Targeted treatment of pyoderma gangrenosum in PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome with the recombinant human interleukin-1 receptor antagonist anakinra

Brenner, Michaela; Ruzicka, Thomas; Plewig, Gerd; Thomas, Peter A.; Herzer, P.

doi:10.1111/j.1365-2133.2009.09404.x

Cited by 208 publications

(121 citation statements)

References 27 publications

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“…Monocytes from PAPAS patients produce significantly higher amount of IL-1␤ compared with those from normal subjects in response to LPS stimulation (8). Furthermore, PAPAS patients respond to anti-IL-1 therapy (9,10). Taken together, these observations suggest that excessive production of IL-1 likely underlie the pathology of PAPAS.…”

supporting

confidence: 56%

Inflammation in Mice Ectopically Expressing Human Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne (PAPA) Syndrome-associated PSTPIP1 A230T Mutant Proteins

Wang

Höing

Patterson

et al. 2013

Journal of Biological Chemistry

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Background: PAPA syndrome is an autoinflammatory disease linked to mutations in the PSTPIP1 gene. Results: Ectopic expression of mutant PSTPIP1 leads to elevated level of circulating proinflammatory cytokines. Conclusion: Ectopic expression of mutant PSTPIP1 in mice partially recapitulates symptoms in human PAPA syndrome patients. Significance: These observations provide the first genetic analysis elucidating the pathophysiological function of PSTPIP1.

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supporting

confidence: 56%

Inflammation in Mice Ectopically Expressing Human Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne (PAPA) Syndrome-associated PSTPIP1 A230T Mutant Proteins

Wang

Höing

Patterson

et al. 2013

Journal of Biological Chemistry

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“…Anakinra has been used to prevent attacks and reduce systemic inflammatory markers in patients with colchicine-resistant FMF, [20][21][22][23][24][25] hyper-IgD syndrome, [26][27][28] and even etanercept-resistant TRAPS. 14,29,30 Similar remarkable responses were also reported in patients with Blau syndrome, 31,32 pyogenic arthritis, pyoderma gangrenosum, and acne 6,33,34 and deficiency of IL-1 receptor antagonist. 5,6 Anakinra has also been shown to be effective during acute gout episodes, 35,36 chronic gout, 35 and pseudogout 37,38 and in the management of Schnitzler syndrome, [39][40][41][42][43][44][45] systemic-onset juvenile idiopathic arthritis, [46][47][48] and adult-onset Still disease.…”

Section: Il-1-targeted Therapy In Other Autoinflammatory Diseasessupporting

confidence: 57%

Therapy of autoinflammatory syndromes

2009

Journal of Allergy and Clinical Immunology

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The therapy of autoinflammatory syndromes is an excellent example of the power of translational research. Recent advances in our understanding of the molecular and immunologic basis of this newly identified classification of disease have allowed for the application of novel, effective, targeted treatments with life-changing effects on patients. Although colchicine and TNF-α inhibitors are important therapies for specific autoinflammatory syndromes, the novel IL-1-targeted drugs are particularly effective for many of these diseases. Recently, the pharmaceutical industry has adopted a strategy of confirming the efficacy of new targeted drugs in often-ignored patients with orphan diseases, and US Food and Drug Administration policies have allowed for accelerated approval of these drugs, creating a win-win situation for patients and industry. This article reviews the general approach to the therapy of autoinflammatory diseases, focusing on current approved therapies and novel approaches that might be used in the future. Keywords Autoinflammatory; IL-1; inflammasomeThe traditional clinical classification of immune-mediated diseases, including allergy, immunodeficiency, and autoimmunity, is based on differences in immunologic mechanisms and clinical symptomatology and has defined the medical specialties caring for patients with immune-mediated illnesses for more than 60 years. However, in the last 10 years, a new category of immunologic disease, known as autoinflammatory diseases, has been created to account for disorders that did not fit well into the classical disease groups. 1 Although patients with these disorders can present with classic rheumatologic symptoms, including inflammation involving the joints, skin, muscles, and eyes, the underlying inflammatory mechanisms do not involve autoantibodies or antigen-specific T cells. 2 Some patients also display episodic or precipitated symptoms, including urticaria and conjunctivitis, similar to those seen in allergic patients, but there is no evidence of IgE-mediated inflammation. Recurrent fever is a common feature of both autoinflammatory disorders and infections caused by immune deficiency. However, insufficient immune response to pathogens is not an immunologic characteristic of autoinflammatory diseases.Reprint requests: Hal M. Hoffman, MD, University of California at San Diego, School of Medicine, 9500 Gilman Dr, La Jolla, CA 92093-0635. hahoffman@ucsd.edu. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptThe autoinflammatory disorders are characterized by dysregulation of innate immunity, the arm of the immune system considered to be more primitive and less specific. Instead of lymphocyte or antibody responses to specific antigens based on a memory of prior exposure, innate immune cells, such as macrophages and dendritic cells, sense conserved pathogenassociated molecular patterns. The primary effectors of the innate immune response are myeloid cells, such as neutrophils and monocytes, and proinflammatory cytokines...

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“…It was discovered that the PAPA-inducing mutation in PSTPIP1 results in aberrant inflammasome activation and IL-1β-driven pathology in patients, suggesting that PSTPIP1 is a novel negative regulator of inflammasomes (23)(24)(25)(26). In line with this, IL-1 blockade therapies including Anakinra treatment have proven effective in controlling inflammatory flares in PAPA syndrome patients (27,28). Both PSTPIP1 and PSTPIP2 share an N-terminal Fer-CIP4 homology (FCH) domain and a central coiled coil domain (19).…”

Section: Discussionmentioning

confidence: 78%

Critical role for inflammasome-independent IL-1β production in osteomyelitis

Lukens¹,

Gross²,

Calabrese

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

107

122

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The immune system plays an important role in the pathophysiology of many acute and chronic bone disorders, but the specific inflammatory networks that regulate individual bone disorders remain to be elucidated. Here, we characterized the osteoimmunological underpinnings of osteolytic bone disease in Pstpip2 cmo mice. These mice carry a homozygous L98P missense mutation in the Pombe Cdc15 homology family phosphatase PSTPIP2 that is responsible for the development of a persistent autoinflammatory disease resembling chronic recurrent multifocal osteomyelitis in humans. We found that improper regulation of IL-1β production resulted in secondary induction of inflammatory cytokines, inflammatory cell infiltration in the bone, and unremitting bone inflammation. Aberrant Il1β expression precedes the development of osteolytic damage in young Pstpip2 cmo mice, and genetic deletion of Il1r and Il1β, but not Il1α, rescued osteolytic bone disease in mutant mice. Intriguingly, caspase-1 and nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain containing 3 activation in the inflammasome complex were dispensable for Pstpip2 cmo -mediated bone disease. Thus, our findings establish a critical role for inflammasome-independent production of IL-1β in osteolytic bone disease and identify PSTPIP2 as a negative regulator of caspase-1-autonomous IL-1β production.osteoimmunology | interleukin-1 | autoinflammation

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Targeted treatment of pyoderma gangrenosum in PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome with the recombinant human interleukin-1 receptor antagonist anakinra

Cited by 208 publications

References 27 publications

Inflammation in Mice Ectopically Expressing Human Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne (PAPA) Syndrome-associated PSTPIP1 A230T Mutant Proteins

Inflammation in Mice Ectopically Expressing Human Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne (PAPA) Syndrome-associated PSTPIP1 A230T Mutant Proteins

Therapy of autoinflammatory syndromes

Critical role for inflammasome-independent IL-1β production in osteomyelitis

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