Lori Y. Kam

An open-label pilot study of low-dose thalidomide in chronically active, steroid-dependent Crohn's disease.

BACKGROUND & AIMS Thalidomide decreases production of tumor necrosis factor alpha, a proinflammatory cytokine associated with Crohns disease (CD). In this study the safety, tolerance, and efficacy of low-dose thalidomide were evaluated for treatment of moderate-to-severe, steroid-dependent CD. METHODS Twelve adult male patients with Crohns Disease Activity Index (CDAI) scores of > or = 250 and < or = 500 despite > or = 20 mg prednisone/day were enrolled. The first 6 patients received 50 mg thalidomide every night, the next 6 received 100 mg every night. Steroid doses were stable during the first 4 weeks of treatment, then tapered during weeks 5-12. CDAI was used to assess response. RESULTS (1) Disease activity improved consistently in all patients during weeks 1-4: 58% response, 17% remission. (2) Clinical improvement was generally maintained despite steroid taper during weeks 5-12. All patients were able to reduce steroids by >/=50%. Forty-four percent discontinued steroids entirely. In weeks 5-12, 70% of patients responded and 20% achieved remission. (3) Side effects were mild and mostly transient, with the most common being drowsiness, peripheral neuropathy, edema, and dermatitis. CONCLUSIONS Low-dose thalidomide appears to be well tolerated and effective over a 12-week period. Results of this pilot study support the need for controlled multicenter trials of thalidomide for treatment of CD.

Outcome of cytomegalovirus infections in patients with inflammatory bowel disease

OBJECTIVE: The aim of this study was to determine the outcome of cytomegalovirus (CMV) infections complicating the course of inflammatory bowel disease (IBD). METHODS: The records and clinical courses were reviewed for all IBD patients who were evaluated at the IBD Center of the Cedars-Sinai Medical Center and who developed CMV infection. RESULTS: Ten patients with severe, medically refractory IBD (five ulcerative colitis, three Crohn’s colitis, and two indeterminate colitis) developed CMV infection. All but two were hospitalized with exacerbation of their underlying disease and were receiving immunosuppressive treatment with steroids, thiopurines, and/or cyclosporine at the time CMV infection was recognized. Eight patients had documented colonic CMV (one had concurrent upper GI tract involvement), one developed interstitial CMV and Pneumocystis carinii pneumonia, and one developed primary CMV mononucleosis. Prompt treatment with ganciclovir and withdrawal of immunosuppressive treatment resulted in gradual improvement and induction of remission of the underlying IBD in five patients. The patient with concomitant CMV and P. carinii pneumonitis died. In two patients, treatment with ganciclovir did not alter the clinical course of their IBD, and one of them underwent colectomy. In one patient CMV was found on the resected colonic specimen. One patient with primary CMV infection responded also to ganciclovir treatment. CONCLUSIONS: CMV infection may aggravate the course of seemingly refractory IBD in patients who either fail to respond or experience worsening of symptoms despite immunosuppressive therapy. Expedient evaluation, prompt treatment intervention with ganciclovir, and withdrawal of immunosuppressive treatment may avoid complications and mortality. This regimen leads to improvement of the underlying IBD in most patients.

An open-label pilot study using thioguanine as a therapeutic alternative in Crohn's disease patients resistant to 6-mercaptopurine therapy

Background and AimsA substantial number of patients with inflammatory bowel disease (IBD) fail to achieve a complete clinical response with 6-mercaptopurine (6-MP) and azathioprine (AZA). Inability to achieve therapeutic 6-thioguanine nucleotide (6-TGN) levels due to the preferential overproduction of 6-methylmercaptopurine ribonucleotides (6-MMPR) upon dose escalation characterizes a newly described subgroup of IBD patients resistant to 6-MP/AZA therapy. Treatment with 6-thioguanine (6-TG), a related thiopurine, which forms 6-TGNs more directly may be beneficial in such patients. This pilot study evaluated the safety, tolerance, and efficacy of 6-TG in the subgroup of Crohns disease (CD) patients failing to attain adequate disease control with traditional 6-MP/AZA therapy. MethodsTen CD patients with preferential 6-MMPR production upon 6-MP/AZA dose escalation were enrolled in an open-label pilot study. Seven of 10 patients had experienced dose-related 6-MP toxicities. ResultsSeventy percent of the patients (7 of 10) responded or were in remission at week 16. Clinical response was evident by week 4 in most. 6-TGN levels were nine-fold higher with 6-TG treatment than with 6-MP, whereas 6-MMPR levels were undetectable. No patient developed a recurrence of hepatic or hematological toxicity. Conclusions6-TG was a safer and more efficacious thiopurine in this subgroup of IBD patients resistant to 6-MP therapy. Larger controlled trials are warranted to further evaluate both the short-and long-term safety and efficacy in this subgroup of patients as well as a broader spectrum of IBD patients.

Treatment with infliximab is associated with increased markers of bone formation in patients with Crohn's disease.

Objective: Osteoporosis is a common complication of Crohns disease (CD). Glucocorticoid use and detrimental effects of inflammatory cytokines including tumor necrosis factor-alpha (TNF-α) can lead to osteoporosis. The aim of this study was to assess the ability of treatment with the TNF-α antagonist infliximab to increase bone formation as measured by surrogate markers of bone turnover in patients with active CD. Methods: Sera from 38 prospectively enrolled CD patients were examined for levels of bone alkaline phosphatase (BAP), N-telopeptide of type I collagen (NTX), immunoreactive parathyroid hormone (iPTH), calcium, and pro-inflammatory cytokines at baseline and 4 weeks following infliximab infusion. Crohns Disease Activity Index (CDAI), Inflammatory Bowel Disease Questionnaire (IBDQ), and glucocorticoid dose also were collected. Results: In this cohort, CDAI and IBDQ scores were significantly improved at week 4 (P < 0.001). Infliximab therapy was associated with an increase in BAP, a marker of bone formation (P = 0.010), whereas NTX, a marker of bone resorption, was not increased (P = 0.801). Among 22 patients who were taking glucocorticoids, mean glucocorticoid dose decreased 36% (P < 0.001; −7.9 mg). Conclusions: Treatment with infliximab was associated with increased markers of bone formation (BAP) without increasing bone resorption (NTX). This effect may be due to a beneficial effect of TNF-α blockade on bone turnover, a beneficial effect on CD activity resulting in decreased glucocorticoid dose, or both. Studies of longer duration are needed to assess the effect of infliximab on bone mineral density.

Efficacy of mycophenolate mofetil in patients failing 6-mercaptopurine or azathioprine therapy for Crohn's disease

Summary: Mycophenolate mofetil (MMF) is a novel immunomodulator that may be effective in the treatment of chronic active and perianal Crohns disease (CD). The aim of this study is to assess the efficacy of MMF in CD patients who failed or were intolerant of 6‐mercaptopurine (6‐MP) or azathioprine (AZA). Eleven CD patients were treated with MMF after a failed course of 6‐MP/AZA, and their records reviewed retrospectively. Reasons for 6‐MP/AZA intolerance or failure were recorded. Response to MMF was determined by calculation of the Harvey‐Bradshaw index and ability to taper steroids. Adverse reactions to MMF were recorded. Eleven patients were identified who failed a previous trial of 6‐MP/AZA and other immunomodulators and required immunomodulator therapy. Of 11 patients who started MMF, four had early adverse reactions within 8 weeks and stopped the medication. Of the remaining seven patients who took MMF for at least 8 weeks, one had a complete response, two had a partial response, and four had no response to the medication. In patients who failed 6‐MP/ AZA, MMF was of benefit in 3 of 11 patients with only one complete responder. This lower‐than‐expected response rate may indicate that patients who are resistant to 6‐MP or AZA may also be resistant to MMF.

TNF-α antagonists for the treatment of Crohn’s disease

New medical therapies that inhibit the bioactivity of TNF-α represent a major breakthrough in the treatment of Crohn’s disease (CD). Anti-TNF-α, monoclonal, chimeric antibody (infliximab) is now FDA approved for use in patients with active CD. Other investigational drugs that also inhibit TNF-α activity include new ‘humanised’ anti-TNF-α antibodies (CDP571), thalidomide, new analogues of thalidomide, and TNF-α receptor fusion proteins. This review will summarise the key clinical data for each of these categories of TNF-α inhibition and discuss the potential economic impact of these new compounds on the cost of CD management.

Cytokine-based therapies in inflammatory bowel disease.

Cytokine-based therapy for inflammatory bowel disease (IBD) has significantly advanced in the last year. This review highlights some of the exciting progress that has occurred. The efficacy of anti-tumor necrosis factor (TNF) monoclonal antibody therapy in Crohns disease has promoted further research and the development of other anti-TNF therapies, such as thalidomide, phosphodiesterase type IV inhibitors, and new-generation anti-TNF monoclonal antibodies. Current research is also focused on more proximal events in the inflammatory cascade to modify T-cell regulation and to decrease the production and activity of proinflammatory proteins, cytokines, and nuclear regulatory factors. Concurrently, the emerging role of interleukin (IL)-11, IL-12, and IL-18 in the perpetuation of chronic inflammation continues to stimulate much interest. All of these new advancements reveal an exciting future for IBD therapy.