Tildrakizumab efficacy and safety in patients with psoriasis and concomitant metabolic syndrome: post hoc analysis of 5-year data from reSURFACE 1 and reSURFACE 2.

BACKGROUND: Limited data are available on long-term efficacy and safety of biologics in patients with psoriasis and metabolic syndrome (MetS), a common comorbidity. OBJECTIVES: This analysis updates tildrakizumab efficacy and safety for up to 5 years in patients with and without MetS. METHODS: This was a post hoc analysis of the double-blind, randomized, placebo-controlled, phase 3 reSURFACE 1 (NCT01722331) and reSURFACE 2 (NCT01729754) trials in adult patients with moderate to severe chronic plaque psoriasis. Analyses included data through Week 244 from patients who continuously received tildrakizumab 100 (TIL100) or 200 mg (TIL200) and entered the extension studies, stratified by baseline MetS status. Efficacy was assessed via Psoriasis Area and Severity Index (PASI) scores. Safety was evaluated from exposure-adjusted incidence rates (EAIRs) of treatment-emergent adverse events (TEAEs). RESULTS: reSURFACE 1 and reSURFACE 2 analyses included 26 and 44 TIL100-treated patients with MetS, 98 and 167 TIL100-treated patients without MetS, 34 and 30 TIL200-treated patients with MetS, and 111 and 130 TIL200-treated patients without MetS, respectively. There were no clinically relevant differences in PASI 75/90/100 response rates at Week 244 between patients with vs without MetS. The proportion of patients with vs without MetS achieving absolute PASI score <3 at Week 244 was 53.8% vs 69.4% and 77.3% vs 80.8% in reSURFACE 1 and 2, respectively, for TIL100-treated patients and 58.8% vs 72.1% and 63.3% vs 72.3%, respectively, for TIL200-treated patients. In both studies, median reduction from baseline PASI score at all time points in patients with vs without MetS was >83% vs >89% for TIL100 and >85% vs >90% for TIL200. Pooled EAIRs of TEAEs, serious TEAEs, and TEAEs of special interest were similar in patients with and without MetS. CONCLUSIONS: Tildrakizumab maintains efficacy and a favorable safety profile over 5 years in patients with psoriasis regardless of MetS status.

Network meta-analysis of biologic treatments for psoriasis using absolute Psoriasis Area and Severity Index values ≤1, 2, 3 or 5 derived from a statistical conversion method.

BACKGROUND: In practice, the goal of treatment for patients with psoriasis is to achieve almost clear or clear skin and maintain disease control, regardless of baseline disease severity. However, identifying absolute Psoriasis Area and Severity Index (PASI) values for new treatment goals is challenging, as most clinical trials report relative PASI 50, 75, 90 or 100 improvements but rarely absolute PASI values achieved. OBJECTIVE: Our objective was to illustrate a statistical conversion method that was developed to derive absolute PASI values from available clinical trial data on relative PASI improvements. The results of network meta-analyses (NMAs) based on these derived data were then compared with those of NMAs based on the corresponding relative PASI improvement data for selected biologics for moderate-to-severe psoriasis. METHODS: The PASI statistical conversion method was applied to relative PASI improvement data for 11 biologic treatment regimens and placebo at 12 weeks using data from 50 published studies. The respective proportions of patients reaching absolute PASI values ≤1, 2, 3 or 5 were then calculated. Frequentist NMAs (Rücker method) were subsequently used to compare efficacy results across relative and absolute PASI data. RESULTS: The ranking of included treatment regimens for patients achieving absolute PASI 0 to 8 was aligned with results for relative PASI scores (from 100 to 60) at end of induction therapy. Across the range of PASI scores considered, the most effective treatment regimens based on both absolute and relative PASI NMAs were brodalumab 210 mg every 2 weeks and ixekizumab 80 mg every 2 weeks, followed by guselkumab 100 mg every 8 weeks and risankizumab 150 mg every 12 weeks. CONCLUSION: Data generated using this mathematical model will be useful to inform ongoing scientific discussions on treatment goals in the absence of primary absolute PASI data for all available treatments for moderate-to-severe plaque psoriasis.

Phase III randomized study of the proposed adalimumab biosimilar GP2017 in psoriasis: impact of multiple switches.

BACKGROUND: Adalimumab is used to treat several inflammatory diseases, including plaque psoriasis. GP2017 is a proposed adalimumab biosimilar. OBJECTIVES: To assess the impact of multiple switches between GP2017 and reference adalimumab (ref-ADMB) following the demonstration of equivalent efficacy and similar safety and immunogenicity, in adult patients with active, clinically stable, moderate-to-severe plaque psoriasis. METHODS: This 51-week double-blinded, phase III study randomly assigned patients to GP2017 (n = 231) or ref-ADMB (n = 234) 80 mg subcutaneously at week 0, then 40 mg biweekly from week 1. At week 17, patients were rerandomized to switch (n = 126) or continue (n = 253) treatment. The primary end point was patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 16, with equivalence confirmed if the 95% confidence interval (CI) for the difference in PASI 75 between treatments was ± 18%. The key secondary end point was the change from baseline to week 16 in continuous PASI. Other end points were PASI over time; PASI 50, 75, 90 and100; pharmacokinetics; safety; tolerability and immunogenicity for the switched and continued treatment groups. RESULTS: Equivalent efficacy between GP2017 and ref-ADMB was confirmed for the primary (66·8% and 65·0%, respectively; 95% CI -7·46 to 11·15) and key secondary end points (-60·7% and -61·5%, respectively; 95% CI -3·15 to 4·84). PASI improved over time and was similar between treatment groups at week 16, and the switched and continued groups from weeks 17 to 51. There were no relevant safety or immunogenicity differences between GP2017 and ref-ADMB at week 16, or the switched and continued groups from weeks 17 to 51. No hypersensitivity to adalimumab was reported upon switching. CONCLUSIONS: Following the demonstration of GP2017 biosimilarity to ref-ADMB, switching up to four times between GP2017 and ref-ADMB had no detectable impact on efficacy, safety or immunogenicity.

Ixekizumab treatment for psoriasis: integrated efficacy analysis of three double-blinded, controlled studies (UNCOVER-1, UNCOVER-2, UNCOVER-3).

BACKGROUND: Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin (IL)-17A, is approved for the treatment of moderate-to-severe psoriasis. OBJECTIVES: This analysis represents an overview of the efficacy outcomes from three phase III psoriasis studies. METHODS: Data were integrated from the 12-week induction period of three studies in which patients received ixekizumab 80 mg every 2 weeks (IXE Q2W; n = 1169) or every 4 weeks (IXE Q4W; n = 1165) after an initial 160-mg dose for both; etanercept (50 mg biweekly; n = 740; two studies) or placebo (n = 792). The coprimary end points were the percentages of patients with response of static Physician's Global Assessment (sPGA; score 0 or 1) and ≥ 75% improvement in baseline Psoriasis Area and Severity Index (PASI 75) at week 12. Response rates were compared between treatments using the Cochran-Mantel-Haenszel test stratified by study. Treatment comparisons with placebo included data from three studies, whereas etanercept comparisons were based on two studies. RESULTS: Ixekizumab treatment was superior to placebo (P < 0·001) and etanercept (P < 0·001) on sPGA (0, 1) and PASI 75, with significant differences in PASI improvement at week 1. With IXE Q2W, at week 12, the frequencies of patients achieving PASI 75, 90 and 100 were nearly 90%, 70% and 40%, respectively. Ixekizumab-treated patients showed significantly greater improvement vs. placebo and etanercept in percentage body surface area involvement and fingernail psoriasis. IXE Q2W was superior to IXE Q4W on all treatment outcomes. CONCLUSIONS: Ixekizumab therapy at both dosing regimens demonstrated rapid onset and superior efficacy to placebo and etanercept, with IXE Q2W providing better outcomes than IXE Q4W during the first 12 weeks of treatment.

Long-term optimization of outcomes with flexible adalimumab dosing in patients with moderate to severe plaque psoriasis.

BACKGROUND: The recently updated dosing recommendation for adalimumab for moderate to severe plaque psoriasis states that patients with inadequate response to adalimumab every other week (EOW) after 16 weeks may benefit from an increase in dosing frequency to 40 mg every week (EW). OBJECTIVE: To determine the long-term efficacy of adalimumab in patients with psoriasis with flexibility to escalate and de-escalate between EOW and EW dosing. METHODS: Data from an open-label study in patients with psoriasis who had received adalimumab in phase 2/3 studies and their extensions were included. Patients initially received 40 mg adalimumab EOW for 24 weeks. From weeks 24-252, patients whose Psoriasis Area and Severity Index response was <50% (PASI 50) could have their dose-escalated to 40 mg EW and were re-evaluated at 6 and 12 weeks and then every 12 weeks thereafter. Patients who had their dose-escalated and achieved a PASI 75 response were de-escalated to EOW and could re-escalate to EW if response fell below PASI 50 again; no further de-escalation was allowed. Changes in PASI scores were reported at the last visit before dose escalation or de-escalation. RESULTS: By week 24, 64.1% of patients in the overall population (n = 1256) achieved ≥PASI 75 response, 40.3% ≥PASI 90 response and 21.7% PASI 100 response. Patients who had a

Extension of ustekinumab maintenance dosing interval in moderate-to-severe psoriasis: results of a phase IIIb, randomized, double-blinded, active-controlled, multicentre study (PSTELLAR).

BACKGROUND: Phase III studies showed that some patients maintained response for ≥ 6 months following ustekinumab discontinuation. OBJECTIVES: To assess clinical responses with extended ustekinumab maintenance dosing intervals. METHODS: Adults with moderate-to-severe plaque psoriasis received ustekinumab at weeks 0, 4 and 16 during open-label treatment. Patients achieving a week-28 Physician's Global Assessment (PGA) score of cleared/minimal (PGA = 0/1) were randomized 1 : 4 to group 1 [approved every 12 weeks (q12 wk) maintenance] or group 2 (q12-24 wk; response-based dosing determined by time to loss of PGA = 0/1). Key end points included the number of visits with PGA = 0/1 (primary end point) and ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) between weeks 88 and 112, and PGA/PASI responses between weeks 28 and 112. RESULTS: Overall, 378 patients achieved PGA = 0/1 at week 28 and were randomized to group 1 (n = 76) or group 2 (n = 302). Patients in group 1 had numerically greater mean numbers of visits with PGA = 0/1 than group 2 and also with PASI 75 from week 88 to 112. A higher proportion of patients in group 1 (55%) than group 2 (39%) had PGA = 0/1 at all seven visits from week 88 to 112. Maintenance of response was observed with dose-interval extension beyond q12 wk in a subset of patients. Extending the dosing interval did not affect antibody development or safety. CONCLUSIONS: Efficacy was better maintained among week-28 PGA responders randomized to continue q12 wk ustekinumab vs. extending maintenance dosing based on clinical response, although some patients maintained high levels of efficacy with up to q24 wk dosing.

Rapid improvements in health-related quality of life and itch with ixekizumab treatment in randomized phase 3 trials: results from UNCOVER-2 and UNCOVER-3.

BACKGROUND: Patients with moderate-to-severe psoriasis report impaired health-related quality of life (HRQoL). OBJECTIVE: To assess speed of onset of ixekizumab-induced clinically relevant improvement in HRQoL. METHODS: This post hoc analysis used pooled data from patients randomized in UNCOVER-2 and UNCOVER-3, and treated with 80 mg ixekizumab every 2 weeks (IXEQ2W), 80 mg ixekizumab every 4 weeks (IXEQ4W), 50 mg etanercept (ETN) twice weekly or placebo (PBO) for 12 weeks. HRQoL and pruritus were assessed using the Dermatology Life Quality Index (DLQI) and Itch Numeric Rating Scale (NRS), respectively. Minimally clinical important differences (MCID) in DLQI and Itch NRS were defined as ≥5-point and ≥4-point improvements from baseline, respectively. Time to response from randomization was estimated using Kaplan-Meier methodology and the log-rank test. Hazard ratios between treatments were calculated using a Cox proportional hazards regression model adjusting for studies. RESULTS: A total of 2570 patients were included: 361 PBO; 740 ETN; 733 IXEQ4W and 736 IXEQ2W. Significantly greater differences in time to DLQI ≥5 point or Itch NRS ≥4 point improvement for IXEQ2W or IXEQ4W compared with ETN and PBO (P < 0.001) were observed. The median time when 50% of patients reached a ≥5-point reduction in DLQI was shorter for ixekizumab-treated patients (2 weeks, both schedules) compared with ETN- (4 weeks) or PBO-treated (>12 weeks) patients. Likewise, the median time when 50% of patients reached a ≥4-point reduction in Itch NRS was shorter for ixekizumab-treated patients (2 weeks, both schedules) compared with ETN- (8 weeks) or PBO-treated (>12 weeks) patients. Significantly more ixekizumab-treated patients were likely to achieve MCIDs in DLQI or itch reduction compared with ETN or PBO after 12 weeks of treatment. CONCLUSION: Ixekizumab-treated patients achieved more rapid improvements both in HRQoL and itch compared with patients treated with ETN and PBO.

Lack of tropomyosin correlates with the absence of stress fibers in transformed rat kidney cells.

We have utilized epithelial rat kidney cells and their Kirsten viral transformant (442) to examine the role of actin-binding proteins in cellular morphogenesis. Normal rat kidney cells are well spread while the transformed cells are more spherical, poorly adherent, and lack actin stress fibers (Rubin, R.W., Warren, R.H., Lukeman, D.S. and Clements, E. (1978) J. Cell Biol. 78, 28-35). By immunofluorescence, antitropomyosin prominently stains normal rat kidney cell stress fibers while only a weak, nonspecific fluorescence is observed in 442 cells. Using two-dimensional gel electrophoresis, tropomyosin can be detected in normal rat kidney cells homogenates. The tropomyosin subunits are enriched in Triton-extracted filamentous normal rat kidney cell models, and in extracts of normal rat kidney cell homogenate produced by using a rapid myosin affinity technique to isolate actin and actin-associated proteins. The identity of the tropomyosin subunits has been confirmed by electrophoretic mobility, lack of proline, and the peptide map generated by limited proteolysis. None of these techniques have detected tropomyosin in the corresponding 442 preparations. Our results suggest that the transformation of normal rat kidney cells has led to an overall reduction in tropomyosin content. This may be related to the inability of 442 cells to organize filamentous actin stress fibers.

Analysis of the polymerase chain reaction in the detection of herpesvirus DNA from fixed and stained tissue sections.

BACKGROUND AND DESIGN: The polymerase chain reaction (PCR) is a molecular diagnostic technique that has been applied to many infectious processes. Stained and unstained Tzanck smears, vesicle fluid swabs, and crusts have all been used as the source for template DNA for the PCR to document evidence of herpes simplex virus and varicella-zoster virus infection. Thirty-five cases with histologic evidence of acute herpesvirus infection were retrieved from archival tissue blocks that were up to 5 years old. Paraffin and hematoxylin-eosin-stained tissue sections obtained from routinely prepared glass slides from these cases were then examined for herpesvirus DNA using the PCR. RESULTS: The PCR-detected herpesvirus DNA from 34 (97.1%) of 35 paraffin tissue samples. Herpes simplex virus and varicella-zoster virus DNA were detected in eight and 26 of these cases, respectively. For hematoxylin-eosin-stained tissue samples, PCR detected herpesvirus DNA sequences in 16 (45.7%) of 35 cases. Herpesvirus DNA was isolated from paraffin tissue sections and recently prepared hematoxylin-eosin-stained tissue samples obtained from archival tissue blocks that were up to 5 and 2 years old, respectively. CONCLUSIONS: The PCR can detect herpesvirus DNA in extremely high yield from unstained paraffin-embedded tissue samples with histologic evidence of acute herpesvirus infection that are up to 5 years old. Herpesvirus DNA can also be identified in approximately 50% of these cases from hematoxylin-eosin-stained tissue sections obtained from routinely prepared glass slides.

Disseminated infection with Trichosporon beigelii. Report of a case and review of the cutaneous and histologic manifestations.

BACKGROUND: Trichosporonosis is a potentially life-threatening disseminated infection with Trichosporon beigelii, the causative agent of the white piedra. Systemic infection by this fungus has been most frequently described in immunocompromised hosts with neutropenia, but one case has been reported in the acquired immunodeficiency syndrome setting. We report a second case of trichosporonosis in a patient with acquired immunodeficiency syndrome and review the clinical and histologic characteristics of cutaneous involvement with this opportunistic fungal pathogen. OBSERVATIONS: Trichosporonosis occurs most commonly in neutropenic patients receiving chemotherapy. We describe the second case developing in the acquired immunodeficiency syndrome setting. Cutaneous involvement occurred in approximately 30% of patients and most frequently presented as purpuric papules and nodules with central necrosis or ulceration. Biopsy specimens of these lesions revealed dermal invasion by fungal elements, and culture was positive in greater than 90% of the cases. CONCLUSIONS: Disseminated infection with T beigelii can occur in immunosuppressed patients, including those with acquired immunodeficiency syndrome particularly if associated with neutropenia. Cutaneous involvement is common, presenting as purpuric papules and nodules. Biopsy and culture of cutaneous findings can help establish an accurate diagnosis resulting in rapid and appropriate treatment.

Seborrheic keratoses from the genital region may contain human papillomavirus DNA.

Sections from paraffin-embedded tissues of lesions interpreted as seborrheic keratoses localized to the pubic, genital, and crural regions were assayed for the presence of human papillomavirus types 6, 11, 16, 18, and 33 using DNA amplification followed by specific hybridization. Lesions with the histologic characteristics of condyloma were excluded from the study. Human papillomavirus DNA sequences were found in 24 (42%) of 57 seborrheic keratosis-like lesions from the genital region. No human papillomavirus DNA was detected in 27 control specimens that represented a variety of other processes occurring in this area. We conclude that human papillomavirus infection cannot be excluded in genital seborrheic keratoses.

Identification of Mycobacterium tuberculosis DNA in five different types of cutaneous lesions by the polymerase chain reaction.

BACKGROUND AND DESIGN: A spectrum of skin lesions are believed to be secondary to the presence of Mycobacterium tuberculosis. Demonstration of M tuberculosis directly or in culture in some of these eruptions can be difficult. We used the polymerase chain reaction and a primer/probe set specifically for M tuberculosis complex DNA to evaluate five types of skin lesions clinically considered to represent infection by, or reaction to, M tuberculosis. OBSERVATIONS: Mycobacterium tuberculosis DNA was demonstrated in paraffin-embedded sections of these five cases, representing a variety of clinical and histologic patterns. In two cases, M tuberculosis could not be demonstrated by routine cultural methods. CONCLUSION: DNA diagnostic methods such as the polymerase chain reaction can be used to rapidly identify cutaneous lesions produced by M tuberculosis.

Efalizumab-induced autoimmune pancytopenia.

Efalizumab is a recombinant, humanized monoclonal anti-CD11a antibody used for the treatment of moderate to severe plaque psoriasis. Immune-mediated thrombocytopenia and anaemia have previously been reported with this therapy. We describe the first case of immune-mediated pancytopenia in a patient treated with efalizumab. Close monitoring of all blood cell counts is warranted in light of this case.

The tumour necrosis factor-alpha inhibitor adalimumab rapidly reverses the decrease in epidermal Langerhans cell density in psoriatic plaques.

BACKGROUND: The pathophysiology of psoriasis is poorly understood, and the mechanism of action of biological agents interfering with tumour necrosis factor (TNF)-alpha that improve psoriatic plaques is completely unknown. OBJECTIVES: To begin to unravel the mechanism of action, cellular changes occurring in plaques following administration of adalimumab, a humanized monoclonal antibody against TNF-alpha, were investigated. METHODS: Thirteen different patients underwent sequential biopsies as part of a clinical trial. Each biopsy was immunostained and evaluated to calculate the relative density of epidermal Langerhans cells (LCs) before and after treatment (days 2, 7, 28, 84). To explore the basis for reduced epidermal LC densities in plaques, a SCID-Hu animal model was utilized. Acute psoriatic lesions were created within 2 weeks by injection of superantigen-activated CD4+ T cells into engrafted symptomless skin. RESULTS: Compared with symptomless skin, untreated plaques had a significantly reduced density of epidermal LCs. There was a rapid increase in density of epidermal LCs in plaques following treatment with adalimumab beginning as early as day 7. The paucity of epidermal LCs in plaques was contrasted to the prominent density of LCs in other skin disorders with chronic inflammation and alterations in keratinization, including lichen planus and inflamed seborrhoeic keratosis. Rapid creation of plaques using the SCID-Hu model was accompanied by loss of epidermal LCs, indicating that diminished LC density occurs at an early stage of lesion formation. CONCLUSIONS: These data shed light on a new immunopathological perspective highlighting a rapid loss of epidermal LCs in acute psoriatic lesions, with sustained decreased density of LCs in chronic plaques. Furthermore, an unexpected insight into the mechanism of action was uncovered for adalimumab, in which rapid restoration of epidermal LC density was observed.

Identification of Mycobacterium tuberculosis DNA in a case of lupus vulgaris.

A variety of cutaneous lesions are believed to result from the presence of Mycobacterium tuberculosis. Demonstration of M. tuberculosis directly or in culture in some of these eruptions can be difficult. We studied a typical case of lupus vulgaris that had been followed for several years with frequent unrewarding biopsies and cultures to see if M. tuberculosis DNA could be demonstrated in skin biopsy specimens. We used the polymerase chain reaction and a primer/probe set specific for a region in the gene for the 65 kd antigen of M. tuberculosis to search for M. tuberculosis complex DNA. M. tuberculosis complex DNA was demonstrated in archival skin biopsy specimens from the lesion of lupus vulgaris. The polymerase chain reaction and specific primer/probe sequences can be used to demonstrate M. tuberculosis complex DNA in skin lesions. A variety of skin lesions believed to be related to tuberculosis (tuberculids) can be revisited with these techniques and studied for the presence of an infectious agent.