The Comparative One-Year Performance ofAnti–Tumor Necrosis Factor � Drugs in PatientsWith Rheumatoid Arthritis, Psoriatic Arthritis,and Ankylosing Spondylitis: Results From aLongitudinal, Observational, Multicenter StudyMARTE SCHRUMPF HEIBERG,1 WENCHE KOLDINGSNES,2 KNUT MIKKELSEN,3 ERIK RØDEVAND,4

CECILIE KAUFMANN,5 PETTER MOWINCKEL,1 AND TORE K. KVIEN1

Objective. To compare the 1-year retention rates of anti–tumor necrosis factor � (anti-TNF�) medications in patients withrheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) with complementary analyses of the effecton health status.Methods. Our analyses comprised 847, 172, and 249 anti-TNF� treatment courses in patients with RA, PsA, and AS,respectively. Crude drug survival was compared and hazard ratios (HRs) for treatment termination were calculated withadjustments for age, sex, investigator’s global assessment, and concomitant methotrexate (MTX). Adjusted changes inhealth-related quality of life (HRQOL) were compared among the groups.Results. Unadjusted 1-year retention rates were 65.4%, 77.3%, and 77.5% in the RA, PsA, and AS groups, respectively.The adjusted HRs for treatment termination were 0.76 (95% confidence interval [95% CI] 0.53–1.07) for PsA versus RAand 0.66 (95% CI 0.47–0.92) for AS versus RA. High baseline disease activity and female sex were significantly associatedwith premature treatment termination, whereas concomitant MTX was associated with better drug survival. However, theimpact of MTX was apparent for RA and PsA, but not for AS in stratified analyses. The improvements in HRQOL weresuperior in patients with PsA and AS compared with RA.Conclusion. Our results suggest that survival of anti-TNF� treatment is superior in AS and PsA patients compared withRA patients. Larger improvements in HRQOL in patients with spondylarthritides may contribute to the differences indrug survival. Concomitant MTX was associated with better retention rates in RA and PsA patients, but not AS patients.

INTRODUCTION

The introduction of biologic therapies has changed thetreatment strategies for inflammatory arthritides, in partic-ular ankylosing spondylitis (AS), for which therapeuticoptions were previously scarce (1). Three different anti–

tumor necrosis factor � (anti-TNF�) drugs (infliximab,etanercept, and adalimumab) are approved for patientswith rheumatoid arthritis (RA), AS, and psoriatic arthritis(PsA). Their efficacy has been demonstrated in severalrandomized clinical trials (RCTs) for each diagnosticgroup separately (2–10), but less is known about the com-

Supported by The Norwegian Women’s Public Health As-sociation and Eastern Norway Regional Health Authority.The Norwegian Disease-Modifying Antirheumatic Drugstudy has received unrestricted grant support from Abbott,Amgen, Wyeth, Aventis, MSD, Schering-Plough/Centocor,and the Norwegian Directorate for Health and Social Af-fairs.

1Marte Schrumpf Heiberg, MD, Petter Mowinckel, MSc,Tore K. Kvien, MD, PhD: Diakonhjemmet Hospital, Oslo,Norway; 2Wenche Koldingsnes, MD, PhD: University Hospi-tal Northern Norway, Tromsø, Norway; 3Knut Mikkelsen,MD: Lillehammer Hospital for Rheumatic Diseases, Lille-hammer, Norway; 4Erik Rødevand, MD: St. Olav Hospital,Trondheim, Norway; 5Cecilie Kaufmann, MD: BuskerudCentral Hospital, Drammen, Norway.

Dr. Heiberg has received speaking fees and honoraria(less than $10,000) from Abbott and consultancy fees (lessthan $10,000) from Wyeth. Dr. Koldingsnes has receivedspeaking fees (less than $10,000 each) from Schering-Plough, Wyeth, and Abbott. Dr. Mikkelsen has receivedhonoraria (less than $10,000 each) from Roche and Bristol-Myers Squibb. Dr. Kvien has received consultancies andspeaking fees (less than $10,000 each) from Abbott, Schering-Plough, and Wyeth.

Address correspondence to Marte Schrumpf Heiberg, MD,Department of Rheumatology, Diakonhjemmet Hospital,Box 23 Vinderen, 0319 Oslo, Norway. E-mail: marte.schrumpf@diakonsyk.no.

Submitted for publication March 27, 2007; accepted inrevised form July 3, 2007.

Arthritis & Rheumatism (Arthritis Care & Research)Vol. 59, No. 2, February 15, 2008, pp 234–240DOI 10.1002/art.23333© 2008, American College of Rheumatology

ORIGINAL ARTICLE

234

parative effectiveness across the different diagnoses. Drugsurvival is considered a surrogate marker for effect (11).However, other factors, such as available treatment op-tions, concomitant medication, patient characteristics, andtight followup, may influence the retention rates. The com-parative drug survival between diagnostic groups has beenexplored previously in a few observational studies (12,13),but ours is the first study to provide data on drug survivalwith concurrent analyses of effects on health status. Weanalyzed data from a Norwegian register of disease-modi-fying antirheumatic drug (DMARD) prescriptions (includ-ing biologic therapies) for patients with inflammatory ar-thropathies. Our goal was to compare the 1-year retentionrates in patients with RA, PsA, and AS who receivedanti-TNF� treatment. As an additional measure of effec-tiveness, we explored the comparative change in health-related quality of life (HRQOL) between the diagnosticgroups.

PATIENTS AND METHODS

Setting. The Norwegian DMARD (NOR-DMARD) regis-ter was established in December 2000 (14). Five Norwe-gian rheumatology departments consecutively includedall patients with inflammatory arthritides who started aDMARD regimen. Patients were registered as a new casewhen they switched to another DMARD regimen, whichalso included adding, for example, an anti-TNF� drug tomethotrexate (MTX) monotherapy. The study design was aphase IV, multicenter, longitudinal, observational study.We managed to enroll �85% of the patients who startedwith DMARD therapy into the register. The remaining15% were either missed for inclusion, refused enrollment,were excluded due to language barriers or inclusion inRCTs, etc. By August 2006, a total of 5,811 cases wereenrolled in the NOR-DMARD register.

Patients. Patients were eligible for the present analysesif they had been diagnosed with RA, PsA, or AS by thetreating rheumatologist (i.e., they were given the diagnosesM05.8, M05.9, M06.0, L40.5 plus M07.0, M07.2, M07.3, orM45 according to the World Health Organization Interna-tional Statistical Classification of Diseases and RelatedHealth Problems, Tenth Revision) and received an anti-TNF� drug, with or without concomitant MTX. A total of1,019 patients (645 RA, 150 PsA, 224 AS) received a totalof 1,268 anti-TNF� treatment courses (847 RA, 172 PsA,249 AS) that were included in the analyses. Two or moretreatment courses were registered in 153 (24%) of the RApatients, 18 (12%) of the PsA patients, and 22 (10%) of theAS patients. The most common dosing regimen for inflix-imab was 3–5 mg/kg at baseline, after 2 and 6 weeks, andthen every 8 weeks for patients with RA and PsA and 5mg/kg at baseline, after 2 and 6 weeks, and then every 6weeks for patients with AS. The dosing regimen for etan-ercept was 25 mg twice weekly and for adalimumab, 40 mgevery 2 weeks. The patients gave written informed consentbefore participation. The study was evaluated by the re-gional ethical committee, and the storage of data was ap-proved by the Data Inspectorate.

Assessments. Demographic variables are recorded forall patients in the NOR-DMARD register at baseline. Fur-thermore, patients are assessed at baseline and after 3, 6,and 12 months and then yearly with measures of diseaseactivity and health status that are applicable not only inRA but also in other inflammatory arthritides. All treat-ment terminations and reasons for withdrawal are re-corded. Reasons for withdrawal are classified as lack ofefficacy, adverse event (AE), both lack of efficacy and AE,patient’s preference, remission, or other reason/unknown.In the present analyses, the combination of lack of efficacyand AE was classified as AE.

The Medical Outcomes Study 36-item Short FormHealth Survey (SF-36) (15) is a commonly used healthstatus measure. It contains 36 questions measuring healthacross 8 different dimensions: physical functioning, rolelimitations due to physical health problems, bodily pain,vitality, social functioning, role limitations due to emo-tional problems, mental health, and general health. Ascore is computed within each dimension with a valuefrom 0 (worst possible health state) to 100 (best possiblehealth state). The SF-36 is a generic measure, which there-fore can be used to assess health status across differentdiagnoses. The investigator’s global assessment of diseaseactivity, measured on a 100-mm visual analog scale (0 �not active, 100 � extremely active), was used as a genericmeasure of disease activity.

Statistical analyses. The crude drug retention rateswere explored with Kaplan-Meier analyses using the logrank test to compare the survival curves. The hazard ratios(HRs) for treatment withdrawal were assessed with adjust-ments for age, sex, investigator’s global assessment of dis-ease activity, and concomitant MTX use in Cox regressionanalyses. The model was tested for proportionality. Wealso explored the impact of disease duration, number ofprevious DMARDs, and type of anti-TNF� drugs by usingthese variables as covariates in the Cox regression analy-ses. The 6- and 12-month changes in SF-36 scores wereassessed using analyses of covariance (16) with adjust-ments for age, sex, concomitant MTX use, and the baselinevalue of the dependent variable. Changes in SF-36 scoreswere examined with a last observation carried forward(LOCF) approach when values were missing, with at least1 followup examination required. Some patients had notbeen included in the register for a sufficient time to have afollowup examination, whereas others had terminatedtreatment prior to the 3-month assessment. Therefore, datafor the LOCF analyses were not available in 13%, 12%,and 17% of the RA, PsA, and AS cases, respectively.Robustness analyses were performed including only thepatients who had never previously taken anti-TNF�agents. A significance level of 5% was used in all analyses.No correction for multiple comparisons was performed.Statistical analyses were performed with SPSS software,version 14.0 (SPSS, Chicago, IL).

RESULTS

A total of 1,268 treatment courses were eligible for theanalyses (847 anti-TNF� regimens in RA patients, 172 in

Anti-TNF� Drugs in Patients With RA, PsA, and AS 235

PsA patients, and 249 in AS patients). A larger proportionof RA patients were women, and RA patients were olderthan patients in the PsA and AS groups. More RA patientshad previously been exposed to anti-TNF� drugs. Amongthe RA patients, 77% were positive for rheumatoid factor(RF) and 73% had erosive disease. Of the PsA and ASpatients, 87% and 25%, respectively, had peripheral ar-thritis. Group characteristics and baseline values areshown in Table 1.

The crude 1-year survival rates of anti-TNF� drugs were65.4%, 77.3%, and 77.5% among patients with RA, PsA,and AS, respectively (P � 0.003 for RA versus PsA and P �0.001 for RA versus AS) (Figure 1). The withdrawal ratesfor the different anti-TNF� drugs are shown in Table 2.After adjusting for age, sex, investigator’s global assess-ment, and concomitant MTX, the respective HRs (95%confidence interval [95% CI]) for treatment termination inPsA and AS patients versus RA patients were 0.76 (0.53–1.07) and 0.66 (0.47–0.92). Female sex and higher baselinedisease activity, as measured by the investigator’s global

assessment, were associated with a higher risk of treatmenttermination, whereas concomitant MTX was associatedwith a lower risk of treatment termination (Table 3). Theassociation between baseline disease activity and drugsurvival was consistent across the diagnoses and the dif-ferent anti-TNF� drugs.

We also explored the impact of disease duration andnumber of previous DMARDs by introducing these vari-ables as covariates in the Cox regression analysis. Theywere not statistically significant covariates and they didnot influence the model. There were also no interactionsbetween disease duration and diagnosis or type of anti-TNF� drug. There was a statistically significant differencebetween the 3 anti-TNF� drugs in favor of etanercept ver-sus infliximab and adalimumab regarding overall drug sur-vival. However, etanercept was prescribed more often asthe first anti-TNF� drug than the other 2. We also per-formed a subanalysis including only patients who hadnever previously taken anti-TNF� drugs. There was nolonger a difference between the 3 drugs, otherwise theresults remained similar. In a subanalysis including onlythe RA patients, we found no difference in drug survivalbetween the RF-positive and RF-negative patients.

The combination of an anti-TNF� drug and MTX washighly associated with a lower risk of treatment termina-tion compared with anti-TNF� monotherapy, with an HR(95% CI) of 0.53 (0.43–0.65). We also compared the sur-vival of monotherapy and combination therapy usingKaplan-Meier plots, stratified for diagnoses (Figure 2). Astatistically significant difference in favor of combination

Table 1. Demographic and clinical characteristics at baseline*

CharacteristicRA

(n � 847)PsA

(n � 172 )AS

(n � 249)

Age, years 52.8 � 13.5 45.7 � 10.8 43.4 � 10.5Female sex, % 74.3 36.6 26.1Disease duration, years 11.4 � 9.3 12.1 � 9.3 14.0 � 10.2No. previous DMARDs 3.9 � 2.4 2.6 � 1.6 1.1 � 1.2VAS investigator’s global 48.3 � 19.9 43.9 � 19.3 39.5 � 37.0Concomitant MTX, % 66.7 68.0 30.5Anti-TNF� drug, no. (%)

Infliximab 214 (25.2) 48 (27.9) 113 (45.4)Etanercept 345 (40.7) 96 (55.8) 122 (49.0)Adalimumab 288 (34.1) 28 (16.3) 14 (5.6)

Anti-TNF� naive, % 64 73 78

* Values are the mean � SD unless otherwise indicated. RA � rheumatoid arthritis; PsA � psoriaticarthritis; AS � ankylosing spondylitis; n � number of treatment courses; DMARDs � disease-modifyingantirheumatic drugs; VAS investigator’s global � investigator’s global assessment on a visual analog scale;MTX � methotrexate; TNF� � tumor necrosis factor �.

Figure 1. The crude 1-year survival of anti–tumor necrosis factor� drugs in patients with rheumatoid arthritis (RA), psoriatic ar-thritis (PsA), and ankylosing spondylitis (AS; Kaplan-Meier ana-lyses, P � 0.003 for RA versus PsA and P � 0.001 for RA versusAS, log rank test).

Table 2. The withdrawal rates for the differentanti–tumor necrosis factor � drugs within each

diagnostic group*

RA PsA AS

Etanercept 29.9 24.0 24.6Infliximab 37.1 25.0 19.5Adalimumab 38.4 14.3 28.6

* Values are the percentage. See Table 1 for definitions.

236 Heiberg et al

therapy was observed for both RA patients (P � 0.001) andPsA patients (P � 0.02), whereas no difference was ob-served between monotherapy and combination therapy forAS patients (P � 0.29).

The reasons for discontinuing treatment among patientswith RA, PsA, and AS, respectively, were distributed asfollows: lack of efficacy in 39.0%, 17.9%, and 36.4%; AEsin 49.3%, 69.2%, and 43.6%; patient’s request in 4.8%,5.1%, and 1.8%; and other reasons/unknown in 6.9%,7.7%, and 18.2%. No combination treatment courses werediscontinued due to lack of efficacy among patients withPsA.

The SF-36 scores at baseline were similar across thegroups, except that the mean physical function score androle physical score were higher in the AS group comparedwith the 2 other groups (results not shown). The adjustedchanges were numerically superior in PsA and AS patientsversus RA patients across all 8 SF-36 dimensions at both 6and 12 months (Figure 3), although the changes were notstatistically significant for the mental and social dimen-sions.

DISCUSSION

The anti-TNF� drugs represent a new biologic treatmentera for patients with rheumatic conditions, and the effi-cacy has been demonstrated through several RCTs (2–10).However, it is also important to document the effective-ness of these costly drugs, i.e., how well they performunder real-life conditions, as strict inclusion criteria andshort duration often limit the external validity of resultsfrom RCTs (17,18). A longitudinal, observational study isthe preferred design for studying effectiveness (19).

In the present observational study, we assessed the sur-vival of treatment with anti-TNF� drugs in a large numberof patients with RA, PsA, and AS, and complementaryanalyses of the effect on health status were performed. Thecrude Kaplan-Meier analyses showed that a larger propor-tion of anti-TNF� treatment courses were terminated pre-maturely in RA patients compared with PsA patients andAS patients during the first year. This finding correspondswith the results from other observational studies. Carmonaand Gomez-Reino analyzed data from the Spanish registryBase de Datos de Productos Biologicos de la SociedadEspanola de Reumatologıa (BIOBADASER) and found anHR for treatment discontinuation of 0.66 for spondylar-thritides versus RA after adjustment for age, sex, and use ofinfliximab (12). In a retrospective study, Duclos and col-leagues found an HR of 1.60 for continuing anti-TNF�treatment for spondylarthritis versus RA (13).

Although drug survival is regarded as a surrogate markerfor efficacy, other factors may influence the retention rates,e.g., the access to alternative treatments. Anti-TNF� treat-ment is the only effective treatment for AS patients withaxial disease for whom nonsteroidal antiinflammatorydrugs are insufficient (1), whereas several other treatmentalternatives are available for patients with PsA and RA.Thus, the comparative retention rates between these diag-nostic groups must be interpreted with caution.

The present study is the first to combine analyses of drugsurvival with assessments of comparative changes inHRQOL between patients with RA, PsA, and AS. As

Figure 2. The crude 1-year survival of anti–tumor necrosis factor � (anti-TNF�) drugs, with and without concomitant methotrexate (MTX),in patients with A, rheumatoid arthritis (RA), B, psoriatic arthritis (PsA), and C, ankylosing spondylitis (AS; Kaplan-Meier analyses, Pvalues for anti-TNF� plus MTX versus anti-TNF� monotherapy: P � 0.001 for RA, P � 0.02 for PsA, P � 0.29 for AS). Solid line �anti-TNF� plus MTX; broken line � anti-TNF�.

Table 3. Adjusted HRs for discontinuing anti–tumornecrosis factor � drugs (Cox regression analysis)*

HR (95% CI) P

DiagnosisRA (reference) 1.00PsA 0.76 (0.53–1.07) 0.12AS 0.66 (0.47–0.92) 0.01

Age 1.003 (1.00–1.01) 0.42Sex

Male (reference) 1.00Female 1.51 (1.19–1.93) 0.01

VAS investigator’s global† 1.06 (1.001–1.13) 0.01Concomitant MTX 0.53 (0.43–0.65) �0.001

* HR � hazard ratio; 95% CI � 95% confidence interval; see Table1 for additional definitions.† HR for a 10-mm increase in VAS investigator’s global assessment.

Anti-TNF� Drugs in Patients With RA, PsA, and AS 237

shown in Figure 3, the changes in SF-36 scores were nu-merically superior in PsA and AS patients compared withRA patients across all SF-36 dimensions, although thesechanges were statistically significant primarily for thephysical dimensions. A ceiling effect for the mental di-mensions may have reduced the chance of detecting groupdifferences, as the baseline values for social functioning,mental health, and role mental were high (score range50–70), and therefore limited the potential for improve-ment. We have also previously demonstrated that HRQOLimproved more in patients with AS receiving anti-TNF�drugs than in those with RA receiving these drugs (20), butthe increased health benefit in patients with PsA versusthose with RA is a novel finding and supports the idea that

superior effectiveness contributes to the longer retentionrates in spondylarthritis patients. There was also a ten-dency of larger improvements in AS patients comparedwith PsA patients, although the difference was statisticallysignificant only for the SF-36 physical function score at the6-month assessment.

The overall impression from our results is that a gradientis observed for both retention rates and health benefit, witha relatively larger benefit in patients with pure axial man-ifestations versus peripheral arthritides. As in our study,Carmona and Gomez-Reino also found that the differencein drug survival between the PsA subgroup and RA wasnot statistically significant after adjustment for other im-portant factors, whereas there was still a statistically sig-nificant difference between RA and AS (12).

In the Cox regression analyses, we found that femalesex and high baseline disease activity were associated witha higher risk of treatment termination, whereas concomi-tant MTX was strongly associated with better drug sur-vival. This finding contradicts the finding from the Frenchretrospective analysis that showed a significantly bettersurvival of anti-TNF� treatment without concomitantDMARDs (13), whereas the impact of concomitant MTXuse was not addressed in the Spanish study (12). RCTsand observational studies have demonstrated that anti-TNF� drugs, in combination with MTX, have a superioreffect on disease activity compared with anti-TNF� mono-therapy in patients with RA (6,21–24), whereas the role ofconcomitant MTX is less clear for the spondylarthritides.It is known that anti-TNF� therapy, especially infliximab,may induce antibody formation against the drug in pa-tients with RA, and that concomitant MTX can preventthis antibody formation (25). Less is known about antibodyformation against the anti-TNF� drugs in patients withPsA and AS, although a Dutch study recently demon-strated that clinical response to infliximab in patients withAS is also correlated to antiinfliximab antibody formation(26). Whether this can be prevented by concomitant im-munosuppressive therapy is not known. Unfortunately,antibodies in serum are not measured in the NOR-DMARDregister and frozen sera are not available. In the stratifiedKaplan-Meier analysis, we found a statistically significantdifference in retention rates between combination therapyand monotherapy for both RA and PsA patients, whereasthe retention rates were similar in AS patients. Interest-ingly, no combination treatment courses were prematurelyterminated due to lack of efficacy in patients with PsA,whereas lack of efficacy was the reason for �40% of themonotherapy discontinuations. Kristensen et al also foundthat lack of concomitant MTX was a predictor of prema-ture treatment termination in patients with PsA (27). Pre-vious RCTs of anti-TNF� drugs in patients with PsA havefailed to demonstrate superior clinical improvement inpatients receiving concomitant MTX versus monotherapy(2,8,9).

Duclos et al found significantly better survival of the firstanti-TNF� treatment course compared with the second orthird treatment course (13), whereas in a large UK cohortstudy, Hyrich et al recently demonstrated that contin-uation rates were high in patients with RA who switchedto a second anti-TNF� drug (28). We found a tendency

Figure 3. Changes in Short Form 36 scores after A, 6 months andB, 12 months in patients with rheumatoid arthritis (RA), psoriaticarthritis (PsA), and ankylosing spondylitis (AS; adjusted for age,sex, concomitant methotrexate, and baseline score). ** P � 0.001versus RA. * P � 0.05 versus RA. § P � 0.02 AS versus PsA. PF �physical functioning; RP � role limitations due to physical healthproblems; BP � bodily pain; GH � general health; VI � vitality;MH � mental health; RM � role limitations due to emotionalproblems; SF � social functioning. Solid bars � RA; shadedbars � PsA; open bars � AS.

238 Heiberg et al

toward longer retention rates for the first course of anti-TNF� treatment, but the association was not statisticallysignificant. Nevertheless, we performed robustness analy-ses, including only the patients who had never previouslyreceived anti-TNF� drugs, and our results remained simi-lar. Like Duclos et al, we found no significant differencebetween the 3 anti-TNF� drugs, whereas other groups havefound significant differences between the 3 drugs in ob-servational studies (12,22). However, caution should beapplied in the interpretation of treatment comparisons in anonrandomized context due to the possibility of con-founding by indication.

In summary, we found that the 1-year survival of anti-TNF� drugs was superior in patients with AS and PsAcompared with those with RA, and the gradient for thecomparative improvement in HRQOL was similar to thegradient regarding retention rates across the diagnosticgroups. Concomitant MTX was associated with better re-tention rates in patients with RA and PsA, but not inpatients with AS. These results, taken together with find-ings from other observational studies, support that theeffectiveness of anti-TNF� treatment is graded across thediseases, with the relatively lowest benefit in patients withRA.

AUTHOR CONTRIBUTIONS

Dr. Heiberg had full access to all of the data in the study andtakes responsibility for the integrity of the data and the accuracyof the data analysis.Study design. Mikkelsen, Kvien.Acquisition of data. Heiberg, Koldingsnes, Mikkelsen, Rødevand,Kaufmann, Kvien.Analysis and interpretation of data. Heiberg, Koldingsnes, Mow-inckel, Kvien.Manuscript preparation. Heiberg, Koldingsnes, Rødevand, Mow-inckel, Kvien.Statistical analysis. Heiberg, Mowinckel.

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