Biologic disease-modifying antirheumatic drugs (DMARDs) demonstrate varying impact on the symptoms and progression of rheumatoid arthritis.
Todd Cooperman, PharmD, RPh, PAHM Russel Allinson, RPh, MS
Several biologic disease-modifying antirheumatic drugs (DMARDs) are currently approved for the treatment of rheumatoid arthritis (RA). There are 5 agents that either can be self-injected or could be self-injected with appropriate instruction. Of these, 4 are antibodies directed specifically toward tumor necrosis factor (TNF)-alpha, which is 1 of the primary mediators of the inflammatory process. The other product is directedtoward interleukin-1, which is also amediator of the inflammatory process.
All of these agents have shown benefits in impacting the symptoms and progression of RA. Due to the availability of multiple biologic products—as well as several nonbiologic medications with significant data to demonstrate benefit—and the large range in monthly costs for patients, there is a significant opportunity for pharmacists to monitor patients and ensure that they are obtaining optimal benefits from their therapy, or identify when a change in therapy may be needed.
In 2008, the American College of Rheumatology (ACR) updated its recommendations for the use of both nonbiologic and biologic medications. Within these recommendations, various treatment options are designated to specific patient cohorts based on disease duration, disease activity, and prognostic factors. Disease duration can be broken down into early (<6 months), intermediate (6-24 months), and long (>24 months) duration. Disease activity can be measured through multiple validated disease measures, including the Disease Activity Score 28, Simplified Disease Activity Index, Clinical Disease Activity Index, and Rheumatoid Arthritis Disease Activity Index. In the majority of patients, a nonbiologic agent DMARD should be the initial therapeutic choice, with methotrexate being the most probable choice, unless there is a compelling reason for the prescriber to choose another agent.
Those patients who fail a nonbiologic DMARD or have a high disease activity in conjunction with poor prognostic factors are typical candidates for initiation of a biologic agent. Poor prognostic factors include radiographic erosion, elevated levels of rheumatoid factor, and several other laboratory measures. Poor prognostic factors not associated with laboratory results include poorer physical functioning (evaluated through the use of the Health Assessment Questionnaire), current smoking status, female gender, extra-articular manifestations, and older age.1 Patients who fail 1 or more trials of a nonbiologic DMARD, have a high disease activity, and/or have poor prognostic factors would be candidates for a biologic agent.
All TNF antagonists are considered equally efficacious in the management of RA, and are most often the first choice in the selection of initial biologic therapy. The ACR guidelines consider all TNF agents to be interchangeable, and therefore the selection of an agent is typically determined based on a prescriber’s experience with a specific agent. In addition, a biologic is usually given in conjunction with a DMARD, most often methotrexate, unless there is a compelling reason not to use a DMARD. Once started, patients should be maintained on therapy for a minimum of 3 months to properly assess their response to therapy. A lack of response at 3 months is suggestive that a change in therapy may be indicated. Several studies indicate that patients who stop therapy due to lack of effectiveness could demonstrate an improvement in disease activity through the use of a secondary TNF agent.2,3 Most often when patients discontinue use of a secondary TNF agent, it is due to intolerances to therapy.4
Pharmacists maximize their patients’ opportunities to achieve a benefit from therapy by monitoring for potential adherence issues and side effects. Adherence is critical during the 3-month trial period because therapy failure will drive movement from 1 agent to the next and eventually to other therapeutic classes. When assessing patients for exhibition of side effects, the most common are development of an infection, injection-site reactions, and exacerbation of underlying cardiac disease in those patients with an underlying disease. The majority of injection- site reactions can be properly managed through injection training.
Those patients with underlying cardiac disease should be encouraged to monitor and document their blood pressure daily and notify their doctor if they notice an increase that varies from their normal blood pressure patterns. Pharmacists who notice a dose escalation in a patient’s antihypertensive medication in the presence of a TNF agent may want to consult with the prescribing physicians for both the antihypertensive agent and the TNF to ensure that both are aware of the 2 therapies.
Biologic DMARDs represent a therapeutic option for those patients with specific characteristics or positions on the therapeutic progression scale for RA. Once started, patients should be advised that it will require at least 3 months todetermine whether or not the therapy is beneficial for them. During the trial period, adherence is imperative and monitoring by both the prescriber and the pharmacist is needed to ensure that potential issues that could impact adherence are addressed. Those patients either fail initial trials or are intolerant to a TNF antagonist can be placed on a secondary TNF agent.
1. Saag KG, et al. American College of Rheumatology 2008 Recommendations for the Use of nonbiologic and Biologic Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis. Arthritis & Rheumatism 2008; 59 (6): 762-784.
2. K. L. Hyrich, M. Lunt, W. G. Dixon, K. D. Watson, D. P. M. Symmons. Effects of switching between anti-TNF therapies on HAQ response in patients who do not respond to their first anti-TNF drug. Rheumatology 2008: 47 (7): 1000-1005.
3. S N Nikas,P V Voulgari, Y Alamanos, C G Papadopoulos, A I Venetsanopoulou, A N Georgiadis, A A Drosos. Efficacy and safety of switching from infliximab to adalimumab: a comparative controlled study. Ann Rheum Dis 2006;65:257-260
4. KL Hyrich, ML, KD Watson, et al. Outcomes after switching from one anti—tumor necrosis factor α agent to a second anti–tumor necrosis factor α agent in patients with rheumatoid arthritis: Results from a large UK national cohort study. Arthritis & Rheumatism 2006; 56 (1): 13-20.
5. Humira [package insert]. North Chicago, IL: Abbott Laboratories; 2006.
6. Kineret [package insert]. Thousand Oaks, CA: Amgen; 2006.
7. Simponi [package insert]. Horsham, PA: Centocor Ortho Biotech; 2009.
8. Cimzia [package insert]. Smyrna, GA: UCB, Inc.; 2009.
9. Enbrel [package insert]. Thousand Oaks, CA:Amgen; 2010.
Dr. Cooperman is director of research and developmentand Mr. Allinson is chief executive officer and chief clinical officer of Therigy, LLC.