Pain is the most common complaint for which most patients seek rheumatologic. Chronic Pain From Rheumatoid Arthritis

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1 PRINTER-FRIENDLY VERSION AVAILABLE AT PAINMEDICINENEWS.COM Chronic Pain From Rheumatoid Arthritis ROLAND STAUD, MD Director, Musculoskeletal Pain Research Professor University of Florida College of Medicine Gainesville, Florida DAVID L. LAZAR, MD Second Year Fellow Rheumatology and Clinical Immunology University of Florida College of Medicine Gainesville, Florida Editorial Advisory Board Member Pain Medicine News New York, New York Drs. Staud and Lazar reported no relevant financial disclosures. Pain is the most common complaint for which most patients seek rheumatologic consultation. Unfortunately, many physicians have a limited understanding of the mechanisms and treatment of chronic pain due to rheumatoid arthritis (RA). Rheumatologists often consider pain the direct result of peripheral tissue changes, such as inflammation or erosions. However, there is great discordance between pain severity and such RA-related peripheral tissue changes (eg, cartilage degradation and erosions). Rheumatoid arthritis is an inflammatory chronic illness that transforms the synovium of the joints and erodes the cartilage and bones resulting in deformities, chronic pain, and considerable dysfunction. Over the past decade, new medications have helped reduce the PAIN MEDICINE NEWS SPECIAL EDITION DECEMBER

2 Case Report A 54-year-old woman with RA for more than 20 years has been treated with multiple medications including methotrexate, sulfasalazine, hydroxychloroquine, adalimumab (Humira, AbbVie), etanercept (Enbrel, Amgen), abatacept (Orencia, Bristol-Myers Squibb), and tocilizumab (Actemra, Genentech). Each of these medications improved her symptoms for periods of 1 to 3 years, until she would experience worsening of her RA. She was near remission on abatacept over the last 3 years. However, the abatacept infusions recently became less efficacious. Finally, abatacept was discontinued and she was started on rituximab (Rituxan, Genentech). Today, her synovial swelling has completely resolved and her high sedimentation rate has normalized. However, she still has moderate to severe joint pains in her knees, hands, wrists, and feet. She is not able to sleep through the night because of pain. X-rays revealed advanced joint space narrowing of the affected joints but only a few erosions. She describes her pain as achy, worsening as the day progresses. The patient s physician discussed nonsteroidal anti-inflammatory drugs with her but she declined their use, as these medications are associated with cardiovascular and renal toxicities that make them challenging for the aging population. To control her pain, she was started on 1 to 2 tablets of tramadol 50 mg 3 times daily with a 325-mg tablet of acetaminophen. This provided significant pain relief throughout most of the day and evening. Because the patient was concerned about side effects of opioids, she was switched to duloxetine, which has provided her with good control of her musculoskeletal pain. inflammatory tissue changes of RA. However, even with effective treatments, many patients still suffer from chronic pain due to mechanical joint symptoms (secondary osteoarthritis [OA]), myofascial pain, and/or continuing pain hypersensitivity. Chronic RA pain can be divided into peripheral and central mechanisms. Peripheral pain mechanisms stem from sensitization of nociceptors, leading to local areas of enhanced pain sensitivity. The most common peripheral mechanism for chronic pain is peripheral sensitization, which plays an important role for patients with OA and RA. 1 Central pain mechanisms depend on activation of the spinal cord and brain pathways, leading to enhanced, and often widespread, pain sensitivity. Patients with RA with evidence of central sensitization demonstrate augmented pain processing (ie, minor stimuli will result in often severe pain), and they frequently display widespread hyperalgesia (heightened pain response to normally painful stimuli) and allodynia (pain in response to normally nonpainful stimuli). 2 Today, RA can be remarkably well controlled with biologic and nonbiologic therapies, 3 but physicians are often faced with the challenge of how to treat the chronic pain that can remain after the inflammation is under optimal control. Frequently, patients with RA have secondary OA, which can result in significant pain. The current treatments for OA are mostly based on topical and systemic medications, intra-articular injections, physical or occupational therapy, braces, or splints. More severe pain, including resting pain, requires the use of short- and/or long-lasting opioids. The often advanced age of patients with RA needs to be considered during treatment discussions. Over the last decade, new treatments have had a profound and positive effect on RA. However, chronic pain often remains after successful control of joint inflammation. Because it is often quite difficult to treat, a comprehensive approach with pharmacologic and nonpharmacologic therapies, including physical therapy, braces, or splints, has been advocated by most rheumatologists. Newer treatments for chronic RA pain, such as the use of serotonin norepinephrine reuptake inhibitors, have demonstrated promising results for patients with OA and may be effective for RA pain. 4,5 Because many patients still experience chronic pain despite good response of joint inflammation with advanced therapies, physicians are challenged to find the best way to control the chronic pain associated with RA. References 1. Schaible HG, Ebersberger A, Natura G. Update on peripheral mechanisms of pain: beyond prostaglandins and cytokines. Arthritis Res Ther. 2011;13(2): Staud R. The important role of CNS facilitation and inhibition for chronic pain. Int J Clin Rheumatol. 2013;8(6): Smolen JS, Aletaha D. Rheumatoid arthritis reappraisal: strategies, opportunities and challenges. Nat Rev Rheumatol. 2015;11(5): Radner, H, Ramiro S, Buchbinder, et al. Pain management for inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and other spondylarthritis) and gastrointestinal or liver comorbidity. Cochrane Database Syst Rev. 2012;1:CD Ramiro S, Radner H, van der Heijde DM, et al. Combination therapy for pain management in inflammatory arthritis: a Cochrane systematic review. J Rheumatol Suppl. 2012;90: PAINMEDICINENEWS.COM

3 The Specialty Pharmacist s Perspective RENEE BAIANO, PHARMD Clinical Program Manager Walgreens Specialty Pharmacy Carnegie, Pennsylvania Dr. Baiano reported no relevant financial disclosures. In the United States, it is estimated that annual direct and indirect costs attributable to rheumatoid arthritis (RA) and other rheumatic conditions are approximately $128 billion.1 This burdensome disease affects approximately 0.5% to 1% of the general population. 2 Early, aggressive treatment of RA can greatly improve outcomes. However, managing this chronic condition can be a challenge for providers and patients. Some barriers to controlling RA include therapy nonadherence, presence of comorbidities, and disease activity. 3 Because there is no known cure for RA, the primary goal of therapy is to reach low disease activity or remission. 3 Achieving this goal results in improved quality of life, prevention of new joint destruction, and reduced pain and inflammation. 4 With the development of new medications and treatment guidelines urging early interventions, the outcomes for RA patients have drastically improved. Current treatments allow for proper management and improved clinical outcomes for a complex disease once known for causing debilitating deformities. Without treatment, the disease can cause pain, inflammation, and ultimately irreversible bone erosion. The specialty pharmacist plays a key role in educating the patient on the importance of following the prescribed treatment plan. Additionally, by counseling the patient about medication administration, side effects, and disease activity, the specialty pharmacist can help the patient best manage his or her disease. An Autoimmune Disorder The most common type of autoimmune arthritis, RA affects at least 1.3 million US adults. 5 Of those affected, about 75% are women. 5 Although RA can start at any age, it most commonly begins between the fourth and sixth decades of life. 5 In RA, the body s immune system mistakenly attacks the synovium, which is the tissue that lines the joints. This can lead to irreversible erosion of cartilage and bone. The small joints in the hands and feet are most commonly affected. Pain, stiffness, and swelling are usually worse in the morning and can last 30 minutes or longer after waking. 5 Although RA may sound like a disease that exclusively affects the joints, it actually is a systemic inflammatory process. In addition to joint involvement, RA can present with symptoms such as fever, loss of appetite, and fatigue. The disease can manifest in other organs, including the lungs, blood vessels, eyes, and kidneys. 6 One of the most common extra-articular manifestations of RA is the development of nodules firm lumps under the skin which present in up to 30% of patients. 7 Early and aggressive therapy depends on an accurate diagnosis, which can be a challenge, in part because the symptoms of RA are often nonspecific. 2 Additionally, there is no single test that can diagnose RA, and therefore diagnosis is based on physical symptoms, blood work results, and various examinations. Rheumatoid factor, an antibody found in about 80% of RA patients, and antibodies to cyclic citrullinated peptides, found in about 60% to 70% of RA patients, can be used to aid diagnosis. 5 Also, RA patients often present with an elevated erythrocyte sedimentation rate and anemia. 5 The physician may also perform radiography, MRI, and ultrasonography examinations to assess disease progression and measure the severity of the disease. 5 Current RA Therapies Although the pathogenesis of RA is not completely understood, recent advances have allowed for targeted therapies that result in improved clinical outcomes. Cytokines, such as tumor necrosis factor (TNF)-α and various interleukins (ILs), are often found to play a key role in T-cell and B-cell proliferation and inducing an inflammatory response, which ultimately causes inflammation and joint damage. 8 Biologic medications on the market today work to block the activity of these cytokines, as well as other immune response pathways. Treatment of RA is guided by disease duration, disease activity, and prognostic features. According to the American College of Rheumatology (ACR) RA treatment guidelines, a patient is categorized to have PAIN MEDIC INE NEWS SPEC IAL EDITIO N DEC EMBER

4 Case Report FC is a 53-year-old man with a history of rheumatoid arthritis (RA). In 2008, he was prescribed the tumor necrosis factor (TNF) inhibitor adalimumab (Humira, AbbVie), and has been receiving monthly medication and supplies from Walgreens Specialty Pharmacy (WSP). When FC began receiving his medication and patient management support from WSP, his insurance copay/ financial responsibility was more than $500 per month. At the initiation of therapy with WSP, the WSP insurance team researched several options to assist FC with his monthly financial expense and, through a copay assistance program, was able to decrease FC s monthly outlay to $5. Every month before each prescription refill a WSP Patient Care Coordinator (PCC) contacts FC proactively. During these outreach assessments, the PCC, using the WSP proprietary disease management application Connected Care, will review if the patient missed any doses, experienced any disease-state flares in the past 30 days, and had any other adverse events. These scheduled monthly assessments promote medication adherence and facilitate patient-specific disease management requirements. Upon identification of any issues or concerns based on the Connected Care algorithms, the patient speaks with a WSP specialty-trained pharmacist. During a recent patient interaction before a scheduled refill, the WSP PCC, using the Connected Care application, identified that FC had missed several injections. The Connected Care algorithm prompted the patient to be transferred to a WSP pharmacist to discuss adherence, with the goal of uncovering any obstacles to adherence and providing the necessary support. During the pharmacist consultation, FC reported that he was recovering from an elbow injury, and his rheumatologist was treating him with oral prednisone to prevent a flare while holding his dose a clinically appropriate reason for missing a dose, which was identified and entered into the patient s record. During a subsequent patient assessment, FC indicated that he missed an injection due to insurance changes. He was counseled by a WSP specialty-trained pharmacist on the potential adverse effects of missing his dose. The patient was also provided support regarding his updated insurance benefits, and he was able to obtain his medication. Recently, FC mentioned he would prefer to use the prefilled syringe dosage form of his medication instead of the pen device. Based on this information, the WSP specialty-trained pharmacist contacted FC s physician and obtained an updated prescription. Because of the collaborative efforts made by the staff at WSP, FC s treating physician, and the patient, FC has been and remains adherent to his medication regimen. This case study demonstrates the key roles that a specialty pharmacy can have in assisting RA patients to manage their treatment. early or established RA based on how long the disease symptoms have been present (<6 or >6 months, respectively). 9 The disease activity is determined as low, moderate, or high according to a validated patient scale, such as the Patient Activity Score-II, Disease Activity Score in 28 joints, or Clinical Disease Activity Index. Lastly, the patient s prognostic features are evaluated. Poor prognostic features include extra-articular disease, positive rheumatoid factor, positive anti cyclic citrullinated peptide antibodies, bony erosions, and functional limitations. 9 Tools to quantify functional limitations, such as the HAQ-II (Health Assessment Questionnaire), can assess a patient s ability to participate in daily life activities. Review of all of these elements assists the rheumatologist in determining the appropriate therapy. Disease-modifying antirheumatic drugs (DMARDs) are the cornerstone of RA treatment. The ACR considers leflunomide, hydroxychloroquine, sulfasalazine, minocycline, and methotrexate as the primary nonbiologic DMARDs. These medications are often used as first-line monotherapy or combination therapy, depending on disease activity and prognosis. 9 Methotrexate, which inhibits dihydrofolate reductase, is often the DMARD of choice due to efficacy rates and ability to slow radiographic progression. 10 The entry of biologic DMARDs into the market delivered another treatment option to improve function and decrease disease progression. These medications target abnormalities of the immune system responsible for inflammation. Biologic DMARDs consist of TNF-α antagonists, IL-6 antagonists, IL-1 antagonists, and medications that modulate T cells and B cells and are administered by IV infusion or subcutaneous injection (Table). Biologics are recommended by the ACR for patients who failed to respond to traditional nonbiologic DMARDs and, in some cases, as first-line therapy for more severe disease. 9 Biologics are often used with the nonbiologic DMARDs. In fact, the PREMIER study, which compared the use of the biologic adalimumab (Humira, AbbVie) and methotrexate combination therapy with adalimumab or methotrexate monotherapy, showed that combination therapy significantly improved disease symptoms and progression. 11 TNF-α antagonists are often the first biologics used in RA therapy. There are 5 FDA-approved TNF-α antagonists on the market for RA: adalimumab, certolizumab, (Cimzia, UCB Pharma), etanercept (Enbrel, Amgen), infliximab (Remicade, Janssen Biotech), and golimumab (Simponi, Janssen Biotech). 22 PAINMEDICINENEWS.COM

5 Table. FDA-Approved Biologic Medications Indicated To Treat Rheumatoid Arthritis Mechanism of Action TNF-α inhibitor IL-1 antagonist IL-6 antagonist Modulation of T-cell activation Binding to CD20, depletion of B cells Medication Company Available Forms Dosage Adalimumab (Humira) Etanercept (Enbrel) Certolizumab (Cimzia) Golimumab (Simponi) Infliximab (Remicade) Anakinra (Kineret) Tocilizumab (Actemra) AbbVie Amgen UCB Pharma Janssen Biotech Janssen Biotech prefilled pen SureClick pen, vials vials SmartJect autoinjector, vials (Simponi Aria) Vials SC: 40 mg every other week SC: 50 mg weekly Abatacept (Orencia) Rituximab (Rituxan) Sobi Prefilled syringe SC: 100 mg daily Genentech Bristol-Myers Squibb vial vials SC induction: 400 mg at 0, 2, and 4 wk Maintenance: 200 mg every other week thereafter Maintenance alternative: 400 mg every 4 wk can be considered SC: 50 mg every 4 wk IV induction: 2 mg/kg at 0 and 4 wk Maintenance: 2 mg/kg every 8 wk thereafter IV induction: 3 mg/kg at 0, 2, and 6 wk Maintenance: 3 mg/kg every 8 wk thereafter SC: Weight <100 kg: 162 mg every other week, followed by an increase to every week based on clinical response; weight 100 kg: 162 mg every week IV: 4 mg/kg every 4 wk followed by an increase to 8 mg/kg every 4 wk based on clinical response SC: 125 mg once weekly, may be initiated with or without an IV loading dose. If initiating with IV loading dose: Give a single IV loading dose (per body weight), followed by the first 125-mg SC injection within a day of the IV infusion IV: Induction: initially then at 2 and 4 wk after the first infusion Maintenance: Every 4 wk thereafter. Weight <60 kg: 500 mg. Weight kg: 750 mg. Weight >100 kg: 1,000 mg Genentech Vials IV: 2 1,000-mg infusions separated by 2 wk. Subsequent courses should be administered every 24 wk or based on clinical evaluation, but not sooner than every 16 wk IL, interleukin; SC, subcutaneous; TNF, tumor necrosis factor Medications in this class have a black box warning for infections, malignancy, and tuberculosis. 12 Tocilizumab (Actemra, Genentech) is an IL-6 antagonist available as an IV infusion or a subcutaneous injection. It is important to monitor the absolute neutrophil and platelet counts, as well as liver function tests, in patients taking tocilizumab. 10 The IL-1 antagonist on the market for RA is anakinra (Kineret, Sobi), a daily subcutaneous injection. Abatacept (Orencia, Bristol-Myers Squibb), which modulates T-cell activation, is available as a subcutaneous injection and an IV infusion. 10 Lastly, rituximab (Rituxan, Genentech) is a biologic available as an IV infusion. Rituximab has a black box warning for progressive multifocal leukoencephalopathy, which is an infection caused by the reactivation of the John Cunningham virus. 10 In 2012, tofacitinib (Xeljanz, Pfizer) was approved by the FDA. Tofacitinib is an oral Janus kinase inhibitor, PAIN MEDICINE NEWS SPECIAL EDITION DECEMBER

6 indicated for moderately to severely active RA in patients who have had an inadequate response or intolerance to methotrexate. 13 The Specialty Pharmacist s Role: Improving Quality of Life Although evidence is clear that early, aggressive treatment is crucial in preventing irreversible joint damage in RA, medication adherence rates range from 30% to 80%. 14 In addition to negatively affecting clinical outcomes, nonadherence has a major effect on health care costs. There were more than 15,600 hospitalizations in 2009 among individuals with RA in the United States. 2 When addressing adherence concerns with a patient, it is important to be mindful of some of the potential barriers that patients may face. Patient-driven undertreatment is one of the most common causes of nonadherence. 3 It appears that patient concern lies more with the current status of the disease than with future disease control. Disease improvement is misinterpreted as not needing to take medication. 3 This error in perception of a reduced need for medication and the fear of side effects are major factors to consider when counseling about compliance. The specialty pharmacist can play a key role in identifying opportunities for intervention with RA patients. For example, patients who cannot remember to take a weekly dose of their injection may benefit from switching to a medication that offers once-monthly dosing. Also, a pen device versus a prefilled syringe could be more appealing to a patient with a fear of needles. Additionally, pharmacists can help support patients who have comorbid conditions. RA patients are approximately twice as likely to be diagnosed with heart failure as non-ra individuals. 15 Lung disease, depression, and anemia are also more prevalent in the RA population. 15 Whether it is counseling about proper administration technique or notifying the prescriber about a new side effect, these interventions are essential for improving patients quality of life by managing their disease and therapy. Walgreens Specialty Pharmacy offers education on specialty disease states and medications in the form of pharmacist counseling and educational material, including Wellness Planners, which are disease-specific educational booklets. Conclusion The continual interaction between the patient and the specialty pharmacy is fundamental in the continuity of care for RA patients. Specialty pharmacists can improve the quality of life for these patients by providing expert advice and support of treatment regimens and disease states, as well as encouraging medication adherence. References 1. Centers for Disease Control and Prevention. National and state medical expenditures and lost earnings attributable to arthritis and other rheumatic conditions United States, MMWR Morb Mortal Wkly Rep. 2007;56(1): Centers for Disease Control and Prevention. Rheumatoid arthritis. Accessed November 18, Tymms K, Zochling J, Scott J, et al. Barriers to optimal disease control for rheumatoid arthritis patients with moderate and high disease activity. Arthritis Care Res. 2014;66(2): Tkacz J, Ellis LA, Myer R, et al. Quality process measures for rheumatoid arthritis: performance from members enrolled in a national health plan. J Manag Care Spec Pharm. 2015;21(2): American College of Rheumatology. Rheumatoid arthritis. www. rheumatology.org/practice/clinical/patients/diseases_and_ Conditions/Rheumatoid_Arthritis/. Accessed November 18, Arthritis Foundation. Rheumatoid arthritis symptoms. Accessed November 18, Cojocaru M, Cojocaru IM, Silosi I, et al. Extra-articular manifestations in rheumatoid arthritis. Maedica (Buchar). 2010;5(4): Jung OY, Kim HA. Recent paradigm shifts in the diagnosis and treatment of rheumatoid arthritis. Korean J Intern Med. 2012;27(4): Singh JA, Furst DE, Bharat A, et al 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): Kahlenberg JM, Fox DA. Advances in the medical treatment of rheumatoid arthritis. Hand Clin. 2011;27(1): Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006;54(1): Giezen TJ, Mantel-Teeuwisse AK, Straus SM, et al. Safety-related regulatory actions for biologics approved in the United States and the European Union. JAMA. 2008;300(16): Xeljanz [package insert]. New York, NY: Pfizer Labs; Joplin S, Van der Zwan R, Joshua F, et al. Medication adherence in patients with rheumatoid arthritis: the effect of patient education, health literacy, and musculoskeletal ultrasound. Biomed Res Int. 2015;2015: Gabriel SE, Michaud K. Epidemiological studies in incidence, prevalence, mortality and comorbidity of the rheumatic diseases. Arthritis Res Ther. 2009;11: PAINMEDICINENEWS.COM