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Frequency and duration of drug-free remission after 1 year of treatment with etanercept versus sulfasalazine in early axial spondyloarthritis: 2 year data of the ESTHER trial
  1. In-Ho Song1,
  2. Christian E Althoff2,
  3. Hildrun Haibel1,
  4. Kay-Geert A Hermann2,
  5. Denis Poddubnyy1,
  6. Joachim Listing3,
  7. Anja Weiß3,
  8. Svetlana Djacenko4,
  9. Gerd R Burmester5,
  10. Martin Bohl-Bühler6,7,
  11. Bruce Freundlich8,
  12. Martin Rudwaleit1,
  13. Joachim Sieper1,3
  1. 1Department of Rheumatology, Charité Medical University, Campus Benjamin-Franklin, Berlin, Germany
  2. 2Department of Radiology, Charité Medical University, Campus Mitte, Berlin, Germany
  3. 3Epidemiology Unit, German Rheumatism Research Centre, Berlin, Germany
  4. 4Department of Rheumatology, Schlossparkklinik, Berlin, Germany
  5. 5Department of Rheumatology and Clinical Immunology, Charite University Hospital, Berlin, Germany
  6. 6Department of Rheumatology, Private Practice, Potsdam, Germany
  7. 7Endokrinologikum Berlin, Private Practice, Berlin, Germany
  8. 8Division of Rheumatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  1. Correspondence to Joachim Sieper, Charité, Department of Rheumatology, Campus Benjamin Franklin, Med. Clinic I, Rheumatology, Hindenburgdamm 30, 12200 Berlin, Germany; joachim.sieper{at}


Purpose The aims of this study were (1) to assess the frequency and duration of drug-free remission and efficacy of etanercept (ETA) treatment after flare in patients with early active axial spondyloarthritis who were treated with ETA (n=40) versus sulfasalazine (SSZ, n=36) for 48 weeks and (2) to analyse the efficacy of ETA treatment in patients in year 2 who did not reach remission at week 48.

Method At week 48, patients who reached study remission (Assessment of Spondyloarthritis international Society (ASAS) plus MRI remission) were followed up without active treatment up to 1 year. In case of a flare, patients were treated with ETA for another year. All patients who were not in ASAS plus MRI remission at week 48 were treated with ETA in year 2.

Results ASAS plus MRI remission at week 48 was reached significantly more often in ETA-treated compared to SSZ-treated patients (33% vs 11%, p=0.03). However, the flare rate was not different between these two groups: 69% in the ETA group versus 75% in the SSZ group. Only 8% of patients initially treated with ETA versus 3% of those initially treated with SSZ reached permanent drug-free remission (not significant). After treatment with ETA over 1 year, patients with flare showed an improvement in all clinical and imaging variables.

Conclusion Patients with axial spondyloarthritis treated with ETA over 1 year did not reach drug-free remission in a higher percentage compared to patients from a control group treated with SSZ.

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Recently, we reported on the results of a prospective randomised trial of etanercept (ETA) versus sulfasalazine (SSZ) in patients with early axial spondyloarthritis (SpA), showing superiority of ETA in all measured outcome parameters including decrease of active inflammation on whole-body MRI.1 2

Taking into account the excellent response of patients with axial SpA who are treated early with a tumour necrosis factor alpha (TNFα)-blocker,1 3 4 it was of special interest to assess whether drug-free remission could be obtained in these patients. Here, we report on the percentage of patients remaining in drug-free remission, the percentage of patients with flare, time to flare and the response to ETA after re-treatment.

Patients and methods

Study design in year 2

Patients with axial SpA with a symptom duration of less than 5 years were enrolled in the prospective randomised controlled trial and were treated with ETA (n=40) versus SSZ (n=36) over 48 weeks (year 1).1

At week 48, patients were assessed as to whether they achieved study remission defined as reaching Assessment of Spondyloarthritis international Society (ASAS) remission and being free of active inflammation on whole-body MRI in the spine and sacroiliac (SI) joints (ASAS plus MRI remission). The decision regarding the presence or absence of active inflammatory lesions was made by one radiologist who was blinded to the treatment arms and the clinical (remission) status.

Patients in ASAS plus MRI remission at week 48 were followed up every 6 weeks without active treatment. In case of a flare (defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) increase of 2 points compared to week 48), patients were started again on ETA for another entire year. Patients who did not flare were taken off the study at the end of year 2 according to the study protocol (permanent drug-free remission). Patients who were not in ASAS plus MRI remission at week 48 (either ETA or SSZ group) were treated with ETA in year 2.


Whole-body MRIs, STIR (short tau inversion recovery) and T1 images were obtained at weeks 0, 24, 48 and 104 on a 1.5 T scanner (Avanto TIM, Siemens, Germany) as previously described.1 5 6 Whole-body MRIs were scored for active inflammation according to a recently described protocol1 using the STIR sequences by two radiologists, blinded for treatment arm and MRI time point.


Statistical analysis was performed as an intention-to-treat, last-observation-carried-forward analysis. One-sample t test and Wilcoxon rank test were used to examine changes within groups. Taking small sample sizes into account, the Blyth–Still–Casella method was used to calculate 95% CIs of proportions.


ASAS plus MRI remission at week 48 was reached significantly more frequently by ETA-treated patients than by SSZ-treated patients (33% vs 11%, p=0.03) (figure 1A). These patients were rather male (70.6%), were more human leucocyte antigen B27 positive (94.1%) and had rather non-radiographic axial SpA (64.7%) compared to the whole study population, although these differences were not significant. However, the number of patients remaining in drug-free remission during year 2 (in total only 4 out of 17 patients; 23.5% (95% CI 8.5% to 48.9%)) was not clearly different between the two groups with 3 out of 13 in the ETA group and 1 out of 4 in the SSZ group. Patients who flared in year 2 (13/17) were treated with ETA after the flare. The mean time to flare was not significantly different in the ETA group (24.4 weeks) and the SSZ group (39.6 weeks) (figure 2).

Figure 2

Cumulative probability plot illustrating the duration of drug-free remission in patients who flared after 48 weeks of treatment with ETA (n=9) versus SSZ (n=3). No significant difference between the ETA or SSZ group was found regarding the time until flare. ETA, etanercept; SSZ, sulfasalazine.

Figure 1

(A) The percentage (number) of patients reaching ASAS plus MRI remission at week 48 in ETA-treated patients (n=40) versus SSZ-treated patients (n=36) is shown, as well as the percentage (number) of patients who experienced a flare during year 2 or who stayed in drug-free remission until the end of year 2 (permanent drug-free remission). (B) The percentage (number) of patients with flare or in permanent drug-free remission in relation to patients who were in ASAS plus MRI remission at week 48 is shown. ASAS, Assessment of Spondyloarthritis international Society; ETA, etanercept; SSZ, sulfasalazine.

After (re-)treatment with ETA, patients with flare responded similarly well in all variables; only the yes/no criterion of ASAS remission was reached less frequently (table 1).

Table 1

Efficacy data until week 108 in the groups who reached remission and showed a flare of the disease (groups A and B) and in the non-remission groups (groups C and D)

Patients treated with ETA in the first year who did not reach ASAS plus MRI remission at week 48 (n=22) showed a good sustained clinical and MRI response at week 108 when treated with ETA also during the second year (table 1). Half of these patients even reached ASAS remission, including five patients not in ASAS remission at week 48, while only one patient lost ASAS remission between week 48 and week 104. Furthermore, 3 out of 22 patients (13.6% (3.8% to 32.7%)) reached even ASAS plus MRI remission at week 108.

Patients who switched treatment from SSZ in year 1 to ETA in year 2 (n=26) significantly improved in the BASDAI score (p=0.0013) and Ankylosing Spondylitis Disease Activity Score (ASDAS) (p=0.0019), but the observed improvement in MRI spine and SI joint scores did not reach statistical significance (p=0.09 and p=0.054, respectively). No further improvement in C reactive protein levels was observed in this group (p=0.75) (table 1).

There was a small, but non-significant, improvement of enthesitis on MRI in all subgroups treated with ETA in the second year as shown in table 1.

Regarding scoring of active inflammatory lesions on MRI, the interclass correlation coefficients of the two readers for the spine were 0.956 at baseline, 0.848 at week 48 and 0.866 at week 108; for SI joints, interclass correlation coefficients were 0.953, 0.842 and 0.846, respectively.

Safety, dropouts and drug survival

During year 2, a total of 261 adverse events were observed, including 3 serious adverse events in three patients who were hospitalised: a mild infection in the coccygeal area, a hypersensitivity reaction against analgesic intake and surgery for an umbilical hernia.

There was a total dropout rate of 22.4% (17/76) at year 2. The four patients who reached the end of year 2 in ASAS plus MRI remission were not counted.


In the current study of patients with axial SpA with a symptom duration of less than 5 years, treatment with ETA over 1 year did not induce drug-free remission in a higher percentage or for a longer interval than in a control group of patients treated with SSZ. While remission after 1 year of treatment was clearly reached in a higher percentage of patients in the ETA group, there was no difference in the percentage of patients with flares among these patients (69% of ETA-treated patients vs 75% of SSZ-treated patients).

When patients with drug-free remission were analysed in relation to the number of patients treated initially, a few more ETA-treated patients reached drug-free remission: 3 out of 40 (8%) versus 1 out 36 SSZ-treated patients (3%), but this difference was small and was not significant. However, it is possible that significance might be reached if the patient groups were larger.

In other trials, similar flare rates of up to 97% were seen in patients with ankylosing spondylitis (AS) upon drug discontinuation after several years of treatment with infliximab,7 in 83% of patients with non-radiographic axial SpA after 1 year of adalimumab treatment3 8 and in 60% of patients with axial SpA with a symptom duration of less than 3 years after 16 weeks of infliximab treatment.4 9 None of these trials employed the strict remission criteria used in the current study. Also, flare rates were less strictly defined in these studies.

The discrepancy between the number of patients reaching ASAS plus MRI remission at week 48 in the current analysis and the number of these patients in our previous report1 is explained by the fact that the decision on remission on MRI yes or no (and subsequent interruption of treatment if patients were also in clinical remission) had to be made on the spot by one radiologist in comparison to a blinded MRI reading by two radiologists in a later systemic analysis of these data.1 Of note, if only those 6 ETA-treated patients who were in ASAS plus MRI remission according to both readers were analysed,1 the flare rate (66.6% (4 out of 6)) would have been similar, compared to the 13 patients analysed here.

These data may indicate that either the treatment with TNFα-blockers was not started early enough or that this kind of treatment, although suppressing inflammation effectively, does not restore the disturbed disease process. New diagnostic approaches,10 11 new classification criteria for axial SpA12 and screening programmes for earlier identification of patients with axial SpA in primary care13 14 will hopefully allow investigators to address this question in patients with even shorter symptom duration.

In patients with rheumatoid arthritis with a symptom duration of less than 1 year15 or 2 years,16 TNFα-blocker-free remission rates (or low disease activity rates) were achieved in 25%15 and 70% of patients, respectively. 16 Complete drug-free remission (including methotrexate) was only reached in a small percentage (14.8%) of patients followed up over 5 years.16

In the current study, patients who were re-treated with ETA obtained a similarly high level of response compared to initial treatment, indicating that anti-TNF treatment can safely be interrupted in patients in remission to identify the 20–30% of patients who do not need further treatment.

The percentage of patients remaining on ETA over 1 year and 2 years was good, with a drug survival rate similar to what has been reported in AS trials with longer symptom duration.17,,19 Also, the level of response remained stable over 2 years of treatment. However, the plateau for mean values of BASDAI, ASDAS or MRI inflammatory scores for SI joint or spine was already reached after 24 weeks of treatment, although a few more patients fulfilled the clinical remission criteria if treated for a longer period.1 The group of patients treated with SSZ for 1 year improved in all clinical and MRI variables when switched to ETA treatment after 1 year (table 1).

In summary, in this relatively early AS population with axial SpA, only a small percentage of patients in remission were able to stop medication after 48 weeks of treatment. Resultant flares responded well to resumed ETA treatment, leading to a low level of disease activity for up to 2 years.


The authors would like to thank Beate Buß, Kirsten Karberg, Jan Brandt, Eugen Feist, Jan Zernicke, Barbara Wenzel, Carmen Herz, Corinna Beer, Angela Seifert, Rieke Alten, Christof Pohl, Marina Heese, Silke Zinke, Kristin Lunkwitz, Frank Mielke and Martina Stoll for performing the studies. The authors also thank Sabine Achtelstetter for data preparation.



  • Funding This study was supported by Wyeth/Pfizer.

  • Competing interests IS, HH, DP: Pfizer/Wyeth Pharmaceuticals, Merck Sharp Dohme/Schering Plough, Abbott Immunology Pharmaceuticals: consulting fees or other remuneration. GB, MB, MR and JS: Pfizer/Wy eth Pharmaceuticals, Merck Sharp Dohme/Schering Plough, Abbott Immunology Pharmaceuticals, UCB: consulting fees or other remuneration. BF: Former employee of Pfizer/Wyeth. CA, KGH, JL, AW, SD: none.

  • Ethics approval Ethics approval was granted by Landesamt für Gesundheit und Soziales, Geschäftsstelle der Ethik-Kommission des Landes, Berlin, Germany.

  • Provenance and peer review Not commissioned; externally peer reviewed.