The World Health Organization defines adherence as “the extent to which a person’s behavior—taking medication, following a diet, and/or executing lifestyle changes—corresponds with agreed recommendations from a healthcare provider.”1 In the context of medication adherence, this reflects the degree to which a medication is used as prescribed (e.g., strength, dosing frequency) and can involve both underuse and overuse.^2,3 Non-adherence to medical therapies is associated with poorer individual- and population-health outcomes, as well as inflated healthcare costs.⁴ An estimated 50-60% of individuals living with a chronic health issue experience challenges with adherence, and rheumatoid arthritis (RA) is no exception.⁵

For patients with RA , the backbone of current treatment strategies includes conventional, biologic, and synthetic disease modifying anti-rheumatic drugs (DMARDs) utilized in a treat-to-target approach.⁶ This approach has been shown to slow or stop disease progression, improve symptoms, and enhance health-related quality of life.⁷ However, the full benefits of these therapies can only be recognized if patients are adherent to their medication regimen. Nonadherence has been shown to translate to higher levels of disease activity and radiological progression, greater loss of function, and reduced quality of life.^8,9 Furthermore, unrecognized nonadherence is an important potential explanation for subpar effectiveness of treatment.⁹

Adherence to RA Medications: Real-World Observations

Marie is a 46-year old female who has been your patient for the last 7 months. She works full-time as a licensed practical nurse (LPN) in a long-term care facility and has 3 children, ages 15, 12, and 10 years old. Marie initially presented to your office with laboratory results and physical symptoms strongly suggestive of RA. After a full work-up, the diagnosis of RA was confirmed.

At baseline, Marie’s disease activity score in 28 joints (DAS28) was 4.8, indicating moderate disease activity. The decision was made to initiate therapy with oral methotrexate (MTX) 10 mg/week, folic acid, and a short course of low-dose prednisone. The MTX dose was titrated to 15 mg/week after 4 weeks. A month later, Marie had stopped taking prednisone and was up to 20 mg/week of MTX. Her DAS28 score was down only slightly to 4.5.

It was decided to increase Marie’s MTX to 25 mg/week and reassess her disease activity at month 3. Unfortunately, Marie’s DAS28 score did not substantially improve at this next milestone. She also mentioned being increasingly frustrated as she kept waiting for her medication to help her pain and daily morning stiffness, but it seemed to have little effect. As a result, she admitted to occasionally missing a dose.

In the literature, adherence rates to prescribed medication regimens in patients with RA have been reported to range from 30% to 80%,2 with a recent meta-analysis reporting an overall adherence rate to DMARD therapy of 66%.¹⁰ When looking at DMARD therapy by class, a systematic review evaluating MTX adherence in patients with RA found that adherence rates were highly variable, ranging from 14% to 107%.¹¹ Similarly wide variability in adherence to biological DMARDs has been reported, ranging from 11% to 88%.¹² Much of the available real-world data is focused on tumor necrosis factor (TNF) inhibitors, while real-world data evaluating adherence to non-TNF inhibitors and synthetic biologic DMARD therapies are more limited.

Determining rates of adherence to various DMARDs has proven challenging given the wide heterogeneity in study design, patient population, medications included in the analysis, length of follow-up, standard reference measures, and terminology. However, following medication recommendations as measured by medication possession ratio (MPR = total days supplied/# of days between first and last refill) is commonly used as a marker for adherence. “Patients who score 0.8 (≥80%) or greater are considered adherent.¹³ Despite the earlier caveats, data suggest the following broad themes:

1. Biologic DMARD therapy may be associated with higher rates of adherence compared with conventional DMARDs

Patient adherence rates were evaluated through a retrospective analysis of claims data (1998-2001) for commercial and Medicare patients with RA enrolled in a U.S. health plan who initiated therapy with MTX (n=1,668), etanercept (n=853), or infliximab (n=141), either as monotherapy or in combination with other DMARDs. Over the 365-day follow-up period, a significantly higher proportion of patients receiving infliximab (80.9%) were found to be adherent to treatment compared with those receiving etanercept (68.4%) or MTX (63.7%); the differences between etanercept and MTX were statistically significant as well.¹⁴

Another study used Tennessee Medicaid claims data (1995-2004; N=14,932 patients) to evaluate adherence to 12 different newly prescribed DMARD regimens in patients with RA, using MTX as the reference therapy. The DMARD regimens included within the evaluation included monotherapy with methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, infliximab, etanercept, or adalimumab; or therapy involving methotrexate in combination with hydroxychloroquine, infliximab, etanercept, adalimumab, or anakinra. Follow-up intervals were variable as cohort members were followed from the time they entered the study to the end of the study. Adherence was significantly higher for patients prescribed monotherapy with leflunomide, infliximab, etanercept, and adalimumab compared with MTX. In contrast, sulfasalazine monotherapy and all MTX-based combination regimens were associated with significantly reduced adherence compared with methotrexate monotherapy. Adherence to hydroxychloroquine monotherapy was comparable to methotrexate.¹⁵

2. Adherence rates can vary between different medications within the same drug class (e.g., TNF inhibitors)

While the majority of clinical data indicate that different TNF inhibitors have comparable efficacy and safety,7 differences in adherence rates between different TNF inhibitors has been reported. TNF inhibitors differ from one another in route of administration (e.g., intravenous vs. subcutaneous) as well as frequency of dosing (e.g., weekly, biweekly, monthly, bimonthly), both of which can impact adherence.

Researchers studying a cohort of biologic-naïve patients with RA (N=822) derived from Texas Medicaid data (2003-2011) reported that 1-year adherence rates were highest in patients treated with infliximab (38%), followed by adalimumab (21%), and etanercept (16%).¹⁶

Other studies have compared TNF inhibitors with the same route of administration but different dosing schedules. An analysis of U.S. claims data (2005-2012; N=3,892) evaluated adherence over a 1-year follow-up period in patients with RA receiving subcutaneous golimumab, adalimumab, or etanercept. In this study, 59% of patients prescribed golimumab had history of prior biologic DMARD use, whereas, the majority of adalimumab (16%) and etanercept (9%) users were biologic DMARD-naïve. This study found a significantly higher proportion of patients receiving golimumab were adherent to therapy (82%) compared with adalimumab (71%) and etanercept (62%).¹⁷

Similar results were reported in an analysis of private and public Canadian databases (2010-2014) evaluating adherence to subcutaneous TNF inhibitors in the treatment of patients with inflammatory arthritis (N=4,035) who initiated therapy with either golimumab, adalimumab, etanercept, or certolizumab pegol. The vast majority of patients (≥85%) were biologic DMARD-naïve at baseline, with patients receiving golimumab most likely to have tried a prior biologic. Over the 24-month follow-up period, 76% of overall patients were adherent to their prescribed TNF inhibitor. A significantly higher proportion (87%) of patients receiving golimumab were adherent to therapy compared with patients receiving adalimumab, etanercept, and certolizumab pegol (75%, 73%, and 71%, respectively).¹²

It has been suggested the greater adherence observed with subcutaneous golimumab may in part be explained by its once-monthly dosing schedule, a finding that is consistent with other non-RA chronic disease studies that have found inverse relationships between dosing frequency and adherence, as well as patient preference for longer dosing intervals.^12,17

3. Data evaluating adherence to non-TNF inhibitors and synthetic DMARDs (e.g., tofacitinib and baracitinib) compared with TNF inhibitors appears mixed

Adherence to tofacitinib, adalimumab, etanercept, or abatacept, either as monotherapy or in combination with a conventional DMARD, was evaluated in a cohort of biologic DMARD-experienced RA patients derived from U.S. commercial and Medicare supplemental claims databases (2012-2014; N=1,252). One year after initiating therapy, the proportion of patients who were persistent with tofacitinib (42.6%) therapy was similar to those treated with adalimumab (37.6%), etanercept (42.4%), and abatacept (43.5%). Likewise, adherence (mean percentage of days covered) was similar between tofacitinib (0.55), adalimumab (0.57), and etanercept (0.59); adherence to abatacept (0.44), however, was significantly lower.¹⁸

Contrasting results were reported in another analysis of U.S. commercial and Medicare supplemental claims data (2011-2014). In this study, adherence rates were assessed for patients with RA (N=21,832) who had previously received treatment with MTX and were starting monotherapy or DMARD-based combination therapy treatment with another DMARD, tofacitinib, a TNF inhibitor, or non-TNF biologic. After one year of follow-up, adherence to therapy (MPR ≥80%) rates were highest in patients treated with non-TNF biologics (53.3%), followed by TNF inhibitors (44.0%), tofacitinib (27.7%), and non-biologic DMARDs (26.6%).¹⁹

4. Complexity of treatment regimens may impact adherence to therapy, with simpler regimens appearing to fare better

A retrospective study of the Texas Medicaid database (2003-2010) found that patients with RA who initiated DMARD therapy were more adherent to monotherapy regimens compared with combination therapy (32.6% vs 17.1%, respectively).²⁰ Similarly, a large retrospective analysis (2009-2013) evaluated adherence and persistence rates in a cohort of privately insured patients with RA receiving either dual therapy with etanercept + MTX (n=3,742) or triple therapy with nonbiologic DMARDs (n=818). At one year, patients receiving dual therapy were nearly twice as likely to be adherent to therapy compared with those receiving triple therapy; >80% of those receiving triple therapy were nonadherent to therapy. Similar trends were observed for persistence, with 29.4% and 23.2% of patients receiving dual and triple therapies respectively, continuing with treatment at the 1-year mark.²¹

Adherence vs non-adherence: associated factors

Broadly speaking, adherence reflects the extent to which a patient’s behavior matches an agreed upon prescribed treatment protocol. Importantly, adherence to therapy can be fluid, with a previously adherent patient becoming nonadherent at some point in their disease progression.²

Nonadherence can be categorized as intentional (don’t fill, refill, and/or take as prescribed) or non-intentional (forgets, misunderstands, inaccessibility, polypharmacy).⁹ Studies have shown that nonadherence is frequently intentional.²² Intentional nonadherence typically reflects patients’ personal beliefs about their illness and its treatment, and is a result of a patient balancing the perceived benefits of therapy (e.g., reduced symptoms, prevention of functional loss, cure of disease) against perceived risks and other concerns (e.g., medication side effects, cost).^2,23 Data in the literature widely indicates that a patient’s faith in the necessity, effectiveness, and safety of treatment for managing rheumatic disease is a key contributor to and influencer of treatment adherence.^9,24,25 This is consistent with findings in the general health population that have shown that patients who report more negative beliefs about medication are 53% less likely to adhere to medication regimens than those with positive beliefs.²⁶ The impact of medication side effects on adherence will be discussed later in this issue of Rheumatology Nurse Practice.

Other Factors Influencing Adherence

Patients with RA who are nonadherent to treatment recommendations have proven challenging to characterize, as adherence behavior reflects the complex interplay of 5 different domains, including socioeconomic factors, healthcare provider and systems factors, disease characteristics, therapy-related factors, and patient-related factors.¹ Furthermore, studies evaluating factors associated with adherence behaviors have found conflicting results at times, yielding no clear or consistent patterns.² For example, older age has been found to have both negative and positive association with adherence.⁹

owever, awareness of factors that may influence medication adherence in patients with RA could help healthcare providers identify patients who are potentially at risk of nonadherence and tailor possible interventions. In the literature, some factors that have been found to potentially associated with adherence are presented in Table 1.

Navigating the Maze

Given the lack of Marie’s treatment response to MTX monotherapy, you discuss with her the possible addition of a second DMARD to her treatment regimen. When discussing treatment options, it becomes clear that Marie has a strong preference for a self-administered subcutaneous injection over an IV infusion due to the higher level of flexibility and control that would offer. Given Marie’s employment in a long-term care facility, you mention to her that some medication choices, such as non-TNF biologics, may be better than others given her exposure to a patient population with an increased incidence of tuberculosis (TB). After further discussion, you jointly decide to begin therapy with abatacept (weekly 125 mg/mL single-dose autoinjector) in addition to MTX.

You go over Marie’s current medications, health concerns, and recent travel, and decide to administer a TB test. You also review self-injection techniques with her, with assurances that hands-on training will be repeated before she has to administer the first dose of abatacept.

Marie is also instructed to be prepared for potential side effects such as injection site irritation, sore throat, upper respiratory infection, and headaches. Finally, you give her preliminary instructions regarding what to watch for and do if signs or symptoms of an infection such as fever, cough, flu-like symptoms, feeling very tired, or warm, red, or painful skin develop.²⁷
Following this meeting, your office initiates the prior authorization process.

Prior Authorization

The choice of DMARD typically depends on patient and physician preference, disease activity, comorbidities, the benefits of treatment, and potential side effects. In some cases, it will also be influenced by payor coverage and reimbursement criteria.⁶ An increasing number of medications used in the treatment of RA, including biologic and synthetic DMARDs, require a provider to submit a prior authorization form to the health plan for approval before insurance coverage will be provided. There is incredible variation between payors and plans in both the commercial and government insurance space in terms of DMARD coverage criteria and determination, making navigating the coverage process challenging, if not burdensome.

Over time, insurance coverage requirements for biologics have evolved. A study evaluating the change in prior authorization requirement rates for biologics prescribed for patients with psoriasis found that, in 2009, prior authorization was required for only 16% of patients prescribed a biologic; this increased to 75% of patients in 2014. Commensurate with this increase were increases in days between prior authorization submission and approval (3.7 days vs. 6.7 days) as well as denial rates (0% vs. 19%). Failure to try alternative therapies before requesting biologics was the most common reason for coverage denial.²⁸

While these findings were specific to psoriasis, one could reasonably expect similar results for biologics prescribed for patients with RA. Indeed, an analysis of RA coverage policies for the top 10 largest private payers in the United States found that, in 2012, coverage policies were more restrictive than corresponding U.S. Food and Drug Administration (FDA) labels in 69% of all cases, and 33% were more restrictive than American College of Rheumatology (ACR) recommendations. When coverage determinations were more restrictive compared with FDA labels and ACR recommendations, it was typically due to the inclusion of step therapy restrictions.²⁹

Furthermore, there is a lack of consistency across payers on which biologic and synthetic DMARDs require step therapy, as well as the specific requirements of step therapy. For example, UnitedHealthcare’s clinical pharmacy program (commercial) does not require step therapy for adalimumab but does require extensive step therapy for etanercept. Under their program, to be approved for treatment with etanercept, patients with a diagnosis of RA must have the following:

1. A history of failure, contraindication, or intolerance to both of the following:
   1. Two of the three preferred TNF inhibitors (certolizumab, adalimumab, golimumab) AND
   2. Both tocilizumab and tofacitinib OR
2. Patients are currently using etanercept as documented in claims history AND have not received a manufacturer supplied sample at no cost in the prescriber’s office or any form of assistance from Amgen to establish them as a current user of etanercept.³⁰

In contrast, BlueCross BlueShield (Michigan) does not require treatment with other biologic DMARDs before etanercept can be prescribed; instead their only requirement is a 3-month trial with one conventional DMARD.³¹

While processes may vary, when a medication requiring prior authorization is prescribed, typically the patient will sign a medical release allowing the prescribing provider to start the benefit verification and prior authorization process with the health plan/PBM on the patient’s behalf. Depending on the practice set-up, this process may be managed a nurse, a practice manager, a physician, or an advanced practice provider (i.e., nurse practitioner or physician assistant). Alternatively, patients may take prescriptions to their pharmacy, who upon entering the prescription into the system receive an alert that prior authorization is needed. At this point, the prescribing provider is notified and the process is initiated.³² Another common option is for the prescription to be sent to the pharmacy/specialty pharmacy, which then provides assistance for the benefits investigation/prior authorization process.³³ Lastly, many drug manufacturers will contact insurance companies on a patient’s behalf and assist with the benefits investigation and prior authorization process when a patient is initiating treatment with their product.

While limited, data from one study suggest pharmacy-led prior authorization processes may experience faster and higher approval rates compared with usual care. The University of California Davis Health System (UCDHS) compared prior authorization processing time and approval rate between a UCDHS centralized pharmacy-run refill clinic (intervention group) with other UCDHS primary care clinics (usual care). In the usual care model, the prior authorization process was initiated after a pharmacy or patient informed the individual clinic that a prior authorization was needed. At that point, a clinical staff member in the individual clinic entered prior authorization information into the electronic health record and relayed relevant information to the health plan. In contrast, the centralized pharmacy-run refill clinic used a standardized and streamlined protocol. Under this approach, prior authorization requests from individual clinics were entered into the electronic health record and transmitted to the refill clinic. At that point, a pharmacy technician completed a review of the request (e.g., indication, past therapies, insurance, and alternative therapeutic options) and addressed any issues. Once this was done, the completed prior authorization was submitted to the health plan. While this study did not include specialty medications, they found the average prior authorization processing time was 0.53 days for the pharmacy-run clinic vs. 7.02 days for usual care. In addition, prior authorization approval rates were significantly higher in the intervention group compared with usual care, 96% vs 68%.³⁴

Marie’s initial prior authorization for abatacept was denied based on her commercial insurance provider’s step therapy program, which required use (and failure) of at least 2 anti-TNFs before abatacept would be approved. An appeal was submitted, including a letter of medical necessity that explained how Marie was at high risk of contracting TB thanks to her employment as an LPN in a long-term care facility. Copies of published studies showing a lower risk of activation of latent TB in patients taking abatacept compared to other biologic DMARDs was provided, along with current ACR guidelines, to support the appeal.^6,35-38

Appeals Process

In the event of a prior authorization denial, patients and their providers have several options. One is to choose to remain with the prescribed medication and assume responsibility for its full cost, perhaps utilizing foundation or manufacturer co-pay or patient assistance programs. Another is to change the prescription to an alternate drug that is covered by the health plan. The final primary choice is an appeal. Each choice follows a different path.

When a prior authorization is denied, the reason for denial, the appeals process, and appeals form are frequently provided by the insurance company. The appeals process generally entails completion of that form as well a letter of medical necessity, which can include relevant chart notes/labs/assessments from the patient medical record, a detailed documentation of past therapies and results, and any other background information that may help. Providers may also include guidelines or other publications that show why they believe the requested medication is medically necessary in this specific patient.³⁹ Standard internal reviews can take anywhere from 30 to 60 days, although expedited reviews can be requested.⁴⁰ Once prior authorization is granted, the prescription is sent to the pharmacy; in the case of biologic and synthetic DMARDs, it is sent to the specialty pharmacy.

After an expedited review of the filed appeal, Marie received authorization to begin treatment with abatacept. She received notification she was scheduled to receive her first shipment of monthly medication and supplies from a specialty pharmacy.

Specialty Pharmacies

Specialty pharmacies involve a business model focused on specialty medications that are covered under patients’ insurance benefits.⁴¹ In general, specialty medications fit the following criteria:42

• They are used to treat complex, chronic, or life-threatening conditions
• They are expensive
• They are complex to manufacture and require special handling/storage
• They require special patient education and training
• They have limited distribution networks.

The majority of specialty medications are dispensed via mail from a central-fill specialty pharmacy. Increasingly, patients are being required to use the specialty pharmacy that their insurance plan or pharmacy benefit manager either owns and operates or has contracted with.⁴¹

A variety of entities may own a specialty pharmacy, such as healthcare providers (e.g., hospitals, physician groups, health systems), drug manufacturer wholesalers, health insurance companies, retail community pharmacies, practice benefit managers (PBM), and independent specialty pharmacy owners. While not required, specialty pharmacies can undergo accreditation to demonstrate adherence to standards of care, such as consistent patient experience, coordination of care, communication and education, and safe and appropriate medication use. Meeting these standards can demonstrate an individual specialty pharmacy’s capabilities to providers, manufacturers, and third-party payers. The Accreditation Commission for Health Care (ACHC), Utilization Review Accreditation Commission (URAC), and The Center for Pharmacy Practice Accreditation are the primary accrediting organizations.⁴¹

Specialty pharmacies typically offer a wider breadth of patient services than those available to patients filling their prescriptions at community-based retail pharmacies, combining medication dispensing with clinical disease management.^33,43 Pharmacy-based services focused on a variety of programs such as medication therapy management, counselling, patient education, or case-team support have been shown to positively impact patient adherence to therapy and clinical outcomes across numerous disease states, including RA.^44,45 One study compared adalimumab and etanercept adherence rates in patients who received their biologic DMARD through a community-based retail pharmacy (n=1,334) vs. those who filled prescriptions through a specialty pharmacy (n=3,054). Patients utilizing the specialty pharmacy received enhanced therapy management services (in-depth education, regularly scheduled consults to address adherence, 24/7 access to pharmacists and nurses with specialized RA knowledge, and expedited refill/delivery of biologic DMARDs). Over the 3-year study period (2006-2008), patients using specialty pharmacies consistently had significantly higher rates of medication adherence compared with retail pharmacy patients, with average mean adherence rates of 64% and 48%, respectively.⁴³

After Marie heard from the specialty pharmacy, she called your office upset that her insurance co-pay was too expensive. You discussed some of the financial support options that might be available to her and referred her to the drug manufacturer’s website in order to enroll in their clinical and financial support program. After doing this, Marie learned that because she had commercial insurance, she qualified for the abatacept co-pay assistance card, which reduced her monthly out-of-pocket expenses significantly.

Biologic and synthetic DMARDs are unquestionably expensive. According to GoodRx, an online tool that tracks drug pricing and coupons at various pharmacies, the average list price for a 1-month supply of abatacept (1 carton, 4 doses of 50 mg along with SureClick autoinjectors) is currently $5,463.84.⁴⁶ However, out-of-pocket costs to individual patients can be hard to pin down as co-pay/co-insurance amounts vary significantly between commercial and government-sponsored plans and can be affected as well by medical or pharmacy benefit designation. Some studies have found, however, co-insurance requirements as high as 30% to 50% of the drug cost for medications in specialty tiers.⁴⁷ Thus, given the cost-sharing models most healthcare plans utilize, patients are not often spared the burden of expense.

For instance, one study of 2014 Medicare claims found patients treated with self-administered biologic DMARDs at home (Medicare Part D) incurred an average out-of-pocket cost of $835/month.⁴⁸ In general, increasing out-of-pocket costs have been associated with increased rates of prescription abandonment for a newly prescribed specialty drug as well as decreased treatment initiation and adherence.^33,47

Drug Manufacturer Patient Support Programs

Patient support programs, which are becoming increasingly available, are enhanced self-management programs that combine several different types of interventions, such as counselling, education, medication reminders, and practical training. They have been shown to effectively increase rates of adherence, improving humanistic outcomes (e.g., quality of life, functional status), and reducing healthcare utilization across numerous chronic disease states, including RA.⁴⁹

Fortunately, all manufacturers of currently available RA specialty drugs offer comprehensive patient and provider support programs, which may be phone-, web-, email-, or home-based, depending on the manufacturer. These programs are designed to help patients and providers improve the management of RA and optimize outcomes. A variety of types and level of services are offered within these programs, such as insurance specialists who assist with coverage and reimbursement issues, nurse educators/ambassadors/case workers and pharmacy specialists who provide educational and clinical support (e.g., nutrition, practical tips on living with RA, self-injection training), treatment adherence support (e.g., medication and prescription refill reminders, phone/tablet apps), and financial assistance. Types of financial assistance vary depending on manufacturer and type of insurance coverage (commercial, government, under- and non-insured), but may include co-pay savings cards, prescription rebates, patient assistance programs, and help identifying foundations and nonprofit organizations that offer patient financial support resources. Patients can usually enroll in the program specific to their medication via the manufacturer website (see Table 3).

Importantly, participation in specialty drug manufacturer patient support programs has been shown to help improve adherence and persistence rates as well as reduce costs. A retrospective analysis of claims data (2008-2014) evaluated the impact of AbbVie’s patient support program for patients receiving adalimumab across all approved indications. Patients were assigned to either participate in the patient support program (n=1,199) or not (n=1,187). After 12 months, patients in the support program experienced greater adherence and lower discontinuation rates compared with those not enrolled in the support program (67% vs. 59% and 40% vs. 46%, respectively). Furthermore, total healthcare costs were lower for patients enrolled in the patient support program.⁵⁰

Supporting Medication Adherence

After Marie received her first shipment, self-injection techniques were reviewed and demonstrated. She began self-injections with abatacept, but after several doses she called the office concerned that her skin was itchy and red for several hours after each injection. One of her close friends was worried that she might be getting repeated skin infections. After discussing the cause and management of her injection site reactions with you, Marie said she felt more confident she could tolerate and manage this side effect and agreed it was important to continue therapy to see if she responded to it.

Medication-related Side Effects and Adherence

As discussed earlier, there are many factors that can contribute to medication adherence and nonadherence. For patients with RA, side effects can have a substantial impact on medication adherence, with 21.3% of patients in one study reporting side effects as the reason for derailed adherence to a biologic DMARD. Equally interesting, in this same study, concern about potential side effects was strong enough that 19.0% patients never even filled their initial prescription.⁵¹

Data indicate this finding is not limited to injectable DMARDs. One study found that 15% of patients with rheumatic disease (81% with RA) reported at least one episode of intentional nonadherence to oral DMARD therapy; of those, 69% reported side effects as a key contributor to their nonadherence, with another 19% reporting fear of side effects as the primary reason for intentional nonadherence.⁵²

Before treatment initiation, medication guides or other materials should be reviewed with patients and/or their caregivers. This should include a detailed review of possible side effects, practical tips to manage side effects if they arise, if and/or when patients should be concerned, and who to call if they have concerns or questions. The Patient Information section, available at the end of product package inserts, often contains helpful information about the medication, side effects, general information, and how to use and store medication as well as helpful visual aids on self-injection techniques when relevant. Manufacturer websites also often provide patient materials, including self-injection guides. Some specialty pharmacies and manufacturer patient support programs have staff who are available to discuss concerns and answer questions, typically on a 24/7 basis.

Furthermore, assessing and managing treatment adherence is an ongoing and collaborative process, with office or telephone interactions providing an opportunity for nurses to routinely broach a variety of topics, such as the following:1,53

• Actual medication adherence: How regularly does the patient take the medication? How do they keep track of their medication use?
• Soliciting questions or concerns about medication: How well does the patient think the medication is working? Are there any ongoing or new tolerability or side effect issues? What about challenges in the use of the medication (e.g., complexity, schedule, self-injection techniques)? Is cost an issue (e.g., changes in insurance plan, co-payments)?
• Outside influence: Does the patient have any concerns that have arisen from conversations with family or friends, or from anything they may have seen in the media? Do they believe that their prescription medicine is important and will do more good than harm?

Interventions to Improve Adherence

It is increasingly recognized that interventions to improve medication adherence do not involve a one-size-fits-all solution. Rather, the types and intensity of interventions should be individualized to address the root causes of non-adherence and should ideally be carried out by a multidisciplinary team (e.g., rheumatology providers, pharmacists, psychologists).^2,54 Interventions can be solely educational, behavioral, or cognitive behavioral in nature, or utilize a blend of strategies (Table 3), with the overarching goal of supporting improved adherence through increasing knowledge, motivation, and self-efficacy (Table 4).^55,56 Given that most cases of nonadherence are multifactorial, interventions should embrace a comprehensive approach.⁵⁷

That said, studies evaluating the effectiveness of interventions to improve adherence in patients with RA are limited. Simply providing patients with education or adherence aids has not been shown to be particularly effective for changing adherence health behaviors; rather, education coupled with support that fosters the adoption of skills and behaviors has proven to be more effective.⁵⁵ Furthermore, interventions that incorporate patients’ beliefs about their illness, treatment, medication necessity, and concerns about potential adverse effects have been shown to more positively influence adherence.²⁵

A recent literature review of 22 studies evaluated the impact of educational, behavioral, cognitive behavioral, and multicomponent interventions on medication adherence in patients with inflammatory rheumatic disease, including RA. Educational interventions were the most commonly assessed intervention, with mixed results.⁵⁶ One of the larger studies (N=732 in claims data cohorts) included in this review focused solely on patients receiving injectable RA medications through a U.S. PBM. Patients were assigned to participate in a 6-month RA disease therapy management (DTM) program as an enhanced offering to specialty pharmacy services or to receive routine services through either a specialty or community pharmacy. In addition to usual specialty pharmacy services (educational welcome brochure, mail delivery, refill reminders, 24/7 access to pharmacists), patients in the DTM arm had regularly scheduled telephone consultations with an assigned clinician during which patient knowledge was assessed, health concerns were discussed, and RA-specific education on core topics was provided (e.g., pathophysiology, optimization of therapy, medication adherence, symptom/pain/stress management, side effects, financial concerns). Patients in the DTM arm also received personalized care plans following each call as well as monthly RA-specific educational materials. Mean medication adherence was significantly higher in the DTM completer cohort (89%) compared with both the specialty (81%) and community pharmacy cohorts (60%).⁴⁴

Beyond educational interventions, the aforementioned review found that studies evaluating other types of interventions (behavioral, cognitive behavioral, and multicomponent interventions) for improving adherence in patient with RA are scarce.⁵⁶ One study evaluated the use of medication reminders (e.g., calendars, diaries, pill containers) in enhancing adherence to therapy. Overall, 34% of patients in the study reported using some form of a medication reminder. Use of reminders was associated with improved medication adherence, particularly when patients were most likely to forget, such as being busy or away from home.⁵⁸ Another found that the use of cognitive behavioral therapy, with therapy individualized to reflect patient characteristics and treatment priority, increased adherence to medicine at the 6-month follow-up assessment compared to usual medical care.⁵⁹

Drawing from the general medicine population, interventions that have proven effective for improving adherence to long-term treatment include in-person, computer-based, print materials, and telephone-based motivational interviewing, as well as mobile technology programs that deliver information and supportive messaging.⁵⁵ For instance, a mobile health text message-based intervention in patients with diabetes found that patients who received 3 daily text messages for 3 weeks with content ranging from educational/motivational and medication reminders to links to management tools, demonstrated increased medication adherence and self-efficacy.⁶⁰ Other potential approaches include the use of pill-monitoring technology for oral medications and the use of online resources and social media to provide condition-specific peer support, self-monitoring and reporting, and reliable and accurate educational support.⁵⁷

Mobile applications are increasingly emerging as a tool to improve adherence. For example, RxRemind (http://rxremindme.com) has developed a medication adherence app that tracks when a medication was last taken, when the next dose is due, how much is left, and when prescriptions need to be refilled.

Lastly, friends, family, and social media have also been shown to potentially influence adherence. Family, professional, and social support have been found to be positively associated with improved adherence to RA medication, consistent with findings from other chronic disease states.^61,62

In 2012, 81% of U.S. adults reported using the Internet, with 72% of those reporting looking online for health information, most commonly a specific disease or medical problem.⁶³ More recent data indicate that when patients are in information-gathering mode, trusted health websites are the most commonly utilized source (43%), followed by search engines (29%).⁶⁴ Starting a new medication and experiencing side effects has also been shown to be another trigger for online research.⁶⁵ Social media (e.g., blogs, networking sites, discussion forums, content communities, collaborative projects) is being increasingly utilized by patients to seek information and generate support for their medical issues.^65,66 While the potential for misinformation and resultant harm exists, a review evaluating the use of social media in patient and caregiver populations found the most common intended use of social media was to facilitate self-care; this was associated with positive outcomes in the majority of studies.⁶⁶ In addition to manufacturer websites, additional reliable sources for drug-related patient education can be found in Table 5.

Summary

Management of RA is a complex process, with DMARD therapy being a cornerstone of treatment. Unfortunately, adherence to DMARD therapy remains suboptimal for many patients, potentially compromising health and quality of life. It is widely recognized that adherence behaviors are multidimensional and complex; as such, interventions should be individualized to reflect the reasons for treatment non-adherence. Numerous stakeholders, spanning from individual patients to society as a whole, have vested interests in improving medication adherence and thus, health outcomes and related costs. Fortunately, promoting adherence behaviors can occur at multiple touch points in a patient’s treatment journey. In addition to the important work that happens in providers’ offices, specialty pharmacies and drug manufacturers have emerged as potentially powerful partners for supporting improved adherence behaviors.