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Background: Adult-onset immunodeficiency (AOID) due to interferon-gamma autoantibody is a rare, acquired immunodeficiency disease. Reactive neutrophilic dermatoses (RND), predominantly Sweet syndrome (SS), and generalized pustular eruption have been reported repeatedly. Objectives: The aims of this study were to describe the cutaneous manifestations in AOID patients and determine the incidence of RND and associated factors using a larger population size than have been previously reported. Methods: A retrospective chart review of all confirmed AOID cases in Chiang Mai University Hospital from January 2006 to June 2020 was conducted. The demographics and characteristics of RND including type, onset, and laboratory information in every episode of cutaneous manifestations were collected. Generalized estimating equations of binary logistic regression were used to determine the indicators of RND. Results: A total of 146 patients with confirmed AOID were identified. Of these, 57 cases (39%) developed at least one episode of RND. Thirteen cases (23%) of the patients experienced RND twice during the follow-up period. All recurrence of RND displayed the same cutaneous phenotype, with the exception of 2 cases who had both SS and generalized pustular eruption. Finally, 49 episodes of SS and 22 episodes of generalized pustular eruption were included in the analysis. All patients with RND had concomitant active opportunistic infections, of which most were non-tuberculous mycobacterium (NTM) infection. NTM infection (prevalence odds ratio [POR] 2.87), lymphadenopathy (POR 3.30) as well as lower serum alkaline phosphatase (ALP) level (POR 0.71 for every 100-unit increment in ALP) were found to be significantly associated with RND occurrence. Conclusions: 39% of our AOID patients experienced RND once during the course of the disease. Notable factors associated with RND occurrence were concomitant NTM infection, lymphadenopathy, and lower level of ALP.

Background: Generalized pustular psoriasis (GPP; MIM 614204) is a rare and severe pustular autoinflammatory skin disease in which acute generalized erythema and scaling develop with numerous sterile pustules. GPP shares skin manifestations, especially pustular skin reaction, with adult-onset immunodeficiency (AOID) with anti-interferon-γ autoantibodies, an autoimmune disease. Methods: Clinical examinations and whole-exome sequencing (WES) were performed on 32 patients with pustular psoriasis phenotypes and 21 patients with AOID with pustular skin reaction. Immunohistochemical and histopathological studies were performed. Results: WES identified three Thai patients presenting with similar pustular phenotypes—two with a diagnosis of AOID and the other with GPP. A heterozygous missense variant chr18:g.61325778C>A NM_006919.2: c.438G>T; NP_008850.1: p.Lys146Asn; rs193238900 in SERPINB3 was identified in two patients: one with GPP and the other with AOID. The other patient who had AOID carried a heterozygous missense variant chr18:g.61323147T>C NM_006919.2: c.917A>G; NP_008850.1: p.Asp306Gly in SERPINB3. Immunohistochemical studies showed overexpression of SERPINA1 and SERPINB3, a hallmark of psoriatic skin lesions. Conclusions: Genetic variants in SERPINB3 are associated with GPP and AOID with pustular skin reaction. The skin of patients with GPP and AOID carrying SERPINB3 mutations showed overexpression of SERPINB3 and SERPINA1. Clinically and genetically, GPP and AOID appear to share pathogenetic mechanisms.

Protein tyrosine phosphatase non-receptor type 6 (PTPN6) is a key regulatory protein in cellular signal transduction in the control of inflammation and cell death. Impairment of PTPN6 is known to be associated with human inflammatory diseases including neutrophilic dermatosis; however, comprehensive studies of PTPN6-associated neutrophilic dermatosis have not clearly identified the relationships involved. Reports from in vitro and in vivo studies revealed that inflammatory cytokines have increased in the white blood cells from PTPN6-knocked out mice, and systemic inflammation was also increased in these mice, resulting in skin inflammation in this model. Reports of PTPN6 regulatory functions through five pathophysiological mechanisms are summarized and discussed here including inhibition of myeloid differentiation primary response 88, enhancement of the regulatory function of receptor-interacting protein kinase, inhibition of receptor-interacting serine/threonine-protein kinase 3/mixed lineage kinase domain-like protein-dependent necroptosis, inhibition of caspase-8-dependent apoptosis, and inhibition of p38/mitogen-activated protein kinase. Treatments by blocking the pathways involved in signal transduction and inflammatory cytokine release are also summarized. Understanding this underlying mechanism could improve therapeutic strategies for neutrophilic dermatosis.

Background: Generalized pustular psoriasis (GPP; MIM 614204) is a rare multisystemic autoinflammatory disease, characterized by episodes of acute generalized erythema and scaling developed with the spread of numerous sterile pustules. Adult-onset immunodeficiency syndrome (AOID) with anti-interferon-γ autoantibodies is an immunodeficiency disorder associated with disruptive IFN-γ signaling. Methods: Clinical examination and whole exome sequencing (WES) were performed on 32 patients with pustular psoriasis phenotypes and 21 patients with AOID with pustular skin reaction. Histopathological and immunohistochemical studies were performed. Results: WES identified four Thai patients presenting with similar pustular phenotypes—two with a diagnosis of GPP and the other two with AOID—who were found to carry the same rare TGFBR2 frameshift mutation c.458del; p.Lys153SerfsTer35, which is predicted to result in a marked loss of functional TGFBR2 protein. The immunohistochemical studied showed overexpression of IL1B, IL6, IL17, IL23, IFNG, and KRT17, a hallmark of psoriatic skin lesions. Abnormal TGFB1 expression was observed in the pustular skin lesion of an AOID patient, suggesting disruption to TGFβ signaling is associated with the hyperproliferation of the psoriatic epidermis. Conclusions: This study implicates disruptive TGFBR2-mediated signaling, via a shared truncating variant, c.458del; p.Lys153SerfsTer35, as a “predisposing risk factor” for GPP and AOID.

Pustular psoriasis (PuP) is a rare variant of psoriasis with a unique immunopathogenesis, unlike its more prevalent plaque-type counterpart. However, data available are limited due to its low prevalence. This study aimed to describe the demographic profile, precipitating factors, clinical presentations, and treatments among patients with different PuP subtypes from a 15-year retrospective cohort study in Thailand. A total of 60 patients were included in this study. There was female predominance (73.3%) and mean age of onset was 38.1 ± 17.6 years. Generalized PuP (GPP) was the most prevalent subtype (80.0%), followed by acrodermatitis continua of Hallopeau (13.3%) and palmoplantar pustulosis (6.7%). Precipitating factors included corticosteroid withdrawal, upper respiratory tract infection, and pregnancy. One-third of PuP occurred concomitantly with other psoriasis variants, especially the plaque type. The most prescribed systemic and topical treatments were oral acitretin (60.0%) and topical corticosteroids (98.3%), respectively. Only two patients were treated with narrow-band ultraviolet B. In conclusion, four out of every five PuP patients in this center had GPP. Corticosteroid withdrawal, upper respiratory tract infection, and pregnancy are important precipitating factors. Coexistence with other psoriasis variants was identified in one out of every three patients. Acitretin remains the mainstay of systemic treatment.

Adult-onset immunodeficiency syndrome (AOID) with anti-interferon (IFN)-γ autoantibodies is characterized by an AIDS-like illness with disruptive IFN-γ signaling. Patients generally present with recurrent and disseminated opportunistic infections along with neutrophilic dermatoses. Generalized pustular psoriasis (GPP; Online Mendelian Inheritance in Man #614204) is characterized by acute generalized erythema and scaling with numerous aseptic pustules. Mutations in SERPINA3 have been reported as predisposing risk factors for both AOID and GPP. Here, we report two unrelated patients, one with AOID and a pustular skin reaction and the other with GPP, who both carried the same heterozygous variant c.718G>A (p.Val240Met) in SERPINA1. Our observation of a shared mutation in SERPINA1 in AOID and GPP indicate possible pathobiological and disease mechanism similarities in these two disorders. Thus, variants in both SERPINA1, SERPINA3, and potentially other SERPIN family members may be associated with the etiology of GPP and AOID.

Cytomegalovirus causes a myriad of clinical features, potentially affecting any organ system, significantly increasing morbidity and even mortality. Vascular endothelial cell infection by cytomegalovirus has been implicated in the development of vasculopathy, possibly accounting for the clinical association between cytomegalovirus and vascular thrombosis. In contrast with visceral organ involvement, the cutaneous manifestations of cytomegalovirus are variable and rarely described. Malignant atrophic papulosis, commonly known as Degos disease, is an unusual small vessel arteriopathy with a pathognomonic clinical appearance of atrophic porcelain-white central papules surrounded by telangiectatic erythema. As with the arterial occlusive process, Degos disease may be idiopathic or secondary to autoimmune disorders or viral infection. All in all, cytomegalovirus-related Degos-like presentation has never been described. This report describes a case in which disseminated cytomegalovirus disease developed 4 weeks after the onset of drug-induced hypersensitivity syndrome with prominent Degos-like skin lesions. Our case highlights a rare example of Degos-like lesions occurring due to cytomegalovirus disease and emphasizes the importance of early recognition of the characteristic cutaneous eruption as a diagnostic clue leading to the prompt management of this life-threatening infection.