Assessment of Patients With Psoriatic Arthritis

Transcription

1 ARTHRITIS & RHEUMATISM Vol. 50, No. 1, January 2004, pp DOI /art , American College of Rheumatology REVIEW Assessment of Patients With Psoriatic Arthritis A Review of Currently Available Measures Dafna D. Gladman, 1 Philip Helliwell, 2 Philip J. Mease, 3 Peter Nash, 4 Christopher Ritchlin, 5 and William Taylor 6 Introduction Psoriatic arthritis (PsA) is an inflammatory arthritis that is associated with psoriasis. Although there are no widely accepted classification or diagnostic criteria for the disease, several clinical features, identified by Moll and Wright (1), facilitate the diagnosis in these patients. An international effort is currently under way to develop valid and widely acceptable criteria. Although PsA has some of the features of ankylosing spondylitis (AS) and rheumatoid arthritis (RA), there are particular differences between the disorders. For example, at least 50% of patients with PsA have involvement of the distal interphalangeal (DIP) joints, an uncommon finding in RA. Dactylitis, or sausage digit, a hallmark physical manifestation in PsA, is unusual in RA. Furthermore, it has been demonstrated that the joints of patients with PsA are less tender and swollen than are similar joints of patients with RA (2). Flail and ankylosed joints are also typical changes observed in patients with PsA. Perhaps the most important feature distinguishing these 2 diseases is back involvement, observed in at least 40% of the patients with PsA (3). Some patients with PsA have a spondylitis that is indistinguishable from AS, whereas other patients may 1 Dafna D. Gladman, MD, FRCPC: University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada; 2 Philip Helliwell, MD: University of Leeds, Leeds, UK; 3 Philip J. Mease, MD: Seattle Rheumatology Associates, Swedish Hospital Medical Center, and University of Washington School of Medicine, Seattle; 4 Peter Nash, MD: University of Queensland, and Nambour General Hospital, Sunshine Coast, Australia; 5 Christopher Ritchlin, MD: University of Rochester Medical School, Rochester, New York; 6 William Taylor, MB, ChB, FRACP, FAFRM: Wellington School of Medicine & Health Sciences, Wellington, New Zealand. Address correspondence and reprint requests to Dafna D. Gladman, MD, FRCPC, University of Toronto, Toronto Western Hospital, 5-034B Edith Cavell Wing, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada. dafna.gladman@utoronto.ca. Submitted for publication March 9, 2003; accepted in revised form September 4, be totally asymptomatic. Isolated spondylitis is unusual in PsA; only 2 4% of PsA patients have inflammatory back disease without evidence of a peripheral arthritis. Several clinical patterns of peripheral arthritis have been recognized in patients with PsA, including predominant involvement of the DIP joints, oligoarticular disease, and polyarticular disease that may be symmetric or asymmetric. The purpose of this review was to evaluate the measures currently used for the assessment of patients with PsA, and to consider measures that should be further developed for this condition. Although an international working group is currently focused on the development of criteria for the diagnosis and classification of PsA, we hope that this review will set the research agenda for the development of a core set of outcome measures and instruments for the assessment of PsA. Measures of disease activity in PsA The assessment of disease activity in PsA must include the evaluation of disease activity in the joints as well as in the skin. Peripheral joint disease activity. Assessments of PsA disease activity in the joints include the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) joint count, the Ritchie Articular Index, and the modified Ritchie Index (4 6). The ACR joint count. The ACR joint count was initially developed in 1949 for the assessment of patients with RA (7). The ACR joint count documents the number of joints with joint-line tenderness, stress pain, and/or swelling. Included in the joint count are the temporomandibular, sternoclavicular, acromioclavicular, shoulder, elbow, wrist (including the carpometacarpal [CMC] and intercarpal joints as one unit), metacarpophalangeal (MCP), proximal interphalangeal (PIP), DIP, hip, knee, talo-tibial, mid-tarsal (including 24

2 ASSESSMENT OF PsA 25 subtalar), metatarsophalangeal (MTP), and interphalangeal (IP) joints of the toes (proximal and distal joints of each toe counted as one unit). The total joint count, which comprises the number of tender joints and/or swollen joints, may be calculated, or the sum of the number of tender joints and the sum of the number of swollen joints may each be calculated separately. This joint count was found to be valid in RA in its initial description, both in terms of its reproducibility and in terms of its sensitivity to change with time (7). Gladman et al (8) demonstrated that the actively inflamed joint count (i.e., joints with stress pain, jointline tenderness, and/or swelling) is a reliable measure of disease activity in PsA. They used a Youden square design, which, similar to the Latin square design (9), facilitates an analysis of components of variation that may be due to patient or observer differences or due to the order of assessment, but this was modified to account for an unequal number of patients and observers. Five observers evaluated 10 patients with PsA for evidence of joint disease activity. Disease activity was measured by the ACR joint count, based on assessment of 68 joints for tenderness and 66 joints for swelling. Gladman et al found that despite a marked variation among the patients (confirming that the patients were properly selected to identify a spectrum of disease activity), minimal interobserver variation was identified. It should be noted that the same physician trained all of the observers. Further support for the reproducibility of the ACR joint count in PsA comes from a recent study by the SPondyloArthritis Research Consortium of Canada (SPARCC), comprising a group of Canadian investigators who convened to validate clinical measures in spondylarthritis. Using a Latin square design (9), 10 observers evaluated 10 patients, using the ACR joint count (10). The SPARCC also demonstrated that the major source of variation was the patients. Although there was excellent agreement among the observers (intraclass correlation coefficient [ICC] 0.77), there was an observer effect, suggesting that individuals need to receive standardized training to reduce observer variability. Although the ACR joint count has not been tested specifically for sensitivity to change over time, the fact that it has been found to be reliable in PsA provides a basis for pursuing its use in both clinical trials and observational studies in this disease. It is also a good measure for following up patients in clinical practice. The Ritchie Index. The Ritchie Articular Index was also developed initially to evaluate joint disease in patients with RA (5). In its original description, the Ritchie Index did not include individual joints of the hands and feet, but rather, all MCP joints and all MTP joints were considered one area of the hand and foot, respectively. It did, however, include a severity measure for tenderness and swelling, scored on a 0 3 scale. The modified Ritchie Index assesses the individual joints according to the ACR joint count and includes the degree of tenderness and swelling of each joint on a 0 3 scale, but does not include the DIP joints of the feet. The Ritchie Index demonstrated more observer-related variation than did the ACR joint count, in a study comparing 4 methods of joint assessment in RA (11). Thus, the modified Ritchie Index would not be the most useful instrument for the assessment of patients with PsA, either in clinical trials or in clinical care. The 28-joint count. A reduced joint count of 28 joints, including both shoulders, both elbows, both wrists, all MCP joints, all PIP joints of the hands, and both knees, has been studied in RA (12). It has not been validated in PsA. Indeed, a limited joint count in PsA would not be appropriate, since more than 50% of the patients have inflammation of the DIP joints, and in some patients, arthritic manifestations are restricted to these joints. Moreover, foot involvement, particularly with dactylitis, is a particularly common finding and removing these joints from the overall assessment would compromise the assessment of PsA patients. Although a reduced number of joints requiring assessment is attractive both in clinical trials and in clinical care, the 28-joint count will first need to be validated in this patient population before it is included as the routine test for the assessment of PsA. Clinical damage. Moll and Wright appreciated the destructive nature of PsA and recognized arthritis mutilans as 1 of the 5 patterns of joint involvement. Patients with PsA clearly develop clinical deformities. Gladman et al (8) defined clinical damage on the basis of either a restriction of more than 20% in the range of movement (unrelated to inflammation), flexion contractures, ankylosis, or flail joints. Based on these definitions, they demonstrated that the assessment of clinical damage was reliable in their clinic. Progression of clinical damage was demonstrated over time, and both clinical and HLA predictors of the progression of clinical damage were identified (13). The assessment of clinical damage is relevant for stratifying patients in drug trials, and hopefully can be used to demonstrate that with the use of appropriate medications, there is a reduction in damage progression. A high ICC of 0.80 in the assessment of damaged joints was detected in the recent Canadian SPARCC study (10). The assessment of clinical damage is relevant in

3 26 GLADMAN ET AL clinical care and in longitudinal observational cohorts, because clinical damage may lead to disability. Although it is not expected that clinical damage will be modified by any drug therapy designed to control inflammation, clinical damage may be an important long-term outcome measure to assess therapeutic agents with the potential to inhibit cartilage erosion and bone resorption. Spondylitis. Spondylitis occurs in 40% of patients with PsA. It manifests as either sacroiliitis, syndesmophyte formation, or discitis in the spine. The spondylitis of PsA is less severe than that of AS (14). It is not clear, therefore, that measures of axial involvement developed for AS will be sensitive or accurate enough for use in PsA. Assessment of the back includes documentation of the degree of sacroiliac joint tenderness and measurement of back movements. Sacroiliac joint tenderness. The clinical assessment of the sacroiliac joints is a difficult challenge. Since these joints are immobile, and rather inaccessible, the usual measurements of pain on motion or joint-line tenderness cannot be performed. Therefore, maneuvers to produce stress pain have been devised. There are several such maneuvers (15), but they have not proven to have high sensitivity or specificity in AS, and in a recent study in PsA there was not a good agreement among observers with regard to the assessment of sacroiliac tenderness (10). It is therefore unlikely that this measurement will be useful in drug trials in PsA. Back movements. Finger to floor distance. The distance between the tip of the third finger and the floor after the patient bends down with the knees straight is one of the measures of back mobility in AS (16). This measurement was recently assessed in PsA, with a between-observer ICC of 0.77 (10). The determination of finger to floor distance appears to be a good measure among patients with AS (16), and may be just as good among patients with PsA. Schober s test and its modification. The original Schober s test described a 10-cm segment which was placed over the lumbar spine of the patient; the patient would then bend forward from a standing position, and the segment would increase to 16 cm (17). The test was modified because it was recognized that without an anchor point, it would be unreliable, even with the same observer on repeated measurements. According to the description of the modified Schober s test (18), an anchor is established at the L5 S1 level of the lumbar spine (dimples of Venus), from which marks at 10 cm above and 5 cm below are placed, with the patient standing upright; this 15-cm segment should increase to 21 cm when the patient bends forward. However, both of these tests measure movement in the lumbar spine only, whereas early changes in the spondylarthropathies may occur in the thoracolumbar junction. Although the modified Schober s test was found to have an ICC of 0.70 in 2 studies of AS patients (16,19), neither test provided a high ICC in the recent Canadian study of patients with PsA (10). Miller and colleagues enhanced the modified Schober s test by including higher levels of the spine (20). According to this test, an anchor is placed at the level of the dimples of Venus. Three 10-cm segments are then marked on the back while the patient is bending forward with the knees straight. The reduction in these three 10-cm segments is recorded with the patient in full extension. This test proved useful for the differentiation of patients with PsA with or without spondylarthropathy, and thus has face validity in PsA (21). However, there was not good agreement in its measurement among observers in the SPARCC group (10). This measurement has not been tested for sensitivity to change with time. Further studies are necessary before this measure is included in the assessment of patients in drug trials or in longitudinal studies. Lateral flexion of the spine. Lateral flexion of the spine is measured as the distance between the third finger and the floor when the patient bends laterally without bending forward or without bending the knees. Both sides of the spine are examined (16). The distance between the third finger and the fibula on lateral flexion has been used at the University of Toronto PsA Clinic. The 10 SPARCC investigators achieved an ICC of 0.55 when using this method, and an ICC of 0.80 when assessing the distance between the third finger and the floor in 10 patients with PsA. Lateral flexion may also be measured by the difference between the third-finger to floor distance along a rule mounted on the wall when the patient stands erect and the full lateral flexion (patient bends down as far as possible and third-finger to floor distance is measured) (22). This test was not evaluated in PsA. Since the finger to floor distance provides good agreement among observers, it should be further studied for sensitivity to change in clinical trials to assess back involvement in PsA. Spinal rotation. Thoracolumbar rotation has been studied and found to be invalid to assess spinal mobility in AS (19). It has not been tested in PsA. Validity and sensitivity to change of thoracolumbar mobility. Using biplanar radiography as the standard for comparison, few clinical methods have been shown to reflect true thoracolumbar flexion, although clinical methods of measuring extension are more precise (23). With regard to sensitivity to change (improvement),

4 ASSESSMENT OF PsA 27 spinal movements have low discriminant capacity in AS (24), although noticeable changes in response to physical therapy can be obtained in the short term (25). These have not been tested specifically in patients with PsA. Neck movements. Cervical flexion-extension. The distance from the chin to the chest with the head fully bent forward has been used as a measure of cervical flexion. Observations of normal or reduced cervical flexion achieved an interobserver kappa of 0.86 among the SPARCC investigators (10). Cervical extension was not measured reliably among the SPARCC investigators. The tragus to wall distance may serve as a surrogate for cervical extension, and achieved moderate agreement in patients with PsA (10). The assessment of cervical spine movement is important in the evaluation of patients with spondylarthropathy (19), and its measurement in patients with PsA, particularly those with spinal involvement, is necessary. Whether this measure differentiates patients with PsA with or without spinal involvement remains to be tested. It is also unclear whether these measurements will vary with time and treatment in patients with PsA. Other measurements related to spondylitis. The Bath Ankylosing Spondylitis Metrology Index (BASMI) was developed to clinically assess patients with AS (22). This index includes 5 clinical measures: tragus to wall distance, measured as the distance between the tragus of the ear and the wall; lumbar flexion, measured by the Macrae and Wright modification of the Schober s test (18); cervical rotation, measured by the ability of the patient to rotate the neck from side to side; lumbar-side flexion, measured as the difference between the distance from the third finger and the floor when the patient stands straight and when the patient bends sideways with the knees straight; and intermalleolar distance, measured as the distance between the 2 malleoli when the patient lies down with the hips fully abducted. Each of these clinical measures is rated on a score of 0 2, reflecting mild to severe disease involvement. The interobserver reliability of 3 physiotherapists who tested 20 patients was found to be high. The BASMI correlated highly with a larger number of tests performed on 43 patients with AS. Measurements of intermalleolar distance functioned well in the SPARCC study, with an ICC of 0.79 (10), whereas measurements of chest expansion were not highly correlated among the SPARCC investigators (ICC of 0.40) (10). The usefulness of the BASMI and the individual measures included within it in the assessment of the spondylarthropathy in patients with PsA remains to be determined. Other clinical features of PsA Dactylitis. Dactylitis is defined as swelling of the whole digit and is a typical clinical feature in PsA. Although some studies suggest that it occurs in tenosynovitis only (26), it is likely to be related to inflammation in the joints as well as in tendons of the affected digit (27). A recent study demonstrated that digits with dactylitis showed more radiologic progression compared with digits without dactylitis (28). There is no validated measure to assess dactylitis clinically. One study in PsA has incorporated a dactylitis assessment as a measure of tenderness of the whole digit (29). Dactylitis may be acute, manifesting as red, swollen, and very painful digits, or may become a chronic swelling not associated with redness or pain. In recording dactylitis in clinical trials, it is important to consider acute versus chronic presentation. Thus, both the presence of a swollen digit and the degree of inflammation would ideally be included in the assessment of dactylitis for clinical trials. The individual joints of a digit affected with dactylitis should also be considered inflamed and thus be counted in the number of actively inflamed joints. Tendonitis. Patients with PsA often present with tendonitis, which may affect the Achilles tendon, the flexor tendons of the hands, the extensor carpi ulnaris, and the tendons around the ankles. This has not been included in the assessment of PsA patients for drug trials, and there is no validated method to record it. Enthesitis. Enthesitis is a common manifestation of PsA. It is defined as inflammation at the site of insertion of the tendons and ligaments to bone. Common sites of enthesitis in PsA include the insertion of the Achilles tendon to the calcaneous, insertion of the plantar fascia to the calcaneous, insertion of tendons to the tibial tuberosity, and insertion of tendons to the humerus. These have not been systematically evaluated. At a recent meeting of the SPARCC group, the assessment of enthesitis was tested in 4 areas, the plantar fascia, Achilles tendon insertion, tibial tuberosity, and rotator cuff insertion. For assessment of enthesitis in the first 3 areas, the agreement between observers was moderate, but for assessment of the rotator cuff insertion, it was poor. Two measures of enthesitis have been proposed for the spondylarthropathies. The Mander index (30), which includes 66 sites, is somewhat cumbersome to utilize and does not adequately distinguish sites with enthesitis from tender points in fibromyalgia. Recently, the Maastricht Ankylosing Spondylitis Enthesis Score (MASES) was developed and validated (31). The MASES index, which includes 13 anatomic sites, includes the 4 sites tested by the SPARCC group in PsA.

5 28 GLADMAN ET AL Since these are the most common sites of involvement, it is likely that these should be included in the clinical assessment of patients with PsA, both in drug trials and in observational cohort studies. Skin disease. Psoriasis activity is measured by the Psoriasis Area Severity Index (PASI) (32), the Target Lesion Score, and the Dermatologist Static Global Assessment. These scoring methods are traditionally used in psoriasis studies and have been effectively used in studies of PsA (33 36). These scoring systems are focused on scoring the most common form of psoriasis, plaque psoriasis or psoriasis vulgaris, as opposed to less common forms of psoriasis that are not commonly studied in trials, i.e., guttate, pustular, and erythrodermic. The PASI incorporates the degree of erythema, induration, and scale, as well as the area involved, in the head, trunk, and upper and lower extremity. For a patient to be evaluable for PASI scoring, regulatory agencies require involvement of psoriasis on at least 3% of the body surface area. Although it has been found to be quite reliable, the general usability of the PASI by practicing dermatologists is unclear. At the University of Toronto PsA Clinic, the PASI score is recorded at each visit and is used as an outcome measure. It has been a reliable measure in the clinical trials of biologic therapies in PsA as well as in psoriasis (33,34,36,37). There is currently a debate among dermatologists regarding the level of improvement in the PASI that would be necessary to indicate a response in psoriasis. The target lesion score has been used in drug trials and is a measurement of the degree of erythema, induration, and scale of a 2-cm psoriatic lesion selected as a target for response. This score may be particularly useful in a PsA study in which not all patients have 3% body surface area involvement of psoriasis, which is necessary for the calculation of a PASI score. Thus, even in a PsA study, a skin evaluation of all patients with at least 1 appropriately sized lesion may be performed. The Dermatologist Static Global Assessment rates global psoriasis involvement on a 0 5 scale, from clear to very severe disease. Although less quantitative than the PASI score, this scoring system is widely understood in the dermatology community. Nail lesions have not yet been systematically assessed in PsA drug trials. Biologic measures of inflammation. The erythrocyte sedimentation rate (ESR) is elevated in only half of the patients with PsA. However, a high ESR at presentation has been associated with early mortality and with progression of joint disease in patients with PsA (38). In AS, neither the ESR nor the C-reactive protein (CRP) level correlated well with disease activity as measured by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (39). Measures of function and disability Health Assessment Questionnaire (HAQ). The HAQ was developed by Fries et al for the assessment of disability in patients with RA (40). The HAQ focuses on 2 dimensions of health status, physical disability (8 subscales) and pain. A modification of the HAQ for spondylarthropathies (HAQ-S) was also developed, which includes 2 spinal domains (SPAR1 and SPAR2) (41). Both the HAQ and HAQ-S were tested in patients with PsA, and both correlated with disease activity as measured by the actively inflamed joint count and some measures of clinical function, including grip strength, the ACR functional class, and the number of fibromyalgia tender points (42). Overall, the HAQ and HAQ-S scores were almost identical (mean 0.50 and 0.53, respectively). Both the original HAQ and the HAQ-S yielded higher scores in PsA patients with spondylarthropathy (0.61 and 0.63, respectively) in comparison with PsA patients without the back involvement (0.49 and 0.43, respectively). However, these differences were not statistically significant, suggesting that either measure could be used in patients with PsA. A further modification of the HAQ for psoriasis (HAQ-SK), which includes several questions related to the effect of skin disease on health status, was also studied in patients with PsA (43). The HAQ-SK score was similar to the original HAQ score (mean 0.56 versus 0.55, respectively), suggesting that the skin-related questions did not enhance the assessment of health status provided by the original HAQ. Although the HAQ-SK score did not correlate well with the PASI score (r 0.20), it did correlate with both the patients and clinicians ratings of the severity of psoriasis (r 0.49). The HAQ has been used in several PsA therapy trials (44). Thus, the HAQ appears to measure physical disability and pain in patients with PsA and should be included as an outcome measure in PsA clinical trials. The HAQ could also be an instrument to describe health status in longitudinal cohorts of patients with PsA. Although the HAQ has been used as a disability measure, it may not sufficiently incorporate all aspects of disability. The World Health Organization Disability Assessment Schedule II was recently investigated in patients with AS, and was shown to be a useful instrument for the measurement of disability (45). This measure may be applicable to patients with PsA, but it has not yet been tested in this patient population.

6 ASSESSMENT OF PsA 29 Arthritis Impact Measurement Scales (AIMS). The AIMS and AIMS2 questionnaires have also been used for the assessment of functional status in RA. These are detailed questionnaires that ask about physical functioning (6 subscales) and pain (5-item scale). Both instruments have been validated in patients with PsA (46,47). At the University of Toronto PsA Clinic, patients reported that the AIMS questionnaires were very tedious, and therefore the clinic staff has now stopped using these questionnaires. Medical Outcomes Study Short-Form 36 (SF- 36). The SF-36 is a generic health assessment questionnaire developed by the Rand Corporation. It has been studied in a number of chronic diseases including a number of rheumatic disorders. The SF-36 assesses 8 domains of health status including physical functioning, pain, vitality, social functioning, psychological functioning, general health perceptions, and role limitations due to physical and emotional problems. It was found to be reliable in patients with PsA, and could be used to distinguish PsA patients from the general population (48). The SF-36 scales correlated with measures of function and pain, and some scales correlated with disease activity. The SF-36 was equally or more responsive than the HAQ and AIMS to short-term changes in perceived health status and inflammatory disease activity in PsA (49). It has been used in several PsA therapy trials (50). Since the SF-36 allows comparison of patient groups, it is a worthwhile instrument to include in both clinical trials and longitudinal cohorts of patients with PsA. There is an argument, however, for using diseasespecific quality of life instruments in clinical trials, since larger effect sizes can be demonstrated, as recently shown in patients with AS (51). Such a measure has also been developed for the assessment of quality of life in PsA patients (Tennant A: personal communication) and will require further evaluation. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). The BASDAI is a composite index that includes questions on fatigue, axial pain, peripheral pain, stiffness, and discomfort. Responses are reported on a visual analog scale (range 0 10 from none to severe), and the index is calculated as a simple sum of its components. Although this instrument was found to be valid in AS (52), it did not distinguish between patients with PsA with a spondylarthropathy and those without a spondylarthropathy (21). Thus, its role in the assessment of patients with PsA is unclear. Bath Ankylosing Spondylitis Functional Index (BASFI). The BASFI is a self-assessment instrument consisting of 8 specific questions regarding function in AS and 2 questions reflecting the patient s ability to cope with everyday life (53). The responses are recorded on a 10-cm visual analog scale, and the mean of the individual scores provides the BASFI score. It has been found to be reliable and sensitive to change among patients with AS. The BASFI has not been tested in patients with PsA. Fatigue. Fatigue has become an important aspect of the evaluation of patients with rheumatic disorders. There are several measures of fatigue, including a visual analog scale, the Krupp Fatigue Severity Scale (FSS) (54), and recently reported elaborate measures of fatigue such as the Functional Assessment of Chronic Illness Therapy (55) and Multidimensional Fatigue Inventory (MFI) (56). The MFI was studied in patients with AS (57) and was shown to provide information not obtained with the single question on fatigue included in the BASDAI. The Krupp FSS has been studied in PsA. In a study of 70 patients with PsA, the mean SD FSS score was in all PsA patients and in the control subjects (P 0.001). When patients were compared with controls, 57% versus 34%, respectively, had at least moderate fatigue (FSS score 5), and 32% versus 8%, respectively, had severe fatigue (FSS score 7) (58). An assessment of the FSS in patients with PsA over time identified that disease activity, measured by the actively inflamed joint count, was related to changes in the FSS (59). Measures of clinical response in PsA PsA response index. Daunt et al (60) developed an overall index of disease based on pain (visual analog scale), duration of morning stiffness, grip strength, the Ritchie Articular Index, and hemoglobin concentration for patients with PsA. The index was tested in 72 patients with PsA, of whom 30 had symmetric peripheral arthritis that included the DIP joints, 15 had peripheral arthritis without DIP joint involvement (RA-like), 10 had asymmetric arthritis, 10 had oligoarthritis, and 7 had spondylitis. The index of disease activity was reliable only in the patients with symmetric polyarthritis. Thus, the authors suggested that the components of disease activity, rather than the overall index, should be used in clinical trials. They did not validate the Ritchie Index for PsA in this study. Since this disease activity index did not function well in all patients with PsA, it is unlikely to be adopted for either clinical trials or observational cohorts of patients with PsA. PsA response criteria. Clegg et al (61) developed the Psoriatic Arthritis Response Criteria (PsARC) for the study of sulfasalazine in PsA. In the initial study for

7 30 GLADMAN ET AL Table 1. Application of the Psoriatic Arthritis Response Criteria (PsARC) as an outcome measure in recent clinical trials involving patients with psoriatic arthritis Study drug (duration) Sulfasalazine (36 weeks) Etanercept (12 weeks) Infliximab (16 weeks) Etanercept (12 weeks) Etanercept (24 weeks) Leflunomide (24 weeks) Trial PsARC, % responders Drug group Placebo group Ref. 61 (n 220) Ref. 33 (n 60) Ref. 34 (n 100) Ref. 35 (n 205) Ref. 35 (n 205) Ref. 36 (n 188) which the criteria were developed, the PsARC did not demonstrate a clinically important difference between the sulfasalazine-treated patients and the placebotreated patients. A high placebo response was observed. Although the composite score achieved statistical significance, the individual components did not (Table 1). This may have been a reflection of the inability of the instrument to detect important differences, or a reflection of the lack of efficacy of the drug (sulfasalazine). However, several recent PsA therapeutic trials included the PsARC as either the primary or the secondary outcome measure. In these trials, the PsARC demonstrated differences between the drug- and placebo-treated patients (Table 1), supporting their potential value as a valid outcome measure. Moreover, the PsARC response paralleled the findings obtained using the ACR response criteria (see below). Of note, in these latter recent studies, there was a substantially lower placebo response than in the sulfasalazine trial, demonstrating that the PsARC can detect important clinical differences. The ACR 20%, 50%, and 70% improvement response. The ACR response criteria for RA were developed after the identification of a core set of disease activity measures gleaned from the clinical trials previously performed in RA (62). The criteria were derived through a nominal group process and have been used extensively in clinical trials in RA. The preliminary criteria (ACR20) required a 20% reduction in the tender joint count, a 20% reduction in the swollen joint count, and a 20% reduction in 3 of 5 additional measures, including patient and physician global assessments, pain, disability, and an acute-phase reactant. These response criteria were further defined to include a 50% (ACR50) and 70% (ACR70) reduction in these measures, according to the same rule. Felson et al (63) confirmed the discriminant validity of the ACR20 and argued that the use of the ACR50 or ACR70 as the primary response level would compromise the statistical power and necessitate a larger sample size in clinical trials. They also demonstrated that the ACR50 and ACR70 do not have the same discriminant ability as the ACR20. It is unclear whether the same response definition would be derived from studies in PsA. Most importantly, clinicians and investigators need to consider whether the ACR20 end point, in which patients may continue to exhibit a substantial number of actively inflamed joints, is sufficient to demonstrate a clinically meaningful drug response. This is relevant in view of the data indicating that, for each actively inflamed psoriatic joint, there is a 4% increased risk of clinical damage at a subsequent visit (64). Thus, even if a patient reduced the tender/swollen joint count by 50%, from 20 to 10, the patient would still have a 40% risk of progression of damage. In addition, biologic measures of inflammation are included among the ACR response criteria for RA. Before adopting these response criteria for PsA, it is essential to assess the utility of the ESR and the CRP level as measures of disease activity in patients with PsA. Although the ACR response criteria have not been formally validated in patients with PsA, these criteria were included as outcome measures (primary or secondary) in 4 recent studies of new agents in PsA (Table 2). The changes observed in the responses between drug-treated and placebo-treated patients indicate that the ACR response measures for RA have validity in PsA drug trials. It is noteworthy that in these studies, the total number of joints counted was increased to 78 for tenderness and 76 for swelling, to include the DIP joints of the hands and both PIP and DIP joints of the feet. European League Against Rheumatism (EU- LAR) response criteria. The EULAR also developed response criteria for RA (65). These criteria were derived from a discriminant function analysis of patients with active and nonactive disease; the judgment of the disease activity state was made according to whether important treatment changes were initiated by experienced rheumatologists at the time of the measurement. The EULAR response criteria are based on the Disease Activity Score (DAS) which is calculated according to the formula: DAS 0.54 RAI SJC 0.33 LnESR GH,

8 ASSESSMENT OF PsA 31 Table 2. Application of the American College of Rheumatology 20%, 50%, and 70% improvement response criteria (ACR20, ACR50, and ACR70, respectively) as an outcome measure in recent trials involving patients with psoriatic arthritis* Trial Study drug Drug group ACR20 ACR50 ACR70 Placebo group Drug group Placebo group Drug group Placebo group Ref. 33 (n 60) Etanercept Ref. 34 (n 100) Infliximab Ref. 35 (n 205) Etanercept Ref. 35 (n 205) Etanercept Ref. 36 (n 188) Leflunomide NA NA NA NA * Values are the percentage of responders. NA not applicable. Study duration 12 weeks. Study duration 16 weeks. Study duration 24 weeks. from an assessment of the Ritchie Articular Index (indicated as RAI), swollen joint count (indicated as SJC), ESR, general health status (indicated as GH), and visual analog scale. On the basis of changes in the DAS during a clinical trial, patients may be divided into groups of nonresponders (a reduction in the DAS of 0.6 or between 0.6 and 1.2, with a persistent DAS 3.7), moderate responders (a reduction in the DAS between 0.6 and 1.2, with a persistent DAS 3.7), and good responders (improvement of 1.2 in the DAS from baseline and a DAS at followup of 2.4). An analysis of several studies demonstrated comparable validity for the DAS and ACR response criteria in RA (66). The DAS was recently used in the study of infliximab in PsA (Infliximab Multinational Psoriatic Arthritis Controlled Trial [IMPACT]), and a good response to the drug was demonstrated (34). A modification of the DAS, in which only 28 joints are assessed to calculate inflammatory activity, has also been developed for RA and was used in the IMPACT study, and the efficacy of infliximab was again demonstrated. Measures of response in spondylitis. The Assessment in Ankylosing Spondylitis Study Group (ASAS) has defined the core outcome measures for AS (67). These core measures are outlined in Table 3. For domains such as spinal mobility, several tests had already been used. For function, the BASFI was recommended. At the time the ASAS group reported the proposed core set of outcome measures, there was not an appropriate measure to assess enthesitis, but an enthesitis measure with a total of 13 sites was recommended in a subsequent meeting (31). A specific fatigue measure was not recommended at the time. Certainly, the axial measures may be applicable in evaluating PsA patients, particularly those with spondylarthropathy. However, the 44-joint count would not be an adequate measure in this population, because it excludes the DIP joints, and other unique joint manifestations (ankylosis and flail digits) are not captured in these outcome measures. Overall measures of response in PsA. The assessment of response in patients with PsA will likely require a combination of the response criteria for peripheral arthritis and those for spondylitis, and should also include features that are unique to PsA such as dactylitis and enthesitis. Such an outcome measure has not yet been developed, but is the subject of an international effort currently under way. Imaging methods Conventional radiography. Several methods have been developed to interpret radiologic changes in RA (68). The Steinbrocker method classifies joints as being normal (grade 0), having juxtaarticular osteopenia or soft tissue swelling (grade 1), displaying erosion (grade 2), displaying erosion and joint space narrowing (grade 3), or showing total destruction (grade 4). A patient is Table 3. The Assessment in Ankylosing Spondylitis Study Group core outcome measures for ankylosing spondylitis Item Test(s) to be used Function BASFI* Pain Visual analog scale Spinal mobility Chest expansion, modified Schober s test, occiput to wall distance Patient s global assessment Visual analog scale Duration of morning stiffness Minutes of stiffness in the spine Peripheral joint assessment 44-joint count Entheses count Not yet determined Acute-phase reactant Erythrocyte sedimentation rate Radiographic progression Spine and hip radiographs Fatigue Fatigue measure * BASFI Bath Ankylosing Spondylitis Functional Index.

9 32 GLADMAN ET AL graded according to the worst joint (3). The Sharp method grades all of the joints of the hands, including each intercarpal joint, separately for erosions and for joint space narrowing (69). Because of the relative frequency of involvement of certain areas, the joints scored for erosions in RA include the MCP and PIP, first CMC, trapezium-scaphoid, scaphoid-lunate, lunatehamate, radio-carpal, and ulnar-carpal joints. Joint space narrowing is analyzed in the PIP, MCP, radiocarpal, scaphoid-trapezium, scaphoid-capitate, and the third, fourth, and fifth CMC joints. The grading is based on a 0 5 scale for erosions, with 0 being no erosion and 5 being more than 4 erosions in a particular joint, and a 0 4 scale for joint space narrowing, with 0 being none and 4 being substantial joint space loss. The total score is the sum of the scores for both erosions and joint space narrowing (total possible score is 149). A separate erosion score (for 17 joints) and joint space narrowing score (16 joints) can be obtained. Van der Heijde modified the Sharp method to include the feet (70). According to the van der Heijde modification, 16 areas of the hands are scored for erosion, and 15 areas for joint space narrowing. In the feet, all MTP joints, including erosions at each side of the joint, and the IP joints of the first toes are included. Thus, an erosion score of 280 and a joint space narrowing score of 168 for both hands and both feet is obtained. The Larsen method (71) grades each joint from normal (grade 0) to total destruction (grade 5). This method has been modified by Larsen himself, as well as by others (72,73). The Steinbrocker, Sharp, and Larsen methods have shown good agreement in the reading of radiographs from patients with RA (74). A modification of the Steinbrocker method, which assigns a score for each joint (range 0 4) as opposed to the final score being the worst score for each patient, was validated for use in PsA (75). The investigators evaluated the modified Steinbrocker score and the Larsen score at the same time. The investigators assessed all DIP, PIP, and MCP joints of the hand, the wrist (counted as one joint), and all MTP joints and the PIP joints of the first toes in 70 patients with PsA, with repeat films obtained 2 years apart. There was a very high interobserver and intraobserver agreement. Both scoring methods demonstrated sensitivity to change over time. Using the modified Steinbrocker radiographic method, it was shown that sulfasalazine was not able to prevent progression in PsA (76). The Sharp method, modified to include the DIP and the MTP joints of the feet and IP joint of the first toe, was recently used to assess the effect of etanercept on radiographic progression in PsA (77). Patients treated with etanercept had a higher degree of joint damage compared with placebo-treated patients at baseline. Patients treated with etanercept had reduced radiographic progression compared with patients treated with placebo. Based on a previous study in PsA that demonstrated that current damage predicts future damage (63), the etanercept-treated patients were more likely to show progression, thus rendering the treatment response even more significant. Radiographic features associated with PsA (acrolysis, tuft resorption, pencil-incup deformities, and bony ankylosis) were also evaluated in this trial, but there was no change in any of these parameters over the 12-month study period. Future studies would benefit from stratification by radiographic change at baseline. The above-mentioned methods were developed for the radiographic evaluation of patients with RA. However, there are specific radiographic changes noted in the peripheral joints of patients with PsA. These include bony proliferation, both around the joint line and at entheses, marked joint destruction and bone resorption, reflected in the pencil-in-cup change, and the presence of dactylitis, which leads to soft tissue swelling of a whole digit as opposed to the periarticular soft tissue swelling noted in RA. In addition, the distribution of joints involved includes the DIP joints, which are often spared in RA. A recent method was developed to score these additional radiographic changes specific to PsA (78). The method consists of 2 separate scores: a destruction score and a proliferation score. The destruction score grades the joint on the basis of the amount of jointsurface destruction on a scale of 0 5, where 0 is normal, 1 10%, %, %, %, and 5 75% destruction of the joint surface or ankylosis. A total of 40 joints of the hands and feet are scored, with a total possible score ranging from 0 to 200. The proliferation score sums up the extra bone formation typical of PsA, including paraarticular spikes, supracortical bone formation, diaphyseal thickening, and enlargement of the bone (compared with the opposite side or with baseline radiographs), on a scale of 0 4 based on the degree of bony proliferation. The scale defines 0 as normal, 1 as 1 2 mm bony proliferation or bone growth up to 25% of the original size, 2 as 2 3 mm bony proliferation or bone growth of 26 50% of the original size, 3 as 3 mm bony proliferation or 50% of the original size, and 4 as bony ankylosis. A total of 40 joints are scored, with a total score ranging from 0 to 160 per patient. To validate this PsA-specific radiographic method, Wassenberg et al reviewed 2 sets of radio-

10 ASSESSMENT OF PsA 33 graphs, 3 years apart, from 20 patients undergoing therapy with methotrexate (78). There was good agreement within the 2 raters and between the raters for the destruction score, but less so for the proliferation score. This method has not been validated in drug trials and requires comparison with the existing methods to determine whether there is an advantage to the addition of the PsA-specific features. Magnetic resonance imaging (MRI) and ultrasound (US). The utility of MRI and US in the peripheral joint examination of patients with PsA has not been studied. Although both MRI and US are thought to provide a better resolution in the imaging of erosions at some point during the progression of RA, there have not been many longitudinal studies (79). A 2-year followup study suggested that both MRI and US are superior to conventional radiography in demonstrating progression of erosions (80). These techniques can also potentially be effective in assessing the response to therapy. A recent study of intraarticular etanercept injections documented US evidence of resolution of synovitis following the injection (81). Whether these techniques will replace conventional radiography remains to be seen. MRI and US, especially with the aid of contrast, offer a unique advantage over conventional radiography in the evaluation of enthesopathy, a prominent clinical feature of PsA, as well as in the assessment of sacroiliitis. These techniques can better distinguish the presence and extent of inflammatory activity in these lesions, and potentially may be sensitive tools for assessing the response to therapy (82 86). The assessment of entheses is particularly important in PsA, since its role in the pathogenesis of the disease has been emphasized (87). Summary To date, specific measures to assess disease activity in PsA have not been validated. The tools used for assessment of psoriatic peripheral joint disease have been borrowed from the assessment of RA. While, in general, some of these outcome measures perform well in PsA, the distinct distribution of joint involvement coupled with the unique patterns of synovitis and periarticular inflammation demand that these measures be appropriately and carefully adapted. In order to capture the wide variation that characterizes the clinical presentation seen among patients with PsA, a larger number of joints should be assessed. Moreover, because of the frequency and severity of back involvement in PsA, assessment of spinal mobility and pain is required. Many clinical methods used to assess axial disease in AS have not proven to be reliable, and even measures deemed appropriate in AS require validation in PsA. Specific assessment of common features of PsA, including dactylitis, enthesitis, and tendonitis, requires further study. 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