Pathogenesis, and Outcome of Autoinflammatory Diseases, NOMID/CAPS, DIRA, CANDLE, SAVI, NLRC4-MAS, Still's-like Diseases, and other Undifferentiated Autoinflammatory Diseases

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

A. Characterization of SAIDs cohorts and long-term follow up. 1. NOMID: Analyzing long-term outcome data in patients with NOMID who have been treated with the IL-1 blocking treatment anakinra we found good systemic inflammatory control in most treated patients. A subset of patients on chronic high doses of anakinra of mostly >3mg/kg/day develop iatrogenic skin amyloidosis that can disseminate to the kidneys; in fact renal amyloidosis caused by recombinant IL1RA (anakinra) was confirmed by mass spectrometry (Alehashemi S Arthritis Rheum 2024, 194. Nasr SH, Alehashemi S et al Kidney Int. 2024). We have identified other secondary diagnoses, including inflammatory bowel disease (2 patients) and secondary genetic diagnoses (in 4 patients) that are being evaluated. The development of anakinra-associated amyloidosis prompted the launch of a novel imaging protocol to identify, visualize, quantify and monitor the development of systemic amyloidosis and its distribution. This protocol has received IRB approval and is ready to enroll the first patient. In parallel, prevention strategies, such as lower anakinra dosing, combination therapy, and evaluation of alternative treatment approaches to avoid prolonged high-dose anakinra exposure are ongoing. 2. CANDLE, SAVI: Despite clinical improvement on JAKis, particularly baricitinib in patients will biallelic CANDLE caused by PSMB8 mutations, SAVI patients continue with progression of organ damage particularly lung disease even on optimal doses of JAKis, furthermore the IFN signature does not normalize with JAK inhibition. Chronic treatment is needed as dose reductions cause disease flares (Gedik KC et. al. ARD 2024). We piloted targeted interferon blockade in SAVI patients using the anti-IFNβ antibody dazukibart and the anti-IFNAR1 antibody anifrolumab. While dazukibart initially reduced C-reactive protein levels and IFN-I scores, its effects were not durable, and patients experienced rebound inflammation and recurrent vasculitic lesions despite dose adjustments. Combination therapy with baricitinib and tocilizumab provided only partial benefit. In contrast, treatment with anifrolumab in combination with tocilizumab resulted in sustained suppression of IFN-I scores, discontinuation of JAK inhibition, and marked improvement of vasculitic wounds. These findings underscore both the therapeutic challenges in SAVI and the value of IFN-I scores as a theragnostic biomarker, while also highlighting anifrolumab as a promising approach warranting further clinical investigation in SAVI and related interferonopathies (Alehashemi et al Arthritis Rheumatol 2025). B. Development and validation of outcome criteria: Following the development of expert guidance documents for IL-1–mediated diseases (Romano et al., Ann Rheum Dis2022), IFN-β–mediated diseases (Gedik et al., Ann Rheum Dis 2023), and the early management of suspected hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) (Shakoory et al., Ann Rheum Dis2023), important progress has been made in facilitating patient access to therapies and in establishing tools to monitor treatment responses longitudinally, with adjustments tailored to the growing child. Building on this foundation, we continue to develop clinical trial designs and outcome measures that integrate historical data on the natural progression of organ damage. Motivated by a small-sample example in neonatal-onset multisystem inflammatory disease (NOMID), we propose a statistical method for evaluating whether initiation of treatment alters the trajectory of disease progression compared with historical progression prior to treatment. The method estimates the longitudinal trajectory of the outcome variable and incorporates an interaction term between an intervention indicator and time since treatment initiation. This approach is particularly suitable when the intervention is hypothesized to slow or halt the deleterious effects of disease on the outcome, as in our motivating NOMID example. Through simulations in small samples and under scenarios with limited treatment initiation times, we demonstrate that a generalized estimating equations (GEE) framework with small-sample adjustments controls the Type I error rate more effectively than standard GEE or linear mixed models without such adjustments. Additionally, permutation testing—by permuting the timing of treatment initiation—offers another valid and complementary approach. We illustrate the utility of this methodology in a prospective cohort of NOMID patients (Ortega-Villa et al., Stat Med 2024). C. Genetic discovery and characterization of novel auto-inflammatory diseases or variants We characterized a novel dominant-negative (DN) PSMB8 variant causing proteasome-associated autoinflammatory syndrome (PRAAS) with an autoinflammatory and immunodeficiency phenotype. We report 8 patients with DN-PRAAS who presented with early-onset systemic inflammation, panniculitis, cytopenias, infections, and porto-sinusoidal vascular liver disease (PSVD), indicating broader immune dysfunction that partially responds to JAK1/2 inhibition and/or interferon-α/β receptor (IFNAR) blockade (anifrolumab). These features are not seen in CANDLE patients with disease-causing biallelic PSMB8 variants. Through structural modeling and cellular profiling, we characterize mitochondrial and metabolic lipid stress, in addition to intracellular protein aggregates in patients’ T cells that activate the ISR kinases PKR and GCN2 and thus expand the characterization of maladaptive cell stress responses that contribute to immune dysregulation. Our study links maladaptive stress responses to increased apoptotic pathways contributing to the T cell dysfunction that predispose to infections and together with endothelial dysfunction have been linked to distinct liver pathology (Moeller S, Alehashemi S et al, ssrn.5370606). We propose that targeting maladaptive cellular stress responses may preserve the antimicrobial and homeostatic T cell responses and constitute a treatment strategy that may be useful in a broader group of immunedysregulatory diseases. D. Development and validation of biomarkers to characterize the inflammatory response and to monitor organ damage. We assessed the type I IFN signature and serial serum IFNα/β measurements to monitor and optimize treatment dosing in a SAVI patient treated first with an anti-IFNβ antibody and subsequently with IFNAR1 blockade. High-dose JAK inhibitor and anti-IFNβ therapy failed to achieve durable suppression of IFN signaling, whereas the anti-IFNAR antibody anifrolumab consistently reduced IFN scores and showed clinical efficacy. Despite elevated serum IFNα/β levels, signaling was blocked, underscoring the IFN signature as a reliable pharmacodynamic biomarker. In addition, the IFN signature provided valuable readouts for pharmacokinetic–pharmacodynamic (PK/PD) assessments, enabling correlation of drug exposure with biological activity. These findings establish a framework for investigating type I IFN signaling in SAVI and related disorders in future clinical trials (Alehashemi et al., Arthritis Rheum 2025). E. Studies on the role of M2 macrophage contribution to an inflammatory phenotypes are ongoing. F. Use of in vitro cell culture systems to model organ-specific immune dysregulation and organ damage in selected autoinflammatory diseases. CANDLE patients present with type-I interferon mediated inflammatory features but the impact of proteasome mutations on CNS disease that includes cognitive impairment in some patients has not been systematically evaluated. In collaboration with the Boehm laboratory (NHLBI) we had established human induced pluripotent stem cell lines (iPSC) for CANDLE patients (Yu Q, Stem Cell 2022). iPScell derived organoids exhibited impaired neuronal development when compared to COs from healthy control iPSCs. Impaired neuronal maturation in CANDLE COs was correlated with increased polyamines, which were also elevated in CANDLE patient CSF. The exploration of the proteasome-dependent mechanisms leading to proteasome associated neuronal developmental impairment through overproduction of polyamines offer insight into potential therapeutic strategies for CNS-related proteasomal dysfunction. (Winkler CW et al. bioRxiv 2025.08.14.670165).