Immune effector cell (IEC) therapies, including chimeric antigen receptor (CAR) and T cell receptor (TCR) therapies, have opened a new chapter in cancer therapeutics.1 Anti-CD19 CAR-T cell therapies (such as axicabtagene ciloleucel, tisagenlecleucel, brexucabtagene autoleucel, and lisocabtagene maraleucel) have shown clinical benefits and have recently been approved by the U.S. Food and Drug Administration for diffuse large B cell lymphoma, mantle cell lymphoma, and acute lymphoblastic leukemia. However, IEC therapy can cause toxicities including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).1 CRS is the most common toxicity of IEC therapy, and its clinical manifestations include fever, tachycardia, hypotension, dyspnea, and organ dysfunctions. Inflammatory cytokines secreted from activated T cells and bystander immune cells including interleukin (IL)-6, interferon gamma (IFNγ), and granulocyte-macrophage colony stimulating factor (GM-CSF) are thought to play a critical role in CRS.2 ICANS is another toxicity of IEC therapy. Patients with ICANS have various neurologic symptoms including delirium, hallucination, cognitive dysfunction, and/or memory deficits, seizures, ataxia, and encephalopathy.1 The underlying pathogenesis of ICANS is elusive. Treatment for IEC therapy toxicities includes supportive care and immunosuppressants such as tocilizumab, an IL-6 receptor blocker).1 Of note, due to concerns of IEC suppression, steroids are frequently reserved as a second-line therapy for CRS refractory to tocilizumab.1 3 4

Pseudogout, induced by the deposition of calcium pyrophosphate dihydrate (CPPD) crystal, is an autoinflammatory disorder.5 The innate immune system and inflammasomes are known to play an essential role in its pathogenesis.5 Here, we report the first case of newly developed, crystal-proven pseudogout arthritis after infusion of MAGE A4 directed TCR T cells. The patient developed pseudogout arthritis along with CRS and ICANS. Interestingly, tocilizumab, which was used to treat the CRS and ICANS, also worked for the pseudogout arthritis. In parallel, we performed immunoprofiling of the synovial fluid obtained at the pseudogout flare.

Flow cytometry revealed that myeloid cells were most dominant major immune cell subsets in the synovial fluid (94.6% within live single cells) (figure 1A,B). The effector memory population was increased within both CD4⁺ and CD8⁺ T cells, suggesting they may be involved in the pathogenesis of the pseudogout arthritis in our case (figure 1C).

Given the central role of CD4⁺ T cells in immune responses, we focused on CD4⁺ T cells (figure 1D,E). The most abundant CD4⁺ T cell subset was CXCR5^- CD4⁺ effector T cells (54.5% within live CD4⁺ T cells) (figure 1D). Intracellular staining of CD4⁺ T cells showed predominance of IFNγ producing CD4⁺ T helper 1 (Th1) cells and IL-17 producing CD4⁺ T helper 17 (Th17) cells (49.0% and 22.6% within CD4⁺ T cells, respectively) (figure 1E). Multiplex analysis of the SF supernatant revealed the significant levels of IL-6, a key cytokines for Th17 cell differentiation, function, and plasticity (table 2).9

To the best of our knowledge, this is the first report of a case of newly developed, crystal-proven, pseudogout arthritis associated with CRS/ICANS after cell therapy. Of note, the patient’s pseudogout flare was resolved with tocilizumab. Our clinical observation is particularly important as steroids, the first-line therapy for pseudogout arthritis, are frequently avoided for the treatment of IEC-associated toxicities due to their potential lymphocytolytic activity.1 3 4 10 Immunoprofile of synovial fluid revealed the dominance of Th1 and Th17 cells with abundant IL-6.

Innate immune cells, primarily neutrophils and macrophages, are pivotal in the pathogenesis of pseudogout arthritis. Macrophages identify and phagocytose CPPD crystals, activating Nod-like receptor protein inflammasomes, with subsequent secretion of IL-1β, a potent inflammatory cytokine.11 In CRS, inflammatory cytokines secreted from the CAR-T cells can activate bystander immune cells, including macrophages, monocytes, and dendritic cells, with subsequent production of IL-6.12 IL-6 is known to be important for the differentiation, function, and survival of Th17 cells, which are a subset of CD4⁺ T cells involved in many autoimmune diseases.8 9 Interestingly, the proportion of Th17 cells in the synovial fluid in our case was substantially higher than what has been previously reported in classical inflammatory arthritis.13 Thus, it is plausible that, in our case, inflammatory cytokines activated bystander macrophages, which secreted IL-6, thus contributing to Th17 differentiation, function, and survival. In turn, these Th17 cells enhanced recruitment of neutrophils to the site of the CPPD crystal deposition. Taken together, we speculate that in addition to IL-1β induced by the CPPD crystal, an IL-6-Th17-neutrophil axis played a critical role in the pathogenesis of CPPD arthritis in our patient. This hypothesis is supported by the clinical observation that the patient’s pseudogout arthritis was resolved completely with tocilizumab. We show our hypothesis graphically in the figure 1F.

This is the first case reporting pseudogout arthritis in a patient who developed CRS and ICANS after T cell therapy. Importantly, pseudogout arthritis of our patient was resolved with tocilizumab. Because IEC therapy is being increasingly used in various cancers, there may be an increased recognition of CPPD arthritis in patients undergoing IEC therapy, and clinicians, including hematologists, oncologists, and rheumatologists, should be aware that IEC might be associated with the development of arthritis. Immunophenotypic analyses in our case suggest the contribution of a feed-forward loop between macrophages, neutrophils, and Th17 cells in the joint inflammation. Comprehensive analyses of more cases and control samples are warranted to understand the underlying mechanisms of pseudogout arthritis and its potential association with IEC therapy.