Association Between Use of Interferon Beta and Progression of Disability in Patients With Relapsing-Remitting Multiple Sclerosis

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 The Journal of the American Medical Association



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Link: http://jama.jamanetwork.com/article.aspx?articleid=1217239

ABSTRACT

Context  Interferon beta is widely prescribed to treat multiple sclerosis (MS); however, its relationship with disability progression has yet to be established.

Objective  To investigate the association between interferon beta exposure and disability progression in patients with relapsing-remitting MS.


COMMENT




Among patients with relapsing-remitting MS, administration of interferon beta was not associated with a reduction in progression of disability, despite using a clinically relevant, important, and irreversible disability milestone as the main outcome. The lack of evidence for a strong association between interferon beta treatment and disability progression persisted whether a contemporary or a historical (pre–vs post–interferon beta era) untreated comparison cohort was considered, a secondary outcome (EDSS score of 4) was examined, or additional analyses were performed, including a propensity score–adjusted model ( eAppendix). The difference in the direction of the hazard of progression between the contemporary and historical approaches, which is informative for future studies, is of interest.



Previous postmarketing studies have suggested a positive association between interferon beta and MS disability outcomes.4 - 10 ,30 However, conducting adequately controlled longitudinal observational studies is challenging, and many such studies have faced methodological issues. One of the larger studies to date, from 2 Italian centers,10 was susceptible to immortal time bias13 ,15 because of differing baselines for the treated and untreated cohorts. The use of a propensity score method in that study10 could not address immortal time bias. An independent reanalysis found no apparent beneficial association with interferon beta treatment once this bias was considered.13 Another methodological issue included the use of a control group comprising individuals too ill to start interferon beta treatment (owing to significant comorbidities).10 Both of these issues could bias the study to show a treatment effect when one might not exist.12 - 13 Another relatively large Canadian study used patients as their own controls.5 This approach minimized some potential biases but may not have sufficiently acknowledged the variable and unpredictable individual progression profiles of MS patients.5 A sizable UK-based observational study was unable to demonstrate a beneficial association with the use of DMDs in relapsing-remitting MS after 2 years of treatment, finally concluding that further follow-up was needed.31



Our study endeavored to address these shortcomings. First, we considered interferon beta treatment as a time-dependent variable, thereby addressing immortal time bias13 ,15 and accounting for the changing treatment status of patients over time. Second, in the face of no single ideal comparison group, we adopted a dual approach, using both pre–and post–interferon beta era untreated cohorts. Third, we were able to access a large cohort of MS patients with a substantial follow-up and similar rates of disability assessment (thereby minimizing surveillance bias).32 Fourth, the unique health system in Canada allowed linkage between clinical and province-wide health administrative databases, creating a comprehensive and rich data source.



Our findings are also relevant for the design of future related observational studies; we found that patients eligible for interferon beta treatment in the interferon beta era but who chose not to start treatment had a non–statistically significant more favorable overall outcome compared with those who started treatment in the same era. This may be explained by “indication bias,” whereby patients whose clinical status is not improving or is getting worse are prescribed drug therapy.33 This potential bias was also apparent in a reanalysis of the Italian study,10 ,13 which used a contemporary (post–interferon beta era) comparison cohort, but was not evident in our pre–interferon beta era comparison, for which the historical control group did not have the same access to DMD treatment. This provides a possible explanation for the differences in the direction of the HRs in our contemporary and historical approaches and encourages the use of more than 1 control group in observational studies whenever possible.34 Our estimated HR was greater than 1 in the contemporary approach, which may reflect residual confounding by indication, despite the adjustments made.



The decision to start (or not start) treatment is complex, and likely not all factors are captured by observational studies—this can particularly affect any “contemporary” analysis based on a post–interferon beta era untreated comparison cohort. In a health care system with free access to DMDs, possible reasons for not starting a DMD might include stable disease, needle phobia, unwillingness to receive or adhere to a noncurative treatment, planned pregnancy, and personal or religious concerns about using interferon beta, a human albumin–containing product. In our study, the contemporary untreated cohort had a lower annualized relapse rate and longer disease duration but similar disability level (EDSS score) at baseline compared with the treated cohort. Although these factors were adjusted for, they could indicate a more favorable outcome; a low or moderate initial relapse frequency (1-3 relapses during the first 5 years after onset of symptoms) has been associated with a subsequent nonprogressive MS course.35



Our data suggest that the historical control group might be the more appropriate choice; however, it has its own limitations, including the possibility that factors other than drug treatment may have changed over time, such as patient care and management and rates of disease progression. However, strong evidence to suggest a change in disease progression over time was not found in relapsing-onset MS patients in British Columbia.36 Nonetheless, in the event that further studies become available, future meta-analyses of similar observational data may be of value.



Our findings, however, are consistent with the longer-term clinical trial–related studies. A 16-year follow-up of MS patients originally randomized to receive placebo or interferon beta treatment in a 2-year clinical trial was unable to show benefit in the treatment group in terms of progression to an EDSS score of 6 or secondary progressive MS.37 There were few deaths in the study, although an unexpected excess occurred in the original placebo group; findings were considered hypothesis generating by the authors, who cautioned that no survival benefit could be confirmed.37 In addition, no effect of interferon beta treatment on disability progression could be found in patients with clinically isolated syndrome (considered at high risk of developing MS).38 Some have tried to evaluate the impact of delayed vs early or higher vs lower cumulative exposure to interferon beta treatment through open-label extension studies, reporting better outcomes with early or higher cumulative exposure.39 - 40 However, dropouts and lack of blinding have confounded findings.41



We also found that the lower SES quintiles (vs the highest quintile) were associated with a higher hazard of disability progression, although these findings were not statistically significant. Socioeconomic status is a complex concept, reflecting more than just income, and a low SES is a strong determinant of poor overall health.42 We were unable to find another study examining the association between SES and MS disability progression. Given that there are relatively few predictors of MS disease progression, further investigation of potentially modifiable factors such as psychosocial, behavioral, or environmental pathways that may attenuate SES is warranted.



Our study also has some limitations. We considered interferon beta drugs as a single therapeutic class, although given the complexity of the differing approval dates and product switching, a robust comparison between products would be extremely challenging. We were not able to consider neutralizing antibodies—high titers have been associated (somewhat controversially) with reduced interferon beta effectiveness.43 Our study was not designed to examine adverse events associated with interferon beta treatment. Although we considered a broad range of confounders, unmeasured confounding is possible, as with any observational study. We could consider only patients attending a BCMS clinic. This primarily affects recruitment into the untreated cohorts (because of virtual complete capture of patients taking interferon beta for their MS during the study period). It is possible that very mild or very severe disease would prevent attendance at clinic, although systematic occurrence of one of these scenarios appears unlikely.



In addition, we considered 1 main and 1 secondary outcome; both were based on reaching irreversible disability milestones. Although these are clinically relevant and important outcomes, and our conservative definitions served to minimize assessment variation and random fluctuations that have impeded the measurement of disease progression in clinical trials,44 - 45 it remains possible that interferon beta treatment might positively affect other outcomes not considered here. The EDSS has recognized limitations46 ; however, it is the most widely used and internationally recognized disability assessment tool in MS, its use being ubiquitous in MS clinical trials and observational studies. Limitations relevant to the study EDSS end points include reliance on ability to walk and an inability to capture well the myriad MS symptoms (cognition; fatigue; bowel, bladder, or sexual function; visual acuity; or health-related quality of life). Also, despite the propensity score adjustment, residual confounding by indication could still be present, as suggested by the estimated HR of greater than 1 in the contemporary approach. Finally, we cannot rule out the possibility that despite our sample size, our study may have been underpowered to detect an association between interferon beta treatment and disease progression.



In conclusion, we did not find evidence that administration of interferon beta was associated with a reduction in disability progression in patients with relapsing-remitting MS. The ultimate goal of treatment for MS is to prevent or delay long-term disability. Our findings bring into question the routine use of interferon beta drugs to achieve this goal in MS. It is, however, possible that a subgroup of patients benefit from interferon beta treatment and that this association would not be discernable in our comprehensive “real-world” study. Further work is needed to identify these potential patients; perhaps through pharmacogenomic or biomarker studies, paving the way for a tailored, personalized medicine approach. Our findings also encourage the investigation of novel therapeutics for MS.



AUTHOR INFORMATION

ABSTRACT | METHODS | RESULTS | COMMENT | AUTHOR INFORMATION | REFERENCES



Corresponding Author: Helen Tremlett, PhD, Division of Neurology, Department of Medicine, University of British Columbia, Room S178, UBC Hospital, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada (helen.tremlett@ubc.ca).

Author Contributions: Dr Tremlett had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Shirani, Zhao, Kingwell, van der Kop, Petkau, Tremlett.

Acquisition of data: Shirani, Kingwell, van der Kop, Oger, Tremlett.

Analysis and interpretation of data: Shirani, Zhao, Karim, Evans, Kingwell, Oger, Gustafson, Petkau, Tremlett.

Drafting of the manuscript: Shirani, Tremlett.

Critical revision of the manuscript for important intellectual content: Shirani, Zhao, Karim, Evans, Kingwell, van der Kop, Oger, Gustafson, Petkau, Tremlett.

Statistical analysis: Shirani, Zhao, Karim, Gustafson, Petkau.

Obtained funding: Zhao, van der Kop, Gustafson, Petkau, Tremlett.

Administrative, technical, or material support: Shirani, Evans, Kingwell, Oger, Tremlett.

Study supervision: Tremlett.


Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Shirani reports receiving travel grants to present at and attend conferences from the endMS Research and Training Network and the European Committee for Treatment and Research in Multiple Sclerosis. Mr Karim reports having had travel and accommodation costs covered to present at a conference from the endMS Research and Training Network. Dr Evans reports receiving travel grants to present at and attend conferences from the endMS Research and Training Network and the European Committee for Treatment and Research in Multiple Sclerosis. Dr Kingwell reports having had travel and accommodation costs covered to present at and attend conferences from the endMS Research and Training Network, the International Society for Pharmacoepidemiology, and Bayer Schering Pharma. Dr Oger reports receiving speaker honoraria, consulting fees, travel grants, research grants, and/or educational grants from Aventis, Bayer, Biogen-Idec, BioMS, Corixa, Genentech, Novartis, Serono, Shering, Talecris, and Teva-Neurosciences. He receives fees for services from Bayer, Novartis, and Biogen Idec to serve on advisory committees. Dr Petkau reports having received research funds from Bayer Pharma and consulting fees and/or fees for service on data safety monitoring boards from Bayer Canada, Bayer Pharma, Bayhill Therapeutics, BTG International, Merck-Serono, and Novartis. Dr Tremlett reports having received speaker honoraria and/or travel expenses to speak at conferences from the Consortium of MS Centres, US National MS Society, Swiss Multiple Sclerosis Society, University of British Columbia Multiple Sclerosis Research Program, Bayer Pharmaceuticals (invited speaker, honoraria declined), and Teva Pharmaceuticals (invited speaker). Unless otherwise stated, all speaker honoraria are either donated to an MS charity or to an unrestricted grant for use by her research group. No other disclosures were reported.

Funding/Support: This study was s upported by grant MOP-93646 from the Canadian Institutes of Health Research (CIHR; principal investigator: Dr Tremlett) and grant RG 4202-A-2 from the National Multiple Sclerosis Society (NMSS; principal investigator: Dr Tremlett). Dr Shirani is funded through a postdoctoral fellowship from the Multiple Sclerosis Society of Canada and grants from the CIHR (MOP-93646) and the NMSS (RG 4202-A-2). Dr Zhao receives research funding from the CIHR, the Multiple Sclerosis Society of Canada, and the NMSS. Dr Evans is funded through grants from the CIHR (MOP-93646), the NMSS (RG 4202-A-2), and the Michael Smith Foundation for Health Research. Dr Kingwell is supported by postdoctoral fellowships from the Multiple Sclerosis Society of Canada and the Michael Smith Foundation for Health Research. Dr Oger receives support from the Christopher Foundation and the University of British Columbia (UBC). He receives fees for service from the Medical Services Commission of British Columbia. Dr Gustafson is supported by the Natural Sciences and Engineering Research Council of Canada. Dr Petkau holds research grants from the CIHR, the Multiple Sclerosis Society of Canada, the NMSS, and the Natural Sciences and Engineering Research Council of Canada. Dr Tremlett is funded by the Multiple Sclerosis Society of Canada (Don Paty Career Development Award), is a Michael Smith Foundation for Health Research Scholar, and is the Canada Research Chair for Neuroepidemiology and Multiple Sclerosis. She has also received research support from the NMSS, CIHR, and UK Multiple Sclerosis Trust. The BCMS database has been funded from various sources (including the above) and also by an unrestricted grant from Donald Paty, MD, FRCPC, University of British Columbia, and the MS/MRI Research Group.

Role of the Sponsor: The funding institutions had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Online-Only Material: The Author Video Interview is available here.

Additional Contributions: We gratefully acknowledge the BCMS clinic neurologists who contributed to the study through patient examination and data collection (current members listed in alphabetical order): D. Adams, MD, FRCPC (Kelowna MS clinic); D. Craig, MD, FRCPC (Kelowna MS clinic); L. Daly, MD, FRCPC (Prince George MS clinic); V. Devonshire, MD, FRCPC (UBC MS clinic); S. Hashimoto, MD, FRCPC (UBC and Victoria MS clinics); J. Hooge, MD, FRCPC (UBC and Prince George MS clinics); O. Hrebicek, MD, FRCPC (Victoria MS clinic); L. Kastrukoff, MD, FRCPC (UBC and Prince George MS clinics); S. Meckling, MD, FRCPC (Kelowna MS clinic); D. Parton, MD, FRCPC (Victoria MS clinic); A.-L. Sayao, MD, FRCPC (UBC MS clinic); and A. Traboulsee, MD, FRCPC (UBC MS clinic). We also thank P. Rieckmann, MD (Sozialstiftung Bamberg Hospital, Bamberg, Germany) for helpful revisions of the original Canadian Institutes of Health Research grant. None have received compensation for their role in the study. We also thank the UBC MS clinic nurses and staff and the UBC's Clinical Trials Group. We are grateful to Tom Duggan, BA, University of British Columbia, for significant help with data manipulation and conversion and the Pharmacoepidemiology in MS Research Group for research support. We are thankful to Population Data BC and the British Columbia Ministry of Health for support with linkage to British Columbia administrative health care and health services data (hospital separations and medical service plan payment information), as well as PharmaNet for drug information. We also thank Feng Zhu,MSc, University of British Columbia, for help with code development. Finally, we are indebted to all MS patients who participated in this study. Messrs Duggan and Zhu were compensated through study research grants.



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Editorial
Evaluating the Potential Benefit of Interferon Treatment in Multiple Sclerosis
JAMA. 2012;308(3):290-291.


Association Between Use of Interferon Beta and Progression of Disability in Patients With Relapsing-Remitting Multiple Sclerosis

 


Author Video Interviews

Association Between Use of Interferon Beta and Progression of Disability in Patients With Relapsing-Remitting Multiple Sclerosis (5:11)



Author Interview

JAMA: 2012-07-18, Vol. 308, No. 3, Author Interview (5:00)


JAMA ABSTRACT | METHODS | RESULTS | COMMENT | AUTHOR INFORMATION | REFERENCES



Link: http://jama.jamanetwork.com/article.aspx?articleid=1217239