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Switching orDiscontinuingDisease-ModifyingTherapies for MultipleSclerosis

Aaron E. Miller, MD, FAAN

ABSTRACTPurpose of Review: This article reviews the reasons for discontinuation or switchingof multiple sclerosis disease-modifying therapy as well as procedures that might miti-gate risk to the patient under such circumstances.Recent Findings: Recent review of the literature, as well as the author’s extensiveclinical experience, indicate that the discontinuation of multiple sclerosis disease-modifying therapies occurs for many reasons. Often one medication is stopped at therecommendation of the physician in order to switch to another medication. However,often the decision to discontinue medication is made by the patient. Unfortunately, instill other situations, treatment is stopped because of circumstances beyond thecontrol of either patient or physician (eg, a loss of insurance coverage). Currentlyavailable data do not permit a conclusion about whether it is ever safe to discontinuedisease-modifying therapy in a stable patient without the expectation of return ofdisease activity.Summary: Clinicians must help patients avoid unnecessary and undesirable cessationof disease-modifying therapy. While switches of therapy are often necessary, steps tominimize both adverse events and the risk of recurrent disease should be undertaken.Whether disease-modifying therapy can ever be purposely discontinued withoutincurring a significant risk of disease recurrence remains to be determined.

Continuum (Minneap Minn) 2016;22(3):851–863.

INTRODUCTIONAmong the reasons a physician mayadvise a patient with multiple sclerosis(MS) to discontinue a particular ther-apy (often to be replaced by an alter-nate medication) are lack of efficacy,troublesome adverse events, an at-tempt at conception or actual preg-nancy, inadequate adherence to thetreatment regimen, or even recognitionof erroneous diagnosis (Table 9-1).This article also addresses the questionof whether a physician might recom-

mend discontinuation of disease-modifying therapy in a patient withprolonged disease stability while takingthe medication.

Patients may discontinue disease-modifying therapies, unfortunatelysometimes without informing theirphysicians, because of intolerableadverse events. In addition, psycho-logical factors may interfere with apatient’s desire or ability to continuetaking a particular medication or evenany disease-modifying therapy at all.

Address correspondence toDr Aaron E. Miller, 5 E 98th St,Box 1138, New York, NY10029,[email protected].

Relationship Disclosure:Dr Miller serves as editor ofContinuum Audio and as aconsultant for Accordant;Acorda Therapeutics; Alkermes;Biogen; EMD Serono,Inc; Genentech Inc;GlaxoSmithKline; MallinckrodtPharmaceuticals; Novartis AG;and Sanofi Genzyme. Dr Millerhas received personalcompensation for speakingengagements from Biogen andGenentech Inc, and researchsupport from Biogen,Genentech Inc, MallinckrodtPharmaceuticals, Novartis AG,and Sanofi Genzyme. Dr Millerhas provided expert legaltestimony on the diagnosisand management ofmultiple sclerosis.

Unlabeled Use ofProducts/InvestigationalUse Disclosure:Dr Miller reports no disclosure.

* 2016 American Academyof Neurology.

851Continuum (Minneap Minn) 2016;22(3):851–863 www.ContinuumJournal.com

Review Article

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

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DOALL PATIENTSWITHMULTIPLESCLEROSIS OR AT HIGH RISK FORMULTIPLE SCLEROSIS NEED TOBEGIN DISEASE-MODIFYINGTHERAPY?In the United States, most neurolo-gists generally recommend the initia-tion of disease-modifying therapy forvirtually all patients with relapsing formsof MS. In addition, most Americanneurologists with expertise inMS advisepatients with a first neurologic episodecharacteristic of MS who also havebrain MRI lesions (often referred to asclinically isolated syndrome) to starttreatment. This recommendation isbased on the results of several random-ized double-blind placebo-controlledtrials including all the currently avail-able injectable disease-modifyingtherapies1Y4 (except pegylated inter-feron beta-1a) and one oral agent,teriflunomide.5 Each study demon-strated a statistically significant reduc-tion in the conversion to definite MS.Nonetheless, in many countries out-side the United States this is not usualpractice, and some American neurolo-gists continue to defer treatment untilcriteria for definite MS are satisfied.

Inference from modern phase 3trials suggests that patients withmilder disease are being entered intostudies and presumably are morefrequently treated in clinical practice.The fact that relapse rates amongpatients in the placebo arms of clinicaltrials conducted in the 21st centuryare appreciably lower than amongpatients in trials conducted in the late1980s and 1990s supports this notion.The remarkably low relapse ratesamong patients in the active arms inthese more recent trials suggests thatmilder disease is easier to control.This raises the question, indeed, ofwhether all patients with MS needsuch early treatment. Very early treat-ment of patients with mild diseasewill, almost inevitably, increase thelikelihood that after a period of timewith no disease activity evident, theissue of discontinuing therapy will moreoften be raised. This question will beaddressed further later in this article.

DISCONTINUING THERAPYBECAUSE OF SUBOPTIMALRESPONSECurrently, even the most effective ther-apy for relapsing forms of MS fails tocompletely eliminate disease activity inmost patients. Continuing disease activ-ity inevitably prompts consideration ofchanging therapy, which, in presenttreatment paradigms, almost alwaysmeans discontinuing the medicationthe patient is currently taking ratherthan adding another agent. A discussionabout the decision-making process forwhich therapy to switch to is beyondthe scope of this article and is addressedfurther in the articles ‘‘Early RelapsingMultiple Sclerosis’’ by David E. Jones,MD,6 and ‘‘Severe, Highly Active, orAggressive Multiple Sclerosis’’ by MarkS. Freedman, MSc, MD, FAAN, FRCPC,and Carolina A. Rush, MD, FRCPC,7 inthis issue of Continuum. Suffice it to

KEY POINTS

h Among the reasons aphysician may advise apatient to discontinue aparticular therapy arelack of efficacy,troublesome adverseevents, an attempt atconception or actualpregnancy, inadequateadherence to thetreatment regimen, oreven recognition oferroneous diagnosis.

h Patients may discontinuedisease-modifyingtherapies, unfortunatelysometimes withoutinforming their physicians,because of intolerableadverse events. Inaddition, psychologicalfactors may interferewith a patient’s desire orability to continue takinga particular medicationor even anydisease-modifyingtherapy at all.

h The remarkably lowrelapse rates amongpatients with multiplesclerosis in the activearms in more recentclinical trials suggestthat milder disease iseasier to control. Thisraises the question ofwhether all patientswith multiple sclerosisneed very early treatmentin view of the possibilitythat some mayexperience very littledisease activity evenwithout treatment.

TABLE 9-1 Reasons forDiscontinuation ofDisease-ModifyingTherapy

b Suboptimal response

b Intolerability

b Lack of adherence

b Serious adverse events

b Loss of insurance coverage

b Pregnancy

b Incorrect diagnosis

b Disease stability

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Switching or Discontinuing Therapies


say that a pattern of recurring diseaseactivity or new severe disease activitywill likely result in a switch of therapy.The timing of initiation of the replace-ment disease-modifying therapydepends, at least in part, on the mech-anism of action and duration of effectof the medication that is being stoppedas well as on the nature of the effectsof the subsequent treatment. Unfortu-nately, the subject of timing of initia-tion of a replacement medication hasbeen studied very little, so many of thefollowing recommendations representthe author’s own practice, based onwhat little information has been pub-lished or presented, as well as on dis-cussions with colleagues. In general,initiation of a new agent should be doneas quickly as deemed safely possible tominimize the period of time in which apatient is not receiving the potentialbenefit of disease-modifying therapy.

When initiating a new therapy,baseline laboratory studies should beobtained, generally including com-plete blood count and hepatic panel.In addition, obtaining a new baselinebrain MRI (some might add cervicalspine MRI) is advisable. This is oftenobtained a few months after beginningthe new disease-modifying therapybecause disease activity occurring rel-atively soon after the new treatmenthas been initiated would not usuallybe considered as evidence of failure torespond to the new agent.

Switching From Interferons orGlatiramer AcetateBased on their respective mechanismsof action, switching from interferonsor glatiramer acetate does not appearto warrant any washout period. Anynew agent may be initiated as soonas feasible.

Switching From FingolimodVery little information is available toguide the timing of initiation of a new

treatment after discontinuation offingolimod. Because the putativemechanism of action of fingolimodinvolves the trapping of lymphocytesin peripheral lymphoid organs, thecirculating absolute lymphocyte countin patients on this medication is oftenquite low.8 It remains uncertainwhether waiting for the lymphocytecount to rise before beginning the sub-sequent treatment provides any safetyadvantage. However, this might be aprudent course of action when switchingto another agent that might sometimesdepress lymphocyte numbers, albeit bya different mechanism, such as dimethylfumarate or teriflunomide. However,the time course of the return to normallymphocyte counts is uncertain andvariable,9 so this waiting strategy couldexpose the patient to a prolongedperiod without benefit of treatment.Conversely, the mechanism of actionof natalizumab, an agent to whichpatients having a suboptimal responseto fingolimod are often switched, in-volves a blockage of the entrance ofcirculating lymphocytes into the cen-tral nervous system and, hence, typi-cally results in a mild lymphocytosis.From this point of view, little wouldseem to be gained by a strategy of de-laying initiation of natalizumab afterdiscontinuing fingolimod. Whetherearly initiation of natalizumab in apatient whose lymphocyte count isdepressed might increase the risk ofprogressive multifocal leukoenceph-alopathy is completely unknown and,if true, would likely be significant onlyin patients with antibodies to JC virus,the causative agent.

Switching From TeriflunomideTeriflunomide undergoes enterohe-patic circulation and is excreted veryslowly, requiring an average of8 months and as long as 2 years forcomplete elimination. Thus, under

KEY POINT

h In general, initiation of anew agent should bedone as quickly asdeemed safely possibleto minimize the periodof time in which apatient with multiplesclerosis is not receivingthe potential benefit ofdisease-modifyingtherapy.



certain circumstances, an acceleratedelimination procedure must be em-ployed.10 This usually involves the ad-ministration of cholestyramine 3 timesa day for 11 days (and levels ofteriflunomide should be measured)or, alternatively, the use of activatedcharcoal. This would specifically berequired in the case of pregnancy ordesire for conception or in the circum-stance of allergic response to themedication. Teriflunomide has under-gone phase 2 trials in combinationwith both interferon11 and glatirameracetate,12 which showed an advantageto the addition of teriflunomide. As nounusual safety signals were encoun-tered in the combination arms, if apatient is switched from teriflunomideto one of the injectable agents, the useof the accelerated elimination proce-dure appears to be unwarranted. Basedon their respective mechanisms ofaction, initiating natalizumab withoutan accelerated elimination procedureand without a washout period seemsto show little risk, but no data areavailable. On the other hand, theinitiation of natalizumab without usingthe accelerated elimination proceduremight be considered to be counter tothe prescribing information fornatalizumab, which counsels againstthe use of the agent in combinationtherapy.13 The theoretical possibilitythat the persistence of teriflunomidecould potentiate the lymphopenia as-sociated with fingolimod and, lessoften, with dimethyl fumarate, mightwarrant consideration of an acceler-ated elimination procedure forteriflunomide if a switch to one of thealternative oral agents is contemplated.

Switching From DimethylFumarateLittle information is available to guiderecommendations for initiation of al-ternative therapy after discontinuation

of dimethyl fumarate. The mechanismof action of this drug is uncertain, withan antioxidant effect based on activa-tion of the nuclear factor erythroid2-related factor 2 (Nrf-2) pathway theleading postulate.14 This would notseem cause for concern about the rapidinitiation of another medication. How-ever, dimethyl fumarate does, at times,have a lymphopenic effect, whichmightprompt a delay in beginning anotherdrug that depresses lymphocyte counts.Unfortunately, it may take many weeksfor the lymphocyte count to return tonormal after dimethyl fumarate isstopped, which could cause a hazard-ous delay in introduction of the newdisease-modifying therapy.

Switching From NatalizumabNatalizumab is a monoclonal antibodydirected against very late antigen-4(VLA-4) ("4$1), an adhesion moleculeon the surface of lymphocytes. Theantibody presumably prevents theinteraction of the adhesion moleculewith its complementary receptor mol-ecule VCAM-1 on the vascular endo-thelium, thereby preventing entranceof the cells into the central nervoussystem.15 Although the antibody ap-pears to block the adhesion moleculefor at least 2 months and perhaps a bitlonger, based on its mechanism ofaction, it does not appear to be logicalto defer initiation of another therapy ifa switch is deemed appropriate. Al-though earlier practice often involveddelaying several months before ini-tiation of new therapy, recent datasuggest that this practice is morelikely to be associated with return ofdisease activity and sometimes withwhat appears to be excessive activityabove what was expected from theprenatalizumab treatment period (so-called rebound). Studies with a switchto fingolimod, perhaps the mostfrequently administered therapy when

KEY POINT

h Because teriflunomideleaves the body veryslowly, in somecircumstances, such asunexpected pregnancy,an acceleratedelimination proceduremust be employed.




a change from natalizumab has beenmade (often because of JC virus an-tibody positivity rather than subop-timal response to natalizumab), suggestthat a better strategy would be toinitiate the alternative therapy muchearlier.16Y18 Many MS subspecialistsnow recommend a washout period ofnot more than about 2 months whenswitching from natalizumab to anotherdisease-modifying therapy.

DISCONTINUINGDISEASE-MODIFYING THERAPYBECAUSE OF PREGNANCY ORATTEMPTED CONCEPTIONAs MS is commonly and, in fact, in-creasingly a disease of women, manyof whom are of childbearing age, theissue of management of disease-modifying therapy in relation to preg-nancy is very important. Ideally,but unrealistically, all pregnancies inwomen with MS would be planned,and drug discontinuation would occurin a well-reasoned and timely fashion.All reproductive issues, including man-agement of disease-modifying thera-pies, should be thoroughly discussedwith female patients, preferably in-cluding their partners, well in advanceof pregnancy planning. Most currentlyavailable disease-modifying therapiesshould be discontinued during, andpreferably before, pregnancy. A possi-ble exception, in the author’s opinion,is glatiramer acetate. In the currentlyused system of the US Food and DrugAdministration (FDA), glatiramer ace-tate has a Category B pregnancy rat-ing, indicating no evidence of risk tothe fetus in either humans or experi-mental animals, but with no specifictesting having been conducted inpregnant women. I counsel womenthat they might consider remaining onglatiramer acetate while they attemptto conceive and even during thepregnancy. Most of my patients in

these circumstances have elected toremain on glatiramer acetate whileattempting to become pregnant, andthe majority of these have also stayedon the medication throughout preg-nancy. I have not encountered prob-lems with this approach, nor has apregnancy registry implicated in-creased problems for the babies ofmothers who became pregnant whiletaking glatiramer acetate.19Y21

Interferons, which carry a Category Cpregnancy rating, also appear to con-vey little, if any, increased risk offetal malformation.22,23 However,studies have indicated an increasedrisk of spontaneous abortion in exper-imental animals receiving interferon.Whether this is true in humans is un-certain because of inconsistent data.Although most neurologists likely rec-ommend discontinuation of interferonsfor 1 to 2 months before the womanattempts conception, some recom-mend the continuation of medicationuntil pregnancy is confirmed to avoid aprolonged period without disease-modifying therapy should conceptionnot occur quickly.

Fingolimod24 and dimethyl fuma-rate9 have Category C pregnancy rat-ings, and both have been associatedwith fetal abnormalities in experimen-tal animals. As these drugs are smallmolecules, they cross the placenta andare best avoided during pregnancy.No clear guidance based on data canbe given about the washout periodfor these drugs prior to a woman’sattempting to become pregnant. How-ever, based on their respective half-lives, discontinuation of fingolimodfor 2 months and dimethyl fumaratefor 1 month seems reasonable.

The issue of the prolonged excre-tion of teriflunomide after its discon-tinuation has been addressed above.Based at least in part on experiencewith leflunomide, a drug that has been

KEY POINTS

h Patients who discontinuenatalizumab are at riskfor rebound diseaseactivity, which seems topeak 3 to 4 months afterthe drug is stopped.Therefore, many multiplesclerosis specialists nowrecommend a washoutperiod of no more thanabout 2 months whenswitching fromnatalizumab to anotherdisease-modifyingtherapy.

h Women should generallybe counseled todiscontinuedisease-modifyingtherapy when trying tobecome pregnant. Anexception may beconsidered for glatirameracetate, whichhas a Category Bpregnancy rating.



in use for many years for the treat-ment of rheumatoid arthritis and ismetabolized to teriflunomide, the MSdrug has a Category X rating, indicat-ing that it should not be used duringpregnancy. This should be discussedwith the patient before she beginstaking the medication, and the accel-erated elimination procedure must befollowed if she wants to try to becomepregnant or if an unplanned preg-nancy occurs.

Natalizumab, which is designatedCategory C, has an uncertain risk forthe fetus.23 Because its immunologiceffects last approximately 2 months, itis probably advisable for a woman todiscontinue the drug 2 months priorto attempting conception or to stopthe drug promptly if unplanned preg-nancy occurs. Because natalizumab isfrequently used in patients with dis-ease that has been difficult to control,the decision to discontinue the drugprior to pregnancy must be temperedby the risk of recurrent activity after ithas been stopped. Data suggest thatthe risk of disease activity, whichpeaks a few months after natalizumabcessation, is related to the degree ofactivity prior to initiation of the treat-ment.17 For more information regard-ing MS and pregnancy, refer to thearticle ‘‘Pregnancy in the Setting ofMultiple Sclerosis’’ by Michelle Fabian,MD,25 in this issue of Continuum.

DISCONTINUATION RELATED TOISSUES OF ADHERENCE TOMEDICATION USEImproper adherence to an MS disease-modifying therapy is an important andcommonly encountered problem. Apatient’s failure to adhere to thecorrect regimen may have many rootcauses. These include tolerability (ie,side effects), emotional issues, per-sonal schedule, and sometimes simplyforgetting. While minor deviations

from the recommended regimen areprobably unimportant for most of thedisease-modifying therapies, in someinstances incomplete adherence istantamount to discontinuation of themedication as improper usage mayrender the treatment ineffective. Forexample, dimethyl fumarate shouldbe taken 2 times a day, best withmeals. Phase 2 studies suggest thata daily dosage below the recom-mended dose of 240 mg 2 times aday is ineffective.26

In a thorough discussion with apatient prior to initiating therapy, thereason for treatment and expectationsof its effectiveness should be reviewedand a frank and complete explanationof the drug’s side effects and strate-gies to alleviate them offered. Ac-knowledgment of how difficult it is totake medication when one cannot ac-tually perceive a benefit (nor can onebe proven) further strengthens thebond between patient and provider,increasing the likelihood of successfuladherence to the regimen.

The subject of patient adherenceshould be addressed regularly, butalways with a sympathetic and reas-suring demeanor. The provider shouldrecognize that sometimes a patient maysimply not be able to follow a particularregimen and a switch to an alterna-tive medication will be necessary. Bymaintaining a very supportive postureand fostering the concept of a patient-physician partnership, the physicianmay prevent the obviously undesirablesituation of a patient’s simply not takinga medication and perhaps not in-forming the doctor.

With most medications, if a breakin therapy occurs, the treatment cansimply be resumed according toschedule. A special procedure mustbe followed, however, if fingolimod isdiscontinued for a certain period oftime. Because this drug is associated




with bradycardia or other effects onatrioventricular conduction, first-dosemonitoring, generally for 6 hours, isrequired with initiation of treatment. Ifthe patient has been taking the med-ication for at least 1 month and missesmore than 2 weeks of treatment, thefirst-dose monitoring must be repeatedbefore resumption of regular dosing. Ifthe patient misses 1 day or more duringthe first 2 weeks of therapy or morethan 7 days during the third and fourthweeks of treatment, monitoring mustbe repeated (Case 9-1).24

DISCONTINUATION OFTREATMENT IN PATIENTS WITHSECONDARY PROGRESSIVEMULTIPLE SCLEROSISUnfortunately, no disease-modifyingtherapy has been demonstrated to beclearly effective in patients with sec-ondary progressive MS. Very recently,however, ocrelizumab, a monoclonalantibody directed against CD20 andthereby depleting B lymphocytes, hascompleted a successful phase 3 trial inprimary progressive MS.27 A Europeantrial of subcutaneous interferon beta-1b in secondary progressive MS had a

positive effect on disability, whereas aNorth American study failed to repli-cate this benefit.28 The likely explana-tion for this difference is that theEuropean study population was skewedtoward an inflammatory profile, withpatients having a younger mean age,greater relapse activity, and morecontrast-enhancing lesions than thosein the North American trial. Althoughmitoxantrone has been FDA approvedfor use in secondary progressive MS,the Mitoxantrone in Multiple Sclerosis(MIMS) trial on which such regulatoryaction was based had a complicateddesign,29 and it seems likely that thedrug works principally by preventingactive inflammation. Based on the lackof efficacy of disease-modifying thera-pies, little justification exists at presentfor initiating therapy in patients withinsidious secondary progressive dis-ease. Indeed, the position that disease-modifying therapy should not beinitiated for patients with progres-sive nonrelapsing forms of MS wasemphasized as one component of theAmerican Academy of Neurology’s con-tribution to the ‘‘Choosing Wisely’’campaign.30 This recommendation will

KEY POINT

h If a patient has beentaking fingolimod forat least 1 month andmisses more than2 weeks of treatment,first-dose monitoringmust be repeatedbefore resumption ofregular dosing.

Case 9-1A 32-year-old woman with relapsing-remitting multiple sclerosis had beentreated with fingolimod for 6 months and was clinically stable during thattime. Her neurologic examination was normal. She went on a 2-week hikingtrip to Peru with friends and called on the first day of her trip, panicked thatshe had forgotten to pack her medication. She asked what she should do.

Comment. The patient should be reassured that a 2-week ‘‘holiday’’from her fingolimod is not likely to have a significant impact on the courseof her multiple sclerosis (fingolimod has a half-life of about 1 week). It isimportant to inform her that if she misses more than 2 weeks offingolimod, she must undergo repeat first-dose monitoring, according tocurrent recommendations. She may avoid that procedure if she resumesher fingolimod the day she arrives home, assuming she had taken her lastdose just prior to departure. This case emphasizes the importance ofinforming patients about the risks and procedures that occur whenmedications are stopped or a significant number of doses are missed.



likely not apply to primary progressiveMS if and when ocrelizumab is ap-proved by regulatory agencies.

The inclusion of the dictum toavoid prescribing disease-modifyingtherapy for patients with progressivedisease raised substantial protestamong members of the MS profes-sional community. This was likely, atleast in part, because the reality inclinical practice is that many patientsbegin disease-modifying therapy whenthey clearly are in the relapsing-remitting stage of the illness but thentransition to the secondary progres-sive MS phenotype. The difficult ques-tion then arises as to whether suchpatients should discontinue disease-modifying therapies. The interferontrials all showed a reduction in exac-erbations (for patients with secondaryprogressive MS who continued toexperience exacerbations) and newMRI activity even though they didnot show a benefit in reducing con-firmed disability progression. For moreinformation on interferon beta trials inMS, refer to the article ‘‘ProgressiveMultiple Sclerosis’’ by Mary AlissaWillis, MD, and Robert J. Fox, MD,FAAN,31 in this issue of Continuum.Thus, it remains uncertain whethersomething is to be gained by continu-ing disease-modifying therapy in thissituation or whether ongoing treat-ment is futile. For example, might apatient’s cognitive status be better pre-served by continuing therapy in viewof the demonstrated lessening of ad-ditional MRI disease activity? In theabsence of data on such matters, thequestion of whether to stop or con-tinue treatment would seem to be besthandled on an individual basis and thedecision made after frank discussionwith the patient. The psychological im-pact of discontinuing therapy with thepotential loss of hope by the patientalso requires consideration.

SHOULD DISEASE-MODIFYINGTHERAPY BE DISCONTINUEDIN A PATIENT WHOSE DISEASEHAS BEEN STABLE FOR ALONG TIME?In recent years, the concept of ‘‘noevidence of disease activity’’ (NEDA)has gained traction, not only in theassessment of clinical trial data, butalso as a treatment target. To be sure,short of the reversal of neurologic def-icits from MS, NEDA is the holy grail ofMS treatment. Although NEDA, evenover a relatively short time frame, isstill achieved in only a minority ofpatients irrespective of the particularmedication, some people with MS doachieve remarkable stability both clin-ically and on imaging studies forprolonged periods of time (eg, 5 ormore years). Such an absence ofevident disease activity may prompteither the patient or the physician toquestion the continued need fordisease-modifying therapy. Scant dataare available to help answer the ques-tion, but a few investigators have begunto broach the subject.

In one study, Birnbaum32 reportedhis own personal experience in stop-ping disease-modifying therapy amongtwo groups of patients whose diseasehad been stable for 8 to 10 years. Thefirst group included 62 patients forwhom the physician recommendeddiscontinuation of disease-modifyingtherapy. In this group, only 4 of 62worsened on MRI and only one patienthad a clinical change during the variablefollow-up period. The mean age in thisgroup was 62, and of those whoworsened, it was 54. The second groupwas composed of 10 patients whothemselves initiated the discussionabout stopping disease-modifying ther-apy. In this group, which had a meanage of 51, four patients worsened, butthe age difference between those whoworsened and those who did not was

KEY POINTS

h No disease-modifyingtherapy has been shownto be effective forsecondary progressivemultiple sclerosis.However, many patientsbegin disease-modifyingtherapy when theyclearly are in therelapsing-remitting stageof the illness and thentransition to thesecondary progressivemultiple sclerosisphenotype. The difficultquestion then arises as towhether such patientsshould discontinuedisease-modifyingtherapies.

h In recent years, theconcept of ‘‘no evidenceof disease activity’’ hasgained traction, notonly in the assessmentof clinical trial data, butalso as a treatmenttarget for multiplesclerosis. In clinical trials,only a minority ofpatients achieve thisgoal, irrespective of thedrug studied.




not significant. The author speculatedthat patients who are younger andthemselves ask to stop disease-modifying therapy are at greater riskfor disease activity.

Kister and colleagues33 reported anobservational study of patients with norelapses for at least 5 years whostopped first-line (injectable) disease-modifying therapy. Data were derivedfrom the MSBase Registry, an interna-tional prospective Internet-based regis-try. The authors included patients whohad been relapse free for at least 5 yearsand had been treated continuously withdisease-modifying therapy for at least3 years prior to discontinuation; pa-tients were followed for at least 3 yearsafter stopping disease-modifying ther-apy. The cohort included 485 patientscontributed by 28 sites. Patients whorestarted disease-modifying therapywithin 3 months of stopping wereconsidered ‘‘switchers’’ and excludedfrom analysis.

As this was not a planned stoppingtrial, patients discontinued treatmentfor a variety of reasons, including ‘‘lackof improvement’’ (9%), perceived dis-ease progression (10%), intolerance(8%), adverse event (6%), and un-known (66%). The postdiscontin-uation period of observation rangedfrom 3 to 14.7 years, with a median of4.85 years. During the observationperiod, 155 of 426 disease-modifyingtherapy stoppers (36.4%) had a relapse;131 of the 391 disease-modifying ther-apy stoppers (33.5%) had confirmeddisability progression; and 46 of 426disease-modifying therapy stoppers(10.8%) experienced both relapseand confirmed disability progres-sion.33 (Denominators differ becausenot all information was available foreach patient.)

Of 182 patients discontinuingtherapy (numbers updated betweentime of abstract submission and time of

oral presentation), 77 resumed disease-modifying therapies after a median timeoff medication of 22 months. Thesepatients were regarded as ‘‘restarters.’’Interestingly, the disease-modifyingtherapy restarters had a 59% decreasein the rate of confirmed disability pro-gression compared to those patientswho remained off disease-modifyingtherapy. However, the relapse rateswere similar in the two groups. Eachincrease of one point in the ExpandedDisability Status Scale (EDSS) was as-sociated with a 20% decrease in re-lapse rate.

It is very difficult to draw firmconclusions from the Kister data inview of the uncontrolled observationalnature of the studies. Clearly, how-ever, patients discontinuing disease-modifying therapy had a very substan-tial risk of continued disease activity.The authors advocated for a random-ized disease-modifying therapy dis-continuation trial in stable olderpatients with MS. This is clearly theonly way to obtain definitive informa-tion on the relative risk of discon-tinuing disease-modifying therapyafter a period of disease stabilitycompared to remaining on medica-tion. The fact that 28 MSBase sitescould contribute an average of fewerthan seven patients each to this study,however, suggests that recruitmentfor such a study could be very diffi-cult. Case 9-2 illustrates the chal-lenges patients face in the use ofdisease-modifying therapies and cir-cumstances that may warrant discontin-uation of treatment with subsequentclose surveillance.

In the absence of reliable data toguide decisions about discontinuingdisease-modifying therapy, I do notcurrently introduce that possibility,even in patients whose disease hasbeen stable for a long time, unlessvery unusual circumstances exist. If

KEY POINT

h A randomized clinicaltrial is clearly the onlyway to obtain definitiveinformation on therelative risk of patients’discontinuingdisease-modifyingtherapy after a periodof disease stabilitycompared to remainingon medication.



the patient raises the question, I willdiscuss frankly the available, butsparse, information and determinewhether, in the particular circum-stances, the patient wants to acceptthe risk of stopping treatment. Veryrecently, a prospective randomizedtrial of stopping versus continuingtherapy in patients who are over theage of 55 and have had prolongeddisease stability while continuouslytaking disease-modifying therapy hasbeen funded. It is hoped that in a fewyears this trial may be able to providean answer to the question of the safetyof discontinuing disease-modifyingtherapy in stable MS.

DISCONTINUING TREATMENT INPATIENTS MISDIAGNOSED WITHMULTIPLE SCLEROSISIn the absence of any definitive testfor MS, the diagnosis depends on anastute clinician’s judgment based onthe patient’s neurologic history andexamination, buttressed by the resultsof MRI of the brain and, frequently,the spinal cord. Additional diagnosticsupport can come from the results ofCSF examination. It is, of course, in-cumbent on the physician to establishthat the patient satisfies the caveatthat ‘‘there be no better clinical expla-nation,’’ which has essentially beenrequired in every proposed set of

Case 9-2A 47-year-old woman was diagnosed with multiple sclerosis in 2000 afterexperiencing a bout of left optic neuritis and undergoing brain MRI,which demonstrated multiple T2-hyperintense lesions, some of which wereovoid and periventricular. Two lesions enhanced after gadoliniumadministration. Cervical spine MRI revealed a 1-cm sharply circumscribednonenhancing T2-hyperintense lesion at C2. The patient had experienced asimilar episode of blurred vision in the right eye 18 years previously, withfull recovery in a few weeks. Very shortly after diagnosis, the patiententered a trial of oral glatiramer acetate, which was unsuccessful. She thenbegan treatment with injectable glatiramer acetate. She took herinjections regularly and experienced no evidence of disease activity eitherclinically or by MRI. In 2006, she became bothered by lipoatrophy at herinjection sites. By 2009, she stated, ‘‘I’m sick and tired of these injections. Ihate the lumps and the itching.’’ In 2010, she acknowledged that she wastaking two or three injections a week instead of the daily treatmentthat was prescribed. In 2011, she asked to discontinue glatiramer acetate.She was unwilling to initiate an alternative disease-modifying therapy.Her physician emphasized the importance of close clinical and imagingsurveillance as she was off disease-modifying therapy. She was muchhappier off glatiramer acetate, and over the next 4 years experienced noevidence of new disease activity either clinically or by brain MRI.

Comment. This patient illustrates the difficulty of remaining ondisease-modifying therapy, especially an injectable medication, over manyyears. The frequent reminder of multiple sclerosis, as well as the physicaldiscomfort and tissue changes induced by the injections, often leadspatients to inquire whether they can discontinue medication. Littleinformation is available to guide that decision. As illustrated by this case,prolonged disease stability may occur in some instances, but whetherthe outcomes of stopping disease-modifying therapy match those ofcontinuation can only be answered by a properly designed clinical trial.




diagnostic criteria. Although a numberof diagnostic criteria have been pub-lished over the years, today cliniciansmost often rely on the revisedMcDonald criteria.34 These criteriaare imperfect in sensitivity and, mostimportant, in specificity. Solomon andcolleagues,35 in a survey of 122 MSspecialists, found that more than 95%reported seeing at least one patient inthe past year who had been diagnosedwith MS for at least a year but whomthey ‘‘strongly felt’’ did not have MS.On average, these physicians esti-mated that they had seen about fivepatients each with misdiagnosis in thepreceding year. The survey respon-dents estimated that more than one-fourth of these patients were takingdisease-modifying therapy. Although,nonspecific white matter abnormali-ties were most frequently felt to bethe explanation for the incorrect diag-nosis, a large percentage of patientsactually have psychogenic (ie, func-tional) disorders. This population ofpatients is particularly challenging.

When clinicians encounter patientsin whom they believe the diagnosis ofMS is incorrect, they have an ethicalobligation to provide their opinionabout the correct explanation. Forfurther discussion on disclosing a

misdiagnosis of MS, refer to the article‘‘Disclosing a Misdiagnosis of MultipleSclerosis: Do No Harm?’’ by Andrew J.Solomon, MD, and Eran Klein, MD,PhD,36 in the August 2013 Continuumissue on MS. The situation in which apatient with an incorrect diagnosis isreceiving treatment has been referredto as therapeutic mislabeling.37 Insuch circumstances, it is incumbentupon the physician to recommend dis-continuation of disease-modifyingtherapy, despite the challenges of do-ing so, especially for the patient with apsychogenic etiology.37,38 Boissy andFord37 offer a number of strategies forhelping patients who have been mis-diagnosed with MS (Table 9-2).

CONCLUSIONThis article has reviewed many of thecircumstances in which a disease-modifying therapy is discontinued al-together or in order to switch to analternative medication, as well as con-siderations with regard to switchingmedications. It is critically importantto be certain that the diagnosis of MSis based on solid evidence before ini-tiating therapy and that a frank andhonest discussion occur between phy-sician and patient about the risks,

TABLE 9-2 Strategies for Helping Patients With Functional SymptomsThat Mimic Multiple Sclerosisa

b Consider timing (choose the right moment to introduce the possibility thatsymptoms may be psychogenic)

b Develop rapport

b Explore fears and emotions

b Reinforce the partnership

b Choose words carefully

b Encourage appropriate evaluations

a For more details, the reader is encouraged to read the article by Boissy and Ford.37



benefits, and uncertainties about re-spective disease-modifying agents.

Maintaining a very empathic sup-portive relationship with the patientwill help with patient adherence to atherapeutic regimen. Circumstancesmight arise in which the patient orthe physician considers the option ofdiscontinuing disease-modifying ther-apy, but both should recognize theneed for much more data about thelikelihood of success.

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