Methotrexate: Gold Standard Dmard
by Dr. Vaijayanti Lagu-Joshi

As we all know, the management of arthritis and rheumatic disorders is long term and multifaceted. The medications/drugs form mainstay of treatment along with supplementary medications, diet, exercises and stress management. Everyday a number of medicines, come into market; some are in pipeline for treatment of those chronic progressive arthritis with the sole aim of conquering the disease. But in reality, drugs have proven to control the disease very well rather than total cure.

Methotrexate is one of the disease modifying antirheumatic drugs – DMARDS used over 50 years for treatment of rheumatic diseases. It is one of the most durable; frequently, used DMARD, labelled as 'Gold Standard drug worldwide. Methotrexate was introduced for treatment of cancers more than 50 years ago due to its antiproliferative action but it has become the DMARD of choice for rheumatic diseases owing to its anti-inflammatory activities. There are many questions about the drugs, its activity, efficacy, safety and monitoring in patients minds. Some patients are worried at the outset, some start thinking about the side-effect profile as the disease and treatment goes on for years. I will try to answer few queries and commonly asked questions about the drug.

For which rheumatic diseases is methotrexate used?

Methotrexate is mainly used for variety of indications in rheumatology. It serves as an 'Anchor drug' for the destructive rheumatoid arthritis, juvenile inflammatory arthritis, psoriatic arthritis, spondyloartho pathies and Methotrexate is also used for its potent immunosuppressive and “steroid-sparing” effects in disease like SLE, collagen tissue disorders, polymyositis and dermatomyositis and vasculitis, affecting multiple systems like lungs, kidneys apart from joints.

How does methotrexate act?

Methotrexate is a folic acid analogue. It enters the cells via folate receptors. Inside the cells it gets polyglutanated and interferes with several cellular enzymes that are required for pyrimidine synthesis and cellproliferation and functioning is inhibited. Methotrexate increases levels of adenosine that suppresses proinflammatory cytokines like TNF, IL-6, IL8 etc.

How is methotrexate administered to the patients?

Methotrexate is available in tablet as well as injectable form. The tablets are in strengths of 2.5, 5, 7.5, 10, 15, 20 mg. The injections are in form of ampoules / vials with strengths of 7.5 mg/ml, 15 mg/ml or 50 mg/2ml. The dose can be given either as step up or step down format till 25-30 mg per week for rheumatic diseases. The tablet/injection is once or twice a week, advised after food. The injection can be given subcutaneously or intramuscularly over outer aspect of arms, thighs or abdominal wall.

Are injections superior to tablets in efficacy?

The absorption of low dose oral and injectable methotrexate (<15mg /week) is roughly equivalent but once oral dose exceeds 15mg, absorption diminishes upto 30%. The injections are preferred over tablets, when there are lots of gastrointestinal side-effects like nausea, vomiting, diarrhoea, stomatitis with oral methotrexate. The injections bypass the gastrointestinal system and enter the circulation, avoiding the Gl side-effects.
Sometimes due to variable bio availability of drug, clinicians switch to injectable form to have the optimum efficacy of the drug.

How is the drug eliminated from the body?

Methotrexate, after absorption, 50-60% is bound to plasma proteins. It is excreted in urine within 12 hours of administration but its active metabolite, after methotrexate polyglutamate gets eliminated after liver enzymes activity in 3-4 weeks.

What tests are done before starting methotrexate?

Before starting the methotrexate, doctors advise few baseline investigations to ensure normal liver and kidney functioning. Complete blood count – Hemoglobin, white cells count and platelet count is also done as the drug can decrease the cells as its side-effect.
Chest x-ray and USG abdomen are also done as screening tests before administering immunosuppressive drugs.

How long is methotrexate given and how is it monitored?

Methotrexate can be given on long term basis for many years but needs regular monitoring. The drug is safe provided the doses are optimum and blood checks are done periodically to watch for the side-effects. Complete blood count , SGPT (liver enzyme),urine routine & microscopy and serum creatinine need to be monitored every 6-8 weekly.

What are the side effects of methotrexate?

Due to inhibition of dihydrofolate reductase, methotrexate can produce number of side effects.  Common are gastro intestinal manifestations like nausea, stomatitis, Vomiting, low appetite, diarrhoea.
Methotrexate can induce cytopenia in form of drop in hemoglobin, white cell count or platelet due to bone marrow suppression.

Methotrexate lung is hypersensitivity to drug at any time during therapy leading to breathlessness, cough, fever and might need intensive treatment.

Hepatotoxicity, liver damage is correlated with total cumulative dose and can lead to liver cirrhosis.
Infections can occur due to intense immunosuppression by methotrexate during treatment.

Boils (skin infections), respiratory or genitourinary infections can occur during treatment and deserve proper medication & care. Methotrexate if in high doses can be stopped temporarily in presence of active infections.

Can methotrexate be given safely to children of arthritis?

Yes, in fact children tolerate the drug very well. The children of juvenile inflammatory arthritis can receive methotrexate in doses of 0.3 to 1mg/kg/ week, monitoring the laboratory parameters.

Is methotrexate safe in pregnancy & lactational period?

No, methotrexate is known to be teratogenic and can harm fetus hence the drug is absolutely contraindicated in pregnancy and lactational period. The drug is stopped atleast 3 months prior to conception for both male and female patients.

Can patients on methotrexate undergo surgery, vaccination?

Yes, the patients of long term methotrexate undergo surgeries, without any problems. But high doses are withheld temporarily for 2-3 weeks prophylactically. The patients cannot receive live virus vaccine but can receive passive, killed vaccines.

Does methotrexate need any concomitant medication?

Folic acid 5mg/week is needed to avoid few side-effects of methotrexate. Generally it is not given on day of methotrexate but daily or once/twice weekly on days other than methotrexate. Methotrexate can be used as monotherapy in early arthritis but many times it is used in combination with other DMARDS like salazopyrin, leflunomide, hydroxychloroquine and biological agents as well.

Thus no drug is complete and superior. Every drug has effects as well as side-effects. But it needs to be given in right dose, for right indication by an expert doctor with proper monitoring so that the patient gets optimum benefits and control of disease.