BRIEF REPORT

A predictive model for remission and low disease activityin patients with established rheumatoid arthritis receivingTNF blockers

Cristina Pomirleanu & Codrina Ancuta &

Smaranda Miu & Rodica Chirieac

Received: 23 May 2012 /Revised: 1 October 2012 /Accepted: 10 December 2012 /Published online: 6 January 2013# Clinical Rheumatology 2013

Abstract The objective of this study was to identify pre-dictors for remission or low disease activity (LDA) in estab-lished rheumatoid arthritis (RA) at 12 months of anti-TNF-αtherapy. We have performed a prospective observationalstudy in 90 consecutive patients with active RA receivingTNF-α inhibitors. Baseline and standard assessments weredone every 3 months, including individual parameters (clin-ical and biological) and composite activity scores (28-jointdisease activity score, DAS28). The primary outcome mea-sure was DAS28-based EULAR response criteria. The mul-tivariate logistic regression was used to analyze theassociation between disease activity and several RA base-line characteristics. Of the RA, 78.8 % was classified asgood responders based on the EULAR-DAS28 criteria,44.4 % RA achieving remission (DAS28≤2.6) and34.4 %, LDA (DAS28≤3.2). Parameters associated withan increased likelihood of remission and LDA were initialDAS28-erythrocyte sedimentation rate ≤7 (odds ratio (OR)3.3, 95 % confidence interval (CI) 2.03–5.81; OR 1.8, 95 %CI 1.09–6.68), Health Assessment Questionnaire DisabilityIndex ≤2 (OR 7.0, 95 % CI 1.56–31.91; OR 1.3, 95 % CI1.03–5.79), C-reactive protein level ≤20 mg/l (OR 1.5, 95 %CI 0.29–8.22; OR 0.5, 95 % CI0.08–2.97), rheumatoidfactor ≤20 IU/ml (OR 18.9, 95 % CI 10.79–38.36; OR32.9, 95 % CI 4.03–269), anti-cyclic citrullinated peptideantibodies ≤40 IU/ml (OR 3.5, 95 % CI 0.67–18.19; OR 1.2,95 % CI 1.02–1.59), concurrent prednisolone (OR 0.2, 95 %

CI 0.05–0.36; OR 0.2, 95 % CI 0.06–0.63), methotrexate orleflunomide (OR 1.6, 95 % CI 1.2–13.53; OR 2.9, 95 % CI1.20–4.36). A predictive matrix for remission and LDA inestablished active RA patients receiving TNF-α inhibitorswas proposed. Further studies are necessary to confirm thevalue of such matrix in particular RA settings, leading tooptimization of the use of anti-TNF-α therapy.

Keywords Anti-TNF-α agents . Established rheumatoidarthritis . Low disease activity . Predictors . Remission

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatoryimmune-mediated disorder promoting progressive jointdamage, functional disability, impaired quality of life, anda generally shortened life expectancy [1]. The understandingof the molecular pathobiology of the disease has led to thedevelopment of a broad range of biological agents specifi-cally targeting different components of the aberrant immuneresponse in RA [2, 3]. Subsequently, achieving and main-taining either remission or low levels of disease activity(LDA) as the mainstay of the “treat to target” concept hasactually become a realistic goal in the management of RA [4].

However, the current paradigm for molecular, clinical,and imaging biomarkers remains of limited value in accu-rately predicting the response to specific treatment, even inthe era of targeted therapies. In an effort to offer a morepersonalized tailored medical care in RA, strategies havebeen focused on discovering, developing, and validatingnew tools of potential value in making deliberate informeddecisions and optimizing the use of biological therapy [5].Five agents targeting the tumor necrosis factor alpha (TNF-α)inflammatory pathway including infliximab, adalimumab,

C. Pomirleanu : C. Ancuta (*) : S. Miu : R. ChirieacUniversity of Medicine and Pharmacy “Gr. T. Popa”,Iasi, Romaniae-mail: alexia02ro@yahoo.com

C. Pomirleanu : C. Ancuta : S. Miu : R. ChirieacClinical Rehabilitation Hospital, Iasi, Romania

Clin Rheumatol (2013) 32:665–670DOI 10.1007/s10067-012-2146-6

etanercept, golimumab, and certolizumab pegol have alreadydemonstrated their sustained ability in improving disease con-trol, preserving functional ability, and finally, changing dis-ease outcomes in RA [6].

Although several clinical, laboratory, and geneticmarkers are widely recognized as individual predictors ofclinical response to anti-TNF-α [7], up to 30 % of the casesare still discontinuing the TNF-α inhibitor because of eitherlack of efficacy or intolerance [8, 9].

The main aim of our study was to identify predictors forremission or low disease activity in active established RApatients receiving TNF-α inhibitors.

Patients and methods

Ninety consecutive patients, fulfilling the 1987modifiedACRdiagnostic criteria for RA, with severe active disease (28-jointdisease activity score, DAS28>5.1) despite conventionaldisease-modifying antirheumatic drugs (DMARDs) and initi-ating their first TNF-α-blocking agent, were enrolled in a 12-month prospective observational study.

The inclusion and exclusion criteria have been estab-lished according to the guidelines of the Romanian Societyof Rheumatology that supports the use of anti-TNF-α agentsin highly active RA patients with suboptimal response toprevious therapy with at least two synthetic DMARDs [10].Three treatment subgroups were defined as follows: theadalimumab (33 cases), the etanercept (30 cases), and theinfliximab group (27 cases), standard doses and administra-tion pathways being used as recommended by manufac-turers. Concomitant DMARDs (methotrexate, MTX;leflunomide, LEF; sulfasalazine, SSZ; hydroxychloroquine,HCQ) were given to all the patients, while low doses ofcorticosteroids (CS) were permitted only if maintained at astable dose during the first 12 weeks of study.

The eligible patients have attended the RheumatologyDepartment, Clinical Rehabilitation Hospital in Iasi, Roma-nia. The study has been approved by the institutional reviewboard, and a written informed consent was obtained from allthe patients prior to the study inclusion.

At inclusion and at every 3 months, the following datawere recorded: clinical variables such as 28 tender andswollen joint count (TJC, SJC), patient-scored visual analogscale for pain and general health, physician's global assess-ment of disease activity on a 0–100 scale, inflammatorytests (erythrocyte sedimentation rate [ESR] and C-reactiveprotein [CRP]), functional (Health Assessment Question-naire Disability Index [HAQ-DI]) and disease activityscore (DAS28), while the immunological tests (rheuma-toid factor [RF], anti-cyclic citrullinated peptide anti-bodies [anti-CCP]) were assessed at baseline and at 6and 12 months. Anti-CCP IgG isotype was measured

using the fluoro-immuno-enzymatic method (PHA-DIA250; Phadia; cutoff value of 10 IU/ml), while totalRF by latex immunoturbidimetric method (Cobas 800;Roche; cutoff value of 14 IU/ml).

The response to the treatment was appreciated by theEULAR-DAS28 criteria [11], where the DAS28 responsewas defined based on a combination of a significant changefrom baseline and on the level of disease activity attained.The good response was defined as a significant decrease inDAS28 (>1.2) and a low level of disease activity (≤3.2),while non-response was defined as a decrease of ≤0.6 or adecrease of 0.6–1.2 with a DAS28 >5.1; any other scores wereindicative of moderate responses. At the follow-up, patientswith DAS28 ≤2.6 were considered to be in remission, whilethe patients with DAS28≤3.2 were reported as LDA.

Statistical analysis

The baseline characteristics were analyzed by Mann–Whitney U test for continuous variables, whereas chi-square was used for categorical variables. Predictors ofremission or LDA were analyzed by multivariate binarylogistic regression models; the level of significance wassettled at p<0.05.

Results

Baseline characteristics

No significant differences were demonstrated at baselineamong the treatment subgroups except the ESR levels(p=0.009) (Table 1).

Responders

Of the RA patients, 78.8 % were classified as goodresponders based on the EULAR-DAS28 criteria, mean-ing that 44.4 % of all RA achieved remission and34.4 %, LDA. In addition, the subgroup analysis hasdemonstrated the following distribution according to thedisease activity status at the final point: 45.5 % RApatients in remission for adalimumab, 46.6 % patientsfor etanercept, and 44 % patients for the infliximabgroup, while an additional 30.3 % cases for adalimu-mab, 40 % for etanercept, and 36 % for infliximabgroup achieved LDA. The baseline characteristics ofall enrolled patients based on a TNF-α-blocking agentand disease activity at 12 months are shown in Table 2.Only several variables were significantly differentamong patients achieving remission and LDA, particularlyage (p=0.001), baseline HAQ-DI (p=0.001), RF (p=0.001),and anti-CCP levels (p=0.002).

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Regression analysis

We have designed a multivariate logistic regression modelbased on different variables in order to predict a positiveresponse to the biological therapy (Table 3), the EULAR(DAS28-ESR) being recognized as the dependent factor. Sev-eral predictors were used including baseline DAS28-ESR,HAQ-DI, CRP, RF, and anti-CCP antibodies, concomitantDMARDs and CS. Odds ratios (ORs) and 95 % confidenceintervals (CIs) for the remission and LDA predictors arefurther summarized in Fig. 1.

The patients with a DAS28-ESR ≤7 at baseline were signif-icantly more likely to achieve both EULAR remission (OR 3.3,p=0.031) or LDA (OR 1.8, p=0.046) at 12 months. In addi-tion, functional status at baseline as defined by HAQ-DI score<2 was highly associated with more response to TNF-α block-ing therapy at 12 months, either the remission (OR 7.0;p=0.011) or the LDA (OR 1.3; p=0.033). Surprisingly,an initial CRP ≤20 mg/l was not relevant, neither forthe remission (OR 1.5, p=0.608) nor for the LDA statusin the same patient population (OR 0.5; p=0.457).

The RF titer predicted a positive response in RA patients,both remission as wellas LDA being associated with RF

<20 IU/ml (OR 18.9, p=0.000, and OR 32.9, p=0.000, re-spectively). On the other hand, baseline anti-CCP <40 IU/mlwas also significantly associated with LDA (OR 1.2, p=0.013), but not with the EULAR remission (OR 3.5, p=0.134).

The regular use of a stable low dose of prednisoloneshowed a significant trend for predicting both remission (OR0.2, p=0.006) and LDA (OR 0.2, p=0.010) at 12 months.Also, patients receiving TNF-α inhibitors plus either MTX orLEF commonly achieved remission at 12 months (OR1.6, p=0.022, and OR 1.1, p=0.040, respectively).

Moreover, concurrentMTXwas non-significantlymore like-ly to predict LDA compared with other non-MTX DMARDs(OR 4.0, p=0.156), while the association between anti-TNF-αand LEF was a positive predictor of LDA (OR 2.9; p=0.007).Disease duration, gender, individual clinical parameters, andESR did not influence the treatment response in our study.

Discussion

Even if the anti-TNF-α agents have tailored the manage-ment of RA, an extensive proportion of patients are stilldemonstrating either partial or no response to such therapies

Table 1 Demographics and clinical and biological characteristics of RA patients at baseline

Parameter Treatment subgroups p value

Adalimumab Etanercept Infliximab

Age (years)a 53.64±11.93 55.13±9.99 58.37±9.80 0.231

Womenb 29 (87.9 %) 21 (70 %) 23 (85.2 %) 0.161

RA stage 3/4b 24 (72.7 %) 23 (76.7 %) 20 (74.1 %) 0.899

Concomitant CSb 22 (66.7 %) 17 (56.7 %) 11 (40.7 %) 0.134

Concomitant DMARDsb

MTX 5 (15.2 %) 10 (33.3 %) 8 (29.6 %) 0.160LEF 8 (24.2 %) 7 (23.3 %) 13 (48.1 %)

Others 20 (60.6 %) 13 (43.4 %) 6 (22.2 %)

TJC (28)a 18.15±3.01 19.10±3.29 18.36±1.77 0.154

SJC (28)a 11.67±2.52 12.20±2.95 11.52±1.41 0.081

DAS28-ESRa 7.46±0.44 7.42±0.33 7.63±0.40 0.382

HAQ-DI (0–3)a 2.03±0.33 2.03±0.31 2.00±0.34 0.387

ESR (mm/1 h)c 68.58 57.07 75.48 0.009

CRP (mg/l)c 36.71 39.30 32.64 0.254

RF (IU/ml)c 232.57 189.61 270.60 0.245Seropositivityb 24 (72.7 %) 22 (73.3 %) 19 (70.3 %)

Anti-CCP (IU/ml)c 114.36 76.24 107.20 0.578Seropositivityb 22 (66.6 %) 16 (53.3 %) 16 (59.2 %)

Anti-CCP anti-cyclic citrullinated peptide antibody, CRP C-reactive protein, DAS28 disease activity score, DMARDs disease-modifying antirheu-matic drugs, ESR erythrocyte sedimentation rate, HAQ-DI Health Assessment Questionnaire Disability Index, LEF leflunomide, MTX methotrex-ate, CS corticosteroids, RA rheumatoid arthritis, RF rheumatoid factor, SJC swollen joint count, TJC tender joint countaMean±SDb n (%)cMean

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[8]. As a consequence, many authors have attempted toaddress the important question of predictors of response to

the treatment in order to identify those patients who willmaximally benefit from the biologic therapy.

Table 2 Baseline characteristicsaccording to disease activity at12 months of anti-TNF-α

ADA adalimumab, anti-CCPanti-cyclic citrullinated peptideantibody, CRP C-reactive pro-tein, DAS28 disease activityscore, ESR erythrocyte sedimen-tation rate, ETA etanercept,HAQ-DI Health AssessmentQuestionnaire Disability Index,INF infliximab, LEF lefluno-mide, MTX methotrexate, PDNprednisolone, RF rheumatoidfactoraMean+SDbn (%)cMean

Variables Anti-TNF-α agents Remission Low disease activity p value

Age (years)a ADA 46.06±10.55 59±6.87 0.001ETA 51.71±10.30 57.4±8.77

INF 53.18±10.87 62.6±6.98

Womenb ADA 13 (39.3 %) 10 (30.3 %) 0.121ETA 8 (26.6 %) 9 (30 %)

INF 8 (32 %) 8 (32 %)

Concomitant PDNb ADA 12 (36.3 %) 7 (21.2 %) 0.161ETA 9 (30 %) 7 (23.3 %)

INF 6 (24 %) 3 (12 %)

Concomitant MTXb ADA 6 (18.1 %) 5 (15.1 %) 0.292ETA 4 (13.3 %) 6 (20 %)

INF 5 (20 %) 6 (24 %)

DAS28-ESRa ADA 7.57±0.45 7.46±0.34 0.889ETA 7.34±0.22 7.45±0.44

INF 7.53±0.12 7.61±0.38

HAQ-DI (0–3)a ADA 1.84±0.30 2.1±0.27 0.001ETA 1.84±0.21 2.1±0.31

INF 1.84±0.25 2.1±0.32

ESR (mm/1 h)c ADA 73.93 68.1 0.401ETA 62.71 52

INF 71.18 74

CRP (mg/l)c ADA 32.3 40.01 0.171ETA 30.37 35.4

INF 29.7 36.9

RF (IU/ml)c ADA 249.8 166.9 0.001ETA 168.5 157.8

INF 161.1 329.8

Anti-CCP (IU/ml)c ADA 116 99.3 0.002ETA 22.5 219

INF 40.9 233.6

Table 3 Predictors of remission and LDA at 12 months of anti-TNF-α therapy

Variables Remission Low disease activity

Univariate analysis Multivariate analysis Univariate analysis Multivariate analysisOR (95 % CI) OR (95 % CI) OR (95 % CI) OR (95 % CI)

DAS28-ESR≤7 1.4 (1.07–2.23) 3.3 (2.03–5.81) 1.7 (1.14–3.76) 1.8 (1.09–6.68)

HAQ-DI≤2 5.7 (1.73–18.78) 7.0 (1.56–31.91) 1.1 (1.05–4.01) 1.3 (1.03–5.79)

CRP≤20 (mg/l) 1.4 (0.38–5.23) 1.5 (0.29–8.22) 0.7 (0.16–3.10) 0.5 (0.08–2.97)

RF≤20 (IU/ml) 3.1 (1.35–28.46) 18.9 (10.79–38.36) 2.6 (1.27–25.83) 32.9 (4.03–269)

Anti-CCP≤40 (IU/ml) 8.8 (2.21–35.6) 3.5 (0.67–18.19) 1.7 (1.15–3.99) 1.2 (1.02–1.59)

Concomitant MTX 2.6 (1.47–14.77) 1.6 (1.2–13.53) 3.8 (0.67–21.47) 4.0 (0.58–27.94)

Concomitant LEF 1.8 (1.26–2.84) 1.1 (1.02–5.81) 1.6 (1.16–2.27) 2.94 (1.20–4.36)

Without PDN 0.2 (0.06–0.71) 0.2 (0.05–0.36) 0.38 (0.11–0.79) 0.28 (0.06–0.63)

Anti-CCP anti-cyclic citrullinated peptide antibody, CI confidence interval, CRP C-reactive protein, DAS28 disease activity score, ESR erythrocytesedimentation rate, HAQ-DI Health Assessment Questionnaire Disability Index, LEF leflunomide, MTX methotrexate, OD odds ratio, PDNprednisolone, RF rheumatoid factor

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We have performed a prognostic study for a cohort ofconsecutive established RA patients receiving a first TNF-αblocker for their active disease. The patients were found topresent more frequent remissions than either moderate onesor no response if displaying the following characteristics:high disease activity at baseline (DAS28-ESR≤7), mildfunctional impairment (HAQ-DI≤2), low CRP (≤20 mg/l),low RF (≤20 IU/ml), concomitant CS, LEF, and MTX, butnot HCQ. In addition, the following parameters were con-firmed as predictors of LDA status in our study: DAS28-ESR≤7, HAQ-DI≤2, CRP>20 mg/l, RF≤20 IU/ml, andanti-CCP<40 IU/ml, concomitant CS, LEF, and MTX.

Although most parameters defining the predictive modelfor positive response are identical, the relevance of individ-ual variables was different in each model, as demonstratedwith the multivariate regression analysis. Furthermore, sig-nificant differences were identified in age, functional status,and immune biomarkers when performing a subgroup anal-ysis based on the baseline characteristics and on the thera-peutic response at 12 months.

A systematic literature research has revealed a number ofindependent predictors for remission and LDA in RA [12].A highly active RA at baseline is less likely to achieveremission in all models at any time points of assessment[13–15]; moreover, the higher the baseline DAS28, thelesser the chance to achieve remission, the proposed cutofflevels being 7 and 5.1 [15]. As well, the baseline functional

status has been shown to be inversely associated with re-mission in several anti-TNF-α cohorts [12, 15].

The CRP<20 mg/l serum was shown to predict remissionin different RA cohorts [15]; on the other hand, the prog-nostic value of other acute-phase reactants failed to bedemonstrated [13, 16]. In addition, both RF and anti-CCPpositivity and titer have been inversely associated withremission as defined by EULAR and ACR [13]. The ab-sence of RF was considered to be an independent predictorof remission [17], while a positive RF at baseline was lesslikely to achieve remission [14, 18]. However, the predictivevalue of RF was no longer supported when adjusting foranti-CCP [14], concurrent non-biologic [19] and biologicDMARDs [20, 21], and the presence of shared epitopes[22]. Alternatively, the anti-CCP status at baseline wasinversely associated with the remission at 24 months whenadjusting for DAS28 and HAQ-DI, disease duration, andmale gender [12, 14]. The concurrent and previous numberof DMARDs (MTX, non-MTX drugs), CS, and evenNSAIDs have been shown to predict remission in cohortsof RA patients receiving TNF-α inhibitors [12, 16, 20, 21,23]; however, differences have been identified based on theanti-TNF-α agent used [15, 20, 21, 23]. Additionally, itseems that the use of TNF-α inhibitors represents an inde-pendent predictor of remission in the case of an activedisease when adjusting for age, sex, disease duration, andconcurrent drug (CS, previous DMARDs) [12, 24].

Fig. 1 Odd ratios, 95 % CIs, and level of significance for predictors ofremission (a) and LDA (b) at 12 months. anti-CCP anti-cyclic citrulli-nated peptide antibody, CI confidence interval, CRP C-reactive

protein, DAS28 disease activity score, ESR erythrocyte sedimentationrate, HAQ-DI Health Assessment Questionnaire Disability Index, LEFleflunomide, MTX methotrexate, OD odds ratio

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Although two predictive models for positive responsehave been recognized in our RA population, the study hadseveral methodological limits. The major one is based on thespecial requirements for prescribing anti-TNF-α agents inour country, e.g. the history of at least two failed DMARDs,meaning that the addressing RA population has severe,long-standing disease and irreversible joint damage whichmay be less likely to respond to the treatment [24], evenwith anti-TNF-α.

In conclusion, we have suggested a predictive model forachieving remission and LDA with TNF-α blockers inestablished RA. Further studies are necessary to confirmtheir predictive value, in particular RA settings, shapingthe use of the anti-TNF-α therapy.

Disclosures None.

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