Drug allergy and non-HIV immune reconstitution inflammatory syndrome.

Non-HIV immune reconstitution inflammatory syndrome (non-HIV IRIS) is associated with the recovery from an immunocompromised condition. It is defined as inflammatory disorders caused by antigens, including drugs or pathogenic microorganisms present prior to immune recovery, or by the exacerbation of an inflammatory disorder that was already present. Drug-induced hypersensitivity syndrome is a prototype of IRIS, and the pathophysiology of non-HIV IRIS can be recognized in several disorders treated with corticosteroids, immunosuppressants, molecular-targeted drugs, TNF-α antibody drugs, immune checkpoint inhibitors, and dipeptidyl peptidase-4 inhibitors. This review focuses on the relationship between the immune mechanism of non-HIV IRIS and drug allergies, especially severe drug eruption. The antigen recognition mechanism in drug allergy varies depending on the clinical type and the causative drug. The p-i concept is the main mechanism in severe drug eruption such as Stevens-Johnson syndrome/toxic epidermal necrolysis, and drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms. Lymphocytes activated by an antigen other than a drug, such as a virus, can also develop drug allergy by the loose binding of drugs with immune receptors of T cells or human leukocyte antigen. Therefore, fluctuations in the immune environment affect the onset of severe drug eruption. Novel agents that cause major changes in immunity have been marketed mainly for autoimmune diseases and malignant tumors; therefore, it is necessary to consider their effects when treating severe drug eruptions. Moreover, although a list of diagnostic criteria for this syndrome has been drafted, predictive and diagnostic biomarkers for this syndrome needs to be urgently developed.

Clinical features of dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid in Japan: A nationwide retrospective observational study.

Many cases of bullous pemphigoid (BP) have been reported in patients taking dipeptidyl peptidase-4 inhibitors (DPP-4i), which are the most widely used antidiabetic drug for type 2 diabetes mellitus. However, no large-scale survey has been conducted in Japan. This retrospective study investigated the incidence, clinical presentation, and clinical course of DPP-4i-associated BP (DPP-4i-BP) using epidemiological data from a nationwide registry for BP. In 2016, 713 new BP patients at 94 dermatological institutes were registered, 243 (34.1%) with DPP-4i-BP and 461 (64.7%) with non-DPP-4i-BP. The male-to-female ratio was 1.9 and 0.84, respectively. Patients with DPP-4i-BP were predominantly male. Non-inflammatory BP was more common in DPP-4i-BP (33.3%) than in non-DPP-4i-BP (14.6%), while inflammatory BP was common in both. No specific subtype or difference in disease severity was evident in DPP-4i-BP. The most common gliptins administered to DPP-4i-BP patients were vildagliptin (37.2%) and linagliptin (23.8%). DPP-4i intake was discontinued in 79.9% of cases after diagnosis. Some DPP-4i-BP patients (17.6%) achieved spontaneous remission after discontinuing DPP-4i without requiring the use of systemic corticosteroids and/or adjuvant therapy. Mean duration to achieve disease control was 2.87 months. The odds ratio for non-inflammatory BP requiring systemic corticosteroids and/or adjuvant therapy was low (0.52), suggesting that remission was achieved easily with supportive care in that phenotype. Non-inflammatory and mild cases of DPP-4i-BP may resolve spontaneously with supportive care, including the discontinuation of DPP-4i and no oral corticosteroid therapy.

Anti-Cytomegalovirus Therapy: Whether and When to Initiate, Those Are the Questions.

Cytomegalovirus (CMV) reactivation in patients with autoimmune bullous disease (AIBD) or severe drug eruption treated with immunosuppressive therapy was traditionally thought to be merely an epiphenomenon of the underlying immunosuppression. However, a detailed review of the clinical course of these patients revealed that CMV reactivation occurs upon rapid immune recovery, which is termed immune reconstitution inflammatory syndrome (IRIS), and that the timely initiation of anti-CMV therapy, when combined with maintenance doses of immunosuppressive agents, contributes to a rapid resolution of severe infectious complications thought to be refractory to conventional immunosuppressive therapies and unrelated to CMV reactivation. Thus, CMV reactivation resulting in fatal outcomes (CMV-IRIS) can be prevented by the timely detection of CMV DNA or antigens in the blood and by rapidly starting anti-CMV therapy while maintaining immunosuppressive therapy. Anti-CMV therapy is highly recommended for patients with CMV-IRIS or severe drug eruption who have risk factors for CMV reactivation resulting in fatal outcomes.

Case Report: Appearance of Various Disease-Specific Antibodies After the Onset of Dipeptidyl Peptidase-4 Inhibitor-Associated Bullous Pemphigoid.

Bullous pemphigoid (BP) is a rare autoimmune blistering disease, and the prevalence of type 2 diabetes mellitus (T2DM) is relatively high in subjects with BP. It is known that dipeptidyl peptidase-4 inhibitor (DPP-4i), one kind of antidiabetic drugs, can cause BP, although precise mechanism of DPP-4i-related BP remains unclear. In this report, we showed a case with appearance of various disease-specific antibodies after the onset of DPP-4i-related BP. Furthermore, various disease-specific antibodies became positive and showed high titers two years after the onset of DPP-4i-related BP and discontinuation of DPP-4i. These data showed that it is possible for immune tolerance to be broken after the onset of DPP-4i-related BP, and it may be important to check autoimmune antibodies in DPP-4i-related BP subjects even when BP symptoms are improved.

Systemic capillary leak syndrome triggered by anti-programmed death 1 checkpoint inhibitor in psoriasis.

Programmed death 1 (PD-1) inhibitors are increasingly used for the treatment of malignancies. Despite the clinical benefits, unpredictable and potentially fatal side-effects may occur. We report a psoriatic patient who developed systemic capillary leak syndrome (SCLS) after starting a PD-1 checkpoint inhibitor. In order to determine which factors could trigger the development of SCLS in a patient with stable psoriasis after starting anti-PD-1 therapy, serum cytokines were serially measured before and after the development of SCLS in this patient. We also retrospectively reviewed 28 previously reported patients presenting clinical exacerbations of pre-existing psoriasis or the de novo induction of psoriasis after anti-PD-1 therapy. In 16 of the 28 patients (57.1%), the interval between last anti-PD-1 therapy and exacerbations of pre-existing psoriasis or the de novo induction of psoriasis was less than 28 days. The timing of the onset of SCLS in this patient was coincident with the increase in lymphocyte counts and at 22 days after last anti-PD-1 therapy. In 75%, however, anti-PD-1 therapy was able to be restarted and was tolerated well. Increased levels of interleukin (IL)-2, IL-6, interferon-γ and tumor necrosis factor-α, in addition to a persistent increase in vascular endothelial growth factor (VEGF), were detected at onset of SCLS. An increase in pro-inflammatory cytokines and VEGF, when combined with a rapid and sequential recovery of neutrophils and lymphocytes after anti-PD-1 therapy, would predict the development of SCLS. Clinicians need to be aware that patients with psoriasis are at risk of a potentially fatal disease, SCLS, when anti-PD-1 therapy is started.

Prurigo nodularis as a sweat gland/duct-related disorder: resolution associated with restoration of sweating disturbance.

Little attention has been given to the involvement of sweat glands/ducts in the pathogenesis of prurigo nodularis (PN). According to recent studies, PN is likely to develop under conditions characterized by dry skin, such as atopic dermatitis (AD), suggesting a strong impact of skin dryness on PN development. No therapeutic modalities produced complete resolution of PN without exacerbations. We previously reported that increases in skin dryness by sweating disturbance could initiate the development of AD. We investigated whether sweating responses were impaired in refractory PN lesions; and, if so, we asked whether the PN lesions could resolve by restoring sweating disturbance. Using the impression mold technique, which allows an accurate quantification of individual sweat gland/duct activity, we examined basal sweating under quiescent conditions and inducible sweating responses to thermal stimulus in PN lesions and normal-appearing skin in the same patients before and after treatment with a moisturizer or topical corticosteroids. Sweating disturbance, either basal or inducible, was most profoundly detected in the "hub" structure corresponding to the center of PN papule before the treatment. This sweating disturbance was immunohistochemically associated with the leakage of sweat into the dermis. This disturbance was restored by treatment with a moisturizer. Our limitations include a relatively small patient cohort and lack of blinding. Sweating disturbance could be one of the aggravating factors of PN development. Refractory PN with low skin hydration may resolve by restoring sweating disturbance.