Excess Serum Interleukin‐18 Distinguishes Patients With Pathogenic Mutations in PSTPIP1

Abstract

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.

IL-1 and autoinflammatory disease: biology, pathogenesis and therapeutic targeting

“…Although the first patients described with CDC42-associated autoinflammatory disease had a remarkable response to IL-1 blockade 38 , more recent reports have noted that treatment with high dose IL-1 inhibition may not be sufficient to completely resolve symptoms, especially in the face of infection-driven macrophage activation syndrome 39 . In contrast to other autoinflammatory diseases, patients described to date have elevations in IL-18, suggesting a role for either the pyrin 82 – 84 or NLRC4 inflammasome in CDC42-mediated disease. Even though fewer than 10 cases have been described to date, the severity of disease phenotypes highlights the importance of an accurate diagnosis, and the name neonatal-onset cytopenia with dyshaematopoiesis, autoinflammation, rash and haemophagocytic lymphohistiocytosis syndrome has been proposed for CDC42-associated autoinflammatory diseases 39 .…”

“…Even for DIRA, which may be the most obvious example of links between genetics, disease and pathogenesis, patient-to-patient variability in therapeutic response still exists 60 . Similarly, there is increasing recognition of a role for inflammasome-driven IL-18 in some diseases, such as PAPA syndrome 84 , which may explain a lack of uniform responses to IL-1 blockade. Despite the general success in treating autoinflammation, the targeting of such a key mediator of inflammation, as well as the injectable nature of these therapeutics, has resulted in a search for additional therapies.…”

Interleukin-18 Binding Protein in Immune Regulation and Autoimmune Diseases

“…Although IL-18/IL-18BP has significantly dysregulated in the abovementioned MAS-associated diseases, the imbalance of IL-18/IL-18BP has also been noticed in other inflammatory diseases, including rheumatoid arthritis (RA), psoriasis, asthma, lupus erythematosus, multiple sclerosis, atherosclerosis, renal and liver injury, inflammatory bowel disease (IBD), Crohn’s disease (CD), organ transplant rejection together with Graft versus host disease (GvHD), and most recently in pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome [ 15 , 37 , 86 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 ], where cytokine imbalance is a major feature of these autoimmune disorders. The refractory monogenic inflammatory disorder, PAPA, resulted from a dominant mutation with the proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1) gene and is characterized by acne and skin ulceration.…”

“…In addition, the autoimmune neutrophilic destruction of joints and skin is the major clinical presentation of PAPA, but it was not associated with MAS [ 149 , 150 ]. Moreover, a recently published study found that IL-18 is elevated in the patient serum and this elevation was highly associated with the disease outcome, again with no MAS risk [ 148 ].…”

Clinical and Genetic Findings of the First Report of PAPA Syndrome in Brazil

“…Through these interactions, PSTPIP1 regulates several cellular functions, including interleukin-1 β (IL-1 β ) release, cytoskeletal organization, cell migration, and T cell activation [ 3 ]. However, as many patients mimicking PAPA syndrome lack the genetic finding, high levels of serum IL-18 seem to differentiate those who carry genetically pathogenic mutations in the PSTPIP1 gene [ 4 ].…”