Rare, rarer, lung involvement in adult-onset Still's disease: A mini-review

Abstract

Adult-onset Still's disease (AOSD) is a polygenic systemic autoinflammatory disease which is associated with increased morbidity and mortality. Pulmonary involvement is a rare, but serious complication of AOSD. As in AOSD, IL-1b, IL-18, and IL-6 dominate the molecular pathogenesis, which mediate a type 1 and type 3 inflammatory signature of the adaptive immune system. This is evidenced by the success of IL-1- and IL-6 inhibition in the management of AOSD. However, anaphylactic reactions to treatment with IL-1- or IL-6-inhibitors is currently being discussed as a potential trigger for lung involvement inf AOSD, while genetic risk factors have also been identified. Clinically, pulmonary involvement in AOSD can manifest in many different forms. Parenchymal inflammation with peripheral consolidations is the most frequent form while PAH is less common, but often very difficult to manage. This mini-review provides an overview of the pathophysiology as well as the clinical presentation and the diagnostic features of pulmonary involvement in AOSD.

Keywords: IL-1 blocking; IL-6 blocking; adult-onset Still's disease (AOSD); interstitial lung disease; pulmonary arterial hypertension.

Figure 1

Proposed pathophysiological model for AOSD with lung involvement. Processes of general AOSD pathophysiology are shown in blue, those that have specifically been shown in pulmonary involvement are shown in red. PAMPs and DAMPs induce the immune reaction by binding to PRRs: Intracellular activation of the NRLP3 inflammasome and subsequent proteolytic activation of pro-IL18 and pro-IL-1β is a hallmark of the disease. IL-18 activates T_H1 cells and stimulates NK cells to release IFNγ which in turn activates macrophages. These can recruit additional T_H1 cells by secretion of the chemokines CXCL9 and CXCL10. IL-1β induces the production of IL-6 and the combination of the two skews the local cytokine milieu in favor of T_H17 (over T_reg) polarization. This process is supported by TLR7-signaling in DCs. T_H17 cells recruit neutrophils which induce a potent inflammatory reaction that create even more DAMPs to reinforce the immunological cascade. This strong activation of both macrophages and neutrophils leads to a cytokine storm that can affect many organs, including the lungs. PAMP, pathogen-associated molecular pattern; DAMP, danger-associated molecular pattern; PRR, pattern recognition receptor; DC, dendritic cell; TLR7, toll-like receptor 7; NK, natural killer cell; MΦ, macrophage; NG, neutrophilic granulocyte (image created with BioRender, many thanks to Prof. Tobias B. Huber).

Figure 2

Modes of parenchymal lung involvement in AOSD-LD, modified from Rolfes and Kallinich (45). (A) peripheral septal thickening with or without adjacent ground-glass opacities, (B) crazy-paving pattern, (C) peripheral consolidations, (D) peribronchovascular consolidations, (E) predominantly ground-glass opacities (image created with BioRender, many thanks to Prof. Tobias B. Huber).