SEARCH

SEARCH BY CITATION

Keywords:

  • Ankylosing spondylitis;
  • Crohn's disease;
  • Inflammatory bowel disease;
  • Tumor necrosis factor α;
  • Infliximab;
  • Etanercept;
  • Adalimumab

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Objective

Ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) are clinically and pathologically linked. Anti–tumor necrosis factor (anti-TNF) agents are efficacious in treating AS, but not all are equally effective in treating IBD (Crohn's disease [CD] and ulcerative colitis [UC]). The purpose our study was to analyze the incidence of flares and new onset of IBD in patients with AS treated with anti-TNF agents.

Methods

Data from 9 trials, 7 placebo-controlled trials and 2 open studies, were analyzed.

Results

Data were available on 419 AS patients exposed to etanercept (625 patient-years), 366 exposed to infliximab (618 patient-years), 295 exposed to adalimumab (132 patient-years), and 434 placebo patients (150 patient-years). A history of IBD was reported in 76 of 1,130 patients (6.7%). There were 2 reports of IBD while receiving placebo (1.3 per 100 patient-years), 1 while receiving infliximab, and 3 while receiving adalimumab. Among the 14 IBD cases receiving etanercept (2.2 per 100 patient-years) there were 8 CD and 6 UC cases, significantly different from infliximab (P = 0.01) but not from placebo. Patients with a history of IBD had an IBD flare odds ratio of 18.0 (95% confidence interval [95% CI] 2–154) while taking etanercept and 4.2 (95% CI 0.4–44) while taking adalimumab, in comparison with infliximab. The incidence rates of new onset of IBD showed no significant difference between etanercept (0.8 per 100 patient-years) and placebo (0.5 per 100 patient-years).

Conclusion

New onset and flare of IBD are infrequent events in AS patients receiving anti-TNF therapy. Infliximab (but not etanercept) largely prevents IBD activity. More data are required for adalimumab. The incidence of new onset of IBD was statistically not different from placebo for all anti-TNF agents.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Ankylosing spondylitis (AS), a frequent chronic inflammatory rheumatic disease, is the prototype and the most severe form of the spondylarthritides (SpA) (1). The disease affects young patients, most frequently starting in the third decade of life, causing inflammation at diverse sites such as the spine, peripheral joints, and entheses. Furthermore, SpA-related musculoskeletal symptoms are the most frequent extraintestinal manifestations of inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). The overall prevalence of IBD in patients with AS has been estimated at 6% (2). Tumor necrosis factor α (TNFα) has been shown to play a key role in the pathogenesis of AS (1) and IBD (3).

The anti-TNFα compounds infliximab, etanercept, and adalimumab have shown short-term and long-term efficacy regarding disease signs and symptoms in patients with AS (4–17). However, only infliximab, not etanercept (18), was shown to be efficacious in the treatment of signs and symptoms in patients with CD (19–21) and UC (22). Data for adalimumab have yet to be published. However, activity of CD and UC has recently been reported for patients with AS treated with etanercept (4, 11, 23, 24) and adalimumab (15, 17). Therefore, there is reason to study these issues in more detail and with large patient numbers based on the trials performed thus far. In the present study, we calculated the incidence of new onset and flares of IBD (CD and UC) in patients with AS who were treated with infliximab, etanercept, or adalimumab as compared with placebo and as compared with each other.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Although the total number of reports from controlled trials with anti-TNFα agents in the literature is substantial, the number of studies that report on the occurrence of new onset or flare of IBD (CD and UC) during treatment is limited. As part of a systematic literature search using PubMed, we screened for studies on the topic of interest published until July 1, 2006 using the following search terms: ankylosing spondylitis, infliximab, etanercept, adalimumab, incidence and prevalence of Crohn's disease or ulcerative colitis. Some studies were well known to the authors because some of us had participated in the studies. Similarly, source data were collected from the investigators of the randomized controlled trials (RCTs) or directly from the companies, if necessary.

Information was collected on the number of patients included in the studies; the cumulative exposure time to infliximab, etanercept, adalimumab, or placebo; the incidence of CD and UC (=IBD) flares or new onset in general during the placebo-controlled phases in the treatment groups; and the flares or new onset of CD and UC during the open-label phases of the studies. All data were analyzed for the different phases of the studies. The diagnosis of CD and UC was collected based on the expert opinion of the investigator, according to the records of the investigators in the case report forms. The diagnosis was usually confirmed by endoscopy including biopsy in patients with appropriate symptoms. To avoid inclusion of unclear cases, we decided not to count cases of undetermined colitis, which is also considered as a possible form of IBD (25).

Because the number of new onset or flares of IBD depends on the period of observation, we obtained the exposure times of the completers from published data (4, 8, 9, 14–17, 26–28). The exposure time of the dropouts was calculated using information obtained from the source data provided by the investigators or companies. The total exposure time was calculated by summing up the observational times of every patient into years of followup. The number of new onset or flares that occurred during exposure to the drugs was related to the corresponding number of available person-years of followup. Exact Poisson fiducial confidence limits were calculated for the IBD rates per 100 patient-years. StatXact 5.0 software (Cytel Software, Cambridge, MA) was used for the calculations.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Nine trials (7 RCTs with followup open-label phases [5, 9, 10, 13, 16, 17, 27, 28] and 2 open studies [15, 26]) were identified by the search in PubMed. The total number of patients included in the trials was 1,130 (Table 1). The total period of exposure was 618 patient-years for infliximab, 625.4 patient-years for etanercept, 132.3 patient-years for adalimumab, and 150.4 patient-years for placebo (Tables 2, 3, and 4).

Table 1. Patients with a history of Crohn's disease (CD), ulcerative colitis (UC), and inflammatory bowel disease (IBD) in the trials included*
Study, referenceNo.History of CDHistory of UCHistory of IBD
  • *

    Values are the number (percentage) unless otherwise indicated.

Braun et al (5)692 (2.9)
Gorman et al (27)407 (17.5)
Brandt et al (10)301 (3)
Stone et al (26)21303 (14.3)
Calin et al (28)847 (8.3)
Davis et al (12)27719 (6.9)
Braun et al (16)27919 (6.8)
Haibel et al (15)151 (7.0)01 (7.0)
Van der Heijde et al (17)3157 (2.2)10 (3.2)17 (5.4)
Total1,13076 (6.7)
All infliximab34922 (6.3)
All etanercept37826 (6.9)
All adalimumab3308 (2.4)10 (3.2)18 (5.6)
Table 2. Incidence of Crohn's disease (CD) per 100 patient-years by type of treatment and type of study*
 Patients exposed, no.Exposure, yearsIncidence (flares/new onset) of CD, no.Flares or new onset of CD
Per 100 patient-years95% CI
  • *

    95% CI = 95% confidence interval; RCTs = double-blinded placebo-controlled randomized controlled trials.

  • In total, 69 patients were exposed to infliximab during the RCT or the open-label followup.

  • In total, 276 patients were exposed to infliximab during the RCT or the open-label followup.

  • §

    In total, 267 patients were exposed to etanercept during the RCT or open-label study.

  • In total, 30 patients were exposed to etanercept during the RCT or the open-label phase.

  • #

    In total, 38 patients were exposed to etanercept during the RCT or the open-label phase.

  • **

    In total, 84 patients were exposed to etanercept; followup data were provided by the sponsor of the study.

  • ††

    A total of 208 patients were randomized to adalimumab, and 72 placebo patients were also exposed to adalimumab during the early escape phase.

Patients treated with placebo in RCTs     
 Braun et al (5)358.100 
 Davis et al (12)13958.31 (0/1)1.7 
 Brandt et al (10)161.800 
 Van der Heijde et al (9)7834.800 
 Gorman et al (27)205.700 
 Calin et al (28)398.700 
 Van der Heijde et al (17)10733.000 
 Total434150.41 (0/1)0.70–3.7
Patients treated with infliximab in RCTs     
 Braun et al (5)347.800 
 Van der Heijde et al (9)20192.100 
Patients treated with infliximab in open-label studies     
 Braun et al (6)6549.100 
 Braun et al (7)5445.700 
 Braun et al (8)4646.100 
 Braun et al (16)273374.81 (1/0)0.3 
 Stone et al (26)212.400 
Patients treated with infliximab: total3666181 (1/0)0.20–0.9
Patients treated with etanercept in RCTs     
 Davis et al (12)138§59.21 (0/1)1.7 
 Brandt et al (10)146.71 (0/1)14.9 
 Gorman et al (27)20#6.100 
 Calin et al (28)45**9.600 
Patients treated with etanercept in open-label studies     
 Baraliakos et al (37)2645.51 (0/1)2.2 
 Davis et al (12)257§303.42 (2/0)0 
 Gorman et al (27)37#64.800 
 Calin et al (28)81**130.13 (2/1)2.3 
Patients treated with etanercept: total419625.48 (4/4)1.30.6–2.5
Patients treated with adalimumab in RCTs     
 Van der Heijde et al (17)280††108.000 
Patients treated with adalimumab in open-label studies     
 Haibel et al (15)1524.31 (1/0)4.1 
Patients treated with adalimumab: total295132.31 (1/0)0.80.0–4.2
Table 3. Incidence of ulcerative colitis (UC) per 100 patient-years by type of treatment and type of study*
 Patients exposed, no.Exposure, yearsIncidence (flares/new onset) of UC, no.Flares or new onset of UC
Per 100 patient-years95% CI
  • *

    95% CI = 95% confidence interval; RCTs = double-blinded placebo-controlled randomized controlled trials.

  • In total, 69 patients were exposed to infliximab during the RCT or the open-label followup.

  • In total, 84 patients were exposed to etanercept; followup data were provided by the sponsor of the study.

  • §

    In total, 30 patients were exposed to etanercept during the RCT or the open-label phase.

  • In total, 276 patients were exposed to infliximab during the RCT or the open-label followup.

  • #

    In total, 267 patients were exposed to etanercept during the RCT or open-label study.

  • **

    In total, 38 patients were exposed to etanercept during the RCT or the open-label phase.

  • ††

    A total of 208 patients were randomized to adalimumab, and 72 placebo patients were also exposed to adalimumab during the early escape phase.

Patients treated with placebo in RCTs     
 Braun et al (5)358.100 
 Davis et al (12)13958.300 
 Brandt et al (10)16§1.800 
 Van der Heijde et al (9)7834.81 (1/0)2.9 
 Gorman et al (27)205.700 
 Calin et al (28)398.700 
 Van der Heijde et al (17)10733.000 
 Total434150.41 (1/0)0.70–3.7
Patients treated with infliximab in RCTs     
 Braun et al (5)347.800 
 Van der Heijde et al (9)20192.100 
Patients treated with infliximab in open-label studies     
 Braun et al (6)6549.100 
 Braun et al (7)5445.700 
 Braun et al (8)4646.100 
 Braun et al (16)273374.800 
 Stone et al (26)212.400 
Patients treated with infliximab: total366618.0000–0.6
Patients treated with etanercept in RCTs     
 Davis et al (12)138#59.21 (1/0)1.7 
 Brandt et al (10)14§6.700 
 Gorman et al (27)20**6.100 
 Calin et al (28)459.600 
Patients treated with etanercept in open-label studies     
 Baraliakos et al (37)26§45.500 
 Davis et al (12)257#303.44 (4/0)1.3 
 Gorman et al (27)37**64.800 
 Calin et al (28)81130.11 (0/1)0.8 
Patients treated with etanercept: total419625.46 (5/1)1.00.4–2.1
Patients treated with adalimumab in RCTs     
 Van der Heijde et al (17)280††108.02 (2/0)1.9 
Patients treated with adalimumab in open-label studies     
 Haibel et al (15)1524.300 
Patients treated with adalimumab: total295132.32 (2/0)1.50.2–5.5
Table 4. Incidence of inflammatory bowel disease (IBD) per 100 patient-years by type of treatment and type of study*
 Patients exposed, no.Exposure, yearsIncidence (flares/new onset) of IBD, no.Flares or new onset of IBD
Per 100 patient-years95% CI
  • *

    Statistical comparisons: infliximab versus placebo: P = 0.10; etanercept versus placebo: P = 0.56; adalimumab versus placebo: P = 0.67; infliximab versus etanercept: P = 0.001; infliximab versus adalimumab: P = 0.02; etanercept versus adalimumab: P = 1.0. 95% CI = 95% confidence interval; RCTs = double-blinded placebo-controlled randomized controlled trials.

  • In total, 69 patients were exposed to infliximab during the RCT or the open-label followup.

  • In total, 276 patients were exposed to infliximab during the RCT or the open-label followup.

  • §

    In total, 267 patients were exposed to etanercept during the RCT or open-label study.

  • In total, 30 patients were exposed to etanercept during the RCT or the open-label phase.

  • #

    In total, 38 patients were exposed to etanercept during the RCT or the open-label phase.

  • **

    In total, 84 patients were exposed to etanercept; followup data were provided by the sponsor of the study.

  • ††

    A total of 208 patients were randomized to adalimumab, and 72 placebo patients were also exposed to adalimumab during the early escape phase.

Patients treated with placebo in RCTs     
 Braun et al (5)358.100 
 Davis et al (12)13958.31 (0/1)1.7 
 Brandt et al (10)161.800 
 Van der Heijde et al (9)7834.81 (1/0)2.9 
 Gorman et al (27)205.700 
 Calin et al (28)398.700 
 Van der Heijde et al (17)10733.000 
 Total434150.42 (1/1)1.30.2–4.8
Patients treated with infliximab in RCTs     
 Braun et al (5)347.800 
 Van der Heijde et al (9)20192.100 
Patients treated with infliximab in open-label studies     
 Braun et al (6)6549.100 
 Braun et al (7)5445.700 
 Braun et al (8)4646.100 
 Braun et al (16)273374.81 (1/0)0.3 
 Stone et al (26)212.400 
Patients treated with infliximab: total366618.01 (1/0)0.20–0.9
Patients treated with etanercept in RCTs     
 Davis et al (12)138§59.22 (1/1)3.4 
 Brandt et al (10)146.71 (0/1)14.9 
 Gorman et al (27)20#6.100 
 Calin et al (28)45**9.600 
Patients treated with etanercept in open-label studies     
 Baraliakos et al (37)2645.51 (0/1)2.2 
 Davis et al (12)257§303.46 (6/0)1.9 
 Gorman et al (27)37#64.800 
 Calin et al (28)81**130.14 (2/2)0.8 
Patients treated with etanercept: total419625.414 (9/5)2.21.2–3.8
Patients treated with adalimumab in RCTs     
 Van der Heijde et al (17)280††108.02 (2/0)1.9 
Patients treated with adalimumab in open-label studies     
 Haibel et al (15)1524.31 (1/0)4.1 
Patients treated with adalimumab: total295132.33 (3/0)2.30.5–6.6

Prestudy prevalence of IBD.

A history of CD or UC was not an exclusion criterion in the trials included. Information on the prestudy prevalence of IBD was available from the trials, but no detailed information on the prestudy prevalence of CD or UC was available. The overall prestudy prevalence of IBD was similar for all studies: ∼6% of the patients had a history of IBD (Table 1).

Incidence of IBD during the placebo phase.

There were 434 patients who were initially treated with placebo over a period ranging from 6 to 24 weeks. In the placebo phase, 1 flare of CD and 1 flare of UC occurred (Tables 2 and 3), which translated to an incidence of IBD of 1.3 cases per 100 patient-years (95% confidence interval [95% CI] 0.2–4.8) (Table 4).

Incidence of IBD during anti-TNF therapy.

During the double-blind and open-label phases of the studies, a total of 1,080 patients received anti-TNF therapy for a period of 14–156 weeks. Altogether, 366 patients were treated with infliximab, 419 patients were treated with etanercept, and 295 patients were treated with adalimumab (Tables 2, 3, and 4).

The incidence rates of IBD were different for patients receiving anti-TNF agents (Table 4). There was only 1 case of IBD (flare of CD) reported for infliximab (0.2 per 100 patient-years, 95% CI 0–0.9) but 14 cases of IBD (5 new onsets and 9 flares) were reported for etanercept: 8 cases of CD (4 new onsets and 4 flares) and 6 cases of UC (1 new onset and 5 flares). This corresponded to 2.2 cases of IBD per 100 patient-years of treatment with etanercept (95% CI 1.2–3.8). For adalimumab, 3 cases of IBD (all flares) were reported, 1 CD and 2 UC, corresponding to 2.3 cases of IBD per 100 patient-years with adalimumab treatment (95% CI 0.5–6.6). The detailed analysis shows the cases separated for CD (Table 2) and UC (Table 3).

The new onset or flare of IBD occurred after a mean of 242 days (range 57–545 days) or 8.1 months of treatment with etanercept. The flare of CD with infliximab occurred in the open-extension phase after almost 1 year of therapy. Detailed data for the large study with adalimumab could not be obtained from either the original publication or directly from the company.

There was no significant difference in the incidence rates of IBD between all 3 anti-TNF agents and placebo. However, significant differences in the incidence of IBD cases were calculated between infliximab and etanercept (P = 0.001) and between infliximab and adalimumab (P = 0.02). When analyzing CD and UC separately, only the comparison between infliximab and etanercept was statistically significant (P = 0.039 for CD and P = 0.03 for UC).

When the analysis was confined to patients with a history of IBD (n = 66), it was found that 1 of 22 patients taking infliximab, 12 of 26 taking etanercept, and 3 of 18 taking adalimumab had experienced a flare of IBD in comparison with 1 of 26 patients in the placebo group. This corresponded to an odds ratio (OR) of 18.0 (95% CI 2.1–154.4) for etanercept and of 4.2 (95% CI 0.40–44.2) for adalimumab, both in comparison with infliximab. The ORs in comparison with placebo were similar. Given that the exposure times were equally long, 1 flare of IBD occurred in ∼37 patient-years of exposure to infliximab and 12 flares of IBD occurred in ∼39 patient-years of exposure to etanercept. Using the Poisson regression analysis, the relative risk for etanercept was calculated at 11.4 (95% CI 1.4–87.6). The calculation was not possible for placebo and adalimumab because of the shorter time of exposure (9.8 patient-years and 8.1 patient-years, respectively).

Information on the further followup of IBD was available for 11 patients (9 flares and 5 new onsets) treated with etanercept. Of 8 patients with CD, 5 dropped out of the studies (80%) because of IBD disease activity. One patient completed the 12-week study (28) and 2 patients continued the study after having started sulfasalazine as concomitant medication. Of the patients who discontinued, 1 discontinued etanercept due to persistent activity of CD, 1 because of persistent diarrhea, and 3 patients recovered successfully after therapy with infliximab administered to treat CD.

Of 6 patients with UC, 3 dropped out of the studies and 3 received concomitant therapy with a disease-modifying antirheumatic drug (DMARD) for IBD. The 3 patients who received a DMARD discontinued etanercept later. The other 3 patients recovered on treatment with corticosteroids and azathioprine while receiving ongoing medication with etanercept.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

The data of the present study on patients with active AS suggest that the currently available anti-TNF agents may differ in their performance related to concomitant IBD, while their clinical efficacy on musculoskeletal symptoms related to AS disease activity is similar (4, 5, 8–10, 12, 13, 15–17, 26–28). However, no head-to-head comparisons of the impact on IBD in patients with AS have been performed to date. These data collected from all major recently performed anti-TNF trials suggest that although infliximab, etanercept, and adalimumab are similarly effective for the treatment of symptoms related to the spine, joints, entheses, and skin of patients with AS, infliximab appears to be effective in treating concomitant IBD in patients with AS who are in need of anti-TNF therapy. Importantly, this is relevant for less than 10% of all patients with AS. Patients with AS treated with etanercept had more flares and even some new onsets of IBD, as compared with those treated with infliximab. This was also the case for adalimumab, but to a lesser extent than for etanercept. Currently, there is no evidence that the described IBD flares occur more often in patients treated with etanercept than in those treated with placebo, because these differences were not significant. However, the comparison between placebo or adalimumab with the other 2 anti-TNF agents (infliximab and etanercept) is generally difficult because of the considerably shorter periods in which the patients had been treated with placebo (6–24 weeks) compared with the anti-TNF agents (14–156 weeks) in the trials, since this may lead to an underestimation of cases with IBD activity in the placebo group.

Because the patient numbers in individual trials are mostly too small to reach valuable conclusions for infrequent events, we decided to perform a combined analysis of all available anti-TNF studies to calculate the incidence of IBD during anti-TNF therapy in patients with AS. In general, we used a methodology similar to a recent study in which we analyzed the incidence of acute anterior uveitis (AAU) in patients with AS while receiving treatment with infliximab and etanercept (29). Two methodologic aspects differ in the present study: the companies were directly approached to ascertain that only real cases were included, and we also analyzed data for adalimumab.

Our analysis was possible because a history of CD or UC was not an exclusion criterion for participation in the studies. Importantly, the prestudy prevalence of IBD was similar for all 3 agents (∼6%). The incidence of flares of IBD in the placebo group was 1.3 per 100 patient-years. This was somewhat higher than the expected incidence of IBD from the literature, where an incidence of approximately 0.03 per 100 patient-years with similar rates for CD and UC has been reported (30); however, incidence rates for patients with AS are likely to be higher than for the normal population (31). In total, more cases of CD than UC have been observed in the trials, which was also expected from the literature (30).

In the present study, the incidence of IBD in patients treated with infliximab was 0.2 cases per 100 patient-years. In comparison, 2.2 cases per 100 patient-years were observed in the trials with etanercept. Both new onsets and flares were observed, and more flares of IBD (1.3 per 100 patient-years) than new onsets of IBD (0.7 per 100 patient-years) were reported. Because these data include 3 flares in 1 patient, it is clear that in total there were less cases than flares. For adalimumab, all 3 IBD episodes were flares, leading to a calculated incidence of 2.3 per 100 patient-years. In our analysis presented here, the direct comparison between infliximab and etanercept or adalimumab reached a statistically significant difference only between infliximab and etanercept for the incidence of IBD in general and for CD or UC when analyzed individually. The direct comparison between infliximab and adalimumab demonstrated no statistical difference for CD and UC when analyzed separately, only when the data were combined. Thus, the analysis of all cases of IBD, for both CD and UC and for both new onsets and flares, demonstrated a difference in favor of infliximab, especially when compared with etanercept in treating concomitant IBD in patients with AS.

Methodologically, it needs to be mentioned that the total exposure to etanercept was comparatively the longest, somewhat longer than infliximab, and adalimumab had the shortest exposure times. Because Amgen and Wyeth provided a special report on the incidence of IBD to the Food and Drug Administration, we used these data for our analysis. This explains why there may be differences in the data reported in the publications and in abstracts previously published by our group (32). In general, ascertainment of IBD was difficult because it was not possible for us to check whether the diagnosis of CD or UC was based on endoscopy and histology in all cases; we were also not aware of cases where these investigations had not been performed despite suggestive clinical symptoms. For the analysis, we focused our attention on CD and UC, and to avoid including unclear cases we excluded cases with undetermined colitis, although this may well be considered an IBD (25). Finally, we had no possibility to control for the concomitant intake of nonsteroidal antiinflammatory drugs (NSAIDs), which is known to contribute to IBD activity (33). However, NSAID intake is likely to be similar between the groups.

Furthermore, it has to be taken into account that patients with IBD who receive continuous therapy with azathioprine have less flares of CD over 1 year (15%) as compared with patients without such treatment (15% versus 53%) (34), and have fewer recurrences of UC over 1 year (36%) after full remission (35) than patients receiving placebo (36% versus 59%). It should be mentioned that azathioprine (and other DMARDs) were allowed in the etanercept trial and in the large adalimumab trial. However, it is unclear whether and how this may have influenced the results.

Taken together, according to the data provided here the relative risk of a patient with AS with a history of IBD experiencing a flare or a new onset of IBD during anti-TNF treatment was ∼10 times higher for etanercept as compared with infliximab, whereas the difference for placebo was not significant. The relative risk of a patient with AS with a history of IBD developing a flare during adalimumab treatment was also somewhat higher as compared with infliximab but the total exposure was shorter, the numbers were smaller, and the difference was not significant.

The difference between the anti-TNF agents may have been predicted given the different efficacy of the compounds for the treatment of active CD (19–21) and UC (22). Adalimumab may work in CD (36) but the performance in UC is not clear. In the only open study (26) with infliximab included in this evaluation, 3 of 21 patients had active concomitant CD at the time point of inclusion. Their CD-associated symptoms improved after 3 infusions of infliximab but recurred 6 weeks after the discontinuation of infliximab. Our analysis supports the relevance of early case reports about inappropriate control of IBD during treatment of patients with AS with etanercept (23, 24).

The followup information suggests that the cases of CD during etanercept treatment were clinically relevant because 4 of 6 patients discontinued the study while only 3 of 8 UC patients discontinued. Two cases of CD (11, 37) recovered successfully after termination of etanercept and initiation of treatment with infliximab, whereas 3 patients with UC preferred to continue taking etanercept therapy. Therefore, there was a dissociation of efficacy between gut and musculoskeletal symptoms, as in the early case reports (23, 24).

These followup data on etanercept confirm that this anti-TNF agent is rarely, although more frequently than other agents, associated with IBD activity in patients with AS. Because most flares of IBD were observed in patients with a history of IBD, it seems reasonable to recommend that such patients should not be treated with etanercept. However, we do not think that a positive history of IBD should be considered as an absolute contraindication for etanercept or adalimumab therapy in patients with AS. There is also no evidence to screen for silent gut inflammation in patients evaluated for anti-TNF therapy (38).

The fact that, so far, CD (19, 20) and UC (39, 40) can be efficaciously treated with infliximab but not with etanercept suggests a critical difference in the mechanisms of how these drugs work, as recently discussed elsewhere (41). This dissociation of efficacy in rheumatic and gastrointestinal symptoms (42) is an unresolved challenge to the concept of a critical gut-joint axis in the pathogenesis of SpA (43).

There are other disease manifestations in which TNF blockers may perform differently. As recently reported (29), anti-TNF therapy was associated with a significant decrease in the number of AAU flares, which was slightly more pronounced in patients treated with infliximab. Psoriatic skin lesions have occurred in patients treated with infliximab (44). This paradoxical reaction in a few patients that is not yet explained contrasts with the documented efficacy of infliximab for psoriasis and psoriatic arthritis (45), which is similar to etanercept (46, 47) and adalimumab (48, 49).

In conclusion, this analysis of several trials on anti-TNF therapy in patients with severe AS demonstrates that although all 3 available anti-TNFα compounds are clearly efficacious in the treatment of AS-related axial and peripheral signs and symptoms, there seem to be differences regarding the efficacy in patients with AS and IBD. It seems clear that etanercept and potentially adalimumab do not prevent flares and new onset of IBD in patients with active AS. Although this applies to a rather small group of patients with AS we nevertheless propose that AS patients with a history of IBD should not be preferably treated with etanercept, whereas more data are needed for adalimumab. In cases with both active AS and active IBD, treatment with infliximab may be more appropriate.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Dr. Braun 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. Braun, Listing, Sieper.

Acquisition of data. Braun, Baraliakos, Listing, Davis, van der Heijde, Haibel, Rudwaleit, Sieper.

Analysis and interpretation of data. Braun, Davis, van der Heijde, Sieper.

Manuscript preparation. Braun, Baraliakos, Davis, van der Heijde, Sieper.

Statistical analysis. Braun, Baraliakos, Listing, van der Heijde, Sieper.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  • 1
    Braun J, Bollow M, Neure L, Seipelt E, Seyrekbasan F, Herbst H, et al. Use of immunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheum 1995; 38: 499505.
  • 2
    Edmunds L, Elswood J, Kennedy LG, Calin A. Primary ankylosing spondylitis, psoriatic and enteropathic spondyloarthropathy: a controlled analysis. J Rheumatol 1991; 18: 6968.
  • 3
    McCormack G, Moriarty D, O'Donoghue DP, McCormick PA, Sheahan K, Baird AW. Tissue cytokine and chemokine expression in inflammatory bowel disease. Inflamm Res 2001; 50: 4915.
  • 4
    Baraliakos X, Davis J, Tsuji W, Braun J. Magnetic resonance imaging examinations of the spine in patients with ankylosing spondylitis before and after therapy with the tumor necrosis factor α receptor fusion protein etanercept. Arthritis Rheum 2005; 52: 121623.
  • 5
    Braun J, Brandt J, Listing J, Zink A, Alten R, Golder W, et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002; 359: 118793.
  • 6
    Braun J, Brandt J, Listing J, Zink A, Alten R, Burmester G, et al. Long-term efficacy and safety of infliximab in the treatment of ankylosing spondylitis: an open, observational, extension study of a three-month, randomized, placebo-controlled trial. Arthritis Rheum 2003; 48: 222433.
  • 7
    Braun J, Brandt J, Listing J, Zink A, Alten R, Burmester G, et al. Two year maintenance of efficacy and safety of infliximab in the treatment of ankylosing spondylitis. Ann Rheum Dis 2005; 64: 22934.
  • 8
    Braun J, Baraliakos X, Brandt J, Listing J, Zink A, Alten R, et al. Persistent clinical response to the anti-TNFα antibody infliximab in patients with ankylosing spondylitis over 3 years. Rheumatology (Oxford) 2005; 44: 6706.
  • 9
    Van der Heijde D, Dijkmans B, Geusens P, Sieper J, DeWoody K, Williamson P, et al, and the Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy Study Group. Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo controlled trial (ASSERT). Arthritis Rheum 2005; 52: 58291.
  • 10
    Brandt J, Khariouzov A, Listing J, Haibel H, Sorensen H, Grassnickel L, et al. Six-month results of a double-blind, placebo-controlled trial of etanercept treatment in patients with active ankylosing spondylitis. Arthritis Rheum 2003; 48: 166775.
  • 11
    Brandt J, Listing J, Haibel H, Sorensen H, Schwebig A, Rudwaleit M, et al. Long-term efficacy and safety of etanercept after readministration in patients with active ankylosing spondylitis [published erratum appears in Rheumatology (Oxford) 2005;44:569]. Rheumatology (Oxford) 2005; 44: 3428.
  • 12
    Davis JC Jr, van der Heijde D, Braun J, Dougados M, Cush J, Clegg DO, et al. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheum 2003; 48: 32306.
  • 13
    Davis J Jr, Webb A, Lund S, Sack K. Results from an open-label extension study of etanercept in ankylosing spondylitis [letter]. Arthritis Rheum 2004; 51: 3023.
  • 14
    Davis JC, van der Heijde DM, Braun J, Dougados M, Cush J, Clegg D, et al. Sustained durability and tolerability of etanercept in ankylosing spondylitis for 96 weeks. Ann Rheum Dis 2005; 64: 155762. E-pub ahead of print April 20, 2005. URL: http://ard.bmj.com/cgi/content/full/64/11/1557.
  • 15
    Haibel H, Rudwaleit M, Brandt HC, Grozdanovic Z, Listing J, Kupper H, et al. Adalimumab reduces spinal symptoms in active ankylosing spondylitis: clinical and magnetic resonance imaging results of a fifty-two-week open-label trial. Arthritis Rheum 2006; 54: 67881.
  • 16
    Braun J, Sieper J, Geusens P, Dijkmans B, Han J, Xu W, et al. Efficacy and safety of infliximab in patients with ankylosing spondylitis: 102 week results of the ASSERT trial [abstract]. Ann Rheum Dis 2006; 65 Suppl II: 87.
  • 17
    Van der Heijde D, Kivitz A, Schiff MH, Sieper J, Dijkmans BA, Braun J, et al, and the ATLAS Study Group. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2006; 54: 213646.
  • 18
    Sandborn WJ, Hanauer SB, Katz S, Safdi M, Wolf DG, Baerg RD, et al. Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2001; 121: 108894.
  • 19
    Baert FJ, D'Haens GR, Peeters M, Hiele MI, Schaible TF, Shealy D, et al. Tumor necrosis factor α antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn's ileocolitis. Gastroenterology 1999; 116: 228.
  • 20
    Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002; 359: 15419.
  • 21
    Rutgeerts P, Feagan B, Olson A, Johanns J, Travers S, Present D, et al. A randomized placebo-controlled trial of infliximab for active ulcerative colitis: the ACT I trial [abstract]. Gastroenterology 2005; 128 Suppl 2: A105.
  • 22
    Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. Infliximab for induction and maintenance therapy for ulcerative colitis [published erratum appears in N Engl J Med 2006;354:2200]. N Engl J Med 2005; 353: 246276.
  • 23
    Marzo-Ortega H, McGonagle D, O'Connor P, Emery P. Efficacy of etanercept for treatment of Crohn's related spondyloarthritis but not colitis. Ann Rheum Dis 2003; 62: 746.
  • 24
    Oh J, Arkfeld DG, Horwitz DA. Development of Crohn's disease in a patient taking etanercept [abstract]. J Rheumatol 2005; 32: 7523.
  • 25
    Geboes K, De Hertogh G. Indeterminate colitis [review]. Inflamm Bowel Dis 2003; 9: 32431.
  • 26
    Stone M, Salonen D, Lax M, Payne U, Lapp V, Inman R. Clinical and imaging correlates of response to treatment with infliximab in patients with ankylosing spondylitis. J Rheumatol 2001; 28: 160514.
  • 27
    Gorman JD, Sack KE, Davis JC Jr. Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor α. N Engl J Med 2002; 346: 134956.
  • 28
    Calin A, Dijkmans BA, Emery P, Hakala M, Kalden J, Leirisalo-Repo M, et al. Outcomes of a multicentre randomised clinical trial of etanercept to treat ankylosing spondylitis. Ann Rheum Dis 2004; 63: 1594600. E-pub September 2, 2004. URL: http://ard.bmj.com/cgi/content/full/63/12/1594.
  • 29
    Braun J, Baraliakos X, Listing J, Sieper J. Decreased incidence of anterior uveitis in patients with ankylosing spondylitis treated with the anti-tumor necrosis factor agents infliximab and etanercept. Arthritis Rheum 2005; 52: 244751.
  • 30
    Bernstein CN, Blanchard JF, Rawsthorne P, Wajda A. Epidemiology of Crohn's disease and ulcerative colitis in a central Canadian province: a population-based study. Am J Epidemiol 1999; 149: 91624.
  • 31
    Leirisalo-Repo M, Turunen U, Stenman S, Helenius P, Seppala K. High frequency of silent inflammatory bowel disease in spondylarthropathy. Arthritis Rheum 1994; 37: 2331.
  • 32
    Braun J, Baraliakos X, Listing J, Davis JrJC, van der Heijde D, Haibel H, et al. The incidence of flares or new onsets of inflammatory bowel disease in patients with ankylosing spondylitis exposed to anti-TNFα therapy [abstract]. Ann Rheum Dis 2006; 65 Suppl II: 86.
  • 33
    Takeuchi K, Smale S, Premchand P, Maiden L, Sherwood R, Thjodleifsson B, et al. Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2006; 4: 196202.
  • 34
    Vilien M, Dahlerup JF, Munck LK, Norregaard P, Gronbaek K, Fallingborg J. Randomized controlled azathioprine withdrawal after more than two years treatment in Crohn's disease: increased relapse rate the following year. Aliment Pharmacol Ther 2004; 19: 114752.
  • 35
    Hawthorne AB, Logan RF, Hawkey CJ, Foster PN, Axon AT, Swarbrick ET, et al. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ 1992; 305: 202.
  • 36
    Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh D, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. Gastroenterology 2006; 130: 32333.
  • 37
    Baraliakos X, Brandt J, Listing J, Haibel H, Sorensen H, Rudwaleit M, et al. Outcome of patients with active ankylosing spondylitis after two years of therapy with etanercept: clinical and magnetic resonance imaging data. Arthritis Rheum 2005; 53: 85663.
  • 38
    Mielants H, Veys EM, Goemaere S, Goethals K, Cuvelier C, De Vos M. Gut inflammation in the spondyloarthropathies: clinical, radiologic, biologic and genetic features in relation to the type of histology. A prospective study. J Rheumatol 1991; 18: 154251.
  • 39
    Baert FJ, Rutgeerts PJ. Medical therapies for ulcerative colitis and Crohn's disease [review]. Curr Gastroenterol Rep 2000; 2: 44650.
  • 40
    Lichtenstein GR. Is infliximab effective for induction of remission in patients with ulcerative colitis? [letter]. Inflamm Bowel Dis 2001; 7: 8993.
  • 41
    Sieper J, Van Den Brande J. Diverse effects of infliximab and etanercept on T lymphocytes. Semin Arthritis Rheum 2005; 34 Suppl 1: 237.
  • 42
    Marzo-Ortega H, McGonagle D, O'Connor P, Emery P. Efficacy of etanercept in the treatment of the entheseal pathology in resistant spondylarthropathy: a clinical and magnetic resonance imaging study. Arthritis Rheum 2001; 44: 21127.
  • 43
    Baeten D, De Keyser F, Van Damme N, Veys EM, Mielants H. Influence of the gut and cytokine patterns in spondyloarthropathy. Clin Exp Rheumatol 2002; 20 Suppl 28: S3842.
  • 44
    Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 2001; 357: 18427.
  • 45
    Antoni C, Krueger GG, de Vlam K, Birbara C, Beutler A, Guzzo C, et al. Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial. Ann Rheum Dis 2005; 64: 11507.
  • 46
    Leonardi CL, Powers JL, Matheson RT, Goffe BS, Zitnik R, Wang A, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med 2003; 349: 201422.
  • 47
    Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 2000; 356: 38590.
  • 48
    Gladman D, Mease PJ, Sasso E. Adalimumab is efficacious in treating skin disease in psoriatic arthritis: subanalysis by severity of psoriasis in ADEPT [abstract]. Ann Rheum Dis 2006; 65 Suppl II: 639.
  • 49
    Choy E, Gladman D, Sasso E. Adalimumab is efficacious in treating joint disease in early and established psoriatic arthritis: subanalysis of ADEPT [abstract]. Ann Rheum Dis 2006; 65 Suppl II: 211.