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Annals of the Rheumatic Diseases May 2024To study the molecular pathogenesis of PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome, a debilitating hereditary autoinflammatory disease caused by...
OBJECTIVES
To study the molecular pathogenesis of PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome, a debilitating hereditary autoinflammatory disease caused by dominant mutation in .
METHODS
Gene knock-out and knock-in mice were generated to develop an animal model. THP1 and retrovirally transduced U937 human myeloid leukaemia cell lines, peripheral blood mononuclear cells, small interfering RNA (siRNA) knock-down, site-directed mutagenesis, cytokine immunoassays, coimmunoprecipitation and immunoblotting were used to study inflammasome activation. Cytokine levels in the skin were evaluated by immunohistochemistry. Responsiveness to Janus kinase (JAK) inhibitors was evaluated ex vivo with peripheral blood mononuclear cells and in vivo in five treatment-refractory PAPA patients.
RESULTS
The knock-in mouse model of PAPA did not recapitulate the human disease. In a human myeloid cell line model, PAPA-associated mutations activated the pyrin inflammasome, but not the NLRP3, NLRC4 or AIM2 inflammasomes. Pyrin inflammasome activation was independent of the canonical pathway of pyrin serine dephosphorylation and was blocked by the p.W232A mutation, which disrupts pyrin-PSTPIP1 interaction. IFN-γ priming of monocytes from PAPA patients led to IL-18 release in a pyrin-dependent manner. IFN-γ was abundant in the inflamed dermis of PAPA patients, but not patients with idiopathic pyoderma gangrenosum. Ex vivo JAK inhibitor treatment attenuated IFN-γ-mediated pyrin induction and IL-18 release. In 5/5 PAPA patients, the addition of JAK inhibitor therapy to IL-1 inhibition was associated with clinical improvement.
CONCLUSION
PAPA-associated mutations trigger a pyrin-IL-18-IFN-γ positive feedback loop that drives PAPA disease activity and is a target for JAK inhibition.
Topics: Pyoderma Gangrenosum; Arthritis, Infectious; Humans; Animals; Mice; Acne Vulgaris; Inflammasomes; Disease Models, Animal; Interferon-gamma; Janus Kinase Inhibitors; Mice, Knockout; Cytoskeletal Proteins; Feedback, Physiological; Adaptor Proteins, Signal Transducing; Pyrin; Mutation; Phosphoproteins; Gene Knock-In Techniques; Interleukin-18; THP-1 Cells
PubMed: 38408849
DOI: 10.1136/ard-2023-225085 -
Dermatologic Clinics Apr 2024Pyoderma gangrenosum (PG) is an inflammatory neutrophilic dermatosis with variable clinical features. The classic presentation is an ulceration with an erythematous to... (Review)
Review
Pyoderma gangrenosum (PG) is an inflammatory neutrophilic dermatosis with variable clinical features. The classic presentation is an ulceration with an erythematous to violaceous undermined border. Extracutaneous manifestations may occur. Associated systemic diseases include inflammatory bowel disease, inflammatory arthritides, and hematologic disorders. The pathophysiologic mechanism of disease is not completely known but likely related to the cumulative impact of inflammation, immune-mediated neutrophilic dysfunction, and genetic predisposition. Incidence is between 3 and 10 people per million but may be greater due to under recognition. In this article, we will discuss the diagnostic criteria, disease subtypes, systemic associations, and workup.
Topics: Humans; Pyoderma Gangrenosum; Inflammation; Inflammatory Bowel Diseases; Diagnosis, Differential
PubMed: 38423678
DOI: 10.1016/j.det.2023.08.003 -
European Journal of Dermatology : EJD Oct 2023
PubMed: 38297942
DOI: 10.1684/ejd.2023.4587 -
Clinics in Dermatology 2023Hidradenitis suppurativa (HS) is a clinically heterogeneous disease with a broad spectrum of clinical features. Attempts to classify HS into distinct clinical phenotypes...
Hidradenitis suppurativa (HS) is a clinically heterogeneous disease with a broad spectrum of clinical features. Attempts to classify HS into distinct clinical phenotypes could lead to a better understanding of the condition and the development of individualized treatment protocols. We summarize some of the existing phenotype classifications and present our experience with 250 patients and their many clinical presentations. We have emphasized the pathophysiologic and clinical overlap between HS and pyoderma gangrenosum. The more severe presentations can include erosive and ulcerative lesions, sometimes associated with vegetative changes leading to diagnostic quandaries. We propose a new phenotype of pyoderma gangrenosum-like HS in which painful ulcerative or vegetative lesions appear in sites affected by HS, their activity coincides with the flareups of classic inflammatory manifestations of HS, and they heal with cribriform or atrophic scars.
Topics: Humans; Hidradenitis Suppurativa; Pyoderma Gangrenosum; Pain
PubMed: 37652191
DOI: 10.1016/j.clindermatol.2023.08.025 -
Acta Dermatovenerologica Croatica : ADC Nov 2023For over two decades, the acronym PAPA syndrome has been used to describe an autoinflammatory condition caused by missense mutations in the PSTPIP1...
For over two decades, the acronym PAPA syndrome has been used to describe an autoinflammatory condition caused by missense mutations in the PSTPIP1 (proline-serine-threonine phosphatase interacting protein 1) gene and clinically characterized by the presence of pyogenic arthritis, pyoderma gangrenosum (PG), and acne (1,2). Due to the involvement of the PSTPIP1 gene in the regulation of innate immunity, mutations of this gene cause abnormal activation of inflammasomes, complexes of NLRP3/ASC/caspase-1 proteins. As a result, production of interleukin-1β, a key molecule that triggers synthesis of cytokines necessary for the recruitment of neutrophils, is significantly increased (2,3). Additionally, the levels of other pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ) and interleukin 17 (IL-7) are also elevated, which further disrupts inflammatory mechanisms in the microenvironment (4). Since hyperproduction of IL-1 and other involved cytokines is the predominant event in the pathogenesis, these molecules are promising targets in the treatment of PAPA syndrome. Corticosteroids and biologics are currently the most commonly used agents for inducing and hastening remission of symptoms (5). A substantial step forward in the treatment of PAPA syndrome has been the introduction of medications blocking the cytokines crucial in the pathogenesis of this disorder, with TNF-α and IL-1 inhibitors being the most frequent choice of such biological therapy (6). We report the case of a 22-year-old male patient with PAPA syndrome who was referred to our department 18 months ago due to exacerbation of skin changes. Initial presentation and subsequent evolution of disease in this patient matched the typical clinical pattern of PAPA syndrome. The first symptoms occurred at the age of two in the form of unspecific joint disease that was diagnosed as juvenile idiopathic arthritis. Subsequently, in the early adolescence the patient presented with new skin changes manifesting as severe acne and persistent pyoderma gangrenosum-like ulcers. At the same time, severity of joint involvement gradually decreased. After the characteristic phenotype of the disease had fully developed, suspicion of possible syndromic origin of symptoms arose. For this reason, genetic analysis was performed as requested by attending pediatricians at the University Clinical Center in Sarajevo, and E250Q mutation of the PSTPIP1 gene was detected. Thus, the diagnosis of PAPA syndrome was confirmed. Throughout the duration of the disease, several types of medication had been introduced in the treatment with varying success. Earliest joint symptoms were alleviated with non-steroidal anti-inflammatory drugs, while repeated courses of corticosteroids were the mainstay of the therapy during a decade-long period. As a consequence of prolonged steroid therapy, growth disorder, among various other side-effects, had been especially pronounced. Acting as a classic steroid-sparing immunosuppressive agent, methotrexate had also been part of the patient's treatment regimen. Lastly, biologics, including both TNF-α and IL-a inhibitors, had been separately administered as the remaining treatment options. However, adalimumab expressed a predominant effect on joint symptoms, whereas re-activation of previously undetected Hepatitis-B infection occurred during the subsequent therapy with anakinra. Due to this adverse reaction, anakinra treatment was discontinued. At the initial examination, the patient presented with multiple erythematous, partially excoriated papules and nodules, along with residual post-inflammatory hyperpigmented patches and scars on the skin of the whole back, chest, shoulders, and upper arms (Figure 1, Figure 2). The presence of postoperative scars on the elbows, resulting from previously performed surgical procedures of persistently affected joints with the goal of achieving pain relief and functional improvement, was also observed. Several smaller ulcers with undermined edges (Figure 3), as well as residual hyperpigmentation and cicatrices (Figure 4) were visible on the lower extremities. Additionally, the patient reported appearance of pustules and non-healing ulcers after minor trauma, which corresponds to the pathergy phenomenon, a common feature of PAPA syndrome. In contrast to the severity of cutaneous changes, the joint symptoms were mild. After thorough assessment of the patient's medical history and current condition, a multi-agent regimen was initiated, consisting of adalimumab, isotretinoin, and prednisone. Regular check-ups during the 12 months of treatment showed that the applied agents stabilized the patient's condition, alleviated more severe and acute skin changes, and slowed down further exacerbation of symptoms. Due to the rarity of PAPA syndrome, data on its treatment is scarce. Official guidelines are non-existing, and available information is based on case reports, case series, and a few smaller retrospective studies (5,7). In general, response to therapy remains inconsistent between patients, despite introduction of novel drugs. Furthermore, single treatment regimens are often not equally effective for all manifestations of the disease, which in a number of cases results in the administration of multi-agent treatment (2). As described in our case report, we opted for a multi-agent regimen not only due to specific individual role of each drug in the treatment of PAPA syndrome but also because of the possible augmented effect of combined therapy. Initially, a short course of systemic corticosteroid (prednisone 30 mg/day for 3 weeks) was introduced in order to alleviate acute symptoms until other agents started showing their effects. The initial dose of administered corticosteroid was gradually tapered by 5 mg every week and soon discontinued. Adalimumab (40 mg every 2 weeks for 12 months) was chosen since its previous administration was without significant adverse effects and with more acceptable end results, unlike therapy with anakinra (8). In addition, TNF-α inhibitors, such as adalimumab, etanercept, and infliximab, have been generally regarded as a more effective treatment option for cutaneous changes, while anakinra, an anti-IL-1 agent, has been more beneficial in alleviating joint symptoms (9-11). Since the skin of our patient was significantly more affected than the joints, adalimumab was a preferred option for biological treatment. Finally, isotretinoin (0.5 mg/kg/day for 6 months) also found a place in our multi-agent therapy plan as a specific, supportive treatment agent for acne (12). Due to the fact that our national health insurance system covered the costs of treatment with TNF-α inhibitors for only 12 months, adalimumab had to be discontinued after the end of this period. Episodes of acute exacerbation that the patient experienced after the cessation of multi-agent regimen were addressed with systemic corticosteroids and symptomatic therapy. Based on case reports, corticosteroids are usually one of the first agents to be administered in patients diagnosed with PAPA syndrome. They are frequently effective in alleviating joint symptoms, but, on the other hand, high doses of corticosteroids can worsen acne lesions (6). Moreover, due to the multiple side-effects of corticosteroids, such as electrolyte abnormalities, hypertension, hyperglycemia, osteoporosis, growth suppression, and adrenal insufficiency (13), a steroid-sparing agent is typically introduced into treatment together with or after corticosteroid therapy. A substantial step forward in the treatment of PAPA syndrome has been achieved with the introduction of medications targeting cytokines crucial in the pathogenesis of this disorder. The two most commonly used groups of such biological drugs have been those that block TNF-α and IL-1. A longer lasting improvement of symptoms has been achieved in a number of cases with both types of agents. Since other medications have often failed to establish long-term control of PAPA syndrome, such effects can be seen as a valuable accomplishment (6,14). Regardless of this observation, the response to treatment still differs between patients. More variable effects have been documented for IL-1 inhibitors, such as anakinra, while TNF-α inhibitors, such as adalimumab, infliximab, and etanercept, have been associated with more steady responses (4,6,10). The inconsistent effect of biologic therapies could be explained by the fact that PSTPIP1 protein is involved in various biochemical processes in different cells of the immune system. Thuse, none of the medications has an adequate spectrum of activity to control all involved immunological pathways (5,15). Overall, due to scarcity of valid information and guidelines, there is an increasing need for multicentric randomized controlled trials that would provide evidence-based data on effective treatment options for PAPA syndrome. Despite the rarity of this disorder, extensive research should be performed in order to discover therapies that could successfully manage all different manifestations of PAPA syndrome. Consequently, such efforts and breakthroughs would lead to decreased mortality and improved quality of life for patients suffering from this debilitating disease. The case described herein shows that PAPA syndrome can remain undiagnosed for longer periods of time, resulting in delayed treatment. Furthermore, the available therapeutic options are not sufficient to achieve long-term remission in many patients. Thus, continuous and comprehensive research is vital for ensuring adequate care of patients with PAPA syndrome.
Topics: Adult; Humans; Male; Young Adult; Acne Vulgaris; Adalimumab; Adrenal Cortex Hormones; Biological Products; Cicatrix; Cytokines; Etanercept; Immunologic Factors; Infliximab; Interleukin 1 Receptor Antagonist Protein; Isotretinoin; Prednisone; Pyoderma Gangrenosum; Quality of Life; Retrospective Studies; Tumor Necrosis Factor-alpha; Ulcer
PubMed: 38006373
DOI: No ID Found -
Journal of the American Academy of... Nov 2023
Topics: Humans; Scalp; Scalp Dermatoses; Neoplasms
PubMed: 37499983
DOI: 10.1016/j.jaad.2023.07.1009 -
Anais Brasileiros de Dermatologia 2024Skin modification through tattoos is as old as humanity itself. However, this trend is on the rise, and with the use of different types of pigments and application... (Review)
Review
BACKGROUND
Skin modification through tattoos is as old as humanity itself. However, this trend is on the rise, and with the use of different types of pigments and application practices, both cutaneous and systemic complications can arise. Adverse reactions can be grouped into five classes: inflammatory, infectious, neoplastic, aesthetic, and miscellaneous. On histopathology, inflammatory reactions can exhibit a lichenoid pattern or present as spongiotic dermatitis, granulomatous reactions, pseudolymphoma, pseudoepitheliomatous hyperplasia, or scleroderma/morphea-like changes. This article reviews tattoo complications, including their clinical and histopathological characteristics.
METHODS
An open search was conducted on PubMed using the terms "tattoo", "complications", and "skin". No limits were set for period, language, or publication type of the articles.
RESULTS
Reactions to tattoos are reported in up to 67% of people who get tattooed, with papulonodular and granulomatous reactions being the most common. Some neoplastic complications have been described, but their causality is still debated. Any pigment can cause adverse reactions, although red ink is more frequently associated with them. Patients with pre-existing dermatoses may experience exacerbation or complications of their diseases when getting tattoos; therefore, this procedure is not recommended for this patient group.
CONCLUSIONS
Dermatological consultation is recommended before getting a tattoo, as well as a histopathological examination in case of complications. In patients who develop cutaneous inflammatory reactions following tattooing, additional studies are recommended to investigate systemic diseases such as sarcoidosis, pyoderma gangrenosum, atopic dermatitis, and neoplasms. It is important for physicians to be trained in providing appropriate care in case of complications.
Topics: Tattooing; Humans; Skin Diseases; Coloring Agents; Risk Factors; Skin
PubMed: 38521707
DOI: 10.1016/j.abd.2023.07.004 -
Experimental Dermatology Jan 2024Pyoderma gangrenosum (PG) is a rare ulcerative neutrophilic dermatosis that is occasionally associated with primary immunodeficiency. Though contributions from... (Review)
Review
Pyoderma gangrenosum (PG) is a rare ulcerative neutrophilic dermatosis that is occasionally associated with primary immunodeficiency. Though contributions from dysregulation of the innate immune system, neutrophil dysfunction and genetic predisposition have been postulated, the precise pathogenesis of PG has not yet been elucidated. This article reviews reported cases of coexisting PG and primary immunodeficiency in order to gain insight into the complex pathophysiology of PG. Our findings suggest that variations in genes such as RAG1, ITGB2, IRF2BP2 and NFκB1 might play a role in genetically predisposing patients to develop PG. These studies support the feasibility of the role of somatic gene variation in the pathogenesis of PG which warrants further exploration to guide targeted therapeutics.
Topics: Humans; Pyoderma Gangrenosum; Genetic Predisposition to Disease; Dermatitis
PubMed: 37846943
DOI: 10.1111/exd.14954 -
Medicina Clinica Jun 2024
PubMed: 38926039
DOI: 10.1016/j.medcli.2024.03.031 -
Joint Bone Spine Feb 2024
PubMed: 38417693
DOI: 10.1016/j.jbspin.2024.105712