Genetics of autoinflammatory disease discussed at ISR meeting

Irish Society for Rheumatology Autumn Meeting, Radisson Blu Hotel, Little Island, Cork, 18-19 September 2025

At the Irish Society for Rheumatology (ISR) Autumn Meeting, Dr Ivona Aksentijevich, Clinical Molecular Geneticist and Associate Investigator, the National Genome Research Institute, Maryland, US, presented on the genetics of autoinflammatory disease.

Dr Aksentijevich said the discovery of monogenic, autoinflammatory diseases has been instrumental in understanding the regulation of innate immune pathways in humans.

“A genotype-first approach to studying patients with primary immunodeficiencies, including SAIDs [systemic autoinflammatory diseases], has shed light on the spectrum of immune dysregulations and phenotypes associated with these diseases,” she said. “These discoveries have played a vital role in guiding targeted therapies and offering insights for new drug development; for example, IL-18 inhibitors and RIPK1 inhibitors.”

Dr Aksentijevich explained that SAIDs are inherited or acquired diseases of innate immunity resulting from antigen-independent hyperactivation of immune pathways and excessive systemic or organ specific inflammation. They are predominantly mediated by myeloid cells, such as monocytes, macrophages, neutrophils, and dendritic cells, she added. SAIDs are collectively rare diseases, but have provided important insights on the regulation of innate immune responses.

She went on to discuss the rare hereditary autoinflammatory disease TRAPS or TNFR1-associated periodic syndrome, also known as ‘Hibernian Fever’, with over 200 patients reported in the literature. Dr Aksentijevich noted gene discoveries in the area, outlining that there are over 60 genes linked to monogenic SAIDs.

“Autoinflammatory diseases are caused by loss of function mutation(s) in genes that suppress inflammation or by a gain of function mutation in genes that propagate inflammation,” she outlined. “The net effect is that these mutations result in a gain-of-function in various inflammatory pathways. The immune activation occurs spontaneously or with triggering (stress, temperature, infection, vaccination).”

Autoinflammatory diseases – including ‘Familial Mediterranean Fever’; deficiency of ADA2 (DADA2); VEXAS syndrome; haploinsufficiency of A20 (HA20); and RELA haploinsufficiency – are often characterised by recurring episodes of fever and chronic systemic inflammation, and have a variety of skin, musculoskeletal, central nervous system, and haematological abnormalities.

Mechanistically, she explained, these diseases are caused by aberrant activation of immune sensors, dysregulation in cell death pathways, dysregulation in post-translational ubiquitin modifications, dysregulated protein trafficking/recycling, endoplasmic reticulum stress/unfolded protein responses, and a combination of the above dysregulations.

In patients with severe disease, combination therapy may be required, she advised. Treatment usually involves interleukin (IL)-1 inhibitors. 

Dr Matthew Colquhoun, Consultant in Rheumatology and General Medicine, Cork University Hospital, was the last speaker at the meeting. His talk was titled ‘IgG4-related disease (RD): Clinical insights and the expanding role of B-cell directed therapies’.

Dr Colquhoun began by explaining that IgG4-RD is a “chronic immune-mediated condition characterised by inflammation and fibrosis of multiple organs”. It can cause tumefactive lesions and organ dysfunction and is steroid responsive. He recounted the timeline of the discovery and recognition of IgG4-RD. The condition is associated with four dominant phenotypes: Pancreato-biliary; retroperitoneal/aortitis; head and neck limited disease; and Mikulicz/systemic, Dr Colquhoun stated.

IgG4-RD has a broad differential diagnosis. It should be suspected in patients with pancreatitis of unknown origin, sclerosing cholangitis, bilateral salivary and/or lacrimal gland enlargement, retroperitoneal fibrosis, orbital pseudotumor, proptosis, or a mass lesion in the pancreas, biliary tree, orbits, lungs, kidneys, major salivary gland, or lacrimal gland, he added. IgG4-RD is not generally associated with fever and no response to steroids is generally an exclusion criterion, he noted.

Steroids remain the standard of care for induction, but relapse rates are high with monotherapy. Rituximab alone is an option for induction, he added. Some form of maintenance is usually needed with a disease-modifying anti-rheumatic drug (DMARD), such as rituximab, and relapse is common if maintenance is discontinued.

Biopsies can be helpful in aiding diagnosis, he said, but he cautioned that a diagnosis of IgG4-RD cannot be made based on a lymph node biopsy and said histopathology is more important than immunostaining. However, classification is possible without a biopsy and with normal IgG4 levels. Investigations can include urinalysis, serology, PET scan, organ-specific cross-sectional imaging, and biopsy.

Flares and relapses are common with steroid monotherapy, at over 40 per cent, while flares with rituximab monotherapy in the first year are also at about 40 per cent, Dr Colquhoun stated.

He presented evidence outlining the central role of B-cells in IgG4 pathogenesis and noted optimism about anti-CD19 B-cell therapy, based on pathophysiological rationale for a more durable effect. He mentioned that inebilizumab is the first US Food and Drug Administration approved treatment for IgG4-RD, but it is not yet available in Ireland.

At the close of the meeting, a gift was presented to outgoing ISR President Dr John Ryan on behalf of the Society’s board by newly elected President Dr Andrew Cairns, Consultant Rheumatologist, Belfast. Dr Cairns is the first President based in the North of Ireland since Dr Gary Wright in 2012.