Background/Purpose: Autoinflammatory Type I Interferonopathies (IFNopathies) include STINGopathies (e.g., SAVI and COPA syndrome), proteasomopathies (e.g., CANDLE/Proteasome associated autoinflammatory syndrome (PRAAS), and oligonucleotidopathies (e.g., AGS: Aicardi-Goutières syndrome).  High dose JAK inhibition (JAKi) is the current mainstay of treatment, but normalization of IFN-I mediated inflammation is only achieved in milder forms of CANDLE. The recent use of the anti- type I IFNAR monoclonal antibody, anifrolumab, achieves control of the IFN score and allows tapering of JAKi doses. We assessed impact of combination treatment on viral titers.

Methods: A prospectively followed cohort of 30 patients, enrolled in natural history study NCT02974595, (age 2-44, median 18 yrs), 40% female, with IFNopathies: proteasomopathies (n=14), STINGopathies (n=12), and oligonucleotideopathies (n=2), and undiff. IFNopathies (n=2) received the JAKi, baricitinib for 1-12 yrs, median 6 yrs. All receive VZV prophylaxis are monitored for infections and malignancies, BK viral loads in blood and urine; QuantiFEROn gold screening is performed yearly.

Results: The baricitinib dose ranged from 4 to12 mg daily, (median 7 mg/day or 0.3 mg/kg/day). BK viral reactivation in urine developed in 19/30 (60%) on JAKi, with BK viremia in 8.  One 8 yo male with homozygous CANDLE caused by PSMB8 p.T75M, received baricitinib 12 mg daily for 3 yrs. Although under inflammatory control, he developed disseminated mycobacterium kansasii infection involving nasal mucosa, synovium, and spine. With Baricitinib reduction (6 mg daily), and anti-mycobacterial treatment for a year, the infection resolved. On the lower dose of baricitinib he has residual type I IFN mediated inflammation, immune-mediated anemia and thyroiditis.

A 23 yo patient, with AGS type 5, caused by biallelic SAMHD1 deletions, presented with MoyaMoya disease and strokes at the age of , received 8 mg baricitinib daily for 8 yrs, without achieving remission.  At age 21, she developed renal cell carcinoma and bladder cancer, requiring nephrectomy and cystectomy and multidrug resistance klebsiella urinary tract infections. Past treatment included cyclophosphamide. She had baseline BK viral reactivation in urine before starting baricitinib. Chronically elevated titers on baricitinib may have contributed to kidney and bladder cancer. AGS treatment was changed to anifrolumab, leading to inflammatory remission. Baricitinib dose reductions were now tolerated and improved response to treatment of infections.

In total, anifrolumab treatment in 12 additional patients (40%), allowed for baricitinib dose reduction by a median of 57% in 11 patients and discontinuation in one patient with acute BK mediated hemorrhagic cystitis.  BK viral load dropped in urine by a median 2.1 Log (1.9-8 Log10) and was cleared from blood in 4 pts.

Conclusion: Chronic high-dose JAKi exposure in IFNoapthy patients increases the risk of BK viral reactivation and may contribute to development of atypical infections. Chronic BK viruria may contribute to the development of bladder and kidney cancers. IFNAR blockade with anifrolumab allows tapering of JAKi and may be considered in these patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mycobacterial-infection-and-renal-and-bladder-malignancy-in-2-ifnopathy-patients-on-high-doses-of-jak-inhibitors/