Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials.

BACKGROUND: Ixekizumab is a humanised monoclonal antibody against the proinflammatory cytokine interleukin 17A. We report two studies of ixekizumab compared with placebo or etanercept to assess the safety and efficacy of specifically targeting interleukin 17A in patients with widespread moderate-to-severe psoriasis. METHODS: In two prospective, double-blind, multicentre, phase 3 studies (UNCOVER-2 and UNCOVER-3), eligible patients were aged 18 years or older, had a confirmed diagnosis of chronic plaque psoriasis at least 6 months before baseline (randomisation), 10% or greater body-surface area involvement at both screening and baseline visits, at least a moderate clinical severity as measured by a static physician global assessment (sPGA) score of 3 or more, and a psoriasis area and severity index (PASI) score of 12. Participants were randomly assigned (1:2:2:2) by computer-generated random sequence with an interactive voice response system to receive subcutaneous placebo, etanercept (50 mg twice weekly), or one injection of 80 mg ixekizumab every 2 weeks, or every 4 weeks after a 160 mg starting dose. Blinding was maintained with a double-dummy design. Coprimary efficacy endpoints were proportions of patients achieving sPGA score 0 or 1 and 75% or greater improvement in PASI at week 12. Analysis was by intention to treat. These trials are registered with ClinicalTrials.gov, numbers NCT01597245 and NCT01646177. FINDINGS: Between May 30, 2012, and Dec 30, 2013, 1224 patients in UNCOVER-2 were randomly assigned to receive subcutaneous placebo (n=168), etanercept (n=358), or ixekizumab every 2 weeks (n=351) or every 4 weeks (n=347); between Aug 11, 2012, and Feb 27, 2014, 1346 patients in UNCOVER-3 were randomly assigned to receive placebo (n=193), etanercept (n=382), ixekizumab every 2 weeks (n=385), or ixekizumab every 4 weeks (n=386). At week 12, both primary endpoints were met in both studies. For UNCOVER-2 and UNCOVER-3 respectively, in the ixekizumab every 2 weeks group, PASI 75 was achieved by 315 (response rate 89·7%; [effect size 87·4% (97·5% CI 82·9-91·8) vs placebo; 48·1% (41·2-55·0) vs etanercept]) and 336 (87·3%; [80·0% (74·4-85·7) vs placebo; 33·9% (27·0-40·7) vs etanercept]) patients; in the ixekizumab every 4 weeks group, by 269 (77·5%; [75·1% (69·5-80·8) vs placebo; 35·9% (28·2-43·6) vs etanercept]) and 325 (84·2%; [76·9% (71·0-82·8) vs placebo; 30·8% (23·7-37·9) vs etanercept]) patients; in the placebo group, by four (2·4%) and 14 (7·3%) patients; and in the etanercept group by 149 (41·6%) and 204 (53·4%) patients (all p<0·0001 vs placebo or etanercept). In the ixekizumab every 2 weeks group, sPGA 0/1 was achieved by 292 (response rate 83·2%; [effect size 80·8% (97·5% CI 75·6-86·0) vs placebo; 47·2% (39·9-54·4) vs etanercept]) and 310 (80·5%; [73·8% (67·7-79·9) vs placebo; 38·9% (31·7-46·1) vs etanercept]) patients; in the ixekizumab every 4 weeks group by 253 (72·9%; [70·5% (64·6-76·5) vs placebo; 36·9% (29·1-44·7) vs etanercept]) and 291 (75·4%; [68·7% (62·3-75·0) vs placebo; 33·8% (26·3-41·3) vs etanercept]) patients; in the placebo group by four (2·4%) and 13 (6·7%) patients; and in the etanercept group by 129 (36·0%) and 159 (41·6%) patients (all p<0·0001 vs placebo or etanercept). In combined studies, serious adverse events were reported in 14 (1·9%) of 734 patients given ixekizumab every 2 weeks, 14 (1·9%) of 729 given ixekizumab every 4 weeks, seven (1·9%) of 360 given placebo, and 14 (1·9%) of 739 given etanercept; no deaths were noted. INTERPRETATION: Both ixekizumab dose regimens had greater efficacy than placebo and etanercept over 12 weeks in two independent studies. These studies show that selectively neutralising interleukin 17A with a high affinity antibody potentially gives patients with psoriasis a new and effective biological therapy option. FUNDING: Eli Lilly and Co.

The efficacy and safety of infliximab in patients with plaque psoriasis who had an inadequate response to etanercept: results of a prospective, multicenter, open-label study.

BACKGROUND: In patients with psoriasis and inadequate response (IR) to tumor necrosis factor-α antagonist treatment, the incremental benefit of switching to another tumor necrosis factor-α antagonist is unknown. OBJECTIVE: We sought to evaluate the clinical response to an etanercept-to-infliximab switch in patients with psoriasis and IR to etanercept. METHODS: Adults with moderate-to-severe plaque psoriasis and IR to etanercept (≥ 4 months) were eligible for this open-label study (called PSUNRISE). Patients had a Physician Global Assessment (PGA) score of at least 2 (mild) on a 5-point scale with etanercept, with or without concomitant oral systemic methotrexate or cyclosporine at baseline and during the study. Patients received intravenous infusions of infliximab 5 mg/kg at weeks 0, 2, 6, 14, and 22. PGA was used to evaluate efficacy at week 10 (primary end point) and week 26 (durability). Safety was evaluated through the end of the study. RESULTS: Of 215 patients, only 10 received concomitant immunomodulators. At week 10, 65.4% of patients (138 of 211; 95% confidence interval 58.6%-71.8%) achieved a PGA score of clear (0) or minimal (1) (primary end point). This response was durable through week 26, at which time 61.3% (122 of 199; 95% confidence interval 54.2%-68.1%) achieved a PGA score of clear (0) or minimal (1). There were no unexpected side effects or safety concerns. LIMITATIONS: This was an open-label, 26-week study; an incremental change of 1 PGA point, even mild to minimal, was considered clinically significant, as most psoriasis practitioners seek to achieve minimal psoriasis or clear skin. CONCLUSION: After switching to infliximab, a substantial proportion of patients with psoriasis and IR to etanercept experienced rapid and durable improvement.

Safety and efficacy of tacrolimus ointment versus pimecrolimus cream in the treatment of patients with atopic dermatitis previously treated with corticosteroids.

Adult and pediatric patients (n = 347) with atopic dermatitis enrolled in three multicenter, randomized, 6-week studies who had previously used steroids were analyzed to examine the null hypothesis that improvement in atopic dermatitis initiated after prior treatment with steroids eliminates any subsequent treatment differences between tacrolimus ointment and pimecrolimus cream. Of these patients, 171 were randomized to tacrolimus ointment and 176 to pimecrolimus cream. Based on improvement in the Eczema Area and Severity Index at the end of study, tacrolimus ointment was significantly more effective than pimecrolimus cream (p = 0.0002). Tacrolimus ointment was also significantly more effective than pimecrolimus cream at the end of study in all secondary end-points. Overall, the frequency of adverse events was comparable between treatment groups (24.0% for tacrolimus ointment vs. 25.6% for pimecrolimus cream). Tacrolimus ointment is more effective, with a similar safety profile, compared with pimecrolimus cream in patients with atopic dermatitis previously treated with topical corticosteroids.

Nephrogenic systemic fibrosis: a review.

Nephrogenic systemic fibrosis (NSF) is a recently described, debilitating systemic disease most commonly seen in patients with renal insufficiency. Exposure to gadolinium-containing contrast agent has been associated with the onset of symptoms. The epidemiology, pathogenesis, clinical manifestation, diagnosis, histolopathology, differential diagnosis and treatment will be reviewed. Clinicians should have a high index of suspicion in susceptible individuals.

Persistent cutaneous hyperpigmentation due to hydroxychloroquinone one year after therapy discontinuation.

Hydroxychloroquine (HCQ) was initially indicated for the treatment of malaria, but more recently its anti-inflammatory and immune modulating properties have been utilized for treatment of multiple dermatologic and rheumatologic diseases. Mucocutaneous bluish-gray dyschromia is a rare side effect with HCQ and little information exists regarding its duration after drug discontinuation. The few existing case reports primarily describe small focal areas of discoloration. More extensive dyschromia has very rarely been reported with HCQ. We report a case of HCQ induced dyschromia diffusely involving the extremities, with minimal resolution one year after treatment discontinuation.

Off-label uses of biologics in dermatology: interferon and intravenous immunoglobulin (part 1 of 2).

The introduction of a number of biologic therapies into the market has revolutionized the practice of dermatology. These therapies include interferons, intravenous immunoglobulin, infliximab, adalimumab, etanercept, efalizumab, alefacept, and rituximab. Most dermatologists are familiar with the Food and Drug Administration-approved indications of these medications. However, numerous off-label uses have evolved. As part 1 of a 2-part series, this article will review the literature regarding the off-label uses of the interferons and intravenous immunoglobulin in dermatology.

Off-label uses of biologics in dermatology: rituximab, omalizumab, infliximab, etanercept, adalimumab, efalizumab, and alefacept (part 2 of 2).

Recently, dermatologists have witnessed a revolution in our therapeutic armamentarium with the development of several novel biologic immunomodulators. Although psoriasis remains the only condition in dermatology for which the use of biologic immunomodulators has been approved by the Food and Drug Administration, these drugs have the potential to significantly impact the treatment of several inflammatory conditions in dermatology. This article includes a review of the mechanism of action, dosing, and side-effect profile, as well as a review of the current literature on off-label uses of the CD20-positive B-cell antagonist rituximab, the IgE antagonist omalizumab, the tumor necrosis factor-alpha antagonists infliximab, etanercept, and adalimumab, and the T-cell response modifiers efalizumab and alefacept.

A single-center, open-label, prospective pilot study of subcutaneous efalizumab for oral erosive lichen planus.

OBJECTIVE: To evaluate the efficacy of efalizumab in the treatment of oral erosive lichen planus. DESIGN: A single-center, open-label, prospective pilot study. The primary efficacy outcome measure was the change in oral mucosal surface area involvement after 12 weeks of treatment. Secondary outcome measures included the 100-mm visual analog scale (VAS) for pain and a modified Oral Health Impact Profile (OHIP-14) questionnaire. RESULTS: Four adult patients with oral erosive lichen planus were enrolled and treated with efalizumab 0.7 mg/kg subcutaneously at week 0 followed by 1.0 mg/kg weekly from week 1 to week 11. The mean reduction in the affected mucosal surface area was 71.1% (range 57.3% to 96.8%). The mean improvement in the 100-mm VAS for pain was 82%. The mean improvement in the OHIP-14 questionnaire was 69.3%. Significant adverse events included hospitalization for urticaria and a staphylococcal abscess of an artificial hip joint in one patient and drug-induced subacute cutaneous lupus in another patient.

Approach to the acute, generalized, blistering patient.

This article discusses the approach to the acute, generalized, blistering patient from the perspective of the dermatologic consultant. Initially, a case is presented, followed by a discussion of the relevant evaluation, differential diagnosis, and treatment options.

Successful treatment of mucous membrane pemphigoid with etanercept in 3 patients.

BACKGROUND: Mucous membrane pemphigoid (MMP), also known as cicatricial pemphigoid, is a serious, autoimmune, blistering disorder that can result in blindness and other complications as a result of scarring of the mucous membranes. Effective treatment modalities are often toxic. Herein, we describe a novel therapeutic approach that is based on 2 reports in the literature of the successful use of etanercept to treat MMP. OBSERVATIONS: Three patients with MMP were treated with subcutaneous injections of 25 mg of etanercept twice weekly. All 3 patients had oral mucosal involvement, and 1 had severe, recalcitrant, ocular disease. Oral mucosal disease improved in all 3 patients. The patient with ocular involvement experienced stabilization of progression. CONCLUSIONS: Effective treatment modalities for MMP are often toxic. Etanercept may be an effective treatment option for MMP of the oral and ocular mucous membranes. This therapy should be considered as an alternative treatment option for patients who would require other aggressive systemic treatments, such as cyclophosphamide, corticosteroids, azathioprine sodium, and intravenous immunoglobulin.

Nonscarring inflammatory alopecia associated with the epidermal growth factor receptor inhibitor gefitinib.

Gefitinib (ZD1839, Iressa, AstraZeneca, Wilmington, Del) is a novel oral anticancer agent that acts by blocking the function of the epidermal growth factor receptor. Gefitinib and other drugs that block epidermal growth factor receptor function have been associated with a similar and interesting pattern of cutaneous adverse effects, including follicular acneiform eruptions, xerosis, desquamation, seborrheic dermatitis, chronic paronychia, and hair texture changes. These effects appear to reflect the significance of epidermal growth factor receptor signaling in the skin. Here we present a case of a woman who developed an extensive nonscarring inflammatory alopecia after 2 years of gefitinib therapy.

Off-label uses of biologic agents in dermatology: a 2006 update.

The introduction of a number of biologic therapies into the market has revolutionized the practice of dermatology. These therapies include adalimumab, alefacept, efalizumab, etanercept, infliximab, IVIg, omalizumab, and rituximab. Most dermatologists are familiar with the indications of these medications that have been approved by the Food and Drug Administration; however, numerous off-label uses have evolved. To update the reader on more recent uses of the biologics for off-label dermatologic use, this article will emphasize more recent published data from 2005 through the date of submission in May 2006.

Safety and Efficacy of Open-label Subcutaneous Ixekizumab Treatment for 48 Weeks in a Phase II Study in Biologic-naive and TNF-IR Patients with Rheumatoid Arthritis.

OBJECTIVE: To evaluate ixekizumab, an anti-interleukin 17A monoclonal antibody, for safety and effectiveness through 64 weeks in biologic-naive and tumor necrosis factor-inadequate responder (TNF-IR) patients with rheumatoid arthritis. METHODS: Patients completing the 16-week double-blind period of a phase II study were eligible to enter the open-label extension (OLE) for an additional 48 weeks of ixekizumab treatment. After a treatment hiatus between weeks 10 to 16, 232 biologic-naive and 158 TNF-IR patients entered the OLE with all patients receiving 160 mg ixekizumab at weeks 16, 18, and 20, and then every 4 weeks through Week 64. RESULTS: A total of 201 (87%) biologic-naive and 99 (62%) TNF-IR patients completed the OLE. Treatment-emergent adverse events (AE) occurred in 168 (72%) biologic-naive and 115 (73%) TNF-IR patients during the OLE. Most AE were mild to moderate in severity and did not lead to study discontinuation. Serious AE (SAE) occurred in 17 (7%) biologic-naive patients, including 5 (2%) serious infections and 2 (1%) deaths. SAE occurred in 18 (11%) TNF-IR patients, including 4 (3%) serious infections and 1 (1%) death. No mycobacterial or invasive fungal infections were reported. Clinical responses [American College of Rheumatology (ACR) 20, ACR50, ACR70, and 28-joint Disease Activity Score with C-reactive protein] observed at Week 16 were maintained or improved through Week 64. CONCLUSION: Ixekizumab was well tolerated, and safety findings in the OLE were consistent overall with those in the double-blind period of this study. Clinical improvements observed with ixekizumab through Week 16 were maintained or improved in patients participating in the OLE through Week 64. TRIAL REGISTRATION NUMBER: NCT00966875.

Synopsis of antinuclear antibodies in dermatology.

Antinuclear antibodies (ANA) provide a powerful tool in diagnosing the connective tissue diseases. The fundamentals of antinuclear antibody testing and the sensitivity, specificity, and prognostic value of antinuclear antibodies and their associated illnesses will be discussed. As skin manifestations are common with connective tissue diseases, knowledge of the diagnostic and prognostic value of ANA testing is essential to the nurse in dermatology.