Adalimumab medium-term dosing strategy in moderate-to-severe hidradenitis suppurativa: integrated results from the phase III randomized placebo-controlled PIONEER trials.

BACKGROUND: Weekly adalimumab (Humira® ) is approved for the treatment of hidradenitis suppurativa (HS) based on the 12-week placebo-controlled periods of the two phase III PIONEER trials. OBJECTIVES: Using PIONEER integrated trial results, we aimed to evaluate the optimal medium-term adalimumab maintenance dosing strategy for moderate-to-severe HS. METHODS: Each trial had two double-blind periods; 12-week Period A and 24-week Period B. Patients randomized to adalimumab 40 mg every week (ADAew) (Period A), were rerandomized in Period B to ADAew (ADAew/ew), ADA every other week (ADAew/eow), or placebo (ADAew/pbo). Placebo-randomized patients were reassigned in Period B to ADAew (PIONEER I) or placebo (PIONEER II). The primary outcome was HS Clinical Response (HiSCR). Patients who lost response during Period B were discontinued from the study and offered an option to enter the open-label extension (OLE) to receive ADAew. Results are reported across the two study periods, and data were combined from the two study periods and the OLE. RESULTS: For week-12 HiSCR achievers, the HiSCR week-36 rate was 48·1% (ADAew/ew) vs. 46·2% (ADAew/eow) and 32·1% (ADAew/pbo). Combining (post hoc) these patients with week-12 partial responders further differentiated outcomes in Period B (ADAew/ew 55·7% vs. ADAew/eow 40·0% and ADAew/pbo 30·1%). Period-B adverse-event rates were ADAew/ew 59·6% vs. ADAew/eow 57·4% and ADAew/pbo 65·0%. One patient (ADAew/ew) reported a serious infection. CONCLUSIONS: Weekly adalimumab treatment, effective throughout 36 weeks, was the optimal maintenance medium-term dosing regimen for this population. At least partial response after 12 weeks with continued weekly dosing had better outcomes than dose reduction or interruption. Patients who do not show at least a partial response to weekly adalimumab by week 12 are unlikely to benefit from continued therapy. No new safety risks were identified. What's already known about this topic? Hidradenitis suppurativa (HS) is a chronic inflammatory disease, commonly misinterpreted as an infection and treated with long-term antibiotic regimens or surgical incisions. Based on the chronicity of HS and the lack of evidence for efficacious and safe long-term HS treatments, it is important to evaluate medium- to long-term therapies for HS. Weekly adalimumab (Humira® ) is approved for the treatment of moderate-to-severe HS based on the two phase III PIONEER trials. What does this study add? This study pooled data from the two PIONEER trials, providing a more robust assessment of outcomes. After at least partial treatment success with weekly adalimumab short-term therapy (12 weeks), continuing weekly dosing during the subsequent 24 weeks had better outcomes than dose reduction or treatment interruption. Patients who do not show at least a partial response to weekly adalimumab by week 12 are unlikely to benefit from continued therapy.

Effectiveness of systemic treatments for pyoderma gangrenosum: a systematic review of observational studies and clinical trials.

BACKGROUND: Pyoderma gangrenosum (PG) is a neutrophilic dermatosis with substantial morbidity. There is no consensus on gold-standard treatments. OBJECTIVES: To review the effectiveness of systemic therapy for PG. METHODS: We searched six databases for 24 systemic therapies for PG. Primary outcomes were complete healing and clinical improvement; secondary outcomes were time to healing and adverse effects. RESULTS: We found 3326 citations and 375 articles underwent full-text review; 41 studies met the inclusion criteria. There were 704 participants in 26 retrospective cohort studies, three prospective cohort studies, seven case series, one case-control study, two open-label trials and two randomized controlled trials (RCTs). Systemic corticosteroids were the most studied (32 studies), followed by ciclosporin (21 studies), biologics (16 studies) and oral dapsone (11 studies). One RCT (STOP-GAP, n = 121) showed that prednisolone and ciclosporin were similar: 15-20% of patients showed complete healing at 6 weeks and 47% at 6 months. Another RCT (n = 30) found that infliximab was superior to placebo at 2 weeks (46% vs. 6% response), with a 21% complete healing rate at 6 weeks. Two uncontrolled trials showed 60% and 37% healing within 4 months for canakinumab and infliximab, respectively; other data suggest that patients with concurrent inflammatory bowel disease may benefit from biologics. The remaining studies were poor quality and had small sample sizes but supported the use of corticosteroids, ciclosporin and biologics. CONCLUSIONS: Systemic corticosteroids, ciclosporin, infliximab and canakinumab had the most evidence in treating PG. However, current literature is limited to small and lower-quality studies with substantial heterogeneity.

The prevalence of anxiety in patients with psoriasis: a systematic review of observational studies and clinical trials.

Psoriasis and anxiety are chronic conditions with significant morbidity and there is evidence that they may exacerbate one another. There is little data on the prevalence of anxiety in psoriasis and the effect of psoriasis treatment on comorbid anxiety. The objective of this study was to perform a systematic review of the literature to describe the prevalence and severity of clinical anxiety disorders or anxiety symptoms among adult patients with psoriasis and characterize the effect of anti-psoriatic interventions on clinical anxiety disorders or anxiety symptoms. We searched PubMed, EMBASE, and the Cochrane Database using search terms 'psoriasis' and 'anxiety'. Results were tabulated and verified by two independent reviewers. Meta-analyses were not performed due to heterogeneity of data. Of 213 publications identified, 938 194 patients from 15 papers were included. The mean age ranged from 31.9-59.4 years old, with a mean PASI score of 7.65-22.8 (reported by nine studies) and a body surface area involvement of 25.9-39.8% (reported by two studies). The prevalence of anxiety in patients with psoriasis was 7-48%, which was significantly higher than healthy controls in two of three studies (HR 1.29-1.31, P = 0.001 and OR 2.91 [95% CI, 2.01-4.21], P < 0.001). Four of five studies (n = 2029) demonstrated an improvement in anxiety symptoms with psoriasis treatment. This review demonstrates a high prevalence of anxiety of adult patients with psoriasis suggesting that patients would benefit from systematic screening. Although the data suggest that anxiety may be improved through various psoriasis treatments, larger prospective randomized trials are needed to confirm this effect.

Psoriasis and adverse pregnancy outcomes: a systematic review of observational studies.

Psoriasis is a chronic inflammatory disorder with significant physical and psychological sequelae. The majority of individuals experience disease onset in early adult life - for women this often occurs during their reproductive years. While some autoimmune diseases have been shown to affect pregnancy outcomes adversely, such a relationship has not been well studied in psoriasis. We searched PubMed, Embase and the Cochrane database for published articles examining psoriasis and adverse pregnancy outcomes, and included observational studies and clinical trials evaluating direct measures of maternal and fetal morbidity and mortality. Four of the nine included articles reported a statistically significant increase in the risk of at least one outcome, including spontaneous abortion, caesarean delivery, low birth weight, macrosomia, large-for-gestational age, and a composite outcome consisting of both prematurity and low birth weight. However, these associations were not always consistent across studies. Overall, there was no clear evidence of increased adverse outcomes in pregnant women with psoriasis.

Effect of biologics on depressive symptoms in patients with psoriasis: a systematic review.

BACKGROUND: Twenty to fifty percent of patients with psoriasis have depressive symptoms. OBJECTIVE: To describe the effects of biologics (tumour necrosis factor inhibitors [TNFi] or interleukin 12/23 inhibitors [IL-12/23i]) on depressive symptoms in patients with psoriasis. METHODS: Electronic databases were searched for randomized controlled trials (RCTs) examining the effects of biologics on depressive symptoms in adults with psoriasis. RESULTS: Of the 305 publications identified, three RCTs were included in a systematic review. In a trial evaluating ustekinumab, mean change in Hospital and Anxiety Depression Rating Scale at 24 weeks from baseline was 3.1 with ustekinumab (P < 0.001) vs. 0.21 with placebo (not significant). In a trial evaluating adalimumab, mean change in Zung Self-Rating Depression Scale at 12 weeks from baseline was -6.7 with adalimumab vs. -1.5 with placebo. In a trial evaluating etanercept, the between-group difference at 12 weeks in Beck Depression Inventory Scale was 1.8 (95% CI: 0.6, 2.90) in favour of etanercept over placebo. Limitations are that diagnostic criteria for depression were not used and scales and data from individual RCTs could not be combined. CONCLUSION: Adalimumab, etanercept and ustekinumab were associated with statistically significant reductions in depressive symptom scores using various scales in patients with moderate-to-severe psoriasis.

Experience with ustekinumab for the treatment of moderate to severe hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a severe chronic inflammatory follicular disease characterized by nodules and abscesses affecting apocrine gland-bearing regions. HS is not well-controlled with conventional medical therapies such as topical therapy, oral antibiotics and retinoids, however, abrogation of tumour necrosis factor-α (TNF-α) function has proven effective in some patients. OBJECTIVE: To assess the safety and efficacy of the interleukin-12/23 inhibitor, ustekinumab for treatment of HS in three patients with moderate-severe disease. METHODS: The subjects received 3-45 mg subcutaneous injections of ustekinumab at 0, 1 and 4 months. Improvement was assessed by the dermatology life quality index (DLQI), visual analogue scale of pain (VAS) and physician's global assessment (PGA) at each monthly visit. RESULTS: Prior to treatment, subjects had moderate-severe HS (Hurley stage II-III) with a DLQI score between 8 and 12. At 6 months, one patient showed complete disease remission, while a 25-49% improvement was seen in a second patient and no change in a third. A moderate but statistically significant relationship was observed between VAS and DLQI scores (r=0.75; P<0.01). CONCLUSION: Ustekinumab may provide a safe and effective new treatment strategy for HS in some patients. Interleukin 12/23 inhibition is a potential therapeutic option for patients in which other therapies prove ineffective.

Cumulative life course impairment in psoriasis: patient perception of disease-related impairment throughout the life course.

Psoriasis is associated with significant physical, psychological, social and economic burden, the cumulative effect of which may result in failure to achieve 'full life potential' in some patients, termed 'cumulative life course impairment' (CLCI). In this concept, the burden of stigmatization, and physical and psychological comorbidities (risk factors for cumulative impairment) and coping strategies and external factors (having potential moderating effects), interact to cause lifetime impairment. Components of CLCI are supported by cross-sectional data; however, the cumulative nature of impairment in patients with psoriasis is not yet established. Nonetheless, CLCI makes intuitive sense to many dermatologists who recognize the cumulative impact of psoriasis on the lives of some patients. This supplement explores the causes and mechanisms of CLCI qualitatively by presenting cases which are representative of typical patients with moderate-to-severe psoriasis. These cases demonstrate the effect of psoriasis in influencing major life-changing decisions and altering the course of patients' lives, preventing patients from attaining their life goals, pursuing their chosen career, gaining a desired educational level, developing social relationships, gaining full pleasure from family life or having children. All these patients believe that their lives would have taken a different course had they not had psoriasis. Additional research to determine how CLCI occurs and to identify the risk factors for cumulative impairment is required. Understanding the key risk factors for CLCI may help physicians identify patients who are more vulnerable to the cumulative impact of psoriasis, resulting in more appropriate treatment decisions earlier in the disease course.

Long-term safety and tolerability of pimecrolimus cream 1% and topical corticosteroids in adults with moderate to severe atopic dermatitis.

OBJECTIVE: This randomized, double-blind, multi-centre study compared the long-term safety and tolerability of pimecrolimus cream 1% and topical corticosteroids (TCS) in 658 adults with moderate-severe atopic dermatitis (AD). METHODS: Patients applied either pimecrolimus or TCS (i.e. 0.1% triamcinolone acetonide cream and/or 1% hydrocortisone acetate cream) twice daily to all affected areas until complete clearance or for up to 1 year. The study was approved by the institutional review board or ethics committee at each centre. RESULTS: A majority of patients treated with either pimecrolimus or TCS used the drug on a continuous basis over 1 year. In patients who had >30% of the body surface involved by AD, the incidence rate of all skin infections was significantly lower in the pimecrolimus group than in the TCS group (95% CI of the treatment difference: -25.3% to -3.4%). The most frequent application site reaction was burning (25.9% of patients on pimecrolimus and 10.9% on TCS), which was transient and mild-moderate in most cases. Three TCS-treated patients reported skin striae. There were no treatment-related serious or clinically significant systemic adverse events. Efficacy was better in patients on continuous TCS therapy, although patients completing the study were similarly well-controlled in both groups. About 42% of the pimecrolimus-treated patients were maintained for 1 year without TCS. CONCLUSION: Pimecrolimus demonstrated a favourable safety profile when used to treat adult patients with moderate-severe AD for up to 1 year. A significant proportion of patients could be maintained without TCS for a year.

The treatment of moderate to severe psoriasis with a new anti-CD11a monoclonal antibody.

BACKGROUND: Anti-CD11a (hu1124) is a humanized monoclonal antibody directed against the CD11a subunit of LFA-1. This study investigated whether treatment with anti-CD11a antibody provides clinical benefit to patients with moderate to severe plaque psoriasis. METHODS: This was a double-blind, placebo-controlled, phase II, multicenter study. In total, 145 patients with minimum Psoriasis Area and Severity Index scores of 12 and affected body surface area of 10% or more were sequentially enrolled into low-dose (0.1 mg/kg, n = 22) or high-dose (0.3 mg/kg, n = 75) groups. Within groups, patients were randomized to treatment or placebo (n = 48) in a 2:1 ratio. Drug was administered intravenously at weekly intervals for 8 weeks. RESULTS: The percentage of subjects achieving more than 50% improvement in physician's global assessment at day 56 (1 week after final dose) was 15% and 48% for placebo and 0.3 mg/kg of drug, respectively (P =.002). A physician's global assessment of excellent (>75% improvement) was greater in the 0.3 mg/kg group versus placebo (25% vs 2%, P =.0003). Average Psoriasis Area and Severity Index scores at day 56 were 13.9 +/- 7.5 (placebo) and 10.9 +/- 8.4 (0.3 mg/kg) (P <.0001). Epidermal thickness was reduced in the 0.3 mg/kg group compared with the placebo group (37% vs 19%, P =.004). Treatment was well tolerated; mild to moderate flu-like complaints were the most common adverse events. White blood cell counts and lymphocyte counts transiently increased. Depletion of circulating lymphocytes did not occur. CONCLUSIONS: Anti-CD11a antibody administered intravenously in 8 weekly doses of 0.3 mg/kg was well tolerated and induced clinical and histologic improvements in psoriasis.

Cyclosporine in the treatment of psoriasis.

The efficacy of cyclosporine is well documented in multiple clinical trials. Patients with severe psoriasis who require systemic treatment should be considered for this therapeutic agent. The need for both a careful evaluation prior to therapy and strict monitoring of the patient cannot be over emphasized because untreated hypertension, renal dysfunction, and other disorders may lead to serious, nonreversible morbidity. Physicians are encouraged to follow the published guidelines for controlling psoriasis in their patients and lowering the risk of potential drug toxicity.

Increased bioavailability and improved efficacy, in severe psoriasis, of a new microemulsion formulation of cyclosporin.

Cyclosporin, as the microemulsion formulation Neoral, was given to two groups of patients with severe psoriasis (Psoriasis Area and Severity Index: PASI > 12.0). Group A (10 patients) were receiving the traditional formulation of cyclosporin, Sandimmun, at the start of the study, with a partial clinical response, and were switched to Neoral at the same dose (3.3 mg/kg per day). Group B patients, who had previously been treated with Sandimmun but were treatment failures, were given Neoral, 3.5 mg/kg per day. This led to rapid improvement in psoriasis in both groups. In Group A mean PASI fell from 22.3 to 11.6 on Sandimmun, after 82 +/- 30 weeks, and to 4.0 (P < 0.05) after 32 weeks of Neoral. In Group B mean PASI decreased from 20.3 to 3.7 (P < 0.05) at a dose of 3.1 mg/kg per day. Pharmacokinetic data demonstrated significant decrease in tmax from 2.3 to 1.4 hours. After 2 weeks Cmax and the area under the curve (AUC) (0-4 h) were significantly increased by 41% and 61%, respectively. Further pharmacokinetic data at 3 months showed similar results. No significant changes in renal function from pre-treatment status were seen in either group. None of the patients developed hypertension. No serious adverse events were reported. The microemulsion formulation of cyclosporin showed greater efficacy and bioavailability. Improved outcome was seen at doses which were on average 15% lower than with the traditional formulation, leading to a reduction in cost of treatment.

Human papillomavirus 16 DNA immortalizes two types of normal human epithelial cells of the uterine cervix.

Premalignant cervical lesions occur at the squamo-columnar junction and in endocervical epithelium and squamous ectocervical epithelium, in descending order of frequency. However, previously only ectocervical cells have been clearly shown to be immortalized in vitro by the oncogenic human papillomaviruses (HPVs). This report describes the immortalization of normal human ecto- and endocervical epithelial cells by the intact HPV 16 genome. Ectocervical epithelial cells (HEC) became immortalized (HEC-16) without crisis while endocervical cells (HEN) were immortalized (HEN-16) after undergoing crisis. HEN-16 and HEC-16 contained integrated HPV 16 DNA, expressed E6 and E7 mRNA, and were aneuploid and nontumorigenic. They also expressed cytokeratins in a pattern similar to their distinct normal parental cells. These results suggest that both squamous and simple epithelial cells of uterine cervix are targets for immortalization by HPV 16.

In vitro interaction of 7,12-dimethylbenz[a]anthracene and its biliary metabolites with dietary fiber.

This in vitro study examined the ability of various dietary fiber components to bind 7,12-dimethylbenz[a]anthracene (DMBA), a hydrocarbon carcinogen known to contaminate food. Bile salt solutions of DMBA were incubated with individual fiber materials under various conditions, and the degree of binding was assessed. Binding of DMBA from simple bile salt solution was greatest with delipidated bran greater than acid lignin greater than alpha-cellulose greater than unprocessed bran. Binding to acid lignin was slowly reversible, was constant within the pH range 4-8, and appeared independent of a bile salt-fiber interaction. Acid lignin bound DMBA from a mixed lipid-bile salt solution significantly, but less effectively than from pure bile salt solutions. DMBA biliary metabolites from Sprague-Dawley rats were bound less extensively to all the fiber materials than was the parent hydrocarbon, but following hydrolysis of the metabolites by beta-glucuronidase binding was significantly increased. These results indicate that there is considerable potential for dietary fiber to interact with DMBA and its metabolites in the lumen of the gastrointestinal tract, possibly influencing hydrocarbon carcinogen bioavailability.