ABSTRACT
BACKGROUND: Weight loss is reported with oral roflumilast, which is approved for chronic obstructive pulmonary disease (COPD). Recently, the drug has shown efficacy in psoriasis, a disease strongly linked to overweight/obesity. OBJECTIVE: To describe the effects of oral roflumilast on body weight and cardio-metabolic parameters in patients with psoriasis. METHODS: Posthoc analyses from the PSORRO study, where patients with moderate-to-severe plaque psoriasis were randomized 1:1 to oral roflumilast 500 µg once-daily or placebo for 12 weeks, followed by active, open-label treatment through week 24 in both groups. Changes in body weight, blood pressure, gastrointestinal symptoms, and laboratory tests were registered. No lifestyle or dietary interventions were applied. RESULTS: Forty-six patients were randomized. Baseline characteristics across groups were comparable; mean weight was 103.6 kg. In patients receiving roflumilast, median weight change was -2.6% and -4% at week 12 and 24, respectively. Corresponding numbers were 0.0% and 1.3% in patients initially allocated to placebo. Reduced appetite was more frequent with active therapy. No changes in blood pressure or laboratory tests were observed. LIMITATIONS: Posthoc analyses and low numbers. CONCLUSION: Oral roflumilast induced weight loss and reduced appetite, which support the growing evidence of roflumilast as an attractive treatment alternative for patients with psoriasis.
Subject(s)
Aminopyridines , Benzamides , Cyclopropanes , Phosphodiesterase 4 Inhibitors , Psoriasis , Weight Loss , Humans , Aminopyridines/administration & dosage , Aminopyridines/therapeutic use , Cyclopropanes/administration & dosage , Cyclopropanes/therapeutic use , Cyclopropanes/adverse effects , Male , Female , Middle Aged , Psoriasis/drug therapy , Benzamides/administration & dosage , Benzamides/therapeutic use , Benzamides/adverse effects , Adult , Administration, Oral , Phosphodiesterase 4 Inhibitors/administration & dosage , Phosphodiesterase 4 Inhibitors/therapeutic use , Weight Loss/drug effects , Double-Blind Method , Body Weight/drug effects , Aged , Blood Pressure/drug effects , Treatment Outcome , Severity of Illness IndexABSTRACT
Knowledge about the molecular mechanisms underlying the systemic inflammation observed in psoriasis remains incomplete. In this study, we applied mass spectrometry-based proteomics to compare the plasma protein levels between patients with psoriasis and healthy individuals, aiming to unveil potential systemically dysregulated proteins and pathways associated with the disease. Plasma samples from adult patients with moderate-to-severe psoriasis vulgaris (N = 59) and healthy age- and sex-matched individuals (N = 21) were analyzed using liquid chromatography-tandem mass spectrometry. Patients did not receive systemic anti-psoriatic treatment for four weeks before inclusion. A total of 776 protein groups were quantified. Of these, 691 were present in at least 60% of the samples, providing the basis for the downstream analysis. We identified 20 upregulated and 22 downregulated proteins in patients with psoriasis compared to controls (p < 0.05). Multiple proteins from the complement system were upregulated, including C2, C4b, C5, and C9, and pathway analysis revealed enrichment of proteins involved in complement activation and formation of the terminal complement complex. On the other end of the spectrum, periostin was the most downregulated protein in sera from patients with psoriasis. This comprehensive proteomic investigation revealed significantly elevated levels of complement cascade proteins in psoriatic plasma, which might contribute to increased systemic inflammation in patients with psoriasis.
Subject(s)
Complement System Proteins , Proteomics , Psoriasis , Humans , Psoriasis/blood , Psoriasis/metabolism , Male , Female , Proteomics/methods , Adult , Complement System Proteins/metabolism , Middle Aged , Case-Control Studies , Tandem Mass Spectrometry , Proteome/metabolism , Biomarkers/blood , Chromatography, LiquidABSTRACT
AIM: To examine whether adults with mild to moderate atopic dermatitis (AD) had reduced insulin sensitivity and/or exhibited other gluco-metabolic disturbances compared with carefully matched healthy controls. MATERIALS AND METHODS: Sixteen adult, non-obese, non-diabetic patients with mild to moderate AD and 16 gender-, age- and body mass index (BMI)-matched healthy controls underwent a hyperinsulinaemic euglycaemic clamp (insulin infusion rate: 40 mU/m2 /minute) and an oral glucose tolerance test (OGTT) with frequent blood sampling for gut and pancreatic hormones. RESULTS: The two groups were similar in age (33 ± 3 vs. 33 ± 3 years, mean ± standard error of the mean [SEM]), gender (56% women), BMI (24.5 ± 0.7 vs. 24.4 ± 0.7 kg/m2 ), physical activity level, fasting plasma glucose and HbA1c. Patients with AD had a mean Eczema Area and Severity Index score of 8.5 ± 1.0 (moderate disease) and a mean AD duration of 28 ± 3 years. During the OGTT, circulating glucose, insulin, C-peptide, glucagon and glucose-dependent insulinotropic polypeptide, respectively, were similar in the two groups, except glucagon-like peptide-1, which was higher in patients with AD. The clamp showed no differences in insulin sensitivity between groups (M-value 9.2 ± 0.6 vs. 9.8 ± 0.8, P = .541, 95% CI -1.51; 2.60), or circulating insulin, C-peptide and glucagon levels. CONCLUSIONS: Using OGTT and the hyperinsulinaemic euglycaemic clamp technique, we found no difference in insulin sensitivity or other gluco-metabolic characteristics between patients with mild to moderate AD and matched healthy controls, suggesting that the inflammatory skin disease AD has little or no influence on glucose metabolism.
Subject(s)
Dermatitis, Atopic , Eczema , Insulin Resistance , Adult , Blood Glucose , Female , Gastric Inhibitory Polypeptide , Glucose , Humans , Incretins , Insulin , Male , Pancreatic HormonesABSTRACT
BACKGROUND: Patients with psoriasis have increased risk of type 2 diabetes. The pathophysiology is largely unknown, but it is hypothesized that systemic inflammation causes insulin resistance. Insulin sensitivity has only been sparsely investigated in patients with psoriasis, and previous studies have used suboptimal methodology. The hyperinsulinemic euglycemic clamp remains the gold standard for quantifying whole-body insulin sensitivity. OBJECTIVE: We sought to investigate if normal glucose-tolerant patients with psoriasis exhibit impaired insulin sensitivity. METHODS: Three-hour hyperinsulinemic euglycemic clamps were performed in 16 patients with moderate to severe, untreated psoriasis and 16 matched control subjects. RESULTS: The 2 groups were similar with regard to age, gender, body mass index, body composition, physical activity, fasting plasma glucose, and glycosylated hemoglobin. Mean ± SEM psoriasis duration was 23 ± 3 years and Psoriasis Area and Severity Index score was 12.7 ± 1.4. Patients with psoriasis exhibited reduced insulin sensitivity compared with control subjects (median M-value 4.5 [range 1.6-14.0] vs 7.4 [range 2.1-10.8] mg/kg/min, P = .046). There were no differences between groups in plasma glucose, insulin, C-peptide, and glucagon during the clamp. LIMITATIONS: The classic hyperinsulinemic euglycemic clamp technique does not allow assessment of endogenous glucose production. CONCLUSION: Patients with psoriasis were more insulin resistant compared with healthy control subjects. This supports that psoriasis may be a prediabetic condition.
Subject(s)
Insulin Resistance , Psoriasis/metabolism , Adult , Anthropometry , Blood Glucose/analysis , C-Peptide/analysis , Case-Control Studies , Diabetes Mellitus, Type 2/epidemiology , Female , Glucagon/blood , Gluconeogenesis , Glucose Clamp Technique , Glucose Intolerance , Humans , Hyperinsulinism/blood , Inflammation , Insulin , Male , Middle Aged , Prediabetic State/epidemiology , Prediabetic State/metabolism , Psoriasis/epidemiology , RiskABSTRACT
Communicating with scientific journals is a central part of the publication process, yet sparsely covered in the medical literature. A cover letter to the editor(s) should always accompany new submissions, whereas response (or rebuttal) letters relate to revisions and replying to referees' comments following peer review. This review describes the two types of letters, focusing on content, style, and structure, and provides helpful tips for handling challenging reviewer scenarios.
Subject(s)
Correspondence as Topic , Periodicals as Topic , Writing , Periodicals as Topic/standards , Writing/standards , Peer Review, Research/standards , Editorial Policies , Humans , Guidelines as Topic , Publishing/standardsABSTRACT
Recent case reports suggest that treatment with glucagon-like peptide-1 (GLP-1) agonists results in clinical improvement of psoriasis. The purpose of this study was to determine whether GLP-1 receptors (GLP-1Rs) are found in the skin of healthy volunteers and psoriasis patients and if so, whether GLP-1Rs are located on keratinocytes or immune cells. Three mm-punch skin biopsies were taken for gene expression analysis from six healthy volunteers and from affected and unaffected skin of six psoriasis patients. In addition, a blood sample was obtained from all participants. Cultured human keratinocytes were either untreated or incubated with tumor necrosis factor- α (TNF-α), interferon-γ (IFN-γ) or a combination of TNF-α and IFN-γ for 48 h. Total RNA was extracted from all the samples, reversely transcribed and analysed for the expression of GLP-1R using real-time PCR. Gene expression analysis showed expression of GLP-1Rs in five of six skin biopsies from psoriasis plaques, in one of six biopsies from unaffected psoriatic skin and in one of six biopsies from healthy skin. GLP-1R expression was found in the blood of both healthy volunteers and psoriasis patients. No GLP-1R expression was found in either stimulated or unstimulated cultured human keratinocytes. Our results show increased presence of GLP-1Rs in psoriasis plaques and that this most likely is due to infiltration with immune cells. This offers a possible explanation for the positive effect of treatment with GLP-1R agonists in patients with psoriasis.
Subject(s)
Gene Expression Regulation , Psoriasis/metabolism , Receptors, Glucagon/metabolism , Skin/metabolism , Adult , Biopsy , Cells, Cultured , Female , Gene Expression Profiling , Glucagon-Like Peptide-1 Receptor , Humans , Interferon-gamma/metabolism , Keratinocytes/cytology , Male , Middle Aged , Skin/pathology , Time Factors , Tumor Necrosis Factor-alpha/metabolism , Young AdultABSTRACT
INTRODUCTION: Calcific uremic arteriolopathy is a life-threatening cutaneous condition in patients with chronic kidney disease. Often, clinical diagnosis is accompanied by histopathologic evaluations demonstrating vascular calcium deposits. We aimed to investigate the presence of cutaneous calcifications in non-lesional tissue in patients with chronic kidney disease, and the relation to systemic vascular calcification. METHODS: We investigated the presence of cutaneous vascular calcifications in non-lesional skin biopsies from patients with current or previous calcific uremic arteriolopathy and patients with different stages of chronic kidney disease without calcific uremic arteriolopathy, and explored their association with vascular calcification in other vascular beds. Systemic vascular calcification was examined by mammography and lumbar X-ray. RESULTS: Thirty-nine adults were enrolled (current or previous calcific uremic arteriolopathy, n = 9; end-stage chronic kidney disease, n = 12; chronic kidney disease stage 3b-4, n = 12; healthy controls, n = 6). All calcific uremic arteriolopathy patients had end-stage kidney disease. Cutaneous vascular calcifications were not present in any of the non-lesional skin punch biopsies. Breast arterial calcification was demonstrated in patients with calcific uremic arteriolopathy (75%) and chronic kidney disease (end-stage 67% and stage 3b-4 25%, respectively), but in none of the controls. All chronic kidney disease patients had systemic calcification on lumbar X-ray (median score 21, 22, and 15 in patients with calcific uremic arteriolopathy, end-stage kidney disease and chronic kidney disease stage 3b-4). The serum calcification propensity was significantly different between groups. DISCUSSION: Despite a high burden of systemic vascular calcification, cutaneous calcium deposits in non-lesional tissue could not be demonstrated histopathologically in patients with chronic kidney disease (with or without current or previous calcific uremic arteriolopathy). Further studies to determine whether these findings are representative or attributed to other factors are warranted.
Subject(s)
Calcinosis Cutis , Calciphylaxis , Kidney Failure, Chronic , Vascular Calcification , Adult , Humans , Cross-Sectional Studies , Calcium , Calciphylaxis/etiology , Calciphylaxis/complications , Vascular Calcification/diagnostic imaging , Vascular Calcification/complications , Kidney Failure, Chronic/complicationsABSTRACT
OBJECTIVE: The effect of oral glucose-induced release of gastrointestinal hormones on satiety and appetite independently of prevailing plasma glucose excursions is unknown. The objective is to investigate the effect of oral glucose on appetite and satiety sensations as compared to isoglycemic IV glucose infusion (IIGI) in healthy volunteers. DESIGN: A crossover study involving two study days for each participant. PARTICIPANTS: Nineteen healthy participants (6 women, mean age 55.1 [SD 14.2] years; mean body mass index 26.7 [SD 2.2]â kg/m2). INTERVENTIONS: Each participant underwent a 3-h 50-g oral glucose tolerance test (OGTT) and, on a subsequent study day, an IIGI mimicking the glucose excursions from the OGTT. On both study days, appetite and satiety were indicated regularly on visual analog scale (VAS), and blood was drawn regularly for measurement of pancreatic and gut hormones. PRIMARY OUTCOMES: Difference in appetite and satiety sensations during OGTT and IIGI. RESULTS: Circulating concentrations of glucose-dependent insulinotropic polypeptide (P < .0001), glucagon-like peptide 1 (P < .0001), insulin (P < .0001), C-peptide (P < .0001), and neurotensin (P = .003) increased significantly during the OGTT as compared to the IIGI, whereas glucagon responses were similarly suppressed (P = .991). Visual analog scale-assessed ratings of hunger, satiety, fullness, thirst, well-being, and nausea, respectively, were similar during OGTT and IIGI whether assessed as mean 0-3-h values or area under the curves. For both groups, a similar, slow increase in appetite and decrease in satiation were observed. Area under the curve, for prospective food consumption (P = .049) and overall appetite score (P = .044) were slightly lower during OGTT compared to IIGI, whereas mean 0-3-h values were statistically similar for prospective food consumption (P = .053) and overall appetite score (P = .063). CONCLUSIONS: Despite eliciting robust responses of appetite-reducing and/or satiety-promoting gut hormones, we found that oral glucose administration has little or no effect on appetite and satiety as compared to an IIGI, not affecting the release of appetite-modulating hormones. TRIAL REGISTRY NO: ClinicalTrials.gov: NCT01492283 and NCT06064084.
Subject(s)
Gastrointestinal Hormones , Glucose , Humans , Female , Middle Aged , Appetite/physiology , Blood Glucose , Cross-Over Studies , Glucagon , Insulin , Satiation , SensationABSTRACT
Background: Roflumilast is a targeted inhibitor of phosphodiesterase (PDE)-4 and has been approved for treatment of severe chronic obstructive pulmonary disease for more than a decade. Generic versions are available in the United States. PDE-4 is involved in the psoriasis pathogenesis, but the efficacy and safety of oral roflumilast in patients with psoriasis have not previously been studied. Methods: A company-independent, multicenter, randomized, double-blind, placebo-controlled trial (ClinicalTrials.govNCT04549870). Patients were randomized 1:1 to receive monotherapy with oral roflumilast 500 µg once daily or placebo. At week 12, placebo patients were switched to open-label roflumilast through week 24. The primary endpoint was a 75% or greater reduction from baseline in the psoriasis area and severity index (PASI75) at week 12. Findings: In all, 46 patients were randomized (roflumilast, n = 23; placebo, n = 23). At week 12, significantly more patients in the active arm achieved PASI75 (8 of 23 patients [35%]) vs. placebo (0 of 23 patients [0%], with a difference vs. placebo of 8 [35%] patients, 95% CI: 3 [13%]-13 [57%] patients) (p = 0.014). At week 24, 15 (65%), 10 (44%), 5 (22%), and 2 (9%) of patients treated with roflumilast from week 0 had PASI50, PASI75, PASI90, and PASI100 responses (key secondary endpoints), respectively. The most prevalent, drug-related adverse events in both treatment groups were transient gastrointestinal symptoms, weight-loss, headache, and insomnia. A total of three patients (roflumilast n = 2; placebo, n = 1) discontinued therapy due to adverse events. Interpretation: Oral roflumilast was efficacious and safe in treating moderate-to-severe plaque psoriasis over 24 weeks. With generic versions available, this drug may represent an inexpensive and convenient alternative to established systemic psoriasis treatments. Funding: Financial support was received from Herlev and Gentofte Hospital, University of Copenhagen, and independent grants from private foundations in Denmark. No pharmaceutical company, including the market authorization holder of roflumilast, was involved in the study at any point.
ABSTRACT
Psoriasis is a common, chronic inflammatory skin disease associated with a large number of comorbidities. Though management of moderate-to-severe plaque psoriasis has greatly improved in recent years, patients with refractory disease or contraindications to available treatments still constitute therapeutic challenges. Oral roflumilast, a selective phosphodiesterase-4 (PDE-4) inhibitor, is approved for chronic obstructive pulmonary disease. Experimental studies have shown increased PDE-4 activity in psoriatic skin, and inhibition results in down-regulation of key inflammatory cytokines. Based on mode-of-action and available literature, we hypothesize that oral roflumilast is a future treatment for plaque psoriasis. Contrary to most existing psoriasis therapies, roflumilast has a favorable safety profile and holds the potential to improve not only skin manifestations but also commonly seen comorbidities. If efficacy and safety are confirmed in randomized settings, roflumilast can fill in a large unmet need and may represent a novel, relatively inexpensive, and convenient therapy positioned before biologics.
Subject(s)
Phosphodiesterase 4 Inhibitors , Psoriasis , Pulmonary Disease, Chronic Obstructive , Humans , Aminopyridines/therapeutic use , Aminopyridines/pharmacology , Chronic Disease , Phosphodiesterase 4 Inhibitors/therapeutic use , Psoriasis/drug therapyABSTRACT
BACKGROUND: The evidence for adding small-molecule drugs to an ongoing biologic treatment is sparse, but combination therapies appear to be advantageous in appropriately selected patients with psoriasis. To our knowledge, efficacy and safety of combination therapy with apremilast and biologics has not previously been reviewed. MATERIALS AND METHODS: A literature search was performed on Medline (PubMed), Embase, Web of Science, and the Cochrane Library. Inclusion criteria were a diagnosis of psoriasis, age ≥ 18 years, concomitant treatment with apremilast and a specified biologic agent, and available safety and/or efficacy results. All papers written in English and published from database inception to August 2021 were included. No limit was set regarding study size. RESULTS: The literature search yielded 447 citations. Of these, 19 studies published from 2015 to 2020 were included in the review. All papers referred to retrospective studies, comprising case reports (n = 9), case series (n = 8), or cohort studies (n = 2). A total of 172 patients with psoriasis were identified. Clinical subtypes included plaque psoriasis (n = 164), palmoplantar pustulosis (n = 7), and acute pustular psoriasis (n = 1). The observation period ranged from 3 weeks to 24 months. Geographical origin of studies was North America (n = 11), Europe (n = 4), and Asia (n = 4). In general, apremilast-biologic combination therapy was reported to be safe; across papers, one serious adverse event was registered (hospitalization due to weight loss). Adverse events (AEs) were otherwise mostly mild and gastrointestinal. No differences in AEs were observed in studies comparing apremilast mono- and combination therapy. In several papers, sufficient information about AEs was not reported or could not be extracted. Clinical response to combination treatment was evaluated at various time points, and only few studies used validated scores. In the remaining papers, efficacy data were descriptive and/or in photographic form, or not available. In total, two patients discontinued therapy due to lack of efficacy. CONCLUSION: Evidence for combined treatment with apremilast and biologics is limited and restricted to retrospective studies of various quality. Based on available data, apremilast may constitute an efficacious and safe add-on treatment to biologic therapy, but properly conducted clinical investigations are needed.
Subject(s)
Biological Products , Psoriasis , Thalidomide , Adolescent , Biological Products/therapeutic use , Drug Therapy, Combination/adverse effects , Exanthema , Humans , Psoriasis/drug therapy , Retrospective Studies , Thalidomide/analogs & derivatives , Thalidomide/therapeutic useSubject(s)
Granuloma, Foreign-Body/chemically induced , Hypercalcemia/chemically induced , Nephrocalcinosis/chemically induced , Oils/adverse effects , Paraffin/adverse effects , Weight Lifting , Granuloma, Foreign-Body/diagnosis , Humans , Injections, Intramuscular , Male , Oils/administration & dosage , Paraffin/administration & dosage , Positron-Emission Tomography , Tomography, X-Ray Computed , Young AdultABSTRACT
Insulin pump therapy and the use of flash or continuous glucose monitoring in children is increasing. The diabetes devices are attached to the skin for several days to weeks with a strong adhesive, and recently, several cases of allergic contact dermatitis in children caused by components of the adhesive have been reported. In this review, we discuss such problems. The most frequent cause of allergic contact dermatitis is acrylates in the adhesive material, and the problem is serious and calls for rapid development of devices used in the treatment and monitoring of Type 1 diabetes without allergenic agents.
Subject(s)
Dermatitis, Allergic Contact , Diabetes Mellitus , Insulins , Acrylates , Blood Glucose , Blood Glucose Self-Monitoring , Camphanes , Child , Dermatitis, Allergic Contact/diagnosis , Dermatitis, Allergic Contact/etiology , HumansABSTRACT
BACKGROUND: Fasting hyperglucagonemia can be detrimental to glucose metabolism in patients with type 2 diabetes (T2D) and may contribute to metabolic disturbances in obese and/or prediabetic subjects. However, the mechanisms underlying fasting hyperglucagonemia remain elusive. METHODS: We evaluated the interrelationship between fasting hyperglucagonemia and demographic and biochemical parameters in 106 patients with T2D (31% female, age: 57 ± 9 years [mean ± standard deviation; body mass index (BMI): 30.1 ± 4.4 kg/m2; fasting plasma glucose (FPG): 9.61 ± 2.39 mM; hemoglobin A1c (HbA1c): 57.1 ± 13.1 mmol/mol] and 163 nondiabetic control subjects (29% female; age: 45 ± 17 years; BMI: 25.8 ± 4.1 kg/m2; FPG: 5.2 ± 0.4 mM; and HbA1c: 35.4 ± 3.8 mmol/mol). Multiple linear regression analysis was applied using a stepwise approach with fasting plasma glucagon as dependent parameter and BMI, waist-to-hip ratio (WHR), blood pressure, hemoglobin A1c, FPG, and insulin concentrations as independent parameters. RESULTS: Fasting plasma glucagon concentrations were significantly higher among patients with T2D (13.5 ± 6.3 vs. 8.5 ± 3.8 mM, P < 0.001) together with HbA1c (P < 0.001), FPG (P < 0.001), and insulin (84.9 ± 56.4 vs. 57.7 ± 35.3 mM, P < 0.001). When adjusted for T2D, HbA1c and insulin were significantly positive determinants for fasting plasma glucagon concentrations. Furthermore, WHR comprised a significant positive determinant. CONCLUSIONS: We confirm that fasting plasma glucagon concentrations are abnormally high in patients with T2D, and show that fasting plasma glucagon concentrations are influenced by WHR (in addition to glycemic control and fasting plasma insulin concentrations), which may point to visceral fat deposition as an important determinant of increased fasting plasma glucagon concentrations.