Tag Archives: infliximab

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:

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:

Vedolizumab and Infliximab: Expected Dosing When Switching From IV to SC Routes

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Z Wang et al. Clin Gastroenterol Hepatol 2023; 3188-3190. Therapeutic Drug Monitoring Can Guide the Intravenous-to-Subcutaneous Switch of Infliximab and Vedolizumab: A Simulation Study

The authors performed population pharmacokinetic (popPK) simulations to determine optimal dosing recommendations.

Key points:

  • Infliximab: “The Q2W SC dosing regimen of infliximab has been selected with the purpose of exceeding a C,trough,ss of 5 mg/L.” This tends to align with 5 mg/kg Q8W IV dosing.
  • Infliximab: “Patients on Q6W or Q8W IV infliximab can safely switch to Q2W SC infliximab…only patients on Q4W IV infliximab need Q1W SC dosing”
  • Vedolizumab: “Only patients on Q4W IV vedolizumab should switch to Q1W SC dosing”
  • Both agents: “Switching 4 instead of 8 weeks after the last IV dose can hit SS[steady state] faster, thereby avoiding the risk of temporary underexposure.”

My take: It is still important to see how switching from IV to SC route affects clinical outcomes in real-world cohorts. This study, though, does provide a good starting point when trying to provide the right dose frequency to achieve good therapeutic troughs.

Related blog posts:

Japanese Maple tree

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.

Granulomatous Lung Disease: Case for GI Doctors

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JB McCannon et al. NEJM 2023; 389: 1902-1911. Case 35-2023: A 38-Year-Old Woman with Waxing and Waning Pulmonary Nodules

In this case report, A 38-year-old woman was evaluated because of dyspnea, chest discomfort, and waxing and waning pulmonary nodules. She had a prior history of ulcerative colitis. This article reviews reasons for pulmonary nodules including cancer, infection, vasculitis, connective tissue disorders, sarcoidosis and inflammatory bowel disease (IBD) which has a number of pulmonary manifestations including necrobiotic nodules.

In this case, the granulomatous lung disease was attributed to be an extraintestinal manifestation of IBD. She was treated with TNF-alpha targeted therapy which has been effective in a prior case report (J Crohns Colitis 202; 14: 480-489).

My first reaction to this article — I have seen this! However, our case was atypical in that the 15 year old patient presented with respiratory symptoms (no preceding GI diagnosis). It was noted that her gastric wall was severely thickened as an incidental finding on her chest CT which showed extensive tiny pulmonary nodules. Her endoscopy showed disease isolated to her stomach. Both her gastric findings and CT of her chest resolved with infliximab treatment. This included mucosal healing of her stomach on followup endoscopy.

CT scan showing severely thickened gastric wall
Mucosal appearance of stomach with erythema and numerous ulcerations prior to treatment

Related blog post: IBD Update January 2015 (Part 1) NEJM 2014; 371: 2418-27 -case report of 9 yo with  Crohn’s Disease and pulmonary nodules

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.

Alpha-Gal Reaction to Infliximab

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G Polanco, et al. JPGN Reports 4(3):p e322, August 2023. Open Access! Delayed Hypersensitivity Reaction to Infliximab Due to Mammalian Meat Allergy

Briefly noted: Case report of a 17 yo with Crohn’s disease who developed urticaria and pruritus approximately 6 hours after her very first infliximab infusion; the patient was diagnosed with Alpha-Gal and responded to change to adalimumab which  is not glycosylated with alpha-gal.

Related blog post: Nonanaphylactic Alpha-Gal and Chronic Gastrointestinal Symptoms

Sigal Music Museum (Greenville, SC) -has a large number of very old harpsichords and pianos. A harpsichord plucks strings to make the sound whereas a piano has a small hammer that strikes the strings to make the sound. This musical instrument is a harpsichord.

IBD Brief Updates: Anti-TNF Loss of Response, Upadacitinib for ASUC, Risk Factors for Developing IBD

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EHJ Savelkoul et al. Inflamm Bowel Dis 2023; 29: 1633-1647. Open Access! Systematic Review and Meta-analysis: Loss of Response and Need for Dose Escalation of Infliximab and Adalimumab in Ulcerative Colitis

Methods: A systematic search was conducted from August 1999 to July 2021 for studies (50 studies identified) reporting loss of response and dose escalation during infliximab and/or adalimumab use in ulcerative colitis patients with primary response

Key findings:

  • Annual loss of response was 10% for infliximab and 13% for adalimumab, with higher rates during the first year.
  • The annual LOR incidences were higher during the first 65 weeks of treatment for both IFX (14%) and ADA (23%).
  • Annual dose escalation rates were 14% (infliximab) and 21% (adalimumab), with clinical benefit in 72% and 52%, respectively

CH Zinger et al. Inflamm Bowel Dis 2023; 29: 1667-1669. Upadacitinib for Acute Severe Ulcerative Colitis

Key finding: 4 patients (age 18-25 yrs) received upadacitinib for acute severe ulcerative colitis (ASUC) after failing to respond to infliximab and IV steroids. 3 of 4 responded to treatment (45 mg/day) between 4 to 8 days. Three months later, two of these patients were in steroid-free clinical-endoscopic remission and one had maintained a clinical response.

In their discussion, the authors note a similar response rate to tofacitinib, another JAK inhibitor, for ASUC; though, the authors speculate that upadacitinib may be efficacious.

N Narula et al. Clin Gastroenterol Hepatol 2023; 21: 2649-2659. Associations of Antibiotics, Hormonal Therapies, Oral Contraceptives, and Long-Term NSAIDS With Inflammatory Bowel Disease: Results From the Prospective Urban Rural Epidemiology (PURE) Study

In a a prospective cohort study of 133,137 individuals between the ages of 20 and 80 from 24 countries, the authors examined the relationship between exposures to antibiotics, NSAIDs and hormonal therapies with the development of IBD over a median 11 year period.

Key findings:

  • Incident IBD was associated significantly with baseline antibiotic (aOR, 2.81; P = .0001) and hormonal medication use (aOR, 4.43; P = .001).
  • Nonsteroidal anti-inflammatory drug users also were observed to have increased odds of IBD (aOR, 1.80 P = .002), which was driven by long-term use (aOR, 5.58; P < .001)
Near Cassis, France

COMBO-IBD Study -Combination Immunomodulator Use and Thresholds

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AJ Yarur et al. Clin Gastroenterol Hepatol 2023; 21: 2908-2917. Open Access! Combination Therapy With Immunomodulators Improves the Pharmacokinetics of Infliximab But Not Vedolizumab or Ustekinumab

In this prospective cohort with 369 patients, treatment included the following 113 infliximab, 133 vedolizumab, and 123 ustekinumab. All patients received standard dosing (eg. 5 mg/kg/dose every 8 weeks with infliximab). Per Table 1, dose of thiopurine was 100 mg (range 50-150, “using a 2:1 ratio of azathioprrine and mercaptopurine”); most patients received methotrexate at a dose of 12.5 mg. Key findings:

  • Infliximab levels were much improved in patients receiving combination therapy with either a thiopurine or methotrexate. In those patients receiving a thiopurine, a threshold of 6-TGN ≥146 was considered optimal.
  • Patients receiving combination therapy with methotrexate or a thiopurine and a 6-TGN concentration ≥146 pmol per 8 × 108 RBCs, and those with baseline infliximab level ≥12.3 μg/mL had a lower rate of secondary nonresponse when compared with those on monotherapy, thiopurine with 6-TGN <146 pmol per 8 × 108 RBCs, and baseline infliximab level <12.3 μg/mL (88.2 vs 11.8% [P = .04], 71.2 vs 45.5% [P = .04])
  • Ustekinumab and vedolizumab levels were NOT increased in patients receiving an immunomodulator

My take: This study reinforces the idea that there are pharmacokinetic benefits of combination therapy with infliximab (and extrapolated to other anti-TNF agents); there is a lack of benefit for most patients receiving ustekinumab and vedolizumab. Even with ustekinumab and vedolizumab, it is possible that patients with more severe disease may still benefit independent of pharmacokinetic effects on biologic agent.

Higher doses of infliximab monotherapy with therapeutic drug monitoring may achieve similar results as combination therapy. However, patients switching from one anti-TNF to another due to immunogenicity/antidrug antibodies are particularly likely to benefit from combination therapy. In addition, a recent ImproveCareNow study showed better outcomes for pediatric patients who received methotrexate with adalimumab (see below).

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.

CCFA 2023 (Atlanta) -Part 1

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I recently attended a regional CCFA conference. David Rubin gave several terrific lectures. Here are some of my notes and some slides from this lecture. My notes may contain transcription errors as well as important omissions. Can get access to full set of slides here: Biologics and Their Biosimilars

“Biologics and Their Biosimilars“

What is a Biologic Therapy?

Dr. Rubin makes a point of explaining the term to patients.  It is a protein made in a living cell that targets another protein.  Term “biologic” can sound scary to patients.  Usually given IV because they cannot be absorbed through the small bowel.

IBD Treatment Revolutions

  • Steroids -overnight changed mortality in IBD
  • Anti-TNF Therapy in IBD -taught many lessons. Treat earlier –>better outcomes. 

Anti-TNF Therapy

  • Frequent loss of response.
  • Earlier treatment with biologics result in better outcomes.
  • Immunogenicity is mainly an issue with anti-TNF agents and not much of an issue with other biologics. Episodic therapy is a big risk factor for anti-drug antibodies. 
  • If staying with in-class medication, after anti-drug antibodies, need to take additional measures to prevent anti-drug antibodies (eg. Immunomodulators).
  • Combination therapy is more effective (SONIC, UC SUCCESS trials).  This is due to using multiple mechanisms of disease control, reduction in anti-drug antibodies, and elevated serum drug levels.
  • Good therapeutic levels appears to deliver similar results as combination therapy
  • Pre-week 6 level of 17 or greater, associated with good response in maintenance.  If level is low, presumption is that higher dosing will be beneficial.
  • Higher levels of infliximab trough levels needed for perianal fistula healing (improved with ciprofloxacin).  Higher levels could be causally-related to healing or could be a marker that there is less inflammation and a patient is responding.
  • Anti-TNFs do not appear to increase risk of infections (see PUCCINI study)

Anti-23 and Anti-IL-12/IL-23

  • Tissue selective targeted therapy –>excellent safety profile
  • IV loading and SC maintenance
  • Excellent for bowel and skin
  • IL-23 is not expressed in joints
  • Ustekinumab is effective for perianal disease and ulcerative colitis
  • Risankizumab is superior to ustekinumab in plaque psoriasis.  If loss of response to ustekinumab, can still respond to Risankizumab

Anti-Integrins:

  • Natalizumab (not used frequently in IBD)
  • Vedolizumab.  Affects mucosa (can explain frequent nasopharyngitis)
  • Vedolizumab -terrific safety profile.  No PML, no malignancy risk

Biosimilars:

  • If biosimilar found effective for one approved condition, extrapolation given to all indications
  • IBD switching studies have NOT shown increased loss of response.  Consider reassess prior to switch to help determine if patient truly in remission prior to switch. Switching often blamed for loss of response when many times the disease was not under good control prior to switch
  • Interchangeable indicates that the drug can be switched by pharmacists
  • Biosimilars are saving insurers money but no proof that this is saving patients money
  • Anti-drug antibodies will cross-react to biosimilars

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.

Infliximab: Reach Higher and Be Stronger

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M Gibson et al. JPGN 2023; 77: 207-213. Safety and Durability of Accelerated Infliximab Dosing Strategies in Pediatric IBD: A Single Center, Retrospective Study

This pediatric retrospective study (n=291, 2010-2020) showed a high response to infliximab in patients with inflammatory bowel disease (n=234 Crohn’s disease (CD), n=53 ulcerative colitis (UC)) over a 10-period. Mean duration of treatment among study participants was 2.9 years. Key findings:

  • 53% (n=135) started with doses of 10 mg/kg and 64% (n=87) of those who started on 5 mg/kg were dose-escalated; thus, approximately 76% of patients in their cohort needed doses of 10 mg/kg.
  • Only 12% of patients discontinued treatment over the observed timeframe.
  • Patients with UC (P ≤ 0.01) and patients with extensive disease (P = 0.01) had lower durability, despite a higher starting dose of IFX (P = 0.03).  Figure 2 indicated that durability in CD was ~93% compared to ~60% for UC with HR of 5.12. The HR for extensive disease (n=77) was 3.74 compared to those with limited disease (n=108). Still, ~75% of those with extensive disease continued on treatment
  • Common adverse events included 18 with skin findings (14 with psoriasis, 3 nonspecific rash, 1 with lupus), 23 with infusion reactions, 7 with AST/ALT >3 times ULN (or >120 IU/L), and 3 with serious infections.

Like the theme song from the 1996 Olympics (Reach, Gloria Estefan) reaching higher (dosing) resulted in being stronger (i.e.. better outcomes).

My take: This study showed really good outcomes associated with “accelerated” infliximab dosing.

Related blog posts:

The view before starting a climb at NRocks (Circleville, WV)
Highest point of our climb

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.