Background/Purpose: Signaling of most cytokine receptors occurs through the JAK-STAT pathway. This is true of cytokines linked to the etiology of systemic lupus erythematosus (SLE) and Sjogren’s syndrome (SS), such as type I interferon (IFN-I), IFNg, and IL-6. Thus, the JAK-STAT pathway is a potential target for the treatment of these diseases. IFN-I is of particular interest because a majority of SLE and SS patients have an IFN signature suggesting that levels of IFN are high in these patients. SLE is ameliorated in mice lacking the receptor for IFN-I (IFNAR) indicating that this cytokine is essential to the development of disease. In human SLE, blocking IFN-I binding to IFNAR with an anti-IFNAR mAb was efficacious in a phase 2 clinical trial in SLE patients that exhibited a high IFN signature. We show here that prophylactic and therapeutic treatment with a JAK1-selective inhibitor prevents and reverses disease in lupus-prone mice.

Methods: NZB/W-F₁ mice were prophylactically or therapeutically administered a JAK-1 inhibitor daily by gavage. Prophylactic treatment of NZB/W-F₁ mice began at 26 weeks of age, while therapeutic treatment was initiated after mice developed high proteinuria. Proteinuria was monitored weekly by urinalysis, and at study termination blood and spleen cells were analyzed by flow cytometry. Additionally, histological and gene transcription analyses of kidney, spleen, and salivary glands were performed.

Results: Prophylactic and therapeutic administration significantly impacted the number of splenic naïve B cells, germinal center B cells and plasmablasts. It also impacted splenic CD4 T cells, but not CD8 T cells. Daily administration of inhibitor prophylactically blocked development of proteinuria and extended survival in NZB/W-F₁ mice. Most significantly, JAK1 inhibition reversed established, severe proteinuria and extended survival. In agreement, the kidneys of therapeutically treated mice exhibited reduced inflammation compared to control mice, and the kidney and blood exhibited a lower IFN-I signature compared to controls. JAK1 inhibition also prevented a loss of saliva production and salivary gland inflammation.

Conclusion: JAK1 inhibition is efficacious in preventing the onset of nephritis and sialadenitis, and can reverse already ongoing nephritis in NZB/W-F₁ mice. Resolution of ongoing nephritis results in low or normal urine protein levels. Thus, JAK1 inhibition may be an efficacious therapeutic strategy in the treatment of SLE and SS.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/prophylactic-and-therapeutic-administration-of-a-jak1-selective-inhibitor-blocks-and-reverses-nephritis-and-sialadenitis-in-nzbw-f1-mice/