Rheumatoid Arthritis: Halting the Progression

Newer treatments have greatly improved outcomes for patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by severe pain, stiffness, inflammation, and deformity of the joints, which can negatively impact one’s optimal quality of life. The Centers for Disease Control and Prevention estimates that RA affects 1.5 million adults in the United States. Tremendous strides have been made in gaining a greater insight into the etiology, treatment, and causes of RA, but research is ongoing. Although the exact cause of RA is unknown, many experts think that RA may be linked to genetic, environmental, hormonal, immunologic, and infectious factors.^1,2 Women are 2.5 to 3 times more likely to have RA than are men.^1,2 According to the American College of Rheumatology and the US Department of Health and Human Services, an estimated 70% to 75% of those affected by RA are women.³ RA commonly manifests between 30 and 60 years of age, but it can occur at any age.³

Over time and without early intervention, RA can worsen and make simple, everyday tasks cumbersome. The severity of RA varies from individual to individual, so treatment should be tailored to meet the needs of each patient. RA not only affects the joints but can also impinge on an individual’s ability to function and can negatively influence his or her overall quality of life. RA can affect practically every aspect of an individual’s life: unfortunately, many patients with RA sometimes also experience depression, anxiety, low self-esteem, and feelings of helplessness.^1,2,4 One study reported that more than 25% of women with RA stopped working within 4 years of being diagnosed with RA1 (online Table 1).

Table 1: RA Facts from the Arthritis Foundation and the NIH

• Exact cause of RA is unknown
• Genetic factors are thought to have a pivotal role in the development of RA
• Affects women 2.5 times more than men
• Average age of onset is between 30 and 60 years
• RA is a high risk for disability and mortality and accounts for 22% of all deaths from arthritis and other rheumatic conditions
• Symptoms typically begin in the small joints of the fingers, wrist and feet
• Joints of both sides of the body are normally affected and over time may lead to joint deformities
• RA can cause damage to lung tissue, increase risk of hardening of the arteries, spinal injury if neck bones are affected
• May cause rheumatoid vasculitis (inflammation of the blood vessels) which may result skin, nerve, heart and brain issues

Information for table obtained from the

• Arthritis Foundation website at http://www.arthritis.org/files/images/newsroom/media-kits/Rheumatoid_Arthritis_Fact_Sheet.pdf
• National Institutes of Health’s Medline Plus website. http://www.nlm.nih.gov/medlineplus/ency/article/000431.htm

Typically, the signs and symptoms associated with RA manifest gradually and become additive over time.^1,2 The hallmark characteristic of RA is persistent synovitis (also known as persistent symmetric polyarthritis), which affects the joints of the hands and feet.⁵ Synovitis typically develops gradually and symmetrically, often involving the joints of the hands, wrists, knees, or feet.^5,6 Common signs and symptoms associated with RA include low-grade fever, fatigue, malaise, generalized stiffness, myalgias, or generalized arthralgias.^1-3,5 Patients also often complain of morning stiffness, and some patients develop rheumatoid nodules—lumps of tissue that form under the skin.^5,6

Treating Rheumatoid Arthritis

Although there is no cure for RA, in recent years, newer treatments have greatly improved outcomes for RA patients. Treatment of RA typically involves a multi-treatment approach and may involve a combination of nonpharmacologic measures, such as adequate nutrition, physical measures, exercise, and rest, in conjunction with pharmacologic therapy (online Table 2). Some patients may require surgery and/or physical therapy. RA is treated and managed with various classes of pharmacologic agents, including analgesics (acetaminophen and nonsteroidal anti-inflammatory drugs), corticosteroids, and disease-modifying antirheumatic drugs (DMARDs).^1,2,5 DMARDs are classified into 2 subtypes, including nonbiologic and biologic. Examples of nonbiologic DMARDs include hydroxychloroquine, azathioprine, sulfasalazine, methotrexate, leflunomide, cyclosporine, and minocycline.^5,7,8 The newest category of pharmacologic agents approved for RA is a subset of DMARDs called biologic response modifiers, or biologics. Table 3 (online) lists available agents approved for treating RA.

Table 2 : General Goals of Treatment^1,5

• Relief or reduction of pain

• Prevention or reduction of inflammation

• To slow down or stop progression of joint damage and disability

• Improve a person’s sense of well-being and ability to function.

• Reduction/Prevention of long term disease complications

The American College of Rheumatology published updated guidelines for treating RA in the May 2012 issue of Arthritis Care and Research. The guidelines stress the importance of (1) aggressive therapy during early RA to increase the incidence of better patient outcomes and (2) helping patients to maintain the use of affected joints and improve their overall quality of life.^7,23 The new guidelines favor early treatment with the use of triple-combination DMARD regimens or a biologic with or without methotrexate for patients with high disease activity and a poor prognosis.^7,23 However, biologics are not recommended for treating early RA in patients with low to moderate disease activity and without a poor prognosis.^7,23 The guidelines also address special considerations and recommendations for the use of biologic agents in high-risk patients and screening for tuberculosis for all patients beginning or receiving biologics.^7,23 In addition, the guidelines make recommendations for certain vaccinations (eg, pneumococcal, influenza, hepatitis B, human papillomavirus, herpes zoster) for patients taking DMARDs or biologic agents.^7,23 The guidelines also encourage physicians to consider the risks and benefits of treatment for each patient.

Many experts think that aggressive and early RA treatment may delay or decrease joint destruction.^7,9,10 In general, the goals of treatment include pain relief, reduction in joint inflammation and damage, and improvement of the patient’s quality of life and ability to perform daily tasks.^1,5,7

Early implementation of therapy with DMARDs has become the standard of care and the most important method of effectively managing RA, as studies reveal that initiating early therapy (<6 months after the onset of symptoms) with these agents not only delays the progression of RA more effectively than later treatment but may also prompt more remissions in patients.^5-10 Various studies have shown that the use of DMARDs can slow or prevent disease progression, joint destruction, and subsequent loss of function.^5,9,10 In addition, researchers think that that proper use of DMARDs may also decrease or eliminate the need for other anti-inflammatory or analgesic medications; however, until the full therapeutic effect of DMARDs takes effect, anti-inflammatory or analgesic medications may be required as supplemental drug therapy to help reduce pain and swelling.^5,9,10

Table 3: Examples of Biologic DMARDs Agents Used to Treat RA^7-22

Drug Class

Examples

Generic(brand name)/Manufacturer

Comments

Tumor necrosis factor (TNF) inhibitors

• etanercept (Enbrel)/Amgen
• infliximab (Remicade),/Janssen
• adalimunab (Humira)/AbbVie Inc
• certolizumab pegol (Cimzia) /UCB Inc
• golimumab (Simponi)./Janssen

Patients may experience fever, chills, body aches, and headache associated with the infusion of biologics. Administered either via injection as subcutaneously or IV route depending upon agent and each manufacturer’s recommendations. These agents are used as monotherapy or in conjunction with methotrexate. The most common effects of TNF inhibitors include upper respiratory infections, pneumonia, urinary tract infections, and skin infection, nausea.

T-cell Costimulatory Blocking agent

abatacept (Orencia)/Bristol Myers Squibb

Administered either via IV or sub q route. Responses typically observed within 3 months of therapy. As with other biological DMARDS infections are increased in patients receiving abatacept. Common ADRs include head, sore throat and nausea

B-cell Depletion

rituximab (Rituxan)/Genentech

Administered via IV route. Patients should receive IV corticosteroid 30 minutes before each infusion, Common adverse effects may include hives, itching, swelling, difficulty breathing, fever, chills, and changes in blood pressure

Interleukin-6 (IL-6) receptor antagonist

Tocilizumab (Actemra)/Genentech

Administered via IV infusion. Indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more DMARDs. Common ADRs reported as upper respiratory

tract infections, nasopharyngitis, headache, hypertension, increased ALT.

Human recombinant IL-1 receptor antagonist

Anakinra (Kineret)/Sobi Inc

Administered subcutaneously. Most common ADRs: pain at injection site, erythema, itching , fever, nausea

In November 2012, the FDA approved a new oral agent in a new class of drugs known as JAK inhibitors for the treatment of RA. JAK inhibitors block janus kinase pathways, which are involved in the immune system.^24-26 Tofacitinib (Xeljanz, Pfizer Inc) is the first oral DMARD approved in almost a decade. This agent provides a new treatment option for adults with moderately to severely active RA who have an inadequate response to, or may be intolerant of, methotrexate.^24-26

The FDA reports that the use of tofacitinib is associated with an increased risk of serious infections, including opportunistic infections, tuberculosis, cancers, and lymphoma.^24-26 This agent currently carries a boxed warning regarding these safety risks. In addition, the use of this agent is associated with increases in cholesterol and liver enzyme tests and decreases in blood counts.^24-26 Tofacitinib is administered orally twice a day without regard to food, and its most common adverse effects include upper respiratory tract infections, headache, diarrhea, and nasopharygitis.^24-26 The use of tofacitinib should not be initiated in patients with an active infection, including localized infections.^24-26 It may be used as monotherapy or in conjunction with methotrexate or other non-biologic DMARDs.^24-26 It should not be used in combination with biologic DMARDs or potent immunosuppressants such as cyclosporine.^24-26

Conclusion

Pharmacists can help RA patients by keeping them abreast of the treatment options. Patients should be aware that aggressive and early treatment may significantly improve their condition, be encouraged to discuss their treatment options with their primary health care provider, and remain compliant with the prescribed therapy to ensure optimal therapeutic effects.

Fortunately, current treatment strategies, rest, exercise, patient education, and support programs enable most people with RA to lead active, productive lives. In recent years, research has led to a greater understanding of RA and has increased the probability that, in time, researchers will find even more effective ways to halt the progression of RA and decrease the potential for joint damage and deformity, organ damage, and disability.²⁷ One area of research is investigating the use of antibodies in RA treatment, and some drugs are in phase II clinical trials. Patients should be encouraged to learn all they can about RA, including monitoring their symptoms, communicating with their rheumatologist, being proactive in their treatment plan, and maintaining routine follow-up appointments.

Ms. Terrie is a clinical pharmacy writer based in Haymarket, Virginia.

References

• National Institute of Arthritis and Musculoskeletal and Skin Diseases. What is rheumatoid arthritis? www.niams.nih.gov/Health_Info/Rheumatic_Disease/rheumatoid_arthritis_ff.asp. Accessed July 26, 2013.
• Centers for Disease Control and Prevention. Rheumatoid arthritis. www.cdc.gov/arthritis/basics/rheumatoid.htm. Accessed July 26, 2013.
• American College of Rheumatology. Rheumatoid arthritis. www.rheumatology.org/practice/clinical/patients/diseases_and_conditions/ra.asp. Accessed July 26, 2013.
• Arthritis Foundation. Depression in people with RA. www.arthritis.org/research/funded-research/research-update/journal-summaries/depression-ra/. Accessed July 26, 2013.
• Temprano K. Rheumatoid arthritis. http://emedicine.medscape.com/article/331715-overview#aw2aab6b2b2. Accessed July 26, 2013.
• Wilke W. Rheumatoid arthritis. www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/rheumatology/rheumatoid-arthritis. Accessed July 26, 2013.
• 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 (Hoboken). 2012;64(5):625-639.
• Department of Health and Human Services Agency for Healthcare Research and Quality. Drug therapy for rheumatoid arthritis in adults: an update. www.effectivehealthcare.ahrq.gov/ehc/products/203/1044/CER55_DrugTherapiesforRheumatoidArthritis_FinalReport_20120618.pdf. Accessed July 26, 2013.
• Verstappen SM, Albada-Kuipers GA, Bijlsma JW, et al, for the Utrecht Rheumatoid Arthritis Cohort Study Group (SRU). A good response to early DMARD treatment of patients with rheumatoid arthritis in the first year predicts remission during follow up. Ann Rheum Dis. 2005;64:38-43.
• Aletaha D, Funovits J, Keystone EC, Smolen JS. Disease activity early in the course of treatment predicts response to therapy after one year in rheumatoid arthritis patients. Arthritis Rheum. 2007;56:3226-3235.
• The John Hopkins Arthritis Center. Rheumatoid arthritis treatment. www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-treatment/#tnf. Accessed July 26, 2013.
• Stone J. Tumor necrosis factor inhibitors: an overview of adverse effects. www.uptodate.com/contents/tumor-necrosis-factor-alpha-inhibitors-an-overview-of-adverse-effects. Accessed July 26, 2013.
• Orencia [prescribing information]. Bristol-Myers Squibb. http://packageinserts.bms.com/pi/pi_orencia.pdf. Accessed July 26, 2013.
• Enbrel [prescribing information]. Amgen Inc website. http://pi.amgen.com/united_states/enbrel/derm/enbrel_pi.pdf. Accessed July 26, 2013.
• Remicade [prescribing information]. Janssen website. www.remicade.com/shared/product/remicade/prescribing-information.pdf. Accessed July 26, 2013.
• Humira [prescribing information]. AbbVie Inc website. www.rxabbvie.com/pdf/humira.pdf. Accessed July 26, 2013.
• Cimzia [prescribing information]. UCB Inc. www.cimzia.com/rheumatoidarthritis/hcp/. Accessed July 26, 2013.
• Simponi [prescribing information]. www.simponi.com/shared/product/simponi/prescribing-information.pdf. Accessed July 26, 2013.
• Rituxan [prescribing information]. www.gene.com/download/pdf/rituxan_prescribing.pdf. Accessed July 26, 2013.
• Actemra [prescribing information]. Genentech. www.gene.com/download/pdf/actemra_prescribing.pdf. Accessed July 26, 2013.
• Kineret [prescribing information]. Sobi Inc. www.kineretrx.com/fileadmin/user_upload/kineretus/documents/Kineret_Full_Prescribing_Information.pdf. Accessed July 26, 2013.
• FDA approves Xeljanz for rheumatoid arthritis. FDA website. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm327152.htm. Accessed July 26, 2013.
• 2012 Treatment guidelines for rheumatoid arthritis: an update from the American College of Rheumatology. Healthcare Professionals Network. www.hcplive.com/publications/targeted-therapies-publications/2012/Arthritis/2012-Treatment-Guidelines-for-Rheumatoid-Arthritis-An-Update-from-the-American-College-of-Rheumatology. Accessed July 26, 2013.
• Medications for rheumatoid arthritis. Arthritis Foundation website. www.arthritistoday.org/about-arthritis/types-of-arthritis/rheumatoid-arthritis/treatment-plan/medication-overview/ra-medications.php. Accessed July 26, 2013.
• Xeljanz [prescribing information]. Pfizer. www.xeljanz.com/oral-medication. Accessed July 26, 2013.
• National Institutes of Health. New rheumatoid arthritis drug targets NIH discovered protein. www.nih.gov/news/health/dec2012/niams-04.htm. Accessed July 26, 2013.
• Arthritis Foundation. Rheumatoid arthritis. www.arthritis.org/conditions-treatments/disease-center/rheumatoid-arthritis/. Accessed July 26, 2013.