PERSONALISED IMMUNOLOGY IN THE MANAGEMENT OF COMPLEX AUTOIMMUNITY

P PURI1, G WALTERS1,3, K GIBSON1, A COOK2, D FULCHER3, C VINUESA2,3, SJIANG1,2,3
1The Canberra Hospital , Canberra City., Australia, 2Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Canberra City , Australia, 3Centre for Personalised Immunology, NHMRC Centre for Research Excellence, Canberra city,  Australia

A 72-year-old male presented with severe hypophosphatemia, hypokalaemia and hypomagnesaemia associated with recurrent pathological fractures. His background included a steroid-dependant eosinophilia-associated autoimmune disease (EAAD), associated with hypogammaglobulinaemia. Investigations demonstrated hyperphosphaturia (85mmol/24 hours) with normal renal function, parathyroid hormone (PTH) and 25- and 1,25-dihydroxycholecalciferol levels. Serum fibroblast growth factor (FGF23) levels ranged between 56 – 900ng/L suggestive of tumour-induced osteomalacia (TIO). Venous sampling and DOTATATE CT-PET were non-diagnostic. Aside from persistent eosinophilia, autoimmune serology was negative.
Treatment: Phosphate was corrected with parenteral phosphate (dose 80mmol/12hr) and calcitriol (3ug/daily). The patient was trialled on methotrexate, hydroxyurea, and secukinumab with limited clinical efficacy.  Despite normalization of eosinophilia by mepolizumab he remained prednisolone dependant requiring 15mg/day to maintain EAAD remission. Due to the severity of his autoimmune disease and steroid dependency, the patient underwent immunophenotyping and exome sequencing through the Canberra Hospital Glomerulonephritis clinic and ANU Centre for Personalised Immunology. Immunophenotyping demonstrated an increase in CD8+ T cells (61.1%vs 36.8% (58.5-63.8) of CD3+ in healthy controls (HC) p=0.005) and T regulatory cells (Tregs) (CD3+CD4+CD25+CD127-) (17.05 vs 5.54 (4.65-5.54) HC, p=<0.0001). CD8+ subsets demonstrated reduced naïve CD8+ (CD3+CD8+CCR7+CD45RA+) (8.5% vs 46.7 (37.8-58.8) p=0.0009) and expansion of CD8+ TEMRA (CD3+CD8+CCR7-CD45RA+) (66.4% vs 13.9 (11.1 – 19.6), p<0.0001) suggesting a state of chronic activation. We commenced tacrolimus aiming levels between 5-7ng/ml to control CD8+ activity. 2 months after initiation the patient was tapering on 9mg prednisolone with no inflammatory arthritis. Repeat immunophenotyping demonstrated a decline in Tregs (17.05 to 8.5% post-treatment) and CD8+ TEMRA (66.4 – 57.2% post-treatment).
Discussion: Immunophenotyping and genome sequencing may assist in individualising aetiology, pathophysiology and therefore therapeutic targets in difficult to treat or undifferentiated autoimmune disease.


Biography:
I am a first year Renal trainee at the Canberra hospital. I have an interest in renal immunology and transplantation. I hope to undertake more research in these fields over the course of my training both in a lab and clinical setting.

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