Initial predictors of skin thickness progression in patients with diffuse cutaneous systemic sclerosis: Results from a multicentre prospective cohort in Japan.

OBJECTIVE: To identify initial parameters that predict worsening of skin thickening in patients with diffuse cutaneous systemic sclerosis (dcSSc) using a multicentre, prospective, observational cohort in Japan. METHODS: A total of 171 patients with dcSSc were selected from a prospective cohort database based on the following criteria: dcSSc, modified Rodnan total skin thickness score (mRSS) ≥7, disease duration <60 months, and valid mRSS data at one year. Worsening of skin thickness was defined as an increase in mRSS ≥3 points and an increase ≥25% from baseline to one year. Initial demographic and clinical parameters useful for predicting the progression of skin thickness were identified using univariate and multivariable analysis, and prediction models of skin thickening progression were built based on combinations of independent predictive parameters. RESULTS: Only 23 patients (13.5%) experienced worsening mRSSs at one year. Short disease duration, low mRSS, absence of nailfold bleeding, arthritis, and a high erythrocyte sedimentation rate at diagnosis were identified as predictors of subsequent worsening of the mRSS even after adjusting for the treatment. Assessment of the best predictive model revealed that patients with a disease duration ≤12 months and mRSS ≤19 had a risk of mRSS worsening within one year, with a sensitivity of 73.9% and specificity of 81.1%. CONCLUSION: Identification of predictors of subsequent worsening of skin thickness in dcSSc patients is useful for identifying patients who require intensive treatment with potential disease-modifying agents and for improving clinical trial design by characterizing eligible progressors in the Japanese population.

Clinical course of Japanese patients with early systemic sclerosis: A multicenter, prospective, observational study.

OBJECTIVES: To investigate the clinical course of Japanese patients with early diffuse cutaneous systemic sclerosis (dcSSc) and early SSc with interstitial lung disease (ILD). METHODS: We prospectively analyzed the clinical features of 207 Japanese patients with early dcSSc (n = 150) and limited cutaneous SSc (lcSSc) with ILD (n = 57) in 10 medical centers every year for 7 consecutive years. RESULTS: Mean modified Rodnan total skin thickness score (mRSS) was 18.3 and 67.4% of the cohort had ILD. Most patients started immunosuppressive therapy and vasodilators during 7 years (83.4% and 87.9%, respectively). Mean value of mRSS of total patients was significantly reduced from the initial registration after the first year. However, other parameters for physical function associated with skin sclerosis including fist closure, hand extension, and oral aperture were not so ameliorated during the study period. Health Assessment Questionnaire-disability index and serum KL-6 levels were constant throughout the course. Percent vital capacity and the presence of ILD, clinically suspected pulmonary arterial hypertension, and digital ulcers were gradually exacerbated during the period. CONCLUSION: In Japanese early dcSSc patients and SSc patients with ILD, mRSS was continuously reduced during 7 years of follow-up, but there was little improvement of physical disability and organ involvement.

Prediction of organ involvement in systemic sclerosis by serum biomarkers and peripheral endothelial function.

OBJECTIVES: To identify prognostic factors among serum biomarkers and endothelial vasodilator function findings in patients with systemic sclerosis (SSc). METHODS: This is a clinical observational study. We assessed 60 consecutive SSc patients (44 limited cutaneous-type, 16 diffuse cutaneous-type). Circulating growth differentiation factor-15 (GDF-15), placenta growth factor (PlGF), endostatin, vascular endothelial growth factor (VEGF), and pentraxin 3 (PTX3) were measured by ELISA. Peripheral endothelial function was measured by forearm blood dilatation response to brachial artery occlusion using noninvasive plethysmography (EndoPAT2000), which is associated with nitric-oxide-dependent vasodilatation and yields a reactive hyperemia index (RHI). We evaluated whether abnormalities in these values were associated with type of SSc - namely, diffuse cutaneous SSc (dcSSc) or limited cutaneous SSc (lcSSc) - or organ involvement including interstitial lung disease (ILD), digital ulcer (DU) and estimated right ventricular systolic pressure (RVSP) by echocardiography >30 mmHg. RESULTS: SSc patients showed significantly elevated serum GDF-15, PlGF, endostatin and VEGF but not PTX3 compared with controls. GDF-15 and PlGF were high in dcSSc patients. EndoPAT-RHI was low, and incidence of RVSP >30 mmHg was high in dcSSc. Multivariate analysis revealed that elevated GDF-15 was highly predictive of dcSSc, ILD or RVSP >30 mmHg. PlGF for DU was also found. Conversely, a low EndoPAT-RHI value was predictive of the presence of dcSSc, ILD or DU. CONCLUSIONS: This is the first study to inclusively investigate the relationships among biomarkers, EndoPAT-RHI and organ involvement in patients with SSc. Our data suggest a complex pathological progression of SSc through fibrotic impairment and microvascular damage.

The wound/burn guidelines - 6: Guidelines for the management of burns.

Burns are a common type of skin injury encountered at all levels of medical facilities from private clinics to core hospitals. Minor burns heal by topical treatment alone, but moderate to severe burns require systemic management, and skin grafting is often necessary also for topical treatment. Inappropriate initial treatment or delay of initial treatment may exert adverse effects on the subsequent treatment and course. Therefore, accurate evaluation of the severity and initiation of appropriate treatment are necessary. The Guidelines for the Management of Burn Injuries were issued in March 2009 from the Japanese Society for Burn Injuries as guidelines concerning burns, but they were focused on the treatment for extensive and severe burns in the acute period. Therefore, we prepared guidelines intended to support the appropriate diagnosis and initial treatment for patients with burns that are commonly encountered including minor as well as moderate and severe cases. Because of this intention of the present guidelines, there is no recommendation of individual surgical procedures.

The wound/burn guidelines - 2: Guidelines for the diagnosis and treatment for pressure ulcers.

The Wound/Burn Guidelines Committee consists of members commissioned by the Board of Directors of the Japanese Dermatological Association (JDA). It held several meetings and evaluations in writing since October 2008, and drafted five guidelines for the diagnosis and treatment including commentaries on wounds in general and the Guidelines for the Diagnosis and Treatment for Pressure Ulcers by taking opinions of the Scientific Committee and Board of Directors of JDA into consideration.

The wound/burn guidelines - 4: Guidelines for the management of skin ulcers associated with connective tissue disease/vasculitis.

The Japanese Dermatological Association prepared guidelines focused on the treatment of skin ulcers associated with connective tissue disease/vasculitis practical in clinical settings of dermatological care. Skin ulcers associated with connective tissue diseases or vasculitis occur on the background of a wide variety of diseases including, typically, systemic sclerosis but also systemic lupus erythematosus (SLE), dermatomyositis, rheumatoid arthritis (RA), various vasculitides and antiphospholipid antibody syndrome (APS). Therefore, in preparing the present guidelines, we considered diagnostic/therapeutic approaches appropriate for each of these disorders to be necessary and developed algorithms and clinical questions for systemic sclerosis, SLE, dermatomyositis, RA, vasculitis and APS.

The wound/burn guidelines - 1: Wounds in general.

The Japanese Dermatological Association determined to prepare the Wound/Burn Guidelines focusing on treatments, catering to needs for the clinical practice of dermatology. Among these guidelines, "Wounds in General" was intended to explain knowledge necessary "to heal wounds" without specifying particular disorders.

The wound/burn guidelines - 3: Guidelines for the diagnosis and treatment for diabetic ulcer/gangrene.

We aimed to prepare guidelines for the management of diabetic ulcer/gangrene with emphasis on the diagnosis and treatment of skin symptoms. They serve as a tool to improve the quality of the diagnosis and treatment in each patient and, further, to improve the level of the care for diabetic ulcer in Japan by systematically presenting evidence-based recommendations for clinical judgments by incorporating various viewpoints.

The wound/burn guidelines - 5: Guidelines for the management of lower leg ulcers/varicose veins.

Varicose veins are treated at multiple clinical departments, but as patients often visit the dermatology clinic first due to leg ulcers, the present Guidelines for the Management of Lower Leg Ulcers/Varicose Veins were prepared in consideration of the importance of the dermatologist's role. Also, the disease concept of chronic venous insufficiency or chronic venous disorders and the CEAP classification of these disorders are presented. The objective of the present guidelines is to properly guide the diagnosis and treatment of lower leg ulcers/varicose veins by systematically presenting evidence-based recommendations that support clinical decisions.

Serum adhesion molecule levels as prognostic markers in patients with early systemic sclerosis: a multicentre, prospective, observational study.

OBJECTIVE: To assess the utility of circulating adhesion molecule levels as a prognostic indicator of disease progression in systemic sclerosis (SSc) patients with early onset disease. METHODS: Ninety-two Japanese patients with early onset SSc presenting with diffuse skin sclerosis and/or interstitial lung disease were registered in a multicentre, observational study. Concentrations of intercellular adhesion molecule (ICAM) -1, E-selectin, L-selectin, and P-selectin in serum samples from all patients were measured by enzyme-linked immunosorbent asssay (ELISA). In 39 patients, adhesion molecule levels were measured each year for four years. The ability of baseline adhesion molecule levels to predict subsequent progression and severity in clinical and laboratory features were evaluated statistically. RESULTS: At their first visit, serum levels of ICAM-1, E-selection, P-selectin were significantly elevated and serum L-selectin levels were significantly reduced in patients with SSc compared with healthy controls. Overall, serum ICAM-1 levels at each time point were significantly inversely associated with the %vital capacity (VC) of the same time and subsequent years by univariate analysis. The initial serum ICAM-1 levels were significantly inversely associated with the %VC at the fourth year by multiple regression analysis. The initial serum P-selectin levels were significantly associated with the health assessment questionnaire disability index (HAQ-DI) at the fourth year by multiple regression analysis. Initial adhesion molecule levels were not significantly associated with other clinical features including skin thickness score. Baseline adhesion molecule levels were not significantly associated with subsequent rate of change of clinical parameters. CONCLUSION: In patients with SSc, serum levels of ICAM-1 and P-selectin may serve as prognostic indicators of respiratory dysfunction and physical disability, respectively. Further longitudinal studies of larger populations are needed to confirm these findings.

Autoantibodies to RuvBL1 and RuvBL2: a novel systemic sclerosis-related antibody associated with diffuse cutaneous and skeletal muscle involvement.

OBJECTIVE: To identify and characterize a novel systemic sclerosis (SSc)-related autoantibody directed against a complex consisting of RuvBL1 and RuvBL2 (RuvBL1/2) and to assess its clinical correlations. METHODS: We first analyzed 316 consecutive patients with SSc who were evaluated at Kanazawa University Hospital. Controls included 290 patients with other connective tissue diseases, interstitial lung disease alone, or autoimmune hepatitis, and 50 healthy subjects. Autoantibody specificities were analyzed using RNA and protein immunoprecipitation assays. Autoimmune targets were affinity purified using patients' sera and subjected to liquid chromatography mass spectrometry. SSc patients in another institution in Japan and the University of Pittsburgh cohort were also included in analysis for evaluating clinical correlations. RESULTS: By protein immunoprecipitation assay, 6 SSc sera (1.9%) reacted with doublets with molecular weights of ∼50 kd. Liquid chromatography mass spectrometry of the partially purified autoantigen and additional immunoblot-based analyses revealed that this antibody specificity recognized RuvBL1/2. Anti-RuvBL1/2 antibody was exclusively detected in SSc patients. SSc patients with anti-RuvBL1/2 in both the Japanese and Pittsburgh cohorts consistently had higher frequencies of SSc in overlap with myositis and diffuse skin thickening than those without anti-RuvBL1/2. Compared with other autoantibodies related to SSc/myositis overlap (anti-PM-Scl and anti-Ku), anti-RuvBL1/2 was distinctive in terms of its associations with older age at SSc onset, male sex, and a high frequency of diffuse cutaneous involvement. CONCLUSION: Anti-RuvBL1/2 antibody is a novel SSc-related autoantibody associated with a unique combination of clinical features, including myositis overlap and diffuse cutaneous involvement.

Yusho patients show increased serum IL-17, IL-23, IL-1ß, and TNFα levels more than 40 years after accidental polychlorinated biphenyl poisoning.

The Yusho poisoning incident, caused by rice oil contaminated with polychlorinated biphenyls (PCBs), polychlorinated quarterphenyls (PCQs), and polychlorinated dibenzofurans (PCDFs) generated by heat-denatured PCBs, occurred in 1968 in western Japan. Although severe symptoms are rarely observed today, the levels of PCBs and PCDFs in the sera of Yusho patients remain high. The aryl hydrocarbon receptor (AhR), which also acts as a dioxin receptor, is a transcriptional regulator that mediates dioxin toxicity. Recent studies show that dioxin mediates its immune toxic effects via AhR and that AhR activation induces dysregulation of interleukin (IL)-17- producing T (TH17) cells. This study therefore hypothesized that Yusho patients would show dysregulated TH17 cell-mediated immune responses. To validate the hypothesis, levels of IL-17 and IL-22, each secreted by TH17 cells, along with IL-1ß and IL-23 were measured in serum samples from 40 Yusho patients and 40 age-matched controls. Levels of tumor necrosis factor (TNF)-α potentially secreted by TH17 cell-stimulated neutrophils and macrophages were also measured. The results indicated that serum IL-17 levels, as well as those of IL-1ß, IL-23, and TNFα, were significantly higher in Yusho patients than in controls. In contrast, serum IL-22 levels were significantly lower in the Yusho patients. These results suggest that Yusho patients have dysregulated TH17 cell-mediated immune responses that may be linked to inflammation.

Increased circulating soluble vascular adhesion protein-1 levels in systemic sclerosis: association with lower frequency and severity of interstitial lung disease.

AIM: To determine circulating soluble vascular adhesion protein-1 (sVAP-1) levels and their clinical associations in patients with systemic sclerosis (SSc). METHOD: Serum VAP-1 levels were examined by enzyme-linked immunosorbent assay in 71 SSc patients, 13 systemic lupus erythematosus patients and 50 healthy individuals. RESULTS: Serum sVAP-1 levels were significantly elevated in SSc patients (617.2 ± 338.7 ng/mL) compared with healthy individuals (320.2 ± 144.2 ng/mL; P < 0.001) and patients with systemic lupus erythematosus (329.0 ± 176.1 ng/mL; P < 0.001). Among SSc patients, there were no differences in serum sVAP-1 levels between those with limited cutaneous SSc and those with diffuse cutaneous SSc. SSc patients with raised sVAP-1 levels had interstitial lung disease and decreased percent vital capacity less often than those with normal sVAP-1 levels. sVAP-1 levels were positively correlated with percent vital capacity in patients with SSc. CONCLUSION: Serum sVAP-1 levels were increased in patients with SSc, and associated with a lower frequency and severity of interstitial lung disease in SSc, suggesting that sVAP-1 plays a role in the pathogenesis of interstitial lung disease in SSc.

Exogenous application of hydrogen sulfide donor attenuates inflammatory reactions through the L-selectin-involved pathway in the cutaneous reverse passive Arthus reaction.

H2S has been highlighted recently as an endogenous, gaseous signaling molecule, especially in inflammations. The deposition of IC induces an acute inflammatory response with tissue injury. To assess the roles of H2S in the IC-induced diseases, the cutaneous, reverse passive Arthus reaction was conducted using NaHS as a H2S donor. Furthermore, we conducted similar experiments using selectin(-/-) mice to determine the involvement of selectin molecules in the H2S-mediated pathway. Exogenous application of NaHS dramatically attenuated inflammatory reactions in WT mice associated with Arthus reaction. Namely, mRNA expressions of TNF-α, IFN-γ, and neutrophil numbers were reduced significantly in the lesional skins of NaHS-treated WT mice relative to untreated ones. NaHS treatment significantly reduced these three parameters in the lesional skins of E- and P-selectin(-/-) mice but not in those of L-selectin(-/-) mice. Quite similar results were obtained in the blocking study using WT mice injected with mAb to E-, P-, and L-selectin. Our results indicated that the exogenous application of NaHS attenuates inflammatory responses in reverse passive Arthus reaction through a L-selectin-involved pathway but not through E- or P-selectin pathways.

Serum chemokine levels as prognostic markers in patients with early systemic sclerosis: a multicenter, prospective, observational study.

OBJECTIVE: To assess the utility of serum chemokine levels as a prognostic indicator of disease progression in systemic sclerosis (SSc) patients with early onset disease. METHODS: Seventy Japanese patients with early onset SSc presenting with diffuse skin sclerosis and/or interstitial lung disease were registered in a multicenter, observational study. Concentrations of CCL2, CCL5, CXCL8, CXCL9, and CXCL10 in serum samples from all patients were measured using cytometric beads array. In 33 patients, chemokine levels were measured each year for 4 years. The ability of baseline chemokine levels to predict changes in clinical features were evaluated statistically by multiple regression analysis. RESULTS: At their first visit, serum levels of CCL2, CCL5, CXCL8, CXCL9, and CXCL10 were significantly elevated in patients with SSc compared with healthy controls. There were significant associations between CCL2 and CXCL8 levels and between CXCL9 and CXCL10 levels in patients. The initial serum CXCL8 levels were significantly associated with the HAQ-DI at the fourth year while the %VC of baseline tended to be negatively associated with HAQ-DI at the fourth year. Initial chemokine levels were not associated with other clinical features including skin thickness score and the respiratory function. CONCLUSION: Serum CXCL8 level may serve as a prognostic indicator of the physical dysfunction in SSc. Further longitudinal studies of larger populations are needed to confirm these findings.

Attenuation of an adult T-cell leukemia skin lesion after treatment of a concomitant herpes simplex infection: a case study.

We report the development and treatment of eczema herpeticum in a 51-year-old male suffering from adult T-cell leukemia (ATL). Lesions of eczema herpeticum coexisted with the skin lesions of ATL. Treatment of eczema herpeticum resulted in a concomitant improvement in the symptoms of ATL, including a reduction in the size of the ATL plaques, for over 2 months before relapse.

Increased serum levels of soluble CD163 in patients with scleroderma.

CD163 is a 130-kDa, type I transmembrane protein belonging to group B of the cysteine-rich scavenger receptor family. Expression of CD163 is constitutive and/or induced by some stimuli on circulating monocytes and most tissue macrophages. An approximately 130-kDa soluble form of human CD163 is released from the cell surface by proteolysis after oxidative stress or inflammatory stimuli. Thus, an elevated level of circulating soluble CD163 (sCD163) has been reported in diabetes mellitus, which is one of the oxidative conditions. We have already acknowledged that scleroderma (SSc) is one of the oxidative conditions. Therefore, we conducted the measurement of serum sCD163 in SSc patients. After receiving the informed consents, 56 SSc patients were examined; 20 dermatomyositis patients were used as disease controls and 40 persons were used as healthy controls. Blood samples were collected, and the concentration of serum sCD163 was measured by ELISA (human CD163, R&D Systems). Other parameters in the blood of SSc patients were also examined. Statistical analyses were performed using Mann-Whitney U test, and the relationship between parameters was statistically examined by Spearman's rank test. Serum sCD163 levels were elevated in SSc patients compared with normal controls (p < 0.01), with similar levels between limited SSc and diffuse SSc patients. SSc patients with pulmonary fibrosis had increased serum levels of sCD163 than those without pulmonary fibrosis (p < 0.05). SSc patients with elevated sCD163 levels had increased serum levels of IgG than those with normal sCD163 levels (p < 0.05). Serum sCD163 levels correlated positively with pulsatility index in SSc patients (p = 0.0009, r = 0.534). These results suggest that oxidative stress may play an important role in immunological abnormalities, renal circulation, and pulmonary fibrosis of SSc.

Myositis-specific anti-155/140 autoantibodies target transcription intermediary factor 1 family proteins.

OBJECTIVE: To identify the 140-kd autoantigen recognized by anti-155/140 autoantibodies that are associated with adult cancer-associated dermatomyositis (DM) and juvenile DM and to determine the clinical relevance of anti-155/140 antibodies in a large cohort. METHODS: Sera from 456 DM patients were assessed for the presence of anti-155/140 antibodies by immunoprecipitation using K562 cell extracts as substrate. Using immunoprecipitation and Western blotting, we then examined whether anti-155/140-positive sera recognized transcription intermediary factor 1α (TIF-1α), TIF-1ß, and TIF-1γ. The clinical associations of antigen reactivity were also evaluated. RESULTS: Anti-155/140-positive sera reacted with 140-kd TIF-1α in addition to 155-kd TIF-1γ. Among sera from 456 DM patients, 52 were reactive with both TIF-1α and TIF-1γ, while another 25 were reactive with TIF-1γ alone. Additionally, 7 were reactive with TIF-1ß. Malignancy was more frequently found in adult patients with both anti-TIF-1α and anti-TIF-1γ antibodies than in those with anti-TIF-1γ antibodies alone (73% versus 50%; P < 0.05). In addition to juvenile DM patients and middle-aged and older DM patients with high percentages of malignancy, 8 "young adult" DM patients without malignancy had these autoantibodies. CONCLUSION: Anti-155/140 antibodies target TIF-1 family proteins, TIF-1α and TIF-1ß, in addition to TIF-1γ. Since TIF-1 proteins have significant roles in oncogenesis, these antibodies may be produced during misdirected antitumor immunity.