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.
http://jama.jamanetwork.com/article.asp ... oc120048-6
"Наши результаты также поощряют исследование новых терапевтических средств для лечения РС." (c, из КИ)
Скучно.. Правда?
Можно ограничиться в обсуждении высказыванием в данном КИ.. -
Мы знаем, что этот класс препаратов может быть очень полезен в снижении частоты рецидивов. Мы не рекомендуем пациентам прекращать прием этих препаратов (из КИ)
Можно и продолжить...
Все интерфероны БЕСПОЛЕЗНЫ! (Kira)
Так забавнее..
Мне просто понятна ваша позиция, вернее непонятна - РС и дан для того, чтобы что-то в себе скорректировать, что не все соответствует гармонии вашего "Я" и окружающего Вас мира, что в нормале Вы не справляетесь с этой корректировкой, РС - это помощь для изменений в себе.
