Autoimmune Bullous Dermatoses Research Articles

Tetracyclines revisited: tetracyclines in the field of dermatology.

Tetracyclines are a class of broad-spectrum antibiotics favored by dermatologists. Over the last decade, the clinical efficacy of tetracyclines has expanded into various dermatoses. This review tries to encompass the possible indications of tetracycline in the field of dermatology and possible mechanisms of action. This comprehensive review encompasses all possible indications of tetracyclines besides acne vulgaris and rosacea: hidradenitis suppurativa, autoimmune bullous dermatoses, vitiligo, alopecia, prurigo pigmentosa, granulomatous dermatoses, Kaposi sarcoma, cold urticaria, atopic dermatitis, scrub typhus, scarring, and miscellaneous dermatoses. We also focus on the recently approved sarecycline, a third generation narrow-spectrum tetracycline, and its clinical efficacy and potential impact on the microbiome. Our review provides a better understanding of this extremely familiar drug class and encourages its use in a wider spectrum of dermatologic diseases and symptoms.

Case report: A novel high-dose intravenous immunoglobulin preparation for the treatment of severe pemphigus vulgaris failing standard therapy.

Pemphigus vulgaris (PV) is a severe autoimmune bullous dermatosis that is characterized by autoantibodies against epidermal adhesion proteins causing painful mucosal and skin blistering. Standard treatments for PV include corticosteroids, steroid-sparing immunosuppressants, or intravenous monoclonal anti-CD20-antibody therapy. The European guidelines suggest high-dose intravenous immunoglobulin (IVIg) therapy as a promising approach for severe or treatment-resistant cases. We report on a 65-year-old woman with severe and recurrent disease who achieved long-term disease stabilization with IVIg treatment. Because of recurrent fatigue and headache, the patient was switched to an alternative IVIg preparation with a novel manufacturing process, thus ensuring high purity and better tolerability. We observed excellent efficacy, yet side effects remained largely unchanged. Further studies are necessary to evaluate the long-term efficacy and tolerability of this new IVIg preparation.

Diagnosis of autoimmune bullous dermatoses: Comparative analysis of immunohistochemical staining using C4d, C3d, IgG, and IgG4 in lesional tissues and perilesional frozen skin samples

Immunohistochemical staining with immunoglobulins and complements may aid the diagnosis of patients whose clinical and histological findings are consistent with autoimmune bullous dermatoses (AIBD). We aimed to investigate the diagnostic value of immunohistochemical markers in lesional biopsy and perilesional frozen samples in AIBD. We included 136 cases from whom lesional biopsies and perilesional samples for direct immunofluorescence (DIF) examination were collected with a preliminary diagnosis of AIBD between January 2019 and January 2023. All diagnoses were reconfirmed by evaluating the clinical, histopathological, and serological findings and DIF results (C3, IgG, IgA, or IgM positivity compatible with the clinical diagnosis) altogether, although DIF results were considered a priority. After confirming the diagnoses, the samples were categorized as AIBD or the others. The perilesional tissues obtained for DIF simultaneously with skin biopsy and stored at −80 °C were thawed, and FFPE tissues were prepared. We performed immunohistochemical staining (C4d, C3d, IgG, and IgG4) on FFPE tissues of both lesional and perilesional samples. Strong, linear, or granular staining patterns at the dermoepidermal junction or the intraepidermal blistering space were considered positive in line with the diagnosis of the case. Cases other than AIBD were used as negative control tissues to assess the specificity of immunohistochemical markers. Of the 136 cases, 52 were diagnosed with AIBD. In lesional samples, the sensitivity of C4d, C3d, IgG, and IgG4 was 80.6 %, 69.4 %, 75 %, and 5.7 % with corresponding specificity of 100 %, 98.7 %, 89.6 %, and 97.4 %, respectively in pemphigoid diseases compared to a sensitivity of 18.2 %, 9.1 %, 70 %, and 9.1 % and specificity of 98.7 %, 100 %, 89.6 %, and 97.4 %, respectively in pemphigus diseases. In frozen samples, we detected expression in a limited number of cases. The sensitivity of C4d, C3d, IgG, and IgG4 was 8.7 %, 2.2 %, 19.4 %, and 2.2 %, with corresponding specificity of 100 %, 100 %, 98.5 %, and 98.6, respectively. There was a none to slight concordance rate between the IHC results of lesional tissues and perilesional frozen samples. Kappa coefficients for C4d, C3d, IgG, and IgG4 were 0.120 (P = 0.029), 0.111 (P = 0.050), 0.203 (P = 0.003), and - 0.15 (P = 0.846), respectively. Immunohistochemical staining with C4d, C3d, IgG, and IgG4 on biopsy samples collected from lesions may guide the diagnosis of AIBD, thereby eliminating the need for an additional biopsy and accelerating the diagnostic process.

Assessment of the acceptability and feasibility of HIV self-testing in vulnerable population groups in Togo

Background: The aim of this study was to assess the acceptability and feasibility of HIV self-testing in vulnerable population groups. Methods: This was a quantitative and qualitative study conducted in April 2022 in thirteen pilot centers of the national AIDS program. The target populations were men who had sex with men (MSM), female sex workers (FSWs), and street adolescents. Results: During the study period, 802 people were included in this study, among whom 51.4% were male. The study population consisted mainly of FSWs (34.4%), MSM (24.4%), and people from the general population (23.2%). The median age of the participants was 23 years, ranging from 13 to 77 years. The overall acceptability of the self-test was estimated to be 97.1% (n = 779). Six participants refused to do it immediately yet suggested that they might do it later, and 17 (2.1%) outright refused to do it. Acceptability was 100% among street adolescents, transgender people, and drug users. The lowest level of acceptability (93.5%) was found among the FSWs. Self-testing was considered feasible for 99.7% (n = 777) IC95% (99.1-100.0) of the participants. Conclusion: Our study showed that self-testing is a highly acceptable and practical strategy for MSM, FSWs, and adolescents in Togo. Therefore, in order to accelerate the implementation of population screening programs in our country, it is important to bring all innovative interventions to scale if we are to achieve the UNAIDS 95-95-95 targets by 2026. Key words: Autoimmune bullous dermatoses, Pemphigus, Bullous pemphigoid, Togo

Artificial intelligence in autoimmune bullous dermatoses

Dermatologists treating patients with autoimmune bullous dermatoses (AIBDs), as well as the patients themselves, encounter challenges at every stage of their interaction, including dermatologic and comorbidities assessment, diagnosis, prognosis evaluation, treatment, and follow-up monitoring. We summarize the current and potential future clinical applications of artificial intelligence (AI) in the field of AIBDs. Recent research and AI models have demonstrated their potential to enhance or may already be contributing to advancements in every phase of the comprehensive diagnosis and personalized treatment process in AIBDs, providing patients, clinicians, and administrators with valuable support. Image recognition AI systems might assist precise clinical diagnoses of various diseases, including AIBDs, and could offer consistent and reliable scoring of disease severity. Automated and standardized AI-assisted laboratory methods could improve the accuracy and decrease the time and cost of gold-standard tests such as direct and indirect immunofluorescence. The studies and tools discussed in this contribution, although in the early stages, might be a small precursor to a transformative shift in the way we take care of patients with chronic skin diseases, including AIBDs.

Successful Treatment of Severe Pemphigus Vulgaris with Reduced Side Effects Using a Novel IVIg Preparation.

Pemphigus vulgaris (PV) is a rare autoimmune bullous dermatosis (AIBD) characterized by painful blistering of the skin and mucosa caused by autoantibodies that lead to loss of adhesion in the epidermis. Standard therapy for PV is corticosteroids, either alone or in combination with steroid-sparing immunosuppressants or infusions with rituximab. According to the published European guideline, high-dose intravenous immunoglobulin (IVIg) therapy with a dosage of 2g per kg body weight distributed over 2-5days every 4weeks is a promising treatment option, especially for severe or refractory disease. This report describes a 73-year-old female patient with severe and recurrent disease who achieved stabilization with IVIg treatment. However, the patient experienced side effects such as headaches, nausea, and vomiting, which affected daily life. Hence, she was transitioned to a new IVIg preparation with a new manufacturing process, resulting in fewer side effects and an improved quality of life. Further follow-up is necessary to fully evaluate the effectiveness and tolerability of this new IVIg product.

Human leukocyte antigen class II (DRB1 and DQB1) alleles frequencies in patients with various forms of pemphigus among the Russian population

BACKGROUND: Autoimmune bullous dermatoses are known to be the most severe blistering conditions of skin. HLA-DRB1 and DQB1 alleles might play a crucial role in their onset. In pemphigus HLA class II molecules stimulate the division of T helper cells, which in turn stimulate B cells to produce antibodies to epidermal keratinocytes causing acantholysis. The HLA-DRB1 and DQB1 alleles’ frequencies studied in pemphigus in a vast variety of populations worldwide. However, as of yet, this mechanism was not investigated in Russian population. AIM: To estimate the prevalence of the HLA-DRB1 and DQB1 alleles at a low- and high-resolution levels in patients with various forms of pemphigus. We observed 86 patients with pemphigus vulgaris, 13 ― with pemphigus foliaceus, 6 patients with paraneoplastic pemphigus and 92 healthy volunteers. MATERIALS AND METHODS: HLA typing for DRB1 and DQB1 was performed with 50 nanogram DNA extraction and polymerase chain reaction. RESULTS: At a low-resolution level HLA-DRB1*4 and DRB1*14 alleles were statistically significant more frequent in pemphigus vulgaris and pemphigus foliaceus patients compared to those in control subjects, whereas HLA-DRB1*11, DRB*16, and DRB1*3 alleles were more frequent in healthy volunteers. At a high-resolution level, DRB1*04:02 allele was observed to show its statistically significant higher frequency in all variants of pemphigus, including paraneoplastic pemphigus. However, DRB1*14:05 HLA allele was more frequent in pemphigus vulgaris and pemphigus foliaceus patients, whereas DRB1*11:04 one was found to be 3.7 times more frequent in healthy controls. Additionally, at a low-resolution level for HLA-DQB1 alleles no statistically significant results were observed. However, at a high-resolution level the chances for more frequent indication of DQB1*03:02 allele were 7.09 times higher in pemphigus foliaceus group and 2.49 higher in pemphigus vulgaris patients compared to healthy volunteers. Moreover, DQB1*05:03 was identified more frequently in pemphigus vulgaris and paraneoplastic pemphigus groups of patients, whereas DQB1*03:01 allele was shown to be increased in the group of healthy donors. CONCLUSION: HLA-DRB1*4, DRB1*14, DRB1*04:02, DRB1*14:05, DQB1*03:02 and DQB1*05:03 alleles might be considered as the genetic markers for pemphigus vulgaris susceptibility, while HLA-DRB1*11, DRB*16, DRB1*3, DRB1*11:04 and DQB1*03:01 allelic groups appear to be protective for Russian population.

Hospitalization and mortality in Asian autoimmune bullous dermatosis patients: A 17-year retrospective study.

Limited data exist on the factors associated with hospitalization and mortality in Asian inpatients with autoimmune bullous dermatoses (AIBDs). This study aimed to elucidate the risk factors affecting hospitalization and mortality rates in Asian patients with AIBDs. A retrospective analysis of patients with AIBDs treated at Siriraj Hospital during a 17-year period was performed using the International Classification of Diseases 10th revision codes. The characteristics of inpatients and outpatients were compared, and mortality rates and associated factors were identified. The study included 360 AIBD patients (180 inpatients, 180 outpatients). Inpatients were significantly younger than outpatients. The identified risk factors for hospitalization were malignancy (odds ratio [OR] 2.83, 95% confidence interval [CI] 1.13-8.04; p = 0.034), moderate to severe disease (OR 2.52, 95% CI 1.49-4.34; p < 0.001), systemic corticosteroid use ≥15 mg/day (OR 2.27, 95% CI 1.21-4.41; p = 0.013) and oral cyclophosphamide treatment (OR 9.88, 95% CI 3.82-33.7; p < 0.001). Kaplan-Meier analysis revealed mortality rates of 26%, 36% and 39% for inpatients with pemphigus at 1, 3 and 5 years, respectively. For inpatients with pemphigoid, the corresponding rates were 28%, 38% and 47%. Infections, particularly pneumonia, were the predominant cause of death in both conditions. This study confirmed that both Asian ethnicity and healthcare disparities may be correlated with adverse outcomes in patients with AIBDs. Pemphigus mortality rates were substantially greater in Asian patients than in Caucasian patients. Continuous monitoring of factors contributing to hospitalization and mortality is imperative to improve treatment outcomes.

Ocular manifestations in patients with autoimmune bullous dermatoses: A hospital-based retrospective study

Background: Ocular involvement in autoimmune bullous dermatoses (AIBD) remains underappreciated. Objectives: The objective was to study the prevalence and characteristics of ocular involvement in patients with AIBD. Methods: The medical records of 25 patients (males: females 11:14) aged between 27 and 85 years (mean ± standard deviation = 44.9 ± 15.6 years) with AIBD were analyzed retrospectively for clinico-epidemiological attributes and the presence of ocular abnormalities. Results: There were 20 (80%) pemphigus patients, of which most were pemphigus vulgaris (PV, n = 14) and pemphigus foliaceus (PF, n = 6). Other 5 (20%) patients included bullous pemphigoid (BP, n = 4) and cicatricial pemphigoid (CP, n = 1). Seventeen (68%) patients comprising 11 (78.6%) of PV, 3 (50%) of PF, 2 (50%) of BP, and 1 (100%) of CP had 27 ocular abnormalities. Erosions of lid margins (n = 3, 27.3%), blepharitis with meibomitis (n = 1, 9.1%), chalazion (n = 1, 9.1%), and conjunctival vesicles over bulbar conjunctivae (n = 2, 18.2%), conjunctivitis (PV = 5, 45.5%, PF = 1, 33.3%), and symblepharon and keratoconjunctivitis sicca in one (9.1%) patient each, respectively, were major ocular manifestations in pemphigus. Entropion with trichiasis, shallow fornices, and corneal opacities were major abnormalities in patients with BP (n = 2, 100%) and CP (n = 1, 100%). Conclusion: Ocular comorbidities vary in prevalence and severity between subtypes of AIBD. These are mainly from complications of ocular surface disease predominantly affecting the anterior segment of the eye. They are more severe in patients with CP compared to others. The study is limited by a single-center, retrospective-study design, a small number of patients in each group for stratification, and long-term follow-up.

New Onset and Exacerbation of Autoimmune Bullous Dermatosis Following COVID-19 Vaccination: A Systematic Review.

Cases of autoimmune bullous dermatosis (AIBD) have been reported following COVID-19 vaccination. We aimed to provide an overview of clinical characteristics, treatments, and outcomes of AIBDs following COVID-19 vaccination. We conducted a systematic review and searched the Embase, Cochrane Library, and Medline databases from their inception to 27 March 2024. We included all studies reporting ≥ 1 patient who developed new-onset AIBD or experienced flare of AIBD following at least one dose of any COVID-19 vaccine. We included 98 studies with 229 patients in the new-onset group and 216 in the flare group. Among the new-onset cases, bullous pemphigoid (BP) was the most frequently reported subtype. Notably, mRNA vaccines were commonly associated with the development of AIBD. Regarding the flare group, pemphigus was the most frequently reported subtype, with the mRNA vaccines being the predominant vaccine type. The onset of AIBD ranged from 1 to 123 days post-vaccination, with most patients displaying favorable outcomes and showing improvement or resolution from 1 week to 8 months after treatment initiation. Both new-onset AIBD and exacerbation of pre-existing AIBD may occur following COVID-19 vaccination. Healthcare practitioners should be alert, and post-vaccination monitoring may be essential.

Comorbidities of autoimmune bullous dermatoses in North-Eastern Romania

Comorbidities of autoimmune bullous dermatoses in North-Eastern Romania

Rheumatic diseases associated with autoimmune bullous dermatoses

Rheumatic diseases associated with autoimmune bullous dermatoses

Epidemiological Study of Autoimmune Bullous Dermatoses in Northeastern Romania.

Autoimmune bullous diseases (ABDs) are a rare but significant group of dermatoses that pose great challenges to the treating dermatologist. ABDs are characterized by the presence of tissue-bound and circulating autoantibodies directed against disease-specific target antigens of the skin. Most epidemiological studies have focused on a single ABD. More than that, there are few data about the incidence and prevalence of autoimmune blistering diseases in Romania. In this study, between 2015 and 2019, we retrospectively investigated a total of 225 patients with autoimmune bullous diseases from the northeastern region of Romania. The diagnosis was based on the clinical and histo- and immunohistological findings. Pemphigus was the most frequently encountered ABD, with an incidence of 8.16/1,000,000 inhabitants, representing 58.7% (132 cases), followed by 24% cases of bullous pemphigoid (54 cases), 15.4% of patients were diagnosed with dermatitis herpetiformis (37 cases), and 0.9% other subepidermal autoimmune bullous dermatoses. The average age of onset of pemphigus vulgaris was 59.4 years, the majority of patients being male, while the average age of patients diagnosed with bullous pemphigoid was 73.8 years, the majority being female. Pemphigus vulgaris is the most frequently encountered ABDs in the northeast of Romania, with a higher incidence than in Western European countries, and this may be due to specific peculiarities of the geographical area, as well as to a genetic susceptibility of the population in this region.

Pemphigus vulgaris

Pemphigus vulgaris is a chronic autoimmune bullous dermatosis that results from the production of autoantibodies against desmogleins 1 and 3. It is the most frequent and most severe form of pemphigus, occurring universally, usually between 40 and 60 years of age. It usually begins with blisters and erosions on the oral mucosa, followed by lesions on other mucous membranes and flaccid blisters on the skin, which can be disseminated. There is a clinical variant, pemphigus vegetans, which is characterized by the presence of vegetating lesions in the large folds of the skin.

Autoimmune bullous dermatoses in cancer patients treated by immunotherapy: a literature review and Italian multicentric experience.

Cutaneous immune-related adverse events are frequently associated with immune checkpoint inhibitors (ICIs) administration in cancer patients. In fact, these monoclonal antibodies bind the cytotoxic T-lymphocyte antigen-4 and programmed cell death-1/ligand 1 leading to a non-specific activation of the immune system against both tumoral cells and self-antigens. The skin is the most frequently affected organ system appearing involved especially by inflammatory manifestations such as maculopapular, lichenoid, psoriatic, and eczematous eruptions. Although less common, ICI-induced autoimmune blistering diseases have also been reported, with an estimated overall incidence of less than 5%. Bullous pemphigoid-like eruption is the predominant phenotype, while lichen planus pemphigoides, pemphigus vulgaris, and mucous membrane pemphigoid have been described anecdotally. Overall, they have a wide range of clinical presentations and often overlap with each other leading to a delayed diagnosis. Achieving adequate control of skin toxicity in these cases often requires immunosuppressive systemic therapies and/or interruption of ICI treatment, presenting a therapeutic challenge in the context of cancer management. In this study, we present a case series from Italy based on a multicenter, retrospective, observational study, which included 45 patients treated with ICIs who developed ICI-induced bullous pemphigoid. In addition, we performed a comprehensive review to identify the cases reported in the literature on ICI-induced autoimmune bullous diseases. Several theories seeking their underlying pathogenesis have been reported and this work aims to better understand what is known so far on this issue.

Epidemiological, clinical and therapeutic aspects of dermatitis herpetiformis at Yalgado Ouédraogo University Hospital Centre, Burkina Faso

Background: Dermatitis herpetiformis is a rare autoimmune bullous dermatosis that predominantly affects Caucasians, adults or children, with a sex ratio of 1.8. Materials and Methods: The aim of this study was to document the clinical and epidemiological profiles of dermatitis herpetiformis and to detail its treatment in a hospital setting in order to increase our knowledge about this disease in our context and so to improve its management. We conducted a retrospective, cross-sectional study of the records of all patients seen in consultation or hospitalized at the dermatology department of Yalgado Ouédraogo University Hospital Centre, Ouagadougou, a public hospital in Burkina Faso, from January 2016 to December 2020. Results: We collected 14 cases (0.12%) of dermatitis herpetiformis among 11,456 patients seen. The mean age was 8 years (ranging from 4 to 27 years). The sex ratio was 1.33. The majority of the patients were schoolchildren living in rural areas (8 cases). The duration of the disease ranged from five days to one year (mean duration: 59.35 days). Eight patients had a history of digestive problems such as abdominal pain and diarrhea. Pruritis was the principal functional sign. In all patients, the lesions were polymorphous: disseminated vesicular bullae, papules, erosive, and excoriated lesions, sometimes forming clusters. Mucosal involvement was rare (3 cases). A gluten-free diet and dapsone 2 mg/kg/day were proposed to all patients and resulted in the improvement of the lesions. Conclusion: Our study confirmed that dermatitis herpetiformis is rare in our context. It is more frequent in young children and predominantly affects boys. It is intensely pruritic, and generalized polymorphous lesions were present in all our patients. Treatment is essentially based on a gluten-free diet and dapsone, which is a therapeutic test in the absence of supplementary investigations to establish a definitive diagnosis. Key words: Dermatitis Herpetiformis; Clinical Medicine; Dapsone; Gluten Intolerance

Features of clinical diagnosis of IgA-pemphigus in a patient with a long history of the disease

Ige-dependent pemphigus is a rare autoimmune vesicular disease and is characterized by painful and itchy vesicular rashes on the skin. Ige-dependent pemphigus is one of the rarest forms of autoimmune bullous dermatoses.&#x0D; The article describes the clinical case of patient T., aged 82 y.o., who applied to the Novosibirsk Regional Clinical Dermatovenerologic Dispensary with complaints of rashes on the skin of the trunk, limbs, periodically accompanied by itching. For the first time, rashes began to appear 20 years ago, more often in the summer. She was observed by a rheumatologist with a diagnosis of chronic vasculitis, during exacerbation, against the background of therapy with systemic glucocorticosteroids, the rashes regressed. During the last exacerbation after suffering a Novel coronavirus infection at the age of 82 y.о., patient turned to a dermatologist against the background of an injection of a solution with betamethasone, with partially regressed rashes, which made it difficult to establish a diagnosis. After 2 weeks, against the background of discontinuation of therapy, another exacerbation occurred, characterized by obvious clinical manifestations of neutrophilic bullous dermatosis in the form of flaccid pustulеs on the skin of the trunk, upper extremities, as well as serous-purulent crusts arranged in the form of rings and garlands. Based on the history, clinical features and laboratory studies, without the use of immunofluorescence, a provisional diagnosis of IgA-dependent pemphigus was made, systemic glucocorticoid therapy was prescribed with a long-term gradual withdrawal, with a positive effect.

Graves' disease and autoimmune bullous dermatosis

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Autoimmune bullous dermatoses

Autoimmune bullous dermatoses (AIBD) are a heterogeneous group of about a dozen diseases characterized clinically by erosions and blisters and immunopathologically by autoantibodies against structural proteins of the skin or transglutaminase 2/3. The diagnosis of AIBD has made tremendous progress in the last decade due to the availability of standardized serological assays that, knowing the clinical picture, allow the diagnosis in the vast majority of patients. The development of various in vitro and in vivo models of the most common AIBD, namely, bullous pemphigoid, pemphigus vulgaris, mucous membrane pemphigoid, and the rare epidermolysis bullosa acquisita, allows identification of key molecules and inflammatory pathways as well as preclinical evaluation of the effect of new anti-inflammatory agents. The approval of rituximab for moderate and severe pemphigus vulgaris and the development of national and international guidelines for the most common AIBD have considerably advanced the care of these patients. Nevertheless, the limited therapeutic armamentarium is the main challenge for the management of AIBD. Several phase II and III randomized controlled clinical trials provide hope for new, effective, and safe therapeutic options in the coming years. This review summarizes the epidemiology, clinic, diagnosis, pathophysiology, and therapy of AIBD and gives an outlook on both current diagnostic and therapeutic needs as well as future developments.

A pen sketch for oral pemphigus vulgaris: A review

Pemphigus is a rare chronic mucocutaneous autoimmune bullous dermatosis. Based on clinical features and pathophysiology the various subtypes include pemphigus Vulgaris (PV), pemphigus foliaceus (PF), IgA pemphigus, and paraneoplastic pemphigus (PNP). Autoantibodies against desmogleins 1 and 3 cause pemphigus Vulgaris which results in acantholysis, or the loss of cell-to-cell adhesion ultimately causing potentially lethal bullae and erosion formation. 80 to 90% of patients develop oral lesions that are manifested before mucocutaneous lesions in more than half of patients.Dental professionals are pivotal and can thus diagnose the disease and prevent skin involvement through proper therapy. Treatment should include systemic corticosteroids and immunosuppressive drugs. Intravenous pulse therapy is instituted in severe cases of pemphigus. This article is an attempt to present clinical manifestations, pathophysiology, and newer medical treatment modalities of pemphigus.