Diseases associated with hypersensitivity reactions (HRs) are extremely common and can affect the quality of life of millions of people, sometimes with life-threatening severity. In order to diagnose, treat, cure, or potentially prevent these diseases, clinicians and scientists need a better understanding of the entire immune process, from its initiation through the central mechanism to the effector phase. A new classification is needed, primarily because earlier classifications defined HRs almost exclusively by their effector mechanisms. However, outstanding achievements in immunological science over the past decades have revealed the critical, decision-making roles of initiation and central mechanisms in shaping the well-known effector phases. In addition, a crucially important group of HRs consists of small-molecule drug-induced reactions, which include both immunological and non-immunological pharmacological processes; therefore, the incorporation of these entities represents a key aspect of the revised classification. This review article provides a historical overview of the evolution of the main HR classifications, and proposes a new, expanded classification that (a) considers the initiation, central, and effector phases of HRs as interconnected, equally important processes; (b) highlights the role of peripheral barrier tissues in the breakdown of tolerance, thereby contributing to the development of HRs, and (c) distinguishes between classic and non-classic HRs (e.g., pharmacological interaction with immune receptors [p-i] reactions and pseudoallergies). Adoption of this new classification may expand the possibilities for developing preventive and causal therapies and help physicians appropriately interpret and thus effectively treat the heterogeneous phenotypes of hypersensitivity diseases.

Muscle and skin involvement are well defined in dermatomyositis but other symptoms contribute significantly to the disease burden and their treatment is not well characterized. This post hoc analysis of ProDERM assessed the effect of intravenous immunoglobulin (IVIg) treatment on other manifestations of dermatomyositis beyond muscular and cutaneous involvement. ProDERM was a randomized, placebo-controlled study. For weeks 0–16, patients with dermatomyositis received 2.0 g/kg IVIg (Octagam, 10

BACKGROUND:Efgartigimod is approved in multiple regions for the treatment of gMG, ITP, and CIDP, and is being evaluated in multiple IgG-mediated autoimmune diseases. Here, we report the long-term safety profiles of efgartigimod IV and PH20 SC across different dosing regimens and diseases where efgartigimod has received regulatory approval. RESEARCH DESIGN AND METHODS:Efgartigimod safety was assessed across dosing regimens and administration routes in Phase 2, placebo-controlled Phase 3, and OLE studies in participants with gMG, ITP, and CIDP. Analyses were performed on all participants who received ≥ 1 dose or partial dose of efgartigimod or placebo. Data from efgartigimod-treated participants were pooled per disease. Event rates were calculated as events per PYFU. RESULTS:Pooled data included 715 participants representing > 850 PYFU. In efgartigimod-treated participants, most TEAEs were mild-to-moderate in severity, with consistently low event rates for TEAE-related treatment discontinuation (range: 0.05-0.47). Severe and serious infection rates were comparable between placebo- and efgartigimod-treated participants. Rates of TEAEs, severe and serious infections, and treatment discontinuation did not increase with prolonged efgartigimod exposure. Efgartigimod did not reduce albumin or increase LDL cholesterol levels. CONCLUSIONS:Across clinical trials in IgG-mediated autoimmune diseases, efgartigimod was well tolerated with similar safety profiles regardless of dosing regimen.

OBJECTIVES:The phase 3 ProDERM study demonstrated intravenous immunoglobulin (IVIg) was safe and effective in patients with dermatomyositis (DM). This analysis assessed clinical and serological predictors of IVIg response in DM patients from ProDERM. METHODS:ProDERM was a prospective, randomized, placebo-controlled study of DM patients. For weeks 0-16, patients received 2.0 g/kg IVIg (Octagam, 10%) or placebo every 4 weeks. Eligible patients entered the open-label extension phase, where all received IVIg to week 40. Univariate and multivariate analyses examined associations between baseline variables and total improvement score (TIS), including myositis disease activity assessment tool (MDAAT; assessing different organ involvement), and myositis-specific and myositis-associated autoantibodies. RESULTS:Ninety-five patients were enrolled. Univariate analyses found no significant association between TIS at week 16 or 40 and age; sex; ethnicity; disease duration/activity; cutaneous, skeletal, gastrointestinal or muscle disease activity; or previous failed or concomitant medications. Multivariate analysis found patients with higher MDAAT cutaneous scores had a better chance of at least minimal TIS improvement. Higher MDAAT pulmonary scores were associated with a lower, but still considerable, chance of improvement. Patients with TIF1-γ antibodies had a better TIS response; however, after controlling for cutaneous disease activity, there was no significant association between antibody classification (including anti-TIF1-γ) and efficacy outcome. CONCLUSION:IVIg was effective in treating DM patients regardless of demographic features and autoantibody status (for most autoantibodies). Patients with higher cutaneous disease activity and/or anti-TIF1-γ responded best to IVIg, while pulmonary disease activity predicted a lower, but still effective, IVIg response, warranting further investigation. TRIAL REGISTRATION:ClinicalTrials.gov, http://clinicaltrials.gov, NCT02728752.

We are aiming to summarize the main clinical and histopathological correlations of most known vasculitides which involve the small-, and medium-sized vessels of the skin. In general, vasculitides can be classified into three major groups: systemic vasculitis with cutaneous involvement, systemic vasculitis with skin limited appearance and single organ vasculitis. We also highlight the importance on the recognition of the clinicopathologic patterns of the corresponding vasculitides, with special emphasis on the histopathologic features and their underlying pathologies.

Background Dermatomyositis is an idiopathic inflammatory myopathy characterised by rashes and progressive muscle weakness. The recent ProDERM (Progress in DERMatomyositis) study is the first large randomised, placebo-controlled trial to establish the efficacy and safety of intravenous immunoglobulin (IVIg) in adult patients with dermatomyositis. Objectives of this analysis were to closely examine the safety and tolerability of IVIg in patients from the ProDERM study. Methods ProDERM was a double-blind, randomised, placebo-controlled, multicentre, phase 3 study. In the first period (weeks 0–16), adults with active dermatomyositis received 2.0 g/kg IVIg (Octagam 10%; Octapharma AG) or placebo every 4 weeks. In the open-label extension period (weeks 16–40), all patients received IVIg for 6 additional cycles; dose reduction (1.0 g/kg) was permitted if patients were stable. Treatment-emergent adverse events (TEAEs) were documented. Results The 95 patients enrolled were randomised to receive IVIg ( N = 47) or placebo ( N = 48) in the first period, with 5 switching from placebo to IVIg. Overall, 664 IVIg infusion cycles were administered. During the first period, 113 TEAEs were possibly/probably related to treatment in 30/52 patients (57.7%) receiving IVIg and 38 in 11 patients (22.9%) on placebo. Eight patients discontinued therapy due to IVIg-related TEAEs. Eight thromboembolic events (TEEs) occurred in six patients on IVIg; six in five patients were deemed possibly/probably related to IVIg. Patients with TEEs exhibited more baseline TEE risk factors than those without TEEs (2.4–15.2-fold higher). Lowering infusion rate reduced the rate of TEEs, and none occurred at the lower IVIg dose. No haemolytic transfusion reactions or deaths occurred. Conclusions Results from this study demonstrate that IVIg has a favourable safety profile for treatment of adult dermatomyositis patients and provides evidence that will help to inform treatment choice for these patients. Dermatomyositis patients receiving high-dose IVIg should be monitored for TEEs, and a low rate of infusion should be used to minimise TEE risk, particularly in those with pre-existing risk factors. Trial registration ProDERM study (NCT02728752).

In the psoriatic non-lesional (PS-NL) skin, the tissue environment potentially influences the development and recurrence of lesions. Therefore, we aimed to investigate mechanisms involved in regulating tissue organization in PS-NL skin. Cytokine, chemokine, protease, and protease inhibitor levels were compared between PS-NL skin of patients with mild and severe symptoms and healthy skin. By comparing mild and severe PS-NL vs. healthy skin, differentially expressed cytokines and chemokines suggested alterations in hemostasis-related processes, while protease inhibitors showed no psoriasis severity-related changes. Comparing severe and mild PS-NL skin revealed disease severity-related changes in the expression of proteases, cytokines, and chemokines primarily involving methyl-CpG binding protein 2 (MECP2) and extracellular matrix organization-related mechanisms. Cytokine and chemokine expression in clinically resolved versus healthy skin showed slight interleukin activity, differing from patterns in mild and severe PS-NL skin. Immunofluorescence analysis revealed the severity-dependent nuclear expression pattern of MECP2 and decreased expression of 5-methylcytosine and 5-hydroxymethylcytosine in the PS-NL vs. healthy skin, and in resolved vs. healthy skin. Our results suggest distinct cytokine-chemokine signaling between the resolved and PS-NL skin of untreated patients with varying severities. These results highlight an altered inflammatory response, epigenetic regulation, and tissue organization in different types of PS-NL skin with possibly distinct, severity-dependent para-inflammatory states.

The proper functioning of mesenchymal stem cells (MSCs) is of paramount importance for the homeostasis of the body. Inflammation and infection can alter the function of MSCs, which can also affect the regenerative potential and immunological status of tissues. It is not known whether human herpes simplex viruses 1 and 2 (HSV1 and HSV2), well-known human pathogens that can cause lifelong infections, can induce changes in MSCs. In non-healing ulcers, HSV infection is known to affect deeper tissue layers. In addition, HSV infection can recur after initially successful cell therapies. Our aim was to study the response of adipose-derived MSCs (ADMSCs) to HSV infection in vitro. After confirming the phenotype and differentiation capacity of the isolated cells, we infected the cells in vitro with HSV1-KOS, HSV1-532 and HSV2 virus strains. Twenty-four hours after infection, we examined the gene expression of the cells via RNA-seq and RT-PCR; detected secreted cytokines via protein array; and determined autophagy via Western blot, transmission electron microscopy (TEM) and fluorescence microscopy. Infection with different HSV strains resulted in different gene-expression patterns. In addition to the activation of pathways characteristic of viral infections, distinct non-immunological pathways (autophagy, tissue regeneration and differentiation) were also activated according to analyses with QIAGEN Ingenuity Pathway Analysis, Kyoto Encyclopedia of Genes and Genome and Genome Ontology Enrichment. Viral infections increased autophagy, as confirmed via TEM image analysis, and also increased levels of the microtubule-associated protein light chain 3 (LC3B) II protein. We identified significantly altered accumulation for 16 cytokines involved in tissue regeneration and inflammation. Our studies demonstrated that HSV infection can alter the viability and immunological status of ADMSCs, which may have implications for ADMSC-based cell therapies. Alterations in autophagy can affect numerous processes in MSCs, including the inhibition of tissue regeneration as well as pathological differentiation.

Recently, there has been a great interest in melanoma and stromal cell-to-cell interactions behind the progressive behavior of melanoma. By in vitro co-culturing and using sequential seeding conditions imitating the niche properties, the gained hybrid variants are visualized by high content fluorescent microscopy. The co-culture experiment applied a consecutive seeding order of the primarily plated HDF-RFP-ZeoR fibroblast monolayer as the "soil" and the delayed spreading of the UACC 257-GFP-NeoR melanoma cells as the "seeds". Using only the single zeocin selection provides double advantages in eliminating the parental melanoma cells and preserving the zeocin resistant fibroblast as stroma to elongate the lifespan of the rare hybrid cells. The observed heterotypic interactions underwent detailed morphological analysis and classification in vitro, followed by ex vivocharacterization of human melanoma tissue samples. The morphology of the identified interactions included cell internalization, living cell-in-cell structures, intermediate hybrids, transient and definitive myofibroblast-like or resting fibroblast-like variants. The heterotypic melanoma-fibroblast interactions are classified as mainly defensive cancer cannibalism by the stromal cells, which may result in a paradoxical heterotypic cell fusion showing melanoma-to-stromal cell mimicry. The resulted definitive hybrids gained stromal phenotype indistinguishable from the surrounding stromal parental cells. The study strengthens the complexity of the cancer-stromal interactions in the cancer niche providing new fields on histopathologic diagnostics as well as on cancer-microenvironment research.

Background Dermatomyositis (DM) is a rare autoimmune disease characterized by skin involvement, with or without proximal muscle weakness. Recently, following the ProDERM study, intravenous immunoglobulin (IVIg) was approved for treatment of DM. Until ProDERM evidence from large, placebo-controlled studies supporting its use for dermatological symptoms, was lacking. Here we present efficacy data from ProDERM of IVIg versus placebo for treatment of the cutaneous aspect of DM. Methods ProDERM was a double-blind, randomized, multicenter, Phase 3 study. In the First Period (Weeks 0-16), adults with active DM received 2.0 g/kg IVIg (Octagam 10%; Octapharma AG) or placebo every 4 weeks. In the open-label Extension Period (Weeks 16-40), all patients received IVIg for 6 additional cycles. Cutaneous disease was assessed using measures including modified cutaneous DM disease area and severity index activity (CDASI-A) and damage (CDASI-D) scores, and myositis disease activity assessment tool (MDAAT) including visual analogue scale (VAS). This trial is registered with ClinicalTrials.gov, NCT02728752. Findings The study took place from February 2017 to November 2019. 95 patients received IVIg (N = 47) or placebo (N = 48) in the First Period. Together, 664 IVIg infusion cycles were administered (median dose, 2.0 g/kg). At Week 16, mean CDASI-A change from baseline was -9.36 (95% CI: -12.52, -6.19) in the IVIg group versus -1.16 (-3.32, 0.99) in placebo group (p < 0.0001). At the end of the Extension Period, mean changes from baseline were -10.44 (95% CI: -13.94, -6.94) and -10.03 (-13.12, -6.94), respectively. Similar changes were seen for CDASI-D and VAS of MDAAT. These observations were seen regardless of baseline disease severity. Interpretation ProDERM is the first large prospective, randomized trial to demonstrate the efficacy of IVIg to improve the cutaneous manifestations of DM. IVIg treatment significantly improved dermatological symptoms in patients with DM, regardless of disease severity before treatment, suggesting that IVIg is effective for even the most severe cutaneous DM. Funding This study was sponsored by Octapharma Pharmazeutika Produktionsges m.b.H. Copyright (c) 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BackgroundLivedoid vasculopathy (LV) and cutaneous arteritis (CA) are rare cutaneous diseases. A consideration of these two conditions as different entities is debatable, because thrombosis and inflammation are closely related in their pathogenesis mechanisms. Varying reports on the effectiveness of anticoagulant and immunosuppressant therapies in LV and CA also point to diagnostic challenge and overlap in these conditions.ObjectivesWe sought to assess the therapeutic effect of anticoagulation therapy in adult patients with CA, who were recalcitrant to immunosuppressive modalities.MethodsA monocentric retrospective analysis of adult patients who were diagnosed with CA between 2010 and 2018, was carried out.ResultsWe describe 8 cases of long-term recalcitrant CA, in whom anticoagulation therapy significantly reduced the pain and cutaneous symptoms. All patients had cutaneous symptoms compatible with CA along with clinical features also characteristic of LV, including underlying procoagulative disorders in the majority (87.5%), as confirmed by screening for thrombophilia. We also review current concepts regarding LV and CA, and suggest vascular occlusion is a common link between these two entities.ConclusionsAlthough current knowledge advocates segregating vasculopathy from vasculitis by means of histopathological examination in LV and CA, clinical experience suggests some overlap and common complex underlying pathomechanisms. image