Evaluation of Psoriasis Area and Severity Index Thresholds as Proxies for Systemic Inflammation on an Individual Patient Level.

BACKGROUND: Psoriasis is a chronic and systemic inflammatory disease with a loss of up to 5 life years, which is thought to be reduced by biologic treatment. Disease severity and eligibility for systemic treatment are often based on the cutaneous psoriasis area and severity index (PASI) with a cut-off of 10 in several European countries. However, it is unclear how well this cut-off reflects systemic inflammation and, consequently, the risk for the development of comorbidity. OBJECTIVES: (1) To assess whether specific PASI thresholds, in particular PASI 10, predict elevated biomarkers of systemic inflammation and cardiovascular risk on an individual patient level. (2) To assess the association of PASI and psoriatic arthritis with biomarkers of systemic inflammation and cardiovascular risk. METHODS: Retrospective cross-sectional study of 72 psoriasis patients without systemic treatment. RESULTS: Overall, 68, 42, and 50% of patients had cardiovascular risk level neutrophil-to-lymphocyte ratio (NLR), C-reactive protein, and elevated platelet-to-lymphocyte ratio (PLR) values, respectively. The respective positive predictive values of PASI 10 were 70, 45, and 70. The performance of the optimal PASI cut-offs according to the Youden index was similarly weak. Subgrouping of patients with a PASI below 10 did not result in a considerably improved reflection of systemic inflammation. PLR was significantly higher in patients with moderate-to-severe compared to mild psoriasis and significantly correlated with PASI in patients with a PASI above 2 (rs = 0.266, n = 64). NLR was significantly higher in patients with psoriatic arthritis. CONCLUSION: Specific PASI thresholds were not well suited to predict elevated biomarkers of systemic inflammation and cardiovascular risk on an individual patient level. Therefore, PASI, and possibly other purely cutaneous measures, may not be ideal as stand-alone parameters to define disease severity and eligibility for systemic treatment. Our results are relevant for the ongoing discussion on the definition of psoriasis severity and eligibility for systemic treatment. Further research addressing the added value of a set of biomarkers of systemic inflammation in the assessment of psoriasis severity would be desirable.

Detailed Long-term Dynamics of Neutrophil-to-Lymphocyte Ratio under Biologic Treatment Reveals Differential Effects of Tumour Necrosis Factor-alpha and Interleukin 12/23 Antagonists.

Psoriasis is thought to be associated with a reduced life expectancy through systemic inflammation. A comparative, retrospective analysis of neutrophil-to-lympho-cyte ratio, a biomarker of systemic inflammation and cardiovascular risk, under 196 treatments with tumour necrosis factor-α and interleukin-12/23 antagonists was performed. Neutrophil-to-lympho-cyte ratio decreased significantly within 3 months of initiation of treatment and remained stable at reduced levels for at least 33 months. Dynamics were more pronounced and neutrophil-to-lympho-cyte ratio under treatment was lower in patients treated with tumour necrosis factor-α compared with interleukin-12/23 antagonists (geometric mean (95% confidence interval): 2.03 (1.9, 2.1) vs 2.63 (2.2, 3.2), respectively, p = 0.014). tumour necrosis factor-α antagonist treatment and baseline neutrophil-to-lympho-cyte ratio were independent predictors of a median low cardiovascular risk neutrophil-to-lympho-cyte ratio (< 2.15) during treatment (odds ratio (95% confidence interval): 0.53 (0.4-0.8) and 4.68 (1.0-19.1), p = 0.001 and p = 0.032, respectively). These results demonstrate a rapid and sustained reduction in biomarkers of systemic inflammation under biologic treatment. Furthermore, these data suggest class-specific effects on systemic inflammation, which may be relevant for the prevention of psoriasis co-morbidity by systemic treatment.

Evaluation of Psoriasis Area and Severity Index as a Proxy for Bio-markers of Systemic Disease under Treatment with Tumour Necrosis Factor-alpha and Interleukin 12/23 Antagonists in Patients with Psoriasis: A Retrospective Cohort Study of 186 Treatment Cycles.

The efficacy of psoriasis treatments is usually evaluated using the Psoriasis Area and Severity Index (PASI). However, there is a lack of systematic statistical assessments of PASI as a proxy for systemic disease in individual patients. Therefore, a retrospective study of 186 treat-ments with adalimumab, etanercept, and ustekinumab for psoriasis (341 patient-years) was performed. While PASI significantly and independently correlated with biomarkers of systemic inflammation (especially neutrophil-to-lymphocyte ratio, C-reactive protein), the strengths were only weak-to-moderate and varied considerably inter-individually. A decrease in PASI indicated a neutrophil-to-lymphocyte ratio decrease and a C-reactive protein decrease or stable low margin C-reactive protein in ≥ 80%. Sensitivity, specificity, and positive predictive value of PASI 0 and PASI 2.75 (optimal Youden Index) for low cardiovascular risk C-reactive protein were 24%, 92%, 85%, and 62%, 61%, 76%, respectively. Performance was similar using absolute thresholds and PASI 100 or PASI 75, and overall worse for low cardiovascular risk neutrophil-to-lympho-cyte ratio and if psoriasis arthritis was present. In conclusion, PASI allows robust low-order estimates of systemic inflammation, but cannot substitute for laboratory biomarkers for more precise assessments.

Long-term safety of combination treatment with methotrexate and tumor necrosis factor (TNF)-α antagonists versus TNF-α antagonists alone in psoriatic patients.

Methotrexate, a folic acid analog, is the conventional systemic anti-psoriatic agent most commonly chosen for combination with biologics in the treatment of psoriasis. Real-world long-term safety data of this combination versus biologic treatment alone in dermatological practice are sparse. Here, we present results of a comparative retrospective study of laboratory dynamics and adverse events in psoriatic patients receiving a tumor necrosis factor (TNF)-α antagonist (adalimumab or etanercept) with and without concomitant methotrexate (176 treatment courses, mean duration of 629 days). Co-treatment with methotrexate significantly (P < 0.05) correlated with a decrease of leukocyte, neutrophil and erythrocyte counts and an increase of glutamate pyruvate transaminase (GPT) (Pearson correlation, n > 148). The relative risk for a Common Terminology Criteria for Adverse Events (CTCAE) grade 1-2 laboratory adverse event was significantly elevated to 1.11 for anemia and 1.16 for a GPT increase if the patients received concomitant methotrexate at the time the laboratory test was performed. Combination treatment was given for equal or more than 30% of the time (MTX≥30% ) during 12% of the treatment courses. During these treatment courses, dynamics of leukocyte (-8.1%), neutrophil (-8.1%), erythrocyte (-3.2%) counts and GPT (+16.9%) from baseline to average under treatment were significantly more pronounced. CTCAE grade 3-4 laboratory adverse events occurred in 9.5% and 5.2% of treatment courses with and without MTX≥30% , respectively (p = 0.70), and affected transaminases in 90% of the cases. Methotrexate was discontinued due to CTCAE grade 3-4 laboratory adverse events in 4.25% of the treatment courses with MTX of 30% or more. Elevated baseline γ-glutamyl transferase levels significantly predicted the occurrence of CTCAE grade 3-4 laboratory adverse events and should trigger investigations for pre-existing liver disease or alcohol abuse. In conclusion, our comparative data supplement previous short-term studies and support a tolerable long-term safety profile of the combination treatment. However, given the additional toxicities and low evidence for benefits, alternative options such as biologic monotherapy or switching to a different biologic should be considered in a dermatological setting.

Scleromyxedema.

Scleromyxedema is a rare, cutaneous deposition disorder from the group of mucinoses, which can affect multiple organs and is virtually always associated with a monoclonal gammopathy. Cutaneous manifestations are usually generalized, 2 to 3 mm sized, dome-shaped or flat-topped, waxy, slightly red to skin-colored papules and sclerodermoid indurations. Neurological, rheumatological, cardiovascular, gastrointestinal, respiratory tract, renal and ophthalmologic manifestations can occur, with decreasing frequency. A serious and potentially lethal complication is the dermato-neuro syndrome which manifests with flu-like prodromes followed by fever, convulsions and coma. Untreated, scleromyxedema usually takes an unpredictable and potentially lethal progressive disease course over several years. According to a widely acknowledged classification by Rongioletti a diagnosis of scleromyxedema can be rendered when (1) generalized, papular and sclerodermoid eruption, (2) a histological triad of mucin deposition, fibroblast proliferation and fibrosis, and (3) monoclonal gammopathy are present, and (4) thyroid disease is absent. Apart from the classic microscopic triad, an interstitial granuloma annulare like pattern was also described. The pathogenesis of scleromyxedema is unknown. A potential role for various, as yet unknown serum factors has been discussed. An unequivocal causal relationship between paraproteinemia and disease manifestations could not be established to date. High dose intravenous immunoglobulins (IVIg) are the first-line treatment of choice according to the most recent European guidelines.

High-Dose Intravenous Immunoglobulin in Skin Autoimmune Disease.

The immunomodulatory potential and low incidence of severe side effects of high-dose intravenous immunoglobulin (IVIg) treatment led to its successful application in a variety of dermatological autoimmune diseases over the last two decades. IVIg is usually administered at a dose of 2 g per kg body weight distributed over 2-5 days every 4 weeks. They are most commonly used as a second- or third-line treatment in dermatological autoimmune disease (pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane pemphigoid, epidermolysis bullosa acquisita, dermatomyositis, systemic vasculitis, and systemic lupus erythematosus). However, first-line treatment may be warranted in special circumstances like concomitant malignancy, a foudroyant clinical course, and contraindications against alternative treatments. Furthermore, IVIg can be considered first line in scleromyxedema. Production of IVIg for medical use is strictly regulated to ensure a low risk of pathogen transmission and comparable quality of individual batches. More common side effects include nausea, headache, fatigue, and febrile infusion reactions. Serious side effects are rare and include thrombosis and embolism, pulmonary edema, renal failure, aseptic meningitis, and severe anaphylactic reactions. Regarding the mechanism of action, one can discriminate between functions of the Fcγ region and the F(ab)2 region and their effects on a cellular level. These functions are not mutually exclusive, and more than one pathway may contribute to the beneficial effects. Here, we present a historical background, details on manufacturing, hypotheses on the mechanisms of action, information on the clinical application in the abovementioned conditions, and a brief outlook on future directions of IVIg treatment in dermatology.

High-dose intravenous immunoglobulins for the treatment of dermatological autoimmune diseases.

Based on their immunomodulatory properties, high-dose intravenous immunoglobulins (IVIGs) are successfully used in the treatment of various dermatological autoimmune diseases, in particular pemphigus vulgaris and dermatomyositis. In autoimmune bullous diseases, IVIGs can be used in an adjuvant setting (second- or third-line therapy) once combined immunosuppressive regimens have failed. In dermatomyositis, IVIGs may already be employed as an adjuvant second-line therapy after failure of corticosteroid monotherapy. In scleromyxedema, IVIGs may be considered as first-line treatment, given the lack of effective and safe alternatives. Other potential indications for IVIGs may include severe recalcitrant cases of systemic vasculitis and systemic lupus erythematosus. Toxic epidermal necrolysis may be an indication for high-dose IVIGs if administered early. Common, readily manageable side effects include nausea, headache, fatigue, and febrile infusion reactions. Severe adverse events such as thromboembolic events, anaphylaxis, and acute renal failure are very uncommon. The risk of viral transmission is very low. Potential mechanisms of action include upregulation of inhibitory Fc receptors, reduction of the half-life of endogenous immunoglobulins due to displacement from protective receptor sites, neutralization of autoantibodies by anti-idiotypic antibodies, as well as inhibition of complement activation.

Neutrophil extracellular traps in dermatology: Caught in the NET.

Neutrophil, or polymorphonuclear granulocytes (PMN) constitute the most abundant type of leucocytes in peripheral human blood. One of the major advances in the last decade was the discovery of neutrophil extracellular trap (NET) formation: a process by which neutrophils externalize web-like chromatin strands decorated with antimicrobial peptides. These structures were soon implicated in immune defense and auto-immunity alike and now link neutrophils to the pathogenesis of a variety of diseases of dermatological relevance. Currently, NET formation is mainly subdivided into suicidal and vital NETosis. Controversy exists regarding the capacity of NETs to kill pathogens, and little is known about the way NETs are formed in vivo. Here, we discuss the current terminology, methods for NET quantification, pathways leading to NET formation, and the role of NETs in systemic and cutaneous immune defense and auto-immunity, with a focus on psoriasis and systemic lupus erythematosus.

Interindividual variation of NETosis in healthy donors: introduction and application of a refined method for extracellular trap quantification.

Neutrophil extracellular trap (NET) formation is a mechanism of innate immune defence by which neutrophil (polymorphonuclear) granulocytes (PMN) produce net-like structures of decondensed chromatin decorated with antimicrobial peptides for trapping and possibly killing microorganisms. If this process leads to cell death, it is termed NETosis. Alterations of this particular mechanism have been reported to be involved in the pathogenesis of chronic inflammatory diseases including psoriasis and lupus erythematosus. Still, quantification of NETosis poses a considerable challenge. We report and test a refined protocol for morphological NET quantification in healthy human donors that encompasses isolation, stimulation, DNA staining, live imaging and semi-automated offline analysis. The results were highly reproducible and in good agreement with manual counting. The average intra-donor coefficient of variation of NETosis rates to phorbol myristate acetate (PMA) stimulation was low compared to the respective interdonor coefficient of variation (10% vs 82%, n=4, respectively, if experiments were repeated on the same day, and 38% vs 74%, n=6, respectively, if experiments were repeated on average 42±34 days apart). Overall, the interdonor coefficient of variation was 67% (n=10). These findings altogether support the existence of a distinct predisposition of PMN from different donors for undergoing NETosis. Picogreen fluorescence correlated stronger to cell death than to morphological NETosis (r2 =.89, P<.001, n=8, and r2 =.68, P=.012, n=8, respectively). This indicates that cytotoxicity may confound Picogreen fluorescence. Our results and the related protocol may help investigators with the quantification of NETosis and the design of respective basic and translational research studies.

Synaptic Conductance Estimates of the Connection Between Local Inhibitor Interneurons and Pyramidal Neurons in Layer 2/3 of a Cortical Column.

Stimulation of a principal whisker yields sparse action potential (AP) spiking in layer 2/3 (L2/3) pyramidal neurons in a cortical column of rat barrel cortex. The low AP rates in pyramidal neurons could be explained by activation of interneurons in L2/3 providing inhibition onto L2/3 pyramidal neurons. L2/3 interneurons classified as local inhibitors based on their axonal projection in the same column were reported to receive strong excitatory input from spiny neurons in L4, which are also the main source of the excitatory input to L2/3 pyramidal neurons. Here, we investigated the remaining synaptic connection in this intracolumnar microcircuit. We found strong and reliable inhibitory synaptic transmission between intracolumnar L2/3 local-inhibitor-to-L2/3 pyramidal neuron pairs [inhibitory postsynaptic potential (IPSP) amplitude -0.88 ± 0.67 mV]. On average, 6.2 ± 2 synaptic contacts were made by L2/3 local inhibitors onto L2/3 pyramidal neurons at 107 ± 64 µm path distance from the pyramidal neuron soma, thus overlapping with the distribution of synaptic contacts from L4 spiny neurons onto L2/3 pyramidal neurons (67 ± 34 µm). Finally, using compartmental simulations, we determined the synaptic conductance per synaptic contact to be 0.77 ± 0.4 nS. We conclude that the synaptic circuit from L4 to L2/3 can provide efficient shunting inhibition that is temporally and spatially aligned with the excitatory input from L4 to L2/3.

Baseline anti-dsDNA concentrations and previous treatments predict response to Adalimumab and Etanercept: a retrospective investigation of 146 psoriasis patients.

BACKGROUND: Adalimumab and Etanercept are TNF-α antagonists commonly used for treatment of moderate-to-severe psoriasis and psoriatic-arthritis. Reliable instruments to assist the selection of patients for a specific treatment in a real-world scenario are unavailable. OBJECTIVE: To identify patient characteristics and baseline laboratory parameters predicting response to Adalimumab- and Etanercept-treatment. METHODS: We report a retrospective observational study including 116 and 64 psoriasis-patients treated with Adalimumab and Etanercept, respectively, at a dermatological outpatient clinic of a university hospital. Thirty four patients contributed data to both biologics. First occurrence of either loss-of-response or serious-side-effects (LOR/SSE) was chosen as clinical endpoint and predictors were identified using Cox-regression. RESULTS: Baseline anti-double-stranded DNA (anti-dsDNA) concentrations, number of previous treatments with TNF-α antagonists in general and previous treatment with Etanercept in particular significantly predicted LOR/SSE to Adalimumab. The predictive effect of baseline anti-dsDNA was conserved in TNF-α antagonist naïve patients. Number of previous systemic treatments other than TNF-α antagonists significantly predicted LOR/SSE to Etanercept. Age and baseline psoriasis area and severity index (PASI) did not predict response to either biologic in a clinically significant manner. CONCLUSION: Our data suggests that treatment with Adalimumab may promise best results in psoriasis-patients with (A) low baseline anti-dsDNA concentrations, and (B) no previous TNF-α antagonist treatment. A clinically significant predictive effect of age and baseline PASI on response to Adalimumab and Etanercept is unlikely.

Analysis of high-dose intravenous immunoglobulin therapy in 16 patients with refractory autoimmune blistering skin disease: high efficacy and no serious adverse events.

High-dose intravenous immunoglobulin (IVIG) therapy is used in patients with severe autoimmune blistering diseases that are refractory to standard immunosuppressive therapy. To determine the efficacy and frequency of adverse events of IVIG therapy, we retrospectively analysed data for 16 patients with pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, bullous pemphigoid and paraneoplastic bullous pemphigoid. Frequency of adverse reactions and efficacy of IVIG were analysed over time with a scoring system for every 6 months of IVIG therapy. Headache (43.8%) and fatigue (43.8%) were the most common side-effects recorded; serious adverse reactions did not occur. There was good overall efficacy, as measured by clinical response rates using a clinical score, as well as indicated by a mean reduction of 75.8% in the starting steroid dose.

Combined nevus with dermally located pagetoid cells in the perianal region: a new variant of site-related histological atypia.

Nevi with site-related histological atypia have been reported in various locations, mainly on the female genitalia, along the anatomical milk line and in skin folds. Therefore, the literature focuses clearly on the atypical nevi of the female genitalia. In the present case, we describe a unique case of a combined perianal melanocytic nevus with architectural and cytologic atypia that differ from the histopathologic features of accepted criteria for atypical genital nevi. A suspicion of malignant melanoma was raised, but few pivotal histological features, the age of the patient and the clinical follow-up for 10 years proved otherwise. This case contributes to the collection of necessary information about perianal nevi that show obvious variations in site-related histological atypia compared with atypical genital nevi. Although the malignant potential of such lesions remains unclear, it is important to prevent overdiagnosis of malignant melanoma with the associated devastating surgery, especially in young patients.