Ichthyotic‐Appearing Skin Changes Associated with Childhood Morphea,Systemic Sclerosis,and Systemic Lupus Erythematosus/Scleroderma Overlap

Abstract: Ichthyotic‐appearing skin changes have been associated with autoimmune disorders, including systemic lupus erythematosus and systemic sclerosis in adults. We report three children with ichthyotic‐appearing skin changes that may be an early feature reflecting underlying dermal sclerosis. Detection of these subtle skin changes may be predictive of more widespread cutaneous involvement, ultimately prompting earlier treatment.     

Autoantibody profiles in systemic sclerosis: Predictive value for clinical evaluation and prognosis

Systemic sclerosis (SSc) is thought to be an autoimmune disease, as autoantibodies against a variety of extractable nuclear antigens can be detected in patient sera. Subgrouping patients based on the type of autoantibodies present can be useful in diagnosis and management. Anti-centromere antibodies (ACA) and anti-topoisomerase I antibodies (anti-topo I) are the classic autoantibodies associated with SSc. ACA are associated with limited cutaneous involvement and isolated pulmonary hypertension, whereas anti-topo I are associated with diffuse skin involvement and pulmonary fibrosis. ACA are predictors for a favorable prognosis, while anti-topo I are correlated with a poor prognosis and SSc-related mortality. Additionally, anti-RNA polymerase antibodies (anti-RNAP) are associated with diffuse cutaneous disease and renal involvement. Anti-nucleolar antibodies define multiple subgroups of patients with SSc. Of these, anti-Th/To antibodies (anti-Th/To) and anti-PM-Scl antibodies (anti-PM-Scl) are associated with limited cutaneous SSc (lSSc), whereas anti-U3RNP antibodies (anti-U3RNP) are associated with diffuse cutaneous SSc (dSSc). In addition, anti-Th/To and anti-U3RNP can be predictors for a less favorable prognosis with a higher frequency of organ involvement, such as pulmonary fibrosis, pulmonary hypertension and renal crisis. Other autoantibodies are less frequently reported: anti-Ku antibodies, anti-U1RNP antibodies, anti-human upstream-binding factor, and anti-U11/U12 antibodies. These antibodies are generally less specific to SSc, but also define clinically distinct patient subsets. Thus, characterization of autoantibodies in SSc together with knowledge of disease characteristics intrinsic to distinct patient populations is helpful for assessing the clinical presentation and prognosis of this disease, and for monitoring patients with SSc.     

The phenotypic profile of dermatomyositis and lupus erythematosus: a comparative analysis

Background: The mechanisms which regulate cutaneous inflammation in the setting of collagen vascular disease have been a topic of recent interest; emphasis has been placed on type I interferon‐associated recruitment of CXCR3+ lymphocytes in dermatomyositis (DM). Methods: On a total of 42 biopsies from patients with DM, systemic lupus erythematosus (SLE), discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE) comprehensive phenotypic studies were performed to explore the practical value of phenotypic analysis in the subclassification of lesions of collagen vascular disease. Results: The infiltrate in DM was of mild intensity compared to lupus erythematosus (LE). The dominant mononuclear cell in DM exhibited a CD4/CXCR3‐positive phenotype while biopsies of SLE typically showed a dearth of CXCR3‐positive cells. CD8 and CD20 lymphocytes were greatest in SLE and DLE, respectively. CD123 plasmacytoid dendritic cells, seen in most cases, were most frequent in cases of SCLE; CD83 expression was minimal. Endothelial MXA expression was a characteristic feature of DM. CD123 and MXA expression within inflammatory cells and keratinocytes was most conspicuous in areas of interface injury. Cutaneous lymphocyte antigen (CLA) expression was diminished in the dermal infiltrate in most cases of DM and LE. T regulatory cells never exceeded 15% of the infiltrate and were the least in the setting of DM and LE. Conclusions: An interferon‐α‐inducible cytokine milieu is common in SLE, DLE, SCLE and DM. In addition, there are phenotypic differences as alluded to above that may be of some practical value in separating these distinctive subsets. Features not previously emphasized such as MXA endothelial cell staining in DM and the lack of staining for CD83 and CLA in lesions of collagen vascular disease may be of diagnostic value. Magro CM, Segal JP, Crowson AN, Chadwick P. The phenotypic profile of dermatomyositis and lupus erythematosus: a comparative analysis.     

Serum levels of anti‐Fcγ receptor IIB/C antibodies are increased in patients with systemic sclerosis

Systemic sclerosis (SSc) is a systemic autoimmune disorder that results in fibrosis of the skin and multiple internal organs. Although the precise mechanism is unknown, it appears to result from the overproduction of extracellular matrix proteins and aberrant immune activations. Receptors for the Fc region of immunoglobulin (Ig)G (FcγR) are members of the Ig superfamily that modulate both activation and inhibition of immune responses. FcγRIIB is the sole inhibitory member, which has an intrinsic cytoplasmic immunoreceptor tyrosine‐based inhibitory motif. The present study was undertaken to investigate the circulating concentrations of anti‐FcγRIIB/C antibodies (Ab) in patients with SSc. Serum levels of anti‐FcγRIIB/C Ab were significantly increased in patients with SSc compared to those in controls and in patients with localized scleroderma. Serum levels of anti‐FcγRIIB/C Ab in patients with limited cutaneous SSc were similar to those in patients with diffuse cutaneous SSc. Among SSc patients, serum levels of anti‐FcγRIIB/C Ab were increased in those with nail‐fold bleeding and decreased in those with diffuse pigmentation and calcinosis. These findings support the notion that increased serum anti‐FcγRIIB/C Ab levels are involved in aberrant immune responses in SSc.     

Natural killer and natural killer-T cells in psoriasis

Psoriasis is characterized by a dermal and epidermal infiltrate comprised predominantly of CD4(+) and CD8(+) T cells, respectively. These cells behave in an antigen-dependent manner, which suggests that psoriasis may be a T-cell-mediated autoimmune disease. Psoriasis shares certain immunological features with recognized autoimmune conditions such as type I diabetes mellitus and multiple sclerosis, in both of which a pathogenic role is postulated for natural killer (NK) cells and natural killer-like T (NK-T) cells. However, there are few studies assessing the role of NK and NK-T cells in psoriasis. We sought to determine whether NK and NK-T cells are present in psoriasis. Skin biopsies were taken from the active edge of a psoriasis plaque and from uninvolved skin at least 5 cm away from involved skin of ten patients with chronic plaque psoriasis. Skin from four normal subjects was used as controls. Using an immunoperoxidase technique, cryostat sections were stained using antibodies to T-cell markers CD2, CD3, CD4 and CD8; cutaneous leucocyte associated antigen; NK cell markers CD16, CD56, CD57, CD94 and CD158a; and the NK-T cell marker CD161. There were significantly more cells expressing T cell markers, NK cell markers CD16, CD57, CD94 and CD158a and NK-T cell marker CD161 in involved skin than in uninvolved or normal skin ( P<0.01). There was no difference in the number of cells expressing CD56. Cells expressing NK markers were found most commonly in the papillary dermis immediately subjacent to the dermoepidermal junction. Cells expressing CD57 were found in significantly higher numbers in the epidermis and reticular dermis of involved skin. This study demonstrates that cells expressing NK markers and NK-T cell markers are present in plaques of psoriasis. The exact roles of NK and NK-T cells in psoriasis are unclear, although they may modulate autoimmune inflammation and act as a source of Th(1) cytokines important in the psoriatic process.     

Coexistence of pemphigus foliaceus and acquired hemophilia A: A case report

Pemphigus foliaceus (PF) is an autoimmune bullous dermatosis with anti‐desmoglein‐1 autoantibodies. Acquired hemophilia A (AHA) is a rare coagulation disorder with a high mortality rate, caused by anti‐factor VIII immunoglobulin G antibodies leading to spontaneous severe hemorrhages into skin, muscles or soft tissues. This coagulopathy may be associated with malignancies, drug reactions and autoimmune disorders including bullous dermatoses. Herein, we demonstrate a first report of AHA in the course of pemphigus foliaceus. A 55‐year‐old woman presenting with extensive, erosive, crusted, scaly skin lesions was diagnosed with PF based on histopathological and immunofluorescent examination, confirmed by the presence of anti‐desmoglein‐1 antibodies on enzyme‐linked immunoassay. She developed extensive internal hemorrhages and prolonged external bleeding after laparotomy. Based on coagulation tests, AHA was diagnosed. Simultaneous remission of pemphigus and coagulopathy occurred with immunosuppressants and recombinant activated factor VII.     

Augmented production of soluble CD93 in patients with systemic sclerosis and clinical association with severity of skin sclerosis

Background The cell surface protein CD93, expressed on endothelial and myeloid cells, mediates phagocytosis, inflammation and cell adhesion. A soluble form of CD93 (sCD93) is released during inflammation. Objectives To determine the serum sCD93 level and its association with clinical parameters in patients with systemic sclerosis (SSc). Methods Serum sCD93 levels were examined by enzyme‐linked immunosorbent assay in 59 patients with SSc, 24 patients with systemic lupus erythematosus and 47 healthy individuals. The expression of CD93 in skin tissues was examined immunohistochemically. In a retrospective longitudinal study, sera from 11 patients with SSc were analysed. Results Serum sCD93 levels were increased in patients with SSc compared with healthy individuals (P < 0·001). Patients with diffuse cutaneous SSc showed greater levels of sCD93 than those with limited cutaneous SSc (P < 0·01) or systemic lupus erythematosus (P < 0·01). Serum sCD93 levels correlated positively with the severity of skin sclerosis. Strong CD93 immunostaining was observed on endothelial cells in lesional skin tissues. In the longitudinal study, sCD93 levels decreased in parallel with improvement in skin sclerosis. Conclusions Serum sCD93 levels are increased in patients with SSc and correlate with the severity and activity of skin sclerosis. CD93 may contribute to the development of skin fibrosis in SSc.     

Serum levels of soluble programmed death‐1 and programmed death ligand‐1 in systemic sclerosis: Association with extent of skin sclerosis

The interaction of programmed death‐1 (PD‐1) with its ligand, programmed death ligand‐1 (PD‐L1), has been considered to play a key role in the negative regulation of immune responses. Patients with diffuse cutaneous systemic sclerosis (SSc) had higher levels of soluble PD‐1 (sPD‐1) than those with limited cutaneous SSc and healthy individuals. Serum sPD‐1 levels positively correlated with the severity of skin sclerosis. In contrast, serum sPD‐L1 levels were significantly increased in patients with SSc compared with healthy individuals. Moreover, serum sPD‐L1 levels were not associated with the extent of skin sclerosis and were elevated not only in patients with diffuse cutaneous SSc, but also in those with limited cutaneous SSc. These results suggested that serum sPD‐1 levels may increase in patients with SSc and correlate with the severity of skin sclerosis. PD‐1/PD‐L1 interaction may contribute to the development of skin sclerosis in SSc.     

Efficacy of low-dose methotrexate in the treatment of dermatomyositis skin lesions

A limited number of case series has indicated that methotrexate (MTX) might be a useful drug in the treatment of dermatomyositis (DM), a rare autoimmune disease involving the skin and muscles. However, these earlier studies mainly focused on the efficacy of MTX on DM muscular symptoms. To analyse the efficacy of MTX on skin lesions in DM, the records of 34 patients with DM seen between 2004 and 2009 were retrospectively analysed, and the DM skin disease activity at different time points was determined, with specific focus on cutaneous features using the validated Cutaneous Dermatomyositis Activity Index (CDASI) score. The lesional inflammation was scored in primary skin biopsies. Additionally, we performed a systematic review of the available literature. In our series, 11 patients with DM received MTX, and in 8 of them, MTX led to a significant reduction of the DM skin lesions. CDASI scores decreased from 15.7 to 6.4 (P < 0.01) within 2-3 months, supporting the effectiveness of MTX in skin disease in DM. The lymphocytic infiltrate in primary skin lesions of MTX responders was significantly more pronounced than that in nonresponders. These results indicate that MTX might be an effective drug to treat the cutaneous symptoms of DM, as measured by the validated CDASI. Interestingly, MTX responders histologically presented a significantly stronger lesional lymphocytic inflammatory infiltrate than did nonresponders. These findings suggest that the functional inhibition of lymphocyte migration in the skin might be an important mechanism of MTX in the treatment of DM.     

Serum periostin levels are correlated with progressive skin sclerosis in patients with systemic sclerosis

Background Periostin, a matricellular protein, serves as a regulator of wound healing and fibrosis. The role of periostin in the pathogenesis of systemic sclerosis (SSc) is unknown. Objective To determine periostin levels in association with severity of skin fibrosis in patients with SSc. Methods Expression of periostin was immunohistochemically examined in skin obtained from patients with SSc and healthy controls. Enzyme‐linked immunosorbent assay was performed to evaluate serum periostin levels in association with clinical characteristics in 56 patients with SSc [diffuse cutaneous SSc (dSSc), n = 16; and limited cutaneous SSc (lSSc), n = 40] and 66 healthy controls. Results Periostin was strongly expressed in the affected dermis from patients with SSc. Periostin was colocalized in α‐smooth muscle actin‐positive myofibroblasts and platelet endothelial cell adhesion molecule‐1‐positive endothelial cells in SSc dermis. Serum levels of periostin in patients with dSSc were markedly elevated compared with those in patients with lSSc and control subjects. Patients with lSSc had increased periostin levels compared with healthy controls. In addition, significantly higher levels of periostin were observed in patients with dSSc with disease duration ≤ 5 years compared with those with disease duration > 5 years. Furthermore, the modified Rodnan total skin thickness score (MRSS) was positively correlated with periostin levels in patients with SSc. Serial analysis revealed a correlation between periostin and MRSS; namely, MRSS decreased in line with decreased periostin levels in some patients with dSSc as the disease progressed. Conclusion An elevated periostin level in patients with SSc is associated with severity of skin sclerosis. Periostin may be a potential biomarker for progressive skin fibrosis in SSc.     

Plasma homocysteine levels are positively associated with interstitial lung disease in dermatomyositis patients with anti‐aminoacyl‐tRNA synthetase antibody

Homocysteine is a sulfhydryl‐containing amino acid that is derived from dietary methionine, and there has been increasing evidence that elevated plasma homocysteine levels are associated with increased risk of central and peripheral vascular disorders, including carotid, coronary and peripheral arterial diseases, and Raynaud’s phenomenon. Recently, associations of plasma homocysteine levels with autoimmune diseases such as systemic lupus erythematodes and systemic sclerosis have been reported. However, no study analyzed the association between plasma homocysteine levels and dermatomyositis (DM). The objective of this study was to examine plasma homocysteine levels and their clinical associations in patients with DM. Plasma homocysteine levels in 28 Japanese patients with DM and 22 healthy controls were examined. We found that the plasma homocysteine levels in DM patients were significantly higher than those in healthy individuals (15.8 ± 1.1 vs 8.5 ± 0.5 µmol/L, P < 0.01). Presence of mechanic’s hand, complication of interstitial lung disease (ILD), high serum Krebs von den Lungen‐6 (KL‐6), surfactant protein‐D and creatine kinase levels, and anti‐aminoacyl‐tRNA synthetase (ARS) antibody (Ab) positivity were significantly more prevalent among DM patients with elevated plasma homocysteine levels. The plasma homocysteine levels in DM patients with mechanic’s hand, ILD and anti‐ARS Ab were significantly higher than those in DM without those features. Furthermore, the plasma homocysteine levels were positively correlated with serum KL‐6 levels. These results suggest that the pathogenesis of elevated plasma homocysteine levels may be associated with ILD in DM patients, especially with anti‐ARS Ab, and further examination is required.     

Case of diffuse cutaneous systemic sclerosis with anti‐Ku and anti‐centromere antibodies

We report the case of a 58‐year‐old man who had an ulcer on the right middle finger that was cured by surgery 4 years before consultation with our department. A few years after the surgery, he noticed recurrence of the ulcer and sclerosis of the skin. At the initial examination, skin sclerosis was observed from the fingers to the upper arms and from the feet to the thighs. Pitting scars on the fingertips and punctured hemorrhages of the nail‐fold capillaries were also present. Gastroscopy showed slight reflex esophagitis. Laboratory findings were positive for antinuclear antibody (ANA; 1:640) with a speckled and discrete speckled pattern. Anti‐topoisomerase I (anti‐topo I) antibody and anti‐RNA polymerase III were negative, but anti‐centromere antibody was positive in an enzyme‐linked immunosorbent assay. Anti‐Ku antibody was positive in an immunoprecipitation assay using extracts of the leukemia cell line K562. Therefore, the patient was diagnosed with diffuse cutaneous systemic sclerosis with anti‐Ku and anti‐centromere antibodies. Treatment with an oral antiplatelet agent, vitamin E, a proton pump inhibitor, and i.v. lipoprostaglandin E1 were started. Subsequently, there has been repeated recurrence of finger ulcers, but no muscle involvement has been detected since his first visit. This is the first reported case of systemic sclerosis with anti‐Ku and anti‐centromere antibodies.     

Cutaneous lymphocyte antigen expression in benign and neoplastic cutaneous B- and T-cell lymphoid infiltrates

Background: Cutaneous lymphocyte‐associated antigen (CLA) is expressed in resident cutaneous T lymphocytes, high endothelial venules, peripheral monocytes, granulocytes and a small percentage of memory B cells. It has been postulated to be an important factor in homing of lymphocytes to the skin because of its function as a ligand for E‐selectin expressed on cutaneous endothelial cells. Design: We investigated the expression of CLA using the HECA‐452 antibody on paraffin‐embedded, formalin‐fixed tissue in a variety of reactive, neoplastic and preneoplastic cutaneous lymphoid infiltrates of T‐ and B‐cell derivation. Results: CLA was expressed at high levels in various types of inflammatory dermatoses with the exception of lupus erythematosus. High levels of CLA expression were seen in epidermotropic T‐cell dyscrasias and epidermotropic T‐cell lymphomas including mycosis fungoides (MF) and adult T‐cell leukemia/lymphoma (ATCLL). A loss of CLA in tumors normally positive for CLA was a feature of disease progression best exemplified by tumor‐stage MF and acute ATCLL. There was a lack of CLA expression in those lymphocytic infiltrates manifesting subcutaneous localization including lupus profundus, panniculitis‐like T‐cell lymphoma and atypical lymphocytic lobular panniculitis. CLA expression was not only observed in primary cutaneous anaplastic large cell lymphoma but also seen in cases of nodal anaplastic large cell lymphoma secondarily involving the skin and was negative in cases of nodal anaplastic large cell lymphoma without any established skin involvement. An oligodot pattern defined a novel reaction pattern in those aggressive systemic dyscrasias with a proclivity to involve the skin. CLA was negative in the majority of B‐cell lymphomas. Conclusions: CLA plays a role in the pattern of T‐cell lymphocyte migration in the skin and subcutis in both reactive and neoplastic states. An alteration in the expression of this marker, whether it is in the context of the acquisition of expression in a cell that is normally CLA negative or its loss of expression, may define a key event in determining cutaneous and extracutaneous hematopoietic cell distribution.     

Epidermal multinucleated keratinocytes: a histopathologic clue to dermatitis artefacta

Dermatitis artefacta is a psycho‐cutaneous disorder characterized by self‐inflicted cutaneous injuries, often in association with an underlying psychiatric disorder or as a response to external stressors. Cutaneous lesions suggestive of dermatitis artefacta are dependent on the means of injury and thus may be morphologically variable, but typically have geometric shapes, spare hard‐to‐reach anatomic areas, and are present in variable stages of evolution at any specific time. Although a dermatologist may be suspicious of dermatitis artefacta in a given patient, making a definitive diagnosis is extremely challenging. Patients often clinically evade questioning and deny creating skin lesions, and histopathologic evaluation of lesional biopsies usually reveals non‐specific epidermal and dermal changes and inflammation. Thus, identification of clues that lend support to a diagnosis of dermatitis artefacta would be welcomed by both clinicians and pathologists. Here we present a case of dermatitis artefacta with a unique, yet previously reported, histopathological finding of multinucleated keratinocytes within the epidermis. Although probably uncommon and dependent on the etiology of cutaneous injury, we believe this finding is important for dermatopathologists to be aware of as a potential diagnostic clue when evaluating biopsies in patients suspected to have dermatitis artefacta.     

Associations between anti‐melanoma differentiation‐associated gene 5 antibody and demographics,clinical characteristics and laboratory results of patients with dermatomyositis: A systematic meta‐analysis

Anti‐melanoma differentiation‐associated gene 5 (MDA5) antibody is a specific biomarker in patients with dermatomyositis (DM). Results from several studies that examined the relationship between anti‐MDA5 antibody and the demographics, clinical characteristics and laboratory results of DM patients have been conflicting. The purpose of this study was to identify the relationship, if any, of anti‐MDA5 antibody with demographics, clinical characteristics and laboratory results of DM patients. PubMed, Web of Science, Embase and the Cochrane Library databases were searched for studies without language restrictions conducted before 16 March 2017. Stata version 12.0 software was used to calculate pooled odds ratios or weighted mean differences and corresponding 95% confidence intervals to determine the relationship between anti‐MDA5 antibody and patient characteristics. Twenty studies comprising 1500 cases were included in this meta‐analysis. Anti‐MDA5 antibody was strongly associated with clinically amyopathic DM (CADM) and rapidly progressive interstitial lung disease (RPILD). Anti‐MDA5 antibody also increased the risk of developing eight characteristics comprising Gottron's sign or papules, mechanic's hand, V rash, skin ulcers, panniculitis, alopecia, arthritis/arthralgia and pneumomediastinum, but reduced the risk of muscle weakness, classic DM (CDM) and elevated creatine kinase (CK). Our meta‐analysis indicated that anti‐MDA5 antibody is related to muscle weakness, Gottron's sign or papules, mechanic's hand, V rash, skin ulcers, panniculitis, alopecia, arthritis/arthralgia, pneumomediastinum, RPILD, CDM, CADM and elevated CK in patients with DM.