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.

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.

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.

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.

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.

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.

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.

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.

Studies on fungal polysaccharide. XVII. A new glucuronan "protuberic acid" produced by a fungus Kobayashia nipponica.

A water-soluble glucuronan "protuberic acid", [alpha] 22-D minus 83.6 degrees, was isolated and purified from Kobayashia Nipponica, and its physicochemical properties were investigated. The purified protuberic acid was homogeneous as shown by zone electrophoresis, gel filtration over Sepharose 4B, and ultracentrifugation. The sedimentation coefficient was 1.8 S and its intrinsic viscosity was 1.1 dl/g. By gel filtration the molecular weight was estimated to be about 170 000. The results of periodate oxidation, methylation analysis, and partial acid hydrolysis indicated that this acidic polysaccharide has a linear structure of mainly 1, 4-linkages and containing an acid-labile linkage. Reduced protuberic acid, [alpha] 22-D minus 44 degrees, is also described.

Stratum corneum activation of complement through the antibody-independent alternative pathway.

We provide evidence that stratum corneum (SC) activates complement through the alternative pathway to generate C5a anaphylatoxin. By immunofluorescence studies it was shown that in addition to circulating IgG autoantibody, there were anti-SC antibodies of IgM and IgA classes in the sera from normal individuals. However, all the titers were significantly lower than the level of C3 deposition between corneocytes. By contrast, no C1q deposition occurred. Immunoelectrophoretically the orthokeratotic SC homogenates were found to induce the conversion of C3 from native C3 to C3b in fresh human serum even when the classic pathway was blocked by Ca2+-chelation. Enzyme immunoassay showed that factor B split product, Bb, was generated by the SC homogenates in the Ca2+-chelated serum. Radioimmunoassay for C5a also demonstrated that the SC homogenates could generate C5a anaphylatoxin in serum to an extent similar to that in non-treated serum when restricted to the alternative pathway activation; neutrophil chemotactic activity was generated in Ca2+-chelated serum at levels comparable to that generated in non-treated fresh serum. We separated the SC samples into a cornified envelope and soluble and keratin fractions. The cornified envelope was more effective in activating complement. This activity resided in heat-stable and non-lipid substances of corneocytes. Our hypothesis is that when the SC comes in contact with serum, it activates complement mainly through the alternative pathway to induce chemotactic C5a anaphylatoxin. Hence, inflammation in normal individuals after a traumatic injury to the skin or rupture of acne comedones, or epidermal cysts and possibly the formation of subcorneal sterile pustules noted in several dermatoses are explainable through this mechanism.

Mechanism of human polymorphonuclear leukocyte adhesion to serum-treated corneocytes.

The accumulation of polymorphonuclear leukocytes (PMN) beneath the stratum corneum is a characteristic histopathologic finding in various aseptic pustular dermatoses. To elucidate the pathomechanism involved in this phenomenon, we investigated whether PMN also attach to a sheet of corneocytes in vitro. A 1-cm2 corneocyte sheet was attached to a sterile glass slide with double adhesive tape used for skin graft surgery before incubating with human serum. The PMN suspension then was applied to the sheet. Attached cells were stained with May-Grunwald-Giemsa and counted with a computer image analyzer. We quantitatively assessed PMN adhesion to the serum-treated corneocyte sheets, which was mediated by activation of the alternative complement pathway. Addition of either anti-CD18 or anti-CD11b antibody to the assay system resulted in a marked reduction of PMN adhesion. We also demonstrated immunohistochemically that iC3b was formed on the serum-treated corneocytes. These findings suggest that PMN attach to serum-treated corneocytes through an interaction of CR3 expressed on PMN with iC3b-coated corneocytes. In addition, we found that this adhesion was enhanced by activation of PMN with phorbol myristate acetate. From these results, we speculate that complement activation by corneocytes occurs in the cutaneous lesions of aseptic pustular dermatoses and that PMN can be stimulated by the interaction with iC3b-opsonized corneocytes as well as by chemotaxins, leading to damage of the surrounding epidermal keratinocytes.

C3 production of cultured human epidermal keratinocytes is enhanced by IFNgamma and TNFalpha through different pathways.

We investigated the regulation of C3 production by human cultured epidermal keratinocytes by enzyme-linked immunosorbent assay. The results showed that IFNgamma and TNFalpha enhanced the synthesis of C3 by epidermal keratinocytes in a concentration-dependent manner. Moreover, a protein kinase C (PKC) inhibitor blocked C3 production, whereas PMA enhanced it. There was a synergistic effect between IFNgamma and TNFalpha. In experiments to investigate the role of protein tyrosine kinase (PTK) in C3 production, we found that treatment with herbimycin A, a specific inhibitor for the c-Src-related PTK, caused significant enhancement of the C3 production induced by IFNgamma or TNFalpha, suggesting that c-Src-type PTK(s) provides a negative signal to C3 production. Each competitive inhibitor of PTK, genistein or tyrphostin, substantially increased the C3 production by IFNgamma at lower concentrations, although each agent had little effect on TNFalpha-associated production of C3 at the same concentrations. The data show that pro-inflammatory cytokines IFNgamma and TNFalpha synergistically augment C3 production by epidermal keratinocytes by different pathways.

Production and pharmacologic modulation of the granulocyte-associated allergic responses to ovalbumin in murine skin models induced by injecting ovalbumin-specific Th1 or Th2 cells.

Because interferon-gamma, interleukin-4, and interleukin-5 have been identified at the mRNA and protein levels in the lesional skin of patients with atopic dermatitis, we investigated the roles played by granulocytes as effector cells in allergic inflammation by using two unique murine skin models. In vitro generated Th1 and Th2 cells from naïve splenocytes of antiovalbumin T cell receptor transgenic BALB/C mice were adoptively transferred with ovalbumin into the ear pinnae or air-pouches produced in the back skin of naïve, nontransgenic BALB/C mice. The injection of Th1 cells with ovalbumin induced delayed type ear swelling that peaked at 48 h, whereas that of Th2 resulted in ear swelling that peaked at a much earlier time, 24 h. Histologic study of the swollen ear skin and granulocytes recruited into the air-pouch demonstrated that, although the Th1-induced inflammation caused a neutrophil-predominant infiltrate with few eosinophils, larger numbers of eosinophils accumulated in the Th2-induced inflammation. Using these murine models, we further evaluated the effects of drugs used for the treatment of atopic diseases. The results showed that FK506 administration could effectively reduce skin inflammation induced by either Th cells. Interestingly, the neutrophil elastase inhibitor ONO-6818 efficiently inhibited Th1-induced inflammation. In contrast, a leukotriene receptor antagonist, ONO-1078, specifically suppressed Th2-induced inflammation. We also found that each ONO drug exerted direct influence on specified granulocytes, as neither affected in vitro production of relevant Th cytokines. Thus, we succeeded in developing animal skin inflammation models in which we can evaluate the contribution of protein antigen-specific Th1 or Th2 cells through the action of granulocytic effector cells.

Mice lacking histidine decarboxylase exhibit abnormal mast cells.

Histidine decarboxylase (HDC) synthesizes histamine from histidine in mammals. To evaluate the role of histamine, we generated HDC-deficient mice using a gene targeting method. The mice showed a histamine deficiency and lacked histamine-synthesizing activity from histidine. These HDC-deficient mice are viable and fertile but exhibit a decrease in the numbers of mast cells while the remaining mast cells show an altered morphology and reduced granular content. The amounts of mast cell granular proteases were tremendously reduced. The HDC-deficient mice provide a unique and promising model for studying the role of histamine in a broad range of normal and disease processes.

Molecular events occurring behind ultraviolet-induced skin inflammation.

We reviewed a recent advance in the studies of the molecular mechanisms for 'ultraviolet responses', paying special attention to two transcription factors, nuclear factor kappa B and p53, and to a balance noted between an anti-apoptotic phosphatidylinositol 3-kinase-Akt pathway and its inhibitory ceramide-caveolin-1 pathway. These studies were mostly carried out using in vitro or animal models. On the basis of these results, we determined that phase by phase molecular events clarified in these studies correspond well with the three phases of ultraviolet-induced inflammation observed, i.e. the early vasodilatory phase, the second inflammatory phase in which many inflammatory cells such as neutrophils and T cells accumulate in the skin, and the last regressive phase based on several anti-inflammatory events.

Mediators of inflammation involved in UVB erythema.

In this review, we discuss the mediators and inflammatory cells involved in UVB-induced inflammatory changes phase by phase. We especially stress the importance of IFNgamma secreted by activated CD4(+) T cells in the development of UVB erythema. We also speculate on the mechanism underlying regression of UVB erythema.

Dehydroepiandrosterone may be one of the regulators of cytokine production in atopic dermatitis.

Previous studies in mice have shown that dehydroepiandrosterone (DHEA) increases the production of Th1-associated lymphokines, and of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), by lymphocytes. However, there are no reports concerning the effect of DHEA on the production of Th2-associated lymphokines, IL-4 and IL-5, by lymphocytes in humans. We examined serum DHEA levels in patients with atopic dermatitis (AD), which is thought to be associated with a higher activity of Th2 cells than of Th1 cells. We also studied the effects of DHEA on the production of IL-4 and IL-5 by human lymphocytes. Serum DHEA concentrations in 47 adult male patients with AD aged 19-30 years were significantly lower than those of 53 age-matched healthy male controls. Preincubation of peripheral blood mononuclear cells (PBMCs) with DHEA reduced the IL-4 production by concanavalin A-stimulated PBMCs. Their IL-5 production also showed a tendency to decrease. These results suggest that DHEA may be one of the regulators of IgE synthesis and eosinophil proliferation in patients with AD and it may act by controlling IL-4, IL-5 and IL-2 production by lymphocytes.

Leukocyte chemotactic properties of soluble horny contents in epidermal cysts.

Epidermal cysts are one of the most common tumors of the skin. Although asymptomatic ordinarily, they may sometimes become severely inflamed with massive invasion of polymorphonuclear leukocytes (PMN). We studied in vitro PMN chemotactic properties of the aqueous extract prepared from the horny material of epidermal cysts obtained from three patients. A crude aqueous extract of the horny content of the cysts showed PMN chemotactic activity, which, however, was less than that of a horny layer extract prepared from normal skin. Characterization of PMN chemotactic activity using a Sephadex G-75 column showed a peak in the low molecular weight fractions eluting between the vitamin B12 and phenol red markers, which corresponds with the peak of absorbance at 280 nm. The chemotactic substances withstood boiling and trypsin or protease digestion. Although the chemotactic activity was partially ether-extractable, the presence of leukotriene B4 was not demonstrated by radioimmunoassay. In addition to their own chemotactic activity, the horny extracts of epidermal cysts showed cytotaxigenic properties in the presence of fresh serum.