Thalidomide for severe refractory ankylosing spondylitis: a 6-month open-label trial

OBJECTIVE: To examine the efficacy of thalidomide in the treatment of active ankylosing spondylitis (AS) refractory to conventional therapies. METHODS: In a 6-month open-label trial, we studied 13 men with different subtypes of active AS: 3 juvenile AS, 9 adult AS, and one AS with psoriasis. All patients were resistant to conventional nonbiologic therapies including nonsteroidal antiinflammatory drugs, sulfasalazine, and methotrexate. After 3 months' observation on a preexisting regimen, oral thalidomide was added, starting at 100 mg/day for 1 week, then 200 mg/day for another 23 weeks. Outcome measures included the Bath AS Disease Activity Index (BASDAI), Functional Index (BASFI), Global Index (BAS-G), IgA, C-reactive protein (CRP), and eosinophil sedimentation rate (ESR). Response to treatment was defined following the Ankylosing Spondylitis Assessment criteria. RESULTS: Three patients withdrew due to rash. Two patients were lost to followup due to lack of efficacy. Eight patients completed the trial. Four patients attained > 50% improvement (2 juvenile AS, 1 peripheral AS, and 1 psoriatic arthritis). Four patients attained > 20% improvement (2 axial and 2 peripheral AS). Total response rate accordingly was 80% (8/10). Mean BASDAI improved significantly from baseline to Week 24 (4.97 vs 3.1; p = 0.0156). Mean BASFI improved from baseline to Week 24 (5.24 vs 3.06; p = 0.0078), and BAS-G from 6.02 to 3.21 (p = 0.0078). Significant laboratory improvements were found in ESR (from 69.5 to 34.2 mm/h; p = 0.0156), but not CRP (from 6.08 to 3.01 mg/dl; p = 0.078) or IgA (from 496 to 505 mg/dl; p = 0.375). Dry mouth, constipation, and dizziness were common, but no severe adverse events were found. CONCLUSION: Thalidomide is a promising treatment for patients with active AS who are resistant to conventional therapies other than biologics.     

Long-term results with azathioprine therapy in patients with corticosteroid-dependent Crohn's disease: open-label prospective study

BACKGROUND: A substantial number of patients with Crohn's disease (CD) become dependent on steroids after induction therapy. Treatment with azathioprine (AZA) may be beneficial in such patients. The present open-label study evaluated the long-term safety and efficacy of AZA in steroid-dependent CD patients. METHODS: Adult patients with steroid-dependent CD were enrolled for AZA therapy over a 7-year period. The average dose of AZA was 2.0-3.0 mg/kg per day, adjusted according to clinical response and occurrence of adverse effects. Steroid therapy was tapered off according to a predefined schedule. Long-term outcome and adverse reactions were evaluated. RESULTS: Sixty-nine patients were prospectively included. Steroid-free remission was achieved in 68-81% of patients, partial response in 14.5-27.3% and failure to respond to AZA in 4-15.9% over the initial 48 months. However, the rate of wean from steroid therapy decreased to 53-60% while the rate of failure increased from 6.7% to 17.6% after this period. A breakthrough of symptoms during continuous AZA therapy was common, particularly after 48 months on AZA. The mean leukocyte count at the end of 12 months of therapy was significantly lower in patients who achieved complete response on AZA than in the non-responders (5197 +/- 1250 cells/mm(3) vs 8340 +/- 1310 cells/mm(3), respectively; P < 0.01). Azathioprine was relatively well-tolerated and the incidence of serious adverse effects was small. CONCLUSIONS: Azathioprine was relatively safe and moderately effective for long-term maintenance of steroid-free clinical remission in corticosteroid-dependent CD patients. Patients were more successfully weaned from prednisone treatment, and clinical remission was more often maintained during the first 48 months of AZA therapy. A significant decrease in the white blood cell count at the end of 12 months on AZA was the single factor associated with weaning from steroid dependence.     

Medical therapy for refractory pediatric Crohn's disease.

Crohn's disease is a common indication for referral to pediatric gastroenterology. While most patients with Crohn's disease respond to standard induction therapy, steroid-refractory or steroid-dependent disease is a frequently encountered problem. This review discusses the data existing in both the adult and pediatric literature for medical therapy of refractory pediatric Crohn's disease.     

Thalidomide therapy in patients with refractory or relapsed multiple myeloma

We treated seven refractory or relapsed myeloma patients resistant to conventional chemotherapy with thalidomide. We started thalidomide at 100 mg daily and the dose was increased up to 300 mg if the patient could tolerate it. The patients were evaluated at four weeks and 12 mg of dexamethasone was added for four days when the patient failed to respond to thalidomide treatment. One patient was excluded from the study because of general fatigue. Two of the six patients responded to thalidomide alone and three of the remaining four patients responded to the combination with dexamethasone. The most common adverse effect was sleepiness which was seen in three patients. Two patients showed pancytopenia (Grade 3), constipation and skin eruption. Of the six patients four needed reduction of the thalidomide dose to 200 mg because of adverse effects. Plasma levels of TNF-alpha, IL-6, bFGF and VEGF were measured before and after four weeks. High plasma bFGF levels were seen in responding patients. In conclusion, treatment with thalidomide alone or in combination with dexamethasone is feasible and effective in refractory or relapsed myeloma patients. Further study is required to clarify the role of thalidomide in the therapeutic strategy for multiple myeloma.     

Open label trial of clarithromycin therapy in Japanese patients with Crohn's disease

BACKGROUND AND AIM: The pathogenesis of Crohn's disease is unclear, but many studies suggest that luminal bacteria play an important role in chronic intestinal inflammation in patients with this condition. Clarithromycin is a macrolide antibiotic with immunomodulatory activity. The aim of this study was to evaluate the effect of clarithromycin therapy in Japanese patients with Crohn's disease. METHODS: Fourteen patients with active Crohn's disease (12 with ileocolonic, one with colonic, one with small bowel type) were treated with oral clarithromycin 200 mg twice daily for 4 weeks. Patients who showed a clinical response within 4 weeks continued the therapy for up to 24 weeks. Four patients also received azathioprine. Clinical activity was assessed with the Crohn's Disease Activity Index (CDAI) at entry and at 4, 12, and 24 weeks after starting clarithromycin. RESULTS: The mean CDAI score at entry was 343.5. Within 4 weeks, eight (57.1%) of the 14 patients showed clinical improvement, and five (35.7%) of the eight patients achieved remission. All of those eight patients continued clarithromycin therapy after 4 weeks, and six (42.9%) were in clinical remission at 12 weeks. Of the 14 total patients, four (28.6%) continued clarithromycin for more than 24 weeks, and have remained in remission. Patients who received azathioprine concomitantly had a better response to clarithromycin therapy. No severe side-effects were observed during the study period. CONCLUSIONS: This open label study showed encouraging results of clarithromycin therapy in Japanese patients with active Crohn's disease.     

Filgrastim in refractory Crohn's disease with an intra-abdominal abscess

The application of recombinant human granulocyte colony-stimulating factor (filgrastim) seems to be a safe, well tolerated and potentially effective therapy for active Crohn's disease. We report the case of an adolescent boy with Crohn's disease and intra-abdominal abscess associated who had a significant response to treatment with recombinant human granulocyte colony-stimulating factor after all standard treatments had failed.     

Rituximab for refractory polymyositis: an open-label prospective study

OBJECTIVE: To report the efficacy and toxicity of rituximab in the treatment of refractory polymyositis. METHODS: Adult patients with active polymyositis as evidenced by persistent proximal muscle weakness, elevated creatine kinase (CK) level, and features of active myositis on electromyography who were refractory to corticosteroids and at least 2 other immunosuppressive agents were recruited. While immunosuppressive agents were continued, rituximab (375 mg/m2) was given by intravenous infusion weekly for 4 consecutive weeks. Patients were followed up 4-weekly for serial assessment of muscle power, serum muscle enzymes, physician's and patient's global impression of disease activity, disability, and quality of life scores. RESULTS: Four patients (3 women, 1 man) were studied. The mean age was 53 +/- 11 years and the mean duration of polymyositis was 4.8 +/- 3.3 years. All had persistently active myositis for at least 2 years. At Week 28, significant improvement in the mean proximal muscle power scores and reduction in CK levels in comparison to baseline were observed. Two patients had return of full muscle power with significant drop in CK level. There was a trend of improvement in disability scores and both the mental and physical components of the Medical Outcomes Study Short Form-36 Health Survey scores. Rituximab was well tolerated. CONCLUSION: Rituximab is an option to be considered in refractory polymyositis, but further controlled trials are necessary to confirm its efficacy.     

Vitamin A therapy in patients with Crohn's disease

Vitamin A therapy has been claimed in isolated reports to be of benefit to patients with Crohn's disease. To investigate this further, 86 patients were entered into a long-term double-blind study of vitamin A, 50,000 U twice daily, as compared with placebo. After a mean of 14.1 mo of treatment there was no significant difference between the groups as measured by a variety of activity indices (including the National Cooperative Crohn's Disease Activity Index), the number of acute attacks, and the surgical rate. No toxic effects of vitamin A were observed during the study. In this study vitamin A has not been shown to be of benefit to patients with Crohn's disease who are in remission.     

Controlled trial of antimycobacterial therapy in Crohn's disease

In order to study the effect of clofazimine, a powerful antimycobacterial and antiinflammatory agent, 49 patients with active Crohn's disease were randomized to either corticosteroids plus clofazimine 100 mg daily (N = 25) or to steroids and matching placebo (N = 24). A total of 28 patients (58%) went into disease remission (clofazimine 16, placebo 12; P = NS) with a fall in disease activity score from 10.5 +/- 4.4 to 3.3 +/- 3.5. Patients were treated for a further eight months with clofazimine or placebo and 18 of 28 maintained their remission and completed the study (clofazimine 12, placebo 6; P = NS). Side effects were minor and consisted of skin rash and increased pigmentation. Clofazimine as a solitary antimycobacterial agent appears ineffective in inducing remission in Crohn's disease but may have a role in either disease maintenance or combination chemotherapy.     

Autologous hematopoietic stem cell transplantation in patients with refractory Crohn's disease

BACKGROUND & AIMS: Crohn's disease (CD) is an immunologically mediated inflammatory disease of the gastrointestinal tract. Due to a high morbidity and/or an increase in mortality in refractory cases, a new treatment approach is needed. In theory, maximum immune ablation by autologous hematopoietic stem cell transplantation (HSCT) can induce a remission. METHODS: We conducted a phase 1 HSCT study in 12 patients with refractory CD. Candidates were younger than 60 years of age with a Crohn's Disease Activity Index (CDAI) of 250-400 despite conventional therapies including infliximab. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte colony-stimulating factor and CD34 + enriched. The immune ablative (conditioning) regimen consisted of 200 mg/kg cyclophosphamide and 90 mg/kg equine antithymocyte globulin. RESULTS: The procedure was well tolerated with anticipated cytopenias, neutropenic fever, and disease-related fever, diarrhea, anorexia, nausea, and vomiting. The median days for neutrophil and platelet engraftment were 9.5 (range, 8-11) and 9 (range, 9-18), respectively. The initial median CDAI was 291 (range, 250-358). Symptoms and CDAI improved before hospital discharge, whereas radiographic and colonoscopy findings improved gradually over months to years following HSCT. Eleven of 12 patients entered a sustained remission defined by a CDAI < or =150. After a median follow-up of 18.5 months (range, 7-37 months), only one patient has developed a recurrence of active CD, which occurred 15 months after HSCT. CONCLUSIONS: Autologous HSCT may be performed safely and has a marked salutary effect on CD activity. A randomized study will be needed to confirm the efficacy of this therapy.     

Thalidomide induces mucosal healing in Crohn＇s disease： Case report

Crohn’s disease is a chronic inflammatory disorder of the gastrointestinal tract that is defi ned by relapsing and remitting episodes. Tumor necrosis factor alpha (TNF-α) appears to play a central role in the pathophysiology of the disease. Standard therapies for inflammatory bowel disease fail to induce remission in about 30% of patients. Biological therapies have been associated with an increased incidence of infections, especially infection by Mycobacterium tuberculosis (Mtb). Thalidomide is an oral immu...     

Etanercept in the treatment of active refractory Crohn's disease: a single-center pilot trial

OBJECTIVES: Etanercept, an injectable tumor necrosis factor (TNF) receptor fusion protein, binds and inactivates human TNF and is used in active rheumatoid arthritis. Blocking TNF with monoclonal antibodies has also been beneficial in Crohn's disease. We attempted to determine the efficacy and safety of etanercept for induction of clinical, endoscopic, and histological improvement in patients with moderate to severe Crohn's disease despite standard treatment. METHODS: Ten patients with active Crohn's disease were treated with etanercept (25 mg s.c.) twice per week for 12 wk. Background therapy was kept stable during the trial. Crohn's disease activity index (CDAI), Inflammatory Bowel Disease Questionnaire, and C-reactive protein levels were measured at weeks 0, 2, 4, 8, and 12. Colonoscopies were performed before and after therapy in responders; endoscopic biopsies were scored for inflammation. RESULTS: At week 2 after the start, a clinical response (deltaCDAI > or = 70) was observed in 6/10 patients (median = 305 [294-418] to 166 [107-392]), with reduction in serum C-reactive protein levels (median = 17.2 [6.8-67.2] to 9.1 [0.9-17.2] mg/dl). Colonoscopies showed a reduction in inflammatory lesions in the four patients who attained remission (CDAI < 150), whereas the inflammatory score of the biopsies did not decrease significantly. No moderate or severe adverse events were observed. CONCLUSIONS: Etanercept may be effective in Crohn's disease refractory to standard therapy.     

Methotrexate in refractory Crohn's disease

BACKGROUND: Recent trials suggested that methotrexate may be effective in refractory Crohn's disease (CD). We analyzed the data of 20 patients treated with methotrexate because of corticodependent or refractory CD. METHODS: Between January 1995 and June 1997, 20 azathioprine-resistant or -intolerant patients with active CD requiring continuous glucocorticosteroid treatment were treated with parenteral methotrexate. Clinical response was assessed by the Harvey-Bradshaw clinical activity index. Concomitant steroid use and steroid withdrawal rates were recorded. Patients were assessed at 12 weeks, 6 months, 9 months, and 12 months after the start of methotrexate therapy. RESULTS: At 12 weeks, a clinical response was obtained in 14/20 patients (70%). These response rates decreased to 10/20 patients at 6 months, 8/17 patients at 9 months, and 4/14 evaluable patients at 12 months. In initial responders (n = 14), maintenance of remission was observed in 9/14, 6/11, and 3/9 patients at 6, 9, and 12 months, respectively. Methotrexate allowed corticosteroid tapering in 85% of patients and discontinuation in 60% of patients at 6 months. Side effects were rather frequent but usually mild and prompted discontinuation in two patients. CONCLUSIONS: In this retrospective study, parenteral methotrexate appeared to be effective in inducing a clinical response in 70% of azathioprine-resistant or -intolerant CD patients and often permitted corticosteroid tapering, with an acceptable short-term toxicity. The potential of methotrexate to maintain long-term remission in refractory patients, however, appears less convincing.     

Tolcapone in elderly patients with Parkinson's disease: a prospective open-label multicenter non-interventional trial

Safety and efficacy of tolcapone was studied in 237 patients with advanced Parkinson's disease (PD) in a prospective, open-label, multicenter, non-interventional trial. Main outcome measures were tolerability (adverse events=AE) and safety parameters (liver enzymes). A subgroup analysis was performed for patients at < 70 years and > or = 70 years of age. Improvement of symptoms based on investigator global assessment was reported in 84% of all patients: 14.8% greatly improved, 42.6% improved, and 27% slightly improved. Slight worsening was reported in only 2.6% of subjects. There were no significant differences concerning the treatment efficacy between the age subgroups (p=0.74). The incidence of AE was slightly higher in the subgroup of patients > or = 70 years than in the subgroup of patients < 70 years (relative risk, RR=3.03; 95% confidence interval, CI=1.04-8.96; p=0.03), but AE judged as potentially related to tolcapone were equally distributed among both groups (8.5% vs. 2.9%, RR: 2.91; CI=0.82-10.27; p=0.08). Diarrhea was the most common potentially tolcapone-related AE in both groups. Elevations of liver enzymes (aspartate aminotransferase=AST, and alanine aminotransferase=ALT) above the upper limit of normal were observed in 19% (CI=8.3-23.4) of all patients with slightly but not statistically significant higher percentages in the young patients group compared to older patient group (RR=0.54; CI=0.28-1.04; p=0.06). This observational study provides evidence that tolcapone can be effectively and safely used for the treatment of response fluctuations in elderly patients with PD.