Two Phase 3 Trials of Adalimumab for Hidradenitis Suppurativa.

BACKGROUND: Hidradenitis suppurativa is a painful, chronic inflammatory skin disease with few options for effective treatment. In a phase 2 trial, adalimumab, an antibody against tumor necrosis factor α, showed efficacy against hidradenitis suppurativa. METHODS: PIONEER I and II were similarly designed, phase 3 multicenter trials of adalimumab for hidradenitis suppurativa, with two double-blind, placebo-controlled periods. In period 1, patients were randomly assigned in a 1:1 ratio to 40 mg of adalimumab weekly or matching placebo for 12 weeks. In period 2, patients were reassigned to adalimumab at a weekly or every-other-week dose or to placebo for 24 weeks. The primary end point was a clinical response, defined as at least a 50% reduction from baseline in the abscess and inflammatory-nodule count, with no increase in abscess or draining-fistula counts, at week 12. RESULTS: We enrolled 307 patients in PIONEER I and 326 in PIONEER II. Clinical response rates at week 12 were significantly higher for the groups receiving adalimumab weekly than for the placebo groups: 41.8% versus 26.0% in PIONEER I (P=0.003) and 58.9% versus 27.6% in PIONEER II (P<0.001). Patients receiving adalimumab had significantly greater improvement than the placebo groups in rank-ordered secondary outcomes (lesions, pain, and the modified Sartorius score for disease severity) at week 12 in PIONEER II only. Serious adverse events in period 1 (excluding worsening of underlying disease) occurred in 1.3% of patients receiving adalimumab and 1.3% of those receiving placebo in PIONEER I and in 1.8% and 3.7% of patients, respectively, in PIONEER II. In period 2, the rates of serious adverse events were 4.6% or less in all the groups in both studies, with no significant between-group differences. CONCLUSIONS: Treatment with adalimumab (40 mg weekly), as compared with placebo, resulted in significantly higher clinical response rates in both trials at 12 weeks; rates of serious adverse events were similar in the study groups. (Funded by AbbVie; ClinicalTrials.gov numbers, NCT01468207 and NCT01468233 for PIONEER I and PIONEER II, respectively.).

Anti-p40 antibodies ustekinumab and briakinumab: blockade of interleukin-12 and interleukin-23 in the treatment of psoriasis.

The choice of therapeutic agents for patients with moderate-to-severe psoriasis has expanded significantly in the past decade. With new understanding of the immunologic basis of psoriasis, multiple new potential targets for therapy have been identified. It is likely that a series of new medications to focus on the newly identified pathways is on the horizon. The first pathway targeted by new medications focuses on the p40 subunit that is shared by interleukin (IL)-12 and IL-23. Two human anti-p40 antibodies have been used therapeutically in psoriasis to date, ustekinumab (CNTO-1275, Stelara, Centocor, Horsham, PA) and briakinumab (ABT-874, Abbott, Abbott Park, IL). Ustekinumab was recently approved by the United States Food and Drug Administration, making it the first medication approved in the United States to work by this pathway while briakinumab is currently in phase III clinical trials.

Long-term efficacy of biologics in the treatment of psoriasis: what do we really know?

Psoriasis is a chronic inflammatory condition that often requires life-long treatment. Conventional therapies have not fully met the needs of psoriatic patients, because of limited efficacy, adverse effects with cumulative use, and patient inconvenience. In the past decade, biologic immunotherapies have become accepted treatments for psoriasis as a result of perceived efficacy and safety on the part of patients and practitioners. However, most data on these medications come from relatively limited short-term trials. In this review, we will focus on the available long-term data on the efficacy of the biologic agents. We will emphasize the strengths and weakness of the available data of the biologic agents that are Food and Drug Administration (FDA)-approved for the treatment of moderate to severe psoriasis (alefacept, efalizumab,* etanercept, infliximab, and adalimumab), with the inclusion of a newer agent currently under FDA evaluation (ustekinumab).

Treating psoriasis with adalimumab.

Psoriasis is a common, chronic, inflammatory skin disease that can have a significant impact on the quality of life of those who are afflicted. Recent advances in the understanding of the pathophysiology of psoriasis have led to the development of new, genetically engineered, targeted therapies for this disease. Among the most successful strategies for treatment has been the use of biologic immunotherapies targeting tumor necrosis factor alpha (TNF). Recent research has evaluated the efficacy and safety of a new anti-TNF agent, adalimumab. Adalimumab is a human monoclonal antibody that is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of rheumatoid arthritis and psoriatic arthritis. Recently released data from large, randomized clinical trials suggests that adalimumab has significant efficacy for the treatment of chronic plaque psoriasis and is well tolerated. Thus, adalimumab seems to be a promising therapeutic approach for patients who suffer from moderate to severe plaque psoriasis.

Survival rates for breast cancers detected in a community service screening mammogram program.

BACKGROUND: This single-institution long-term prospective study was performed in the setting of community service screening mammography to evaluate the association between the methods of breast cancer detection and survival rates. METHODS: From 1994 through 2001, data on 1237 patients with breast cancer were collected concurrent with definitive surgical treatment and entered into a comprehensive database. RESULTS: Mammography was the sole method of detection for 517 (44%) of 1179 Tis-T2 breast cancers. Fifty-seven percent of invasive cancers detectable by mammography alone were less than 1 cm in diameter. For 1049 patients with invasive cancers, the 5-year overall observed survival rates were 94% for 372 whose cancers were detectable by mammogram alone and 87% for 677 whose cancers were detectable by palpation (alone or in combination with mammography) (P = .0002). CONCLUSIONS: Most of the contribution to breast cancer mortality reduction is from the detection of small nonpalpable cancers, not from adjuvant therapy.

Axillary recurrence after sentinel node biopsy.

BACKGROUND: Sentinel node biopsy (SNB) has evolved as the standard of care in the surgical staging of breast cancer. This technique is accurate for surgical staging of axillary nodal disease. We hypothesized that axillary recurrence after SNB is rare and that SNB may provide regional control in patients with microscopic nodal involvement. METHODS: With institutional review board approval, SNB was performed with peritumoral injection of 99mTc-labeled sulfur colloid. From 1996 to 2003, 1167 patients were entered into a prospective cancer database after surgical therapy; 916 patients consented to long-term follow-up. Fifty-two patients (5.7%) did not map successfully and were excluded, leading to a study population of 864 patients. The median follow-up was 27.4 months (range, 1-98 months). RESULTS: The median number of sentinel nodes harvested was 2, and 633 (73%) patients had negative sentinel nodes. Thirty (4.7%) of those sentinel node-negative patients underwent completion axillary dissection, whereas 592 (94%) patients were followed up with observation. A total of 231 (27%) had positive sentinel nodes: 158 (68%) of these patients underwent completion axillary dissection, and 73 (32%) were managed with observation alone. Two (.32%) patients who were sentinel node negative had an axillary recurrence; one of these patients had undergone completion axillary dissection. No patient in the observed sentinel node-positive group had an axillary recurrence (odds ratio, .37; P = .725). CONCLUSIONS: On the basis of a median follow-up of 27.4 months, axillary recurrence after SNB is extraordinarily rare regardless of nodal involvement, thus indicating that this technique provides an accurate measure of axillary disease and may impart regional control for patients with node-positive disease.

Failure of sentinel lymph node mapping in patients with breast cancer.

BACKGROUND: Lymphatic mapping with sentinel lymphadenectomy (SL) has become more widely used as an alternative to axillary dissection for the staging of breast cancer. This study was conducted to evaluate the potential associations of patient and tumor characteristics with the lymphatic mapping failure rate. STUDY DESIGN: Between September 1996 and April 2003, 1,094 breast cancer patients participated in a single-institution prospective SL protocol, which was conducted using technetium 99 m sulfur colloid alone to identify sentinel lymph nodes. During the validation phase, consisting of the first 80 patients, all patients had SL followed by axillary dissection. Beginning with the 81st patient, the standard technique consisted of radiolabeled colloid injection in a peritumoral distribution 16 to 24 hours before the operation, followed by SL alone for node-negative patients. RESULTS: Of 1,094 consecutive patients, 62 (5.7%) did not map. Patients having more than 10 involved lymph nodes had a significantly higher incidence of mapping failure (40.9%) than those who were node-negative (5.3%) (odds ratio = 9.19, p = 0.002). Age was a factor predictive of mapping failure for node-negative patients 70+ years of age (odds ratio = 3.14, p = 0.018). Biopsy technique, tumor size, tumor location, cell type, and surgeon experience were not predictors of mapping failure, regardless of node status. CONCLUSIONS: The lymphatic mapping failure rate was associated with both anatomic and pathologic factors. Patients with extensive nodal involvement had a significantly greater chance of mapping failure. Among node-negative patients, those who were older were more likely to have mapping failure than those who were younger, suggesting that decreased breast density in postmenopausal women might provide an anatomic explanation for nonmapping.

Recovery of neuromuscular function after cardiac surgery: pancuronium versus rocuronium.

UNLABELLED: The use of pancuronium in fast-track cardiac surgical patients may be associated with delays in clinical recovery. Our objective in this study was to evaluate the incidence and severity of residual neuromuscular blockade after cardiac surgery in patients randomized to receive either pancuronium (0.08-0.1 mg/kg) or rocuronium (0.6-0.8 mg/kg). Eighty-two patients undergoing cardiopulmonary bypass were randomized to a pancuronium (n = 41) or rocuronium (n = 41) group. Intraoperative and postoperative management was standardized. In the intensive care unit, train-of-four (TOF) ratios were measured each hour until weaning off ventilatory support was initiated. Neuromuscular blockade was not reversed. After tracheal extubation, patients were examined for signs and symptoms of residual paresis. When weaning of ventilatory support was initiated, significant neuromuscular blockade was present in the pancuronium subjects (TOF ratio: median, 0.14; range, 0.00-1.11) compared with the rocuronium subjects (TOF ratio: median, 0.99; range, 0.87-1.21) (P < 0.05). Patients in the rocuronium group were more likely to be free of signs and symptoms of residual paresis than patients in the pancuronium group. Our findings suggest that the use of longer-acting muscle relaxants in cardiac surgical patients is associated not only with impaired neuromuscular recovery, but also with signs and symptoms of residual muscle weakness in the early postoperative period. IMPLICATIONS: The use of long-acting muscle relaxants in fast-track cardiac surgical patients is associated with significant residual neuromuscular block in the intensive care unit, including signs and symptoms of residual paresis.