In this systematic review, a total of 995 adult patients were included from 18 observational studies (4 prospective and 14 retrospective), 1 nonrandomized controlled trial, and 1 subgroup analysis of a randomized controlled trial.
Biologic dose de-escalation was associated with relapse rates as high as 50% at 1 year. Overall, clinical relapse occurred in 0%–54% of patients who dose de-escalated biologic therapy (17 studies).
Lower rates of relapse (10%–25%) were reported in studies involving patients with endoscopic and/or histologic remission
These results are in agreement with a previous meta-analysis, which found a 1-year risk of relapse after discontinuation of anti-TNF therapy of 36% in CD and 28% in UC ( Gisbert JP, et al.. Am J Gastroenterol 2016;111:632–47).
My take: This study shows that dose de-escalation of biologic therapy in IBD seems to be associated with high rates of clinical relapse
In this national multicenter retrospective cohort study in 207 adult patients with either active or inactive perianal Crohn’s disease (pCD) who received ustekinumab (2017-2018). The majority had received multiple biologics (~85% had at least 2 anti-TNF agents, 28% had received vedolizumab) and prior anal surgeries (mean 2.8).
Methods: Success of ustekinumab was defined by (i) clinical success at 6 months of treatment assessed by the physicians’ judgment, with (ii) no need for dedicated medical treatment for perianal lesions (antibiotics and/or topics) nor (iii) unscheduled surgical treatment. For perianal disease evaluation, clinical success was defined in the study protocol, by the absence of draining pus for fistulas, and no anal ulcers
In patients with active pCD, success was reached in 57/148 (38.5%) patients.
Among patients with setons at initiation, 29/88 (33%) had a successful removal.
In patients with inactive pCD at initiation, the probability of recurrence-free survival was 86.2% and 75.1% at weeks 26 and 52, respectively.
The absence of ustekinumab optimization was associated with upper odds of success (OR 2.74). “We can suppose in our present study that optimization of treatment was needed in severe refractory patients with no or insufficient response to ustekinumab. Thus, in these nonresponders, success was not achieved despite optimization.”
My take (partly borrowed from authors): “This large multicenter dedicated study adds substantial evidence to the growing literature on ustekinumab effectiveness in refractory CD.” For pCD, optimization of ustekinumab has a low likelihood of improving response.
Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.
A Dige et al. Gastroenterol 2019; 156: 2208-16. This study evaluated the efficacy of freshly collected autologous adipose tissue injection for healing of perianal fistulas in Crohn’s disease. The overall healing rate was 57% and the treatment had a good safety profile.
HK Somineni et al. Gastroenterol 2019; 156: 2254-65. The researchers found that DNA methylation patterns (from ~850,000 sites) in blood samples from pediatric patients with Crohn’s disease (n=164) were associated with inflammation and resolved with treatment of inflammation; thus, the changes in DNA methylation are less likely to be a causative agent in disease development or progression and more likely a biomarker of inflammation.
OB Kelly et al. Inflamm Bowel Dis 2019; 25: 1066-71. Among 316 patients who underwent A/P CT scan for any reason, 49 (16%) had evidence of sacroilitis, indicating this is underdiagnosed in patients with IBD.
BG Feagan et al.Inflamm Bowel Dis 2019; 25: 1028-35. In a post hoc analysis of GEMINI 1 trial (n=769 patients: 149 placebo, 620 vedolizumab), a randomized placebo-controlled trial of vedolizumab for ulcerative coliis, compared to placebo ~40% more patients receiving a full induction of vedolizumab had a sustained clinical remission after 52 weeks of therapy. Of patients in clinical remission at week 14, 66.5% achieved a sustained clinical remission at week 52 compared with 267% of placebo-treated patients based on partial Mayo score.. Sustained clinical remission was based on partial Mayo score and rectal bleeding subscore..
A recent consensus report (AH Steinhart, R Panaccione et al. Inflamm Bowel Dis 2019; 1-13) provides updated guidelines for the management of perianal fistulizing Crohn’s disease (CD).
As an aside, the article starts off with an extremely lengthy disclosure (of financial interests) –more than 30 lines of extremely small font!
The scope of the problem:
About 21% of CD patients have developed perianal fistulizing disease by 10 yrs and 26% after 20 years.
This complication leads to significant morbidity/reduced quality of life and about 70% require surgical treatment during long-term followup.
The substance of the article are summarized in Table 4 and Figure 1. The recommendations all are considered to be based on either low quality of evidence or very low quality of evidence:
In those with active fistulizing disease, the authors recommend imaging (EUS or MRI)
In those with evidence of complicated fistulizing disease, “we suggest surgical consultation.”
In those with active fistulizing CD, “we suggest the use of antibiotic therapy for initial management.”
In those with active fistulizing CD, “we recommend the use of anti-TNF therapy” for induction and maintenance.
In those with active fistulizing CD, “when starting anti-TNF therapy, we suggest it be combined with thiopurine or methotrexate over monotherapy to optimize pharmacokinetic parameters.”
In those with active fistulizing CD, surgical management is recommended in those when there is an inadequate response to medical management.
Some additional pointers:
Early surgical consultation is recommended in setting of suspected clinical abscess (eg. pain, fever, leukocytosis).
The authors’ algorithm suggests that if early surgical intervention is not required, then patients should first receive antibiotics for initial symptom control, followed by imaging, and, if uncomplicated fistulizing disease on imaging, followed by anti-TNF therapy (with either MTX or thiopurine). If complicated fistulizing disease, then surgical intervention may be needed prior to institution of anti-TNF therapy.
“The rate of fistula healing was 43% with medical therapy alone and 53% with combination surgical and medical therapy” based on a systematic review of 8 cohort studies.
My take: This article helps simplify/streamline the approach to this troubling complication.
Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.
A total of 174 children and adolescents were treated with adalimumab as their first anti-TNF therapy…The mean age at the time of Crohn’s disease diagnosis was 13 years and, on average, they started adalimumab at 14.5 years of age…
At 3 months after adalimumab was started, all 174 were still on the medication, and 69-71% were in steroid-free remission
At 6 months after adalimumab was started, of the 174 who had a clinic visit, 95% were still on the medication, and 75-77% were in steroid-free remission
At 12 months after adalimumab was started, of the 154 who had a clinic visit, 94% were still on the medication, and 79-80% were in steroid-free remission
At 24 months after adalimumab was started, of the 71 who had a clinic visit, 97% were still on the medication, and 91-94% were in steroid-free remission
At 36 months after adalimumab was started, of the 39 who had a clinic visit, 80-86% were still on the medication, and 81-86% were in steroid-free remission
No positive or negative effect on remission was seen with concomitant immunomodulator therapy. However, the number of patients studied during the retrospective analysis is too small to detect all but the greatest impact of this approach.
EC Maxwell et al. JPGN 2017; 65: 299-305 CHOP experience with diverting ileostomy for severe IBD (2000-2014).
In this retrospective study, a diverting ileostomy in 24 patients had improvement: 71% –>22% on chronic steroids, improved growth, hemoglobin, blood transfusion and hospitalization.
10 patients underwent subsequent colectomy, 7 had successful reanastomosis, and 7 remain diverted.
Diversion allowed a definitive diagnosis in 7 subjects (initially 13 patients were considered IBD-U).
Surgical complications were common (n=13 in 7 subjects) and included stoma obstruction, stoma prolapse, and resection of ischemic bowel.
One notable feature regarding this cohort was that 50% were 5 or younger when diagnosed with IBD.
The authors conclude that a diverting ileostomy can induce clinical stability and allow time to clarify diagnosis.
A Assa et al. JPGN 2017; 65: 293-98. In this study involving findings from 234 patients extracted from the ImageKids database (prospective multicenter cohort), the authors found that pediatric patients with perianal Crohn’s disease have a greater inflammatory burden; however, this was driven mainly by those who had fistulizing disease.
L Lian et al. Clin Gastroenterol Hepatol 2017; 15: 1226-31. This retrospective study from the Cleveland Clinic compared outcomes of endoscopic balloon dilation (EBD) (n=176) or surgery (n=131) for Crohn’s disease-related strictures (1998-2013). Patients who had EBD had an “average time to surgery delayed by 6.45 years.” Immediate success rate for EBD was 91.3%; the perforation rate was 1.1%.. Ultimately, 52% of patients who had EBD required surgery. Earlier surgery lowered the risk of further surgery but also was associated with significant perioperative complications. In the operative group, 8.8% of patients experienced complications, mainly intra-abdominal abscesses and enterocutaneous fistula. Thus, in the right hands and with careful selection, EBD may be useful.
I Lawrance et al. Clin Gastroenterol Hepatol 2017; 15: 1248-55. This study reported the results of 11 patients who received rectal tacrolimus for resistant ulcerative proctitis. Dosing: The concentration of tacrolimus was 0.5 mg/mL and 3 mL was administered twice a day.Clinical response, using the Mayo Clinic score, was achieved in 73% of tacrolimus subjects compared with 10% (n=1) of placebo-treated subjects. Mucosal healing at week 8 was noted in 73% of tacrolimus-treated patients, as well.
A recent study (S Singh et al. Alimentary Pharmacology & Therapeutics; 2015: 42: 783-92; article first published online: 11 AUG 2015. DOI: 10.1111/apt.13356) gives more specific data regarded the outcomes of fecal diversion for perianal Crohn’s disease. While diversion can be helpful, the meta-analysis indicates that only one-sixth of patients were able to achieve successful bowel continuity/reconnection. The authors did not note a significant improvement in successful bowel continuity restoration in the era of biologics compared with prebiologic era (17.6% vs13.7%).
I am fortunate to work closely with several well-qualified pediatric surgeons and colorectal surgeons. When faced with perianal fistulas, I have discussions with them to help optimize therapy. Understanding exactly what and why the surgeons do what they do has not always been clear to me. Four recent articles provide guidelines for the management of Crohn’s perianal disease. The color figures in the articles make understanding what is done pretty obvious.
Schwartz DA et al. Inflamm Bowel Dis 2015; 21: 723-30. Overview.
Ong EMW et al. Inflamm Bowel Dis 2015; 21: 731-36. Focus on imaging.
Schwartz DA et al. Inflamm Bowel Dis 2015; 21: 737-52. Critical evaluation of Medications
Fichera A, Zoccali M. Inflamm Bowel Dis 2015; 21: 753-58. Critical evaluation of Surgical Approaches
The first guideline provides a summary statement combining aspects of both medical and surgical management. Basic anatomy and classification are reviewed (a color figure similar to reproduction below helps describe the types of fistula).
Simple vs Complex fistula is reviewed. A “Simple fistula is a superficial, intersphincteric or low transspincteric fistula that has only 1 opening and is not associated with an abscess and/or does not connect to an adjacent structure such as the vagina or bladder.” All others are complex fistulas. The MRI classifcation is also reviewed (Figure 5).
For fistulizing disease, top-down cotherapy (anti-TNF/immunomodulator) therapy is recommended. Antibiotics are recommended in the short term.
Placement of a draining seton (for complex fistulas) helps to maintain fistula drainage until the track becomes inactive on medical treatment.
A treatment algorithm (Figure 7) notes that endoscopy, imaging (EUS or MRI) and exam under anesthesia are key first steps. Decision tree then divides based on whether there is rectal inflammation, and whether fistula is simple or complex.
Surgical options include fistulotomy, fibrin glue, fistula plug, seton placement, advancement flaps and proctectomy.
Bottomline: These set of articles should serve as a useful reference when managing perianal disease.
A recent report provides a useful reference for the often difficult care of pediatric perianal Crohn disease (JPGN 2013; 57: 401-412).
The statement reviews the background, etiology, presentation and classification systems. Most helpful are Figures 2 & 3.
Figure 2 provides an algorithm for assessment and treatment of perianal fistula.
History/Physical (including rectal exam for stricture) along with colonoscopy
Next either exam under anesthesia (with or without endoscopic ultrasound) or MRI
consider antibiotics, anti-TNF, and immunomodulators
in some cases a noncutting seton or fistulotomy will be needed
consider advancement flap in rectovaginal fistulae
Figure 3 provides an algorithm for assessment and treatment of perianal abscess.
History/Physical (including rectal exam for stricture) along with colonoscopy
Next either exam under anesthesia (with or without endoscopic ultrasound) or MRI
Incision and drainage
Noncutting seton if perianal fistula
Treatment of intestinal disease
After outlining these algorithms, the report details the treatments. Almost all treatments that are effective or questionable for Crohn’s disease are discussed. The report reiterates that ‘corticosteroids must be used with caution in treatment of perianal fistula; studies have shown worse fistula outcomes for steroid-treated patients.
With regard to noncutting setons, the authors note that they do not prevent treatment with biologic agents and help prevent abscess formation. They “usually deteriorate and fall out on their own in about 1 year.” Medical therapy often allows for seton removal.
Ostomy diversion can be helpful in patients with severe perianal disease; however, “the risk of the ostomy becoming permanent is significant.”
Rectal strictures are typically dilated with multiple sessions with general anesthesia. The goal is at least 18 mm in younger patients and at least 24 mm in adolescents.
-Clin Gastro & Hep 2010; 8: 13. Another algorithm. For simple fistula, Rx w abx & medical (thiopurine or Remicade). If not better, fistulotomy, &/or Rx as complex fistula. For complex fistula, seton placement, abx, anti-TNF. If not better, consider tacrolimus or proctectomy.
-JPGN 2010; 50: 99. Perianal dz in young children may be due to autoimmune neutropenia.
-Clin Gastro & Hep 2009; 7: 1037. MRI study of choice for perianal fistulas. Algorithm: If superficial fistula, Rx c fistulotomy & Abx If deeper, noncutting seton c Abx, 6-MP +/- infliximab; if not effective, try tacrolimus; if not effective, surgery
-Ann Intern Med 2001; 135: 906-918.
-IBD 2008; 14: 1236. Anal skin tag description
-JPGN 2005; 41: 667. Discusses several cases of highly destructive perianal dz. -Gastro 2003; 125: 1503-1507, 1508-1530. Technical review.
-Gastro 2003; 125: 291. Bourne test to detect occult bladder fistula. Following nondiagnostic barium enema, urine can be collected, centrifuged, and xrayed to determine if there is a connection.