The systemic autoinflammatory disorders for dermatologists. Part 2: disease examples.

The systemic autoinflammatory disorders (SAIDS) or periodic fever syndromes are disorders of innate immunity, which can be inherited or acquired. They are almost all very rare and easily overlooked; typically, patients will have seen multiple specialities prior to diagnosis, so a high level of clinical suspicion is key. It is important to note that these are 'high-value' diagnoses as the majority of these syndromes can be very effectively controlled, dramatically improving quality of life and providing protection against the development of irreversible complications such as AA amyloidosis. In Part 1 of this review, we took an overview of SAIDS and described the common features; in this article, we take a more in-depth look at the better recognized or more dermatologically relevant conditions.

Diacylglycerol Kinase ζ Regulates Macrophage Responses in Juvenile Arthritis and Cytokine Storm Syndrome Mouse Models.

Dysregulation of monocyte and macrophage responses are often observed in children with systemic juvenile idiopathic arthritis (sJIA) and cytokine storm syndrome (CSS), a potentially fatal complication of chronic rheumatic diseases. Both conditions are associated with activation of TLR signaling in monocyte and macrophage lineage cells, leading to overwhelming inflammatory responses. Despite the importance of TLR engagement in activating proinflammatory macrophages, relatively little is known about activation of intrinsic negative regulatory pathways to attenuate excessive inflammatory responses. In this study, we demonstrate that loss of diacylglycerol (DAG) kinase (Dgk) ζ, an enzyme which converts DAG into phosphatidic acid, limits inflammatory cytokine production in an arthritic mouse model dependent on TLR2 signaling and in a CSS mouse model dependent on TLR9 signaling. In vitro, Dgkζ deficiency results in reduced production of TNF-α, IL-6, and IL-1ß and in limited M1 macrophage polarization. Mechanistically, Dgkζ deficiency decreases STAT1 and STAT3 phosphorylation. Moreover, Dgkζ levels are increased in macrophages derived from mice with CSS or exposed to plasma from sJIA patients with active disease. Our data suggest that Dgkζ induction in arthritic conditions perpetuates systemic inflammatory responses mediated by macrophages and highlight a potential role of Dgkζ-DAG/phosphatidic acid axis as a modulator of inflammatory cytokine production in sJIA and CSS.

NK cell defects in X-linked pigmentary reticulate disorder.

X-linked reticulate pigmentary disorder (XLPDR, Mendelian Inheritance in Man #301220) is a rare syndrome characterized by recurrent infections and sterile multiorgan inflammation. The syndrome is caused by an intronic mutation in POLA1, the gene encoding the catalytic subunit of DNA polymerase-α (Pol-α), which is responsible for Okazaki fragment synthesis during DNA replication. Reduced POLA1 expression in this condition triggers spontaneous type I interferon expression, which can be linked to the autoinflammatory manifestations of the disease. However, the history of recurrent infections in this syndrome is as yet unexplained. Here we report that patients with XLPDR have reduced NK cell cytotoxic activity and decreased numbers of NK cells, particularly differentiated, stage V, cells (CD3-CD56dim). This phenotype is reminiscent of hypomorphic mutations in MCM4, which encodes a component of the minichromosome maintenance (MCM) helicase complex that is functionally linked to Pol-α during the DNA replication process. We find that POLA1 deficiency leads to MCM4 depletion and that both can impair NK cell natural cytotoxicity and show that this is due to a defect in lytic granule polarization. Altogether, our study provides mechanistic connections between Pol-α and the MCM complex and demonstrates their relevance in NK cell function.

Perifolliculitis capitis abscedens et suffodiens treatment with tumor necrosis factor inhibitors: A case report and review of published cases.

Perifolliculitis capitis abscedens et suffodiens (PCAS) or dissecting cellulitis is a rare condition presenting deep follicular occlusions, follicular ruptures and follicular infections in the scalp area with unknown etiology, which consequently cause primary neutrophilic cicatricial alopecia by the repeated follicular inflammation. PCAS is categorized as one of the "follicular occlusion tetrad" along with hidradenitis suppurativa, acne conglobata and pilonidal cyst. In the pathogenesis of the follicular occlusion tetrad, the involvement of neutrophils and its activator tumor necrosis factor (TNF) have been discussed. Here, we report a case of PCAS that was successfully treated with adalimumab, a human anti-TNF monoclonal antibody. This is the first Asian case of PCAS that was improved by a TNF inhibitor.

Localized unilateral basaloid follicular hamartoma along Blaschko's lines on face.

Basaloid follicular hamartoma (BFH) is a rare hamartoma of hair follicle. Clinical presentations may vary but are united by the same histopathological features in the form of folliculocentric basaloid or squamoid cell proliferation in the superficial dermis, which represents malformed and distorted hair follicles. It is important to recognize this entity as its simulant is basal cell carcinoma, a low-grade malignancy. Here, we report a case of localized unilateral BFH in a Blaschkoid distribution on the face of a 14-year-old female.

Primary cutaneous amyloidosis associated with autoimmune hepatitis-primary biliary cirrhosis overlap syndrome and Sjögren syndrome: A case report.

RATIONALE: Primary cutaneous amyloidosis (PCA) is a localized skin disorder characterized by the abnormal deposition of amyloid in the extracellular matrix of the dermis. The association between PCA and other diseases, although rare, has been documented for various autoimmune diseases. PCA associated with autoimmune hepatitis-primary biliary cirrhosis (AIH-PBC) overlap syndrome and Sjögren syndrome (SS) has not been previously reported in the literature. PATIENT CONCERNS: A 50-year-old woman presented with progressive abnormal liver enzyme levels and was referred to our department. DIAGNOSES: Due to the patient's symptoms, laboratory test results, radiographic findings, and pathologic results, she was diagnosed with PCA associated with AIH-PBC overlap syndrome and SS. INTERVENTIONS: She was subsequently treated with a combination of ursodeoxycholic acid (UDCA), prednisone, and azathioprine. OUTCOMES: While this treatment can achieve therapeutic success, it cannot prevent complications from cirrhosis. This patient remains alive but experienced an emergent gastrointestinal hemorrhage. LESSONS: While we acknowledge that this is a single case, these findings extend our knowledge of immunological diseases associated with PCA and suggest a common, immune-mediated pathogenic pathway between PCA, AIH-PBC overlap syndrome, and SS. After 12 years of follow up, clinical manifestations have developed, and these autoimmune diseases have progressed. The combination of UDCA, prednisone, and azathioprine can achieve therapeutic success but cannot prevent disease progression. Routine follow up for this patient is necessary to document disease progression.

Successful Short Desensitization Treatment Protocol with Narrowband UVB Phototherapy (TL-01) in Polymorphic Light Eruption.

INTRODUCTION: Polymorphic light eruption (PLE) is a common idiopathic photodermatosis that typically presents with pruritic papular or papulovesicular lesions on sun-exposed skin between spring and autumn. In many subjects PLE is mild, and can usually be prevented by the use of broad-spectrum topical sunscreens and a gradual increase in sunlight exposure. However, in some individuals, sunlight exposure results in florid PLE and they often benefit from prophylactic desensitization treatment using phototherapy in early spring, an artificial method that induces a "hardening" phenomenon. OBJECTIVE: To describe and evaluate the efficacy of a short desensitization protocol, based on a one-month-treatment, administered twice a week with narrow band UVB in subjects with severe polymorphic light eruption (PLE). METHODS: A retrospective, open planned and non-randomized study to assess the efficacy of UVB phototherapy in prevention of polymorphic light eruption. RESULTS: Fifteen subjects diagnosed with severe PLE were treated with the standard protocol in our Photobiology Unit between 2014 and 2015. The effect of hardening was sustained during follow up in 87.5% of desensitization treatments. A statistically significant association (p<0.05) between the years of duration of the PLE and the response to treatment was found. CONCLUSIONS: The effect of hardening was maintained in the vast majority of subjects, obtaining a good benefit with no PLE episodes during all the summer. We demonstrate that our standard protocol is effective, and produces a successful outcome for the majority of PLE subjects. Our protocol is shorter than those currently applied, being favourable both for the patient and the physician.

Comparative study of p16 protein expression in squamous cell carcinomas from patients with epidermodysplasia verruciformis and patients without the disease.

Epidermodysplasia verruciformis (EV) is a rare genodermatosis associated with susceptibility to beta-human papilloma virus (HPV) infection. EV patients develop disseminated warts and non-melanoma skin cancer, mainly squamous cell carcinomas (SCC) that are locally aggressive. EV pathogenesis is not yet fully understood, but alterations in the p16 gene play a role in the pathogenesis of neoplasms caused by high-risk genital HPV. To explore its role in EV lesions, we compared p16 expression in SCC from patients with and without EV. Tissue microarray slides composed of 27 SCC from EV patients, and 35 from non-EV patients were stained with an anti-p16 antibody. Twenty (74%) EV tumors exhibited diffuse (nuclear and cytoplasmic) p16 expression, one (4%) displayed focal expression, and six (22%) displayed no p16 staining. Eleven (31%) SCC from non-EV patients presented diffuse p16 staining, 14 (40%) displayed focal expression and 10 (29%) did not express p16. The frequency of diffuse p16 expression was higher in EV tumors than in SCC from patients without EV. The frequency of diffuse p16 expression in moderately and poorly differentiated EV-SCC was similarly higher than non-EV tumors with the same degree of differentiation. The diffuse expression of p16 in EV-SCC suggests that changes in the p16 gene, probably resulting in a functionally defective protein, may be one factor determining the locally aggressive clinical behavior of SCC in young EV patients.

Cutaneous amyloidosis associated with autoimmune hepatitis-primary biliary cirrhosis overlap syndrome.

Cutaneous amyloidosis is a rare disease characterized by the deposition of amyloid in the dermis. It can be primary or secondary, depending on associated diseases. It has been linked to various autoimmune diseases, including primary biliary cirrhosis. We present the case of a patient with an autoimmune hepatitis-primary biliary cirrhosis overlap syndrome with concomitant cutaneous amyloidosis, a very unusual association, and discuss similar cases and possible pathophysiological implications.

Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis.

Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections of the skin, nail, oral, and genital mucosae with Candida species, mainly C. albicans. Autosomal-recessive (AR) IL-17RA and ACT1 deficiencies and autosomal-dominant IL-17F deficiency, each reported in a single kindred, underlie CMC in otherwise healthy patients. We report three patients from unrelated kindreds, aged 8, 12, and 37 yr with isolated CMC, who display AR IL-17RC deficiency. The patients are homozygous for different nonsense alleles that prevent the expression of IL-17RC on the cell surface. The defect is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers. However, in contrast to what is observed for the IL-17RA- and ACT1-deficient patients tested, the response to IL-17E (IL-25) is maintained in these IL-17RC-deficient patients. These experiments of nature indicate that human IL-17RC is essential for mucocutaneous immunity to C. albicans but is otherwise largely redundant.

[Effect of proteflazid on TLRs expression by mononuclear leukocytes of peripheral blood and epithelial cells of mucous membranes and skin in patients with herpes-associated erythema multiforme and erythema annulare centrifugum].

The article reports survey data on 23 patients with erythemas, including 19 patients with herpes-associated erythema multiforme (HAEM) and 4 patients with Darier's erythema annulare centrifugum (DEAC). Patients in the initial state (baseline) and after two weeks of therapy with proteflazid were characterized by measuring the levels of Toll-like receptor (TLR) expression in peripheral blood mononuclear cells (PBMC) and in epithelial cells of the throat and the skin. The TLR expression in PBMC and skin was assessed by flow cytometry with monoclonal antibodies (ICA) (Caltag Laboratories, USA; Hycult Biotech, Netherlands) against relevant antigens. In addition, patients were also characterized by the content of subpopulations of lymphocytes expressing surface markers CD3, CD4, CD8, CD16, CD21, CD23, CD72, CD25, and HLA-DR in the peripheral blood, which was measured by flow cytometry. The therapy with proteflazid in patients with both HAEM and DEAC led to normalization of the level of both T-cell and B-cell immunity, which was manifested by an increase in the total number of lymphocytes, CD3+, CD4+, CD21+, and CD72+. Measurements of the dynamics of TLR expression in the course of immunotherapy showed an increase in the number of TLR 2, 3, 4, 7, 8, and 9 in PBMC (which was especially pronounced for TLR2) and in epithelium of the pharyngeal mucosa and skin (increased expression of TLR3, 7, and 9).

Gene therapy and the skin.

Significant progress has been made during the past decade in corrective gene therapy of the skin. This includes advances in vector technology, targeted gene expression, gene replacement, gene correction, and the availability of appropriate animal models for a variety of candidate diseases. While non-viral integration of large genes such as essential basement membrane proteins has been mastered, new challenges such as the control of immune responses lie ahead of the research community. Among the first skin diseases, patients with junctional epidermolysis bullosa (JEB) and xeroderma pigmentosum (XP) will enter clinical trials.