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.
Pediatric Coronavirus Disease 2019 (pCOVID-19) is rarely severe; however, a minority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might develop multisystem ...inflammatory syndrome in children (MIS-C), with substantial morbidity. In this longitudinal multi-institutional study, we applied multi-omics (analysis of soluble biomarkers, proteomics, single-cell gene expression and immune repertoire analysis) to profile children with COVID-19 (n = 110) and MIS-C (n = 76), along with pediatric healthy controls (pHCs; n = 76). pCOVID-19 was characterized by robust type I interferon (IFN) responses, whereas prominent type II IFN-dependent and NF-κB-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation. The association of MIS-C with the combination of HLA A*02, B*35 and C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load than pCOVID-19 and pHC. These results identify distinct immunopathological signatures in pCOVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapy.
This case report describes 2 patients with iatrogenic amyloidosis secondary to subcutaneous injections of anakinra to manage neonatal-onset multisystem inflammatory disease.
Gain-of-function mutations in
cause the monogenic interferonopathy, SAVI, which presents with early-onset systemic inflammation, cold-induced vasculopathy and/or interstitial lung disease. We ...identified 5 patients (3 kindreds) with predominantly peripheral vascular disease who harbor 3 novel
variants, p.H72N, p.F153V, and p.G158A. The latter two were predicted by a previous cryo-EM structure model to cause STING autoactivation. The p.H72N variant in exon 3, however, is the first SAVI-causing variant in the transmembrane linker region. Mutations of p.H72 into either charged residues or hydrophobic residues all led to dramatic loss of cGAMP response, while amino acid changes to residues with polar side chains were able to maintain the wild type status. Structural modeling of these novel mutations suggests a reconciled model of STING activation, which indicates that STING dimers can oligomerize in both open and closed states which would obliviate a high-energy 180° rotation of the ligand-binding head for STING activation, thus refining existing models of STING activation. Quantitative comparison showed that an overall lower autoactivating potential of the disease-causing mutations was associated with less severe lung disease, more severe peripheral vascular disease and the absence of a robust interferon signature in whole blood. Our findings are important in understanding genotype-phenotype correlation, designing targeted STING inhibitors and in dissecting differentially activated pathways downstream of different STING mutations.
To analyze early and midterm results of endovascular treatment of visceral aneurysms regarding technical considerations, technical success rate, aneurysm rupture, and end-organ ischemia.
Endovascular ...treatment of 41 visceral and renal artery aneurysms (VAAs) in 40 consecutive patients (25 women; mean age, 59.4 y ± 16.2) was retrospectively reviewed. The series included 30 true aneurysms and 11 pseudoaneurysms in renal (n = 17), splenic (n = 13), hepatic (n = 4), celiac (n = 4), gastroduodenal (n = 2), and middle colic (n = 1) arteries. Demographic, clinical, procedural, and follow-up data were analyzed.
Forty-one aneurysms underwent endovascular treatment. Hypertension (73%) and hyperlipidemia (32%) were the most common associated comorbidities. Nineteen patients presented with symptoms of pain (15%) or rupture (32%) in 10 pseudoaneurysms (91%) and nine true aneurysms (30%; P = .0007). The most commonly used technique (93%) was coil embolization with (15%) or without (78%) other endovascular agents. The rate of technical success (cessation of hemorrhage or blood flow into aneurysm sac) was 98%. There was no periprocedural mortality. Mean hospital stays were 1 and 2 days for asymptomatic and symptomatic patients, respectively. Mean clinical follow-up was 44.5 months; mean imaging follow-up was 11.7 months. The only complication was an intraprocedural thromboembolic event in one case (3%). Follow-up imaging evidence of end-organ partial infarct was detected in six patients (21%), with no clinical evidence of organ insufficiency.
Endovascular treatment of VAAs is a safe and highly successful procedure. Associated side effects such as distal embolization and end-organ infarcts were not found to be clinically significant.
Mutations in genes coding for proteasome subunits and/or proteasome assembly helpers typically cause recurring autoinflammation referred to as chronic atypical neutrophilic dermatosis with ...lipodystrophy and elevated temperatures (CANDLE) or proteasome-associated autoinflammatory syndrome (PRAAS). Patients with CANDLE/PRAAS present with mostly chronically elevated type I interferon scores that emerge as a consequence of increased proteotoxic stress by mechanisms that are not fully understood. Here, we report on five unrelated patients with CANDLE/PRAAS carrying novel inherited proteasome missense and/or nonsense variants. Four patients were compound heterozygous for novel pathogenic variants in the known CANDLE/PRAAS associated genes,
PSMB8
and
PSMB10
, whereas one patient showed additive loss-of-function mutations in
PSMB8
. Variants in two previously not associated proteasome genes,
PSMA5
and
PSMC5
, were found in a patient who also carried the
PSMB8
founder mutation, p.T75M. All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes. Our observations expand the spectrum of PRAAS-associated genetic variants and improve a molecular diagnosis and genetic counseling of patients with sterile autoinflammation.
To examine the risk of hematologic malignancies in older adults with ankylosing spondylitis (AS).
We used US Medicare data from January 1, 1999, to December 31, 2010, to identify a population-based ...cohort of beneficiaries with AS. We also included beneficiaries with inflammatory bowel disease (IBD) as disease controls and beneficiaries without AS or IBD as unaffected controls. We excluded those treated with tumor necrosis factor inhibitors in this period. We followed up each group for new diagnosis claims for hematologic malignancies until September 30, 2015.
We included 12,451 beneficiaries with AS, 234,905 with IBD, and 10,975,340 unaffected controls, with a mean follow-up of 9.9, 9.3, and 8.0 years, respectively. We identified 297 hematologic malignancies in the AS group, 4538 malignancies in the IBD group, and 128,239 malignancies in unaffected controls. The standardized incidence ratio in AS vs unaffected controls was 1.39 (95% CI, 1.05 to 1.61) for non-Hodgkin lymphoma, 1.50 (95% CI, 1.17 to 1.92) for chronic lymphocytic leukemia, and 1.52 (95% CI, 1.12 to 2.06) for multiple myeloma. Risks of acute myeloid leukemia and chronic myeloid leukemia were not elevated in AS, and there were too few cases of Hodgkin lymphoma to compute risks. Risks were comparable to those of beneficiaries with IBD. We also performed a systematic literature review of the risk of hematologic malignancy in AS, focusing on age associations, which have not been previously examined. We identified 21 studies in the systematic literature review, which included mainly young or middle-aged patients. Results suggested that AS was largely not associated with an increased risk of hematologic malignancies. Two cohort studies reported an increased risk of multiple myeloma in AS.
The risks of non-Hodgkin lymphoma, chronic lymphocytic leukemia, and multiple myeloma are increased among elderly patients with AS.
Abstract
Objectives
Patients with osteoarthritis and ankylosing spondylitis have lower cancer-related mortality than the general population. We examined risks of solid cancers at 16 sites in elderly ...patients with knee or hip osteoarthritis (KHOA) or ankylosing spondylitis.
Methods
In this population-based retrospective cohort study, we used US Medicare data from 1999 to 2010 to identify cohorts of persons with KHOA or ankylosing spondylitis, and a general population group without either condition, who were followed through 2015. We compared cancer incidence among groups, adjusted for age, sex, race, socioeconomic characteristics, geographic region, smoking and comorbidities.
Results
We studied 2 701 782 beneficiaries with KHOA, 13 044 beneficiaries with ankylosing spondylitis, and 10 859 304 beneficiaries in the general population group. Beneficiaries with KHOA had lower risks of cancer of the oropharynx, oesophagus, stomach, colon/rectum, hepatobiliary tract, pancreas, larynx, lung, and ovary than the general population. However, beneficiaries with KHOA had higher risks of melanoma, renal cell cancer, and cancer of the bladder, breast, uterus and prostate. Associations were similar in ankylosing spondylitis, with lower risks of cancer of the oesophagus, stomach, and lung, and higher risks of melanoma, renal cell cancer, and cancer of the renal pelvis/ureter, bladder, breast, and prostate.
Conclusion
Lower risks of highly prevalent cancers, including colorectal and lung cancer, may explain lower cancer-related mortality in patients with KHOA or ankylosing spondylitis. Similarities in cancer risks between KHOA and AS implicate a common risk factor, possibly chronic NSAID use.
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