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Cross-sectional evaluation of transmural healing in patients with Crohn’s disease on maintenance treatment with anti-TNF alpha agents
Digestive and Liver Disease, May 2017, Volume 49, Issue 5, Pages 484-489
Transmural healing (TH) of Crohn’s disease (CD) is a still unexplored and interesting outcome correlated to concept of deep remission.
To assess the rate of TH in CD patients treated with anti-TNF alpha agents using two cross-sectional procedures: bowel sonography (BS) and magnetic resonance enterography (MRE).
We performed a 2-year observational longitudinal study, evaluating steroid-free clinical remission (CR), mucosal healing (MH), and TH in CD patients who would complete a 2-year treatment period with anti-TNFs. All patients underwent endoscopy, BS, and MRE before and after 2 years of treatment.
Forty out of 80 CD patients were treated with anti-TNFs for 2 years. CR was achieved in 24 patients (60%) while MH in 14 (35%). Using BS, TH was observed in 10 patients (25%), while using MRE, TH was observed in 9 patients (23%) (k = 0.90; P < 0.01). A good agreement was observed between MH and TH, both using BS (k = 0.63; P < 0.01) and MRE (k = 0.64; P < 0.01). A poor agreement was found between CR and TH, with both BS and MRE (k = 0.27 and 0.29, respectively; P < 0.01); even though all patients with TH had achieved CR.
TH can be achieved in about 25% of CD patients treated with anti-TNFs, as shown by BS and MRE. BS could be used as the first cross-sectional procedure to detect TH.
Keywords: Crohn’s disease, Magnetic resonance, Transmural healing, Ultrasonography.
Crohn’s disease (CD) is a disabling chronic inflammatory disease of the bowel that can affect any portion of the gastrointestinal tract and is usually characterized by transmural inflammatory lesions interspersed with zones of regular mucosa  . The persistent transmural inflammation often determines structural bowel damage and intestinal complications such as strictures, fistulae, and abscesses, which frequently require the patient to undergo resective surgery  .
Currently, in presence of steroid-dependency, perianal fistulising complications and prognostic factors of disabling disease ( e.g. extensive small bowel disease, rectal involvement, extra-intestinal manifestations), CD is treated with immunosuppressors ( e.g. thiopurines) and anti-TNF alpha agents ( e.g. infliximab, adalimumab)  . As several studies demonstrate, treatment with immunosuppressors and anti-TNF alpha agents induces, in most patients, a remission of the clinical features mentioned above 4 5 6 . Recent research has shown that mucosal healing (MH) can be achieved mainly through the administration of anti-TNF alpha agents. Currently, MH is a critical endpoint in CD as it represents a predictor of lower demand for steroids, hospitalization, and surgery in the years following the treatment 6 7 8 9 10 . For this reason, MH has been used as an outcome measurement in numerous clinical trials [7 11] and has shown to predict maintenance of clinical remission (CR).
However, CD is characterised by transmural inflammation and it is still not clear whether MH corresponds to the complete healing of this inflammation, the occurrence of what we have called Transmural Healing (TH). TH in CD patients treated with anti-TNF alpha (and/or other drugs) has, to our knowledge, been explored in a limited number of patients [10 11] . Starting from these assumptions, the aim of this study was to assess the rate of TH in patients with CD on maintenance treatment with biologics. BS and MRE, two non-invasive cross-sectional procedures, were used for the evaluation.
2 Materials and methods
Between January 2013 and June 2015, we performed an observational longitudinal prospective study evaluating steroid-free CR, MH, and TH in patients with CD that attended our IBD Unit and completed at least 2 years of maintenance treatment with anti-TNF α agents during the course of our study.
Diagnosis of CD was made according to the current European Crohn’s and Colitis Organisation (ECCO) guidelines [1 4] ; moreover, the indications for using biologics in CD patients (infliximab and adalimumab) followed ECCO and Italian guidelines [4 12] .
All patients involved in the study underwent endoscopy, BS and MRE before and two years after starting the therapy; the 3 procedures were performed within 2 weeks. A serological evaluation of inflammatory parameters (erythrocyte sedimentation rate, C-reactive protein [CRP]) was performed on all patients every 6 months, and/or in case of clinical recurrence. Furthermore, the Crohn’s Disease Activity Index (CDAI) score was calculated before the beginning of the treatment and after two years. Concomitant medications were allowed when indicated (see Table 1 ).
|Mean age||32 (17–64)||–|
|CD duration (months)||36 (4–66)||–|
|Crohn’s Disease Activity Index||324 (172–430)||–|
|Therapy with azathioprine (%)||2 (13)||–|
|Course of steroids (%)||12 (30)|
|5-ASA (%)||11 (27)|
|Increased CRP (%)||35 (88)||–|
|Small bowel CD extension, mean + SD (cm)||45 ± 15|
|Perianal disease (%)||12 (30)||–|
|Extra-intestinal manifestations (%)||14 (35)||–|
|SES-CD, mean ± SD||12.1 ± 10.2 a||8.6 ± 2.3 b||<0.01|
|BWT at BS scan ± SD||6.1 ± 2.9 a||3.9 ± 0.7 b||<0.01|
|BWT at MRE scan ± SD||6.4 ± 2.8 a||3.7 ± 0.8 b||<0.01|
a Before starting anti-TNF.
b After starting anti-TNF.
2.1 Steroid-free clinical remission
2.2 Ileocolonoscopy and mucosal healing
Ileocolonoscopy was performed by an operator, who was blinded respect to the outcome of the other diagnostic procedures, using a conventional colonoscope (Olympus Exera CV-190) after a standard bowel cleansing with a 4-L solution of polyethilenglicole (PEG). Endoscopic diagnosis of CD was made in accordance with current ECCO guidelines  . Endoscopic activity of CD and occurrence of MH after 2 years of treatment were assessed using the Simple Endoscopic Score for Crohn’s Disease (SES-CD) [13 14] . MH was defined in absence of ulcerations in bowel segments (SES-CD < 2)  .
2.3 Bowel sonography and transmural healing
BS was performed after overnight fasting using a Logiq S7 ultrasound system with linear and convex probes (5–9 MHz). No special preparation and/or contrast and/or paralytic agents were administered. The ultrasound procedure was performed by two gastroenterologists experienced with BS (AR, AT) who were blinded respect to the outcome of the other diagnostic procedures. Each patient underwent a systematic scanning of the abdomen.
In accordance with Maconi et al.  , the presence of strictures was indicated in BS by a coexistence of the following features: thickened (>4 mm) intestinal wall that stiffened when a moderate pressure was applied, narrowed intestinal lumen, and fluid-distended or echogenic content-filled loops just above the thickened intestinal tract. Entero-cutaneous, entero-enteric, and entero-mesenteric fistulas were present when hypo echoic duct-like structures, with fluid or air content, were observed between skin and intestinal loops, between 2 intestinal loops, or between the intestinal loop and the mesentery, respectively  . The presence of abscesses was evaluated in accordance with general recommendations of current literature [16 17] .
Bowel wall thickness (BWT) was considered normal in presence of values ≤3 mm  . Positive BS was defined as the occurrence of concentric and regular increased BWT >3 mm  . The BS definition of complicated disease was defined in accordance with literature. After diagnosing CD, the gastroenterologist described the exact location and extension of the disease.
2.4 Magnetic resonance enterography and transmural healing
MRE was performed by an expert radiologist (PPM) who was blinded respect to the outcome of the other diagnostic procedures.
In order to obtain a distension of the small bowel, patients fasted for 6 h before the MRE examination, and consumed 1500 mL of PEG solution (34.8 g/500 mL) 60 min before the procedure. An intravenous administration of 20 mg of N -butylscopolamine (Buscopan; Boehringer, Ingelheim, Germany) helped to reduce small bowel motility. MRE images acquisition and protocol were obtained by using a 3T MR unit (Siemens, Erlangen, Germany) in accordance with current literature. Axial and coronal single-shot turbo spin echo with and without fat suppression (RARE, half-Fourier rapid acquisition with relaxation enhancement), balanced gradient echo (True FISP, true fast imaging with steady-state precession), and coronal T1-weighted fat-suppressed 3-dimensional spoiled gradient-recalled echo sequence (VIBE, volume interpolated breath-hold examination) images were acquired. VIBE images were obtained 30 and 70 s before and after the injection of a dose (0.2 mmol/kg) of gadopentetate dimeglumine (Magnevist; Berlex Laboratories, Wayne, NJ) at 3 mL/s in a vein of the arm, followed by a saline chaser (20 mL). A single late acquisition in the axial plane was achieved 3 min after the contrast agent injection with the same T1-3D VIBE sequence 21 22 23 .
Bowel wall was considered thickened if it measured >3 mm. A thickened bowel wall (BWT >3 mm), paired with-hypervascularization, was considered the main diagnostic parameter in CD diagnosis. Pathologic bowel wall enhancement was defined with a bowel wall’s intensity greater than that of a normal bowel wall after an intravenous gadolinium administration  . Also in this case, a decrease in BWT to values ≤3 mm without signs of hypervascularization was diagnostic of TH using MRE.
2.5 Statistical analysis
Data was analysed using the Statistical Package for Social Sciences (SPSS software v.15.0, Chicago IL, United States) for Windows. The descriptive statistics included the calculation of mean values and standard deviation (SD) of the continuous variables, and the calculation of the percentages and proportions of the categorical variables.
Statistical analysis was performed using chi-square and Mann–Whitney U test, when appropriate. To test the concordance between BS and MRE about TH and the agreement between CR/MH, CR/TH and MH/TH, Cohen’s k measure was applied after these variables had been dichotomized (CR: yes/no; MH: yes/no; TH: yes/no). For what concerns the correlation between BS/MRE, in absence of a surgical/pathological gold standard, MRE was assumed to be the reference standard for TH definition. Furthermore, we performed a univariate analysis including all the baseline features ( Table 1 ) in order to detect factors associated to TH. The continue variables were dichotomized: age (<40), CD duration (<2 years); CDAI (<150), location (L1 vs L2/L3), Behaviour (B1 vs B2/B3), CD extension (<30 cm), SES-CD (<6).
A p value <0.05 was considered significant.
Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of BS and MR enterography in assessing TH were calculated using the Stats Direct statistical software.
During the period under assessment, a total of 80 patients diagnosed with CD started therapy with anti-TNF alpha agents. Nevertheless, only forty patients (50%) continued the therapy for at least 2 years. In fact, 30 patients had to interrupt the treatment with biologics, 15 of them because of adverse events (7 cases of severe infections; 5 cases of allergy; 3 cases of skin disorders), 7 of them because of primary unresponsiveness to the drug, and 8 of them because of intestinal complications, which required surgery. The remaining 10 subjects were excluded from the study because of personal contraindications to MRE ( e.g. patients with metal implants or suffering from claustrophobia). The mean duration of anti-TNF therapy for the entire cohort (80 patients) was 1.4 ± 0.6 years. Among 7 patients with primary non-response to the drug, no patient achieved TH after 2 years and the mean BWT in these subjects was 5.9 ± 3.1. On the other hand, among 8 subjects who underwent surgery for intestinal complications (fistulas and abscesses), BWT was 6.9 ± 2.8 mm.
For what concerns the type of drug used, 15 patients out of 40 (38%) were treated with infliximab while 25 (62%) were treated with adalimumab. As for the schedule protocol of anti-TNF alpha used, 3 of the 15 patients (18%) on infliximab treatment needed reduction in the infusion interval (from every 8 weeks to every 6 weeks), whereas 6 of the 25 patients (20%) on adalimumab had to increase the dosage (from 40 mg every 2 weeks to 40 mg weekly). Only 2 patients treated with infliximab (13%) received combination therapy with thiopurines (combo therapy).
All 40 patients underwent BS, ileocolonoscopy and MRE; in all cases, endoscopy allowed for a complete exploration of the colon and the terminal (or neoterminal) ileum. Baseline features of CD patients are reported in Table 1 .
3.1 Clinical remission
After two years of biologic therapy, 24 of the 40 patients treated (60%) achieved steroid free CR; 10 subjects (42%) were treated with infliximab and 14 (58%) with adalimumab. Twelve patients treated with biologics (30%) needed a course of steroids during the period of observation. Poor agreement was observed between CR and CRP levels, after 2 years of treatment (k = 0.56; P = 0.02). No patient with a clinically active disease achieved MH and TH ( Table 2 ).
|TH at BS vs TH at MRE||0.84||<0.01|
|TH at BS vs MH||0.63||<0.001|
|TH at BS vs CR||0.27||<0.01|
|TH at BS vs CRP||0.79||0.02|
|TH at MRE vs MH||0.64||<0.01|
|TH at MRE vs CR||0.29||<0.01|
|TH at MRE vs CRP||0.77||0.02|
BS: bowel sonography.
MRE: magnetic resonance enterography.
MH: mucosal healing.
CR: clinical remission.
CRP: C reactive protein.
3.2 Mucosal healing
Fourteen out of 40 patients (35%) treated with anti-TNF alpha agents achieved MH; 7 subjects (50%) were treated with infliximab and 7 (50%) with adalimumab. The mean SES-CD in the study population was 12.1 ± 8.2 before biologics therapy, and 8.6 ± 6.3 after anti-TNF alpha treatment (P < 0.01); CD patients with a lower basal SES-CD and patients with a shorter disease duration (<2 years) showed the best response to anti-TNF alpha agents in terms of MH. Poor agreement was found between CR and MH (k = 0.34; P < 0.01), whereas there was fair concordance between MH and CRP levels (k = 0.67; P = 0.04). In accordance with CD behavior, only 1 of 6 patients with strictures (16%) and no patient with penetrating CD achieved MH.
3.3 Evaluation of transmural healing using bowel sonography
After 2 years of treatment, TH was observed in 10 patients (25%) on biologics. The type of anti-TNF used did not determine a significant difference in TH outcomes (P = NS). The mean BWT on BS decreased significantly after treatment with biologics (mean BWT before starting the treatment: 6.1 ± 2.9 versus 3.9 ± 0.7 after 2 years of therapy; P < 0.01). Fig. 1 A and B shows the ultrasound findings before and after treatment, respectively. Furthermore, the main CD extension decreased significantly (mean small bowel CD extension before treatment 35 ± 18 cm versus 20 ± 11 after therapy; P < 0.01). As for MH, the factors that seemed to be related to TH were the SES-CD scores preceding treatment and the mean duration of CD. In fact, a lower basal SES-CD and a short period of disease (<2 years) were associated with the best response to anti-TNF alpha agents in terms of TH.
The results of our study showed good agreement between the BS evaluation of TH and MH (k = 0.63; P < 0.01). In particular, all but 4 cases of TH were associated with MH. Poor agreement was found between TH and CR (k = 0.27; P < 0.01), even if all patients reaching TH were in CR. Good concordance was found between TH and CRP levels (k = 0.79; P = 0.02). When considering CD behavior, only 1 in 6 patients with strictures (16%) and no patient with penetrating CD achieved TH ( Table 2 ).
3.4 Evaluation of transmural healing using magnetic resonance enterography
After 2 years of treatment, TH was observed in 9 patients (23%) on biologics. There was no significant difference in TH outcomes in relation to the type of anti-TNF alpha used (P = NS). Also in this case, the mean BWT on MRE decreased significantly after treatment with biologics (BWT before treatment 6.4 ± 2.8 versus 3.7 ± 0.8 mm after 2 years of therapy; P < 0.01). Fig. 2 A–D shows MRE findings before and after 2 years of treatment, respectively. Furthermore, the main CD extension decreased significantly (mean small bowel CD extension before treatment 45 ± 15 cm versus 18 ± 12 after therapy; P < 0.01). In addition, the post-contrast enhancement at MRE decreased significantly in 19 patients (47%). As for MH, the factors that seemed to be related to TH were lower basal SES-CD scores and shorter duration of CD (<2 years). Moreover, good agreement was found between TH evaluated by MRE and MH (k = 0.64; P < 0.001). Poor agreement was found between TH and CR (k = 0.29; P < 0.01); however, as for BS, all patients achieving TH were in CR. Good concordance was found between TH and CRP levels (k = 0.77; P = 0.02) ( Table 2 ).
3.5 BS vs MRE
A comparison of the diagnostic accuracy of the two imaging techniques used to assess transmural healing, showed a high agreement between the procedures (k = 0.90; P < 0.01). In fact, using BS, TH was observed in 10 patients (25%) while, using MRE, TH was observed in 9 patients (23%) on biologics. Only one false positive ultrasound case of TH was observed. In particular, this patient with a terminal ileitis showed a BWT of 3 mm on BS in comparison with a 5 mm BWT evidenced at MRE. The final diagnosis was made by ileoscopy which showed a mild aphthous ileitis. Fig. 3 summarizes all results, while Table 3 shows the features of patients who achieved TH vs subjects without TH.
|Mean age||31 (16–65)||32 (17–63)||NS|
|CD duration (months)||19 (4–24)||26 (6–36)||<0.01|
|Crohn’s Disease Activity Index||118 (65–140)||289 (165–415)||<0.01|
|Clinical remission, n (%)||10 (100)||14 (46)||<0.01|
|Normal CRP levels, n (%)||8 (80)||10 (33)||<0.01|
|Mucosal healing, n (%)||10 (100)||4 (13)||<0.01|
|BWT at BS scan ± SD||2.5 ± 0.4||6. 4 ± 0.6||<0.01|
|BWT at MRE scan ± SD||2.6 ± 0.3||6.5 ± 0.7||<0.01|
MRE: magnetic resonance enterography.
CRP: C reactive protein.
TH: transmural healing.
BWT: bowel wall thickness.
According to current guidelines, the main outcomes in the management of Crohn’s disease are steroid-free CR and MH  . In this paper, our team evaluated a still unexplored but interesting therapeutic endpoint: transmural healing.
TH, that is the normalization of the BWT evaluated by cross-sectional techniques and, therefore, the possible expression of the healing of all inflamed bowel segments of CD, can be obtained in about 25% of patients treated with anti-TNF alpha.
In absence of a gold standard procedure to assess TH, we chose two noninvasive and accurate procedures: bowel ultrasound and magnetic resonance enterography. Several reviews and meta-analyses support our decision to use such procedures 18 19 20 .
Our team, in a study conducted in 2013  , compared the efficiency of BS in CD diagnosis to that of MRE. We concluded that BS is as accurate as MRE in diagnosing small bowel CD, more available, and less costly.
First, using BS, we observed that 25% of our study population treated with anti-TNF alpha achieved TH. This observation confirmed our previous results  and supported the findings of Paredes et al.  , that reveal sonographic normalization in 5 of the 24 patients with CD (20%) treated with anti-TNF alpha. Then, using MRE, we observed TH in 9 patients on biologics (23%). The similar results obtained show that there is a high agreement between the 2 procedures (k = 0.90; P < 0.01). To the best of our knowledge, this is the first study directly comparing the efficiency of two accurate cross-sectional procedures in assessing TH.
Few studies have explored the role of MRE in assessing the effects of therapy on transmural lesions in CD patients. In a recent study, Van Assche et al.  reported an improved MRE index in 44% of patients at week 2 and in 80% at week 26. The authors also reported that complete absence of inflammatory lesions was observed in 0/18 patients at week 2 and in 13% (2/15) at week 26. The Authors concluded that improvements of MRE index are likely to occur from the third week of treatment with infliximab onwards. The healing rate reported by Van Assche was lower than that found in our research, probably because of the prolonged period of treatment (2 years) of our study.
In our study, the factors that seemed to be related to TH both in BS and MRE were the pretreatment SES-CD scores and the mean duration of CD. Our findings are compliant with the results of trials with biologic agents used in an early stage of the disease [6 7] and suggest that “early” CD patients respond better to anti-TNF alpha agents, also in terms of TH.
Moreover, in our study, we found a good agreement between MH and TH evaluated by BS (k = 0.63; P < 0.001), strengthening our previous results  ; at the same time, a good agreement was found between TH and MH evaluated by MRE (k = 0.64; P < 0.001), and, in all but 4 cases, TH was associated with the underlying MH. On the basis of these conclusions, the presence of TH on both BS and MRE could be considered a strong predictor for MH and could potentially lower the need for follow-up endoscopies.
Additionally, our results underline the poor correlation between endoscopic, sonographic, radiological (MRE), biochemical findings and CR in patients with CD. It is well known that CDAI does not significantly correlate with endoscopic findings  . In fact, we found poor agreement between CR and CRP levels after 2 years of treatment (k = 0.56; P = 0.02); poor agreement was also observed between CR and TH, both using BS and MRE (k = 0.27 and 0.29, respectively; P < 0.01). By contrast, we found a good concordance between TH and CRP levels, both using BS and MRE (k = 0.79 and 0.77, respectively; P = 0.02).
Our work presents some limitations. Both procedures, BS and MRE, did not evaluate stratification of the bowel wall, vascular signals, Power Doppler and CEUS behavior  . However, in our experience, studying stratification and vascularization is very difficult when BWT is <3 mm (the accepted normal value of BWT). Furthermore, when reporting outcomes in terms of TH, we considered only BWT rather than stricturing and/or penetrating complications, because the increased thickness of the bowel wall is a “ conditio sine qua non ” for the occurrence of such complications in CD. In effect, all patients with strictures or intestinal fistulas showed an increased and pathological BWT and, as a consequence, they were automatically excluded from the definition of TH.
Recently, as above mentioned, Rimola et al.  reported a MRE score ( i.e. MaRIA index) highly correlating with endoscopic findings in CD. However, since the purpose of such a scoring system was not to determine TH, the Authors did not properly define TH. After considering these limitations, we decided not to use MaRIA index for MRE definition of TH.
In conclusion, this study confirmed our previous results about TH and demonstrated, directly comparing two noninvasive and safe imaging methods, that TH can be reached in CD patients treated with anti-TNF alpha agents. After validation in larger series, ultrasound could be a preferred modality for the follow-up of patients with CD once TH will be accepted as a treatment target.
Conflict of interest
The Authors thank Dr. Manuela Pignata for the revision of English language and her precious technical support.
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