NATURAL REMISSION IN INFLAMMATORY POLYARTHRITIS: ISSUES OF DEFINITION AND PREDICTION

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1 British Journal of Rheumatology 1996;3S:1096-l 100 NATURAL REMISSION IN INFLAMMATORY POLYARTHRITIS: ISSUES OF DEFINITION AND PREDICTION B. J. HARRISON, D. P. M. SYMMONS, P. BRENNAN, E. M. BARRETT* and A. J. SILMAN ARC Epidemiology Research Unit, Stopford Building, Oxford Road, Manchester M13 9PT and *Norfolk Register, St Michaers Hospital, AyLsham, Norfolk NRll 6NA Arthritis SUMMARY This paper reports the frequency and predictors of remission (no arthritis on examination and no treatment with second-line drugs or steroids within the previous 3 months) in 358 patients with early inflammatory polyarthritis (IP) referred to the Norfolk Arthritis Register. Two years after referral, 91 patients (25%) were in remission, 32 of whom had also been in remission at 1 yr. Remission rates were twice as high in patients with undifferentiated inflammatory polyarthritis at baseline as in those who satisfied criteria for rheumatoid arthritis. To identify predictors of remission, a logistic regression model was developed on a random two-thirds of the patients and validated on the remaining one-third. Remission at 2 yr was associated with male gender and fewer than six tender joints at baseline. However, even the best-fitting model was not sensitive enough to be useful clinically. Thus, amongst patients with early IP in the community, remission rates at 2 yr are low. Further, it was impossible, using simple clinical measures, to predict those patients whose arthritis would resolve. KEY WORDS: Arthritis, Inflammatory polyarthritis, Rheumatoid arthritis, Remission. PATIENTS with inflammatory polyarthritis (IP) vary considerably in terms of their clinical features and outcome. There has been much interest in trying to identify factors, measured soon after onset, which could be used to predict a patient's future disease course [1]. In addition to predicting those patients who will do badly, it would also be helpful to be able to identify those patients whose arthritis will resolve. These patients could be reassured, and their treatment adjusted accordingly [2]. Amongst patients with rheumatoid arthritis (RA), it has been claimed that remission, if it does occur, tends to occur early in the disease [3] and thus it is important to study patients as soon as possible after disease inception. In order to study remission in patients with IP, it is necessary to establish an acceptable definition. In 1981, Pinals et al. [4] proposed remission criteria for RA which were adopted by the American Rheumatism Association (ARA) (Table I). These were later modified in order to define response to treatment in RA [5]. However, there is still no universally accepted definition of remission, which makes it difficult directly to compare remission rates between studies (Table II). In this paper, we have defined 'natural remission' as 'no arthritis on examination in a patient who has not taken second-line drugs or steroids in the preceding 3 months'. Amongst patients with RA, the reported rate of remission varies from 16% at 2 yr [9] to 3% at 7 yr [7]. Amongst patients with undifferentiated inflammatory polyarthritis (UIP), remission rates appear to be much higher [10]. However, most of these studies are hospital or clinic based, and are thus hampered by referral and selection bias, as patients attending hospital clinics are Submitted 13 December 1995; revised version accepted 4 June likely to have a more severe or sustained form of the disease. Some workers have attempted to identify factors, measured close to onset, which might be used to predict future remission. For patients with RA, lower baseline Health Assessment Questionnaire (HAQ) scores [9], increasing age and male gender [13] have been found to be associated with remission. Amongst patients with UIP, being negative for rheumatoid factor (RF) has been found to be associated with resolution of disease [10, 11]. In none of these studies did the variables identified as being associated with remission or resolution have sufficient predictive power to be useful clinically. Our aim was to determine the rates of natural remission in a community-based inception cohort of patients with IP and to identify variables, measured at baseline, which could be used to predict remission 2 yr after the patients werefirstseen. The community-based nature of the study reduced the referral and selection bias associated with a hospital or clinic-based population. Additionally, in studying very early disease, we hoped to include cases who might otherwise have resolved prior to recruitment, thus avoiding left censorship. Finally, we did not wish to restrict the study to patients with 'RA' as defined by the 1987 ARA criteria [14], which do not perform well in early disease. METHODS Study population The study population consisted of individuals referred to the Norfolk Arthritis Register (NOAR), a community-based inception cohort of patients with IP who are registered with a GP in the Norwich Health Authority. AH patients had a disease onset after January IP is denned as swelling of at least two joint areas which has persisted for a minimum of 4 weeks British Society for Rheumatology

2 HARRISON ET AL.: NATURAL REMISSION IN INFLAMMATORY POLYARTHRITIS 1097 TABLE I ARA preliminary criteria for clinical remission in RA* [4] 1. Morning stiffness <15min 2. No history of fatigue 3. No history of joint pain 4. No joint tenderness or pain on motion 5. No soft tissue swelling of joint or tendon sheath 6. ESR <20mm/h in males or <30mm/h in females Five or more of the criteria must be fulfilled for at least two consecutive months. Patient appraisal Patients are seen, within 2 weeks of notification, by metrologists who take a structured history and examination, and administer the HAQ [15]. Blood is taken for analysis of RF with a titre of ^1:40 being regarded as positive. Patients are reviewed at 1 and 2yr. Patient group By December 1994, 992 patients had been appropriately notified to NOAR, of whom 358 were reviewed at 2 yr and had a disease duration of < 12 months when first seen. A total of 75/992 (7.6%) patients were lost to follow-up (44 refused and 31 could not be traced) and 22 (2.2%) had died. The remaining patients were not yet due for their assessments. The study population thus consisted of 358 individuals of whom 302 (84%) had RF information at baseline. Disease classification Patients were classified as having RA or UIP according to whether or not they satisfied the 1987 ARA criteria [14] at baseline. The criteria were applied in two ways: (i) the traditional 'list' format, in which patients are classified as having RA if they satisfy at least four of the six criteria (excluding X-rays); (ii) the 'classification tree', in which metacarpophalangeal (MCP) swelling or wrist swelling can be substituted for missing X-ray or RF information, respectively. Authors Short and Bauer Nissila et al. Alarcon et al. Eberhardt el al. Wolfe et al. Turin and Bacon Suarez-Almazor et al. Suarez-Almazor el al. Year Ref. no UTP, undifferentiated inflammatory Setting hospital admissions ref. from GPs and clinics tertiary referral clinic ref. from primary care Wichita arthritis centre early arthritis clinic inception cohort with 1985 onset inception cohort with 1985 onset TABLE II Studies of remission in inflammatory polyarthritis. Patients 250 RA 376 RA and 107 non-specific arthritis with < 6/12 disease 181 Americans and 44 Peruvians with established RA 89 RA with <2 yr disease 503 RA and 638 UIP* with <2 yr disease 65 peripheral symmetrical synovitis with <6/12 disease 128 RA 128 RA 1 Vflf 2 v«ni 27 In rantfuton 13 In miiuion fiuulmr) 188p«raiitant 19 «i mntaion (Tuonmd*) 23 In rwnteion 50pentitant Fio. 1. Rates of remission at I and 2 yr in patients with RA and UIP. Remission criteria Patients were said to be in remission if they had no evidence of arthritis (soft-tissue swelling) on examination and had received no treatment with second-line drugs or steroids in the preceding 3 months. These criteria were applied at 1 and 2 yr. Statistical analysis Patient data were entered and analysed using the Statistical Package for the Social Sciences (SPSS) [16] and STATA [17]. Univariate analysis. The following baseline variables were assessed for their ability to predict: (i) remission at 1 yr; (ii) remission at 1 and 2 yr. Clinical: absence of arthritis (swelling of any joint within the joint area) of the following: proximal interphalangeal joints (PIP), MCP joints, wrists, elbows, shoulders, knees, ankles or metatarsophalangeal joints (MTP); arthritis of <3 polyarthritis Definition of remission no symptoms and no synovitis no symptoms opinion of rheumatologist ARA remission criteria [4] no symptoms 'self-limiting synovitis' ARA remission criteria [4] short remission criteria [6] % in remission 15 7 RA 59 non-specific 14 American 39 Peruvian 16 8 RA 54 UIP' Time 'at latest assessment' 3 yr at time of assessment 2yr average 6.9 yr 1 yr 6-7 yr 6-7 yr

3 1098 BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO. 11 TABLE III Univanate analysis for predicting remission at 2 yr using total patient sample; n = 358 (variables shown in order of LRs) Variable Not RA No arthritis of hand joints HAQ score of 0 No MCP* < 5 swollen joints HAQ score <0.5 Arthritis <3 joint areas < 6 tender joints EMS <60min No symmetry Not RAJ HAQ score <0.25 HAQ score <0.75 Age <45 yr RF negative HAQ score < 1 No PIP* No large jointst < 15 tender joints Male gender Sensitivity 42/91 15/91 15/91 34/91 42/91 41/91 33/91 43/91 41/91 38/91 59/91 19/91 51/91 31/91 64/75 61/89 34/91 68/91 72/91 37/91 46% 17% 17% 37% 46% 45% 36% 47% 45% 42% 65% 21% 56% 34% 85% 69% 37% 75% 79% 41% Specificity 1.R 209/ / / / / / / / / / / / / /267 88/ / / / / /267 78% : 11 92% ; >.O 92% : %.8 74%.8 75%.8 78%.7 71%.6 71%.5 72%.5 57%.5 86%.5 63%.5 76%.4 39%.4 51%.4 73%.4 42%.3 41%.3 69%.3 *No swelling in any of the joints within the joint area, ti.e. swelling of knee, elbow, or shoulder. JRA as denned by satisfying at least four of the six 1987 ARA 'list' criteria, excluding X-rays. RA according to the 1987 ARA 'classification tree'. joint areas; no arthritis of the hand joints; no arthritis of the large joints (elbow, shoulder, knee); total number of tender joints (divided into tertiles: 0-5, 6-14, > 14); total number of swollen joints (divided into tertiles: 0-4, 5-12, >12); early morning stiffness (EMS) <60min; no symmetry, no nodules; HAQ score (0, <0.25, <0.5, <0.75, <1); failure to satisfy the 1987 ARA criteria by the 'list' method; and failure to satisfy ARA criteria by the 'tree' method. Laboratory: RF negative (titre < 1:40). Demographic: age (divided into quartiles); gender; and disease duration, i.e. the length TABLE IV Baseline characteristics of prediction and validation samples Median age (yr) [range] Median disease duration (days) [range] Females RA* RAt RF positive Second-line drugs or steroids Prediction sample n [19-88] 115 [4-364] % % % 61 31% % Validation sample n [19-86] 120 [24-352] 66 64% 51 50% 77 75% 38 37% 56 54% RA as defined by satisfying at least four of six criteria. tra as defined by classification tree. JMann-Whitney l/-test (two-tailed). Ever used. % difference [95% CI] P = 0.96J P t 0 [ 11, 12] 5 [ - 6, 18] -4[- 14,7] 6[ 18, 5] -2[- 15,9] of time from symptom onset to the baseline assessment (divided into tertiles). The variables were compared in terms of their sensitivity, specificity and likelihood ratios (LR). The LR expresses the improvement in prediction over the baseline situation (which is the population prevalence of the outcome). Multivariate analysis. For this analysis, the 56 patients without RF information were excluded. The dependent variables were (i) remission at 2 yr and (ii) remission at 1 and 2 yr. The models were developed on a random sample of 66% of the group ('prediction sample', n = 199) and then tested on the remaining 33% ('validation sample'; n = 103) to determine their accuracy. Variables measured at baseline which had an LR of 3? 1.3 were entered into a backwards stepwise logistic regression model, along with use of second-line drugs or steroids within the previous 2 yr. An LR of 1.3 is considered a low cut-off point and was chosen so that only those variables with a very weak association with remission would be excluded from multivariate analysis. Variables were excluded from the logistic regression model if they had a weak association with the outcome, as judged by a P value of > 0.2. The final models were then tested for their ability to predict remission using the 'validation sample'. RESULTS Approximately half (52%) of the 358 patients in the study population were classified as having RA according to the 'list' format and. 72% using the classification 'tree'. Only one-third of the group were seropositive for RF at baseline, which reflects the fact that this is a community-based sample of patients with early disease. At 1 yr, 51 patients (14%) were in remission, 32 of whom (9% of the whole cohort) were also in remission at 2 yr. At 2 yr, the total number of patients in remission was 91 (25% of the whole cohort). In addition to our own definition of remission, we also used four of the ARA remission criteria (information on the ESR and fatigue is not collected). These were applied on the day the patient was seen rather than over a 2 month period as specified by the ARA. The proportions of patients who satisfied the individual criteria were: EMS of <15min (57%); no history of joint pain (49%); no joint tenderness (22%); no joint swelling (33%). Only 43 patients (12%) satisfied all four of these criteria at 2 yr. Figure 1 shows the remission rates at 1 and 2 yr amongst patients classified as having RA (using the classification tree) and those with UIP. Remission rates at 2yr were 19% (RA) and 42% (UIP). The TABLE V Variables selected by backwards stepwise logistic regression to predict remission at 2 yr Variable OR [95% CI] No treatment with second-line drugs/steroids 8.7 [ ] Male gender 3.9 [ ] < 6 tender joints 3.8 [ ]

4 HARRISON ET AL;. NATURAL REMISSION IN INFLAMMATORY POLYARTHRITIS 1099 corresponding rates for remission at 1 and 2 yr were 5% (RA) and 19% (UIP). Of patients in remission at 2 yr, fewer met the classification criteria for RA at baseline, using either the 'list' format (35%) or the 'tree' format (54%). Fewer had also been treated with second-line drugs or steroids during the preceding 2 yr (20 vs 60%). The results of univariate analysis are shown in Table III for those variables with an LR of at least 1.3 for predicting remission at 2 yr. The highest LRs were obtained from failure to satisfy the classification criteria for RA using the 'tree' method, no arthritis of the hand joints, HAQ score of zero, no MCP swelling and < 5 swollen joints. For predicting remission at 1 and 2 yr, the results were similar, with the addition of arthritis of < 3 joint areas and absence of symmetry. However, none of the variables had particularly high LRs, which reflects the fact that an outcome such as remission cannot be explained by the effect of a single clinical variable. Multivariate analysis allows the effect of each variable to be combined, so that their individual effects are adjusted for those of all the other variables. The baseline characteristics of the prediction and validation samples were very similar (Table IV). A logistic regression model (Table V) was developed to predict which patients would be in remission at 2 yr. Patients who had been treated with second-line drugs or steroids at any time during the 2 yr were less likely to be in remission. This may partly reflect the fact that drug usage is a marker of disease severity, and also that our definition of remission excluded patients who had recently received treatment with second-line drugs or steroids. Baseline variables associated with remission were male gender and < 6 tender joints. The validation sample was used to test the model's ability to identify correctly those individuals who would be in remission at 2 yr. The model was correct in 75/103 (73%) cases. Specificity was high (69/79 = 87%), but sensitivity was low (6/24 = 25%). When the same technique was used to predict patients who would be in remission at 1 and 2 yr, the sensitivity was zero, i.e. the model was unable to assign any individual a probability >0.5 of having this outcome. DISCUSSION Of 358 patients with early IP, 91 (25%) were in remission 2 yr after their initial presentation, 32 of whom had also been in remission at 1 yr. This is a low proportion considering that the study population was derived from a community-based inception cohort of patients with early IP. None of the patients in remission had taken second-line drugs within the previous 3 months. If we had simply defined remission as being 'no arthritis on examination' (thereby including treated patients), then a further 24 patients could be classified as being in remission at 2 yr. If, on the other hand, we had used the ARA remission criteria, it is likely that the number of patients in remission in our cohort would have been much lower. The rates from previous studies have been variable (Table II). Eberhardt et al. [9] found that 16% of patients with early RA satisfied the ARA remission criteria at 2 yr. Nissila et al. [7], also studying early disease, found that only 6.5% of patients with RA were asymptomatic at 3 yr. The differences might be due to the definition of remission used; however, they may also be ascribed to methods of patient referral and selection. Remission is a state of inactive disease as judged by both the patient and the clinician, and may either occur naturally or be drug induced. The disease runs a fluctuating course, so that a patient may be classified as being in remission one week and having active disease the next. Resolution, on the other hand, implies complete arrest of the disease process, while the patient is not taking any treatment (akin to a 'cure' in the natural history of cancer). However, even a patient who has been disease free for a prolonged period may relapse in the future, and so many people prefer the term 'sustained remission'. To illustrate the problem with applying remission criteria at a single point in time, 51 of our patients were in remission at 1 yr, but only 32 remained so at 2 yr. Tunn and Bacon [11] found that over half of 65 patients with peripheral symmetrical polyarthritis had no evidence of disease 12 months later. These patients were described as having 'self-limiting synovitis'; however, this might not have been the case if they had been reviewed at a later date. In common with previous workers who have stressed the difference in outcome between patients with RA and those with UIP [7, 10], this study found rates of remission to be more than twice as high in patients with UIP. Also in agreement with other studies, we have found that males were more likely to resolve [13,18]. Short [18] found that younger patients were more likely to remit, whereas Wolfe and Hawley [13] found the opposite. We found no strong association with age. In contrast to other workers [10, 11], we found no association with disease duration. The effect of this variable, however, depends on the observed disease duration within the study population, and also on the length of follow-up. The median disease duration in our study was ~4 months. This is slightly longer than that reported by Tunn and Bacon [11], who restricted entry to patients with <6 months disease. Although our aim was to study patients as close as possible to disease inception, there were a number of inevitable delays. Firstly, in order for the patient to be eligible for referral to NOAR, a minimum symptom duration of 4 weeks was required, and secondly, following notification, there was a 2-3 week delay until the patient was visited at home by a NOAR metrologist. Other studies have reported that being RF negative is an important predictor of resolution. Two-thirds of our patients were seronegative for RF, which may explain why it did not emerge as a strong predictor. A number of possible predictors were not investigated in this study, (i) X-ray: results were not available at baseline and, further, of those patients X-rayed at 1 yr,

5 1100 BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO. 11 almost two-thirds were non-erosive, which would limit the specificity of this measure, (ii) Education level: this has been found to be a prognostic marker mainly in studies from the USA [19]. In the NOAR cohort, however, most patients were born in the 1930s, when very few people were educated beyond secondary level, (iii) HLA-DR4 status: the aim of this study was to identify simple clinical predictors which are easily measured at baseline. The role of DR4 alleles is, however, being explored elsewhere. This study is unique, being a true inception cohort of patients with IP in the community. Other studies have suggested that IP in the community is a mild disease with a benign course [20,21]. It is thus interesting to note that remission rates were low in this group. Although some weak predictors have been identified, it was impossible to predict with any degree of certainty who would resolve. Therefore, it has to be assumed that all patients will have persistent disease and early attempts should be made to control their symptoms. ACKNOWLEDGEMENTS This work was funded by the Arthritis and Rheumatism Council. We would like to acknowledge the contribution of the NOAR staff and metrologists: Diane Bunn, Linda Galpin, Sue Ivins, Angela Langrish-Smith, Pramilla van Poortvliet, Margaret Sommerville and Sue Whiting. We are also grateful to the GPs of the Norwich Health Authority for their dedication in referring patients to the register. REFERENCES 1. Hochberg MC. Predicting the prognosis of patients with rheumatoid arthritis: Is there a crystal ball? J Rheumatol 1993;20: Hunter T. The prognosis of early rheumatoid arthritis: How early is early? J Rheumatol 1993;20: Emery P. The disease course, prognosis and outcome of rheumatoid arthritis. Rheumatol Eur 1995;24(suppl. 2): Pinals RS, Masi AT, Larsen A. Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum 1981;24: Scott DL, Spector TD, Pullar T, McConkey B. What should we hope to achieve when treating rheumatoid arthritis? Ann Rheum Dis 1989;48: Short CL, Bauer W. The course of rheumatoid arthritis in patients receiving simple medical and orthopaedic measures. N Engl J Med 1948;238: Nissila M, Isomaki H, Kaarela K, Kiviniemi P, Martio J, Sarna S. Prognosis of inflammatory joint diseases. A three-year follow-up study. Scand J Rheumatol 1983; 12: Alarcon GS, Blackburn WD Jr, Calvo A, Castaneda O. Evaluation of the American Rheumatism Association preliminary criteria for clinical remission in rheumatoid arthritis: A prospective study. J Rheumatol 1987; 14: Eberhardt KB,- Rydgren LC, Pettersson H, Wollheim FA. Early rheumatoid arthritis onset, course and outcome over 2 years. Rheumatol Int 1990;10: Wolfe F, Ross K, Hawley DJ, Roberts FK, Catbey MA. The prognosis of rheumatoid arthritis and undifferentiated polyarthritis syndrome in the clinic: a study of 1141 patients. / Rheumatol 1993;20: Tunn EJ, Bacon PA. Differentiating persistent from self-limiting symmetrical synovitis in an early arthritis clinic. Br J Rheumatol 1993;32: Suarez-Almazor ME, Soskolne CL, Saunders D, Russell AS. Outcome in rheumatoid arthritis: a 1985 inception cohort study. J Rheumatol 1994;21: Wolfe F, Hawley DJ. Remission in rheumatoid arthritis. J Rheumatol 1985;12: Arnett FC, Edworthy SM, Bloch DA et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31: Fries JF, Spitz PW, Kraines RG. Measurement of patient outcome in arthritis. Arthritis Rheum 1980;23: Statistical package for the social sciences. SPSS Inc., Chicago, Stata Statistical Software: release 4.0. College Station, TX: STATA Corp., Short CL. Long remissions in rheumatoid arthritis. Medicine 1964;43: Pincus T, Callahan LF. Formal education as a marker for increased mortality and morbidity in rheumatoid arthritis. J Chron Dis 1985;38: Mikkelsen WM, Dodge H. A four year follow-up of suspected rheumatoid arthritis: The Tecumseh, Michigan, community health study. Arthritis Rheum 1966; 12: Cathcart ES, O'Sullivan JB. Follow-up evaluation of the effect of criteria on rates in Sudbury, Massachusetts. Ann Intern Med 1972;76:573-7.