None of the patients had a family history of consanguinity. Because of the complex nature of their disease, whole-exome sequencing (WES) was performed in all patients and identified 3 distinct ...monoallelic, heterozygous, possibly pathogenic de novo variants in CDC42. Immunophenotypic changes in monocytes and natural killer cells (Fig 1, A and B) were also noted. Because of the complex nature of the disease, WES was performed and identified a heterozygous and possibly pathogenic de novo variant in CDC42 c.563G>A (p.C188Y; Fig 1). At 8 months, he was found to have retinal detachment, phthisis of his right eye and papilledema of the left eye, both of which were presumed to be secondary to his inflammatory disease and increased intracranial pressure. Because of the patient's phenotypic similarities to patients with NOMID, he was started on prednisone and anakinra at age 8 months, with resolution of systemic inflammation and cytopenias. Patient 1 Patient 2 Patient 3 Patient 4 CDC42 variant c.563G>A (p.C188Y) c.563G>A (p.C188Y) c.556C>T (p.R186C) c.576A>C (stop lost p.*192C*24) Dose of anakinra (d) Before anakinra 1 mg/kg 2.5 mg/kg Before anakinra 6 mg/kg 5 mg/kg Before anakinra 3 mg/kg 8.5 mg/kg Canakinumab, 8 mg/kg/mo Before anakinra 3 mg/kg 4.5 mg/kg Clinical presentation Facial dysmorphism Mild frontal bossing, mild hypertelorism, depressed nasal bridge Frontal bossing, macrocephaly, thin sparse hair, depressed nasal bridge None Mild frontal bossing Weight (percentile) <3rd <3rd 5th <3rd <3rd 5th 3rd 3rd 3rd 5th <3rd <3rd 10th Appetite Poor Improved Normal Poor Improved Improved Poor Improved Improved Normal Poor Decreased Normal Spleen size∗ (cm patient age; SM or normal, UL for age) 11.4 (12 mo; SM, UL 8.0) 8 (15 mo; normal, UL 8.0) 8 (18 mo; normal, UL 8.0) 11.2 (neonatal; SM, UL 6.0) NA 10.1 (12 mo; SM, UL 8.0) 9.2 (neonatal; SM, UL 6.0) 9.9 (5 mo; SM, UL 6.5) 10.8 (16 mo; SM, UL 8.0) 11.9 (6 y; SM, UL 10.0) Hepatomegaly and SM 6.7 (15 mo old; normal, UL 8.0) NA Painful rash Daily None None Bimonthly Monthly None Daily Resolved Resolved Resolved Daily Recurrent None Ibuprofen intake Daily None None None None None None None None None None None None Severe infections None None None None None None None Lymphadenitis Lymphadenitis Lymphadenitis, streptococcal sepsis None Yes† Lymphadenitis Yes‡ Biological parameters Platelet (103/μL) 72 155 141 182 267 276 13 22 148 202 54 381 307 Hemoglobin (g/dL) Transfusion-dependent anemia (Hb, <7 g/dL) 13.8 13.3 Transfusion-dependent anemia (Hb, <7 g/dL) 11.2 11.7 8.1 7.9 10.1 12.3 7.4 13.3 13.5 RBC transfusion Monthly None None Q2-3 mo None None Weekly or biweekly Sporadic Rare Rare Multiple None None Platelet transfusion None None None None None None Multiple Sporadic Rare Rare Multiple None None LDH (ng/mL) 540 NA 547 584 269 271 817 998 1,115 1,633 NA 284 353 ESR (mm/h) >130 16 32 51 22 40 62 65 39 22 140 26 21 CRP (mg/L) 55 2 4 56 3.4 8.8 14.2 3.6 5.6 0.2 Increased 28.8 1.54 Ferritin (ng/mL <400) 2,364 801 680 614 316 126 5,191 3,682 1,329 557 NA 172 51 IL-6 (pg/mL <5) 18 NA <5 NA NA NA NA NA 15.9 11.0 NA NA NA IL-18§ (pg/mL 100-500) 35,616 27,803 22,690 36,479‖ NA 83,268 NA NA 28,407 26,402 NA 19,025 21,535 IL-18BP§ (pg/mL 1,000-6,000) 14,418 8,557 6,264 NA NA 14,653 NA NA 11,803 NA NA 23,986 9,626 CXCL9§ (pg/mL 500-3,500) 8,457 2,978 4,975 NA NA 2,064 NA NA 3,942 NA NA 11,473 4,278 Table I Clinical phenotype and biological parameters of the reported patients before and after therapy with IL-1 inhibitors TKS C-terminal∗ mutations in CDC42 Group 1 Group 2 Group 3 Clinical presentation Failure to thrive, postnatal weight (weight <2 SD) 3/5 2/4 3/4 4/4 Intellectual disability 5/5 4/4 2/6 1/4 Facial dysmorphism, including frontal bossing and large forehead 2/5 2/4 1/6 3/4 Cardiac abnormality 3/5 2/4 2/5 0/4 Rash 0/5 0/4 0/5 4/4 Recurrent severe infections 4/5 3/4 1/6 3/4 (2/3 were receiving immunosuppression) Biological parameters Thrombocytopenia 4/4 1/3 0/5 4/4 Anemia NA NA NA 4/4 Systemic inflammatory syndrome: increased CRP level, ESR, and ferritin level NA NA NA 4/4 Table E1 Comparison of the clinical phenotypes and biological parameters of patients with TKS and of our cohort of 4 patients with a de novo heterozygous C-terminal mutation in CDC42 Patient 1 CDC42 c.563G>A p.C188Y De novo Possibly pathogenic: 0.337∗ Patient 2 CDC42 LYST LPIN2 MEFV c.563G>A c.1686G>C c.446C>T c.442G>C p.C188Y p.Q562H p.P149L p.E148Q De novo Possibly pathogenic: 0.337∗ Possibly pathogenic: 0.035 Possibly pathogenic: 0.049 Likely benign: 0.024 Patient 3 CDC42 LYST UNC13D c.556C>T c.4545G>C c.2764G>A p.R186C p.E1515D p.A922T De novo Heterozygous from father Heterozygous from mother Possibly pathogenic: 0.053∗ Likely benign: 0.003 Possibly pathogenic: 0.047 Patient 4 CDC42 WAS c.576A>C (stop lost) c.706G>A p.*192C*24 p.A236T De novo X-linked from mother Possibly pathogenic: 0.053∗ Possibly pathogenic: 0.964 Table E2 WES analysis of all 4 reported patients No.
Savvy About SAVI Liptzin, Deborah R; Cole, Lyndsey; Schulte, Greg ...
American journal of respiratory and critical care medicine,
2024-Apr-17, 2024-04-17, 20240417
Journal Article
Abstract Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) or proteasome‐associated autoinflammatory syndrome is a rare autoinflammatory disorder that ...typically presents in infancy with characteristic symptoms, including recurrent fever, panniculitis, and progressive lipodystrophy, among other findings. We present a case of mother and child with CANDLE syndrome. The child was eventually started on baricitinib with normalization of rash and systemic findings.
Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of ...specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN-, type II IFN-, and NF-κB-dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients' first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 sST2, NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.
Abstract
Systemic Autoinflammatory diseases (SAIDs) present with chronic sterile inflammation. NLRP3 mutation cause the IL-1 mediated SAID Neonatal-Onset Multisystem Inflammatory Disease (NOMID), ...that presents early in life with fever, rash, neutrophilic meningitis, hearing loss and eye inflammation. Chronic Atypical Neutrophilic Dermatosis, Lipodystrophy and Elevated Temperature (CANDLE) caused by additive loss-of-function mutations in proteasome genes including PSMB8, leads to chronic type 1 interferon signaling, characterized by early-onset fever, neutrophilic panniculitis, lipodystrophy, cytopenias, myositis and lymphocytic meningitis. IL-1 blocking treatments are approved for NOMID, and JAK-inhibitors show efficacy in CANDLE treatment.
We used proteomic analysis to compare differentially-regulated proteins in active NOMID and CANDLE compared to healthy children before and after treatment to identify inflammatory pathways that distinguish NOMID and CANDLE and are uniquely responsive to either IL-1 or IFN signaling blockade.
Serum samples from active NOMID (n=12) and CANDLE (n=7) before and after treatment and healthy controls (n=7) were subjected to proteomic profiling using SomaLogic platform (n=1129 proteins). Enriched pathways were identified in REACTOME and KEGG. Cytoscape was used for network extraction and visualization.
Differentially expressed proteins in NOMID vs CANDLE suggested endothelial cell function, coagulation and complement cascades and inflammation related pathways dysregulation. Distinct protein markers (i.e. cytokine and chemokines) are consisted the different immune dysregulation in NOMID and CANDLE; and uniquely respond to either IL-1 or IFN signaling blockade.
Background
The interleukin‐1 (IL‐1) mediated systemic autoinflammatory diseases, including the cryopyrin‐ associated periodic syndromes (CAPS), tumour necrosis factor receptor‐associated periodic ...syndrome (TRAPS), mevalonate kinase deficiency (MKD) and deficiency of the IL‐1 receptor antagonist (DIRA), belong to a group of rare immunodysregulatory diseases that primarily present in early childhood with variable multiorgan involvement. When untreated, patients with severe clinical phenotypes have a poor prognosis, and diagnosis and management of these patients can be challenging. However, approved treatments targeting the proinflammatory cytokine IL‐1 have been life changing and have significantly improved patient outcomes.
Objective
To establish evidence‐based recommendations for diagnosis, treatment and monitoring of patients with IL‐1 mediated autoinflammatory diseases to standardise their management.
Methods
A multinational, multidisciplinary task force consisting of physician experts, including rheumatologists, patients or caregivers and allied healthcare professionals, was established. Evidence synthesis, including systematic literature review and expert consensus (Delphi) via surveys, was conducted. Consensus methodology was used to formulate and vote on statements to guide optimal patient care.
Results
The task force devised five overarching principles, 14 statements related to diagnosis, 10 on therapy, and nine focused on long‐term monitoring that were evidence and/or consensus‐based for patients with IL‐1 mediated diseases. An outline was developed for disease‐specific monitoring of inflammation‐induced organ damage progression and reported treatments of CAPS, TRAPS, MKD and DIRA.
Conclusion
The 2021 EULAR/American College of Rheumatology points to consider represent state‐of‐the‐art knowledge based on published data and expert opinion to guide diagnostic evaluation, treatment and monitoring of patients with CAPS, TRAPS, MKD and DIRA, and to standardise and improve care, quality of life and disease outcomes.
Objective
To describe a 41‐year‐old woman with a history of neonatal onset multisystem inflammatory disease, on treatment with daily subcutaneous injections of 600 mg of recombinant interleukin‐1 ...receptor antagonist (IL‐1Ra) protein, anakinra, since the age of 28, who presented with golf‐ball size nodules at the anakinra injection sites, early satiety, new onset nephrotic syndrome in the context of normal markers of systemic inflammation.
Methods
Clinical history and histologic evaluation of biopsies of skin, gastric mucosa, and kidney with Congo‐red staining and proteomic evaluation of microdissected Congo red–positive amyloid deposits by liquid chromatography‐tandem mass spectrometry.
Results
The skin, stomach, and kidney biopsies all showed the presence of Congo red–positive amyloid deposits. Mass spectrometry‐based proteomics demonstrated that the amyloid deposits in all sites were of AIL1RAP (IL‐1Ra protein)‐type. These were characterized by high spectral counts of the amyloid signature proteins (apolipoprotein AIV, apolipoprotein E, and serum amyloid P‐component) and the amyloidogenic IL‐1Ra protein, which were present in Congo red–positive areas and absent in Congo red–negative areas. The amino acid sequence identified by mass spectrometry confirmed that the amyloid precursor protein was recombinant IL‐1Ra (anakinra) and not endogenous wild‐type IL‐1Ra.
Conclusion
This is the first report of iatrogenic systemic amyloidosis due to an injectable protein drug, which was caused by recombinant IL1Ra (anakinra).
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