Vasculitis in Cystic Fibrosis

Abstract

Cystic fibrosis (CF) is an autosomal-recessive multi-organ disease characterized by airways obstruction, recurrent infections, and systemic inflammation. Vasculitis is a severe complication of CF that affects 2-3% of CF patients and is generally associated with poor prognosis. Various pathogenic mechanisms may be involved in the development of CF-related vasculitis. Bacterial colonization leads to persistent activation of neutrophilic granulocytes, inflammation and damage, contributing to the production of antineutrophil cytoplasmic autoantibodies (ANCAs). The presence of ANCA may on the other hand predispose to bacterial colonization and infection, likely entertaining a vicious circle amplifying inflammation and damage. As a result, in CF-associated vasculitis, ongoing inflammation, immune cell activation, the presence of pathogens, and the use of numerous medications may lead to immune complex formation and deposition, subsequently causing leukocytoclastic vasculitis. Published individual case reports and small case series suggest that patients with CF-associated vasculitis require immune modulating treatment, including non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, hydroxychloroquine, and/or disease-modifying anti-rheumatic drugs (DMARDs). As immunosuppression increases the risk of infection and/or malignancy, which are both already increased in people with CF, possible alternative medications may involve the blockade of individual cytokine or inflammatory pathways, or the use of novel CFTR modulators. This review summarizes molecular alterations involved in CF-associated vasculitis, clinical presentation, and complications, as well as currently available and future treatment options.

Keywords: cystic fibrosis; damage; immune complex; inflammation; pathophysiology; treatment; vasculitis.

Figure 1

Palpable purpuric rash on lower limbs of a patient with CF-associated vasculitis.

Figure 2

Histopathology of leukocytoclastic vasculitis. ANCA recognize their targets on activated neutrophils' surface. This leads to the formation of immunocomplexes and to an increase in adhesion molecule expression by neutrophils. As a result, neutrophils bind to endothelial cells and release NETs that cause endothelial damage and the recruitment of additional immune cells, such as dendritic cells (DCs), monocytes, and other neutrophils. ANCA, antineutrophil cytoplasmic antibodies; ROS, reactive oxygen species.

Figure 3

Proposed model of ANCA involvement in the development of vasculitis and chronic inflammation in CF (13, 33). Several hypotheses have been made on what triggers ANCA production in pwCF. ANCA presence leads to a reduced defense against microbes and to vascular endothelial damage due to free LPS. Bacterial colonization leads to further neutrophil activation, inflammation, and increased release of neutrophil granules. Here starts the vicious cycle that leads to additional ANCA formation, decrease of microbicidal capacity, immune cells activation, and tissue damage, causing vasculitis. BPI, bactericidal permeability increasing protein; LPS, lipopolysaccharide; ANCA, antineutrophil cytoplasmic antibodies; PAD4, peptidyl arginine deiminase 4; PR3, proteinase 3; MPO, myeloperoxidase; NE, neutrophil elastase.

Figure 4

Induction of suicidal NETosis. NADPH oxidase assembles and activates the production of ROS. These stimulate PAD4 and, in an MPO dependent way, also NE activity. PAD4 trans-locates to the nucleus and hypercitrullinates histones that are simultaneously processed and cleaved by NE and MPO. This process leads to chromatin decondensation. ANCA, antineutrophil cytoplasmic antibodies; PAD4, peptidyl arginine deiminase 4; PR3, proteinase 3; MPO, myeloperoxidase; NE, neutrophil elastase; TNFα, tumor necrosis factor α; ROS, reactive oxygen spices; NADPH oxidase, nicotinamide adenine dinucleotide phosphate oxidase.

Figure 5

Increased platelet activation and reduced LXA₄/neutrophil ratio result in increased neutrophil activity. Platelets-monocytes interaction leads to the production of LXA₄, involved in the suppression of neutrophil activation. A reduced LXA₄/neutrophil ratio in CF and may contribute to chronic inflammation and to the development of vasculitis. LXA₄, lipoxin A₄.

Figure 6

Pathogenic mechanisms involved in the development of vasculitis in CF. Deficiency or impaired function of CFTR leads to intracellular ionic alterations that can trigger inflammasome activation. This results in the release of pro-inflammatory cytokines that, together with persistent bacterial presence, induce NETosis. NETs activate dendritic cells (DCs) that stimulate ANCA autoantibody production that are involved in neutrophil activation and, possibly, immune complexes formation. Furthermore, thrombocytes form complexes with monocytes and fail to produce LXA₄ that usually contributes to inflammation resolution. All these factors, and the increased release of IL-8 by endothelial cells contribute to continuous immune cell recruitment and NETosis, finally resulting in vasculitis. ANCA, antineutrophil cytoplasmic antibodies; LPS, lipopolysaccharide; DC, dendritic cell; NET, neutrophil extracellular trap; IC, immune complex.