Use of Upadacitinib to Treat a Severe Flare-Up of Rheumatoid Arthritis During Anti-PD-1 Immune Checkpoint Inhibitor Therapy for Stage IV Squamous Cell Carcinoma of the Lung

Abstract

Background: Immune checkpoint inhibitor (ICI) therapy is becoming the standard of care for the treatment of advanced non-small-cell lung cancer. However, T-cell activation by ICIs frequently induces a flare-up of preexisting autoimmune diseases such as rheumatoid arthritis (RA). Janus kinase (JAK) inhibitors are increasingly used in the treatment of RA, but they could interfere with the efficacy of ICIs by inhibiting interferon signaling. Case Report: Here, we describe a case in which upadacitinib, a JAK1-selective inhibitor, was used to manage a severe RA flare-up occurring during ICI therapy with pembrolizumab, an anti-programmed cell death protein-1 antibody. A 54-year-old man with RA was diagnosed with grade IV lung squamous cell carcinoma. The patient had maintained RA remission for 4 years at the time of lung cancer diagnosis. After seven cycles of pembrolizumab therapy, the size of the primary tumor was markedly reduced, but a severe RA flare-up and organizing pneumonia (OP)-like pulmonary lesions occurred. Considering the severity of the flare-up, pembrolizumab was discontinued. Upadacitinib induced swift recovery from the RA flare-up and OP. Eleven months after the last pembrolizumab use, almost all metastatic lesions in the body had disappeared. We did not observe recurrence of lung cancer for more than 1 year during upadacitinib therapy. Conclusions: Upadacitinib could be a safe and effective option to treat severe RA flare-ups occurring during anti-PD-1 ICI therapy.

Keywords: Janus kinase inhibitor; immune checkpoint inhibitor; lung cancer; pembrolizumab; rheumatoid arthritis; upadacitinib.

Figure 1

Chest radiographs. (A) At lung cancer diagnosis, a large mass (yellow arrows) and pleural effusion (orange arrow) were observed in the right lung. (B) Five months after the start of chemotherapy and ICI therapy, the tumor size had reduced. (C) Eleven months after the last ICI injection, tumor expansion was not observed. ICI, immune checkpoint inhibitor.

Figure 2

PET-CT images at lung cancer diagnosis. (A) Multiple abnormal signals were observed. (B) A large mass with strong abnormal uptake was prominent in the right upper lobe of the lung. Abnormal uptakes were also detected in pleural effusion and nodules in the right lung and multiple bones (breastbone and vertebral bodies). (C) High metastatic activity was observed in hilar and mediastinal lymph nodes on both sides. (D) Multiple bone metastases were detected in vertebral bodies, bilateral ribs, and bilateral iliac bones. (E) Abnormal uptake was detected in the right adrenal gland. PET, positron emission tomography; CT, computed tomography; ICI, immune checkpoint inhibitor.

Figure 3

Clinical course with relevant treatment. During upadacitinib therapy, the patient suffered from COVID-19 infection (23 August 2023), but his symptoms were mild. The red line represents serum CRP values and the blue line represents CDAI values. TCZ, tocilizumab; LC, lung cancer; CRP, C-reactive protein; CDAI, clinical disease activity index; COVID-19, coronavirus infectious disease-19.

Figure 4

Chest HRCT scans. (A) At the onset of knee arthritis, a small consolidation appeared in the right lower lobe (S6). (B) At the time the patient developed polyarthritis, patchy consolidations and ground-glass opacities spread from S6 to S10. (C) Two months after the start of UPA and Dex therapies, consolidation was improved but ground-glass attenuation remained. (D) Ten months after the start of UPA and Dex therapies, abnormal shadows completely disappeared. HRCT, high-resolution computed tomography; UPA, upadacitinib; Dex, dexamethasone.

Figure 5

PET and PET-CT images after ICI therapy. (A) PET images (not combined with CT), taken before and 15 months after the start of ICI therapy. Before the start of ICI therapy, multiple abnormal signals were observed (red arrowheads). (B) PET-CT image taken 15 months after the start of ICI therapy. Abnormal uptake diminished in the primary tumor and disappeared in other multiple lesions. (C) PET-CT image taken 15 months after the start of ICI therapy. Residual small uptake remained in the right hilar lymph node (red arrow). PET, positron emission tomography; CT, computed tomography; ICI, immune checkpoint inhibitor.