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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSORS
  8. REFERENCES

Objective

To investigate the effect of etanercept therapy on radiographic progression in patients with ankylosing spondylitis (AS).

Methods

Patients with AS who had previously participated in a 24-week randomized, double-blind, placebo-controlled trial of etanercept therapy were enrolled in a 72-week open-label extension. Radiographs of the cervical and lumbar spine from patients who received etanercept (25 mg twice weekly) for up to 96 weeks were compared with radiographs from patients in a large prevalence cohort (Outcome Assessments in Ankylosing Spondylitis International Study [OASIS]) who had not been treated with anti–tumor necrosis factor α (anti-TNFα) agents. Radiographs obtained at 2 time points up to 96 weeks apart from patients in both study populations were digitized and read by 2 independent readers who were blinded with regard to patient group and sequence. The primary end point was the 96-week change in the modified Stoke AS Spine Score (mSASSS).

Results

A total of 257 patients treated with etanercept were compared with 175 unselected patients from the OASIS study. There was no significant difference in the change in the mSASSS from baseline among patients who received etanercept (mean ± SD 0.91 ± 2.45) versus those from the OASIS group (0.95 ± 3.18).

Conclusion

Unlike other inflammatory rheumatic diseases such as rheumatoid arthritis and psoriatic arthritis, structural progression in AS seems to be independent of TNF, despite the fact that TNF is responsible for the signs and symptoms due to inflammation in this disease.

Ankylosing spondylitis (AS) belongs to a family of rheumatic diseases known as spondylarthritides that characteristically cause spinal joint inflammation and bony fusion of the spine. AS is the prototype of the spondylarthritides and is typified by ankylosis of the axial skeleton. Radiographic damage known to result from AS primarily includes fusion of entheses of the sacroiliac joints and of the posterior articulations and ligaments of the spine. These fusions can lead to impaired spinal mobility and in turn decreased ability to perform daily activities and severely reduced health-related quality of life (1).

Tumor necrosis factor α (TNFα) has been shown to play an important role in the inflammatory response observed in AS. It has been found at increased levels in the serum and synovium of patients with AS (2, 3), and treatment with TNFα-blocking agents (etanercept, adalimumab, and infliximab) has been shown to safely and effectively reduce the signs and symptoms of AS (4–6) and significantly improve health-related quality of life (1). In addition, these agents have been shown to suppress bony inflammation as detected on magnetic resonance imaging (7–9).

TNFα also plays a significant proinflammatory role in rheumatoid arthritis (RA) and psoriatic arthritis (PsA), 2 inflammatory rheumatic diseases that are dominated by bone destruction rather than bone formation. TNFα-blocking agents have been effective in reducing disease activity as well as halting the destructive process of these diseases (10–13). This relationship between disease activity (inflammation) and bone damage in RA is well established, and prevention of radiographic damage through the suppression of the inflammatory process is a widely recognized treatment goal.

A similar relationship between inflammation and bone damage has not been demonstrated in AS (14). In fact, studies in animal models of AS have suggested an uncoupling of inflammation and bone formation in the spine (15, 16), and there is increasing evidence that bone formation in the spine is under the influence of bone morphogenetic protein (16, 17) and the Wnt signaling pathway (18). The role of TNF in this process is still not fully elucidated. Findings of a number of uncontrolled clinical studies have suggested that, analogous to the situation in RA and PsA, anti-TNF agents may inhibit progression of structural damage in AS (19, 20). To date, however, these anecdotal observations are not corroborated by solid evidence from controlled studies. In the present study, using a 3-way blinded radiograph reading design with 2 independent readers and adjudication methodology, we investigated whether 96-week radiographic progression in a cohort of patients treated with the TNF-blocking agent etanercept differed from the 96-week radiographic progression in an unrelated observational cohort of patients who had never been treated with anti-TNFα agents.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSORS
  8. REFERENCES

Patients and study design.

Patients in the etanercept arm of this controlled study were enrolled in a 24-week multicenter, double-blind, placebo-controlled randomized controlled trial (RCT) followed by a 72-week open-label extension during which all patients received etanercept (ClinicalTrials.gov NCT00356356) (5). In the RCT, 277 AS patients (139 in the placebo arm and 138 in the etanercept arm) were followed up for 24 weeks. Eligible patients were then given the option to enroll in an open-label extension to evaluate the safety and efficacy of etanercept treatment for up to 96 weeks. Patients were treated with etanercept 25 mg subcutaneously twice weekly, and were allowed to receive concomitant nonsteroidal antiinflammatory drugs (NSAIDs), analgesics, and disease-modifying antirheumatic drugs (DMARDs) including corticosteroids. All patients from the RCT and the open-label extension who received at least 1 dose of etanercept and had baseline radiographs of the cervical and lumbar spine were analyzed. Therefore, patients who received etanercept in the RCT could have received up to 96 weeks of continuous etanercept treatment, and patients who received placebo in the RCT could have received up to 72 weeks of continuous etanercept treatment.

Patients in the control arm of the present study were enrolled in the Outcome Assessment in Ankylosing Spondylitis International Study (OASIS) (21). The OASIS study was an international observational study on outcome in AS patients from 3 different countries (Belgium, France, and The Netherlands). It included consecutive patients who were followed up for 10 years according to a predefined protocol, including assessment of radiographs of the cervical and lumbar spine at baseline, at 1-year and 2-year followup, and every 2 years thereafter. Patients were treated according to common practice guidelines including the use of NSAIDs, analgesics, and regular exercise therapy. All patients from the OASIS study with radiographs at baseline and at 2 years, except patients with complete spinal fusion at baseline (n = 5), were evaluated as controls for the present study (n = 175).

Procedures and end points.

Radiographs of the lateral cervical and lateral lumbar spine, obtained at baseline and at 96 weeks in patients in the etanercept arm and the control arm, were digitized and patient identifiers and temporal indicators removed, to ensure blinding. Radiographs were scored independently by 2 trained readers who were blinded with regard to treatment, temporal sequence, and patient group, using a computer-assisted masked reading system. Radiographs were scored using the modified Stoke AS Spine Score (mSASSS) (22), identified as the preferred radiographic scoring method in AS by the ASsessment in Ankylosing Spondylitis International Working Group (ASAS) and Outcome Measures in Rheumatology Clinical Trials group (22, 23). In the mSASSS, all anterior corners (from the lower corner of T12 to the upper corner of S1 and from the lower corner of C2 to the upper corner of T1) are scored for the presence of erosions, sclerosis, and/or squaring (1 point per site), nonbridging syndesmophytes (2 points per site), and bridging syndesmophytes (3 points per site). The mSASSS, which is the sum of the scores at all individual sites, ranges from 0 to 72. In order to assess intrareader variability, 12.5% of the patients' radiographs were reread by each reader. These patients were selected to equally represent 4 quartiles of change from baseline, determined in the initial reading. Intrareader reliability for status scores (assessed by intraclass correlation coefficient) was >0.9 for each of the readers, and interreader reliability was 0.81.

The primary analysis was a direct comparison of the 96-week change from baseline in the mSASSS between all patients who had baseline radiographs in the etanercept group and those in the control group, adjusted for baseline mSASSS. Missing information on 96-week change from baseline in the mSASSS due to missing postbaseline radiographs was imputed using the median change from baseline score observed among control patients with the same baseline score.

A secondary sensitivity analysis included a comparison between all patients who had baseline and 96-week radiographs in the etanercept group and those in the control group. Two sensitivity analyses were performed on a subpopulation: a comparison between all patients who had baseline radiographs in the etanercept group and those from the OASIS study who would have fulfilled the entry criteria for the RCT, and a comparison between all patients who had baseline and 96-week radiographs in the etanercept group and those from the OASIS study who would have fulfilled the entry criteria for the RCT.

Other sensitivity analyses involved simultaneous adjustment for multiple characteristics of disease activity at baseline (i.e., mSASSS, Bath Ankylosing Spondylitis Functional Index [BASFI] [24], Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] [25], and C-reactive protein level) in the primary and secondary patient populations described above, or comparison of patients in the etanercept group and in the control group after stratification according to whether they regularly took NSAIDs during the study. Regular NSAID use was defined as taking usual antiinflammatory doses of medications throughout the duration of the study. Patients who discontinued regular NSAIDs, took NSAIDs only as needed for control of symptoms, or took NSAIDs at less than the usual antiinflammatory doses were not considered to be regular NSAID users. Further comparisons included analyses in which patients were stratified by duration of treatment (etanercept patients who received etanercept for ≥48 weeks, ≥72 weeks, or ≥96 weeks), by treatment during the initial 24 week RCT (patients who received placebo or etanercept during the RCT), and by response status (according to the ASAS 40% response criteria [ASAS40]) (26).

Statistical analysis.

Baseline characteristics of the patients in the etanercept trial and patients in the OASIS study were compared by chi-square test for categorical variables and t-test for continuous variables. Radiographic progression was compared between the patients in the etanercept trial and those in the OASIS study using Quade rank analysis of covariance, adjusted for baseline mSASSS on the change in mSASSS from baseline to 96 weeks.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSORS
  8. REFERENCES

Patient characteristics at enrollment.

A total of 93% of the patients (257 of 277) who had previously received either placebo (n = 139) or etanercept (n = 138) in the RCT enrolled in the open-label extension and had data available for radiographic analysis. Of the 257 patients, 76% received etanercept for at least 48 weeks and 50% for at least 72 weeks. Figure 1 shows the disposition of patients in the RCT and open-label extension. A total of 175 of the 219 original OASIS patients had available radiographs for analysis. Of these 175 patients, none had received therapy with etanercept or another anti-TNFα agent. Forty-three percent of them (n = 76) would have met the inclusion criteria for the RCT at baseline.

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Figure 1. Patient disposition in the initial randomized controlled trial (RCT) and the open-label extension (OLE). AE = adverse event; ISR = injection site reaction.

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Demographic and baseline clinical data on the etanercept-treated patients and the control patients are shown in Table 1. Mean age, disease duration, male/female distribution, and frequency of HLA–B27 positivity were similar between the 2 groups. A significantly smaller proportion of patients from the OASIS cohort were taking DMARDs at baseline, compared with the proportion of patients receiving etanercept (10% versus 32%; P < 0.0001). As would be expected, OASIS patients also had significantly less active disease, as indicated by lower values for patient global assessment, BASFI, and BASDAI (all P < 0.0001). These values were more comparable when the analysis was limited to OASIS patients meeting the entry criteria for the RCT. Notwithstanding these differences in disease activity variables, measures assessing severity such as the mSASSS, and spinal mobility scores were similar between patients in the 2 groups.

Table 1. Baseline characteristics of the patients*
Baseline characteristicOASIS (n = 175)OASIS meeting RCT entry criteria (n = 76)Etanercept (n = 257)
  • *

    “Baseline” refers to the baseline of the Outcome Assessment in Ankylosing Spondylitis International Study (OASIS) or the randomized controlled trial (RCT) of etanercept; n values are the number of patients with baseline radiographs. AS = ankylosing spondylitis; CRP = C-reactive protein; DMARD = disease-modifying antirheumatic drug; BASFI = Bath Ankylosing Spondylitis Functional Index; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; mSASSS = modified Stoke Ankylosing Spondylitis Spine Score.

  • P < 0.0001 versus etanercept-treated patients.

Age, mean ± SD years44 ± 12.548 ± 12.341 ± 10.2
Male, no. (%)121 (69.1)54 (71.1)194 (75.5)
Duration of AS, mean ± SD years11 ± 8.512 ± 9.810 ± 8.5
CRP, mean ± SD mg/dl1.5 ± 1.981.50 ± 1.812.0 ± 2.20
Patients with CRP level outside normal range of 0–1.00 mg/dl, no. (%)10 (5.7)3 (3.9)2 (0.8)
DMARD use at baseline, no. (%)18 (10.3)4 (5.3)83 (32.3)
 Methotrexate1 (0.6)1 (1.3)30 (11.7)
 Sulfasalazine17 (9.7)3 (3.9)56 (21.8)
 Hydroxychloroquine0 (0.0)0 (0.0)4 (1.6)
HLA–B27 positive, no. (%)142 (81.1)64 (84.2)201 (78.2)
Patient global assessment (0–100), mean ± SD38 ± 27.827 ± 27.263 ± 18.0
BASFI, mean ± SD34 ± 25.555 ± 16.654 ± 20.7
BASDAI, mean ± SD35 ± 20.947 ± 19.863 ± 20.9
Modified Schober score, mean ± SD2.9 ± 1.42.3 ± 1.43.0 ± 1.7
mSASSS, mean ± SD14 ± 17.619 ± 20.816 ± 18.3

Efficacy.

The changes in radiographic scores among patients in the etanercept arm and those in the control arm (OASIS) were similar between the 2 groups (mean ± SD 0.91 ± 2.45 and 0.95 ± 3.18, respectively; P = 1.00) (Table 2). The probability plot of mean change in the mSASSS illustrated that the change was close to 0 in most patients (Figure 2). When mean change in the mSASSS was compared between patients who received etanercept and OASIS patients who met RCT entry requirements at baseline, they were again found to be similar, as indicated by the closely overlapping probability plots (Figure 3). In the latter group, the mean ± SD change was 1.27 ± 3.64 (P not significant versus patients who received etanercept) (Table 2). Twenty-nine patients in the etanercept group (11%) had missing postbaseline radiographs, while no patients in the OASIS cohort had missing postbaseline radiographs. When mean change in the mSASSS was compared between the etanercept-treated patients without missing postbaseline radiographs (n = 228) and the OASIS patients, no significant difference was detected (P = 0.0.83).

Table 2. Changes in radiography scores at 96 weeks*
 OASIS (n = 175)OASIS meeting RCT entry criteria (n = 76)Etanercept (n = 257)
  • *

    Values are the mean ± SD change from baseline. There were no statistically significant differences between groups in the mean change in score. See Table 1 for definitions.

mSASSS0.95 ± 3.181.27 ± 3.640.91 ± 2.45
Cervical radiography score0.42 ± 2.110.53 ± 2.290.49 ± 1.40
Lumbar radiography score0.53 ± 1.880.73 ± 2.000.42 ± 1.84
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Figure 2. Probability plot of 2-year progression in the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) in patients receiving etanercept and patients in the Outcome Assessment in Ankylosing Spondylitis International Study (OASIS), for whom baseline and 2-year radiographs were available.

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Figure 3. Probability plot of 2-year progression in the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) in patients receiving etanercept and patients in the Outcome Assessment in Ankylosing Spondylitis International Study (OASIS) who met the entry criteria for the randomized controlled trial at baseline, for whom baseline and 96-week radiographs were available.

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Changes in mean baseline cervical and lumbar radiography scores were also compared between patients receiving etanercept and, as 2 separate groups, patients from the OASIS cohort overall and patients from the OASIS cohort who met entry criteria for the RCT. Again, there was no significant difference in the change in cervical or lumbar radiography scores between the patients receiving etanercept and the OASIS patients (P = 0.28 and P = 0.29, respectively). Similarly, there was no significant difference between the mean changes in cervical or lumbar radiography scores between patients receiving etanercept and the OASIS patients who met entry criteria for the RCT (P = 0.66 and P = 0.17, respectively). The mean changes in cervical or lumbar radiography scores were also found to be similar when the OASIS patients were compared with only the etanercept-treated patients who had postbaseline radiographs (as opposed to imputation of data for etanercept-treated patients from whom postbaseline radiographs were not available) (P = 0.23 and P = 0.36, respectively).

In multiple subgroup analyses, there were also no significant differences in the mean change in the mSASSS. When etanercept-treated patients were subgrouped according to duration of treatment, the mean change in the mSASSS in each subgroup (≥48 weeks, ≥72 weeks, or ≥96 weeks) was similar to the mean change in OASIS patients (P = 0.98, P = 0.82, and P = 0.92, respectively). There was no significant difference in the mean change in mSASSS when OASIS patients were compared with either open-label etanercept–treated patients who received etanercept during the RCT (P = 0.61) or those who received placebo during the RCT (P = 0.55), or when OASIS patients were compared with either etanercept-treated patients who were ASAS40 responders (P = 0.60) or those who were ASAS40 nonresponders (P = 0.38). A total of 145 of 257 etanercept-treated patients (56%) and 92 of 175 OASIS patients (53%) were characterized as regular NSAID users. Stratifying patients by regular use of NSAIDs during the study did not affect the results. Additionally, adjustment for multiple covariates had no effect on the outcome.

An exploratory analysis was performed to investigate the character of the radiographic changes observed in each cohort (Figure 4). While radiographic changes occurred at only a small percentage of the sites analyzed, the prevailing type of change that did occur was compatible with syndesmophyte formation or syndesmophyte growth (bridging). There were no differences between the 2 groups in this analysis. These results support the hypothesis that progression in AS is due to syndesmophyte formation and growth (inappropriate bone formation), rather than to erosions and squaring (bone resorption).

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Figure 4. Distribution of the type of radiographic changes. Values are the percentage of sites at which the given type of change (as determined by change in radiography score from baseline) was noted. OASIS = Outcome Assessment in Ankylosing Spondylitis International Study.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSORS
  8. REFERENCES

Results of this study, the first blinded, controlled trial of radiographic changes in AS patients treated with the TNFα antagonist etanercept, provide evidence that etanercept does not inhibit syndesmophyte formation in AS. Findings of previous uncontrolled studies have suggested that TNF blockers (both etanercept and infliximab) may slow the progression of structural damage in AS compared with that which occurs in patients not taking TNF blockers (19, 20). However, results of these uncontrolled studies should be interpreted with great caution for several reasons. Multiple readers who were aware of the origin of the radiographs (patient group) were used. In addition, these studies used scores that were assigned by readers who were blinded with regard to time order and compared them with results from the literature that were obtained based on known time order. This may have a major effect on the observed progression rate, which is substantially lower if the reader is blinded with regard to the sequence of the films (27). Finally, readers may have been biased against progression, knowing that all radiographs they read originated from trials with TNF-blocking drugs.

A randomized placebo-controlled trial would have the highest validity in assessing the effect of TNF-blocking drugs on radiographic progression. However, feasibility of such a trial in patients with AS is very limited (28). The slow rate of radiographic progression in AS requires a minimum followup of 2 years, and an appropriate comparator with clinical efficacy for signs and symptoms similar to that obtained with TNF blockade is not available. In addition, appropriate prognostic factors for radiographic progression, allowing selection of patients prone to progression, as in RA, have not been identified until recently (29). Also, TNF inhibitors rapidly and effectively control clinical symptoms in a large number of patients with AS and are now available for their treatment. For these reasons, a 2-year placebo-controlled study is not considered feasible or ethical by most rheumatologists. If performed, such a study would be complicated by a high dropout rate early in the trial with many patients crossing over to TNF blockers, limiting the ability for detection of a treatment effect. The best alternative to a concurrently controlled study is comparison with existing radiographs from patients who were not treated with TNF-blocking drugs.

Use of a historic control group imposes special requirements. Historic control patients should be unselected and representative of the entire population of patients with AS, should have never been treated with TNF blockers, should be well characterized, and should have radiographs available with a 2-year interval by protocol. The OASIS cohort, consisting of patients who were enrolled in an observational study and were followed up for many years, fulfills these requirements.

Radiographs from the patients in the historic control group and from the patients treated with a TNF blocker should be scored in one session. Also, readers should be blinded with regard to the origin of the radiograph, the clinical data, and the sequence of the radiographs. Once more, all of these requirements were fulfilled in the present study.

There was a difference in disease activity between patients in the OASIS study, who were unselected and had a wide range of disease activity, and patients in the etanercept group, all of whom had active disease. However, disease activity in AS may be unrelated to structural progression (30). In the OASIS cohort and in a separate cohort of AS patients, signs of clinical disease activity have proven to be unrelated to structural progression as assessed radiographically (31). The validity of our observations is supported by the fact that the results were not altered when the comparison was limited to patients in the OASIS cohort who would have fulfilled the disease activity entry criteria for the RCT or to etanercept-treated patients who had postbaseline radiographs (as opposed to imputing the missing data for those without postbaseline radiographs), or after adjustment for duration of exposure to etanercept, disease activity at baseline, or NSAID use.

There are methodologic issues that may have confounded the results and deserve attention. DMARD use was more frequent among patients in the etanercept group than among those in the OASIS group. There are, however, no data showing that DMARDs can inhibit structural progression, and if so, this would result in a lower rather than a higher progression rate in the etanercept group. In addition, NSAID use was more frequent in the etanercept group at baseline, and similar proportions of patients in the etanercept cohort and the OASIS cohort were classified as regular NSAID users. There has been some indication that NSAIDs, especially if used continuously, are able to inhibit syndesmophyte formation (32), yet as noted above, no difference was detected when our analyses were adjusted for NSAID use.

Based on experience regarding radiographic assessments of patients with RA (and PsA), many rheumatologists expected that TNF-blocking drugs would inhibit structural progression in AS. These expectations may have been unrealistic. There are major differences in pathophysiologic mechanisms between RA and AS: structural damage in AS is dominated by inappropriate bone formation (syndesmophytes), while in RA the destructive process is mainly due to bone resorption. Syndesmophytes may reflect inappropriate repair that is induced, but not necessarily maintained, by inflammatory stress in AS (33). In contrast to AS, the destructive process that dominates in RA is well characterized and is regulated by TNF and RANKL, leading to activation of osteoclasts, while inhibitors of Wnt proteins, such as Dkk-1 (18), cause a decrease in osteoblast formation. The net result is the rapid formation of erosions without sufficient repair. In AS, bone formation dominates the picture. Bone formation is regulated by the transforming growth factor/bone morphogenetic protein family as well as the group of Wnt proteins. Wnt signaling activates osteoprotegerin, which counteracts RANKL-induced osteoclast activation, a TNF-dependent process. It has recently been shown that Dkk-1 levels are decreased in AS and increased in RA (18), suggesting that Wnt signaling cascades are switched on in AS while being suppressed in RA.

These pathophysiologic considerations are supported by clinical observations. In a recent investigation, as well as in this study, it was confirmed that syndesmophyte formation is the dominant feature of structural progression in AS, while erosions at the corners of the vertebrae play only a minor role (34). Moreover, we and others have identified clear causal relationships between inflammation and formation of erosions in RA (35, 36), while a relationship between inflammation and syndesmophyte formation in AS could not be established. The current controlled study confirms what might be expected on pathophysiologic grounds, i.e., that the formation of syndesmophytes may not be influenced by inhibition of TNF-regulated inflammation. Additional evidence that TNF inhibition may not play a role in syndesmophyte formation comes from a recent preliminary report that infliximab, a monoclonal antibody that blocks TNF activity, also failed to inhibit radiographic progression in AS patients after 2 years of use (37).

Despite all of the evidence that TNF blockade does not inhibit syndesmophyte formation, many investigators still believe there could be a relationship between inflammation as a trigger and syndesmophyte formation as a result. Such an assumption implies that an alternative explanation for the lack of a treatment effect should be sought. The average disease duration of the etanercept-treated AS patients in this study was ∼10 years. Assuming that inflammation triggers the initiation of syndesmophyte formation, it could be hypothesized that earlier intervention in the disease process, before the reparative processes have started, could prevent further bone formation. Another hypothesis is that inflammation would have to be suppressed for a longer period of time before the inhibitory effects can be seen on radiographs. Such a hypothesis would gain support if, with longer followup (e.g., 4 years), a reduction in radiographic progression over time could be detected in comparison with the control group.

In conclusion, this first large, controlled study did not demonstrate inhibition of structural progression of spine disease in AS patients treated with etanercept for nearly 2 years, even though etanercept has been shown to be highly effective in treating clinical signs and symptoms. This differential effect may be due to dissociation of the TNF-dependent inflammatory processes and the TNF-independent bone formation processes in AS.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSORS
  8. REFERENCES

Dr. van der Heijde had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Van der Heijde, Landewé, Einstein, Vosse, Tsuji, Davis.

Acquisition of data. Landewé, Einstein, Ory, Vosse, Lin, Tsuji, Davis.

Analysis and interpretation of data. Van der Heijde, Landewé, Einstein, Vosse, Ni, Lin, Tsuji, Davis.

Manuscript preparation. Van der Heijde, Landewé, Vosse, Lin, Tsuji, Davis, and Dr. Marc. D. Kubasak (nonauthor; Amgen Inc.).

Statistical analysis. Landewé, Ni, Lin, Tsuji.

Reading of radiographs. Ory, Vosse.

ROLE OF THE STUDY SPONSORS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSORS
  8. REFERENCES

Marc D. Kubasak, PhD (Amgen Inc.), assisted with the writing and preparation of the manuscript. Immunex Corporation, a wholly owned subsidiary of Amgen Inc., and Wyeth Pharmaceuticals facilitated the study design and the writing of the manuscript, and reviewed and approved the manuscript prior to submission. The authors independently collected the data, interpreted the results, and had the final decision to submit the manuscript for publication.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSORS
  8. REFERENCES
  • 1
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  • 2
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