Tofacitinib for the treatment of refractory immune checkpoint inhibitor-associated immune nephritis

Abstract

Immune checkpoint inhibitor (ICI)-associated immune nephritis or acute interstitial nephritis (AIN) is one of the rare but known complication of ICI therapy. Guidelines recommend treatment of ICI-associated AIN with steroids, then TNF-alpha inhibitor infliximab. However, some cases are refractory to these therapies, potentially due to insufficient cytokine blockade. This is the first case where a 65-year-old female with metastatic lung adenocarcinoma, requiring high maintenance doses of steroids for immune nephritis was treated with tofacitinib, an oral Janus kinase (JAK) inhibitor. Tofacitinib enabled successful steroid tapering and might be a therapy option for refractory immune nephritis.

Keywords: acute interstitial nephritis; immune checkpoint inhibitors; immune nephritis; immune-related adverse events; tofacitinib.

Figure 1:

(a) Treatment course of a patient with ICI-associated immune nephritis. The patient had an initial response to prednisone (gray columns) and infliximab (5 mg/kg dose, red arrow). Despite extended glucocorticoid therapy and repeated infliximab infusions, the patient required a high maintenance dose of prednisone. The addition of tofacitinib (5 mg daily) enabled prednisone tapering. Urine was collected before and after starting tofacitinib (asterixis). (b and c) Representative biopsy images. (b) Severe tubulointerstitial inflammation with numerous eosinophils and acute tubular injury [hematoxylin and eosin (H&E), 40×]. (c) non-necrotizing granuloma (black arrow) (H&E, 20×). (d) Cytokines associated with Janus kinase (JAK) signaling were analyzed in a urine specimen collected before starting tofacitinib (pre-tofacitinib, pink columns) and after starting tofacitinib (post-tofacitinib, blue columns). Abbreviations: IL, interleukin; IFN, interferon; A, alpha; B, beta; G, gamma; and CXCL, C-X-C chemokine ligand.