The Original Anti-TNF Therapy: Thalidomide

A recent study (M Lazzerini et al. Clin Gastroenterol Hepatol 2017; 15: 1382-9) used data from 2 multicenter trials of 70 children to assess the efficacy of thalidomide in pediatric patients with refractory inflammatory bowel disease (37 with Crohn’s disease, 23 with ulcerative colitis)

Key findings:

  • 42 patients (60%) had clinical remission & 45 (64%) had clinical response at week 8
  • 38 patients (54%) had clinical remission or response at week 52. 29 of these patients had mucosal healing (no erosions or ulcerations) & 20 patients had histologic healing
  • 7 patients dropped out from study prior to 52 weeks due to side effects (n=5) or clinical relapse (n=2)

My take: I have not used thalidomide therapy and remain concerned about long term side effects (eg. peripheral neuropathy).  Though, the authors are correct that its safety “may be acceptable compared with the safety of other” treatments, especially if there are few remaining options.

Related blog posts:

Notable Briefs for IBD -December 2016

MI Abdalla et al. Inflamm Bowel Dis 2016; 22: 2658-64.  This article reviewed the impact of an ostomy on QOL (quality of life) for Crohn’s disease patients. n=402 with ostomy compared with 4331 CD patients without.

Key findings:

  • Patients with ostomy were more likely to be in remission: 48.5% versus 31.35%.
  • Having an ostomy did not impact overall health-related quality of life but did reduce social role satisfaction.
  • Conclusion: “ostomy is well tolerated…particularly when clinical remission is achieved.”

WKM Liew et al. J Pediatr 2016; 178: 227-32. In this study with 16 patients (aged 6-24 years) who received thalidomide, more information on neuropathy is provided.  “All subjects with cumulative doses greater than 60 g developed polyneuropathy.”  4 of 5 subjects receiving the drug for >20 months developed neuropathy. Two important points:

V Collij et al. Inflamm Bowel Dis; 2016; 22: 2562-70. “We identified drugs that target the proteins encoded by IBD candidate genes.” Key finding: There were 113 drugs that could potentially be used in IBD treatment, including 14 known IBD drugs, 48 drugs that are/have been tested for IBD, 19 being tested for other inflammatory diseases, and 32 new investigational medications.

from one of the best days all year

from one of the best days all year on board “Bufflehead”

Desperate Measures in Refractory IBD

The often cited, ‘desperate times call for desperate measures,’ resonates in the setting of refractory inflammatory bowel disease (IBD).  [Of course, this saying could be used to justify about anything you want to do.]  For IBD, two recent studies point out potential remedies:

  • SA Merkley, et al. Inflamm Bowel Dis 2015; 21: 1854-59.
  • M Lazzerini, et al. Inflamm Bowel Dis 2015; 21: 1739-49, with editorial by A Bousvaros (1750-51)

In the first study, the authors retrospectively analyzed date from 24 IBD patients who were treated with intravenous immunoglobulin (IVIG) at a dose of 0.4 g/kg/day for 3 days, then 0.4 g/kg once a month. Key findings: 16 (67%) had a response and 3 (12.5%) obtained remission. Measures of improvement included CRP, ESR, Simple Endoscopic Score for Crohn’s disease, and the Harvery-Bradshaw Index. The researchers speculate that IVIG has anti-inflammatory and immunomodulator effects.  In addition, they note that IVIG can be given with concurrent infections.

In the second study, the authors studied thalidomide(1.5-2.5 mg/kg/day) in a double-blind, placebo-controlled randomized pediatric clinical trial in children with refractory active ulcerative colitis. Key findings: at week 8, clinical remission was achieved in 10/12 (83%) of thalidomide arm compared with 2/11 (19%) of control patients.  Then, among control patients who were switched, 8 of 11 (72%) reached remission as well. Peripheral neuropathy and amenorrhea were reported adverse effects. In the accompanying editorial, Dr. Bousvaros notes that there has been some data to suggest thalidomide efficacy in ulcerative colitis since 1979.  However, due to widespread bad publicity related to thalidomide-induced teratogenicity (eg. phocomelia) and side effects including neuropathy, it has not been used with much frequency. He notes that this study, as well, requires replication and speculates that “the primary focus on drug development will focus on newer small molecules and biologics, and this potentially useful medication may be left on the sidelines.” It is worth noting that the authors response (pg 1752) to this editorial was that the stigma of thalidomide is unwarranted and that teratogenicity can be avoided. “No case was observed out of 124,000 patients enrolled in the thalidomide distribution risk management program for more than 6 years.”

Bottomline: Both thalidomide and IVIG may be beneficial to desperate patients (and desperate doctors).  While small trials appear promising, larger trials are needed.  Don’t hold your breath waiting … will they ever happen?

Related blog posts:

JAMA Thalidomide Study for Crohn’s Disease

The link (from KT Park’s twitter feed): media.jamanetwork.com/news-item/drug-improves-remission-crohn-disease-among-children-adolescents/ …

An except:

The study included 56 children and was conducted August 2008-September 2012 in 6 pediatric care centers in Italy. Children were randomized to thalidomide or placebo once daily for 8 weeks. The primary measured outcomes were a reduction in the Pediatric Crohn Disease Activity Index (PCDAI) score of ≥ 25 percent or ≥ 75 percent at weeks 4 and 8 (clinical remission). Nonresponders to placebo received thalidomide for an additional 8 weeks. All responders continued to receive thalidomide for an additional minimum 52 weeks.

The researchers found that clinical remission was achieved by more children treated with thalidomide (13/28 [46.4 percent] vs. 3/26 [11.5 percent]). Responses were not different at 4 weeks, but greater improvement was observed at 8 weeks in the thalidomide group. Of the nonresponders to placebo who began receiving thalidomide, 11 of 21 (52.4 percent) subsequently reached remission at week 8. Overall, 31 of 49 children treated with thalidomide (63.3 percent) achieved clinical remission, and 32 of 49 (65.3 percent) achieved 75 percent response.

Average duration of clinical remission in the thalidomide group was 181 weeks vs. 6.3 weeks in the placebo group.

Related blog post:

When nothing else is working

The situation when “nothing else is working” comes up with a number of pediatric gastroenterology phenotypes, including inflammatory bowel disease, encopresis, and functional abdominal pain.  With severe refractory Crohn’s disease, the use of Thalidomide has been explored (JPGN 2012; 54: 28-33).  In this recent description of 12 refractory patients (three females), followed over an average of 4.6 years, thalidomide was associated with improvement in many outcome measures.  All patients were refractory to multiple other medical therapies (particularly infliximab and adalimumab).  Five of seven patients with fistulas had complete resolution, Harvey-Bradshaw index improved (11.8–>3.9), steroid dependency improved (daily dose 13.9–>2.3mg/day), sedimentation rate improved (35–>14), and both hospitalizations & surgeries decreased.

However, 42% developed peripheral neuropathy and adverse reactions resulted in discontinuation in nine of the patients.  The peripheral neuropathy developed on average 43 months into treatment (range 12-79 months) and clinically resolved in all patients within 2-3 months after discontinuation.  All patients enrolled participated in close monitoring as required by the FDA STEPS program —system of thalidomide education and prescribing safety.

Additional references:

  • -JPGN 2003; 37: 522, UK experience. 4/6 developed peripheral neuropathy.
  • -J Pediatr 2004; 145: 856. use for JRA
  • -JPGN 2001; 32: 322-25. Irreversible neuropathy noted in patient after 9 months of Rx.
  • -JPGN 1999; 28: 214.  Response w/in one month
  • -Pediatrics 1999; 103: 1295. (in Behcet’s)
  • -Gastroenterology 1999; 117: 1271 & 1278.  22 men c refractory Crohn’s, dosed @ 200mg qhs: 9 clinical remission & 16 c response. 12 steroid-dependent men @50 or 100mg qhs: 44% off steroids over 12 weeks.
  • -JPGN 2000; 31 (supp 2) A611. Dose 1.5-2mg/kg/day in 5 males.