What Happens After The First Anti-TNF Agent Doesn’t Work?

A recent intriguing retrospective study (MJ Casanova et al. Inflamm Bowel Dis 2020; 26: 606-16, editorial 617-18) examines a large cohort (n=1122) who received either a 2nd or 3rd anti-TNF agent.  This relied on the ENEIDA registry which is a prospectively maintained registry from Spain with 11,866 patients. In this study, clinical remission was gauged with a Harvey Bradshaw Index score of ≤4 in Crohn’s disease (CD) or a partial Mayo score of ≤2 in ulcerative colitis (UC).

Key findings:

  • 45% of patients achieved remission with the second anti-TNF at 12 weeks (short-term); loss of response was 19% per patient-year subsequently. Patients with intolerance to the first drug had higher remission rates compared to those who switched due to secondary failure (52% vs 42%) or primary failure (52% vs 39%).
  • Among the 45% who responded to a second anti-TNF agent, 77% maintained remission at 1 year following switch.
  • There was similar initial response to a second anti-TNF among patients with CD and UC: 46% vs 41%, though patients with UC were more likely to lose efficacy.
  • Combination therapy was associated with a higher likelihood of failure, HR 2.4 (possibly as an indicator of more aggressive disease)
  • Among the 71 patients who progressed to a 3rd anti-TNF agent, 55% achieved remission at 12 weeks. 


  • The authors in their discussion not that “primary failure is considered a class effect phenomenon…However, our results indicate that remission may still be achieved with a second anti-TNF in approximately 50% of patients.”
  • The editorial notes that the results need to be interpreted with caution.  Therapeutic drug monitoring (TDM) which is not incorporated in this study is crucial in optimizing response and switching.  “Importantly, nearly two-thirds of patients with therapeutic drug levels in the study form the Mayo Clinic had no active inflammation.  Thus, a change in therapy would be inappropriate in this population.”

My take: This study indicates that a 2nd anti-TNF agent can be effective in those who do not respond to a 1st.  At the same time, careful assessment including TDM is needed when changing agents, especially in view of the limited number of effective therapies.

Related blog posts:

From Atlanta Botanical Garden

IBD Shorts March 2020

Ustekinumab Predictor. At recent ACG meeting, PS Dulai presented data on 781 adult patients that was used to determine likelihood of ustekinumab response. Source: GIHepNews: New ustekinumab response predictor in Crohn’s called ‘brilliant’

Variable  & Points:

  • No prior anti-TNF agents:  2 points
  • No prior bowel surgery: 2 points
  • No smoking (current or prior): 1 point
  • No active fistulas: 1 point
  • Baseline albumin: >4.3    3 points, >3.9-4.3     2 points, >.3.2-3.9   0 points,     >2.5-3.2    -1 point, 2.5 or less   -3 points

Probability of Response Interpretation:

  • High if ≥5 points
  • Intermediate if 2-4 points
  • Low if 0 or 1 points

Infliximab outperformed golimumab for moderate-to-severe ulcerative colitis. S Singh et al. Clin Gastroenterol Hepatol 2020; 18: 424-31. Using data from three phase 3 trials (1793 patients), the authors found that infliximab worked more rapidly and with greater efficacy than golimumab.  At week 6, patient reported outcome of clinical remission was 50.0% and 38.9% (aOR 2.0).  After adjusting for patient variables, infliximab was superior in achieving clinical remission with aOR 3.01 (39% vs. 21%).

Increasing incidence of inflammatory bowel disease in Latin America and Caribbean. PG Kotze et al. Clin Gastroenterol Hepatol 2020; 18: 304-12. This systematic review examined incidence & prevalence of IBD over the last 30 years. In Brazil, for example, the incidence of Crohn’s disease jumped from 0.08 per 100,000 person-years in 1988 to 5.5 per 100,000 person-years in 2015.

IBD Passport Website: IBD Passport homepage. “IBD Passport is an award winning website that aims to provide comprehensive, practical and reliable information on all aspects of travelling with Crohn’s Disease or Ulcerative Colitis (Inflammatory Bowel Disease). IBD Passport is the first website to combine this information into one resource to make planning your trip easy. IBD Passport is a UK registered non-profit charity (Registered number: 1171268) with a global reach aimed to support IBD travellers of all nations and regions in the world.”

Adverse Effects of Low-Dose Methotrexate (≤20 mg/week). DH Solomon et al. Ann Intern Med. 2020. DOI: 10.7326/M19-3369. n=4786, median age 66 years. This was a secondary analyses of a double-blind, placebo-controlled, randomized trial. “With the exception of increased risk for skin cancer (HR, 2.05 [CI, 1.28 to 3.28]), the treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal AEs.” There were increased risks of gastrointestinal, infectious, pulmonary, and hematologic AE.




Appropriate Proactive Therapeutic Drug Monitoring

This blog post and tomorrow’s post highlights two articles on proactive therapeutic drug monitoring (pTDM) for inflammatory bowel disease.  The first article (K Papmichael et al.  Clin Gastroenterol Hepatol 2019; 17: 1655-68) summarizes a meeting of 13 international IBD specialists who reached consensus on 24 statements after a review of the literature.

Full Text Link:  Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases

Key Recommendations:

  • For anti-tumor necrosis factor (anti-TNF) therapies, proactive TDM was found to be appropriate after induction and at least once during maintenance therapy, but this was not the case for the other biologics.
  • Reactive TDM was appropriate for all biologic agents both for primary non-response and secondary loss of response

Background/Rationale for pTDM:

  • “Numerous studies have demonstrated a positive correlation between serum biologic drug.concentrations and favorable therapeutic outcomes”
  • “Low or undetectable drug concentrations can lead to immunogenicity and treatment failures”
  • “TDM…is an important tool for optimizing biologic therapy…Data suggest that pTDM, with drug titration to a target trough concentration, performed in patients with clinical response/remission can also improve the efficacy of anti-TNFs”

Table 4  Scenarios of Applying Therapeutic Drug Monitoring of Biological Therapy in Patients With Inflammatory Bowel Disease

1-4: Anti-TNFs:

  • It is appropriate to order drug/antibody concentration testing in responders at the end of induction for all anti-TNFs.
  • It is appropriate to order drug/antibody concentration testing at least once during maintenance for patients on all anti-TNFs.
  • It is appropriate to order drug/antibody concentration testing of anti-TNFs at the end of induction in primary non-responders.
  • It is appropriate to order drug/antibody concentration testing for all anti-TNFs in patients with confirmed secondary loss of response.

5-8: Vedolizumab -agreement only on ordering TDM in non-responders or those with loss of response

9-12: Ustekinumab  -agreement only on ordering TDM in non-responders or those with loss of response

From Table 5: Biological Drug Concentrations and Anti-Drug Antibodies When Applying Therapeutic Drug Monitoring in Inflammatory Bowel Disease

  • Infliximab: 15. In the presence of adequate trough drug concentrations, anti-drug antibodies are unlikely to be clinically relevant.
  • Infliximab: 19. The minimal trough concentration for infliximab post-induction at week 14 should be greater than 3 μg/mL, and concentrations greater than 7 μg/mL are associated with an increased likelihood of mucosal healing.
  • Adalimumab: 22. The minimum drug concentration at week 4 for adalimumab should at least be 5 μg/mL. Drug concentrations greater than 7 μg/ml are associated with an increased likelihood of mucosal healing.
  • Certolizumab: 24 & 25: The minimum concentrations for certolizumab pegol at week 6 should be greater than 32 μg/mL and 15 μg/mL during maintenance.
  • Golimumab 26 & 27: The minimum drug concentration at week 6 for golimumab should at least be 2.5 μg/mL and 1 μg/mL.during maintenance

My take: This article provides extensive literature to reinforce their recommendations.  Most of the trough levels mentioned are minimum levels that need to be achieved.


Safer Than You Think: Biologic Therapies for IBD and Risk of Infection and Malignancy

While there have been a number of studies which have highlighted the potential risks of biologic agents, many studies have NOT identified any risk of infection or malignancy.

Another recent systematic review/meta-analysis (S Bonovas et al. Clin Gastroenterol Hepatol 2016; 14: 1385-97) provides reassuring data regarding the following biologics: infliximab, adalimumab, certolizumab, golimumab, natalizumab, and vedolizumab.

The authors identified 49 randomized placebo-controlled studies with 14,590 participants.

Key findings:

  • There was a moderate infection risk with odds ratio of 1.19 (19% increase in odds of developing an infection) and significant increase in opportunistic infections (eg. tuberculosis) OR 1.90
  • Risk of serious infections was NOT increased in patients treated with biologics with OR 0.89.  In studies with low risk of bias, the risk of serious infections had OR of 0.56.
  • No increase in malignancy risk was identified with OR 0.90 but the authors note that data was insufficient in terms of exposure and follow-up to be conclusive.

The authors note that the studies including in this review challenge some of the findings of observational studies. “However, observational studies lack the experimental random allocation of participants…the discrepancies between observational studies and randomized trial evidence might be explained by the inability of observational designs to fully address the complex and important differences between the IBD patients receiving and those not receiving biologics.”

Study limitations include “sponsorship bias -because the trials were supported by pharmaceutical companies and limited followup of 24 months. In addition, most of the trials in the meta-analysis were judged to be at high or unclear risk of bias because of their methodological characteristics.

My take: This study indicates that biologic therapies do not appear to increase the risk of serious infections and may not increase the overall risk of malignancy.

Related blog posts:

Portland Fish Market

Portland Fish Market



Sticky Decisions with IBD Therapy – When an Infection or Malignancy Develops

A recent review article provides advice for management of biologics and immunomodulators when an infection or malignancy develops (Inflamm Bowel Dis 2014; 20: 926-35).  Serious infections are noted in 3-5% of adults receiving either thiopurines or anti-tumor necrosis factor agents (anti-TNFs); less than 0.1% of adults develop treatment-related lymphoma.  The recommendations are provided in 5 separate tables.

Table 1 addresses the issue of bacterial infectionsFor mild infections, the authors recommend that thiopurines (azathiopurine, 6-mercaptopurine) as well as anti-tumor necrosis factor agents (infliximab, adalimumab, certolizumab, golimumab) be continued.  Examples of these ‘mild’ infectious included E. coli UTI and strep pharyngitis.  For severe bacterial infections (eg. pneumococcal pneumonia), for both these therapies, the authors recommend: “stop, but may restart once treated.”  For bacterial opportunistic infections (eg. mycobacterium), for latent infections, “do not start until 2 to 4 wk INH” whereas for active infections, the authors recommend (for anti-TNFs) “stop, only restart after full treatment, and if IBD is severe.”

  • Table 2 addresses fungal infections.
  • Table 3 addresses viral infections (eg. CMV, EBV).  For EBV, the authors recommend stopping thiopurines and not restarting in male patients.
  • Table 4 addresses malignancy: solid tumors, hepatosplenic T-cell, EBV-associated lymphoma, and lymphoproliferative lymphoma.
  • Table 5 addresses skin cancers.

Towards the end of the review, the authors provide some context for the risks with thiopurines and anti-TNFs.  “The majority of side effects associated with thiopurines and anti-TNFs are mild, self-limited and reversible…the risk of a lymphoma developing on AZA/6-MP (4/10,000 patient-years) is comparable with the lifetime risk of dying from drowning (1/1112) or dying in a bicycle accident (1/5000).  The risk is much less than the risk of dying in an automobile accident (1/108).  Patients are willing to accept risks..if their disease is severe and the chance of a clinical response outweighs the risk.”

With regard to dual therapy, the authors note, “it has been our practice to lower the concomitant AZA/6-MP in patients on combination therapy with anti-TNF and then to stop the thiopurine in patients in deep remission for 3 years. However, this decision must be individualized, and for patients with severe, disabling disease, we generally do not alter treatment.”

Bottomline: This is a useful advice/handy reference for the sticky situation of managing IBD in the face of infections and malignancy.

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.


Comparing Biologics for Ulcerative Colitis

A recent study has reviewed biologic therapies for ulcerative colitis (Ann Intern Med. 2014;160(10):704-711). Here’s the abstract link: bit.ly/1o5PpRX.

Data Synthesis: ..There were 7 double-blind, placebo-controlled trials that were rated as low risk of bias and showed that all biological agents (adalimumab, golimumab, infliximab, and vedolizumab) resulted in more clinical responses, clinical remissions, and mucosal healings than placebo for induction therapy. The results of network meta-analysis suggested that infliximab is more effective to induce clinical response (odds ratio, 2.36 [95% credible interval, 1.22 to 4.63]) and mucosal healing (odds ratio, 2.02 [95% credible interval, 1.13 to 3.59]) than adalimumab. No other indirect comparison reached statistical significance. For maintenance, 6 double-blind, placebo-controlled trials that were rated high risk of bias showed that all biological agents have greater clinical efficacy than placebo. The occurrence of adverse events was not different between biological agents and placebo.

Limitation: Few trials, no head-to-head comparisons, and inadequate follow-up in maintenance trials.

Conclusion: Biological agents are effective treatments for UC, but head-to-head trials are warranted to establish the best therapeutic option.

Related blog posts:


In PURSUIT of Better Treatment for Ulcerative Colitis

Patient education materials:

#1  Ulcerative Colitis For Dummies | UC Patient Resource This link connects to a free educational book promoted by Salix pharmaceuticals.  In order to receive a free download, you have to register and include your email.  I have not read this book but other similar books (eg. Colonoscopy for Dummies) by Salix have been well-written.

#2 This link, ow.ly/sPX95, is to the ImproveCareNow visit planner website.  It poses of ~ 8 questions and a text box  for “my list of things I’m concerned about and questions that I have.”  Families that use this planner may help themselves achieve more comprehensive care.

Anyone who follows this blog knows that I really enjoy a good study acronym.  The Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment (PURSUIT) is responsible for two papers in the most recent Gastroenterology issue:

  • Gastroenterol 2014; 146: 85-95
  • Gastroenterol 2014; 146: 96-109

PURSUIT is composed of >200 sites from around the world.  The first study was a combined phase 2 and phase 3 study. It enrolled 1064 adults with moderate to severe ulcerative colitis (UC) who were randomly assigned to either placebo, 200/100 mg or 400/200 mg of SC golimumab at 0 and 2 weeks.  All patients were naive to previous anti-TNF therapies. The average duration of disease was 6 years among the participants. The primary endpoint of the phase 3 part of this study was the clinical response at 6 weeks.  Clinical response was at least a 30% improvement and a ≥3-point improvement in the Mayo score. At baseline, the average Mayo score was 8.

  • The golimumab groups had response rates of 51.8% and 55.0% respectively compared to 29.7% for placebo.
  • Approximately 18% of patients achieved a clinical remission with treatment compared with 6% of placebo patients.
  • Approximately 10% had healed mucosa compared with ~4% in the placebo group.
  • Adverse events: Rates of serious infection were 1.8% for the active treatment group compared with 0.5% for placebo-treated patients.  In the 400/200 mg dosing group, there was 1 death attributed to peritonitis and sepsis after multiple procedures for ischiorectal abscess repair.  In addition, a single case of demyelination was noted in this group.

The second study, a phase 3 double-blind trial, evaluated the efficacy of maintenance treatment of 50 mg or 100 mg SC every 4 weeks in those with a successful induction (n=464).  This study took place at 251 centers between 2007-2011. At 54 weeks, the actively-treated gourds had maintained a clinical response, using the Mayo score, in 47.1% and 50.6% respectively compared to 31.4% for placebo.  Antibodies to golimumab developed in 2.9%, two-thirds of these antibodies were neutralizing.  Antibody formation was lower in those receiving concomitant immunomodulators. 4 cases of tuberculosis were noted from endemic regions despite previous screening.  Overall, infections occurred in 28% of those treated with placebo compared with 39% of those treated with golimumab.

During the course of the study, three deaths were reported, all in the 100 mg golimumab maintenance group.  The causes were malnutrition/sepsis, cardiac failure/thrombosis, and disseminated tuberculosis (patient was receiving isoniazid). After the study, another 6 deaths were reported, including two in the placebo group.  Three malignancies were reported through week 54 in patients receiving golimumab maintenance, two of these presented in the induction period while receiving placebo rectal cancer and thyroid cancer) and one (lung adenocarcinoma) occurred in a patient with a 40-year smoking history who received golimumab for induction and maintenance.

Taken together, about 25% of patients randomized to and maintained on golimumab achieved a clinical response lasting >1 year; similarly, about 17% had clinical remission at 1 year.

In the commentary (page 13-15), Stephen Hanauer notes that better response was noted with higher serum levels and there remains “a strong possibility that optimal dosing was not achieved.”  He and the authors comment on the observation that less-severe patients had a better response, indicating that  “greater disease severity may be correlated with more rapid clearance.”

Bottomline: These studies demonstrate that golimumab is an effective treatment for UC with a similar risk of adverse reactions as other anti-TNF agents.  The published studies are complicated and take some time to analyze.

Plus more references:

Gastroenterol 2014; 146: 110-18. “Adalimumab therapy is associated with reduced risk of hospitalization in patients with ulcerative colitis.” Data for this studies was derived from ULTRA1 and ULTRA2 trials with 963 patients.  Risk for hospitalization, whether due to UC or all-causes, was reduced between 40-50% compared to placebo within the first 8 weeks of adalimumab administration.

Clin Gastroenterol Hepatol 2013; 11: 1538-49.  Excellent review on pouchitis. Figure 5 (pg 1545) provides a nice treatment algorithm.  Initial approach is antibiotics (metronidazole or ciprofloxacin); in those responsive, either prn therapy or chronic treatment.  In those not responsive, look for pathogens (eg. CMV and C difficile) or determine it is immune-mediated (PSC-associated, IgG4-associated, or autoimmune).  The immune-mediated may respond to 5-ASA/budesonide or immunomodulators.

Clin Gastroenterol Hepatol 2013; 11: 1601-08. This case-control study with 141 UC controls and 59 patients who developed colorectal neoplasia found that increased inflammation was associated with colorectal neoplasia.  Use of immune modulators reduced the risk of colorectal neoplasia.

Related blog post:

Simponi (Golimumab) Approved for Ulcerative Colitis | gutsandgrowth

Anti-TNF therapy for IBD

In the same issue as the vedolizumab phase 3 studies, there is a succinct review of tumor necrosis antagonist therapy (anti-TNF) therapy for IBD (NEJM 2103; 369: 754-62).

Useful points about IBD:

  • Prevalence of ulcerative colitis (UC) and Crohn’s disease (CD) in North America: 780,000 and 630,00 respectively
  • In first 10 years of CD, cumulative rate of surgery is 40-55%.
  • In first 20 years of UC, rate of colectomy is ~15%.
  • “Recent meta-analysis do not indicate that this drug (mesalamine) has any clinically relevant efficacy in patients with” Crohn’s disease.

Anti-TNF agents:

  • Agents for IBD include infliximab, adalimumab, certolizumab pegol, and golimumab.
  • No head-to-head comparisons have been studied, though the “clinical trials suggest similar efficacy among the available drugs.”
  • Newest approved anti-TNF is golimumab which is administered subcutaneously at a dose of 200 mg at week 0, followed by 100 mg at week 2 and then 100 mg every 4 weeks.
  • A “considerable number of patients with Crohn’s disease (10-40%, depending on selection criteria) do not have a clinically relevant response to currently available TNF inhibitors (primary treatment failure) and among patients with ulcerative colitis, this proportion may be as high as 50%.”
  • “In addition, only about one third to one half of patients with Crohn’s disease have a complete remission, and about two thirds of patients do not have a response that is sustained during 12 months of continuous treatment (secondary treatment failure).”  Many of these patients will respond to dose escalation.
  • The “annual projected cost of each biologic agent for a 70-kg patient with inflammatory bowel disease is approximately $19,000 in the first year and $15,000 in subsequent years.”  These figures exclude the costs associated with administration and dose escalation.

Areas of uncertainty according to the authors:

  • “The value of concomitant treatment with immunosuppressive agents and TNF inhibitors has been debated intensely.”  Combination therapy results in superior efficacy and lower rates of antibodies to anti-TNF agents.  However, “the benefit of combined treatment for more than 12 months is uncertain.”
  • “There are no data to confirm that it (top-down treatment) is actually superior to conventional step-up therapy in terms of disease progression”

Related blog links: