Proteasome inhibitor-associated histiocytoid Sweet's syndrome: Clinical and histological similarities to Nakajo-Nishimura syndrome suggest a potential mechanism.

Histiocytoid Sweet's syndrome (HSS) is a variant of Sweet's syndrome (SS) that clinically resembles SS but differs histologically by infiltrates, predominantly composed of immature cells of the myeloid lineage. Medications such as proteasome inhibitors have been reported to cause HSS but there has been little discussion on the underlying mechanism. Here we report two cases of HSS associated with a proteasome inhibitor. Both patients were on ixazomib for the treatment of multiple myeloma and presented with acute erythematous plaques on the upper half of the body. Pathological findings were consistent with HSS. Similarities between proteasome inhibitor-induced HSS and Nakajo-Nishimura syndrome, an inherited inflammatory disease, can be identified both clinically and histologically, suggesting a potential explanation of the mechanism behind proteasome inhibitor-associated HSS.

Presence of immunoglobulin E-expressing antibody-secreting cells in the dermis close to bullous pemphigoid lesions.

Antibody-secreting cells (ASCs) produce immunoglobulin (Ig) G and IgE autoantibodies in secondary lymphoid organs. Evidence also suggests their existence in the skin in various chronic inflammatory conditions, and in association with CXCL12 and CXCL13, they regulate the recruitment/survival of ASCs and germinal center formation to generate ASCs, respectively. However, the presence of IgG and IgE in bullous pemphigoid (BP) lesions needs to be addressed. Here, we aimed to analyse BP skin for the presence of IgG and IgE and the factors contributing to their generation, recruitment, and persistence. Skin samples from 30 patients with BP were stained to identify ASCs and the immunoglobulin type they expressed. The presence of tertiary lymphoid organ (TLO) elements, which generate ASCs in non-lymphoid tissues, and the chemokines CXCL12 and CXCL13, which regulate the migration/persistence of ASCs in lymphoid tissues and formation of TLOs, respectively, were evaluated in BP skin. BP skin harboured ASCs expressing the two types of antibodies IgG and IgE. ASCs were found in high-grade cellular aggregates containing TLO elements: T cells, B cells, CXCL12+ cells, CXCL13+ cells and high endothelial venules. IgG+ ASCs were detected among these aggregates, whereas IgE+ ASCs were dispersed throughout the dermis. CXCL12+ fibroblast-like cells were located close to ASCs. The inflammatory microenvironment of BP lesions may contribute to the antibody load characteristic of the skin of patients with BP by providing a site for the presence of ASCs. CXCL13 and CXCL12 expression may contribute to the generation and recruitment/survival of ASCs, respectively.

Activation of the pentose phosphate pathway in macrophages is crucial for granuloma formation in sarcoidosis.

Sarcoidosis is a disease of unknown etiology in which granulomas form throughout the body and is typically treated with glucocorticoids, but there are no approved steroid-sparing alternatives. Here, we investigated the mechanism of granuloma formation using single-cell RNA-Seq in sarcoidosis patients. We observed that the percentages of triggering receptor expressed on myeloid cells 2-positive (TREM2-positive) macrophages expressing angiotensin-converting enzyme (ACE) and lysozyme, diagnostic makers of sarcoidosis, were increased in cutaneous sarcoidosis granulomas. Macrophages in the sarcoidosis lesion were hypermetabolic, especially in the pentose phosphate pathway (PPP). Expression of the PPP enzymes, such as fructose-1,6-bisphosphatase 1 (FBP1), was elevated in both systemic granuloma lesions and serum of sarcoidosis patients. Granuloma formation was attenuated by the PPP inhibitors in in vitro giant cell and in vivo murine granuloma models. These results suggest that the PPP may be a promising target for developing therapeutics for sarcoidosis.

Neutrophilic epitheliotropism, proposed as an auto-inflammatory condition of neutrophilic urticarial dermatosis including Schnitzler syndrome, is also observed in Japanese cases.

Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by bone pain, recurrent fever, leukocytosis, and elevated C-reactive protein, along with an urticaria-like rash and monoclonal immunoglobulin (Ig)M or IgG gammopathy. Notably, the condition is distinguished by a relatively persistent recurrent urticarial-like rash. Histopathological features observed in the skin comprise diffuse neutrophil infiltration into the dermis, absence of dermal edema, and vascular wall degeneration, all of which classify SchS as a neutrophilic urticarial dermatosis (NUD). Accumulated histological data from skin biopsies of patients with NUD have revealed a sensitive histopathological marker for NUD, acknowledged as neutrophilic epitheliotropism, which has been proposed as reflecting an autoinflammatory condition. In this report, we present three SchS patients: two men (ages 55 and 68) and a woman (age 75), all displaying neutrophilic epitheliotropism in their skin biopsy specimens. Additionally, a review of eight previously reported SchS cases in Japan identified neutrophilic epithliotropism in five cases. These findings suggest that the inclination of neutrophils toward the epithelial tissue could aid in confirming diagnoses of NUD in most cases that need to be differentiated from conventional urticaria. Consequently, we emphasize that acknowledging neutrophilic epithelial predilection as a hallmark of NUD is critical for expediting early diagnosis and appropriate treatment for SchS.

Tofacitinib, a suppressor of NOD2 expression, is a potential treatment for Blau syndrome.

Introduction: Blau syndrome is a rare autosomal dominant autoinflammatory granulomatous disease caused by a mutation in the NOD2 gene. It is characterized by a clinical trial of granulomatous dermatitis, arthritis, and uveitis. Tofacitinib is a pan Janus kinase (JAK) inhibitor used for treatment of Blau syndrome and idiopathic sarcoidosis. Here, we evaluated its effect on inflammatory pathways associated with Blau syndrome. The effect of tofacitinib on downstream pathways regulated by mutant NOD2 was analyzed using luciferase assays with overexpression of NOD2 mutants. Methods: The effect of tofacitinib on the upstream pathway for the induction of NOD2 expression and proinflammatory cytokine production was assessed using monocytic cell lines differentiated from Blau syndrome patient-derived induced pluripotent stem cells. Results: Tofacitinib did not suppress the increased spontaneous transcriptional activity of NF-κB by mutant NOD2. In addition, mutant NOD2 was not involved in the transcription of ISRE and GAS, which are activated by type 1 and type 2 interferons (IFN), respectively. On the other hand, IFNγ induced the expression of NOD2, which led to the production of inflammatory cytokines by an autoinflammatory mechanism only in cells with mutant NOD2. Discussion: Tofacitinib suppressed the induction of NOD2 by IFNγ, thereby inhibiting the production of pro-inflammatory cytokines. Thus, tofacitinib showed anti-inflammatory effects through suppression of NOD2 expression. The JAK inhibitor tofacitinib is a potential therapeutic agent for Blau syndrome because it suppresses the autoinflammation seen in Blau syndrome by inhibiting the expression of NOD2.

Human RELA dominant-negative mutations underlie type I interferonopathy with autoinflammation and autoimmunity.

Inborn errors of the NF-κB pathways underlie various clinical phenotypes in humans. Heterozygous germline loss-of-expression and loss-of-function mutations in RELA underlie RELA haploinsufficiency, which results in TNF-dependent chronic mucocutaneous ulceration and autoimmune hematological disorders. We here report six patients from five families with additional autoinflammatory and autoimmune manifestations. These patients are heterozygous for RELA mutations, all of which are in the 3' segment of the gene and create a premature stop codon. Truncated and loss-of-function RelA proteins are expressed in the patients' cells and exert a dominant-negative effect. Enhanced expression of TLR7 and MYD88 mRNA in plasmacytoid dendritic cells (pDCs) and non-pDC myeloid cells results in enhanced TLR7-driven secretion of type I/III interferons (IFNs) and interferon-stimulated gene expression in patient-derived leukocytes. Dominant-negative mutations in RELA thus underlie a novel form of type I interferonopathy with systemic autoinflammatory and autoimmune manifestations due to excessive IFN production, probably triggered by otherwise non-pathogenic TLR ligands.

Similarities and differences in autoinflammatory diseases with urticarial rash, cryopyrin-associated periodic syndrome and Schnitzler syndrome.

Cryopyrin-associated periodic syndromes (CAPS) and Schnitzler syndrome (SchS) are autoinflammatory diseases that present with urticaria-like rashes. CAPS is characterized by periodic or persistent systemic inflammation caused by the dysfunction of the NLRP3 gene. With the advent of IL-1-targeted therapies, the prognosis of CAPS has improved remarkably. SchS is considered an acquired form of autoinflammatory syndrome. Patients with SchS are adults of relatively older age. The pathogenesis of SchS remains unknown and is not associated with the NLRP3 gene. Previously, the p.L265P mutation in the MYD88 gene, which is frequently detected in Waldenström macroglobulinemia (WM) with IgM gammopathy, was identified in several cases of SchS. However, because persistent fever and fatigue are symptoms of WM that require therapeutic intervention, it is a challenge to determine whether these patients truly had SchS or whether advanced WM was misidentified as SchS. There are no established treatments for SchS. The treatment algorithm proposed with the diagnostic criteria is to use colchicine as first-line treatment, and systemic administration of steroids is not recommended due to concerns about side effects. In difficult-to-treat cases, treatment targeting IL-1 is recommended. If targeted IL-1 treatment does not improve symptoms, the diagnosis should be reconsidered. We hope that the efficacy of IL-1 therapy in clinical practice will serve as a stepping stone to elucidate the pathogenesis of SchS, focusing on its similarities and differences from CAPS.

Summary of the current status of clinically diagnosed cases of Schnitzler syndrome in Japan.

BACKGROUND: Schnitzler syndrome is a rare disorder with chronic urticaria, and there is no report summarizing the current status in Japan. METHODS: A nationwide survey of major dermatology departments in Japan was conducted in 2019. We further performed a systematic search of PubMed and Ichushi-Web, using the keywords "Schnitzler syndrome" and "Japan" then contacted the corresponding authors or physicians for further information. RESULTS: Excluding duplicates, a total of 36 clinically diagnosed cases were identified from 1994 through the spring of 2022, with a male to female ratio of 1:1. The median age of onset was 56.5 years. It took 3.3 years from the first symptom, mostly urticaria, to reach the final diagnosis. The current status of 30 cases was ascertained; two patients developed B-cell lymphoma. SchS treatment was generally effective with high doses of corticosteroids, but symptoms sometimes recurred after tapering. Colchicine was administered in 17 cases and was effective in 8, but showed no effect in the others. Tocilizumab, used in six cases, improved laboratory abnormalities and symptoms, but lost its efficacy after several years. Rituximab, used in five cases, was effective in reducing serum IgM levels or lymphoma mass, but not in inflammatory symptoms. Four cases were treated with IL-1 targeting therapy, either anakinra or canakinumab, and achieved complete remission, except one case with diffuse large B-cell lymphoma. CONCLUSIONS: Since Schnitzler syndrome is a rare disease, the continuous collection and long-term follow-up of clinical information is essential for its appropriate treatment and further understanding of its pathophysiology.

Assessment of type I interferon signatures in undifferentiated inflammatory diseases: A Japanese multicenter experience.

Purpose: Upregulation of type I interferon (IFN) signaling has been increasingly detected in inflammatory diseases. Recently, upregulation of the IFN signature has been suggested as a potential biomarker of IFN-driven inflammatory diseases. Yet, it remains unclear to what extent type I IFN is involved in the pathogenesis of undifferentiated inflammatory diseases. This study aimed to quantify the type I IFN signature in clinically undiagnosed patients and assess clinical characteristics in those with a high IFN signature. Methods: The type I IFN signature was measured in patients' whole blood cells. Clinical and biological data were collected retrospectively, and an intensive genetic analysis was performed in undiagnosed patients with a high IFN signature. Results: A total of 117 samples from 94 patients with inflammatory diseases, including 37 undiagnosed cases, were analyzed. Increased IFN signaling was observed in 19 undiagnosed patients, with 10 exhibiting clinical features commonly found in type I interferonopathies. Skin manifestations, observed in eight patients, were macroscopically and histologically similar to those found in proteasome-associated autoinflammatory syndrome. Genetic analysis identified novel mutations in the PSMB8 gene of one patient, and rare variants of unknown significance in genes linked to type I IFN signaling in four patients. A JAK inhibitor effectively treated the patient with the PSMB8 mutations. Patients with clinically quiescent idiopathic pulmonary hemosiderosis and A20 haploinsufficiency showed enhanced IFN signaling. Conclusions: Half of the patients examined in this study, with undifferentiated inflammatory diseases, clinically quiescent A20 haploinsufficiency, or idiopathic pulmonary hemosiderosis, had an elevated type I IFN signature.

Decreased peripheral basophil counts in urticaria and mouse model of oxazolone-induced hypersensitivity, the latter suggesting basopenia reflecting migration to skin.

A decrease in the number of basophils in the peripheral blood, or basopenia, has been noted, reflecting the activity of chronic spontaneous urticaria (CSU). Infiltration of basophils into the skin has also been reported, but the mechanism of basopenia in CSU has not been clarified. The phenomenon of basopenia during the active phase of urticaria was confirmed, and basophil numbers increased following symptom improvement in 15 out of 17 patients treated with omalizumab and in 13 of 15 patients treated with antihistamines. Our examination by immunostaining also revealed basophil infiltration of the CSU lesions, as in previous reports, but since most of our patients were already taking oral steroids, it was not considered appropriate to examine the relationship between basophil numbers in tissue and peripheral blood. Then, we used mouse model of contact hypersensitivity with a single application of oxazolone, which is known to stimulate basophil infiltration, and investigated basophil counts in the skin, peripheral blood, and bone marrow. In this model, a decrease in peripheral blood basophil numbers was observed one day after challenge, but not after 2 days, reflecting supplementation from the bone marrow. Indeed, when cultured basophils expressing GFP were transplanted into the peripheral blood, GFP-positive basophil numbers in the peripheral blood remained low even after 2 days of challenge. Despite differences among species and models, these results suggest that one reason for the decrease of basophils in the peripheral blood in CSU may involve migration of circulating basophils into the skin.

Incomplete penetrance of NOD2 C483W mutation underlining Blau syndrome.

BACKGROUND: Blau syndrome (BS) is a rare autoinflammatory disorder with NOD2 gain-of-function mutation and characterized by autoactivation of the NFκB pathway. Classically considered a disease of high penetrance, reports on NOD2 mutations underlining BS with incomplete penetrance is limited. CASE PRESENTATION: The proband is a 9-year-old girl presented with brownish annular infiltrative plaques and symmetric boggy polyarthritis over bilateral wrists and ankles. Her skin biopsy revealed noncaseating granulomas inflammation with multinucleated giant cells. A novel C483W NOD2 mutation was identify in the proband and her asymptomatic father. Functional examinations including autoactivation of the NFκB pathway demonstrated by in vitro HEK293T NOD2 overexpression test as well as intracellular staining of phosphorylated-NFκB in patient's CD11b+ cells were consistent with BS. CONCLUSIONS: We reported a novel C483W NOD2 mutation underlining BS with incomplete penetrance. Moreover, a phosphorylated-NFκB intracellular staining assay of CD11b+ was proposed to assist functional evaluation of NFκB autoactivation in patient with BS.

The Potential Role of Basophils in Urticaria.

Urticaria is a symptom of acute skin allergies that is not clearly understood, but mast cell histamine is hypothesized to cause swelling and itching. Omalizumab, an anti-human IgE antibody that traps IgE and prevents its binding to high-affinity IgE receptors, is effective in treating urticaria. We recently experienced a case of urticaria refractory to antihistamine therapy in which the peripheral-blood basophil count responded to omalizumab therapy and its withdrawal. Furthermore, the peripheral-blood basophils showed an unexpected increase in the expression of a cell surface activation marker. This phenomenon has been reported by other analyses of basophil and mast cell dynamics during omalizumab treatment. Here, we analyze these observations and formulate a hypothesis for the role of basophils in urticaria. Specifically, that activated basophils migrate to the local skin area, lowering peripheral-blood counts, omalizumab therapy alters basophilic activity and causes their stay in the peripheral blood. We hope that our analysis will focus urticaria research on basophils and reveal new aspects of its pathogenesis.

Potential Benefits of TNF Targeting Therapy in Blau Syndrome, a NOD2-Associated Systemic Autoinflammatory Granulomatosis.

Blau syndrome is a systemic autoinflammatory granulomatous disease caused by mutations in the nucleotide-binding oligomerization domain 2 (NOD2) gene. NOD2 is an intracellular pathogen recognition receptor. Upon binding to muramyl dipeptide (MDP), NOD2 activates the NF-κB pathway, leading to the upregulation of proinflammatory cytokines. Clinical manifestations of Blau syndrome appear in patients before the age of four. Skin manifestations resolve spontaneously in some cases; however, joint and eye manifestations are progressive, and lead to serious complications, such as joint contracture and blindness. Currently, there is no specific curative treatment for the disease. Administration of high-dose oral steroids can improve clinical manifestations; however, treatments is difficult to maintain due to the severity of the side effects, especially in children. While several new therapies have been reported, including JAK inhibitors, anti-IL-6 and anti-IL-1 therapies, anti-TNF therapy plays a central role in the treatment of Blau syndrome. We recently performed an ex vivo study, using peripheral blood and induced pluripotent stem cells from patients. This study demonstrated that abnormal cytokine expression in macrophages from untreated patients requires IFNγ stimulation, and that anti-TNF treatment corrects the abnormalities associated with Blau syndrome, even in the presence of IFNγ. Therefore, although the molecular mechanisms by which the genetic mutations in NOD2 lead to granuloma formation remain unclear, it is possible that prior exposure to TNFα combined with IFNγ stimulation may provide the impetus for the clinical manifestations of Blau syndrome.