What protein kinases are crucial for acantholysis and blister formation in pemphigus vulgaris? A systematic review.

Pemphigus vulgaris (PV) is a potentially fatal autoimmune blistering disease characterized by cell-cell detachment (or acantholysis) and blister formation. While the signaling mechanisms that associate with skin/mucosal blistering are being elucidated, specific treatment strategies targeting PV-specific pathomechanisms, particularly kinase signaling, have yet to be established. Hence, the aim of this review was to systematically evaluate molecules in the class of kinases that are essential for acantholysis and blister formation and are therefore candidates for targeted therapy. English articles from PubMed and Scopus databases were searched, and included in vitro, in vivo, and human studies that investigated the role of kinases in PV. We selected studies, extracted data and assessed risk of bias in duplicates and the results were reported according to the methodology outlined by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). The risk of bias assessment was performed on in vivo studies utilizing SYRCLE's risk of bias tool. Thirty-five studies were included that satisfied the pathogenicity criterion of kinases in PV, the vast majority being experimental models that used PV sera (n = 13) and PV-IgG (n = 22). Inhibition of kinase activity (p38MAPK, PKC, TK, c-Src, EGFR, ERK, mTOR, BTK, and CDK2) was achieved mostly by pharmacological means. Overall, we found substantial evidence that kinase inhibition reduced PV-associated phosphorylation events and keratinocyte disassociation, prevented acantholysis, and blocked blister formation. However, the scarce adherence to standardized reporting systems and the experimental protocols/models used did limit the internal and external validity of these studies. In summary, this systematic review highlighted the pathogenic intracellular events mediated by kinases in PV acantholysis and presented kinase signaling as a promising avenue for translational research. In particular, the molecules identified and discussed in this study represent potential candidates for the development of mechanism-based interventions in PV.

Evaluating the risk-to-benefit ratio of using cotrimoxazole as a pneumocystis pneumonia preventative intervention among pemphigus patients treated with rituximab: A retrospective study with 494 patients.

Rituximab is widely used as the first-line treatment for pemphigus patients. Since it depletes the B cells, it increases the risk of infections. Here, we evaluated the prophylactic efficacy of cotrimoxazole in decreasing the risk of pneumocystis pneumonia (PCP) infection in the pemphigus patients treated with rituximab. The medical records of confirmed pemphigus patients receiving rituximab were evaluated in two groups; those who received cotrimoxazole as a prophylactic after rituximab and patients who only received rituximab without any prophylaxis. The occurrence of PCP infection was determined in each group and compared. Medical records of 494 patients, including 301 women and 193 men, with the mean age of 46.74 years were analyzed. The phenotypes of the disease were mucocutaneous (n = 364), mucosal (n = 88), and cutaneous (n = 42). Among them, 235 cases had received cotrimoxazole as a prophylaxis and 259 patients did not. The incidence of PCP in total patients was 2 (0.4%), one in each group. Accordingly, no significant difference was observed in the incidence of PCP between two groups (p = 0.84). Also, no cotrimoxazole-related side effect was observed in the treated group. It seems that due to the low incidence of PCP in pemphigus patients treated with rituximab, prophylactic cotrimoxazole therapy is not necessary and it only increases the overall therapy cost and might cause cotrimoxazole-related adverse effects in some patients. However, regarding its probable beneficial effect in patients with long-term history of immunosuppressive therapy, more studies are required.

Rituximab in autoimmune pemphigoid diseases: Indications, optimized regimens, and practice gaps.

Rituximab is a monoclonal antibody targeting CD20 on B cells with proven efficacy for pemphigus vulgaris, now an FDA-approved indication. Other autoimmune bullous diseases can be challenging to treat and have significant associated morbidity and mortality, but data supporting the use of rituximab in pemphigoid group diseases remain limited. Although rituximab demonstrates efficacy for clinical improvement and remission in pemphigoid, concern for adverse events may also limit the use of this medication. We review the current evidence fo rthe use of rituximab in pemphigoid diseases, pertinent dosing schedules and laboratory monitoring, and the associated common and rare adverse events. Review of the literature to date not only supports consideration of rituximab for treatment of refractory pemphigoid group diseases but also reflects tolerability and an acceptable safety profile.

FR-Rituximab, una revolución en el tratamiento del pénfigo / RF-Rituximab: Revolutionizing the Treatment of Pemphigus

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Valuation of pemphigus vulgaris and pemphigus foliaceus health states: a convenience sample experiment.

BACKGROUND: Health-related quality of life (HRQoL) in pemphigus has been widely investigated; nevertheless, utility values for economic evaluations are still lacking. OBJECTIVES: To estimate health utilities for hypothetical pemphigus vulgaris (PV) and pemphigus foliaceus (PF) health states in a general population sample. METHODS: Three health states (uncontrolled PV, uncontrolled PF and controlled pemphigus) were developed based on a systematic literature review of HRQoL studies in pemphigus. Utilities were obtained from a convenience sample of 108 adults using a visual analogue scale (VAS) and 10-year time trade-off (TTO). Lead-time TTO was applied for health states regarded as worse than dead with a lead time to disease time ratio of 1 : 1. RESULTS: The mean VAS utility scores for PV, PF and controlled pemphigus were 0·25 ± 0·15, 0·37 ± 0·17 and 0·63 ± 0·16, respectively. Corresponding TTO utilities were as follows: 0·34 ± 0·38, 0·51 ± 0·32 and 0·75 ± 0·31. Overall, 14% and 6% judged PV and PF as being worse than dead. For both VAS and TTO values, significant differences were observed between all health states (P < 0·001). VAS utilities were rated significantly lower compared with TTO in each health state (P < 0·001). CONCLUSIONS: This is the first study that reports health utility values for PV and PF. Successful treatment of pemphigus might result in significant utility gain (0·24-0·41). These empirical findings with respect to three health states in pemphigus may serve as anchor points for further utility studies and cost-effectiveness analyses.

Aplicación de un Plan de Cuidados Enfermeros utilizando el modelo de Virginia Henderson (catorce necesidades) a una persona que presenta lesiones causadas por pénfigo vulgar / Implementation of a plan of care using the model of Virginia Henderson (fourteen needs), to a person who presents lesions caused by pemphigus vulgaris

Presentamos un caso clínico cuyo interés es mostrar el Plan de Atención de Cuidados Enfermeros (PLACE). La metodología guiada está basada en la taxonomía NANDA, NOC y NIC, la cual utiliza el modelo de Virginia Henderson de las catorce necesidades, esto con la finalidad de difundir la labor diaria del profesional de enfermería. En el PLACE planteamos la posibilidad también, de referirse a éste, como tratamiento enfermero en un futuro más próximo, cuyos objetivos son aplicar los conocimientos científicos fundamentados, razonados y planeados, a fin de resolver necesidades de salud centrados en la persona desde su padecimiento hasta su rehabilitación, orientados con su método principal: el Proceso de Atención de Enfermería (PAE), el cual permite aplicar cuidados a personas sanas o enfermas, pudiéndose aplicar desde una clínica de heridas y ostomías hasta para la gran diversidad de personas en distintas edades que se encuentren en servicios de hospitalización, clínica o a domicilio, así como en aquellas que presenten diferentes necesidades de atención en su salud. El caso clínico difundido es de una mujer con diagnóstico médico de pénfigo vulgar, que presenta lesiones epidérmicas en una gran superficie corporal y úlceras por presión de IV grado a nivel sacro, la cual es intervenida interdisciplinariamente en una Clínica de Heridas y Ostomías (CHO). De acuerdo con lo antes mencionado, haremos énfasis en el tratamiento de enfermería

We present a clinical case where the interest is to show a Plan of Nursing Care (PLACE) with a guided methodology based on the taxonomy NANDA, NIC and NOC using the Virginia Henderson model of the fourteen needs, with the purpose of disseminating the daily work of the nursing professional; for the purpose of disseminating the daily work of the nursing professional; in the place we have the possibility also to refer to this as treatment nurse in a near future; whose objectives are to apply sound scientific knowledge, reasoned and planned, in order to resolve health needs focusing on the person from their disease, and follow him to his rehabilitation, oriented with its main method: The process of Nursing Care (PAE), that allows you to apply care to people healthy or diseased, which could be applied from a clinic of wounds and ostomies, to the great diversity people in different ages, who are in hospitalization services, clinic or home, as well as in those who present different care needs in their health. He clinical case spread, is a female person with a medical diagnosis of pemphigus vulgaris, which presents epidermal injury in a large body surface area and pressure ulcers of level IV degree to sacrum, which is operated in an interdisciplinary way in a clinic of wounds and Ostomies (CHO). According to the described we will place emphasis on the treatment of nursing

Peptide-mediated desmoglein 3 crosslinking prevents pemphigus vulgaris autoantibody-induced skin blistering.

In pemphigus vulgaris, a life-threatening autoimmune skin disease, epidermal blisters are caused by autoantibodies primarily targeting desmosomal cadherins desmoglein 3 (DSG3) and DSG1, leading to loss of keratinocyte cohesion. Due to limited insights into disease pathogenesis, current therapy relies primarily on nonspecific long-term immunosuppression. Both direct inhibition of DSG transinteraction and altered intracellular signaling by p38 MAPK likely contribute to the loss of cell adhesion. Here, we applied a tandem peptide (TP) consisting of 2 connected peptide sequences targeting the DSG adhesive interface that was capable of blocking autoantibody-mediated direct interference of DSG3 transinteraction, as revealed by atomic force microscopy and optical trapping. Importantly, TP abrogated autoantibody-mediated skin blistering in mice and was effective when applied topically. Mechanistically, TP inhibited both autoantibody-induced p38 MAPK activation and its association with DSG3, abrogated p38 MAPK-induced keratin filament retraction, and promoted desmosomal DSG3 oligomerization. These data indicate that p38 MAPK links autoantibody-mediated inhibition of DSG3 binding to skin blistering. By limiting loss of DSG3 transinteraction, p38 MAPK activation, and keratin filament retraction, which are hallmarks of pemphigus pathogenesis, TP may serve as a promising treatment option.

Inhibition of FAK prevents blister formation in the neonatal mouse model of pemphigus vulgaris.

Pemphigus vulgaris (PV) is an autoimmune blistering skin disease characterized by suprabasal acantholysis and by autoantibodies against desmoglein 3 localized on desmosomes. In addition, caspases also seem to participate in this blistering disease. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase involved in cytoskeleton remodelling and formation and disassembly of cell adhesion structures. We have previously demonstrated that HER (human epidermal growth factor receptor related) isoforms, Src (Rous sarcoma) and mammalian target of rapamycin (mTOR), three molecules implicated in signalling processes, take part in suprabasal acantholysis and apoptosis induced by PV-IgG in a mouse model. Our aim was to investigate whether upregulation of FAK is implicated in the development of PV lesions. Herein, using a mouse model, PV-IgG administration showed an increased level of FAK phosphorylated on 397 and 925 tyrosine residues in the basal layer of epidermis. When mice were pretreated with a FAK inhibitor (FI), the acantholysis of the basal layer of epidermis was absent. More interestingly, we observed that phosphorylated FAK (Y397/925) decreased when HER isoforms, Src, mTOR and pan-caspases inhibitors were employed before PV-IgG administration. In addition, pretreatment with the FI before PV-IgG injection prevented the changes in both Bax and Bcl-2 expression and caspase-9 and caspase-3 activities induced by PV-IgG. Finally, FI reduced the expression of phosphorylated Src and mTOR in the basal cells of epidermis. In conclusion, our data reveal a novel role of phosphorylated FAK (Y397/925) in PV development involving HER isoforms, Src and mTOR kinases.

Protective endogenous cyclic adenosine 5'-monophosphate signaling triggered by pemphigus autoantibodies.

Pemphigus vulgaris (PV) is an autoimmune skin disease mediated by autoantibodies directed against the cadherin-type cell adhesion molecules desmoglein (Dsg) 3 and Dsg1 and is characterized by loss of keratinocyte cohesion and epidermal blistering. Several intracellular signaling pathways, such as p38MAPK activation and RhoA inhibition, have been demonstrated to be altered following autoantibody binding and to be causally involved in loss of keratinocyte cohesion. In this paper, we demonstrate that cAMP-mediated signaling completely prevented blister formation in a neonatal pemphigus mouse model. Furthermore, elevation of cellular cAMP levels by forskolin/rolipram or ß receptor agonist isoproterenol blocked loss of intercellular adhesion, depletion of cellular Dsg3, and morphologic changes induced by Ab fractions of PV patients (PV-IgG) in cultured keratinocytes. Incubation with PV-IgG alone increased cAMP levels, indicating that cAMP elevation may be a cellular response pathway to strengthen intercellular adhesion. Our data furthermore demonstrate that this protective pathway may involve protein kinase A signaling because protein kinase A inhibition attenuated recovery from PV-IgG-induced cell dissociation. Finally, cAMP increase interfered with PV-IgG-induced signaling by preventing p38MAPK activation both in vitro and in vivo. Taken together, our data provide insights into the cellular response mechanisms following pemphigus autoantibody binding and point to a possible novel and more specific therapeutic approach in pemphigus.

IgA pemphigus associated with monoclonal gammopathy completely resolved after achievement of complete remission of multiple myeloma with bortezomib, cyclophosphamide and dexamethasone regimen.

Monoclonal gammopathy-associated IgA pemphigus is a debilitating skin disorder with inconsistent response to treatment. A 61-year-old woman with IgA pemphigus and monoclonal gammopathy of unknown significance had been treated unsuccessfully with cyclophosphamide/dexamethasone and then with rituximab. When the monoclonal gammopathy progressed to multiple myeloma, the patient received treatment with cyclophosphamide/doxorubicin/dexamethasone but there was no clinical response. Second-line therapy with a thalidomide/cyclophosphamide/dexamethasone combination led to severe exacerbation of the skin disorder. However, therapy with a combination regimen that included bortezomib, cyclophosphamide and dexamethasone resulted in complete and durable remission of multiple myeloma and IgA pemphigus. This suggests that bortezomib-based therapy is useful for the treatment of the rare dermatologic disorder associated with IgA gammopathy.

[Recent advances in autoimmune blistering disease].

Systemic application of steroids is the first-line treatment. In intractable cases, immunosuppressants, plasma exchange therapy and intravenous immunoglobulin therapy are performed. We recently experienced the efficacy of high dose intravenous immunoglobulin therapy for pemphigus by double blind, placebo-controlled clinical trial. We also examined the disease course of pemphigus patients who have been treated at our outpatient department. Of the 69 patients, 26 (37.7%) were found to be free from the disease (without symptoms or circulating pemphigus antibody and not requiring any treatment for more than 1 year).

p38MAPK inhibition prevents disease in pemphigus vulgaris mice.

Pemphigus vulgaris (PV) is a life-threatening autoimmune blistering skin disease characterized by detachment of keratinocytes (acantholysis). It has been proposed that PV IgG might trigger signaling and that this process may lead to acantholysis. Indeed, we recently identified a rapid and dose-dependent phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and heat shock protein (HSP) 27 after binding of PV antibodies to cultured keratinocytes. In human keratinocyte cultures, inhibitors of p38MAPK prevented PV IgG-induced phosphorylation of HSP27 and, more importantly, prevented the early cytoskeletal changes associated with loss of cell-cell adhesion. This study was undertaken to (i) determine whether p38MAPK and HSP25, the murine HSP27 homolog, were similarly phosphorylated in an in vivo model of PV and (ii) investigate the potential therapeutic use of p38MAPK inhibition to block blister formation in an animal model of PV. We now report that p38MAPK inhibitors prevented PV blistering disease in vivo. Targeting the end-organ by inhibiting keratinocyte desmosome signaling may be effective for treating desmosome autoimmune blistering disorders.

Tolerance induction by the blockade of CD40/CD154 interaction in pemphigus vulgaris mouse model.

Pemphigus vulgaris (PV) is an autoimmune blistering disease caused by IgG autoantibodies against desmoglein 3 (Dsg3). We have recently developed an active disease mouse model for PV by adoptive transfer of splenocytes from Dsg3(-/-) mice. The purpose of this study was to determine the role of CD40/CD154 interaction in the pathogenic antibody production and development of the disease in PV model mice. When anti-CD154 monoclonal antibody (mAb) was administered to recipient mice prior to adoptive transfer, anti-CD154 mAb almost completely blocked the anti-Dsg3 IgG production and prevented blister formation. The blockade of CD40/CD154 interaction induced tolerance against Dsg3 as the suppression of antibody production was observed through day 70, and it was maintained even after challenge by immunization with recombinant mouse Dsg3 or by adoptive transfer of immunized Dsg3(-/-) splenocytes. Furthermore, the tolerance to Dsg3 was transferable because cotransfer of splenocytes from anti-CD154 mAb-treated mice and naïve Dsg3(-/-) splenocytes significantly suppressed anti-Dsg3 IgG production in recipient mice. In contrast, when anti-CD154 mAb was injected after the mice had developed the PV phenotype, no significant suppression of the production of anti-Dsg3 IgG was observed. These findings indicate that the CD40/CD154 interaction is essential for the induction of pathogenic anti-Dsg3 IgG antibodies and that antigen-specific immune-regulatory cells induced by anti-CD154 mAb would hold a therapeutic option for autoimmune diseases.

Treatment of recalcitrant pemphigus vulgaris with the tumor necrosis factor alpha antagonist etanercept.

The treatment of pemphigus vulgaris (PV) is generally regarded as challenging. Patients with the disease require long-term systemic therapy, creating concern for the toxicities of these treatments. Corticosteroids, as drugs of first choice, often must be combined with steroid-sparing agents to prevent hazardous long-term side effects. We describe a 62-year-old woman with long-standing PV whose cutaneous disease responded to therapy with the tumor necrosis factor alpha (TNF-alpha) antagonist etanercept, which was started for treatment of her inflammatory seronegative arthritis. To our knowledge, this is the first report of its efficacy in the treatment of PV.

PEMPHIGUS: an acronym for a disease with multiple etiologies.

The acronym PEMPHIGUS is suggested to encompass the numerous factors involved in the pathogenesis and course of the disease. In the following review the authors present studies documenting these factors. The acronym can serve as a handy tool to direct the physician's investigation of a case of pemphigus, aiding in its diagnosis and in the prevention of future flare-ups.

The plant lectin wheat germ agglutinin inhibits the binding of pemphigus foliaceus autoantibodies to desmoglein 1 in a majority of patients and prevents pathomechanisms of pemphigus foliaceus in vitro and in vivo.

Pemphigus foliaceus (PF) is a life-threatening autoimmune blistering skin disease caused by pathogenic IgG autoantibodies against desmoglein 1 (dg1), a desmosomal cadherin-type adhesion glycoprotein. Using lectins and glycosidases, we have shown that dg1 displays an N-glycosylation pattern of the complex triantennary type. We have found that lectins and glycosidases interfere with N-bound sugar residues on the amino-terminal ectodomain of dg1 and completely abolish, in vitro, the antigenicity of dg1 in most of the patients' sera. Moreover, in an ex vivo model using punch biopsies from normal human skin, we demonstrate that preincubation of the epidermis in wheat germ agglutinin (WGA) prevents PF autoantibody binding, acantholysis, and subcorneal blistering. In addition, we show that topical treatment with WGA inhibits PF autoantibody binding to keratinocytes in both newborn BALB/c mice and in organotypic human epidermis grafted onto the back of SCID mice. The epidermis of these pretreated animals displays a regular morphology, whereas control animals develop the immunopathologic phenotype of PF. These findings suggest that WGA may interfere with autoantibody binding to dg1, preventing experimental PF without affecting the adhesive function of dg1. Our observations may provide a new approach to the therapy of PF.

Precautions and suggestions for pemphigus patients.

The onset and course of pemphigus are often the result of an interaction between predisposing genetic factors and environmental triggering agents. The latter are heterogeneous, numerous and increasing, ranging from drug intake (the commonest cause of pemphigus induction) to the exposure to physical agents (heat, UV and ionizing rays, surgical and cosmetic procedures), viral infections (especially by herpesvirus), contact dermatitis, certain diet ingredients and even emotional stress. Alerting physicians and pemphigus patients to the effects that unsuspected precipitating factors may have on the progression of the disease is an important task. In fact, avoiding or limiting deleterious habits (e.g. overindulging in unnecessary drugs) and suggesting alternative ways (e.g. substituting potentially pemphigus-inducing drugs with others considered harmless in this respect) may be a useful precaution in the management of pemphigus patients, since it can improve the efficacy of conventional treatments, reduce the risks of relapses and sometimes result in a cure.

Anti-idiotype antibodies neutralize in vivo the blistering effect of Pemphigus foliaceus IgG.

Idiotypes are molecular clues used to explore the specificity and diversity of immune response. In the present study, anti-idiotype antibodies were used to neutralize the pathogenic effects induced by the injection of pemphigus immunoglobulin(Ig)G into BALB/c mice. To achieve our goal, antidesmoglein 1 IgG was obtained from a patient with pemphigus foliaceus with high titer of antiepithelial antibodies. The IgG was isolated by ion exchange chromatography, then digested by pepsin. F(ab')2 fragments were purified in Sephacryl S-300 and injected in rabbits to produce anti-idiotype antibodies. The rabbit sera reacted with the pemphigus F(ab')2 fragments. Eleven pemphigus foliaceus sera were recognized by the anti-idiotype serum at the light or heavy chains whereas bullous pemphigoid and normal IgG were negative. Neonatal BALB/c mice injected with pemphigus IgG developed intraepidermal blisters, mimicking the clinical and immunopathological features of the pemphigus. In contrast, the animals treated with anti-idiotype antibodies and pemphigus IgG did not develop blisters. Thus, anti-idiotype antibodies neutralize in vivo the pathogenic effects of pemphigus IgG.

Patterns of remission in pemphigus vulgaris.

BACKGROUND: The incidence of remissions in pemphigus is unclear because these are usually reported at a single point in the evolution of the disease. Thus it is uncertain whether treatment simply suppresses the manifestations of the disease and consequently must be continuously administered, or induces complete and long-lasting remissions that permit therapy to be discontinued. OBJECTIVE: To answer this question, we investigated the incidence of remission in a long-term longitudinal study. METHODS: The induction of complete and long-lasting remissions (lesion free with no systemic therapy for at least 6 months) was studied in 40 patients with pemphigus vulgaris treated conventionally and followed up for an average of 7.7 years by the same investigator. RESULTS: Five (5%) of the patients died of the disease. Complete and long-lasting remissions were induced in 25%, 50%, and 75% of patients 2, 5, and 10 years, respectively, after diagnosis. Most of the remaining patients were in partial remission or had mild disease controlled with a small dose of steroids. The course of the disease followed different patterns, with some patients rapidly entering complete and long-lasting remissions, whereas others never entered into a complete remission. The induction of complete remission was related to the initial severity and extent of disease and to early response to treatment. CONCLUSION: It is possible to eventually induce complete and durable remissions in most patients with pemphigus that permit systemic therapy to be safely discontinued without a flare in disease activity. The proportion of patients in whom this can be achieved increases steadily with time, and therapy can be discontinued in approximately 75% of patients after 10 years.