Multicenter randomized, double-blind, placebo-controlled, clinical trial of dapsone as a glucocorticoid-sparing agent in maintenance-phase pemphigus vulgaris.

OBJECTIVE: To determine the efficacy of dapsone as a glucocorticoid-sparing agent in maintenance-phase pemphigus vulgaris (PV). DESIGN: A randomized, double-blind, placebo-controlled study with a crossover arm for those who failed treatment. SETTING: A US multicenter outpatient study. Patients A total of 19 subjects enrolled among 5 centers, 9 randomized to receive dapsone and 10 to receive placebo. Inclusion criteria were biopsy and direct immunofluorescence-proven PV controlled with glucocorticoids and/or cytotoxic agents, disease in maintenance phase, and aged 18 to 80 years. Physicians had tried at least 2 tapers of glucocorticoids unsuccessfully and had 30 days of stable steroid dosage. Treatment for any patient unable to taper glucocorticoids by more than 25% within 4 months was declared a failure, and the patient was allowed to switch to the opposite medication while maintaining the double-blind. Main Outcome Measure The ability of patients to taper to 7.5 mg/d or less within 1 year of reaching the maximum dosage of the study drug. RESULTS: Of the 9 patients receiving dapsone, 5 were successfully treated, 3 failed treatment, and 1 dropped out of the study. Of the 10 patients receiving placebo, 3 were successfully treated, and 7 failed treatment. This primary end point favored the dapsone-treated group but was not statistically significant (P = .37). Four patients who failed treatment while receiving placebo were switched to treatment with dapsone. Of these, 3 were successfully treated after switching to dapsone treatment, and 1 failed treatment. We found that, overall, 8 of 11 patients (73%) receiving dapsone vs 3 of 10 (30%) receiving placebo reached the primary outcome of a prednisone dosage of 7.5 mg/d or less. CONCLUSION: This trial demonstrates a trend to efficacy of dapsone as a steroid-sparing drug in maintenance-phase PV.

Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis.

OBJECTIVE: This study was designed to evaluate the long-term safety and efficacy of 0.1% tacrolimus ointment in adult and pediatric patients with atopic dermatitis (AD). METHODS: A total of 408 adult and 391 pediatric patients with AD who had participated in a previous clinical trial of tacrolimus ointment were enrolled in this long-term, open-label, noncomparative trial. Tacrolimus ointment 0.1% was applied twice daily either intermittently or continuously to the affected areas. Efficacy and safety assessments included percent body surface area affected, Eczema Area and Severity Index score, individual signs of AD, and the incidence of adverse events. RESULTS: A total of 799 patients were evaluated, of whom 300 (37.5%) were followed for more than 3 years (maximum 49 months). Improvements in efficacy parameters were observed within 1 week of treatment and continued for the duration of the study. Common adverse events included skin burning, pruritus, skin infection, skin erythema, flu-like symptoms, and headache. The incidence of adverse events, including cutaneous infections, did not increase with time on study. CONCLUSION: Tacrolimus ointment therapy is a rapidly effective and safe treatment for the management of AD in pediatric and adult patients for up to 4 years.

Tacrolimus ointment is safe and effective in the treatment of atopic dermatitis: results in 8000 patients.

OBJECTIVE: We sought to evaluate the safety and efficacy of tacrolimus ointment in a large cohort of adult and pediatric patients with atopic dermatitis (AD). METHODS: A cohort of 3964 adult and 3959 pediatric patients with AD were enrolled in this open-label noncomparative study. Patients applied tacrolimus 0.03% or 0.1% ointment twice daily to the affected areas. Efficacy and safety assessments included percentage of body surface area affected and incidence of adverse events, respectively. RESULTS: A total of 7923 patients were evaluated; 95.5% had severe or moderate AD at baseline. There was a 52% decrease from baseline in the mean percentage of body surface area affected at month 1 and a 91% decrease at month 18. Two of the most common adverse events, skin burning and pruritus, were generally mild, transient in nature, and decreased in prevalence as AD improved. Severity and frequency of other common adverse events were consistent with expected rates in the general population. CONCLUSION: Tacrolimus ointment monotherapy in almost 8000 pediatric and adult patients led to continuous improvement in AD and revealed no change in the safety profile reported in previous clinical trials.

Pneumococcal seroconversion after vaccination for children with atopic dermatitis treated with tacrolimus ointment.

OBJECTIVE: We sought to determine the effect of treatment with topical tacrolimus on B- and T-cell immunity including the primary antibody response to pneumococcal polysaccharide vaccine in children with atopic dermatitis. METHODS: In this open-label, noncomparative study, 23 children aged 2 to 12 years with moderate to severe atopic dermatitis were treated with tacrolimus 0.03% ointment twice daily for 7 weeks, immunized with a 23-valent pneumococcal polysaccharide vaccine after 3 weeks of treatment, and had their antibody response measured (for 12 pneumococcal serotype antigens present in the vaccine) before and 4 weeks after vaccination. None had received pneumococcal vaccine before the study. Patient antibody and cellular immune responses were assessed at each study visit (baseline, week 3, and week 7). RESULTS: No significant changes in complete blood cell count, lymphocyte subsets, CD4/CD8 ratio, immunoglobulin levels, antibody titers to tetanus and Haemophilus influenzae , or lymphoproliferative responses were noted during the tacrolimus ointment treatment period. Tacrolimus blood levels were 1 ng/mL or less in all 23 children. Protective pneumococcal titers to all 12 serotypes were observed in 2 of 23 (9%) children prevaccination and in 16 of 23 (70%) children postvaccination. All 6 children who had protective titers to 0 to 5 of the 12 serotypes developed protective titers to an additional 5 to 11 serotypes. Of the patients, 91% had a greater than 4-fold increase in titer for at least 4 of 12 pneumococcal serotypes. CONCLUSION: Topical application of tacrolimus ointment does not affect the serologic response to pneumococcal vaccine or interfere with preexisting T- and B-cell immune responses.

Tacrolimus ointment is more effective than pimecrolimus cream with a similar safety profile in the treatment of atopic dermatitis: results from 3 randomized, comparative studies.

OBJECTIVE: To compare the efficacy and safety of tacrolimus ointment and pimecrolimus cream in adult and pediatric patients with mild to very severe atopic dermatitis (AD). METHODS: One thousand and sixty-five patients were randomized to treatment in 3 multicenter, randomized, investigator-blinded, 6-week studies. RESULTS: Based on the Eczema Area Severity Index (EASI), tacrolimus ointment was more effective than pimecrolimus cream at the end of the study in adults (54.1% vs. 34.9%, respectively; P < .0001), in children with moderate/severe disease (67.2% vs. 56.4%, respectively; P = .04), in the combined analysis (52.8% vs. 39.1%, respectively; P < .0001), and at week 1 in children with mild disease (39.2% vs. 31.2%, respectively; P = .04). Tacrolimus was also more effective than pimecrolimus based on the Investigator Global AD Assessment (IGADA), improvement in percentage of total body surface area affected, and improvement in itch scores (P < or = .05), with a faster onset of action. There was no significant difference in the incidence of adverse events (AEs), including application site reactions in the 2 studies involving 650 children. Adults treated with tacrolimus experienced a greater number of local application site reactions on day 1; both groups reported a similar incidence of application site reactions thereafter. More pimecrolimus-treated patients than tacrolimus-treated patients withdrew from the studies because of a lack of efficacy (P < or = .03) or adverse events (P = .002; pediatric mild). CONCLUSION: Tacrolimus ointment is more effective and has a faster onset of action than pimecrolimus cream in adults and children with AD; their safety profiles are similar.

Tacrolimus ointment for the treatment of atopic dermatitis is not associated with an increase in cutaneous infections.

OBJECTIVE: The purpose of this study was to evaluate the risk of cutaneous infection in patients with atopic dermatitis treated with tacrolimus ointment. METHODS: Data for 1554 patients with atopic dermatitis, treated with tacrolimus ointment in 5 clinical trials, were analyzed. RESULTS: In 3 controlled studies, the 12-week adjusted incidence of all cutaneous infections in patients treated with the vehicle, 0.03%, and 0.1% tacrolimus ointment, respectively, was 18.0%, 24.8%, and 17.7% for adult patients, and 20.9%, 19.6%, and 23.6% for pediatric patients. The incidence of any individual cutaneous infection was not significantly higher in the tacrolimus group than in the vehicle group, with the exception of folliculitis in adults. In two open-label studies, there was no evidence of an increased risk of cutaneous infections with long-term use of 0.1% tacrolimus ointment (up to 1 year), based on the incidence of adverse events, incidence by cumulative length of exposure, or hazard rates. CONCLUSION: Treatment with tacrolimus ointment (0.03% or 0.1%) does not increase the risk of cutaneous bacterial, viral, or fungal infections in patients with atopic dermatitis.

Tacrolimus ointment for the treatment of atopic dermatitis: clinical and pharmacologic effects.

The topical immunomodulator tacrolimus ointment has been shown to be safe and effective in the treatment of atopic dermatitis in clinical trials involving over 16,000 patients. Clinical trial results focusing on tacrolimus' safety and efficacy are summarized. Minimal systemic absorption results from topical application in patients with atopic dermatitis. Although the exact mechanism of action of tacrolimus ointment in atopic dermatitis is unknown, tacrolimus is known to inhibit up-regulation of cytokine production following T cell activation and to decrease Fc epsilon RI expression on dendritic antigen-presenting cells in skin. Additional mechanisms of action of tacrolimus relevant in the pathogenesis of inflammatory skin disorders are discussed.