Multiple sclerosis (MS) is a chronic, degenerative neurological disease that causes inflammation and lesions in the brain, spinal cord, and optic nerves, although the specific regions affected vary widely among patients (1, 2, 3). Prevalence estimates in the U.S. range from 250,000 to 350,000 patients, with about 1 in 1,000 people affected (1, 2). MS usually becomes symptomatic when people are in their late twenties, and two-thirds of patients are women.
MS shortens life expectancy only slightly, but it causes both acute and chronic disability for most patients and often severely affects functioning and quality of life (QOL). These effects vary widely across patients. About 50% of patients reach the following disability milestones: loss of employment (10 years after diagnosis), need for assistive walking devices (15 years), and inability to walk (25 years) (4). Additional impacts can include loss of arm function, loss of cognitive function, fatigue, weakness, pain, tremor, vision problems, urinary dysfunction, bowel dysfunction, muscle spasticity, swallowing disorders, sexual dysfunction, depression, anxiety, and others (1, 2, 3). The heterogeneity of MS poses a challenge for development of clinical guidelines because very different types of clinical interventions may be needed for different patients.
Neurologists have defined four main types or courses of MS (1, 2, 3). They are directly pertinent for clinical guidelines because therapies effective for one course are often not effective for others.
- Relapsing-remitting (RRMS) – About 85% of patients begin with this course, which is characterized by episodic exacerbations or "relapses" that include symptoms and signs developing over several days, stabilizing, and then improving within weeks. Disability progression is minimal. About 15% of patients overall are not severely affected for more than 20 years and are classified as having benign MS. About 70% have secondary progression of disability over time and move to the second type.
- Secondary progressive (SPMS) – This stage is characterized by less recovery from relapses, gradual worsening between relapses, and steadily increasing neurological deficits.
- Primary progressive (PPMS) – About 10% to 15% of patients begin with this course, which is characterized by continuous deterioration and absence of relapses.
- Progressive relapsing (PRMS) – About 5% of patients begin with this course, which includes both steady progression of the disease and relapses.
The cost of MS is high, at about $47,000 per patient per year including direct medical and non-medical costs, production losses, and informal care (4, 5). This figure indicates high economic stakes and a need for clinical guidelines that can steer spending to the most effective interventions for different types of patients.
MS Clinical Guidelines in the National Guideline Clearinghouse
The National Guideline Clearinghouse (NGC) includes 10 summaries of guidelines for diagnosis and treatment of multiple sclerosis, listed here in chronological order:
- Immunization and multiple sclerosis: a summary of published evidence and recommendations. American Academy of Neurology. 2002 (reviewed by the guideline developer and still considered current as of December 2006).
- Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. American Academy of Neurology. 2002 (reviewed by the guideline developer and still considered current as of October 2003).
- The utility of MRI in suspected MS: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurological Society. American Academy of Neurology. 2003.
- The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. American Academy of Neurology. 2003.
- Multiple sclerosis: national clinical guideline for diagnosis and management in primary and secondary care. United Kingdom National Institute for Clinical Excellence. 2004.
- EFNS guideline on treatment of multiple sclerosis relapses: report of an EFNS task force on treatment of multiple sclerosis relapses. European Federation of Neurological Societies. 2005.
- Guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis: report of and EFNS Task Force on IFN-beta antibodies in multiple sclerosis. European Federation of Neurological Societies. 2005.
- EFNS guidelines on the use of neuroimaging in the management of multiple sclerosis. European Federation of Neurological Societies. 2006.
- Natalizumab for the treatment of adults with highly active relapsing-remitting multiple sclerosis. United Kingdom National Institute for Clinical Excellence. 2007.
- Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. American Academy of Neurology. 2007.
Review of MS Clinical Guidelines
Four themes emerge from review of these clinical guidelines:
- Breadth of progress in MS treatment. As recently as the 1980s few treatment options were available for the underlying MS disease process, and options for managing the many symptoms caused by the disease were more limited than they are today. At that time medical management of MS was often characterized as "diagnose and adios." These MS clinical guidelines document advances made in the past two decades in development of a range of disease-modifying therapies (DMTs), including interferon beta in several forms, glatiramer acetate, mitoxantrone, and natalizumab, earlier diagnosis of MS using magnetic resonance imaging (MRI) technology, and treatment of the acute relapses, symptoms, and disabilities caused by MS. Although none of the DMTs provides a cure, they do inhibit the underlying disease process in RRMS. Moreover, their success has encouraged development and testing of newer, potentially more effective DMTs (6, 7, 8).
- International variation in the style and content of MS clinical guidelines. Development of these MS clinical guidelines was sponsored by three organizations in the United States and Europe: the American Academy of Neurology (AAN; 5 guidelines); the European Federation of Neurological Societies (EFNS; 3 guidelines); and the U.K. National Institute for Health and Clinical Excellence (NICE; 2 guidelines). Their methodologies vary in several ways.
The NICE guidelines are unique in at least six aspects. First, NICE was the only sponsor to address the full spectrum of MS diagnosis, medical treatment, symptom management, rehabilitation, and patient self-management topics in one guideline. As a result, its comprehensive 2004 guideline is by far the longest (197 pages), with a total of 189 treatment recommendations. The other guidelines each address only one topic and have no more than 21 pages and 28 recommendations.
Second, NICE includes Level A recommendations (based on evidence from randomized controlled trials) on several topics that are absent from the AAN and EFNS guidelines. These include providing information to patients about MS at the time of diagnosis, providing rehabilitation services to patients experiencing new limitations from MS, treatments for several types of symptoms, and eating foods high in linoleic acid to slow disease progression. Overall, NICE includes a mix of Level A and other recommendations on 19 different symptoms of MS that often cause significant loss of functioning and QOL. The AAN and EFNS guidelines do not address symptoms.
Third, NICE includes recommendations based on patient-reported outcomes (PROs). The AAN and EFNS guidelines include only studies utilizing physician-reported outcomes, such as Expanded Disability Status Scale (EDSS) scores, the frequency of acute MS relapses, MRI results, and diagnosis of clinically definite MS. NICE also includes results of studies on QOL, fatigue, depression, and other PRO scales and rehabilitation outcomes such as activities of daily living (ADLs). QOL and ADL impacts of MS are fundamental concerns for most patients, so including studies focusing on those outcomes is important for MS clinical guidelines. The literature on interventions to improve QOL in MS is limited but growing. A recent review sponsored by the MS International Federation highlighted several such studies (9).
Fourth, the NICE guidelines include health economics and cost-effectiveness analysis, which are absent from the AAN and EFNS guidelines. This has been a topic of controversy for DMTs since NICE deemed several to be not cost-effective, and the U.K. National Health Service (NHS) subsequently required pharmaceutical companies to join a financial risk-sharing scheme rather than provide full NHS coverage for those drugs. The more recent NICE guideline for natalizumab (2007) analyzed the cost-effectiveness of that new DMT for subsets of RRMS patients. NICE determined that natalizumab is not cost-effective for patients who failed to respond to interferon beta treatment, even though the manufacturer had received a license to market natalizumab for that group. At the same time, NICE found this drug to be cost-effective for rapidly evolving severe RRMS patients, with that group defined by having both a higher relapse rate and MRI evidence of disease progression.
Fifth, a 2008 audit process used the 2004 NICE guideline to evaluate the quality of MS services in the U.K. (10) It found that services fell well short of those recommended by NICE. This kind of detailed follow-up has not been conducted for the AAN or EFNS guidelines; doing so would be an important way to assess the impact of those guidelines and enable professional societies and patient groups to focus their efforts on quality improvement.
Sixth, NICE developed a companion document for MS patients and their families; it explains the clinical guideline in lay language and reviews its implications for patients and families (11). The AAN and EFNS guidelines do not provide similar consumer-oriented guidance. Given the high degree of patient and family involvement in MS care, including everything from adherence to pharmaceutical prescriptions, getting diagnostic testing performed in a timely manner, assistance with activities of daily living, transportation for treatments, and emotional and social support, expanding patient and family knowledge about MS is critically important.
These many differences between the methodologies used in the NICE guidelines and the AAN and EFNS guidelines raise interesting questions about the appropriate scope and role of clinical guidelines. Clearly, practicing physicians are unlikely to read and absorb the entire 186 recommendations in the NICE guideline. In addition, a majority of the NICE recommendations are Level D (based on expert committee reports or opinions or extrapolated from controlled or descriptive studies) rather than Level A as NICE acknowledged was necessary given the broad scope of its guideline. However, the NICE approach does provide more comprehensive guidance for public policy, based on the best information available. The NICE approach may thus reflect the fact that the U.K. health care system is more government-driven than U.S. or some other European systems.
- The need to reconcile differences in guideline recommendations. The AAN and EFNS developed guidelines on several of the same topics, and they did not always agree in their recommendations. For example, the EFNS recommended that MS patients stop taking interferon beta if neutralizing antibodies (NABs) develop at high titers. EFNS also recommended specific types of laboratory tests for measuring NABs and how frequently the tests should be done. EFNS indicated that these recommendations are backed by Level A evidence. In contrast, the AAN acknowledged that NABs at high titers are probably associated with a reduction in the therapeutic effects of interferon beta; however, the AAN indicated that evidence is insufficient to make specific recommendations on when patients should stop interferon therapy, what types of laboratory tests to use for measuring NABs, and how often the tests should be done.
In this situation of widely varying recommendations between guidelines, some type of comparative review process should be developed for sorting out the differences. For example, the expert panels that developed each guideline could be asked to provide commentary on the other guideline and its analysis of the evidence. The conclusion from this comparative review might be that differences arise from varying interpretations of the evidence, but the point is that such differences should at least be formally reviewed and discussed.
- The speed with which MS diagnosis and treatment technologies are changing. The 2003 AAN guideline on DMTs needs to be updated to include natalizumab, which is the focus of the 2007 NICE guideline. Treatment recommendations for natalizumab have been widely discussed in other U.S. sources, such as the 2007 edition of a leading MS medical textbook and in the National Multiple Sclerosis Society's Consensus Statement on MS disease-modifying therapy (12, 13). Both those sources recommend natalizumab as a second-line therapy, appropriate for patients who have failed to respond to the first-line therapies reviewed in the AAN guideline. Moreover, several new MS DMTs are in clinical trials and may be approved for treatment soon (6, 7). If this happens, further updates to both the AAN and NICE guidelines will be needed.
Both the AAN and EFNS guidelines on MRI applications for diagnosis of MS highlight enhancements to MRI technology and new imaging techniques being tested, a new focus on brain atrophy measurement in clinical research, and the potential for those new technologies to change their recommendations. Future guideline development efforts are expected to include literature on these new technologies that may provide more sensitive and specific guidance on MS diagnosis and possibly also extend the role of MRI into MS treatment.
The current NGC inclusion criteria require clinical guidelines to be current as of the past 5 years. For MS treatment, this standard may be inadequate given the rapidly changing technologies. A shorter time period for clinical guideline updates, such as every 3 years, may be more appropriate for diseases or topics where technology is known to be changing rapidly, as it clearly is for MS. Guideline sponsors also need to be encouraged to provide more frequent updates in these situations.
Topics for Future Guidelines
The 10 MS guidelines in the NGC provide a detailed set of recommendations on DMTs, treatment of acute relapses, and applications of MRI technology in MS diagnosis and treatment. Additional guidelines are needed on symptomatic treatment, rehabilitation therapies, and other topics that are focused on improving or maintaining QOL and other PROs for people with MS. The 2004 NICE guideline provides one example of what a more comprehensive MS guideline can include, although the AAN, EFNS, and other potential guideline sponsors need to broaden their efforts as well.
For example, NICE included a checklist in its guideline to prompt physicians and other MS clinicians to ask patients periodically about new symptoms that often remain "hidden" in MS. These include fatigue and pain that, surprisingly, were often discounted by physicians as major clinical concerns in MS until just the past decade. These symptoms are now recognized as central issues in clinical management of MS because they cause a great deal of suffering for patients. Several organizations have provided clinical recommendations on these and other QOL-related topics, including the National Multiple Sclerosis Society's expert opinion paper on treatment of fatigue, the German MS Society's guidelines on symptomatic treatment, and the Cochrane Library's recent systematic review of evidence regarding rehabilitation treatment in MS (14, 15, 16). More formal clinical guidelines on these topics would be a useful addition to the NGC.
Another positive development is that clinical trials for new MS drugs are now including PROs in addition to the more traditional outcome measures of EDSS scores, relapses, and lesions documented by MRI. This should provide additional evidence on QOL impacts in coming years and expand attention on PRO-related interventions in future MS guidelines.
Interactions among guideline sponsors need to be expanded. The NGC includes multiple MS guidelines from three different sponsoring organizations: AAN, EFNS, and NICE. These organizations do not often cite or discuss each other's guidelines. The wide range of topics in MS diagnosis and treatment, the heterogeneous impacts of the disease, rapid technological change in some areas of MS treatment, and the need to reconcile differing guidelines are important reasons for expanding interactions and consultations among the guideline sponsors.
Michael G. Trisolini, PhD, MBA
The views and opinions expressed are those of the author and do not necessarily state or reflect those of the National Guideline Clearinghouse™ (NGC), the Agency for Healthcare Research and Quality (AHRQ), or its contractor, ECRI Institute.
Potential Conflicts of Interest
Dr. Trisolini reports that he is the Principal Investigator on a research grant from the National Multiple Sclerosis Society and on a research grant from Novartis Pharmaceuticals Corporation.
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