Objective
Dominantly inherited PSTPIP1 mutations cause a spectrum of autoinflammatory manifestations epitomized by PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) ...syndrome.). The connections between PSTPIP1 and PAPA syndrome are poorly understood, although evidence suggests involvement of pyrin inflammasome activation. Interleukin‐18 (IL‐18) is an inflammasome‐activated cytokine associated with susceptibility to macrophage activation syndrome (MAS). This study was undertaken to investigate an association of IL‐18 with PAPA syndrome.
Methods
Clinical and genetic data and serum samples were obtained from patients referred to institutions due to symptoms indicative of PAPA syndrome. Serum IL‐18, IL‐18 binding protein (IL‐18BP), and CXCL9 levels were assessed by bead‐based assay, and free IL‐18 levels were assessed by enzyme‐linked immunosorbent assay.
Results
The symptoms of PSTPIP1‐positive patients with PAPA syndrome overlapped with those of mutation‐negative patients with PAPA‐like conditions, but mutation‐positive patients had earlier onset and a greater proportion had a history of arthritis. We found uniform elevation of total serum IL‐18 in treated PAPA syndrome patients at levels nearly as high as those seen in NLRC4‐associated autoinflammation with infantile enterocolitis patients, and well above levels found in most familial Mediterranean fever patients. Serum IL‐18 elevation in PAPA syndrome patients persisted despite fluctuations in disease activity. Levels of the soluble IL‐18 antagonist IL‐18BP were modestly elevated, and PAPA syndrome patients had detectable free IL‐18. PAPA syndrome was rarely associated with elevation of CXCL9, an indicator of interferon‐γ activity, but no PAPA syndrome patients had a history of MAS.
Conclusion
PAPA syndrome is a refractory and often disabling monogenic autoinflammatory disease associated with chronic and unopposed elevation of serum IL‐18 levels but not with risk of MAS. These findings affect our understanding of the diseases in which IL‐18 is overproduced and suggest a link between pyrin inflammasome activation, IL‐18, and autoinflammation, without susceptibility to MAS.
The role of the potent proinflammatory cytokine IL‐1 in disease could clinically be investigated with the development of the IL‐1 blocking agent anakinra (Kineret
®
), a recombinant IL‐1 receptor ...antagonist. It was first tested in patients with sepsis without much benefit but was later FDA approved for the treatment of patients with rheumatoid arthritis. More recently IL‐1 blocking therapies are used successfully to treat a new group of immune‐mediated inflammatory conditions, autoinflammatory diseases. These conditions include rare hereditary fever syndromes and pediatric and adult conditions of Still's disease. Recently the FDA approved two additional longer acting IL‐1 blocking agents, for the treatment of cryopyrin‐associated periodic syndromes (CAPS), an IL‐1 dependent autoinflammatory syndrome. The study of autoinflammatory diseases revealed mechanisms of IL‐1 mediated organ damage and provided concepts to a better understanding of the pathogenesis of more common diseases such as gout and Type 2 diabetes which show initial promising results with IL‐1 blocking therapy.
Recent research has led to novel findings in inflammasome biology and genetics that altered the diagnosis and management of patients with autoinflammatory syndromes caused by NLRP3-, Pyrin-, NLRP1-, ...and NLRC4-inflammasomes and spurred the development of novel treatments. The use of next-generation sequencing in clinical practice allows for rapid diagnosis and the detection of somatic mutations that cause autoinflammatory diseases. Clinical differences in patients with NLRP3, pyrin, and NLRP1 inflammasomopathies, and the constitutive elevation of unbound free serum IL-18 that predisposes to the development of macrophage activation syndrome (MAS) in patients with gain-of function mutations in
led to the screening and the characterization of novel diseases presenting with constitutively elevated serum IL-18 levels, and start to unravel the biology of "high IL-18 states" that translate into the use of biomarkers that improve diagnosis and monitoring of disease activity and investigations of treatments that target IL-18 and IFN-gamma which promise to improve the management and outcome of these conditions. Lastly, advances in structural modeling by cryo-electron microscopy (cryo-EM) of gasdermin, and of NLRP3- and NLRC4-inflammasome assembly, and the characterization of post-translational modifications (PTM) that regulate inflammasome activation, coupled with high-throughput screening (HTS) of libraries of inflammasome-inhibiting compounds, promise a new generation of treatments for patients with inflammasome-mediated diseases.
Monogenic autoinflammatory syndromes present with excessive systemic inflammation including fever, rashes, arthritis, and organ-specific inflammation and are caused by defects in single genes ...encoding proteins that regulate innate inflammatory pathways. Pathogenic variants in two interleukin-1 (IL-1)-regulating genes, NLRP3 and IL1RN, cause two severe and early-onset autoinflammatory syndromes, CAPS (cryopyrin associated periodic syndromes) and DIRA (deficiency of IL-1 receptor antagonist). The discovery of the mutations that cause CAPS and DIRA led to clinical and basic research that uncovered the key role of IL-1 in an extended spectrum of immune dysregulatory conditions. NLRP3 encodes cryopyrin, an intracellular "molecular sensor" that forms a multimolecular platform, the NLRP3 inflammasome, which links "danger recognition" to the activation of the proinflammatory cytokine IL-1β. The success and safety profile of drugs targeting IL -1 in the treatment of CAPS and DIRA have encouraged their wider use in other autoinflammatory syndromes including the classic hereditary periodic fever syndromes (familial Mediterranean fever, TNF receptor-associated periodic syndrome, and hyperimmunoglobulinemia D with periodic fever syndrome) and additional immune dysregulatory conditions that are not genetically well defined, including Still's, Behcet's, and Schnitzler diseases. The fact that the accumulation of metabolic substrates such as monosodium urate, ceramide, cholesterol, and glucose can trigger the NLRP3 inflammasome connects metabolic stress to IL-1β-mediated inflammation and provides a rationale for therapeutically targeting IL-1 in prevalent diseases such as gout, diabetes mellitus, and coronary artery disease.
Population pharmacokinetic (popPK) modeling was used to characterize the PK profile of the oral Janus kinase (JAK)1/JAK2 inhibitor, baricitinib, in 18 patients with Mendelian interferonopathies who ...are enrolled in a compassionate use program. Patients received doses between 0.1 to 17 mg per day. Covariates of weight and renal function significantly influenced volume‐of‐distribution and clearance, respectively. The half‐life of baricitinib in patients less than 40 kg was substantially shorter than in adult populations, requiring the need for dosing up to 4 times daily. On therapeutic doses, the mean area‐under‐the‐concentration‐vs.‐time curve was 2,388 nM*hr, which is 1.83‐fold higher than mean baricitinib exposures in adult patients with rheumatoid arthritis receiving doses of 4 mg once‐daily. Dose‐dependent decreases in interferon (IFN) biomarkers confirmed an in vivo effect of baricitinib on type‐1 IFN signaling. PopPK and pharmacodynamic data support a proposal for a weight‐ and estimated glomerular filtration rate‐based dosing regimen in guiding baricitinib dosing in patients with rare interferonopathies.
Clinical application of several rapidly evolving technologies-next-generation DNA sequencing, biomarker discovery, and targeted cytokine blockade-has been particularly beneficial to understanding an ...expanding spectrum of genetically defined autoinflammatory diseases.1 Our understanding of the pathways that cause hemophagocytic disorders, such as macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH), is evolving similarly. MAS and HLH are life-threatening sepsis-like conditions notable for hyperferritinemia, acute cytopenias, and hepatitis. If not promptly recognized and treated, they can progress to consumptive coagulopathy, hemophagocytosis, multiorgan failure, and high mortality. HLH is classically associated with genetic defects in cytotoxicity, whereas MAS is observed as a complication of rheumatic diseases.1
Objective
Recent observations in systemic juvenile idiopathic arthritis (JIA) suggest an increasing incidence of high‐mortality interstitial lung disease often characterized by a variant of pulmonary ...alveolar proteinosis (PAP). Co‐occurrence of macrophage activation syndrome (MAS) and PAP in systemic JIA suggests a shared pathology, but patients with lung disease associated with systemic JIA (designated SJIA‐LD) also commonly experience features of drug reaction such as atypical rashes and eosinophilia. This study was undertaken to investigate immunopathology and identify biomarkers in systemic JIA, MAS, and SJIA‐LD.
Methods
We used SOMAscan to measure ~1,300 analytes in sera from healthy controls and patients with systemic JIA, MAS, SJIA‐LD, or other related diseases. We verified selected findings by enzyme‐linked immunosorbent assay and lung immunostaining. Because the proteome of a sample may reflect multiple states (systemic JIA, MAS, or SJIA‐LD), we used regression modeling to identify subsets of altered proteins associated with each state. We tested key findings in a validation cohort.
Results
Proteome alterations in active systemic JIA and MAS overlapped substantially, including known systemic JIA biomarkers such as serum amyloid A and S100A9, and novel elevations in the levels of heat‐shock proteins and glycolytic enzymes. Interleukin‐18 levels were elevated in all systemic JIA groups, particularly MAS and SJIA‐LD. We also identified an MAS‐independent SJIA‐LD signature notable for elevated levels of intercellular adhesion molecule 5 (ICAM‐5), matrix metalloproteinase 7 (MMP‐7), and allergic/eosinophilic chemokines, which have been previously associated with lung damage. Immunohistochemistry localized ICAM‐5 and MMP‐7 in the lungs of patients with SJIA‐LD. The ability of ICAM‐5 to distinguish SJIA‐LD from systemic JIA/MAS was independently validated.
Conclusion
Serum proteins support a systemic JIA–to‐MAS continuum; help distinguish systemic JIA, systemic JIA/MAS, and SJIA‐LD; and suggest etiologic hypotheses. Select biomarkers, such as ICAM‐5, could aid in early detection and management of SJIA‐LD.
Objective
To describe the pregnancy course and outcome and the use of anakinra, a recombinant selective interleukin‐1 receptor blocker, during pregnancy in patients with cryopyrin‐associated periodic ...syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle‐Wells syndrome (MWS), and neonatal‐onset multisystem inflammatory disease (NOMID).
Methods
Women with CAPS who were currently enrolled in natural history protocols and had been pregnant were included. Subjects underwent a structured, standardized interview with regard to maternal health, pregnancy, and fetal outcomes. Medical records were reviewed.
Results
Nine women (4 with FCAS, 2 with MWS/NOMID overlap, and 3 with NOMID) reported 1–4 pregnancies (a total of 15 pregnancies in women with FCAS, 3 in women with MWS, and 6 in women with NOMID). Six births to women with FCAS and 3 births to women with NOMID or MWS/NOMID overlap occurred while the patients were receiving anakinra. In women who became pregnant while taking anakinra, the anakinra treatment was continued; the prepregnancy dosage was maintained except in the case of 1 woman whose dosage was increased during a pregnancy with twins. No preterm births or serious complications of pregnancy were observed. One fetus of the twin pregnancy had renal agenesis and died in utero. Genetic testing showed that the deceased twin carried the same NLRP3 c.785T>C, p.V262A mutation as the mother. The other twin was healthy and mutation negative.
Conclusion
Anakinra was continued during pregnancy in women with CAPS and provided significant, persistent symptom relief while continuing to prevent the long‐term sequelae of CAPS. Anakinra was well tolerated. Although a causal relationship between anakinra and renal agenesis seems unlikely, further safety data are needed.
Patients with autoinflammatory diseases present with noninfectious fever flares and systemic and or disease-specific organ inflammation. Their excessive proinflammatory cytokine and chemokine ...responses can be life threatening and lead to organ damage over time. Studying such patients has revealed genetic defects that have helped unravel key innate immune pathways, including excessive IL-1 signaling, constitutive NF-κB activation, and, more recently, chronic type I IFN signaling. Discoveries of monogenic defects that lead to activation of proinflammatory cytokines have inspired the use of anticytokine-directed treatment approaches that have been life changing for many patients and have led to the approval of IL-1-blocking agents for a number of autoinflammatory conditions. In this review, we describe the genetically characterized autoinflammatory diseases, we summarize our understanding of the molecular pathways that drive clinical phenotypes and that continue to inspire the search for novel treatment targets, and we provide a conceptual framework for classification.
Our understanding of the etiology of autoinflammatory disease is growing rapidly. Recent advances offer new opportunities for therapeutic intervention and suggest that the definition of what ...constitutes an autoinflammatory disease should be reassessed.
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