Continuing Education Activity

Disease-modifying antirheumatic drugs (DMARDs) are a class of drugs indicated for the treatment of several inflammatory arthritides, including rheumatoid arthritis (RA), as well as for the management of other connective tissue diseases and some cancers. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of DMARDs, pertinent for members of the interprofessional team in the treatment of patients with autoimmune disorders that will respond to such therapy.

Objectives:

• Explain the difference between traditional and biological DMARDs.
• Identify the indications for various DMARD agents.
• Outline the adverse effects and contraindications to biologic DMARD therapy.
• Describe the importance of improving care coordination among the interprofessional team to enhance care delivery for patients when using either traditional or biologic DMARDs.

Indications

Disease-modifying antirheumatic drugs (DMARDs) are a class of drugs indicated for the treatment of inflammatory arthritides, 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.[1][2][3]

DMARDs are immunosuppressive and immunomodulatory agents and are classified as either conventional DMARDs or biologic DMARDs. Commonly used conventional DMARDs include methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine. Biologic DMARDs were introduced in the early 1990s and are usually prescribed after the failure of conventional DMARD therapy (ongoing disease activity or clinical or radiographic disease progression). Some biologic agents include infliximab, adalimumab, etanercept, rituximab, abatacept, rituximab, tocilizumab, tofacitinib, among others. Biologic DMARDs are highly specific and target a specific pathway of the immune system. Some of these drugs are monoclonal, chimeric humanized fusions antibodies, while others are receptors that have been fused to a part of the human immunoglobulin or small molecules such as Janus kinase (JAK) inhibitors.

DMARDs in Rheumatoid Arthritis

Although many medications can be used in the treatment of RA, methotrexate is the most commonly used agent as an initial treatment. RA treatment is complicated, with several factors playing a role in decision making, including disease activity and severity, comorbidities, and patient preference (including cost, route of administration, and frequency of monitoring). RA treatment can be either monotherapy or combination therapy, although several randomized controlled trials have shown the superiority of combination therapy of a biologic DMARD with a conventional DMARD such as methotrexate over either agent alone. Treatment goals shall include achieving remission or low disease activity and preventing radiographic progression of the disease. The initiation of therapy early in the disease has been shown to prevent radiographic progression, most of which occurs within the first few months of the disease.

Mechanism of Action

Each DMARD has a unique mechanism of action, ultimately interfering with 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. Leflunomide inhibits dihydroorotate dehydrogenase resulting in inhibition of pyrimidine synthesis hence blocking lymphocyte proliferation. Sulfasalazine mediates its anti-inflammatory effects by preventing oxidative, nitrative, and nitrosative damage. On the other hand, hydroxychloroquine is a very mild immunomodulatory agent that inhibits intracellular toll-like receptor TLR9.

Biologics, on the other hand, are very selective in their mechanism of action. The overarching functions of biologics include (1) interfering with cytokine function or production, (2) inhibiting the “second signal” required for T-cell activation, or (3) depleting B-cells or inhibiting factors that active B-cells. Tofacitinib is a small molecule inhibitor of JAK, a protein tyrosine kinase involved in mediating cytokine signaling.[4][5]

Administration

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

Adverse Effects

Although most conventional DMARDs have similar adverse effects, there are several adverse effects unique to each agent.

Hydroxychloroquine is unique in this respect as it has the best safety profile out of all the conventional DMARDs. Compared to other conventional DMARDs, hydroxychloroquine does not increase the risk of severe infections, nor does it cause hepatotoxicity or renal dysfunction. Common adverse effects of hydroxychloroquine include rash, diarrhea. A rare but significant adverse effect of hydroxychloroquine is retinopathy/maculopathy, which is seen with a higher cumulative dose. Risk factors for hydroxychloroquine maculopathy include more than 5 mg/kg/day dose, more than 5 years of therapy, advancing age, and chronic kidney disease. Patients on hydroxychloroquine are recommended to have regular ophthalmology evaluation with ocular coherence tomography, which is a very sensitive test for maculopathy and can diagnose it well before visual field defects occur. Other rare adverse effects of hydroxychloroquine include anemia, leukopenia, myopathy, and cardiomyopathy.

Methotrexate, leflunomide, and sulfasalazine are similar in their adverse effect profile. Gastrointestinal distress (nausea, abdominal pain, diarrhea), rash/allergic reaction, bone marrow suppression, hepatotoxicity, and higher incidence of common and sometimes serious infections are common adverse effects of all these agents. Both methotrexate and leflunomide can cause alopecia. Other adverse effects unique to methotrexate include interstitial lung disease, folic acid deficiency, and liver cirrhosis. Leflunomide can cause hypertension, peripheral neuropathy, and weight loss. Sulfasalazine has a very high risk of gastrointestinal distress. It can rarely cause DRESS syndrome as well.[6]

The most concerning adverse effect of all biologic DMARDs is an increased risk of common and serious infections, including bacterial, fungal, and viral infections. Reactivation of tuberculosis, herpes zoster, and hepatitis B/C can also occur. Rarely, bone marrow suppression and hepatotoxicity have been reported with biologic DMARDs. Anti TNF agents can cause worsening of severe congestive heart failure, drug-induced lupus, demyelinating central nervous system (CNS) diseases. Lymphomas and non-melanoma skin cancers may be associated with Anti-TNF agents as well. Hyperlipidemia, elevated liver function test, and pancytopenia can be caused by IL-6 inhibitors and JAK inhibitors. Worsening of chronic obstructive airway disease has been reported secondary to abatacept. IL-17 inhibitors can cause/worsen inflammatory bowel disease. Progressive multifocal leukoencephalopathy has been reported in patients treated with rituximab. 

Drug Interactions

Several medications such as non-steroidal anti-inflammatory agents (NSAIDs), proton pump inhibitors, sulfasalazine, and amoxicillin can interfere with renal excretion of methotrexate, increasing its efficacy and increasing the risk of adverse effects.

While the combination of a biologic DMARD with a conventional DMARD and the use of multiple conventional DMARDS is considered safe, it is not recommended to use a combination of different biologic DMARDs due to an increased risk of severe immunosuppression leading to severe and potentially life-threatening infections.

Contraindications

DMARDs, especially biologic DMARDs, shall be avoided in patients with an active infection, those with preexisting bone marrow hypoplasia, leukopenia, or immunodeficiency syndromes. Methotrexate and leflunomide shall be avoided in patients with severe liver disease.

Pregnancy and Lactation

Methotrexate and leflunomide are contraindicated in pregnancy and lactation due to their teratogenic effects. Sulfasalazine can cause jaundice in the infant, especially if used in the third trimester of pregnancy, and shall be used with caution in lactation. While hydroxychloroquine can cross the placenta, no cases of fetal ocular toxicity have been reported, and it is considered safe to be used in pregnancy and is actually strongly recommended to be used in pregnant females with systemic lupus erythematosus as it prevents flares of the disease in pregnancy.

There is limited safety data on the biologic DMARDs in pregnancy. However, of all biologics, certolizumab is the only one that does not cross the placenta due to the larger size of the molecule and is considered relatively safer to be used in pregnancy.

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.[7][8][9]

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.

Toxicity

High-dose methotrexate, especially when delivered intravenously in patients to treat some cancers, can cause severe pancytopenia and transaminitis. In these cases, leucovorin rescue is used to terminate methotrexate toxicity.[10]

Enhancing Healthcare Team Outcomes

Disease-modifying antirheumatic drugs (DMARDs) are a class of drugs indicated for treating rheumatoid arthritis (RA) and many other autoimmune disorders, including systemic sclerosis, vasculitis, spondyloarthritis, inflammatory myositis, inflammatory bowel disease, systemic lupus erythematosus, and some types of cancers. Due to the high complexity involved in the appropriate use of these agents and monitoring for adverse effects, DMARDs shall be ideally prescribed by an appropriate specialist such as a rheumatologist, gastroenterologist, or dermatologist. The prescribing provider shall be familiar with these agents, their indications, and their adverse effects and should coordinate with the pharmacist regarding dosing, potential interactions, and adverse events. Nursing can also provide patient counseling and coordinate with the pharmacist and clinician to monitor the patient since all patients prescribed DMARDs need to be closely followed to monitor their effectiveness and side effects. The interprofessional approach will provide the best chances of positive patient outcomes with the fewest adverse events. [Level 5]