Disease-modifying antirheumatic drugs (DMARDs) for Rheumatologic Conditions

Rheumatologic condition is an umbrella term for various autoimmune disorders attacking the musculoskeletal system, often affecting the joints.³ Rheumatologic conditions include rheumatoid arthritis, osteoarthritis, psoriatic arthritis, spondyloarthritis, fibromyalgia, gout and lupus etc.¹ In this article, we will be focusing on DMARDs in the treatment of rheumatoid arthritis (RA).

DMARDs is a relatively new medication class useful for delaying rheumatoid arthritis progression, inducing and then maintaining clinical remission of rheumatoid arthritis.⁴ bDMARDs have yet to gain popularity in Malaysia mainly due to their high cost, while csDMARDs are limited due to their side effect profile. However, the 2019 CPG Malaysia Rheumatoid Arthritis recommended that a DMARD be started as soon as the diagnosis of RA is made.⁴ Bridging therapy with corticosteroids is mandatory to ensure treatment success, as the onset of DMARDs is generally slow.⁴

Type of DMARDs 

DMARDs can be categorized into four different groups⁴:

1. Conventional DMARDs
   • Methotrexate, leflunomide, hydroxychloroquine and sulfasalazine
2. Targeted synthetic DMARDs
   • Janus-kinase inhibitors (JAK): Tofacinitib and Baricitinib
3. Biologic DMARDs
   • Anti-Tumour Necrosis Factor (anti-TNF): infliximab (IFX), etanercept (ETN), adalimumab (ADA) and golimumab (GOL)
   • Interleukin-6 (IL-6) receptor blocker: tocilizumab (TCZ)
   • Anti-B cell agent: rituximab (RTX)
4. Biosimilar DMARDs
   • Currently, only biosimilars of Adalimumab and infliximab are available in the market

DMARDs as Immunomodulators

All patients should be screened for infections, vaccination history, serology and history of malignancy before starting immunomodulators.^2,5 Killed vaccines such as pneumococcal, influenza and hepatitis B are recommended at all times; the same goes for recombinant vaccines such as Human Papillomavirus vaccines.⁴ Live attenuated vaccines such as herpes zoster vaccines are encouraged before and after starting DMARDs, except in anti-TNF and non-TNF biologics.⁴

Screening for hepatitis C, hepatitis B, and latent tuberculosis are also recommended.⁵ During serious infections, all DMARDs must be ceased until the conditions are resolved.⁴  The non-exhaustive list of severe infections includes sepsis, abscess, hepatitis B, and active TB (before completing TB treatment).⁴ Some signs of severe or opportunistic diseases to look out for before and after starting DMARDs are persistent fever, itching or painful rash (shingles due to herpes reactivation) or other signs of infection.²

DMARDs and Teratogenicity

Pregnancy status should be assessed in all females initiating DMARDs so that an appropriate choice of DMARD can be made. As DMARDs may affect pregnancy outcomes, men and women within the childbearing age starting on DMARDs should be given proper counselling on family planning.⁴ For CsDMARDs, methotrexate and leflunomide are contraindicated if the patient is pregnant or lactating.⁴ Methotrexate should be stopped at least three months before conception, while leflunomide should be washed out.⁴ The washout procedure includes 8 g colestyramine three times daily (or 50 g activated charcoal four times daily) for 11 days.² Hydroxychloroquine is safe to use in pregnancy and breastfeeding mothers.⁴ Sulfasalazine is safer to use during pregnancy if folate supplementation is provided with the therapy.⁴ It is safe to breastfeed a healthy, full-termed baby while taking sulfasalazine.⁴ However, care should be taken to eliminate the possibility of the infant having a premature infant, hyperbilirubinemia, and glucose-6-phosphate dehydrogenase (G6PD) deficiency.⁴

Regarding biologics, adalimumab and infliximab can be continued up to gestational week 20.⁴ Etanercept can be used in pregnant ladies up to weeks 30 to 32 of the gestational week.⁴ Rituximab may be considered only if other alternatives are unavailable or unsuitable in early gestational weeks.⁴ Neonates exposed to rituximab can have various forms of cytopenia.⁴ Adalimumab, infliximab and etanercept can be continued throughout pregnancy if indicated.⁴ Golimumab has limited evidence of safety in pregnancy, while tocilizumab is contraindicated in pregnancy.⁵ All biologics are compatible with lactation except tocilizumab.⁴

Targeted synthetic DMARDs should be avoided in pregnancy.⁴ Tofacitinib should be ceased two months before pregnancy, while insufficient data supports the use of baricitinib in lactating and pregnant mothers.⁴

Other comorbidities

American guidelines recommend laboratory assessments to determine complete blood count, serum creatinine and aminotransferase, as there are risks of myelosuppression, as well as renal and hepatic toxicity with DMARDs.⁵ Symptoms of myelosuppression to watch out for in the population taking methotrexate and sulfasalazine include malaise, increased incidences of unusual bruising and severe infections.⁵ It is possible for some DMARDs, such as methotrexate, leflunomide, abatacept, rituximab, sulfasalazine and TNF inhibitor to cause lung damage.⁵ Hence, care should be taken to screen patients with lung diseases.⁵ In patients with renal diseases, Methotrexate should be avoided.⁵

TNF alpha antagonists, especially etanercept and golimumab, should be avoided if the patient has heart failure, which may worsen the condition.^2,5 Peripheral neuropathy is possible with a few DMARDs, such as Leflunomide.⁵ It can manifest as numbness or tingling in your fingers or toes.⁵ Routine monitoring for lipid levels is required for patients on tsDMARDs and IL-6 inhibitors as they may raise the level of cholesterol.⁵ These two classes of DMARDs can increase the risk of gastrointestinal (GI) perforation due to the tendency to develop diverticulitis while on these medications.⁵ The risk of developing GI perforation with these medications can be dose-related.²

Epilogue

So why talk about DMARDs when they are uncommon in our daily practice? With the expiration and imminent expiration of a few DMARDs, it is time for us to consider adopting them into the long-term treatment plan for RA. As pharmacists, we must stay on top of the latest drug development and be the ones who inform the multidisciplinary team about the latest drug information to maintain our competitive edges.

References:

1. American College of Rheumatology. Diseases and Conditions [Internet]. Atlanta: American College of Rheumatology; [cited 2023 Apr 21]. Available from: https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions
2. Australian medicines handbook online [Internet]. Adelaide (AU): Australian Medicines Handbook Pty Ltd; 2000. [updated 2023 Jan; cited 2023 April 17]. Available from: https://amhonline-amh-net-au.ezproxy.library.uq.edu.au/
3. Centers for Disease Control and Prevention. Rheumatic Diseases and Pain [Internet]. GA: Centers for Disease Control and Prevention; [updated 2022 Aug 15; cited 2023 April 21]. Available from: https://www.cdc.gov/arthritis/communications/features/rheumatic-diseases-and-pain.html
4. Clinical Practice Guideline: Management of Rheumatoid Arthritis [Internet]. Putrajaya: Malaysia Health Technology Assessment Section (MaHTAS), Malaysia; 2019. Available from: https://www.moh.gov.my/moh/resources/Penerbitan/CPG/Rheumatology/CPG_Rheumatoid_Arthritis-17052021.pdf
5. Moreland L and Canella A. General principles and overview of management of rheumatoid arthritis in adults [Internet]. WA: UpToDate; [updated 2023 Mar 7; cited 2023 Apr 21] Available from: https://www.uptodate.com/contents/general-principles-and-overview-of-management-of-rheumatoid-arthritis-in-adults?search=dmard&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2

The information provided should not be used for diagnosing or treating a health problem or disease, and those seeking personal medical advice should consult with a licensed physician. Always seek the advice of your doctor or other qualified health providers regarding a medical condition.