Disease Modifying Anti-Rheumatic Drugs (DMARD)


Article Author:
Onecia Benjamin


Article Editor:
Sarah Lappin



Managing Editors:
Frank Smeeks
Scott Dulebohn
Erin Hughes
Pritesh Sheth
Mark Pellegrini
James Hughes
Richard Ciresi
Phillip Hynes


Updated:
10/27/2018 12:31:32 PM

Indications

Disease-modifying antirheumatic drugs (DMARDs) are a class of drugs indicated for the treatment of rheumatoid arthritis (RA), which is a symmetric, inflammatory, polyarthritis of unknown etiology. These drugs are immunosuppressives designed to slow the damage done to joints, and they can induce or maintain remission, reduce the frequency of flare-ups, and allow for tapering of steroids while sustaining disease control. They can also be used to in the treatment of other autoimmune disorders such as scleroderma, vasculitis, spondyloarthritis, inflammatory myositis, inflammatory bowel disease, systemic lupus erythematosus, and some types of cancers.

There are 2 main types of DMARDs: traditional and biologics. Traditional DMARDs include methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine. Others include cyclophosphamide, cyclosporine, and tacrolimus (FK506), but these are of limited use. Biologic DMARDs came to market in the early 1990s and are usually prescribed after evidence of disease progression and structural joint damage despite treatment with steroids and conventional therapy. Some biologic agents include abatacept, etanercept, infliximab, rituximab, tocilizumab, among others. These drugs are made of monoclonal antibodies, antibodies that are chimeric fusions, agents that are humanized, and some are receptors that have been fused to another part of the human immunoglobulin. Their design is highly specific and targeted to affect immune function. Additionally, Janus kinase (JAK) inhibitors such as tofacitinib, are also used in treatment. They are administered either intravenously or subcutaneously. Although many medications can be used in the treatment of RA, methotrexate is the most commonly used as an initial treatment.

In the treatment of rheumatoid arthritis, many factors come into play. Factors include severity of disease and disability, the location of the joint injury, comorbidities, patient preferences (including cost and frequency of monitoring), the presence of adverse prognostic signs, among others. Ultimately, treatment will include either monotherapy or a combination of therapies. A recent meta-analysis of 20, randomized, clinical trials studying the safety and efficacy of combination therapy throughout the years concluded that tocilizumab (an IL-6 receptor blocker) and methotrexate (a dihydrofolate reductase inhibitor) were the best combinations of medications for the treatment of rheumatoid arthritis. However, in cases where methotrexate is contraindicated or not tolerated, alternative non-biologics can be considered. These can include hydroxychloroquine or sulfasalazine. The goal of escalating therapy is to help slow joint damage. If these interventions remain unsuccessful, biologic DMARDs (etanercept, infliximab) can be considered. Joint damage can be seen very early in the disease course (as early as 2 years into the disease), so treatment should be initiated as soon as the diagnosis is made.

Prior to starting, resuming or significantly increasing the dosage of biologics or non-biologics, patients are screened for hepatitis B and C, especially if they have a history of intravenous drug abuse or if they exercise high-risk sexual behaviors. In other cases, a PPD skin test or an interferon-gamma release assay is conducted to establish a baseline for latent tuberculosis infection. A baseline chest x-ray should also be done, as some of these meds can cause interstitial lung disease.

Mechanism of Action

The class of DMARDs is extensive, and traditional DMARDs act via various mechanisms. They interfere in combinations of critical pathways in the inflammatory cascade. Methotrexate, for example, stimulates adenosine release from fibroblasts, reduces neutrophil adhesion, inhibits leukotriene B4 synthesis by neutrophils, inhibits local IL-1 production, reduces levels of IL-6 and IL-8, suppresses cell-mediated immunity, and inhibits synovial collagenase gene expression. Other medications in this class serve to inhibit proliferation or cause dysfunction of lymphocytes.

Biologics, on the other hand, are very selective in their mechanism of action. The overarching functional of biologics include (1) interfering with cytokine function or production, (2) inhibiting the “second signal” required for T-cell activation, and (3) depleting B-cells or inhibiting factors that active B-cells (rituximab and belimumab). Tofacitinib is a small molecule inhibitor of JAK, a protein tyrosine kinase involved in mediating cytokine signaling.

Administration

DMARDs (biologics and non-biologics) can be administered orally or intravenously (IV).

Adverse Effects

DMARDs are very powerful drugs which modulate sequences in the immune system. Their adverse effects can range from mild (rash, nausea, vomiting, stomatitis) to severe, life-threatening infections; therefore, frequent monitoring is required. As a group, conventional DMARDs can cause gastrointestinal (GI) distress, bone marrow suppression, neutropenia, interstitial lung disease, and hepatotoxicity. Methotrexate has been known to cause neurotoxicity, pneumonitis and liver disease including cirrhosis. Of note, a recent study suggests methotrexate (in combination with bisphosphonates) is a risk-factor for bisphosphonate-induced osteonecrosis of the jaw. In another case, hydroxychloroquine (HCQ) can cause retinopathy (macular damage) and rash. Leflunomide can cause diarrhea, alopecia, and elevated liver transaminases.

Biologic agents also have increased the risk of fatal viral, bacterial, and/or fungal infections. Reactivation or primary viral infections of herpes zoster or hepatitis B/C is also common. Specifically, the anti-CD20 (rituximab) and IL-1 receptor antibody can cause possible congestive heart failure and demyelinating central nervous system (CNS) disease. JAK inhibitors can cause elevated creatinine, LFTs, and hypertension. Cyclosporine can cause nephrotoxicity, hypertension, and gum hyperplasia on rare occasions.

Life-threatening adverse effects of these meds warrant immediate suspension of the drugs.

Contraindications

DMARDs are not to be taken by patients who have an active infection, those with preexisting bone marrow hypoplasia, leukopenia, chronic liver disease, or immunodeficiency syndromes. Methotrexate is contraindicated in pregnancy.

Monitoring

  • Most DMARDs which cause myelosuppression and hepatotoxicity can be monitored with a complete blood count (CBC) and liver function tests every 2 weeks to monthly.
  • Those that cause macular damage (hydroxychloroquine) should be monitored with funduscopic exams twice yearly.
  • Cyclophosphamide, which can cause hemorrhagic cystitis and bladder cancer, can be monitored with a CBC and urinalysis every 2 weeks.
  • Cyclosporine and FK506 (tacrolimus) can cause renal insufficiency, hypertension, and anemia and should be monitored with blood pressure and creatinine checks bi-monthly, along with periodic CBC, potassium levels, and liver enzymes.
  • Biologics including etanercept and infliximab can allow for systemic infection as well as injection site infection. They can be monitored with PPD before initiating or re-starting therapy as well as periodic CBC.

Toxicity

High dose methotrexate is delivered IV and is used over 4 to 36 hours for CNS prophylaxis in patients with leukemia, high-risk lymphomas, osteosarcomas, among others, and for eradicating leptomeningeal spread. Because such a powerful dose is used, a "leucovorin rescue" is used to terminate the toxicity of the drug on the kidneys.


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Disease Modifying Anti-Rheumatic Drugs (DMARD) - References

References

Optimizing conventional DMARD therapy for Sjögren's syndrome., van der Heijden EHM,Kruize AA,Radstake TRDJ,van Roon JAG,, Autoimmunity reviews, 2018 Mar 8     [PubMed]
[Homeostasis and Disorder of Musculoskeletal System.Progress in the treatment of rheumatoid arthritis.], Tanaka Y,, Clinical calcium, 2018     [PubMed]
Low-dose methotrexate in rheumatoid arthritis: a potential risk factor for bisphosphonate-induced osteonecrosis of the jaw., Mathai PC,Andrade NN,Aggarwal N,Nerurkar S,Kapoor P,, Oral and maxillofacial surgery, 2018 Mar 5     [PubMed]
[Pharmacological treatment of rheumatoid arthritis and its comorbidities]., Krüger K,, Der Internist, 2018 Mar 5     [PubMed]
Starting of biological disease modifying antirheumatic drugs may be postponed in rheumatoid arthritis patients with multimorbidity: Single center real life results., Armagan B,Sari A,Erden A,Kilic L,Erdat EC,Kilickap S,Kiraz S,Bilgen SA,Karadag O,Akdogan A,Ertenli I,Kalyoncu U,, Medicine, 2018 Mar     [PubMed]
Evidence of significant radiographic damage in rheumatoid arthritis within the first 2 years of disease., Fuchs HA,Kaye JJ,Callahan LF,Nance EP,Pincus T,, The Journal of rheumatology, 1989 May     [PubMed]
A host of novel agents for treating psoriasis, psoriatic arthritis stir interest., Lamberg L,, JAMA, 2003 Jun 4     [PubMed]
Life table analysis of 879 treatment episodes with slow acting antirheumatic drugs in community rheumatology practice., Morand EF,McCloud PI,Littlejohn GO,, The Journal of rheumatology, 1992 May     [PubMed]
Toxicity of anti-rheumatic drugs in a randomized clinical trial of early rheumatoid arthritis., van Jaarsveld CH,Jahangier ZN,Jacobs JW,Blaauw AA,van Albada-Kuipers GA,ter Borg EJ,Brus HL,Schenk Y,van Der Veen MJ,Bijlsma JW,, Rheumatology (Oxford, England), 2000 Dec     [PubMed]
The Efficacy and Safety of Mainstream Medications for Patients With cDMARD-Naïve Rheumatoid Arthritis: A Network Meta-Analysis., Cai W,Gu Y,Cui H,Cao Y,Wang X,Yao Y,Wang M,, Frontiers in pharmacology, 2018     [PubMed]

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