scholarly journals Anti-RA33 antibodies are present in a subset of patients with immune checkpoint inhibitor-induced inflammatory arthritis

2021 ◽  
Author(s):  
Laura Cappelli ◽  
Clifton O. Bingham III ◽  
Patrick M. Forde ◽  
Valsamo Anagnostou ◽  
Julie Brahmer ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Inflammatory Arthritis ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Demographic Data ◽  
Healthy Controls ◽  
Before And After ◽  
Early Inflammatory Arthritis ◽  
Serial Samples ◽  
Relationship Of

Abstract Background Patients with inflammatory arthritis (IA) associated with immune checkpoint inhibitor (ICI) treatment for cancer are typically seronegative for anti-CCP antibodies and rheumatoid factor, but little is known about the presence of other autoantibodies described in early inflammatory arthritis in this patient population. We investigated the prevalence and characteristics of anti-RA33 antibodies in patients with ICI-induced IA. Methods Anti-RA33 ELISAs were performed on sera from four groups of patients: 79 with ICI-induced IA, 52 with rheumatoid arthritis (RA), 35 treated with ICIs without IA during follow-up, and 50 healthy controls. Anti-RA33 positivity and titer, clinical and demographic data were compared across groups. Results Anti-RA33 antibodies were found in 9/79 (11.4%) patients with ICI-induced IA but in 0/35 patients treated with ICIs who did not develop IA (0%; p=0.04). Of the 9 patients positive for anti-RA33, two had sera available from before ICI treatment; anti-RA33 antibodies were present in both pre-ICI treatment. In RA patients, 7.7% were positive for anti-RA33 antibodies as were 2% of healthy controls. In ICI-induced IA, anti-RA33 antibodies were associated with anti-CCP antibodies (p=0.001). We found no statistically significant differences in other clinical characteristics in those with and without anti-RA33 antibodies, but we observed trends toward anti-RA33 antibodies being more common in women and those receiving prior radiation therapy. Conclusions Anti-RA33 antibodies are present in a subset of patients with ICI-induced IA and may be a biomarker for developing IA. Additional studies evaluating serial samples before and after ICI treatment will further establish the temporal relationship of these antibodies to IA development.

scholarly journals Association of HLA-DRB1 shared epitope alleles and immune checkpoint inhibitor-induced inflammatory arthritis

Rheumatology ◽  
2018 ◽  
Vol 58 (3) ◽  
pp. 476-480 ◽  
Author(s):  
Laura C Cappelli ◽  
Mehmet T Dorak ◽  
Maria P Bettinotti ◽  
Clifton O Bingham ◽  
Ami A Shah
Keyword(s):  
Immune Checkpoint ◽  
Inflammatory Arthritis ◽  
Immune Checkpoint Inhibitor ◽  
Shared Epitope ◽  
Checkpoint Inhibitor ◽  
Hla Class I ◽  
Hla Typing ◽  
Healthy Controls ◽  
European Descent ◽  
Allele Positivity

Abstract Objective To evaluate the frequency of HLA class I and II alleles associated with traditional forms of inflammatory arthritis in patients with immune checkpoint inhibitor (ICI)-induced inflammatory arthritis as compared with population controls. Methods High-resolution HLA typing was performed on 27 patients with ICI-induced inflammatory arthritis and 726 healthy controls. Genotyping at the shared epitope (SE) locus (HLA DRB1) was performed on 220 RA cases. Allele-positivity rates and frequency of having at least one SE allele were compared using Fisher’s exact test between ICI-induced inflammatory arthritis and healthy controls. Frequency of having at least one SE allele was also compared between ICI-induced inflammatory arthritis and RA cases. Results Twenty-six patients with ICI-induced inflammatory arthritis were of European descent, and one was African American. In those 26 patients, 16 (61.5%) had at least one SE allele, significantly different from healthy controls of European descent, in whom 299 (41.2%) had at least one SE allele (odds ratio 2.3, P = 0.04). The allele-positivity rate of DRB1*04: 05 was also higher in the ICI-induced inflammatory arthritis group. The ICI-induced inflammatory arthritis population and RA patients of European descent did not differ in frequency of having at least one SE allele, but ICI-induced inflammatory arthritis patients were more likely to be autoantibody-negative for RF and anti-CCP antibodies. Conclusion Patients with ICI-induced inflammatory arthritis of European descent were more likely to have at least one SE allele than healthy controls. Further studies are needed to validate these findings and investigate whether a unique immunogenetic framework increases risk for different immune-related adverse events.

scholarly journals A COMMON PITUITARY AUTOANTIBODY IN TWO PATIENTS WITH IMMUNE CHECKPOINT INHIBITOR-MEDIATED HYPOPHYSITIS: ZCCHC8

2020 ◽  
Vol 6 (4) ◽  
pp. e151-e160
Author(s):  
Amanda Leiter ◽  
Sacha Gnjatic ◽  
Mary Fowkes ◽  
Seunghee Kim-Schulze ◽  
Ilaria Laface ◽  
...  
Keyword(s):  
Pituitary Gland ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitor ◽  
Severe Fatigue ◽  
Metastatic Urothelial Cancer ◽  
Before And After ◽  
Serial Samples ◽  
First Time

Objective: Hypophysitis is an increasingly recognized adverse effect of immune checkpoint inhibitor (ICI) therapy for malignancy. However, the mechanisms through which ICIs induce hypophysitis are largely unknown. We aim to describe 2 cases of ICI-mediated hypophysitis and perform autoantibody profiling on serial samples from these patients to determine if common autoantibodies could be identified. Methods: We describe 2 cases of patients with metastatic urothelial cancer who received ICI therapy and subsequently developed severe fatigue, prompting a hormonal workup consistent with hypopituitarism. Patient 1 received the ICI ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4) and patient 2 received the ICI pembrolizumab (anti-programmed cell death protein 1). Both patients had serial seromic immune biomarker profiling using high-density protein arrays before and after developing hypophysitis. Once a common autoantibody was found, zinc finger CCHC-type containing 8 (ZCCHC8), we used immunohistochemistry to assess its presence in pituitary tissue. Results: Of a limited number of increased autoantibodies detected, those to ZCCHC8 were the only common antibodies to increase at least 3-fold post-hypophysitis in both patients. Using immunohistochemistry staining, we show for the first time that ZCCHC8 is expressed in pituitary gland tissue. Conclusion: Seromic profiling identified a common autoantibody, ZCCHC8, in 2 patients who developed hypophysitis on ICI therapy, and other serial autoantibody increases in each patient. These findings warrant validation in other cohorts to determine if the response is to self or tumor antigen, and may reveal novel insights into pituitary gland physiology and the pathogenesis of ICI-mediated hypophysitis.

Hydroxychloroquine is a safe and effective steroid-sparing agent for immune checkpoint inhibitor–induced inflammatory arthritis

2019 ◽  
Vol 38 (5) ◽  
pp. 1513-1519 ◽  
Author(s):  
Janet Roberts ◽  
Michael Smylie ◽  
John Walker ◽  
Naveen S. Basappa ◽  
Quincy Chu ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Inflammatory Arthritis ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Steroid Sparing

scholarly journals Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation

2019 ◽  
Vol 79 (3) ◽  
pp. 332-338 ◽  
Author(s):  
Tawnie J Braaten ◽  
Julie R Brahmer ◽  
Patrick M Forde ◽  
Dung Le ◽  
Evan J Lipson ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Inflammatory Arthritis ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Tumour Response ◽  
Cox Proportional Hazards ◽  
Immunomodulatory Treatment ◽  
The Impact

ObjectiveWe sought to investigate the long-term outcomes of patients who develop immune checkpoint inhibitor (ICI)-induced inflammatory arthritis (IA), to define factors associated with IA persistence after ICI cessation, the need for immunosuppressants and the impact of these medications on underlying malignancies.MethodsWe conducted a prospective observational study of patients referred for IA associated with ICIs. Patients were recruited from June 2015 to December 2018. Information was obtained at the baseline visit, and follow-up visits occurred at varying intervals for up to 24 months from ICI cessation. Kaplan-Meier curves were developed to characterise IA persistence. Cox proportional hazards models were used to assess the influence of various factors on IA persistence. Logistic regression was used to evaluate the impact of IA treatment on tumour response.ResultsSixty patients were monitored with a median follow-up after ICI cessation of 9 months. A majority (53.3%) had active IA at their most recent follow-up. IA was less likely to improve in those with longer duration of ICI use, in those receiving combination ICI therapy, and in patients with multiple other immune-related adverse events. Tumour response did not appear to be impacted by immunosuppression. Although not statistically significant, persistent IA was correlated with a better tumour response (complete or partial response).ConclusionICI-induced IA can become a long-term disease necessitating management by rheumatology for immunomodulatory treatment. Importantly, the use of immunomodulatory treatment has not been shown to impact cancer outcomes in this study.

scholarly journals Metastatic joint involvement or inflammatory arthritis? A conundrum with immune checkpoint inhibitor-related adverse events

Rheumatology ◽  
2018 ◽  
Vol 57 (4) ◽  
pp. 760-762 ◽  
Author(s):  
Jemima Albayda ◽  
Clifton O Bingham ◽  
Ami A Shah ◽  
Ronan J Kelly ◽  
Laura Cappelli
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Inflammatory Arthritis ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Joint Involvement

scholarly journals Clinical presentation of immune checkpoint inhibitor-induced inflammatory arthritis differs by immunotherapy regimen

2018 ◽  
Vol 48 (3) ◽  
pp. 553-557 ◽  
Author(s):  
Laura C. Cappelli ◽  
Julie R. Brahmer ◽  
Patrick M. Forde ◽  
Dung T. Le ◽  
Evan J. Lipson ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Inflammatory Arthritis ◽  
Immune Checkpoint Inhibitor ◽  
Clinical Presentation ◽  
Checkpoint Inhibitor

scholarly journals Immune checkpoint inhibitor–induced inflammatory arthritis as a model of autoimmune arthritis

2020 ◽  
Vol 294 (1) ◽  
pp. 106-123 ◽  
Author(s):  
Laura C. Cappelli ◽  
Mekha A. Thomas ◽  
Clifton O. Bingham ◽  
Ami A. Shah ◽  
Erika Darrah
Keyword(s):  
Immune Checkpoint ◽  
Inflammatory Arthritis ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Autoimmune Arthritis

scholarly journals 817 Activated osteoarthritis following immune checkpoint inhibitor treatment: an observational study

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A854-A854
Author(s):  
Pankti Reid ◽  
David Liew ◽  
Rajshi Akruwala ◽  
Anne Bass ◽  
Karmela Chan
Keyword(s):  
Adverse Events ◽  
Observational Study ◽  
Immune Checkpoint ◽  
Inflammatory Arthritis ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Joint Involvement ◽  
Inflammatory Drugs ◽  
Disease Modifying ◽  
Anti Inflammatory

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but can result in toxicities, known as immune-related adverse events (irAEs), due to a hyperactivated immune system. ICI-related inflammatory arthritis has been described in literature, but herewith we introduce and characterize post-ICI activated osteoarthritis (ICI-aOA).MethodsWe conducted a multi-center, retrospective, observational study of patients with cancer treated with ICIs and diagnosed with ICI-aOA by a rheumatologist. ICI-aOA was defined by (1) an increase in non-inflammatory joint pain after ICI initiation, (2) in joints characteristically affected by osteoarthritis and (3) lack of inflammation on exam. Cases were graded using the CTCAE (Common Terminology Criteria for Adverse Events) V6.0 rubric for arthralgia. RECIST (Response evaluation criteria in solid tumors) V.1.1 (v.4.03) guidelines determined tumor response. Results were analyzed using Chi-squared tests of association and multivariate logistic regression.ResultsThirty-six patients had ICI-aOA with mean age at time of rheumatology presentation of 66 years (51–81yrs). Most patients had metastatic melanoma (10/36, 28%) and had received a PD1/PDL1 inhibitor monotherapy (31/36, 86%) with 5/36 (14%) combination therapy. Large joint involvement (hip/knee) was noted in 53% (19/36), small joints of hand 25% (9/36), and spine 14% (5/36). Two-thirds (24/36) suffered multiple joint involvement. Three of 36 (8%) had CTCAE grade 3, 14 (39%) grade 2 and 19 (53%) grade 1 manifestations. Symptom onset ranged from six days to 33.8 months with median of 5.2 months after ICI initiation; 5 patients suffered ICI-aOA after ICI cessation (0.6, 3.5, 4.4, 7.3 and 15.4 months after ICI cessation) (figure 1). Most common form of therapy was intra-articular corticosteroid injections only (15/36, 42%) followed by NSAIDs only (7/36, 20%) (figure 2). Twenty patients (56%) experienced other irAEs, with rheumatic and dermatologic being the most common. All three patients with high-grade ICI-aOA also had another irAE diagnosis at some point after ICI initiation.ConclusionsICI-aOA should be recognized as an adverse event of ICI immunotherapy. Early referral to a rheumatologist can facilitate the distinction between ICI induced inflammatory arthritis from post-ICI mechanical arthropathy, the latter of which can be managed with local therapy that will not compromise ICI efficacy.Ethics ApprovalCollection of patient data was approved by local Institutional Review Boards at respective institutions: Hospital for Special Surgery in New York (HSS IRB # 2017–1898), University of Chicago in Chicago, Illinois (IRB150837) and Austin Health in Melbourne, Victoria, Australia (HREC/18/Austin/102).Abstract 817 Figure 1Incidence of ICI-aOA (activated osteoarthritis after immune-checkpoint inhibitor) ranged from the first month after ICI initiation up until month 22 after ICI initiation, with most cases occurring in the first 6 months after start of ICI. Five of 36 patients experienced ICI-aOA after ICI cessation (0.6, 3.5, 4.4, 7.3 and 15.4 months after ICI cessation), corresponding to presentation after ICI initiation as follows: 2.0, 9.6, 19.1, 8.7 and 16.1 months after ICI initiation, respectively (as denoted in darker color). ICI: Immune-checkpoint inhibitor, NSAIDs: Non-steroidal anti-inflammatory drugs, DMARDs: Disease modifying anti-rheumatic drugsAbstract 817 Figure 2Therapeutic option most used was local or intra-articular corticosteroid therapy, followed by conservative management with physical therapy only then NSAIDs. Most patients experienced improvement in signs and symptoms with treatment. ICI: Immune-checkpoint inhibitor, NSAIDs: Non-steroidal anti-inflammatory drugs, DMARDs: Disease modifying anti-rheumatic drugs

First use of tofacitinib to treat an immune checkpoint inhibitor-induced arthritis

2021 ◽  
Vol 14 (2) ◽  
pp. e238851
Author(s):  
Kieran Murray ◽  
Achilleas Floudas ◽  
Ciara Murray ◽  
Aurelie Fabre ◽  
John Crown ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Inflammatory Arthritis ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Personalised Medicine ◽  
Case Series ◽  
Janus Kinase ◽  
Sustained Remission ◽  
Cellular Immune

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.

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