Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target inhibitory molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or its ligand, programmed cell death protein ligand 1 (PD-L1), and lead to immune activation in the tumor micro-environment. ICIs can induce durable treatment responses in patients with advanced cancers, but they are commonly associated with immune related adverse events (irAEs) such as rash, colitis, hepatitis, pneumonitis, and endocrine and musculoskeletal disorders. Almost all patients experience some form of irAE, but high grade irAEs occur in approximately half of those on combination therapy (eg, anti-CTLA-4 plus anti-PD-1), and up to one quarter receiving ICI monotherapy. Fatal irAEs occur in approximately 1.2% of patients on CTLA-4 blockade and 0.4% of patients receiving PD-1 or PD-L1 blockade, and case fatality rates are highest for myocarditis and myositis. IrAEs typically occur in the first three months after ICI initiation, but can occur as early as one day after the first dose to years after ICI initiation. The mainstay of treatment is with corticosteroids, but tumor necrosis factor inhibitors are commonly used for refractory irAEs. Although ICIs are generally discontinued when high grade irAEs occur, ICI discontinuation alone is rarely adequate to resolve irAEs. Consensus guidelines have been published to help guide management, but will likely be modified as our understanding of irAEs grows.

It was confirmed that mice bearing many transplantable tumors are infected with a virus-like agent which causes a 5- to 10-fold elevation in the plasma lactic dehydrogenase activity of infected mice without tumors. The agent is non-identical with the polyoma virus and without effect on adult rats and hamsters. Maximum titers of 109 to 1010 ID50 per ml of plasma were observed within 36 hours after infection. Subsequently the titer decreased to 105 to 107 ID50 per ml and remained constant thereafter. The plasma lactic dehydrogenase reached maximum activity about 96 hours after infection and remained elevated indefinitely. The virus was present in feces and in a variety of tissues and organs in relatively high concentrations. Liver and spleen yielded the highest titers.Five electrophoretically distinct forms (isozymes) of lactic dehydrogenase were separated from mouse tissues. Infection of mice resulted in an increase of the slowest migrating isozyme in the plasma. Liver, spleen, and erythrocytes were each found to contain only this isozyme while other tissues and organs contained mixtures of lactic dehydrogenase isozymes. The plasma of tumor-bearing mice contained more of the slowest migrating isozyme than infected mice without tumors.

Background. Checkpoint inhibitor therapy is widely known to cause a number of immune-related adverse events. One rare adverse effect that is emerging is eosinophilic fasciitis, a fibrosing disorder causing inflammatory infiltration of subcutaneous fascia. It is characterized clinically by edema and subsequent induration and tightening of the skin and subcutaneous tissues. The condition is rare, yet at our institutions we have seen four cases in the past 3 years. We describe our 4 cases and review 11 other cases reported in the literature. Case Presentation. We present four cases of eosinophilic fasciitis following treatment with programmed cell death protein 1 or programmed cell death-ligand 1 blockade. All patients had extremity involvement with characteristic skin changes ranging from peripheral edema to induration, tightening, and joint limitation. The patients had varying degrees of peripheral eosinophilia. In two of our patients, the diagnosis was made by full-thickness skin biopsy showing lymphocytic infiltration of the subcutaneous fascia, with CD4+ T cells predominating in one case and CD8+ T cells in the other. In the other two cases, the diagnosis was made on the basis of characteristic imaging findings in the context of clinical features consistent with the diagnosis. All four patients were treated with glucocorticoids with varying degrees of success; immunotherapy had to be discontinued in all four. Patients with advanced melanoma who experienced this adverse effect had either a partial response or a complete response to therapy. Conclusion. Eosinophilic fasciitis can occur as a result of checkpoint inhibitor therapy. Although a tissue diagnosis is the gold standard, imaging studies may facilitate the diagnosis in the presence of consistent clinical features, but a degree of suspicion is key to recognizing the condition early. Therapy requires a collaborative approach by oncology, rheumatology, and dermatology; physical therapy is an important adjunct in treatment. For advanced melanoma, it may be a good prognostic indicator. The Oncologist 2020;25:140-149 Implications for Practice: It is important for clinicians to recognize that eosinophilic fasciitis is a potential immune-related adverse event (irAE) as a consequence of immune checkpoint inhibitor therapy. The presentation is quite stereotypical; the diagnosis can be made by imaging in the absence of a full-thickness skin biopsy. Early intervention is important to limit morbidity. This irAE may be a good prognostic sign among patients with melanoma.

No abstract

IntroductionImmune checkpoint inhibitors (ICI) are a novel cancer therapeutic that have been successful in treating advanced malignancies; however, they also cause immune-related adverse events (irAE). Given that some irAE are clinically similar to traditional autoimmune diseases, autoantibodies have been suggested as possible biomarkers of irAE. However, there are very little data on autoantibody investigation prior to ICI. Our aim was to determine if specific baseline autoantibodies were associated with irAE and see if changes in autoantibody concentration corresponded with irAE development.MethodsThis study used data from an oncologic clinical trial of adaptive dosing combination ICI therapy in patients with advanced melanoma. Plasma was collected at baseline and 6 weeks after ICI initiation and tested in a microarray of 120 autoantigens commonly associated with autoimmune disease, as well as antinuclear antibody (ANA), rheumatoid factor (RF), and anti-cyclic citrullinated peptide antibody (anti-CCP). Autoantibody concentrations were compared between patients experiencing an organ-specific event versus not. Heatmaps, volcano plots and hierarchical clustering were used to determine autoantibody concentration differences among irAE patient clusters as defined by signal intensity of autoantibodies. Kaplan-Meier curves were created and a log-rank test was performed to assess differences in survival.ResultsThe microarray analysis demonstrated that patients who experienced specific irAE had fewer differentially expressed autoantibodies at baseline than those that did not have those specific irAE, and a greater fold change (FC) in antibody concentration from baseline to 6 weeks corresponded with specific irAE development. However, no autoantibodies were identified as being predictive of specific events. Time to first irAE was less than 6 weeks in 69% of patients, and these patients had less autoantibodies at baseline. Considering ANA, RF and CCP autoantibodies, there were no significant differences between the seropositive and seronegative patients in irAE development, severity, timing or survival.ConclusionPatients with low autoantibody concentrations at baseline as well as a greater FC in autoantibody concentration over 6 weeks developed more distinct organ-specific irAE. This may suggest differences in the balance of cellular immunity and humoral pathways that are relevant in the pathogenesis of irAE, though further investigation is needed.

Background: Immune-related adverse events (irAEs) from immune checkpoint inhibitors (ICIs) are sometimes associated with autoantibodies, but we do not know how frequently or whether these autoantibodies are present before ICI initiation. Our aim was to determine the positivity rate of autoantibodies in patients with organ-specific ICI-associated irAEs and determine their value as pretreatment biomarkers. Methods:We searched for all English, peer-reviewed publications from MEDLINE, Embase, and Cochrane Library through February 20, 2020, and included any publication describing patients with irAEs and reporting results of any autoantibody investigation. Three reviewers independently extracted data, and 1 reviewer verified all data for accuracy and quality of reporting. Results:We identified 515 publications. Most reports described endocrine, rheumatic, gastrointestinal/hepatic, and myositis/myasthenia/myocarditis irAEs. Autoantibodies were present in close to 50% of patients with ICI-associated endocrinopathies. Anti-BP180 was found in more than 50% of patients with skin irAEs. Antibodies were also common in patients with the triad of myositis/myasthenia/myocarditis including striational antibodies (49%), acetylcholine receptor antibodies (40%), and myositis-associated antibodies (27%). Only 11% of patients with arthritis had either rheumatoid factor or cyclic citrullinated peptide antibodies, and only 30% of patients with sicca had Sjögren antibodies. Autoantibodies were also relatively uncommon in patients with hepatitis (antinuclear antibody, 18%) and colitis (perinuclear antineutrophil cytoplasmic antibody, 19%). Some cohort studies analyzing pre-ICI seropositivity suggest there may be a role for autoantibodies as biomarkers of irAEs.Conclusions: Reported autoantibody positivity is high in irAEs involving the endocrine organs, skin, and muscle, but lower in irAEs affecting other organ systems. Autoantibody investigations in pre-ICI treatment patients have yielded mixed results regarding their utility as a biomarker of irAEs.

Immune checkpoint inhibitor (ICI) therapies that promote T cell activation have improved outcomes for advanced malignancies yet also elicit harmful autoimmune reactions. The T cell mechanisms mediating these iatrogenic autoimmune events remain unclear. Here we assayed T cells from joints of patients affected by ICI-induced inflammatory arthritis (ICI-arthritis), which can present clinically indistinguishable from rheumatoid arthritis (RA). Compared to the autoimmune arthritides RA and psoriatic arthritis (PsA), ICI-arthritis joints contained an expanded CD38hi CD127− CD8+ T cell subset that displays cytotoxic, effector, and interferon (IFN) response signatures. The abundance of CD38hi CD8 T cells in ICI-arthritis resulted from a limited number of clones that could be found proliferating in the joint. Exposure of synovial T cells to Type I IFN, more so than IFN-γ, induces the CD38hi cytotoxic phenotype. Relative to other CD8+ T cell subsets in the joints, the CD38hi population is distinct from a dysfunctional population and clonally most related to TCF7+ memory populations. Examination of synovial tissue from bilateral knee arthroplasty demonstrated considerable sharing of TCR clonotypes in the CD38hi CD8 T cell fraction from both knees. These results define a distinct CD8 T cell subset that may be directly activated by ICI therapy and mediate a tissue-specific autoimmune cellular reaction in patient joints.

Objective. To describe clinical features associated with cancer outcomes of patients with immune checkpoint inhibitor (ICI)-associated arthritis. Methods. Observational study of patients with ICI-arthritis enrolled in a single-center registry. Arthritis phenotype and activity, medications, and cancer status were recorded at every visit. We used descriptive statistic, and Kaplan-Meier curves using two-sided log-rank test and Cox regression analysis were used to identify factors associated with cancer progression-free survival (PFS). Results. Forty-two patients with ICI-arthritis were followed for a median (interquartile range [IQR]) of 7.4 (1.7, 14.7) months. Fifty-seven percent were female, 33% had melanoma, and 69% received anti-programmed death ligand 1 monotherapy. Median time from ICI initiation to arthritis onset was 2.8 (0.8, 11.2) months. Sixty-two percent had a rheumatoid arthritis (RA)-like small-joint presentation; 27% of all patients were rheumatoid factor and/or cyclic citrullinated peptide positive. Median (IQR) Clinical Disease Activity Index (CDAI) on presentation was 15 (8, 24); 62% required systemic glucocorticoids, 55% required disease-modifying antirheumatic drugs (DMARDs), and 69% had ongoing arthritis at 6 months. Arthritis led to ICI discontinuation in five patients. In univariate analysis, baseline CDAI, DMARD use, earlier arthritis onset, and longer duration of follow-up were associated with shorter PFS. In multivariable Cox regression analysis controlling for DMARD use and time to arthritis onset, CDAI was a significant predictor of cancer progression (hazard ratio 1.09, 95% confidence interval [CI] 1.00-1.19, P = 0.05) Conclusion. ICI-arthritis most commonly presents with an RA-like phenotype. High disease activity, as measured by CDAI, may portend cancer progression.