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BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.

Objective: Autoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome‐associated autoinflammatory syndrome (CANDLE/PRAAS), stimulator of interferon genes (STING)–associated vasculopathy with onset in infancy (SAVI), and Aicardi‐Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of "points to consider" to improve diagnosis, treatment, and long‐term monitoring of patients with these rare diseases. Methods: Members of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates, and an allied health care professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires, and consensus methodology, "points to consider" to guide patient management were developed. Results: The Task Force devised consensus and evidence‐based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment, and long‐term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI, and AGS. Conclusion: These points to consider represent state‐of‐the‐art knowledge to guide diagnostic evaluation, treatment, and management of patients with CANDLE/PRAAS, SAVI, and AGS and aim to standardize and improve care, quality of life, and disease outcomes. [ABSTRACT FROM AUTHOR]

The antibody profile against autoantigens previously associated with autoimmune diseases and other human proteins in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that 30% of adults with COVID-19 had autoantibodies against the lung antigen KCNRG, and 34% had antibodies to the SLE-associated Smith-D3 protein. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute onset of insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren's syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring in vivo decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Further testing of IgG and/or IgA antibodies against a subset of potential targets identified by published autoantigen array studies of MIS-C failed to detect autoantibodies against most (16/18) of these proteins in patients with MIS-C who had not received IVIG. However, Troponin C2 and KLHL12 autoantibodies were detected in 2 of 20 and 1 of 20 patients with MIS-C, respectively. Overall, these results suggest that IVIG therapy may be a confounding factor in autoantibody measurements in MIS-C and that antibodies against antigens associated with autoimmune diseases or other human proteins are uncommon in MIS-C. [ABSTRACT FROM AUTHOR]

Objective: To identify novel heterozygous LPIN2 mutations in a patient with Majeed syndrome and characterize the pathomechanisms that lead to the development of sterile osteomyelitis. Methods: Targeted genetic analysis and functional studies assessing monocyte responses, macrophage differentiation, and osteoclastogenesis were conducted to compare the pathogenesis of Majeed syndrome to interleukin‐1 (IL‐1)–mediated diseases including neonatal‐onset multisystem inflammatory disease (NOMID) and deficiency of the IL‐1 receptor antagonist (DIRA). Results: A 4‐year‐old girl of mixed ethnic background presented with sterile osteomyelitis and elevated acute‐phase reactants. She had a 17.8‐kb deletion on the maternal LPIN2 allele and a splice site mutation, p.R517H, that variably spliced out exons 10 and 11 on the paternal LPIN2 allele. The patient achieved long‐lasting remission receiving IL‐1 blockade with canakinumab. Compared to controls, monocytes and monocyte‐derived M1‐like macrophages from the patient with Majeed syndrome and those with NOMID or DIRA had elevated caspase 1 activity and IL‐1β secretion. In contrast, lipopolysaccharide‐stimulated, monocyte‐derived, M2‐like macrophages from the patient with Majeed syndrome released higher levels of osteoclastogenic mediators (IL‐8, IL‐6, tumor necrosis factor, CCL2, macrophage inflammatory protein 1α/β, CXCL8, and CXCL1) compared to NOMID patients and healthy controls. Accelerated osteoclastogenesis in the patient with Majeed syndrome was associated with higher NFATc1 levels, enhanced JNK/MAPK, and reduced Src kinase activation, and partially responded to JNK inhibition and IL‐1 (but not IL‐6) blockade. Conclusion: We report 2 novel compound heterozygous disease‐causing mutations in LPIN2 in an American patient with Majeed syndrome. LPIN2 deficiency drives differentiation of proinflammatory M2‐like macrophages and enhances intrinsic osteoclastogenesis. This provides a model for the pathogenesis of sterile osteomyelitis which differentiates Majeed syndrome from other IL‐1–mediated autoinflammatory diseases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Autoinflammatory syndromes include an expanding list of conditions characterized by unprovoked recurrent attacks of systemic inflammation with lack of auto-antibodies or autoreactive T cells. Many of these syndromes are genetic diseases with a Mendelian inheritance. Neurological manifestations may be one of the major clinical features and, in some cases, the presenting symptom of these syndromes. The purpose of this review is to increase the recognition among neurologists of the Mendelian-inherited autoinflammatory syndromes by highlighting the neurological manifestations in the context of other symptoms that should lead physicians to suspect these syndromes. Most important for neurologists are the cryopyrin-associated periodic syndromes that include familial cold autoinflammatory syndrome, Muckle–Wells syndrome and neonatal-onset multisystem inflammatory disease (called chronic infantile neurological cutaneous and articular syndrome in Europe). We also review other syndromes with less common neurological involvement, including familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, and hyperimmunoglobulinemia D syndrome. Because these syndromes are often treatable and irreversible damage is prevented if they are treated early, it is important to recognize the features that may result in these syndromes presenting to a neurologist, especially in early childhood. [ABSTRACT FROM AUTHOR]