Clinical Review

Adherence to Disease-ModifyingTherapy in Multiple Sclerosis: Part I

Nancy Holland, EdD RNPhyllis Wiesel, BSN RNPamela Cavallo, MSW CSWClayton Edwards, MBA RPh PAHMJuneHalper, MSN ANP FAANRosalind Kalb, PhDLinda Morgante, MSN RN CRRNMarie Namey, MSN RNMargie O'Leary, MSN RNLori Smith-Williamson, MSN RN C-ANP

Multiple sclerosis (MS) is a chronic, debilitating disease forwhich there is no cure. However, the recent introduction of in­jectable immunomodulating agents has made it possible to re­duce thefrequency of relapsing episodes and topossiblyslowitsprogression. The use oftheseagents is recommended by the Na­tionalMS Society, however, their truepotential cannot be real­ized ifpatientsdo not acceptthem and healthcare professionalsdo not promote them. Because MS is unpredictable, and treat­ments can produce side effects, ensuring adherence to the rec­ommended therapy is a complex andchallenging issue. A betterunderstanding of the obstacles to adherence, and the identifica­tionofpossiblesolutions, shouldbe of valueto nurses, whohavenumerous opportunities to encourage patients to initiate andcontinue therapy. This article, which is in two parts, describesthe particularproblems of treatment adherence, and proposesthat the transtheoretical modelofbehavior change can be usefulin achieving treatment goalsin MS and in otherchronic diseasestates. This model is based upon the concept that a patient's"readiness for change" is crucial, andthatattempts at interven­tionshouldbe sensitive to thepatient'schanging conditions andstateofmind. Nurses who workwithpatientswithMS and otherchronic diseases can apply the model to help theirpatients ac­ceptand adhere to thedemands ofongoing treatment.

Multiple sclerosis (MS) is a chronic, sometimes debilitatingdisease. Symptoms vary widely, but MS generally produceswide-ranging levels of motor, sensory, visual, bowel, bladder,and cognitive dysfunction; its diagnosis can be life-altering (Hol­land, Murray, & Reingold, 1996). There is no cure, but the in­troduction of immunomodulating agents in the early 1990s pro­vided the means with which to reduce the frequency of relapsingepisodes and to possibly slow the progression of the disease.The availability for injection of interferon beta-Ib (Betaseron®),interferon beta-1 a (Avonex"), and glatiramer acetate (Copax­one") heralded a new era in the pharmacologic treatment ofMS,but the true potential of these agents can only be realized if

172 Rehabilitation Nursing> Volume 26, Number 5· Sept/Oct 2001

Keywordsimmunomodulating agents, medication adherence, multiple

sclerosis, transtheoretical model of behavior change

Nancy Holland is vice presidentof the clinical programs de­partment at the NationalMultiple Sclerosis Society's home of­fice in New York City. Phyllis Wiesel is a former director ofclinical services at the New York City chapter of the NationalMultiple Sclerosis Society. Pamela Cavallo is a directoremer­itusofthe clinicalprogramsdepartment ofthe NationalMulti­ple Sclerosis Society. Clayton Edwards is the director ofhealth managementat Merck-Medco Managed Care, ILC, inMontvale, NJ. June Halper is the executivedirectorofGimbelMS Center in Teaneck, NJ. RosalindKalb is the directorofIn­formation Resources at the National Multiple Sclerosis Soci­ety. Linda Morgante is the directorof clinical services at theMaimonides Medical Centerin Brooklyn, NY. Marie Namey isan advanced practice nurse at The Mellen Center of theCleveland Clinic Foundation in Cleveland, OB. MargieO'Leary is a clinical nurse at the University of PittsburghMedicalMS Center in Pittsburgh. Lori Smith-Williamson is anadult nurse practitioner at Drs. Cochran, Eberly & Howe,P'C, in Alexandria, VA. Address correspondence to NancyHolland, EdD RN, National Multiple Sclerosis Society, 733ThirdAvenue, New York, NY 10017ore-mail nancy.holland@nmss.org.

patients use them. Because the course of MS is unpredictable,the therapeutic benefit of the immunomodulators is uncertain,and the side effects are possibly bothersome, ensuring adherenceto the recommended therapy is a complex and challenging issue.

Problems with adherence to pharmacologic and nonphar­macologic treatments are well-documented for many diseases,with estimates of noncompliance ranging between 30% and70% (Rheiner, 1995). Data from the North American ResearchCommittee On MS (NARCOMS) Patient Registry showed thatadherence to MS treatment is no better; in a survey of 300 sub­jects in this registry, Hadjirnichael and Vollmer (1999) found a45% rate of discontinuation of disease-modifying agents and a

26% rate of change from one agent to another. More than one­third ofpatients rated their experience with immunomodulatingagents as negative. The majority ofpatients said their physicianadvised them to stop therapy-adherence to medication, there­fore, is not solely a patient-centered issue but is greatly influ­enced by a healthcare provider's willingness to work with a pa­tient to overcome side effects and other negative experiences.

Because nurses constitute the largest segment of the health­care team, and are the conduit for the exchange of informationbetween physicians and patients, they have numerous opportu­nities to emphasize to MS patients the importance of adhering totreatment regimens. To effectivelydo so, they must appreciate theunique perspective of the MS patient, must recognize the nu­merous obstacles to the initiation and maintenance of therapy,and must learn what are the most suitable times to attempt in­terventions that will be successful. This article, the first of two,describes the problems of adherence to MS therapies, then pro­poses an approach to intervention that is based on the transthe­oretical model of behavior change. We believe this model canbe useful in eliciting patient acceptance and achieving treatmentgoals.

Disease characteristicsTo appreciate the problems of adherence to treatment ofMS,

one must understand the disease itself, as well as the demands ofa treatment program. MS is characterized by loss of the myelinsheath that surrounds nerve fiber tracts in the central nervoussystem (CNS). Myelin sheath degeneration manifests as lesionsor plaques scattered throughout the CNS that interfere with theefficiency of electrical conduction.

To appreciate the problems ofadherence to treatment of MS, one must

understand the disease itself, as well as thedemands of a treatment program.

The result is a diverse range of neurologic impairments thatvary in intensity from patient to patient, and within individualpatients from time to time. The major clinical manifestationsmay be sensory and/or motor dysfunction, and cognitive and af­fective disorders. Memory or recall problems and slowed infor­mation processing are commonly reported. Abstract reasoningand problem solving may also be affected.

The clinical course of MS usually falls in one of the follow­ing categories, with the potential for progression from one pat­tern to a more serious one:

Relapsing remitting: Patients have clearly defined episodesof acute worsening of neurologic function, followed by periodswithout disease progression; the majority of persons are diag­nosed in this stage.

Secondary progressive: Patients have relapsing-remittingdisease at onset, followed by progression with or without occa­sional relapses, minor remission, and plateaus.

Progressive relapsing: Patients have progressive diseasefrom the onset, with clear, acute relapses that mayor may not

resolve with full recovery.Primary progressive: Patients experience a nearly contin­

uous worsening of the disease that is not interrupted by distinctrelapses, but may have temporary minor improvements (Lublin& Reingold, 1996).

Before immunomodulating therapies were available, about50% of persons diagnosed with relapsing-remitting MS con­verted to a progressive course within 10 years of initial diagnosis(Runmarker & Andersen, 1993). There are no data as yetregarding how immunomodulating agents have affected thesestatistics.

Treatment with immunomodulating agentsTreatment of MS entails the management ofdifferent symp­

toms, attention to quality-of-life issues, treatment of relapses(usually with intravenous steroids), and reduction in the fre­quency of relapses with injectable immunomodulating agents.The availability of interferon beta-Ib, interferon beta-la, andglatiramer acetate adds to the therapeutic options for MS andoffers hope that they can slow progression of the disease. Thesemedications differ in their mode of preparation, dosage level,side effect profile (see section on side effects and disease pro­gression), and route of administration. Interferon beta-Ia is giv­en in weekly intramuscular injections and is often self-admin­istered; interferon beta-Ib is administered by subcutaneousinjection every other day; and glatiramer acetate is administeredby daily subcutaneous injection. The medication to be used is apatient-provider issue, and patients may change to another agentif the side effects become intolerable, or the treatment provesineffective.

Sustained treatment with the three agents in people with re­lapsing-remitting disease has been associated with several pos­itive outcomes: reduction (290/0-37%) in the frequency and sever­ity of relapses, and reduction in brain lesion development asdetected by magnetic resonance imaging. A recent study byTrapp et al. (1998) suggests that damage to axons is coincidentwith the destruction of the myelin sheath in MS. This could meanthat even early relapses that appear clinically benign may havepermanent neurological consequences, thus strengthening therationale for early intervention. There are also indications thatdisability might be delayed, and, therefore, quality-of-life en­hanced with these treatments.

People who are appropriate candidates for treatment with oneof these agents should be started on it early. For best results, thetreatment should be continued indefinitely to prevent the possi­bility of a resumption of disease activity, with its serious long­term consequences.

The Medical Advisory Board of the 'National Multiple Scle­rosis Society (NMSS) has adopted the following recommenda­tions regarding use of the three agents:• Therapy should be started as soon as possible after a defi­

nite diagnosis of relapsing MS is made.• Therapy should to be continued indefinitely, unless there is

clear lack of benefit, there are intolerable side effects, newdata reveal other reasons for cessation, or better therapybecomes available.

• Patient access to medication should not be limited by the

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Adherence: MS Therapy

frequency of relapses, age, or level of disability.• Treatment should not be stopped during evaluation for

continuing treatment. A change from one immunomodu­lating drug to another should be permitted.

• All three agents should be included in formularies, andcovered by third-party payers so that physicians and pa­tients may determine on an individual basis the most ap­propriate agents.

• Use of any of the three therapies is not contraindicated bymost concurrent medical conditions (NMSS, 1998).

Factors affecting adherence to treatmentFactors that affect a patient's adherence to pharmacologic

treatments are diverse and complex, and, ill the case of chroni­cally ill patients, adherence presents special challenges. In MS,in particular, physical disability, cognitive impairment, unpre­dictable disease course, and a feeling of hopelessness or in­evitable decline can further complicate the challenge of main­taining a self-management plan, even among the most motivatedpatients. However, it is important for nurses to persevere in en­couraging people with MS to participate in their own care, be­cause it empowers patients with a sense of control, and facili­tates their adaptation to the disease (Multiple Sclerosis NurseSpecialists Consensus Committee, 1998).

Because human immunodeficiency virus (HlV) disease sharessome of these factors, studies conducted in that population havesome relevance in MS. For instance, both MS and HN are dis­eases that are optimally treated with drugs that do not produceimmediate benefits. Treatment adherence, therefore, is morechallenging than, for instance, in diabetes, where injections ofinsulin produce immediate and visible benefits. As with HNpatients, symptomatic MS patients may refuse drug therapy thatcan affect quality of life when they are currently "feeling fine."And with both diseases, patients may believe therapy is futile ifeventual disability (or death) is likely.

While strict adherence to a complex anti-retroviral regimenis critical to prevent progression to AIDS, an estimated one-thirdor more patients with HN fail to continue treatment In her ini­tiative to promote adherence in HN-infected patients, Reynolds(1999) categorized several factors that influence treatment-re­lated decisions and adherence. Most of these factors also are ap­plicable to the MS population (Table 1).

Participants at the National MS Society Consensus Confer-

ence on Adherence to MS Disease Modification Protocols (June21, 1999, New York City) identified the following key impedi­ments to acceptance of immunomodulating agents (Table 2):

Lack of knowledge: MS is a complex disease, with conse­quences that require careful explanation to patients and fami­lies. But education alone is not enough to persuade patients toenter treatment. The theory of adult learning holds that people be­come ready to learn when they have a need to know somethingin order to cope more satisfactorily with tasks or problems. Ed­ucators have a responsibility to create conditions and providetools that help learners discover their "need to know," and shouldorganize learning opportunities around real-life applications(Knowles, 1980).

In MS, this concept can be applied by health professionals. Animportant application is to balance their depiction of MS be­tween a realistic view of possible serious disability and opti­mistic hopefulness. Before the disease-modifying agents wereavailable, healthcare providers understandably focused on thepotential for a "benign" course. However, the reality of MS asa progressive, disabling disease must be presented to patientswho need to know about difficult, long-term interventions.

Physical impairment: Poor hand-eye coordination, tremor,and fatigue may be obstacles to optimal self-care, particularlyself-injections. Duration of illness (which strongly relates toseverity of physical symptoms) appears to negatively correlatewith acceptance of treatment. Patients who are physically com­promised may require extra assistance in dealing with treatmentlogistics.

Cognitive deficits: Cognitive changes occur in 40%-60%of people with MS (Halper & Holland, 1997; Rao, Leo,Bernardin, & Unverzagt, 1991). The most frequently reportedcognitive problems are memory loss, difficulty in learning andrecalling new information, slowed information processing speed,and deficits in such functions as problem solving. Cognitive im­pairment may interfere with a patient's ability to understand therationale for treatment, but it can also be a motivator for treat­ment. There are emerging data to support the benefit to cognitivefunction of treatment, and even the possibility ofpreventing cog­nitive decline can be a motivating force for many patients.

Patient expectations and perspectives: Chronically ill pa­tients expect the medical establishment to help them to feel bet­ter, and they are disappointed when much-touted therapies seemto fail. Mohr et al. (1997) reported that up to 50% of patients

Table 1. Factors Affecting Patient Adherence to Treatment Regimens

Patient Characteristics

Level of motivationAvailability of social supportKnowledge and belief systemPrevious level of adherenceSatisfaction with treatmentCoping skillsCognitive functioning

Treatment RegimenlDisease factors

Number of drug treatmentsFrequency of dosingEase of administrationNumber and severity of side effectsAdverse drug-drug interactionsConcomitant medical conditionsLength of illness

Patient-Provider Relationship/Clinical Setting

TrustConsistencySupport/reassurancePerceived competenceClear explanations, full disclosure of potential

side effectsEasy accessibilityBroad scope of services

174 Rehabilitation Nursing> Volume 26, Number 5· Sept/Oct 2001

Table 2. Impediments to Adherence toDisease-Modifying Protocols

Lack of knowledgePhysical disability and fatigueCognitive deficitsUnrealistic expectationsDysphoric moodPsychiatric comorbidityNegative attitudePoor self-esteemDenial of illnessLack of readinessCultural factorsDistrust of physicians and pharmaceutical industryFear of needlesSide effects of treatmentLack of coverage for treatment expenseUnpredictability of illnessNonfatal nature of diseaseContradictory messages from authority figuresLack of family supportLack of professional support

From National MS Society Consensus Conference on Adherence toMS Disease Modification Protocols

who begin therapy with interferon beta-Ib have unrealisticallyoptimistic pretreatment expectations and are significantly lesslikely to adhere to treatment than patients with more realisticperspectives. While treatment with immunomodulating agentsmay be fending off future disability, there is no certain way toascertain the benefit today, and no immediate incentivefor patientsto continue. Nurses and other health professionals can help pa­tients realign their expectations and prepare them for treatmentby guiding them through the course of"what ifs" for the future.It is helpful to realize that, to some patients, agreement to begintreatment means moving from denial to an attitude of acceptanceof the disease. With the provider's help, these patients may beable to view treatment as "taking charge" rather than "giving in."

Dysphoric mood: The diagnosis ofMS carries with it a life­long emotional impact. The high incidence of depression, help­lessness and hopelessness, and an increased suicide rate in theMS population (Bauer & Hanefeld, 1993; Sadovnick, Eisen,Ebers, & Paty, 1991) are strong impediments to taking medica­tions or doing complicated tasks that are designed to improvewell-being. In a study of 85 patients, Mohr et al. (1997) foundthat 41% reported new or increased depression within 6 monthsafter starting therapy, and that they were more likely to discon­tinue therapy than were patients not reporting depression. Whenpatients received treatment for depression--either with antide­pressants or with psychotherapy-they were significantly morelikely to continue on immunomodulating agents.

Side effects and disease progression: Patients can experi­ence side effects from therapy almost immediately Adverseevents, therefore, are much more compelling factors in adher­ence than are the unseen and potential benefits that may be gained

later. It is not known what percentage of patients actually dis­continue treatment because of adverse events. Hadjirnichael andVollmer (1999) reported that 14% of patients stopped therapybecause of flu-like symptoms, and 21% stopped because ofsymptoms they believed were related to the progression of MS.A study of 80 patients by Mohr et al. (1998) found that 11% dis­continued therapy 4 months after initiation, largely because ofsymptoms they believed signaled a worsening of the disease. Itcan be difficult to determine whether, in some cases, symptomsare side effects of the therapy or whether they reflect a worsen­ing of the disease. In either case, the result is often a discontin­uation of therapy. Patients tend to reject therapy if they judge itto be of no benefit. Side effects occur to varying degrees amongpatients and are slightly different for the three agents. Interferonbeta-l a and beta-Ib may cause flu-like symptoms in patients af­ter they are injected, but these symptoms diminish or disappearover time. Interferon beta-Ib may also cause injection site reac­tions, about 5% of which need medical attention. Glatiramer ac­etate can cause redness or pain at the injection site, and some pa­tients experience anxiety, chest tightness, shortness of breath,and flushing that lasts about 15 minutes, with no long-term ef­fects. Health professionals should attempt to discuss, prevent,and treat side effects, especially in the crucial first months oftreatment.

When patients received treatmentfor depression-either with antidepressants

or with psychotherapy-they were significantlymore likely to continue on

immunomodulating agents.

Physicians' attitudes: Many physicians continue to believethat a high percentage ofpatients will have a "benign" course orthat a disease should be in a fairly progressed state before ther­apy is prescribed. Other physicians may begin patients on ther­apy, and then advise them to discontinue it if the patient's con­cerns and complaints about the treatment become tooburdensome. In their study of7oo participants in the NARCOMSpatient registry, Hadjimichael and Vollmer (1999) found thattwo-thirds of the patients who discontinued therapy were ad­vised to do so by their physicians.

A recent study by Vickrey et al. (1999) compared treatmentof people with MS by neurologists who were MS specialistswith treatment by those who were n9t. A notable differencewas the more frequent prescription of the disease-modifyingdrugs by the specialists. For various reasons, patients oftenmust independently seek treatment options, and they get in­consistent messages from different sources. Efforts to educatepeople about treatment for MS should not overlook the pro­fessional community.

Clinical setting: Adequate time must be set aside to educateand counsel newly-diagnosed patients. Provider-patient rela­tionships must be nurtured, because patients who spend 5 min­utes in a clinic are not likely to adhere to a treatment program.Mohr et al. (1999) compared patient management strategies at

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Adherence: MS Therapy

35 clinical trial sites participating in their study of interferonbeta-lb for secondary-progressive MS. They found that siteswhere the professionals were considered more empathetic, wherea sense of purpose was instilled in the patients, and where lessformal relationships with patients were promoted, had the high­est rates of adherence to immunomodulating therapy.

Once patients agree to treatment, a home environment maybe beneficial for teaching purposes. If a patient learns a proce­dure-self-injection, in this case-in the setting where it willbe performed, some barriers to adherence can be identified ear­ly, and the learning process facilitated.

CommentAn understanding of patient-related, treatment-related, and

disease-specific factors is a first step toward helping MS patientsaccept and adhere to treatment options. Healthcare providersmust understand how these individuals perceive their illness,their treatment options, their sense of self-control, and their dai­ly living situations. These personal factors may be more impor­tant in adherence than the caliber of information and supportgiven by the healthcare providers. As one participant at the Con­sensus Conference stated, "Why are we, the healthcare profes­sionals, so much more convinced about the benefits of treatmentthan our patients? We know that having a treatment to offer is apositive message. But how is it that our patients are not gettingthe same message?"

AcknowledgmentSpecial thanks to Caroline Helwick for her help in manu­

script preparation.This article, and the workshop it reflects, were underwritten

by an unrestricted educational grant from BIOGEN Laborato­nes.

Editor's noteThe second part of this article, which describes interventional

approaches to the treatment of MS, will appear in the Novem­berlDecember issue ofRehabilitation Nursing.

ReferencesBauer, HJ., & Hanefeld, F.A. (1993). Multiple sclerosis, its impact from

childhood to old age. London: W.B. Saunders.Hadjimichael, 0., & Vollmer, T.L. (1999). Adherence to injection therapy

in MS: Patients survey. Neurology, April [Supp!. 2], 52.Halper, J., & Holland, N. (1997). Comprehensive nursing care in multiple

sclerosis. New York: Demos Vermande.Holland, N., Murray, T.J., & Reingold, S.C. (1996). Multiple sclerosis: A

guide for the newly diagnosed. New York: Demos Vermande.Knowles, M.S. (1980). The modem practice ofadult education: From ped­

agogy to andragogy. Chicago: Follett Publishing Company.Lublin, F.D., & Reingold, S.C. (1996). Defining the clinical course of mul­

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Mohr, D.C., Goodkin, D.E., Likosky, W., Gatto, N., Baumann, K.A., &Rudick, RA. (1997). Treatment of depression improves adherence tointerferon beta-lb therapy for multiple sclerosis. Archives of Neurolo­gy, 54, 531-533.

Mohr, D.C., Goodkin, D.E., Masuoka, L., Dick, L.P., Russo, D., Eckhardt,J., Boudewyn, A.C., & Bedell, L. (1999). Treatment adherence and pa­tient retention in the first year of a phase ill clinical trial for the treat­ment of multiple sclerosis. Multiple Sclerosis, 5, 192-197.

Mohr, D.C., Likosky, W., Boudewyn, A.C., Marietta, P., Dwyer, P., VanDer Wende, J., & Goodkin, D.E. (1998). Multiple sclerosis: Side effectprofile and adherence to the treatment of multiple sclerosis with inter­feron beta-Ia. Multiple Sclerosis, 4, 487-489.

Multiple Sclerosis Nurse Specialist Consensus Committee. (1998). Multi­ple sclerosis: Key issues in nursing management. Columbia, MD: Med­icalliance.

National Multiple Sclerosis Society. (1998). Disease management consen­sus statement. In Clinical Bulletin [Pamphlet]. New York: Author.

Rao, S.M., Leo, GJ., Bernardin, L., & Unverzagt, F. (1991). Cognitivedysfunction in multiple sclerosis 1. Frequency, patterns, and prediction.Neurology, 41, 685-691.

Reynolds, N.R (1999, JanuarylFebruary). H1V infection: Initiatives to pro­mote adherence in HIV-infected patients. The AIDS Reader, 53-56..

Rheiner, N.W. (1995). A theoretical framework for research on client com­pliance with a rehabilitation program. Rehabilitation Nursing Research,4(3),90-97.

Runmarker, B., & Andersen, O. (1993). Prognostic factors in a multiplesclerosis incidence cohort with twenty-five years of follow-up. Brain,116,117-134.

Sadovnick, A.D., Eisen, K., Ebers, G.C., & Paty, D.W. (1991). Cause ofdeath in patients attending multiple sclerosis clinics. Neurology, 41,1193-1196.

Trapp, B.D., Peterson, J., Ransohoff, RM., Rudick, R, Mork, S., Lars, B.(1998). Axonal transection in the lesions of multiple sclerosis. NewEngland Journal ofMedicine, 338, 278-285.

Vickrey, B.G., Edmonds, Z.W., Shatin, D., Shapiro, M.F., Delrahim, S.,Belin, T.R, Ellison, G.W., & Myers, L.W. (1999). General neurologistand subspecialist care for multiple sclerosis. Patients' perceptions. Neu­rology, 53, 1190-1197.

This continuing education offering(code number RNC-182) will provide 1contact hour to those who read this articleand complete the application form on page202. This independent study offering is ap­propriate for all rehabilitation nurses. Byreading this article, the learner will achievethe following objectives:1. Describe the disease characteristics of multiple

sclerosis.2. Identify the immunomodulating agents used to treat

multiple sclerosis.3. Discuss the factors affecting adherence to treatment

with the disease-modifying therapies.