Rheumatoid Arthritis Treatment

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes joint pain, stiffness, swelling, and decreased joint movement.¹ According to the American College of Rheumatology (ACR), RA affects over 1.3 million individuals in the United States and approximately 75% are women.¹ Unfortunately, there is no cure for the condition but early treatment can reduce joint pain and swelling and improve patients’ ability to perform daily activities. As drug information experts, pharmacists are well equipped to help patients select the most appropriate RA treatment option and educate them about potential drug and disease state interactions as well as lifestyle modifications to improve symptoms (see Table 19-23).

Treatment Options and Drug Interactions

Pharmacologic treatment options for RA include conventional disease-modifying antirheumatic drugs (DMARDs), biologic DMARDs, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids. Therapies are available orally, as injections, or as intravenous infusions^.2-4 The ACR recommends using the treat-to-target approach, which involves setting a therapeutic goal and working with patients to achieve the best health outcomes.² Conventional DMARDs can take several weeks for patients to experience the full benefits, but they improve active RA symptoms, slow the disease course, and improve radiographic outcomes.^2,3 Examples of conventional DMARDs include methotrexate (eg, Rheumatrex, Trexall), sulfasalazine (Azulfidine), leflunomide (Arava), and hydroxychloroquine (Plaquenil).^3,4 

Conventional DMARDs

The ACR recommends methotrexate as the first-line DMARD for RA because most patients continue to take the therapy after 5 years based on its efficacy and tolerability.^2,3 Pharmacists should advise patients to take methotrexate once weekly and not daily to prevent toxicity; many fatal errors have been reported to the Institute for Safe Medication Practices regarding this high-alert medication.⁵ As methotrexate can cause hepatotoxicity, patients should limit alcohol- containing beverages to no more than 1 to 2 per week.³ Folic acid supplementation can help reduce the incidence of hepatotoxicity and of gastrointestinal (GI) adverse effects (AEs) associated with the drug.⁶ Patients should avoid taking the antibiotic trimethoprim because it can increase methotrexate levels and cause nephrotoxicity and myelosuppression (low blood counts).^3,5 If trimethoprim is necessary in the event there is no alternative antibiotic, the methotrexate should be held that week. Caution should be exercised if NSAIDs are used with methotrexate because of an increased risk of methotrexate toxicity; patients should be closely monitored.³ In addition, the herbal supplement echinacea also can cause hepatotoxicity and its use should be avoided with methotrexate.⁷ 

Concomitant use of sulfasalazine and NSAIDs can increase the risk of GI bleeding. Patients taking leflunomide should limit alcohol consumption because it can cause liver damage.^3,8 Higher doses of hydroxychloroquine for COVID-19 treatment has been associated with QTc prolongation.⁹ However, evidence suggests that lower doses of the drug for RA treatment should not itself increase the risk of QTc prolongation or the fatal arrhythmia torsades de pointes.⁹ Pharmacists should review patients’ medication profiles for possible drugs that could cause QTc prolongation in individuals taking hydroxychloroquine, especially those with heart conditions.

Medications that can cause QTc prolongation include¹⁰:

• antipsychotics (eg, haloperidol, ziprasidone, risperidone);
• antiarrhythmics (eg, amiodarone, quinidine);
• antibiotics (eg, azithromycin, fluoroquinolones); 
• antidepressants (eg, amitriptyline);
• methadone; and
• ondansetron.

Biologic DMARDs

Tumor necrosis factor (TNF) inhibitors were the first biological DMARDs to be approved for the treatment of RA.

TNF inhibitors include the following^2,3:

• etanercept (Enbrel; Amgen, Inc);
• infliximab (Remicade; Janssen Biotech, Inc);
• adalimumab (Humira; AbbVie Inc);
• certolizumab pegol (Cimzia; UCB, Inc); and
• golimumab (Simponi; Janssen Biotech, Inc).

Adalimumab-fkjp (Hulio; Mylan Pharmaceuticals Inc) is a biosimilar to Humira that was approved in 2020 to potentially reduce cost and improve patient access.¹¹ Because reactivation of hepatitis B can occur with TNF treatment, it is important to screen patients prior to their starting therapy.^2,3 An increased risk of infection exists with TNF inhibitors, and ongoing studies are evaluating the temporary hold of any biologic DMARD in patients with an active infection and antibiotic use.³ Abatacept (Orencia; Bristol-Myers Squibb Company) is the first medication of the T-cell costimulation modulator class.^3,12 Its concomitant use with TNF inhibitors is not recommended because of an increased risk of serious infections and no added efficacy.¹² Rituximab (Rituxan; Genentech, Inc) is a B-cell therapy, and its biosimilar rituximab-arrx (Riabni; Amgen, Inc) was approved in 2020.¹¹ As hepatitis B reactivation can occur in patients taking rituximab, individuals should be screened before receiving treatment.³

Interleukin-6 (IL-6) receptor blockers include tocilizumab (Actemra; Genentech, Inc) and sarilumab (Kevzara; Regeneron and Sanofi Genzyme).^8,13 Patients taking medications including warfarin or theophylline should have their blood levels monitored closely, with possible dose adjustments when starting or discontinuing tocilizumab or sarilumab.^8,13

The Janus kinase (JAK) inhibitors tofacitinib (Xeljanz; Pfizer), baricitinib (Olumiant; Eli Lilly and Company), and upadacitinib (Rinvoq; AbbVie Inc) are the only oral biologic DMARDs for RA.⁸ The FDA recently issued an updated drug safety communication regarding preliminary safety trial results for tofacitinib; compared with TNF inhibitors, both doses of the drug showed an increased risk of serious heart-related problems and cancer for patients with RA.¹⁴ The agency previously added a boxed warning, in 2019, when evidence showed an increased risk of blood clots and death with the higher 10-mg twice daily dose.^14,15 Baricitinib and upadacitinib also include boxed warnings about the risk of blood clots.^16,17 Pharmacists can play an important role in counseling patients about these risks, especially individuals who have a history of cardiovascular conditions and cancer. The administration of tofacitinib or upadacitinib with strong cytochrome P450 3A4 (CYP3A4) inducers (eg, rifampin) should be avoided, as the JAK inhibitor efficacy can be decreased.^15,16 Additionally, the tofacitinib dose should be decreased for patients who are also taking strong CYP3A4 inhibitors (eg, ketoconazole) or a moderate CYP3A4 inhibitor with a strong CYP2C19 inhibitor (eg, fluconazole).¹⁵Further, a baricitinib dose should be reduced when the drug is taken concomitantly with a strong organic anion transporter 3 inhibitor (eg, probenecid).¹⁷ 

NSAIDs and Corticosteroids

Adjunctive treatments for RA include NSAIDs and corticosteroids, which can reduce inflammation and control pain.³ Many NSAIDs are available OTC and include aspirin, ibuprofen, and naproxen; co-administration with a proton pump inhibitor can prevent the GI bleeding associated with NSAIDs.³ Counseling patients about avoiding multiple products that contain NSAIDs by reading the OTC drug facts label is critical to prevent serious AEs. Additionally, as NSAIDs can increase the risk of cardiovascular events and impair renal function,^3,4 their long-term use should be avoided, especially in patients with heart disease or renal dysfunction. Corticosteroids (eg prednisone, methylprednisolone) should be used short-term for treatment and tapered before discontinuing.^3,18 They can increase blood glucose levels, therefore patients with diabetes should be closely monitored. Individuals can also develop osteoporosis.¹⁸ Further, patients with a history of mental illness may be at an increased risk of developing neuropsychiatric AEs (eg, aggression, insomnia, depression, psychosis) with corticosteroid therapy, but these symptoms can also occur in those without such history.¹⁸ 

References

1. Rheumatoid arthritis. American College of Rheumatology. Updated March 2019. Accessed March 14, 2021. https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Rheumatoid-Arthritis
2. Singh JA, Saag KG, Bridges Jr SL, et al; American College of Rheumatology. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 2016;68(1):1-25. doi:10.1002/acr.22783
3. Rheumatoid arthritis treatment. Johns Hopkins Arthritis Center. Accessed March 20, 2021. https://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-treatment/ 
4. Rheumatoid arthritis. Mayo Clinic. March 1, 2019. Accessed March 20, 2021. https://www.mayoclinic.org/diseases-conditions/rheumatoid-arthritis/symptoms-causes/syc-20353648 
5. Severe harm and death associated with errors and drug interactions involving low-dose methotrexate. Institute for Safe Medication Practices. October 8, 2015. Accessed March 20, 2021. https://www.ismp.org/resources/severe-harm-and-death-associated-errors-and-drug-interactions-involving-low-dose doi:10.1097/RHU.0000000000000810
6. Chua D. Chronic use of echinacea should be discouraged. Am Fam Physician. 2003;68(4):617.
7. Pflugbeil S, Böckl K, Pongratz R, Leitner M, Graninger W, Ortner A. Drug interactions in the treatment of rheumatoid arthritis and psoriatic arthritis. Rheumatol Int. 2020;40(4):511-521. doi:10.1007/s00296-020-04526-3
8. Pareek A, Sharma TS, Mehta RT. Hydroxychloroquine and QT prolongation: reassuring data in approved indications. Rheumatol Adv Pract. 2020;4(2):rkaa044. doi:10.1093/rap/rkaa044
9. Farzam K, Tivakaran VS. QT prolonging drugs. StatPearl. Updated November 27, 2020. Accessed March 20, 2021. https://www.ncbi.nlm.nih.gov/books/NBK534864/
10. New drug therapy approvals 2020. FDA. Updated January 8, 2021. Accessed March 20, 2021. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2020 
11. Orencia. Prescribing information. Bristol-Myers Squibb Company; 2020. Accessed March 20, 2021. https://packageinserts.bms.com/pi/pi_orencia.pdf
12. Actemra. Prescribing information. Genentech; 2021. Accessed March 20, 2021. https://www.gene.com/download/pdf/actemra_prescribing.pdf
13. Xeljanz, Xeljanz XR (tofacitinib): drug safety communication – initial safety trial results find increased risk of serious heart-related problems and cancer with arthritis and ulcerative colitis medicine. FDA. February 4, 2021. Accessed March 20, 2021. https://www.fda.gov/safety/medical-product-safety-information/xeljanz-xeljanz-xr-tofacitinib-drug-safety-communication-initial-safety-trial-results-find-increased 
14. Xeljanz. Prescribing information. Pfizer; 2020. Accessed March 20, 2021. http://labeling.pfizer.com/ShowLabeling.aspx?id=959#section-7
15. Rinvoq. Prescribing information. AbbVie Inc; 2020. Accessed March 20, 2021. https://www.rxabbvie.com/pdf/rinvoq_pi.pdf 
16. Olumiant. Prescribing information. Eli Lilly and Company; 2020. Accessed March 20, 2021. https://uspl.lilly.com/olumiant/olumiant.html#s10
17. Yasir M, Goyal A, Bansal P, Sonthalia S. Corticosteroid adverse effects. StatPearls. Updated March 3, 2021. Accessed March 20, 2021. https://pubmed.ncbi.nlm.nih.gov/30285357/
18. Rheumatoid arthritis. American College of Rheumatology. Updated March 2019. Accessed March 21, 2021. https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Rheumatoid-Arthritis 
19. Rheumatoid arthritis: is exercise important? Mayo Clinic. July 31, 2020. Accessed March 21, 2021. https://www.mayoclinic.org/diseases-conditions/rheumatoid-arthritis/in-depth/rheumatoid-arthritis-exercise/art-20096222 
20. Foods that can help RA symptoms. Arthritis Foundation. Accessed March 21, 2021. https://www.arthritis.org/health-wellness/treatment/treatment-plan/tracking-your-health/foods-that-can-help-ra-symptoms 
21. Forsyth C, Kouvari M, D’Cunha NM, et al. The effects of the Mediterranean diet on rheumatoid arthritis prevention and treatment: a systematic review of human prospective studies. Rheumatol Int. 2018;38(5):737-747. doi:10.1007/s00296-017-3912-1
22. Meena N, Chawla SPS, Garg R, Batta A, Kaur S. Assessment of vitamin D in rheumatoid arthritis and its correlation with disease activity. J Nat Sci Biol Med. 2018;9(1):54-58. doi:10.4103/jnsbm.JNSBM_128_17