Exploring the Clinical Assessment, Guidelines, and Options for the Treatment of Generalized Pustular Psoriasis [Podcast].

Acute episodes of generalized pustular psoriasis (GPP), known as "flares", are characterized by the widespread appearance of pustules with surrounding skin erythema, and are often accompanied by systemic symptoms. The clinical course of GPP is unpredictable, and symptoms vary in extent and severity; the disease may be relapsing-remitting with recurrent episodes of pustulosis, or be more persistent. The triggers that may lead to flares include withdrawal of corticosteroids, stress, pregnancy, and infections. GPP-specific assessment tools, such as the Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) and the General Pustular Psoriasis Area and Severity Index (GPPASI), were developed to evaluate the severity of disease, and to monitor the patient's response to therapy during clinical trials. Spesolimab is the first GPP-specific treatment available in the United States for the treatment of GPP flares in adults, and was approved by the US FDA in September 2022. To date, spesolimab has been approved by regulatory agencies in almost 40 countries, including Japan, Mainland China, and the European Union. Spesolimab is a first-in-class humanized monoclonal antibody that targets the interleukin-36 receptor, and blocks the downstream effects of the interleukin-36 pathway, which is associated with GPP pathogenesis. Data from clinical trials demonstrate the safety and efficacy of spesolimab in providing rapid clinical improvement for patients with GPP flares. Standardized international guidelines for the diagnosis and management of GPP are needed, and no recent GPP guidelines are available in the US. This podcast discusses clinical assessment tools for GPP (GPPGA and GPPASI), the evolution of GPP management guidelines, the therapeutic landscape of GPP, efficacy and safety data for spesolimab, and examines important considerations for patients living with this condition.

Colorectal Cancer Screening Knowledge and Practices Among Practicing Obstetrician-Gynecologists and Residents.

Background: Colorectal cancer (CRC) is the second leading cause of cancer death in the US, the third most diagnosed cancer in women, and the second leading cause of cancer death in women. The aims of our study are to (1) investigate knowledge of and adherence to CRC screening guidelines by obstetrician-gynecologists (Ob/Gyns) and (2) assess whether this knowledge/adherence vary by demographic and practice characteristics. Methods: An anonymous cross-sectional survey was distributed to a convenience sample of 142 practicing Obs/Gyns drawn from National Medical Association section members/conference attendees and hospital Ob/Gyn department members. Results: Most respondents (80.3%) viewed colorectal screening within the scope of Ob/Gyn practice, and 71.8% used the American College of Obstetricians and Gynecologists guidelines for screening. Most respondents were knowledgeable regarding CRC screening but not in all areas. On average they only identified half of the 10 risk factors listed and only one-quarter correctly identified the age when screening can stop. Residents were somewhat more knowledgeable about screening guidelines and risk factors than attendings. More than half of respondents (57.8%) reported always initiating CRC screening for the appropriate age and risk factors. Respondents identified education and awareness (56.3%) and patients' unwillingness to undergo an invasive procedure (75.4%) as barriers to screening. Conclusions: Knowledge regarding CRC screening was less than optimal and differed by attending/resident status. Greater emphasis should be placed on CRC screening and guidelines training for primary care providers like Ob/Gyns. Some of this could be accomplished through maintenance of certification and continued integration into residency education.

Brodalumab to the Rescue: Efficacy and Safety of Brodalumab in Patients with Psoriasis and Prior Exposure or Inadequate Response to Biologics.

While biologic therapies for psoriasis are effective for many patients, some patients may lose response, have inadequate control of disease, or develop intolerance to certain biologic agents. It may therefore be beneficial for patients whose psoriasis fails to respond to one biologic to switch to a different biologic therapy, in particular one with a different mechanism of action. However, it remains unclear how prior biologic exposure or lack of response affects the efficacy and safety of subsequent biologics in patients with moderate-to-severe psoriasis. Brodalumab, a fully human anti-interleukin-17 receptor A monoclonal antibody, has previously been shown to be efficacious in treating moderate-to-severe psoriasis in three large phase 3 trials (AMAGINE-1, AMAGINE-2, and AMAGINE-3). In this review, we summarize the efficacy and safety of brodalumab in patients with moderate-to-severe psoriasis and a history of biologic exposure. Further, we describe improvements in skin clearance and quality of life measures as well as safety in patients who had inadequate response to ustekinumab and who were rescued with brodalumab therapy. Lastly, we discuss improvements in skin clearance following rescue with brodalumab in patients whose disease failed to respond to secukinumab and ixekizumab. The findings of our review suggest that brodalumab is a safe and efficacious treatment regardless of past biologic use or lack of response to prior biologic therapy.

Importance of Complete Skin Clearance in Psoriasis as a Treatment Goal: Implications for Patient-Reported Outcomes.

Psoriasis is associated with physical, psychological, social, and economic burdens that lead to substantial impairment over a patient’s lifetime. It is important to understand how different skin clearance levels may relate to patient perceptions of psoriasis symptoms and health-related quality of life. Here, we highlight notable advantages to complete skin clearance relative to high levels of efficacy without complete skin clearance, including meaningful improvements in patient-reported signs and symptoms of psoriasis, a higher mean proportion of symptom-free days, and significant improvements in quality of life. We also review biologic therapies associated with high percentages of complete skin clearance and significant improvements in signs and symptoms of psoriasis, notably brodalumab. These therapies are likely to play important roles in the future treatment of moderate-to-severe psoriasis, given that improvement in quality of life is of significant value relative to biologics or other systemic therapies associated with lower rates of complete skin clearance. J Drugs Dermatol. 2020;19(5): doi:10.36849/JDD.2020.4957.

Malignancy Rates in Brodalumab Clinical Studies for Psoriasis.

BACKGROUND: Brodalumab is a fully human anti-interleukin-17 receptor A monoclonal antibody efficacious for the treatment of adults with moderate-to-severe plaque psoriasis. OBJECTIVE: This study summarizes malignancy rates in psoriasis clinical studies of brodalumab. METHODS: Data were pooled from one phase II study and three large, multicenter, phase III randomized studies of brodalumab for the treatment of psoriasis, including two studies with randomization to brodalumab, ustekinumab, or placebo. Data from the 52-week (brodalumab and ustekinumab) and long-term (brodalumab) pools were summarized as exposure-adjusted or follow-up time-adjusted event rates per 100 patient-years (PY). RESULTS: Exposure-adjusted event rates per 100 PY at 52 weeks were lower with brodalumab (n = 4019; 3446 total PY of exposure) than with ustekinumab (n = 613; 495 total PY of exposure), including adjudicated malignancies (0.9 vs 2.6) and Surveillance, Epidemiology, and End Results (SEER)-adjudicated malignancies (0.3 vs 0.4). The exposure-adjusted event rate of adjudicated malignancies in the brodalumab group remained stable in the long-term analysis (0.9 [82 events]). CONCLUSIONS: Rates of malignancy among brodalumab-treated patients with psoriasis were generally low. TRIAL REGISTRY: ClinicalTrials.gov identifier NCT00975637; NCT01101100; NCT01708590 (AMAGINE-1); NCT01708603 (AMAGINE-2); NCT01708629 (AMAGINE-3).

Impact of Clinical Specialty Setting and Geographic Regions on Disease Management in Patients with Psoriatic Arthritis in the United States: A Multicenter Observational Study.

BACKGROUND: Information on the factors that influence treatment management decisions for psoriatic arthritis (PsA) is limited. OBJECTIVE: Our objective was to evaluate the impact of clinical specialty setting and geographic region on the management of patients with PsA in the USA. METHODS: LOOP was a multicenter, cross-sectional, observational study conducted across 44 sites in the USA. Patients were aged ≥ 18 years with a suspected or established diagnosis of PsA and were routinely visiting a rheumatologist or dermatologist. All patients enrolled in the study were assessed by both a rheumatologist and a dermatologist. Primary outcomes were the times from symptom onset to PsA diagnosis; PsA diagnosis to first conventional synthetic disease-modifying antirheumatic drug (csDMARD); PsA diagnosis to first biologic DMARD (bDMARD); and first csDMARD to first bDMARD. RESULTS: Of 681 patients enrolled in the study, 513 had a confirmed diagnosis of PsA and were included in this analysis. More patients were recruited by rheumatologists (71.3%) than by dermatologists (28.7%). The median time from symptom onset to diagnosis of PsA was significantly shorter for patients enrolled by rheumatologists than for those enrolled by dermatologists (1.0 vs. 2.6 years; p < 0.001). Disease activity and burden were generally similar across enrolling specialties. However, patients in western areas of the USA had less severe disease than those in central or eastern areas, including measures of joint involvement, enthesitis, and dactylitis. CONCLUSIONS: There was a substantial delay in the time from symptom onset to diagnosis in this study population, and this was significantly longer for patients enrolled in the dermatology versus the rheumatology setting. This supports the need for collaboration across specialties to ensure faster recognition and treatment of PsA.

Nasal fractures in children and adolescents: Mechanisms of injury and efficacy of closed reduction.

OBJECTIVES: To determine the most common mechanisms of traumatic nasal deformity referred to pediatric otolaryngology. To examine the efficacy of closed reduction of nasal fractures in children and adolescents based on the parents' and surgeons' ratings of post-reduction nasal symmetry. METHODS: Case series and chart review within an urban, tertiary pediatric otolaryngology practice. RESULTS: 100 cases of traumatic nasal deformity met inclusion criteria over a 3-year study period. The mean age at presentation was 13 years (4 weeks-18 years); 55% were male and 70% were over the age of 12 years. The most common mechanism of injury was sports-related trauma (28%), followed by accidental trauma (21%), interpersonal violence (10%), motor vehicle collision (6%) and alcohol-related (2%). Of these 100 cases, 22% underwent closed reduction within a 14-day period following injury. All patients achieved symmetry in the operating room immediately following reduction. 21 of 22 post-reduction patients were assessed for nasal symmetry at the postoperative visit (7-10 days following surgery). The operating surgeon was satisfied with nasal symmetry in 43% of cases and the parent(s) satisfied in 81% of cases. Both parent and surgeon were satisfied with post-reduction symmetry 33% of the time. CONCLUSION: The most common sources of traumatic nasal deformity in children and adolescents vary by age. In cases meriting operative intervention, parents appear to be satisfied with early postoperative results following closed reduction in approximately 80% of cases, however a result in which both parent and surgeon agree with successful re-establishment of symmetry occurs in only one-third of cases.

Thiol-ene/acrylate substrates for softening intracortical electrodes.

Neural interfaces have traditionally been fabricated on rigid and planar substrates, including silicon and engineering thermoplastics. However, the neural tissue with which these devices interact is both 3D and highly compliant. The mechanical mismatch at the biotic-abiotic interface is expected to contribute to the tissue response that limits chronic signal recording and stimulation. In this work, novel ternary thiol-ene/acrylate polymer networks are used to create softening substrates for neural recording electrodes. Thermomechanical properties of the substrates are studied through differential scanning calorimetry and dynamic mechanical analysis both before and after exposure physiological conditions. This substrate system softens from more than 1 GPa to 18 MPa on exposure to physiological conditions: reaching body temperature and taking up less than 3% fluid. The impedance of 177 µm(2) gold electrodes electroplated with platinum black fabricated on these substrates is measured to be 206 kΩ at 1 kHz. Specifically, intracortical electrodes are fabricated, implanted, and used to record driven neural activity. This work describes the first substrate system that can use the full capabilities of photolithography, respond to physiological conditions by softening markedly after insertion, and record driven neural activity for 4 weeks.

Three-Dimensional Flexible Electronics Enabled by Shape Memory Polymer Substrates for Responsive Neural Interfaces.

Planar electronics processing methods have enabled neural interfaces to become more precise and deliver more information. However, this processing paradigm is inherently 2D and rigid. The resulting mechanical and geometrical mismatch at the biotic-abiotic interface can elicit an immune response that prevents effective stimulation. In this work, a thiol-ene/acrylate shape memory polymer is utilized to create 3D softening substrates for stimulation electrodes. This substrate system is shown to soften in vivo from more than 600 to 6 MPa. A nerve cuff electrode that coils around the vagus nerve in a rat and that drives neural activity is demonstrated.

Treatment of moderate to severe plaque psoriasis with concomitant efalizumab and narrow-band ultraviolet B phototherapy.

BACKGROUND: Efalizumab therapy and narrow-band ultraviolet B (NB-UVB) phototherapy have different mechanisms of action; combined therapy may be more effective than either treatment alone in treating moderate to severe plaque psoriasis. METHODS: This study investigated the efficacy and safety of efalizumab (1 mg/kg/wk) combined with NB-UVB 3 times a week for 12 weeks, followed by efalizumab monotherapy for 12 additional weeks. RESULTS: Twenty patients were enrolled with mean Psoriasis Area and Severity Index (PASI) of 12.8 +/- 7.4, mean physician's global assessment (PGA) of 5 +/- 1, and mean body surface area (BSA) affected of 18.2% +/- 15.3% at baseline. At week 12, 65% of patients (n = 13) achieved PASI 75; mean PGA was 2 +/- 1, corresponding to a 60% reduction; and mean BSA was 4.7% +/- 4.1%, corresponding to a 74% reduction. The improvements seen at week 12 were maintained during the ensuing efalizumab monotherapy. CONCLUSION: Combination of efalizumab and NB-UVB followed by efalizumab monotherapy was effective and well tolerated, this warranting further investigation.

Open label trial of alefacept in palmoplantar pustular psoriasis.

BACKGROUND: Palmoplantar pustular psoriasis (PPP) is difficult to treat. We assessed the effectiveness of alefacept in PPP and the safety of a 30 mg/week dose. METHODS: Fifteen individuals with PPP were started on 15 mg/week intramuscularly (IM) alefacept. Efficacy was measured by the PPP severity instrument (PSI). Treatment was continued for 16 weeks, and the alefacept dose was increased to 30 mg/week IM at week 9 if the PSI did not decrease by at least 25%. Other outcomes included physician's global assessment (PGA), reported adverse events and CD4+ T-lymphocyte counts. Clinical response was observed for 12 weeks after the last injection. RESULTS: The severity of PPP improved in both the PSI and the PGA (p<0.0001 and p = 0.0009, respectively). Much of the improvement occurred after 10 weeks of therapy. Nail severity scores improved (p = 0.0003). CD4+ counts decreased, but all remained >250 cells/mm3. There were no severe adverse effects or discontinuations due to adverse events. CONCLUSIONS: Alefacept in doses up to 30 mg/week was well tolerated in patients with PPP and appeared to have some efficacy. The use of concomitant therapy, the lack of a comparator, and the small sample size are limitations of the study.

alpha1-Antitrypsin deficiency presenting with panniculitis and incidental discovery of chronic obstructive pulmonary disease.

A 60-year-old man presented to the Emergency Department (ED) with large, painful, indurated plaques on the right thigh, left abdomen, left chest, and right chest, which began without any preceding trauma on the right thigh 3 weeks prior to presentation in the ED. He was initially treated with cefazolin 1 g three times daily as home infusions. When the lesions continued to progress, he was admitted to the hospital and placed on amoxicillin/clavulanate and vancomycin. He had a single episode of fever of 102 degrees F, but his white blood cell count and differential remained normal. An initial biopsy showed a dermal inflammatory infiltrate composed primarily of neutrophils and eosinophils with rare flame figures in the dermis. There was minimal fat seen in this biopsy. A differential diagnosis of Wells or Sweet's syndrome was entertained, and he was placed on 60 mg/day prednisone with no resolution of his symptoms. The patient's past medical history included hypertension, hyperlipidemia, peripheral neuropathy, and hiatal hernia. His family history was significant for emphysema in both parents and coronary artery disease in his father. Both of his parents smoked cigarettes. His grandfather, who was a coal miner, also had emphysema. Whilst on antibiotics and prednisone, the plaques on the patient's right thigh, right abdomen, and left chest expanded and ulcerated, draining an oily liquid (Figs 1 and 2). An incisional biopsy was obtained from his thigh. Histopathology showed a septal and lobular panniculitis with fat necrosis, neutrophils, and histiocytes (Fig. 3). Special stains for organisms were negative. Tissue sent for bacterial and fungal culture had no growth. Amylase and lipase levels were normal. Rheumatoid factor, antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), cryoglobulins, and antiphospholipid antibodies were all normal. The alpha1-antitrypsin level was low at 25 mg/dL (ref. 75-135). The alpha1-antitrypsin phenotype was PiZZ. The patient had a normal glucose-6-phosphate dehydrogenase level and was placed on dapsone 200 mg/day. The inflammation resolved and, over the course of several months, the involved areas healed with scarring. The patient denied any pulmonary complaints but, during his hospitalization, was found incidentally to have an oxygen saturation of 88% on room air. He was sent for evaluation by a pulmonologist, and pulmonary function tests revealed a mixed restrictive and obstructive pattern with a forced expiratory volume in 1 to forced vital capacity (FEV(1)/FVC) ratio of 63% of predicted. He had never smoked. He was placed on supplemental oxygen but, as his pulmonary disease has been stable, he has not been treated with intravenous antitrypsin inhibitor.

Contact urticaria from curcumin.

Turmeric, a spice derived from the rhizome of the plant Curcuma longa, contains the chemical curcumin, which is responsible for turmeric's taste, color, and biologic properties. Curcumin is used as a spice in foods, as a treatment in traditional medicine, as a dye for fur, and as a component in nutritional supplements. A few cases of allergic contact dermatitis from curcumin have been reported. We report two cases of contact urticaria from curcumin. These cases are mediated by two different mechanisms of contact urticaria: nonimmunologic and immunologic (immunoglobulin-E mediated).

Lesions resembling malignant atrophic papulosis in a patient with progressive systemic sclerosis.

Malignant atrophic papulosis (MAP), or Degos syndrome, is a rare disorder of unknown etiology. It is characterized by a deep subcutaneous vasculopathy resulting in atrophic, porcelain-white papules. We report the case of a 42-year-old woman with a history of progressive systemic sclerosis who presented with painful subcutaneous nodules on her abdomen along with chronic atrophic papules on her upper and lower limbs. Biopsy results of both types of lesions revealed vascular thrombi without surrounding inflammation. We briefly review the literature on MAP and its association with various connective tissue diseases. To our knowledge, there have been no previous reports of a patient with the clinical and histologic presentations described here. Although the histologic appearance of the subcutaneous nodules was very similar to that of the atrophic papules, the clinical characteristics of the 2 types of lesions were strikingly different. It is fair to theorize that Degos lesions do not start as atrophic porcelain-white papules but rather evolve from a primary lesion. We hypothesize that these lesions start as painful red nodules and may represent part of the disease spectrum in the evolution of MAP.

Alefacept: a novel biologic in the treatment of psoriasis.

Recognition of psoriasis as a T-cell-mediated immune disease has led to the development of various therapeutic approaches directed against the T cell and T-cell processes such as activation, trafficking and cytokine release. The novel and selective biologic agent alefacept, with an effect of selective apoptotic reduction in memory-effector T cells, has been given FDA approval for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy. The clinical profile of this novel biologic agent is presented here. Two pivotal multicenter, randomized, placebo-controlled, double-blind studies enrolling 1060 patients were designed to support the efficacy and safety of alefacept in the treatment of moderate to severe chronic plaque psoriasis. With either intramuscular or intravenous administration, well over half of patients treated with a single course of alefacept achieved a 50% reduction in PASI (Psoriasis Area and Severity Index), and a second course of therapy provided further benefit by increasing response rates and providing long-lasting off-treatment responses regardless of the route of administration. In all studies, alefacept was well tolerated. There was no evidence of an increased risk of infections or malignancies and no opportunistic infections were reported. Consistent with its composition as a fully human fusion protein, alefacept had a low incidence of immunogenicity and no evidence of an increased rate of antibody development over time. There was no evidence that primary or secondary responses to a new antigen or memory response to a recall antigen were blunted in patients treated with alefacept. In conclusion, alefacept is the first biologic therapy to demonstrate positive effects in an immune-mediated disease while maintaining immune responses to novel and recall antigens. This selective effect on the immune system distinguishes alefacept from immunosuppressive therapies that are nonselective.

Relapsing polychondritis.

A 43-year-old Chilean man presented with a 5-month history of progressive hypertrophy of the ears bilaterally. He was seen initially by a dermatologist in Chile for complaints of erythema and swelling of the ears, and had been treated unsuccessfully with topical steroids and antimicrobial ointments. On presentation to our clinic, the hypertrophy had stabilized and the erythema had resolved, but he complained of decreased hearing due to narrowing of the external auditory canal. Associated symptoms included occasional pruritus, but he denied any pain. He also denied a history of sinus problems, respiratory symptoms, ocular pain, chest pain, and arthralgias. Physical examination revealed firm hypertrophy of the collagenous areas of both ears, sparing the ear lobes (Fig. 1). No pain was elicited on palpation. No conjunctivitis was noted and the nasal passages were clear. His chest was clear to auscultation. Histologic examination revealed a minimal perivascular infiltrate of lymphocytes and plasma cells in the dermis with fibrosis of the subcutis (Fig. 2). Blood tests showed a normal complete blood count, antinuclear antibody, and rheumatoid factor. Anti-collagen II antibodies were elevated at 29.2 Eu/ml (normal, 0-20 Eu/ml; borderline, 20-25 Eu/ml; elevated, > 25 Eu/ml).