Tag Archives: infliximab

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:

AGA Guidelines for the Use of Thiopurines and Anti-TNF Agents for Crohn’s

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The link (from KT Park’s twitter feed): gastrojournal.org/article/S0016-5085(13)01521-7/fulltext …

Some of the key points/recommendations for adults with Crohn’s disease:

  • In clinical practice, CD of moderate severity is defined as disease requiring systemic corticosteroids for symptom control.

For Induction of Remission:

  • We Suggest Against Using Thiopurine Monotherapy to Induce Remission in Patients With Moderately Severe CD (Weak Recommendation, Moderate-Quality Evidence)
  • We Suggest Against Using Methotrexate to Induce Remission in Patients With Moderately Severe CD (Weak Recommendation, Low-Quality Evidence)
  • We Recommend Using Anti–TNF-α Drugs to Induce Remission in Patients With Moderately Severe CD (Strong Recommendation, Moderate-Quality Evidence)
  • We Suggest Using Anti–TNF-α Drugs in Combination With Thiopurines Over Anti–TNF-α Drug Monotherapy to Induce Remission in Patients Who Have Moderately Severe CD (Weak Recommendation, Moderate-Quality Evidence)

Maintenance of Remission:

  • We Recommend Using Thiopurines Over No Immunomodulator Therapy to Maintain a Corticosteroid-Induced Remission in Patients With CD (Strong Recommendation, Moderate-Quality Evidence)
  • We Suggest Using Methotrexate Over No Immunomodulator Therapy to Maintain Corticosteroid-Induced Remission in Patients With CD (Weak Recommendation, Low-Quality Evidence)
  • We Recommend Using Anti–TNF-α Drugs Over No Anti–TNF-α Drugs to Maintain Corticosteroid- or Anti–TNF-α—Induced Remission in Patients With CD (Strong Recommendation, High-Quality Evidence)
  • We Make No Recommendation for or Against the Combination of an Anti–TNF-α Drug and a Thiopurine Versus an Anti–TNF-α Drug Alone to Maintain Remission Induced by a Combination of These Drugs in Patients With CD (No Recommendation, Low-Quality Evidence)

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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:

TNF Antagonists and Psoriasis

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Using data from the adverse event reporting system (AERS) from the FDA, the authors of a recent report identified a large number of psoriasis rashes which developed among patients receiving tumor necrosis factor α (TNF) antagonists (Inflamm Bowel Dis 2013; 19: 1164-72).

From more than 13 million AERS reports (2004-2011), a total of 5432 reports of psoriasis were noted: 1789 for infliximab, 3475 for adalimumab, and 168 for certolizumab compared with 88 for a control group which consisted of the following medications: propranolol, melamine, and lithium. While the absolute number for certolizumab is lower, the relative risk is similar to infliximab when adjusted for frequency of usage.

The AERS database relies on voluntary reporting and there are numerous reporting biases.  Given that AERS captures only a fraction of all true adverse events, the authors extrapolate that more 15,000 psoriasisiform adverse events occur each.  They note that these reactions typically occur in individuals without a personal or family history of psoriasis.  The onset is variable, but typically occurs 9-11 months after initiating therapy.

Additional references:

  • -IBD 2011; 17: 2512.  n=50.  Skin reactions with adalimumab.  62% of pts develop skin reactions: eczema, acne-like dermatitis, psoriasis-like (6 of 50).  Adalimumab d/c’d in 22%.
  • -JPGN 2010; 52: 230. 6 of 73 pts (8%) developed IFX-induced psoriasis -managed with topical Rx.
  • -Clin Gastro & Hep 2010; 8: xxiv. Image of psoriaform rash assoc with infliximab
  • -Aliment pharmacol Ther 2009; 29: 921-27. Review of psoriaform rash assoc with infliximab. Majority improved when TNF stopped.  Options: Rx w steroids for 3 days around Rx or add MTX.
  • -NEJM 2009; 361: 496. Review of psoriasis.

Unrelated link:

For those of you who do not have teenage sons, perhaps you are not familiar with Jimmy Kimmel’s:  This Week in Unnecessary Censorship – YouTube

Rethinking top-down treatment?

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Given the effectiveness of biologic therapy and the potential for disease modification, the threshold for “top-down” treatment has been lower at this time as compared with “step-up” treatment.  What about long-term outcomes, does starting soon increase or decrease the likelihood of doing well?  A recent study suggests that “early biologic therapy did not improve disease activity or quality of life” (Inflamm Bowel Dis 2013; 19: 1397-1403).

In this retrospective chart review involving 93 patient’s with Crohn’s disease (between 2004 and 2010), patients whose data was prospectively maintained were categorized into either early biologic therapy or a step-up group. For these patients, the mean age at diagnosis was 28 years.  There were no apparent differences in demographic variables between the groups; however, the early biologic therapy group had higher disease activity and lower quality of life scores at baseline. 20% were current smokers and 61% never smoked.  Disease location was similar in both groups; overall, 35% had ileal disease, 13% colonic disease, 34% ileocolonic, and 7% isolated upper tract disease.

Results:

  • Mean Harvey-Bradshaw index and Short Inflammatory Bowel Disease Questionnaire scores at 3, 6, and 12 months were not different between the groups.
  • Early biologic therapy group had more hospitalizations.
  • No difference in steroid use or surgeries was noted at one year.

Take-home message: This study suggests that differences in outcomes between “top-down” therapy and step-up therapy are more pronounced early in the treatment course but may wane after 1 to 2 years.  However, early biologic therapy “may be a more effective strategy in patients with Crohn’s disease with higher disease activity.”

Relating blog posts:

More data on DILI

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Using a population-based cohort, the authors of a recent study from Iceland performed a prospective study, collecting data on 96 individuals with drug-induced liver injury (DILI) from 2010-2011 (Gastroenterol 2013; 144: 1419-25 & editorial 1335-36).  This study benefitted from a centralized medical care system with about 250,000 adults.  Patients with acetaminophen toxicity were excluded.

Results:

  1. DILI occurred in 19 cases per 100,000 persons per year.  This is higher than previous DILI estimates in other populations and may be due to identifying more subclinical cases.
  2. DILI increased markedly with age from 9 per 100,000 among 15-29 year olds to 41 per 100,000 among those >70; however, this paralleled the increase use of medications.
  3. Eight drugs were implicated in more than 1 case with subsequent risk estimates:
  • Augmentin 1 per 2350 users
  • Azathioprine 1 per 133  (mostly anicteric cases)
  • Infliximab 1 per 148
  • Nitrofurantoin 1 per 1369
  • Isotretinoin 1 per 732
  • Atorvastatin 1 per 3693
  • Diclofenac 1 per 9148
  • Doxycycline 1 per 16,339

Some commonly implicated drugs did not show up on the list: fluoroquinolones, macrolide antibiotics, minocycline, valproic acid, and cancer chemotherapeutic agents (except one case due to imatinib).  The editorialist notes that these agents are not commonly used in Iceland.  Also, 16% of cases were due to herbals and dietary supplements.

Consequences of DILI: 27% developed jaundice, 12% required hospitalization, and 1 patient died.  The median time for liver tests to normalize in those that recovered was 64 days.

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Treating Allergic Reactions to Infliximab

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This week on the GI bulletin board there was a brief discussion about overcoming allergic/anaphylactic reactions to infliximab.  A reference and a thoughtful response by Athos Bousvaros (in italics) follows:

Inflamm Bowel Dis. 2001 Feb;7(1):34-7. Successful desensitization and therapeutic use of infliximab in adult and pediatric Crohn’s disease patients with prior anaphylactic reaction. Puchner TC, Kugathasan S, Kelly KJ, Binion DG.   

 IN summary:

1.  Premed with 4 days of steroids (1mg/kg up to 40mg), and hydrocortisone day of the infusion.

2.  Give two test doses (0.1 mg, 1 mg), each over 10 minutes,

3.  If no problems, run the infusion over 4 hours instead of two.

 

Getting antibodies to infliximab before the challenge may also be helpful.  If high levels of antibodies are present, the patient may be more likely to fail the challenge. WE can “rescue” about half our patients using this protocol, and keep them on infliximab. IMPORTANT that a physician is around during the challenge.

Given the potential for adverse reactions and the importance of not depleting useful treatments, it is definitely worthwhile to read the entire cited reference rather than the aforementioned summary.

Related blog entry:

Overcoming ATIs | gutsandgrowth

Neurological Complications Associated with Inflammatory Bowel Disease

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Though I have not seen much in the way of neurological complications in our pediatric inflammatory bowel disease (IBD) population, nevertheless I worry about them.  A recent article provides some insight into the incidence, the pathophysiology and approach to these complications (Inflamm Bowel Dis 2013; 19: 864-72).

Types of neurologic complications: The most common neurologic complication is peripheral neuropathy.  The frequency is quite variable based on data collection method.  In large administrative healthcare data, the prevalence has been reported around 2% whereas in cohort studies the range has been 8-15%. Other complications include meylopathy, cerbrovascular disease, cranial nerve palsy (eg. Melkersson-Rosenthal syndrome), seizures, and demyelinating diseases.

With regard to demyelinating diseases, this has gained additional attention in the setting of biologic agents which have been associated with this complication.  However, the authors note that a pre-biologic treatment study from Olmstead County, observed a prevalence of multiple sclerosis of 1% which was 3.7 times higher than expected.  In addition, similar studies have confirmed this finding.

Potential mechanisms vary greatly depending on the neurologic complication. With regard to cerebrovascular disorders, “venous thromboembolism (VTE) has been shown to occur 3 times more frequently in patients with IBD (the risk increases to 8-10-fold in patients with active colitis) than the general population.”  Hence, VTE prophylaxis is recommended by the authors in hospitalized IBD patients, especially if they are experiencing a disease exacerbation.

In addition to the underlying disease, vitamin deficiencies (eg. Vitamin B12) and medications can trigger neurologic complications.

  • Natalizumab: progress multifocal leukoencephalopathy (PML)
  • Metronidazole: peripheral neuropathy (typically reversible with drug discontinuation)
  • Anti-TNF-α agents (infliximab, adalimumab, certolizumab): demyelination, rarely seizures, and rarely PML
  • Cyclosporine: various neurotoxicity in ~25%

Related blog entries:

Anti-TNF Therapy for Eosinophilic Gastroenteritis

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A recent report highlights the use of anti-TNF therapy (eg. infliximab (IFX) and adalimumab [ADA])  for eosinophilic enterocolitis/eosinophilic gastroenteritis in eight patients who had not responded to other treatments (JPGN 2013; 56: 492-97).

The mean age of these patients was 8 years with a range of 1 to 14 years.  Prior to use of IFX therapy, multiple therapies had been used.  Four patients had been treated with complete elemental diet; medications that were used included montelukast, hydroxyzine, sodium cromogylcate, budesonide, amitriptyline, prednisone, ketotifen, cyproheptadine, thiopurines, and methotrexate (Table 1 in study).

Complete clinical remission was noted to occur in 6 (75%) with IFX induction treatment; this was associated with mucosal healing in 3, mucosal improvement in 2, and unknown in 1 patient.

The six responders were followed for a median of 7 years.  During that timeframe, four of six had secondary loss of response and were switched to ADA.  Three of these four maintained a clinical response with ADA using high doses (80 mg EOW).

Additional References:

  • -Clin Gastroenterol Hepatol 2011; 9: 950.  40% of Eosinophili gastroenteritis resolved.
  • -JPGN 2010; 51: 723. n=91.  Incidental gastric eosinophils does not predict a worse response to fluticasone then isolated EoE.
  • -NEJM 2009; 361: 1387.  Description of a case of eosinophilic gastroenteritis.
  • -Gut 2009; 58: 721-32. Review of primary Eos d/o of GI tract.
  • -JPGN 2008; 47: 234-8.  EGIDs.

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.

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