1 Department of Gastroenterology/Rheumatology, Charité, Medical University Berlin, Campus Benjamin Franklin, 2 Epidemiology Department, German Rheumatism Research Center Berlin, 3 Immanuel Hospital Berlin, Berlin, 4 Wyeth Pharma, Münster and 5 Center of Rheumatology Ruhrgebiet, Herne, Germany.
Correspondence to: J. Braun, Rheumazentrum Ruhrgebiet, Landgrafenstrasse 15, 44652 Herne, Germany. E-mail: J.Braun{at}rheumazentrum-ruhrgebiet.de
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Abstract |
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Methods. In this 54-week open observational study, 26 AS patients received 25 mg etanercept subcutaneously twice weekly after several months of discontinuation following a 6-month RCT with the same agent. All patients who developed high disease activity after cessation of etanercept, defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 4 and pain
4 on a numerical rating scale, entered the study. Standard assessment tools, such as the Bath Ankylosing Spondylitis functional index (BASFI), were used. An intention-to-treat (ITT) and a completer analysis were performed. The results were compared with the baseline values of the open study.
Results. Out of the initial 30 patients, 26 (87%) were eligible for the open extension study after a mean of about 27 weeks. At week 54, 23/26 patients (88%) were still on treatment with etanercept. The ITT analysis showed that 58% (95% confidence interval 3974%) of the patients achieved a 50% improvement of BASDAI at week 54. According to the Assessments in Ankylosing Spondylitis working group criteria, 8/26 patients (31%) were in partial remission at week 54. Function, metrology and quality of life improved significantly. Only one patient had a serious adverse event that resulted in discontinuation.
Conclusions. This study shows that treatment with etanercept is efficacious and safe after readministration over 1 yr in patients with active AS not taking DMARDs or steroids.
KEY WORDS: Therapy of ankylosing spondylitis, Tumour necrosis factor , Etanercept
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Introduction |
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In the past, AS has been treated mainly with non-steroidal anti-inflammatory drugs (NSAIDs) and physiotherapy. In contrast to RA, no disease-modifying anti-rheumatic drugs (DMARDs) are currently approved for the treatment of AS [6]. None of the few studies of DMARDs in AS has shown efficacy in axial disease. While methotrexate was found to have limited efficacy in a few studies of AS patients in which no control groups were used [7], sulphasalazine has limited efficacy in peripheral arthritis only in controlled trials [8].
In a recent randomized, placebo-controlled 3-month-trial we have shown that etanercept is significantly superior to placebo for the treatment of many of the manifestations of AS [9], including disease activity, function, spinal motility, peripheral arthritis, enthesitis and quality of life. In contrast to other randomized controlled trials (RCTs) which have basically led to the same results [10, 11], patients in our studies did not take other DMARDs, such as sulphasalazine and methotrexate. Altogether, these data have shown that etanercept is very efficacious for the short-term treatment of patients with severe AS who are insufficiently treated by NSAIDs.
In the previous study we also reported that, after discontinuation of etanercept, 75% of the patients showed a relapse after a mean of 6 weeks within a follow-up period of 3 months [9]. In the present study all patients who showed high disease activity after cessation of etanercept were retreated over a period of 1 yr. Here we report on the efficacy and safety of this retreatment.
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Methods |
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Patients and study protocol
This open observational 54-week-study was an open extension of a 6-month RCT on etanercept in AS which has been published previously [9]. In this study we showed that etanercept but not placebo was highly effective in the treatment of active AS.
Initially, 33 patients had been enrolled between March 2001 and July 2001. Patients were eligible for the study if they had a definite diagnosis of AS [12] and if they had active disease with a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI [13]) score of 4 and a score of
4 on a 010 numerical rating scale (NRS) for spinal pain. Concomitant DMARDs and oral corticosteroids had been withdrawn at least 4 weeks before screening. Patients were allowed to continue to take NSAIDs during the study but the dosage could not be increased over the baseline level during the course of the trial. However, the dosage could be reduced, and dosage reductions were recorded (the mean dosage of the last week was asked for at all visits). Patients had been randomly assigned to receive placebo or etanercept at a dosage of 25 mg subcutaneously (s.c.) twice weekly for 6 weeks and then in the same dosage for an additional 6 weeks.
After the end of this 3-month-treatment period with etanercept, all patients discontinued therapy with etanercept for a mean of 26.8 weeks (S.D. 6.6) before they were screened for eligibility for this 54-week open study. One major reason for this study design was a lack of study medication.
During the period without etanercept therapy, patients were assessed every 3 weeks using standard outcome measures. This allowed calculation of the time until relapse. A relapse was defined as a BASDAI of 4 and a score of
4 on a 010 NRS for physician global assessment in correlation to the recently proposed the Assessment in Ankylosing Spondylitis (ASAS) working group consensus statement for the use of anti-TNF agents in patients with AS [14].
Only patients who had completed the RCT were eligible for the open study. In addition they needed to have had definite high disease activity after cessation of the study medication despite conventional therapy. This was defined as a BASDAI score of 4 and a score of
4 on a 010 NRS for spinal pain despite treatment with NSAIDs, which is similar to the criteria used for the RCT. Patients were examined every 3 weeks for a total observational period of 54 weeks.
All patients provided written informed consent, and the trial was approved by the local ethics committees of the Free University of Berlin and Westfälische Wilhelms-Universität in Münster, Germany.
Study medication
Etanercept was administered s.c. at a dose of 25 mg twice weekly for 54 weeks.
Procedure
The core set for end-points recently proposed by the ASAS working group [15] was used to measure the clinical benefit of etanercept therapy in AS. The following validated tools, mostly questionnaires, were used. (i) The BASDAI was used to measure disease activity [13]. This is based on six questions relating to fatigue, spinal pain, peripheral arthritis, enthesitis and morning stiffness (both quantitatively and qualitatively). (ii) The Bath Ankylosing Spondylitis Functional Index (BASFI) was used to assess function [16]. This is based on 10 questions about daily functioning. (iii) An NRS, scored 010 (10 = very bad and 0 = very good), was used to measure spinal pain and the patient's and physician's global assessments. (iv) The Bath Ankylosing Spondylitis Metrology Index (BASMI) [17] was used to grade mobility of the spine and hip by measuring the distance from the tragus to the wall, lumbar flexion, cervical rotation, lumbar side flexion, and intermalleolar distance on a scale of 110, as evaluated in each patient by the same rheumatologist. (v) A 68-joint count was used to assess the number of swollen joints. The 12 most commonly involved enthesitic sites in AS were assessed clinically by a trained study nurse. In addition, 20% improvement and partial remission criteria recently proposed by the ASAS group [15] were assessed. According to these criteria, 20% improvement is defined as an improvement of not less than 20% and an absolute improvement of at least 1 unit (on a scale of 010) in at least three of the following four domains: patient's global assessment, pain, function (represented by the BASFI score), and inflammation (represented by the mean of the two morning stiffness-related BASDAI NRS scores). Furthermore, there must be an absence of deterioration, which is defined as worsening of not more than 20% and net worsening of not more than 1 unit (on a scale of 010), in the potential remaining domain. Partial remission was defined as a score of 2 (on a scale of 010) in each of the four domains.
Moreover, recently proposed criteria for short-term improvement after the use of anti-TNF- therapy in AS with good discriminating capacity and the advantage of the inclusion of two objective domains were performed by ASAS [18]. The so-called five-out-of-six improvement criteria defined improvement as a reduction in at least 20% in five out of the six following domains: pain, patient's global assessment (both represented by 010 NRS), function (represented by the BASFI score), morning stiffness (represented by the mean of the two morning stiffness-related BASDAI NRS scores), spinal mobility (represented by the BASMI score), and C-reactive protein levels. In addition, the ASAS 40% response criteria were used; these have the advantage of setting a high threshold and a good discriminating capacity, but only in patient-reported outcome [18]. According to these criteria, 40% improvement is defined as an improvement of not less than 40% and an absolute improvement of at least 2 units (on a scale of 010) in at least three of the four domains used for the ASAS 20% criteria.
Assessments of health-related quality of life were performed using the Short Form-36 (SF-36) instrument [19]. The scoring algorithm of the Medical Outcome Trust [20] was used to check and calculate the SF-36 as well as for the handling of single missing items in this questionnaire. All outcome measures were evaluated every 3 weeks, with the exception of the SF-36, which was performed every 6 weeks.
As the primary outcome parameter we defined the response rate on the basis of individual scores of >50% improvement in the BASDAI between baseline and week 54. As secondary end-points we used the mean improvements in several scores: BASFI, BASMI, SF-36, the ASAS response criteria, and the five-out-of-six response criteria, as well as improvement in the serum C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR) at different time points during the 12 months of treatment.
Statistical analysis
The analysis was done according to the intention-to-treat (ITT) principle. All patients who entered the open study (n = 26) were included in each analysis. Patients who withdrew were counted as non-responders for every missing visit. The last observation carried forward method was applied to include these patients in the calculation of mean values. The scoring method of Wilson was used to generate the 95% confidence intervals (CIs) for frequencies. For comparisons between visits, the paired t-test and the paired Wilcoxon rank sum test were applied. All comparisons were two-sided. A significance level of 5% was used. No adjustment for repeated significance testing was done. Statistical analyses were performed with SPSS software (release 11.0.1; SPSS, Chicago, IL, USA).
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Results |
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According to the five-out-of-six improvement criteria, 65% (95% CI 4681%) of the patients responded to treatment. Eight out of 26 patients (31%; 95% CI 1750%) were in partial remission after 54 weeks of treatment with etanercept (Fig. 3).
The BASDAI decreased from 6.4 ± 1.6 at baseline of the open extension trial to 2.8 ± 2.3 (P<0.0001) at week 54 (Fig. 4).
All single items of the BASDAI analysed separately improved also significantly. In detail, there was a mean (±S.D.) improvement between baseline and week 54 from 7.1 ± 1.5 to 3.7 ± 2.7 (P<0.0001) for fatigue, from 7.3 ± 1.6 to 3.3 ± 2.8 (P<0.0001) for spinal pain, from 5.0 ± 3.0 to 2.1 ± 2.4 (P = 0.0001) for peripheral joint pain, from 6.5 ± 1.8 to 2.6 ± 2.6 (P<0.0001) for entheseal pain, and from 5.9 ± 2.1 to 2.2 ± 2.3 (P<0.0001) for morning stiffness.
The same differences and trends that were observed with the BASDAI scores were found when analysing the BASFI and BASMI scores (Fig. 4). Between baseline and week 54 the BASFI scores improved significantly (P<0.0001) from 6.0 ± 2.1 to 3.5 ± 2.8 and the BASMI scores improved from 3.3 ± 2.0 to 2.5 ± 2.1 (P = 0.004).
Signs and symptoms of patients with peripheral arthritis and enthesitis improved somewhat after 54 weeks of etanercept therapy. Ten patients (38.5%) had peripheral arthritis and 16 had enthesitis (61.5%) at baseline. At week 54, two patients still had peripheral arthritis and three had enthesitis (P = 0.039 for arthritis, P = 0.0002 for enthesitis). The 5% trimmed mean number of swollen joints decreased from 0.7 ± 4.0 at baseline to 0.0 ± 1.8 at week 54 (P = 0.043), whereas the number of enthesitic sites was reduced from 2.4 ± 2.6 to 0.6 ± 1.8 (P = 0.002).
NSAID use stopped completely in 20 out of 24 patients (83%).
In comparison with the baseline, the mean concentration of CRP in serum and ESR fell significantly after 54 weeks from 14.4 ± 8.5 to 6.3 ± 2.7 mg/l and from 22.8 ± 15.3 to 9.5 ± 8.3 mm/h respectively (P<0.0001).
Between baseline and week 54, quality of life improved substantially in all single components of the SF-36, as shown in Fig. 5 (all 0.03).
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Safety
The one serious adverse event of clinical concern was a new onset of Crohn's disease in a 46-yr-old female 21 weeks after the start of etanercept therapy. The diagnosis was made by a gastroenterologist on the basis of the clinical picture (diarrhoea), endoscopy and a positive biopsy. The patient recovered after discontinuation of the study medication on treatment with corticosteroids and mesalazine. This case was thought to be probably related to etanercept.
Other treatment-related adverse events were mild to moderate in severity (Table 2). The other four reported serious adverse events were unlikely to have been related to the study medication. The patients had to be hospitalized for other reasons. The further course was uncomplicated. Etanercept injections were generally well tolerated.
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Discussion |
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The efficacy of this anti-TNF agent was further demonstrated on several levels with multiple different established instruments, including BASDAI, BASFI and BASMI. Most efficacy end-points were already reached at week 6 and this was maintained over 54 weeks (Figs 3 and 4). The completer analysis suggested ongoing improvement of disease activity and low BASDAI levels for the whole period (Fig. 4). This implies that the patients remained in a state of low disease activity over 1 yr.
Etanercept provides quantifiable benefits consistent with improvement of the overall disease state, not only regarding pain and disease activity but also in physical function and mobility, as assessed by BASFI and BASMI. The improvement of spinal mobility found in this study confirms recent results [9] which had already suggested that this measure is sensitive to change, even on a short-term basis [9]. This observation shows that the proportion of the functional loss in AS patients that is caused by spinal inflammation is reversible if effective anti-inflammatory therapy is provided, while the loss of function that remains is likely to be due to chronic damage, which mainly means new bone formation and ankylosischanges that may not be reversible by conservative therapy at all.
Moreover, etanercept also leads to substantial improvement of quality of life as assessed by the SF-36. In contrast to previous reports [9, 21] all eight single components of the SF-36 improved. Interestingly, quality of life approached the level found in the normal population (Fig. 5).
Since anti-TNF therapy is likely to have disease-controlling properties, assessment of improvement in this area of therapy might well include domains such as spinal mobility and acute-phase reactants. These measures are known not to be substantially influenced by NSAIDs, while, in contrast, it has been shown that both parameters are improved by anti-TNF treatment [21, 22]. The recently proposed ASAS five-out-of-six improvement criteria require a 20% improvement that includes these potentially more objective parameters [15]. In the present trial 65% of the patients fulfilled these criteria after 1 yr. The other recently introduced set of response criteria for anti-TNF treatment in AS with good discriminating capacity were the ASAS 40% criteria [18], which use a higher threshold of 40% improvement, but only in patient-reported outcomes. Using these criteria, 62% of the patients responded at week 54 in the present study, which confirms the almost equal performance of these two sets of criteria. Furthermore, there was no substantial difference in this study in BASDAI 50% improvement, which was used in previous TNF-blocker studies [9, 21, 22] and which was recently agreed to be a major response criterion for decisions on continuation or discontinuation of anti-TNF therapy [14].
Similar to the original RCT [9], the unconventional design of our study mainly had pragmatic reasons. However, we believe that the design finally chosen is capable of providing clinical data relevant to both experience after readministration and to long-term safety and efficacy. Importantly, all completers of the first trial established a flare after discontinuation of treatment with etanercept (Fig. 1), indicating that 3 months of treatment with etanercept is insufficient to induce sustained remission in AS and that treatment has to be continued in the long term in patients with active AS.
The observation that readministration of etanercept was efficacious and safe after several months of discontinuation has important clinical implications, since various clinical situations are conceivable in which withdrawal of etanercept is needed. Furthermore, there are possible economic implications, since anti-TNF therapy is costly. When patients have ongoing benefit for several weeks, discontinuations at regular intervals could be planned. However, this cannot be recommended on the basis of the present data. Further controlled studies are needed to clarify this issue.
However, our results also demonstrate that spontaneous remission is rather rare in patients with active AS. It remains to be seen whether long-lasting remission can be induced by longer treatment periods with etanercept. When etanercept was readministered, no substantial decrease in efficacy or increase in side-effects was observed in our relatively small study population, suggesting that the immunogenicity of etanercept, with the potential of tolerance induction, does not play a major role.
It cannot be excluded that the observed efficacy of etanercept and the percentage of responders might have been overestimated in this study. This is because the results were obtained in a subgroup of patients who were already known to have responded to and tolerated etanercept. More experience with long-term treatment without discontinuation will be needed to shed more light on this issue.
The rate of discontinuations of 12% noted in this trial is comparable to the rates reported in RA trials, for example in the ERA trial [23]. Only one of three patients was withdrawn from the present study because of a side-effect that might be attributed to etanercept (4%). This female patient showed new onset of Crohn's disease in this study. Two similar cases of patients with SpA treated with etanercept have been reported from Leeds [24]. Furthermore, in the recently published RCT with 277 AS patients, new onset of Crohn's disease was observed in five patients treated with etanercept compared with two of the controls [11]. Thus, at least etanercept did not prevent the occurrence of Crohn's disease, which is in accordance with a study showing that etanercept does not work in patients with active Crohn's disease using the conventional dosage [25]. It is not entirely clear whether etanercept can rarely even induce Crohn's disease or whether this was due to chance. As it stands now, we do not recommend the use of etanercept in patients with Crohn's disease and discontinue such medication in the case of new gut symptoms. However, looking at the low total numbers of cases reported internationally, there is no clear evidence to date that the reported relatively high prevalence of asymptomatic Crohn's disease like gut lesions in patients with AS represents a clinically relevant risk factor for the initiation of etanercept.
This open study not only confirms the clear-cut efficacy of etanercept in the long-term treatment of active AS patients despite conventional NSAID therapy, but, in comparison with two recently published US trials and one European trial [10, 11, 26] it also shows that no additional therapy with DMARDs and steroids is needed to obtain this result. This is important because many active AS patients are treated with DMARDs and glucocorticoids [4] despite lack of proven efficacy and approval simply because no other medical therapy had been available [6]. There is very limited evidence for a definite effect of sulphasalazine treatment on spinal involvement in AS [27], while there is some evidence for its efficacy in patients with peripheral arthritis [8]. Besides uncontrolled open and retrospective studies yielding both positive and negative results, there is no evidence for the efficacy of methotrexate, either for peripheral or for axial involvement in AS [28]. As in our previous studies with infliximab [21, 22], in this study we focused on axial involvement: only 39% of the patients had peripheral joint manifestations.
In conclusion, a beneficial clinical response to readministered etanercept was demonstrated in patients with AS throughout a 1-yr period. Patients with active disease despite taking NSAIDs experienced a clear clinical improvement with etanercept. This study underlines the pathogenetic role of TNF- in AS and indicates a paradigm shift of the expectations for pharmacotherapy of AS. Observation of this AS cohort is ongoing. Further studies are needed to assess the efficacy of etanercept on structural changes as assessed by MRI and X-rays.
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Acknowledgments |
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A.S. is an employee of Wyeth Pharma GmbH, Münster, Germany. J.S. and J. Braun received honoraria for giving advice and for giving talks from Wyeth and Amgen. The other authors have declared no conflicts of interest.
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References |
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