First use of tofacitinib to treat an immune checkpoint inhibitor-induced arthritis Kieran Murray , 1 Achilleas Floudas, 1,2 Ciara Murray, 3 Aurelie Fabre, 3 John Crown, 3 Ursula Fearon, 1,2 Douglas Veale 1,3 Case report
1 EULAR Centre for Arthritis and Rheumatic Disease, St. Vincent’s University Hospital, Dublin, Ireland 2 Molecular Rheumatology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland 3 Pathology, Oncology and Medicine, University College Dublin, Dublin, Ireland
added, but again there was minimal clinical response. Given the poor response to the conventional antirheu- matic medications, treatment with targeted therapies were considered. Tofacitinib effectively reduces inflam- mation in synovial tissue, especially in targeting patho- genic CD4+ Tcells as demonstrated in the biopsy, in addition to a potential rapid onset of action (<2 weeks), 5 the patient consented to off-licence treatment with tofacitinib at a dose of 5mg two times per day. Initially, severe metacarpal joint synovitis was apparent, and there was a dramatic reduction in erythema and swelling following tofacitinib treat- ment (figure 1A). A rapid decrease of tender joint count, swollen joint count, C-reactive protein (CRP) and a DAS28-CRP (figure 1B) indicative of disease remission were also observed. Additionally, proximal muscle strength improved from 4/5 to 5/5 in all limbs. At 2 weeks, the patient had a dramatic clinical response. He entered complete clinical disease remission (DAS28-CRP <2.6) at week 20. INVESTIGATIONS Routine investigations revealed a highly elevated CRP (217mg/dL), a negative rheumatoid factor (1.2IU/ mL) and anticitrullinated protein antibodies (1.7U/ mL), but significantly raised antinuclear antibody titre
SUMMARY Immune checkpoint inhibitors have revolutionised cancer treatment; however, immune-related adverse events do occur, with up to 7% developing inflammatory arthritis. Common rheumatoid arthritis therapies such as methotrexate, prednisolone and biologics have been used to treat this arthritis in small, uncontrolled case series with varying success. In this case of personalised medicine, we report the first use of tofacitinib, a small molecular inhibitor of the Janus kinase-signal transducer and activator of transcription pathway, to treat checkpoint inhibitor-related inflammatory arthritis. This resulted in a rapid clinical response and complete, sustained remission of the arthritis with associated marked reduction in synovial molecular and cellular immune response. BACKGROUND Immune checkpoint inhibitors (ICIs) have dramatically improved the prognosis of many cancers. 1 2 ICI-related adverse events (irAEs) include systemic inflammatory reactions, most often affecting the skin and gastrointes- tinal tract. Inflammatory arthritis is reported in up to 7% of ICI-treated patients. 3 4 We report the clinical and immunological characteristics of ICI-induced inflam- matory arthritis in a patient with pulmonary adenocar- cinoma and successful, sustained remission following tofacitinib therapy. CASE PRESENTATION A 56-year-old man presented in 2018 with haemop- tysis and changes in cognitive function. He was diag- nosed with programmed death-ligand 1 (PD-L1) positive pulmonary adenocarcinoma with temporal and parietal lobe brain metastases. He reported a sister with rheumatoid arthritis. The lung cancer was treated successfully with the programmed cell death protein 1 (PD-1) inhibitor, pembrolizumab, and he received stereotactic radiotherapy for the metastatic brain lesions. Six months after commencing pembrolizumab, the patient developed acute pain and swelling in the small joints of his hands and in his knees consistent with a polyarthritis. The patient had no other irAEs. Given his complete tumour response and significant irAEs, pembrolizumab treatment was stopped on the advice of the oncology team. However, the joint symptoms remained severe and incapacitating. Treatment with etoricoxib (COX-2 specific inhibitor, 90mg once daily), weekly oral methotrexate 10mg and sulfasala- zine 1g two times per day was commenced but with little clinical benefit. Prednisolone 20mg daily was then
Correspondence to Professor Douglas Veale; d ouglas.veale@u cd.ie
Accepted 19 January 2021
Figure 1 Clinical course and remission before and after treatment with tofacitinib. Images of joint inflammation with bilateral metacarpophalangeal joint synovitis (arrows) before and after treatment with tofacitinib (A). Reduction in TJC, SJC, DAS28-CRP and CRP scores from commencement of tofacitinib treatment at time 0 and remission at week 31 (B). Dashed red line (DAS28-CRP) indicates clinical remission (>2.6) at week 20. CRP, C- reactive protein; SJC, swollen joint count; TJC, tender joint count.
To cite: Murray K, Floudas A, Murray C, et al . BMJ Case Rep 2021; 14 :e238851. doi:10.1136/bcr-2020- 238851 © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
Murray K, et al . BMJ Case Rep 2021; 14 :e238851. doi:10.1136/bcr-2020-238851
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