Materiały źródłowe

• #1 Granuloma Annulare – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459377/

  Granuloma annulare (GA) is a cutaneous granulomatous disease of unknown etiology. The etiology and pathogenesis of granuloma annulare are largely unknown. However, the disease has been associated with diabetes mellitus, thyroid disease, mild trauma, hyperlipidemia, infections (Ebstein-Barr Virus, human immunodeficiency virus, varicella-zoster virus, tuberculosis), vaccines, malignancy, and certain drugs (TNF-alpha inhibitors). […] Some believe that granuloma annulare is caused by a delayed-type hypersensitivity reaction, more specifically a Th1 reaction involving IFN-gamma stimulating macrophages to release matrix metalloproteinases. This ultimately results in connective tissue degradation. […] Impaired neutrophil chemotaxis has been found in patients with granuloma annulare. The authors of this study postulated that macrophages take over an inflammatory site because of the impaired neutrophil response, which leads to the granulomatous inflammation seen in granuloma annulare as opposed to a suppurative neutrophil type inflammation.

• #2 Granuloma Annulare: An Updated Review of Epidemiology, Pathogenesis, and Treatment Options

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8423598/

  Granuloma annulare (GA) is an inflammatory granulomatous skin disease that can be localized (localized GA) or disseminated (generalized GA), with patch, perforating, and subcutaneous subtypes being less common variants of this benign condition. […] Recently, new research has emerged that further elucidates GA epidemiology and etiopathogenesis; importantly, new therapeutic options for GA have also been described, although there remains a paucity of randomized controlled studies. […] Likely owing to its relative rarity, little is known about its etiopathogenesis. Recent studies have implicated T-helper 1 (Th1) axis and Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway dysregulation in GA. […] An important inconsistency between the work by Min et al. and Wang et al. is that Wang et al. did not find upregulation of the Th2 pathway that was reported by Min et al.

• #3 Granuloma annulare preceding the diagnosis of Sjögren’s syndrome | Volume 37 – Issue 3 – September 2022 | Archives of Rheumatology

  https://archivesofrheumatology.org/full-text/1355

  Granuloma annulare is a benign, inflammatory, noninfectious, granulomatous skin disorder characterized by variable clinical presentations, including papular, subcutaneous, patch (macular form), and central perforating forms. […] Although the pathogenesis of granuloma annulare is not clarified, it has been proposed to be associated with diabetes mellitus, autoimmune thyroid diseases, dyslipidemia, various malignancies, and connective tissue diseases. […] Granuloma annulare is a poorly understood condition characterized by variable clinical presentations with two predominant histopathologic patterns: palisading and interstitial granulomatous inflammation. […] Although granuloma annulare has a benign and self-limiting course, it is potentially connected to variable systemic diseases. […] Sjgrens syndrome, dermatomyositis, morphea, and systemic sclerosis are some of the connective tissue diseases reported to be associated with granuloma annulare.

• #4 Granuloma Annulare: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1123031-overview

  Proposed pathogenic mechanisms for GA have included cell-mediated immunity (type IV), immune complex vasculitis, and an abnormality of tissue monocytes. Other possible mechanisms have included primary degeneration of connective tissue leading to granulomatous inflammation, lymphocyte-mediated immune reaction with macrophage activation, and cytokine-mediated degradation of connective tissue. […] The etiology of GA has not been defined, and the pathogenetic mechanisms are poorly understood, with the vast majority of cases occurring in patients who are otherwise healthy. The range of predisposing events and associated diseases is diverse, and GA is thought to represent a reaction pattern with many different initiating factors. […] Familial cases of GA observed in identical twins and siblings in several generations, along with an association of GA with human leukocyte antigen (HLA) phenotypes, have suggested the possibility of a hereditary component in some cases. The HLA-B8 level has been reported to be increased in localized GA; HLA-A29 and HLA-BW35 levels have been reported to be increased in generalized GA.

• #5 Granuloma Annulare | Plastic Surgery Key

  https://plasticsurgerykey.com/granuloma-annulare-4/

  The cause is unknown, and the pathogenesis is poorly understood. […] The etiology of granuloma annulare is unknown, and the pathogenesis is poorly understood. […] The pathogenetic mechanisms that result in foci of altered connective tissue surrounded by a granulomatous inflammatory infiltrate are not understood. Proposed mechanisms include (1) a primary degenerative process of connective tissue initiating granulomatous inflammation, (2) a lymphocyte-mediated immune reaction resulting in macrophage activation and cytokine-mediated degradation of connective tissue, and (3) a subtle vasculitis or other microangiopathy leading to tissue injury.

• #6 Generalized granuloma annulare

  https://escholarship.org/uc/item/6kq1p6t8

  Granuloma annulare is an inflammatory condition that is primarily idiopathic, but it has been associated with certain diseases, most notably diabetes mellitus. […] The pathogenesis of granuloma annulare is unknown. There is some evidence to suggest that it is an immunologic disease. A study has shown that the primary cell types involved are interferon- producing Th-1 lymphocytes and macrophages that express TNF- and matrix metalloproteinases, which possibly contribute to a delayed-type hypersensitivity reaction. […] Although granuloma annulare tends to be idiopathic, there is an association with diabetes mellitus. There are also weaker associations with Bacillus Calmette-Guerin vaccination, drugs (allopurinol, zalcitabine), viral infections (Epstein Barr virus, human immunodeficiency virus, hepatitis C, parvovirus B19, and herpes simplex virus), autoimmune thyroiditis, and malignant conditions (Hodgkin disease, pulmonary adenocarcinoma, breast carcinoma, and ovarian cancer).

• #7

  https://link.springer.com/article/10.1007/s13671-024-00430-2

  It is hypothesized that GA involves an immunologically mediated reaction leading to inflammation around the blood vessels. […] Recently, two studies have aimed to explain the pathogenesis of GA. Both studies describe the role of lymphocytes T and cytokines produced by them. One study reported the upregulation of Th1 and Th2 pathways in GA lesions. Cytokines associated with the Th1 pathway include TNF-, IL-1, IFN-, and IL-12/23p4, while IL-4 and IL-31 are linked to the Th2 pathway. […] Both research groups pay attention to the fact that cytokines involved in GA pathogenesis, signal through the JAK-STAT pathway.

• #8 Granuloma Annulare | 5-Minute Clinical Consult

  https://www.unboundmedicine.com/5minute/view/5-Minute-Clinical-Consult/1688819/all/Granuloma_Annulare?q=Thyroid+cancer

  Granuloma annulare (GA) is a benign skin condition characterized by groups of skin-colored to erythematous papules that are usually in an annular (ring-like) pattern and typically located on the dorsal aspects of the hands and feet. […] The etiology of GA remains unknown; however, recent studies have helped to further elucidate its underlying cause. It is hypothesized to be related to upregulation of T-helper (Th) 1 and Th2 pathways in GA lesions. Increased cytokine expression was subsequently noted to include tumor necrosis factor alpha (TNF-), interleukin (IL)-1, IL-4, interferon (IFN)-, IL-12/IL-23p40, and IL-31. Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways were also found to be activated in GA. Response by M1 and M2 macrophages was described, which can be related to histopathologic findings of collagen degradation followed by tissue remodeling and mucin deposition, respectively. […] There is some evidence for a genetic predisposition. Two studies reported an increased frequency of HLA-Bw35 in patients with generalized GA. Of note, HLA-Bw35 has also been associated with thyroid disease.

• #9 Granuloma Annulare: An Updated Review of Epidemiology, Pathogenesis, and Treatment Options

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8423598/

  The upregulation of IL-4 mRNA expression was particularly pronounced, with a 15,600-fold increase in GA lesional skin versus control skin. […] The regression of GA in response to oral and topical tofacitinib is consistent with the studies by Min et al. and Wang et al., both of which identify JAK-STAT pathway dysregulation in GA. […] Thus, JAK inhibitors may represent targeted upstream therapies for GA. […] Recent studies lend further support to the efficacy of phototherapy, yet not all patients treated with phototherapy respond robustly and some fail to respond altogether. […] The excellent response of GA to anti-TNF therapy seen in several patients supports recent studies that implicate overactivation of the Th1 pathway in GA. […] The response of GA to dupilumab suggests that the Th2 pathway may also be hyperactive in GA, supporting the study by Min et al., which found a marked increase in IL-4 mRNA expression in GA lesional skin compared with non-lesional skin.

• #10 Treatment of granuloma annulare and suppression of proinflammatory cytokine activity with tofacitinib – EM consulte

  https://www.em-consulte.com/article/1443629/treatment-of-granuloma-annulare-and-suppression-of

  Granuloma annulare (GA) is a common cutaneous inflammatory disorder characterized by macrophage accumulation and activation in skin. Its pathogenesis is poorly understood, and there are no effective treatments. […] We sought to better understand GA pathogenesis and evaluate a molecularly targeted treatment approach for this disease. […] Using single-cell RNA sequencing, we found that in GA lesions IFN- production by CD4+ T cells is upregulated and is associated with inflammatory polarization of macrophages and fibroblasts. In particular, macrophages upregulate oncostatin M, an IL-6 family cytokine, which appears to act on fibroblasts to alter extracellular matrix production, a hallmark of GA. IL-15 and IL-21 production appears to feed back on CD4+ T cells to sustain inflammation. […] The Janus kinase-signal transducer and activator of transcription pathway is activated in GA, likely in part through the activity of IFN- and oncostatin M, and Janus kinase inhibitors appear to be an effective treatment.

• #11 Treatment of Granuloma Annulare Using Tapinarof Cream 1% – JDDonline – Journal of Drugs in Dermatology

  https://jddonline.com/articles/treatment-of-granuloma-annulare-using-tapinarof-cream-1-S1545961624P8321X/

  Granuloma annulare is a benign, non-infectious cutaneous granulomatous disease. Its pathogenesis is not completely elucidated but has recently been thought to involve immunologic and cytokine receptor signaling dysregulation. This includes the involvement of both Th1 and Th2 pathways as well as Th17 and Th22 axes and the Janus kinase/signal transducers and activators of the transcription (JAK-STAT) pathway. […] The pathogenesis of the disease remains elusive. Current theories involve immunologic and cytokine receptor signaling responses. Newer research highlights GA as an immunologically driven condition elucidating the involvement of both Th1 and Th2 pathways as well as Th17 and Th22 axes and the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway. […] Given the recent evidence implicating these immunologic mechanisms, including Th1, Th2, and Th17 pathways, in the pathogenesis of GA, we hypothesized that treatment with tapinarof cream 1% may improve GA symptoms.

• #12 Granuloma annulare on the palms: A clinicopathological study of seven cases – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/granuloma-annulare-on-the-palms-a-clinicopathological-study-of-seven-cases/

  We found collagen tissue alteration like collagen thickening, increased basophilia, loss of normal fibrillary structure and collagenolysis was seen in 2 and 4 out of 7 cases. Gnes et al., found collagen degeneration of varying intensity in all 38 biopsies they studied and proposed that primary events in the pathogenesis of GA involve collagen as well as elastic fiber damage. […] One of the interesting finding seen in our study was presence of peri-eecrine and perineural granulomas in a biopsy from a patient who complained of severe pain. These findings were not present initially, but were seen in a repeat biopsy done during an acute episode of the same patient who showed classical palisading granuloma initially. […] Histopathological features seen in our study were comparable to studies on generalized GA. Solar elastosis, elastophagocytosis, peri-neural and peri-eccrine granulomas were additional features found in our study.

• #13 Granuloma annulare pathology

  https://dermnetnz.org/topics/granuloma-annulare-pathology

  The scanning view of the histology of granuloma annulare shows a granulomatous inflammatory pattern situated within the superficial and mid dermis. […] Closer inspection reveals palisading of histiocytes around a focus of necrobiosis and increased mucin deposition. […] The intervening dermis appears normal. Multinucleated giant cells are frequently seen. […] A mild perivascular and interstitial lymphocytic infiltrate may be seen in the surrounding dermis with scattered neutrophils and eosinophils. Plasma cells are rare. […] Associated vascular fibrin deposition and nuclear dust suggestive of vasculitis appears to be a rare finding. […] In this variant the inflammatory infiltrate is predominantly within the deep dermis and extends into the subcutaneous tissue. […] Large areas of necrobiosis can be seen along with increased numbers of eosinophils.

• #14 Granuloma annulare pathology

  https://dermnetnz.org/topics/granuloma-annulare-pathology

  While typically mitotically activity is low, there is recognised a mitotically active variant which may otherwise raise concern about a proliferative lesion. […] Here the inflammatory infiltrate can be seen to be eliminated through the epidermis via a channel formed between epidermal downgrowths. […] While the histology may be identical to typical GA, the infiltrate may be sparse and retained within the papillary dermis. […] The low power pattern is different, showing a 'busy dermis’ and lacking the necrobiotic and mucinous foci. […] High power reveals the interstitial infiltrate of benign appearing histiocytes. […] While less conspicuous, increased mucin is frequently seen around the inflammatory infiltrate. […] In the presence of many eosinophils and interface changes an interstitial granulomatous drug reaction should be considered.

• #15 Granuloma annulare

  https://dermnetnz.org/topics/granuloma-annulare

  Granuloma annulare may be a delayed hypersensitivity reaction to a component of the dermis or a reaction pattern to numerous triggers. […] Inflammation is mediated by tumour necrosis factor alpha (TNF). The reason this occurs is unknown. […] There have also been a number of associations reported with systemic conditions including autoimmune thyroiditis, diabetes mellitus, other organ-specific autoimmune diseases, hyperlipidaemia, and rarely with lymphoma, HIV infection and solid tumours. […] Skin biopsy usually shows necrobiotic degeneration of dermal collagen surrounded by an inflammatory reaction. […] Actinic granuloma is considered by some to be a photo-aggravated variant of granuloma annulare, and by others to be a distinct entity. […] Systemic therapy may be considered in widespread granuloma annulare. The following treatments have been reported to help at least some cases of disseminated granuloma annulare. None of these can be relied upon to clear it, and there are potential adverse effects. […] Biologics particularly TNF inhibitors such as adalimumab and infliximab.

• #16 Granuloma annulare preceding the diagnosis of Sjögren’s syndrome | Volume 37 – Issue 3 – September 2022 | Archives of Rheumatology

  https://archivesofrheumatology.org/full-text/1355

  Granuloma annulare and Sjgrens syndrome coexistence is described in localized form with the interstitial histopathological type. […] The current case is distinctive from other cases reported in the literature since palisading granulomatous inflammation was histopathologically demonstrated in our patients skin biopsy. […] Consequently, dermatologists should keep in mind the relationship between granuloma annulare and connective tissue diseases, including Sjgrens syndrome.

• #17 Granuloma Annulare and Morphea: Correlation with Borrelia burgdorferi Infections and Chlamydia-related Bacteria | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-2831

  Granuloma annulare (GA) and morphea (localized scleroderma) are skin reactions with unknown aetiology. One of the possible causative agents is Borrelia burgdorferi sensu lato, a spirochete transmitted to humans via tick bites. […] According to our results on the prevalence of Borrelia DNA, we propose that infections with B. burgdorferi can trigger GA in some cases, but the direct causal role seems unlikely. […] Members of the Chlamydiales, Chlamydia-related bacteria are naturally resistant to beta-lactam antibiotics, including amoxicillin and ceftriaxone used in the treatment of Borrelia infections. However, Chlamydia-related bacteria should be sensitive to doxycycline. In our study, 8 patients with GA positive for Chlamydiales DNA were treated with doxycycline, but none of them was cured. This speaks against a direct causative role of Chlamydiales in the pathogenesis of GA. Thus, only a triggering effect for GA is possible.

• #18 Granuloma Annulare and Morphea: Correlation with Borrelia burgdorferi Infections and Chlamydia-related Bacteria | HTML | Acta Dermato-Venereologica

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-2831

  In conclusion, Chlamydiales DNA is frequently detected in skin lesion in GA and morphea. In GA, the Chlamydiales diversity differs from that in healthy skin and resembles the diversity observed in Ixodes ricinus ticks, suggesting a tick-derived origin. In morphea, however, the diversity of Chlamydiales sequences was close to that in healthy skin. The occasional presence of Borrelia DNA and the tick-like Chlamydiales diversity in GA lesions combined with poor response to antibiotic treatment favours a possible triggering role of these tick-mediated infections in GA. Their correlation with morphea, however, is unlikely.

• #19 Granuloma annulare: Who gets and causes

  https://www.aad.org/public/diseases/a-z/granuloma-annulare-causes

  Its still unclear what causes this skin condition. […] It may be that granuloma annulare is a reaction that occurs in the skin. It may require a trigger, such as injuring your skin. Granuloma annulare often appears after people injure their skin. […] Because this skin condition doesnt develop in everyone who injures their skin, its possible that the people who develop it are especially sensitive to whatever injured their skin. […] Granuloma annulare may also be more common if someone has a disease, such as the human immunodeficiency virus (HIV), thyroid disease, or diabetes. Not everyone who has one of these diseases will develop granuloma annulare. Again, its possible that the skin is reacting to whats going on inside the body. […] Before we know for sure what causes granuloma annulare, more research is needed.

• #20 Photoinduced Granuloma Annulare Confirmed by Experimental Exposure to UVA Light | Actas Dermo-Sifiliográficas

  http://www.actasdermo.org/en-photoinduced-granuloma-annulare-confirmed-by-articulo-S157821902030398X

  GA is a benign and self-limiting inflammatory dermatosis of uncertain origin. It is characterized by the presence of dermal papules with no appreciable epidermal component and a tendency to coalesce to form mainly asymptomatic arcuate or annular plaques. The specific etiology of GA is unknown, although it has been linked to a multitude of comorbidities, including malignant neoplasms, viral infections, and drug treatment. Although most resolve spontaneously, even after biopsy, some lesions can leave permanent scars. […] Disseminated GA has been more specifically related to systemic conditions such as diabetes mellitus and, in rare cases, sun exposure. […] There are few published cases of GA induced by light radiation. According to some studies, solar radiation is considered one of the potential causes of GA. Attempts have been made to reproduce GA lesions using ultraviolet light, without success. We believe that this is the first reported case of photoinduced granuloma annulare in experimental conditions in the context of a photobiological study. […] Despite the absence of medication, we believe that in our case a preformed antigen may have undergone a conformational change upon exposure to UVA, triggering GA-like granulomatous dermatitis.

• #21 Photoinduced Granuloma Annulare Confirmed by Experimental Exposure to UVA Light | Actas Dermo-Sifiliográficas

  https://actasdermo.org/en-photoinduced-granuloma-annulare-confirmed-by-articulo-S157821902030398X

  GA is a benign and self-limiting inflammatory dermatosis of uncertain origin. It is characterized by the presence of dermal papules with no appreciable epidermal component and a tendency to coalesce to form mainly asymptomatic arcuate or annular plaques. The specific etiology of GA is unknown, although it has been linked to a multitude of comorbidities, including malignant neoplasms, viral infections, and drug treatment. […] There are few published cases of GA induced by light radiation. According to some studies, solar radiation is considered one of the potential causes of GA. Attempts have been made to reproduce GA lesions using ultraviolet light, without success. We believe that this is the first reported case of photoinduced granuloma annulare in experimental conditions in the context of a photobiological study. […] Despite the absence of medication, we believe that in our case a preformed antigen may have undergone a conformational change upon exposure to UVA, triggering GA-like granulomatous dermatitis.

• #22 Granuloma annulare – Wikipedia

  https://en.wikipedia.org/wiki/Granuloma_annulare

  Granuloma annulare is an idiopathic condition, though many catalysts have been proposed. Among these is skin trauma, UV exposure, vaccinations, tuberculin skin testing, and Borrelia and viral infections. […] The mechanisms proposed at a molecular level vary even more. In 1977, Dahl et al. proposed that since the lesions of GA often display a thickening of, occlusion of, or other trauma to blood vessels, blood vessels may be responsible for GA. From their study of 58 patients, they found that immunoglobin M (IgM), complement, and fibrinogen were in the blood vessels of GA areas, suggesting that GA may share similarities with an immune-mediated, type 3 reaction or that chronic immune vasculitis may be involved in the pathogenesis. […] Umbert et al. (1976), proposed an alternative pathogenesis: cell-mediated immunity. Their data suggests that lymphokines, such as macrophage-inhibiting factor (MIF), leads to sequestration of macrophages and histiocytes in the dermis. Then, upon lysosomal enzyme release by these sequestered cells, connective tissue damage ensues, which results in GA. Later, these authors found data suggesting that activation of macrophages and fibroblasts are involved in the pathogenesis of GA and that fibrin and the rare IgM and C3 deposition around vessels were more likely a delayed-type hypersensitivity with resulting tissue and vessel changes rather than an immune-complex mediated disease. Further data has been collected supporting this finding.

• #23 Generalized and patch granuloma annulare in a patient with psoriasis and multiple sclerosis after treatment with fingolimod

  https://www.termedia.pl/Generalized-and-patch-granuloma-annulare-in-a-patient-with-psoriasis-and-multiple-sclerosis-after-treatment-with-fingolimod,56,53951,1,1.html

  Granuloma annulare is an inflammatory cutaneous disorder which may present with localized, generalized, patch, perforating and subcutaneous forms. […] It has been suggested that activation of T helper (Th) 1 and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways might play a role in the etiopathogenesis of granuloma annulare. […] The mechanism of drug-induced granuloma annulare remains unknown as well as complicated. For instance, granuloma annulare can be triggered by TNF-a inhibitors and also treated with them. […] Since fingolimod affects lymphocyte functions through sphingosine 1-phosphate (S1P) receptor subtype S1P1, T lymphocytes may have a potential role in the development of fingolimod-induced granuloma annulare.

• #24 Nivolumab-Induced Granuloma Annulare | MDedge

  https://medauth2.mdedge.com/content/nivolumab-induced-granuloma-annulare

  Granuloma annulare (GA) is a benign, cutaneous, granulomatous disease of unclear etiology. […] Granuloma annulare has been associated with various medications and medical conditions, including diabetes mellitus, hyperlipidemia, thyroid disease, and HIV. More recently, immune-checkpoint inhibitors (ICIs) have been reported to trigger GA. […] Recent evidence suggests that GA might be caused in part by a cell-mediated hypersensitivity reaction that is regulated by a helper T cell subset 1 inflammatory reaction. Through release of cytokines by activated CD4+ T cells, macrophages are recruited, forming the granulomatous pattern and secreting enzymes that can degrade connective tissue. Nivolumab and other ICIs can thus trigger this reaction because their blockade of PD-1 enhances T cell-mediated immune reactions. In addition, because macrophages themselves also express PD-1, ICIs can directly enhance macrophage recruitment and proliferation, further increasing the risk of a granulomatous reaction. […] The nature of this association with granulomatous reactions in general and with GA specifically remains to be determined.

• #25

  https://journals.lww.com/ijd/fulltext/9900/dupilumab_induced_granuloma_annulare__a.53.aspx

  Granuloma annulare (GA) is an inflammatory granulomatous skin disease. […] Its pathogenesis remains unclear; however, several triggers, including medications, have been reported in the literature. […] Although its exact mechanism driving this association remains unclear, our case study brings awareness of the rare side effect of dupilumab, given its widening spectrum of clinical applications in a wide array of other cutaneous dermatoses. […] Granuloma annulare (GA) is a condition characterized by granulomatous inflammation, the underlying cause of which is not yet fully understood. […] The impact of newer medications such as dupilumab has rarely been reported. […] A possible explanation is that perhaps GA shares the same pathophysiologic mechanism as atopic dermatitis by mediating disease activity to the T helper 2 (Th2) immune-mediated pathways.

• #26

  https://journals.lww.com/ijd/fulltext/9900/dupilumab_induced_granuloma_annulare__a.53.aspx

  Recently, studies have advanced our understanding of GA pathogenesis by showing the upregulation of Th1 and Th2 pathways in GA lesions compared with healthy skin. […] While primarily an idiopathic disorder, multiple triggers, including medications, infections, and comorbidities, have been described in the literature. […] Although multiple hypotheses may be postulated for this association, we believe that a better understanding of the pathogenesis of GA and further evaluation of how dupilumab affects the Th1/Th2 immune axis may help refine our hypothesis.

• #27 Granuloma Annulare – Warrington, PA DermatologistGranuloma Annulare – Warrington, PA Dermatologist

  https://www.warringtonderm.com/blog/920182-granuloma-annulare/

  Granulomas are one of your body’s many defense mechanisms and often get mistaken for foreign invaders because of how they manifest and operate. […] The formation of a granuloma or granulomas is a fascinating process. Foreign invaders, infections, or inflammations set off an inflammatory trigger that causes tiny macrophages to gravitate towards the site of infection. The formation and dispersal of these macrophages is an innate immune response that the body carries out naturally without external intervention. […] If the initial swarm of macrophages isn’t enough to stop the spread of infection, more granulomas form and flee to the scene. While this is a necessary step to keep an infection or foreign invader from spreading into your bloodstream, it can result in problems. The issue is that granulomas don’t always go away on their own. They may stick around long after the infection has healed.

• #28 Granuloma Annulare | Scott Sanders Dermatology, LLC | Dermatologist In New City, NY

  https://www.scottsandersdermatology.com/articles/aad_education_library/920182-granuloma-annulare/

  Granulomas are one of your body’s many defense mechanisms and often get mistaken for foreign invaders because of how they manifest and operate. […] The formation of a granuloma or granulomas is a fascinating process. Foreign invaders, infections, or inflammations set off an inflammatory trigger that causes tiny macrophages to gravitate towards the site of infection. The formation and dispersal of these macrophages is an innate immune response that the body carries out naturally without external intervention. […] While this is a necessary step to keep an infection or foreign invader from spreading into your bloodstream, it can result in problems. The issue is that granulomas don’t always go away on their own. They may stick around long after the infection has healed.

• #29 Granuloma annulare: modern concepts of pathogenesis and pathogenetically based therapy (literature review) – Pahalage – Russian Journal of Skin and Venereal Diseases

  https://rjsvd.com/1560-9588/article/view/637126/zh_CN

  Granuloma annulare is a chronic, benign, non-infectious skin disorder that causes ring-shaped papules, most commonly on the hands and feet. The pathogenesis of granuloma annulare has not been fully deciphered; nevertheless, comparative analysis of a wide range of biomarkers in biopsies of affected skin has shown differences in the expression of genes involved in regulation of innate immunity, Th1 and Th2 lymphocytes, and Janus kinases. […] Associations of granuloma annulare with endocrine, immune, and autoimmune diseases, malignant neoplasms, as well as the triggering role of infections and vaccinations, are subjects of discussion, despite advances in understanding the molecular mechanisms of disease development. […] Currently, TNF- inhibitors, JAK inhibitors and IL-23 inhibitors are proposed as targeted therapy for granuloma annulare. The basis for this recommendation is the latest information about the pathogenesis of granuloma annulare. […] The presented literature review systematizes modern concepts of molecular and cellular mechanisms of granuloma annulare development, infectious and non-infectious triggers of inflammation, the role of endocrine, immune and oncological pathology as predisposing factors.

• #30 Granuloma Annulare: Causes, Symptoms, Treatment | Doctor

  https://patient.info/doctor/granuloma-annulare-pro

  Granuloma annulare is a benign inflammatory condition of unknown aetiology with dermal papules and annular plaques. Histology reveals foci of degenerative collagen with palisaded granulomatous inflammation. […] Aetiology is essentially not known. Associations with systemic illnesses including diabetes, thyroid disease, malignancy and hyperlipidaemia have been suggested but not proven. It is thought to be due to a delayed hypersensitivity reaction to some part of the dermis with inflammation mediated by tumour necrosis factor alpha (TNF alpha). […] The TNF inhibitor infliximab – may be useful in recalcitrant cases. Adalimumab has also been reported to be effective.

• #31 Therapeutic success of tofacitinib in granuloma annulare: A retrospective case series of 15 patients – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/therapeutic-success-of-tofacitinib-in-granuloma-annulare-a-retrospective-case-series-of-15-patients/

  Granuloma annulare (GA) is a necrobiotic granulomatous disorder that may sometimes be resistant to treatment, especially the generalised form. […] The pathogenesis of GA involves T-cell dysregulation, with implications of Th1 and possibly Th2 pathways. Recently, Wang et. al reported the activation of Th17 and the JAK-STAT pathway in GA. Elevated levels of cytokines like interferon-gamma (IFN-) and oncostatin M have been observed in GA patients, which decrease after treatment with tofacitinib, a JAK-STAT inhibitor. Cytokines such as IFN-, IL-21, and chemokines, released from T-cells activates macrophages and fibroblasts which leads to the formation of granulomas in GA. JAK-STAT inhibitors blocks this activation of macrophages and fibroblasts, thereby resulting in the resolution of granulomas.

• #32 Therapeutic success of tofacitinib in granuloma annulare: A retrospective case series of 15 patients – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/therapeutic-success-of-tofacitinib-in-granuloma-annulare-a-retrospective-case-series-of-15-patients/

  Damsky et al. demonstrated the activation of STAT 1 and 3 in cutaneous granulomas of sarcoidosis and GA, reporting subsequent improvement after treatment with tofacitinib. Wang et al. observed that three out of five patients achieved complete resolution of lesions and two had partial resolution at 6 months of treatment with tofacitinib. Other authors have observed similar response to tofacitinib in cases of recalcitrant generalised GA.

• #33 Granuloma Annulare: An Updated Review of Epidemiology, Pathogenesis, and Treatment Options

  https://ouci.dntb.gov.ua/works/l1pjGZY4/

  Granuloma annulare: pathogenesis, disease associations and triggers, and therapeutic options. […] Granuloma annulare can occur on a scar, mimicking sarcoidosis. […] Granuloma annulare is a benign inflammatory skin condition characterized by firm discolored papules or nodules classically arranged in an annular pattern. […] We highlight that baricitinib could be a plausible treatment option as a new molecular-targeted therapy for refractory generalized granuloma annulare. […] The presented case emphasizes that PGA should be considered in the differential diagnosis of keratotic/umbilical papules on the dorsum of the hand. […] Granuloma annulare: strengthening potential associations and pentoxifylline as a therapeutic option. […] Janus kinase inhibition induces disease remission in cutaneous sarcoidosis and granuloma annulare.

• #34 Apremilast in the Management of Generalized Granuloma Annulare: A Case Series | SKIN The Journal of Cutaneous Medicine

  https://skin.dermsquared.com/skin/article/view/2054

  Granuloma annulare is a difficult disease to treat and can lead to anxiety and frustration for both patients and providers. The pathogenesis of granuloma annulare is unknown, resulting in few thoroughly studied or consistently effective treatments. […] To explore the possible pathogenesis of granuloma annulare and the mechanism of apremilast in treating this disease. […] This case series illustrates a novel therapy, apremilast, a phosphodiesterase-4 inhibitor, in the treatment of patients with generalized granuloma annulare and explores possible mechanisms behind the success of this treatment.

• #35 Granuloma Annulare: An Updated Review of Epidemiology, Pathogenesis, and Treatment Options

  https://ouci.dntb.gov.ua/en/works/l1pjGZY4/

  Successful treatment of two individual cases of generalized granuloma annulare with amoxicillin/clavulanic acid and a combination of doxycycline and pentoxifylline. […] Hydroxychloroquine for generalized granuloma annulare: 35% response rate in a retrospective case series of 26 patients. […] Treatment of granuloma annulare and suppression of proinflammatory cytokine activity with tofacitinib. […] Recalcitrant generalized granuloma annulare treated successfully with dupilumab. […] Methotrexate for generalized granuloma annulare: A 60% response rate in a retrospective case series of 15 patients. […] Granuloma annulare mimicking eruptive dermatofibroma in an HIV-positive male: a challenge with distinct dermatoscopic findings. […] Granuloma annulare triggered by SARS-CoV-2 infection: immunohistochemical staining. […] Granuloma annulare: a focused review of therapeutic options. […] Granuloma annulare: clinical and histologic variants, epidemiology, and genetics. […] Granuloma annulare: pathogenesis, disease associations and triggers, and therapeutic options.

• #36 Granuloma Annulare

  https://www.massgeneral.org/condition/granuloma-annulare

  Researchers dont yet know what causes it. It may be linked to other illnesses, genes, or other skin injury or conditions. Some researchers think it may be linked to diabetes, but that has not been proven. […] Granuloma annulare is hard to treat. You may need to try a few treatments to find one that works. […] Researchers dont know how to prevent granuloma annulare.

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