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Long-Term Monitoring of Infliximab Therapy for Perianal Fistulizing Crohn's Disease by Using Magnetic Resonance Imaging
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2011;9:130 –136
Long-Term Monitoring of Infliximab Therapy for Perianal Fistulizing Crohn’s Disease by Using Magnetic Resonance Imaging KONSTANTINOS KARMIRIS,* DIDIER BIELEN,‡ DIRK VANBECKEVOORT,‡ SÉVERINE VERMEIRE,* GEORGES COREMANS,* PAUL RUTGEERTS,* and GERT VAN ASSCHE* Departments of *Gastroenterology and ‡Radiology (Abdominal Imaging), University Hospital Gasthuisberg, Leuven, Belgium
BACKGROUND & AIMS: Magnetic resonance imaging (MRI) is used to assess the outcome of infliximab (IFX) therapy in patients with perianal fistulizing Crohn’s disease (pfCD). However, few long-term data are available about its efficacy. METHODS: We assessed 59 patients with pfCD by MRI and clinical evaluation at baseline. Treated patients then received paired clinical and MRI examinations for a median time period of 36 (11–53.3) weeks. Short-, mid-, and long-term effects of therapy, as well as the ability of MRI to predict treatment outcome and need for surgery, were evaluated. RESULTS: Compared with the baseline MRI, the short-term follow-up MRI (n ⫽ 29) revealed a reduced number of fistula tracks in 13.8% and in the inflammatory activity in 55.2% of patients, respectively; mid-term MRI (n ⫽ 25) in 56% and in 52%, respectively; and long-term MRI (n ⫽ 13) in 15.4% and in 31%, respectively. Improvement of pfCD based on MRI results coincided with clinical improvement in 54.7% of the patients. Shortterm and mid-term (but not long-term) MRI showed a significant decrease in the activity score. Therapy outcome was worse among patients with persisting fistulas (P ⫽ .01), collections (P ⫽ .009), and rectal wall involvement (P ⫽ .01) in the final MRI. Patients with single-branched fistulas (P ⬍ .0001) and collections (P ⫽ .006) in their baseline MRI were more likely to undergo surgery. CONCLUSIONS: MRI is a useful technique for evaluation of pfCD during the first year of followup. In the long-term, the MRI improvement coincides with clinical and endoscopic response to IFX in 50% of the patients. Keywords: Inflammatory Bowel Disease; Anti–TNF-␣ Agents; Abdominal Surgery; Abdominal Imaging.
P
erianal fistulizing Crohn’s disease (pfCD) comprises a wide spectrum of clinical manifestations ranging from low simple fistulas to a dense network of complex fistulas often accompanied by perianal abscesses and local sepsis. PfCD is notoriously refractory to standard medical therapy, and clinicians are usually confronted with therapeutic dilemmas.1 Tumor necrosis factor-alpha (TNF-␣) holds a pivotal role in the pathogenesis of CD2 and specifically of pfCD.3 Infliximab (IFX) is a chimeric monoclonal immunoglobulin G1 antibody that blocks TNF-␣ and is used for inducing and maintaining clinical response and remission in patients with pfCD. Cessation of drainage from at least 50% (defined as response) or all (defined as remission) fistulas, as judged by standard physical examination, is the primary end point used in clinical trials to monitor the outcome of IFX therapy.4 – 6
Magnetic resonance imaging of the pelvis (MRI) is established as a reliable technique for imaging pfCD. MRI provides clinicians with an excellent intrinsic tissue contrast (making it suitable for the demonstration of sepsis and adjacent anatomical structures) and an ability for multiplanar image acquisition while carrying no radiation hazard.7,8 In a previous study with MRI for monitoring IFX therapy in pfCD patients, we showed that complete resolution of the internal fistula tracks does not occur in response to short-term treatment, despite healing of the external orifices.9 This result was confirmed by 2 similar studies10,11 and also with the use of endoanal ultrasound.12 However, long-term evolution of the inflammatory process in the fistula tracks and relationship between clinical and imaging findings have been recently reported but in a limited size cohort.11 Therefore, the aims of our study were (1) to evaluate longterm usefulness of MRI in following up IFX treatment in pfCD patients and (2) to investigate whether MRI can predict treatment outcome and need for surgery.
Materials and Methods Patients This is an observational cohort study carried out at a single tertiary care center. Medical records of all patients with pfCD who had been treated with IFX were reviewed. Eligible patients were men and women who (1) had a pfCD diagnosis of ⱖ3 months from baseline, on the basis of endoscopic, histopathologic, radiologic, and clinical criteria with an indication for IFX treatment; (2) demonstrated at least intermittent drainage from 1 or more perianal fistula orifices before inclusion; (3) had undergone a baseline MRI within 2 weeks before IFX therapy initiation; and (4) went through an examination under anesthesia by an experienced proctologist, during which any clinically relevant collections were drained. Modified Vienna classification was used for assessing CD location and behavior.13 After a thorough baseline clinical assessment, all patients received 5 mg/kg of IFX at weeks 0, 2, and 6 and every 8 weeks thereafter. Follow-up was conducted with consecutive MRIs that were scheduled at regular intervals regardless of clinical outcome, paired with clinical assessment. MRI score and cliniAbbreviations used in this paper: IFX, infliximab; IQR, interquartile range; MRI, magnetic resonance imaging; pfCD, perianal fistulizing Crohn’s disease; TE, time to echo; TNF-␣, tumor necrosis factor-alpha; TR, repetition time. © 2011 by the AGA Institute 1542-3565/$36.00 doi:10.1016/j.cgh.2010.10.022
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cal status were evaluated short-term (10 –12 weeks from baseline), mid-term (26 –52 weeks), and long-term (beyond 56 weeks), and any concordance between imaging and clinical findings was investigated. All MRIs were done in the Department of Abdominal Imaging of the University Hospital of Leuven. In a subgroup of patients, a rectoscopy was conducted before baseline and in the vicinity of a follow-up MRI, and endoscopic findings were compared with the MRI results. All patients gave informed consent under the Flemish Study for Genetics of Crohn’s Disease and Ulcerative Colitis (VLECC) patient cohort platform for retrospective analysis of clinical and imaging data.
Study Parameters Imaging results were evaluated by using an MRI-based score for the severity of pfCD, described and validated in a previous study.9 Briefly, this 22-scale score consists of 6 parameters, 3 anatomical and 3 inflammatory, each one with a different significance in the total score (Table 1). Anatomical criteria were based on St Mark’s classification.14 MRI-based improvement of pfCD was defined as a ⱖ50% reduction in the total score from baseline. A reduction in the inflammatory activity of a fistula track was defined as a decrease of at least 1 scale in the subscore representing hyperintensity on T2-weighted images. The American Gastroenterological Association technical classification system was used for pfCD clinical assessment.1 Rectovaginal fistulas were separately assessed. Clinical improvement in pfCD was defined as a ⱖ50% decrease in the number of draining perianal fistulas from baseline during at least 2 consecutive treatment visits and remission as complete closure of all draining fistulas according to the treating physician’s assessment. Endoscopic improvement in pfCD was defined as partial and remission as complete rectal mucosa healing in follow-up rectoscopy. Overall degree of concordance between the last follow-up MRI score change and clinical and endoscopic status change of
Table 1. MRI-Based Score for Severity of pfCD No. of fistula tracks None Single, unbranched Single, branched Multiple Location Intersphincteric Trans-sphincteric Extrasphincteric Extension Infralevator Supralevator Hyperintensity on T2-weighted images Absent Mild Pronounced Collections (cavities ⬎3-mm diameter) Absent Present Rectal wall involvement Normal Thickened
0 1 2 3 1 2 3 1 2 0 4 8 0 4 0 2
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the study participants by the end of follow-up was evaluated by the treating physician.
Imaging MRIs were performed on a Siemens Magnetom Sonata Vision with a magnetic field of 1.5 tesla (Siemens, Erlangen Germany). A body phased array coil was used in all patients, providing T2-weighted, spin-echo, multiplane high-resolution Kiefer sequences. Also T1-weighted images with and without gadolinium were obtained. For the T2 Kiefer sequences in the axial and coronal plane, the scan time was 2 minutes 59 seconds, the repetition time (TR) was 8440 milliseconds, the time to echo (TE) was 136 milliseconds, and the flip angle was 180 degrees. The pixel size was 0.7 ⫻ 0.63 mm, with a slice thickness of 6 mm. A T2-weighted suppression sequence was also performed in the axial and sagittal plane with a scan time of 3 minutes 23 seconds, a TR of 6500 milliseconds, a TE of 114 milliseconds, and a flip angle of 180 degrees. The pixel size was 1.2 ⫻ 0.7 mm, with a slice thickness of 5.0 mm. Finally, T1-weighted gadolinium-enhanced fat suppression sequences were obtained in the coronal and axial plane, with a scan time of 5 minutes 36 seconds, a TR of 991 milliseconds, a TE of 11 milliseconds, a flip angle of 180 degrees, and a pixel size of 1.0 ⫻ 0.7 mm. Slice thickness for these sequences was 4.0 mm. Two experienced radiologists (D.B., D.V.) independently evaluated the MRI images, unaware of the paired clinical assessment of the patients and of the overall clinical response to IFX therapy.
Statistical Analysis The SPSS 15.0 software package (SPSS Inc, Chicago, IL) was used for performing all appropriate statistical analyses. Medians with interquartile range (IQR) were calculated for continuous data, and percentages were computed for discrete data. The 2 test was used for comparison of categorical data, and odds ratios were provided where appropriate. Differences between independent groups were traced with the use of the Mann–Whitney U test or the Kruskal–Wallis test for non-normally distributed values. For differences between dependent groups the Wilcoxon signed-rank test was used. Logistic proportional hazard models were conducted for the detection of any factors predicting therapy outcome and the need for a surgical intervention. A P value ⬍.05 was considered significant.
Results Baseline Study Parameter Findings A total of 59 patients fulfilled the inclusion criteria and had their baseline MRI conducted between May 1996 and September 2007. They subsequently received IFX and were followed up for a median (IQR) of 9.8 (1.4 – 46.1) months until the end of September 2008. Patients’ baseline characteristics are listed in Table 2. Baseline clinical assessment revealed draining external orifices in 95% of the patients, whereas in 5% an external orifice was detected but no drainage was present. Eighty-five percent of these fistulas were considered as complex. An external vaginal orifice was observed in 52.8% of the female patients. Forty of 59 (67.8%) patients underwent a rectoscopy before baseline MRI, and in 17 of 40 (42.5%) the rectal mucosa was inflamed.
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Table 2. Patients’ Baseline Characteristics (n ⫽ 59) Female/male (%) Smokers/nonsmokers at first MRI (%) Median (IQR) age at diagnosis (y) Median (IQR) pfCD duration until first MRI (mo) Luminal disease location (%) Ileitis/colitis/ileocolitis Median (IQR) follow-up under IFX therapy (mo) Median (IQR) interval between first and last MRI (wk) Patients with complex fistulas at baseline (clinical exam) Concomitant IMS at first MRI Concomitant antibiotics at first MRI Patients with surgical interventions (pfCD related) before first MRI
37/22 (62.7/37.3) 24/29 (49/41) 23.1 (17.5–32.8) 107.5 (33.4–189.2)
16 (27)/19 (32)/23 (39) 9.8 (1.4–46.1) 36.0 (11.0–53.3) 50 (84.7%) 37 (62.7%) 12 (20.3%) 53 (89.8%)
IMS, immunosuppressants.
Baseline MRI detected fistula tracks in 91.5% of the patients, of which 94.5% were characterized as active (T2 hyperintensity of the fistula track). Rectovaginal fistulas were seen in 34.4% of the female patients. At least 1 collection ⬎3 mm was seen in 52.5% of the patients. Rectal wall thickening was present in 13 of 17 patients, with mucosal inflammation at baseline rectoscopy. No difference was found between baseline rectoscopy and MRI regarding rectal wall inflammatory involvement rate (2 test, P ⫽ NS).
Follow-up Study Parameter Findings By the end of follow-up, clinical benefit with IFX therapy was seen in 77% (41% in remission, 36% responded) of the patients, whereas in 23% clinical response was absent (Figure 1). Adjustment of the IFX dosing scheme until the end of follow-up was needed in 12 of 56 patients (21.4%). Twenty-seven of 59 patients (46%) had at least 1 seton placed before baseline MRI. In 21 of 27 patients (77.7%) these were removed permanently during follow-up (median [IQR] period until seton removal, 11.1 [9.4 –29.1] weeks). Removal was based on the findings of the examination under anesthesia. Repeated rectoscopy was conducted at variable time points in 13 of 40 (32.5%) of the patients who had a baseline examination, and rectal wall inflammation was present in 2 of 13 (15.4%). Both patients had inflammation at baseline rectoscopy also. Short-term follow-up MRI was available in 29 patients (median [IQR] period, 11.0 [10.0 –12.5] weeks; median [IQR] number of IFX infusions, 3.0 [3.0 – 6.2]). Fistula tracks were present in 26 of 29 patients (89.7%) and were also active (hyperintense and/or with fluid-filled cavities) in 23. Although all collections detected at baseline were drained, at least 1 collection ⬎3 mm was present in 12 of 29 (41.4%) and rectal wall involvement was present in 13 of 29 (44.8%). When compared with baseline MRI, short-term MRI showed a reduction in the number of fistula tracks in 4 of 29 patients (13.8%) and in the inflammatory activity in 16 of 29 (55.2%). Collections were found always in fistula tracks that had been originally identified but not always in the same track. Mid-term follow-up MRI was available in 25 patients (median [IQR] period, 44.0 [28.7– 46.3] weeks; median [IQR] number of IFX infusions, 6.0 [3.7– 8.2]). Fistula tracks were present
in 21 of 25 (84%), and in 20 of 21 these tracks were also active. At least 1 collection ⬎3 mm was detected in 9 of 25 (36%) and rectal wall involvement in 13 of 25 (52%). When compared with baseline MRI, mid-term MRI showed a reduction in the number of fistula tracks in 14 of 25 patients (56%) and in the inflammatory activity in 13 of 25 (52%). In 12 patients both short-term and mid-term MRIs were available. The latter showed a reduction in the number of fistula tracks in 8 of 12 (66.7%) and in the inflammatory activity in 6 of 12 (50%) compared with the former. Long-term follow-up MRI was available in 13 patients (median [IQR] period, 94.5 [75.3–139.3] weeks; median [IQR] number of IFX infusions, 11.0 [7.5–16.0]). Fistula tracks were present in 12 of 13 (92.3%), and in 9 of 12 these tracks were also active. At least 1 collection ⬎3 mm was detected in 3 of 13 (23%) and rectal wall involvement in 12 of 13 (92.3%). When compared with baseline MRI, long-term MRI showed a reduction in the number of fistula tracks in 2 of 13 patients (15.4%) and in the inflammatory activity in 4 of 13 (31%). In 8 patients both mid-term and long-term MRIs were available. No patient showed a reduction in the number of fistula tracks, and 3 of 8 showed a reduction in the inflammatory activity in the latter compared with the former. Rectovaginal fistulas were present in 42.3% of the female patients in the last follow-up MRI. Interestingly, both patients with proctitis at follow-up endoscopy showed no signs of rectal wall inflammation at last follow-up MRI, and patients with rectal wall involvement at last follow-up MRI revealed no inflammation at rectoscopy. Overall, with MRI as the tool for assessing pfCD improvement under IFX therapy, we observed persisting fistula tracks in 79.2% of the patients, with an improvement in the inflammation in 53.8% and an improvement in rectal wall thickness in 24.5%. Improvement of pfCD seen in MRI coincided with clinical improvement in 54.7% and with endoscopic improvement in 46.2% of the patients.
Magnetic Resonance Imaging Score Change and Correlation Between Findings MRI-based activity score was also evaluated short-term, mid-term, and long-term. A significant decrease in the score was observed short-term (median [IQR] score, 10.5 [5.5–15.0], P ⫽ .002) and mid-term (9.0 [5.2–13.2], P ⬍ .0001) but not long-
Figure 1. Clinical outcome of IFX therapy in our cohort of pfCD patients.
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Figure 2. MRI score change short-term, mid-term, and longterm in pfCD patients under IFX therapy.
term (11.5 [6.2–14.0], P ⫽ .1) compared with baseline score (17 [9 –20]) (Figure 2). Individual MRI score change in each patient throughout follow-up is shown in the total cohort (Figure 3A) and also in the different groups according to clinical response (Figure 3B–D). The patients who went into clinical remission under IFX therapy demonstrated a larger decrease in mid-term MRI score compared with those who still had draining fistulas at the same study period (median [IQR] mid-term MRI score, 6 [2– 8] vs 13 [9 –18], P ⬍ .0001 and median [IQR] MRI score decrease from baseline, ⫺13 [⫺17 to ⫺11] vs ⫺4 [⫺9 to 0], respectively, P ⫽ .004) (Supplementary Figure 1). No difference was observed between the 2 groups regarding short-term and long-term MRI score change. Changes in the MRI score at any time point were not different between the patients who demonstrated concordance among clinical or endoscopic and imaging assessment and those who did not and also between patients who were taking antibiotics and/or immunosuppressants at baseline and those who were not. The patients with a seton in place at baseline demonstrated a higher overall MRI-clinical pfCD assessment concordance (2 test: odds ratio, 8.4 [2.4 –29.8], P ⬍ .001). No correlation was found between the placement of a seton at baseline and detection of a collection in subsequent MRIs at any time point. The MRI images in Figure 4 demonstrate the evolution of a perianal horseshoe fistula in a young male patient with CD after 1 year of IFX therapy.
Use of Magnetic Resonance Imaging for Predicting Clinical Outcome and Need for Surgery By the end of follow-up, the patients who still had active pfCD at clinical evaluation demonstrated more frequently persisting fistula tracks (P ⫽ 0.01), especially multiple fistulas (P ⫽ .01), collections (P ⫽ .009), and rectal wall inflammatory involvement (P ⫽ .01) at last MRI compared with those who were under clinical remission. In the multivariate analysis,
none of these MRI score parameters turned out to be significant. Twenty patients (34%) needed at least 1 surgical intervention between initiation of IFX treatment and last follow-up MRI. The median [IQR] time for the first intervention was 12 [7–19] weeks. Surgery was more frequent in the patients who demonstrated single-branched fistulas (P ⬍ .0001) and collections (P ⫽ .006) at baseline MRI, although no correlation was found with the total baseline MRI score. In the multivariate analysis, none of these MRI score parameters turned out to be significant.
Discussion IFX was the first immunoglobulin G1 monoclonal antibody introduced in the clinic for the treatment of refractory CD including pfCD.4,5 The end point used in the pivotal randomized trial but also in subsequent studies evaluating treatment efficacy was cessation of drainage from cutaneous orifices. This condition was forced by the lack of a clinically oriented, reproducible, and prospectively validated activity index that could be used for monitoring therapy of pfCD.1 We showed in a previous study that although clinically more relevant, cessation of drainage from the external orifices after IFX therapy does not accurately reflect what is happening to the internal fistula tracks,9 and this observation was confirmed by other groups.10 –12 Pelvic MRI was used as the monitoring tool for coming to this conclusion because this imaging modality has demonstrated its sensitivity and specificity for detecting pelvic complications in pfCD and offers the advantage of a broader application and central reading compared with endoscopic ultrasound.7,12,15 In the present study consecutive pelvic MRIs were used for long-term evaluation of IFX therapy on pfCD. Median MRI follow-up time was 36 weeks, which is longer than the one described in other relevant studies.10,16 In a recently published
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Figure 3. Individual MRI score change in the total cohort (A) and according to complete (B), partial (C), and absent (D) clinical response.
cohort, follow-up with MRI was 52 weeks, but in our trial longer follow-up was available for a sizeable proportion of patients.11 There was a lower detection rate of rectovaginal fistulas at baseline MRI compared with the rate of external vaginal orifices seen on clinical examination. This is probably due to the lower spatial resolution of the body phased array coil used in this study compared with the much more sensitive endoluminal coil in detecting these specific fistulas.17 On the other hand, baseline MRI demonstrated a similar sensitivity with endoscopy in detecting rectal wall involvement. In a recent study by Tougeron et al,16 MRI underestimated rectal wall involvement (11.5% vs 50% for endoscopy, P ⫽ .02). This discrepancy is probably due to the different MRI devices used and is possibly due to different sequences implemented. The unusual correlation that we observed between last MRI and endoscopy could be explained from a possible nonhomogenous healing of the inflammatory components in the different tissue layers of the rectal wall. Of course, patient numbers are too small to draw any firm conclusion. Short-term MRI revealed improvement in the number and inflammatory component of the fistula tracks in 14% and 55% of the patients, respectively. Interestingly, clinically relevant collections were still detected shortly after drainage of all collections found at baseline examination, indicating the lack of a diagnostic modality with adequate sensitivity to detect all relevant collections.18 Mid-term MRI demonstrated an improvement in the number and inflammation of fistula tracks similar to the one described in clinical trials (55%– 60%). On the contrary, long-term MRI (beyond 1 year of IFX treatment) did not
detect more patients with an improvement in pfCD status compared with mid-term MRI. MRI-based activity score significantly decreased short-term and mid-term but not long-term. In the study by Tougeron et al,16 a decrease in the same MRI score was seen in 18.5 ⫾ 14 months. This observation, in combination with the lack of an acceptable concordance in the last follow-up examinations, indicates that MRI can be considered a reliable imaging modality during the first year of IFX therapy, but long-term monitoring beyond this period is not superior to clinical evaluation in assessing pfCD status. However, not all patients received a long-term MRI re-evaluation, and we cannot exclude a type II error as a result of the relatively moderate sample size. In our previous study, we reported that especially the inflammatory items of the MRI-based score improved after short-term treatment with IFX. However, in this cohort of long-term follow-up the inflammatory (hyperintensity, rectal wall thickening, collections) scores showed no more improvement than the anatomical criteria. In line, neither the complexity nor extension of the fistula tracks or the relation to the sphincter apparatus changed over time on MRI (data not shown). Last follow-up MRI detected persistent fistula tracks in 79.2% of our patients, with an improvement in the inflammation in only 50%, although 77% of the patients reported clinical benefit from IFX therapy. The same observation was apparent in the previous study from our group,9 indicating that not only short-term but also long-term complete resolution of the internal fistula tracks does not occur in response to IFX with signs of inflammation. Therefore, our results question the concept of
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Figure 4. MRI images of a perianal horseshoe fistula in a young male patient with CD before and 3 months and 1 year after IFX therapy. Note that the inflammatory component (T2 hyperintensity and collections) markedly improved, but that the fistula track is still present after 1 year.
complete fistula healing in patients with pfCD and justify the need for long-lasting therapy with IFX. Improvement in pfCD, as seen in last MRI, coincided with clinical improvement in only half of our patients, suggesting that external orifices tend to obliterate and stop draining shortly after IFX therapy initiation probably as a result of different healing rates between cutaneous and internal soft tissue structures of the fistula track. A similar concordance rate regarding improvement of pfCD was also observed between the MRI and the endoscopy, reflecting the inappropriateness of MRI in evaluating rectal mucosa inflammatory status. A recently published cohort from St Mark’s Hospital in London, UK of patients treated with IFX and adalimumab long-term also has shown that MRI improvement of internal fistula tracks takes longer than clinical improvement, but that once MRI healing is achieved, scheduled antiTNF re-treatment is able to maintain this healing.11 However, it is not clear from this cohort whether ongoing anti-TNF therapy is required for this maintained benefit on MRI. Several predicting factors have been proposed for determining clinical outcome of pfCD under IFX therapy,19 –22 but MRI has only been used for predicting surgical outcome in perianal fistulas not accompanying pfCD.23,24 Patients with persisting fistula tracks, more multiple fistulas, collections, and rectal wall involvement in last MRI were less frequently in clinical remis-
sion in univariate analysis, but this was not confirmed in multivariate analysis, suggesting that these predictors were interacting. Tougeron et al16 also found no difference between clinical responders and nonresponders in the total MRI score and in the subscore of fistula activity, but they did not comment on other parameters of the MRI score (type of fistulas, collections, etc). Surgical interventions were more frequent in patients with more complex fistulas and signs of perianal sepsis at baseline MRI again only in univariate analysis. In conclusion, MRI can be considered a reliable imaging modality for monitoring IFX therapy in patients with pfCD for the first year of treatment, but its long-term results are in agreement with clinical and endoscopic response to IFX in only half of the patients. Moreover, MRI seems effective only during the first year of surveillance. After this time period, clinical assessment is equally reliable or even superior to MRI in evaluating therapy outcome and would save health care resources given to cost of repeated MRI. Patients with more complicated disease, judged by baseline or last follow-up MRI score, demonstrated a worse prognosis compared with patients with less complicated disease, reinforcing the applicability of the MRIbased activity score used in this study. However, we believe that suggesting a risk stratification of patients on the basis of the results of our study is still premature. More prospectively de-
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signed and adequately powered studies in larger cohorts are needed to replicate and strengthen our results.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org and doi:10.1016/ j.cgh.2010.10.022. References 1. Sandborn WJ, Fazio VW, Feagan BG, et al. AGA technical review on perianal Crohn’s disease. Gastroenterology 2003;125:1508 – 1530. 2. Papadakis KA, Targan SR. Tumor necrosis factor: biology and therapeutic inhibitors. Gastroenterology 2000;119:1148 –1157. 3. Tozer PJ, Whelan K, Phillips RK, et al. Etiology of perianal Crohn’s disease: role of genetic, microbiological and immunological factors. Inflamm Bowel Dis 2009;15:1591–1598. 4. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulae in patients with Crohn’s disease. N Engl J Med 1999;340:1398 –1405. 5. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004; 350:876 – 885. 6. Schnitzler F, Fidder H, Ferrante M, et al. Long-term outcome of treatment with infliximab in 614 Crohn’s disease patients: results from a single center cohort. Gut 2009;58:501–508. 7. Haggett PJ, Moore NR, Shearman JD, et al. Pelvic and perineal complications of Crohn’s disease: assessment using magnetic resonance imaging. Gut 1995;36:407– 410. 8. Halligan S, Stoker J. Imaging of fistula in Ano. Radiology 2006; 239:18 –33. 9. Van Assche G, Vanbeckevoort D, Bielen D, et al. Magnetic resonance imaging of the effects of infliximab on perianal fistulizing Crohn’s disease. Am J Gastroenterol 2003;98:332–339. 10. Bell SJ, Halligan S, Windsor CJ, et al. Response of fistulating Crohn’s disease to infliximab treatment assessed by magnetic resonance imaging. Aliment Pharmacol Ther 2003;17:387– 393. 11. Ng SC, Plamondon S, Gupta A, et al. Prospective evaluation of anti-tumor necrosis factor therapy guided by magnetic resonance imaging for Crohn’s perineal fistulas. Am J Gastroenterol 2009; 104:2973–2986. 12. Van Bodegraven AA, Sloots CE, Felt-Bersma RJ, et al. Endosonographic evidence of persistence of Crohn’s disease-associated fistulas after infliximab treatment, irrespective of clinical response. Dis Colon Rectum 2002;45:39 – 45. 13. Silverberg MS, Satsangi J, Ahmad T, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a working party of the 2005 Montreal world congress of gastroenterology. Can J Gastroenterol 2005; 19(Suppl A):5A–36A. 14. Parks AG, Gordon PH, Hardcastle JD. A classification of fistula-inano. Br J Surg 1976;63:1–12.
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15. Schwartz DA, Wiersema MJ, Dudiak KM, et al. A comparison of endoscopic ultrasound, magnetic resonance imaging, and exam under anesthesia for evaluation of Crohn’s perianal fistulas. Gastroenterology 2001;121:1064 –1072. 16. Tougeron D, Savoye G, Savoye-Collet C, et al. Predicting factors of fistula healing and clinical remission after infliximab-based combined therapy for perianal fistulizing Crohn’s disease. Dig Dis Sci 2009;54:1746 –1752. 17. Stoker J, Rociu E, Schouten WR, et al. Anovaginal and rectovaginal fistulas: endoluminal sonography versus endoluminal MR imaging. AJR Am J Roentgenol 2002;178:737–741. 18. Lunnis PJ, Barker PG, Sultan AH, et al. Magnetic resonance imaging of fistula-in-ano. Dis Colon Rectum 1994;37:708 –718. 19. Parsi MA, Lashner BA, Achkar JP, et al. Type of fistula determines response to infliximab in patients with fistulous Crohn’s disease. Am J Gastroenterol 2004;99:445– 449. 20. Parsi MA, Achkar JP, Richardson S, et al. Predictors of response to infliximab in patients with Crohn’s disease. Gastroenterology 2002;123:707–713. 21. Arnott ID, McNeill G, Satsangi J. An analysis of factors influencing short-term and sustained response to infliximab treatment for Crohn’s disease. Aliment Pharmacol Ther 2003;17:1451–1457. 22. Vermeire S, Louis E, Carbonez A, et al. Demographic and clinical parameters influencing the short-term outcome of anti-tumor necrosis factor (infliximab) treatment in Crohn’s disease. Am J Gastroenterol 2002;97:2357–2363. 23. Chapple KS, Spencer JA, Windsor AC, et al. Prognostic value of magnetic resonance imaging in the management of fistula-in-ano. Dis Colon Rectum 2000;43:511–516. 24. Spencer JA, Chapple K, Wilson D, et al. Outcome after surgery for perianal fistula: predictive value of MR imaging. AJR Am J Roentgenol 1998;171:403– 406.
Reprint requests Address requests for reprints to: Gert Van Assche, MD, Department of Gastroenterology, University Hospital Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium. e-mail: [email protected]; fax: 32-16-34-44-19. Conflicts of interest The authors disclose the following: Dirk Vanbeckevoort has received speaker fees from Abbott. Severine Vermeire has received grants/ research support from UCB; consultancy for AstraZeneca, Ferring, and Pfizer; speakers bureau for Schering–Plough, Abbott, Ferring, and UCB; and advisory committee for Shire and Ferring. Paul Rutgeerts has received research grants, lecture fees, and consultant fees from Abbott, Centocor, Schering–Plough, and UCB. Gert Van Assche has received speaker fees/research support from Centocor, Schering– Plough, Abbott, and UCB. The remaining authors disclose no conflicts. Funding This study was supported with a grant from the Hellenic Society of Gastroenterology. Gert Van Assche and Séverine Vermeire hold a clinician-scientist position at the FWO Flanders.
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Supplementary Figure 1. Midterm MRI score change in patients in remission in comparison with those with draining fistulas.
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Long-Term Monitoring of Infliximab Therapy for Perianal Fistulizing Crohn’s Disease by Using Magnetic Resonance Imaging KONSTANTINOS KARMIRIS,* DIDIER BIELEN,‡ DIRK VANBECKEVOORT,‡ SÉVERINE VERMEIRE,* GEORGES COREMANS,* PAUL RUTGEERTS,* and GERT VAN ASSCHE* Departments of *Gastroenterology and ‡Radiology (Abdominal Imaging), University Hospital Gasthuisberg, Leuven, Belgium
BACKGROUND & AIMS: Magnetic resonance imaging (MRI) is used to assess the outcome of infliximab (IFX) therapy in patients with perianal fistulizing Crohn’s disease (pfCD). However, few long-term data are available about its efficacy. METHODS: We assessed 59 patients with pfCD by MRI and clinical evaluation at baseline. Treated patients then received paired clinical and MRI examinations for a median time period of 36 (11–53.3) weeks. Short-, mid-, and long-term effects of therapy, as well as the ability of MRI to predict treatment outcome and need for surgery, were evaluated. RESULTS: Compared with the baseline MRI, the short-term follow-up MRI (n ⫽ 29) revealed a reduced number of fistula tracks in 13.8% and in the inflammatory activity in 55.2% of patients, respectively; mid-term MRI (n ⫽ 25) in 56% and in 52%, respectively; and long-term MRI (n ⫽ 13) in 15.4% and in 31%, respectively. Improvement of pfCD based on MRI results coincided with clinical improvement in 54.7% of the patients. Shortterm and mid-term (but not long-term) MRI showed a significant decrease in the activity score. Therapy outcome was worse among patients with persisting fistulas (P ⫽ .01), collections (P ⫽ .009), and rectal wall involvement (P ⫽ .01) in the final MRI. Patients with single-branched fistulas (P ⬍ .0001) and collections (P ⫽ .006) in their baseline MRI were more likely to undergo surgery. CONCLUSIONS: MRI is a useful technique for evaluation of pfCD during the first year of followup. In the long-term, the MRI improvement coincides with clinical and endoscopic response to IFX in 50% of the patients. Keywords: Inflammatory Bowel Disease; Anti–TNF-␣ Agents; Abdominal Surgery; Abdominal Imaging.
P
erianal fistulizing Crohn’s disease (pfCD) comprises a wide spectrum of clinical manifestations ranging from low simple fistulas to a dense network of complex fistulas often accompanied by perianal abscesses and local sepsis. PfCD is notoriously refractory to standard medical therapy, and clinicians are usually confronted with therapeutic dilemmas.1 Tumor necrosis factor-alpha (TNF-␣) holds a pivotal role in the pathogenesis of CD2 and specifically of pfCD.3 Infliximab (IFX) is a chimeric monoclonal immunoglobulin G1 antibody that blocks TNF-␣ and is used for inducing and maintaining clinical response and remission in patients with pfCD. Cessation of drainage from at least 50% (defined as response) or all (defined as remission) fistulas, as judged by standard physical examination, is the primary end point used in clinical trials to monitor the outcome of IFX therapy.4 – 6
Magnetic resonance imaging of the pelvis (MRI) is established as a reliable technique for imaging pfCD. MRI provides clinicians with an excellent intrinsic tissue contrast (making it suitable for the demonstration of sepsis and adjacent anatomical structures) and an ability for multiplanar image acquisition while carrying no radiation hazard.7,8 In a previous study with MRI for monitoring IFX therapy in pfCD patients, we showed that complete resolution of the internal fistula tracks does not occur in response to short-term treatment, despite healing of the external orifices.9 This result was confirmed by 2 similar studies10,11 and also with the use of endoanal ultrasound.12 However, long-term evolution of the inflammatory process in the fistula tracks and relationship between clinical and imaging findings have been recently reported but in a limited size cohort.11 Therefore, the aims of our study were (1) to evaluate longterm usefulness of MRI in following up IFX treatment in pfCD patients and (2) to investigate whether MRI can predict treatment outcome and need for surgery.
Materials and Methods Patients This is an observational cohort study carried out at a single tertiary care center. Medical records of all patients with pfCD who had been treated with IFX were reviewed. Eligible patients were men and women who (1) had a pfCD diagnosis of ⱖ3 months from baseline, on the basis of endoscopic, histopathologic, radiologic, and clinical criteria with an indication for IFX treatment; (2) demonstrated at least intermittent drainage from 1 or more perianal fistula orifices before inclusion; (3) had undergone a baseline MRI within 2 weeks before IFX therapy initiation; and (4) went through an examination under anesthesia by an experienced proctologist, during which any clinically relevant collections were drained. Modified Vienna classification was used for assessing CD location and behavior.13 After a thorough baseline clinical assessment, all patients received 5 mg/kg of IFX at weeks 0, 2, and 6 and every 8 weeks thereafter. Follow-up was conducted with consecutive MRIs that were scheduled at regular intervals regardless of clinical outcome, paired with clinical assessment. MRI score and cliniAbbreviations used in this paper: IFX, infliximab; IQR, interquartile range; MRI, magnetic resonance imaging; pfCD, perianal fistulizing Crohn’s disease; TE, time to echo; TNF-␣, tumor necrosis factor-alpha; TR, repetition time. © 2011 by the AGA Institute 1542-3565/$36.00 doi:10.1016/j.cgh.2010.10.022
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cal status were evaluated short-term (10 –12 weeks from baseline), mid-term (26 –52 weeks), and long-term (beyond 56 weeks), and any concordance between imaging and clinical findings was investigated. All MRIs were done in the Department of Abdominal Imaging of the University Hospital of Leuven. In a subgroup of patients, a rectoscopy was conducted before baseline and in the vicinity of a follow-up MRI, and endoscopic findings were compared with the MRI results. All patients gave informed consent under the Flemish Study for Genetics of Crohn’s Disease and Ulcerative Colitis (VLECC) patient cohort platform for retrospective analysis of clinical and imaging data.
Study Parameters Imaging results were evaluated by using an MRI-based score for the severity of pfCD, described and validated in a previous study.9 Briefly, this 22-scale score consists of 6 parameters, 3 anatomical and 3 inflammatory, each one with a different significance in the total score (Table 1). Anatomical criteria were based on St Mark’s classification.14 MRI-based improvement of pfCD was defined as a ⱖ50% reduction in the total score from baseline. A reduction in the inflammatory activity of a fistula track was defined as a decrease of at least 1 scale in the subscore representing hyperintensity on T2-weighted images. The American Gastroenterological Association technical classification system was used for pfCD clinical assessment.1 Rectovaginal fistulas were separately assessed. Clinical improvement in pfCD was defined as a ⱖ50% decrease in the number of draining perianal fistulas from baseline during at least 2 consecutive treatment visits and remission as complete closure of all draining fistulas according to the treating physician’s assessment. Endoscopic improvement in pfCD was defined as partial and remission as complete rectal mucosa healing in follow-up rectoscopy. Overall degree of concordance between the last follow-up MRI score change and clinical and endoscopic status change of
Table 1. MRI-Based Score for Severity of pfCD No. of fistula tracks None Single, unbranched Single, branched Multiple Location Intersphincteric Trans-sphincteric Extrasphincteric Extension Infralevator Supralevator Hyperintensity on T2-weighted images Absent Mild Pronounced Collections (cavities ⬎3-mm diameter) Absent Present Rectal wall involvement Normal Thickened
0 1 2 3 1 2 3 1 2 0 4 8 0 4 0 2
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the study participants by the end of follow-up was evaluated by the treating physician.
Imaging MRIs were performed on a Siemens Magnetom Sonata Vision with a magnetic field of 1.5 tesla (Siemens, Erlangen Germany). A body phased array coil was used in all patients, providing T2-weighted, spin-echo, multiplane high-resolution Kiefer sequences. Also T1-weighted images with and without gadolinium were obtained. For the T2 Kiefer sequences in the axial and coronal plane, the scan time was 2 minutes 59 seconds, the repetition time (TR) was 8440 milliseconds, the time to echo (TE) was 136 milliseconds, and the flip angle was 180 degrees. The pixel size was 0.7 ⫻ 0.63 mm, with a slice thickness of 6 mm. A T2-weighted suppression sequence was also performed in the axial and sagittal plane with a scan time of 3 minutes 23 seconds, a TR of 6500 milliseconds, a TE of 114 milliseconds, and a flip angle of 180 degrees. The pixel size was 1.2 ⫻ 0.7 mm, with a slice thickness of 5.0 mm. Finally, T1-weighted gadolinium-enhanced fat suppression sequences were obtained in the coronal and axial plane, with a scan time of 5 minutes 36 seconds, a TR of 991 milliseconds, a TE of 11 milliseconds, a flip angle of 180 degrees, and a pixel size of 1.0 ⫻ 0.7 mm. Slice thickness for these sequences was 4.0 mm. Two experienced radiologists (D.B., D.V.) independently evaluated the MRI images, unaware of the paired clinical assessment of the patients and of the overall clinical response to IFX therapy.
Statistical Analysis The SPSS 15.0 software package (SPSS Inc, Chicago, IL) was used for performing all appropriate statistical analyses. Medians with interquartile range (IQR) were calculated for continuous data, and percentages were computed for discrete data. The 2 test was used for comparison of categorical data, and odds ratios were provided where appropriate. Differences between independent groups were traced with the use of the Mann–Whitney U test or the Kruskal–Wallis test for non-normally distributed values. For differences between dependent groups the Wilcoxon signed-rank test was used. Logistic proportional hazard models were conducted for the detection of any factors predicting therapy outcome and the need for a surgical intervention. A P value ⬍.05 was considered significant.
Results Baseline Study Parameter Findings A total of 59 patients fulfilled the inclusion criteria and had their baseline MRI conducted between May 1996 and September 2007. They subsequently received IFX and were followed up for a median (IQR) of 9.8 (1.4 – 46.1) months until the end of September 2008. Patients’ baseline characteristics are listed in Table 2. Baseline clinical assessment revealed draining external orifices in 95% of the patients, whereas in 5% an external orifice was detected but no drainage was present. Eighty-five percent of these fistulas were considered as complex. An external vaginal orifice was observed in 52.8% of the female patients. Forty of 59 (67.8%) patients underwent a rectoscopy before baseline MRI, and in 17 of 40 (42.5%) the rectal mucosa was inflamed.
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Table 2. Patients’ Baseline Characteristics (n ⫽ 59) Female/male (%) Smokers/nonsmokers at first MRI (%) Median (IQR) age at diagnosis (y) Median (IQR) pfCD duration until first MRI (mo) Luminal disease location (%) Ileitis/colitis/ileocolitis Median (IQR) follow-up under IFX therapy (mo) Median (IQR) interval between first and last MRI (wk) Patients with complex fistulas at baseline (clinical exam) Concomitant IMS at first MRI Concomitant antibiotics at first MRI Patients with surgical interventions (pfCD related) before first MRI
37/22 (62.7/37.3) 24/29 (49/41) 23.1 (17.5–32.8) 107.5 (33.4–189.2)
16 (27)/19 (32)/23 (39) 9.8 (1.4–46.1) 36.0 (11.0–53.3) 50 (84.7%) 37 (62.7%) 12 (20.3%) 53 (89.8%)
IMS, immunosuppressants.
Baseline MRI detected fistula tracks in 91.5% of the patients, of which 94.5% were characterized as active (T2 hyperintensity of the fistula track). Rectovaginal fistulas were seen in 34.4% of the female patients. At least 1 collection ⬎3 mm was seen in 52.5% of the patients. Rectal wall thickening was present in 13 of 17 patients, with mucosal inflammation at baseline rectoscopy. No difference was found between baseline rectoscopy and MRI regarding rectal wall inflammatory involvement rate (2 test, P ⫽ NS).
Follow-up Study Parameter Findings By the end of follow-up, clinical benefit with IFX therapy was seen in 77% (41% in remission, 36% responded) of the patients, whereas in 23% clinical response was absent (Figure 1). Adjustment of the IFX dosing scheme until the end of follow-up was needed in 12 of 56 patients (21.4%). Twenty-seven of 59 patients (46%) had at least 1 seton placed before baseline MRI. In 21 of 27 patients (77.7%) these were removed permanently during follow-up (median [IQR] period until seton removal, 11.1 [9.4 –29.1] weeks). Removal was based on the findings of the examination under anesthesia. Repeated rectoscopy was conducted at variable time points in 13 of 40 (32.5%) of the patients who had a baseline examination, and rectal wall inflammation was present in 2 of 13 (15.4%). Both patients had inflammation at baseline rectoscopy also. Short-term follow-up MRI was available in 29 patients (median [IQR] period, 11.0 [10.0 –12.5] weeks; median [IQR] number of IFX infusions, 3.0 [3.0 – 6.2]). Fistula tracks were present in 26 of 29 patients (89.7%) and were also active (hyperintense and/or with fluid-filled cavities) in 23. Although all collections detected at baseline were drained, at least 1 collection ⬎3 mm was present in 12 of 29 (41.4%) and rectal wall involvement was present in 13 of 29 (44.8%). When compared with baseline MRI, short-term MRI showed a reduction in the number of fistula tracks in 4 of 29 patients (13.8%) and in the inflammatory activity in 16 of 29 (55.2%). Collections were found always in fistula tracks that had been originally identified but not always in the same track. Mid-term follow-up MRI was available in 25 patients (median [IQR] period, 44.0 [28.7– 46.3] weeks; median [IQR] number of IFX infusions, 6.0 [3.7– 8.2]). Fistula tracks were present
in 21 of 25 (84%), and in 20 of 21 these tracks were also active. At least 1 collection ⬎3 mm was detected in 9 of 25 (36%) and rectal wall involvement in 13 of 25 (52%). When compared with baseline MRI, mid-term MRI showed a reduction in the number of fistula tracks in 14 of 25 patients (56%) and in the inflammatory activity in 13 of 25 (52%). In 12 patients both short-term and mid-term MRIs were available. The latter showed a reduction in the number of fistula tracks in 8 of 12 (66.7%) and in the inflammatory activity in 6 of 12 (50%) compared with the former. Long-term follow-up MRI was available in 13 patients (median [IQR] period, 94.5 [75.3–139.3] weeks; median [IQR] number of IFX infusions, 11.0 [7.5–16.0]). Fistula tracks were present in 12 of 13 (92.3%), and in 9 of 12 these tracks were also active. At least 1 collection ⬎3 mm was detected in 3 of 13 (23%) and rectal wall involvement in 12 of 13 (92.3%). When compared with baseline MRI, long-term MRI showed a reduction in the number of fistula tracks in 2 of 13 patients (15.4%) and in the inflammatory activity in 4 of 13 (31%). In 8 patients both mid-term and long-term MRIs were available. No patient showed a reduction in the number of fistula tracks, and 3 of 8 showed a reduction in the inflammatory activity in the latter compared with the former. Rectovaginal fistulas were present in 42.3% of the female patients in the last follow-up MRI. Interestingly, both patients with proctitis at follow-up endoscopy showed no signs of rectal wall inflammation at last follow-up MRI, and patients with rectal wall involvement at last follow-up MRI revealed no inflammation at rectoscopy. Overall, with MRI as the tool for assessing pfCD improvement under IFX therapy, we observed persisting fistula tracks in 79.2% of the patients, with an improvement in the inflammation in 53.8% and an improvement in rectal wall thickness in 24.5%. Improvement of pfCD seen in MRI coincided with clinical improvement in 54.7% and with endoscopic improvement in 46.2% of the patients.
Magnetic Resonance Imaging Score Change and Correlation Between Findings MRI-based activity score was also evaluated short-term, mid-term, and long-term. A significant decrease in the score was observed short-term (median [IQR] score, 10.5 [5.5–15.0], P ⫽ .002) and mid-term (9.0 [5.2–13.2], P ⬍ .0001) but not long-
Figure 1. Clinical outcome of IFX therapy in our cohort of pfCD patients.
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Figure 2. MRI score change short-term, mid-term, and longterm in pfCD patients under IFX therapy.
term (11.5 [6.2–14.0], P ⫽ .1) compared with baseline score (17 [9 –20]) (Figure 2). Individual MRI score change in each patient throughout follow-up is shown in the total cohort (Figure 3A) and also in the different groups according to clinical response (Figure 3B–D). The patients who went into clinical remission under IFX therapy demonstrated a larger decrease in mid-term MRI score compared with those who still had draining fistulas at the same study period (median [IQR] mid-term MRI score, 6 [2– 8] vs 13 [9 –18], P ⬍ .0001 and median [IQR] MRI score decrease from baseline, ⫺13 [⫺17 to ⫺11] vs ⫺4 [⫺9 to 0], respectively, P ⫽ .004) (Supplementary Figure 1). No difference was observed between the 2 groups regarding short-term and long-term MRI score change. Changes in the MRI score at any time point were not different between the patients who demonstrated concordance among clinical or endoscopic and imaging assessment and those who did not and also between patients who were taking antibiotics and/or immunosuppressants at baseline and those who were not. The patients with a seton in place at baseline demonstrated a higher overall MRI-clinical pfCD assessment concordance (2 test: odds ratio, 8.4 [2.4 –29.8], P ⬍ .001). No correlation was found between the placement of a seton at baseline and detection of a collection in subsequent MRIs at any time point. The MRI images in Figure 4 demonstrate the evolution of a perianal horseshoe fistula in a young male patient with CD after 1 year of IFX therapy.
Use of Magnetic Resonance Imaging for Predicting Clinical Outcome and Need for Surgery By the end of follow-up, the patients who still had active pfCD at clinical evaluation demonstrated more frequently persisting fistula tracks (P ⫽ 0.01), especially multiple fistulas (P ⫽ .01), collections (P ⫽ .009), and rectal wall inflammatory involvement (P ⫽ .01) at last MRI compared with those who were under clinical remission. In the multivariate analysis,
none of these MRI score parameters turned out to be significant. Twenty patients (34%) needed at least 1 surgical intervention between initiation of IFX treatment and last follow-up MRI. The median [IQR] time for the first intervention was 12 [7–19] weeks. Surgery was more frequent in the patients who demonstrated single-branched fistulas (P ⬍ .0001) and collections (P ⫽ .006) at baseline MRI, although no correlation was found with the total baseline MRI score. In the multivariate analysis, none of these MRI score parameters turned out to be significant.
Discussion IFX was the first immunoglobulin G1 monoclonal antibody introduced in the clinic for the treatment of refractory CD including pfCD.4,5 The end point used in the pivotal randomized trial but also in subsequent studies evaluating treatment efficacy was cessation of drainage from cutaneous orifices. This condition was forced by the lack of a clinically oriented, reproducible, and prospectively validated activity index that could be used for monitoring therapy of pfCD.1 We showed in a previous study that although clinically more relevant, cessation of drainage from the external orifices after IFX therapy does not accurately reflect what is happening to the internal fistula tracks,9 and this observation was confirmed by other groups.10 –12 Pelvic MRI was used as the monitoring tool for coming to this conclusion because this imaging modality has demonstrated its sensitivity and specificity for detecting pelvic complications in pfCD and offers the advantage of a broader application and central reading compared with endoscopic ultrasound.7,12,15 In the present study consecutive pelvic MRIs were used for long-term evaluation of IFX therapy on pfCD. Median MRI follow-up time was 36 weeks, which is longer than the one described in other relevant studies.10,16 In a recently published
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Figure 3. Individual MRI score change in the total cohort (A) and according to complete (B), partial (C), and absent (D) clinical response.
cohort, follow-up with MRI was 52 weeks, but in our trial longer follow-up was available for a sizeable proportion of patients.11 There was a lower detection rate of rectovaginal fistulas at baseline MRI compared with the rate of external vaginal orifices seen on clinical examination. This is probably due to the lower spatial resolution of the body phased array coil used in this study compared with the much more sensitive endoluminal coil in detecting these specific fistulas.17 On the other hand, baseline MRI demonstrated a similar sensitivity with endoscopy in detecting rectal wall involvement. In a recent study by Tougeron et al,16 MRI underestimated rectal wall involvement (11.5% vs 50% for endoscopy, P ⫽ .02). This discrepancy is probably due to the different MRI devices used and is possibly due to different sequences implemented. The unusual correlation that we observed between last MRI and endoscopy could be explained from a possible nonhomogenous healing of the inflammatory components in the different tissue layers of the rectal wall. Of course, patient numbers are too small to draw any firm conclusion. Short-term MRI revealed improvement in the number and inflammatory component of the fistula tracks in 14% and 55% of the patients, respectively. Interestingly, clinically relevant collections were still detected shortly after drainage of all collections found at baseline examination, indicating the lack of a diagnostic modality with adequate sensitivity to detect all relevant collections.18 Mid-term MRI demonstrated an improvement in the number and inflammation of fistula tracks similar to the one described in clinical trials (55%– 60%). On the contrary, long-term MRI (beyond 1 year of IFX treatment) did not
detect more patients with an improvement in pfCD status compared with mid-term MRI. MRI-based activity score significantly decreased short-term and mid-term but not long-term. In the study by Tougeron et al,16 a decrease in the same MRI score was seen in 18.5 ⫾ 14 months. This observation, in combination with the lack of an acceptable concordance in the last follow-up examinations, indicates that MRI can be considered a reliable imaging modality during the first year of IFX therapy, but long-term monitoring beyond this period is not superior to clinical evaluation in assessing pfCD status. However, not all patients received a long-term MRI re-evaluation, and we cannot exclude a type II error as a result of the relatively moderate sample size. In our previous study, we reported that especially the inflammatory items of the MRI-based score improved after short-term treatment with IFX. However, in this cohort of long-term follow-up the inflammatory (hyperintensity, rectal wall thickening, collections) scores showed no more improvement than the anatomical criteria. In line, neither the complexity nor extension of the fistula tracks or the relation to the sphincter apparatus changed over time on MRI (data not shown). Last follow-up MRI detected persistent fistula tracks in 79.2% of our patients, with an improvement in the inflammation in only 50%, although 77% of the patients reported clinical benefit from IFX therapy. The same observation was apparent in the previous study from our group,9 indicating that not only short-term but also long-term complete resolution of the internal fistula tracks does not occur in response to IFX with signs of inflammation. Therefore, our results question the concept of
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Figure 4. MRI images of a perianal horseshoe fistula in a young male patient with CD before and 3 months and 1 year after IFX therapy. Note that the inflammatory component (T2 hyperintensity and collections) markedly improved, but that the fistula track is still present after 1 year.
complete fistula healing in patients with pfCD and justify the need for long-lasting therapy with IFX. Improvement in pfCD, as seen in last MRI, coincided with clinical improvement in only half of our patients, suggesting that external orifices tend to obliterate and stop draining shortly after IFX therapy initiation probably as a result of different healing rates between cutaneous and internal soft tissue structures of the fistula track. A similar concordance rate regarding improvement of pfCD was also observed between the MRI and the endoscopy, reflecting the inappropriateness of MRI in evaluating rectal mucosa inflammatory status. A recently published cohort from St Mark’s Hospital in London, UK of patients treated with IFX and adalimumab long-term also has shown that MRI improvement of internal fistula tracks takes longer than clinical improvement, but that once MRI healing is achieved, scheduled antiTNF re-treatment is able to maintain this healing.11 However, it is not clear from this cohort whether ongoing anti-TNF therapy is required for this maintained benefit on MRI. Several predicting factors have been proposed for determining clinical outcome of pfCD under IFX therapy,19 –22 but MRI has only been used for predicting surgical outcome in perianal fistulas not accompanying pfCD.23,24 Patients with persisting fistula tracks, more multiple fistulas, collections, and rectal wall involvement in last MRI were less frequently in clinical remis-
sion in univariate analysis, but this was not confirmed in multivariate analysis, suggesting that these predictors were interacting. Tougeron et al16 also found no difference between clinical responders and nonresponders in the total MRI score and in the subscore of fistula activity, but they did not comment on other parameters of the MRI score (type of fistulas, collections, etc). Surgical interventions were more frequent in patients with more complex fistulas and signs of perianal sepsis at baseline MRI again only in univariate analysis. In conclusion, MRI can be considered a reliable imaging modality for monitoring IFX therapy in patients with pfCD for the first year of treatment, but its long-term results are in agreement with clinical and endoscopic response to IFX in only half of the patients. Moreover, MRI seems effective only during the first year of surveillance. After this time period, clinical assessment is equally reliable or even superior to MRI in evaluating therapy outcome and would save health care resources given to cost of repeated MRI. Patients with more complicated disease, judged by baseline or last follow-up MRI score, demonstrated a worse prognosis compared with patients with less complicated disease, reinforcing the applicability of the MRIbased activity score used in this study. However, we believe that suggesting a risk stratification of patients on the basis of the results of our study is still premature. More prospectively de-
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signed and adequately powered studies in larger cohorts are needed to replicate and strengthen our results.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org and doi:10.1016/ j.cgh.2010.10.022. References 1. Sandborn WJ, Fazio VW, Feagan BG, et al. AGA technical review on perianal Crohn’s disease. Gastroenterology 2003;125:1508 – 1530. 2. Papadakis KA, Targan SR. Tumor necrosis factor: biology and therapeutic inhibitors. Gastroenterology 2000;119:1148 –1157. 3. Tozer PJ, Whelan K, Phillips RK, et al. Etiology of perianal Crohn’s disease: role of genetic, microbiological and immunological factors. Inflamm Bowel Dis 2009;15:1591–1598. 4. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulae in patients with Crohn’s disease. N Engl J Med 1999;340:1398 –1405. 5. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004; 350:876 – 885. 6. Schnitzler F, Fidder H, Ferrante M, et al. Long-term outcome of treatment with infliximab in 614 Crohn’s disease patients: results from a single center cohort. Gut 2009;58:501–508. 7. Haggett PJ, Moore NR, Shearman JD, et al. Pelvic and perineal complications of Crohn’s disease: assessment using magnetic resonance imaging. Gut 1995;36:407– 410. 8. Halligan S, Stoker J. Imaging of fistula in Ano. Radiology 2006; 239:18 –33. 9. Van Assche G, Vanbeckevoort D, Bielen D, et al. Magnetic resonance imaging of the effects of infliximab on perianal fistulizing Crohn’s disease. Am J Gastroenterol 2003;98:332–339. 10. Bell SJ, Halligan S, Windsor CJ, et al. Response of fistulating Crohn’s disease to infliximab treatment assessed by magnetic resonance imaging. Aliment Pharmacol Ther 2003;17:387– 393. 11. Ng SC, Plamondon S, Gupta A, et al. Prospective evaluation of anti-tumor necrosis factor therapy guided by magnetic resonance imaging for Crohn’s perineal fistulas. Am J Gastroenterol 2009; 104:2973–2986. 12. Van Bodegraven AA, Sloots CE, Felt-Bersma RJ, et al. Endosonographic evidence of persistence of Crohn’s disease-associated fistulas after infliximab treatment, irrespective of clinical response. Dis Colon Rectum 2002;45:39 – 45. 13. Silverberg MS, Satsangi J, Ahmad T, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a working party of the 2005 Montreal world congress of gastroenterology. Can J Gastroenterol 2005; 19(Suppl A):5A–36A. 14. Parks AG, Gordon PH, Hardcastle JD. A classification of fistula-inano. Br J Surg 1976;63:1–12.
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15. Schwartz DA, Wiersema MJ, Dudiak KM, et al. A comparison of endoscopic ultrasound, magnetic resonance imaging, and exam under anesthesia for evaluation of Crohn’s perianal fistulas. Gastroenterology 2001;121:1064 –1072. 16. Tougeron D, Savoye G, Savoye-Collet C, et al. Predicting factors of fistula healing and clinical remission after infliximab-based combined therapy for perianal fistulizing Crohn’s disease. Dig Dis Sci 2009;54:1746 –1752. 17. Stoker J, Rociu E, Schouten WR, et al. Anovaginal and rectovaginal fistulas: endoluminal sonography versus endoluminal MR imaging. AJR Am J Roentgenol 2002;178:737–741. 18. Lunnis PJ, Barker PG, Sultan AH, et al. Magnetic resonance imaging of fistula-in-ano. Dis Colon Rectum 1994;37:708 –718. 19. Parsi MA, Lashner BA, Achkar JP, et al. Type of fistula determines response to infliximab in patients with fistulous Crohn’s disease. Am J Gastroenterol 2004;99:445– 449. 20. Parsi MA, Achkar JP, Richardson S, et al. Predictors of response to infliximab in patients with Crohn’s disease. Gastroenterology 2002;123:707–713. 21. Arnott ID, McNeill G, Satsangi J. An analysis of factors influencing short-term and sustained response to infliximab treatment for Crohn’s disease. Aliment Pharmacol Ther 2003;17:1451–1457. 22. Vermeire S, Louis E, Carbonez A, et al. Demographic and clinical parameters influencing the short-term outcome of anti-tumor necrosis factor (infliximab) treatment in Crohn’s disease. Am J Gastroenterol 2002;97:2357–2363. 23. Chapple KS, Spencer JA, Windsor AC, et al. Prognostic value of magnetic resonance imaging in the management of fistula-in-ano. Dis Colon Rectum 2000;43:511–516. 24. Spencer JA, Chapple K, Wilson D, et al. Outcome after surgery for perianal fistula: predictive value of MR imaging. AJR Am J Roentgenol 1998;171:403– 406.
Reprint requests Address requests for reprints to: Gert Van Assche, MD, Department of Gastroenterology, University Hospital Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium. e-mail: [email protected]; fax: 32-16-34-44-19. Conflicts of interest The authors disclose the following: Dirk Vanbeckevoort has received speaker fees from Abbott. Severine Vermeire has received grants/ research support from UCB; consultancy for AstraZeneca, Ferring, and Pfizer; speakers bureau for Schering–Plough, Abbott, Ferring, and UCB; and advisory committee for Shire and Ferring. Paul Rutgeerts has received research grants, lecture fees, and consultant fees from Abbott, Centocor, Schering–Plough, and UCB. Gert Van Assche has received speaker fees/research support from Centocor, Schering– Plough, Abbott, and UCB. The remaining authors disclose no conflicts. Funding This study was supported with a grant from the Hellenic Society of Gastroenterology. Gert Van Assche and Séverine Vermeire hold a clinician-scientist position at the FWO Flanders.
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Supplementary Figure 1. Midterm MRI score change in patients in remission in comparison with those with draining fistulas.
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