Yukiko Ushigome

Short- and long-term outcomes of 34 patients with drug-induced hypersensitivity syndrome in a single institution.

BACKGROUND Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe systemic hypersensitivity reaction caused by specific drugs, in which herpesvirus reactivations and organ dysfunction occur during the course of the disease. Although recent reports have documented the development of autoimmune disease after complete resolution of DIHS/DRESS, relatively little is known about long-term outcomes after complete resolution of the disease. OBJECTIVE The aim of this study was to retrospectively analyze complications and sequelae in the early and late phases of DIHS/DRESS according to treatment. METHODS In all, 34 patients were classified into 2 groups: 14 patients with oral corticosteroid treatment; and 20 with noncorticosteroid treatment. The disease time course was divided into 2 periods: the first 6 months after onset of the drug reaction (early phase); and the period thereafter (late phase). Investigations to detect the presence of viral/bacterial infectious diseases, organ dysfunction, and autoantibodies were performed in both early and late phases. RESULTS Herpesvirus infections and pneumonia were detected in 6 and 2 patients, respectively, in the corticosteroid treatment group in the early phase. In the noncorticosteroid treatment group, 2 patients developed autoimmune diseases, namely lupus erythematosus and autoimmune thyroiditis. Autoantibodies were detected in 44.4% of patients examined in the late phase of the disease. LIMITATIONS This study only evaluated a small number of autoantibodies. CONCLUSION The need for anti-inflammatory effects from systemic corticosteroids should be balanced with the risk of infectious diseases and the benefits of preventing the appearance of later autoimmune conditions in patients with DIHS/DRESS.

Crucial Role of Viral Reactivation in the Development of Severe Drug Eruptions: a Comprehensive Review

A growing number of cells, mediators, and pathways have been implicated in severe drug eruptions. Fifteen years ago, we published landmark studies that sparked the current advances in our understanding of the role of viral reactivations in severe drug eruptions. Viral reactivations then became critically important as diagnostic tools, but how precisely they participated in the pathogenesis remained less well-defined. The question of whether viral reactivations are pathogenic or are instead as epiphenomenon of severe tissue damage has plagued the field of drug allergy for some decades. Recent evidence points to a crucial role for tissue-resident memory T (TRM) cells in immune protection against viral infections. Yet immune protection against viral infections is but one side of a coin, the other side of which comprises effector cells capable of mediating severe immunopathology: Once drug antigen is cross-recognized by these T cells, they could be activated to kill surrounding epidermal cells, resulting in drug-induced tissue damage. Such TRM cells could persistently reside in the skin lesions of fixed drug eruptions (FDE) and are most likely a major cell type responsible for the development of FDE. We also discuss the role of regulatory T (Treg) cells in the setting of drug allergy, in which herpesviruses are reactivated in sequence. Although many details of the complicated interactions among viruses, anti-viral immune responses, TRM cells, and Treg cells remain to be elucidated, we review the current status of this rapidly advancing field.

Human Herpesvirus 6 Reactivation in Drug-induced Hypersensitivity Syndrome and DRESS Validation Score

We read with great interest the article entitled, “The DRESS Syndrome: A Literature Review” by Cacoub et al. The authors classified 172 cases reported as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome in the literature by using the RegiSCAR scoring system. They concluded that the vast majority of cases could be defined as “probable/definite” DRESS cases. Among various terms to refer to this syndrome, the criteria for drug-induced hypersensitivity syndrome (DIHS) proposed by a Japanese severe cutaneous adverse reaction

Longitudinal analysis of antibody profiles against plakins in severe drug eruptions: emphasis on correlation with tissue damage in drug-induced hypersensitivity syndrome and drug reaction with eosinophilia and systemic symptoms

The evidence for severe drug eruption as a trigger for autoimmune disease has recently increased. No information is available on how tissue damage in severe drug eruptions can induce autoimmune responses.

Localized hypohidrosis is an unrecognized sequela of herpes zoster.

The effectiveness of PRP is based on its high level of growth factors such as PDGF, TGF, and EGF. These growth factors are important in modulating mesenchymal cell proliferation, and extracellular matrix synthesis during healing. PRP has shown to be effective at propagating new healthy tissue growth in a wide range of medical conditions such as diabetic foot ulcers, venous stasis ulcers, and tendonopathy. The vast majority of published literature shows that autologous PRP has minimal risk of scar tissue formation or serious adverse events (SAEs). Previously, 1 study examined injections of a combination of PRP and fat-derived mesenchymal cells in 15 women with VLS. The authors reported that ‘‘all patients reported total disappearance of pain and symptoms.’’ However, a significant limitation of the study was that 2 concurrent interventions were performed, which limited the ability to determine which intervention was efficacious or necessary. In addition, no objective measures of efficacy were used. In contrast, our study used an objective endpoint (decrease in histopathologic inflammation) measured by masked evaluators. Limitations of this study are the small sample size, lack of placebo control, and short-term follow-up. However, the statistically significant results suggest that PRP decreased histopathologic inflammation in women with VLS without the potential side effects associated with topical or systemic immunomodulators.

IgA vasculitis with severe gastrointestinal symptoms may be an unusual manifestation of varicella-zoster virus reactivation

Immunoglobulin A vasculitis (IAV), formerly called Henoch-Schonlein purpura, is an acute leukocytoclastic vasculitis of unknown etiology that is manifested as palpable purpura or petechiae associated with arthralgia, abdominal pain, and nephritis.1, 2 This article is protected by copyright. All rights reserved.

Sweat as an Efficient Natural Moisturizer.

Although recent research on the pathogenesis of allergic skin diseases such as atopic dermatitis has focused on defects in skin genes important for maintaining skin barrier function, the fact that excreted sweat has an overwhelmingly great capacity to increase skin surface hydration and contains moisturizing factors has long been ignored: the increase in water loss induced by these gene defects could theoretically be compensated fully by a significant increase in sweating. In this review, the dogma postulating the detrimental role of sweat in these diseases has been challenged on the basis of recent findings on the physiological functions of sweat, newly recognized sweat gland-/duct-related skin diseases, and therapeutic approaches to the management of these diseases. We are now beginning to appreciate that sweat glands/ducts are a sophisticated regulatory system. Furthermore, depending on their anatomical location and the degree of the impairment, this system might have a different function: sweating responses in sweat glands/ducts located at the folds in hairy skin such as on the trunk and extremities could function as natural regulators that maintain skin hydration under quiescent basal conditions, in addition to the better-studied thermoregulatory functions, which can be mainly mediated by those at the ridges. The normal functioning of sweat could be disturbed in various inflammatory skin diseases. Thus, we should recognize sweating disturbance as an etiologic factor in the development of these diseases.

Monocytes are involved in the balance between regulatory T cells and Th17 cells in severe drug eruptions

Drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a distinct phenotype of severe drug eruptions characterized by sequential reactivations of herpesviruses. Although a progressive loss of suppressive function in regulatory T cells (Tregs) occurred during the course of DiHS/DRESS, but not in Stevens‐Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), no previous studies investigated the mechanism. Given the recent finding that Treg development could be differentially regulated by CD16+ patrolling monocytes (pMOs) and CD14+ classical monocytes (cMOs), we can hypothesize that a differential fine‐tuned interaction between Tregs and monocytes is the driving force behind the possible shift from Tregs to Th17 cells over a prolonged period of time in DiHS/DRESS.

Immune reconstitution inflammatory syndrome observed in the setting of drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS)

Immune reconstitution inflammatory syndrome (IRIS) is originally described in association with antiretroviral therapy (ART) for HIV infected patients. IRIS consists of a broad spectrum of inflammatory diseases, such as infectious inflammatory, neoplastic, and autoimmune diseases, that present after starting an effective ART, leading to CD4+ cells increase and plasma HIV-RNA reduction. IRIS reflects either worsening of an already-diagnosed infection or presentation of previously subclinical infection. Opportunistic pathogens include cryptococcus, mycobacterium, herpesviruses, or also auto-antigens. The paradoxical worsening of clinical symptoms as observed in IRIS is also the phenomenon of drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS). In the course of DIHS/DRESS, cytomegalovirus diseases and herpes zoster are observed coincidently with the increase in lymphocytes or rapid reduction of systemic corticosteroids. Based on the similar manifestations between IRIS and DIHS/DRESS, DIHS/DRESS can be seen in a broad context as another manifestation of IRIS. Although the mechanisms of IRIS is complex and variable, depending on the latent pathogens and shift of immune status, use of the concept of IRIS can help our recognition of various manifestations that occur in the setting of DIHS/DRESS. The understanding of IRIS may improve the morbidity and mortality rates of DIHS/DRESS.

Autoimmune sequelae in severe drug eruptions

It remains unknown how autoimmunity is elicited, although many different mechanisms have been involved. There is a major difficulty in establishing a correlation between triggering events and the actual autoimmune disease because of long prodromal period. In this regard, previous studies reported that sera obtained from the acute stage of SJS/TEN and erythema multiforme contain autoantibodies (autoAbs) against epidermal proteins. Unfortunately, however, it remains to be determined whether generation of these autoAbs could be a mere epiphenomenon of epidermal damage or if there could be a link between SJS/TEN and the subsequent risk of developing autoAbs and autoimmune blistering disease. Thus, there is a great need for longitudinal analyses are generated by using samples obtained at various time points including those during the acute stage of the disease and long after their clinical resolution.We retrospectively analyzed sera serially collected from 27 DiHS, 9 TEN, 30 SJS and 7 healthy controls for the presence of autoAbs against epidermal proteins such as plakins and recombinant periplakinN1-324. These autoAbs were detected in 23.3% (SJS), 55.6% (TEN) and 48.1% (DiHS) of patients, respectively. These autoAbs tended to disappear much earlier in SJS/TEN than in DiHS. Because the existence of these autoAbs was not restricted to patients with SJS/TEN but was extended to those with DiHS characterized by no epidermal damage. These results clearly indicate that those autoAbs are not the cause of epidermal damage. According to our previous study, the time-dependent defective regulatory T cell (Treg) responses occur during the acute stage (SJS/TEN) and after clinical resolution (DiHS), respectively. The defects of Treg function could provide explanation of why autoimmune responses can be generated during the acute stage(SJS/TEN)and after resolution (DiHS), respectively. Surprisingly, our analysis of the effect of systemic corticosteroids during the acute stage of DiHS on the generation of those autoAbs showed that achievement of early resolution by corticosteroids was associated with a lower risk of subsequently generating autoAbs. In conclusion, self-inflicted immune responses occurring during the acute stage of severe drug eruptions could be a trigger for the subsequent development of AutoAbs. Longitudinal analyses of these autoAbs offer the possibility for screening high-risk patients at a time before the development of overt autoimmune disease.