The safety profile and sustained remission associated with response to multiple courses of intramuscular alefacept for treatment of chronic plaque psoriasis.

BACKGROUND: Safety and efficacy of up to 3 courses of alefacept intramuscular (IM) in the treatment of chronic plaque psoriasis have been demonstrated in earlier trials. OBJECTIVE: We sought to determine the safety and efficacy of up to 5 courses of alefacept IM in treating plaque psoriasis. METHODS: A standard treatment course was defined as 15 mg of alefacept IM once weekly for 12 weeks, followed by 12 weeks of treatment-free observation. Patients with chronic plaque psoriasis, who had previously received alefacept IM, received up to 3 additional courses (A, B, and C). Efficacy was evaluated by Physician Global Assessment. RESULTS: Safety profiles were similar to those for a single course of treatment. There were no cumulative adverse effects. At 2 weeks postdosing, 16%, 22%, and 19% of patients were rated clear or almost clear by Physician Global Assessment in courses A, B, and C, respectively, with 35%, 42%, and 42% achieving this response at any time during these courses. Patients who achieved clear or almost clear at 2 weeks postdosing remained so for a median duration of 214 and 126 days after courses A and B, respectively. LIMITATIONS: This was an extension study and therefore contained no control group. CONCLUSIONS: Up to 5 courses of alefacept IM may provide extended treatment-free, symptom-free periods in responders while maintaining the safety profile.

Three times weekly tacrolimus ointment reduces relapse in stabilized atopic dermatitis: a new paradigm for use.

OBJECTIVE: Long-term, safe and effective therapeutic options for managing the chronic relapsing nature of atopic dermatitis are essential for improving patient quality of life. To minimize the risks of continued topical corticosteroid usage and potentially reduce the incidence of flares, we tested the efficacy and safety of a rotational paradigm of initial brief application of topical corticosteroid followed by long-term intermittent application of non-steroidal tacrolimus ointment to previously inflamed sites of dermatitis. METHODS: In this 2-phase study, patients who were 2 to 15 years of age and had moderate to severe atopic dermatitis were randomly assigned to 4 days of twice-daily double-blind therapy with either alclometasone ointment 0.05% or tacrolimus ointment 0.03% (Phase I acute), followed by up to 16 weeks of twice-daily open-label tacrolimus ointment 0.03% (Phase I short-term). Patients whose disease stabilized underwent new randomization to double-blind tacrolimus ointment 0.03% or vehicle applied once daily, 3 times per week to clinically normal-appearing skin for up to 40 weeks (Phase II). Corticosteroid use was prohibited. RESULTS: Of 206 randomly assigned patients, 152 completed Phase I; 105 of 152 were randomly assigned into Phase II (68 tacrolimus ointment and 37 vehicle). There were no differences in adverse events between alclometasone and tacrolimus (Phase I) or between tacrolimus and vehicle (Phase II). In the acute period, alclometasone-treated patients showed greater improvement in atopic dermatitis signs and symptoms; thereafter, when all patients applied tacrolimus ointment (short-term), there were no differences. In Phase II, tacrolimus-treated patients had significantly more disease-free days compared with vehicle, significantly longer time to first relapse, and significantly fewer disease relapse days. CONCLUSIONS: For patients with stabilized moderate to severe atopic dermatitis, long-term intermittent application of tacrolimus ointment to normal-appearing but previously affected skin was significantly more effective than vehicle at maintaining disease stabilization, with a safety profile similar to vehicle.

Intermittent therapy for flare prevention and long-term disease control in stabilized atopic dermatitis: a randomized comparison of 3-times-weekly applications of tacrolimus ointment versus vehicle.

BACKGROUND: Intermittent dosing of a topical calcineurin inhibitor for preventing atopic dermatitis (AD) disease relapse in patients with stabilized AD has not been evaluated. OBJECTIVE: We sought to evaluate the long-term efficacy and safety of 3-times-weekly use of tacrolimus ointment in preventing AD disease relapse. METHODS: Adult and pediatric patients with moderate to severe AD who were clear of disease after up to 16 weeks of treatment with tacrolimus ointment were randomized in a double-blind fashion to 3-times-weekly treatment with either tacrolimus ointment (0.03% or 0.1%) or vehicle for 40 weeks. The primary end point was the number of flare-free treatment days. RESULTS: A total of 125 patients were randomized to tacrolimus and 72 patients to vehicle. The mean number of flare-free treatment days was 177 for tacrolimus and 134 for vehicle (P = .003). Median time to first relapse was 169 days for tacrolimus and 43 for vehicle (P = .037). LIMITATIONS: Generalizability to all patients seen in clinic may be limited because only patients who responded to tacrolimus ointment in the stabilization phase were randomized into the maintenance phase of the trial. CONCLUSIONS: Maintenance therapy with tacrolimus ointment was associated with significantly more flare-free days compared with vehicle, and a significantly longer time until first disease relapse.

Adult patients with moderate atopic dermatitis: tacrolimus ointment versus pimecrolimus cream.

The objective of this study was to compare the efficacy and safety of tacrolimus ointment and pimecrolimus cream in adults with moderate atopic dermatitis (AD). A randomized, investigator-blinded, 6-week, multicenter study enrolled patients (> or =16 years) with mild to very severe AD. Patients with moderate AD at baseline were analyzed. At study completion, tacrolimus ointment-treated patients had significantly greater improvement in Eczema Area Severity Index score compared with pimecrolimus cream-treated patients (59% versus. 43% reduction, respectively; P=.01). Significantly more tacrolimus ointment-treated patients than pimecrolimus cream-treated patients improved by 1 or more grades on the Investigators' Global Atopic Dermatitis Assessment (P<.02). A total of 5 pimecrolimus cream-treated patients discontinued the study early due to lack of efficacy compared with no tacrolimus ointment-treated patients (P=.02). Overall, reported adverse events occurred at a similar frequency for both treatment groups. Tacrolimus ointment is more effective than pimecrolimus cream in the management of adults with moderate AD.

Alefacept revisited: Our 3-year clinical experience in 200 patients with chronic plaque psoriasis.

BACKGROUND: Alefacept was the first biologic agent approved in the United States for the treatment of moderate to severe chronic plaque psoriasis (January 2003). Standard prescription is 12 weekly intramuscular doses. The mechanism of action involves the inhibition of T-cell activation and the selective induction of apoptosis of memory T cells. A proportion of patients responding to therapy have been reported to experience remissions of approximately 7 to 8 months, characterized by disease-free and treatment-free intervals. OBJECTIVE: We sought to evaluate the efficacy and safety of alefacept treatment in patients with psoriasis during routine clinical practice. METHODS: We conducted a retrospective chart analysis of data involving 201 patients and 296 courses of alefacept from February 2003 to January 2006. Standard informed consent was obtained. RESULTS: Of the 62 patients (32.6%) who achieved an excellent response, 45% received dosage regimens defined as alternative and 73% had concomitant therapy in at least one of the treatment courses that they received. The average remission time of these patients who achieved an excellent response was approximately 7 months, with a maximum of up to 25 months. Adverse events were generally manageable and rarely led to treatment discontinuation. LIMITATIONS: Study data rely on retrospective analysis of chart-documented clinical examination findings, and patient compliance with visit schedules. CONCLUSION: Alefacept is a long-term treatment option for psoriasis with long-term remissions noted in a proportion of patients.

Tacrolimus ointment is more effective than pimecrolimus cream in adult patients with moderate to very severe atopic dermatitis.

OBJECTIVE: To compare the efficacy and safety of tacrolimus ointment 0.1% and pimecrolimus cream 1% in adult patients with moderate to very severe atopic dermatitis (AD). METHODS: A total of 281 patients (141 treated with tacrolimus and 140 treated with pimecrolimus) were randomized to a multicenter, investigator-blinded, 6-week study. RESULTS: Tacrolimus-treated patients had significantly greater improvements in the Eczema Area Severity Index score compared with pimecrolimus-treated patients (mean percent reduction from baseline to study end: 57% vs 39%, respectively; p=0.0002). Treatment success was also significantly greater among the tacrolimus-treated patients compared with pimecrolimus-treated patients (40% vs 22% at study end; p=0.001), as was the improvement in percentage of total body surface area affected (a reduction of 49% vs 34% at study end; p=0.01). Both treatment groups had similar improvements in patient assessment of itch. There were no significant differences in the incidences of adverse events, including application-site burning and application-site pruritus, the two most commonly reported adverse events. Significantly more pimecrolimus-treated patients than tacrolimus-treated patients withdrew from the study due to lack of efficacy (10 vs 1, p=0.005). CONCLUSION: Tacrolimus ointment is more effective than pimecrolimus cream in adults with moderate to very severe AD. Both agents have a similar safety profile.

Pharmacokinetics of tacrolimus following topical application of tacrolimus ointment in adult and pediatric patients with moderate to severe atopic dermatitis.

OBJECTIVE: To characterize the pharmacokinetics of tacrolimus after topical application in adult and pediatric patients with moderate to severe atopic dermatitis from all clinical trials in which tacrolimus blood levels were obtained. METHODS: Tacrolimus ointment 0.03% or 0.1% was applied twice daily. In the adult and pediatric pharmacokinetic studies, serial blood samples were obtained after single and repeated topical application. During the 12 clinical efficacy trials of tacrolimus ointment, single blood samples were obtained at various times relative to tacrolimus ointment application. RESULTS: In the pharmacokinetic studies, 89% to 95% of tacrolimus whole blood concentration samples were less than 1 ng/mL; mean maximum concentrations ranged from 0.2 to 1.6 ng/mL and mean area under the blood concentration-time curves (0-12 hours) ranged from 1.4 to 13.1 ng x hr/mL. Likewise, in the clinical efficacy trials, the majority (85%-99%) of tacrolimus concentration samples were less than 1 ng/mL. CONCLUSIONS: Tacrolimus ointment is associated with minimal systemic absorption and no evidence of systemic accumulation in patients with moderate to severe atopic dermatitis and extensive disease.

Tacrolimus ointment 0.03% is safe and effective for the treatment of mild to moderate atopic dermatitis in pediatric patients: results from a randomized, double-blind, vehicle-controlled study.

OBJECTIVE: This study was designed to compare the safety and efficacy of tacrolimus ointment 0.03% with vehicle ointment for the treatment of mild to moderate atopic dermatitis (AD) in pediatric patients. METHODS: A total of 317 patients (2-15 years of age) with mild to moderate AD were randomized to receive tacrolimus ointment or vehicle ointment twice daily in a 6-week, multicenter, double-blind study. Efficacy evaluations, including the Investigators' Global Atopic Dermatitis Assessment, eczema area and severity index, percentage of total body surface area affected, and patient assessment of itch occurred at baseline, day 4, and weeks 2, 4, and 6. Cutaneous adverse events were recorded to evaluate safety. RESULTS: At the end of study, 50.6% (80 of 158) of the patients were treated successfully with tacrolimus ointment based on Investigators' Global Atopic Dermatitis Assessment scores, a significant improvement compared with patients treated with vehicle ointment (25.8% [41 of 159]). The percent improvement from baseline in eczema area and severity index scores was also significantly greater in tacrolimus-treated patients (54.8%) compared with vehicle-treated patients (20.8%). There was also a significant improvement in the percentage of total body surface area affected of tacrolimus-treated patients (50.5% reduction from baseline) compared with vehicle-treated patients (16.4%). Patient itch scores were significantly lower in tacrolimus-treated patients (2.1) versus vehicle-treated patients (3.7). Overall, the incidence of cutaneous adverse events reported was similar for both treatment groups. There was no significant difference in the incidence of burning or stinging between treatment groups. Significantly fewer tacrolimus-treated patients prematurely discontinued from the study because of a cutaneous adverse event in the treatment area or experienced increased itching and erythema at the application site. CONCLUSION: Monotherapy with tacrolimus ointment 0.03% is a safe and effective treatment alternative for pediatric patients with mild to moderate AD.

Non-melanoma skin cancer in patients with atopic dermatitis treated with topical tacrolimus.

OBJECTIVE: To determine whether atopic dermatitis (AD) patients treated with tacrolimus ointment experienced an increased risk of non-melanoma skin cancer (NMSC). METHODS: Data were collected from 9813 adult and paediatric patients with AD who applied 0.03% or 0.1% tacrolimus ointment twice daily and were examined every 3 months during the tacrolimus ointment development programme. RESULTS: Thirteen adult patients were diagnosed with NMSC during the follow-up period. All patients with NMSC were white adults and 12 were over 40 years of age. Based on 1718 patient-years of tacrolimus ointment exposure in patients 40 years of age, the calculated incidence of NMSC did not suggest an increased risk of first NMSC over that of a similarly aged US cohort. CONCLUSION: This study does not indicate an increased risk for the development of NMSC in patients with AD treated with tacrolimus ointment for a mean duration of 208 days with a maximum observation period of 1479 days.

Tacrolimus ointment 0.03% shows efficacy and safety in pediatric and adult patients with mild to moderate atopic dermatitis.

BACKGROUND/OBJECTIVE: Tacrolimus ointment is approved for the treatment of moderate to severe atopic dermatitis (AD). We sought to evaluate the efficacy and safety of tacrolimus ointment 0.03% compared with vehicle in the treatment of patients with mild to moderate AD. METHODS: Two identically designed, independent, randomized, double-blind, 6-week studies--one pediatric and one adult--in patients with mild to moderate AD were conducted. Combined data from 617 patients were used in the analysis. The primary efficacy end point was percentage of patients with treatment success (defined as "clear" or "almost clear" on the Investigator's Global AD Assessment) at end of study. RESULTS: As early as day 4, treatment success occurred in 17.7% of patients treated with tacrolimus compared with 9.8% of patients treated with vehicle ( P = .003), and by study end had increased to 49.7% for tacrolimus versus 29.0% for vehicle (P < .0001). Tacrolimus was associated with significantly less application site pruritus than vehicle (29.0% vs 37.5%; P = .03). There was no difference between tacrolimus and vehicle in the incidence of application site skin burning and stinging. CONCLUSION: Tacrolimus ointment 0.03% is effective and safe for the management of mild to moderate AD in both adult and pediatric patients, and has a rapid onset of action.

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.