Background

By targeting T cell inhibitory molecules and reinvigorating exhausted T cells, immune checkpoint inhibitors (ICIs) have opened the new chapter in cancer treatment [1]. Types of ICIs currently approved include cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death ligand-1 (PD-L1) inhibitors [2]. Despite their clinical benefits, ICIs have distinct toxicity, causing a myriad of immune-related adverse events (irAE). Inflammatory arthritis following ICI therapy has been reported and is thought to be primarily autoimmune, although its etiology remains unclear [3–7], to date, no cases of crystal arthritis following ICI therapy have been reported.

Crystal arthritis are autoinflammatory disorders, and inflammasome and innate immune system play key roles in their pathogenesis [8]. Gout and pseudogout are the two most common types of crystalline arthritis. We report the first case of crystal-proven pseudogout after treatment with nivolumab, a PD-1 inhibitor. The patient had recurrent pseudogout flares after each nivolumab infusion. After initiating treatment with prophylactic colchicine, the patient well tolerated several additional nivolumab infusions. In parallel, we performed immunoprofiling of the synovial fluid obtained at each flare.

Case presentation

A 63 year old male with renal cell carcinoma underwent nephrectomy in 2015. He was under active surveillance until 2017, when he presented with metastatic disease in lymph nodes and lungs. The patient received nivolumab combined with ipilimumab, a CTLA-4 inhibitor, for 3 months followed by nivolumab monotherapy at a dose of 250 mg every 2 weeks. After 6 months of treatment, he developed immune-related type I diabetes, starting insulin, and continued immunotherapy. After receiving 14 infusions of nivolumab, 253 days after the first infusion, he developed acute left knee pain and swelling and was referred to the rheumatology clinic. Patient denied any prior similar episodes, but had a remote history of injury to his left knee, decades before, with ligament damage, for which he underwent arthroscopy.

Past medical history included hypertension, hypothyroidism and stage 2 chronic kidney disease, all diagnosed prior to immunotherapy. He had no history of recent trauma. One of his children had gout.

Physical exam revealed a large effusion in the left knee with erythema, tenderness, and limited range of motion. Arthrocentesis was performed and synovial fluid analysis showed 6715 white blood cells per μL, 72% of neutrophils, and numerous intracellular and extracellular calcium pyrophosphate dihydrate (CPPD) crystals (Table 1). Gram, acid-fast bacilli (AFB), and fungal stains, and cultures were negative. Anti-nuclear antibody, rheumatoid factor, and anti-cyclic citrullinated peptide (CCP) antibody were negative. Knee x-ray showed tricompartmental degenerative changes without fractures or bony metastases. Although very subtle, the x-ray showed chondrocalcinosis of fibrocartilage, hyaline cartilage and suprapatellar bursal synovium. Patient received an intra-articular injection of 40 mg triamcinolone, with an excellent response. Nivolumab was held, and restarted 3 weeks later as the patient had complete resolution of his left knee arthritis. A few days after the infusion, the patient had another flare of left knee pain and swelling. Knee arthrocentesis followed by intra-articular triamcinolone injection was performed with an excellent clinical response within 2 weeks. Synovial fluid again showed CPPD crystals. Two weeks later, after complete resolution, nivolumab was resumed, however, once again, a few days later, he developed left knee arthritis with CCPD crystals in the synovial fluid, and patient received intra-articular triamcinolone. Of note, his thyroid-stimulating hormone (TSH) levels were elevated during the 2nd and 3rd pseudogout flares. Tumor staging showed stable disease, and the patient decided to continue nivolumab therapy despite the recurrent pseudogout flares. He initiated colchicine 0.6 mg orally daily as prophylaxis. After resolution of his knee symptoms, he resumed nivolumab treatment. Patient has continued nivolumab treatment with colchicine prophylaxis and has received three additional nivolumab infusions at the same dose without pseudogout flares. He is now receiving nivolumab 480 mg monthly with good tolerance and only mild pain after the infusions. As of last follow-up he had minimal knee effusion with no pain, tenderness, or limitation in the range of motion. He was able to ambulate and perform activities of daily living. He has had one additional episode of left knee arthritis, but much milder than previous ones, and no arthrocentesis was performed. His magnetic resonance imaging (MRI) of the knee showed primarily partial meniscal tears and damage to his anterior cruciate ligaments.

Discussion and conclusions

We report the first case of crystal-proven pseudogout after ICI treatment. After having received several infusions of nivolumab over 35 weeks with no articular adverse events, the patient developed recurrent pseudogout flares, about a week to 10 days after each infusion. Notably, with colchicine prophylaxis, he was able to tolerate subsequent infusions without acute recurrence, and only mild symptoms. The proportion of inflammatory IL-17-producing CD4⁺ T cells and amount of IL-17 were notably increased in synovial fluid with every recurrent flair, and correlated with the increase in number of synovial neutrophils, suggesting a potential role of Th17 cells in neutrophil recruitment and neutrophil-driven inflammatory pathways resulting in pseudogout arthritis induced by immune checkpoint inhibitor therapy.

We and others have reported cases of immune-related arthritis in patients receiving irAE [3–7]. This type of arthritis can involve both large and small joints, and is more commonly seen in patients receiving PD-1 inhibitors, rather than CTLA-4 inhibitors. Rheumatoid factor and anti-CCP antibody are often negative; however, it has been assumed that these cases may represent autoimmune events triggered by the up-regulation of the immune system induced by ICI [14]. To date no cases of crystal arthritis after ICI treatment have been reported. Most studies on the pathophysiology of crystal arthritis have studied gout, rather than pseudogout, but it is thought that the triggering inflammatory mechanisms are similar for both conditions. Crystal arthritis is primarily a neutrophil-driven autoinflammatory disorder with no apparent role for adaptive immunity [15], while ICI mechanism of action primarily reactivates T cells [1]. Thus, our case suggests a potential impact of inflammatory T cells on the initiation and progression of crystal arthritis in patients receiving ICI.

The cells mostly studied in crystal arthritis are neutrophils and macrophages. Macrophages sense and phagocytose crystals, activating NLRP inflammasome with subsequent secretion of pro-inflammatory cytokines, especially IL-1β and tumor necrosis factor (TNF) α [16–18]. In addition, CPPD crystals bind to Toll–like receptor (TLR) 2 and 4 that leads to NF-kB activation and release of cytokines, TNFα, IL-6, and IL-8. Secretion of IL-1β, TNFα, IL-6, and IL-8 by monocytes increases expression of adhesive molecules on endothelial cells that attract neutrophils to the site of crystal deposition [19]. Recently, Pang et al. showed that CPPD crystals induce formation of neutrophil extracellular traps (NETs) which are associated with both autophagy and IL-1β production [20]. Of note, neutrophil cytoplasts, detected only after the formation of NETs [21], induce Th17 differentiation in severe asthma [22]. It is plausible that macrophage and neutrophil derived cytokines such as IL-6 and IL-1β may have contributed in our patient to Th17 differentiation. In turn, through IL-17, Th17 cells enhance endothelial expression of neutrophilic chemokines C-X-C chemokine ligand (CXCL) 1 and CXCL2, and neutrophil influx to the sites of inflammation.

Interestingly, the patient successfully resumed nivolumab treatment while on colchicine prophylaxis. By inhibiting tubulin assembly and suppressing microtubule formation, colchicine inhibits cell proliferation, mainly in neutrophils in pseudogout [19]. Colchicine also inhibits formation of inflammasome and decreased IL-1β secretion by CPPD-stimulated macrophages [16]. In addition, colchicine may have had direct or indirect effects on T cell activation, differentiation and memory T cell responses.

Endocrine and metabolic diseases including diabetes, hypothyroidism, hyperparathyroidism, hypomagnesemia, hypophosphatemia, and hemochromatosis are known risk factors for pseudogout arthritis [23]. Interestingly, our patient had hypothyroidism prior to the immunotherapy, and immunotherapy-induced type I diabetes, which may have contributed to his pseudogout arthritis.

This is the first case reporting pseudogout arthritis after ICI. Crystal arthritis may occur more frequently in these patients, and may be underecognized by both oncologists and rheumatologists, as the attention has been primarily on de novo presenting as an irAE, with a possible autoimmune mechanism. We expect our report will lead to increased recognition of crystal arthritis in patients undergoing cancer immunotherapy, and be included in the differential diagnoses. Immunophenotypic analyses suggested contribution of a feed-forward loop between Th17 cells and neutrophils in the joint inflammation. Comprehensive analyses with additional cases and control samples will be needed to further describe this newly recognized ICI-induced adverse event.