Tag Archives: anti-TNF therapy

Do Setons Improve Outcomes in Anti-TNF Treatment for Fistulas?

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J McCurdy et al. AP&T 2025; https://doi.org/10.1111/apt.70081. The Impact of Setons on Perianal Fistula Outcomes in Patients With Crohn’s Disease Treated With Anti-TNF Therapy: A Multicentre Study

This study included 221 patients — 81 with setons and 140 without setons. Patients were treated with their first anti-TNF therapy for perianal fistulizing Crohn’s disease (PFCD) after undergoing a pelvic MRI between 2005 and 2022 from 6 North American centers. Our primary outcome was major adverse fistula outcome (MAFO), a composite of repeat local surgical intervention, hospitalization, or fecal diversion for PFCD.

Key findings:

  • Patients with setons had similar rates of MAFO (HR 1.23; 95% CI, 0.68–2.21) and fistula remission at 6 months (OR, 0.81; 95% CI, 0.41–1.59) and 12 months (OR, 0.63; 95% CI, 0.31–1.27) compared to patients without setons
  • In patients with abscesses, there were lower rates of MAFO (HR, 0.49; 95% CI, 0.19–1.25) but not statistically significant in patients with setons

My take: This study indicates that seton placement may not be needed in patients who are starting anti-TNF therapy with fistulizing disease, especially if there is not an abscess present.

Related blog posts:

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.

Is It RISKy Not To Use Anti-TNF Therapy for Pediatric Crohn’s Disease?

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D Geem et al (Senior author: Subra Kugasthasan). Clin Gastroenterol Hepatol 2024; 22: 368-376. Progression of Pediatric Crohn’s Disease Is Associated With Anti–Tumor Necrosis Factor Timing and Body Mass Index Z-Score Normalization

Congratulations to my colleagues at Emory who led/participated in this study.

This study examined 5-year longitudinal data from the pediatric multicenter RISK cohort (n=1075). RISK=risk stratification and identification of immunogenetic and microbial markers of rapid disease progression in children

Key findings:

  • For children with a low BMIz at diagnosis (n = 294), BMIz normalization within 6 months of diagnosis were associated with a decreased risk for surgery (HR 0.47). Patients without BMIz normalization were enriched for genes in cytokine production and inflammation.
  • Unsurprisingly, baseline B2 (stricturing disease) and B2+B3 (stricturing and penetrating disease) were associated with increased risk of surgery with HR, 4.20 and HR, 8.24 respectively
  • Earlier anti-TNF therapy was associated with a lower hazard rate (HR) of needing surgery


My take: It appears that early anti-TNF therapy lowers the risk of surgery. Improved BMI with treatment is another good prognostic variable. There may be an early window in which effective treatment prevents long-term damage to the GI tract in pediatric patients with Crohn’s disease.

This study has overlapping findings (also with RISK cohort) by Adler et al showing early treatment preventing perianal fistulas. Blog post: Early Treatment Can Prevent Fistulas in Pediatric Crohn’s Disease

Related article: JC McCurdy et al. Clin Gastroenterol Hepatol 2024; 22: 377-385. Open Access! Comparative Effectiveness of Biologic Therapies in Preventing Penetrating Complications in Patients With Crohn’s Disease

In this observational retrospective study with 40,693 patients: 93% anti-TNF, 3% UST (ustekinumab), and 4% VDZ (vedolizumab), “Anti-TNF therapy was associated with a lower risk of LPD and PPD [luminal and perianal penetrating disease] compared with VDZ, and lower risk of LPD compared with UST.”

Related blog posts:

Early Treatment Can Prevent Fistulas in Pediatric Crohn’s Disease

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J Adler et al. Inflamm Bowel Dis 2024; https://doi.org/10.1093/ibd/izae020.056. EARLY TUMOR NECROSIS FACTOR ANTAGONIST TREATMENT PREVENTS PERIANAL FISTULA IN PEDIATRIC CROHN’S DISEASE

The authors utilized the prospectively-enrolled RISK cohort to assess the effect of early ANTI-TNF therapy and the development of perianal fistulizing complications (PFCs); this included 621 propensity-matched pediatric patients without PFCs at enrollment. ”The study included a moderately ill population, including 21% with growth delay, 43% with deep ulcers, and 70% with weighted pediatric Crohn’s disease activity index (wPCDAI) >30.”

Key findings:

  • Anti-TNF therapy was associated with 79% reduced odds of developing PFCs
  • The presence of perianal lesions increased the risk of PFCs more than 3-fold

My take: This study, in agreement with others (see below), shows that early treatment with effective therapy reduces the risk of disease complications like perianal fistulas.

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Immune Mediated Disorders Associated with TNF Inhibitors Can Involve the Liver Too

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Yesterday’s post highlighted immune-mediated disorders likely caused by anti-TNF therapy; this includes rheumatoid arthritis, psoriasis, hidradenitis suppurativa, and chronic recurrent multifocal osteomyelitis. Anti-TNF inhibitors can be the reason for drug-induced liver disease (DILI) including autoimmune hepatitis (AIH) as well. 

  • In one study, 8% of children receiving anti-TNF therapy developed a new elevation in ALT.
  • Most often liver enzyme elevation is mild and transient
  • Differential diagnosis for persistent elevation can be due to DILI, autoimmune liver disease (eg. PSC, AIH), or rarely due to a combination (autoimmune drug-induced liver disease). The latter can improve with drug cessation and with corticosteroid treatment.

Some slides on this topic (courtesy of William. Balistreri):

My take: Serious liver injury related to anti-TNF therapy is rare. When liver enzymes are persistently elevated, consider DILI including anti-TNF agents.

Related blog posts:

IBD Updates

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  1. Allopurinol makes thiopurines more effective. A Vasudevan et al. AP&T 2023; https://doi.org/10.1111/apt.17831 Clinical trial: Combination allopurinol-thiopurine versus standard thiopurine in patients with IBD escalating to immunomodulators (the DECIDER study)

This was  a multicenter, randomized, placebo-controlled trial to compare the efficacy and safety of thiopurine-allopurinol versus thiopurine with placebo for adults commencing a thiopurine for IBD in 102 patients. Allopurinol was dosed at 100 mg. Key findings:

  • A higher proportion achieved the primary outcome (improved clinical score and fecal calprotectin <150) in the thiopurine-allopurinol group (50% vs 35%, p = 0.14) and fewer participants stopped their allocated therapy due to adverse events (11% vs 29%, p = 0.02

Related blog posts:

2. Newer treatments and lower colectomy rates in pediatric UC. D Ley et al. AJG 2023; 118:1997-2004 New Therapeutic Strategies Are Associated With a Significant Decrease in Colectomy Rate in Pediatric Ulcerative Colitis. Thanks to Ben Gold for this reference.

Medication exposure and disease outcomes were compared between 3 diagnostic periods: 1988 to 1993 (period [P] 1; pre-IS era), 1994 to 2000 (P2; pre-anti-TNF era), and 2001 to 2011 (P3; anti-TNF era).

  • Key finding: The risk of colectomy at 5 years decreased significantly over time (P1, 17%; P2, 19%; and P3, 9%; P = 0.045, P-trend = 0.027) and between the pre-anti-TNF era (P1 + P2, 18%) and the anti-TNF era (P3, 9%) (P = 0.013). 

Related blog posts:

3. More data indicating that anti-TNF therapy does not increase post-operative complications. D Bajzat et al. Inflamm Bowel Dis 2023; 29: 1971-1980. Safety Analysis of Preoperative Anti-TNF-α Therapy in Pediatric IBD After Intestinal Resection: A Systematic Review and Meta-analysis

In this systematic review, the authors identified 8 eligible articles with 526 pediatric patients with IBD. Key finding: “There is no significant association between preoperative anti-TNF-α therapy and postoperative complications in children with IBD after intestinal resection.”

Related blog posts:

Pics from Island Ford/Chattahoochee River

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.

Genetic Test to Help Determine Need for Combination Therapy with Anti-TNF

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V Solitano et al. Clin Gastroenterol Hepatol 2023; 21: 3019-3029. HLA-DQA1∗05 Genotype and Immunogenicity to Tumor Necrosis Factor-α Antagonists: A Systematic Review and Meta-analysis

Key findings:

  • On meta-analysis of 13 studies (3756 patients; median follow-up, 12 months; 41% with variants), HLA-DQA1∗05 variants were associated with 75% higher risk of immunogenicity compared with non-carriers (relative risk, 1.75) with considerable heterogeneity (I2 = 62%) (low certainty evidence).
  • In addition, patients with HLA-QQA1*05 variants had clinical loss of response (LOR) in 67% compared to 30% in those without this variant (wild-type); thus, a 124% higher risk of LOR.
  • Positive and negative predictive values of HLA-DQA1∗05 variants for predicting immunogenicity were 30% and 80%, respectively
  • Proactive therapeutic drug monitoring, but not concomitant use of IMMs, IMIDs, and TNF-α antagonist-type, modified this association.

My take:

  • The ~40% of individuals with HLA-DQA1*05 variants are at higher risk of LOR and are more likely to benefit from both therapeutic drug monitoring and probably from use of combination (with immunomodulator) therapy.
  • The positive predictive value (30%) is low indicating that the majority of patients with these variants will not develop anti-drug antibodies within 12 months.
  • In those with negative testing for HLA-DQA1*05 (~60%), the higher negative predictive value indicates a patient is more likely to do well with monotherapy.
  • HLA-DQA1*05 testing is available commercially (usually part of Celiac HLA typing).

Related blog posts:

This is the Initiation Well at Quinta da Regaleira in Sintra, Portugal.
It is pretty cool because it seems to start at ground level and then goes down many floors.
There is an exit to a number of tunnels at the lower level.

High Relapse Rates with Anti-TNF Withdrawal Even with Endoscopic Remission

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R Mahmoud et al. Clin Gastroenterol Hepatol 2023; 21: 750-760. Open Access! Complete Endoscopic Healing Is Associated With Lower Relapse Risk After Anti-TNF Withdrawal in Inflammatory Bowel Disease

This was a prospective observational study (n=81). In order to participate, patients (all adults) had to be in confirmed baseline steroid-free clinical remission (for at least 6 months) and endoscopic healing;  endoscopic healing was defined as endoscopic Mayo score <2 or Simple Endoscopic Score for CD (SES-CD) <5 without large ulcers. Endoscopic healing was subclassified as complete endoscopic healing (Mayo 0/SES-CD 0–2) versus partial endoscopic healing (Mayo 1/SES-CD 3–4).

Key findings:

  • At 12 months, 70% (7 of 10) versus 35% (25 of 71) of patients with partial versus complete endoscopic healing relapsed, respectively (adjusted hazard rate [aHR], 3.28; 95% confidence interval [CI], 1.43–7.50)
  • Mesalamine use was associated with fewer relapses in UC/IBDU patients (aHR, 0.08; 95% CI, 0.01–0.67)
  • Thirty patients restarted anti-TNF, and clinical remission was regained in 73% at 3 months.

The authors highlight the lower relapse rate between those with complete endoscopic healing and those with partial healing. They acknowledge that those eligible for anti-TNF de-escalation are highly selected (~7% in a prior study) and “few patients with an unfavorable IBD phenotype, such as stricturing or penetrating CD, anti-TNF for perianal fistulizing CD, young age at diagnosis, or prior biological failure, were included in this study. Therefore, our findings may not be generalizable to patients with a more severe IBD phenotype.

My take: Even in those with complete endoscopic healing, there is a high rate of relapse. In addition, stopping anti-TNF therapy likely increases risk of not responding to anti-TNF therapy when it is restarted. This study does show that transitioning from anti-TNF therapy to mesalamine therapy in those with ulcerative colitis (or IBDU) could be a reasonable consideration.

Related blog posts:

Is There An Increased Risk of Infections with Anti-TNF Therapy?

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J Holmgren et al. Inflamm Bowel Dis 2023; 29: 339-348. Open Access! The Risk of Serious Infections Before and After Anti-TNF Therapy in Inflammatory Bowel Disease: A Retrospective Cohort Study 

Methods: Retrospective study with 980 patients at 5 centers participating in the Swedish IBD Quality Register. Serious infections, defined as infections requiring in-patient care, the year before and after the start of anti-TNF treatment were evaluated.

A decline in the incidence rate can first be seen beyond 1 year of treatment with anti-TNF, with an incidence rate of 1.22 (95% CI, 0.90-1.66) events per 100 person year compared with 2.19 (95% CI, 1.43-3.36) events per 100 person year the year before treatment. This is a significant reduction of infections, with an incidence rate ratio of 0.56 (95% CI, 0.33-0.95; P = .030).

Key findings:

  • A 72.0% reduction in the incidence rate of perianal abscesses and intra-abdominal abscesses during treatment with anti-TNF was found compared with before treatment.
  • Figures 2 & 3 show than most infection rates decreased with treatment. CMV infection did not change significantly with 0.10 per 100 person-years prior to treatment and 0.14 per 100 person-years after starting anti-TNF therapy
  • ” In the current study, patients younger than 20 years old experienced a substantial decrease of infection incidence rate ratio (0.11) with the introduction of anti-TNF treatment. The results could be explained by the fact that young patients have a more active disease with increased risk of infection before treatment with anti-TNF.”
  • “The most common type of infection after anti-TNF treatment was pneumonia. The high incidence of pneumonia confirms earlier data.9,36,37” However, the authors show that the rate of pneumonia dropped from 0.51 to 0.27 per 100 person-years after starting anti-TNF therapy.

The authors note that a prior study by “Zabana et al showed that patients with IBD had an increased risk for serious infection after starting immunosuppressive treatment compared with before treatment (median follow-up 3 years before and 5 years after)… the discrepancy in the result may be explained by selection bias. We included all patients starting anti-TNF treatment. However, Zabana et al included only patients who suffered from infections during immunosuppressive treatment and retrospectively examined the risk of infection before start of treatment.24“

Limitations of study: several other important factors affecting infections were not captured in this study including steroid exposure and nutritional status.

My take (from authors): “The incidence rate of serious infection among IBD patients did not increase with anti-TNF therapy. Instead, serious infections seemed to decrease more than 1 year after initiation of anti-TNF treatment.”

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Improving Natural History of Pediatric Crohn’s Disease with Biologic Therapy -Two Studies

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D Ley et al. Clin Gastroenterol Hepatol 2022; 20: 2588-2597. Open Access! New Therapeutic Strategies Have Changed the Natural History of Pediatric Crohn’s Disease: A Two-Decade Population-Based Study

This retrospective study dating back to 1988 examined 1007 patients diagnosed with CD who were followed up for a median duration of 8.8 years.

Key findings:

  • The risk for intestinal resection at 5 years decreased significantly over time (P1, 35%; P2, 31%; and P3, 22%; P = .0003. This decrease in resections coincided with increased use of immunosuppressive (IS) and anti-TNF therapy: IS and anti-TNF exposure rate at 5 years increased from 33.9% (in P1) to 76.5% (in P3) and from 0% (in P1) to 50.5% (in P3).
  • The risk for progression from inflammatory to stricturing behavior decreased significantly over time (P1, 27%; P2, 28%; and P3, 20%)

LE Targownik et al. Clin Gastroenterol Hepatol 2022; 20: 2607-2618. Earlier Anti-TNF Initiation Leads to Long-term Lower Health Care Utilization in Crohn’s Disease but Not in Ulcerative Colitis

Methods: The authors “used health administrative data from Manitoba, Canada to identify all persons with a new diagnosis of inflammatory bowel disease (IBD) between 2001 and 2018 who received tumor necrosis factor antagonists (anti-TNF) therapy and had at least 1 year of post anti-TNF initiation follow-up.”

Key findings:

  • Among 742 persons with CD, early anti-TNF initiators had fewer IBD-specific and overall hospitalizations over the 5 years following the start of therapy
  • Incidence of resective surgery was also lower in earlier anti-TNF initiators with CD if the first year following initiation was excluded from the analysis.
  • In 318 cases of UC, there was no impact of the timing of anti-TNF therapy on the rates of hospitalization and surgery.

My take: These two studies show that use of biologic therapy is associated with better outcomes in Crohn’s disease including fewer intestinal resections and fewer hospitalizations. It appears that earlier use may alter the natural history in part by reducing the likelihood of stricturing disease. Interestingly, the RISK study showed a reduction in penetrating disease with early use of biologics but not a reduction in stricturing disease (Related blog post: CCFA: Updates in Inflammatory Bowel Disease 2017 (part 3))

What Happens When Infliximab is Stopped in Patients in Deep Remission Plus One

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S Buhl et al. NEJM 2022; DOI:https://doi.org/10.1056/EVIDoa2200061. Discontinuation of Infliximab Therapy in Patients with Crohn’s Disease

Design: This was a multicenter, randomized, double-blind, placebo-controlled withdrawal study of infliximab in patients (n=115) with Crohn’s disease who were in clinical, biochemical, and endoscopic remission after standard infliximab maintenance therapy for at least 1 year. Patients were randomly assigned 1:1 to continue infliximab therapy or to receive matching placebo for 48 weeks.

Key finding:

  • At the end of the trial at week 48, relapse-free survival was 100% in the infliximab-continuation group and 51% in the infliximab-discontinuation group

My take (borrowed from authors): Discontinuation of infliximab for patients with Crohn’s disease receiving long-term infliximab therapy and in clinical, biochemical, and endoscopic remission leads to a considerable risk of relapse

Related blog posts:

Figure from NEJM Evidence Twitter Feed

S Sassine et al. AJG 2022; Volume 117 – Issue 4 – p 637-646. doi: 10.14309/ajg.0000000000001650. Risk Factors of Clinical Relapses in Pediatric Luminal Crohn’s Disease: A Retrospective Cohort Study

Key findings–The following variables were associated with clinical relapse:

  • female sex (adjusted hazard ratio [aHR] = 1.52, P = 0.0007)
  • exposure to oral 5-ASA (aHR = 1.44, P = 0.04),
  • use of immunomodulatory agents compared with tumor necrosis factor-alpha inhibitors (methotrexate aHR = 1.73, P = 0.003; thiopurines aHR = 1.63, P = 0.002)
  • presence of granulomas (aHR = 1.34, P = 0.02)
  • increased eosinophils on intestinal biopsies (aHR = 1.36, P = 0.02)
  • high levels of C-reactive protein (aHR = 1.01, P < 0.0001)
  • fecal calprotectin (aHR = 1.08, P < 0.0001)
  • low serum infliximab levels (<7 mcg/mL) (aHR = 2.32, P = 0.001).