Disease-modifying antirheumatic drugs

Vinod Meena

Post graduate resident, Department of Medicine, LHMC

Disease-modifying antirheumatic drugs (DMARDs) are a class of drugs indicated for the treatment of several inflammatory arthritis, including rheumatoid arthritis (RA), as well as for the management of other connective tissue diseases and some cancers.

DMARDs work to suppress the body’s overactive immune and/or inflammatory systems. They take effect over weeks or months and are not designed to provide immediate relief of symptoms.

Other medicines, such as pain relievers, nonsteroidal anti-inflammatory drugs (NSAIDs; eg, ibuprofen or naproxen), and, sometimes, prednisone, are given to provide faster relief of ongoing symptoms. DMARDs are often used in combination with these medications to reduce the total amount of medication needed and to prevent damage to joints.

INDICATIONS

Disease-modifying antirheumatic drugs (DMARDs) are a class of drugs indicated for the treatment of inflammatory arthritis, including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS).

They can also be used in the treatment of other disorders, including connective tissue diseases such as systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and Sjogren syndrome (SS), as well as in the treatment of inflammatory myositis, vasculitis, uveitis, inflammatory bowel disease, and some types of cancers

CLASSIFICATION OF DMARDs

DMARDs are immunosuppressive and immunomodulatory agents and

are classified as

Conventional DMARDs (csDMARDs)
Biologic and Targeted synthetic DMARDs.(bDMARDs , tsDMARDs)

CONVENTIONAL DMARDs

The most common conventional DMARDs are methotrexate, sulfasalazine, hydroxychloroquine, and leflunomide. Azathioprine and other drugs are used much less frequently. Other names for this group of drugs are conventional synthetic DMARDs or traditional DMARDs.

Methotrexate — Methotrexate was originally used as a chemotherapy treatment for cancer. When used in much lower doses for rheumatoid arthritis and other rheumatic diseases, methotrexate works to reduce inflammation and decrease joint damage. These lower doses are much less toxic and are better tolerated than the doses used for cancer. It is taken weekly (on the same day each week) as a pill, liquid, or injection. It may require four to six weeks of treatment to begin to see an improvement in symptoms. Methotrexate may be combined with other conventional DMARDs or with a biologic agent or other targeted synthetic DMARD if methotrexate alone does not adequately control disease

Common side effects include upset stomach and mouth sores. Methotrexate can rarely interfere with the bone marrow’s production of blood cells. Low blood cell counts can cause fever, infections, swollen lymph nodes, easy bruising, and bleeding. Liver function problems can occur, even with low doses, and therefore regular blood tests are necessary for anyone taking methotrexate. People using methotrexate should also limit alcohol use because of the increased risk of liver injury with this combination. Rare injury to the lungs can occur, and methotrexate should be stopped if the person develops a new cough and shortness of breath. Women should not become pregnant or breastfeed while taking methotrexate. Women and men should stop methotrexate one to three months prior to attempting to conceive a child.

Sulfasalazine— Sulfasalazine is used in the treatment of rheumatoid arthritis and of arthritis associated with ankylosing spondylitis and inflammatory bowel disease (ulcerative colitis and Crohn disease). Sulfasalazine may exert its effects through the gastrointestinal immune system. It may be combined with other DMARDs if a person does not respond adequately to one medication. It is typically taken as one to three pills two times per day, and it is usually started at a low dose and is increased slowly to minimize side effects. It may take one to two months of treatment before symptoms improve.

Side effects of sulfasalazine include changes in blood counts, nausea or vomiting, sensitivity to sunlight, skin rash, and headaches. People who are allergic to sulfonamide medications, such as sulfamethoxazole-trimethoprim, may have a cross-reaction to sulfasalazine and should therefore not take it. Periodic blood tests are recommended to monitor the blood count on a regular basis.

Hydroxychloroquine — Hydroxychloroquine, originally developed as a treatment for malaria, was later found to improve symptoms of arthritis. It can be used early in the course of rheumatoid arthritis and is often used in combination with other DMARDs. It is also very frequently used for treatment of systemic lupus erythematosus. It can be combined with steroid medications to reduce the amount of steroid needed. It is usually taken in pill form once or twice per day, and can take two to three months or longer to improve symptoms.

The main toxicity of hydroxychloroquine is the risk of damage to the retina of the eye. Current screening tests allow early detection of this toxicity and drug discontinuation prior to clinically apparent visual loss.

Leflunomide — Leflunomide inhibits production of inflammatory cells to reduce inflammation. It may be used alone or in combination with methotrexate for people who have not responded adequately to methotrexate alone. It may also be used with a biologic agent. It is taken by mouth once daily.

Side effects include rash, temporary hair loss, abnormal liver function tests, nausea, diarrhea, weight loss, abdominal pain, and neuropathy (nerve damage). High blood pressure can occur in up to 10 percent of people. Testing for prior exposure to hepatitis and regular blood testing while on therapy are needed to monitor for liver damage and other toxicities. Women should not become pregnant while taking leflunomide or while it is still detectable in the body.

Azathioprine — Azathioprine has been used in the treatment of cancer, rheumatoid arthritis, lupus, and a variety of other inflammatory illnesses since the 1950s. It has also been used in organ transplantation to prevent rejection of the transplanted organ. Its use for rheumatoid arthritis is now much less frequent than in the past.

The most common side effects of azathioprine include nausea, vomiting, decreased appetite, liver function abnormalities, low white blood cell counts, and infection. It is usually taken by mouth once daily. Regular blood testing is recommended during treatment with azathioprine.

BIOLOGIC AND TARGETED SYNTHETIC DMARDs

Biologic disease-modifying antirheumatic drugs (DMARDs), also known as “targeted biologic agents,” “biologic agents,” or simply “biologics,” are DMARDs that are produced using molecular biology (recombinant DNA) techniques. These agents were designed to prevent or reduce the inflammation that damages joints. Biologics target molecules on cells of the immune system, joints, and the products that are secreted in the joints, all of which can promote inflammation and joint destruction.

There are several types of biologics, each of which targets a specific type of molecule involved in this process:

Tumor necrosis factor (TNF) inhibitors, such as etanercept, adalimumab, infliximab, certolizumab pegol, and golimumab
Biologics that target other molecules, including abatacept, rituximab, tocilizumab, sarilumab, and anakinra
Another group of DMARDs, called kinase inhibitors, includes tofacitinib, baricitinib, upadacitinib, and filgotinib.

Unlike conventional DMARDs, which can take a month or more to begin working, biologics and kinase inhibitors tend to work more rapidly, within two weeks for some medications and within four to six weeks for others.

Side effects — Biologic agents and kinase inhibitors interfere with the immune system’s ability to fight infection and should not be used in people with serious infections. To help reduce the risk of certain infections, it is also important to make sure you have received all recommended vaccines before starting DMARD therapies, and to continue to get the influenza (flu) vaccine each year. The risk of herpes zoster (shingles) is higher with the kinase inhibitors than other medications, but this risk can be lowered with recombinant zoster vaccination prior to treatment.

Testing for tuberculosis (TB) is necessary before starting biologic DMARDs, particularly anti-TNF therapy, and before starting kinase inhibitors. People who have evidence of prior TB infection should be treated because there is an increased risk of developing active TB while receiving anti-TNF therapy.

Anti-TNF agents are not recommended for people who have certain health conditions such as multiple sclerosis or lymphoma (or who have been treated for lymphoma in the past); people with rheumatoid arthritis, especially those with severe disease, have an increased risk of lymphoma regardless of what treatment is used. Anti-TNF agents have been associated with a further increase in the risk of lymphoma in some studies

CHOOSING BETWEEN DMARDS

The choice of disease-modifying antirheumatic drug (DMARD) depends on a number of factors, including the stage and severity of the person’s condition, the balance between possible side effects and expected benefits, other medical conditions, and personal preference. Before treatment begins, the patient and clinician should discuss the benefits and risks of each type of therapy, including possible side effects and toxicities, dosing schedule, monitoring frequency, and expected results. Certain screening tests, including blood tests for past exposure to certain infections, may be needed before starting some of these medications.

In some cases, one DMARD is used. In others, combinations may be recommended. Sometimes a person must try different medicines or combinations to find one that works best and that has the fewest side effects. A person who does not respond completely to a single DMARD may be given a combination of DMARDs, such as methotrexate plus another medication.

Definition of resistance to initial therapy with conventional synthetic DMARDs

Failure to achieve remission or low disease activity within three to six months of initiating methotrexate (MTX) or other csDMARD therapy in maximally tolerated doses within the usual therapeutic range. A therapeutic trial of greater than three months is generally used in patients with partial responses showing progressive improvement, particularly in those with low to moderate levels of disease activity and with limited functional impairment. Treatment should be appropriate for the patient’s overall medical status and comorbidities and should take into consideration the patient’s treatment goals and preferences.

A requirement, in addition to DMARDs, for chronic glucocorticoid therapy in a dose of greater than approximately 5 mg/day of prednisone or equivalent to achieve or maintain remission or low disease activity after three to six months of treatment with DMARDs. A requirement for multiple courses of treatment with glucocorticoids, in excess of doses used for chronic therapy, for the treatment of recurrent disease flares in patients whose medication doses have been increased to the maximally tolerated or acceptable level. Continued progression of erosive disease or structural damage that is not accounted for by prior joint damage.

DMARD Combination Therapies

Double therapy

This treatment combines methotrexate with another DMARD, such as azathioprine (Azasan), cyclosporine, hydroxychloroquine, leflunomide, or sulfasalazine.

Methotrexate plus leflunomide or methotrexate plus sulfasalazine seem to be the most effective two-drug combinations of conventional DMARDs. Another version of this treatment combines two or more biologic drugs.

DMARD plus a biologic

This combination therapy adds a biologic drug to methotrexate.

“Biologic” DMARDs are usually most effective when paired with a “nonbiologic” DMARD, such as methotrexate. (mtx+etn , mtx+ada)

Triple therapy

If two drugs don’t relieve your symptoms, you can move up to triple therapy with three medicines. The most common triple therapy is methotrexate, sulfasalazine, and hydroxychloroquine.

Monitoring

Prior to starting a DMARD, patients shall be screened for hepatitis B and C. Additionally, screening for tuberculosis is strongly recommended before initiating any biologic DMARD.

Some of these agents are teratogenic, while safety has not been established in pregnancy for other agents. In women of childbearing age, a pregnancy test shall be done before initiating these agents. Further, all women of childbearing age using these agents (especially methotrexate or leflunomide) must be on appropriate contraception.

Myelosuppression and hepatotoxicity are more common early in therapy, although they can occur at any time in a patient on a DMARD. Therefore, more frequent monitoring is recommended early in therapy, and less frequent but regular monitoring shall be continued as long as the patient is on the DMARD once early safety has been established. Complete blood count and liver function test shall be performed monthly for at least 3 months initially, and every 2 to 3 months thereafter in patients initiated on agents including methotrexate, leflunomide, sulfasalazine, tocilizumab, tofacitinib, and sarilumab.

Lipid panel shall be monitored at baseline and then every 3 months for at least 6 months and then every 6 months thereafter in patients initiated on tocilizumab, tofacitinib, and sarilumab.

CBC shall be monitored every 6 months in patients on any of the biologic DMARDs.

Since many of these agents require dose adjustment in renal insufficiency, close monitoring of renal function every 3 to 6 months is also recommended in patients on DMARDs.

Comprehensive ophthalmology exams including visual field testing and ocular coherence tomography are necessary at baseline, at 5 years, and then annually in patients on hydroxychloroquine.