Beyond the skin: B cells in pemphigus vulgaris, tolerance and treatment.

Pemphigus vulgaris (PV) is a rare autoimmune bullous disease characterized by blistering of the skin and mucosa owing to the presence of autoantibodies against the desmosome proteins desmoglein 3 and occasionally in conjunction with desmoglein 1. Fundamental research into the pathogenesis of PV has revolutionized its treatment and outcome with rituximab, a B-cell-depleting therapy. The critical contribution of B cells to the pathogenesis of pemphigus is well accepted. However, the exact pathomechanism, mechanisms of onset, disease course and relapse remain unclear. In this narrative review, we provide an overview of the fundamental research progress that has unfolded over the past few centuries to give rise to current and emerging therapies. Furthermore, we summarize the multifaceted roles of B cells in PV, including their development, maturation and antibody activity. Finally, we explored how these various aspects of B-cell function contribute to disease pathogenesis and pave the way for innovative therapeutic interventions.

Pemphigus vulgaris (PV) is a rare autoimmune disease, in which the immune system attacks itself and causes blisters on the skin and inside the mouth. This happens because the body mistakenly attacks specific proteins (called desmosomes) that keep the skin together. Globally, this disease affects anywhere from 0.5 to 16.1 people per million, often older than 50 years. PV is life-threatening when left untreated. From carrying out research as far back as the 1700s, we have made significant strides in understanding PV. For example, research has led to a new treatment with the antibody rituximab, which works by eliminating the cells of the immune system that attack desmosomes (called B cells). However, after therapy is completed, the disease often returns because the same troublesome B cells reappear. There are multiple places that are involved when the body attacks desmosomes. The problems range from the bone marrow where the B cells are made and selected to the ways these cells change as they move around the body. It takes a rare combination of these changes to switch from a normal immune system to one that causes PV. Clinicians and researchers are currently developing new treatment options to better target this skin disease. We want to emphasize that research should continue to uncover how the disease works because a better understanding promotes the development of new therapies, and perhaps even a cure. This is vital, because PV can significantly lower the quality of life of people living with this skin disease.

Acute myeloid leukemia with paraneoplastic pemphigus successfully treated with a personalized antileukemic and immunosuppressive strategy.

Bullous pemphigoid (BP) is a rare blistering disease often considered a primary sign of a paraneoplastic syndrome. Retrospective studies have established its link with hematological malignancies, particularly lymphoproliferative disorders. Here, we present what we believe to be the inaugural case of successful simultaneous management of BP and de novo acute myeloid leukemia (AML) in a 28-year-old male patient. Given the rarity and severity of both conditions, our treatment strategy aimed to maximize efficacy by combining immunosuppressive therapy (initially plasmapheresis with high-dose corticosteroids, followed by anti-CD20 monoclonal antibody and intravenous immunoglobulins 2 g/m2) with lymphodepleting antileukemic chemotherapy utilizing Fludarabine (FLAG-IDA induction regimen). Following diagnosis, considering the patient's youth and the concurrent presence of two rare and potentially life-threatening diseases, we opted for an aggressive treatment. Upon achieving complete morphological remission of AML with measurable residual disease (MRD) negativity, despite incomplete resolution of BP, we proceeded with high-dose cytarabine consolidation followed by peripheral stem cell harvest and autologous stem cell transplantation (ASCT). Our conditioning regimen for ASCT involved Bu-Cy with the addition of anti-thymocyte globulins. At day + 100 post-ASCT, bone marrow evaluation confirmed morphological remission and MRD negativity. Meanwhile, BP had completely resolved with normalization of BP180 antibody levels.

Chronic exposure to the anti-M3 muscarinic acetylcholine receptor autoantibody in pemphigus vulgaris contributes to disease pathophysiology.

Pemphigus vulgaris (PV) is a potentially lethal autoimmune mucocutaneous blistering disease characterized by binding of IgG autoantibodies (AuAbs) to keratinocytes (KCs). In addition to AuAbs against adhesion molecules desmogleins 1 and 3, PV patients also produce an AuAb against the M3 muscarinic acetylcholine (ACh) receptor (M3AR) that plays an important role in regulation of vital functions of KCs upon binding endogenous ACh. This anti-M3AR AuAb is pathogenic because its adsorption eliminates the acantholytic activity of PV IgG; however, the molecular mechanism of its action is unclear. In the present study, we sought to elucidate the mode of immunopharmacologic action of the anti-M3AR AuAb in PV. Short-term exposures of cultured KCs to PV IgG or the muscarinic agonist muscarine both induced changes in the expression of keratins 5 and 10, consistent with the inhibition of proliferation and upregulated differentiation and in keeping with the biological function of M3AR. In contrast, long-term incubations induced a keratin expression pattern consistent with upregulated proliferation and decreased differentiation, in keeping with the hyperproliferative state of KCs in PV. This change could result from desensitization of the M3AR, representing the net antagonist-like effect of the AuAb. Therefore, chronic exposure of KCs to the anti-M3AR AuAb interrupts the physiological regulation of KCs by endogenous ACh, contributing to the onset of acantholysis. Since cholinergic agents have already demonstrated antiacantholytic activity in a mouse model of PV and in PV patients, our results have translational significance and can guide future development of therapies for PV patients employing cholinergic drugs.

Diagnostic delay in autoimmune oral diseases.

Autoimmune diseases (ADs) affect about 5% of the general population, causing various systemic and/or topical clinical manifestations. The oral mucosa is often affected, sometimes as the only involved site. The misdiagnosis of oral ADs is an underreported issue. This narrative review focuses on diagnostic delay (DD) in oral ADs (oral lichen planus [OLP], oral Pemphigus Vulgaris, mucous membrane pemphigoid, oral lupus erythematosus, orofacial granulomatosis, oral erythema multiforme [EM], and Sjogren syndrome). Extensive literature research was conducted via MEDLINE, Embase and Google Scholar databases for articles reporting the time spent to achieve the correct diagnosis of oral ADs. Only 16 studies reported DD in oral ADs. Oral autoimmune vesiculobullous diseases are usually diagnosed after 8 months from the initial signs/symptoms, the Sjogren Syndrome diagnosis usually requires about 73 months. No data exist about the DD in OLP, oral lupus erythematosus, orofacial granulomatosis, and oral EM. The diagnosis of oral ADs can be difficult due to the non-specificity of their manifestations and the unawareness of dentists, physicians, and dental and medical specialists about these diseases. This can lead to a professional DD and a consequential treatment delay. The delay can be attributed to the physicians or/and the healthcare system (Professional Delay) or the patient (Patient's Delay).

Failure of double filtration plasmapheresis to treat severe pemphigus vulgaris: A case report.

Pemphigus vulgaris (PV) is a chronic, mucocutaneous, autoimmune bullous disease. Double filtration plasmapheresis (DFPP) may be effective when PV fails to be controlled by conventional corticosteroid treatment. The patient was a 64-year-old man with erythema, blisters, and erosions on his head, face, mouth, trunk, limbs, and scrotum for over a month. He was diagnosed with severe PV, and the original rash area continued to expand after treatment with systemic corticosteroids, immunosuppressants, and intravenous immunoglobulin, with massive exudate and ≥5 new blisters and macules still occurring daily. Subsequently, the patient completed three sessions of DFPP. After the first DFPP, the original erosion surface exudate was significantly reduced and gradually healed. After the second DFPP, the erosion area and exudate increased compared with the previous one. After the third DFPP, the rash did not improve further and had a tendency to continue to progress. During the entire three sessions of DFPP, the patient had new blisters and bullae on his limbs every day. The Nikolsky's sign of the limbs turned negative at the initial stage, and then the trunk and limbs Nikolsky's sign became positive again. The titer of autoantibodies did not decrease significantly after the plasmapheresis. The patient eventually died of secondary lung infection and septic shock. The efficacy of DFPP in this patient with refractory severe PV was poor.

Taiwanese dermatological association (TDA) consensus for the management of pemphigus.

Pemphigus is an uncommon but life-threatening autoimmune blistering disease characterized by the presence of antibodies against desmogleins. Without effective treatment, pemphigus can result in significant morbidity and mortality. Existing consensus statements on pemphigus management from international medical groups provide varying guidelines, especially on treatment. Thus, on January 4, 2020, a panel of seven dermatology experts from the Taiwanese Dermatological Association (TDA) and one rheumatology expert convened to develop a consensus for the management of pemphigus. These experts with extensive experience in pemphigus management were recommended by their respective teaching hospitals and primary care clinics in Taiwan and by the TDA. The meeting reviewed the available consensus statements from international dermatology groups, including the European Dermatology Forum (EDF), the European Academy of Dermatology and Venereology (EADV), and the International Bullous Diseases Consensus Group. Using these guidelines as a basis for discussion and consensus formulation, these experts formulated their consensus statement that provides practical, concise but comprehensive recommendations as to the diagnosis, treatment, and monitoring of pemphigus patients in Taiwan. This consensus serves as a clinical reference for physicians for the management of pemphigus in Taiwan or wherever it may be applicable.

A preliminary clinical trial comparing wet silver dressings versus wet-to-dry povidone-iodine dressings for wound healing in pemphigus vulgaris patients.

There is insufficient evidence concerning the efficacy of wet silver-containing dressings for wound healing in pemphigus vulgaris (PV). In this randomized, controlled clinical trial, 58 patients with PV skin erosions (10%-70% body surface area) were assigned to receive either wet silver-containing dressings (n = 28) or wet to dry povidone-iodine dressings as a control (n = 30). The patients in the treatment group demonstrated a significant improvement in the number of dressing changes, wound healing time, and duration of hospital stay compared with the control group. Patients treated with wet silver dressings had significantly lower NRS pain scores and reported better subjective satisfaction compared with the control group. The only adverse reactions were an occasional abnormal discharge or infection, but there was no difference between the two groups. In our study the wet silver-containing dressings were safe and effective for the treatment of wound healing in PV patients.

Double-filtration plasmapheresis combined with immunosuppressive treatment for severe pemphigus: 10 years' experience of a single center in China.

BACKGROUND: Pemphigus is a group of rare and severe autoimmune blistering disease mediated by pathogenic autoantibodies against desmogleins. Plasmapheresis can directly remove autoantibodies from circulation, which has been applied to the treatment of pemphigus as an adjuvant therapy. But the results of the researches are controversial. This study aims to evaluate the efficacy and safety of double filtration plasmapheresis (DFPP) combined with immunosuppressive treatment for patients with severe pemphigus in our single center. METHODS: We retrospectively analyzed 17 patients with severe pemphigus who were unresponsive to high-dose corticosteroid and received DFPP treatment between January 2010 and January 2020. The information on demographic characteristics, clinical and laboratory data, treatment regimens, and clinical outcomes were collected. RESULTS: All the patients were diagnosed as severe pemphigus and had a period of at least 1 week of high-dose prednisone (1-1.5 mg/kg/day), but they were unresponsive to corticosteroid and immunosuppressants treatment. They received DFPP treatment as an adjuvant therapy. After DFPP treatment, the titers of desmogleins antibodies significantly decreased (P < .001), Nikolsky's sign became negative and no new blisters appeared. The dosage of corticosteroid could begin to taper down rapidly in 9 ± 4 days. On discharge, the dosage of prednisone decreased significantly (51 ± 3 mg/day, P < .001). No major adverse events happened that could lead to the termination of DFPP treatment. CONCLUSION: Double filtration plasmapheresis combined with immunosuppressive treatment is an effective and safe therapeutic regimen for severe pemphigus. DFPP can also contribute to the dosage reduction of steroid to avoid more drug-related side effect.

Targeting inducible costimulator expressed on CXCR5+PD-1+ TH cells suppresses the progression of pemphigus vulgaris.

BACKGROUND: Pemphigus vulgaris (PV) is an autoimmune bullous disease mediated by autoantibodies against desmoglein 3 (DSG3). Inducible costimulator (ICOS) is a costimulatory receptor expressed on T cells and influences the activity of T follicular helper (TFH) cells in various autoimmune diseases, but the roles of ICOS and TFH cells in PV remain unclear. OBJECTIVE: We examined the immunological characteristics, antigen specificity, and pathogenicity of CD4+ T-cell subpopulations, as well as the therapeutic effect of anti-ICOS blocking antibodies in PV. METHODS: A mouse model of PV was established by adoptive transfer of immune cells from the skin-draining lymph nodes or spleens of DSG3-expressing skin-grafted Dsg3-/- mice into Rag1-/- mice. The TFH cells and CD4+ T cells in PBMCs from PV patients were examined by flow cytometry. RESULTS: Among CD4+ T cells from the mouse model, ICOS-positive TFH cells were associated with B-cell differentiation and were required for disease induction. Using an MHC class II tetramer, DSG3-specific ICOS+ TFH cells were found to be associated with anti-DSG3 antibody production and expanded in the absence of B cells. In human PV, the frequency of ICOS+CXCR5+PD-1+ memory CD4+ T cells correlated with the autoantibody level. Treatment with anti-ICOS blocking antibodies targeting ICOS+ TFH cells decreased the anti-DSG3 antibody level and delayed disease progression in vivo. CONCLUSIONS: Mouse Dsg3-specific ICOS+ TFH cells and human ICOS+CXCR5+PD-1+ TH cells are associated with the anti-DSG3 antibody response in PV. ICOS expressed on CXCR5+PD-1+ TH cells may be a therapeutic target for PV.

Aetiopathogenesis of severe cutaneous adverse reactions (SCARs) in children: A 9-year experience in a tertiary care paediatric hospital setting.

BACKGROUND: Severe cutaneous adverse reactions (SCARs) are delayed-type hypersensitivity reactions to drugs including as follows: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Acute Generalized Exanthematous Pustulosis (AGEP). Incidence, triggers and management of SCARs have not been investigated in large-scale epidemiological studies on children. OBJECTIVE: The aim of our study was to collect epidemiological, clinical and aetiological data from children with SCARs referred to our tertiary care paediatric hospital of Florence. METHODS: From 2010 to 2018 charts of children with diagnosis of SCAR were reviewed, and data collected during the acute phase and/or the subsequent allergy evaluation. Patients underwent patch tests, intradermal tests and lymphocyte transformation tests. All children were investigated for infectious diseases. RESULTS: Incidence of SCARs in hospitalized children was 0.32% over a 9-year period. Fifty-four children were enrolled (31 M; 23 F; median age 6.5 years): 17 cases of DRESS, 30 SJS, 3 TEN, 2 AGEP, 1 linear immunoglobulin A bullous disease (LABD) and 1 pemphigus. Twenty-eight out of 54 patients underwent drug allergy investigations, and 50% of them resulted positive. Combining clinical history and results of allergy work-up, 74% SCARs seem to be caused by drugs, 18.6% by both drugs and infections, 3.7% by infections, and 3.7% remained idiopathic. No deaths occurred. CONCLUSIONS: In this study, SCARs incidence is in line with literature data. Drugs were most commonly the leading cause. Management of SCARs requires cooperation among professional figures for an early diagnosis and a prompt treatment. Mortality rate seems to be lower in children.

Noncandidal vaginitis: a comprehensive approach to diagnosis and management.

Vaginitis is one of the most common causes of patient visits to gynecologists, primary care providers, and urgent care centers. However, many women leave without a clear diagnosis or experience recurrent symptoms despite treatment. The 3 most common etiologies of vaginitis are trichomonas, bacterial vaginosis, and vulvovaginal candidiasis, which account for an estimated 70% of cases. The remaining 30% may be related to other causes of vaginitis, including atrophic vaginitis, desquamative inflammatory vaginitis, and vaginal erosive disease. The purpose of this review is to describe the noncandidal causes of acute and recurrent vaginitis, with the goal of improving the likelihood of accurate diagnosis as well as efficient and effective therapy. We excluded candidal vaginitis from our review because there was a recently published review on this topic in the Journal. The clinical presentation and evaluation of patients with symptoms of vaginitis can be triaged into 1 of 2 diagnostic pathways: noninflammatory and inflammatory vaginitis. The most common noninflammatory cause is bacterial vaginosis. Features such as irritation, purulent discharge, and the presence of polymorphonuclear neutrophils are more suggestive of an inflammatory process. Trichomoniasis is the most common cause of inflammatory vaginitis. Other well-described forms of inflammatory vaginitis include atrophic vaginitis, desquamative inflammatory vaginitis, and erosive disease. We present a review of the pathogenesis, symptoms, examination findings, diagnostic testing, and treatment for each of these causes of noncandidal vaginitis.

Diagnosis and management of pemphigus: Recommendations of an international panel of experts.

BACKGROUND: Several European countries recently developed international diagnostic and management guidelines for pemphigus, which have been instrumental in the standardization of pemphigus management. OBJECTIVE: We now present results from a subsequent Delphi consensus to broaden the generalizability of the recommendations. METHODS: A preliminary survey, based on the European Dermatology Forum and the European Academy of Dermatology and Venereology guidelines, was sent to a panel of international experts to determine the level of consensus. The results were discussed at the International Bullous Diseases Consensus Group in March 2016 during the annual American Academy of Dermatology conference. Following the meeting, a second survey was sent to more experts to achieve greater international consensus. RESULTS: The 39 experts participated in the first round of the Delphi survey, and 54 experts from 21 countries completed the second round. The number of statements in the survey was reduced from 175 topics in Delphi I to 24 topics in Delphi II on the basis of Delphi results and meeting discussion. LIMITATIONS: Each recommendation represents the majority opinion and therefore may not reflect all possible treatment options available. CONCLUSIONS: We present here the recommendations resulting from this Delphi process. This international consensus includes intravenous CD20 inhibitors as a first-line therapy option for moderate-to-severe pemphigus.

Single-nucleotide polymorphisms associated with pemphigus vulgaris: Potent markers for better treatment and personalized medicine.

Pemphigus vulgaris (PV) is a rare autoimmune blistering disorder, which could affect both skin and mucosal surfaces. There is increasing evidence that genetics plays a critical role in PV development, severity and prognosis. Single-nucleotide polymorphisms (SNPs) are the most common type of genetic variation among people and have been widely evaluated in most diseases. However, there are few studies regarding the roles of SNPs in the PV. Here, we reviewed both pathogenic and protective roles of the SNPs in non-HLA genes regarding the PV. Among the large number of studied SNPs, it was found that several SNPs in different genes might control the susceptibility of PV, including TNFA (rs361525, rs1800629, rs1800629), IL10 (rs1800871, rs1800896, rs1800871, and rs1800872), IL6 (rs1800795), CTLA4 (rs231775), ICOS (rs10932029), CD86 (rs1129055), DSG3 (rs8085532, rs3911655, rs3848485, rs3794925, rs1466379), ST18 (rs2304365, rs17315309) and TAP2 (rs7454108), probably in a population-specific manner. Moreover, SNPs in glucocorticoid receptor, also known as nuclear receptor subfamily 3 group C member 1 (NR3C1) gene, including rs11745958, rs17209237, rs33388, rs7701443 as well as rs116855232 at NUDT15, seem to be associated with therapeutic outcomes in PV patients. Additionally, variations in the other genes involved in the drugs' metabolisms, pharmacokinetics and pharmacodynamics such as rs396991 in FCGR3A gene could be used for the prediction of clinical response to drugs and side effects. Taken together, SNPs seem to be valuable tools for better management of PV patients. Further studies need to be conducted to evaluate SNPs in genes that control immune responses and apoptosis.

Feline pemphigus foliaceus: original case series and a comprehensive literature review.

BACKGROUND: Since the first description of feline pemphigus foliaceus (PF) more than 30 years ago, numerous case reports have been published, while larger case series have remained rare. This large body of information, if extrapolated, could address clinical discrepancies and expand our knowledge about the treatment of feline PF. This manuscript reviews cases of feline PF published between 1950 and 2016 and adds additional 35 original cases to provide further insight into the clinical aspect and treatment outcome of this disease. RESULTS: Feline PF, while being a primary acantholytic pustular dermatosis, presents most often with crusts and erosions that predominantly affect the face and feet. More than half of cats with active disease exhibits non-dermatological signs such as lethargy, fever and/or anorexia. The prognosis of feline PF is good as the majority of cats rapidly achieve disease control even with the most basic treatment such as glucocorticoid monotherapy. Most PF-affected cats, however, require long-term treatment and, like other autoimmune diseases, feline PF has a tendency to relapse spontaneously or with treatment changes. CONCLUSIONS: Therefore, despite the overall good prognosis cats with PF can be given, owners should be informed and prepared for these circumstances, which may reduce the risk of euthanasia in the case of disease relapse, and improve treatment compliance.

World Workshop of Oral Medicine VII: A systematic review of immunobiologic therapy for oral manifestations of pemphigoid and pemphigus.

OBJECTIVE: To assess the evidence for treatment of oral involvement of pemphigus and pemphigoid with biologics. STUDY DESIGN: This systematic review used a comprehensive search strategy to identify literature describing oral involvement of pemphigus or pemphigoid treated with a biologic agent. The primary outcome measures were efficacy and safety of biologic therapy. RESULTS: Inclusion criteria were met by 154 studies including over 1200 patients. Treatment of pemphigus with a total of 11 unique biologic agents and 3 unique combinations of agents is reported. Five randomized controlled trials (RCT) were included in the final analysis that investigated infliximab, IVIg, rituximab, and autologous platelet-rich plasma therapy for pemphigus vulgaris. Three non-RCT studies reported on successful rituximab or IVIg therapy for mucous membrane pemphigoid. Studies demonstrated considerable heterogeneity in agent, methods, and quality. CONCLUSIONS: Evidence clearly describing oral tissue response to biologic therapy is sparse. Two RCTs support use of rituximab, one supports use of IVIg, and one pilot study suggests intralesional injection of autologous platelet-rich plasma aids healing of oral PV lesions. As oral lesions of pemphigus and pemphigoid can be refractory to systemic therapy, drug trials including biologic therapies should document details regarding response of the oral lesions to therapy.

Patient-assigned health utility values for controlled and uncontrolled pemphigus vulgaris and foliaceus.

BACKGROUND: The assessment of health-related quality of life (HRQoL) in patients with pemphigus is now of increasing interest due to the availability of highly effective new therapies. Preference-based HRQoL values or health utilities required for medical and financial decision-making are not yet available directly from pemphigus patients. OBJECTIVE: To obtain health utility values for current health and hypothetical health states from the perspective of pemphigus patients. METHODS: A cross-sectional questionnaire survey was carried out with pemphigus patients. Disease severity was rated by Autoimmune Bullous Skin Disorder Intensity Score (ABSIS). Patients were asked to evaluate their current health as well as three common hypothetical pemphigus health states [uncontrolled pemphigus vulgaris (PV), uncontrolled pemphigus foliaceus (PF) and controlled PV/PF] by using composite time trade-off (cTTO). Multiple regression was applied to explore determinants of utility values. RESULTS: Responses of 108 patients (64.8% women, mean age 57.4 years) were analysed. Mean ABSIS score was 11.6. The mean utility values for the hypothetical uncontrolled PV, uncontrolled PF and controlled PV/PF health states were 0.41, 0.52 and 0.66 with cTTO. The mean cTTO scores for current health were higher compared with the hypothetical health states (0.76; P < 0.001). Patients with higher ABSIS, worse pain intensity scores and those having a caregiver reported lower utility values for current health (P < 0.05). CONCLUSIONS: In pemphigus, HRQoL impairment expressed in utility values seems to be considerable, especially in comparison with other chronic dermatological conditions (e.g. psoriasis, atopic eczema, chronic hand eczema). These health utilities inform physicians, policymakers and funders about the overall extent of health loss in pemphigus and provide evidence to guide medical decisions and cost-effectiveness analyses of treatment strategies. Future research is needed to evaluate the caregiver burden in pemphigus.

Identification of a Functional Risk Variant for Pemphigus Vulgaris in the ST18 Gene.

Pemphigus vulgaris (PV) is a life-threatening autoimmune mucocutaneous blistering disease caused by disruption of intercellular adhesion due to auto-antibodies directed against epithelial components. Treatment is limited to immunosuppressive agents, which are associated with serious adverse effects. The propensity to develop the disease is in part genetically determined. We therefore reasoned that the delineation of PV genetic basis may point to novel therapeutic strategies. Using a genome-wide association approach, we recently found that genetic variants in the vicinity of the ST18 gene confer a significant risk for the disease. Here, using targeted deep sequencing, we identified a PV-associated variant residing within the ST18 promoter region (p<0.0002; odds ratio = 2.03). This variant was found to drive increased gene transcription in a p53/p63-dependent manner, which may explain the fact that ST18 is up-regulated in the skin of PV patients. We then discovered that when overexpressed, ST18 stimulates PV serum-induced secretion of key inflammatory molecules and contributes to PV serum-induced disruption of keratinocyte cell-cell adhesion, two processes previously implicated in the pathogenesis of PV. Thus, the present findings indicate that ST18 may play a direct role in PV and consequently represents a potential target for the treatment of this disease.