Increased understanding of the pathophysiology of psoriasis has been one of the driving forces in the development of new therapies. An understanding of the processes involved is important in the optimal management of the disease. The last 30 years of research and clinical practice have revolutionized our understanding of the pathogenesis of psoriasis as the dysregulation of immunity triggered by environmental and genetic stimuli. Psoriasis was originally regarded as a primary disorder of epidermal hyperproliferation. However, experimental models and clinical results from immunomodulating therapies have refined this perspective in conceptualizing psoriasis as a genetically programmed pathologic interaction among resident skin cells; infiltrating immunocytes; and a host of proinflammatory cytokines, chemokines, and growth factors produced by these immunocytes. Two populations of immunocytes and their respective signaling molecules collaborate in the pathogenesis: (1) innate immunocytes, mediated by antigen-presenting cells (APCs)(including natural killer [NK] T lymphocytes, Langerhans cells, and neutrophils), and (2) acquired or adaptive immunocytes, mediated by mature CD4⁺ and CD8⁺ T lymphocytes in the skin. Such dysregulation of immunity and subsequent inflammation is responsible for the development and perpetuation of the clinical plaques and histological inflammatory infiltrate characteristic of psoriasis.

Although psoriasis is considered to be an immune-mediated disease in which intralesional T lymphocytes and their proinflammatory signals trigger primed basal layer keratinocytes to rapidly proliferate, debate and research focus on the stimulus that incites this inflammatory process. Our current understanding considers psoriasis to be triggered by exogenous or endogenous environmental stimuli in genetically susceptible individuals. Such stimuli include group A streptococcal pharyngitis, viremia, allergic drug reactions, antimalarial drugs, lithium, beta-blockers, IFN-α, withdrawal of systemic corticosteroids, local trauma (Köbner phenomenon), and emotional stress. These stimuli correlate with the onset or flares of psoriatic lesions. Psoriasis genetics centers on susceptibility loci and corresponding candidate genes, particularly the psoriasis susceptibility (PSORS) 1 locus on the major histocompatibility complex (MHC) class I region. Current research on the pathogenesis of psoriasis examines the complex interactions among immunologic mechanisms, environmental stimuli, and genetic susceptibility. After discussing the clinical presentation and histopathologic features of psoriasis, we will review the pathophysiology of psoriasis through noteworthy developments, including serendipitous observations, reactions to therapies, clinical trials, and animal model systems that have shaped our view of the disease process. In addition to the classic skin lesions, approximately 23% of psoriasis patients develop psoriatic arthritis, with a 10-year latency after diagnosis of psoriasis.¹

Principles of Immunity

The immune system, intended to protect its host from foreign invaders and unregulated cell growth, employs 2 main effector pathways—the innate and the acquired (or adaptive) immune responses—both of which contribute to the pathophysiology of psoriasis.² Innate immunity responses occur within minutes to hours of antigen exposure but fail to develop memory for when the antigen is encountered again. However, adaptive immunity responses take days to weeks to respond after challenged with an antigen. The adaptive immune cells have the capacity to respond to a greater range of antigens and develop immunologic memory via rearrangement of antigen receptors on B and T cells. These specialized B and T cells can then be promptly mobilized and differentiated into mature effector cells that protect the host from a foreign pathogen.

Innate and adaptive immune responses are highly intertwined; they can initiate, perpetuate, and terminate the immune mechanisms responsible for inflammation. They can modify the nature of the immune response by altering the relative proportions of type 1 (T_H1), type 2 (T_H2), and the more recently discovered type 17 (T_H17) subset of helper T cells and their respective signaling molecules. A T_H1 response is essential for a cellular immunologic reaction to intracellular bacteria and viruses or cellular immunity. A T_H2 response promotes IgE synthesis, eosinophilia, and mast cell maturation for extracellular parasites and helminthes as well as humoral immunity, while a T_H17 response is important for cell-mediated immunity to extracellular bacteria and plays a role in autoimmunity.³ The innate and adaptive immune responses employ common effector molecules such as chemokines and cytokines, which are essential in mediating an immune response.

Implicating Dysregulation of Immunity

Our present appreciation of the pathogenesis of psoriasis is based on the history of trial-and-error therapies; serendipitous discoveries; and the current immune targeting drugs used in a variety of chronic inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease. Before the mid-1980s, research focused on the hyperproliferative epidermal cells as the primary pathology because a markedly thickened epidermis was indeed demonstrated on histologic specimens. Altered cell-cycle kinetics were thought to be the culprit behind the hyperkeratotic plaques. Thus, initial treatments centered on oncologic and antimitotic therapies used to arrest keratinocyte proliferation with agents such as arsenic, ammoniated mercury, and methotrexate.⁴

However, a paradigm shift from targeting epidermal keratinocytes to immunocyte populations was recognized when a patient receiving cyclosporine to prevent transplant rejection noted clearing of psoriatic lesions in the 1980s.⁵ Cyclosporine was observed to inhibit messenger RNA transcription of T-cell cytokines, thereby implicating immunologic dysregulation, specifically T-cell hyperactivity, in the pathogenesis of psoriasis.⁶ However, the concentrations of oral cyclosporine reached in the epidermis exerted direct effects on keratinocyte proliferation and lymphocyte function in these patients.⁷ Thus, the question was raised as to whether the keratinocytes or the lymphocytes drove the psoriatic plaques. The use of an IL-2 diphtheria toxin-fusion protein, denileukin diftitox, specific for activated T cells with high-affinity IL-2 receptors and nonreactive with keratinocytes, distinguished which cell type was responsible. This targeted T-cell toxin provided clinical and histological clearing of psoriatic plaques. Thus, T lymphocytes rather than keratinocytes were recognized as the definitive driver behind the psoriatic plaques.⁸

Additional studies have demonstrated that treatments that induce prolonged clearing of psoriatic lesions without continuous therapy, such as psoralen plus UVA irradiation, decreased the numbers of T cells in plaques by at least 90%.⁹ However, treatments that require continual therapy for satisfactory clinical results, such as cyclosporine and etretinate, simply suppress T-cell activity and proliferation.^10,11 Further evidence has linked cellular immunity with the pathogenesis of psoriasis, defining it as a T_H1-type disease. Natural killer T cells were shown to be involved through the use of a severe combined immunodeficient mouse model. They were injected into prepsoriatic skin grafted on immunodeficient mice, creating a psoriatic plaque with an immune response showing cytokines from T_H1 cells rather than T_H2 cells.¹² When psoriatic plaques were treated topically with the toll-like receptor 7 agonist imiquimod, aggravation and spreading of the plaques were noted. The exacerbation of psoriasis was accompanied by an induction of lesional T_H1-type interferon produced by plasmacytoid dendritic cell (DC) precursors. Plasmacytoid DCs were observed to compose up to 16% of the total dermal infiltrate in psoriatic skin lesions based on their coexpression of BDCA2 and CD123.¹³ Additionally, cancer patients being treated with interferon alfa experienced induction of psoriasis.¹⁴ Moreover, patients being treated for warts with intralesional interferon alfa developed psoriatic plaques in neighboring prior asymptomatic skin.¹⁵ Patients with psoriasis who were treated with interferon gamma, a T_H1 cytokine type, also developed new plaques correlating with the sites of injection.¹⁶

Intralesional T Lymphocytes

Psoriatic lesions contain a host of innate immunocytes, such as APCs, NK cells, and neutrophils, as well as adaptive T cells and an inflammatory infiltrate. These cells include CD4 and CD8 subtypes in which the CD8⁺ cells predominate in the epidermis, while CD4⁺ cells show preference for the dermis.¹⁷ There are 2 groups of CD8⁺ cells: one group migrates to the epidermis, expressing the integrin CD103, while the other group is found in the dermis but may be headed to or from the epidermis. The CD8⁺ cells residing in the epidermis that express the integrin CD103 are capable of interacting with E-cadherin, which enables these cells to travel to the epidermis and bind resident cells. Immunophenotyping reveals that these mature T cells represent chiefly activated memory cells, including CD2⁺, CD3⁺, CD5⁺, CLA, CD28, and CD45RO⁺.¹⁸ Many of these cells express activation markers such as HLA-DR, CD25, and CD27, in addition to the T-cell receptor (TCR).

T-Lymphocyte Stimulation

Both mature CD4⁺ and CD8⁺ T cells can respond to the peptides presented by APCs. Although the specific antigen that these T cells are reacting to has not yet been elucidated, several antigenic stimuli have been proposed, including self-proteins, microbial pathogens, and microbial superantigens. The premise that self-reactive T lymphocytes may contribute to the disease process is derived from the molecular mimicry theory in which an exuberant immune response to a pathogen produces cross-reactivity with self-antigens.¹⁹ Considering that infections have been associated with the onset of psoriasis, this theory merits consideration. However, it also has been observed that T cells can be activated without antigens or superantigens but rather with direct contact with accessory cells.²⁰ No single theory has clearly emerged. Researchers continue to search for the inciting stimulus that triggers the T lymphocyte and attempt to determine whether T cells are reacting to a self-derived or non–self-derived antigen.

T-Lymphocyte Signaling

T-cell signaling is a highly coordinated process in which T lymphocytes recognize antigens via presentation by mature APCs in the skin rather than the lymphoid tissues. Such APCs expose antigenic peptides via class I or II MHC molecules for which receptors are present on the T-cell surface. The antigen recognition complex at the T-cell and APC interface, in concert with a host of antigen-independent co-stimulatory signals, regulates T-cell signaling and is referred to as the immunologic synapse. The antigen presentation and network of co-stimulatory and adhesion molecules optimize T-cell activation, and dermal DCs release IL-12 and IL-23 to promote a T_H1 and T_H17 response, respectively. The growth factors released by these helper T cells sustain neoangiogenesis, stimulate epidermal hyperproliferation, alter epidermal differentiation, and decrease susceptibility to apoptosis that characterizes the erythematous hypertrophic scaling lesions of psoriasis.²¹ Furthermore, the cytokines produced from the immunologic response, such as tumor necrosis factor (TNF) α, IFN-γ, and IL-2, correspond to cytokines that are upregulated in psoriatic plaques.²²

Integral components of the immunologic synapse complex include co-stimulatory signals such as CD28, CD40, CD80, and CD86, as well as adhesion molecules such as cytotoxic T-lymphocyte antigen 4 and lymphocyte function-associated antigen (LFA) 1, which possess corresponding receptors on the T cell. These molecules play a key role in T-cell signaling, as their disruption has been shown to decrease T-cell responsiveness and associated inflammation. The B7 family of molecules routinely interacts with CD28 T cells to co-stimulate T-cell activation. Cytotoxic T-lymphocyte antigen 4 immunoglobulin, an antibody on the T-cell surface, targets B7 and interferes with signaling between B7 and CD28. In psoriatic patients, this blockade was demonstrated to attenuate the T-cell response and correlated with a clinical and histological decrease in psoriasiform hyperplasia.²³ Biologic therapies that disrupt the LFA-1 component of the immunologic synapse also have demonstrated efficacy in the treatment of psoriasis. Alefacept is a human LFA-3 fusion protein that binds CD2 on T cells and blocks the interaction between LFA-3 on APCs and CD2 on memory CD45RO⁺ T cells and induces apoptosis of such T cells. Efalizumab is a human monoclonal antibody to the CD11 chain of LFA-1 that blocks the interaction between LFA-1 on the T cell and intercellular adhesion molecule 1 on an APC or endothelial cell. Both alefacept and efalizumab, 2 formerly marketed biologic therapies, demonstrated remarkable clinical reduction of psoriatic lesions, and alefacept has been shown to produce disease remission for up to 18 months after discontinuation of therapy.^24-26

NK T Cells

Natural killer T cells represent a subset of CD3⁺ T cells present in psoriatic plaques. Although NK T cells possess a TCR, they differ from T cells by displaying NK receptors comprised of lectin and immunoglobulin families. These cells exhibit remarkable specificity and are activated upon recognition of glycolipids presented by CD1d molecules. This process occurs in contrast to CD4⁺ and CD8⁺ T cells, which, due to their TCR diversity, respond to peptides processed by APCs and displayed on MHC molecules. Natural killer T cells can be classified into 2 subsets: (1) one group that expresses CD4 and preferentially produces T_H1- versus T_H2-type cytokines, and (2) another group that lacks CD4 and CD8 that only produces T_H1-type cytokines. The innate immune system employs NK T cells early in the immune response because of their direct cytotoxicity and rapid production of cytokines such as IFN-γ, which promotes a T_H1 inflammatory response, and IL-4, which promotes the development of T_H2 cells. Excessive or dysfunctional NK T cells have been associated with autoimmune diseases such as multiple sclerosis and inflammatory bowel disease as well as allergic contact dermatitis.^27-29

In psoriasis, NK T cells are located in the epidermis, closely situated to epidermal keratinocytes, which suggests a role for direct antigen presentation. Furthermore, CD1d is overexpressed throughout the epidermis of psoriatic plaques, whereas normally CD1d expression is confined to terminally differentiated keratinocytes. An in vitro study examining cytokine-based inflammation demonstrative of psoriasis treated cultured CD1d-positive keratinocytes with interferon gamma in the presence of alpha-galactosylceramide of the lectin family.³⁰ Interferon gamma was observed to enhance keratinocyte CD1d expression, and subsequently, CD1d-positive keratinocytes were found to activate NK T cells to produce high levels of IFN-γ, while levels of IL-4 remained undetectable. The preferential production of IFN-γ supports a T_H1-mediated mechanism regulated by NK T cells in the immunopathogenesis of psoriasis.

Dendritic Cells

Dendritic cells are APCs that process antigens in the tissues in which they reside, after which they migrate to local lymph nodes where they present their native antigens to T cells. This process allows the T-cell response to be tailored to the appropriate antigens in the corresponding tissues. Immature DCs that capture antigens mature by migrating to the T-cell center of the lymph node where they present their antigens to either MHC molecules or the CD1 family. This presentation results in T-cell proliferation and differentiation that correlates with the required type of T-cell response. Multiple subsets of APCs, including myeloid and plasmacytoid DCs, are highly represented in the epidermis and dermis of psoriatic plaques as compared with normal skin.³¹ Dermal DCs are thought to be responsible for activating both the T_H1 and T_H17 infiltrate by secreting IL-12 and IL-23, respectively. This mixed cellular response secretes cytokines and leads to a cascade of events involving keratinocytes, fibroblasts, endothelial cells, and neutrophils that create the cutaneous lesions seen in psoriasis.³

Although DCs play a pivotal role in eliciting an immune response against a foreign invader, they also contribute to the establishment of tolerance. Throughout their maturation, DCs are continuously sensing their environment, which shapes their production of T_H1- versus T_H2-type cytokines and subsequently the nature of the T-cell response. When challenged with a virus, bacteria, or unchecked cell growth, DCs mature into APCs. However, in the absence of a strong stimulus, DCs fail to mature into APCs and present self-peptides with MHC molecules, thereby creating regulatory T cells involved in peripheral tolerance.³² If this balance between immunogenic APCs and housekeeping T cells is upset, inflammatory conditions such as psoriasis can result.

Cytokines

Cytokines are low-molecular-weight glycoproteins that function as signals to produce inflammation, defense, tissue repair and remodeling, fibrosis, angiogenesis, and restriction of neoplastic growth.³³ Cytokines are produced by immunocytes such as lymphocytes and macrophages as well as nonimmunocytes such as endothelial cells and keratinocytes. Proinflammatory cytokines include IL-1, IL-2, the IL-17 family, IFN-γ, and TNF-α, while anti-inflammatory cytokines include IL-4 and IL-10. A relative preponderance of T_H1 proinflammatory cytokines or an insufficiency of T_H2 anti-inflammatory cytokines induces local inflammation and recruitment of additional immunocyte populations, which produce added cytokines.³⁴ A vicious cycle of inflammation occurs that results in cutaneous manifestations such as a plaque. Psoriatic lesions are characterized by a relative increase of T_H1-type (eg, IL-2, IFN-γ, TNF-α, TNF-β) to T_H2-type (eg, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13) cytokines and an increase in T_H17-type cytokines. Natural killer T cells stimulated by CD1d-overexpressing keratinocytes increase production of proinflammatory IFN-γ without effect on the anti-inflammatory IL-4. In addition to the cytokines produced by T cells, APCs produce IL-18, IL-23, and TNF-α found in the inflammatory infiltrate of psoriatic plaques. Both IL-18 and IL-23 stimulate T_H1 cells to produce IFN-γ, and IL-23 stimulates T_H17 cells. Clearly, a T_H1- and T_H17-type pattern governs the immune effector cells and their respective cytokines present in psoriatic skin.

Tumor Necrosis Factor α

Although a network of cytokines is responsible for the inflammation of psoriasis, TNF-α has been implicated as a master proinflammatory cytokine of the innate immune response due to its widespread targets and sources. Tumor necrosis factor α is produced by activated T cells, keratinocytes, NK cells, macrophages, monocytes, Langerhans APCs, and endothelial cells. Psoriatic lesions demonstrate high concentrations of TNF-α, while the synovial fluid of psoriatic arthritis patients demonstrates elevated concentrations of TNF-α, IL-1, IL-6, and IL-8.³⁴ In psoriasis, TNF-α supports the expression of adhesion molecules (intercellular adhesion molecule 1 and P- and E-selectin), angiogenesis via vascular endothelial growth factor, the synthesis of proinflammatory molecules (IL-1, IL-6, IL-8, and nuclear factor κβ), and keratinocyte hyperproliferation via vasoactive intestinal peptide.³⁵

A role for TNF-α in psoriasis treatment was serendipitously discovered in a trial for Crohn disease in which infliximab, a mouse-human IgG1 anti–TNF-α monoclonal antibody, was observed to clear psoriatic plaques in a patient with both Crohn disease and psoriasis.³⁶ Immunotherapies that target TNF-α, including infliximab, etanercept, and adalimumab, demonstrate notable efficacy in the treatment of psoriasis.^37-39 Tumor necrosis factor α is regarded as the driver of the inflammatory cycle of psoriasis due to its numerous modes of production, capability to amplify other proinflammatory signals, and the efficacy and rapidity with which it produces clinical improvements in psoriasis.

IL-23/T_H17 Axis

A new distinct population of helper T cells has been shown to play an important role in psoriasis. These cells develop with the help of IL-23 (secreted by dermal DCs) and subsequently secrete cytokines such as IL-17; they are, therefore, named T_H17 cells. CD161 is considered a surface marker for these cells.⁴⁰ Strong evidence for this IL-23/T_H17 axis has been shown in mouse and human models as well as in genetic studies.

IL-23 is a cytokine that shares the p40 subunit with IL-12 and has been linked to autoimmune diseases in both mice and humans.³ It is required for optimal development of T_H17 cells⁴¹ from a committed CD4⁺ T-cell population after exposure to transforming growth factor β1 in combination with other proinflammatory cytokines.^42,43 IL-23 messenger RNA is produced at higher levels in inflammatory psoriatic skin lesions versus uninvolved skin,⁴⁴ and intradermal IL-23 injections in mice produced lesions resembling psoriasis macroscopically and microscopically.⁴⁵ Furthermore, several systemic therapies have been shown to modulate IL-23 levels and correlate with clinical benefit.³ Alterations in the gene for the IL-23 receptor have been shown to be protective for psoriasis,^46-48 and the gene coding for the p40 subunit is associated with psoriasis.^46,47

Type 17 helper T cells produce a number of cytokines, such as IL-22, IL-17A, IL-17F, and IL-26; the latter 3 are considered to be specific to this lineage.⁴² IL-22 acts on outer body barrier tissues, such as the skin, and has antimicrobial activity. Blocking the activity of IL-22 in mice prevented the development of skin lesions,⁴⁹ and psoriasis patients have elevated levels of IL-22 in the skin and blood.^50,51 The IL-17 cytokines induce the expression of proinflammatory cytokines, colony-stimulating factors, and chemokines, and they recruit, mobilize, and activate neutrophils.⁵² IL-17 messenger RNA was found in lesional psoriatic skin but not unaffected skin,⁵³ and cells isolated from the dermis of psoriatic skin have been shown to produce IL-17.⁵⁴ IL-17A is not elevated in the serum of psoriatic patients (unlike other autoimmune diseases),⁵⁵ and it is, therefore, thought that T_H17 cells and IL-17A production are localized to the affected psoriatic skin. Consistent with this concept is the finding that treatments such as cyclosporin A and anti-TNF agents decrease proinflammatory cytokines in lesional skin but not in the periphery.^56-58 These cytokines released by T_H17 cells in addition to those released by T_H1 cells act on keratinocytes and produce epidermal hyperproliferation, acanthosis, and hyperparakeratosis characteristic of psoriasis.³

New therapies have been developed to target the IL-23/T_H17 axis. Ustekinumab is approved for moderate to severe plaque psoriasis. This treatment’s effect may be sustained for up to 3 years, it is generally well tolerated, and it may be useful for patients refractory to anti-TNF therapy such as etanercept.⁵⁹ Briakinumab, another blocker of IL-12 and IL-23, was studied in phase 3 clinical trials, but its development was discontinued due to safety concerns.⁶⁰ Newer drugs targeting the IL-23/T_H17 axis include secukinumab, ixekizumab, brodalumab, guselkumab, and tildrakizumab.

Genetic Basis of Psoriasis

Psoriasis is a disease of overactive immunity in genetically susceptible individuals. Because patients exhibit varying skin phenotypes, extracutaneous manifestations, and disease courses, multiple genes resulting from linkage disequilibrium are believed to be involved in the pathogenesis of psoriasis. A decade of genome-wide linkage scans have established that PSORS1 is the strongest susceptibility locus demonstrable through family linkage studies; PSORS1 is responsible for up to 50% of the genetic component of psoriasis.⁶¹ More recently, HLA-Cw6 has received the most attention as a candidate gene of the PSORS1 susceptibility locus on the MHC class I region on chromosome 6p21.3.⁶² This gene may function in antigen presentation via MHC class I, which aids in the activation of the overactive T cells characteristic of psoriatic inflammation.

Studies involving the IL-23/T_H17 axis have shown genetics to play a role. Individuals may be protected from psoriasis with a nonsynonymous nucleotide substitution in the IL23R gene,^47-49 and certain haplotypes of the IL23R gene are associated with the disease^47,49 in addition to other autoimmune conditions.

Genomic scans have shown additional susceptibility loci for psoriasis on chromosomes 1q21, 3q21, 4q32-35, 16q12, and 17q25. Two regions on chromosome 17q were recently localized via mapping, which demonstrated a 6 megabase pairs separation, thereby indicating independent linkage factors. Genes SLC9A3R1 and NAT9 are present in the first region, while RAPTOR is demonstrated in the second region.⁶³SLC9A3R1 and NAT9 are players that regulate signal transduction, the immunologic synapse, and T-cell growth. RAPTOR is involved in T-cell function and growth pathways. Using these genes as an example, we can predict that the alterations of regulatory genes, even those yet undetermined, can enhance T-cell proliferation and inflammation manifested in psoriasis.

Conclusion

Psoriasis is a complex disease whereby multiple exogenous and endogenous stimuli incite already heightened innate immune responses in genetically predetermined individuals. The disease process is a result of a network of cell types, including T cells, DCs, and keratinocytes that, with the production of cytokines, generate a chronic inflammatory state. Our understanding of these cellular interactions and cytokines originates from developments, some meticulously planned, others serendipitous, in the fields of immunology, cell and molecular biology, and genetics. Such progress has fostered the creation of targeted immune therapy that has demonstrated remarkable efficacy in psoriasis treatment. Further study of the underlying pathophysiology of psoriasis may provide additional targets for therapy.

Increased understanding of the pathophysiology of psoriasis has been one of the driving forces in the development of new therapies. An understanding of the processes involved is important in the optimal management of the disease. The last 30 years of research and clinical practice have revolutionized our understanding of the pathogenesis of psoriasis as the dysregulation of immunity triggered by environmental and genetic stimuli. Psoriasis was originally regarded as a primary disorder of epidermal hyperproliferation. However, experimental models and clinical results from immunomodulating therapies have refined this perspective in conceptualizing psoriasis as a genetically programmed pathologic interaction among resident skin cells; infiltrating immunocytes; and a host of proinflammatory cytokines, chemokines, and growth factors produced by these immunocytes. Two populations of immunocytes and their respective signaling molecules collaborate in the pathogenesis: (1) innate immunocytes, mediated by antigen-presenting cells (APCs)(including natural killer [NK] T lymphocytes, Langerhans cells, and neutrophils), and (2) acquired or adaptive immunocytes, mediated by mature CD4⁺ and CD8⁺ T lymphocytes in the skin. Such dysregulation of immunity and subsequent inflammation is responsible for the development and perpetuation of the clinical plaques and histological inflammatory infiltrate characteristic of psoriasis.

Although psoriasis is considered to be an immune-mediated disease in which intralesional T lymphocytes and their proinflammatory signals trigger primed basal layer keratinocytes to rapidly proliferate, debate and research focus on the stimulus that incites this inflammatory process. Our current understanding considers psoriasis to be triggered by exogenous or endogenous environmental stimuli in genetically susceptible individuals. Such stimuli include group A streptococcal pharyngitis, viremia, allergic drug reactions, antimalarial drugs, lithium, beta-blockers, IFN-α, withdrawal of systemic corticosteroids, local trauma (Köbner phenomenon), and emotional stress. These stimuli correlate with the onset or flares of psoriatic lesions. Psoriasis genetics centers on susceptibility loci and corresponding candidate genes, particularly the psoriasis susceptibility (PSORS) 1 locus on the major histocompatibility complex (MHC) class I region. Current research on the pathogenesis of psoriasis examines the complex interactions among immunologic mechanisms, environmental stimuli, and genetic susceptibility. After discussing the clinical presentation and histopathologic features of psoriasis, we will review the pathophysiology of psoriasis through noteworthy developments, including serendipitous observations, reactions to therapies, clinical trials, and animal model systems that have shaped our view of the disease process. In addition to the classic skin lesions, approximately 23% of psoriasis patients develop psoriatic arthritis, with a 10-year latency after diagnosis of psoriasis.¹

Principles of Immunity

The immune system, intended to protect its host from foreign invaders and unregulated cell growth, employs 2 main effector pathways—the innate and the acquired (or adaptive) immune responses—both of which contribute to the pathophysiology of psoriasis.² Innate immunity responses occur within minutes to hours of antigen exposure but fail to develop memory for when the antigen is encountered again. However, adaptive immunity responses take days to weeks to respond after challenged with an antigen. The adaptive immune cells have the capacity to respond to a greater range of antigens and develop immunologic memory via rearrangement of antigen receptors on B and T cells. These specialized B and T cells can then be promptly mobilized and differentiated into mature effector cells that protect the host from a foreign pathogen.

Innate and adaptive immune responses are highly intertwined; they can initiate, perpetuate, and terminate the immune mechanisms responsible for inflammation. They can modify the nature of the immune response by altering the relative proportions of type 1 (T_H1), type 2 (T_H2), and the more recently discovered type 17 (T_H17) subset of helper T cells and their respective signaling molecules. A T_H1 response is essential for a cellular immunologic reaction to intracellular bacteria and viruses or cellular immunity. A T_H2 response promotes IgE synthesis, eosinophilia, and mast cell maturation for extracellular parasites and helminthes as well as humoral immunity, while a T_H17 response is important for cell-mediated immunity to extracellular bacteria and plays a role in autoimmunity.³ The innate and adaptive immune responses employ common effector molecules such as chemokines and cytokines, which are essential in mediating an immune response.

Implicating Dysregulation of Immunity

Our present appreciation of the pathogenesis of psoriasis is based on the history of trial-and-error therapies; serendipitous discoveries; and the current immune targeting drugs used in a variety of chronic inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease. Before the mid-1980s, research focused on the hyperproliferative epidermal cells as the primary pathology because a markedly thickened epidermis was indeed demonstrated on histologic specimens. Altered cell-cycle kinetics were thought to be the culprit behind the hyperkeratotic plaques. Thus, initial treatments centered on oncologic and antimitotic therapies used to arrest keratinocyte proliferation with agents such as arsenic, ammoniated mercury, and methotrexate.⁴

However, a paradigm shift from targeting epidermal keratinocytes to immunocyte populations was recognized when a patient receiving cyclosporine to prevent transplant rejection noted clearing of psoriatic lesions in the 1980s.⁵ Cyclosporine was observed to inhibit messenger RNA transcription of T-cell cytokines, thereby implicating immunologic dysregulation, specifically T-cell hyperactivity, in the pathogenesis of psoriasis.⁶ However, the concentrations of oral cyclosporine reached in the epidermis exerted direct effects on keratinocyte proliferation and lymphocyte function in these patients.⁷ Thus, the question was raised as to whether the keratinocytes or the lymphocytes drove the psoriatic plaques. The use of an IL-2 diphtheria toxin-fusion protein, denileukin diftitox, specific for activated T cells with high-affinity IL-2 receptors and nonreactive with keratinocytes, distinguished which cell type was responsible. This targeted T-cell toxin provided clinical and histological clearing of psoriatic plaques. Thus, T lymphocytes rather than keratinocytes were recognized as the definitive driver behind the psoriatic plaques.⁸

Additional studies have demonstrated that treatments that induce prolonged clearing of psoriatic lesions without continuous therapy, such as psoralen plus UVA irradiation, decreased the numbers of T cells in plaques by at least 90%.⁹ However, treatments that require continual therapy for satisfactory clinical results, such as cyclosporine and etretinate, simply suppress T-cell activity and proliferation.^10,11 Further evidence has linked cellular immunity with the pathogenesis of psoriasis, defining it as a T_H1-type disease. Natural killer T cells were shown to be involved through the use of a severe combined immunodeficient mouse model. They were injected into prepsoriatic skin grafted on immunodeficient mice, creating a psoriatic plaque with an immune response showing cytokines from T_H1 cells rather than T_H2 cells.¹² When psoriatic plaques were treated topically with the toll-like receptor 7 agonist imiquimod, aggravation and spreading of the plaques were noted. The exacerbation of psoriasis was accompanied by an induction of lesional T_H1-type interferon produced by plasmacytoid dendritic cell (DC) precursors. Plasmacytoid DCs were observed to compose up to 16% of the total dermal infiltrate in psoriatic skin lesions based on their coexpression of BDCA2 and CD123.¹³ Additionally, cancer patients being treated with interferon alfa experienced induction of psoriasis.¹⁴ Moreover, patients being treated for warts with intralesional interferon alfa developed psoriatic plaques in neighboring prior asymptomatic skin.¹⁵ Patients with psoriasis who were treated with interferon gamma, a T_H1 cytokine type, also developed new plaques correlating with the sites of injection.¹⁶

Intralesional T Lymphocytes

Psoriatic lesions contain a host of innate immunocytes, such as APCs, NK cells, and neutrophils, as well as adaptive T cells and an inflammatory infiltrate. These cells include CD4 and CD8 subtypes in which the CD8⁺ cells predominate in the epidermis, while CD4⁺ cells show preference for the dermis.¹⁷ There are 2 groups of CD8⁺ cells: one group migrates to the epidermis, expressing the integrin CD103, while the other group is found in the dermis but may be headed to or from the epidermis. The CD8⁺ cells residing in the epidermis that express the integrin CD103 are capable of interacting with E-cadherin, which enables these cells to travel to the epidermis and bind resident cells. Immunophenotyping reveals that these mature T cells represent chiefly activated memory cells, including CD2⁺, CD3⁺, CD5⁺, CLA, CD28, and CD45RO⁺.¹⁸ Many of these cells express activation markers such as HLA-DR, CD25, and CD27, in addition to the T-cell receptor (TCR).

T-Lymphocyte Stimulation

Both mature CD4⁺ and CD8⁺ T cells can respond to the peptides presented by APCs. Although the specific antigen that these T cells are reacting to has not yet been elucidated, several antigenic stimuli have been proposed, including self-proteins, microbial pathogens, and microbial superantigens. The premise that self-reactive T lymphocytes may contribute to the disease process is derived from the molecular mimicry theory in which an exuberant immune response to a pathogen produces cross-reactivity with self-antigens.¹⁹ Considering that infections have been associated with the onset of psoriasis, this theory merits consideration. However, it also has been observed that T cells can be activated without antigens or superantigens but rather with direct contact with accessory cells.²⁰ No single theory has clearly emerged. Researchers continue to search for the inciting stimulus that triggers the T lymphocyte and attempt to determine whether T cells are reacting to a self-derived or non–self-derived antigen.

T-Lymphocyte Signaling

T-cell signaling is a highly coordinated process in which T lymphocytes recognize antigens via presentation by mature APCs in the skin rather than the lymphoid tissues. Such APCs expose antigenic peptides via class I or II MHC molecules for which receptors are present on the T-cell surface. The antigen recognition complex at the T-cell and APC interface, in concert with a host of antigen-independent co-stimulatory signals, regulates T-cell signaling and is referred to as the immunologic synapse. The antigen presentation and network of co-stimulatory and adhesion molecules optimize T-cell activation, and dermal DCs release IL-12 and IL-23 to promote a T_H1 and T_H17 response, respectively. The growth factors released by these helper T cells sustain neoangiogenesis, stimulate epidermal hyperproliferation, alter epidermal differentiation, and decrease susceptibility to apoptosis that characterizes the erythematous hypertrophic scaling lesions of psoriasis.²¹ Furthermore, the cytokines produced from the immunologic response, such as tumor necrosis factor (TNF) α, IFN-γ, and IL-2, correspond to cytokines that are upregulated in psoriatic plaques.²²

Integral components of the immunologic synapse complex include co-stimulatory signals such as CD28, CD40, CD80, and CD86, as well as adhesion molecules such as cytotoxic T-lymphocyte antigen 4 and lymphocyte function-associated antigen (LFA) 1, which possess corresponding receptors on the T cell. These molecules play a key role in T-cell signaling, as their disruption has been shown to decrease T-cell responsiveness and associated inflammation. The B7 family of molecules routinely interacts with CD28 T cells to co-stimulate T-cell activation. Cytotoxic T-lymphocyte antigen 4 immunoglobulin, an antibody on the T-cell surface, targets B7 and interferes with signaling between B7 and CD28. In psoriatic patients, this blockade was demonstrated to attenuate the T-cell response and correlated with a clinical and histological decrease in psoriasiform hyperplasia.²³ Biologic therapies that disrupt the LFA-1 component of the immunologic synapse also have demonstrated efficacy in the treatment of psoriasis. Alefacept is a human LFA-3 fusion protein that binds CD2 on T cells and blocks the interaction between LFA-3 on APCs and CD2 on memory CD45RO⁺ T cells and induces apoptosis of such T cells. Efalizumab is a human monoclonal antibody to the CD11 chain of LFA-1 that blocks the interaction between LFA-1 on the T cell and intercellular adhesion molecule 1 on an APC or endothelial cell. Both alefacept and efalizumab, 2 formerly marketed biologic therapies, demonstrated remarkable clinical reduction of psoriatic lesions, and alefacept has been shown to produce disease remission for up to 18 months after discontinuation of therapy.^24-26

NK T Cells

Natural killer T cells represent a subset of CD3⁺ T cells present in psoriatic plaques. Although NK T cells possess a TCR, they differ from T cells by displaying NK receptors comprised of lectin and immunoglobulin families. These cells exhibit remarkable specificity and are activated upon recognition of glycolipids presented by CD1d molecules. This process occurs in contrast to CD4⁺ and CD8⁺ T cells, which, due to their TCR diversity, respond to peptides processed by APCs and displayed on MHC molecules. Natural killer T cells can be classified into 2 subsets: (1) one group that expresses CD4 and preferentially produces T_H1- versus T_H2-type cytokines, and (2) another group that lacks CD4 and CD8 that only produces T_H1-type cytokines. The innate immune system employs NK T cells early in the immune response because of their direct cytotoxicity and rapid production of cytokines such as IFN-γ, which promotes a T_H1 inflammatory response, and IL-4, which promotes the development of T_H2 cells. Excessive or dysfunctional NK T cells have been associated with autoimmune diseases such as multiple sclerosis and inflammatory bowel disease as well as allergic contact dermatitis.^27-29

In psoriasis, NK T cells are located in the epidermis, closely situated to epidermal keratinocytes, which suggests a role for direct antigen presentation. Furthermore, CD1d is overexpressed throughout the epidermis of psoriatic plaques, whereas normally CD1d expression is confined to terminally differentiated keratinocytes. An in vitro study examining cytokine-based inflammation demonstrative of psoriasis treated cultured CD1d-positive keratinocytes with interferon gamma in the presence of alpha-galactosylceramide of the lectin family.³⁰ Interferon gamma was observed to enhance keratinocyte CD1d expression, and subsequently, CD1d-positive keratinocytes were found to activate NK T cells to produce high levels of IFN-γ, while levels of IL-4 remained undetectable. The preferential production of IFN-γ supports a T_H1-mediated mechanism regulated by NK T cells in the immunopathogenesis of psoriasis.

Dendritic Cells

Dendritic cells are APCs that process antigens in the tissues in which they reside, after which they migrate to local lymph nodes where they present their native antigens to T cells. This process allows the T-cell response to be tailored to the appropriate antigens in the corresponding tissues. Immature DCs that capture antigens mature by migrating to the T-cell center of the lymph node where they present their antigens to either MHC molecules or the CD1 family. This presentation results in T-cell proliferation and differentiation that correlates with the required type of T-cell response. Multiple subsets of APCs, including myeloid and plasmacytoid DCs, are highly represented in the epidermis and dermis of psoriatic plaques as compared with normal skin.³¹ Dermal DCs are thought to be responsible for activating both the T_H1 and T_H17 infiltrate by secreting IL-12 and IL-23, respectively. This mixed cellular response secretes cytokines and leads to a cascade of events involving keratinocytes, fibroblasts, endothelial cells, and neutrophils that create the cutaneous lesions seen in psoriasis.³

Although DCs play a pivotal role in eliciting an immune response against a foreign invader, they also contribute to the establishment of tolerance. Throughout their maturation, DCs are continuously sensing their environment, which shapes their production of T_H1- versus T_H2-type cytokines and subsequently the nature of the T-cell response. When challenged with a virus, bacteria, or unchecked cell growth, DCs mature into APCs. However, in the absence of a strong stimulus, DCs fail to mature into APCs and present self-peptides with MHC molecules, thereby creating regulatory T cells involved in peripheral tolerance.³² If this balance between immunogenic APCs and housekeeping T cells is upset, inflammatory conditions such as psoriasis can result.

Cytokines

Cytokines are low-molecular-weight glycoproteins that function as signals to produce inflammation, defense, tissue repair and remodeling, fibrosis, angiogenesis, and restriction of neoplastic growth.³³ Cytokines are produced by immunocytes such as lymphocytes and macrophages as well as nonimmunocytes such as endothelial cells and keratinocytes. Proinflammatory cytokines include IL-1, IL-2, the IL-17 family, IFN-γ, and TNF-α, while anti-inflammatory cytokines include IL-4 and IL-10. A relative preponderance of T_H1 proinflammatory cytokines or an insufficiency of T_H2 anti-inflammatory cytokines induces local inflammation and recruitment of additional immunocyte populations, which produce added cytokines.³⁴ A vicious cycle of inflammation occurs that results in cutaneous manifestations such as a plaque. Psoriatic lesions are characterized by a relative increase of T_H1-type (eg, IL-2, IFN-γ, TNF-α, TNF-β) to T_H2-type (eg, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13) cytokines and an increase in T_H17-type cytokines. Natural killer T cells stimulated by CD1d-overexpressing keratinocytes increase production of proinflammatory IFN-γ without effect on the anti-inflammatory IL-4. In addition to the cytokines produced by T cells, APCs produce IL-18, IL-23, and TNF-α found in the inflammatory infiltrate of psoriatic plaques. Both IL-18 and IL-23 stimulate T_H1 cells to produce IFN-γ, and IL-23 stimulates T_H17 cells. Clearly, a T_H1- and T_H17-type pattern governs the immune effector cells and their respective cytokines present in psoriatic skin.

Tumor Necrosis Factor α

Although a network of cytokines is responsible for the inflammation of psoriasis, TNF-α has been implicated as a master proinflammatory cytokine of the innate immune response due to its widespread targets and sources. Tumor necrosis factor α is produced by activated T cells, keratinocytes, NK cells, macrophages, monocytes, Langerhans APCs, and endothelial cells. Psoriatic lesions demonstrate high concentrations of TNF-α, while the synovial fluid of psoriatic arthritis patients demonstrates elevated concentrations of TNF-α, IL-1, IL-6, and IL-8.³⁴ In psoriasis, TNF-α supports the expression of adhesion molecules (intercellular adhesion molecule 1 and P- and E-selectin), angiogenesis via vascular endothelial growth factor, the synthesis of proinflammatory molecules (IL-1, IL-6, IL-8, and nuclear factor κβ), and keratinocyte hyperproliferation via vasoactive intestinal peptide.³⁵

A role for TNF-α in psoriasis treatment was serendipitously discovered in a trial for Crohn disease in which infliximab, a mouse-human IgG1 anti–TNF-α monoclonal antibody, was observed to clear psoriatic plaques in a patient with both Crohn disease and psoriasis.³⁶ Immunotherapies that target TNF-α, including infliximab, etanercept, and adalimumab, demonstrate notable efficacy in the treatment of psoriasis.^37-39 Tumor necrosis factor α is regarded as the driver of the inflammatory cycle of psoriasis due to its numerous modes of production, capability to amplify other proinflammatory signals, and the efficacy and rapidity with which it produces clinical improvements in psoriasis.

IL-23/T_H17 Axis

A new distinct population of helper T cells has been shown to play an important role in psoriasis. These cells develop with the help of IL-23 (secreted by dermal DCs) and subsequently secrete cytokines such as IL-17; they are, therefore, named T_H17 cells. CD161 is considered a surface marker for these cells.⁴⁰ Strong evidence for this IL-23/T_H17 axis has been shown in mouse and human models as well as in genetic studies.

IL-23 is a cytokine that shares the p40 subunit with IL-12 and has been linked to autoimmune diseases in both mice and humans.³ It is required for optimal development of T_H17 cells⁴¹ from a committed CD4⁺ T-cell population after exposure to transforming growth factor β1 in combination with other proinflammatory cytokines.^42,43 IL-23 messenger RNA is produced at higher levels in inflammatory psoriatic skin lesions versus uninvolved skin,⁴⁴ and intradermal IL-23 injections in mice produced lesions resembling psoriasis macroscopically and microscopically.⁴⁵ Furthermore, several systemic therapies have been shown to modulate IL-23 levels and correlate with clinical benefit.³ Alterations in the gene for the IL-23 receptor have been shown to be protective for psoriasis,^46-48 and the gene coding for the p40 subunit is associated with psoriasis.^46,47

Type 17 helper T cells produce a number of cytokines, such as IL-22, IL-17A, IL-17F, and IL-26; the latter 3 are considered to be specific to this lineage.⁴² IL-22 acts on outer body barrier tissues, such as the skin, and has antimicrobial activity. Blocking the activity of IL-22 in mice prevented the development of skin lesions,⁴⁹ and psoriasis patients have elevated levels of IL-22 in the skin and blood.^50,51 The IL-17 cytokines induce the expression of proinflammatory cytokines, colony-stimulating factors, and chemokines, and they recruit, mobilize, and activate neutrophils.⁵² IL-17 messenger RNA was found in lesional psoriatic skin but not unaffected skin,⁵³ and cells isolated from the dermis of psoriatic skin have been shown to produce IL-17.⁵⁴ IL-17A is not elevated in the serum of psoriatic patients (unlike other autoimmune diseases),⁵⁵ and it is, therefore, thought that T_H17 cells and IL-17A production are localized to the affected psoriatic skin. Consistent with this concept is the finding that treatments such as cyclosporin A and anti-TNF agents decrease proinflammatory cytokines in lesional skin but not in the periphery.^56-58 These cytokines released by T_H17 cells in addition to those released by T_H1 cells act on keratinocytes and produce epidermal hyperproliferation, acanthosis, and hyperparakeratosis characteristic of psoriasis.³

New therapies have been developed to target the IL-23/T_H17 axis. Ustekinumab is approved for moderate to severe plaque psoriasis. This treatment’s effect may be sustained for up to 3 years, it is generally well tolerated, and it may be useful for patients refractory to anti-TNF therapy such as etanercept.⁵⁹ Briakinumab, another blocker of IL-12 and IL-23, was studied in phase 3 clinical trials, but its development was discontinued due to safety concerns.⁶⁰ Newer drugs targeting the IL-23/T_H17 axis include secukinumab, ixekizumab, brodalumab, guselkumab, and tildrakizumab.

Genetic Basis of Psoriasis

Psoriasis is a disease of overactive immunity in genetically susceptible individuals. Because patients exhibit varying skin phenotypes, extracutaneous manifestations, and disease courses, multiple genes resulting from linkage disequilibrium are believed to be involved in the pathogenesis of psoriasis. A decade of genome-wide linkage scans have established that PSORS1 is the strongest susceptibility locus demonstrable through family linkage studies; PSORS1 is responsible for up to 50% of the genetic component of psoriasis.⁶¹ More recently, HLA-Cw6 has received the most attention as a candidate gene of the PSORS1 susceptibility locus on the MHC class I region on chromosome 6p21.3.⁶² This gene may function in antigen presentation via MHC class I, which aids in the activation of the overactive T cells characteristic of psoriatic inflammation.

Studies involving the IL-23/T_H17 axis have shown genetics to play a role. Individuals may be protected from psoriasis with a nonsynonymous nucleotide substitution in the IL23R gene,^47-49 and certain haplotypes of the IL23R gene are associated with the disease^47,49 in addition to other autoimmune conditions.

Genomic scans have shown additional susceptibility loci for psoriasis on chromosomes 1q21, 3q21, 4q32-35, 16q12, and 17q25. Two regions on chromosome 17q were recently localized via mapping, which demonstrated a 6 megabase pairs separation, thereby indicating independent linkage factors. Genes SLC9A3R1 and NAT9 are present in the first region, while RAPTOR is demonstrated in the second region.⁶³SLC9A3R1 and NAT9 are players that regulate signal transduction, the immunologic synapse, and T-cell growth. RAPTOR is involved in T-cell function and growth pathways. Using these genes as an example, we can predict that the alterations of regulatory genes, even those yet undetermined, can enhance T-cell proliferation and inflammation manifested in psoriasis.

Conclusion

Psoriasis is a complex disease whereby multiple exogenous and endogenous stimuli incite already heightened innate immune responses in genetically predetermined individuals. The disease process is a result of a network of cell types, including T cells, DCs, and keratinocytes that, with the production of cytokines, generate a chronic inflammatory state. Our understanding of these cellular interactions and cytokines originates from developments, some meticulously planned, others serendipitous, in the fields of immunology, cell and molecular biology, and genetics. Such progress has fostered the creation of targeted immune therapy that has demonstrated remarkable efficacy in psoriasis treatment. Further study of the underlying pathophysiology of psoriasis may provide additional targets for therapy.

Increased understanding of the pathophysiology of psoriasis has been one of the driving forces in the development of new therapies. An understanding of the processes involved is important in the optimal management of the disease. The last 30 years of research and clinical practice have revolutionized our understanding of the pathogenesis of psoriasis as the dysregulation of immunity triggered by environmental and genetic stimuli. Psoriasis was originally regarded as a primary disorder of epidermal hyperproliferation. However, experimental models and clinical results from immunomodulating therapies have refined this perspective in conceptualizing psoriasis as a genetically programmed pathologic interaction among resident skin cells; infiltrating immunocytes; and a host of proinflammatory cytokines, chemokines, and growth factors produced by these immunocytes. Two populations of immunocytes and their respective signaling molecules collaborate in the pathogenesis: (1) innate immunocytes, mediated by antigen-presenting cells (APCs)(including natural killer [NK] T lymphocytes, Langerhans cells, and neutrophils), and (2) acquired or adaptive immunocytes, mediated by mature CD4⁺ and CD8⁺ T lymphocytes in the skin. Such dysregulation of immunity and subsequent inflammation is responsible for the development and perpetuation of the clinical plaques and histological inflammatory infiltrate characteristic of psoriasis.

Although psoriasis is considered to be an immune-mediated disease in which intralesional T lymphocytes and their proinflammatory signals trigger primed basal layer keratinocytes to rapidly proliferate, debate and research focus on the stimulus that incites this inflammatory process. Our current understanding considers psoriasis to be triggered by exogenous or endogenous environmental stimuli in genetically susceptible individuals. Such stimuli include group A streptococcal pharyngitis, viremia, allergic drug reactions, antimalarial drugs, lithium, beta-blockers, IFN-α, withdrawal of systemic corticosteroids, local trauma (Köbner phenomenon), and emotional stress. These stimuli correlate with the onset or flares of psoriatic lesions. Psoriasis genetics centers on susceptibility loci and corresponding candidate genes, particularly the psoriasis susceptibility (PSORS) 1 locus on the major histocompatibility complex (MHC) class I region. Current research on the pathogenesis of psoriasis examines the complex interactions among immunologic mechanisms, environmental stimuli, and genetic susceptibility. After discussing the clinical presentation and histopathologic features of psoriasis, we will review the pathophysiology of psoriasis through noteworthy developments, including serendipitous observations, reactions to therapies, clinical trials, and animal model systems that have shaped our view of the disease process. In addition to the classic skin lesions, approximately 23% of psoriasis patients develop psoriatic arthritis, with a 10-year latency after diagnosis of psoriasis.¹

Principles of Immunity

The immune system, intended to protect its host from foreign invaders and unregulated cell growth, employs 2 main effector pathways—the innate and the acquired (or adaptive) immune responses—both of which contribute to the pathophysiology of psoriasis.² Innate immunity responses occur within minutes to hours of antigen exposure but fail to develop memory for when the antigen is encountered again. However, adaptive immunity responses take days to weeks to respond after challenged with an antigen. The adaptive immune cells have the capacity to respond to a greater range of antigens and develop immunologic memory via rearrangement of antigen receptors on B and T cells. These specialized B and T cells can then be promptly mobilized and differentiated into mature effector cells that protect the host from a foreign pathogen.

Innate and adaptive immune responses are highly intertwined; they can initiate, perpetuate, and terminate the immune mechanisms responsible for inflammation. They can modify the nature of the immune response by altering the relative proportions of type 1 (T_H1), type 2 (T_H2), and the more recently discovered type 17 (T_H17) subset of helper T cells and their respective signaling molecules. A T_H1 response is essential for a cellular immunologic reaction to intracellular bacteria and viruses or cellular immunity. A T_H2 response promotes IgE synthesis, eosinophilia, and mast cell maturation for extracellular parasites and helminthes as well as humoral immunity, while a T_H17 response is important for cell-mediated immunity to extracellular bacteria and plays a role in autoimmunity.³ The innate and adaptive immune responses employ common effector molecules such as chemokines and cytokines, which are essential in mediating an immune response.

Implicating Dysregulation of Immunity

Our present appreciation of the pathogenesis of psoriasis is based on the history of trial-and-error therapies; serendipitous discoveries; and the current immune targeting drugs used in a variety of chronic inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease. Before the mid-1980s, research focused on the hyperproliferative epidermal cells as the primary pathology because a markedly thickened epidermis was indeed demonstrated on histologic specimens. Altered cell-cycle kinetics were thought to be the culprit behind the hyperkeratotic plaques. Thus, initial treatments centered on oncologic and antimitotic therapies used to arrest keratinocyte proliferation with agents such as arsenic, ammoniated mercury, and methotrexate.⁴

However, a paradigm shift from targeting epidermal keratinocytes to immunocyte populations was recognized when a patient receiving cyclosporine to prevent transplant rejection noted clearing of psoriatic lesions in the 1980s.⁵ Cyclosporine was observed to inhibit messenger RNA transcription of T-cell cytokines, thereby implicating immunologic dysregulation, specifically T-cell hyperactivity, in the pathogenesis of psoriasis.⁶ However, the concentrations of oral cyclosporine reached in the epidermis exerted direct effects on keratinocyte proliferation and lymphocyte function in these patients.⁷ Thus, the question was raised as to whether the keratinocytes or the lymphocytes drove the psoriatic plaques. The use of an IL-2 diphtheria toxin-fusion protein, denileukin diftitox, specific for activated T cells with high-affinity IL-2 receptors and nonreactive with keratinocytes, distinguished which cell type was responsible. This targeted T-cell toxin provided clinical and histological clearing of psoriatic plaques. Thus, T lymphocytes rather than keratinocytes were recognized as the definitive driver behind the psoriatic plaques.⁸

Additional studies have demonstrated that treatments that induce prolonged clearing of psoriatic lesions without continuous therapy, such as psoralen plus UVA irradiation, decreased the numbers of T cells in plaques by at least 90%.⁹ However, treatments that require continual therapy for satisfactory clinical results, such as cyclosporine and etretinate, simply suppress T-cell activity and proliferation.^10,11 Further evidence has linked cellular immunity with the pathogenesis of psoriasis, defining it as a T_H1-type disease. Natural killer T cells were shown to be involved through the use of a severe combined immunodeficient mouse model. They were injected into prepsoriatic skin grafted on immunodeficient mice, creating a psoriatic plaque with an immune response showing cytokines from T_H1 cells rather than T_H2 cells.¹² When psoriatic plaques were treated topically with the toll-like receptor 7 agonist imiquimod, aggravation and spreading of the plaques were noted. The exacerbation of psoriasis was accompanied by an induction of lesional T_H1-type interferon produced by plasmacytoid dendritic cell (DC) precursors. Plasmacytoid DCs were observed to compose up to 16% of the total dermal infiltrate in psoriatic skin lesions based on their coexpression of BDCA2 and CD123.¹³ Additionally, cancer patients being treated with interferon alfa experienced induction of psoriasis.¹⁴ Moreover, patients being treated for warts with intralesional interferon alfa developed psoriatic plaques in neighboring prior asymptomatic skin.¹⁵ Patients with psoriasis who were treated with interferon gamma, a T_H1 cytokine type, also developed new plaques correlating with the sites of injection.¹⁶

Intralesional T Lymphocytes

Psoriatic lesions contain a host of innate immunocytes, such as APCs, NK cells, and neutrophils, as well as adaptive T cells and an inflammatory infiltrate. These cells include CD4 and CD8 subtypes in which the CD8⁺ cells predominate in the epidermis, while CD4⁺ cells show preference for the dermis.¹⁷ There are 2 groups of CD8⁺ cells: one group migrates to the epidermis, expressing the integrin CD103, while the other group is found in the dermis but may be headed to or from the epidermis. The CD8⁺ cells residing in the epidermis that express the integrin CD103 are capable of interacting with E-cadherin, which enables these cells to travel to the epidermis and bind resident cells. Immunophenotyping reveals that these mature T cells represent chiefly activated memory cells, including CD2⁺, CD3⁺, CD5⁺, CLA, CD28, and CD45RO⁺.¹⁸ Many of these cells express activation markers such as HLA-DR, CD25, and CD27, in addition to the T-cell receptor (TCR).

T-Lymphocyte Stimulation

Both mature CD4⁺ and CD8⁺ T cells can respond to the peptides presented by APCs. Although the specific antigen that these T cells are reacting to has not yet been elucidated, several antigenic stimuli have been proposed, including self-proteins, microbial pathogens, and microbial superantigens. The premise that self-reactive T lymphocytes may contribute to the disease process is derived from the molecular mimicry theory in which an exuberant immune response to a pathogen produces cross-reactivity with self-antigens.¹⁹ Considering that infections have been associated with the onset of psoriasis, this theory merits consideration. However, it also has been observed that T cells can be activated without antigens or superantigens but rather with direct contact with accessory cells.²⁰ No single theory has clearly emerged. Researchers continue to search for the inciting stimulus that triggers the T lymphocyte and attempt to determine whether T cells are reacting to a self-derived or non–self-derived antigen.

T-Lymphocyte Signaling

T-cell signaling is a highly coordinated process in which T lymphocytes recognize antigens via presentation by mature APCs in the skin rather than the lymphoid tissues. Such APCs expose antigenic peptides via class I or II MHC molecules for which receptors are present on the T-cell surface. The antigen recognition complex at the T-cell and APC interface, in concert with a host of antigen-independent co-stimulatory signals, regulates T-cell signaling and is referred to as the immunologic synapse. The antigen presentation and network of co-stimulatory and adhesion molecules optimize T-cell activation, and dermal DCs release IL-12 and IL-23 to promote a T_H1 and T_H17 response, respectively. The growth factors released by these helper T cells sustain neoangiogenesis, stimulate epidermal hyperproliferation, alter epidermal differentiation, and decrease susceptibility to apoptosis that characterizes the erythematous hypertrophic scaling lesions of psoriasis.²¹ Furthermore, the cytokines produced from the immunologic response, such as tumor necrosis factor (TNF) α, IFN-γ, and IL-2, correspond to cytokines that are upregulated in psoriatic plaques.²²

Integral components of the immunologic synapse complex include co-stimulatory signals such as CD28, CD40, CD80, and CD86, as well as adhesion molecules such as cytotoxic T-lymphocyte antigen 4 and lymphocyte function-associated antigen (LFA) 1, which possess corresponding receptors on the T cell. These molecules play a key role in T-cell signaling, as their disruption has been shown to decrease T-cell responsiveness and associated inflammation. The B7 family of molecules routinely interacts with CD28 T cells to co-stimulate T-cell activation. Cytotoxic T-lymphocyte antigen 4 immunoglobulin, an antibody on the T-cell surface, targets B7 and interferes with signaling between B7 and CD28. In psoriatic patients, this blockade was demonstrated to attenuate the T-cell response and correlated with a clinical and histological decrease in psoriasiform hyperplasia.²³ Biologic therapies that disrupt the LFA-1 component of the immunologic synapse also have demonstrated efficacy in the treatment of psoriasis. Alefacept is a human LFA-3 fusion protein that binds CD2 on T cells and blocks the interaction between LFA-3 on APCs and CD2 on memory CD45RO⁺ T cells and induces apoptosis of such T cells. Efalizumab is a human monoclonal antibody to the CD11 chain of LFA-1 that blocks the interaction between LFA-1 on the T cell and intercellular adhesion molecule 1 on an APC or endothelial cell. Both alefacept and efalizumab, 2 formerly marketed biologic therapies, demonstrated remarkable clinical reduction of psoriatic lesions, and alefacept has been shown to produce disease remission for up to 18 months after discontinuation of therapy.^24-26

NK T Cells

Natural killer T cells represent a subset of CD3⁺ T cells present in psoriatic plaques. Although NK T cells possess a TCR, they differ from T cells by displaying NK receptors comprised of lectin and immunoglobulin families. These cells exhibit remarkable specificity and are activated upon recognition of glycolipids presented by CD1d molecules. This process occurs in contrast to CD4⁺ and CD8⁺ T cells, which, due to their TCR diversity, respond to peptides processed by APCs and displayed on MHC molecules. Natural killer T cells can be classified into 2 subsets: (1) one group that expresses CD4 and preferentially produces T_H1- versus T_H2-type cytokines, and (2) another group that lacks CD4 and CD8 that only produces T_H1-type cytokines. The innate immune system employs NK T cells early in the immune response because of their direct cytotoxicity and rapid production of cytokines such as IFN-γ, which promotes a T_H1 inflammatory response, and IL-4, which promotes the development of T_H2 cells. Excessive or dysfunctional NK T cells have been associated with autoimmune diseases such as multiple sclerosis and inflammatory bowel disease as well as allergic contact dermatitis.^27-29

In psoriasis, NK T cells are located in the epidermis, closely situated to epidermal keratinocytes, which suggests a role for direct antigen presentation. Furthermore, CD1d is overexpressed throughout the epidermis of psoriatic plaques, whereas normally CD1d expression is confined to terminally differentiated keratinocytes. An in vitro study examining cytokine-based inflammation demonstrative of psoriasis treated cultured CD1d-positive keratinocytes with interferon gamma in the presence of alpha-galactosylceramide of the lectin family.³⁰ Interferon gamma was observed to enhance keratinocyte CD1d expression, and subsequently, CD1d-positive keratinocytes were found to activate NK T cells to produce high levels of IFN-γ, while levels of IL-4 remained undetectable. The preferential production of IFN-γ supports a T_H1-mediated mechanism regulated by NK T cells in the immunopathogenesis of psoriasis.

Dendritic Cells

Dendritic cells are APCs that process antigens in the tissues in which they reside, after which they migrate to local lymph nodes where they present their native antigens to T cells. This process allows the T-cell response to be tailored to the appropriate antigens in the corresponding tissues. Immature DCs that capture antigens mature by migrating to the T-cell center of the lymph node where they present their antigens to either MHC molecules or the CD1 family. This presentation results in T-cell proliferation and differentiation that correlates with the required type of T-cell response. Multiple subsets of APCs, including myeloid and plasmacytoid DCs, are highly represented in the epidermis and dermis of psoriatic plaques as compared with normal skin.³¹ Dermal DCs are thought to be responsible for activating both the T_H1 and T_H17 infiltrate by secreting IL-12 and IL-23, respectively. This mixed cellular response secretes cytokines and leads to a cascade of events involving keratinocytes, fibroblasts, endothelial cells, and neutrophils that create the cutaneous lesions seen in psoriasis.³

Although DCs play a pivotal role in eliciting an immune response against a foreign invader, they also contribute to the establishment of tolerance. Throughout their maturation, DCs are continuously sensing their environment, which shapes their production of T_H1- versus T_H2-type cytokines and subsequently the nature of the T-cell response. When challenged with a virus, bacteria, or unchecked cell growth, DCs mature into APCs. However, in the absence of a strong stimulus, DCs fail to mature into APCs and present self-peptides with MHC molecules, thereby creating regulatory T cells involved in peripheral tolerance.³² If this balance between immunogenic APCs and housekeeping T cells is upset, inflammatory conditions such as psoriasis can result.

Cytokines

Cytokines are low-molecular-weight glycoproteins that function as signals to produce inflammation, defense, tissue repair and remodeling, fibrosis, angiogenesis, and restriction of neoplastic growth.³³ Cytokines are produced by immunocytes such as lymphocytes and macrophages as well as nonimmunocytes such as endothelial cells and keratinocytes. Proinflammatory cytokines include IL-1, IL-2, the IL-17 family, IFN-γ, and TNF-α, while anti-inflammatory cytokines include IL-4 and IL-10. A relative preponderance of T_H1 proinflammatory cytokines or an insufficiency of T_H2 anti-inflammatory cytokines induces local inflammation and recruitment of additional immunocyte populations, which produce added cytokines.³⁴ A vicious cycle of inflammation occurs that results in cutaneous manifestations such as a plaque. Psoriatic lesions are characterized by a relative increase of T_H1-type (eg, IL-2, IFN-γ, TNF-α, TNF-β) to T_H2-type (eg, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13) cytokines and an increase in T_H17-type cytokines. Natural killer T cells stimulated by CD1d-overexpressing keratinocytes increase production of proinflammatory IFN-γ without effect on the anti-inflammatory IL-4. In addition to the cytokines produced by T cells, APCs produce IL-18, IL-23, and TNF-α found in the inflammatory infiltrate of psoriatic plaques. Both IL-18 and IL-23 stimulate T_H1 cells to produce IFN-γ, and IL-23 stimulates T_H17 cells. Clearly, a T_H1- and T_H17-type pattern governs the immune effector cells and their respective cytokines present in psoriatic skin.

Tumor Necrosis Factor α

Although a network of cytokines is responsible for the inflammation of psoriasis, TNF-α has been implicated as a master proinflammatory cytokine of the innate immune response due to its widespread targets and sources. Tumor necrosis factor α is produced by activated T cells, keratinocytes, NK cells, macrophages, monocytes, Langerhans APCs, and endothelial cells. Psoriatic lesions demonstrate high concentrations of TNF-α, while the synovial fluid of psoriatic arthritis patients demonstrates elevated concentrations of TNF-α, IL-1, IL-6, and IL-8.³⁴ In psoriasis, TNF-α supports the expression of adhesion molecules (intercellular adhesion molecule 1 and P- and E-selectin), angiogenesis via vascular endothelial growth factor, the synthesis of proinflammatory molecules (IL-1, IL-6, IL-8, and nuclear factor κβ), and keratinocyte hyperproliferation via vasoactive intestinal peptide.³⁵

A role for TNF-α in psoriasis treatment was serendipitously discovered in a trial for Crohn disease in which infliximab, a mouse-human IgG1 anti–TNF-α monoclonal antibody, was observed to clear psoriatic plaques in a patient with both Crohn disease and psoriasis.³⁶ Immunotherapies that target TNF-α, including infliximab, etanercept, and adalimumab, demonstrate notable efficacy in the treatment of psoriasis.^37-39 Tumor necrosis factor α is regarded as the driver of the inflammatory cycle of psoriasis due to its numerous modes of production, capability to amplify other proinflammatory signals, and the efficacy and rapidity with which it produces clinical improvements in psoriasis.

IL-23/T_H17 Axis

A new distinct population of helper T cells has been shown to play an important role in psoriasis. These cells develop with the help of IL-23 (secreted by dermal DCs) and subsequently secrete cytokines such as IL-17; they are, therefore, named T_H17 cells. CD161 is considered a surface marker for these cells.⁴⁰ Strong evidence for this IL-23/T_H17 axis has been shown in mouse and human models as well as in genetic studies.

IL-23 is a cytokine that shares the p40 subunit with IL-12 and has been linked to autoimmune diseases in both mice and humans.³ It is required for optimal development of T_H17 cells⁴¹ from a committed CD4⁺ T-cell population after exposure to transforming growth factor β1 in combination with other proinflammatory cytokines.^42,43 IL-23 messenger RNA is produced at higher levels in inflammatory psoriatic skin lesions versus uninvolved skin,⁴⁴ and intradermal IL-23 injections in mice produced lesions resembling psoriasis macroscopically and microscopically.⁴⁵ Furthermore, several systemic therapies have been shown to modulate IL-23 levels and correlate with clinical benefit.³ Alterations in the gene for the IL-23 receptor have been shown to be protective for psoriasis,^46-48 and the gene coding for the p40 subunit is associated with psoriasis.^46,47

Type 17 helper T cells produce a number of cytokines, such as IL-22, IL-17A, IL-17F, and IL-26; the latter 3 are considered to be specific to this lineage.⁴² IL-22 acts on outer body barrier tissues, such as the skin, and has antimicrobial activity. Blocking the activity of IL-22 in mice prevented the development of skin lesions,⁴⁹ and psoriasis patients have elevated levels of IL-22 in the skin and blood.^50,51 The IL-17 cytokines induce the expression of proinflammatory cytokines, colony-stimulating factors, and chemokines, and they recruit, mobilize, and activate neutrophils.⁵² IL-17 messenger RNA was found in lesional psoriatic skin but not unaffected skin,⁵³ and cells isolated from the dermis of psoriatic skin have been shown to produce IL-17.⁵⁴ IL-17A is not elevated in the serum of psoriatic patients (unlike other autoimmune diseases),⁵⁵ and it is, therefore, thought that T_H17 cells and IL-17A production are localized to the affected psoriatic skin. Consistent with this concept is the finding that treatments such as cyclosporin A and anti-TNF agents decrease proinflammatory cytokines in lesional skin but not in the periphery.^56-58 These cytokines released by T_H17 cells in addition to those released by T_H1 cells act on keratinocytes and produce epidermal hyperproliferation, acanthosis, and hyperparakeratosis characteristic of psoriasis.³

New therapies have been developed to target the IL-23/T_H17 axis. Ustekinumab is approved for moderate to severe plaque psoriasis. This treatment’s effect may be sustained for up to 3 years, it is generally well tolerated, and it may be useful for patients refractory to anti-TNF therapy such as etanercept.⁵⁹ Briakinumab, another blocker of IL-12 and IL-23, was studied in phase 3 clinical trials, but its development was discontinued due to safety concerns.⁶⁰ Newer drugs targeting the IL-23/T_H17 axis include secukinumab, ixekizumab, brodalumab, guselkumab, and tildrakizumab.

Genetic Basis of Psoriasis

Psoriasis is a disease of overactive immunity in genetically susceptible individuals. Because patients exhibit varying skin phenotypes, extracutaneous manifestations, and disease courses, multiple genes resulting from linkage disequilibrium are believed to be involved in the pathogenesis of psoriasis. A decade of genome-wide linkage scans have established that PSORS1 is the strongest susceptibility locus demonstrable through family linkage studies; PSORS1 is responsible for up to 50% of the genetic component of psoriasis.⁶¹ More recently, HLA-Cw6 has received the most attention as a candidate gene of the PSORS1 susceptibility locus on the MHC class I region on chromosome 6p21.3.⁶² This gene may function in antigen presentation via MHC class I, which aids in the activation of the overactive T cells characteristic of psoriatic inflammation.

Studies involving the IL-23/T_H17 axis have shown genetics to play a role. Individuals may be protected from psoriasis with a nonsynonymous nucleotide substitution in the IL23R gene,^47-49 and certain haplotypes of the IL23R gene are associated with the disease^47,49 in addition to other autoimmune conditions.

Genomic scans have shown additional susceptibility loci for psoriasis on chromosomes 1q21, 3q21, 4q32-35, 16q12, and 17q25. Two regions on chromosome 17q were recently localized via mapping, which demonstrated a 6 megabase pairs separation, thereby indicating independent linkage factors. Genes SLC9A3R1 and NAT9 are present in the first region, while RAPTOR is demonstrated in the second region.⁶³SLC9A3R1 and NAT9 are players that regulate signal transduction, the immunologic synapse, and T-cell growth. RAPTOR is involved in T-cell function and growth pathways. Using these genes as an example, we can predict that the alterations of regulatory genes, even those yet undetermined, can enhance T-cell proliferation and inflammation manifested in psoriasis.

Conclusion

Psoriasis is a complex disease whereby multiple exogenous and endogenous stimuli incite already heightened innate immune responses in genetically predetermined individuals. The disease process is a result of a network of cell types, including T cells, DCs, and keratinocytes that, with the production of cytokines, generate a chronic inflammatory state. Our understanding of these cellular interactions and cytokines originates from developments, some meticulously planned, others serendipitous, in the fields of immunology, cell and molecular biology, and genetics. Such progress has fostered the creation of targeted immune therapy that has demonstrated remarkable efficacy in psoriasis treatment. Further study of the underlying pathophysiology of psoriasis may provide additional targets for therapy.

This special issue is dedicated to resident education on psoriasis. With that in mind, we hope to address many topics of interest to those in training. Over the years, diet has been a hot topic among psoriasis patients. They want to know how diet affects psoriasis and what changes can be made to their diet to improve their condition. Although they have expected specific answers, my response has usually been that they should, of course, eat an overall healthy and balanced diet, and lose weight if necessary. I have continued, however, that no specific diet has been recommended. However, now we have some information that may start to give us some answers.

The Mediterranean diet has been regarded as a healthy regimen.¹ This diet emphasizes eating primarily plant-based foods, such as fruits and vegetables; whole grains; legumes; and nuts. Other recommendations include replacing butter with healthy fats such as olive oil and canola oil, using herbs and spices instead of salt to flavor foods, and limiting red meat to no more than a few times a month.¹

As we know, psoriasis is a chronic inflammatory disease. The Mediterranean diet has been shown to reduce chronic inflammation and has a positive effect on the risk for metabolic syndrome and cardiovascular events.¹ Phan et al¹ hypothesized a positive effect of the Mediterranean diet on psoriasis. They performed a study to assess the association between a score that reflects the adhesion to a Mediterranean diet (MEDI-LITE) and the onset and/or severity of psoriasis.¹

The NutriNet-Santé program is an ongoing, observational, web-based questionnaire cohort study launched in France in May 2009.¹ Data were collected and analyzed between April 2017 and June 2017. Individuals with psoriasis were identified utilizing a validated online questionnaire and then categorized by disease severity into 1 of 3 groups: severe psoriasis, nonsevere psoriasis, and psoriasis free.¹

During the initial 2 years of participation in the cohort, data on dietary intake (including alcohol) were gathered to calculate the MEDI-LITE score, ranging from 0 (no adherence) to 18 (maximum adherence).¹ Of the 158,361 total web-based participants, 35,735 (23%) replied to the psoriasis questionnaire.¹ Of the respondents, 3557 (10%) individuals reported having psoriasis. The condition was severe in 878 cases (24.7%), and 299 (8.4%) incident cases were recorded (cases occurring >2 years after participant inclusion in the cohort). After adjustment for confounding factors, the investigators found a significant inverse relationship between the MEDI-LITE score and having severe psoriasis (odds ratio [OR], 0.71; 95% CI, 0.55-0.92 for the MEDI-LITE score’s second tertile [score of 8 to 9]; and OR, 0.78; 95% CI, 0.59-1.01 for the third tertile [score of 10 to 18]).¹

The authors noted that patients with severe psoriasis displayed low levels of adherence to the Mediterranean diet.¹ They commented that this finding supports the hypothesis that the Mediterranean diet may slow the progression of psoriasis. If these findings are confirmed, adherence to a Mediterranean diet should be integrated into the routine management of moderate to severe psoriasis.¹ These findings are by no means definitive, but it is a first step in helping us define more specific dietary recommendations for psoriasis.

This issue includes several articles looking at various facets of psoriasis important to residents, including the pathophysiology of psoriasis,² treatment approach using biologic therapies,³ risk factors and triggers for psoriasis,⁴ and the psychosocial impact of psoriasis.⁵ We hope that you find this issue enjoyable and informative.

This special issue is dedicated to resident education on psoriasis. With that in mind, we hope to address many topics of interest to those in training. Over the years, diet has been a hot topic among psoriasis patients. They want to know how diet affects psoriasis and what changes can be made to their diet to improve their condition. Although they have expected specific answers, my response has usually been that they should, of course, eat an overall healthy and balanced diet, and lose weight if necessary. I have continued, however, that no specific diet has been recommended. However, now we have some information that may start to give us some answers.

The Mediterranean diet has been regarded as a healthy regimen.¹ This diet emphasizes eating primarily plant-based foods, such as fruits and vegetables; whole grains; legumes; and nuts. Other recommendations include replacing butter with healthy fats such as olive oil and canola oil, using herbs and spices instead of salt to flavor foods, and limiting red meat to no more than a few times a month.¹

As we know, psoriasis is a chronic inflammatory disease. The Mediterranean diet has been shown to reduce chronic inflammation and has a positive effect on the risk for metabolic syndrome and cardiovascular events.¹ Phan et al¹ hypothesized a positive effect of the Mediterranean diet on psoriasis. They performed a study to assess the association between a score that reflects the adhesion to a Mediterranean diet (MEDI-LITE) and the onset and/or severity of psoriasis.¹

The NutriNet-Santé program is an ongoing, observational, web-based questionnaire cohort study launched in France in May 2009.¹ Data were collected and analyzed between April 2017 and June 2017. Individuals with psoriasis were identified utilizing a validated online questionnaire and then categorized by disease severity into 1 of 3 groups: severe psoriasis, nonsevere psoriasis, and psoriasis free.¹

During the initial 2 years of participation in the cohort, data on dietary intake (including alcohol) were gathered to calculate the MEDI-LITE score, ranging from 0 (no adherence) to 18 (maximum adherence).¹ Of the 158,361 total web-based participants, 35,735 (23%) replied to the psoriasis questionnaire.¹ Of the respondents, 3557 (10%) individuals reported having psoriasis. The condition was severe in 878 cases (24.7%), and 299 (8.4%) incident cases were recorded (cases occurring >2 years after participant inclusion in the cohort). After adjustment for confounding factors, the investigators found a significant inverse relationship between the MEDI-LITE score and having severe psoriasis (odds ratio [OR], 0.71; 95% CI, 0.55-0.92 for the MEDI-LITE score’s second tertile [score of 8 to 9]; and OR, 0.78; 95% CI, 0.59-1.01 for the third tertile [score of 10 to 18]).¹

The authors noted that patients with severe psoriasis displayed low levels of adherence to the Mediterranean diet.¹ They commented that this finding supports the hypothesis that the Mediterranean diet may slow the progression of psoriasis. If these findings are confirmed, adherence to a Mediterranean diet should be integrated into the routine management of moderate to severe psoriasis.¹ These findings are by no means definitive, but it is a first step in helping us define more specific dietary recommendations for psoriasis.

This issue includes several articles looking at various facets of psoriasis important to residents, including the pathophysiology of psoriasis,² treatment approach using biologic therapies,³ risk factors and triggers for psoriasis,⁴ and the psychosocial impact of psoriasis.⁵ We hope that you find this issue enjoyable and informative.

This special issue is dedicated to resident education on psoriasis. With that in mind, we hope to address many topics of interest to those in training. Over the years, diet has been a hot topic among psoriasis patients. They want to know how diet affects psoriasis and what changes can be made to their diet to improve their condition. Although they have expected specific answers, my response has usually been that they should, of course, eat an overall healthy and balanced diet, and lose weight if necessary. I have continued, however, that no specific diet has been recommended. However, now we have some information that may start to give us some answers.

The Mediterranean diet has been regarded as a healthy regimen.¹ This diet emphasizes eating primarily plant-based foods, such as fruits and vegetables; whole grains; legumes; and nuts. Other recommendations include replacing butter with healthy fats such as olive oil and canola oil, using herbs and spices instead of salt to flavor foods, and limiting red meat to no more than a few times a month.¹

As we know, psoriasis is a chronic inflammatory disease. The Mediterranean diet has been shown to reduce chronic inflammation and has a positive effect on the risk for metabolic syndrome and cardiovascular events.¹ Phan et al¹ hypothesized a positive effect of the Mediterranean diet on psoriasis. They performed a study to assess the association between a score that reflects the adhesion to a Mediterranean diet (MEDI-LITE) and the onset and/or severity of psoriasis.¹

The NutriNet-Santé program is an ongoing, observational, web-based questionnaire cohort study launched in France in May 2009.¹ Data were collected and analyzed between April 2017 and June 2017. Individuals with psoriasis were identified utilizing a validated online questionnaire and then categorized by disease severity into 1 of 3 groups: severe psoriasis, nonsevere psoriasis, and psoriasis free.¹

During the initial 2 years of participation in the cohort, data on dietary intake (including alcohol) were gathered to calculate the MEDI-LITE score, ranging from 0 (no adherence) to 18 (maximum adherence).¹ Of the 158,361 total web-based participants, 35,735 (23%) replied to the psoriasis questionnaire.¹ Of the respondents, 3557 (10%) individuals reported having psoriasis. The condition was severe in 878 cases (24.7%), and 299 (8.4%) incident cases were recorded (cases occurring >2 years after participant inclusion in the cohort). After adjustment for confounding factors, the investigators found a significant inverse relationship between the MEDI-LITE score and having severe psoriasis (odds ratio [OR], 0.71; 95% CI, 0.55-0.92 for the MEDI-LITE score’s second tertile [score of 8 to 9]; and OR, 0.78; 95% CI, 0.59-1.01 for the third tertile [score of 10 to 18]).¹

The authors noted that patients with severe psoriasis displayed low levels of adherence to the Mediterranean diet.¹ They commented that this finding supports the hypothesis that the Mediterranean diet may slow the progression of psoriasis. If these findings are confirmed, adherence to a Mediterranean diet should be integrated into the routine management of moderate to severe psoriasis.¹ These findings are by no means definitive, but it is a first step in helping us define more specific dietary recommendations for psoriasis.

This issue includes several articles looking at various facets of psoriasis important to residents, including the pathophysiology of psoriasis,² treatment approach using biologic therapies,³ risk factors and triggers for psoriasis,⁴ and the psychosocial impact of psoriasis.⁵ We hope that you find this issue enjoyable and informative.

In the span of less than 12 hours, the Trump administration took two seemingly contradictory actions that could have profound effects on the insurance marketplaces set up by the Affordable Care Act.

First, officials issued guidance on the morning of Oct. 22 that could weaken the exchanges set up for people who buy their own insurance. The new approach makes it easier for states to get around some ACA requirements, including allowing the use of federal subsidies for skimpier plans that can reject people with preexisting conditions.

Yet, the other move – a proposed rule unveiled that evening – could bolster ACA marketplaces by sending millions of people with job-based coverage there, armed with tax-free money from their employers to buy individual plans.

Both efforts play into the parallel narratives dominating the bitter political debate over the ACA.

The administration, frustrated that Congress did not repeal the law, say some critics and policy experts, is working to undermine it by weakening the marketplaces and the law’s consumer protections. Those efforts make it easier for insurers to offer skimpier policies that bypass the law’s rules, such as its ban on annual or lifetime limits or its protections for people with preexisting conditions. Congress also zeroed out the tax penalty for not having coverage, effective next year. Combined, the moves could reduce enrollment in ACA plans, potentially driving up premiums for those who remain.

The administration and Republicans in Congress say they are looking to assist those left behind by the ACA – people who don’t get subsidies to help them buy coverage and are desperate for less expensive options – even if that means purchasing less robust coverage.

“These are people who were buying insurance before [the law] and then the rules changed and they could not buy it because they could not afford it,” said Joe Antos, a resident scholar at the conservative American Enterprise Institute. “They have been slowly dropping out of insurance coverage altogether.”

The efforts are dramatically reshaping the ACA and the individual insurance market to one that looks more as it did before the 2010 law, when regulation, coverage, and consumer protections varied widely across the country.

“Some states will do everything they can to keep individual markets strong and stable. Others won’t,” said Sabrina Corlette, research professor at the Center on Health Insurance Reforms at Georgetown University.

So what expectations should consumers have? Here are three key takeaways:


 

Protections for preexisting health problems are uncertain

Polls show that keeping the ACA’s guarantees on coverage for people with medical problems is a top concern for Americans, and Democrats have made their defense of the health law a key part of their midterm election campaigns.

Republicans have gotten that message and even those who voted to repeal the ACA or joined a lawsuit by 20 red states to overturn it now say they want to protect people with preexisting conditions. Still, GOP lawmakers have not introduced any plan that would be as protective as the current law.

In August, the administration released a rule allowing expanded use of short-term plans, which are less expensive than ACA policies. To get those lower prices, most of these plans do not cover prescription drugs, maternity care, mental health, or substance abuse treatments.

The move is unlikely to benefit people with health problems, as short-term plans can reject people with preexisting conditions or decline to cover care for those medical problems.

Under the rule, insurers can sell them starting in 2019 for up to a year’s duration, with an option to renew for up to 3 years, reversing an Obama-era directive that limited them to 90 days.

Administration officials estimate such plans could draw 600,000 new enrollees next year, and others have estimated the numbers could be far higher. The concern is if many healthy people in 2019 switch out of the ACA market and choose short-term plans, premiums will rise for those who remain, including those with preexisting conditions, or make the ACA market less attractive for insurers.
 

Where you live matters more

One of the biggest changes ushered in with the ACA was a standard set of rules across all states.

Before the law took effect, consumers buying their own coverage saw tremendous variation in what was offered and what protections they had, depending on the state where they lived.

Most states, for example, allowed insurers to reject people with medical conditions. A few states required insurers to charge similar premiums across the board, but most allowed wide variations based on age, gender or health. Some skimpy plans didn’t cover prescription drugs, chemotherapy, or other medical services.

By standardizing the rules and benefits, the ACA barred insurers from rejecting applicants with medical conditions or charging them more. Women and men get the same premium rates and insurers could charge older people no more than three times what they charged younger ones.

Under the new guidance issued this week giving states more flexibility on what is offered, consumers could again see a wide variation on coverage, premium rules, and even subsidy eligibility.

“It shifts pressure to state politicians,” said Caroline Pearson, a senior fellow at NORC, a nonpartisan research institution at the University of Chicago. That could play into the calculus of whether a state will seek to make broad changes to help people who cannot afford ACA plans, even if the trade-off affects people with medical conditions.

“You risk making some worse off by threatening those markets,” said Pearson. “That is always going to be hard.”
 

Millions more will join the “buy-your-own” ranks

The proposed rule released Oct. 23 allows employers to fund tax-free accounts – called health reimbursement arrangements (HRAs) – that workers can use to buy their own coverage on the ACA marketplaces.

The administration estimates about 10 million people would do so by 2028 – a substantial boost for those exchanges, which policymakers say never hit the enrollment numbers needed to attract enough insurers and hold prices down.

John Barkett, senior director of policy affairs at Willis Towers Watson, a benefits consulting firm, said he expects employers to “seriously consider” the new market. The infusion of workers will improve options by attracting more insurers, he added.

“These people coming in will be employer-sponsored, they’ll have steady jobs,” Barkett noted, and will likely stick with coverage longer than those typically in the individual market.

Currently more than 14 million people buy their own insurance, with about 10 million of those using federal or state ACA marketplaces. The others buy private plans through brokers.

The proposed rule won’t be finalized for months, but it could result in new options by 2020.

If these workers seeking coverage are generally healthy, the infusion could slow premium increases in the overall ACA marketplace because it would improve the risk pool for insurers.

But, if employers with mainly higher-cost or older workers opt to move to the marketplaces, it could help drive up premiums.

In an odd twist, the administration notes in the proposed rule that the ACA has provisions that could protect the marketplace from that type of adverse selection, which can drive up prices. But most of the protective factors cited by the rule have been weakened, removed, or expired, such as the tax penalty for being uninsured and the federal subsidies for insurers to cover lower deductibles for certain low-income consumers.

Benefits consultants and policy experts are skeptical about how many companies will move to the HRA plan, given the tight labor market. Continued uncertainty about the fate of the ACA marketplace may keep them reluctant to send workers out on their own, they say.

Health benefits are a big factor in attracting and retaining workers, said Chris Condeluci, a Washington attorney who previously worked for Sen. Chuck Grassley (R-Iowa) and served as counsel to the Senate Finance Committee during the drafting of the ACA.

“Most employers believe their group health plan will provide better health coverage than an individual market plan,” he said.

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

In the span of less than 12 hours, the Trump administration took two seemingly contradictory actions that could have profound effects on the insurance marketplaces set up by the Affordable Care Act.

First, officials issued guidance on the morning of Oct. 22 that could weaken the exchanges set up for people who buy their own insurance. The new approach makes it easier for states to get around some ACA requirements, including allowing the use of federal subsidies for skimpier plans that can reject people with preexisting conditions.

Yet, the other move – a proposed rule unveiled that evening – could bolster ACA marketplaces by sending millions of people with job-based coverage there, armed with tax-free money from their employers to buy individual plans.

Both efforts play into the parallel narratives dominating the bitter political debate over the ACA.

The administration, frustrated that Congress did not repeal the law, say some critics and policy experts, is working to undermine it by weakening the marketplaces and the law’s consumer protections. Those efforts make it easier for insurers to offer skimpier policies that bypass the law’s rules, such as its ban on annual or lifetime limits or its protections for people with preexisting conditions. Congress also zeroed out the tax penalty for not having coverage, effective next year. Combined, the moves could reduce enrollment in ACA plans, potentially driving up premiums for those who remain.

The administration and Republicans in Congress say they are looking to assist those left behind by the ACA – people who don’t get subsidies to help them buy coverage and are desperate for less expensive options – even if that means purchasing less robust coverage.

“These are people who were buying insurance before [the law] and then the rules changed and they could not buy it because they could not afford it,” said Joe Antos, a resident scholar at the conservative American Enterprise Institute. “They have been slowly dropping out of insurance coverage altogether.”

The efforts are dramatically reshaping the ACA and the individual insurance market to one that looks more as it did before the 2010 law, when regulation, coverage, and consumer protections varied widely across the country.

“Some states will do everything they can to keep individual markets strong and stable. Others won’t,” said Sabrina Corlette, research professor at the Center on Health Insurance Reforms at Georgetown University.

So what expectations should consumers have? Here are three key takeaways:


 

Protections for preexisting health problems are uncertain

Polls show that keeping the ACA’s guarantees on coverage for people with medical problems is a top concern for Americans, and Democrats have made their defense of the health law a key part of their midterm election campaigns.

Republicans have gotten that message and even those who voted to repeal the ACA or joined a lawsuit by 20 red states to overturn it now say they want to protect people with preexisting conditions. Still, GOP lawmakers have not introduced any plan that would be as protective as the current law.

In August, the administration released a rule allowing expanded use of short-term plans, which are less expensive than ACA policies. To get those lower prices, most of these plans do not cover prescription drugs, maternity care, mental health, or substance abuse treatments.

The move is unlikely to benefit people with health problems, as short-term plans can reject people with preexisting conditions or decline to cover care for those medical problems.

Under the rule, insurers can sell them starting in 2019 for up to a year’s duration, with an option to renew for up to 3 years, reversing an Obama-era directive that limited them to 90 days.

Administration officials estimate such plans could draw 600,000 new enrollees next year, and others have estimated the numbers could be far higher. The concern is if many healthy people in 2019 switch out of the ACA market and choose short-term plans, premiums will rise for those who remain, including those with preexisting conditions, or make the ACA market less attractive for insurers.
 

Where you live matters more

One of the biggest changes ushered in with the ACA was a standard set of rules across all states.

Before the law took effect, consumers buying their own coverage saw tremendous variation in what was offered and what protections they had, depending on the state where they lived.

Most states, for example, allowed insurers to reject people with medical conditions. A few states required insurers to charge similar premiums across the board, but most allowed wide variations based on age, gender or health. Some skimpy plans didn’t cover prescription drugs, chemotherapy, or other medical services.

By standardizing the rules and benefits, the ACA barred insurers from rejecting applicants with medical conditions or charging them more. Women and men get the same premium rates and insurers could charge older people no more than three times what they charged younger ones.

Under the new guidance issued this week giving states more flexibility on what is offered, consumers could again see a wide variation on coverage, premium rules, and even subsidy eligibility.

“It shifts pressure to state politicians,” said Caroline Pearson, a senior fellow at NORC, a nonpartisan research institution at the University of Chicago. That could play into the calculus of whether a state will seek to make broad changes to help people who cannot afford ACA plans, even if the trade-off affects people with medical conditions.

“You risk making some worse off by threatening those markets,” said Pearson. “That is always going to be hard.”
 

Millions more will join the “buy-your-own” ranks

The proposed rule released Oct. 23 allows employers to fund tax-free accounts – called health reimbursement arrangements (HRAs) – that workers can use to buy their own coverage on the ACA marketplaces.

The administration estimates about 10 million people would do so by 2028 – a substantial boost for those exchanges, which policymakers say never hit the enrollment numbers needed to attract enough insurers and hold prices down.

John Barkett, senior director of policy affairs at Willis Towers Watson, a benefits consulting firm, said he expects employers to “seriously consider” the new market. The infusion of workers will improve options by attracting more insurers, he added.

“These people coming in will be employer-sponsored, they’ll have steady jobs,” Barkett noted, and will likely stick with coverage longer than those typically in the individual market.

Currently more than 14 million people buy their own insurance, with about 10 million of those using federal or state ACA marketplaces. The others buy private plans through brokers.

The proposed rule won’t be finalized for months, but it could result in new options by 2020.

If these workers seeking coverage are generally healthy, the infusion could slow premium increases in the overall ACA marketplace because it would improve the risk pool for insurers.

But, if employers with mainly higher-cost or older workers opt to move to the marketplaces, it could help drive up premiums.

In an odd twist, the administration notes in the proposed rule that the ACA has provisions that could protect the marketplace from that type of adverse selection, which can drive up prices. But most of the protective factors cited by the rule have been weakened, removed, or expired, such as the tax penalty for being uninsured and the federal subsidies for insurers to cover lower deductibles for certain low-income consumers.

Benefits consultants and policy experts are skeptical about how many companies will move to the HRA plan, given the tight labor market. Continued uncertainty about the fate of the ACA marketplace may keep them reluctant to send workers out on their own, they say.

Health benefits are a big factor in attracting and retaining workers, said Chris Condeluci, a Washington attorney who previously worked for Sen. Chuck Grassley (R-Iowa) and served as counsel to the Senate Finance Committee during the drafting of the ACA.

“Most employers believe their group health plan will provide better health coverage than an individual market plan,” he said.

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

In the span of less than 12 hours, the Trump administration took two seemingly contradictory actions that could have profound effects on the insurance marketplaces set up by the Affordable Care Act.

First, officials issued guidance on the morning of Oct. 22 that could weaken the exchanges set up for people who buy their own insurance. The new approach makes it easier for states to get around some ACA requirements, including allowing the use of federal subsidies for skimpier plans that can reject people with preexisting conditions.

Yet, the other move – a proposed rule unveiled that evening – could bolster ACA marketplaces by sending millions of people with job-based coverage there, armed with tax-free money from their employers to buy individual plans.

Both efforts play into the parallel narratives dominating the bitter political debate over the ACA.

The administration, frustrated that Congress did not repeal the law, say some critics and policy experts, is working to undermine it by weakening the marketplaces and the law’s consumer protections. Those efforts make it easier for insurers to offer skimpier policies that bypass the law’s rules, such as its ban on annual or lifetime limits or its protections for people with preexisting conditions. Congress also zeroed out the tax penalty for not having coverage, effective next year. Combined, the moves could reduce enrollment in ACA plans, potentially driving up premiums for those who remain.

The administration and Republicans in Congress say they are looking to assist those left behind by the ACA – people who don’t get subsidies to help them buy coverage and are desperate for less expensive options – even if that means purchasing less robust coverage.

“These are people who were buying insurance before [the law] and then the rules changed and they could not buy it because they could not afford it,” said Joe Antos, a resident scholar at the conservative American Enterprise Institute. “They have been slowly dropping out of insurance coverage altogether.”

The efforts are dramatically reshaping the ACA and the individual insurance market to one that looks more as it did before the 2010 law, when regulation, coverage, and consumer protections varied widely across the country.

“Some states will do everything they can to keep individual markets strong and stable. Others won’t,” said Sabrina Corlette, research professor at the Center on Health Insurance Reforms at Georgetown University.

So what expectations should consumers have? Here are three key takeaways:


 

Protections for preexisting health problems are uncertain

Polls show that keeping the ACA’s guarantees on coverage for people with medical problems is a top concern for Americans, and Democrats have made their defense of the health law a key part of their midterm election campaigns.

Republicans have gotten that message and even those who voted to repeal the ACA or joined a lawsuit by 20 red states to overturn it now say they want to protect people with preexisting conditions. Still, GOP lawmakers have not introduced any plan that would be as protective as the current law.

In August, the administration released a rule allowing expanded use of short-term plans, which are less expensive than ACA policies. To get those lower prices, most of these plans do not cover prescription drugs, maternity care, mental health, or substance abuse treatments.

The move is unlikely to benefit people with health problems, as short-term plans can reject people with preexisting conditions or decline to cover care for those medical problems.

Under the rule, insurers can sell them starting in 2019 for up to a year’s duration, with an option to renew for up to 3 years, reversing an Obama-era directive that limited them to 90 days.

Administration officials estimate such plans could draw 600,000 new enrollees next year, and others have estimated the numbers could be far higher. The concern is if many healthy people in 2019 switch out of the ACA market and choose short-term plans, premiums will rise for those who remain, including those with preexisting conditions, or make the ACA market less attractive for insurers.
 

Where you live matters more

One of the biggest changes ushered in with the ACA was a standard set of rules across all states.

Before the law took effect, consumers buying their own coverage saw tremendous variation in what was offered and what protections they had, depending on the state where they lived.

Most states, for example, allowed insurers to reject people with medical conditions. A few states required insurers to charge similar premiums across the board, but most allowed wide variations based on age, gender or health. Some skimpy plans didn’t cover prescription drugs, chemotherapy, or other medical services.

By standardizing the rules and benefits, the ACA barred insurers from rejecting applicants with medical conditions or charging them more. Women and men get the same premium rates and insurers could charge older people no more than three times what they charged younger ones.

Under the new guidance issued this week giving states more flexibility on what is offered, consumers could again see a wide variation on coverage, premium rules, and even subsidy eligibility.

“It shifts pressure to state politicians,” said Caroline Pearson, a senior fellow at NORC, a nonpartisan research institution at the University of Chicago. That could play into the calculus of whether a state will seek to make broad changes to help people who cannot afford ACA plans, even if the trade-off affects people with medical conditions.

“You risk making some worse off by threatening those markets,” said Pearson. “That is always going to be hard.”
 

Millions more will join the “buy-your-own” ranks

The proposed rule released Oct. 23 allows employers to fund tax-free accounts – called health reimbursement arrangements (HRAs) – that workers can use to buy their own coverage on the ACA marketplaces.

The administration estimates about 10 million people would do so by 2028 – a substantial boost for those exchanges, which policymakers say never hit the enrollment numbers needed to attract enough insurers and hold prices down.

John Barkett, senior director of policy affairs at Willis Towers Watson, a benefits consulting firm, said he expects employers to “seriously consider” the new market. The infusion of workers will improve options by attracting more insurers, he added.

“These people coming in will be employer-sponsored, they’ll have steady jobs,” Barkett noted, and will likely stick with coverage longer than those typically in the individual market.

Currently more than 14 million people buy their own insurance, with about 10 million of those using federal or state ACA marketplaces. The others buy private plans through brokers.

The proposed rule won’t be finalized for months, but it could result in new options by 2020.

If these workers seeking coverage are generally healthy, the infusion could slow premium increases in the overall ACA marketplace because it would improve the risk pool for insurers.

But, if employers with mainly higher-cost or older workers opt to move to the marketplaces, it could help drive up premiums.

In an odd twist, the administration notes in the proposed rule that the ACA has provisions that could protect the marketplace from that type of adverse selection, which can drive up prices. But most of the protective factors cited by the rule have been weakened, removed, or expired, such as the tax penalty for being uninsured and the federal subsidies for insurers to cover lower deductibles for certain low-income consumers.

Benefits consultants and policy experts are skeptical about how many companies will move to the HRA plan, given the tight labor market. Continued uncertainty about the fate of the ACA marketplace may keep them reluctant to send workers out on their own, they say.

Health benefits are a big factor in attracting and retaining workers, said Chris Condeluci, a Washington attorney who previously worked for Sen. Chuck Grassley (R-Iowa) and served as counsel to the Senate Finance Committee during the drafting of the ACA.

“Most employers believe their group health plan will provide better health coverage than an individual market plan,” he said.

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

BOSTON – Rapid bacterial testing of platelets in a hospital blood bank can result in both significant cost savings and reduced wastage of blood products, investigators said.

ToyToy/Wikimedia Commons/Public Domain

Rapid bacterial testing of 6- or 7-day-old apheresis platelets resulted in projected annual cost savings of nearly $89,000 per year and cut the rate of platelet wastage from expiration by more than half, reported Adam L. Booth, MD, chief resident in the department of pathology at the University of Texas, Galveston, and his colleagues.

“When a person takes all this time to come in and donate, they do it under the impression that they’re going to help somebody, or several people, and you hate to see those platelets wasted. You want them to be used,” he said in an interview at AABB 2018, the annual meeting of the group formerly known as the American Association of Blood Banks.

Platelets typically have a shelf life of just 5 days because longer storage increases the risk for bacterial growth and the potential for transfusion-transmitted infections, Dr. Booth and his colleagues noted in a poster presentation.

A recently published Food and Drug Administration draft guidance for blood banks and transfusion services proposed changing regulations regarding bacterial control of blood products to allow for extended dating if the platelets are collected in an FDA-approved 7-day storage container with labeling that requires testing every product with a bacterial detection device, or if the platelets are individually tested for bacterial detection using an approved device.

To see what effect the regulations, if implemented as expected, might have on acquisition costs and wastage of apheresis platelets, the investigators reviewed their center’s platelet acquisition costs and wastage from expiration 12 months before and 6 months after implementation of a rapid bacterial testing protocol, with 6-month results projected out to 1 year for comparison purposes.

They looked at data on bacterial testing of 6-day and 7-day-old apheresis platelets, and excluded data on platelet units that were due to expire on day 5 because they were not stored in FDA-approved containers.

Prior to testing, 332 units at a mean per-unit cost of $516.96 were wasted, for an annual cost of more than $171,000. After the start of testing, however, the annualized rate of waste dropped to 117 units, for an annualized cost of more than $60,000. The difference – minus the cost of rapid bacterial testing – resulted in an annual savings for the institution of nearly $89,000.

Prior to rapid testing, the annual wastage rate was 24%; after testing, it dropped to an annualized 10% rate, the investigators reported.

The number of units transfused and the associated costs of transfusions were similar between the time periods studied.

“Our findings suggest that rapid bacterial testing can simultaneously enhance the safety of apheresis platelet transfusions and contribute to significant cost savings,” Dr. Booth and his colleagues wrote.

The study was internally funded. The authors reported having no conflicts of interest.

SOURCE: Booth AL et al. AABB18, Abstract INV4.

BOSTON – Rapid bacterial testing of platelets in a hospital blood bank can result in both significant cost savings and reduced wastage of blood products, investigators said.

ToyToy/Wikimedia Commons/Public Domain

Rapid bacterial testing of 6- or 7-day-old apheresis platelets resulted in projected annual cost savings of nearly $89,000 per year and cut the rate of platelet wastage from expiration by more than half, reported Adam L. Booth, MD, chief resident in the department of pathology at the University of Texas, Galveston, and his colleagues.

“When a person takes all this time to come in and donate, they do it under the impression that they’re going to help somebody, or several people, and you hate to see those platelets wasted. You want them to be used,” he said in an interview at AABB 2018, the annual meeting of the group formerly known as the American Association of Blood Banks.

Platelets typically have a shelf life of just 5 days because longer storage increases the risk for bacterial growth and the potential for transfusion-transmitted infections, Dr. Booth and his colleagues noted in a poster presentation.

A recently published Food and Drug Administration draft guidance for blood banks and transfusion services proposed changing regulations regarding bacterial control of blood products to allow for extended dating if the platelets are collected in an FDA-approved 7-day storage container with labeling that requires testing every product with a bacterial detection device, or if the platelets are individually tested for bacterial detection using an approved device.

To see what effect the regulations, if implemented as expected, might have on acquisition costs and wastage of apheresis platelets, the investigators reviewed their center’s platelet acquisition costs and wastage from expiration 12 months before and 6 months after implementation of a rapid bacterial testing protocol, with 6-month results projected out to 1 year for comparison purposes.

They looked at data on bacterial testing of 6-day and 7-day-old apheresis platelets, and excluded data on platelet units that were due to expire on day 5 because they were not stored in FDA-approved containers.

Prior to testing, 332 units at a mean per-unit cost of $516.96 were wasted, for an annual cost of more than $171,000. After the start of testing, however, the annualized rate of waste dropped to 117 units, for an annualized cost of more than $60,000. The difference – minus the cost of rapid bacterial testing – resulted in an annual savings for the institution of nearly $89,000.

Prior to rapid testing, the annual wastage rate was 24%; after testing, it dropped to an annualized 10% rate, the investigators reported.

The number of units transfused and the associated costs of transfusions were similar between the time periods studied.

“Our findings suggest that rapid bacterial testing can simultaneously enhance the safety of apheresis platelet transfusions and contribute to significant cost savings,” Dr. Booth and his colleagues wrote.

The study was internally funded. The authors reported having no conflicts of interest.

SOURCE: Booth AL et al. AABB18, Abstract INV4.

BOSTON – Rapid bacterial testing of platelets in a hospital blood bank can result in both significant cost savings and reduced wastage of blood products, investigators said.

ToyToy/Wikimedia Commons/Public Domain

Rapid bacterial testing of 6- or 7-day-old apheresis platelets resulted in projected annual cost savings of nearly $89,000 per year and cut the rate of platelet wastage from expiration by more than half, reported Adam L. Booth, MD, chief resident in the department of pathology at the University of Texas, Galveston, and his colleagues.

“When a person takes all this time to come in and donate, they do it under the impression that they’re going to help somebody, or several people, and you hate to see those platelets wasted. You want them to be used,” he said in an interview at AABB 2018, the annual meeting of the group formerly known as the American Association of Blood Banks.

Platelets typically have a shelf life of just 5 days because longer storage increases the risk for bacterial growth and the potential for transfusion-transmitted infections, Dr. Booth and his colleagues noted in a poster presentation.

A recently published Food and Drug Administration draft guidance for blood banks and transfusion services proposed changing regulations regarding bacterial control of blood products to allow for extended dating if the platelets are collected in an FDA-approved 7-day storage container with labeling that requires testing every product with a bacterial detection device, or if the platelets are individually tested for bacterial detection using an approved device.

To see what effect the regulations, if implemented as expected, might have on acquisition costs and wastage of apheresis platelets, the investigators reviewed their center’s platelet acquisition costs and wastage from expiration 12 months before and 6 months after implementation of a rapid bacterial testing protocol, with 6-month results projected out to 1 year for comparison purposes.

They looked at data on bacterial testing of 6-day and 7-day-old apheresis platelets, and excluded data on platelet units that were due to expire on day 5 because they were not stored in FDA-approved containers.

Prior to testing, 332 units at a mean per-unit cost of $516.96 were wasted, for an annual cost of more than $171,000. After the start of testing, however, the annualized rate of waste dropped to 117 units, for an annualized cost of more than $60,000. The difference – minus the cost of rapid bacterial testing – resulted in an annual savings for the institution of nearly $89,000.

Prior to rapid testing, the annual wastage rate was 24%; after testing, it dropped to an annualized 10% rate, the investigators reported.

The number of units transfused and the associated costs of transfusions were similar between the time periods studied.

“Our findings suggest that rapid bacterial testing can simultaneously enhance the safety of apheresis platelet transfusions and contribute to significant cost savings,” Dr. Booth and his colleagues wrote.

The study was internally funded. The authors reported having no conflicts of interest.

SOURCE: Booth AL et al. AABB18, Abstract INV4.

CHICAGO – Patients with a first MI were nearly nine times more likely to have detectable IgG antiphospholipid antibodies than were matched controls in a cross-sectional cohort study, Elisabet Svenungsson, MD, PhD, reported at the annual meeting of the American College of Rheumatology.
 

Her case-control study included 805 Swedish patients tested for antiphospholipid antibodies 6-10 weeks after experiencing their first MI and an equal number of age-, sex-, and location-matched controls. Prior to their MIs, none of the patients had been diagnosed with antiphospholipid syndrome, which requires both positive antiphospholipid antibodies and a vascular thrombotic event or obstetric morbidity.

A positive test for IgG anti-cardiolipin antibody was present in 10.9% of the first-MI patients, compared with 0.9% of controls. Similarly, 10.4% of acute MI patients and 0.9% of controls were positive for anti-beta2-glycoprotein-1 antibodies. Most patients who tested positive for one were positive for both. Thus, it’s possible that IgG antiphospholipid antibody positivity is an important silent risk factor that’s present in 1 in 10 MI patients, according to Dr. Svenungsson, professor of rheumatology at the Karolinska Institute in Stockholm.

If these results are confirmed and expanded upon in additional studies, testing for antiphospholipid antibodies could become part of the routine care in patients with an acute MI. Those who test positive would meet the criteria for antiphospholipid syndrome and qualify for long-term oral anticoagulation to reduce their elevated risk of further vascular events, she explained in this video interview.

The study was published in Annals of Internal Medicine simultaneously with the presentation at the ACR annual meeting (Ann Int Med. 2018 Oct 23. doi: 10.7326/M18-2130).

bjancin@mdedge.com

SOURCE: Grosso G et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 855.

CHICAGO – Patients with a first MI were nearly nine times more likely to have detectable IgG antiphospholipid antibodies than were matched controls in a cross-sectional cohort study, Elisabet Svenungsson, MD, PhD, reported at the annual meeting of the American College of Rheumatology.
 

Her case-control study included 805 Swedish patients tested for antiphospholipid antibodies 6-10 weeks after experiencing their first MI and an equal number of age-, sex-, and location-matched controls. Prior to their MIs, none of the patients had been diagnosed with antiphospholipid syndrome, which requires both positive antiphospholipid antibodies and a vascular thrombotic event or obstetric morbidity.

A positive test for IgG anti-cardiolipin antibody was present in 10.9% of the first-MI patients, compared with 0.9% of controls. Similarly, 10.4% of acute MI patients and 0.9% of controls were positive for anti-beta2-glycoprotein-1 antibodies. Most patients who tested positive for one were positive for both. Thus, it’s possible that IgG antiphospholipid antibody positivity is an important silent risk factor that’s present in 1 in 10 MI patients, according to Dr. Svenungsson, professor of rheumatology at the Karolinska Institute in Stockholm.

If these results are confirmed and expanded upon in additional studies, testing for antiphospholipid antibodies could become part of the routine care in patients with an acute MI. Those who test positive would meet the criteria for antiphospholipid syndrome and qualify for long-term oral anticoagulation to reduce their elevated risk of further vascular events, she explained in this video interview.

The study was published in Annals of Internal Medicine simultaneously with the presentation at the ACR annual meeting (Ann Int Med. 2018 Oct 23. doi: 10.7326/M18-2130).

bjancin@mdedge.com

SOURCE: Grosso G et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 855.

CHICAGO – Patients with a first MI were nearly nine times more likely to have detectable IgG antiphospholipid antibodies than were matched controls in a cross-sectional cohort study, Elisabet Svenungsson, MD, PhD, reported at the annual meeting of the American College of Rheumatology.
 

Her case-control study included 805 Swedish patients tested for antiphospholipid antibodies 6-10 weeks after experiencing their first MI and an equal number of age-, sex-, and location-matched controls. Prior to their MIs, none of the patients had been diagnosed with antiphospholipid syndrome, which requires both positive antiphospholipid antibodies and a vascular thrombotic event or obstetric morbidity.

A positive test for IgG anti-cardiolipin antibody was present in 10.9% of the first-MI patients, compared with 0.9% of controls. Similarly, 10.4% of acute MI patients and 0.9% of controls were positive for anti-beta2-glycoprotein-1 antibodies. Most patients who tested positive for one were positive for both. Thus, it’s possible that IgG antiphospholipid antibody positivity is an important silent risk factor that’s present in 1 in 10 MI patients, according to Dr. Svenungsson, professor of rheumatology at the Karolinska Institute in Stockholm.

If these results are confirmed and expanded upon in additional studies, testing for antiphospholipid antibodies could become part of the routine care in patients with an acute MI. Those who test positive would meet the criteria for antiphospholipid syndrome and qualify for long-term oral anticoagulation to reduce their elevated risk of further vascular events, she explained in this video interview.

The study was published in Annals of Internal Medicine simultaneously with the presentation at the ACR annual meeting (Ann Int Med. 2018 Oct 23. doi: 10.7326/M18-2130).

bjancin@mdedge.com

SOURCE: Grosso G et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 855.

Clinicians and even the general public are aware of the dangers of sepsis, the life-threatening illness caused by a body’s response to an infection. Irrespective of one’s perception of pharmaceutical marketing materials or the evidence-based medicine used, awareness about sepsis has led to earlier diagnosis and interventions that have likely saved countless patients’ lives.

Moreover, hospitalists have played a key role in sepsis prevention. In their research, “Improving Survival from Sepsis in Noncritical Units: Role of Hospitalists and Sepsis Team in Early Detection and Initial Treatment of Septic Patients,” Adriana Ducci, MD, and her colleagues showed that a hospitalist-managed sepsis protocol improved sepsis case notifications and patient outcomes.

Although sepsis and respiratory compromise are clearly very different conditions, I believe that greater awareness about respiratory compromise will lead to earlier diagnosis and interventions, which will theoretically improve patient outcomes. Moreover, as with the sepsis awareness campaign, hospitalists can play a key role in recognizing respiratory compromise and in the implementation of appropriate interventions.

As defined by the Respiratory Compromise Institute, “respiratory compromise” is defined as a state in which there is a high likelihood of decompensation into respiratory failure and/or death, but, in which specific interventions – be it therapeutic and/or monitoring – might prevent or mitigate this decompensation.

A significant segment of patients who may be at risk for respiratory compromise are those receiving opioids. The cost of opioid-related adverse events, in terms of both human life and hospital expenses, remains at the forefront of the public eye. It has been estimated that yearly costs in the United States associated with opioid-related postoperative respiratory failure were estimated at $2 billion.

Thomas W. Frederickson MD, FACP, SFHM, MBA, the lead author of the Society of Hospital Medicine guide for Reducing Adverse Drug Events Related to Opioids (RADEO), emphasized in a podcast with the Physician-Patient Alliance for Health & Safety the need to identify patient conditions that pose a greater risk of respiratory compromise.

In particular, Dr. Frederickson pointed out the need to screen for obstructive sleep apnea (OSA): “Patients with obstructive sleep apnea are dependent upon their arousal mechanism in order to avoid respiratory depression and eventual respiratory failure. When these patients receive opioid medication, it decreases this ability for arousal. That puts them at risk for a sudden spiral that includes respiratory insufficiency and respiratory arrest. This can happen very quickly and part of the risk is that the traditional monitoring for sedation that we use in the hospital – that is on a periodic basis and depends upon nursing interventions and questioning – really becomes much less effective in this patient population that can have a respiratory arrest, because of failure to arouse, very quickly. So, a monitoring regimen that takes place every 60 minutes is likely to be ineffective.”

Patient conditions such as OSA should be considered, along with other comorbidities. As the RADEO Guide states: “Before starting opioid therapy, either in surgical or non-surgical settings, it is important to identify any real or potential risks of respiratory depression or other opioid-related adverse effects. Patient comorbidities such as OSA, neurologic disorders, organ impairment, substance abuse history, and other medication use are important aspects to consider.”

Although we have clearly recognized a significant increase in respiratory complications associated with opioid administration, there are other areas, which are non–opioid related, that can create respiratory compromise. We view many patients with stable or underlying respiratory conditions, whether it be COPD, sleep apnea, or preexisting pathophysiology, where either due to sedative agents, or an acute illness – like pneumonia – they can go from a stable condition to respiratory compromise and become at risk for respiratory failure.

A classic example of that in my world of anesthesia has been the well-recognized area of non–operating room anesthesia – in particular, in endoscopy suites where numerous endoscopy procedures are performed under the administration of propofol or other anxiolytic-like drugs. There has been a well-recognized incidence of sentinel events related to oxygenation and ventilation, including death.

Many clinicians see sedation as a benign introduction of relatively limited-effect drugs, which isn’t always true. So, therefore, it is essential that clinicians understand three things:

1. The drugs we employ as sedative agents can have variable effects on individuals depending on their tolerance and their underlying medical condition.

2. The dosages and particular combination of drugs employed may cause an adverse event – for example, the combination of opioids and benzodiazepines.

3. There are factors that can distract from the clinical assessment of routine vital signs, such as respiratory rate, heart rate, and blood pressure. For example, when pulse oximetry is administered with oxygen therapy, there can often be a delay in the recognition of hypoventilation. Consequently, that’s why more and more clinicians are beginning to utilize capnography, or CO₂ monitoring, in the expired gas to earlier detect depressed respiratory rate and/or apnea, as well as signs of hypoventilation or inadequate ventilation.

There clearly are obstacles to continuous patient monitoring, such as the associated cost, familiarity with the utilization, the benefit, as well as the limitations of specific monitors in different clinical situations, which mandates an educational process to employ these. However, currently, patient monitoring provides the best early indicator of a patient’s deterioration and the possibility of respiratory compromise.

In my field, we have become very comfortable with capnography and patient monitoring, because for decades it’s been a standard of care for monitoring in the operating room. The role for utilization of capnography for patients who are receiving an opioid or sedative agent outside of the operating room needs to be further assessed. However, technology is not a silver bullet and should be used as an adjunct to clinical judgment in at-risk populations.

Simple recognition and greater awareness of respiratory compromise, just as with sepsis awareness campaigns, will mean more patients are diagnosed earlier, more appropriate interventions are made, and hopefully more adverse events and patient deaths are averted.

Dr. Vender is the emeritus Harris Family Foundation chairman of the department of anesthesiology at NorthShore University Health System in Evanston, Ill. He is clinical professor at the University of Chicago Pritzker School of Medicine and chairman, Clinical Advisory Committee, Respiratory Compromise Institute. Dr. Vender has consulted with Medtronic.

Clinicians and even the general public are aware of the dangers of sepsis, the life-threatening illness caused by a body’s response to an infection. Irrespective of one’s perception of pharmaceutical marketing materials or the evidence-based medicine used, awareness about sepsis has led to earlier diagnosis and interventions that have likely saved countless patients’ lives.

Moreover, hospitalists have played a key role in sepsis prevention. In their research, “Improving Survival from Sepsis in Noncritical Units: Role of Hospitalists and Sepsis Team in Early Detection and Initial Treatment of Septic Patients,” Adriana Ducci, MD, and her colleagues showed that a hospitalist-managed sepsis protocol improved sepsis case notifications and patient outcomes.

Although sepsis and respiratory compromise are clearly very different conditions, I believe that greater awareness about respiratory compromise will lead to earlier diagnosis and interventions, which will theoretically improve patient outcomes. Moreover, as with the sepsis awareness campaign, hospitalists can play a key role in recognizing respiratory compromise and in the implementation of appropriate interventions.

As defined by the Respiratory Compromise Institute, “respiratory compromise” is defined as a state in which there is a high likelihood of decompensation into respiratory failure and/or death, but, in which specific interventions – be it therapeutic and/or monitoring – might prevent or mitigate this decompensation.

A significant segment of patients who may be at risk for respiratory compromise are those receiving opioids. The cost of opioid-related adverse events, in terms of both human life and hospital expenses, remains at the forefront of the public eye. It has been estimated that yearly costs in the United States associated with opioid-related postoperative respiratory failure were estimated at $2 billion.

Thomas W. Frederickson MD, FACP, SFHM, MBA, the lead author of the Society of Hospital Medicine guide for Reducing Adverse Drug Events Related to Opioids (RADEO), emphasized in a podcast with the Physician-Patient Alliance for Health & Safety the need to identify patient conditions that pose a greater risk of respiratory compromise.

In particular, Dr. Frederickson pointed out the need to screen for obstructive sleep apnea (OSA): “Patients with obstructive sleep apnea are dependent upon their arousal mechanism in order to avoid respiratory depression and eventual respiratory failure. When these patients receive opioid medication, it decreases this ability for arousal. That puts them at risk for a sudden spiral that includes respiratory insufficiency and respiratory arrest. This can happen very quickly and part of the risk is that the traditional monitoring for sedation that we use in the hospital – that is on a periodic basis and depends upon nursing interventions and questioning – really becomes much less effective in this patient population that can have a respiratory arrest, because of failure to arouse, very quickly. So, a monitoring regimen that takes place every 60 minutes is likely to be ineffective.”

Patient conditions such as OSA should be considered, along with other comorbidities. As the RADEO Guide states: “Before starting opioid therapy, either in surgical or non-surgical settings, it is important to identify any real or potential risks of respiratory depression or other opioid-related adverse effects. Patient comorbidities such as OSA, neurologic disorders, organ impairment, substance abuse history, and other medication use are important aspects to consider.”

Although we have clearly recognized a significant increase in respiratory complications associated with opioid administration, there are other areas, which are non–opioid related, that can create respiratory compromise. We view many patients with stable or underlying respiratory conditions, whether it be COPD, sleep apnea, or preexisting pathophysiology, where either due to sedative agents, or an acute illness – like pneumonia – they can go from a stable condition to respiratory compromise and become at risk for respiratory failure.

A classic example of that in my world of anesthesia has been the well-recognized area of non–operating room anesthesia – in particular, in endoscopy suites where numerous endoscopy procedures are performed under the administration of propofol or other anxiolytic-like drugs. There has been a well-recognized incidence of sentinel events related to oxygenation and ventilation, including death.

Many clinicians see sedation as a benign introduction of relatively limited-effect drugs, which isn’t always true. So, therefore, it is essential that clinicians understand three things:

1. The drugs we employ as sedative agents can have variable effects on individuals depending on their tolerance and their underlying medical condition.

2. The dosages and particular combination of drugs employed may cause an adverse event – for example, the combination of opioids and benzodiazepines.

3. There are factors that can distract from the clinical assessment of routine vital signs, such as respiratory rate, heart rate, and blood pressure. For example, when pulse oximetry is administered with oxygen therapy, there can often be a delay in the recognition of hypoventilation. Consequently, that’s why more and more clinicians are beginning to utilize capnography, or CO₂ monitoring, in the expired gas to earlier detect depressed respiratory rate and/or apnea, as well as signs of hypoventilation or inadequate ventilation.

There clearly are obstacles to continuous patient monitoring, such as the associated cost, familiarity with the utilization, the benefit, as well as the limitations of specific monitors in different clinical situations, which mandates an educational process to employ these. However, currently, patient monitoring provides the best early indicator of a patient’s deterioration and the possibility of respiratory compromise.

In my field, we have become very comfortable with capnography and patient monitoring, because for decades it’s been a standard of care for monitoring in the operating room. The role for utilization of capnography for patients who are receiving an opioid or sedative agent outside of the operating room needs to be further assessed. However, technology is not a silver bullet and should be used as an adjunct to clinical judgment in at-risk populations.

Simple recognition and greater awareness of respiratory compromise, just as with sepsis awareness campaigns, will mean more patients are diagnosed earlier, more appropriate interventions are made, and hopefully more adverse events and patient deaths are averted.

Dr. Vender is the emeritus Harris Family Foundation chairman of the department of anesthesiology at NorthShore University Health System in Evanston, Ill. He is clinical professor at the University of Chicago Pritzker School of Medicine and chairman, Clinical Advisory Committee, Respiratory Compromise Institute. Dr. Vender has consulted with Medtronic.

Clinicians and even the general public are aware of the dangers of sepsis, the life-threatening illness caused by a body’s response to an infection. Irrespective of one’s perception of pharmaceutical marketing materials or the evidence-based medicine used, awareness about sepsis has led to earlier diagnosis and interventions that have likely saved countless patients’ lives.

Moreover, hospitalists have played a key role in sepsis prevention. In their research, “Improving Survival from Sepsis in Noncritical Units: Role of Hospitalists and Sepsis Team in Early Detection and Initial Treatment of Septic Patients,” Adriana Ducci, MD, and her colleagues showed that a hospitalist-managed sepsis protocol improved sepsis case notifications and patient outcomes.

Although sepsis and respiratory compromise are clearly very different conditions, I believe that greater awareness about respiratory compromise will lead to earlier diagnosis and interventions, which will theoretically improve patient outcomes. Moreover, as with the sepsis awareness campaign, hospitalists can play a key role in recognizing respiratory compromise and in the implementation of appropriate interventions.

As defined by the Respiratory Compromise Institute, “respiratory compromise” is defined as a state in which there is a high likelihood of decompensation into respiratory failure and/or death, but, in which specific interventions – be it therapeutic and/or monitoring – might prevent or mitigate this decompensation.

A significant segment of patients who may be at risk for respiratory compromise are those receiving opioids. The cost of opioid-related adverse events, in terms of both human life and hospital expenses, remains at the forefront of the public eye. It has been estimated that yearly costs in the United States associated with opioid-related postoperative respiratory failure were estimated at $2 billion.

Thomas W. Frederickson MD, FACP, SFHM, MBA, the lead author of the Society of Hospital Medicine guide for Reducing Adverse Drug Events Related to Opioids (RADEO), emphasized in a podcast with the Physician-Patient Alliance for Health & Safety the need to identify patient conditions that pose a greater risk of respiratory compromise.

In particular, Dr. Frederickson pointed out the need to screen for obstructive sleep apnea (OSA): “Patients with obstructive sleep apnea are dependent upon their arousal mechanism in order to avoid respiratory depression and eventual respiratory failure. When these patients receive opioid medication, it decreases this ability for arousal. That puts them at risk for a sudden spiral that includes respiratory insufficiency and respiratory arrest. This can happen very quickly and part of the risk is that the traditional monitoring for sedation that we use in the hospital – that is on a periodic basis and depends upon nursing interventions and questioning – really becomes much less effective in this patient population that can have a respiratory arrest, because of failure to arouse, very quickly. So, a monitoring regimen that takes place every 60 minutes is likely to be ineffective.”

Patient conditions such as OSA should be considered, along with other comorbidities. As the RADEO Guide states: “Before starting opioid therapy, either in surgical or non-surgical settings, it is important to identify any real or potential risks of respiratory depression or other opioid-related adverse effects. Patient comorbidities such as OSA, neurologic disorders, organ impairment, substance abuse history, and other medication use are important aspects to consider.”

Although we have clearly recognized a significant increase in respiratory complications associated with opioid administration, there are other areas, which are non–opioid related, that can create respiratory compromise. We view many patients with stable or underlying respiratory conditions, whether it be COPD, sleep apnea, or preexisting pathophysiology, where either due to sedative agents, or an acute illness – like pneumonia – they can go from a stable condition to respiratory compromise and become at risk for respiratory failure.

A classic example of that in my world of anesthesia has been the well-recognized area of non–operating room anesthesia – in particular, in endoscopy suites where numerous endoscopy procedures are performed under the administration of propofol or other anxiolytic-like drugs. There has been a well-recognized incidence of sentinel events related to oxygenation and ventilation, including death.

Many clinicians see sedation as a benign introduction of relatively limited-effect drugs, which isn’t always true. So, therefore, it is essential that clinicians understand three things:

1. The drugs we employ as sedative agents can have variable effects on individuals depending on their tolerance and their underlying medical condition.

2. The dosages and particular combination of drugs employed may cause an adverse event – for example, the combination of opioids and benzodiazepines.

3. There are factors that can distract from the clinical assessment of routine vital signs, such as respiratory rate, heart rate, and blood pressure. For example, when pulse oximetry is administered with oxygen therapy, there can often be a delay in the recognition of hypoventilation. Consequently, that’s why more and more clinicians are beginning to utilize capnography, or CO₂ monitoring, in the expired gas to earlier detect depressed respiratory rate and/or apnea, as well as signs of hypoventilation or inadequate ventilation.

There clearly are obstacles to continuous patient monitoring, such as the associated cost, familiarity with the utilization, the benefit, as well as the limitations of specific monitors in different clinical situations, which mandates an educational process to employ these. However, currently, patient monitoring provides the best early indicator of a patient’s deterioration and the possibility of respiratory compromise.

In my field, we have become very comfortable with capnography and patient monitoring, because for decades it’s been a standard of care for monitoring in the operating room. The role for utilization of capnography for patients who are receiving an opioid or sedative agent outside of the operating room needs to be further assessed. However, technology is not a silver bullet and should be used as an adjunct to clinical judgment in at-risk populations.

Simple recognition and greater awareness of respiratory compromise, just as with sepsis awareness campaigns, will mean more patients are diagnosed earlier, more appropriate interventions are made, and hopefully more adverse events and patient deaths are averted.

Dr. Vender is the emeritus Harris Family Foundation chairman of the department of anesthesiology at NorthShore University Health System in Evanston, Ill. He is clinical professor at the University of Chicago Pritzker School of Medicine and chairman, Clinical Advisory Committee, Respiratory Compromise Institute. Dr. Vender has consulted with Medtronic.

Thursday was a big day in my ongoing quest to ask the question, “Why do people act that way?”

Paul Bradbury/Getty Images

You notice I said, “Ask the question.” I can always ask. I just can’t always answer.

Harriet listed her Chief Complaint as “psoriasis on the scalp.”

“My hairdresser says I have psoriasis,” she said.

I took a look. “You do,” I said. “Just one spot, though. Should be easy to control.”

I then ran through the list of what generally bothers people about scalp psoriasis. “It may come back now and then,” I said, “but you don’t have much of it and you haven’t had it long, so it shouldn’t take much effort to keep it under control. Psoriasis doesn’t cause permanent hair loss,” I added. “And you can color and condition your hair any way you want.”

Harriet smiled. That was what she wanted to hear. But it wasn’t all she wanted to hear.

“Why don’t I look you over completely?” I suggested. Harriet agreed. I found only lentigines and seborrheic keratoses all over, and I told her so.

“That’s wonderful,” said Harriet. “Just one more thing.”

“Sure.”

“That psoriasis on my head. It wouldn’t be cancer, would it?”

I opened my mouth to respond, but nothing came out. Sure, patients worry that anything they don’t understand might be cancer. But that’s to start with, not after a whole conversation about psoriasis. Right?

Maybe not.

“Not cancer,” I said. “Just some local inflammation.” Harriet was happy. I was perplexed. There’s always something new about patients to puzzle over.

Which I did for about 2 hours, until that puzzle was muscled out by another. I walked in to meet a very cheery Rory, who was punching his smartphone screen. “Wouldn’t you know it?” he said with a smile. “The same thing happened last time I came here. You walked in just as I was about to start a conference call.”

I thought of several responses, none of them appropriate.

“Last time you cauterized some of these milia thingies on my face,” said Rory. “I was hoping you could do that again.”

I peered at his face. “Sure,” I said, “if you want me to.”

“Just a sec,” said Rory, peering down at his phone. I assumed he was logging off the conference call.

“OK,” he said. “Go ahead.”

I revved up my Hyfrecator, which started to buzz.

“Wait, can they hear that?” Rory asked.

“Can who hear ... ?”

“This is Rory Stiefel,” he spoke into his phone. “Glad we could meet today. I wanted to talk to all of you about our plans to expand our network services into your Upper Midwestern territory.”

“Hold on,” I said (to myself), “You want me to desiccate your face while you’re expanding your network into the Upper Midwest??!!”

Rory motioned for me to continue. “Sure,” he said to his phone, “We can be up and running by the first of next month, no problem.” Apparently, the hum of the Hyfrecator wasn’t interrupting negotiations.

So I buzzed away, while Rory’s interlocutors responded with apparent enthusiasm. By the time he turned his other cheek, I figured he had occupied Minnesota.

“Did you get all the thingies?” Rory stage-whispered.

I nodded.

“Great!” he said, then turned back to his phone. “Well, this was a great meeting,” he said. “I’m glad we’re ready to go live. Talk to you guys next week to firm up logistics.” He punched the screen to sever the connection.

“Thanks for being so efficient,” he said, this time to me.

“No problem,” I said, now-silent Hyfrecator in hand.

“You’re sure you got them all?”
 

“I handed him a mirror. “Yes,” I said. “I got them all.”

“Well that’s terrific,” he said, jumping off the exam table and heading for the door. “Always a pleasure. See you next time!”

I don’t know exactly what he does, but Rory is one awesome multitasker.

As for me, I just have to consult the CPT code book to find the right designation for “Cautery of benign lesions during a corporate conference call, second episode.”

Any help, dear colleagues, with people or coding, will be appreciated.

I can always ask ...
 

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at dermnews@mdedge.com.

Thursday was a big day in my ongoing quest to ask the question, “Why do people act that way?”

Paul Bradbury/Getty Images

You notice I said, “Ask the question.” I can always ask. I just can’t always answer.

Harriet listed her Chief Complaint as “psoriasis on the scalp.”

“My hairdresser says I have psoriasis,” she said.

I took a look. “You do,” I said. “Just one spot, though. Should be easy to control.”

I then ran through the list of what generally bothers people about scalp psoriasis. “It may come back now and then,” I said, “but you don’t have much of it and you haven’t had it long, so it shouldn’t take much effort to keep it under control. Psoriasis doesn’t cause permanent hair loss,” I added. “And you can color and condition your hair any way you want.”

Harriet smiled. That was what she wanted to hear. But it wasn’t all she wanted to hear.

“Why don’t I look you over completely?” I suggested. Harriet agreed. I found only lentigines and seborrheic keratoses all over, and I told her so.

“That’s wonderful,” said Harriet. “Just one more thing.”

“Sure.”

“That psoriasis on my head. It wouldn’t be cancer, would it?”

I opened my mouth to respond, but nothing came out. Sure, patients worry that anything they don’t understand might be cancer. But that’s to start with, not after a whole conversation about psoriasis. Right?

Maybe not.

“Not cancer,” I said. “Just some local inflammation.” Harriet was happy. I was perplexed. There’s always something new about patients to puzzle over.

Which I did for about 2 hours, until that puzzle was muscled out by another. I walked in to meet a very cheery Rory, who was punching his smartphone screen. “Wouldn’t you know it?” he said with a smile. “The same thing happened last time I came here. You walked in just as I was about to start a conference call.”

I thought of several responses, none of them appropriate.

“Last time you cauterized some of these milia thingies on my face,” said Rory. “I was hoping you could do that again.”

I peered at his face. “Sure,” I said, “if you want me to.”

“Just a sec,” said Rory, peering down at his phone. I assumed he was logging off the conference call.

“OK,” he said. “Go ahead.”

I revved up my Hyfrecator, which started to buzz.

“Wait, can they hear that?” Rory asked.

“Can who hear ... ?”

“This is Rory Stiefel,” he spoke into his phone. “Glad we could meet today. I wanted to talk to all of you about our plans to expand our network services into your Upper Midwestern territory.”

“Hold on,” I said (to myself), “You want me to desiccate your face while you’re expanding your network into the Upper Midwest??!!”

Rory motioned for me to continue. “Sure,” he said to his phone, “We can be up and running by the first of next month, no problem.” Apparently, the hum of the Hyfrecator wasn’t interrupting negotiations.

So I buzzed away, while Rory’s interlocutors responded with apparent enthusiasm. By the time he turned his other cheek, I figured he had occupied Minnesota.

“Did you get all the thingies?” Rory stage-whispered.

I nodded.

“Great!” he said, then turned back to his phone. “Well, this was a great meeting,” he said. “I’m glad we’re ready to go live. Talk to you guys next week to firm up logistics.” He punched the screen to sever the connection.

“Thanks for being so efficient,” he said, this time to me.

“No problem,” I said, now-silent Hyfrecator in hand.

“You’re sure you got them all?”
 

“I handed him a mirror. “Yes,” I said. “I got them all.”

“Well that’s terrific,” he said, jumping off the exam table and heading for the door. “Always a pleasure. See you next time!”

I don’t know exactly what he does, but Rory is one awesome multitasker.

As for me, I just have to consult the CPT code book to find the right designation for “Cautery of benign lesions during a corporate conference call, second episode.”

Any help, dear colleagues, with people or coding, will be appreciated.

I can always ask ...
 

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at dermnews@mdedge.com.

Thursday was a big day in my ongoing quest to ask the question, “Why do people act that way?”

Paul Bradbury/Getty Images

You notice I said, “Ask the question.” I can always ask. I just can’t always answer.

Harriet listed her Chief Complaint as “psoriasis on the scalp.”

“My hairdresser says I have psoriasis,” she said.

I took a look. “You do,” I said. “Just one spot, though. Should be easy to control.”

I then ran through the list of what generally bothers people about scalp psoriasis. “It may come back now and then,” I said, “but you don’t have much of it and you haven’t had it long, so it shouldn’t take much effort to keep it under control. Psoriasis doesn’t cause permanent hair loss,” I added. “And you can color and condition your hair any way you want.”

Harriet smiled. That was what she wanted to hear. But it wasn’t all she wanted to hear.

“Why don’t I look you over completely?” I suggested. Harriet agreed. I found only lentigines and seborrheic keratoses all over, and I told her so.

“That’s wonderful,” said Harriet. “Just one more thing.”

“Sure.”

“That psoriasis on my head. It wouldn’t be cancer, would it?”

I opened my mouth to respond, but nothing came out. Sure, patients worry that anything they don’t understand might be cancer. But that’s to start with, not after a whole conversation about psoriasis. Right?

Maybe not.

“Not cancer,” I said. “Just some local inflammation.” Harriet was happy. I was perplexed. There’s always something new about patients to puzzle over.

Which I did for about 2 hours, until that puzzle was muscled out by another. I walked in to meet a very cheery Rory, who was punching his smartphone screen. “Wouldn’t you know it?” he said with a smile. “The same thing happened last time I came here. You walked in just as I was about to start a conference call.”

I thought of several responses, none of them appropriate.

“Last time you cauterized some of these milia thingies on my face,” said Rory. “I was hoping you could do that again.”

I peered at his face. “Sure,” I said, “if you want me to.”

“Just a sec,” said Rory, peering down at his phone. I assumed he was logging off the conference call.

“OK,” he said. “Go ahead.”

I revved up my Hyfrecator, which started to buzz.

“Wait, can they hear that?” Rory asked.

“Can who hear ... ?”

“This is Rory Stiefel,” he spoke into his phone. “Glad we could meet today. I wanted to talk to all of you about our plans to expand our network services into your Upper Midwestern territory.”

“Hold on,” I said (to myself), “You want me to desiccate your face while you’re expanding your network into the Upper Midwest??!!”

Rory motioned for me to continue. “Sure,” he said to his phone, “We can be up and running by the first of next month, no problem.” Apparently, the hum of the Hyfrecator wasn’t interrupting negotiations.

So I buzzed away, while Rory’s interlocutors responded with apparent enthusiasm. By the time he turned his other cheek, I figured he had occupied Minnesota.

“Did you get all the thingies?” Rory stage-whispered.

I nodded.

“Great!” he said, then turned back to his phone. “Well, this was a great meeting,” he said. “I’m glad we’re ready to go live. Talk to you guys next week to firm up logistics.” He punched the screen to sever the connection.

“Thanks for being so efficient,” he said, this time to me.

“No problem,” I said, now-silent Hyfrecator in hand.

“You’re sure you got them all?”
 

“I handed him a mirror. “Yes,” I said. “I got them all.”

“Well that’s terrific,” he said, jumping off the exam table and heading for the door. “Always a pleasure. See you next time!”

I don’t know exactly what he does, but Rory is one awesome multitasker.

As for me, I just have to consult the CPT code book to find the right designation for “Cautery of benign lesions during a corporate conference call, second episode.”

Any help, dear colleagues, with people or coding, will be appreciated.

I can always ask ...
 

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at dermnews@mdedge.com.

Successive screenings to detect congenital hypothyroidism in preterm infants is key to identifying cases that would otherwise lead to permanent and decompensated hypothyroidism, reported Niamh McGrath, MD, of the department of pediatric endocrinology at Children’s University Hospital, Dublin, and her associates in the Journal of Pediatrics.

In a population-based prospective review of 898,424 records between 2004 and 2016, Dr. McGrath and her associates identified all preterm infants less than 33 weeks diagnosed with congenital hypothyroidism and receiving treatment with levothyroxine. Of the infants screened, just 53 were selected to participate in the study, including 26 who were diagnosed at the first thyroid-stimulating hormone (TSH) screening and 27 who had delayed TSH elevation.

Gestational age ranged from 23 to 33 weeks, median birth weight measured 1.2 kg, median serum TSH concentration at the time of diagnosis was 78.3 mU/L, and median free thyroxine concentration was 8.9 pmol/L.

For half of the infants ultimately diagnosed, congenital hypothyroidism was not detected during the initial newborn screening. The authors also noted that 25% of patients with delayed TSH elevation had been exposed to iodine while undergoing surgery for necrotizing enterocolitis; after age 28 days, four of these infants were found to have elevated TSH. They cautioned that while this finding emphasizes the need for close monitoring and repeat screening of infants who have been exposed to iodine for up to 1 month following exposure, they could not be certain that the iodine exposure was responsible for the transient hypothyroidism in these patients.


Dr. McGrath and her associates emphasized the importance of repeat TSH screening for all preterm infants, noting that standard protocol screenings conducted just once at age 2 weeks or 4 weeks are not sufficient to effectively identify all cases of congenital hypothyroidism in which TSH elevation is delayed. Instead, they recommended measuring TSH on days 3-5 and at 1 week, 2 weeks, 4 weeks, and term-corrected gestational age.

“Our data are consistent with studies showing a high incidence of delayed TSH rise, particularly in very-low-birth-weight infants,” the authors wrote. They speculated that delays in detecting primary congenital hypothyroidism could be caused by the suppression of TSH secretion as a result of “hypothalamic-pituitary immaturity, medication administration, and effects of serious neonatal illness.” In fact, had standard, recommended 2-week-only screening protocols been followed with their patient population, fully 48% of infants with delayed TSH elevation would have been overlooked; half of these patients were later found to have decompensated hypothyroidism.

Neurodevelopmental disability caused by congenital hypothyroidism, which affects roughly 1 in every 2,000-4,000 births, is increasingly being prevented with newborn screenings that identify the condition early, but the incidence of congenital hypothyroidism has increased considerably in the past 20 years. The authors attribute this increase to the gradual change in screening cutoff levels and the rise in number of preterm infants who are surviving.

The need for a second screening, as well as appropriate timing and optimal TSH cutoff, are “subjects of active debate,” the authors wrote. The latest European screening guidelines recommend second screenings for preterm and low-birth-weight infants at either 2 weeks of age or 2 weeks following preliminary screening. Although they make no recommendations regarding additional screenings, American Academy of Pediatrics guidelines, published in 2006, cite a “disproportionate incidence” of delayed increase in TSH and congenital hypothyroidism in infants with very low birth weight. Dr. McGrath and her associates speculated that not all screening programs have adopted repeat screening of preterm infants, perhaps because of the low yield results, “the transient nature of most cases” detected, as well as conflicting long-term data on neurodevelopmental outcomes.

Dr. McGrath receives funding from the Children’s Fund for Health. The authors declared no conflicts of interest.

SOURCE: McGrath N et al. J Pediatr. 2018 Oct 24. doi: 10.1016/j.jpeds.2018.09.044.

Successive screenings to detect congenital hypothyroidism in preterm infants is key to identifying cases that would otherwise lead to permanent and decompensated hypothyroidism, reported Niamh McGrath, MD, of the department of pediatric endocrinology at Children’s University Hospital, Dublin, and her associates in the Journal of Pediatrics.

In a population-based prospective review of 898,424 records between 2004 and 2016, Dr. McGrath and her associates identified all preterm infants less than 33 weeks diagnosed with congenital hypothyroidism and receiving treatment with levothyroxine. Of the infants screened, just 53 were selected to participate in the study, including 26 who were diagnosed at the first thyroid-stimulating hormone (TSH) screening and 27 who had delayed TSH elevation.

Gestational age ranged from 23 to 33 weeks, median birth weight measured 1.2 kg, median serum TSH concentration at the time of diagnosis was 78.3 mU/L, and median free thyroxine concentration was 8.9 pmol/L.

For half of the infants ultimately diagnosed, congenital hypothyroidism was not detected during the initial newborn screening. The authors also noted that 25% of patients with delayed TSH elevation had been exposed to iodine while undergoing surgery for necrotizing enterocolitis; after age 28 days, four of these infants were found to have elevated TSH. They cautioned that while this finding emphasizes the need for close monitoring and repeat screening of infants who have been exposed to iodine for up to 1 month following exposure, they could not be certain that the iodine exposure was responsible for the transient hypothyroidism in these patients.


Dr. McGrath and her associates emphasized the importance of repeat TSH screening for all preterm infants, noting that standard protocol screenings conducted just once at age 2 weeks or 4 weeks are not sufficient to effectively identify all cases of congenital hypothyroidism in which TSH elevation is delayed. Instead, they recommended measuring TSH on days 3-5 and at 1 week, 2 weeks, 4 weeks, and term-corrected gestational age.

“Our data are consistent with studies showing a high incidence of delayed TSH rise, particularly in very-low-birth-weight infants,” the authors wrote. They speculated that delays in detecting primary congenital hypothyroidism could be caused by the suppression of TSH secretion as a result of “hypothalamic-pituitary immaturity, medication administration, and effects of serious neonatal illness.” In fact, had standard, recommended 2-week-only screening protocols been followed with their patient population, fully 48% of infants with delayed TSH elevation would have been overlooked; half of these patients were later found to have decompensated hypothyroidism.

Neurodevelopmental disability caused by congenital hypothyroidism, which affects roughly 1 in every 2,000-4,000 births, is increasingly being prevented with newborn screenings that identify the condition early, but the incidence of congenital hypothyroidism has increased considerably in the past 20 years. The authors attribute this increase to the gradual change in screening cutoff levels and the rise in number of preterm infants who are surviving.

The need for a second screening, as well as appropriate timing and optimal TSH cutoff, are “subjects of active debate,” the authors wrote. The latest European screening guidelines recommend second screenings for preterm and low-birth-weight infants at either 2 weeks of age or 2 weeks following preliminary screening. Although they make no recommendations regarding additional screenings, American Academy of Pediatrics guidelines, published in 2006, cite a “disproportionate incidence” of delayed increase in TSH and congenital hypothyroidism in infants with very low birth weight. Dr. McGrath and her associates speculated that not all screening programs have adopted repeat screening of preterm infants, perhaps because of the low yield results, “the transient nature of most cases” detected, as well as conflicting long-term data on neurodevelopmental outcomes.

Dr. McGrath receives funding from the Children’s Fund for Health. The authors declared no conflicts of interest.

SOURCE: McGrath N et al. J Pediatr. 2018 Oct 24. doi: 10.1016/j.jpeds.2018.09.044.

Successive screenings to detect congenital hypothyroidism in preterm infants is key to identifying cases that would otherwise lead to permanent and decompensated hypothyroidism, reported Niamh McGrath, MD, of the department of pediatric endocrinology at Children’s University Hospital, Dublin, and her associates in the Journal of Pediatrics.

In a population-based prospective review of 898,424 records between 2004 and 2016, Dr. McGrath and her associates identified all preterm infants less than 33 weeks diagnosed with congenital hypothyroidism and receiving treatment with levothyroxine. Of the infants screened, just 53 were selected to participate in the study, including 26 who were diagnosed at the first thyroid-stimulating hormone (TSH) screening and 27 who had delayed TSH elevation.

Gestational age ranged from 23 to 33 weeks, median birth weight measured 1.2 kg, median serum TSH concentration at the time of diagnosis was 78.3 mU/L, and median free thyroxine concentration was 8.9 pmol/L.

For half of the infants ultimately diagnosed, congenital hypothyroidism was not detected during the initial newborn screening. The authors also noted that 25% of patients with delayed TSH elevation had been exposed to iodine while undergoing surgery for necrotizing enterocolitis; after age 28 days, four of these infants were found to have elevated TSH. They cautioned that while this finding emphasizes the need for close monitoring and repeat screening of infants who have been exposed to iodine for up to 1 month following exposure, they could not be certain that the iodine exposure was responsible for the transient hypothyroidism in these patients.


Dr. McGrath and her associates emphasized the importance of repeat TSH screening for all preterm infants, noting that standard protocol screenings conducted just once at age 2 weeks or 4 weeks are not sufficient to effectively identify all cases of congenital hypothyroidism in which TSH elevation is delayed. Instead, they recommended measuring TSH on days 3-5 and at 1 week, 2 weeks, 4 weeks, and term-corrected gestational age.

“Our data are consistent with studies showing a high incidence of delayed TSH rise, particularly in very-low-birth-weight infants,” the authors wrote. They speculated that delays in detecting primary congenital hypothyroidism could be caused by the suppression of TSH secretion as a result of “hypothalamic-pituitary immaturity, medication administration, and effects of serious neonatal illness.” In fact, had standard, recommended 2-week-only screening protocols been followed with their patient population, fully 48% of infants with delayed TSH elevation would have been overlooked; half of these patients were later found to have decompensated hypothyroidism.

Neurodevelopmental disability caused by congenital hypothyroidism, which affects roughly 1 in every 2,000-4,000 births, is increasingly being prevented with newborn screenings that identify the condition early, but the incidence of congenital hypothyroidism has increased considerably in the past 20 years. The authors attribute this increase to the gradual change in screening cutoff levels and the rise in number of preterm infants who are surviving.

The need for a second screening, as well as appropriate timing and optimal TSH cutoff, are “subjects of active debate,” the authors wrote. The latest European screening guidelines recommend second screenings for preterm and low-birth-weight infants at either 2 weeks of age or 2 weeks following preliminary screening. Although they make no recommendations regarding additional screenings, American Academy of Pediatrics guidelines, published in 2006, cite a “disproportionate incidence” of delayed increase in TSH and congenital hypothyroidism in infants with very low birth weight. Dr. McGrath and her associates speculated that not all screening programs have adopted repeat screening of preterm infants, perhaps because of the low yield results, “the transient nature of most cases” detected, as well as conflicting long-term data on neurodevelopmental outcomes.

Dr. McGrath receives funding from the Children’s Fund for Health. The authors declared no conflicts of interest.

SOURCE: McGrath N et al. J Pediatr. 2018 Oct 24. doi: 10.1016/j.jpeds.2018.09.044.

Compatible electronic health record (EHR) systems at the US Department of Veterans Affairs (VA) and US Department of Defense (DoD) will ensure quality health care as service members transition to veterans, according to Defense Secretary James Mattis. The VA signed a contract with Cerner Corp last May to replace the 40-year-old Veterans Integrated System Technology Architecture (VistA) records system over the next 10 years with the new Cerner systems, which is in the pilot phase at DoD.

Mattis and VA Secretary Robert Wilkie signed a joint statement reinforcing the departments’ commitment to ensuring a successful transition from a legacy patient-data system to a modernized one. The statement represents “tangible evidence of our commitment to change how we deliver veteran-focused, provider-friendly care,” Wilkie said.

Both departments say the new EHR will be fully interoperable. Among the benefits: The collaboration will ensure that the VA understands the challenges encountered as DoD deploys Military Health System Genesis, its EHR system, the DoD says. It also will allow the VA to apply lessons learned to anticipate and mitigate known issues and assess prospective efficiencies to help deploy faster.

 “The EHR will give health care providers a full picture of patient medical history, driving better clinical outcomes,” Wilkie said. “It will also help us identify veterans proactively who are at higher risk for issues, such as opioid addiction and suicide, so health care providers can intervene earlier and save lives.”

Compatible electronic health record (EHR) systems at the US Department of Veterans Affairs (VA) and US Department of Defense (DoD) will ensure quality health care as service members transition to veterans, according to Defense Secretary James Mattis. The VA signed a contract with Cerner Corp last May to replace the 40-year-old Veterans Integrated System Technology Architecture (VistA) records system over the next 10 years with the new Cerner systems, which is in the pilot phase at DoD.

Mattis and VA Secretary Robert Wilkie signed a joint statement reinforcing the departments’ commitment to ensuring a successful transition from a legacy patient-data system to a modernized one. The statement represents “tangible evidence of our commitment to change how we deliver veteran-focused, provider-friendly care,” Wilkie said.

Both departments say the new EHR will be fully interoperable. Among the benefits: The collaboration will ensure that the VA understands the challenges encountered as DoD deploys Military Health System Genesis, its EHR system, the DoD says. It also will allow the VA to apply lessons learned to anticipate and mitigate known issues and assess prospective efficiencies to help deploy faster.

 “The EHR will give health care providers a full picture of patient medical history, driving better clinical outcomes,” Wilkie said. “It will also help us identify veterans proactively who are at higher risk for issues, such as opioid addiction and suicide, so health care providers can intervene earlier and save lives.”

Compatible electronic health record (EHR) systems at the US Department of Veterans Affairs (VA) and US Department of Defense (DoD) will ensure quality health care as service members transition to veterans, according to Defense Secretary James Mattis. The VA signed a contract with Cerner Corp last May to replace the 40-year-old Veterans Integrated System Technology Architecture (VistA) records system over the next 10 years with the new Cerner systems, which is in the pilot phase at DoD.

Mattis and VA Secretary Robert Wilkie signed a joint statement reinforcing the departments’ commitment to ensuring a successful transition from a legacy patient-data system to a modernized one. The statement represents “tangible evidence of our commitment to change how we deliver veteran-focused, provider-friendly care,” Wilkie said.

Both departments say the new EHR will be fully interoperable. Among the benefits: The collaboration will ensure that the VA understands the challenges encountered as DoD deploys Military Health System Genesis, its EHR system, the DoD says. It also will allow the VA to apply lessons learned to anticipate and mitigate known issues and assess prospective efficiencies to help deploy faster.

 “The EHR will give health care providers a full picture of patient medical history, driving better clinical outcomes,” Wilkie said. “It will also help us identify veterans proactively who are at higher risk for issues, such as opioid addiction and suicide, so health care providers can intervene earlier and save lives.”

The American College of Obstetricians and Gynecologists (ACOG) recommends that girls receive their first reproductive health visit between the ages of 13 and 15 years to discuss healthy relationships in addition to general reproductive health, according to a new committee opinion.

The recommendation, published online Oct. 24, emphasizes that such early visits provide opportunities for ob.gyns. to educate teenage girls and their guardians about age-appropriate health issues, such as sexual relationships, dating violence, and sexual coercion. Between the ages of 13 years and 15 years is an ideal window because middle school is a time that some adolescents develop their first romantic and sexual relationships (Obstet Gynecol. 2018; 132[5]:1317-18 doi: 10.1097/AOG.0000000000002946).

“Creating a nonjudgmental environment and educating staff on the unique concerns of adolescents are helpful ways to provide effective and appropriate care to this group of patients,” the authors wrote.

Ob.gyns. can use the early meeting to discuss key aspects of a healthy relationship with patients, including communication, self-respect, and mutual respect, while helping adolescents identify the characteristics of an unhealthy relationships such as dishonesty, intimidation, disrespect, and abuse, according to the opinion. As part of the discussion, ob.gyns. also may counsel patients to define their current relationship and their expectations for future relationships. Both relationships with and without sexual intimacy should be discussed, the opinion advises.

The recommendation reminds health care professionals to be mindful of federal and state confidentiality laws and that they be aware of mandatory reporting laws when intimate partner violence, teen dating violence, or statutory rape is suspected. In addition, the opinion notes that pregnant and parenting adolescents; lesbian, gay, bisexual, transgender, queer, or questioning (LGBTQ) individuals; and adolescents with physical and mental disabilities are at particular risk of disparities in the health care system.

“The promotion of healthy relationships in these groups requires the obstetrician-gynecologist to be aware of the unique barriers and hurdles to sexual and nonsexual expression, as well as to health care,” the opinion states. “Interventions to promote healthy relationships and a strong sexual health framework are more effective when started early and can affect indicators of long-term individual health and public health.”

The American College of Obstetricians and Gynecologists (ACOG) recommends that girls receive their first reproductive health visit between the ages of 13 and 15 years to discuss healthy relationships in addition to general reproductive health, according to a new committee opinion.

The recommendation, published online Oct. 24, emphasizes that such early visits provide opportunities for ob.gyns. to educate teenage girls and their guardians about age-appropriate health issues, such as sexual relationships, dating violence, and sexual coercion. Between the ages of 13 years and 15 years is an ideal window because middle school is a time that some adolescents develop their first romantic and sexual relationships (Obstet Gynecol. 2018; 132[5]:1317-18 doi: 10.1097/AOG.0000000000002946).

“Creating a nonjudgmental environment and educating staff on the unique concerns of adolescents are helpful ways to provide effective and appropriate care to this group of patients,” the authors wrote.

Ob.gyns. can use the early meeting to discuss key aspects of a healthy relationship with patients, including communication, self-respect, and mutual respect, while helping adolescents identify the characteristics of an unhealthy relationships such as dishonesty, intimidation, disrespect, and abuse, according to the opinion. As part of the discussion, ob.gyns. also may counsel patients to define their current relationship and their expectations for future relationships. Both relationships with and without sexual intimacy should be discussed, the opinion advises.

The recommendation reminds health care professionals to be mindful of federal and state confidentiality laws and that they be aware of mandatory reporting laws when intimate partner violence, teen dating violence, or statutory rape is suspected. In addition, the opinion notes that pregnant and parenting adolescents; lesbian, gay, bisexual, transgender, queer, or questioning (LGBTQ) individuals; and adolescents with physical and mental disabilities are at particular risk of disparities in the health care system.

“The promotion of healthy relationships in these groups requires the obstetrician-gynecologist to be aware of the unique barriers and hurdles to sexual and nonsexual expression, as well as to health care,” the opinion states. “Interventions to promote healthy relationships and a strong sexual health framework are more effective when started early and can affect indicators of long-term individual health and public health.”

The American College of Obstetricians and Gynecologists (ACOG) recommends that girls receive their first reproductive health visit between the ages of 13 and 15 years to discuss healthy relationships in addition to general reproductive health, according to a new committee opinion.

The recommendation, published online Oct. 24, emphasizes that such early visits provide opportunities for ob.gyns. to educate teenage girls and their guardians about age-appropriate health issues, such as sexual relationships, dating violence, and sexual coercion. Between the ages of 13 years and 15 years is an ideal window because middle school is a time that some adolescents develop their first romantic and sexual relationships (Obstet Gynecol. 2018; 132[5]:1317-18 doi: 10.1097/AOG.0000000000002946).

“Creating a nonjudgmental environment and educating staff on the unique concerns of adolescents are helpful ways to provide effective and appropriate care to this group of patients,” the authors wrote.

Ob.gyns. can use the early meeting to discuss key aspects of a healthy relationship with patients, including communication, self-respect, and mutual respect, while helping adolescents identify the characteristics of an unhealthy relationships such as dishonesty, intimidation, disrespect, and abuse, according to the opinion. As part of the discussion, ob.gyns. also may counsel patients to define their current relationship and their expectations for future relationships. Both relationships with and without sexual intimacy should be discussed, the opinion advises.

The recommendation reminds health care professionals to be mindful of federal and state confidentiality laws and that they be aware of mandatory reporting laws when intimate partner violence, teen dating violence, or statutory rape is suspected. In addition, the opinion notes that pregnant and parenting adolescents; lesbian, gay, bisexual, transgender, queer, or questioning (LGBTQ) individuals; and adolescents with physical and mental disabilities are at particular risk of disparities in the health care system.

“The promotion of healthy relationships in these groups requires the obstetrician-gynecologist to be aware of the unique barriers and hurdles to sexual and nonsexual expression, as well as to health care,” the opinion states. “Interventions to promote healthy relationships and a strong sexual health framework are more effective when started early and can affect indicators of long-term individual health and public health.”