Progression of joint damage in early rheumatoid arthritisAssociation with HLADRB1 rheumatoid factor and anticitrullinated protein antibodies in relation to different treatment strategies.код для вставкиСкачать
ARTHRITIS & RHEUMATISM Vol. 58, No. 5, May 2008, pp 1293–1298 DOI 10.1002/art.23439 © 2008, American College of Rheumatology Progression of Joint Damage in Early Rheumatoid Arthritis Association With HLA–DRB1, Rheumatoid Factor, and Anti–Citrullinated Protein Antibodies in Relation to Different Treatment Strategies J. K. de Vries-Bouwstra,1 Y. P. M. Goekoop-Ruiterman,2 K. N. Verpoort,2 G. M. T. Schreuder,2 J. A. P. M. Ewals,3 J. P. Terwiel,4 H. K. Ronday,3 P. J. S. M. Kerstens,5 R. E. M. Toes,2 R. R. P. de Vries,2 F. C. Breedveld,2 B. A. C. Dijkmans,1 T. W. J. Huizinga,2 and C. F. Allaart2 Objective. To determine the association of HLA– DRB1, rheumatoid factor (RF), and anti–citrullinated protein antibody (ACPA) status with progression of joint damage in early rheumatoid arthritis (RA) treated according to different treatment strategies. Methods. The present study was conducted using data from the BeSt study (Behandelstrategieën voor Reumatoide Artritis [treatment strategies for rheumatoid arthritis]), a randomized trial comparing 4 targeted (toward achievement of a Disease Activity Score [DAS] of <2.4) treatment strategies: sequential monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with methotrexate, sulfasalazine, and prednisone (group 3), and initial combination therapy with methotrexate and infliximab (group 4), in 508 patients with early RA. Multivariate logistic regression analysis was used to predict progressive disease (increase of Sharp/van der Heijde score over 2 years beyond the smallest detectable change [4.6]) according to the presence or absence of the shared epitope (SE), DERAA, RF, and ACPA, with correction for other baseline characteristics. Results. Progressive disease could not be predicted by presence of the SE: the odds ratio in groups 1, 2, 3, and 4, respectively, was 1.4, 2.6, 1.9, and 3.0. DERAA carriership did not protect against progressive disease (odds ratio 0.4, 1.4, 0.9, and 0.9 in groups 1, 2, 3, and 4, respectively). RF positivity and ACPA positivity predicted progressive disease in group 1 (odds ratio 4.7 [95% confidence interval 1.5–14.5] for RF and 12.6 [95% confidence interval 3.0–51.9] for ACPA), but not in groups 2–4 (for RF, odds ratio [95% confidence interval] 1.5 [0.5–4.9], 1.0 [0.3–3.3], and 1.4 [0.4–4.8] in group 2, group 3, and group 4, respectively; for ACPA, odds ratio [95% confidence interval] 3.4 [0.8–14.2], 1.7 [0.5–5.4], and 1.8 [0.5–6.8] in group 2, group 3, and group 4). Conclusion. In patients with early RA treated with the goal of tight control of the DAS, no significant association between HLA–DRB1 status and radiographic progression was found. RF and ACPA were predictive of progressive disease only in patients treated with sequential monotherapy. These observations suggest that effective treatment can prevent ISRCTN: 32675862. The BeSt study is supported by a study grant from the Dutch College for Health Insurance; additional funding was provided by Centocor and Schering-Plough. 1 J. K. de Vries-Bouwstra, MD, PhD, B. A. C. Dijkmans, MD, PhD: VU University Medical Center, Amsterdam, The Netherlands; 2 Y. P. M. Goekoop-Ruiterman, MD, PhD, K. N. Verpoort, MD, G. M. T. Schreuder, PhD, R. E. M. Toes, PhD, R. R. P. de Vries, MD, PhD, F. C. Breedveld, MD, PhD, T. W. J. Huizinga, MD, PhD, C. F. Allaart, MD, PhD: Leiden University Medical Center, Leiden, The Netherlands; 3J. A. P. M. Ewals, MD, H. K. Ronday, MD, PhD: Haga Hospital, The Hague, The Netherlands; 4J. P. Terwiel, MD: Spaarne Hospital, Haarlem, The Netherlands; 5P. J. S. M. Kerstens, MD, PhD: Jan van Breemen Institute, Amsterdam, The Netherlands. Dr. de Vries-Bouwstra has received speaking fees (less than $10,000) from Schering-Plough. Dr. Dijkmans has received consulting and speaking fees (less than $10,000) from Schering-Plough, Wyeth, and Abbott. Dr. Allaart has received consulting fees, speaking fees, and/or honoraria (less than $10,000) from Schering-Plough. Address correspondence and reprint requests to J. K. de Vries-Bouwstra, MD, Department of Rheumatology C1R, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail: email@example.com. Submitted for publication February 23, 2007; accepted in revised form January 18, 2008. 1293 1294 DE VRIES-BOUWSTRA ET AL radiographic progression, even in patients with risk factors for severe damage. Positivity for certain HLA class II alleles and for autoantibodies, notably rheumatoid factor (RF) and anti–citrullinated protein antibody (ACPA), is known to be associated with susceptibility to and severity of rheumatoid arthritis (RA) (1,2). The presence of the HLA–DRB1 alleles *0101, *0102, *0401, *0404, *0405, *0408, *0410, *1001, or *1402, all sharing an amino acid sequence in the third hypervariable region (HVR3) (known as the shared epitope [SE]), is associated with susceptibility to RA and more severely destructive RA (2). Other studies have shown the DRB1 alleles *0103, *0402, *1102, *1103, *1301, *1302, and *1304, all containing the DERAA motif in HVR3, to be negatively associated with RA progression (3). The presence of RF is not unique to RA, but has been consistently reported to be associated with more severe joint damage in RA (4). More recently, the presence of ACPAs was shown to be predictive of and highly specific for RA (5). ACPAs are also associated with more destructive disease (1). In order to better prevent severe and destructive disease, treatment of RA can be initiated immediately after diagnosis, and antirheumatic drugs are more frequently being prescribed in combination. In many of the studies demonstrating the association of autoantibodies and/or SE alleles with more severe joint destruction, data were derived from early arthritis inception cohorts that included RA patients who were not treated according to current standards (6,7). Lard et al showed that with early and aggressive treatment, the association between SE positivity and radiographic progression disappears (8). In the BeSt study (Behandelstrategieën voor Reumatoide Artritis [treatment strategies for rheumatoid arthritis]) (9), a comparison of 4 intensive treatment strategies in patients with newly diagnosed RA, treatment was adjusted until low disease activity was achieved. In all treatment groups, this resulted in remarkable suppression of radiographic progression (10). In this unique cohort of patients, we explored the influence of treatment strategies on the association of joint destruction with DRB1, RF, and ACPA status. PATIENTS AND METHODS Patients and treatment protocol. The BeSt study was a randomized, controlled trial of 508 patients with newly diagnosed RA that fulfilled the 1987 criteria of the American College of Rheumatology (formerly, the American Rheumatism Association) (11). None of the patients had received treatment with disease-modifying antirheumatic drugs. The patients were allocated into 4 treatment groups: sequential monotherapy (group 1; n ⫽ 126), step-up combination therapy (group 2; n ⫽ 121), initial combination therapy including high/tapered-dose prednisone (group 3; n ⫽ 133), and initial combination therapy including infliximab (n ⫽ 128). Use of prednisone was allowed only as dictated by the protocol. In all groups the goal was to achieve good clinical response as defined by the Disease Activity Score (DAS) (12). Every 3 months, the DAS, based on a 44-joint count, was calculated. If the DAS was ⬎2.4, treatment was adjusted according to the protocol for the particular treatment group. If the DAS remained at ⱕ2.4 for at least 6 months, the numbers and dosages of drugs were tapered until only 1 drug remained, at a maintenance dosage. Further details on the patient population, treatment protocol, and primary outcomes have been published elsewhere (10). Baseline characteristics. The following parameters were assessed in all patients at study entry: age, sex, current smoking status, duration of symptoms, time between diagnosis and study enrollment, DAS, C-reactive protein (CRP) level, morning stiffness assessed by the patient on a visual analog scale, radiographic damage score (see below), presence of erosions, and functional ability as measured with the Health Assessment Questionnaire (HAQ) (13). HLA genotyping. HLA class II typing was performed in all patients who provided written informed consent for sampling of DNA material (n ⫽ 113, 102, 115, and 111 in groups 1, 2, 3, and 4, respectively). HLA–DRB1 subtyping was performed by polymerase chain reaction using specific primers and hybridization with sequence-specific oligonucleotides. All patients carrying DRB1*0101, *0102, *0401, *0404, *0405, *0408, *0410, *1001, or *1402 were considered to be SE positive; all patients carrying DRB1*0103, *0402, *1102, *1103, *1301, *1302, and *1304 were considered DERAA positive. Based on the subtyping, information on SE carriership was obtained in 417 patients (95% of typed patients). Thirteen patients were homozygous for the SE (n ⫽ 1, 4, 6, and 2 in groups 1, 2, 3, and 4, respectively). DERAA status was determined in 383 patients (87% of typed patients). Autoantibody determination. The presence of RF was determined at baseline at the laboratories of the centers participating in the BeSt study (n ⫽ 19), based on the validated cutoff value at the particular laboratory. At the time of enrollment, testing for ACPA was not commonly performed in the participating centers, and different commercial kits were used (Euro-Diagnostica, Arnhem, The Netherlands and Axis Shield, Dundee, UK). The presence of ACPA was determined using baseline sera from 119 patients. In 309 patients, the presence of ACPA was determined from serum samples obtained during followup. Recent evidence indicates that presence or absence of ACPA is a stable characteristic (14). Therefore, all 428 patients (84%) with available data on ACPA status from either time point were included in the analysis (104 [83%] from group 1, 104 [86%] from group 2, 109 [82%] from group 3, and 111 [87%] from group 4). Determination of radiographic progression. Radiographs of both hands and both feet, obtained at baseline and after 2 years, were available in 455 patients (90%) (111 [88%] from group 1, 105 [87%] from group 2, 123 [92%] from group 3, and 116 [91%] from group 4). Radiographic progression over 2 years was determined independently by 2 observers. GENETIC AND ANTIBODY ASSOCIATIONS WITH RA PROGRESSION, BY TREATMENT 1295 Table 1. Baseline characteristics of the 508 patients with early RA* Treatment group Age, median (IQR) years Female Duration of symptoms, median (IQR) weeks Time between diagnosis and enrollment, median (IQR) weeks HAQ score, median (IQR) DAS, median (IQR) SHS, median (IQR)† Erosive disease† Rheumatoid factor positive ACPA positive‡ Shared epitope positive§ DERAA positive¶ Smoker# Sequential monotherapy Step-up combination therapy Initial combination therapy with prednisone Initial combination therapy with infliximab 54 (45–63) 86 (68) 23 (14–54) 2 (1–5) 54 (45–64) 86 (71) 26 (14–56) 2 (1–4) 55 (43–65) 86 (65) 23 (15–52) 2 (1–4) 54 (45–63) 85 (66) 23 (13–46) 3 (1–5) 1.4 (1.0–1.9) 4.5 (3.9–5.2) 3.5 (1.5–9.5) 89 (72) 84 (67) 68 (65) 69 (64) 19 (19) 45 (37) 1.4 (0.9–1.9) 4.4 (3.9–5.1) 5.0 (1.5–8.1) 82 (70) 77 (64) 61 (59) 60 (62) 10 (11) 44 (39) 1.4 (1.0–2.0) 4.3 (3.8–5.0) 3.5 (1.5–8.5) 93 (71) 86 (65) 60 (55) 75 (69) 16 (16) 44 (35) 1.4 (0.9–1.8) 4.2 (3.7–4.9) 4.0 (1.5–8.5) 93 (73) 82 (64) 72 (65) 74 (71) 22 (23) 40 (32) * Except where indicated otherwise, values are the number (%). RA ⫽ rheumatoid arthritis; IQR ⫽ interquartile range; HAQ ⫽ Health Assessment Questionnaire; DAS ⫽ Disease Activity Score; SHS ⫽ Sharp/van der Heijde score; ACPA ⫽ anti–citrullinated protein antibody. † n ⫽ 455. ‡ n ⫽ 428. § n ⫽ 417. ¶ n ⫽ 383. # n ⫽ 487. Paired (in random order) radiographs of the hands and feet were scored according to the Sharp/van der Heijde method (15), under blinded conditions. The intraobserver coefficients were 0.90 and 0.91, and the interobserver coefficient was 0.94. The mean score from the 2 observers was used for all analyses. Erosive disease was defined as a mean erosion score of ⱖ0.5. Progressive disease was defined as a change in the total Sharp/van der Heijde score (SHS) over 2 years greater than the smallest detectable change (i.e., 4.64) (10). Statistical analysis. Baseline characteristics were compared among subgroups of patients by analysis of variance or Kruskal-Wallis test for comparison of means and medians, and chi-square test for comparison of proportions. Progression of radiographic damage was compared between subgroups of patients, defined based on the presence or absence of SE, DERAA, RF, and ACPA, in each of the 4 treatment groups. Logistic regression analysis was performed to evaluate whether progressive disease was significantly influenced by the presence of SE, DERAA, RF, or ACPA in any of the treatment groups after correction for characteristics significantly associated with radiographic outcome and/or presence of SE, DERAA, RF, or ACPA. The following baseline characteristics were analyzed for possible association with SE carriership, DERAA carriership, presence of RF, presence of ACPA, or progressive disease: sex, age, smoking status, duration of symptoms, DAS, CRP level, duration of morning stiffness, HAQ score, SHS, and erosive disease. All variables shown to be significantly different between patients with and those without the characteristic of interest were entered into the regression analyses as possible confounders (with cutoffs for continuous variables defined by the mean value in the population under study). RESULTS At baseline, disease characteristics of patients in the 4 groups were comparable (Table 1). Sixty-seven percent of the patients were SE carriers and 17% were DERAA carriers, with equal distribution among the treatment groups. Sixty-five percent of the patients were RF positive and 61% were ACPA positive, also with equal distribution among the 4 groups. Over 2 years of followup, radiographic progression (beyond the smallest detectable change) was observed in 44 patients in group 1 (40%), 36 in group 2 (34%), 23 in group 3 (19%), and 21 in group 4 (18%) (P ⬍ 0.001 for comparison of all groups). Radiographic progression was compared between patients with and patients without the SE, DERAA, RF, or ACPA, in each of the treatment groups. Over 2 years of followup, radiographic progression was not significantly different between patients with and those without the SE (Figure 1A), or between patients with and those without DERAA. The median (interquartile range [IQR]) change in the SHS in SE- 1296 DE VRIES-BOUWSTRA ET AL Figure 1. Radiographic progression (Sharp/van der Heijde score; probability plots) over 2 years among rheumatoid arthritis patients in the 4 treatment groups, according to the presence (solid symbols) or absence (open symbols) of the shared epitope (A), rheumatoid factor (B), and anti–citrullinated protein antibody (C). combi ⫽ combination therapy. negative and SE-positive patients, respectively, was 1.0 (⫺0.5, 5.0) and 3.8 (0.1, 11.6) in group 1, 1.0 (0.0, 3.0) and 3.0 (0.5, 10.0) in group 2, 2.1 (0.5, 4.8) and 1.0 (0.0, 5.5) in group 3, and 0.0 (⫺0.5, 1.1) and 1.5 (0.0, 4.0) in group 4 (P ⬎ 0.05 for all comparisons). The change in the SHS in DERAA-negative and DERAA-positive patients, respectively, was 3.3 (0.0, 10.9) and 1.5 (⫺0.5, 5.0) in group 1, 2.0 (0.5, 9.5) and 3.8 (0.8, 10.3) in group 2, 1.0 (0.0, 3.0) and 0.8 (0.0, 3.9) in group 3, and 1.5 (0.0, 4.0) and 1.0 (0.0, 4.0) in group 4 (P ⬎ 0.05 for all comparisons) (probability plots not shown because of the small number of DERAA carriers). Among patients treated with sequential monotherapy, step-up combination therapy, and initial combination therapy including infliximab (groups 1, 2, and 4, respectively), radiographic progression scores were sig- nificantly higher in RF-positive patients compared with RF-negative patients, and in ACPA-positive patients compared with ACPA-negative patients (Figures 1B and C). The median (IQR) change in the SHS in RFnegative and RF-positive patients, respectively, was 0.0 (⫺0.5, 3.9) and 4.8 (0.5, 20.0) in group 1, 1.0 (0.0, 4.0) and 2.5 (0.5, 11.1) in group 2, and 0.5 (0.0, 1.5) and 1.5 (0.0, 4.3) in group 4. In ACPA-negative and ACPApositive patients, respectively, these values were 0.0 (⫺0.5, 2.1) and 5.0 (0.5, 21.5) in group 1, 0.8 (0.0, 3.9) and 3.0 (1.0, 11.5) in group 2, and 0.0 (0.0, 1.5) and 2.0 (0.0, 4.5) in group 4 (P ⬍ 0.05 for all comparisons). Among patients treated with initial combination therapy including prednisone (group 3), radiographic progression scores were comparable between RF-negative and RF-positive patients and between ACPA-negative and GENETIC AND ANTIBODY ASSOCIATIONS WITH RA PROGRESSION, BY TREATMENT 1297 Table 2. Risk (OR [95% confidence interval]) for progressive disease with presence of the shared epitope, DERAA, rheumatoid factor, or ACPA* Treatment group Shared epitope DERAA Rheumatoid factor ACPA Sequential monotherapy Step-up combination therapy Initial combination therapy with prednisone Initial combination therapy with infliximab 1.4 (0.4–5.0) 0.4 (0.1–1.2) 4.7 (1.5–14.5) 12.6 (3.0–51.9) 2.6 (0.8–8.7) 1.4 (0.3–5.5) 1.5 (0.5–4.9) 3.4 (0.8–14.2) 1.9 (0.5–7.4) 0.9 (0.2–3.7) 1.0 (0.3–3.3) 1.7 (0.5–5.4) 3.0 (0.7–13.0) 0.9 (0.2–3.1) 1.4 (0.4–4.8) 1.8 (0.5–6.8) * All odds ratios (ORs) corrected for presence of erosions at baseline. OR for shared epitope corrected for anti–citrullinated protein antibody (ACPA) status and C-reactive protein level at baseline; OR for DERAA corrected for age; OR for rheumatoid factor and ACPA corrected for sex, smoking status, shared epitope status, and Disease Activity Score. ACPA-positive patients (Figures 1B and 1C) (median [IQR] change 0.8 [0.0, 2.0] and 1.0 [0.0, 3.0] in RFnegative and RF-positive patients, respectively, and 1.0 [0.0, 2.5] and 1.0 [0.0, 2.8] in ACPA-negative and ACPA-positive patients, respectively) (P ⬎ 0.05 for both comparisons). Next, logistic regression analyses were performed to correct for possible confounders. SE carriership (corrected for ACPA status, CRP level, and erosions at baseline) did not predict progressive disease in any of the treatment groups. DERAA carriership (corrected for age and erosions at baseline) did not protect against progressive disease. RF and ACPA (both corrected for sex, smoking status, SE, DAS, and erosions at baseline) were predictive of progressive disease in patients treated with sequential monotherapy, but not in the other treatment groups (Table 2). DISCUSSION This analysis of data from the BeSt study showed no significant association between HLA–DRB1 status and radiographic progression in patients with early, active RA who were treated according to closely monitored strategies with protocol-based therapy adjustments. These findings are consistent with earlier observations by Lard et al (8). An association between the presence of RF or ACPA and radiographic progression was observed only in patients treated with sequential monotherapy. Given the relatively small numbers of patients with progressive disease (progression greater than the smallest detectable change), the observed lack of association between radiographic progression and genetic and antibody status could be due to a lack of power (Type II error). However, in groups 1 and 2, a considerable number of patients exhibited progressive disease (44 patients and 36 patients, respectively). In addition, to further confirm our observations, we repeated the regression analyses with radiographic progression defined as a 2-year change in the SHS of ⬎0.5. Fifty-nine percent (n ⫽ 66), 67% (n ⫽ 70), 54% (n ⫽ 66), and 54% (n ⫽ 63) of the patients in groups 1, 2, 3, and 4, respectively, had radiographic progression of ⬎0.5. Results of regression analyses were comparable with those obtained using the smallest detectable change as the cutoff: only among patients in group 1 did the presence of ACPA and RF predict radiographic progression (odds ratio 2.8 [95% confidence interval 1.0–7.9] and odds ratio 3.4 [95% confidence interval 1.2–9.4], respectively). Although several hypotheses have been formulated to explain the contribution of biologic pathways to disease induction and progression, current data suggest that with early and aggressive intervention, a selfperpetuating state of the autoimmune response can be interrupted or even prevented, resulting in less severe joint damage. This could also include a drug-specific effect on antibody-related disease processes. Given the intensive treatment protocol in the BeSt study, involving adjustments of therapy every 3 months as necessary to achieve a DAS of ⱕ2.4, it is difficult to evaluate drug-specific effects in the current context. However, the majority of patients in groups 3 and 4 exhibited good clinical response to the initially prescribed combinations, and radiographic progression was the least frequent in these groups (10). Thus, one could speculate that either high-dose prednisone or the combination of a tumor necrosis factor inhibitor and methotrexate is essential for most effective inhibition of 1298 DE VRIES-BOUWSTRA ET AL joint destruction. By combining methotrexate with a tumor necrosis factor inhibitor, RANK activation is inhibited via at least 2 different pathways (16). Recent basic and clinical research has also demonstrated impressive protective effects of glucocorticoids on development of erosions (17). A significant protective effect of DERAA carriership was not observed in the present study. However, only a small minority of patients in the cohort (67 patients [17%]) were DERAA positive. In the analysis of DERAA, the odds ratio of radiographic progression was 0.4 (95% confidence interval 0.1–1.2) among patients receiving sequential monotherapy (group 1). Consequently, the possibility cannot be ruled out that a protective effect would have been observed among patients receiving this treatment had the group included more patients who were positive for DERAA. In conclusion, no significant association between HLA–DRB1 status and radiographic progression was found in patients with early RA treated with the goal of tight control of the DAS. Autoantibodies were predictive of progressive disease only among patients who received sequential monotherapy. The current observations thus suggest that effective treatment can prevent radiographic progression in RA, even among patients who might be otherwise prone to more severe damage. AUTHOR CONTRIBUTIONS Dr. de Vries-Bouwstra had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study design. De Vries-Bouwstra, Kerstens, Breedveld, Dijkmans, Huizinga, Allaart. Acquisition of data. De Vries-Bouwstra, Goekoop-Ruiterman, Verpoort, Schreuder, Ronday, Ewals, Terwiel, Kerstens, Toes, de Vries, Dijkmans, Allaart. Analysis and interpretation of data. De Vries-Bouwstra, GoekoopRuiterman, Kerstens, de Vries, Breedveld, Huizinga, Allaart. Manuscript preparation. De Vries-Bouwstra, Kerstens, de Vries, Breedveld, Dijkmans, Huizinga, Allaart. Statistical analysis. De Vries-Bouwstra. REFERENCES 1. Berglin E, Johansson T, Sundin U, Jidell E, Wadell G, Hallmans G, et al. 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