Cutaneous Manifestations of Reactions to Biologics

Purpose of Review

The goal of this paper is to review the major adverse cutaneous reactions that have been reported to the most commonly used biologics.

Recent Findings

Anti-TNF agents and immune checkpoint inhibitors have significant, immune-mediated cutaneous manifestations that can necessitate discontinuation. Anti-TNF agents, IL-6 inhibitors, and IL-12/23 inhibitors can paradoxically cause psoriasis flares or unmask previously undiagnosed psoriasis. IL-17 inhibitors are unique in increasing risk for Candida infections. Benign injection site reactions, non-specific rash, cellulitis, and hypersensitivity reactions are relatively common adverse events.

Summary

A wide variety of cutaneous reactions caused by biologics have been reported, ranging from benign injection site reactions to life-threatening cutaneous reactions necessitating discontinuation of the implicated biologic agent.

     

Severe Atopic Dermatitis in Children

Purpose of Review

Severe atopic dermatitis (AD) in childhood leads to significant morbidity including psychosocial problems and infectious complications. There are only a few approved treatment options for these patients. These include topical corticosteroids and tacrolimus ointment, which are associated with potential side effects.

Recent Findings

In order to find better and safer treatments, further understanding of AD mechanisms is needed. Primary skin barrier defects play an important role in the pathogenesis of AD. In addition, the suppression of skin barrier functions by Th2 inflammation also plays an important role in the persistence and recurrence of AD. Cytokines in the Th2 pathway, which includes IL-4, IL-13, TSLP, IL-25, IL-31, and IL-33, are potential therapeutic targets in AD. Other potential targets of AD are Janus kinase, phospholipase A2, aryl hydrocarbon receptor, and skin microbiota.

Summary

A better understanding of the pathogenesis of AD will provide future direction for treatment.

     

Novel Biologicals for the Treatment of Allergic Diseases and Asthma

Purpose of Review

The development of biological therapies has rapidly progressed during the last few years, and major advances were reported for the treatment of allergic diseases, such as atopic dermatitis, allergic rhinitis, urticaria, food allergy, and asthma. Here, we review biologicals targeting the type 2 immune response involving Th2 cells, type 2 innate lymphoid cells, natural killer T cells, mast cells, basophils, and epithelial cells, such as IL-4, IL-5, IL-13, IL-31, tumor necrosis factor alpha (TNF-α), and thymic stromal lymphopoietin (TSLP).

Recent Findings

The biologicals that have been currently approved for asthma are omalizumab targeting IgE and reslizumab and mepolizumab targeting interleukin (IL)-5. Many other monoclonal antibodies are currently in various phases of clinical development. The new biological therapies for allergic diseases will eventually be tailored to the endotypes of these diseases and the identification of novel biomarkers.

Summary

Further development of novel biologicals for the treatment of allergic diseases and asthma will be possible upon improved understanding of mechanisms of allergic diseases. Accordingly, further refinement of endotypes of allergen-specific and non-specific type 2 immune response and related inflammatory mediators is needed for optimal treatment of allergic diseases.

     

Allergic Contact Dermatitis Evaluation: Strategies for the Preschooler

Purpose of Review

The environment for the developing children is complex as they are exposed to a variety of activities and settings where potential environmental allergens may be encountered. Recent evidence supports the clinical benefit of patch testing young children suffering from recalcitrant dermatitis. While patch testing has been recently approved by the Food and Drug Administration in children ages 6–18 years old, patch testing strategies for young children of preschool age (between 2 and 6 years old) have yet to be defined.

Recent Findings

Allergic contact dermatitis is underdiagnosed among pediatric patients, particularly those suffering from concomitant atopic dermatitis as the interplay between the two diseases is complex. Recent reports in literature supported the clinical value, safety, and efficacy of patch testing pediatric patients.

Summary

This review provides an overview of specific pediatric allergens, special considerations, practical modifications, and systematic exposure-driven guidance approaches toward patch testing preschoolers.

     

Examining the Role of and Treatment Directed at IL-1β in Atherosclerosis

Purpose

The purpose of this review was to examine the role of IL-1β in the inflammatory process central to the development of atherosclerosis and to discuss current clinical evidence for treatments targeting IL-1β in coronary artery disease.

Recent Findings

IL-1β has been shown to modulate atherosclerotic plaque progression by upregulating the synthesis of adhesion molecules on endothelial cells, as well increasing activation and proliferation of vascular smooth muscle cells. Animal studies have further suggested that alterations in the balance between agonists and antagonists of IL-1β are important in promoting atherosclerosis. In humans, preliminary assessment of therapy targeting IL-1β noted early reductions in serum inflammatory biomarkers among those with systemic inflammatory or coronary artery disease. The CANTOS trial, a large randomized double-blind study found that canakinumab, a monoclonal antibody targeting IL-1β, reduced ischemic events in patients being treated for secondary prevention.

Summary

Cellular, animal, and now clinical studies have suggested a role for therapies aimed at IL-1β for treatment of CAD. However, given potential side effects and costs of these medications, further study is required to determine which patients may be most suited for treatment above current standard of care.

     

Therapeutic response of patients with adult Still’s disease to biologic agents: multicenter results in Japan

Objective

The efficacy of biologics in treating adult Still’s disease (ASD) is suggested, but the information is still lacking and the validation is insufficient. To determine the efficacy of several biologic agents in refractory ASD in Japan, a multicenter survey was performed.

Method

Clinical data on 16 ASD patients who had been treated with at least 1 of the biological agents (total 24 occasions) were collected retrospectively.

Results

Infliximab was used in 9 cases, etanercept in 4, and tocilizumab in 11. Half of the patients that had been treated initially with infliximab or etanercept were changed to another biologics. Tocilizumab was effective in cases switched from another 2 drugs. Tocilizumab showed efficacy in treating both systemic and arthritic symptoms and showed apparent steroid-sparing effect and the highest continuation rate.

Conclusion

Tocilizumab may be a promising biologic agent in refractory ASD.

     

Immune Modulation in Heart Failure: the Promise of Novel Biologics

Purpose of review

Immune system activation plays a central role in heart failure progression. Large-scale immune modulatory clinical trials targeting tumor necrosis factor-α and broad spectrum immune modulation have been negative. The objective of this review is to highlight past, present, and what is in the horizon for the immunomodulation in heart failure with a focus of biologics.

Recent findings

Strategies targeting interleukin-1 pathway are currently undergoing clinical evaluation and data from pilot studies are promising. The potential of cell therapy for immune modulation is increasingly recognized in clinical trials. Strategies targeting anti-cardiac antibodies such as immunoadsorption and intravenous immunoglobulin have been used in clinical practice with positive outcomes but large pragmatic clinical trials are lacking. The use of an aptamer to block anti-cardiac antibodies is undergoing phase 1 clinical evaluation. Promising targets include inflammasomes, toll-like receptors, chemokines, natural killer cells, and macrophages.

Summary

Large-scale immune modulatory clinical trials have been negative. Nevertheless, the experience gained from them along with increasing understanding of molecular mechanisms of immune pathophysiology in heart failure is leading to rapid recognition of new therapeutic targets and approaches.

     

MicroRNAs in Allergic Disease

Purpose of Review

MicroRNAs (miRNAs) are short, single-stranded, non-coding RNAs that are increasingly being recognized as important epigenetic regulators. They have been implicated in the pathogenesis of many diseases including cancer, cardiovascular diseases, connective tissue diseases, and neuromuscular disorders.

Recent Findings

A few miRNAs have already been recognized as a core set of miRNAs important in allergic inflammation. These include let-7, miR-21, miR-142, and miR-146.

Summary

This review aims to bring together some of the recent findings on how miRNAs regulate allergic inflammation with special focus on asthma, atopic dermatitis, allergic rhinitis, and eosinophilic esophagitis. We will also touch upon extracellular miRNAs and future perspective of this field of study.

     

Idelalisib-induced colitis and skin eruption mimicking graft-versus-host disease

Introduction

Idelalisib is a selective inhibitor of the delta isoform of phosphatidylinositol 3-kinase which was approved by the United States Federal Drug Administration in 2014 for the treatment of relapsed chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma. Drug-induced injury of the gastrointestinal tract is a relatively frequent but usually under-recognized disease entity.

Case presentation

We report the case of a 56-year-old male with a history of relapsed follicular lymphoma status post allogenic bone marrow transplant who developed severe diarrhea with a skin eruption mimicking graft-versus-host disease (GVHD) 6 months after starting idelalisib. He underwent a colonoscopy demonstrating a grossly normal-appearing colon and terminal ileum. Biopsies taken during the procedure revealed mild active ileitis, colitis, and proctitis with frequent epithelial apoptosis, and focal intra-epithelial lymphocytosis. Skin biopsies revealed sub-acute spongiotic dermatitis suggestive of either contact dermatitis or an eczematous drug reaction. Symptoms were attributed to idelalisib given their resolution with withdrawal of the drug in conjunction with the skin and colonic biopsies.

Conclusion

High clinical suspicion and awareness of the histological features of idelalisib-associated colitis is important to distinguish it from potential mimickers such as GVHD and infectious colitis.

     

Pathogenesis of Skin Injury of Systemic Lupus Erythematosus

Purpose of Review

The second most common clinical expression in lupus patients is skin damage that the pathogenesis remains unclear. We discuss the role of pathological factors in the development of skin damage in SLE.

Recent Findings

Skin deposited IgG is a crucial pathologic factor in the development of skin damage in SLE. Macrophages and signaling of TNFα/TNFR1 and IFN/IFNR play an important role in the skin injury of SLE. The intracellular molecules including Syk and calcium/calmodulin 4 and NFAT are involved in the manifestation of skin damage in lupus-prone mice. UV is the most typical environmental factor to trigger skin injury in areas of IgG deposition in SLE.

Summary

These evidences indicate that skin deposited IgG is a crucial pathological factor to trigger skin lesions in SLE and blockade of IgG signaling may be effective target against skin injury of SLE.

     

Novel Therapeutics in Psoriatic Arthritis. What Is in the Pipeline?

Purpose of Review

To highlight the recently approved therapeutic agents in psoriatic arthritis (PsA), drugs in the pipeline, as well as to discuss efficacy with regard to different clinical domains of PsA.

Recent Findings

More than 15 years ago, tumor necrosis factor inhibitors (TNFi) were the first biologic disease modifying anti-rheumatic drugs (bDMARDs) that were approved for the treatment of PsA. Since then, multiple new therapeutic agents inhibiting other targets have emerged including biologics targeting interleukin (IL) 12/23, and IL 17 and oral agents targeting phosphodiesterase 4 (PDE4) and Janus kinases (JAKs). Many new agents with various modes of action including selective inhibition of IL 23, therapies promoting activated T cell apoptosis, inhibition of tyrosine kinase 2 (TYK2), and more are under active assessment in ongoing clinical trials.

Summary

Effective therapies for treating PsA have emerged over the last 15 years and newer agents continue to be discovered, allowing greater therapeutic options for controlling psoriatic disease activity and preventing joint damage and disability. Personalized therapy for patients with PsA is now a possibility.

     

Temporal Regulation by Innate Type 2 Cytokines in Food Allergies

Purpose of Review

Food allergies (FAs) are a growing epidemic in western countries with poorly defined etiology. Defined as an adverse immune response to common food allergens, FAs present heterogeneously as a single- or multi-organ response that ranges in severity from localized hives and angioedema to systemic anaphylaxis.

Recent Findings

Current research focusing on epithelial-derived cytokines contends that temporal regulation by these factors impact initial sensitization and persistence of FA responses upon repeated food allergen exposure. Mechanistic understanding of FA draws insight from a myriad of atopic conditions studied in humans and modeled in mice.

Summary

In this review, we will highlight how epithelial-derived cytokines initiate and then potentiate FAs. We will also review existing evidence of the contribution of other atopic diseases to FA pathogenesis and whether FA symptoms overlap with other atopic diseases.

     

Novel Therapies and Treatment Strategies for Patients with Inflammatory Bowel Disease

Purpose of review

This article reviews current treatment options and strategies and provides an update on the status of drug development programs of new therapeutic agents for inflammatory bowel diseases (IBD).

Recent findings

In the past two decades, tumor necrosis factor antagonist therapy has given clinicians better treatment options. However, not all patients respond to induction therapy with these agents, and of those initially responding, up to 40% ultimately lose response due to suboptimal drug exposure (e.g., caused by immunogenicity), side effects, or other poorly characterized mechanisms. Recently, additional therapies, such as vedolizumab, an integrin blocker that prevents T cell trafficking to the gut, and ustekinumab, an antibody blocking the common p40 subunit of interleukin (IL)-12 and 23, were introduced to the market. In addition, other agents including novel anti-trafficking therapies (e.g., anti-β7 and sphingosine-1-phosphate receptor modulators), antibodies against p19 (unique to IL-23), and small molecules including Janus kinase inhibitors are under investigation in phase II and III trials.Furthermore, the management of IBD has evolved from targeting control of symptoms to suppression of mucosal inflammation. This shift in thinking has been accompanied by the early use of highly effective therapy in poor prognosis patients, accelerated treatment escalation and utilization of a treat to target paradigm approach, and adoption of therapeutic drug monitoring.

Summary

The treatment landscape for IBD is rapidly evolving with the recent approval of novel biologics as well as several other agents in late phase of clinical development. Moreover, we have started to use agents more intelligently with a focus on risk stratification and early use of highly effective therapy in high-risk patients, treat to target using patient-reported outcomes (PROs), biomarkers, endoscopy, and therapeutic drug monitoring.

     

Cost of Transformation among Primary Care Practices Participating in a Medical Home Pilot

Background

Medical home initiatives encourage primary care practices to invest in new structural capabilities such as patient registries and information technology, but little is known about the costs of these investments.

Objectives

To estimate costs of transformation incurred by primary care practices participating in a medical home pilot.

Design

We interviewed practice leaders in order to identify changes practices had undertaken due to medical home transformation. Based on the principles of activity-based costing, we estimated the costs of additional personnel and other investments associated with these changes.

Setting

The Pennsylvania Chronic Care Initiative (PACCI), a statewide multi-payer medical home pilot.

Participants

Twelve practices that participated in the PACCI.

Measurements

One-time and ongoing yearly costs attributed to medical home transformation.

Results

Practices incurred median one-time transformation-associated costs of $30,991 per practice (range, $7694 to $117,810), equivalent to $9814 per clinician ($1497 to $57,476) and $8 per patient ($1 to $30). Median ongoing yearly costs associated with transformation were $147,573 per practice (range, $83,829 to $346,603), equivalent to $64,768 per clinician ($18,585 to $93,856) and $30 per patient ($8 to $136). Care management activities accounted for over 60% of practices’ transformation-associated costs. Per-clinician and per-patient transformation costs were greater for small and independent practices than for large and system-affiliated practices.

Limitations

Error in interviewee recall could affect estimates. Transformation costs in other medical home interventions may be different.

Conclusions

The costs of medical home transformation vary widely, creating potential financial challenges for primary care practices—especially those that are small and independent. Tailored subsidies from payers may help practices make these investments.

Primary Funding Source

Agency for Healthcare Research and Quality

     

Transgenic Expression of Vitamin D Receptor in Gut Epithelial Cells Ameliorates Spontaneous Colitis Caused by Interleukin-10 Deficiency

Background

Vitamin D deficiency is common in patients with inflammatory bowel diseases. The vitamin D receptor (VDR) is a nuclear hormone receptor mediating the activity of vitamin D hormone. Our previous studies showed that intestinal epithelial VDR signaling inhibits colitis by protecting the mucosal epithelial barrier, and this activity is independent of non-epithelial immune VDR actions. Interleukin (IL)-10-deficient mouse is a chronic colitis model that develops colitis due to aberrant immune responses. Here we used IL-10 null (IL-10KO) model to assess the anti-colitic activity of epithelial VDR in the setting of an aberrant immune system.

Methods

We crossed IL-10KO mice with villin promoter-driven human (h) VDR transgenic (Tg) mice to generate IL-10KO mice that carry the hVDR transgene in intestinal epithelial cells (IL-10KO/Tg). IL-10KO and IL-10KO/Tg littermates were studied in parallel and followed for up to 25 weeks.

Results

By 25 weeks of age, accumulatively 79 % IL-10KO mice developed prolapse, whereas only 40 % IL-10KO/Tg mice did so (P < 0.001). Compared with IL-10KO mice, IL-10KO/Tg littermates showed markedly reduced mucosal inflammation in both small and large intestines, manifested by attenuation in immune cell infiltration and histological damage and a marked decrease in pro-inflammatory cytokine production. IL-10KO/Tg mice also showed reduced intestinal epithelial cell apoptosis as a result of diminished PUMA induction and caspase 3 activation.

Conclusion

These observations demonstrate that targeting hVDR expression to intestinal epithelial cells is sufficient to attenuate spontaneous colitis caused by an ill-regulated immune system, confirming a critical role of the epithelial VDR signaling in blocking colitis development.

     

Treatment of acute hepatitis C: recommendations from an expert panel of the Italian Society of Infectious and Tropical Diseases

Aim

This paper is aimed at providing practical recommendations for the management of acute hepatitis C (AHC).

Methods

This is an expert position paper based on the literature revision. Final recommendations were graded by level of evidence and strength of the recommendations.

Results

Treatment of AHC with direct-acting antivirals (DAA) is safe and effective; it overcomes the limitations of INF-based treatments.

Conclusions

Early treatment with DAA should be offered when available.

     

IL-17A Promotes Initiation and Development of Intestinal Fibrosis Through EMT

Background

Intestinal fibrosis is a common complication of Crohn’s disease (CD). Its exact mechanism is still unclear, and effective treatments to control or reverse the fibrosis process are unavailable. Epithelial–mesenchymal transition (EMT) may promote intestinal fibrosis by increasing deposition of extracellular matrix protein. IL-17A is a pro-inflammatory cytokine, and it has been shown as a profibrotic factor as its association with fibrosis of multiple organs was reported.

Aims

To assess the roles of IL-17A and EMT in the initiation and development of intestinal fibrosis and to verify the potential inductive effect of IL-17A on EMT.

Methods

In this study, we evaluated the expression of IL-17A and EMT-related genes in colonic mucosal biopsy tissues of CD patients and control individuals. Then, we examined the changes of EMT-related genes and fibrosis-related genes of IEC-6 cells which cultured for 72 h under increasing concentrations of IL-17A or with TGF-β1, to verify the potential inductive effect of IL-17A on EMT in vitro. We blocked the IL-17A of the mouse model of TNBS-induced experimental intestinal colitis and fibrosis to further verify the potential inductive effect of IL-17A on EMT in vivo.

Results

We found the occurrence of EMT and high-level expression of IL-17A in intestinal mucosa of CD patients. Using IEC-6 cells, we showed that IL-17A may induce EMT in intestinal epithelial cells that come with reduced E-cadherin expression and increased expression of vimentin, snail, and α-SMA. We further found that anti-IL-17A treatment alleviated intestinal fibrosis through reducing EMT in mouse intestine.

Conclusions

Our study confirmed the involvement of IL-17A in the development of intestinal fibrosis through inducing EMT.

     

Epidemiology of Psoriasis and Psoriatic Arthritis in Italy—a Systematic Review

Purpose of Review

Understanding prevalence of diseases within specific regions of a country is important for optimal allocation of healthcare resources/funds. We performed a systematic review to obtain a clearer picture of the epidemiology of psoriasis and psoriatic arthritis across and within specific regions of Italy.

Recent Findings

Prevalence of psoriasis in specific regions showed more variability (0.8–4.5%) than that in the total population (1.8–3.1%). Prevalence of psoriatic arthritis in the general population was reported for only two regions, Chiavari (0.09%) and Marche (0.42%). All other studies reported prevalence of psoriatic arthritis in patients with psoriasis in single centres and Italy-wide (4.7–47.1%). Prevalence of psoriatic arthritis was highest in patients with nail and/or scalp psoriasis and/or intergluteal/perianal region involvement.

Summary

Based on current available data, these conditions appear to affect a substantial number of people and will likely have an important impact on the Italian healthcare system.