The CHOICE trial: adalimumab demonstrates safety, fistula healing, improved quality of life and increased work productivity in patients with Crohn's disease who failed prior infliximab therapy.

BACKGROUND: Adalimumab induces and maintains remission in adults with Crohn's disease. AIM: To evaluate safety, fistula healing, quality of life and work productivity in adalimumab-treated patients who failed infliximab, including primary nonresponders. METHODS: After a ≥8-week infliximab washout, patients with moderate-to-severe Crohn's disease received open-label adalimumab as induction (160/80 mg at weeks 0/2) and maintenance (40 mg every other week) therapies. At/after 8 weeks, patients with flare/nonresponse could receive weekly therapy. Minimum study duration was 8 weeks, continuing until the commercial availability of adalimumab for Crohn's disease. RESULTS: Of 673 patients enrolled, 17% were infliximab primary nonresponders and 83% were initial responders. Three percent of patients had serious infections (mainly abscesses). Complete fistula healing was achieved by 34/88 (39%) patients with baseline fistulas. Improvements in quality of life and work productivity were sustained from week 4 to week 24 for all patients, as well as the subgroup of primary nonresponders. CONCLUSIONS: Blinded clinical trials have shown adalimumab to be both an effective first-line therapy for anti-TNF-naïve patients and an important treatment option for infliximab-refractory or -intolerant patients. This trial presents open-label experience to support further the safety and effectiveness of adalimumab in patients who failed infliximab therapy, including primary nonresponders (NCT00338650).

Early clinical experience with adalimumab in treatment of inflammatory bowel disease with infliximab-treated and naïve patients.

BACKGROUND: Adalimumab, at an induction dose of 160/80 mg followed by 40 mg every other week is approved for treatment of refractory Crohn's disease (CD) and for patients with loss of response to infliximab. AIM: To evaluate the indications for adalimumab, the proportion of inflammatory bowel disease patients who require dose escalation and to identify whether this strategy is effective in inducing or maintaining remission. METHODS: Patients prescribed adalimumab for CD were identified and included for analysis, if they had follow-up of at least 6 weeks. Adalimumab dose was escalated if patients had return of symptoms prior to next dose. Clinical judgment was used to determine severity of disease. A second GI physician confirmed disease severity as determined by the first physician. RESULTS: A total of 48 out of 60 patients met inclusion criteria. Adalimumab was used to treat CD in 47/48 (98%) and ulcerative colitis in one (2%). Most patients had moderate 30/48 (63%) or severe 17/48 (35%) disease. Prior infliximab exposure was present in 42/48 (88%). Adalimumab dose escalation occurred in 14/48 (29%) within an average time of 2.2 months (s.d. 1.5 months). A majority of patients who required dose escalation, nine of 14 (64%) did not improve clinically. Steroids could be discontinued in three of 16 (18.8%). Clinical improvement was noted in 21/48 (43.8%) and one of 48 (2%) patients achieved clinical remission. Adverse drug reactions necessitated drug discontinuation in four of 48 (8%) of patients. CONCLUSIONS: This retrospective review from a single academic medical centre suggests that a minority of patients, who cannot be maintained on 40 mg every other week, of adalimumab benefit from an increased dose. This suggests the need for a treatment with an alternative mode of action in anti-TNF failures.

Ulcerative colitis and sarcoidosis.

A 38-year-old woman with ulcerative colitis subsequently developed sarcoidosis. After ten years of recurrent episodes of colitis, she had presented with respiratory symptoms. The diagnosis of sarcoidosis was confirmed by mediastinal lymph node biopsy. Her respiratory symptoms gradually resolved without any specific treatment. Within the remission period of sarcoidosis, she underwent uneventful subtotal colectomy due to refractory colitis. Alterations in immune function and genetic susceptibility have been suggested to be present in both ulcerative colitis and sarcoidosis. However, the occurrence of both in the same patient has been rare. This is only the nineteenth case reported in the literature.

Cyclosporine in severe ulcerative colitis refractory to steroid therapy.

BACKGROUND: There has been no new effective drug therapy for patients with severe ulcerative colitis since corticosteroids were introduced almost 40 years ago. In an uncontrolled study, 80 percent of 32 patients with active ulcerative colitis refractory to corticosteroid therapy had a response to cyclosporine therapy. METHODS: We conducted a randomized, double-blind, controlled trial in which cyclosporine (4 mg per kilogram of body weight per day) or placebo was administered by continuous intravenous infusion to 20 patients with severe ulcerative colitis whose condition had not improved after at least 7 days of intravenous corticosteroid therapy. A response to therapy was defined as an improvement in a numerical symptom score (0 indicated no symptoms, and 21 severe symptoms) leading to discharge from the hospital and treatment with oral medications. Failure to respond to therapy resulted in colectomy, but some patients in the placebo group who had no response and no urgent need for surgery were subsequently treated with cyclosporine. RESULTS: Nine of 11 patients (82 percent) treated with cyclosporine had a response within a mean of seven days, as compared with 0 of 9 patients who received placebo (P < 0.001). The mean clinical-activity score fell from 13 to 6 in the cyclosporine group, as compared with a decrease from 14 to 13 in the placebo group. All five patients in the placebo group who later received cyclosporine therapy had a response. CONCLUSIONS: Intravenous cyclosporine therapy is rapidly effective for patients with severe corticosteroid-resistant ulcerative colitis.

Efficacy of cyclosporine in treatment of fistula of Crohn's disease.

Sixteen Crohn's disease patients with active fistula who had failed standard medical therapy were treated with intravenous cyclosporine. Ten patients had perirectal disease, four had enterocutaneous fistula, and two had rectovaginal fistula. Patients were initially treated with intravenous cyclosporine, 4 mg/kg/day, and then switched to oral cyclosporine, 6-8 mg/kg/day. Improvement was graded using the Present-Korelitz criteria, and success was defined as moderate to total closure of the fistula. Fourteen of 16 patients (88%) responded in the acute phase to parenteral cyclosporine. Closure of fistula occurred in seven (44%) with moderate improvement in the remaining seven (44%). Subsequently, five patients (36%) relapsed to some degree on oral cyclosporine (three severe and two mild relapses). Nine (64%) patients maintained their improvement in the chronic phase. Chronic steroids could be discontinued in 6/8 (75%) of patients. Mild side effects were common [paresthesias (75%) and hirsutism (19%)]. A single patient had severe paresthesias requiring discontinuation of therapy. Mild hypertension was noted in four (25%) and one patient (6%) had to be withdrawn because of nephrotoxicity, which reversed after stopping cyclosporine. We conclude that intravenous cyclosporine is effective therapy for perianal, rectovaginal, and enterocutaneous fistula in Crohn's disease. Its future role awaits controlled trials as well as determination of the risk-benefit ratio.

Gold-induced colitis: a case report and review of the literature.

A case of severe colitis requiring subtotal colectomy following administration of 35 mg Solganal b for intractable arthritis is described. Abdominal pain and watery diarrhea developed six weeks after the last dose of gold. Colonoscopy revealed mucosal edema and ulceration of the entire colon. Supportive measures failed and the patient required subtotal colectomy. Review of the literature revealed 29 cases, ranging in severity from limited ileal involvement to fulminant panenteritis. Most of the patients responded to intravenous fluids, steroids, and antibiotics, but four required surgery. The case described is notable for the delay in appearance of abdominal symptoms following the cessation of gold therapy. The mechanism of injury is unknown. Abdominal complaints in a patient who has received gold therapy, especially parenteral, merit strict attention, even if occurring several weeks after the final dose, and the diagnosis of gold colitis should be entertained.

Preliminary report: cyclosporin in treatment of severe active ulcerative colitis.

Intravenous cyclosporin (4 mg/kg daily) was given to fifteen patients with severe active ulcerative colitis, fourteen of whom had failed to respond to at least 10 days' treatment with intravenous steroids. In the acute phase of the open trial, eleven patients (73%) improved and avoided colectomy; the mean response time was 5.8 days. Patients who responded were maintained on oral cyclosporin (6-8 mg/kg daily) for a 6-month chronic phase. Six of the eleven patients have been weaned from steroids and remain in clinical and endoscopic remission 5-18 months after discontinuation of cyclosporin; three are well at 5 months and their steroid dose is being tapered; one patient relapsed after 5 months on oral cyclosporin and underwent colectomy; and one patient failed to show continued improvement with oral cyclosporin but is in clinical remission after changing to mercaptopurine treatment. Slight self-limiting adverse side-effects of cyclosporin were seen, but none necessitated withdrawal from the study. Cyclosporin seems to be an effective treatment for patients with severe active ulcerative colitis who have not responded to steroids.

Fecal alpha 1-antitrypsin as a measure of Crohn's disease activity. The effect of therapy and anatomical extent of disease.

Random fecal alpha 1-antitrypsin levels, determined in 35 patients with Crohn's disease, showed a strong correlation with clinical activity (Spearman r = 0.44, p = 0.01). In 85% of the patients, both clinical and fecal measurements of Crohn's disease activity agreed (kappa = 0.368, p = 0.011). Similar agreement occurred in those with colitis (kappa = 0.385, p = 0.035) or ileitis (binomial, p less than 0.001) and those with (binomial, p = 0.006) or without (kappa = 0.492, p = 0.01) prior surgery. There was a reduction in the mean clinical score and fecal levels among all patient groups after treatment. There was good agreement between both disease activity measurements after medical therapy. However, even after apparent surgical "cure," fecal protein levels generally remained at values consistent with diffuse occult intestinal disease. When surgical removal of all diseased bowel was not possible, fecal measurements again appeared superior to clinical assessment in reflecting the residual disease. A good correlation existed between the anatomical extent of disease and fecal levels (r = 0.606, p = 0.028), in contrast to the relationship between extent and clinical score (r = 0.14, p = 0.64). Random fecal alpha 1-antitrypsin determinations provide a measure of the intestinal activity and extent of Crohn's disease. They may be useful in monitoring the response to therapy and the presence of residual disease after surgery.

Erythrocytic sedimentation rate as a measure of clinical activity in inflammatory bowel disease.

To assess the reliability of the erythrocytic sedimentation rate (ESR) as a measure of clinical activity in inflammatory bowel disease, we analyzed the correlations of ESR with a global assessment of clinical activity in 77 patients with varying extents of Crohn's disease and ulcerative colitis. Analysis of all 141 ESR determinations in all 77 patients showed a highly significant correlation between mean ESR and clinical activity score (r = 0.54, p less than 0.001). Analysis of 133 ESR determinations in these 77 patients when their disease activity was either mild, moderate, or severe showed some significant differences among certain disease categories. The highest mean ESRs were in patients with the most extensive colon involvement (Crohn's colitis 40.7 +/- 3.3, universal ulcerative colitis 31.0 +/- 3.9), whereas the lowest mean ESRs were in patients with the most limited disease (ulcerative proctitis and proctosigmoiditis 19.2 +/- 2.1). The rate of increase in ESR with progressively increasing clinical activity from mild to moderate was the same in all disease categories, with the exception of Crohn's disease limited to the small bowel (ileitis or jejunoileitis), in which the ESR was relatively unchanged in a small sample of patients. By the time clinical activity became severe, however, patients in all disease categories manifested similarly high ESRs, with the exception of ulcerative proctitis in which the ESR remained low in the single patient tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Incidence of polypharmacy in a long-term care facility.

The incidence of polypharmacy was investigated in a 200-bed long-term care facility. One hundred residents were drawn at random for the study. The average number of drugs prescribed per patient was 3.33, and the average number of pills was 6.34 daily. The most frequently prescribed drugs were the analgesics, followed in order by antihypertensive agents, cardiotonic preparations and antimicrobials. The literature is reviewed with respect to the incidence, causes and end-results of polypharmacy. It is recommended that long-term care facilities develop enlightened and aggressive pharmacy committees to monitor and evaluate drug use routinely in an institutional setting.