Managing Rheumatoid Arthritis

Rheumatoid arthritis (RA) is the most common chronic inflammatory joint disease, affecting an estimated 0.5% to 1% of the population in Northern Europe and North America. This prevalence may be lower in other, more rural parts of the world.^1,2 There is no clear cause of RA; however, genetic and environmental factors, such as smoking, obesity, and infection, may contribute to the development, persistence, and outcomes of RA.²

Approach to Therapy

The majority of patients with a confirmed diagnosis of RA will require non-biologic disease-modifying antirheumatic drugs (DMARDs) in addition to glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, and other non-pharmacologic treatments such as physical and occupational therapy. Furthermore, the rate of biologic DMARD use is rapidly rising and there are new biologic agents targeting a variety of inflammatory mediators emerging regularly.

The American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) have published guidelines for the use of these agents in RA with an emphasis on early DMARD institution and a stepwise approach to therapy.^3-5 Figure 1 summarizes this basic treatment strategy which is based on 4 main considerations:

• Disease duration
• Level of disease activity
• Presence of poor prognostic features
• Cost or insurance coverage limitations

Typically, non-biologic DMARDs are first-line therapy following RA diagnosis, with methotrexate being the preferred oral agent.⁵ If clinical response is not sufficient following an adequate trial of at least 3 months, then another DMARD, such as hydroxychloroquine (HCQ) or leflunomide (LEF), is added to current therapy. If the patient cannot tolerate their current drug therapy then a switch is made. In more severe cases of RA, or in the presence of poor prognostic features, including high tender and swollen joint counts, evidence of radiographic erosions, elevated levels of rheumatoid factor (RF), and/or anti-cyclic citrullinated peptide (anti-CCP) antibodies, adding or switching to a biologic DMARD is considered.^3-5

The majority of clinical evidence supports the use of anti—tumor necrosis factor (TNF) agents (eg, etanercept, infliximab, adalimumab); however, other, newer agents targeting different inflammatory mediators, such as IL-1 and IL-6, are gaining popularity. The clinical studies of these biologic agents are largely 2-arm studies of the biologic DMARD plus methotrexate versus methotrexate monotherapy. As a result, the evidence to support choosing one biologic DMARD over another is based on indirect comparisons across trials.⁶ In fact, results from the first head-to-head study of biologic DMARDs, the AMPLE study, were just published in January 2013. This study randomized biologic DMARD-naïve patients with moderate to severe RA currently on stable methotrexate doses to either subcutaneous abatacept or adalimumab arms. Results demonstrated equal clinical efficacy and inhibition of radiographic progression with similar rates of adverse events after 1 year.⁷ Additional head-to-head studies are needed to support clinical decision making in deciding which biologic agent to start. At this point, clinical efficacy is considered equivalent across these agents and achieving low disease activity or remission is often the result of trial and error.

As a health-system pharmacist, you may encounter these agents in multiple settings. Patients having a severe flare may be admitted for intravenous (IV) infusion or may be getting routine maintenance infusions at your hospital. Patients coming to your clinic may be newly started on a subcutaneous formulation and have questions regarding cost, adverse effects, monitoring, and administration. Table 1^8-17 provides an overview of the biologic agents with FDA-approved indications for RA.

Prior to Therapy Evaluation

As the pharmacist, there are numerous opportunities to be involved in the decision to start DMARD therapy and the monitoring that is necessary prior to and during therapy. All patients being considered for DMARD therapy require a baseline complete blood count, liver transaminases, and serum creatinine. Beyond 3 months of therapy, routine lab monitoring is recommended every 8 to 12 weeks. Tuberculosis screening is recommended for patients being considered for a biologic DMARD. This involves a tuberculin skin test for all patients and a skin test plus chest radiograph for patients with risk factors for latent tuberculosis (TB) infection.

This recommendation is based on evidence of higher incidence of TB following anti-TNF-α therapy. Additionally, the ACR guidelines support compliance with Centers for Disease Control and Prevention recommendations for periodic pneumococcal and annual influenza vaccinations for all patients as well as completion of the hepatitis B vaccination series for high-risk patients.^3,4 Table 2 provides other general recommendations for baseline evaluation and vaccination in patients receiving biologic and non-biologic DMARDs.^3,4

Patient Counseling

Education is crucial for RA patients newly starting on a DMARD, particularly a biologic agent. Listed below are a few key counseling points that should be addressed before starting one of these drugs.

• Subcutaneous injection technique: -Have patient practice with demo injection devices or perform their first injection with a nurse, physician, or pharmacist.
• Hypersensitivity reactions: -Provide written and verbal education on the signs and symptoms of an allergic reaction (eg, anaphylaxis, angioedema, urticaria) and what to do should a reaction occur.
• Increased risk of infection: -Provide written and verbal education on the signs and symptoms of infection and the increased risk of infection while on drug therapy. -Instruct patient to notify their rheumatologist and discontinue the drug if serious infection or sepsis occurs.
• Black box warning for increased risk of malignancy (TNF-α inhibitors): -All patients should be aware of this black box warning.
• Injection or infusion should be held for 1 week before and after major surgery when infection risk is high.

Suzanne J. Francart, PharmD, BCPS, CPP, is a clinical pharmacist in the University of North Carolina Medical Center Rheumatology Clinic, Chapel Hill, North Carolina.

References:

• Alamanos Y, Drosos AA. Epidemiology of adult rheumatoid arthritis. Automimmunity Reviews. 2005:4(3):130-136.
• Symmons, Deborah PM. Epidemiology of rheumatoid arthritis: determinants of onset, persistence and outcome. Best Pract Research Clin Rheum. 2002;16(5):707-722.
• Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumtatic drugs in rheumatoid arthritis. Arthritis Rheumatism. 2008;59(6):762-784.
• Singh JA, Furst DE, Bharat A, et al. 2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res. 2012;64(5):625-639.
• Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis. 2010:1-12.
• Estellat C, Ravaud P. Lack of head-to-head trials and fair control arms. Arch Intern Med. 2012;172(3):237-244.
• Weinblatt ME, Schiff M, Valenta R. Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis. Arthritis Rheumatism. 2013;16(1):28-38.
• Humira [package insert]. North Chicago, IL: AbbVie Inc; 2013.
• Enbrel [package insert]. Thousand Oaks, CA: Amgen Inc; 2013.
• Remicade [package insert]. Horsham, PA: Janssen Biotech, Inc; 2013.
• Cimzia [package insert]. Smyrna, GA: UCB, Inc; 2012.
• Simponi ARIA [package insert]. Horsham, PA: Janssen Biotech, Inc; 2013.
• Simponi [package insert]. Horsham, PA: Janssen Biotech, Inc; 2013.
• Orencia [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2013.
• Rituxan [package insert]. South San Francisco, CA: Genetech, Inc; 2012.
• Actemra [package insert]. South San Francisco, CA. Genetech, Inc; 2013.
• Kineret [package insert]. Stockholm, Sweden: Swedish Orphan Biovitrum AB; 2012.