Gina A. Montealegre Sanchez

An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome

Inflammasomes are innate immune sensors that respond to pathogen- and damage-associated signals with caspase-1 activation, interleukin (IL)-1β and IL-18 secretion, and macrophage pyroptosis. The discovery that dominant gain-of-function mutations in NLRP3 cause the cryopyrin-associated periodic syndromes (CAPS) and trigger spontaneous inflammasome activation and IL-1β oversecretion led to successful treatment with IL-1–blocking agents. Herein we report a de novo missense mutation (c.1009A>T, encoding p.Thr337Ser) affecting the nucleotide-binding domain of the inflammasome component NLRC4 that causes early-onset recurrent fever flares and macrophage activation syndrome (MAS). Functional analyses demonstrated spontaneous inflammasome formation and production of the inflammasome-dependent cytokines IL-1β and IL-18, with the latter exceeding the levels seen in CAPS. The NLRC4 mutation caused constitutive caspase-1 cleavage in cells transduced with mutant NLRC4 and increased production of IL-18 in both patient-derived and mutant NLRC4–transduced macrophages. Thus, we describe a new monoallelic inflammasome defect that expands the monogenic autoinflammatory disease spectrum to include MAS and suggests new targets for therapy.

Reversal of Alopecia Areata Following Treatment With the JAK1/2 Inhibitor Baricitinib.

Background Alopecia areata (AA) is an autoimmune disease resulting in hair loss with devastating psychosocial consequences. Despite its high prevalence, there are no FDA-approved treatments for AA. Prior studies have identified a prominent interferon signature in AA, which signals through JAK molecules. Methods A patient with AA was enrolled in a clinical trial to examine the efficacy of baricitinib, a JAK1/2 inhibitor, to treat concomitant CANDLE syndrome. In vivo, preclinical studies were conducted using the C3H/HeJ AA mouse model to assess the mechanism of clinical improvement by baricitinib. Findings The patient exhibited a striking improvement of his AA on baricitinib over several months. In vivo studies using the C3H/HeJ mouse model demonstrated a strong correlation between resolution of the interferon signature and clinical improvement during baricitinib treatment. Interpretation Baricitinib may be an effective treatment for AA and warrants further investigation in clinical trials.

Monogenic Autoinflammatory Diseases: Disorders of Amplified Danger Sensing and Cytokine Dysregulation

The pathogenesis of monogenic autoinflammatory diseases converges on the presence of exaggerated immune responses that are triggered through activation of altered pattern recognition receptor (PRR) pathways and result in cytokine/chemokine amplification loops and the inflammatory clinical phenotype seen in autoinflammatory patients. The PRR response can be triggered by accumulation of metabolites, by mutations in sensors leading to their constitutive overactivation, or by mutations in mediator cytokine pathways that lead to amplification and/or inability to downregulate an inflammatory response in hematopoietic and/or nonhematopoietic cells. The study of the pathogenesis of sterile inflammation in patients with autoinflammatory syndromes continues to uncover novel inflammatory pathways.

Insights from Mendelian Interferonopathies: Comparison of CANDLE, SAVI with AGS, Monogenic Lupus.

Autoinflammatory disorders are sterile inflammatory conditions characterized by episodes of early-onset fever and disease-specific patterns of organ inflammation. Recently, the discoveries of monogenic disorders with strong type I interferon (IFN) signatures caused by mutations in proteasome degradation and cytoplasmic RNA and DNA sensing pathways suggest a pathogenic role of IFNs in causing autoinflammatory phenotypes. The IFN response gene signature (IGS) has been associated with systemic lupus erythematosus (SLE) and other autoimmune diseases. In this review, we compare the clinical presentations and pathogenesis of two IFN-mediated autoinflammatory diseases, CANDLE and SAVI, with Aicardi Goutières syndrome (AGS) and monogenic forms of SLE (monoSLE) caused by loss-of-function mutations in complement 1 (C1q) or the DNA nucleases, DNASE1 and DNASE1L3. We outline differences in intracellular signaling pathways that fuel a pathologic type I IFN amplification cycle. While IFN amplification is caused by predominantly innate immune cell dysfunction in SAVI, CANDLE, and AGS, autoantibodies to modified RNA and DNA antigens interact with tissues and immune cells including neutrophils and contribute to IFN upregulation in some SLE patients including monoSLE, thus justifying a grouping of “autoinflammatory” and “autoimmune” interferonopathies. Understanding of the differences in the cellular sources and signaling pathways will guide new drug development and the use of emerging targeted therapies.

Pharmacokinetics, Pharmacodynamics, and Proposed Dosing of the Oral JAK1 and JAK2 Inhibitor Baricitinib in Pediatric and Young Adult CANDLE and SAVI Patients

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.

A173: Cerebrospinal Fluid Cytokines Correlate With Innate Immune Cells in Neonatal Onset Multisystem Inflammatory Disease (NOMID) Patients in Clinical Remission Treated With Anakinra

Neonatal onset multisystem inflammatory disease (NOMID) is a rare autoinflammatory disease caused by NLRP3 mutations that lead to constitutive NLRP3 inflammasome activation and IL‐1β release. Patients present with neutrophilic urticaria, chronic aseptic meningitis, and papilledema. IL‐1β inhibitors improve the inflammatory manifestations, normalize acute phase reactants, decrease CSF WBC and protein, and proinflammatory cytokine levels. We found that cytokine levels decrease with anakinra treatment, but do not normalize during clinical remission. The higher IL‐6 and IP‐10 levels in CSF than in the blood suggest local production in the brain/CSF. Our objective is to examine whether CSF cytokines, particularly IL‐6 and IP‐10, correlate with CSF subpopulations of immune cells and CSF characteristics.

A80: Skeletal Features of Neonatal-Onset Multisystem Inflammatory Disease (NOMID) on Anakinra Treatment: Long-Term Follow-up

Neonatal‐onset multisystem inflammatory disease (NOMID) is an autoinflammatory disease characterized by fever, chronic urticarial rash, CNS manifestations, elevated acute phase reactants, and arthropathy. About 50% of patients with NOMID have de novo missense mutations in NLRP3/CIAS1, leading to constitutive inflammasome activation and IL‐1 production in monocytes, and caspase‐1 mediated persistence of osteoblast progenitor cells that are also found in other fibroblastoid tumors ( ). Poorly differentiated chondrocytes are seen with abnormal enchondral bone formation without inflammatory cells in NOMID arthropathy with bony overgrowth and premature fusion of physis. While blocking IL‐1 with anakinra reduces organ‐specific (central nervous system, inner ear, eye) and systemic inflammation (fever, rash, acute phase reactants), it has little effect on preexisting bone lesions.

Recurrent fevers, progressive lipodystrophy and annular plaques in a child

KEY TEACHING POINTS.

Rash, Fever, and Pulmonary Hypertension in a 6-Year-Old Female

A previously healthy 2-year-old Guatemalan female with an undiagnosed chronic illness characterized by fever and rash had presented with anorexia, weight loss, periorbital edema, abdominal pain and distention. A chest radiograph documented cardiomegaly. An echocardiogram demonstrated a pericardial effusion, dilated right atrium, right ventricle, and main pulmonary artery as well as diminished right ventricular systolic function and pulmonary hypertension. Right ventricular systolic pressure was estimated at 90 mmHg. Computed tomography of her chest was performed. There was no evidence of interstitial lung disease but changes included dilated pulmonary arteries consistent with the presence of pulmonary hypertension as well as acute thrombosis of the superior vena cava and left brachiocephalic vein. These findings suggested thromboembolism as the etiology of pulmonary hypertension. A ventilation / perfusion lung scan also suggested differential lung perfusion. She was placed on systemic anticoagulation transiently. The presence of antiphospholipid antibodies was documented as described below. Rheumatology consultation was requested for consideration of a possible autoimmune / inflammatory etiology. This article is protected by copyright. All rights reserved.

Rilonacept maintains long-term inflammatory remission in patients with deficiency of the IL-1 receptor antagonist

BACKGROUND Deficiency of IL-1 receptor antagonist (DIRA) is a rare autoinflammatory disease that presents with life-threatening systemic inflammation, aseptic multifocal osteomyelitis, and pustulosis responsive to IL-1-blocking treatment. This study was performed (a) to investigate rilonacept, a long-acting IL-1 inhibitor, in maintaining anakinra-induced inflammatory remission in DIRA patients, (b) to determine doses needed to maintain remission, and (c) to evaluate the safety and pharmacokinetics of rilonacept in young children (<12 years). METHODS Six mutation-positive DIRA patients (children, ages 3-6 years), treated with daily anakinra, were enrolled into an open-label pilot study of subcutaneous rilonacept for 24 months. Clinical symptoms and inflammatory blood parameters were measured at all visits. A loading dose (4.4 mg/kg) was administered, followed by once weekly injections (2.2 mg/kg) for 12 months. Dose escalation (4.4 mg/kg) was allowed if inflammatory remission was not maintained. Subjects in remission at 12 months continued rilonacept for an additional 12 months. RESULTS Five of six patients required dose escalation for findings of micropustules. Following dose escalation, all patients were in remission on weekly rilonacept administration, with stable laboratory parameters for the entire study period of 24 months. All children are growing at normal rates and have normal heights and weights. Quality of life improved while on rilonacept. No serious adverse events were reported. CONCLUSION Rilonacept was found to maintain inflammatory remission in DIRA patients. The once weekly injection was well tolerated and correlated with increased quality of life, most likely related to the lack of daily injections. TRIAL REGISTRATION ClinicalTrials.gov NCT01801449. FUNDING NIH, NIAMS, and NIAID.