Radiological progression in early rheumatoid arthritis after DMARDS: a one-year follow-up study in a clinical setting

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1 Rheumatology 2003;42: doi: /rheumatology/keg284, available online at Advance Access publication 16 April 2003 Radiological progression in early rheumatoid arthritis after DMARDS: a one-year follow-up study in a clinical setting R. Sanmarti 1,A.Gomez 1, G. Ercilla 2,J.Gratacos 3,M.Larrosa 2, X. Suris 4,O.Viñas 2,G.Salvador 1,J.Muñoz-Gomez 1 and J. D. Cañete 1 Objective. To analyse the frequency and prognostic factors of radiographic progression in a series of Spanish patients with early rheumatoid arthritis (RA) after 1 yr of treatment with disease-modifying anti-rheumatic drugs (DMARDs). Methods. Sixty patients (47 females, 13 males) with RA with a disease duration shorter than 2 yr wmean (S.D.) duration 9.5"6.6 monthsx were treated with the same therapeutic protocol using gold salts as the first DMARD and methotrexate as a second option, and were followed up for 1 yr. Radiographic progression in the hands and feet (total radiographic Larsen score and the erosion joint count) was used as the outcome variable. Clinical, laboratory, immunogenetic and radiographic data were obtained at study entry. Disease activity and response to therapy were measured at 6 and 12 months. Results. Erosive disease was found in 21.7% of patients at baseline and in 38.3% after 1 yr. Although a substantial reduction in disease activity was observed during the 1 yr follow-up wdisease activity score (DAS28) 5.8"0.8 at entry and 3.9"1.3 at 12 months, P < 0.001x, the Larsen score rose from 1.9"3.3 to 5.6"9.8 after 1 yr. In 26.6% of patients, a raised erosion joint count was observed after 1 yr. Radiographic progression in the total joint radiographic damage (increase in Larsen score of 02) was observed in 36.6%. In the multivariate analysis, baseline pain wvisual analogue scale (VAS)x and the presence of two copies of the shared epitope were associated with radiographic progression in the erosion joint count. Disease duration before study entry, VAS pain and Larsen score at baseline were significant predictors of radiographic progression in total damage (Larsen score). Baseline radiographic damage had the highest positive predictive value for progression. Conclusions. Radiographic progression was observed in up to 36.6% of patients with early RA after 1 yr of DMARD therapy in spite of a significant reduction in disease activity. Baseline factors, such as VAS pain, disease duration until DMARD therapy, damage score at baseline and the presence of two copies of the shared epitope, were associated with radiographic progression. Radiographic joint damage is an important outcome measure in rheumatoid arthritis (RA) w1, 2x, early erosions being markers of poor prognosis w3, 4x. Although recent studies have found linear progression of radiographic changes w5x, the rate of new erosions is high in the first years of the rheumatoid process w4, 6x. Early 1 Hospital Clínic, Rheumatology, Barcelona, 2 Hospital Clínic, Immunology, Barcelona, 3 Hospital Parc Taulí, Rheumatology, Sabadell, Barcelona and 4 Hospital de Granollers, Rheumatology, Granollers, Barcelona, Spain. Submitted 4 July 2002; revised version accepted 16 January Correspondence to: R. Sanmarti, Hospital Clı nic, Rheumatology, Barcelona, Spain. sanmarti@clinic.ub.es 1044 ß 2003 British Society for Rheumatology

2 Radiographic progression in early RA 1045 erosive changes in the hands and feet seem to be predictors of long-term disability w7x. Although initial factors, such as rheumatoid factor w6, 8 10x, are associated with a poor radiographic outcome in almost all early RA series, others, such as the HLA- DRB1 genotype w11x and elevated inflammatory activity at baseline w12x, remain controversial. Progression of joint damage in Mediterranean countries w9x, where the course of the disease may be more benign w13x, has been little studied. We evaluated the frequency and baseline prognostic factors of radiographic progression in Spanish early RA patients after 1 yr of treatment with a therapeutic DMARD (disease-modifying anti-rheumatic drug) protocol. Patients and methods Patients fulfilling American College of Rheumatology (ACR) criteria for RA w14x, with symptoms of <2 yr duration, were included. All were out-patients attending the rheumatology units of the Hospital Clinic of Barcelona or Hospital Parc Taulí of Sabadell between 1998 and 2000, and were followed for 12 months. Patients treated previously with DMARDs or prednisone >10 mguday were excluded. Hospital Clinic ethics committee approval was obtained. All patients underwent clinical examination at baseline and at 3, 6, 9 and 12 months. At baseline we recorded demographic characteristics, disease duration, serum rheumatoid factor, measured by nephelometry, antikeratin antibodies (AKA), measured by indirect immunofluorescence in rat oesophagus w15x, anti-cyclic citrullinated peptide antibodies (CCP), measured by ELISA (enzyme-linked immunosorbent assay) w16x and DRB1 genotype, determined by direct DNA sequencing. At baseline and 6 and 12 months, we recorded the level of pain measured with a visual analogue scale (VAS), the 28 tender and swollen joint count, patient and physician assessments of disease status on a Likert scale, the 28-joint disease activity score (DAS28), functional status by the modified Health Assessment Questionnaire (mhaq) w17x, erythrocyte sedimentation rate and C-reactive protein. Baseline and 12-month hand and foot radiographs were obtained and graded by the Larsen Scott method w18x. Thirtytwo joints were assessed: bilateral thumb interphalangeal (IP) joints, PIP joints 2 5, MCP joints 1 5, IP big toe joints, metatarsophalangeal joints 2 5 and wrists. Each wrist was considered a unit and its score was multiplied by 5. Thus, the Larsen score ranged from 0 to 200. An erosion joint count (EJC) was made, defined as the number of joints with any evidence of cortical erosion out of 32 joints. All radiographs were read by the same observer (RS) chronologically. As a measure of radiographic progression, we used the minimal clinically important difference (MCID) w19x, which was a change of 02 Larsen score units between baseline and 12 months. Any increase (one or more joints with erosions) in the EJC was also considered indicative of radiographic progression. All patients underwent a therapeutic protocol including gold salts (intramuscular sodium aurothiomalate 50 mguweek) as the first-choice DMARD together with methylprednisolone 4mguday. NSAIDs (non-steroidal anti-inflammatory drugs), preferentially indometacin and intra-articular steroid therapy with triamcinolone hexacetonide or acetonide, were used according to clinical judgement. Therapy response was evaluated at 6 and 12 months. Methotrexate at an increasing weekly dose of mg was instituted as DMARD monotherapy if adverse effects without clinical improvement or no ACR20 response was observed at 6 months. If a patient had an ACR50 response, including clinical remission, gold salts were scheduled every 2 3 weeks; if a patient had an ACR20 response but no ACR50 response, combination therapy with gold salts and methotrexate was initiated. Methylprednisolone therapy was tapered according to clinical judgement. Statistical analysis Outcome measures were radiographic progression measured separately by the EJC and Larsen score. The univariate analysis of categorical variables used the x 2 test or Pearson s exact test, and continuous variables were assessed with Student s t-test, or the Mann Whitney test if normality was hard to assume. For paired samples, the t-test, Wilcoxon or McNemar tests were used. Pearson or Spearman correlations were calculated. Marginally significant variables (P<0.15) in the univariate analysis were included in a logistic regression model and removed if the likelihood did not decrease significantly and remaining coefficients did not change by <15%. All two-level interactions were tested. Intra-observer agreement in Larsen score was assessed with the k statistic w20x on 25 randomly chosen pairs of hand and feet radiographs, with a k value of 0.77 w95% confidence interval (CI) x. Positive predictive values of baseline values were calculated to detect radiographic progression in Larsen score, and continuous values were transformed into categorical variables using median values as cut-off points. Results Sixty-five patients were enrolled initially. Five were lost to follow-up. The final cohort included 60 patients. Baseline characteristics are shown in Table 1. Disease duration was less than 6 months in 41% of patients. Mean DAS28 score at baseline was 5.8"0.8; it had decreased significantly after 1 yr to 3.9"1.3 (P < compared with baseline). Sodium aurothiomalate was taken as DMARD monotherapy by 32 (53.3%) patients at month 12. Methotrexate was taken by 38.4% at 12 months with a mean (S.D.) weekly dose of 12.5 (5.3) mg (21.7% as DMARD monotherapy and 16.7% in combination with gold). No DMARD was being taken by five patients at month 12 due to mucocutaneous side-effects of gold therapy; three of these patients were in clinical remission. After 1 yr, 55.3% of patients were still taking methylprednisolone with a mean (S.D.) daily dose of 2.6 (2.3) mg. Radiographic outcome Erosive disease was observed in 13 patients (21.7%) at baseline and in 23 patients (38.3%) at month 12. Mean EJC and Larsen scores increased from 0.6"1.7 to 1.1"1.7 and from 1.9"3.3 to 5.6"9.8 respectively. Radiological progression at 1 yr was observed in 22 (36.6%) patients when progression was defined by an increase of 02 Larsen score units and in 16 (26.6%) patients when it was defined by an increase in the EJC. All but one of the patients with EJC progression had radiographic progression in the Larsen score.

3 1046 R. Sanmarti et al. TABLE 1. Characteristics at baseline and after 6 and 12 months of 60 patients with early RA treated with DMARDs and low doses of methylprednisolone Baseline 6 months 12 months Women (%) 78.3 Age (yr), mean"s.d. 52.2"15.7 Disease duration (months), mean"s.d. 9.5"6.5 VAS pain (mm), mean"s.d. 51.2" "4.4 34" swollen joint count, mean"s.d. 8" " " tender joint count, mean"s.d. 10.2" " "5.3 DAS28, mean"s.d. 5.8" " "1.3 DAS28 <3.2 (%) DAS28 >5.1 (%) ACR20 response (%) ACR50 response (%) ACR70 response (%) Complete remission (%) mhaq, mean"s.d. 1" " "0.5 ESR (mmuh), mean"s.d. 45.3" " "20.6 CRP (mgudl) mean"s.d. 2.9"3.1 2" "1.7 Rheumatoid factor-positive (%) 78.3 AKA-positive (%) 61.7 Anti-CCP-positive (%) 56 HLA-DRB1-04 (%) 50 Shared epitope (%) 74 Shared epitope homozygosity (%) 22.2 Erosive disease (%) EJC, mean"s.d. 0.6" "1.7 Larsen score, mean"s.d. 1.9" "9.8 Patients receiving methylprednisolone 89.5% 71.1% 55.3% Patients receiving methotrexate 0% 6.7% 38.4% Factors predictive of Larsen radiographic progression Baseline variables significantly associated with radiological progression in Larsen score in the univariate analysis were VAS pain (P=0.019) and Larsen score (P=0.039). A non-significant trend was observed with disease duration, mhaq, shared epitope homozygosity and DRB04 alleles. The absence of complete remission at month 6 (P=0.02) and the tender joint count at month 12 (P=0.02) were significantly associated with radiographic progression. Baseline radiographic damage measured by EJC and Larsen scores had the highest positive predictive value for radiographic progression (61.5 and 60.9% respectively) (Table 2). A non-significant trend in radiographic progression was observed in patients without ACR20 and ACR50 responses. No differences were observed between progressors and non-progressors in daily cumulative dose of methylprednisolone or the number of days with 04 mg methylprednisolone (3.5"2.3 mguday vs 3.2"1.7 and 257.7"147.7 days vs 241.6"124 respectively; not significant). In the multiple regression analysis, disease duration wodds ratio (OR) 1.15, 95% CI x, VAS pain at entry (OR 1.02, 95% CI ) and Larsen score at entry (OR 1.06, 95% CI ) were independent factors associated with total radiographic progression. Factors predictive of EJC progression Shared epitope homozygosity was observed in 42.9% of patients with EJC radiographic progression and in 15% without (OR 4.25, 95% CI , P=0.038). HLA-DRB04 alleles (71.4 vs 42.5%, P=0.07) and VAS pain at baseline (59.2"23.4 vs 48"21.2, P=0.08) showed a clear non-significant trend of association. In the regression analysis, shared epitope homozygosity (OR 5.7, 95% CI ) and VAS pain at entry (OR 1.02, 95% CI ) were associated with EJC progression. Discussion The prevalence of erosive disease at entry in this RA cohort was only 21.7%, reflecting the short disease duration prior to DMARD therapy, with a mean of 9.5 months and less than 6 months disease duration in 41% of patients. In patients with RA of less than 2 yr duration, Mottönen et al. w21x found 29% had erosive disease at entry, similar to other studies w22x, although rates of 61 67% in early RA are reported w23, 24x, probably reflecting different erosion criteria. At 1 yr, the percentage with erosive disease rose significantly, from 21.7 to 38.3%. Radiographic progression at 1 yr was found in a significant proportion of patients: in 26.6% when the criterion was a raised EJC and in 36.6% when it was a 2-unit change in Larsen score. Some prospective studies of radiographic damage and predictive factors of joint damage at 1 yr in early RA patients have analysed radiographic damage or erosions at the end of followup rather than radiographic progression w8, 25, 26x. This study used the MCID, which is recommended when using the Larsen Scott method to measure 1 yr

4 Radiographic progression in early RA 1047 TABLE 2. Baseline variables in the cohort of patients with early RA with and without 1 yr radiographic progression (change in Larsen score). Results of the univariate analysis and positive predictive values Baseline variable Progression (n=22) No progression (n=38) OR 95% CI P PPV Gender (% women) 86.3% 73.6% , 9.32 NS 23.1% Age (yr) 53.1" " , 1.18 NS 34.5% Disease duration (months) 11.7" " , % Tender joint count 11.7" " , 1.20 NS 44.8% Swollen joint count 7.1" " , 1.04 NS 25% DAS " " , 3.07 NS 36.7% VAS pain (0 100 mm) 60.3" " , % ESR (mm) 45.1" " , 1.02 NS 31% CRP (mgudl) 2.9" " , 1.21 NS 33.3% mhaq (0 3) 1.2" " , % RF-positive 77% 79% , 1.28 NS 34.8% AKA-positive 55% 66% , 1.83 NS 32.4% Anti-CCP-positive 50% 59% , 1.97 NS 33.3% Erosion joint count 1.1" " , 3.00 NS 61.5% Larsen score 3.1" " , % Shared epitope* 78.9% 71.4% , 5.64 NS 37.5% SE-homozygous* 31.6% 17.1% , 8.24 NS 50% DRB04* 63.2% 42.9% , 7.20 NS 44.4% Results are mean"s.d. or percentage. *DRB typing was analysed in 54 patients. Continuous variables are transformed into categoricals to calculate the positive predictive values of progression (see text). ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; RF, rheumatoid factor; SE, shared epitope; PPV, positive predictive value; NS, not significant. progression in early RA patients w19x, and to our knowledge this is the first study of prognostic factors in early RA to do so. As we used two separate criteria to define radiographic progression, thus identifying similar but not equal populations, it is not surprising that some variables predict radiological progression using one criterion but not the other. For example, homozygosity for the shared epitope was a predictor of progression measured by the appearance of new erosions, and a clear trend was also observed in HLA-DRB04 alleles containing the rheumatoid epitope. By contrast, none of these immunogenetic markers was significantly associated with progression when total Larsen score was the measure of damage progression. Whether immunogenetic traits predict erosive disease rather than more severe structural damage is difficult to ascertain. The exact role of DRB1 genes in the severity of RA remains controversial, some reports showing more substantial radiographic joint damage with DRB04 alleles, in particular with genotypes homozygous for the shared epitope w26, 27x, and others finding no relationship with the severity of radiographic damage w28x or finding it only in patients with seronegative disease w29x. However, a recent report suggests that early DMARD therapy may modify the association between DRB1 genotype and disease severity w30x. Rheumatoid factor, a powerful predictor of joint damage in early RA w1, 6, 8, 11, 13x, was not associated with radiographic progression in our study, although the number of seronegative cases was small, and a type II error due to insufficient sample size cannot be excluded. Rheumatoid factor positivity after 1 yr of DMARD therapy (not analysed in this study) may predict radiographic progression better than seropositivity at entry w31x. Furthermore, some of our seronegative patients may become rheumatoid factor-positive during followup. Neither AKA nor anti-ccp antibodies were associated with radiographic progression in our study, as in other reports w9x, although an independent association of erosions in early RA with these antibodies has been reported w32x. Disease duration until DMARD therapy was associated with progression of total damage score. Although this could be influenced by a worse radiographic score at study entry, a known factor predicting radiographic progression w3, 6, 9x, as in this study, regression analysis showed that disease duration was an independent factor. However, as in the 3 yr prospective study of radiographic progression in early RA by Combe et al. w9x, baseline radiographic damage emerged as one of the most important markers of radiographic progression, with the highest positive predictive values (about 60%) in our study. Unlike comparable studies, all patients received a structured therapeutic regimen using gold salts as the first DMARD, and methotrexate in monotherapy or in combination with gold salts if patients were unresponsive or suffered adverse events. Both drugs cause significant slowing of radiographic damage in RA patients, with no differences between them at 1 and 3 yr of follow-up w33, 34x. However, most patients received lowdose corticosteroids, which could contribute to reduced radiographic progression w35x, although no association between accumulated methylprednisolone doses and radiographic progression was observed in our study. In several studies, disease activity measured by clinical or laboratory parameters at study entry or as a timeintegrated value w36, 37x correlated with structural

5 1048 R. Sanmarti et al. damage, although this was not the case in other surveys w38x. Multivariate analysis identified no factor related to disease activity at baseline or response to therapy during the follow-up period in our study. However, in the univariate analysis, the absence of complete remission at month 6 and a high 1 yr tender joint count was associated with radiographic progression. This probably reflects the fact that both baseline factors and the effects of DMARD therapy on inflammation play a role in structural damage, although the complex interrelationship between these variables is not well understood. Limitations of the present study include the relatively small sample size, which could mean that the associations with some variables were weaker than they really are. Furthermore, as a significant proportion of patients may develop radiographic progression or new erosions after the second year of disease w39x, the results, especially at 1 yr, should be interpreted cautiously. However, the positive predictive values of the baseline variables for progression were mostly lower than 50%, limiting their individual value as progression markers. In conclusion, in one-third of patients with early RA who were treated with DMARDs, a significant increase in radiographic damage was found after 1 yr of followup. Several baseline factors, such as VAS pain, radiographic damage, disease duration and immunogenetic traits, were found to be predictors of progression. Whether these factors can predict structural damage in the long term, and thus warrant more aggressive therapeutic approaches, remains to be determined. Acknowledgements The authors would like to thank Joan Vila of the Municipal Institute of Medical Research (IMIM-Barcelona) for help with the statistics. 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