Primary immune regulatory disorders (PIRD)

Overview

Primary immune regulatory disorders (PIRD) are characterized by a disturbance of immune tolerance and excessive inflammation. Inflammation in the gastrointestinal (GI) tract presenting as colitis (inflammation and ulcers of the bowel wall of the colon) and enteropathy (inflammation of the bowel, especially the small bowel) is a common presentation of PIRD that can significantly affect the quality of life in individuals with PIRD. Colitis can be the presenting manifestation of an underlying broader immune dysregulation (abnormality or impairment in the regulation of some part of the immune system), or it could develop later in the disease course. 

Other types of broader immune dysregulation include multi-system autoimmune conditions, such as low blood cell counts, thyroid failure, pancreatic failure, and arthritis. Lymphoproliferation (excessive lymphocyte production) and susceptibility to infections can co-exist or develop later in the disease course. 

It is important to identify individuals who have colitis or enteropathy as the presenting manifestation of PIRD, as it can help in both early identification and initiation of treatment. This approach can result in better control of disease. Very early onset inflammatory bowel disease (VEO-IBD) is common in this population, but the age of onset should not be the only reason for initiation of immune and genetic evaluation to identify underlying PIRD in individuals with inflammatory bowel disease. 

Clinical presentation

Colitis as a presentation of underlying immune dysregulation can have a varied presentation with regard to age of onset, severity, and pathology findings. Though several of PIRDs present at a younger age with infantile-onset (less than two years) or VEO-IBD (less than six years), a significant proportion of them present with colitis after age 6. Colitis in these individuals can have a slow, gradual onset with frequent small-volume bloody and mucousy diarrhea. Due to the slow onset, it is common for these individuals to have been evaluated for allergic colitis and to have had multiple formula changes for presumed allergic colitis. GI inflammation resulting in perianal fistula can be seen in individuals with IL-10 and IL-10R signaling defects, X-linked inhibitor of apoptosis protein (XIAP) deficiency, and CGD.

On the contrary, the clinical presentation of severe enterocolitis in infants is usually much more dramatic. There is typically explosive large-volume watery diarrhea. This presentation is common in infants with IPEX and IPEX-like disorders. Biopsy findings include villous atrophy and apoptotic enterocolitis.

In addition to colitis, other autoimmune symptoms of PIRD include autoimmune endocrinopathy (such as type 1 diabetes), autoimmune cytopenia (such as immune thrombocytopenia), and lymphoproliferation (generally manifests as enlarged lymph nodes, liver or spleen). 

Furthermore, the presence of unusual or difficult-to-treat infections can be another associated symptom of PIRD. Evaluation of underlying PIRD should be considered if colitis or enteropathy is associated with autoimmune disease or lymphoproliferative disorders, fistula formation, non-responsiveness to first and second-line IBD therapy, recurrent fevers, or difficult-to-treat eczema.