Contents
1 Introduction 129
2 Psoriatic Arthritis Response Criteria 129 3 ACR Response Criteria 129
4 European League Against Rheumatism and the Disease Activity Score 130 5 Remission 131
6 Clinical Damage 131 References 131
1 Introduction
The development of criteria for therapeutic re- sponses in arthritis was attempted as early as 1937, leading to the development of the Com- mittee for Therapeutic Criteria of the New York Rheumatism Association in 1945 [1]. Since then, numerous different criteria have been suggest- ed and employed for the evaluation of RA; how- ever, only one response criterion has been spe- cifically designed for PsA.
2 Psoriatic Arthritis Response Criteria The Psoriatic Arthritis Response Criteria (PsARC) were developed by Clegg et al. in 1996 to assess responses to sulfasalazine in a clinical trial of 221 PsA patients [2]. The PsARC is de- fined as an improvement in at least four of four criteria, one of which must be the tender or swollen joint count, and no worsening in any criteria. The specific measures of improvement are: physician global assessment ≥1 unit on a 5-point scale, patient global assessment ≥1 unit,
tender joint score ≥30%, and swollen joint score ≥30%.
In the study for which these criteria were de- veloped, no significant differences were detect- ed in the sulfasalazine vs. placebo group using the PsARC, perhaps reflecting limited efficacy of sulfasalazine, rather than the performance of the instrument. The PsARC has subsequently been used as an outcome measure in several clinical trials of psoriatic arthritis, including studies with leflunomide, etanercept, and in- fliximab [3–6]. In these studies, the PsARC de- tected differences with each treatment com- pared to placebo groups. For example, in a study of etanercept, 70% of patients receiving etanercept achieved a PsARC response com- pared to only 23% in the placebo arm after 24 weeks of treatment [4]. PsARC responses al- so correlated well in most instances with ACR 20% response criteria used in the same studies.
3 ACR Response Criteria
The ACR criteria for the definition of improve- ment in rheumatoid arthritis were developed in 1995 to standardize outcomes in clinical trials [7]. Prior to the development of the ACR crite- ria, numerous different measures and defini- tions were utilized. The most important clinical factors were selected by a group of rheumatolo- gists evaluating standardized patients and then correlated with clinical trial data sets for their discrimination between treatment and placebo arms. The definition of response established was: a 20% improvement in the tender and swollen joint count plus 20% improvement in three out of five additional ACR core set meas- ures (patient and physician global assessments, patient pain assessment, patient assessed dis- ability, and an acute phase reactant-ESR or CRP).
The ACR 20% response criteria have been widely used as the primary outcome measure in RA clinical trials. Subsequently, ACR re- sponse criteria of 50% and 70% improvement were added with equivalent definitions. Some have questioned whether the ACR 20% im- provement represents a clinically meaningful change in an individual patient. In addition,
Soumya M.Reddy, Clifton O. Bingham III
B Psoriatic Arthritis 129
B Psoriatic Arthritis
Soumya M. Reddy, Clifton O. Bingham III
improvements based on these criteria are rela- tive to baseline and do not give absolute infor- mation regarding the severity of disease. For example, a patient may have an ACR 50% re- sponse with a decrease in tender and swollen joint counts from 18 to 9 and still have signifi- cant disease activity.
The ACR response criteria incorporate sev- eral measures which may also be relevant in the assessment of PsA but have not been fully vali- dated in this disease. These include the health assessment questionnaire (HAQ), and Patient and Physician global assessments of disease ac- tivity. Recent clinical trials of PsA have used a modification of the ACR response criteria with the DIPs of the hands and PIP and DIP joints of the feet (78 tender/76 swollen) used for joint counts [3, 4, 6]. The ACR 20/50/70 response cri- teria detected differences between the treat- ment and placebo groups and correlated well with other parameters. It is important to note, however, that these trials required an elevated joint count and/or ESR or CRP for study entry and it is not known if the ACR criteria would perform equally well in patients with less se- vere disease or without elevation of inflamma- tory markers.
4 European League Against Rheumatism
and the Disease Activity Score Investigators from the Netherlands created the Disease Activity Score (DAS) for the assessment of RA, incorporating tender and swollen joint counts, an acute phase reactant, and a patient assessment of disease activity. The DAS was de- veloped to allow assessment of the aggregate
amount of disease activity at any point in time, thus serving as a continuous variable. In addi- tion, the DAS provides information about changes in disease activity over time, so that a response to a therapeutic intervention can be classified as good, moderate, or poor [8]. The DAS is defined as:
DAS = 0.54 (square root of RAI) + 0.065 (Swollen Joint Count) + 0.33 (ESR mm/hr) + 0.0072
Table B1 shows the European League Against Rheumatism (EULAR) response criteria for RA based on the DAS. Disease activity at a point in time can be defined as low if the DAS is ≤2.4, moderate if the DAS is >2.4 and ≤3.7, and high if the DAS is >3.7 [9].
The DAS has also been validated using a 28 joint swollen and tender joint count. For the DAS28, low disease activity is defined as a DAS
≤3.2, moderate if the DAS is >3.2 and ≤5.1, and high if the DAS is >5.1 [9, 10]. More recently, a DAS and DAS28 using a CRP rather than the ESR have been developed (http://www.das- score.nl/www.das-score.nl) [11, 12]. The DAS and DAS28 have been validated for ability to discriminate between treatment and placebo groups in RA and are associated with progres- sion of radiographic joint damage and changes in functional capacity [8, 13].
The ACR and EULAR response criteria were compared at the OMERACT IV Conference in 1998 [13]. Seven large randomized RA trials were evaluated with ACR and EULAR criteria using the extended and 28 joint counts (ACR, ACR28, EULAR, EULAR28). The investigators found a high level of agreement between all four ACR and EULAR criteria and good corre-
Chapter VIII Clinical Outcome Measurements 130
VIII
DAS at endpoint DAS28 at endpoint Improvement in DAS or DAS28 from baseline
>1.2 >0.6 and ≤1.2 ≤0.6
≤2.4 ≤3.2 Good
>2.4 and ≤3.7 >3.2 and ≤5.1 Moderate
>3.7 >5.1 None
Table B1.EULAR Response Criteria based on DAS [9]
EULAR criteria
lation with patient and investigator assess- ments of global disease activity and with radio- graphic progression.
The DAS has not yet been evaluated in pub- lished clinical trials of PsA. One group has re- cently evaluated correlations between ACR re- sponse criteria, EULAR DAS responses, and the PsARC criteria in thirty-eight patients with PsA [14]. The investigators showed a good correla- tion between the EULAR (DAS better than DAS28) and PsARC criteria, but 21% of patients had conflicting results between the ACR and DAS criteria and between ACR and PsARC [3, 4, 15] (Table B2).
5 Remission
Remission of PsA has been defined by Gladman et al. as a period of at least three consecutive visits with an actively inflamed joint count of 0 (no stress pain, joint line tenderness, or effu- sion) and was noted to occur in 17.6% of pa- tients, lasting an average of 2.6 years; however, half of the patients had flares after a mean of 1.8 years [16]. The EULAR criteria for remission in RA, corresponding to the ARA definition of remission, are a DAS <1.6 and DAS28 <2.6 [17].
These cutoffs should not be used in PsA until they are validated against an accepted defini- tion of remission.
6 Clinical Damage
The assessment of clinical damage has been de- fined by Gladman et al. as the number of de- formed joints, which includes peripheral joints with limitation of >20% of range of motion
that is not attributed to active inflammation, ankylosis, or loosening/subluxation [18]. This measurement has demonstrated reliability between observers. The relevance of clinical damage scores in the assessment of PsA is not known. This parameter is slow to change over time and is not likely to be useful for clinical trials or to monitor routine practice. Disability measures and radiographic changes will likely be more sensitive to change over shorter peri- ods of time.
References
1. Steinbrocker O, Traeger CH, Batterman RC (1949) Therapeutic criteria in rheumatoid arthritis. J Am Med Assoc 140 : 659–662
2. Clegg DO, Reda DJ, Mejias E, Cannon GW, Weisman MH, Taylor T, et al. (1996) Comparison of sulfasala- zine and placebo in the treatment of psoriatic ar- thritis. A Department of Veterans Affairs Coopera- tive Study. Arthritis Rheum 39 : 2013–2020
3. Kaltwasser J, Nash P, Gladman D, Rosen C, Behrens F, Mease P (2003) Leflunomide in the treatment of psoriatic arthritis and psoriasis: data from a dou- ble-blind, randomized, placebo-controlled clinical trial.Ann Rheum Dis 62(Suppl 1) : abstract no.OP0081 4. Mease P, Kivitz A, Burch F, Siegel E, Cohen S, Burge D (2001) Improvement in disease activity in pa- tients with psoriatic arthritis receiving etanercept (Enbrel): results of a phase 3 multicenter clinical trial [abstract]. Arthritis Rheum 44(Suppl 9) : S90 5. Antoni C, Kavanaugh A, Kirkham B, Burmester G,
Weisman M, Keystone E, et al. (2002) The Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT) [abstract]. Arthritis Rheum 46(Suppl 9) : S381
6. Antoni CE, Kavanaugh A, Kirkham B, Burmester G, Manger B, Tutuncu Z, et al. (2003) The Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT): Substantial Efficacy on Synovitis and Psoriatic Lesions With or Without DMARD Therapy.
Ann Rheum Dis 62 (Suppl 1) : abstract no. OP0082 Soumya M.Reddy, Clifton O. Bingham III
B Psoriatic Arthritis 131
Table B2.Table comparing PsARC, ACR 20/50/70 and DAS responses
Drug (duration) Patients PsARC (%) ACR 20/50/70
(n) Drug Placebo Drug Placebo
Leflunomide [3] (24 weeks) 190 59.0 29.7 26.3 (ACR 20) 20 (ACR 20)
Etanercept [4] (24 weeks) 205 70 23 50/37/9 13/4/1
Infliximab [15] (16 weeks) 102 76.5 18 69/49/29 8/0/0
7. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. (1995) American College of Rheumatology. Preliminary definition of im- provement in rheumatoid arthritis. Arthritis Rheum 38 : 727–735
8. van Gestel AM, Prevoo ML, van’t Hof MA, van Rij- swijk MH, van de Putte LB, van Riel PL (1996) De- velopment and validation of the European League Against Rheumatism response criteria for rheuma- toid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Arthritis Rheum 39 : 34–40 9. Piet LCM, van Gestel AM, Scott DL (2000) EULAR
Handbook of Clinical Assessments in Rheumatoid Arthritis. Van Zuiden Communications BV, Alphen aan den Rijn, The Netherlands
10. Prevoo ML, van’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL (1995) Modified disease activity scores that include twenty-eight- joint counts. Development and validation in a pros- pective longitudinal study of patients with rheuma- toid arthritis. Arthritis Rheum 38 : 44–48
11. Paulus HE, Ramos B,Wong WK,Ahmed A, Bulpitt K, Park G, et al. (1999) Equivalence of the acute phase reactants C-reactive protein, plasma viscosity, and Westergren erythrocyte sedimentation rate when used to calculate American College of Rheumatolo- gy 20% improvement criteria or the Disease Activ- ity Score in patients with early rheumatoid ar- thritis. Western Consortium of Practicing Rheuma- tologists. J Rheumatol 26 : 2324–2331
12. Fransen J, Welsing PMJ, De Keijzer RMH, Van Riel PLCM (2003) Disease activity scores using C-reac- tive protein: CRP may replace ESR in the assess- ment of RA disease activity. Ann Rheum Dis 62(Suppl 1) : abstract no. THU0138
13. van Gestel AM, Anderson JJ, van Riel PL, Boers M, Haagsma CJ, Rich B, et al. (1999) ACR and EULAR improvement criteria have comparable validity in rheumatoid arthritis trials. American College of Rheumatology European League of Associations for Rheumatology. J Rheumatol 26 : 705–711
14. Ujfalussy I, Koo E (2003) Measurement of disease activity in psoriatic arthritis. Extended report. Z Rheumatol 62 : 60–65
15. Gladman DD, Helliwell P, Mease PJ, Nash P, Ritchlin C, Taylor W (2004) Assessment of patients with psoriatic arthritis: a review of currently available measures. Arthritis Rheum 50 : 24–35
16. Gladman DD, Hing EN, Schentag CT, Cook RJ (2001) Remission in psoriatic arthritis. J Rheumatol 28 : 1045–1048
17. Prevoo ML, van Gestel AM, van THMA, van Rijswijk MH, van de Putte LB, van Riel PL (1996) Remission in a prospective study of patients with rheumatoid arthritis. American Rheumatism Association pre- liminary remission criteria in relation to the disease activity score. Br J Rheumatol 35 : 1101–1105 18. Gladman DD, Farewell V, Buskila D, Goodman R,
Hamilton L, Langevitz P, et al. (1990) Reliability of measurements of active and damaged joints in psoriatic arthritis. J Rheumatol 17 : 62–64
Chapter VIII Clinical Outcome Measurements 132
VIII
