Considerations in the Management of Rheumatoid Arthritis Among Older Adults in Long-term Care
Abstract
With rising health care costs and strained government funding, cost-effective strategies are needed to treat long-term care residents with rheumatoid arthritis (RA). Methotrexate (MTX) is considered the first-line therapy once an RA diagnosis has been made. Clinical guidelines recommend intense escalation of MTX, orally or subcutaneously, to a dose of 25 mg to 30 mg weekly (with folate supplementation) before switching to, or adding, costly biologic therapy. Despite this, oral MTX dose titration and subcutaneous MTX use are infrequent and underutilized. An overview of RA management in older adults and the long-term care population is provided. Clinical and economic considerations of oral and subcutaneous MTX for these populations is discussed in addition to subcutaneous auto-inject MTX pens, which may be appropriate for select patients.
Introduction
The older adult population (individuals aged 65 years or older) in the United States totaled 49.1 million in 2016—15.2% of the total US population.1 Most long-term services and supports for older adults are provided by family members and friends. This was validated in an overview of a meta-analysis of 11 surveys of caregivers between 2009 and 2014, in which an estimated 37 billion hours of care to an adult with limitations in their daily activities was provided by approximately 40 million US family caregivers.2
In 2012, more than 8.3 million people received support annually from the 5 main types of long-term care (LTC) services: home health agencies (4,742,500), nursing homes (NHs) (1,383,700), hospices (1,244,500), residential care communities (713,300), and adult day service centers (273,200).3 Women were the predominant users of these LTC services compared to men (62.7% vs 37.3%; 67.7% vs 32.3%; 59.7% vs 40.3%; 72% vs 28%; and 59.6% vs 40.4%, respectively).3 In FY2015 (October 1, 2014 through September 30, 2015), Medicaid spending for long-term services and supports, which includes nursing facilities, intermediate care facilities for the intellectually disabled, mental health facilities, home health, and personal care, was nearly $115 billion.4
Regardless of payment sources (eg, out-of-pocket family expenditures or Medicaid), cost of care for the aging is ever-increasing, and government funding is strained. As such, cost-effective and efficient management strategies are needed in the treatment of the older adult population with chronic conditions, including rheumatoid arthritis (RA).
RA is the most common autoimmune inflammatory arthritis in adults, affecting about 1% of the US general population.5 It is a chronic inflammatory disease of the synovium leading to joint and bone damage. While most (63%) of the patients in LTC are aged 65 and older, 37% of them are younger than 64; this accounts for 3.7 million LTC residents.6 The exact number of patients in LTC with RA is not known at this time. RA can occur at any age, but peak onset is between 55 to 64 in women and 75 to 84 in men.7
We provide an overview of the optimal treatment of RA in older adults, taking into consideration current RA management guidelines, treatment and drug costs, and medication administration concerns specific to the LTC setting.
RA Prevalence and Treatment Guidelines
As of 1989, it was estimated that 23% of all NH residents had some form of arthritis.8 It is unclear if this is still the case; it is difficult to ascertain US-specific data on number of NH patients with active RA as most of the data available group all arthritis together. There is a higher prevalence of RA in women, who are 3 or 4 times more likely to be affected compared to men.6 When the initial onset of RA begins in older adults at age 60 or older, it is considered elderly-onset RA; approximately 10% to 33% of RA cases are represented in this subset.9 Nevertheless, it is often misdiagnosed as osteoarthritis among other disorders (Table 1).10,11 Although an arthritis diagnosis alone is not a reason for admission to an LTC facility, residents with arthritis are more likely to have limitations in activities of daily function and require the use of wheelchairs.8
The 2015 American College of Rheumatology (ACR) Guideline for the Treatment of Rheumatoid Arthritis and the updated 2016 European League Against Rheumatism (EULAR) RA Management Recommendations both advise starting with methotrexate (MTX), a conventional synthetic disease-modifying antirheumatic drug (DMARD), as initial RA treatment, then switching to or adding other DMARDs if disease activity remains moderate or high.12,13 Other therapeutic classes/agents recommended by EULAR for the management of RA include other conventional synthetic DMARDs (ie, leflunomide, sulfasalazine); glucocorticoids (GCs); biologic DMARDs, such as antitumor necrosis factor (TNF)-inhibitors (ie, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) or abatacept, rituximab, IL-6 inhibitors, tocilizumab, clazakizumab, sarilumab, and sirukumab; biosimilar DMARDs; and targeted synthetic DMARDs (Janus kinase [JAK] inhibitors, such as tofacitinib and baricitinib).13
In general, MTX is considered to be the pivotal drug once an RA diagnosis has been made, and EULAR now recommends more intense escalation of MTX, orally or subcutaneously, to a dose of 25 mg to 30mg weekly (with folate supplementation).13 However, contraindications and the potential of early intolerance to MTX should still be considered when determining first-line treatment strategy.13 If tolerated, the maximal MTX dose should be sustained for 8 to 12 weeks and include treatment response monitoring.13 Rapid escalation of MTX to 25 mg/week has been shown to improve response rates, resulting in low disease activity (~40%).13 Furthermore, because of growing efficacy and safety data, synthetic DMARD monotherapy with a GC is more strongly suggested now than previously prescribed synthetic DMARD combination therapies, or biologic DMARDs with MTX.13
Due to limitations/capitations in LTC payment models and family caregiver constructs, the utilization of subcutaneous MTX may prove useful for providers who are treating residents with RA and are considering whether to continue MTX use and/or adding or switching to a biologic based on standard treatment guidelines. Ensuring the optimization of MTX treatment in older adults aged 65 years or older with the appropriate MTX dose and duration implemented is recommended.
Oral vs Subcutaneous MTX Administration
The literature has shown that oral MTX has bioavailability issues and adverse gastrointestinal events (including nausea and vomiting), which provide ill effects along with the benefits of the treatment.24,25 Strong evidence suggests that subcutaneous MTX offers better bioavailability, tolerability, and efficacy, with fewer GI side effects than the oral formulation.26,27
A 24-week study compared the efficacy of subcutaneous MTX to oral MTX. The results showed that those receiving subcutaneous MTX achieved a significantly higher ACR20 response (78% vs 70% for oral MTX; P < .05).26 Results of a retrospective analysis of 103 patients with RA indicated that subcutaneous MTX significantly improved disease control vs oral MTX (reduction of Disease Activity Score 28 [DAS28] for Groups A and B; 4.8 to 4.2; P = .006 and 4.1 to 3.0; P = .0001, respectively).19,28 This benefit may be attributable to the increased bioavailability provided by the parent drug (Figure 1).19,29
Results from the observational study of the Canadian Early Arthritis Cohort (CATCH) showed that patients initially treated with subcutaneous MTX had a lower treatment failure rate (HR, 0.55; 95% CI [0.39 to 0.79]; P = .001) and greater reduction in DAS28 scores (-0.38 [95% CI, -0.64 to -0.10]; P = .04) than those receiving oral MTX. There was also higher odds for remission compared with oral MTX (OR, 1.2 [95% CI 1.1 to 1.3]; P = .002) with no noted difference in toxicity.30
Significant decreases in the frequency of adverse GI events has been shown in patients with RA when switching MTX administration from oral to subcutaneous therapy.19,24,25 Financial benefits have also been demonstrated. Lee et al analyzed patient-claims data for 35,640 patients and their treatment pathways over a 5-year period and found that the patients who switched to subcutaneous MTX incurred lower costs than patients who only used oral MTX before using biologics (Figure 2).31 They found older patients continued to use oral MTX compared to the other cohorts, with women being more likely to switch to subcutaneous MTX.31 The authors found that the cost differences between the cohorts were the result of using biologic treatments, since nondrug costs were similar across the groups.31
Drawbacks to subcutaneous MTX administration include cytotoxicity and concomitant concerns of patient/caregiver manipulation of vials, needles, and syringes.32 As such, all individuals who come in contact with subcutaneous MTX are required to undergo formal training, follow specific protocols for spillage cleanup, and provide special monitoring of individuals exposed to MTX to identify any biological effects.32,33 While most patients prefer oral medications to injecting themselves, the side effects associated with oral MTX may make subcutaneous MTX a better option, as demonstrated above.26,34,35 In the past, subcutaneous MTX was used less often due to functional/dexterity limitations (ie, joint pain or reduced grip strength) in RA patients.36-38 As such, their ability to measure and inject subcutaneous MTX was inhibited.36,37,39 With the recent availability of prefilled, subcutaneous MTX auto-injector pens, these concerns can be alleviated.39,40,41
Since the goals of LTC medication pass systems are to increase resident safety and decrease medication errors,42 prefilled auto-injector pens can improve resident care. They are compact, have a fine needle for virtually painless administration, are viewed as an improvement over vials/syringes, and increase nurse satisfaction. Overall, the pen is considered safer to use than a prefilled syringe.43 Various studies have demonstrated that patients experienced less pain self-administering via the pen (and auto-inject system) and preferred its use vs syringes, as the pen was easier/more convenient to use43-45 and associated with less psychological trauma.44,45
Use of the auto-injector MTX pen is mainly for convenience/ease of administration. While in a NH, the patient caregiver is able to draw up and inject the subcutaneous MTX; however, if a patient is discharged from the NH, being able to draw up the right amount and injecting themselves may be difficult. This is where the recommendation of auto-injecting pens may be appropriate. The phase 2 multicenter trial for MTXAI showed that it was well tolerated and easy to use by patients.46 In determining which to prescribe, the provider should consider patient compliance and their ability to draw up the right amount as well as a patient’s residence. For example, in patients with joint deformities or those living alone, the provider may want to consider the use of pen rather than syringes.
It should be noted that although studies have shown that pens are considered safer than prefilled syringes, pens are much more expensive than the syringes and may not be used in every patient. Pens should be considered on a case-by-case basis.
Treatment Selection Considerations
RA is an extremely debilitating disease that affects LTC residents in their activities of daily living. Not only can RA affect the body physically, it has adverse mental effects that can play a huge role in maintaining quality of life. Depression and anxiety, along with feelings of hopelessness, are very common. Fear, anger, and pain can also increase stress levels. Most patients with RA suffer from other comorbid conditions such as hypertension, diabetes, dyslipidemia, and osteoporosis. The presence of these comorbidities impacts the choice of treatment a clinician may decide on for patients with RA.
Treatment strategies depend on the course of the disease (ie, whether active or in remission) and desired outcomes. Regardless of the treatment option selected, the goals are the same: to relieve pain, reduce inflammation and joint damage, and improve quality of life. Achieving RA pain management in the LTC setting can be challenging. A holistic strategy that encompasses medication therapy with complementary nonpharmacologic approaches is often the most effective in improving or maintaining quality of life in these residents. Concomitant use of alternative treatment approaches with medication therapy can be very beneficial for residents with RA (Box 1).
Collaboration among the multidisciplinary team is required to determine the most effective medications, taking into consideration costs and potential side effects, since many LTC residents are often prescribed multiple medications. In a study to assess the comorbid conditions associated with RA and its management, the authors found that GCs (80%) were the most prescribed, followed by MTX (74%) and biologics (41%).14 They also found that the presence of obesity, hepatitis, and diabetes could worsen in patients taking MTX. Patients on MTX have to be assessed for pregnancy, lipid profile, blood sugar level, and liver function.14
Considered the primary DMARD for treatment of RA, MTX is most frequently administered orally.12,13,15,16 In addition to reducing pain and swelling, MTX can slow joint damage and disease progression over time.15 Yet, real-world evidence has shown that higher-dose titration of oral MTX and the use of subcutaneous MTX are infrequent and underutilized.17,18 With the introduction of anti-TNF inhibitors, there has been less aggressive dosing of MTX and a decline in duration of treatment before switching to biologics.19 It is important to optimize MTX prior to switching to biologics, per guidelines. In a retrospective review of 1403 adult patients, those receiving biologic DMARDs (n = 434), had greater frequency of adverse events than those treated with synthetic DMARDs (n = 969) (hazard ratio [HR], 1.98; 95% CI, 1.64-2.39; P < .001).20 Of note, those treated with less than 10 mg/week of MTX had a greater risk of any adverse event compared to those receiving higher MTX doses.20 MTX also has been shown to actually decrease mortality by 70% in patients with RA when used for over a year, even among those switched to another therapy.21Table 2 shows usage comparison of MTX to TNF inhibitors.
Article continues below Table.
It is well-known among LTC practitioners that polypharmacy is prevalent in LTC residents, which places them at greater risk for medication errors, adverse drug reactions, decreased quality of life, and increased costs.22 Kourbeti et al conducted a meta-analysis of 70 trials where they found that the risk of acquiring opportunistic infection (ie, viral, tuberculosis, and other mycobacterial infections) was higher with biologics than with placebo or DMARDs/conventional therapies, corresponding to 1.7 opportunistic infections per 1000 treated patients (OR, 1.79; 95% CI, 1.17-2.74; P =.42).23
Economic Considerations
EULAR notes that it is the treating rheumatologist’s responsibility to consider the economic implications when selecting treatment for RA.13 Barlow and colleagues evaluated the impact of specialty pharmacy on biologic treatment costs for RA.47 Results showed that the total adjusted health care costs (medical and pharmacy) were higher for specialty pharmacy patients than for retail pharmacy patients for each year of the study.47 For each group, biologic RA medications represented a majority of the prescription drug costs (approximately 70%-75%).47
Patients with RA achieve long-term clinical benefit from MTX.19 Lopez-Olivo and colleagues conducted a meta-analysis of the results of 7 clinical trials comprising 732 patients, with a treatment duration ranging from 12 to 52 weeks and a weekly MTX dosage ranging from 7.5 mg to 25 mg, compared with placebo.19,48 The results showed that MTX monotherapy produced clinically important and significant improvements in the ACR50 response rate.19,48
Studies show that switching to subcutaneous MTX can also be cost-effective. A retrospective study by a Glasgow hospital showed that it saved the facility the equivalent of $13,827 per-patient per-year when switching from oral to subcutaneous MTX instead of using biologic therapy.49 A UK pharmacoeconomic study found that, based on the entire population, the National Health Service could save nearly $42 million per year by switching to subcutaneous MTX before biologics.49
In a study to compare the 5-year health care cost for patients with RA, the authors found that the cost of oral MTX per patient was $47,464 while the cost per patient for subcutaneous MTX was $59,058.31 The same study found that for patients who started on subcutaneous MTX and then added on a biologic, the cost went up to $175,391 while those who started on oral MTX and then switched to a biologic, the cost was $212,595.31
Conclusion
Study findings have suggested that increasing the use of oral or subcutaneous MTX in appropriate patients can shift patients from higher-cost treatment pathways to lower-cost treatment pathways. Patients who are switched to subcutaneous MTX have been shown to incur lower costs than patients who only used oral MTX before using biologics. Since older adults are a significant population with multiple comorbidities, avoiding or delaying the use of expensive biologic therapies for this population will alter the cost distribution and may reduce the economic burden of RA for all stakeholders, therefore providing support for patients and residents to appropriately balance cost concerns with quality.
Affiliations, Disclosures, & Correspondence
Authors: Nader Tavakoli, MD, CMD, FAAFP1; Chioma Akwara, MD, MPH1; Peggy Kish, RN, DON2
Affiliations:
1 Prince George’s Hospital, Cheverly, MD
2 Zandex Corporation, Zanesville, OH
Disclosures:
Dr Tavakoli reports that he has been a speaker for Sanofi and consultant for Strategic Healthcare Alliance.
Dr Akwara and Ms Kish report no relevant financial relationships. This paper was funded by Medac Pharma.
Address correspondence to:
Nader Tavakoli, MD, CMD, FAAFP
Clinical Director of Family Medicine
Residency Program & Chairman,
Department of Family Medicine,
University of Maryland–Prince
George’s Hospital 3001 Hospital Drive Cheverly, MD 20785
Phone: (301) 352-7118
Fax: (301) 352-7779
Email: nader.tavakoli@dimensionshealth.org
References
1. United States Census Bureau. Quick Facts. https://www.census.gov/quickfacts/fact/table/US/PST045216. Updated July 1, 2017. Accessed June 26, 2018.
2. Reinhard SC, Feinberg LF, Choula R, Houser A. Valuing the Invaluable: 2015 Update. AARP Public Policy Institute. https://www.aarp.org/content/dam/aarp/ppi/2015/valuing-the-invaluable-2015-update-new.pdf. Accessed July 9, 2018.
3. Centers for Disease Control and Prevention (CDC). Vital and Health Statistics. Long-Term Care Services in the United States: 2013 Overview. CDC website. https://www.cdc.gov/nchs/data/nsltcp/long_term_care_services_2013.pdf. Published December 2013. Accessed June 26, 2018.
4. Henry Kaiser Family Foundation (KFF). Distribution of fee-for-service Medicaid spending on long term care FY2015. KFF website. https://kff.org/medicaid/state-indicator/spending-on-long-term-care/?currentTimeframe=0&sortModel=%7B%22colId%22:%22Location%22,%22sort%22:%22asc%22%7D. Accessed June 26, 2018.
5. American College of Rheumatology (ACR). Rheumatoid Arthritis. ACR website. https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Rheumatoid-Arthritis. Updated March 2017. Accessed June 26, 2018.
6. Drosos A. Methotrexate intolerance in elderly patients with rheumatoid arthritis: what are the alternatives? Drugs Aging. 2003;20(10):723-736.
7. Simmons J. RA Statistics. RheumatoidArthritis.net. https://rheumatoidarthritis.net/what-is-ra/ra-statistics/. Published September 2013. Accessed June 26, 2018.
8. Guccione AA, Meenan RF, Anderson JJ. Arthritis in nursing home residents. A validation of its prevalence and examination of its impact on institutionalization and functional status. Arthritis Rheum. 1989;32(12):1546-1553.
9. Oliveri I, Palazzi C, Peruz G, Padula A. Management issues with elderly-onset rheumatoid arthritis: An update. Drugs Aging. 2005;22(10):809-822.
10. Sharecare Inc. Rheumatoid arthritis. Sharecare website. https://www.sharecare.com/health/rheumatoid-arthritis/can-rheumatoid-arthritis-mistaken-osteoarthritis. Accessed June 26, 2018.
11. Soubrier M, Tatar Z, Couderc M, Mathieu S, Dubost JJ. Rheumatoid arthritis in the elderly in the era of tight control. Drugs Aging. 2013;30(11):863-869.
12. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):1-26.
13. Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960-977.
14. Al-Bishri J, Attar SM, Bassuni N, et al. Profile among patients with rheumatoid arthritis and the impact on prescriptions trend. Clin Med Insights Arthritis Musculoskelet Disord. 2013;6:11-18.
15. Arthritis Foundation. Understanding Methotrexate. Arthritis Foundation website. https://www.arthritis.org/living-with-arthritis/treatments/medication/drug-types/disease-modifying-drugs/understanding-methotrexate.php. Accessed June 26, 2018.
16. Rau R, Herborn G. Benefit and risk of methotrexate treatment in rheumatoid arthritis. Clin Exp Rheumatol. 2004;22(5 suppl 35):S83-S94.
17. Curtis JR, Zhang J, Xie F, et al. Use of oral and subcutaneous methotrexate in rheumatoid arthritis patients in the United States. Arthritis Care Res (Hoboken). 2014;66(11):1604-1611.
18. Rohr MK, Mikuls TR, Cohen SB, Thorne JC, O’Dell JR. The underuse of methotrexate in the treatment of RA: a national analysis of prescribing practices in the US. Arthritis Care Res (Hoboken). 2017;69(6):794-800.
19. Bello AE, Perkins EL, Jay R, Efthimiou P. Recommendations for optimizing methotrexate treatment for patients with rheumatoid arthritis. Open Access Rheumatol. 2017;9:67-79.
20. Lampropoulos CE, Orfanos P, Bournia VK, et al. Adverse events and infections in patients with rheumatoid arthritis treated with conventional drugs or biologic agents: a real world study. Clin Exp Rheumatol. 2015;33(2):216-224.
21. Wasko MC, Dasgupta A, Hubert H, Fries JF, Ward MM. Propensity-adjusted association of methotrexate with overall survival in rheumatoid arthritis. Arthritis Rheum. 2013;65(2):334-342.
22. Radcliffe S, Grosso M. Med pass makeover. Provider. https://www.providermagazine.com/archives/archives-2011/Pages/0911/Med-Pass-Makeover.aspx. Published September 2011. Accessed June 26, 2018.
23. Kourbeti IS, Ziakas PD, Mylonakis E. Biologic therapies in rheumatoid arthritis and the risk of opportunistic infections: a meta-analysis. Clin Infect Dis. 2014;58(12):1649-1657.
24. Kromann CB, Lage-Hansen PR, Koefoed M, Jemec GB. Does switching from oral to subcutaneous administration of methotrexate influence on patient reported gastro-intestinal adverse effects? J Dermatolog Treat. 2015;26(2):188-190.
25. Li D, Yang Z, Kang P, Xie X. Subcutaneous administration of methotrexate at high doses makes a better performance in the treatment of rheumatoid arthritis compared with oral administration of methotrexate: a systematic review and meta-analysis. Semin Arthritis Rheum. 2016;45(6):656-662.
26. Braun J, Kästner P, Flaxenberg P, et al for the MC-MTX.6/RH Study Group. Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. Arthritis Rheum. 2008;58(1):73-81.
27. Bianchi G, Caporali R, Todoerti M, Mattana P. Methotrexate and rheumatoid arthritis: current evidence regarding subcutaneous versus oral routes of administration. Adv Ther. 2016;33(3):369-378.
28. Hameed B, Jones H. Subcutaneous methotrexate is well tolerated and superior to oral methotrexate in the treatment of rheumatoid arthritis. Int J Rheum Dis.2010;13(4):e83-e84.
29. Pichlmeier U, Heuer KU. Subcutaneous administration of methotrexate with a prefilled autoinjector pen results in a higher relative bioavailability compared with oral administration of methotrexate. Clin Exp Rheumatol. 2014;32(4):563-571.
30. Hazlewood GS, Thorne JC, Pope JE, et al for the CATCH Investigators. The comparative effectiveness of oral versus subcutaneous methotrexate for the treatment of early rheumatoid arthritis. Ann Rheum Dis. 2016;75(6):1003-1008.
31. Lee J, Pelkey R, Gubitosa J, Henrick MF, Ganz ML. Comparing healthcare costs associated with oral and subcutaneous methotrexate or biologic therapy for rheumatoid arthritis in the United States. Am Health Drug Benefits. 2017;10(1):42-49.
32. US Department of Labor, Occupational Safety and Health Administration (OSHA). Controlling occupational exposure to hazardous drugs. OSHA website. https://www.osha.gov/SLTC/hazardousdrugs/controlling_occex_hazardousdrugs.html. Accessed June 26, 2018.
33. Bedford Laboratories. Material safety data sheet-Methotrexate. Vaxserve website. https://www.vaxserve.com/image.cfm?doc_id=11570&image_type=msds_sheet. Published May 29, 1996. Revised July 17, 2007. Accessed June 26, 2018.
34. Fitzpatrick R, Scott D, Keary I. Cost-minimisation analysis of subcutaneous methotrexate versus biologic therapy for the treatment of patients with rheumatoid arthritis who have had an insufficient response or intolerance to oral methotrexate. Clin Rheumatol. 2013;32(11):1605-1612.
35. Pachon JA, Kivitz AJ, Heuer KU, Pichlmeier U. Assessing usability, label comprehension, pen robustness and pharmacokinetics of a self-administered prefilled autoinjector pen of methotrexate in patients with rheumatoid arthritis. Sage Open Med. 2014;2:2050312114564241.
36. Schiff M, Jaffe J, Freundlich B, Madsen P. New autoinjector technology for the delivery of subcutaneous methotrexate in the treatment of rheumatoid arthritis. Expert Rev Med Devices. 2014;11(5):447-455.
37. Sharma P, Scott DG. Optimizing methotrexate treatment in rheumatoid arthritis: the case for subcutaneous methotrexate prior to biologics. Drugs. 2015;75(17):1953-1956.
38. Horsten NC, Ursum J, Roorda LD, Van Schaardenburg D, Dekker J, Hoeksma AF. Prevalence of hand symptoms, impairments and activity limitations in rheumatoid arthritis in relation to disease duration. J Rehabil Med. 2010;42(10):916-921.
39. Keystone E, Freundlich B. Methotrexate in rheumatoid arthritis: benefits, limitations and the emerging value of subcutaneous administration. Int J Clin Rheumatol. 2014;9(4):345-351.
40. Rasuvo injection [package insert]. Chicago, IL: Medac Pharma; November 2014. https://cdn.rasuvo.com/assets/pdf/Prescribing-Information-current.pdf. Accessed June 26, 2018.
41. Otrexup injection [package insert]. Ewing, NJ: Antares Pharma; March 2016. www.otrexup.com/files/7814/6112/8269/PrescribingInformation.pdf. Accessed June 26, 2018.
42. Allen C. Medication pass fundamentals part 1: preparation, errors, safety, security and controlled substances. Omnicare Pharmacy Services. https://www.mmlearn.org/hubfs/docs/Med%20Pass%20Fundamentals%201a.pdf. Published April 2014. Accessed June 26, 2018.
43. Kivitz A, Cohen S, Dowd JE, et al. Clinical assessment of pain, tolerability, and preference of an autoinjection pen versus a prefilled syringe for patient self-administration of the fully human, monoclonal antibody adalimumab: The TOUCH trial. Clin Ther. 2006;28(10):1619-1629.
44. Lugaresi A, Durastanti V, Gasperini C, et al; CoSa Study Group. Safety and tolerability in relapsing-remitting multiple sclerosis patients treated with high-dose subcutaneous interferon-beta by Rebiject autoinjection over a 1-year period: the CoSa study. Clin Neuropharmacol. 2008;31(3):167-172.
45. Demary W, Schwenke H, Rockwitz K, et al. Subcutaneously administered methotrexate for rheumatoid arthritis, prefilled syringes versus prefilled pens: patient preference and comparison of the self-injection experience. Patient Prefer Adherence. 2014;8:1061-1071.
46. Freundlich B, Kivitz A, Jaffe JS. Nearly pain-free self-administration of subcutaneous methotrexate with an autoinjector: results of a phase 2 clinical trial in patients with rheumatoid arthritis who have functional limitations. J Clin Rheumatol. 2014;20(5):256-260.
47. Barlow JF, Faris RJ, Wang W, Verbrugge RR, Garavaglia SB, Aubert RE. Impact of specialty pharmacy on treatment costs for rheumatoid arthritis. Am J Pharm Benefits. 2012;4(special issue):SP49-SP56.48. Lopez-Olivo MA, Siddhanamatha HR, Shea B, Tugwell P, Wells GA, Suarez-Almazor ME. Methotrexate for treating rheumatoid arthritis. Cochrane Database Syst Rev. 2014;6:CD000957.
48. Lopez-Olivo MA, Siddhanamatha HR, Shea B, Tugwell P, Wells GA, Suarez-Almazor ME. Methotrexate for treating rheumatoid arthritis. Cochrane Database Syst Rev. 2014;6:CD000957.
49. Jay R. Methotrexate revisited: considerations for subcutaneous administration in RA. Clin Rheumatol. 2015;34(2):201-205.
50. Rheumatoid Arthritis Treatment Options. Johns Hopkins Arthritis Center website. https://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-treatment/. Accessed December 4, 2017.
51. REDBOOK Online® Micromedex® TruvenHealth Analytics; 2017. Accessed December 11, 2017.
52. Iliades C. Treating rheumatoid arthritis: DMARDS vs. biologics. Everyday Health Web site. https://www.everydayhealth.com/hs/rheumatoid-arthritis-treatment-management/dmards-biologics/. Accessed December 4, 2017.
