Efficacy of guselkumab in a subpopulation with pustulotic arthro-osteitis through week 52: an exploratory analysis of a phase 3, randomized, double-blind, placebo-controlled study in Japanese patients with palmoplantar pustulosis.

BACKGROUND: Previous studies of guselkumab have demonstrated clinical benefits in patients with plaque-type psoriasis, generalized pustular psoriasis, erythrodermic psoriasis and palmoplantar pustulosis (PPP). OBJECTIVE: The aim of this exploratory analysis of a double-blind, multicenter, placebo-controlled, phase 3 study in Japanese patients with PPP was to evaluate the efficacy of guselkumab in the subset of patients with pustulotic arthro-osteitis (PAO). METHODS: Patients were randomized to receive guselkumab 100 or 200 mg at weeks 0, 4, 12 and every 8 weeks, or placebo with cross-over to guselkumab 100 or 200 mg at week 16 (placebo group). Efficacy endpoints were changes from baseline in magnetic resonance imaging (MRI) score, EuroQOL-5 dimensions (EQ-5D) index score, EQ-5D pain/discomfort dimension score and C-reactive protein (CRP, mg/L) level in all PAO patients through week 52. Data from both guselkumab groups were combined and presented as results for a single overall guselkumab group. RESULTS: Among 159 patients with PPP, 66 with PAO were randomized across treatment groups. For patients with MRI data for all regions assessed, the proportion of patients in the guselkumab group with PAO characterized as severe decreased from 23.8% (10/42) at baseline to 5.4% (2/42) at week 52. The mean (SD) change from baseline at week 52 in EQ-5D index score was 0.20 (0.17) among PPP patients with PAO and 0.15 (0.17) among those without PAO in the guselkumab group. Among all PAO patients, the proportions with an EQ-5D pain/discomfort dimension score of no or slight pain/discomfort in the guselkumab group increased from baseline to week 52 [33.3% (7/21) vs. 87.5% (35/40)]. The mean (SD) CRP levels decreased in all PAO patients in the guselkumab group at week 52 compared to baseline [-1.71 (8.16) mg/L]. CONCLUSION: Guselkumab treatment showed beneficial outcomes for PAO signs and symptoms in Japanese patients with PPP.

Spotlight on Japanese physicians: An exploration of their professional experiences elicited by means of narrative facilitators.

BACKGROUND: While investigation of physicians' work experience is often limited to issues of satisfaction or burnout, a broader view of their experiences is lacking. OBJECTIVE: To explore professional experiences, we asked Japanese physicians (N = 18, 12 men and 6 women) of a general hospital to react to so-called "narrative facilitators". METHODS: The narrative facilitators - inspired by clinical psychology, visual sociology and purpose-designed techniques - oriented physicians' narratives towards clinical practise, relationship with peers and context. Transcribed interviews were subject to thematic analysis. RESULTS: The thematic analysis of participants' narratives revealed a lonely physician with a tough job, torn between the ideal of patient-centred care and a clinical reality, which limits these aspirations. Patients emerged as anxious and burdensome consumers of medicine. Feeling neither supported by peers nor the institution, physicians also perceived the society as somewhat negligent, delegating its problem to medicine. Communication difficulties, with patients and peers, and the absence of joyful aspects of the profession constituted fundamental elements of their narratives. CONCLUSIONS: Comprehensive investigation of physicians' lived professional experience could become a key to conceive ways to support them.

Impact of ixekizumab treatment on skin-related personal relationship difficulties in moderate-to-severe psoriasis patients: 12-week results from two Phase 3 trials.

BACKGROUND: Psoriasis symptoms may decrease quality of life for patients. Skin-related personal relationship difficulties in psoriasis patients are common, under-reported and poorly understood. OBJECTIVE: To assess the effect of ixekizumab (IXE) treatment on skin-related personal relationship difficulties in patients with moderate-to-severe psoriasis. METHODS: Pooled data (N = 2570) on skin-related relationship problems were obtained from two large phase 3 trials (UNCOVER-2 and UNCOVER-3) in patients with moderate-to-severe plaque psoriasis randomized to subcutaneous placebo (PBO, N = 361), etanercept (ETN; 50 mg twice weekly, N = 740), or 80 mg IXE as one injection every 4 (IXEQ4W, N = 733) or 2 weeks (IXEQ2W, N = 736) for 12 weeks, following a 160-mg initial dose. The Dermatology Life Quality Index (DLQI) Personal Relationships Domain (PRD) (Items 8 and 9) was used to assess how much the skin caused any personal relationship difficulties at weeks 0, 2, 4 and 12. Improvement was compared for IXE vs PBO and ETN using logistic models. Factors associated with improvement were assessed using multiple linear regressions. DLQI Item 9, assessing sexual difficulties, was also analysed separately. RESULTS: PRD scores (mean ± standard deviation) at baseline were similar across all treatment groups (PBO: 1.8 ± 1.9; ETN: 1.7 ± 1.8; IXEQ4W: 1.6 ± 1.8; IXEQ2W: 1.7 ± 1.8). Treatment with IXE rapidly and significantly improved the mean PRD score compared to PBO and ETN (P < 0.001 at all time points). Baseline PRD score was the strongest negative predictor of improvement. IXE enabled significantly more patients with moderate-to-severe plaque psoriasis to reduce their skin-related sexual difficulties at Week 12 compared to PBO (P < 0.001) or ETN (P < 0.001). CONCLUSION: Ixekizumab improves patient-reported skin-related PRD difficulties in patients with moderate-to-severe psoriasis.

Site-specific differences in central processing of visceral stimuli from the rectum and the descending colon in men.

BACKGROUND: It has been reported that different brain activation areas are demonstrated during somatosensory and visceral stimulation. However, no study thus far has investigated how activated patterns in the human brain differ during visceral stimulation of different sites of the digestive tracts. The aim of this study was to determine possible site-specific differences in brain responses and perceptions during visceral stimulation of two different sites, the intraluminal distentions of the rectum and descending colon. METHODS: Regional cerebral blood flow was assessed in 32 healthy right-handed male subjects using H(2)(15)O positron emission tomography during distention of the rectum (R group, n = 16) or descending colon (DC group, n = 16) at 40 or 20 mmHg. KEY RESULTS: R group reported significantly higher scores of abdominal pain (P < 0.05) and urge to defecate (P < 0.001) during the application of stimulus at 40 mmHg compared with DC group but not of abdominal bloating or anxiety. In comparisons of response to the 40-mmHg stimulus, R group showed significantly greater activation in posterior midcingulate cortex (MCC) and right anterior and posterior insula, whereas DC group showed greater activation in subgenual anterior cingulate cortex (ACC), perigenual ACC and left orbitofrontal and superior temporal cortices. CONCLUSIONS & INFERENCES: These findings suggest that central projections of painful visceral stimulation from the rectum and descending colon differ in affective, cognitive and nociceptive processing in the brain, which may result in different perceptions of visceral stimulation from different sites.

Hypereosinophilic syndrome with various skin lesions and juvenile temporal arteritis.

Hypereosinophilic syndrome (HES) is a multisystem disease with a high mortality rate. It is characterized by peripheral blood eosinophilia and eosinophilic infiltration of the skin and many other organs. The commonest cutaneous features include erythematous pruritic maculopapules and nodules, angio-oedema or urticarial plaques. However, some case reports have indicated that eosinophilic cellulitis, cutaneous necrotizing eosinophilic vasculitis, Raynaud's phenomenon and digital gangrene may also occur as cutaneous features of HES. Juvenile temporal arteritis (JTA) of unknown cause is characterized by an asymptomatic nodule in the temporal artery area in young adults. Histologically, the lesion is characterized by a significant intimal thickening with moderate eosinophilic infiltrates, constriction or occlusion of the vascular lumen and absence of giant cells. We report a patient with HES presenting with eosinophilic cellulitis, Raynaud's phenomenon, digital gangrene and JTA. JTA may also be one of the features of HES.

Immunohistochemical investigation of mid-dermal elastolysis with a history of erythema.

Elastic fibers are essential extracellular matrix macromolecules comprising an elastin core surrounded by fibrillin-rich microfibrils. Fibulin-5, a microfibril, has been identified as one of the secreted extracellular matrix proteins that shows function as a scaffold for elastic fibers. However, the distribution of fibulin-5 in the skin is not clear. We report a case of a 43-year-old woman with erythema and subsequent wrinkling that met the clinical and histological criteria for mid-dermal elastolysis. We investigate the mechanism by which this disease occurs. The distribution of elastin, CD68, matrix metalloproteinase (MMP)-9, and fibulin-5 was examined immunohistochemically from both erythematous and wrinkled skin. There were numerous CD68 and MMP-9-producing histiocytes and giant cells in the erythematous lesions. Faint fibrillar staining of fibulin-5 was found in the deep dermis. In the wrinkled skin, there were few CD68 histiocytes or giant cells. Elastin immunoreactivity disappeared from the mid-dermis. Fibulin-5 colocalized in the lower dermis, shorter than in the erythema. Mid-dermal elastolysis may be initiated by MMP-9 produced by histiocytes and giant cells through its degradation of elastic fibers. In the lower dermis of the wrinkled skin, the fragmented expression of fibulin-5 was associated with the incomplete reproduction of the elastic fibers.

Metastatic ovarian carcinoma-associated subepidermal blistering disease with autoantibodies to both the p200 dermal antigen and the gamma 2 subunit of laminin 5 showing unusual clinical features.

Anti-p200 pemphigoid is an autoimmune subepidermal blistering disease characterized by autoantibodies to an unknown 200-kDa acidic noncollagenous glycoprotein of the lower lamina lucida, whereas antilaminin 5 mucous membrane pemphigoid is characterized by autoantibodies to a major basement membrane extracellular matrix, laminin 5. We report a 64-year-old Japanese woman with a subepidermal blistering disease associated with lymph node metastasis of ovarian clear cell carcinoma 10 years after its surgical treatment. Clinical features showed severe blisters and erosions on multiple mucous membranes (i.e. lip, oral cavity, nose, eye, genitalia and anus) and on both the periungual and subungual regions. This is the first report in which an immunoblot analysis revealed the unusual combination of autoantibodies to both the p200 antigen and the gamma 2 subunit of laminin 5.

p53 homologue, p51/p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity.

p53 homologue, p51/p63, predominantly expressed in keratinocyte stem cells, is indispensable for the formation of epidermis. Notch1, another such gene indispensable for the process, induces growth arrest and differentiation in keratinocytes. We found that exogenous expression of DeltaNp51B (DeltaNp63alpha), one of the isoforms of p51 specifically expressed in basal keratinocytes, blocked Notch 1-dependent growth arrest and differentiation in mouse keratinocytes by inhibiting p21 expression and maintaining integrins expression. Furthermore, DeltaNp51B by itself was found to have ability to induce expression of integrin alpha6beta4, which promotes attachment of basal cells to basal membrane thereby keeping the cells in immature state. Therefore, we conclude that DeltaNp51B expression warrants integrin expression even under the influence of Notch1 and that DeltaNp51B is a long-sought factor required to maintain basal cell keratinocytes immaturity by inhibiting Notch1 activity. We will postulate a plausible model explaining the maintenance of the squamous epithelium architectures as well as offering mechanistic explanations for pathological features of skin diseases, including cancers, psoriasis along with physiological wound healings.

Involvement of transforming growth factor-beta and thrombopoietin in the pathogenesis of myelodysplastic syndrome with myelofibrosis.

We investigated the cause of myelofibrosis and proliferation of megakaryocytes in myelodysplastic syndrome with myelofibrosis (MDS-MF (+)). Plasma-transforming growth factor-beta1 (PTGF-beta1) concentrations closely correlated with myelofibrosis grade in MDS-MF (+) and were higher than those in idiopathic myelofibrosis (IMF), essential thrombocythemia (ET), idiopathic thrombocytopenic purpura (ITP), MDS-without MF (MDS-MF (-)) or healthy volunteers (HV). Peripheral blood mononuclear cells from MDS-MF (+) patients expressed more TGF-beta1 mRNA than those from IMF, MDS-MF (-) or HV. When we immunostained bone marrow specimens of MDS-MF (+) for TGF-beta, the intensity of blasts was apparently higher than that of megakaryocytes, while in MDS-MF (-), megakaryocytes were immunostained with a similar intensity as that in MDS-MF (+), but blasts were negative for staining. In IMF, megakaryocytes, monocytes and small mononuclear cells representing CD34+ cells were all similarly stained with a much lower intensity than that of blasts in MDS-MF (+). The number of bone marrow megakaryocytes were increased the most in MDS-MF (+), followed by ET, ITP, MDS-MF (-) and NHL and correlated with plasma thrombopoietin (TPO) levels or with plasma TGF-beta1 levels, respectively, in each disease. Thus, in MDS-MF (+), both myelofibrosis and the increased megakaryocytes were ascribed to overproduction of TGF-beta1 from blasts.

Inhibition of scratching behaviour caused by contact dermatitis in histidine decarboxylase gene knockout mice.

A neuronal system dedicated to itch consists of primary afferent and spinothalamic projection neurons. Histamine is thought to be one of the main mediators for the transmission of itch sensation. However, there are little available information on the role of histamine in scratching behaviour and sensory transmission of atopic dermatitis and chronic eczema. In the present study, the role of histamine in scratching behaviour and neural conduction of sensation in the chronic eczema model was investigated by using l-histidine decarboxylase (HDC) gene knockout mice lacking histamine. The chronic contact dermatitis was induced with daily application of diphenylcyclopropenone (DCP) on a hind paw of HDC (+/+) and HDC (-/-) mice for 2 months. The observation of scratching behaviour and the hot-plate test were performed in both mice. Histological studies were performed in the skin and spinal cord tissues. Histological examination revealed that both HDC (+/+) and HDC (-/-) mice displayed the similar extent of inflammatory cell infiltration, hyperplastic epidermis and newly spreading of neuronal processes in the skin tissue. Scratching behaviour was exclusively induced in HDC (+/+) mice, whereas it was barely observed in HDC (-/-) mice. The expression of c-Fos was specifically upregulated in HDC (+/+) mice in lamina I of the spinal dorsal horn following repeated DCP application. Scratching behaviour in chronic contact dermatitis in mice was thought mainly mediated with histamine. The afferent pathway of sensation in chronic contact dermatitis model may connect with the central nervous system through lamina I of the spinal dorsal horn.