复旦大学：《循证医学》课程教学资源（参考教材）Unit 08 生命质量的分析评价（主讲教师：姜林娣）.pdf_大学文库

Pharmacoeconomics 2008; 26 (10): 831-846 REVIEW ARTICLE 1170-7690/08/0010-0831/$48.00/0 © 2008 Adis Data Information BV. All rights reserved. Quality-of-Life Assessment in Rheumatoid Arthritis Anthony S. Russell Rheumatic Disease Unit, Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 831 1. Quality of Life (QOL) in Patients with Rheumatoid Arthritis (RA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 832 2. Clinical Assessment of RA Disease Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 833 3. QOL Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 833 3.1 Generic Instruments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 833 3.2 Health Utilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835 3.3 Disease-Specific Instruments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 836 4. Use of Assessment Instruments in Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 836 5. Do Current Treatments Improve QOL in RA? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 837 5.1 Infliximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 837 5.2 Adalimumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 837 5.3 Etanercept . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 838 5.4 Anakinra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 838 5.5 Rituximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839 5.6 Abatacept . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839 5.7 Summary of Health-Related QOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842 6. Economic Implications of QOL in RA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844 Abstract Rheumatoid arthritis (RA) is a chronic and lifelong autoimmune disorder that results in significant pain, disability and excess mortality if untreated or inadequately treated. Quality-of-life (QOL) assessments are particularly important in the absence of a cure for RA. Generic and disease-specific patient-reported QOL instruments, such as the Health Assessment Questionnaire (HAQ) Disability Index and the SF-36, have proven validity and sensitivity for assessment of changes in QOL in clinical trials of disease-modifying anti-rheumatic drugs (DMARDs). However, these instruments are rarely utilized in clinical practice, and patients have reported that the actual clinical assessments alone do not address important parameters, such as fatigue and disturbed sleep, which significantly affect QOL. New biological DMARDs have shown significant efficacy in improving clinical and QOL parameters in randomized controlled trials. However, the high cost of biological DMARDs compared with non-biological DMARDs is a factor in the increasing health costs associated with the treatment of RA. Generic health utility instruments that measure QOL parameters enable calculation of the increased QALYs associated with more costly treatment in patients with RA. The costs per QALY associated with biological DMARDs in RA appear to be

832 Russell comparable to those of other accepted medical interventions. Interest in incorporating QOL parameters in formulary and public health decision making concerning the use of new agents for RA is increasing. 1. Quality of Life (QOL) in Patients with is decreasing because of rising healthcare costs.[4] Rheumatoid Arthritis (RA) For example, the cost for the new biological diseasemodifying anti-rheumatic drugs (DMARDs), such Rheumatoid arthritis (RA) is a common chronic as those that target tumour necrosis factor (TNF)-α, autoimmune disorder characterized by inflammation approaches $US16 000–20 000 (year 2007 pricing) annually per patient.[6] and damage of the articular cartilage, tendons and joints. The progressive nature of RA, especially if Use of DMARDs has transformed therapy of RA untreated or poorly treated, results in deformity of and is recommended early in the disease process the small joints of the hands and feet, the joints of (within 3 months of onset) to reduce disease activity wrists and shoulders, as well as rupture of damaged and achieve remission if possible.[7] A wide range of tendons in affected joints. In addition to causing biological and non-biological DMARDs are availdebilitating pain, swelling and stiffness of the affect- able, with the introduction of several new biological ed joints, RA may also cause extra-articular mani- agents in the last 5 years.[8] However, DMARDs festations (such as anaemia, interstitial inflamma- control rather than cure RA, and although complete tion of the lungs and glands, and nodules in the remission has been an infrequent occurrence with lungs, skin and eyes) that reduce survival. The pres- traditional DMARDs, a greater remission frequency ence of severe extra-articular manifestations, such may be possible with biological DMARDs.[8] as vasculitis, pericarditis, pleuritis or Felty’s syn- The chronic and lifelong nature of RA has shifted drome, has been associated with a particularly poor interest from purely symptomatic treatment to imprognosis that may result in premature mortality.[1] proving or restoring quality of life (QOL) as an RA is associated with significant morbidity and important therapeutic goal. The WHO defines QOL functional impairment. Study results have shown as “individuals’ perception of their position in life in that, within the first 18 months of RA onset, patients the context of their culture and value system in experience a substantial burden on physical func- which they live and in relation with their goals, tioning and emotional well-being that is comparable expectations, standards, and concerns.”[9] Healthto diabetes or heart failure.[2] In addition, RA results related QOL (HR-QOL) relates to the functional in a substantial economic burden to patients, their effects of an illness and of its therapy upon a patient, families, the healthcare system and society at large. and is often assessed using patient-completed quesFautrel and Guillemin[3] reported that the costs asso- tionnaires. In RA, HR-QOL includes several dimenciated with rheumatic diseases were even greater sions of health consequences, including pain, physithan those for either cancer or cardiovascular dis- cal functioning, stiffness, mental health, social funcease. tioning, fatigue and sleep disturbances.[10] The The economic burden of RA is only partially profound impact of RA on day-to-day life is reattributable to direct medical costs, which include flected in these HR-QOL dimensions. office visits, medications, surgeries and hospitaliza- Consequently, patient-reported outcomes, such tions. Indirect costs, which also contribute to the as HR-QOL, may be considered an important comeconomic burden, have been considered to be sub- ponent of therapeutic efficacy evaluations.[11] The stantially higher than direct costs.[4] These indirect increasing role of patient-reported outcomes is emcosts include lost productivity associated with work phasized by the recent US FDA draft guidance for disability and lost earnings.[4] It has been estimated industry on construction and use of appropriate inthat 50% of patients with RA are unable to function struments for measurement of these outcomes in at work within 10 years of disease onset.[5] How- clinical trials.[11] Additionally, HR-QOL may be ever, the difference between direct and indirect costs used in clinical practice to evaluate the overall im- © 2008 Adis Data Information BV. All rights reserved. Pharmacoeconomics 2008; 26 (10)

QOL Assessment in Rheumatoid Arthritis 833 pact of ther y and to aid in treatment decisions for lobal health The several advantages of the DAS28 include its ability to evaluate disease ac. practice,physicians primarily evaluate the succe tivity and response to treatment independent of pre treatment status:its ability to discriminate betweer high and low disease activity:its sensitivity to treat Several validated instruments are available for clinical trials and clinical practice. statu fic dim en 3.QOL Assessment tings for aid in healthcare policy decisions.This article re. 3.1 Generic Instruments views several instruments that measure health status and HR-QOL in RA and provides examples of their There is no universal fo RA G of approac 2.Clinical Assessment of RA and table While ideally adi。 specific Disease Activity instrument should be used for many dise such instruments have not yet been developed for all There is no'gold standard'for measuring disease activity and remission in RA:however,physical, Although generic HR-QOL radiographic and laboratory measurements have tra ments are usually designed for the broadest possible se across a var ety or diseases,dilferent J01 an sme dcdneandd pain and icular appro Clinicians often rely on the American Colleg of population.These HR-QOL in Rheumatology (ACR)20.ACR50 or ACR70 res- struments are not only important in providing a ponse criteria to monitor a patient's response to means of comparison of effectiveness,but are also treatment.The ACR20 criteria have been validated key parameters that are incorporated into economic for use in clinical trials to define clinically signif analyses by capturing both benefi cial and detrimen provement(i.e tal effects tment on the individual.They are so use on across disease ve to the nu nd" An ted out the following nt as s is that of the mi an sessment,physician assessm difference (MCID).Clinical trial endpoints are gen of disability,and the value for one acute r erally evaluated for statistically significant differ. reactant (i.e.erythrocyte sedimentation rate [ESR] ences between treatment groups.However.what is or C-reactive protein [CRPD). statistically significant may not necessarily reflect a Another measurement of disease clinic Disease Activity S albenefit to the patient fa large enouh core (DAS)v is the which has d,even sm ences b er goticacaichtwiCe4gnicatwiho dinde that is based on of the MCID vid that dis n statistical and and tender joints (of 28 joints).the ESR,and a visual clinical relevance The MCI refers to the small- analogue scale score (0-100)of patients'general or est difference in an outcome that is perceived by the 2008 Adis Data Information BV.All rights reservod. Pha conomics2008:26(10)

QOL Assessment in Rheumatoid Arthritis 833 pact of therapy and to aid in treatment decisions for global health.[14] The several advantages of the the individual patient. However, in current clinical DAS28 include its ability to evaluate disease acpractice, physicians primarily evaluate the success tivity and response to treatment independent of preof therapy from a clinical perspective and rarely treatment status; its ability to discriminate between assess HR-QOL.[10,11] high and low disease activity; its sensitivity to treatSeveral validated instruments are available for ment effects; as well as its validation for use both in clinical trials and clinical practice.[13] evaluation of HR-QOL, and while some of these instruments characterize the health status of an individual or population with regard to specific dimen- 3. QOL Assessment sions or domains, others can be used to derive utility weightings for use in economic evaluations, and to 3.1 Generic Instruments aid in healthcare policy decisions. This article reviews several instruments that measure health status There is no universally accepted definition of, or and HR-QOL in RA and provides examples of their method for measuring, disease-specific HR-QOL in use in clinical trials of the newest biological RA. General features of approaches utilized to mea- DMARDs for the treatment of RA. sure HR-QOL in RA are represented in figure 1[15,16] and table I.[15,17-20] While ideally a disease-specific 2. Clinical Assessment of RA instrument should be used for many diseases, such Disease Activity instruments have not yet been developed for all There is no ‘gold standard’ for measuring disease disease states, and generic instruments are often utilized.[15,20] activity and remission in RA; however, physical, Although generic HR-QOL instruradiographic and laboratory measurements have tra- ments are usually designed for the broadest possible ditionally been used, often in combination. use across a variety of diseases, different medical [8] These interventions and a wide range of populations, measures include counting of inflamed joints, as- [21] sessment of degree and duration of pain and stiff- specific or targeted instruments may be more approness, and clinician and patient global assessments. priate than generic measures for a particular setting, [8] or in a defined population.[21] Clinicians often rely on the American College of These HR-QOL inRheumatology (ACR) 20, ACR50 or ACR70 res- struments are not only important in providing a ponse criteria to monitor a patient’s response to means of comparison of effectiveness, but are also treatment. The ACR20 criteria have been validated key parameters that are incorporated into economic for use in clinical trials to define clinically signif- analyses by capturing both beneficial and detrimenicant levels of improvement. tal effects of treatment on the individual. They are [12] Patients are required to have a minimum level of improvement (i.e. 20%, also useful for outcomes comparison across disease 50% or 70%) relative to baseline in the number of states and can aid in policy decisions. swollen joints and tender joints, and in any three of An important concept in patient-reported outthe following disease-activity measures: patient as- comes is that of the minimal clinically important sessment, physician assessment, pain scale, degree difference (MCID). Clinical trial endpoints are genof disability, and the value for one acute phase erally evaluated for statistically significant differreactant (i.e. erythrocyte sedimentation rate [ESR] ences between treatment groups. However, what is or C-reactive protein [CRP]).[8] statistically significant may not necessarily reflect a Another measurement of disease activity is the clinical benefit to the patient (i.e. if a large enough Disease Activity Score 28 (DAS28), population is used, even small differences between [13] which has been more frequently used in Europe, but is gaining treatments may be statistically significant without being of actual clinical value).[25] wider acceptance in the US in clinical trials as well as in clinical practice. This scoring system is a The concept of the MCID was initiated to provide combined index that is based on a count of swollen a measure that distinguishes between statistical and and tender joints (of 28 joints), the ESR, and a visual clinical relevance.[26] The MCID refers to the smallanalogue scale score (0–100) of patients’ general or est difference in an outcome that is perceived by the © 2008 Adis Data Information BV. All rights reserved. Pharmacoeconomics 2008; 26 (10)

834 Russell Indirect Health-related quality of life: Taxonomy Health status Value or preference Describes health states and impact on function and disability Global value assigned to the health state Health state classification system Direct Rating scale Time trade-off Standard gamble Objective • joint count • exercise tests • visual acuity Subjective • reports, ratings • functional capacity • symptoms • feelings • behaviour Generic SF-36 Disease-specific HAQ-DI Fig. 1. Taxonomy of instruments to measure health-related quality of life.[15,16] Reproduced from Khanna et al.[15] with permission from Scleroderma Care and Research. HAQ-DI = Health Assessment Disability Index. patient to be of clinical benefit; the MCID is unrela- Correlation of HAQ-DI scores with improveted to statistical significance. Although MCID is ments in various physical parameters in RA has often applied to QOL measures, it may also be allowed determination of the MCID in HAQ-DI derived for other clinically relevant or patient-re- scores, defined as the smallest difference that paported outcomes.[27] MCID is currently considered tients perceive as beneficial. In the RA setting, an improvement of at least 0.22 is considered indica- as an efficacy outcome for trials in a variety of tive of improved functional status, while smaller disease states, and its derivation, usefulness and improvements are considered unimportant.[30,31] The limitations have been discussed.[25,27] Personal-Impact HAQ (PI-HAQ), developed in the The Health Assessment Questionnaire (HAQ)[28] UK, adapts the HAQ for assessing the personal was among the first instruments created that focused impact of disability. This instrument accounts for on patient self-reported measures of functional sta- the value placed by the patient on specific disabilitus and disability. Although the HAQ is not disease ties by using an individualized impact scale.[32] specific, it was developed for use in patients with While this scale may enhance the contextual interRA and was validated in this population.[29] The pretation of the HAQ, it has yet to be accepted as a HAQ has subsequently become the most widely standard measurement instrument. Although the used measure of functional disability in RA.[18] The HAQ does not directly measure psychological doversion most often used in RA assessment is the mains, responses on the HAQ appear to reflect patient psychological status.[33] HAQ Disability Index (HAQ-DI), which consists of 20 questions that assess eight domains of disability: The SF-36 is a well validated generic instrument dressing, arising, eating, reaching, gripping, walk- for evaluating health status, and is frequently used in ing, activities and hygiene. The total score of the the assessment of HR-QOL in RA. This instrument HAQ-DI ranges from 0 to 3, with scores of 0–1 includes eight scales, each of which evaluates a indicating mild/moderate disability, 1–2 moderate/ particular domain (physical functioning, role limitasevere disability and 2–3 severe/very severe disabil- tions due to physical health, bodily pain, general ity.[29] health perceptions, vitality, social functioning, role © 2008 Adis Data Information BV. All rights reserved. Pharmacoeconomics 2008; 26 (10)

QOL Assessment in Rheumatoid Arthritis 835 limitations due to emotional health, and mental (utility score) that describes a particular health health), as well as two summary scores, one each for state.[37] Utilities are derived from health status by the physical and mental components.[34,35] An im- assigning population-based weights based on preferprovement in any of the domains of three points is ences for health states, and are usually expressed on considered to be a change that represents the MCID. a continuum from perfect health (1) to death (0), The SF-36 is one of the most commonly used HR- although health states worse than death can also be QOL instruments and has been translated into over valued.[37] 50 different languages.[36] Two common health utilities are the standard gamble and the time trade-off, which assess what 3.2 Health Utilities trade-offs (such as increased risk of death or how In contrast with the above generic instruments, many months of life) the patient would make for a better health state.[37] which describe an individual’s health status by eval- Scores on these tests may uating different domains, generic health utilities are range from 0.0 to 1.0. Another type of approach is measures that summarize HR-QOL as a single value the rating scale and as described above, patients rate Table I. Characteristics of commonly used health-related quality-of-life (HR-QOL) instruments in rheumatoid arthritis (RA)[15,17-20,22-24] Measure Items (n) Aspects assessed Minutes to Advantages Disadvantages complete Generic measures HAQ-DI 20 Activities of daily living: dressing, 5 Can be used across diseases and May not be as sensitive to arising, eating, walking, hygiene, populations; allows comparison change as disease-specific reach, grip, activities across diseases, levels of health and measures; may not age ranges; self-administered provide a single summary score SF-36 36 Physical function, role limitations 5 Can be used across diseases and May not be as sensitive to due to physical problems, health populations; allows comparison change as disease-specific perception, vitality, pain, social across diseases, levels of health, and measures; may not function, mental health role age ranges; self-administered provide a single summary limitations due to emotional score problems RA-specific measures AIMS 67 Physical activity, activities of daily 15 Self-administered; high reliability, Only applicable to certain living, dexterity, mobility, social validity, and sensitivity; more sensitive diseases or conditions role and activity, pain, depression, to change than generic measures; anxiety validity for specific population RAQoL 30 Mood/emotion, social life, hobbies, 6 Self-administered; high reliability, Only applicable to certain everyday tasks, personal/social validity, and sensitivity; more sensitive diseases or conditions relationships, physical contact to change than generic measures; validity for specific population Health utility measures HUI2 15 or Sensation (vision, hearing, Provides a single HR-QOL number May not be as sensitive to 40 speech), mobility, emotion, change as health status cognition, self-care, pain measures HUI3 15 or Vision, hearing, speech, As above As above 40 ambulation, dexterity, emotion, cognition, pain SF-6D 11 Physical function, role limitation, As above As above social function, pain, mental health, vitality EQ-5D 6a Mobility, usual activities, self-care, As above As above pain, anxiety a Five items plus a visual analogue scale. AIMS = Arthritis Impact Measurement Scales; HAQ-DI = Health Assessment Questionnaire Disability Index; HUI = Health Utilities Index; RAQoL = Rheumatoid Arthritis Quality of Life. © 2008 Adis Data Information BV. All rights reserved. Pharmacoeconomics 2008; 26 (10)

836 Russell their health on a continuum from perfect health (1) quantity and quality of life into a single measure to death(0).although health states worse than death For economic analyses,the cost per QALY can be can also be valued and aregenerally represented by negative Index (HUI and sused to calculate OALYs should be n he fully correlated with patient behaviour before these instruments are not interehane eable.caution must be values are used in healthcare decision making.44 3.3 Disease-Specific Instruments The EO-5D.a generic health index developed in the 1990s,derives and evaluates utilities associated Among the most widely used disease-specific with HR-QOL.Although the original form included instruments in RA are the Arthritis Impact Measure. six attributes,the current version is composed of two e e m R and the Rheumatoid Arthritis Quality of nd co e do usual activities.pain/discomfort and anxiety/dep ial inte and affect).A sion.Scores on the EQ-5D range from 1 (perfect ture of the AIMS2 is a section on prior which patients can select three of 12 areas in which health)to-o 59 (worse than dead).A short adminis- tration time and the availability of pre-scored nor- they would like to see improvements during treat- mative values in several populations make the ment (e.g.pain,mobility,work).RAQoL,a 30-item EQ-5D easy to h a yes/no response format,assesse RA.Homajor mood.so ial life,hobbi veryday tasks.person d ha RAOo d the Neth other me ed fo validated in RA.4 Two HUI question cluding sweden ia.Turkey Australia.Its advantages include a direct rele speech ambulation.dexterity vance to items and issues of importance to patients. emotion.cognition and pain)that are scaled on as well as ease of use and short administration time. making it accessible for use in clinical practice. several levels from normal to highly impaired,4 and the HUI2,while similar to the HUI3,is also &eoaeeeatnnmentn ng sens In general,heumatologists have not yet incorpo rated rout of pat health)to (dead) s HR-QOL The SE-6D.another health utility instrum ent.is such 、E based on the SE-36 and SE-12 22 Six domains from rheumatologists who do utilize these instruments in the SF-36 (physical functioning,role limitations everyday practice,the effect on decision making is social functioning.pain.mental health and vitality) not clear are used to calculate a utility score based on weight To address this issue in part,the sixth biannual conference of the Outcome Measures in Rheuma toid Arthritis Clinical Trials group(OMERACT) lues are use developed to combine h

836 Russell their health on a continuum from perfect health (1) quantity and quality of life into a single measure.[43] to death (0), although health states worse than death For economic analyses, the cost per QALY can be can also be valued and are generally represented by estimated and compared among the evaluated theranegative values (i.e. <0).[37] pies. However, it has been suggested that the underThe EQ-5D, Health Utilities Index (HUI) and lying assumptions associated with health utility SF-6D are multi-attribute generic instruments that measures used to calculate QALYs should be carecan be used to calculate utility values. fully correlated with patient behaviour before these [37] Since these values are used in healthcare decision making.[44] instruments are not interchangeable, caution must be taken when comparing studies that have used these different instruments. 3.3 Disease-Specific Instruments [37] The EQ-5D, a generic health index developed in Among the most widely used disease-specific the 1990s, derives and evaluates utilities associated instruments in RA are the Arthritis Impact Measure- with HR-QOL. Although the original form included ment Scales (AIMS)-2, a revised version of the six attributes, the current version is composed of two AIMS,[45] and the Rheumatoid Arthritis Quality of parts, a questionnaire and visual analogue self-rating Life (RAQoL) questionnaire.[23] The multi-dimen- scale.[38,39] The questionnaire includes components sional AIMS2 contains items in 12 areas of health of functionality, pain and psychiatric well-being, that can be grouped in five major domains (physical, and focuses on the five domains: mobility, self-care, social interaction, pain, work and affect). A unique usual activities, pain/discomfort and anxiety/depres- feature of the AIMS2 is a section on priorities, in sion. Scores on the EQ-5D range from 1 (perfect which patients can select three of 12 areas in which health) to –0.59 (worse than dead). A short adminis- they would like to see improvements during treat- tration time and the availability of pre-scored nor- ment (e.g. pain, mobility, work). RAQoL, a 30-item mative values in several populations make the instrument with a yes/no response format, assesses EQ-5D easy to use. The EQ-5D is now widely used mood, social life, hobbies, everyday tasks, personal/ internationally, has been translated into most major social relationships and physical contact.[23] The languages[38] and has been validated in RA.[40] RAQoL was developed in the UK and the Nether- Another health utility measure, the HUI, is a lands,[23] and has been adapted for use in several multi-attribute classification system that has been countries, including Sweden, Estonia, Turkey and validated in RA.[40] Two HUI questionnaires are Australia.[46-48] Its advantages include a direct rele- currently used: the HUI3 consists of eight attributes vance to items and issues of importance to patients, (vision, hearing, speech, ambulation, dexterity, as well as ease of use and short administration time, emotion, cognition and pain) that are scaled on making it accessible for use in clinical practice. several levels from normal to highly impaired,[41] and the HUI2, while similar to the HUI3, is also 4. Use of Assessment Instruments in complementary by providing assessment of inde- Clinical Practice pendent attributes, including sensation, mobility, emotion, cognition, pain, fertility and self-care.[42] In general, rheumatologists have not yet incorpoUtility scores on the HUI range from 1 (perfect rated routine assessment of patient-reported outhealth) to 0 (dead). comes such as HR-QOL into everyday clinical pracThe SF-6D, another health utility instrument, is tice, mainly because of time considerations.[49] For based on the SF-36 and SF-12.[22] Six domains from rheumatologists who do utilize these instruments in the SF-36 (physical functioning, role limitations, everyday practice, the effect on decision making is social functioning, pain, mental health and vitality) not clear. are used to calculate a utility score based on weight- To address this issue in part, the sixth biannual ed preferences for health states derived from exten- conference of the Outcome Measures in Rheumasive interviews in the general population.[22] toid Arthritis Clinical Trials group (OMERACT)[50] Instruments that determine utility values are use- has encouraged novel ways to incorporate patient ful for calculating QALYs, developed to combine perceptions into outcomes research. Patients partici- © 2008 Adis Data Information BV. All rights reserved. Pharmacoeconomics 2008; 26 (10)

QOL Assessment in Rheumatoid Arthritis 837 ating in this confer the HAQ that were clinically relevant and statistical- ly significant compared with patients who received mspacR methotrexate monotherapy.QOL benefits were also uggested by significant improvements from base. well-being.Is Instruments with on-the-spot scoring line in the physical component summary score and te)shoul a broaden the applicability of pa puter sys outcomes in clinical practice indivdWhile general health.vitality and social unction s were also significantly 5.Do Current Treatments Improve QOL in RA? ent summary score.In contrast.when Han et eutic a nts such as the biolo cal DMARDs.sev studies were in RA)given infliximab at similar eral of which are available for use in the yreatment doses plus methotrexate at various time points for up were found. of RA.Biological DMARDs currently approved to 1 year,different rsu At the firs we in on for the treatment of RA include infliximab time point of e adalimumab.etanercept,anakinra,rituximab and or ents in the aysical com ase progres re.in addition to small though statistically signif onent sum add ntial to in rove HR-QOL has results in Maini et al,paralleled improvements in clinical outcomes with significantly less radiograph- 5.1 Infliximab ic progression and a significantly than ong patien Infliximab is a chimeric(murine/human)mono erapy clonal antibody against TNFo,a cytokine secreted as a reaction to injury during the inflammatory res- 5.2 Adalimumab inflammation and incr ses Adalimumab,like infliximab,is an anti-TNFo ing immune cells to g the TNFo of infl ons of ce ab is cells t57 Adalim ated ing signs and symptoms.inhibiting the for reducing signs and symptoms.inducing major clinical response,inhibiting the progression of struc. tural damage and improving physical function in dult patients with moderately to severely active Functional and QOL outcomes associated with use of infliximab (3 mg/kg or 10 mg/kg every 4 or me mbinatio hile a in a 2 otherapy.as -ye with tha ed th ks of the dalimumab ther apy alone.more Using data from two trials of adalimumab plus from baseline in physical function as measured by methotrexate versus methotrexate alone in patients conomics2008:26(100

QOL Assessment in Rheumatoid Arthritis 837 pating in this conference agreed that standard core the HAQ that were clinically relevant and statisticalRA criteria do not adequately capture some conse- ly significant compared with patients who received quences of the disease that are of importance to methotrexate monotherapy. QOL benefits were also them, including fatigue, disturbed sleep and sense of suggested by significant improvements from basewell-being.[51] Instruments with on-the-spot scoring line in the physical component summary score and and technology (such as touch-screen computer sys- individual physical domain components of the tems) should also broaden the applicability of pa- SF-36.[59] While general health, vitality and social tient-reported outcomes in clinical practice.[52] functioning subscale scores were also significantly improved compared with baseline and methotrexate, 5. Do Current Treatments Improve QOL no significant changes were noted on the mental in RA? component summary score. In contrast, when Han et al.[60] analysed results from four studies in patients A better understanding of the pathophysiology of with inflammatory rheumatic disease (of which two RA has resulted in the development of new thera- studies were in RA) given infliximab at similar peutic agents such as the biological DMARDs, sev- doses plus methotrexate at various time points for up eral of which are available for use in the treatment to 1 year, different results were found. At the first of RA. Biological DMARDs currently approved assessment time point of either 6 weeks in one study for the treatment of RA include infliximab, or 10 weeks in the second study, data from these adalimumab, etanercept, anakinra, rituximab and studies showed patients with RA had significant abatacept.[53-58] These agents not only control symp- improvements in the physical component summary toms and slow radiographic disease progression, but score, in addition to small though statistically signif- hold forth the possibility of achieving disease remis- icant improvements in the mental component sum- sion. In addition to their established clinical effi- mary score compared with baseline.[60] The QOL cacy, their potential to improve HR-QOL has been results in Maini et al.[59] paralleled improvements in evaluated in several studies. clinical outcomes with significantly less radiographic progression and a significantly better ACR res- 5.1 Infliximab ponse rate among patients in the infliximab groups than with methotrexate monotherapy. Infliximab is a chimeric (murine/human) monoclonal antibody against TNFα, a cytokine secreted 5.2 Adalimumab as a reaction to injury during the inflammatory response. TNFα promotes inflammation and increases Adalimumab, like infliximab, is an anti-TNFα blood vessel permeability, enabling immune cells to agent. Although adalimumab is a fully human antiinfiltrate the joints.[58] By blocking the actions of body, in contrast to the chimeric properties of inflixTNFα, infliximab reduces the number of inflamma- imab, the mechanism of action is the same: binding tory cells migrating into the joints. When combined of TNFα, whether soluble or on the surface of with methotrexate, infliximab is indicated for reduc- TNFα-expressing cells.[57] Adalimumab is indicated ing signs and symptoms, inhibiting the progression for reducing signs and symptoms, inducing major of structural damage, and improving physical func- clinical response, inhibiting the progression of struction in patients with moderately to severely active tural damage and improving physical function in RA.[58] adult patients with moderately to severely active Functional and QOL outcomes associated with RA, and may be used as monotherapy or in combination with methotrexate or other DMARDs.[57] use of infliximab (3 mg/kg or 10 mg/kg every 4 or 8 weeks) in combination with methotrexate were While adalimumab is approved for monotherapy, as evaluated in a 2-year study (placebo controlled for observed with other anti-TNFα therapies, combina- 1 year then open label) by Maini et al. tion with methotrexate is more effective than [59] They adalimumab therapy alone.[57] reported that, after 102 weeks of therapy, patients who received infliximab showed improvements Using data from two trials of adalimumab plus from baseline in physical function as measured by methotrexate versus methotrexate alone in patients © 2008 Adis Data Information BV. All rights reserved. Pharmacoeconomics 2008; 26 (10)

838 Russell with RA.Torrance et al.reported changes in activity (numeric rating scale).patient general o e orms.as a meas treatmen ecei ed Hr-OOl n therapy hac QOL POP ciated with significantly s with lower scores in those HUI attributes that may be ed the HA-DI.com ared with those expected to be reduced as a result of RA:pain, who received either monotherapy.Improvements in dexterity and ambulation.However,other attributes HR-QOL were more rapid and were sustained long er in the combination therapy group than in eithe lation norms monotherapy group (combination vs methotrexate in total HUI3 Crreres.ved with adalimum p=0.005:combi 30.00 exter the duration of the trials.which ained ma e,p as lon nd than with 1 vear.These im ments wer significantly - thotrexate perior to those observed with methotrexate mono In contrast,Farahani et al.conducted a 1-year therapy.While improvements in ambulation were community-based study that compared patients with also noted,this only reachec statistical significance RA who were able to obtain etanercept after its relative to methotrexate in the 1-year study.Higher on into the Canadian market (active treat ment,n=223)with those unable to obtain this agen pumher of OALYs lone.Th ined tients a other the 12-m ate was 0.145 and 0.104 in the two studies.and was cause of improved physical (rather than emotional statistically significant (p<0.001). or mental)parameters,improvements in QOL were documented within the first 6 months in patients who received etanercept compared with those who While is als nti-TN did not.However,this difference between groups ne onsignificant r some QOL e of .es tigue inten y,dur y he and adalimumab.Etanercept is a recombinant obtained in the TEMPO(Trial of Etane cept and Methotrexate with radioo nhic patient outeomes trial of etanercept and methotrexate2 highlight the for red inducing major clinic differences that may often be observed betweer 10 also carry over into economic analyses. Patient-reported outcome 5.4 Anakinro were evaluated in a I-vear randomized double-blind clinical trial of Anakinra is a recombinant interleukin(IL)-1 re- etanercept in combination with methotrexate com- eptor antagonist that is similar to the endogenous pared with either DMARD as monotherapy.Out- IL-1 receptor antagonist (IL-Ira).Like TNFo,IL- s a pro-infla heDe truments such as and th Q-5D visual ana receptor,anaki mmatory response Ahodowaegu ough anakinra h

838 Russell with RA, Torrance et al.[61] reported changes in activity (numeric rating scale), patient general health utility using the HUI3, compared with popu- health assessment (visual analogue scale) and palation norms, as a measure of HR-QOL.[61] Baseline tient satisfaction with treatment.[62] Patients who HUI3 scores were significantly lower (p < 0.001) received combination therapy had significantly imthan population norms,[61] and this reduction in HR- proved HR-QOL and were more likely to achieve QOL was primarily associated with significantly population norms with regard to function, as indicatlower scores in those HUI attributes that may be ed by scores on the HAQ-DI, compared with those expected to be reduced as a result of RA: pain, who received either monotherapy. Improvements in dexterity and ambulation. However, other attributes HR-QOL were more rapid and were sustained longalso showed significant reductions relative to popu- er in the combination therapy group than in either lation norms.[61] Rapid improvements from baseline monotherapy group (combination vs methotrexate, in total HUI3 scores, as well as in the attributes of p = 0.005; combination vs etanercept, p = 0.002; pain and dexterity, were observed with adalimumab etanercept vs methotrexate, p = 0.780).[62] Patients plus methotrexate treatment and were sustained over also reported significantly greater satisfaction with the duration of the trials, which was as long as combination and etanercept monotherapy than with 1 year. These improvements were significantly su- methotrexate monotherapy.[62] perior to those observed with methotrexate mono- In contrast, Farahani et al.[63] conducted a 1-year therapy.[61] While improvements in ambulation were community-based study that compared patients with also noted, this only reached statistical significance RA who were able to obtain etanercept after its relative to methotrexate in the 1-year study. Higher introduction into the Canadian market (active treatproportions of adalimumab-treated patients ment, n = 223) with those unable to obtain this agent achieved or exceeded HUI3 population norms than (control, n = 208). As a reflection of actual clinical patients treated with methotrexate alone.[61] The practice, these patients had no previous treatment number of QALYs gained per year among with etanercept, and no restrictions were placed on adalimumab-treated patients relative to methotrex- other therapies during the 12-month study.[63] Beate was 0.145 and 0.104 in the two studies, and was cause of improved physical (rather than emotional statistically significant (p < 0.001). or mental) parameters, improvements in QOL were documented within the first 6 months in patients 5.3 Etanercept who received etanercept compared with those who While etanercept is also an anti-TNF did not. However, this difference between groups α agent that decreased or became nonsignificant for some QOL binds to TNF and blocks its interaction with cell variables, especially pain severity and fatigue inten- receptors on the cell surface, it is a different type of sity, during the second 6 months.[63] The apparent entity from the monoclonal antibodies infliximab inconsistency between these QOL results and those and adalimumab. Etanercept is a recombinant obtained in the TEMPO (Trial of Etanercept and human fusion protein for the soluble TNFα recep- Methotrexate with radiographic Patient Outcomes) tor.[56] It may be used as monotherapy or in combi- trial of etanercept and methotrexate[62] highlight the nation with methotrexate, and is indicated for reduc- differences that may often be observed between ing signs and symptoms, inducing major clinical clinical trials and clinical practice, and which may response, inhibiting the progression of structural also carry over into economic analyses.[63] damage and improving physical function in patients with moderately to severely active RA.[56] 5.4 Anakinra Patient-reported outcomes were evaluated in a 1-year randomized double-blind clinical trial of Anakinra is a recombinant interleukin (IL)-1 reetanercept in combination with methotrexate com- ceptor antagonist that is similar to the endogenous pared with either DMARD as monotherapy. Out- IL-1 receptor antagonist (IL-1ra). Like TNFα, IL-1 comes included standard QOL instruments such as is a pro-inflammatory cytokine, and by blocking its the HAQ-DI and the EQ-5D visual analogue scale, access to the IL-1 receptor, anakinra may downreguas well as patient global assessment of RA disease late the inflammatory response. Although anakinra © 2008 Adis Data Information BV. All rights reserved. Pharmacoeconomics 2008; 26 (10)