Tag Archives: anti-TNF therapy

Superiority of Anti-TNF Therapy in Children

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This study’s conclusion comes as no surprise:

“In children newly diagnosed with comparably severe CD, early monotherapy with anti-TNFα produced better overall clinical and growth outcomes at 1 year than early monotherapy with an immunomodulator. Further data will be required to best identify children most likely to benefit from early treatment with anti-TNFα therapy.”

Here’s the reference:

Gastroenterology Volume 146, Issue 2 , Pages 383-391, February 2014

Here’s a link to the full text article:  Increased Effectiveness of Early Therapy with Anti-Tumor Necrosis Factor-α Versus an Immunomodulator in Children with Crohn’s Disease

Methods: “From 2008 through 2012 at 28 pediatric gastroenterology centers in North America. Patients were managed by physician dictate. From 552 children (median age, 11.8 y; 61% male; 63% with pediatric CD activity index scores >30; and median C-reactive protein level 5.6-fold the upper limit of normal), we used propensity score methodology to identify 68 triads of patients matched for baseline characteristics who were treated with early anti-TNFα therapy, early immunomodulator, or no early immunotherapy.”

Another reference/link from same issue:

Accuracy of Magnetic Resonance Enterography in Assessing Response to Therapy and Mucosal Healing in Patients with Crohn’s Disease

IBD Update 2014 (part 2)

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5. Inflamm Bowel Dis 2013; 19: 2927-36.  This reference is another article that tries to help discuss the risks and benefits of biologic therapy for pediatric inflammatory bowel disease.  After reviewing the potential risks, the authors provide their “Option Grid” (Page 2932).  The authors state, “in summary, the adult literature supports the concept of the early use of combination therapy…the risks associated with anti-TNF therapy are really not significantly different as compared with thiopurine therapy and perhaps in some cases safer.  Therefore, we should be moving closer to the idea of using anti-TNF therapy early, with or without an immunomodulator.  In the sickest patients, combination therapy probably adds benefit, and then once in remission, consideration can be given for stopping one of the medications, more likely the thiopurine.

6. Gut 2013; 62: 689-94.  Risk of ischemic heart disease in patients with inflammatory bowel disease: a nationwide Danish cohort study.  From 1997 to 2009, the authors compared 28,833 IBD persons to >4.5 million persons without IBD who were matched for age, gender, socioeconomic status, and calendar year.  With a mean follow-up of 13 years, they identified a 59% higher incidence rate of ischemic heart disease in patients with IBD.  Long-term use of immunosuppressive medications, such as azathioprine and anti-tumor necrosis factor-alpha agents, was not associated with an increased risk of ischemic heart disease.

7.   Gastroenterol 2013; 145: 1459-63.  AGA Guideline for Use of Thiopurines, Methotrexate, and Ant-TNF-alpha Biologic Drugs for the Induction and Maintenance of Remission in Inflammatory Crohn’s Disease. This reference was previously noted in blog (with a link) AGA Guidelines for the Use of Thiopurines and Anti … – gutsandgrowt.  The print version does have a nice algorithm (pg 1463).  The accompanying technical review: Gastroenterol 2013; 145: 1464-78.

8. BMJ 2013;347:f6633. Free full-text BMJ article PDF. (Thanks to Mike Hart for this reference) From the abstract:  During 3 421 972 person years of follow-up, we documented 284 cases of Crohn’s disease and 363 cases of ulcerative colitis. The risk of Crohn’s disease was inversely associated with physical activity (P for trend 0.02). Compared with women in the lowest fifth of physical activity, the multivariate adjusted hazard ratio of Crohn’s disease among women in the highest fifth of physical activity was 0.64 (95% confidence interval 0.44 to 0.94). Active women with at least 27 metabolic equivalent task (MET) hours per week of physical activity had a 44% reduction (hazard ratio 0.56, 95% confidence interval 0.37 to 0.84) in risk of developing Crohn’s disease compared with sedentary women with ❤ MET h/wk. Physical activity was not associated with risk of ulcerative colitis (P for trend 0.46). The absolute risk of ulcerative colitis and Crohn’s disease among women in the highest fifth of physical activity was 8 and 6 events per 100 000 person years compared with 11 and 16 events per 100 000 person years among women in the lowest fifth of physical activity, respectively. Age, smoking, body mass index, and cohort did not significantly modify the association between physical activity and risk of ulcerative colitis or Crohn’s disease (all P for interaction >0.35). Conclusion In two large prospective cohorts of US women, physical activity was inversely associated with risk of Crohn’s disease but not of ulcerative colitis.

Comment: While physical activity may directly reduce the risk of Crohn’s disease, it could also be an epiphenomenon of another unmeasured variable (eg. dietary habits) that modifies this risk.

Related blog post:

Understanding IBD Therapy Risks -A Good Link | gutsandgrowth  Provides link to useful 6-minute internet video for families.

Reporting Bias: Infections with TNF Inhibitors

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A recent article (Clin Infect Dis 2013; 57: 1318-30 -thanks to Jeff Lewis for this reference) summarized the pediatric literature on infectious complications associated with tumor necrosis factor-α (TNF) inhibitors for both Juvenile Idiopathic Arthritis (JIA) and Inflammatory Bowel Disease (IBD).

In total 33 studies for JIA were included and 39 studies for IBD.  Many others were excluded due to overlapping cohorts or lack of sufficient data.

For JIA, the authors identified 296 infliximab (IFX) patients, 2465 etanercept patients, and 242 adalimumab patients.  Most infectious were mild and mainly viral etiology.  For example, 1016 upper respiratory illnesses with etanercept were reported.  However there were a significant number of more serious infections which included lower respiratory infections (n=37), cellulitis/abscess (n=15), histoplasmosis (n=2), and meningitis (n=4). Four patients had infectious fatalities.

Similarly, for IBD, most patients had mild infections.  Among 1407 IFX patients and 241 adalimumab (ADA) patients, there were 105 URIs noted.  Again, more serious infectious were noted in many.  Four fatalities were reported; 1 was due to disseminated CMV, 1 due to bacterial sepsis, and 2 were due to central line infections.

When examining this report, the question of reporting bias cannot be avoided. The various reports that were summarized included 30 prospective studies, 23 retrospective studies, and 19 various reports (case reports, case series, and FDA reports).  The composite, in my view, likely overestimates the risk of serious infections.  In addition, many of the infections may have been due to concurrent immunosuppressive therapy, but the details for this are lacking.

With regard to microbiology:

  • 5 JIA patients had tuberculosis; there were no tuberculosis cases reported in the IBD cohort
  • Varicella/zoster was the most frequent viral infection and was frequently severe.  In JIA cohort, there were 39 VZV cases (11 severe); among IBD cohort, there were 16 VZV cases (3 severe).

Bottomline: Given the frequent use of anti-TNF agents, better prospective pediatric data are needed.  In addition, careful analysis of the data is needed for better attribution; the risk for many of these infections is likely due to concurrent medications like corticosteroids.

Also Noted:

Clin Gastroenterol Hepatol 2013; 11: 826-31.  In a prospective cohort of 200 anti-TNF-naive adult patients (100 treated with IFX and 100 with ADA), the effectiveness was similar for IFX and ADA at both 1 and 2 year followup.  Improved efficacy was noted when these agents were combined with immunomodulators, though this was statistically significant for IFX. The total patient response was 63.5% at 1 year and 45% at 2 years.

Related posts:

Anti-TNF therapy for IBD

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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:

Understanding IBD Therapy Risks -A Good Link

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This link was posted on the GI Bulletin Board.  It is a 6 minute internet video overview of the treatments for IBD -it would be a useful resource for most families:

http://www.youandibd.com/en/understanding-ibd/understanding-the-risks-and-benefits-of-ibd-therapies.html

Some related blog posts:

Liver Injury from Anti-TNF Agents

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While anti-TNF agents have been associated with drug-induced liver injury (DILI), it has been difficult to get a handle on how much importance to place on this.  A recent study provides more data and some reassurance (Clin Gastroenterol Hepatol 2013; 11: 558-64).

The authors searched the U.S. DILI Network database from 2003 to 2011 and describe 6 cases of anti-TNF DILI; in addition, they searched PubMed for articles related to anti-TNF agent associated hepatotoxicity and identified an additional 28 cases. Other causes of liver disease were excluded in these patients, including reactivation of hepatitis B, and acute viral hepatitis (eg. hepatitis C, hepatitis E).

Results of anti-TNF hepatotoxicity:

  • 26 cases due to infliximab, 4 cases due to etanercept, and 4 due to adalimumab.
  • Based on scoring system, the anti-TNF agent was considered a definite cause of DILI in 1 (3%), very likely in 21 (62%) and probable in 12 (35%).
  • Median latency (duration of therapy before onset of DILI) was 13 weeks with a range of 2-104 weeks.
  • 22 (67%) had positive anti-nuclear and/or smooth muscle antibodies.  15 of 17 of these patients had liver biopsy features consistent with autoimmunity.
  • Among those 22 with autoimmune features, there was a higher peak alanine aminotransferase compared with the 12 without these features (784 vs 528 U/L)
  • Favorable outcome: all but one patient improved after discontinuation of the implicated drug; 12 received corticosteroids. One patient with underlying cirrhosis underwent liver transplantation after infliximab-induced liver injury.

While the authors note the potential for a class effect of anti-TNF agents, in studies from patients with psoriasis, there was a lack of cross-toxicity between etanercept and infliximab.

Take-home messages:

The risk of hepatocellular injury from anti-TNF agents is very low.  DILI due to anti-TNFs often have autoimmune features. The prognosis is favorable, and alternative anti-TNFs can be given after resolution.

Related blog links:

CCFA IBD Update -Conference Notes (part 2)

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As noted in previous blog post, I wanted to share some notes from recent Atlanta CCFA talk.

The fourth lecture by Jeffry Katz discussed optimizing biologic therapy.  Overall this was an excellent review.  He discussed his general preference for combination therapy since the publication of the SONIC study. Also, he highlighted a smaller study that showed better efficacy with combination therapy in ulcerative colitis as well (DDW 2011, Abstract #835).

With regard to withdrawal of therapy when doing well on combination treatment, he indicated that he sometimes reduces (or stops) dosage of immunomodulator after 1 year but tries to avoid stopping anti-TNF agents.  Relapse rates after stopping infliximab in Crohn’s disease are approximately 50% at 1 year and 75% at 5 years.

His talk reviewed antibodies to infliximab and low therapeutic levels. This has been discussed on this blog previously:

He reviewed risks of the IBD medications.  With regard to psoriasis reactions, he stated that developing skin lesions occur in about 5% and this necessitates drug withdrawal in 1%.  As these skin reactions are often a ‘class effect,’ use of an alternative may be needed.  He stated that he had used ustekinumab in this setting (“but this entails a fight with the insurance company”).

The 5th talk by Doug Wolf reviewed pregnancy in IBD.  Much of the information has also been discussed in this blog recently: Anti-TNFs and Pregnancy | gutsandgrowth

His key points:

  • Probably stop infliximab at gestational week 32
  • Likely give adalimumab up until week 34-36
  • If patient in remission, consider stopping stopping drugs earlier
  • In PIANO registry (n=1000), use of anti-TNFs and immunomodulators was not associated with any complication, including prematurity, spontaneous abortion, intrauterine growth retardation or specific birth defects.  However, there was a significant increase in infant infections up to 12 months of life in the combination therapy group.
  • No live virus vaccines (eg. rotavirus) for first 6 months for infants exposed to infliximab

The last talk that I attended was a pediatric case presentation from Cary Sauer. He presented a teenage boy who had mild disease based on bloodwork and endoscopy who had more severe and extensive disease on magnetic resonance enterography (MRE) (More imaging needed? | gutsandgrowth) and video capsule endoscopy.  He argued that small bowel assessment is worthwhile in every patient at the time of diagnosis as more severe findings could influence the choice to start with top-down therapy.

The final aspect worth mentioning were some of the patient-related information:

1. A pediatric, adolescent, and parent support group will have its first meeting April 23rd 6-7:30 pm at Scottish Rite Children’s Hospital (Main auditorium).  Followup meetings are scheduled for August 27, and October 22. All meetings are free.  Contact CCFA mball@ccfa.org or 646-623-4869 (cell) for more information.

2. CCFA also has “Power of Two.”  This contacts patients/parents with peer mentors.  Interested patients can contact mball@ccfa.org or 404-982-0616.

Quality improvement and better outcomes in Pediatric Inflammatory Bowel Disease

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More information on outcomes and quality improvement (QI) efforts are available from Cincinnati Children’s Hospital (JPGN 2012; 55: 679-88).  The QI efforts at Cincinnati are part of a broader effort in QI in pediatric IBD that has been discussed on a previous post (see below).

Our group has rejoined Improve Care Now (ICN) and I look forward to gaining more first hand experience.  Some of the ICN target goals:

  • 80% remission rate among each center and sustained remission rate of 45%
  • 76% steroid-free remission
  • 90% checking TPMT if using thiopurine
  • 95% checking PPD/chest xray if using biologic therapy
  • 95% using accepted methotrexate dosing

As I look at these goals, I wonder whether the remission rate is feasible and about the variation in different centers. For example, among the groups with >75% enrollment of their patients, one center reports a 89% remission rate and another center 64% remission rate.  Given the limited number of therapeutic agents, how could there be such a difference?  Some explanations could include variation in the use of more potent biologic agents as well as capturing/assuring followup of more patients who are doing well.

Given this backdrop, I looked at this most recent publication to learn how their QI practices could translate into better care for my patients.

In this retrospective chart review study of 505 patients, who were followed from 2007-2010 at the IBD center, the remission rate increased from 59% to 76%.  The data were captured prospectively.  This corresponded to improved patient global assessment (>7) from 69% to 80%.  Repeated steroid use dropped from 17% to 10%.  Vitamin D (25-OH D) improved and this also correlated with quiescent disease.

Remission rates were defined by a pediatric Crohn clinical disease index, the sPCDAI, or PUCAI for Ulcerative colitis.

Key observations:

  • There was a trend towards increased use of anti-TNFα therapy (along with decreased use of 6-mercaptopurine) during the study period, but this did not reach statistical significance. No statistical difference was identified in the use of any major IBD medication class.
  • Despite target goals, the only drug class with a statistically significant change in dosing was 5-ASA (from 42 mg/kg to 50 mg/kg).
  • Fecal calprotectin monitoring increased.  The QI team recommended that IBD patients with ‘inactive’ disease have a fecal calprotectin measured every 6 months.  Those with elevated values had therapeutic drug monitoring implemented.  “Fecal calprotectin >400 μg/g is associated with a higher chance of relapse in a pediatric cohort.”
  • Starting in 2009, increased vitamin D monitoring was implemented (every 6 months).  In patients with a serum 25-OHD level < 30 ng/mL, treatment with 50,000 units weekly (for 6-8 weeks) was recommended (8000 units if weight <20 kg).  Once serum 25-OHD was >30 ng/mL, patients were maintained on monthly dosing.
  • Preclinic planning also increased and corresponded to improved remission rates which were 67% in 2009 and 76% in 2010.
  • The authors conclude: “Our results show that significant improvement in patient outcomes were achieved following QI efforts that did not rely on new medications or therapies, rather through initiating novel care processes and standardization of care.”

I think this conclusion is misleading.  First of all, as the authors point out, they did change their therapeutic approach.  They started vitamin D in more patients, used anti-TNFα therapy in more patients, and increased dosing of 5-ASA agents.  Other gains in remission rate could have been related to improved followup of patients who were doing well.

Despite my skepticism about the conclusion, I think the overall achievements are laudable.  Decreasing variation of care and assuring that all patients receive the best care possible with our diagnostic tests and current therapies is certainly worthwhile.  When patient care is studied carefully, this makes sure that “standard” practice like checking TPMT status before thiopurine use, checking PPDs before anti-TNFα therapy, and using optimal drug dosing occur in virtually all patients.

Developing a checklist for each patient can help assure that best practices occur.  For those with electronic medical records, this may mean putting in more “hard stops.”  A hard stop means the physician cannot sign out of a chart without paying attention to a specific detail.  For example, if a physician orders methotrexate, a “hard stop” could come up if the dosing was not in the typical target range.

Useful link:

Link for disease classification (quiescent, mild, moderate, severe):

http://links.lww.com/MPG/A129

Related blog entries:

Adding Methotrexate to anti-TNF therapy

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While new therapies are emerging for inflammatory bowel disease as noted in recent blog entries on Vedolizumab and Tofacitinib, many patients have refractory disease and require management with available treatments.  One strategy in this situation has been to add methotrexate (Inflamm Bowel Dis 2012; 18: 1488-92).

This case series from the Mayo clinic reported their experience with 14 pediatric Crohn’s patients (10 males) who had methotrexate added to anti-TNF therapy.

Clinical remission was achieved in 50% (PCDAI <15) within 6 weeks with methotrexate (dose: 15 mg/meter squared –average dose 17.5mg SC weekly).  All patients received folate supplementation (1 mg daily). In this study, the average duration of methotrexate use was only 8.2 months & average followup was only 10 months.

Discussion notes that prior to methotrexate all patients had active disease despite anti-TNF therapy & most had received thiopurines. Most patients tolerated methotrexate. Four patients had Clostridium difficile infection; two cases were de novo.  Even after treatment of the infection, patients with Clostridium difficile were refractory to methotrexate treatment.

Of the initial 14 patients, two patients had severe nausea; this resulted in medication discontinuation in one patient and dose reduction in another patient.  No liver or kidney toxicity was identified.

Patients who did not respond to methotrexate, subsequent care including the following: three had surgery, one received tacrolimus/corticosteroids, one received natalizumab, one received certolizumab, and one received adalimumab/corticosteroids (while awaiting screening for certolizumab).

A prospective study of methotrexate is needed to confirm the its effectiveness in refractory Crohn’s and to determine long-term safety and efficacy.

Patient information on methotrexate (from my office website):  Methotrexate

Related blog entries:

Drug levels for inflammatory bowel disease

Methotrexate and liver toxicity

Additional methotrexate references:

-IBD 2011; 17: 2521. Methotrexate therapy: ~25% remission at 1yr, 16% at 2yrs.. n=93.
-JPGN 2011;53: 389. n=64. Supports use of zofran for 1st few months to prevent nausea.
-JPGN 2010; 51: 714. Use of MTX after thiopurines. n=27. 48% in remission at 6 months.
-JPGN 2009; 48: 526. Use in pediatric CD, n=25. 64% response