Crohn’s disease is a chronic, idiopathic, relapsing inflammatory disorder of the intestinal tract. The pathogenesis of Crohn’s disease is incompletely understood, but the disease is characterized by genetic susceptibility, immune dysregulation, and environmental influence. The production of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) has been shown to be increased in Crohn’s disease.1
In the past few decades significant progress has been made in medical therapy for Crohn’s disease with immunomodulating agents such as azathioprine/6-mercaptopurine and methotrexate, and biological agents such as infliximab, adalimumab, and certolizumab. Despite these advances, 45% of Crohn’s disease patients have chronically active disease, many remain steroid-dependent, and approximately one third have fistulizing disease. Although biological therapies are highly effective, a substantial number of patients do not respond to, or lose their response to, these drugs over time.2 Eventually two thirds of patients with Crohn’s disease will require surgery at 10 years. The long-term management of these disease variants and complications remains a challenge for clinicians, and alternative therapies are still needed.
Thalidomide, originally marketed as a sedative drug, was withdrawn from the market in 1961 because of its teratogenic effects. During the last decade it has reemerged as a potent anti-inflammatory and immunosuppressive drug and has been shown to be effective in malignant and inflammatory conditions including chronic cutaneous lupus, Behcet syndrome, sarcoidosis, pyoderma gangrenosum, human immunodeficiency virus wasting syndrome, graft-versus-host disease, and Crohn’s disease.3–7 The effects of thalidomide relate, in part, to the downregulation of TNF-α and the inhibition of angiogenesis.8 It also inhibits NF κB activity and suppresses interleukin-12.9
In uncontrolled studies of pediatric and adult luminal and fistulizing CD, thalidomide is effective and has steroid-sparing properties. In an open-label study of 12 male patients with steroid-dependent luminal Crohn’s disease treated with low-dose thalidomide at 50 to 100 mg daily, 70% of patients responded and 20% were in remission by 3 months.10 A separate study using higher doses of thalidomide up to 300 mg each night reported that three quarters of patients responded at 1 month and 40% were in remission at 3 months.11 Most of the patients were naive to biological drugs in both of these studies.
Thalidomide also has a role in pediatric and adult subjects with intractable Crohn’s disease.12–16 In a retrospective series of 25 treatment-refractory Crohn’s patients in whom many have failed anti-TNF therapies, 75% and 60% with luminal and fistulizing disease, respectively, responded at 12 months.15 Furthermore, in patients who have responded to infliximab, thalidomide can be used as a bridging therapy to maintain remission.16 Until recently, randomized, controlled trials on the efficacy of thalidomide in Crohn’s disease patients are lacking. A recent multicenter, double-blind, placebo-controlled, randomized clinical trial of 56 children with active Crohn disease refractory to immunosuppressive treatment has shown that clinical remission was achieved in significantly more children treated with thalidomide than with placebo at week 8 (46.4% vs. 11.5%). Nonresponders to placebo were treated with thalidomide and followed up in an open-label extension for an additional 8 weeks, and clinical remission was achieved in 52% of subjects.17
In this issue of the Journal of Clinical Gastroenterology, Scribano et al18 reported the effect and tolerability of thalidomide in 3 patients with moderate-to-severe Crohn’s disease who had failed anti-TNF-α therapies. Treatment duration ranged from 4 to 8 years. All 3 cases achieved complete clinical remission and endoscopic healing of mucosal lesions at a low dose of thalidomide (50 to 150 mg/d). The first 2 patients had concurrent perianal fistulas with luminal disease that responded to thalidomide, whereas the third patient had upper gastrointestinal Crohn’s lesions and an inflammatory ileocolonic stricture that resolved with treatment. This is a small case series and patient selection is heterogenous. The strength, however, lies in the long-term follow-up and endoscopic assessment, which demonstrated mucosal healing in all subjects. Consistent with the existing literature, these cases illustrated several important points. First, thalidomide is effective in a subgroup of patients with refractory Crohn’s disease, including those who had failed first-line and second-line immunosuppressive therapies. Second, response is usually rapid and can occur within 1 month. Third, thalidomide is effective in healing the mucosa and anorectal fistulas. Finally, low-dose thalidomide can be a well-tolerated therapy for maintaining long-term remission.
Thalidomide-associated toxicity remains an important concern for both patients and physicians. Side effects of thalidomide include drowsiness, peripheral neuropathy teratogenicity, and rash. Long-term use is often limited by toxicity in particularly peripheral neuropathy. Peripheral neuropathy has been reported in up to 50% of patients, and in most cases it is mild and reversible. The incidence of neuropathy is related to the total cumulative dosage, and most cases of neuropathy occur after up to 50 g of thalidomide. Baseline neurological examination is important and nerve conduction study can be performed if available locally, although no studies have evaluated the significance of abnormal baseline nerve conduction study on clinical outcome. Strict contraceptive measures are crucial while on thalidomide and patients must not conceive during treatment, or for least 6 months after stopping the drug.19
In summary, these cases highlighted the fact that a subgroup of difficult-to-treat Crohn’s disease patients may benefit from this therapy. The adverse effect profile associated with this drug makes it necessary to ensure close medical follow-up during treatment; nevertheless, thalidomide remains a valuable treatment drug for patients with resistant disease. Although long-term use is often limited because of side effects, particularly the cumulative dose effect of peripheral neuropathy, this drug has great potential in the short-to-medium term to bring disease under control and even into remission. In the treatment of fistulizing disease, it may be possible to cure some patients before toxicity becomes a problem.
The future of thalidomide is promising if controlled data in the pediatric population can be replicated in the adult population to definitively define the clinical utility of this treatment in resistant Crohn’s disease. Altogether it calls for longer-term controlled studies with endoscopic remission as endpoints apart from clinical remission.
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