Clinical significance of serum soluble T-cell immunoglobulin and mucin domain 3 levels in systemic sclerosis: Association with disease severity.

T-cell immunoglobulin and mucin domain 3 (TIM-3) has been thought to play a crucial role in the negative regulation of immune responses. Here, we examined the levels of serum soluble TIM-3 (sTIM-3) in patients with systemic sclerosis (SSc) and evaluated the results with respect to the clinical features of the disease. Patients with diffuse cutaneous SSc (dcSSc) had higher levels of sTIM-3 than those with limited cutaneous SSc and healthy individuals. Serum sTIM-3 levels were positively correlated with the severity of skin sclerosis in early phase dcSSc. Moreover, serum sTIM-3 levels were increased more often in patients with renal crisis and cardiac involvement than in those with normal sTIM-3 levels. These results suggest that serum sTIM-3 levels may be increased in patients with early phase dcSSc and associated with cardiac involvement and renal crisis. Measurement of serum sTIM-3 may be useful for risk stratification in the early stage of the disease.

Biologic treatments for elderly patients with psoriasis.

The number of elderly patients with psoriasis is increasing in Japan. However, biologic treatment is generally considered to be challenging in elderly patients, due to their increased risk of complications compared with younger patients. Our retrospective study aimed to evaluate the safety profile and efficacy of biologics in senior elderly patients (≥75 years old) with psoriasis. The study involved a cohort of 27 patients aged 75-88 years who were being treated with biologics over a period of more than 1 year. Initial biologics administrated to were adalimumab (five cases) and ustekinumab (22 cases). Eight patients discontinued treatment: two developed cancer; one was transferred to hospital; and five others experienced either bone fracture, interstitial pneumonia, cerebral hemorrhage resulting in death, decrepitude or developed hepatopathy following prophylactic tuberculosis treatment. Efficacy, evaluated by the percentage of patients achieving 75% reduction of Psoriasis Area and Severity Index score, was 76.9% at week 16 (n = 26), 88.0% at week 24 (n = 25) and 90.5% at week 52 (n = 21). Biologic treatments thus show clear efficacy in elderly patients with psoriasis, however, the increased frequency of adverse events requires rigorous patient observation.

Impact of anti-tumor necrosis factor-α agents on serum levels of KL-6 and surfactant protein-D in patients with psoriasis.

We longitudinally examined the influence of anti-tumor necrosis factor (TNF)-α treatment on serum levels of KL-6 and surfactant protein-D (SP-D). The study group comprised 22 patients with psoriasis treated with infliximab or adalimumab and with no history of interstitial lung disease (ILD). KL-6 and SP-D levels were measured in serum samples. Twelve of the 22 patients (55%) showed at least a 20% increase in KL-6 levels compared with baseline. Of these 12 patients, none exhibited any signs of ILD on chest computed tomography and nine who showed an increase in KL-6 levels (75%) showed at least a 20% increase in SP-D levels. Some patients showed simultaneous increases in KL-6 and SP-D levels after treatment with anti-TNF-α agents. Although these patients may have undetectable or subtle alveolar damage, careful observation is needed.

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.

IL-10-producing regulatory B cells are decreased in patients with psoriasis.

BACKGROUNDS: Interleukin (IL)-10-producing regulatory B cells (B10 cells) have been shown to ameliorate psoriasis in mice. Human B10 progenitor cells are characterized as CD19(+)CD24(hi)CD38(hi) B cells that exert their regulatory functions via the production of IL-10. However, the role of B10 cells in the pathogenesis of psoriasis remains unclear. OBJECTIVES: We examined B10 cells in patients with psoriasis and healthy controls. METHODS: Peripheral blood mononuclear cells were isolated from psoriasis patients without a history of receiving any immunosuppressants during the 6-month period before enrollment in the study. Using flow cytometry, we determined the frequencies of blood B cell subsets, B10 progenitor cells, and B10 cells for 31 patients with psoriasis and 26 healthy controls. RESULTS: Both psoriasis patients and healthy controls showed similar frequencies of total B cells, IgD(+)CD27(-) naïve B cells, and IgD(-)CD27(+) memory B cells. However, the frequency of CD19(+)CD24(hi)CD38(hi) B10 progenitor cells was significantly higher in patients with psoriasis than in the healthy controls. In contrast, the frequency of B10 cells in patients with psoriasis was significantly lower than that in healthy controls. Furthermore, treatment with immunosuppressants resulted in a decrease in B10 progenitor cells and an increase in B10 cells. CONCLUSION: B10 progenitor cells were increased, while IL-10-producing regulatory B10 cells were decreased in patients with psoriasis, suggesting that B10 cells may be functionally impaired in patients with psoriasis.

Four cases of Japanese patients with psoriatic arthritis in whom effective treatments by anti-tumor necrosis factor-α drugs were evaluated by magnetic resonance imaging together with improvement of skin lesions.

Because psoriatic skin lesions of psoriatic arthritis (PsA) usually precede the onset of joint symptom, dermatologists are in an ideal position to screen and find individuals with PsA early in the disease course. There have been no reports from the dermatology field evaluating the effect of anti-tumor necrosis factor (TNF)-α drugs on joint disorders using magnetic resonance imaging (MRI) in PsA patients. The purpose of this study was to elucidate the effectiveness of MRI in the evaluation of anti-TNF-α drugs on joint disease of Japanese PsA patients. Data were collected from four adult Japanese male PsA patients. MRI of the affected hand was performed at baseline and 1-7 months after infliximab or adalimumab treatment. T1 -weighted gadolinium-enhanced images with fat suppression were acquired in the coronal, sagittal and/or axial planes. We determined the apparent improvement of synovitis, periarticular inflammation, tenosynovitis and/or bone marrow edema by MRI after anti-TNF-α treatments in all the patients together with the improvement of skin lesions. We also determined in one patient that these symptoms detected by MRI before treatment were alleviated within 1 month and had disappeared 6 months after treatment, suggesting the potentially early detection of the effect of anti-TNF-α drugs on joint disease. We present four cases of Japanese patients with PsA in whom effective treatments by anti-TNF-α drugs were evaluated by contrast-enhanced MRI. This imaging enables dermatologists and radiologists to assess and monitor early inflammatory changes, and to grant PsA patients earlier access to modern treatment such as biologics.

Ustekinumab treatment in patients with psoriasis undergoing hemodialysis.

Patients with psoriasis undergoing hemodialysis have additional difficulties in treatment compared with general patients. Conventional treatments such as cyclosporin, retinoids and methotrexate are not widely administrated due to the chances of an increase in adverse effects and the possibility of risk to patient survival. Recently, biologic treatments have been recognized as having sufficient efficacy for severe psoriasis with low incidence of organ toxicities. For this reason, biologic treatments may be more preferable for patients on hemodialysis; however, there is not sufficient evidence. We have treated three patients with psoriasis with ustekinumab for 1 year, who had been undergoing hemodialysis. They were previously treated with conventional treatments before ustekinumab treatments; however, they did not respond to these treatments sufficiently. Following treatment with ustekinumab, rapid and maintained improvement in psoriasis was observed. Over the course of treatments, two of the three patients encountered no adverse events during their first year of treatment. The other patient discontinued ustekinumab due to elevated levels of C-reactive protein. These findings suggest that ustekinumab may be an appropriate treatment for patients undergoing hemodialysis who are suffering from psoriasis. However, the risk of developing infection remains higher than in general patients.

Efficacy and safety of ustekinumab treatment in elderly patients with psoriasis.

The ratio of the elderly among psoriasis patients has been increasing. However, satisfactory long-term management of psoriasis for the elderly is challenging because of the more frequent presence of comorbidities, and the higher risk of adverse events from systemic therapeutic agents than younger patients. The use of ustekinumab (UST) appears to be an appropriate systemic treatment because it is considered less likely to cause adverse events than other systemic treatments, as well as necessitating fewer hospital visits. Our retrospective study aimed to evaluate the efficacy and safety profile of UST in elderly patients with psoriasis. The study included 24 patients aged over 65 years (range, 65-88 years; mean, 73.1 years) with moderate to severe plaque psoriasis with impaired quality of life. Efficacy and safety were assessed over a 1-year period using the Psoriasis Area and Severity Index (PASI) and the Dermatology Live Quality Index (DLQI). The efficacy was evaluated by the proportion of subjects who achieved ≥75% reduction in PASI score (PASI 75). PASI 75 responses were 56.5% at week 16, 59.1% at week 28, and 60.0% at week 52. None of the patients developed any serious infection during the 1-year treatment. The mean DLQI score at weeks 0, 16, 28, and 52 was 7.8 ± 6.0, 2.5 ± 3.4, 1.4 ± 1.7, and 1.2 ± 1.7, respectively. UST showed sufficient efficacy for elderly patients with psoriasis without any serious infection over the 1-year treatment. Our results suggest that UST is the preferable agent for the treatment of elderly patients with psoriasis.

Impact of obesity on the efficacy of ustekinumab in Japanese patients with psoriasis: a retrospective cohort study of 111 patients.

Obesity is thought to be involved in the pathogenesis of psoriasis, although its impact on the therapeutic response to systemic treatments remains unclear. The aim of this study was to examine the association of body mass index (BMI) with the efficacy of ustekinumab in Japanese patients with psoriasis. Clinical data from a cohort of 111 Japanese patients treated with ustekinumab 45 mg between July 2011 and March 2014 were retrospectively evaluated. The measured outcome was improvement in the psoriasis area and severity index (PASI) score at week 16. Patients with BMI ≥ 25 and BMI < 25 had comparable rates of ≥50 and 75 % improvement in PASI (PASI-50 and PASI-75, respectively), whereas patients with BMI ≥ 25 had significantly lower PASI-90 and PASI-100 response rates. Patients with BMI ≥ 25 also showed significantly lower percent reduction in PASI than those with BMI < 25 at week 16 (85 vs. 74 %, P < 0.004). BMI was negatively correlated with percent reduction in PASI, whereas body weight was not. These results show that a higher BMI, but not body weight, is associated with lower effectiveness of ustekinumab for psoriasis. BMI ≥ 25 could therefore be a negative predictor of achieving PASI-90 and PASI-100 in patients with psoriasis when starting ustekinumab.

Drug survival rates in patients with psoriasis after treatment with biologics.

Clinically, patients' adherence to biologic treatment is not only related to efficacy but also to adverse events, cost and other factors. To evaluate long-term viability of biologic treatment, both the percentage of and reasons for discontinuation of treatment were investigated. In this study, patients treated with infliximab (n = 38), adalimumab (n = 59) and ustekinumab (n = 30) were included and observed for 12 months. Clinical efficacy was evaluated using a 75% reduction of Psoriasis Area and Severity Index score (PASI-75), and patients who discontinued treatment were considered as not having achieved PASI-75. In addition, drug survival rate (DSR) was investigated. In patients treated with infliximab, PASI-75 was 68.4% and DSR was 73.3% by the end of treatment. In patients treated with adalimumab, PASI-75 was 50.8% and DSR was 79.7%. In patients treated with ustekinumab, PASI-75 was 63.3% and DSR was 96.7%. Several patients discontinued treatment because of insufficient efficacy due to secondary failure in infliximab or primary failure in adalimumab. To increase treatment efficacy, it will be necessary for these patients to use an additional concomitant treatment. Higher efficacy is expected with biologics than with conventional treatments; however, the actual clinical efficacy over a long period of time may be insufficient if they are used without any concomitant treatments.