremer JM, Hamilton RA. The effects of nonsteroidal antiinflammatory drugs on methotrexate (MTX) pharmacokinetics: impairment of renal clearance of MTX at weekly maintenance doses but not at 7.5 mg. J Rheumatol. 1995;22(11):2072-2077. https://pubmed.ncbi.nlm.nih.gov/8596147/

[8] Uwai Y, Suzuki R, Iwamoto K. Yakugaku Zasshi. 2011;131(5):853-861. doi:10.1248/yakushi.131.853 https://pubmed.ncbi.nlm.nih.gov/21532282/

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Methotrexate as the Anchor Drug for Rheumatoid Arthritis

Methotrexate (MTX) had been developed in 1951, but only in 1985 MTX had been introduced into rheumatology. MTX soon became an anchor drug in the treatment of rheumatoid arthritis. Still there are other indications, in which we aren’t so sure if it is as successful as in rheumatoid arthritis. If you look at effectiveness, tolerability, and cost, you will have a hard time finding an equal drug. EULAR and ACR guidelines have MTX as first line therapy (without the need of combination – combination comes later and MTX is very useful in any combination). An article by Walter Alexander: „Methotrexate Underutilized in RA“ stimulated this blogpost.

Oral MTX is widely used, but subcutaneous MTX offers advantages. Yet even oral MTX is underutilized. J.R. O’Dell, who introduced triple combination therapy (MTX + SSZ + HCQ), and colleagues looked at different strategies using MTX (2). They concluded, that “initial MTX monotherapy with the option to step-up to combination therapy results in similar outcomes to immediate combination therapy”.

How does MTX work? Good question! There are five proposed mechanisms of action: anti-inflammatory, apoptosis, cytokines, cytostatic, and immunosuppressive – please have a look at the link for details (3).

There’s a study by G.S. Hazlewood and colleagues addressing the issue of subcutaneous vs. oral MTX (4). They looked at 666 patients (417 oral MTX, 249 subcutaneous MTX) [OT: N=666 – honi soit qui mal y pense. Rev. 13:18]. They concluded: “nitial treatment with subcutaneous MTX was associated with lower rates of treatment changes, no difference in toxicity and some improvements in disease control versus oral MTX over the first year in patients with ERA [Early Rheumatoid Arthritis].”

M.H. Schiff and colleagues published a head-to-head study on oral and SC MTX (5): “Head-to-head, randomised, crossover study of oral versus subcutaneous methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at doses ≥15 mg may be overcome with subcutaneous administration.” Their conclusions: “Unlike oral MTX, the systemic exposure of SC MTX did not plateau over the doses studied, particularly at doses ≥15 mg/week. In this study, higher systemic MTX exposure was not associated with increases in AEs. Patients with an inadequate clinical response to oral MTX may benefit from higher drug exposure by switching to SC MTX.” The article can be freely accessed, so you should have a look at the graph. But I think that SC MTX also plateaus but only at doses above 30 mg per week, which is supported by the slower ascend of the curve between 20 and 25 mg per week.

Take home messages:

·         MTX is a drug with excellent effectiveness and tolerability

·         About the mode of action quite a lot, but not all is known

·         Oral MTX works good till 15 mg per week, but has no advantage above this dosage

·         SC MTX works better and the dosage might be increased up to 25 mg per week

·         MTX is good combination partner

·         It remains unclear, why this anchor drug still is underutilized

Links:

(1) http://www.rheumatologynetwork.com/news/methotrexate-underutilized-ra?GUID=71CAAEF6-94A2-4616-B379-17C18CF13750&XGUID=&rememberme=1&ts=12012017

(2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4768726/ (full article available)

(3) http://rheumatologe.blogspot.de/2014/01/methotrexate-mode-of-action.html

(4) https://www.ncbi.nlm.nih.gov/pubmed/25979945

(5) https://www.ncbi.nlm.nih.gov/pubmed/24728329

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Methotrexate in Knee Osteoarthritis Revisited

There had been an article on methotrexate (MTX) in knee osteoarthritis (OA), which had been published in 2014. As it had been a double-blind, randomized controlled trial, I had had a closer look at the article back then (1). Abou-Raya and colleagues submitted and published: "Methotrexate in the treatment of symptomatic knee osteoarthritis: randomised placebo-controlled trial". I had been critical about the article and the results of the study. Today I revisited the article, as I wanted to know more on subsequent trials.

I was quite surprised that the article had been retracted. The Annals of Rheumatic diseases discussed the decision (2). They listed eight points of “great concern”. And the Investigation Committee’s report concluded: “There is an unintentional mistake in the statistical process, with errors in collection of data in some groups”.

Let’s hope that Sarah R. Kingsbury and colleagues fare better with their study: “Pain reduction with oral methotrexate in knee osteoarthritis, a pragmatic phase III trial of treatment effectiveness (PROMOTE): study protocol for a randomized controlled trial”. (3) Discussion: “The PROMOTE trial is designed to examine whether MTX is an effective analgesic treatment for OA. The MRI substudy will address the relationship between synovitis and symptom change. This will potentially provide a much needed new treatment for knee OA.” The follow-up should have been completed by December 2016, so we should get results during 2017. Allow me already to voice some doubts. MTX is an immunosuppressant and any reduction of pain is due to this mode of action (4). Chronic low-grade inflammation is thought as a major driver of joint degradation in osteoarthritis (5); and it's unclear if MTX suppresses this kind of inflammation. “Despite the clear role of inflammation in OA, recent trials of potent anti-inflammatory therapies, including use of systemic and intra-articular biologic agents to inhibit TNFα and IL-1β, proved disappointing [Hunter, 2008].” 

But let’s wait for the publication of the PROMOTE study, which I’ve just misspelled as PRO MORTE. 

Links:

http://rheumatologe.blogspot.de/2015/05/methotrexate-in-knee-osteoarthritis.html (1)

http://ard.bmj.com/content/early/2016/06/08/annrheumdis-2013-204856 (2)

http://rheumatologe.blogspot.de/2015/05/methotrexate-in-knee-osteoarthritis.html (3)

http://rheumatologe.blogspot.de/2014/01/methotrexate-mode-of-action.html (4)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638313/ (5)

What’s in the names of drugs in rheumatology?

As soon as I see drug names, I associate something. What’s in the names of drugs in rheumatology? I’ll show you some associations. Maybe you have even more or others; feel free to post these. Drugs in rheumatology doesn’t mean that only approved drugs will appear here.

Abatacept – close to abattoir.

Arava – do you also see the colorful parrot? And Ava like Ava Gardner. Some patients call the drug avara, which is close to awaara (awaara hoon, Hindi for I am a vagabond).

Celebrex - Oh, a celebration!

Cimzia – like the Italian female name Cinzia. But as the drug was introduced to Germany we thought more of Zimtzicke (bitchy cow).

Etanercept – too bad, eta are the outcasts in feudal Japanese society. Eta (穢多) means abundance of filth.

Guselkumab – looks a bit gruselig (creepy, gruesome). Or even like Gruselkabinett (chamber of horrors).

Humira – human, but the second half ira is Latin for wrath.

Lantarel – nobody could have expected, that later there’ll be a Lana del Rey. On the other hand lanta is Finnish for manure. Oops!

Leflunomide – Le flu comes to my mind, but in French it’s la gripe for flu.

Methotrexate – luckily people abbreviated methotrexate to MTX and not to Meth.

Orencia – I have called it Horrencia because of the high price and the German word horrend (horrendous). There also lies horror in the word.

Remicade – there is a tie or draw in the word because of remis.

RoActemra – in Germany tocilizumab is marketed as RoActemra and not as Actemra. Ro(che) acts on RA (rheumatoid arthritis). Good choice, but a but – ro in German means raw (roh).

Simponi – looks like symphony. The Supremes sang: “… I hear a symphony”. And that’s what you get, when you search on Twitter for instance, Indonesian or Malayan kids talking about simponi (songs, symphony). There’s even an Indonesian Pop band with the name Simponi.

… might be continued.