Safety of Preoperative Tumor Necrosis Factor  Inhibitor Exposure in Patients With Inflammatory Bowel Disease Undergoing Intra-abdominal Surgery

BL Cohen et al. Gastroenterol; 2022; 163: 204-221. Prospective Cohort Study to Investigate the Safety of Preoperative Tumor Necrosis Factor Inhibitor Exposure in Patients With Inflammatory Bowel Disease Undergoing Intra-abdominal Surgery

Key finding:

  • Preoperative TNFi exposure was not associated with postoperative infectious complications in a large prospective multicenter cohort. Any infection (18.1% vs 20.2%, P = .469) and SSI (12.0% vs 12.6%, P = .889) rates were similar in patients currently exposed to TNFis and those unexposed.

IBD Updates: Microbiome afer surgery, Anti-TNF agents NOT changing hospitalizations/surgeries, Biobanking Genetics

X Fang et al. Inflamm Bowel Dis 2021; 27: 603-616. Full Text: Gastrointestinal Surgery for Inflammatory Bowel Disease Persistently Lowers Microbiome and Metabolome Diversity

  • Methods: The UC San Diego IBD Biobank was used to prospectively collect 332 stool samples (every 6 months) from 129 subjects (50 ulcerative colitis; 79 Crohn’s disease). Of these, 21 with Crohn’s disease had ileocolonic resections, and 17 had colectomies.
  • Key finding: Intestinal surgeries in IBD patients seem to reduce the diversity of the gut microbiome and metabolome in IBD patients. Colectomy has a larger effect than ileocolonic resection.
  • Limitations: Confounding variables (eg. antibiotics) and selection bias (patients with more severe disease

C Verdon et al. Inflamm Bowel Dis 2021; 27: 655-661. No Change in Surgical and Hospitalization Trends Despite Higher Exposure to Anti-Tumor Necrosis Factor in Inflammatory Bowel Disease in the Québec Provincial Database From 1996 to 2015

Key findings:

  • 34,644 newly diagnosed patients with IBD (CD = 59.5%)
  • The probability of first and second hospitalizations remained unchanged in Québec and the probability of major surgery was low overall but did increase despite the higher and earlier use of anti-TNFs. However, the authors note that “in the present study, biologics use under the public reimbursement plan was 13% in patients with UC and 16% in patients with CD.”
  • My take: This study is provocative but probably misleading; it is quite likely that use of anti-TNF agents do lower the risk of hospitalization and surgery.

K Gettler et al. Gastroenterol 2021; 160: 1546-1557. Full text PDF: Common and Rare Variant Prediction and Penetrance of IBD in a Large, Multi-ethnic, Health System-based Biobank Cohort

  • Methods: The authors used the Mount Sinai BioMe Biobank, which contains genetic data on
    32,595 patients. After rigorous phenotype validation, 19,541 individuals were retained, of whom 339 were IBD patients (273 CD, 28 UC, and 37 individuals who were classified as both) and 19,202 were controls
  • Key findings: In this study, the authors identified several rare VEO-IBD variants with high genetic penetrance using the biobank samples and then replicated results in large case control African American and European data sets.
  • One of the variants with the highest genetic penetrance located in the gene LRBA was predicted to result in a deleterious change to the amino acid structure. Reduced expression of CTLA-4 secondary to the variants we identified in LRBA may result in autoinflammation that contributes to IBD. “Targeting reduced CTLA-4 expression is an exciting treatment venue, because expression of CTLA-4 has been shown to be increased by chloroquine treatment in vitro.”
  • Enteropathy is present in 63% of all known individuals with LRBA deficiency, with 27% having chronic diarrhea as the presenting symptom

Mangroves in John Pennekamp State Park (Key Largo)

How to Make a Study Look Favorable for Reflux Surgery Compared to Medical Treatment

A recent study (SJ Spechler et al. NEJM 2019; 381: 1513-23) on first glance appears to support surgery as more effective than medical treatment for refractory heartburn.

Only ~20% of enrolled patients were included in the reported outcomes!

Here’s what happened.  Among a cohort of VA patients (n=360, mean age 48 years) who were reportedly refractory to PPI-treatment:

  • 78 were excluded during prerandomization
  • 42 had relief of their heartburn during a 2-week omeprazole lead-in (20 mg BID)
  • 70 did not complete trial procedures
  • 23 had non-GERD disorders
  • 99 had functional heartburn

This left 78 patients who underwent randomization.  All patients in this highly-selected group had undergone endoscopy with biopsy, impedance-pH testing, and esophageal manometry.  18 of 27 (67%) had treatment success with surgery compared to 7 of 25 patients treated with baclofen/PPI and 3 of 26 with control medical treatment (PPI alone).

Key points:

  • Careful evaluation is needed in any patient with refractory heartburn, especially if contemplating surgery.  Most will either respond to PPI treatment or have a disorder other than reflux; the authors note that 122 patients (out of 360 patients) did NOT have reflux –99 had functional heartburn.
  • Careful instruction in PPI use can be helpful.  Omeprazole and similar agents should be taken 30 minutes before meals.
  • The authors noted that in addition to reflux, that reflux hypersensitivity can “respond to fundoplication…treatment success was 71% among the 14 with reflux hypersensitivity and 62% among the 13 with abnormal acid reflux.”

Limitations: The VA population is not representative of the general population; this trial had a predominance of white males. Also, it is hard to exclude that some of the ‘success’ of the procedure could relate to a powerful placebo response.

My take: This trial reinforces the notion that reflux surgery is helpful in very few highly-selected patients.

Related blog posts:

Fewer Surgeries with Crohn’s Disease

Briefly noted: NE Burr et al. Clin Gastroenterol Hepatol 2019; 17: 2042-49.

In a retrospective cohort (1994-2013) using a primary care database from England, the authors identified decreasing risk of surgeries with Crohn’s diseae (CD).

  • From 1994-2003, the risk of first surgery dropped from 44% to 21%.
  • The risk of a second resection dropped as well, from 40% in 1994 to 17% in 2003 (with 10-year followup)

The reasons for this reduction are not certain but could include better clinical care or reduction in other risk factors (like smoking).

Atlanta Botanical Garden

Do Anti-TNF Agents Reduce Surgeries and Hospitalizations?

Briefly noted:

A recent study (; SK Murthy et al. BMJ indicates that anti-TNF therapy has not been effective in significantly lowering CD-related hospitalizations or surgeries.

Full Text Link (from Eric Benchimol twitter feed): Introduction of anti-TNF therapy has not yielded expected declines in hospitalisation and intestinal resection rates in inflammatory bowel diseases: a population-based interrupted time series study)

My take: While big changes in the frequency of these outcomes were not demonstrated in this large study, prior studies, including the RISK study, have shown that anti-TNF therapy can be disease-modifying and reduce the risk of penetrating disease in Crohn’s disease.

Related blog post: CCFA Updates in IBD


AntiTNF Therapy Associated with Reduced Surgical Resections

Full text: Increased prevalence of anti‐TNF therapy in paediatric inflammatory bowel disease is associated with a decline in surgical resections during childhood JJ Ashton et al. Alim Pham Ther 2019;

From absract:

Design: All patients diagnosed with PIBD within Wessex from 1997 to 2017 were assessed. The prevalence of anti‐TNF‐therapy and yearly surgery rates (resection and perianal) during childhood (<18 years) were analysed

Results: Eight‐hundred‐and‐twenty‐five children were included (498 Crohn’s disease, 272 ulcerative colitis, 55 IBD‐unclassified), mean age at diagnosis 13.6 years (1.6‐17.6), 39.6% female. The prevalence of anti‐TNF‐treated patients increased from 5.1% to 27.1% (2007‐2017), P = 0.0001. Surgical resection‐rate fell (7.1%‐1.5%, P = 0.001), driven by a decrease in Crohn’s disease resections (8.9%‐2.3%, P = 0.001)…

Patients started on anti‐TNF‐therapy less than 3 years post‐diagnosis (11.6%) vs later (28.6%) had a reduction in resections, P = 0.047. Anti‐TNF‐therapy prevalence was the only significant predictor of resection‐rate using multivariate regression (P = 0.011).

Conclusion: The prevalence of anti‐TNF‐therapy increased significantly, alongside a decrease in surgical resection‐rate. Patients diagnosed at younger ages still underwent surgery during childhood. Anti‐TNF‐therapy may reduce the need for surgical intervention in childhood, thereby influencing the natural history of PIBD.

Related blog posts:

Surgery as Placebo

A recent summary by 538 website details how surgery can be a powerful placebo: Surgery Is One Hell of a Placebo

Here’s an excerpt:

“expectations matter, and we know they matter because of a bizarre research technique called sham surgery. In these fake operations, patients are led to believe that they are having a real surgical procedure…

2014 review of 53 trials that compared elective surgical procedures to placebos found that sham surgeries provided some benefit in 74 percent of the trials and worked as well as the real deal in about half.1 Consider the middle-aged guy going in for surgery to treat his knee pain. Arthroscopic knee surgery has been a common orthopedic procedure in the United States, with about 692,000 of them performed in 2010,2 but the procedure has proven no better than a sham when done to address degenerative wear and tear, particularly on the meniscus

Even without a robust placebo effect, an ineffective surgery may seemhelpful. Chronic pain often peaks and wanes, which means that if a patient sought treatment when the pain was at its worst, the improvement of symptoms after surgery could be the result of a condition’s natural course, rather than the treatment. That softening of symptoms from an extreme measure of pain is an example of the statistical concept of regression to the mean.

My take: Both with medicine and surgery, sometimes improvement occurs even when the treatment itself is not effective.

Dupont Forest, NC

Surgical Reset for Anti-TNF Therapy with Crohn’s Disease

A recent study (A Assa et al. Inflamm Bowel Dis 2017; 23: 791-97) indicates that after surgery, anti-TNFα treatment is worth another try.

In this retrospective study with 53 children, 18 had “pharmacodynamic failure” with anti-TNFα medications (PK group) and 35 were controls. “Phamacocynamic failure is characterized by either a lack of improvement of CD symptoms or  loss of response after initial improvement in the setting of adequate serum drug levels without ADAs” [antidrug antibodies].

Key findings:

  • Mean age at time of intestinal resection was 14.8 years
  • Median time from resection to anti-TNF initiation was 8 months
  • Compared to the control group, the PK group had similar response to anti-TNF therapy.   “Similar proportions of patients from both groups were in clinical remission on anti-TNF treatment after 12 months and at the end of follow-up (1.8 years)”
  • At 12 months, remission rates were 89% (PK) versus 88.5% (control)

The authors propose an explanation: “A plausible explanation for this finding is that in severely inflamed tissue with high inflammatory burden, local high levels of TNFα serves as a sink for anti-TNFα antibodies and that tissue injury and local hypoxia might further limit drug penetrance to its target.”

My take: This information is useful.  Many patients who have surgery may respond to anti-TNFα therapy subsequently.  The unanswered question: Could more frequent dosing of anti-TNFα therapy have averted surgery in some patients by overcoming areas of intense disease?


Does Staying Up All Night Affect Surgery the Next Day?

According to a recent study (A Govindarajan et al. NEJM 2015; 373: 845-33), the answer is no.  That being said, my preference would be for a well-rested surgeon.

Some of the details:

The authors conducted a retrospective, population-based, matched cohort study in Ontario, Canada.  Twelve procedures were analyzed from 1448 physicians and involving 38,978 patients.  The same physicians had his/her procedures compared when they were done after treating patients from midnight to 7am to when these were done on days that were not preceded by night call.  The physicians included in the study were attending physicians; thus this does not provide insight into whether residents or fellows would perform similarly.

Key finding:

  • No difference in any primary outcome: death, readmission, or complication.  This primary outcome occurred in 22.2% after night call and 22.4% without night call.

Here’s a graph below -which depicts, from top to bottom, odds ratio for cholecystectomy (n=9322 patients, 479 physicians), gastric bypass (n=320 patients, 25 physicians), colon resection (n=2214 patients, 315 physicians), hysterectomy (n=7020 patients, 384 physicians), knee arthroplasty (n-2504 patients, 192 physicians), hip arthroplasty (n=1564 patients, 154 physicians), repair hip fracture (n=1192 patients, 166 physicians), lung resection (n=550 patients, 55 physicians), CABG (n=460 patients, 48 physicians), Spine surgery (n=3456 patients, 104 physicians), Craniotomy (n=1396patients, 66 physicians), Angioplasty (n=8980 patients, 130 physicians)

From NEJM Twitter Feed

From NEJM Twitter Feed

CCFA Conference Notes 2014 (part 2)

Yesterday’s notes highlighted the most useful discussion at this year’s meeting regarding mucosal healing (MH) in inflammatory bowel disease.

Many points were intriguing but often at odds. For example, the speakers noted that symptoms and scoring systems like CDAI are unreliable in establishing remission.  It was noted that the FDA is mandating more objective measures (like endoscopic improvement) in future studies. Yet, the studies cited for their arguments often were derived from studies which did not use objective endpoints. Similarly, some of the arguments were based on small studies and yet experts often caution to use evidence-based medicine.

Bo Shen (Cleveland Clinic) “Surgerical Options in IBD”

  • 50-71% of CD patients require some type of surgery within 10 years of diagnosis
  • End-ileostomy may be a cure for some CD patients,  For UC, end-ileostomy 98% are cured.  2% develop enteritis.
  • Can use infliximab after surgery.  Immune system different after surgery and may work even
  • ‘Don’t operate until a CD patient develops a complication. But, don’t wait until further complications develop.’

Different type strictures –web-like strictures are suitable for dilatation, others are more difficult: spindle-like (longer) , ulcerated stricture, and anastomotic.

  • Classification: Gast Endosc 2013; 78: 8181-35.
  • Etiology: primary, secondary (anastomotic), benign, malignant
  • Short-long: Length (<4cm) if dilating
  • Degree: high-grade, low-grade
  • Number: single, multiple
  • Associated conditions: abscess, others

Determining resection margin –does not depends on absence of histologic activity (Ann Surg 1996; 224: 563-71).  Try to save as much bowel as possible, often based on how thick bowel is rather than histologic margins.

Save the gut –stricturoplasty.  1st surgery –usually is a resection rather than stricture plasty.  Heineke-Mikulicz (most common) <10 cm for short , Finney for strictures 10-20 cm, Michelassi >20 cm (sid-to-side isoperistaltic). (Dis Colon Rectum 2007) Stricturoplasty –best for mid small bowel, minimum inflammation, no fistula

Fistula –Hollow-organ to hollow-organ fistula –treat surgically. Whereas if fistula is perianal, start with medical treatment. Perianal fistulas often treated with seton; seton often kept in place for a long time (“forever if not bothering patient”).

Abscess—avoid surgical drainage if possible.  Delineate anatomy and consider elective surgery later.  If less than 3 cm, could aspirate and not leave in drain. If >3 cm, start with interventional radiology

Post-op management –Ruttgerts score.  Rescope 6 months post-op to determine if needs more aggressive treatment.

UC Surgery: issues: preoperative biologics, 2- or 3-stage operations, what type of pouch

  • There may be increased risk with biologics (studies have not shown this consistently) –depends on type of surgery.  If very sick, use 3-stage rather than 2-stage operation.  Don’t do pouch at time of 1st operation if very sick DCR 2013; 56: 1243-52).
  • J-pouch now standard.  Kock pouch –catheterize pouch/no ostomy.  S-pouch –problemswith mechanical obstruction.
  • Even with mucosectomy (vs. stapler/no mucosectomy)–can still develop cuffitis and malignancy.  Mucosectomy may increase risk of incontinence.

Edward Loftus (Mayo Clinic) “Optimizing Biologic Therapy: Maximizing Benefit and Minimizing Risk”

Is azathioprine an effective drug? Should we be using biologics sooner?

Key points:

  • ACT1 and ACT2 were pivotal studies for infliximab approval for UC.  1/3rd chance of going into full remission, 1/3rd chance of response, 1/3rd chance of not responding.  Infliximab lowers risk of colectomy.  Favorable studies of other anti-TNFs as well: adalimumab (Gastroenterol 2012; 142: 257-65) and golimumab (Gastroenterol 2014; 46: 85-95 & 96-109). No head-to-head anti-TNF trials.
  • Crohn disease:  5-ASA products don’t work for Crohn disease.  Reviewed pivotal trials of anti-TNF agents (infliximab, adalimumab, certolizumab)-30% in remission.
  • Natalizumab (anti-alpha 4 integrin) for refractory disease was discussed (NEJM 2005; 353: 1912-25).  Takes longer to work then anti-TNFs but maintenance data look good. PML risk: 395 cases among 118,100 patients treated as of August 2013.  Lots of paperwork and physicians have to be certified.  If you are JC virus serology is negative, “your risk is about 1 in one million in the next year. If you are positive, about a 1% risk in the following year.”
  • Azathioprine (AZA) not very effective (Gastroenterol 2013; 145: 766-74 & 758-65).  Prospective double-blind Spanish study (n=131) –no statitistical benefit.  2nd reference is French study. N=132. No significant difference at 36 months in patients with added AZA.  In U.S., most “thought leaders” going straight to anti-TNFs.
  • Combination therapy works best in adults (SONIC study for Crohn disease, UC Success for UC).  UC Success only studied 16 weeks, no maintenance therapy trial.  However, methotrexate (MTX) with anti-TNFs combination has not been proven to be effective (Gastroenterol 2014; 146: 681-8).  Reason this was a negative study, per lead author, may have been related to steroid use.

Other pointers:

  • Don’t rely on symptoms alone.  Symptoms/CDAI do not correlate with CDEIS (endoscopic improvement).  FDA mandating all future trials have an endoscopic endpoint and not rely on use of CDAI alone. Other factors cause symptoms including IBS, infections, and bacterial overgrowth. Take-home point: Need to look (endoscopy) if someone is not doing well.
  • In the SONIC trial –if there was inflammation on endoscopy, there was an impressive 30% delta in response to treatment (with combination therapy compared with AZA monotherapy). Whereas if you have no lesions, combination therapy no more effective than either monotherapy agent.  Patients whose complaints are due to irritable bowel rather than inflammation do not respond well to treatment.
  • OLD paradigm –treat based on symptoms.  NEW paradigm–treat based on biologic/radiographic markers or endoscopic findings.  “Treat to target” has been approach used by Dr. Sandborn. Target mucosal healing and then assess mucosal healing every 6 months until target achieved, then less frequently.  Yet mucosal healing cannot be achieved in many/most patients.
  • Therapeutic drug monitoring.  For example, 6-TGN >235 associated with better response to AZA (OR 5.0)
  • Pharmacokinetics of anti-TNFs: lower clearance if concomitant use of immunomodulators, increased clearance if high CRP, higher BMI
  • New drugs: Ustekinumab –three phase 3 trials underway.  Should be available in about 2 yrs for Crohn disease. Vedolizumab –under FDA review (NEJM 2013; 369: 699-710).  Infusion (similar to remicade frequency). Blocks lymphocyte homing in the gut. UC data much more robust than with CD, but probably will be approved for both.  Rate of adverse events were low. Etrolizumab—similar to Vedolizumab, but SC administered. Currently, this drug is in phase 2 studies.

Eva Szigethy (Pittsburgh Pediatrics) “Psychological evaluation and assessment in IBD”

Key points:

  • Anxiety/depression ~25-40% of pediatric IBD.  Occurs in both active and inactive disease.
  • IBD effects on brain: inflammation, drugs (steroids, biologics)–both have direct effects on brain.
  • 15% of kids and 25% of adults are having thoughts of death on screening tools. Pain is frequent trigger for suicidal thoughts.
  • Simple depression screen: Mood, Energy, Sleep, Suicide/Self-esteem, Anhedonia (lack of pleaure), Guilt, Eating (change in appetite)
  • We should not ignore adjustment disorders.  We may be able to prevent a full-blown psychiatric disorder.  Each time we let problems like anxiety or depression go untreated, this can leave long-term changes in brain.
  • Anxiety screen: Tense, Tired, Recurrent worries/fear, Restless, Avoidance, Poor sleep/nightmares, Poor concentration
  • Important to look at patient perspective of their disease: identity (what they see as their symptoms), cause/etiology, timeline (how long the patient believes that the illness will last), consequences, cure/control.
  • Catastrophizing –more persistent pain and increased visceral hyperalgesia.  Abnormal brain activation. Poor coping drives development of depression and anxiety.
  • With adult IBD, 20% of patients consume up to 80% of medical costs.  Chronic pain and depression are key factors (Binion et al 2010).
  • Management of anxiety/depression: Cognitive Behavioral therapy –changing behaviors and thinking, problem-solving. ACT –activities, calm (relaxation, guided imagery, hypnosis), think positive (cognitive reframing). Antidepressants: TCA, SSRI, SNRI.  SSRI/SNRI –few side effects or drug interactions.  Overdose risk is highest with TCA (but typically using low doses of these agents).  No pediatric studies in IBD and only small studies in adults. If inactive IBD, SSRI often 1st line. If active IBD, Bupropion often used as 1st line.
  • For anxiety, most likely use SSRI if comorbid anxiety
  • For pain, most likely use SNRI  or low dose TCA
  • Opiates are problematic due to psychological/physical dependence, increased mortality/infection risk, narcotic bowel
  • Sleep –don’t go to bed if not tired, aim for consistency, if not asleep in 20 minutes, then do something else.  1st line pharmacology: consider antihistamines or melatonin.

Sachin Kunde (Michigan State University, Helen DeVos Children’s Hospital) “FMT for IBD”

Key points:

  • Microbial diversity altered in IBD –can we modulate dysbiosis to treat IBD?
  • Issues with cause and effect.  Is dysbiosis due to IBD or causing IBD.
  • FMT –“the ultimate probiotic.” Application of FMT.  For recurrent C difficile, cure rate nearly 90% –?better with lower GI route. For any indication besides C difficile infection (CDI), can only be given through clinical trials (FDA IND).  Currently 9 ongoing trials for IBD (1 pediatric, 3 in U.S).

FMT in IBD: Studies:

  1. -Anderson et al.  Aliment Phar Ther 2012: 13/18 without CDI had some resolution of IBD symptoms.
  2. -Kunde et al JPGN 2013: n=10. PUCAI decrease by 15 indicated response found in 78% (7/9) at 1 week, and 67% (6/9) at 1 month, 3 (33%) went into remission.
  3. -Kump et al IBD 2013: n=6. FMT for UC was not effective.  Transient improvement in 2/6 patients, 1/6 improved on Mayo sub score.

Bottomline for FMT & IBD: More questions than answers: efficacy, route of administration, # of infusions needed, fresh vs. frozen, adverse effects, best donor, etc.

For today’s post today and yesterday’s post, I may have made some transcription errors and these notes were not reviewed with the speakers.  Also, due to brevity, some useful information was not included.  Thus, the disclaimer with these posts is particularly important.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  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.

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