HSCT is effective in patients with PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome

Laberko, Alexandra; Burlakov, V.I.; Maier, Sarah; Abinun, Mario; Skinner, Roderick; Kozlova, A.; Suri, Deepti; Lehmberg, Kai; Müller, Ingo; Balashov, Dmitry; Novichkova, Galina; Holzinger, Dirk; Gennery, Andrew R.

doi:10.1016/j.jaci.2020.11.043

Cited by 20 publications

(19 citation statements)

References 25 publications

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“…Both groups’ treatment history reflected the often recalcitrant nature of these symptoms, with many patients having been treated with glucocorticoids and >1 biologic medicine (Supplementary Table 1). Two patients had clinical features of PAPA syndrome in addition to cytopenias, organomegaly, and mutations associated with the hyperzincemia/hypercalprotectinemia syndrome (11). No patients with PAPA syndrome or PAPA‐like conditions had a history of MAS.…”

Section: Resultsmentioning

confidence: 99%

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

Stone

Ombrello

Aróstegui

et al. 2022

Arthritis & Rheumatology

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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.

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Section: Resultsmentioning

confidence: 99%

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

Stone

Ombrello

Aróstegui

et al. 2022

Arthritis & Rheumatology

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“…In remaining cases, also the steroid-sparing drugs, such as the anti-cytokines biologics, may result not be completely effective in preventing the long-term complications. Hematopoietic stem cell transplantation has been recently proposed for the management of severe hematological manifestations (i.e., cytopenia) in complicated forms not responsive to conventional anti-cytokine treatments (6).…”

Section: Introductionmentioning

confidence: 99%

Kidney Involvement in PSTPIP1 Associated Inflammatory Diseases (PAID): A Case Report and Review of the Literature

et al. 2021

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Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, and the proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated myeloid-related proteinemia inflammatory (PAMI) syndrome are two distinct clinical conditions caused by heterozygous mutations of the PSTPIP1 gene. While skin and joint involvements are shared by both conditions, PAMI is characterized by hepatosplenomegaly, pancytopenia, and growth failure. Kidney involvement is exceptional in PSTPIP1-mediated disorders. The two missense PSTPIP1 variants associated with PAMI syndrome are p.E250K and p.E257K. Long-term treatment with interleukin (IL)-1 inhibitors is effective to control inflammatory manifestations and is usually well-tolerated. We report a case of a patient carrying the PSTPIP1 p.E250K mutation who developed a late-onset kidney involvement despite a long treatment with canakinumab and anakinra. Kidney biopsy showed focal segmental glomerulosclerosis that was treated with tacrolimus (0.1 mg/kg/day in two doses). A literature revision with the aim to assess the proportion and type of kidney involvement in PAMI syndrome revealed that heterogeneous nephropathies may be part of the clinical spectrum. Our study supports the importance of a periodic diagnostic work-up, including kidney laboratory tests and kidney biopsy, in individuals affected with PAMI syndrome. Kidney and liver functions may be impaired regardless of anti-cytokines treatments and additional therapy approaches (i.e., multi-drugs, hematopoietic stem cell transplantation) should be carefully considered.

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“…Jesus et al also hypothesized that a partial response to IL-1 inhibition suggested the involvement of additional cytokine pathways (36). Laberko A et al reported five PAMI patients with PSTPIP1 E250K who underwent a successful hematopoietic stem cell transplantation (37). However, bone marrow transplantation has not been reported in PAPA patients, to the best of our knowledge.…”

Section: Discussionmentioning

confidence: 98%

Case Report: Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne: A Single-Center Experience and Literature Review

Wang

et al. 2021

Front. Immunol.

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ObjectivesThis study aims to describe the characteristics of patients diagnosed with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome at a single center in China and provide an up-to-date literature review.MethodsThe clinical data and genotype of three Chinese Han patients were carefully documented and studied. We also conducted a systematic literature review on PAPA syndrome.ResultsA total of three patients were diagnosed with PAPA syndrome at our center from 2018 to 2020. Arthritis was observed in all three patients, while pyoderma gangrenosum (PG) was found in two patients and acne in one patient. Other manifestations included pathergy reaction, intermittent fever, oral ulcer, keratitis, proteinuria, and hematuria. The PSTPIP1 A230T mutation was identified in two patients, and a novel Y119C variation was revealed in a sporadic patient. A total of 76 patients with PAPA syndrome reported in 29 articles were included in our literature review. The classical triad of arthritis, PG, and acne was visible in only 16 (25.4%) patients, while 24 (38.1%) exhibited only one major symptom. Skin lesions were more commonly seen in patients with adult-onset disease than those with childhood-onset disease (100 vs. 83%), whereas arthritis was less common (50 vs. 98.1%). Steroid and/or biological agents were effective in most patients.ConclusionsThe rarity and phenotypic heterogeneity associated with PAPA syndrome make the diagnosis a huge challenge to physicians, especially in adult patients. A significant portion of patients did not exhibit the full spectrum of the classical triad. Accordingly, gene testing is critically helpful for diagnosis.

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HSCT is effective in patients with PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome

Cited by 20 publications

References 25 publications

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

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

Kidney Involvement in PSTPIP1 Associated Inflammatory Diseases (PAID): A Case Report and Review of the Literature

Case Report: Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne: A Single-Center Experience and Literature Review

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