Stopping Disease-modifying Therapies Research Articles

Multiple Sclerosis and Family Planning: A Survey Study of the Patient Experience.

Multiple sclerosis (MS) commonly affects women in their childbearing years, necessitating discussion between patients and their MS treatment team around the issues of family planning, pregnancy, and postpartum experiences. This study assessed the impact of a diagnosis of MS on women's reproductive decision-making and on their perception of counseling received surrounding pregnancy. It also sought to evaluate trends in pregnancy and postpartum experiences and determine whether experiences differed by race, ethnicity, and zip code. Women with an MS diagnosis seen at the University of Virginia MS Clinic or at Virginia Commonwealth University (VCU) MS Clinic were invited to participate in a survey study. MS disease and pregnancy history, and, when appropriate, reasons for pregnancy avoidance were collected. Respondents who had >1 pregnancy following MS diagnosis were asked to evaluate the counseling they received from medical professionals and to share their pregnancy experiences including complications during pregnancy, delivery outcomes, and postpartum experience including breastfeeding. Of the 280 respondents, 76.6% were currently receiving MS specialty care. Most of them (79.3%) had not been pregnant following MS diagnosis. Of them, 20.1% indicated that this decision was driven by MS-related concerns: MS worsening with pregnancy (47%); ability to care for child secondary to MS (35%); passing MS onto child (19%); stopping disease-modifying therapies to attempt pregnancy (14%); lack of knowledge about options for pregnancy and MS (9%). Women with a more recent estimated decade of pregnancy were more likely to report neurologist counseling regarding MS and pregnancy (pregnancy before 2000: 40%, 2000-2010: 64.7%, 2010- present: 83.3%; χ2 0.020). Breastfeeding initiation was reported in 71.4% of postdiagnosis pregnancies (median duration 6 months, interquartile range 1.75-11). Over the past few decades, women with MS have received a wide range of evolving guidance surrounding family planning, pregnancy, and postpartum care. Survey data suggest improvements in MS/pregnancy counseling and medical management in recent years, which may be driven by an increase in research in the field. There remains an important need and opportunity to improve counseling of women with MS who are considering pregnancy.

037 Treating secondary progressive multiple sclerosis in the UK: use of guidelines and stopping criteria

BackgroundAs new treatment approaches emerge for progressive forms of multiple sclerosis (MS), it is important to understand the factors underlying current practice.MethodsWe used a structured questionnaire to interview 59 healthcare professionals (HCPs) from geo- graphically-dispersed UK MS centres about current disease modifying therapy (DMT) management of patients with suspected/confirmed secondary progressive MS (SPMS).ResultsOf 43 HCPs (73%) who follow guidelines for DMT management of patients transitioning from relapsing-remitting multiple sclerosis (RRMS) to SPMS, most (n=37/43, 86%) use the NHS England (NHSE) algorithm; 7/43 (16%) use ABN guidance. Fifty-eight (98%) HCPs use DMTs to treat patients with RRMS whom they suspect may be transitioning to SPMS and 30 (51%) for (a minority of) patients with newly- diagnosed SPMS. Expanded Disability Status Scale (EDSS) 7.0 was the most frequently-reported criterion used for stopping DMTs (n=29, 49%), however, a variety of other criteria were used and a small majority of HCPs reported continuing DMTs beyond EDSS 7.0 in certain circumstances (most commonly recent relapse activity [n=32, 54%] or in younger patients [n=20, 34%]).ConclusionsAlthough most HCPs follow NHSE guidelines, a range of DMT stopping criteria are employed in clinical practice and treatment decisions may be based on individual patient circumstances.katherine.rhys@novartis.com

Stopping disease-modifying therapy in relapsing and progressive multiple sclerosis.

To assess the reasons for considering discontinuation of disease-modifying therapies (DMTs)in patients with multiple sclerosis (MS). Relevant aspects of the natural history, pathology, and immunology are analyzed. A number of retrospective observational studies in aggregate indicate that stopping DMTs may be attempted in older individuals with stable disease. Prognostic factors have been identified informing about the risk of recurrence of disease activity after DMT discontinuation. Several clinical scenarios provide a rationale to stop DMTs in people with MS. Cumulative evidence has been gathered recently allowing us to more precisely weigh the risks against the benefits. This information aids in the decision process.

Stopping disease modifying therapy in patients over age 50 with presumed benign multiple sclerosis (2057)

Stopping disease modifying therapy in patients over age 50 with presumed benign multiple sclerosis (2057)

EMCAM (Multiple Sclerosis Autonomous Community of Madrid) document for the management of patients with multiple sclerosis during the SARS-CoV-2 pandemic

The current SARS-CoV-2 pandemic is forcing neurologists to carry out a series of adaptations in the management of multiple sclerosis. Neurologists must weigh up the need to start or continue disease-modifying treatments against the risk of infection, the risk of complications from the infection, and the risk of multiple sclerosis activity. Since this is an unprecedented situation, most decisions are being made on the basis of a theoretical approach and the criteria of each neurologist. The aim of this study is conduct a literature search to collect available evidence on the relationship between disease-modifying therapies in multiple sclerosis and SARS-CoV-2 infection. This evidence, together with the experience of the authors in the management of patients with multiple sclerosis during the pandemic, will make it possible to offer some proposals for the treatment and follow-up of patients in this epidemiological context. After the literature search and our experience in the management of patients, a number of proposals for treatment are established for each drug, which must necessarily be individualised for each patient, since, in these exceptional circumstances, their peculiarities can affect the prognosis. The neurologist should be aware of current evidence to assess the risk-benefit of starting, maintaining and stopping disease-modifying therapies in multiple sclerosis during the pandemic.

Author response: Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

To review evidence on starting, switching, and stopping disease-modifying therapies (DMTs) for multiple sclerosis (MS) in clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and progressive MS forms.Relevant, peer-reviewed research articles, systematic reviews, and abstracts were identified (MEDLINE, CENTRAL, EMBASE searched from inception to November 2016). Studies were rated using the therapeutic classification scheme. Prior published Cochrane reviews were also used.Twenty Cochrane reviews and an additional 73 full-text articles were selected for data extraction through an updated systematic review (completed November 2016). For people with RRMS, many DMTs are superior to placebo (annualized relapses rates [ARRs], new disease activity [new MRI T2 lesion burden], and in-study disease progression) (see summary and full text publications). For people with RRMS who experienced a relapse on interferon-β (IFN-β) or glatiramer acetate, alemtuzumab is more effective than IFN-β-1a 44 μg subcutaneous 3 times per week in reducing the ARR. For people with primary progressive MS, ocrelizumab is probably more effective than placebo (in-study disease progression). DMTs for MS have varying adverse effects. In people with CIS, glatiramer acetate and IFN-β-1a subcutaneous 3 times per week are more effective than placebo in decreasing risk of conversion to MS. Cladribine, immunoglobulins, IFN-β-1a 30 μg intramuscular weekly, IFN-β-1b subcutaneous alternate day, and teriflunomide are probably more effective than placebo in decreasing risk of conversion to MS. Suggestions for future research include studies considering comparative effectiveness, usefulness of high-efficacy treatment vs stepped-care protocols, and research into predictive biomarkers.

Perspectives of individuals with multiple sclerosis on discontinuation of disease-modifying therapies

Background: Therapeutic research in multiple sclerosis (MS) has focused on the development of treatments with little investigation regarding the possibility of discontinuation of disease-modifying therapies (DMTs). Objective: To understand the opinion of individuals with MS concerning stopping DMTs and the factors that influence the decision-making process. Methods: A mixed method approach was used starting with three focus groups from which a survey was developed. This survey was sent to 1000 participants in the North American Research Committee on Multiple Sclerosis registry who met inclusion criteria (age ⩾45 years; on most recent DMT for ⩾5 years). Descriptive analysis and structural equation modeling were used. Results: Of 1000 participants receiving the survey, 377 provided complete responses and met inclusion criteria. Only 11.9% of participants reported that if their disease was considered stable, they would consider coming off medications. A high level of external locus of control in influential others such as physicians significantly decreased the likelihood of considering discontinuation. Conclusions: Most individuals with MS report being unlikely to consider stopping MS therapy if their disease was considered “non-active.” As the results of studies concerning DMT discontinuation are obtained, information from providers will be an important part of individuals’ decision-making process.

Changes in patient-reported outcomes between continuers and discontinuers of disease modifying therapy in patients with multiple sclerosis over age 60

BackgroundThe risk benefit ratio of continuing immunomodulating disease modifying therapy (DMT) in older MS patients is unknown. To date, only retrospective observational studies on DMT discontinuation have been published. In these studies, DMT discontinuation was based solely on disease stability and patients frequently had to restart treatment. Our prior study demonstrated that discontinuing DMT can be more successful when age is also considered. The impact of discontinuing DMT on patients’ quality of life has not been previously explored. The objective of this study is to determine changes in outcomes over time between those who continued versus discontinued DMT using patient-reported outcomes (European Quality of Life 5 Dimensions (EQ-5D) index, Performance Scales (PS), and Patient Health Questionnaire (PHQ9)) and walking speed (Timed 25-foot walk) in MS patients over age 60. MethodsWe conducted a retrospective, observational study in which we identified patients from our MS clinics who were 60 years of age or older and had been on DMT ≥2 years. We compared outcome evolution over time among treatment groups (continuers, discontinuers before discontinuation (DBD), and discontinuers after discontinuation (DAD)), by creating separate mixed-effects linear regression models that included an interaction term between time from age 60 and treatment group to study outcome trajectories. Independent variables were time from age 60 and treatment group, with the following covariates: age at diagnosis, gender, disease course at MS diagnosis, time on DMT, baseline DMT, and ambulation status at age 60. Results178 of 600 patients discontinued DMT, and 89.3% (n = 159) of those who discontinued remained off DMT. Only the EQ-5D mixed-effects linear regression model with the interaction term was statistically significant (omnibus p-value = 0.043). The slope relating time to EQ-5D was significantly different when comparing continuers to DBD (0.009, 95% CI 0.002–0.016, p-value = 0.015). The slopes were not significantly different when comparing continuers to DAD, or when comparing the before and after discontinuation slopes among the discontinuers. With the interaction term removed, there were no significant differences between the three groups for any other outcome. ConclusionMost patients over age 60 who discontinued DMT remained off treatment. Among the outcomes, only EQ-5D demonstrated significant differences over time, with continuers having lower quality of life scores compared to DBD. There were no significant group differences in PS, T25FW and PHQ-9. Overall, stopping DMT appears to have minimal effect on outcomes over the study period in patients over age 60.

Predictors of relapse and disability progression in MS patients who discontinue disease-modifying therapy

BackgroundDiscontinuation of disease-modifying therapies (DMTs) for MS is common. MSBase, a large global observational registry, affords a unique opportunity to investigate predictors of ‘post-DMT’ relapses and confirmed disability progression (CDP) in a diverse group of patients exposed to different DMTs. Materials/methodsMain inclusion criteria: clinician-confirmed MS diagnosis (2010 McDonald criteria); age ≥ 18 at index DMT start; ≥12 months on index DMT prior to discontinuation; ≥24 months of follow-up post-discontinuation; did not restart DMT for ≥6 months. Predictors of time to first relapse and 3-month CDP were analyzed using Cox proportional hazards regression adjusted for age, gender, baseline EDSS, EDSS stability and relapse-free period for ≥1 year prior to discontinuation, calendar epoch, index DMT and reason for discontinuation. Results4842 patients (74.2% female) from 20 MSBase Centers met our inclusion criteria. 3556 (73%) discontinued one of IFNβ preparations, 849 (18%) - glatiramer acetate, 308 (6%) - natalizumab and 129 (3%) – fingolimod; other DMTs were excluded because too few records were available. Overall post-discontinuation annualized relapse rate (95% CI) was 0.224 (0.219, 0.229) and CDP rate was 8.23 (7.72, 8.76) per 100 person-years. Risk of post-DMT relapse was higher in younger patients, female patients, those with moderate disability and a relapse within 1 year of discontinuation. Hazard of CDP increased with increasing disability at baseline and disease progression within 3 years prior to stopping DMT. Of all the DMTs, only natalizumab was associated with increased risk of both post-DMT relapse and CDP. ConclusionsKnowledge of post-DMT relapse and disability progression rates and predictors of post-DMT disease activity allows for a more informed discussion of DMT discontinuation in those patients who are considering this option.

Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

To review evidence on starting, switching, and stopping disease-modifying therapies (DMTs) for multiple sclerosis (MS) in clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and progressive MS forms. Relevant, peer-reviewed research articles, systematic reviews, and abstracts were identified (MEDLINE, CENTRAL, EMBASE searched from inception to November 2016). Studies were rated using the therapeutic classification scheme. Prior published Cochrane reviews were also used. Twenty Cochrane reviews and an additional 73 full-text articles were selected for data extraction through an updated systematic review (completed November 2016). For people with RRMS, many DMTs are superior to placebo (annualized relapses rates [ARRs], new disease activity [new MRI T2 lesion burden], and in-study disease progression) (see summary and full text publications). For people with RRMS who experienced a relapse on interferon-β (IFN-β) or glatiramer acetate, alemtuzumab is more effective than IFN-β-1a 44 μg subcutaneous 3 times per week in reducing the ARR. For people with primary progressive MS, ocrelizumab is probably more effective than placebo (in-study disease progression). DMTs for MS have varying adverse effects. In people with CIS, glatiramer acetate and IFN-β-1a subcutaneous 3 times per week are more effective than placebo in decreasing risk of conversion to MS. Cladribine, immunoglobulins, IFN-β-1a 30 μg intramuscular weekly, IFN-β-1b subcutaneous alternate day, and teriflunomide are probably more effective than placebo in decreasing risk of conversion to MS. Suggestions for future research include studies considering comparative effectiveness, usefulness of high-efficacy treatment vs stepped-care protocols, and research into predictive biomarkers.

Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

To develop recommendations for disease-modifying therapy (DMT) for multiple sclerosis (MS). A multidisciplinary panel developed DMT recommendations, integrating findings from a systematic review; followed an Institute of Medicine-compliant process to ensure transparency and patient engagement; and developed modified Delphi consensus-based recommendations concerning starting, switching, and stopping DMTs pertinent to people with relapsing-remitting MS, secondary progressive MS, primary progressive MS, and clinically isolated syndromes of demyelination. Recommendations were supported by structured rationales, integrating evidence from one or more sources: systematic review, related evidence (evidence not from the systematic review), principles of care, and inference from evidence. Thirty recommendations were developed: 17 on starting DMTs, including recommendations on who should start them; 10 on switching DMTs if breakthrough disease develops; and 3 on stopping DMTs. Recommendations encompassed patient engagement strategies and individualization of treatment, including adherence monitoring and disease comorbidity assessment. The panel also discussed DMT risks, including counseling about progressive multifocal leukoencephalopathy risk in people with MS using natalizumab, fingolimod, rituximab, ocrelizumab, and dimethyl fumarate; and made suggestions for future research to evaluate relative merits of early treatment with higher potency DMTs vs standard stepped-care protocols, DMT comparative effectiveness, optimal switching strategies, long-term effects of DMT use, definitions of highly active MS, and effects of treatment on patient-specified priority outcomes. This guideline reflects the complexity of decision-making for starting, switching, or stopping MS DMTs. The field of MS treatment is rapidly changing; the Academy of Neurology development process includes planning for future updates.

Discontinuation of disease-modifying therapy in patients with multiple sclerosis over age 60

Background: The risk–benefit ratio of continuing immunomodulating disease-modifying therapy (DMT) in older multiple sclerosis (MS) patients is unknown. Objective: To evaluate clinical and patient-reported outcomes after stopping DMT in older MS patients. Methods: Retrospective, observational study identifying patients from our MS clinics who were aged over 60 and on DMT > 2 years. Cause-specific Cox proportional hazards regression modeled time to discontinuation and time to reinitiation of therapy. Pre- and post-discontinuation comparisons of Performance Scales (PS), Timed 25-Foot Walk, and Patient Health Questionnaire-9 (PHQ9) were analyzed using linear mixed models. Results: A total of 600 patients were included, with 178 (29.7%) discontinuing. Discontinuers were 2.2 years older, had 3.2 years longer disease duration, and 1.6 years lesser treatment exposure. Providers initiated discontinuation more than patients (68.0%). Only one clinical relapse occurred in discontinuers. A proportion (10.7%) reinitiated DMT. Provider-initiated discontinuers restarted less often (hazard ratio (HR): 0.34; 95% confidence interval (CI): 0.12–0.9). In discontinuers, relapsing-remitting patients had lower PS on average than primary progressive. Provider-initiated discontinuation was associated with lower PS than patient- initiated discontinuation. PHQ9 scores appeared higher in those stopping intravenous (IV) therapies than interferons. Lower PS and PHQ9 indicate better outcomes. Conclusion: Most patients over age 60, who discontinued DMT, remained off DMT. This study provides real-world data that may guide clinicians considering discontinuing DMT.

Stopping Disease-Modifying Therapy in Nonrelapsing Multiple Sclerosis: Experience from a Clinical Practice.

Current disease-modifying therapies (DMTs) are of benefit only in people with relapsing forms of multiple sclerosis (RMS). Thus, safely stopping DMTs in people with secondary progressive MS may be possible. Two groups of patients with MS were studied. Group A consisted of 77 patients with secondary progressive MS and no evidence of acute central nervous system inflammation for 2 to 20 years. These patients were advised to stop DMTs. Group B consisted of 17 individuals with RMS who stopped DMTs on their own. Both groups were evaluated at treatment cessation and for a minimum of 1 year thereafter. Multiple variables were assessed to determine those that predicted recurrent acute disease. Nine patients in group A (11.7%) and ten patients in group B (58.8%) had recurrent acute disease, almost always within 1 to 2 years of stopping treatment. The only variable of significance in group A distinguishing stable and relapsing patients was age (P = .0003), with relapsing patients being younger. Group B patients were younger and had significantly lower Expanded Disability Status Scale scores than group A, with no significant differences in age between relapsed and stable patients. The DMTs can be stopped safely in older patients with MS (≥7 decades) with no evidence of acute disease for 2 years or longer, with an almost 90% probability of remaining free of acute recurrence. The high proportion of untreated patients with RMS experiencing recurrent acute disease is consistent with published data.

Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: a propensity score-matched study

BackgroundDiscontinuation of injectable disease-modifying therapy (DMT) for multiple sclerosis (MS) after a long period of relapse freedom is frequently considered, but data on post-cessation disease course are lacking.Objectives(1) To compare...

Long-term persistence with injectable therapy in relapsing-remitting multiple sclerosis: an 18-year observational cohort study.

Disease modifying therapies (DMTs) reduce the frequency of relapses and accumulation of disability in multiple sclerosis (MS). Long-term persistence with treatment is important to optimize treatment benefit. This long-term, cohort study was conducted at the Calgary MS Clinic. All consenting adults with relapsing-remitting MS who started either glatiramer acetate (GA) or interferon-β 1a/1b (IFN-β) between January 1st, 1996 and July 1st, 2011 were included. Follow-up continued to February 1st, 2014. Time-to-discontinuation of the initial and subsequently-prescribed DMTs (switches) was analysed using Kaplan-Meier survival analyses. Group differences were compared using log-rank tests and multivariable Cox regression models. Analysis included 1471 participants; 906 were initially prescribed GA and 565 were initially prescribed IFN-β. Follow-up information was available for 87%; 29 (2%) were lost to follow-up and 160 (11%) moved from Southern Alberta while still using DMT. Median time-to-discontinuation of all injectable DMTs was 11.1 years. Participants with greater disability at treatment initiation, those who started treatment before age 30, and those who started between 2006 and 2011 were more likely to discontinue use of all injectable DMTs. Median time-to-discontinuation of the initial DMT was 8.6 years. Those initially prescribed GA remained on treatment longer. Of 610 participants who discontinued injectable DMT, 331 (54%) started an oral DMT, or a second-line DMT, or resumed injectable DMT after 90 days. Persistence with injectable DMTs was high in this long-term population-based study. Most participants who discontinued injectable DMT did not remain untreated. Further research is required to understand treatment outcomes and outcomes after stopping DMT.

‘Doctor, can I stop my medicine?’ Analysis of disease course after stopping disease-modifying therapy in stable MS patients (P5.192)

‘Doctor, can I stop my medicine?’ Analysis of disease course after stopping disease-modifying therapy in stable MS patients (P5.192)

Stoppers and non-starters of disease-modifying treatment in multiple sclerosis

To explore the frequency of non-starters and stoppers of disease-modifying therapy (DMT) in a cohort of people recently diagnosed with multiple sclerosis (MS) and to identify reasons for non-starting or stopping DMT measured by demographic variables, social support [The Interpersonal Support Evaluation List (ISEL)] and disease-related stress [The Impact of Event Scale (IES)]. A multicentre retrospective cohort study using postal surveys completed by people with MS was performed, comprising all patients diagnosed with MS during 2000-2007 at four university clinics in Norway. Of the 424 respondents, 180 (42%) were still using the first prescribed DMT, 83 (20%) were using DMT after switching DMT at least once, 53 (12.5%) had ended DMT, and 108 (25.5%) had never started DMT. The risk of non-starting DMT was associated with increasing age at diagnosis, the region, disease-related stress and avoidant trauma coping. The risk factors for stopping therapy after the first prescribed DMT were adverse events and high education. Disease-related stress, avoidant trauma coping, age at diagnosis and education should be considered when motivating people with MS to use DMT. Hence, the challenges to starting and continuing treatment will probably also remain a problem with orally administered DMT.

End of Life Care: A Curricular and Practice Need

ABSTRACT End of life (EOL) care is a subset of palliative care during the terminal phase of an illness. It primarily aims to provide psychosocial supports and symptomatic relief employing a step-ladder approach to management of physical pain, breathlessness and other distressing symptoms. Futile aggressive and invasive treatments are either withheld or withdrawn. The EOL care accepts the principles of stopping disease-modifying therapy after all possible reversible factors of the illness are excluded. It does not imply the non-use of curative treatment whenever it is considered useful. In case of the ‘double-effect’ of a drug, it gives preference to symptomrelieving over the harmful effects, which are accepted as of secondary importance. EOL care is governed by well established moral principles and individual's freedom of choice. It allows the normal and natural process of death to happen for an incurable and end-stage disease. How to cite this article Jindal SK. End of Life Care: A Curricular and Practice Need. J Postgrad Med Edu Res 2012;46(3): 117-121.