Relapsing bullous amyloidosis of the oral mucosa and acquired cutis laxa in a patient with multiple myeloma: a rare triple association

It is well known that primary systemic amyloidosis [light chain (AL) amyloidosis] is associated with hidden dyscrasia or multiple myeloma. Acquired cutis laxa (cutis laxa acquisita; CLA) has also been described in patients with plasma cell dyscrasias, including multiple myeloma. We report a case in which haemorrhagic oral bullae were the first sign of an undiagnosed primary systemic amyloidosis related to multiple myeloma IgG‐λ and previously diagnosed CLA. There is only one report in literature of this rare triple association; however, in that case the patient did not have oral mucosal involvement or bullous amyloidosis.     

Clear association between serum levels of adipokines and T‐helper 17‐related cytokines in patients with psoriasis

Background. Psoriasis represents one of the T‐helper (Th)17‐mediated autoimmune diseases, and has been shown to be associated with metabolic syndrome (MetS). It has been reported that some adipokines and Th17‐related cytokines are altered in patients with psoriasis. Aim. To examine the relationship between levels of adipokines and Th17‐related cytokines in the serum of patients with psoriasis compared with healthy controls. Methods. We enrolled 30 patients with psoriasis and 30 normal controls in the study, and used ELISA to measure serum adipokines and Th17‐related cytokines. The association between each adipokine and each cytokine was determined using Pearson correlation analysis. Multiple regression analysis using all adipokines and Th17‐related cytokines as covariates was also performed. Results. Pearson correlation analysis showed a strong positive association between chemerin and resistin levels and between adiponectin and high molecular weight adiponectin in normal controls. By contrast, in patients with psoriasis, resistin levels were significantly positively associated with tumour necrosis factor‐α, while there was a strong negative association between retinol binding protein‐4 and interleukin (IL)‐6 levels. Interestingly, a marked positive correlation between IL‐22 and adiponectin was also found in patients with psoriasis. Leptin levels correlated positively with IL‐6 in patients with psoriasis, but this did not reach significance. The correlations identified by the multiple regression analyses were almost identical to those from the Pearson analyses. Conclusions. These data suggest that distinct interaction between adipokines and Th17 cytokines is involved in the pathogenesis of psoriasis.     

Cellular sources of IL‐17 in psoriasis: a paradigm shift?

Psoriasis is a common chronic inflammatory skin disease that results from interplay between the immune system and the epithelium. In the light of very successful anticytokine therapies for psoriasis, the focus has been directed towards the adaptive immune system. Expression studies, genetic studies and treatments specifically targeting players of the IL‐23/IL‐17 pathway, point at an important role for IL‐17 in the pathogenesis of psoriasis. IL‐17 stimulates the keratinocytes to produce psoriasis‐associated molecules, eventually leading to chronic skin inflammation. The current opinion is that IL‐17 is mainly produced by T cells, so‐called T‐helper 17 (Th17) cells, in psoriasis. However, evidence is accumulating that cells of the innate immune system, like neutrophils, mast cells, γδ T cells and innate lymphoid cells are the main source of IL‐17 in psoriasis, rather than T cells. The paradigm in this field of research is shifting. With this viewpoint article, we will address this novel concept by critically summarizing the current literature on this subject. In psoriatic arthritis and atherosclerosis, important conditions related to psoriasis, it was also found that the majority of IL‐17 is associated with cells of the innate immune system. This new concept changes our view of IL‐17. Blocking IL‐17 with targeted treatments might be more far‐reaching than previously thought; not only IL‐17 production by T cells but also by innate immune cells is blocked. Furthermore, therapies specifically targeting IL‐17 may not only improve psoriasis, but also comorbidity that is associated with the IL‐17 pathway, hereby preventing serious complications on the long term.     

Formation of immunoglobulin light chain amyloid oligomers in primary cutaneous nodular amyloidosis

Background Primary cutaneous nodular amyloidosis (PCNA) is thought to be a plasma cell dyscrasia. The amyloid deposits are found in the dermis and subcutis, and they contain clonal immunoglobulin light chains, produced by a local proliferation of plasma cells. New insights into amyloid diseases have revealed that the pathology is due more to the presence of small, misfolded protein species termed oligomers than to the deposition of fibrillar material. Objectives To demonstrate the presence of amyloid oligomers in PCNA and to provide evidence that cutaneous amyloid diseases share a common pathogenic pathway similar to other amyloid diseases. Methods Immunohistochemical staining with conformation‐specific and sequence‐specific antibodies was used to localize different amyloid species of light chain immunoglobulins in a case of PCNA. Additionally, in vitro characterization of immunoglobulin oligomers and fibrils was performed to determine, through toxicity studies in a human keratinocyte cell line, which amyloidogenic form of the immunoglobulin is toxic in PCNA. Results Amyloid oligomers were identified in PCNA. Oligomers were mainly formed by lambda light chain immunoglobulins, and kappa light chain oligomers were detected in lesser amounts. Amyloid species were detected intra‐ and extracellularly. In addition, amyloid oligomers and fibrils, derived from unknown protein sources, were detected. This finding suggests that immunoglobulin amyloids can act as seeds capable of inducing the aggregation of heterogeneous proteins in the skin. Furthermore, cytotoxicity studies demonstrated that immunoglobulin oligomers, but not monomers or fibrils, are toxic to human keratinocytes. Conclusions These data indicate that PCNA has common pathways with other amyloid diseases with respect to protein misfolding and pathogenesis. Immunoglobulin oligomers may prove to be targets for the treatment of PCNA.     

Secukinumab for treatment of psoriasis: does secukinumab precipitate or promote the presentation of cutaneous T‐cell lymphoma?

Secukinumab is an interleukin (IL)‐17 monoclonal antibody inhibiting T‐helper (Th)1‐mediated immune response. It has proven high efficacy for moderate to severe psoriasis but data on its long‐term toxicities are limited. We describe two patients who received secukinumab for clinically presumed psoriasis, but were subsequently diagnosed with mycosis fungoides (MF) following skin biopsies triggered by skin deterioration while on secukinumab. Previous studies suggested decreased numbers of regulatory T cells (Tregs) with increasing stage of MF, which may lead to the shift in the Treg/Th17 balance towards the Th17 pathway. Theoretically, the use of IL‐17 monoclonal antibodies to inhibit Th17 pathway may lead to further immunosuppression and disease progression in cutaneous T‐cell lymphoma (CTCL) by shifting the balance towards Tregs, although this hypothesis has not been proven. With uncertainty over the role of IL‐17 and Treg/Th17 as well as diagnostic challenges in CTCL, we recommend that patients should have a confirmatory skin biopsy prior to the commencement of biologic therapy.     

Extended survival of patients with primary systemic amyloidosis.

Systemic amyloidosis can produce a wide variety of clinical manifestations, including characteristic cutaneous findings. Large series of patients with primary systemic amyloidosis have shown that systemic amyloidosis, with or without associated myeloma, has a median survival of no more than twenty-four months. We present a case of systemic amyloidosis that has been present in a woman for eighteen years, as manifested by periorbital purpura and an immunoglobulin G kappa light chain paraproteinemia. She was otherwise healthy; results of bone marrow examination showed no overt myeloma. We speculate that kappa light chain paraproteinemia could prove to be a marker for a more benign type of systemic amyloidosis.     

无明显内脏损害的原发性系统性淀粉样变病2例

报告2例原发性系统性淀粉样变病患者,均表现为皮肤瘀斑,皮肤组织病理也可见大片的淀粉样物质在血管壁上的沉积。两例患者均伴有血清IgA和尿κ轻链升高,但尚未发现明显的内脏受累。患者1免疫电泳有单克隆条带,骨髓浆细胞增生,符合骨髓瘤诊断标准;患者2缺乏免疫产物单克隆增生的证据,骨髓无明显浆细胞增生,只能诊断浆细胞失调,但其疾病未来的转归尚有待长期观察。     

Monoclonal gammopathies and associated skin disorders

The monoclonal gammopathies are characterized by clonal proliferation of plasma cells and other clonally related cells in the B-cell lineage. These disorders include monoclonal gammopathy of undetermined significance, multiple myeloma, Waldenstr?m macroglobulinemia, heavy chain diseases, plasmacytoma, and primary amyloidosis. Many skin disorders have been described in association with monoclonal gammopathies. This article provides an introduction to the definition, detection, natural course, and spectrum of monoclonal gammopathies and a brief discussion of pathogenesis. The article also reviews the skin disorders associated with monoclonal gammopathies, categorizes the association, and evaluates the strength of the association.     

间充质干细胞及其外泌体与Th17/Treg对银屑病发病机制的研究进展

【摘要】 Th17/Treg细胞失衡是银屑病发病机制中被普遍认可的免疫发病机制之一。间充质干细胞（MSC）可抑制Th17细胞的增殖分化,诱导Treg细胞增殖。MSC分泌的外泌体是 MSC进行细胞间信息交流与物质转运的重要载体。研究发现,MSC源性外泌体有与MSC类似的免疫调节作用,可抑制Th17细胞增殖,诱导Treg细胞分化。近年来许多研究表明,银屑病患者骨髓及皮损处皮肤MSC的异常与银屑病的发生有关,但其机制尚不清楚。本文阐述正常MSC及其外泌体对维持Th17/Treg平衡的作用,为研究银屑病患者骨髓及皮损处皮肤MSC异常是如何参与到银屑病的发病提供思路。     

Perianal condyloma-like lesions in multiple myeloma associated amyloidosis

Systemic types of amyloidosis include those associated with plasma cell dyscrasia, as in multiple myeloma. Here we describe a 57-year-old woman who was diagnosed as having multiple myeloma IgG lambda. Six months after the diagnosis of myeloma, mucocutaneous lesions began to develop, with ecchymoses in the body folds and eyelid and periorbital purpura. Pedunculated condylomatous tumours began to develop in the perianal area. The excisional biopsy of a perianal nodule revealed a faintly eosinophilic, amorphous material replacing almost the entire dermis, in association with ectatic, endothelial-lined vascular spaces. The dermal deposits showed affinity with Congo Red stain. There were no histopathological features typical of condylomata acuminata. A diagnosis of cutaneous myeloma-associated amyloidosis was established. To our knowledge, this is the second reported case of condyloma-like perianal lesions in multiple myeloma-associated amyloidosis.     

Development of psoriasis by continuous neutrophil infiltration into the epidermis

Remarkable effects of anti‐IL‐17A and anti‐IL‐23 antibodies on psoriasis indicate deep involvement of IL‐23/Th17 axis in the pathogenesis of psoriasis. According to the current immune theory, activation of dendritic cells initiates the generation of this axis. However, this theory is not enough to explain the mechanism, because the process of this activation is obscure and the antigen that is recognized by antigen‐presenting cells and pathogenic T cells has long been unidentified. Therefore, I thought of another theory as follows. Neutrophils are attracted by LTB4 at subcorneal portion and infiltrate into the epidermis. At the time of neutrophil migration through the basement membrane, basal keratinocytes in G0/G1 phase enter the cell cycle and begin to proliferate, according to the principle, “detachment‐mediated cell proliferation.” This passing is continuously repeated and leads to elongation of rete ridges. The IL‐23/Th17 axis is generated by interactions between infiltrated neutrophils and keratinocytes. Briefly, neutrophils infiltrated into the epidermis secrete IL‐17A, which acts on keratinocytes to express CCL20, a ligand for the chemokine receptor CCR6. Keratinocytes perturbed by neutrophil infiltration produce HSP70, followed by production of IL‐23 via TLR4 using HSP70 as an endogenous ligand for TLR4. Natural Th17 cells expressing CCR6 are recruited to psoriatic epidermis and expand there in the presence of IL‐23 and IL‐1β. In this manner, the framework of the IL‐23/Th17 axis is created, which acts to maintain or exacerbate psoriasis. Noteworthy is the fact that this axis causes positive feedback loop, starting from IL‐17A production by neutrophils and ending in IL‐17A production by nTh17 cells. Therapeutic mechanisms of anti‐IL‐17A and anti‐IL‐23 antibodies, targeting neutrophils, were also described.     

miRNA miR‐17‐92 cluster is differentially regulated in the imiqumod‐treated skin but is not required for imiqumod‐induced psoriasis‐like dermatitis in mice

MicroRNAs (miRNAs) play very important roles in the control of immune cell and keratinocyte development and function and are implicated in skin inflammatory diseases, including psoriasis. miRNA miR‐17‐92 was reported to promote the differentiation of Th1 and Th1 cells and to regulate cell proliferation and apoptosis. Here we showed that imiquimod (IMQ) differentially regulates the expression of miR‐17‐92 cluster in the mouse skin, upregulating miR‐17 and miR‐19 families and downregulating miR‐92. To investigate whether miR‐17‐92 cluster is functionally involved in the psoriasis, we have generated three mutant mice with specific deletion or overexpression of miR‐17‐92 cluster in keratinocytes, or with deletion of miR‐17‐92 cluster in T cells. Interestingly, deletion or overexpression of miR‐17‐92 cluster in keratinocytes, or deletion of miR‐17‐92 in T cells did not significantly affect IMQ‐induced psoriasis‐like dermatitis development in the mutant mice compared with wild‐type littermates. Thus, miRNA miR‐17‐92 cluster may not be a key factor regulating imiqumod‐induced psoriasis‐like dermatitis.     

The role of the interleukin-23/Th17 pathway in cardiometabolic comorbidity associated with psoriasis

Alterations in the innate and adaptive immunity underpin psoriasis pathophysiology, with the Th17 cells subset now recognized as the fundamental cells in the key controlling pathway involved in its pathogenesis. Since psoriasis is a systemic disease with important comorbidity, further knowledge on the interleukin (IL)-23/Th17 axis led to the hypothesis that there may be shared pathogenic pathways between primary skin disease and comorbidity. Psoriasis has been identified as a risk factor for cardiovascular and metabolic disease, and increasing evidence gives support to this epidemiological observation from the clinical-pathologically field. As an example, increased levels of IL-23 and IL-23R have been found in human atherosclerotic plaque, and levels correlated with symptom duration and mortality. Also, upregulation of IL-23/IL-17 seems to play an important role in both myocardial damage and stroke, with interesting reports on deleterious effect neutralization after administration of related anti-bodies in both associated conditions. In diabetic patients, increased levels of IL-23/IL-17 have also been observed and available data support a synergistic role of IL-23/IL-17 in β-cells damage. In obesity, signs of an expansion of Th17 subset in adipose tissue have been reported, as well as elevated concentrations of IL-23 in obese patients. In non-alcoholic fatty liver disease, closely related to metabolic syndrome, but also in other mentioned cardiometabolic disorders, a predominance of IL-23 and other related pro-inflammatory factors has been identified as participating in their pathogenesis. Thus, the involvement of the IL-23/Th17 axis in these shared psoriasis-cardiometabolic pathogenic mechanisms is reviewed and discussed in the light of the existing preclinical and clinical evidence, including that from comorbid psoriasis patients.     

Coexpression of CCR6 and CD146 (MCAM) is a marker of effector memory T-helper 17 cells

Effector memory T (T_EM) cells are a subpopulation of memory T cells that express receptors mediating migration to inflamed tissues and produce various cytokines. Effector memory T‐helper (Th)17 (Th17_EM) cells are thought to be essential for inflammation in Th17‐mediated diseases, but have not been studied in detail. To identify superior surface markers to isolate a homogeneous population of Th17_EM cells from peripheral blood, CD4⁺ T cells were isolated from the peripheral blood of healthy donors based on the expression of CCR7, CCR6 and CD146 using six‐color flow cytometry. After 4 days of culture in the presence of anti‐CD3/28 beads, intracellular cytokines were determined by flow cytometric analysis. To investigate the relevance of Th17_EM cells in Th17‐mediated disease, the frequencies of T_EM‐cell subsets in psoriasis were quantified using six‐color flow cytometry. An enzyme‐linked immunosorbent assay was performed to confirm the interleukin (IL)‐17‐producing capacity of T_EM‐cell subsets from the peripheral blood of a patient with psoriasis. CCR6⁺CD146⁺ T_EM (CD4⁺CD45RA^?CCR7^?) cells had a greater capacity to produce IL‐17 than CCR6⁺CD146^? or CCR6^?CD146⁺ T_EM cells. Although the percentage of CCR6⁺CD146⁺ cells in T_EM cells was not significantly different between patients with psoriasis and controls, three of eight patients had a higher percentage of CCR6⁺CD146⁺ T_EM cells than the mean +5 standard deviations of the controls. Coexpression of CCR6 and CD146 is a useful marker for Th17_EM cells. Increasing the number of CCR6⁺CD146⁺ Th17_EM cells in peripheral blood may facilitate estimation of systemic Th17‐cell activity in Th17‐mediated diseases.     

Histopathological and immunohistochemical study of amyloidosis cutis nodularis atrophicans—Comparison with systemic amyloidosis

Three cases of amyloidosis cutis nodularis atrophicans (ACNA) were investigated histologically and immunohistochemically to determine the nature and origin of the deposited amyloid. A pulmonary lesion from a case of nodular pulmonary amyloidosis, and cutaneous lesions from three cases of primary systemic amyloidosis, two cases of secondary systemic amyloidosis and three cases of secondary cutaneous amyloidosis following basal cell epithelioma were also examined for comparison. Histology showed infiltration of numerous plasma cells adjacent to amyloid deposits in ACNA and nodular pulmonary amyloidosis, but not in systemic amyloidosis. Immunohistochemically, the cytoplasm of the plasma cells was stained with anti-immunoglobulin light chain or anti-Bence-Jones protein antisera or both, and amyloid material stained with anti-AL antiserum in ACNA and nodular pulmonary amyloidosis. These results suggest that, in ACNA, the plasma cells may produce and secrete immunoglobulin light chains or Bence-Jones protein or both, which undergo proteolysis to protein AL or amyloid fibril proteins which have the same immunoglobulin determinants as protein AL. The product is then deposited locally to form nodules in the dermis.     

The Akkermansia muciniphila is a gut microbiota signature in psoriasis

Psoriasis is an immune‐mediated chronic inflammatory skin disease. Although its pathogenesis is not fully understood, Th17 cells and the cytokines they produce, such as IL‐17, IL‐22 and IL‐23, play critical roles in the pathogenesis of psoriasis. Evidence has demonstrated that psoriasis has some common features, including immune responses (due to Th17 cells) and inflammatory cytokine profiles, with systematic diseases including inflammatory bowel diseases (IBDs) and obesity. Recently, studies have demonstrated that the gut microbiota plays a crucial role in host homoeostasis and immune response, particular in Th17 cells, but the role of the gut microbiota in psoriasis remains unclear. To study the relationship between gut microbiota and psoriasis, we analysed microbiota profiles in psoriasis using a 16S rDNA sequencing platform, and we found that the abundance of Akkermansia muciniphila was significantly reduced in patients with psoriasis. A. muciniphila is believed to have an important function in the pathogenesis of IBD and obesity; therefore, A. muciniphila, which is an indicator of health status, may be a key node for psoriasis as well as IBD and obesity. Taken together, our study identified that gut microbiota signature and function are significantly altered in the gut of patients with psoriasis, which provides a novel angle to understanding the pathogenesis of psoriasis.     

Primary localized cutaneous amyloidosis with unusual clinical features in a patient with Sjögren's syndrome

A 69‐year‐old woman presented with a 2‐year history of an eczematous lesion covering the genital area. Histopathological examination showed deposits of amorphous, eosinophilic material and an infiltrate of plasma cells through the entire dermis into the subcutaneous fatty tissue. Congo red‐stained deposits showed apple‐green birefringence with polarizing microscopy. On immunohistochemistry, the deposited material was positively stained with anti‐κ light chain antibodies but not with anti‐λ light chain. A diagnosis of primary localized cutaneous amyloidosis (PLCA) was made, and the patient was also diagnosed as having Sjögren's syndrome (SjS) based on clinical and laboratory findings. The lesion of PLCA has spontaneously regressed over a period of 18 months. We report a unique case of PLCA and SjS that clinically demonstrated genital eczematous features and spontaneous involution, and we also describe a possible association between PLCA and SjS.     

Gene rearrangement studies in the diagnosis of primary systemic and nodular primary localized cutaneous amyloidosis

Difficulties may arise in the diagnosis of patients with clinical features suggestive of plasma cell dyscrasia-related amyloidosis (amyloidosis L), but without evidence of a paraprotein. We have employed gene rearrangement methodology to demonstrate the clonality of bone marrow cells not only in a patient with myeloma-associated systemic amyloidosis, but also in a patient with "primary" systemic amyloidosis without overt myeloma or a detectable paraprotein. Furthermore, we have shown the clonality of the amyloid-producing plasma cells within a skin nodule of a patient with primary localized cutaneous amyloidosis; by contrast, clonal rearrangement was not detected in bone marrow cells from this patient. This finding provides definitive proof that organ-limited nodular primary localized cutaneous amyloid deposits arise in relation to cutaneous plasmacytomas. Gene rearrangement studies may enable early diagnosis and initiation of treatment in patients with systemic amyloidosis L, as well as their differentiation from patients with organ-limited nodular cutaneous amyloidosis, who do not require aggressive therapy.     

Impaired expression of Tim-3 on Th17 and Th1 cells in psoriasis

Psoriasis is a chronic skin disease mediated by Th17 and/or Th1 cells. Tim-3 is a cell surface molecule preferentially expressed on Th17 and Th1 cells. The interaction of Tim-3 with Tim-3 ligand inhibits cytokine production. To assess whether T cells in psoriasis have functional abnormalities, expression of cell surface Tim-3 on blood T cells producing interleukin-17 (Th17/Tc17 cells) or interferon-γ (Th1/Tc1 cells) was examined by flow cytometry. Psoriasis patients had higher numbers of Th17 and Tc17 cells, as well as Th1 and Tc1 cells, than healthy donors. However, Th17, Th1 and Tc1 cells in psoriasis did not efficiently express Tim-3 upon activation, compared with those from atopic dermatitis and healthy donors. Tim-3- cells showed more potent cytokine production than Tim-3+ cells. Impaired Tim-3 expression allows Th17, Th1 and Tc1 cells to escape from Tim-3-mediated negative regulatory systems and may contribute to the pathogenesis of psoriasis.     

IL‐33 is secreted by psoriatic keratinocytes and induces pro‐inflammatory cytokines via keratinocyte and mast cell activation

IL‐33 is a novel pro‐inflammatory cytokine and ligand for the orphan receptor ST2. Although originally defined as an inducer of Th2‐mediated responses, IL‐33 was recently found to be involved in arthritis, a Th1/Th17‐mediated disease. Here, we assessed the ability of IL‐33 to promote inflammation via mast cells (MCs) and keratinocytes (KCs) activation in psoriasis. IL‐33 resulted elevated in the skin but not in the serum of psoriasis patients. IL‐33 was secreted by psoriasis KCs and HaCaT cells after TNF‐α stimulation. In HMC‐1, TNF‐α, but not IL‐17, could induce a robust increase in IL‐33 expression. In HaCaT cells, TNF‐α was able to induce IL‐6, MCP‐1 and VEGF, and the addition of IL‐33 reinforced these increases. TNF‐α + IL‐33 combination showed similar results in primary KCs and ex vivo skin organ culture. In conclusion, our study suggests that IL‐33 may be involved in psoriasis biology via MCs and KCs.