Objective To investigate if a glucocorticoid (GC) response at 2 weeks, defined by EULAR response criteria, can predict active disease (Disease Activity Score (DAS)>2.4) at 3 months.
Methods For this study, data of the Treatment in the Rotterdam Early Arthritis Cohort study (tREACH), an ongoing clinical trial that evaluates different induction therapies in early rheumatoid arthritis, were used. We selected patients who had a high probability of progressing to persistent arthritis (>70% based on the prediction model of Visser). All patients within the high-probability stratum, who had a baseline DAS>2.2 and a DAS assessment at 2 weeks after randomisation, were included (n=120). Besides GC response at 2 weeks, we investigated which other factors were associated with active disease (DAS>2.4) after 3 months of disease-modifying antirheumatic drug (DMARD) treatment. All variables with a p≤0.25 were assessed in our logistic regression model with backward selection. Variables were eliminated until all remaining variables had a significant association (p<0.05).
Results Patients who did not respond to GC bridging therapy at 2 weeks had an overall OR of having active disease at 3 months of 10.29 (95% CI 3.34 to 31.64; p<0.001) in comparison with responders. The corrected OR was 14.00 (95% CI 3.31 to 59.21; p<0.001). Our final model predicting response at 3 months included the following variables: gender, GC response, induction therapy arms and baseline DAS, which had an explained variance of 39%.
Conclusions GC response at 2 weeks is a useful tool for recognising those patients who will probably have active disease (DAS>2.4) after 3 months of DMARD treatment.
- Early Rheumatoid Arthritis
- Disease Activity
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The EULAR treatment guideline recommends that rheumatologists strive, in patients with newly diagnosed rheumatoid arthritis (RA), for remission or at least low disease activity within 3 months in order to obtain better functional and radiological outcomes.1 ,2 Since the time span for the optimal effect of disease-modifying antirheumatic drugs (DMARDs) is at least 6–12 weeks,3 the right choice of the initial DMARD has an important role in obtaining recommended treatment goals. The guideline recommends methotrexate (MTX) as anchor drug, but studies show that only about 70% of patients will respond sufficiently to the initial treatment.4 ,5 Moreover, we recently showed that a combination of DMARDs shows better remission rates than MTX monotherapy in the early phase of RA.5 Therefore it would be helpful to be able to predict treatment response to the initial DMARD treatment as early as possible, ultimately leading to a ‘tailor-made’ treatment approach.
The huge body of prognostic research till now has mainly focused on predicting long-term destructive and disabling disease in order to guide the initial choice of treatment.6 In contrast, studies evaluating prediction of treatment response are sparse. Aletaha et al7 demonstrated that high disease activity during the first 3 months of treatment are significantly related to high disease activity at 1 year, which subsequently leads to more destructive and disabling disease. Besides some possible pharmacogenetic markers (eg, TYMS polymorphisms affect efficacy of MTX in RA), a clinical applicable predictor for treatment response to classic DMARDs in a very early stage, is unknown.8
In line with studies performed in polymyalgia rheumatica a clinical applicable predictor for treatment response in a very early stage might be the initial response to glucocorticoids (GCs).9 It is well known that GCs have a rapid anti-inflammatory effect, and therefore are often used as bridging therapy to treat active disease in the period between initiation of DMARD treatment and onset of their therapeutic effect.10 However, in RA clinical responses to GCs differ between patients. Sliwinska-Stanczyk et al11 showed that steroid sensitivity of peripheral blood mononuclear cells of patients with RA is related to their own observed clinical response to GCs. However, clinical data linking the early effect of GCs to DMARD response in RA are missing. Therefore our objective was to investigate whether the GC response at 2 weeks, defined according to the EULAR response criteria,12 predicts DMARD response at 3 months.
Patients and methods
For this study data were used from a current clinical trial (ISRCTN26791028), Treatment in the Rotterdam Early Arthritis Cohort (tREACH).13 The tREACH study, a multicentre, stratified single-blinded trial to evaluate different induction treatment strategies in early RA, is being carried out in eight rheumatology centres in the Netherlands. The medical ethics committee at each participating centre approved the study protocol, and all patients gave written informed consent before inclusion.
An extended description of the material and methods section of the tREACH study has already been published.13 Inclusion criteria for the tREACH study are age ≥18 years, arthritis ≥1 joint and symptom duration <1 year. Eligible patients were stratified into three groups according to their likelihood of progressing to persistent arthritis based on the prediction model of Visser.14 The three strata (low, intermediate and high) correspond to probability tertiles of developing persistent arthritis according to the Visser model. The Visser algorithm and 2010 criteria for RA have similar discriminative abilities to identify patients at risk of persistent arthritis at 1 year.15
For our analysis we selected all patients who had a high probability of developing persistent arthritis and a Disease Activity Score (DAS) assessment at 2 weeks after randomisation. Not all patients in the high-probability stratum had a DAS assessment at 2 weeks, because this assessment was part of a substudy, primarily evaluating differences in GC sensitivity, embedded in the tREACH. Furthermore patients with a DAS≤2.2 and/or DAS28≤3.3 were excluded, because the EULAR response criteria are only valid in patients having a baseline DAS>2.2 (DAS28>3.3).12
Patients were randomised, using variable block randomisation stratified for centre, into one of three initial treatment strategies (later referred to as ‘induction therapy arms’):
Combination therapy (MTX, sulfasalazine (SSZ) and hydroxychloroquine (HCQ)) with GCs intramuscularly);
Combination therapy with an oral GCs tapering scheme;
MTX with an oral GCs tapering scheme.
DMARD dosages were: MTX 25 mg/week orally or subcutaneously (starting dose 10 mg/week, maximum dosage reached after 3 weeks); SSZ first week 1 g/day, thereafter 2 g/day; HCQ 400 mg/day. GCs were either given as a single intramuscular dose at randomisation (methylprednisolone 120 mg or triamcinolone 80 mg) or prednisolone in an oral tapering scheme (week 1–4: 15 mg/day, week 5–6: 10 mg/day, week 7–8: 5 mg/day and week 9–10: 2.5 mg/day).
We used a treat-to-target approach, with patients being examined every 3 months. Treatment decisions were based, every 3 months, upon the DAS thresholds for low disease activity.16 When ‘treatment failure’ occurred, defined as DAS>2.4, medication was intensified to MTX with etanercept (50 mg/week). Treatment intensifications were the same in each stratum for each treatment arm.
Demographic and disease characteristics of each patient were recorded at baseline. After 2 weeks and 3 months the following variables were assessed: a 44-joint count for swelling, a graded 53-joint count for tenderness,17 general health and erythrocyte sedimentation rate, which we used to calculate the DAS and 28-joint count DAS (DAS28). At 2 weeks we also determined the EULAR response criteria.12 EULAR response criteria are based on attained level and change in DAS.
First, we investigated whether a GC response at 2 weeks, defined according to EULAR response criteria, was associated with DMARD response at 3 months of treatment. Active disease at 3 months was defined as DAS>2.4. The discriminative ability of GC response at 2 weeks for identifying active disease at 3 months was expressed by sensitivity and specificity. To overcome confounding by medication we also carried out a stratified analysis for induction therapy arms. All analyses were also performed for the DAS28; active disease was defined as DAS28>3.2.18
Furthermore, we determined which other factors were associated with active disease at 3 months by comparing the baseline characteristics of patients with and without active disease after 3 months of DMARD induction therapy. Statistical comparison between baseline characteristics was made by the Student t test, χ2 test, or the Wilcoxon rank-sum test, as appropriate. All variables with a p≤0.25 together with known prognostic factors (age, gender, disease duration, rheumatoid factor (RF), anti-citrullinated peptide antibodies (ACPA) and baseline DAS) were analysed using univariate and multivariate logistic regression (with backward selection). In our backward selection procedure the variable with the highest p value was eliminated from the model, until all variables in the model had a significant association (p<0.05).
All statistical analyses were carried out using STATA V.11.1. A p<0.05 was considered statistically significant.
Of the 281 tREACH patients within the high-probability stratum, 132 (47%) had a DAS assessment at 2 weeks after randomisation. Of those patients 12 (9%) were excluded because of a baseline DAS≤2.2. All those patients had a DAS≤2.4 at 3 months of follow-up. Table 1 shows the baseline characteristics of the 120 patients. Patients were more often female (65%) and had a median symptom duration of 161 days (97–210 days, IQR). RF and/or ACPA positivity was present in 92 patients (77%), of those 70 (76%) were both RF and ACPA positive. At baseline 20 patients (17%) had ≥1 erosion typical for RA. Active disease (DAS>2.4) was found in 113 patients (94%).
The relation between GC response at 2 weeks, defined according to the EULAR response criteria, and having active disease after 3 months of induction DMARD treatment is shown in table 2A. A total of 39 out of 78 patients with a DAS≤2.4 after 3 months of DMARD treatment (50%), were classified as good GC responders, whereas this was only the case for six out of 42 patients(14%) who still had active disease (DAS>2.4). Vice versa, in patients with a DAS≤2.4 only 12 of 78 patients (15%) did not respond initially to GC bridging therapy as distinct from 19 of 42 patients (45%) who had an active disease who were GC non-responders. Patients who do not respond to GC bridging therapy at 2 weeks had an overall OR of having active disease at 3 months of 10.29 (95% CI 3.34 to 31.64; p<0.001) in comparison with responders.
Table 2B demonstrates the relationship between GC response and disease activity states stratified for induction therapy arms. The OR (95% CI) for active disease of being a non-GC responder relative to a good-GC responder for treatment arms (A), (B) and (C) is, respectively, 4.2 (0.75 to 23.18); 10.7 (0.98 to 115.7) and infinite. In treatment arm C, with current recommended induction therapy, all GC non-responders have active disease at 3 months. The same analysis was performed for DAS28 instead of DAS, and showed similar results (see online supplementary tables S1 and S2).
To determine the discriminative ability of GC response at 2 weeks for identifying active disease at 3 months, the following two cut-off points were used: (1) being a non-responder to GC or not and (2) being a non-responder or moderate responder to GC or not. The sensitivity (95% CI) and specificity (95% CI) of GC response to identify active disease, using the first cut-off point, were, respectively, 45% (30% to 61%) and 85% (75% to 92%). For the second cut-off point the calculated sensitivity (95% CI) and specificity (95% CI) were, respectively, 86% (72% to 95%) and 50% (39% to 62%).
Second, we investigated which other factors were associated with having active disease after 3 months of DMARD treatment (table 3). Besides known prognostic factors (age, gender, disease duration, RF, ACPA and baseline DAS), other possible variables associated with active disease after 3 months of DMARD treatment are type of induction therapy (treatment arm (A), (B) or (C)), presence of erosions and the components of the baseline DAS, except swollen joint count. Table 4 shows the univariate logistic regression (4A) and final multivariate model (4B), after backward selection, for the prediction of active disease after 3 months of DMARD induction therapy. The final model had an explained variance of 39%. The same analysis was performed for DAS28 instead of DAS, which showed similar results (see online supplementary table S3).
We investigated if a GC response at 2 weeks, defined by EULAR response criteria, can predict active disease after 3 months of DMARD induction therapy. Patients who do not respond to GC bridging therapy at 2 weeks have an overall OR of having active disease at 3 months of 10.29 (95% CI 3.34 to 31.64; p<0.001) in comparison with responders. If we stratify for induction therapy arms ORs (95% CI) were 4.2 (0.75 to 23.18); 10.7 (0.98 to 115.7) and infinite for respectively treatment arms (A), (B) and (C). In treatment arm C, MTX with an oral GCs tapering scheme, all GC non-responders have active disease after 3 months of DMARD treatment. Until now a clinical applicable predictor for treatment response of classical DMARDs in the very early stage was missing. However, we have shown that assessment of disease activity at 2 weeks, reflecting initial response to GCs, might be a predictor of active disease after 3 months of induction DMARD treatment.
Although our data do not necessarily indicate a direct causal association it is tempting to speculate about possible synergistic effects of GCs and DMARDs. GCs and DMARDs have mutual anti-inflammatory pathways. The anti-inflammatory actions of GCs are mediated via the GC receptor and include an transrepressive effect on the transcription factor nuclear factor kappa B (NF-κB).19 Other studies have shown that SSZ and MTX both suppress activation of NF-κB by inhibiting degradation of IκBα in vitro.20 ,21 Another mutual pathway might be the effect of GCs and DMARDs on the intracellular levels of cyclic AMP (cAMP). GCs and DMARDs elicit a rise in intracellular cAMP levels, resulting in inhibition of proinflammatory cytokine production.22 ,23 Because of these mutual anti-inflammatory pathways it can be hypothesised that GC response reflects DMARD response, especially with MTX and/or SSZ usage.
Other non-modifiable baseline predictors associated with active disease after 3 months of DMARD induction therapy are gender and baseline DAS. The only modifiable baseline predictor is the choice of induction therapy. First, the relationship between gender and active disease is probably found because women experience more pain, resulting in higher DAS values and more functional impairment than men.24 ,25 Second, the baseline disease activity is an important predictor of disease activity (states) during follow-up, which is reconfirmed in our study.26 Finally, the choice of induction therapy, which is the only modifiable predictor at presentation, determines the clinical response.
The EULAR treatment guideline recommends a treat-to-target approach in which rheumatologists should strive for remission or low disease activity within 3 months, in patients with newly diagnosed RA with active disease.2 Until the desired target is reached, treatment should be altered every 1–3 months.2 Recommended induction therapy consists of MTX with or without GCs.1 However, some points in the mentioned recommendation can be discussed.
First, the choice of induction therapy wherein DMARD monotherapy is preferred over a combination of DMARDs. Current guidelines are based upon a systematic review,27 which concluded that in DMARD-naïve patients the efficacy/toxicity ratio favours MTX monotherapy over combination therapy. However, in this review, triple DMARD therapy versus MTX monotherapy in DMARD-naïve patients was not compared. Furthermore, trials favouring triple DMARD treatment (BeSt, FIN-RACo and COBRA trial) were excluded from this review.4 ,28 ,29 In a previous publication we have already shown that in patients with early RA a combination of DMARDs is better than MTX monotherapy in achieving low disease activity after 3 months,5 which is supported by a recent systematic review by Graudal and Jürgens.30
Second, the time span for the optimal effect of DMARDs takes at least 6–12 weeks,3 and thus the right choice of induction DMARD treatment has an important role in obtaining recommended treatment goals. Furthermore, several studies have shown that only about 70% will respond sufficiently to the initial treatment.4 ,5 A tailor-made treatment approach might be preferable, however, no clinical applicable predictors for early treatment response are available.
Therefore in daily practice we advise starting with a combination of DMARDs. However, if MTX monotherapy is preferred, either by the rheumatologist or patient, we recommend combining MTX with a GC bridging scheme and determining the response to GCs after 2 weeks. Patients who do not respond to GCs after 2 weeks have a higher risk of not reaching the treatment goals and therefore a higher risk of a poorer outcome. It seems sensible to intensify the DMARD treatment, if patients do not respond to GCs after 2 weeks.
Our study had certain limitations. First, sample size calculations were not based upon our research question and therefore we had a small sample size, especially restricting the stratified analysis for induction therapy arms. Despite the small sample size we found significant ORs for active disease after 3 months of DMARD treatment of approximately 10 for non-responders relative to good responders.
Second, not all patients in the high-probability stratum had a DAS assessment at 2 weeks, which possibly introduces a selection bias. The DAS assessment at 2 weeks was part of a substudy, primarily evaluating differences in GC sensitivity. Inclusion in the tREACH and the mentioned substudy started concurrently, with all randomised patients automatically enrolled in the substudy. The DAS assessment at 2 weeks was terminated, because the substudy had reached its predefined sample size. Therefore we think that a significant selection bias did not arise.
Third, the requirements for EULAR response criteria are a baseline DAS>2.2, as a result of which 12 patients (9%) were excluded from the analyses. Consequently, in daily practice we cannot use a GC response to predict DMARD response in patients with a low baseline DAS. In our study, however, we showed that none of the patients with a baseline DAS≤2.2 had active disease after 3 months of DMARD treatment. Therefore, if adequate DMARD treatment is initiated, we can assume that patients with a baseline DAS≤2.2 will respond to this treatment. Future research is necessary to validate our findings and to evaluate the clinical applicability of GC response as a prediction tool in daily practice.
In conclusion, determining GC response at 2 weeks is a useful tool for recognising those patients who will probably have active disease (DAS>2.4) after 3 months of DMARD treatment.
We thank all patients who are enrolled in the tREACH trial. Without their active cooperation, our trial would not be possible. The tREACH trial comprises the following rheumatology centres: Erasmus MC, Rotterdam; Sint Franciscus Gasthuis, Rotterdam; Maasstad Ziekenhuis, Rotterdam; Vlietland Ziekenhuis, Schiedam; Admiraal de Ruyter Ziekenhuis, Goes and Vlissingen; Zorgsaam Ziekenhuis, Terneuzen; Albert Schweitzer Ziekenhuis, Dordrecht. We thank the following people from all centres (listed alphabetically) for their contribution to the tREACH trial: Aartsen R, Alfenaar C, Alves C, Arendse R, Arnoldus M, Baak-Dijkstra M, Bal-overzier J, Barendregt P, Basoski N, Beer S, Berkel D, Bonte F, Born van den M, Breukelen van D, Bron S, Buijs H, Buijs N, Cambier M, Claessen S, Colin E, Dekker A, Dolhain R, Donze M, Fodili F, Gerards A, Grillet de B, Haasnoot H, Hamelink B, Han K, Houdt van Y, Hove van L, Huisman M, Jager de J, Jager de M, Jasperse J, Jonkers C, Joziasse S, Klootwijk K, Krommenhoek T, Krugten van M, Lam Tse W, Leemput van H, Legierse C, Lubbe van de P, Maclean P, Man de Y, Matena D, Molenaar A, Mous L, Nijs J, Paassen van H, Quax R, Reijnierse J, Romme A, Rotte de M, Schaeybroeck B, Schardijn G, Schrauwen S, Sonnaville de P, Sturm L, Sutter T, Tchetverikov I, Tusschenbroek D, Veldman R, Voordt van der A, Voorneveld H, Vroed de M, Walravens M, Walter M, Werff van de N, Westeinde van het A, Wiele J, Willemse M, Wouter J, Zandbergen W, Zeben van D, Zwart H.
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Files in this Data Supplement:
- Data supplement 1 - Online tables
Handling editor Tore K Kvien
Contributors All authors had a substantial contribution to the conception and design of the study, drafting/revising of the article and final approval of the version to be published.
Funding The study was supported by an unrestricted grant from Pfizer bv (0881-102217).
Competing interest None.
Ethics approval Medical ethics committee Erasmus MC, Rotterdam, The netherlands.
Provenance and peer review Not commissioned; externally peer reviewed.
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