Dear All,

‘Suppress rheumatoid arthritis early and leave the pyramid for the Egyptians’ was the title of the 1990 paper by the father of the modern-day DMARD-combination therapy for the treatment of rheumatoid arthritis (RA) - Daniel J. McCarty. Since those seminal publications by the great American rheumatologist from Milwaukie, several groups of rheumatologists around the world took upon themselves the responsibility of proving and establishing aggressive DMARD combination treatment of RA as their mission. The leaders were the Finnish rheumatologists, whose first publication, the now-famous FinRACo-trial (first published in 2002), showed the high efficacy of DMARD combination in RA. The landmark papers by James O’Dell and colleagues in 1995, the fountainhead of the present day famous TEAR study, firmly established the high efficacy, safety, and cost-effectiveness of the triple-DMARD treatment of RA. It has been accepted as the definition of the triple-DMARD combination treatment in the 2015 American College of Rheumatology (ACR) treatment recommendations. Soon, several groups around the world engaged themselves in further confirmation of the efficacy of this treatment approach. Of course, with rapid advancements in disease assessment methodologies and other research tools, including more robust statistical methods, their results became more reliable with the grade of evidence becoming higher and higher. COBRA, CIMESTRA, CAMERA, and their follow-up publications and the famous BeSt study left no doubts about the high efficacy, safety, and cost- effectiveness of the early aggressive DMARD combination treatment in RA. But there have been distractors; ‘monotherapy, especially with methotrexate is as good as ‘DMARD-combos’, ‘all the DMARD-combos have used glucocorticoids and therefore, the results are not valid, so on and so forth…… This is why the CARDERA factorial study (and its follow-up) is considered such a pivotal trial; it demolished such flimsy arguments once and for all. And then came biologicals! High-pressure marketing (including first-class air tickets for round-the-world junkets with dining and wining) and related market forces were so strong that even the most conservative rheumatologists accepted that this discovery was a quantum change in the treatment of RA. I heard them saying, ‘these are the first molecules that inhibit joint erosions!’ Thankfully, the saner voices were steadfast in their belief. They had to prove that DMARDs were as good (or occasionally superior) as the biologicals. SWEFOT and the TEAR trials (and their follow-up publications) finally demolished any such arguments. It has now become clear that O’Dell’s regimen may pip biologicals at the lipid-CVD post. The 2 other recent trials that need special mention are the tREACH study by de Jong in ‎2014 (Results for Early RA Treatments), and by DL Scott’s group in UK ‘Cost-effectiveness of combination nonbiologic disease-modifying antirheumatic drug strategies in patients with early rheumatoid arthritis’. A few additional facts need to be pointed out in favor of conventional synthetic (cs) DMARD combinations over the early use of biologicals after the failure of LD-MTX monotherapy. The proper and correct use of the pivotal drug, discovered by a genius, an unsung hero, an American of Indian origin, Yella Pragada Subbarow (mind the spelling of Subbarow), who could have won the Nobel Prize but for the colour of his skin, low-dose methotrexate (LD-MTX), is central to the success of this treatment approach. The ‘E3 initiative’ laying down the ground rules of the dose and dosage of LD-MTX, and the more recent work of Hazlewood and colleagues clearly establishing the superiority of initiating LD-MTX through the parenteral route must be followed in letter and spirit. NICE has recently recommended that biologicals should not be initiated unless csDMARDs combinations have shown a suboptimal response. At EULAR 2016 in London, the issue of suboptimal dosing of MTX and not using the parenteral route from the time of initiating treatment with MTX was extensively discussed. One gets the feeling that at least in the UK, where the NHS is funded by public money, soon it may become compulsory to treat RA aggressively with csDMARDs-combos with parenteral MTX in full recommended doses upfront. Only those with suboptimal response to this treatment may be allowed biologicals. India is a much more resource-constrained country. Why should IRA also not recommend the same strategy for Indian RA patients?

That brings me to the final point. Is this aggressive csDMARDs-combo regimen possible in the Indian setting? I think it is possible. It is possible even in a crowded hospital OPD rheumatology clinic if one has an organized clinic. Such a clinic should have an electronic health record system, 2-3 specialist nurses, 2 good medical secretaries, 2 or 3 physical medicine experts to help, and 2-3 consultants aided by 2-3 fellows/residents. In such a setting, we were able to achieve a remission rate of nearly 80%, following the treatment strategy discussed above. Our 2010 paper in Ind J Rheum and a recent paper of mine (2016, ClinRheumatol) have given the details. My 2016 paper has provided the details of the previous treatments received by the patients; it also provided details regarding their caregivers. It was observed that a significant number of RA patients under treatment were in the high or moderate disease activity state. More surprising was the fact that about a third of them were treated by rheumatologists. Of course, one cannot be sure if they were indeed rheumatologists because in India, misleading signboards by poorly trained doctors are not unusual. But, I have a lurking feeling that some of the colleagues have not been able to overcome the ‘the cancer drug’ stigma for LD-MTX, which could be the main stumbling block in using it in optimal doses. Our use of biologicals has been <5%. This shows that when there is a will, there is a way. With so much advancement in the knowledge related to LD-MTX and that it is a different drug from the one used in the treatment of cancer (including our 2010 paper in Int J Rheum Dis on this issue and my CME talks at so many venues around the country on the same topic; another accepted paper on the same topic in ‘Current Rheumatology Reviews’), the failure to use LD-MTX in effective doses and the failure to use the proper route of administration are inexcusable.

Let us start believing in science and not in rumors and half-truths. Let us remember the stalwarts who gave us such a sensational drug, starting from Subbarow, Gubner, McCarty, Cronstein, Kremer, Thompsom, Williams and Willkens, Weinblatt, O’Dell, and many more (refer to my paper ‘landmark papers on the discovery of MTX). The treatment RA has dramatically changed from the time I was a fellow in clinical immunology in Boston; much of the credit for it goes to LD-MTX. Use it early, use it optimally, and use it in combination.

[The reference details have not been provided due to a 1-day notice for writing this ‘Editorial’. Therefore, the fellows/DM-DNB students/trainees are encouraged to trace down each of these quoted references and read them carefully. Most of these references have been posted on ‘My Yahoo group’ over the years. This would be a good teaching and training exercise for the students. Only if after a sincere effort some of the references are not traceable, I would be happy to help].

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Sincerely,



Prof. Anand N. Malaviya,
MD, FRCP (Lond.), ACR 'Master', FACP, FICP, FAMS, FNASc,
(Ex-Head of the Department of Medicine, and Chief of Clinical Immunology and Rheumatology Services, All-India Institute of Medical Sciences, New Delhi)
Consultant Rheumatologist, 'A&R Clinic'
Visiting Sr. Consultant Rheumatologist ISIC Superspeciality Hospital, New Delhi.