Tag Archives: natalizumab

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

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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.

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IBD References 10/13

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Recent useful references:

Inflamm Bowel Dis 2013; 19: 2490-2500.  “Endemic Fungal Infections in Inflammatory Bowel Disease Associated with Anti-TNF Antibody Therapy”

  • Reviews histoplasmosis, blastomycosis, & coccidioidomycosis. Provides endemic maps (which are available at CDC website), diagnostic tips, and treatment recommendations.  Of these three infections, blastomycosis is endemic in Northern Georgia.
  • Histoplasmosis can be diagnosed with urinary antigen, Blastomycosis is most commonly diagnosed with sputum cultures or bronchial washings for cytology, and coccidioidomycosis can be identified with serology (Coccidioides immittis)
  • Generally a good idea to get a chest radiograph in patients with respiratory symptoms, fever, chills, myalgias, and headaches.
  • CDC Fact Sheet – Centers for Disease Control and Prevention  Map for several endemic fungal diseases, including histoplasmosis and blastomycosis.
  • CDC Features – Valley Fever: Awareness is Key Map for endemic coccidiomycosis.

Inflamm Bowel Dis 2013; 19: 2457-2463. “Efficacy and Safety of Natalizumab in Crohn’s Disease Patients Treated at 6 Boston Academic Hospitals”

  • 44 of 64 with adequate evaluation had either a partial or complete clinical response.  In this select group of complicated patients, about one-third had clinical improvement for more than a year.
  • No cases of PML noted in this cohort.

Inflamm Bowel Dis 2013; 19: 2433-2439. “Serum IL-17A in Newly Diagnosed Treatment-Naive Patients with Ulcerative Colitis Reflects Clinical Disease Severity and Predicts the Course of Disease”

  • Mucosal mRNA expression of IL-17A was 99.8 times higher in ulcerative colitis patients compared to controls.
  • Serum IL-17A correlated with clinical disease severity and was a marker for disease course over the following 3 years.

Inflamm Bowel Dis 2013; 19: 2440-2443. “Assessment of the Relationship Between Quality of Sleep and Disease Activity in Inflammatory Bowel Disease Patients”

  • Data found an association between poor sleep quality and disease activity.  Furthermore, patients in clinical remission with abnormal sleep have a high likelihood of subclinical disease activity (another question for the EPIC smartform?).

Inflamm Bowel Dis 2013; 19: 2423-2432. “Nationwide Temporal Trends in Incidence of Hospitalization and Surgical Intestinal Resection in Pediatric Inflammatory Bowel Diseases in the United States from 1997-2009”

  • Annual percent increase (API) of 2.1% noted in incidence of intestinal resection for Crohn’s disease.  Stable colectomy rate for ulcerative colitis during this period.
  • Annual incidence of hospitalization was 5.7 per 100,000 for Crohn’s and 3.5 per 100,000 for ulcerative colitis; there was a significant increases during study period: 3.8% API for Crohn’s and 4.5% for ulcerative colitis.

Coming Soon to a Pharmacy Near You (part 1)…

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Vedolizumab!

Two articles indicate that Vedolizumab will be an important agent for treating Ulcerative Colitis (UC).  The first article, NEJM 2013; 369: 699-710, describes two integrated studies (GEMINI 1 studies) in the use of this agent for induction and then for maintenance therapy of UC.

Background: Vedolizumab is a gut-selective blocker of lymphocyte trafficking (see previous post: Vedolizumab -another new IBD treatment | gutsandgrowth).  It is similar to natalizumab which was approved in 2008 for Crohn’s disease.  In phase 3 trials, natalizumab was demonstrated a response in 48% of patients with moderate-to-severe disease, but its large-scale use has been precluded by the potential for reactivation of the John Cunningham (JC) virus and progressive multifocal leukoencephalopathy (PML).

Study design: this study was a phase 3, randomized, double-blind, placebo-controlled study conducted at 211 medical centers in 34 countries from 2008-2012.  At baseline some of the assessments included blood tests, stool for enteric pathogens, chest radiography, stool calprotectin, QuantiFERON-TB Gold assay and sigmoidoscopy.  Intravenous vedolizumab was administered at a dose of 300 mg or placebo at days 1 and 15 during induction; also patients were stratified for glucocorticosteroids, use of immunosuppressives and prior use of TNF antagonists.  In total, 746 patients received vedolizumab and 149 received placebo.

Some of the baseline patient characteristics:

  • Mean age: 40.3 yrs
  • Median prednisone dose: 20 mg
  • Average fecal calprotectin: 899 mcg/gr.
  • Site of disease: 37% pancolitis, 13% rectum/sigmoid only, 37.9% left-sided disease, 12.2% disease proximal to splenic flexure.
  • Prior anti-TNF therapy: 48.2%

Results:

  • Induction: at week 6, 47.1% of vedolizumab and 25.5% of placebo-treated patients had a clinical response
  • Maintenance: at week 52, of patients randomly assigned to continue receiving vedolizumab, 44.8% every 4 weeks, 41.8% every 8 weeks were in clinical remission compared with 15.9% receiving placebo
  • Glucocorticoid-free remission at 52 weeks in 45.2% of patients receiving vedolizumab every 4 weeks, 31.4% receiving every 8 week treatment, and 13.9% of placebo-treated patients.
  • Figure 1 details important changes in Partial Mayo score, IBDQ score, Fecal calprotectin, and prednisone dose changes.  With regard to fecal calprotectin, at week 6 the median calprotectin level had dropped approximately 70%.  Smaller decreases were noted in patients continuing vedolizumab at week 52.
  • Safety: “no important differences” according to the authors between vedolizumab and placebo.  Specifically, there were no cases of PML; however, routine JC virus testing was not performed in this study.  Infusion reactions were seen in three cases (two with detectable antibody). a mild increase in nasopharyngitis was noted.
  • Cancer: 1.1% of placebo-treated patients developed a malignancy (1 colon cancer, 1 transitional-cell carcinoma, 1 squamous-cell carcinomas of skin) and 0.2% of vedolizumab (1 colon cancer)
  • Drug levels: mean vedolizumab concentrations at every 4 week dosing: 38.3 mcg/mL and at every 8 week dosing: 11.2 mcg/mL
  • Antibodies: 3.7% had samples that were positive for anti-vedolizumab antibodies at any time.  1% developed persistent antibody positivity.

Bottom-line: This large study shows that vedolizumab is effective in a large number of patients with UC, many who were refractory to other treatments, including anti-TNF agents.

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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%

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Running out of options

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A series of articles on natalizumab were published which give practical advice for this drug which clinicians often turn to when ‘running out of options’ (Gastroenterol Hepatol 2012; 8: 4-17).

Slides from these articles should be available soon (not online on 1/2/13):

http://www.clinicaladvances.com/index.php/our_publications/gastro_hep-issue/gh_november_2012/

According to an algorithm on page 7, in patients with moderate-severe Crohn’s disease who have failed conventional therapies and anti-TNF drugs (or unable to tolerate), the next step is to obtain anti-JCV (John Cunningham Virus) antibody status.  Patients who test negative are ‘Okay to treat with natalizumab’ due to very low risk of progressive multifocal leukoencephalopathy (PML).  Repeated testing at least once a year is then recommended.

For patients who test positive for anti-JCV at any time point, natalizumab can be considered if no other treatment options are available, but the risk of PML is much greater. Previous blog entries (below) have discussed this in greater detail and have provided additional references:

Another article published the experience in 36 Mayo clinic patients between April 2008-September 2010 (Inflamm Bowel Dis 2012; 18: 2203-08).  Consecutive patients who received natalizumab were prospectively followed.  Of the 36 treated with natalizumab, 30 agreed to participate in the study.  23 patients had failed two anti-TNF agents and 7 had failed one anti-TNF agent.  Median age was 35 years.

Results:

  • 14 (46%) had a complete clinical response, 12 had a partial response, and four had no response.  Cumulative probability of a complete response within 1 year was 56%.
  • Time to response: 10% after 1st dose, 50% of patients had complete response after 4th dose
  • Adverse events were common –though this rarely caused drug cessation. Common events included headache and infections (listed in Table 4 of article).  Some infections prompted holding natalizumab for up to 8 weeks.
  • 11 stopped natalizumab due to lack of improvement.

Quantifying Risk of PML with Natalizumab

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Given the limited number of treatment options for inflammatory bowel disease, when Natalizumab became available, there was a great deal of enthusiasm.  This quickly diminished as reports of progressive multifocal leukoencephalopathy (PML) emerged.  So far, I have not prescribed this agent.

Due to its efficacy for multiple sclerosis and IBD, there has been continued interest in understanding the risk for PML (NEJM 2012; 366: 1870-80, editorial pg 1938-39).

Key findings:

  • 212 cases of PML among 99,571 patients treated with natalizumab (2.1 cases per 1000)
  • Three main risk factors: positive JC-virus antibody, previous use of immunosuppressants, and receiving natalizumab more than 2 years

Patients who were negative for anti-JC virus antibodies had an incidence of 0.09 cases or less per 1000 patients.  Among patients who test positive for anti-JC virus antibodies, the risk remained <1 per 1000 patients if no use of immunosuppressants and 2 per 1000 if prior use of immunosuppressants during the first two years of therapy.  The risks were five-fold higher after 2 years in both groups.

While the risks are becoming more clear, the benefits of natalizumab are fairly well-established for multiple sclerosis.  Natalizumab decreased the annualized rate of relapse among patients with relapsing–remitting multiple sclerosis by 68%.

Additional references:

  • -NEJM 2009; 361: 1067, 1075, 1081.  Asymptomatic detection of JC virus common in urine noted in patients Rx’d with natalizumab (19% baseline to 63% on Rx); actual leukoencephalopathy ~1/1000 patients.
  • -Gastroenterol 2007; 132: 1672.  ENCORE trial.
  • -JPGN 2007; 44: 185. n=31 children/adolescents.  55% response, 29% remission; dosed at 3mg/kg.
  • -IBD 2007; 13: 2.  n=79.  Trial of combination natalizumab & infliximab.
  • -NEJM 2006; 354: 899, 911, 924.  Natalizumab slows progression of MS.  Risk of PML due to JC virus 1:1000 in 18 months of Rx.
  • -NEJM 2005; 353: 1912/1965.  Natalizumab not significantly effective for Crohn’s in this study
  • -NEJM 2005; 353: 362, 369, 375, 414.  3 cases of PML associated with Natalizumab
  • -JPGN 2004; 39: S49 [abstract 0107].  Natalizumab in 38 adolescents was effective (Hyams et al).
  • -Gastroenterol 2004; 126: 1574-81. review.  Natalizumab benefitted subjects with elevated CRP. (dosing 300mg every 4 weeks.)
  • -NEJM 2003; 24-32 & 68.  Natalizumab improved response rates in pts c Crohn’s dz (similar to infliximab).  Drug blocks alpha4 integrins which are required for lymphocytes to enter the intestine.
  • -Gastroenterol 2001; 121: 268-74. Infusion of 3mg/kg decreases CDAI in Crohn’s dz.