Tab Application Banner
  • Users Online: 1024
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
Year : 2018  |  Volume : 13  |  Issue : 2  |  Page : 137-138

Supplementing pyridoxine and cobalamin in addition to folic acid in patients on methotrexate therapy

1 Consultant Rheumatologist, ‘A&R Clinic’ and Visiting Sr consultant Rheumatologist at Indian Spinal Injuries Centre, Superspeciality Hospital, New Delhi, India
2 Rheumatology at Indian Spinal Injuries Centre, New Delhi, India
3 Rheumatology Nurse at Indian Spinal Injuries Centre, New Delhi, India

Date of Web Publication24-May-2018

Correspondence Address:
Dr. Shubha Bhalla
Indian Spinal Injuries Centre, Sector-C, Vasant kunj, New Delhi - 110 070
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_29_18

Rights and Permissions

How to cite this article:
Malaviya AN, Bhalla S, Verma S, Rawat R. Supplementing pyridoxine and cobalamin in addition to folic acid in patients on methotrexate therapy. Indian J Rheumatol 2018;13:137-8

How to cite this URL:
Malaviya AN, Bhalla S, Verma S, Rawat R. Supplementing pyridoxine and cobalamin in addition to folic acid in patients on methotrexate therapy. Indian J Rheumatol [serial online] 2018 [cited 2022 Aug 11];13:137-8. Available from:

Dear Editor,

Low-dose methotrexate (LD-MTX) at doses <25–30 mg weekly as minipulses is currently the standard of care for the treatment of rheumatoid arthritis (RA) and is considered the “anchor” drug for this disease. Several features of LD-MTX are very appealing both for the patients and for the providers and have been discussed in depth. For these reasons, LD-MTX is now widely used not only for the treatment of RA but also for the treatment of several other systemic immunoinflammatory rheumatic diseases (SIRDs).[1]

Despite high efficacy of LD-MTX in the treatment of SIRDs, one main stumbling block in the long-term retention of LD-MTX is the so-called “methotrexate intolerance,” representing a constellation of nonspecific symptoms that are classified as “associative,” “anticipatory,” and “behavioral” in nature.[2] In addition, transaminitis, mucositis, and rarely, bone marrow suppression are the other adverse effects of LD-MTX that may preclude its long-term use. Folic acid supplementation has been empirically found to offset much of these adverse effects. A recent Cochrane review has discussed this issue in depth and strongly recommends folic acid supplementation in every patient being treated with LD-MTX.[3] For these reasons, folic acid supplementation is now accepted as the standard of care in patients receiving LD-MTX. The dose of folic acid supplementation has been systematically studied recently.[4] It would seem that any dose from 5 mg to 30 mg/week is satisfactory without interfering with the efficacy of LD-MTX.[4]

The cause of MTX intolerance is most likely due its interference with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase, thus blocking the conversion of AICAR to folyl-AICAR, thus increasing the level of AICAR causing a rise of extracellular levels of adenosine.[1] Adenosine interacts with receptors on a variety of inflammatory cells (e.g., neutrophils and mononuclear cells) that contribute to MTX's anti-inflammatory effects. However, adenosine also reacts with receptors in central nervous system that seem to be the major cause of “methotrexate intolerance.”[5] Caffeine being a competitive inhibitor of adenosine has been reported to be effective in offsetting “MTX intolerance” without interfering with the efficacy of LD-MTX.[5] Thus, folic acid supplementation and addition of a few additional cups of strong coffee helps in the retention of LD-MTX treatment over long term.

There is evidence of pyridoxine (vitamin B6) deficiency at the tissue level in inflammatory diseases such as RA.[6] It was observed that lower levels of circulating pyridoxal 5'-phosphate in RA reflect a decrease in hepatic pyridoxal 5'-phosphate pools and plasma pyridoxal 5'-phosphate which is a good indicator of liver B6 status during inflammation. This was based on the hypothesis that the proinflammatory cytokine interleukin-6 might stimulate the activity of pyridoxal phosphatase in hepatocytes, and the elevated enzyme may result in reduced plasma pyridoxal 5'-phosphate concentrations. Therefore, it has been suggested to supplement pyridoxine in the treatment of RA.[6] Cobalamin (vitamin B12) deficiency is another issue that needs to be kept in mind, especially in a largely vegetarian population of India. Studies in northern India have shown widespread B12 deficiency in the population.[7] Therefore, it would seem reasonable to supplement B6 as well as B12 in the treatment of RA and possibly other SIRDs. A study of anemia in patients with RA has also shown deficiency of folate, B12, and iron as causes of anemia in RA, besides chronic inflammation-related anemia.[8]

One of the most common multivitamin combinations in the Indian market is B1 + B6 + B12 + folic acid (10 mg, 3 mg, 1500 μg, 1.5 mg, respectively). It is cheap, costing Rs. ~7.5/capsule. Given on 4 days in a week would provide 6 mg of FA, 12 mg of B6, and 6000 μg of B12, which should be sufficient for supplementation. Singh has also mentioned the use of multivitamin capsule in such situations as an easy way of supplementing FA.[9]

Iron-deficiency anemia is common in RA with prevalence of 48.4% in Indian patients.[8] However, in our experience, oral iron supplementation causes nonspecific abdominal complaints in many patients. Therefore, despite the easy availability of iron + FA + B12 combination capsules in the market, it may not be suitable for every patient. If the issue is that of tolerability of oral iron supplementation, ferric carboxymaltose intravenous infusion is quick and a safe method of restoring iron reserve. The only disadvantage is that it needs an hour of intravenous infusion in a clinic or a hospital in the outpatient. Furthermore, the preparation is rather expensive (Rs. 2226/500 mg).

Unfortunately, there is no reported controlled trial of the effect of these supplementations in the treatment outcome of RA. However, analysis of our RA patients has shown a high percentage of them achieving satisfactory disease control (remission in 77.8% and low disease activity in 12.5%).[10] This is despite the fact that these patients were not prescribed biological or targeted synthetic disease modifying antirheumatic drug. This observation makes us ponder that coadministering multivitamins with disease modifying antirheumatic drugs may augment its effect in mitigating inflammation and result in good treatment response.

This may stimulate some workers to carry out a controlled trial of supplementation Vitamin B6, B12, and folic acid in patients with RA. Till then, we would continue supplementing these vitamins. After all, many people are, anyway, so fond of taking vitamins in their daily life!

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Malaviya AN. Low-dose methotrexate (LD-MTX) in rheumatology practice – A most widely misunderstood drug. Curr Rheumatol Rev 2016;12:168-76.  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
Lopez-Olivo MA, Siddhanamatha HR, Shea B, Tugwell P, Wells GA, Suarez-Almazor ME, et al. Methotrexate for treating rheumatoid arthritis. Cochrane Database Syst Rev 2014;6:CD000957.  Back to cited text no. 3
Dhir V, Sandhu A, Kaur J, Pinto B, Kumar P, Kaur P, et al. Comparison of two different folic acid doses with methotrexate – A randomized controlled trial (FOLVARI study). Arthritis Res Ther 2015;17:156.  Back to cited text no. 4
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. 5
Chiang EP, Smith DE, Selhub J, Dallal G, Wang YC, Roubenoff R, et al. Inflammation causes tissue-specific depletion of Vitamin B6. Arthritis Res Ther 2005;7:R1254-62.  Back to cited text no. 6
Chahal JS, Raina SK, Sharma KK, Kaur N. How common is Vitamin B12 deficiency – A report on deficiency among healthy adults from a medical college in rural area of North-West India. International journal of Nutrition, Pharmacology, Neurological disease 2014;4:241-6.  Back to cited text no. 7
Agrawal S, Misra R, Aggarwal A. Anemia in rheumatoid arthritis: High prevalence of iron-deficiency anemia in Indian patients. Rheumatol Int 2006;26:1091-5.  Back to cited text no. 8
Singh JA. Folic acid supplementation for rheumatoid arthritis patients on methotrexate: The good gets better. Cochrane Database Syst Rev 2013;2-5. ED000063.  Back to cited text no. 9
Zaheer Q, Agarwal VK, Bagheal SS. Disease activity status of patients with rheumatoid arthritis in follow-up in a busy rheumatology outpatient department: A cross sectional study. Indian J Rheumatol 2017;125 Suppl 1:S51-2.  Back to cited text no. 10


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article

 Article Access Statistics
    PDF Downloaded291    
    Comments [Add]    

Recommend this journal