Comparing anti-tumor and anti-self immunity in a patient with melanoma receiving immune checkpoint blockade.

BACKGROUND: Tumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken to investigate the functional relationship between anti-tumor and anti-self immunity, to facilitate irAE management while promoting anti-tumor immunity. METHODS: Multiple biopsies from tumor and inflamed tissues were collected from a patient with melanoma experiencing both tumor regression and irAEs on ICB, who underwent rapid autopsy. Immune cells infiltrating melanoma lesions and inflamed normal tissues were subjected to gene expression profiling with multiplex qRT-PCR for 122 candidate genes. Subsequently, immunohistochemistry was conducted to assess the expression of 14 candidate markers of immune cell subsets and checkpoints. TCR-beta sequencing was used to explore T cell clonal repertoires across specimens. RESULTS: While genes involved in MHC I/II antigen presentation, IFN signaling, innate immunity and immunosuppression were abundantly expressed across specimens, irAE tissues over-expressed certain genes associated with immunosuppression (CSF1R, IL10RA, IL27/EBI3, FOXP3, KLRG1, SOCS1, TGFB1), including those in the COX-2/PGE2 pathway (IL1B, PTGER1/EP1 and PTGER4/EP4). Immunohistochemistry revealed similar proportions of immunosuppressive cell subsets and checkpoint molecules across samples. TCRseq did not indicate common TCR repertoires across tumor and inflammation sites, arguing against shared antigen recognition between anti-tumor and anti-self immunity in this patient. CONCLUSIONS: This comprehensive study of a single patient with melanoma experiencing both tumor regression and irAEs on ICB explores the immune landscape across these tissues, revealing similarities between anti-tumor and anti-self immunity. Further, it highlights expression of the COX-2/PGE2 pathway, which is known to be immunosuppressive and potentially mediates ICB resistance. Ongoing clinical trials of COX-2/PGE2 pathway inhibitors targeting the major COX-2 inducer IL-1B, COX-2 itself, or the PGE2 receptors EP2 and EP4 present new opportunities to promote anti-tumor activity, but may also have the potential to enhance the severity of ICB-induced irAEs.

Treatment Patterns and Effectiveness of Tofacitinib in Patients Initiating Therapy for Rheumatoid Arthritis: Results From the CorEvitas Rheumatoid Arthritis Registry.

OBJECTIVE: This real-world analysis assessed baseline demographics/characteristics and treatment patterns/effectiveness in patients with rheumatoid arthritis (RA) initiating tofacitinib (TOF) in the US CorEvitas RA Registry. METHODS: The primary analysis of this study included patients with RA initiating TOF with a 12-month follow-up visit from November 2012 to January 2021. Outcomes included baseline demographics/characteristics and TOF initiation/discontinuation reasons, treatment patterns, and effectiveness (disease activity and patient-reported outcomes [PROs] at 12 months); the primary effectiveness outcome was Clinical Disease Activity Index low disease activity (CDAI LDA). All data, analyzed descriptively, were stratified by TOF regimen (monotherapy vs combination therapy), line of therapy (second- to fourth-line), time of initiation (2012-2014, 2015-2017, or 2018-2020), and dose (5 mg twice daily vs 11 mg once daily). RESULTS: Of 2874 patients with RA who initiated TOF, 1298 had a qualifying 12-month follow-up visit; of these, 43.1% were monotherapy and 66.5% were fourth-line therapy. Overall, tumor necrosis factor inhibitors (40.8%) were the most common treatment immediately prior to TOF initiation. The most common reason for TOF initiation (among those with a reason) was lack/loss of efficacy of prior treatment (67.7%). Overall, at 12 months, 31.9% and 10.1% had achieved CDAI LDA and remission, respectively; 22.4%, 10.4%, and 5% had achieved ≥ 20%, ≥ 50%, and ≥ 70% improvement in modified American College of Rheumatology core set measures, respectively; and improvements in PROs were observed. Effectiveness was generally similar across TOF stratifications. CONCLUSION: TOF effectiveness (CDAI LDA) was observed in a US real-world setting of patients with RA regardless of TOF regimen, line of therapy, time of initiation, and dose. (ClinicalTrials.gov: NCT04721808).

Immune checkpoint inhibitor-induced inflammatory arthritis as a model of autoimmune arthritis.

The development of inflammatory arthritis in patients receiving immune checkpoint inhibitor therapy is increasingly recognized due to the growing use of these drugs for the treatment of cancer. This represents an important opportunity not only to define the mechanisms responsible for the development of this immune-related adverse event and to ultimately predict or prevent its development, but also to provide a unique window into early events in the development of inflammatory arthritis. Knowledge gained through the study of this patient population, for which the inciting event is known, could shed light into the pathogenesis of autoimmune arthritis. This review will highlight the clinical and immunologic features of these entities to define common elements for future study.

Comparative safety and effectiveness of TNF inhibitors, IL6 inhibitors and methotrexate for the treatment of immune checkpoint inhibitor-associated arthritis.

OBJECTIVES: To compare the safety and effectiveness of biologic and conventional disease-modifying antirheumatic drugs (DMARDs) for immune checkpoint inhibitor-associated inflammatory arthritis (ICI-IA). METHODS: The retrospective multicentre observational study included patients with a diagnosis of ICI-IA treated with a tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL6Ri) and/or methotrexate (MTX); patients with pre-existing autoimmune disease were excluded. The primary outcome was time to cancer progression from ICI initiation; the secondary outcome was time to arthritis control from DMARD initiation. Cox proportional hazard models were used to compare medication groups, adjusting for confounders. RESULTS: 147 patients were included (mean age 60.3 (SD 11.9) years, 66 (45%) women). ICI-IA treatment was TNFi in 33 (22%), IL6Ri 42 (29%) and MTX 72 (49%). After adjustment for time from ICI initiation to DMARD initiation, time to cancer progression was significantly shorter for TNFi compared with MTX (HR 3.27 (95% CI 1.21 to 8.84, p=0.019)) while the result for IL6Ri was HR 2.37 (95% CI 0.94 to 5.98, p=0.055). Time to arthritis control was faster for TNFi compared with MTX (HR 1.91 (95% CI 1.06 to 3.45, p=0.032)) while the result for IL6Ri was HR 1.66 (95% CI 0.93 to 2.97, p=0.089). A subset analysis in patients with melanoma gave similar results for both cancer progression and arthritis control. CONCLUSION: The treatment of ICI-IA with a biologic DMARD is associated with more rapid arthritis control than with MTX, but may be associated with a shorter time to cancer progression.

Baseline predictors of disease severity in immune checkpoint inhibitor-induced inflammatory arthritis.

OBJECTIVES: To determine baseline risk factors for requiring immunosuppression and having persistent arthritis in patients with immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA). METHODS: Participants were adults with rheumatologist diagnosed ICI-IA. The primary outcome was requirement of conventional synthetic (cs) or biologic (b) DMARDs; other outcomes were persistence of IA > 6 months after ICI cessation and requirement of corticosteroids. Logistic regression models evaluated associations between clinical features and primary and secondary outcomes, with adjustment for potential confounders, as appropriate. RESULTS: 126 patients with ICI-IA were included; 53 patients (42%) required a csDMARD/bDMARD. In univariate logistic regressions, higher CDAI, tenosynovitis, longer symptom duration before first rheumatology visit, and longer ICI duration were significantly associated with a higher likelihood of requiring DMARDs; there was a trend toward those treated with prior chemotherapy being less likely to need DMARDs. After adjustment, tenosynovitis, longer symptom duration, and higher CDAI remained associated with requiring DMARDs, while those with prior chemotherapy were significantly less likely to require DMARDs. Combination anti-CTLA-4/PD-1 therapy and steroid use at baseline were associated with a higher risk of persistent IA. CONCLUSION: Higher levels of disease activity, tenosynovitis, and longer symptom duration prior to rheumatology referral were associated with requiring DMARDs for ICI-IA, while those treated previously with chemotherapy were less likely to require additional immunosuppression. The presence of risk factors for severe disease at baseline may indicate a role for higher initial steroid dose, earlier rheumatology referral, and adoption of immunosuppression beyond steroids to improve outcomes.

Checkpoint Inhibitor-Associated Arthritis: A Systematic Review of Case Reports and Case Series.

OBJECTIVE: We performed a systematic literature review to identify all reports of immune checkpoint inhibitor-associated inflammatory arthritis to describe it phenotypically and serologically. METHODS: PubMed, Embase, and Cochrane databases were searched for reports of musculoskeletal immune-related adverse events secondary to ICI treatment. Publications were included if they provided individual patient level data regarding the pattern of joint involvement. Descriptive statistics were used to summarize results. RESULTS: A total of 4339 articles were screened, of which 67 were included, encompassing 372 patients. The majority of patients had metastatic melanoma (57%), and they were treated with anti-PD1 or anti-PDL1 therapy (78%). Median time to onset of arthritis was 4 months (range, 1 day to 53 months). Forty-nine percent had polyarthritis, 17% oligoarthritis, 3% monoarthritis, 10% arthralgia, and 21% polymyalgia rheumatica. More than half of patients were described as having a "rheumatoid arthritis-like" presentation. Nine percent tested positive for rheumatoid factor or anti-cyclic citrullinated peptide antibodies. Seventy-four percent required corticosteroids, and 45% required additional medications. Sixty-three percent achieved arthritis control, and 32% were ultimately able to discontinue antirheumatic treatments. Immune checkpoint inhibitors were continued in 49%, transiently withheld in 11%, and permanently discontinued due to musculoskeletal immune-related adverse events in 13%. CONCLUSIONS: Half of reported immune checkpoint inhibitor-associated arthritis cases present with polyarthritis (often RA-like), but only 9% are seropositive. Polymyalgia rheumatica is also common. Most patients respond to steroids alone, but about half require additional medications. Further studies are needed to determine long-term musculoskeletal outcomes in these patients, and the impact of arthritis treatment on cancer survival.

Immune checkpoint inhibitor toxicities: systems-based approaches to improve patient care and research.

Immune checkpoint inhibitors (ICIs) have now been approved in numerous and diverse cancer types and combination regimens. Effective recognition and treatment of ICI toxicities, which might occur acutely, affect any organ system, and produce many distinct clinical syndromes, have emerged as essential goals of ICI management. Thus, developing robust diagnostic and management approaches for ICI toxicity across the health-care system is an urgent and unmet clinical need. In this Personal View, we describe barriers to high-quality care that have constrained the most effective management of patients with cancer receiving ICI treatment. We review education initiatives to enhance patient and physician awareness, which is necessary given the broad spectrum of ICI toxicities often experienced by patients, and assess various systems-based approaches that maximise the chances of appropriate management. In addition, we describe research pipelines that broaden evidence-based approaches and the pathobiology of these novel events. Developing effective, systematic approaches for the recognition and treatment of ICI toxicities will continue to grow in importance as these agents proliferate in cancer care.

Treatment of immune checkpoint inhibitor-induced inflammatory arthritis.

PURPOSE OF REVIEW: This review summarizes the current evidence on treatment strategies for inflammatory arthritis because of cancer treatment with immune checkpoint inhibitors (ICI), prognosis of ICI-induced arthritis, and management of patients with preexisting inflammatory arthritis receiving ICI therapy. RECENT FINDINGS: Inflammatory arthritis is the most common rheumatic immune-related adverse event observed in patients receiving ICI therapy. Most patients can successfully be treated with low doses of corticosteroids or conventional synthetic disease modifying anti-rheumatic drugs (DMARDs). A small minority will develop severe symptoms requiring biologic therapy including TNF inhibitors and IL-6 receptor inhibitors. Many cases of inflammatory arthritis will resolve with cessation of ICI therapy. Some patients will develop persistent arthritis despite discontinuation. Patients with preexisting inflammatory arthritis (e.g. rheumatoid arthritis) commonly flare on ICI therapy, but can usually be managed with corticosteroids. SUMMARY: Inflammatory arthritis following ICI therapy for cancer is relatively common and the practicing rheumatologist should be able to recognize and manage it in conjunction with Oncology. The majority of patients respond to corticosteroids, but some will need treatment with conventional synthetic or biologic DMARDs. Additional studies should investigate the effects of immunosuppression on tumor response and the use of ICI therapy in patients with preexisting autoimmune disease.

Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation.

OBJECTIVE: We 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. METHODS: We 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. RESULTS: Sixty 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). CONCLUSION: ICI-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.

Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy.

BACKGROUND: The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy. SUBJECTS, MATERIALS, AND METHODS: Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB). RESULTS: Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor ß (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sjögren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low. CONCLUSION: ICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sjögren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term. IMPLICATIONS FOR PRACTICE: Sicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sjögren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.

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

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.

A Multidisciplinary Toxicity Team for Cancer Immunotherapy-Related Adverse Events.

BACKGROUND: Immune checkpoint inhibitors (ICIs) may cause immune-related adverse events (irAEs). Methods to obtain real-time multidisciplinary input for irAEs that require subspecialist care are unknown. This study aimed to determine whether a virtual multidisciplinary immune-related toxicity (IR-tox) team of oncology and medicine subspecialists would be feasible to implement, be used by oncology providers, and identify patients for whom multidisciplinary input is sought. PATIENTS AND METHODS: Patients treated with ICIs and referred to the IR-tox team in August 2017 through March 2018 were identified. Feasibility was defined as receipt of electronic referrals and provision of recommendations within 24 hours of referral. Use was defined as the proportion of referring providers who used the team's recommendations, which was determined through a postpilot survey. Demographics and tumor, treatment, and referral data were collected. Patient features and irAE associations were analyzed. RESULTS: The IR-tox team was found to be feasible and used: 117 referrals from 102 patients were received in 8 months, all providers received recommendations within 24 hours, 100% of surveyed providers used the recommendations, and 74% changed patient management based on IR-tox team recommendations. Referrals were for suspected irAEs (n=106; 91%) and suitability to treat with ICIs (n=11; 10%). In referred patients, median age was 64 years, 54% were men, 13% had prior autoimmunity, and 46% received ICI combinations versus monotherapy (54%). The most commonly referred toxicities were pneumonitis (23%), arthritis (16%), and dermatitis (15%); 15% of patients had multisystem toxicities. Multiple referrals were more common in those treated with combination ICIs (odds ratio [OR], 6.0; P=.035) or with multisystem toxicities (OR, 8.1; P=.005). The IR-tox team provided a new multidisciplinary forum to assist providers in diagnosing and managing complex irAEs. This model identifies educational and service needs, and patients with irAEs for whom multidisciplinary care is most sought. CONCLUSIONS: A virtual multidisciplinary toxicity team for irAEs was a feasible and used service, and facilitated toxicity identification and management.

Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathways have demonstrated survival improvements in multiple advanced cancers, but also cause immune-related adverse events (IRAEs). IRAEs with clinical features similar to rheumatic diseases have not been well described. We report patients with inflammatory arthritis and sicca syndrome secondary to ICIs. METHODS: We report patients evaluated in the Johns Hopkins Rheumatology clinics from 2012 to 2016 identified as having new rheumatological symptoms in the context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) for solid tumours. RESULTS: We identified 13 patients who received ICIs and developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included melanoma, non-small cell lung cancer, small cell lung cancer and renal cell carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1 MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis, colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were positive in 5 out of 13 patients. All 13 patients were treated with corticosteroids with varying response. Two patients were treated with methotrexate and antitumor necrosis factor therapy for inflammatory arthritis. CONCLUSIONS: As ICIs are increasingly used for a range of malignancies, new cases of rheumatic IRAEs are likely to emerge. Further research is required to understand mechanisms, determine risk factors and develop management algorithms for rheumatic IRAEs.

Anti-Peptidylarginine Deiminase 4 Autoantibodies and Disease Duration as Predictors of Treatment Response in Rheumatoid Arthritis.

BACKGROUND: Given that autoantibodies to peptidylarginine deiminase 4 (PAD4) are associated with erosive disease in established rheumatoid arthritis (RA), this study was conducted to compare the clinical and prognostic use of anti-PAD4 antibodies in patients with early and established RA. METHODS: Sera from patients with early (duration <2 years; n = 422) or established (duration ≥2 years; n = 359) RA from two randomized clinical trials of tofacitinib ± methotrexate compared with adalimumab + MTX or MTX alone were evaluated for the presence of anti-PAD4 and anti-PAD3/4 antibodies at baseline and posttreatment time points. Summary statistics were calculated for demographic, clinical, and serological characteristics, and generalized estimating equations were used to model clinical outcomes by disease duration according to anti-PAD4 status. RESULTS: Anti-PAD4 antibodies were present in 22% and 40% of patients with early and established RA, respectively, stable following treatment, and associated with baseline joint damage only in established RA. In early RA, baseline anti-PAD4 antibodies were associated with a greater improvement in disease activity score 28-joint count using C-reactive protein levels after treatment compared with individuals with negative anti-PAD4 (P = 0.049). Tofacitinib ± MTX was more broadly efficacious than MTX alone at improving clinical outcomes in early and established RA, irrespective of anti-PAD4 status (P < 0.05 for all), whereas adalimumab + MTX exhibited differential benefits in achieving disease activity score remission in early RA (P = 0.036) and American College of Rheumatology 20 responses in established RA (P = 0.002). CONCLUSION: Differences in prevalence, clinical associations, and treatment-response outcomes according to anti-PAD4 antibody status in early and established RA suggests the existence of a therapeutic window to prevent the accumulation of irreversible joint damage in early patients with RA with anti-PAD4 antibodies.

Immune Checkpoint Inhibitor-induced Inflammatory Arthritis: Current Approaches to Management.

The introduction of immune checkpoint inhibitors (ICIs) has changed the landscape of the treatment of cancer. Several immune-related adverse events (irAEs) have now been described such as ICI-inflammatory arthritis (IA), sicca syndrome, polymyalgia rheumatica, myositis, and vasculitis as a consequence of immune activation. The onset of the ICI-IA can vary from after the first infusion of ICIs to a delayed presentation a year or more after ICI initiation. Ultimately, baseline patient and tumor characteristics, the types of immunotherapies used, pre-existing autoimmune diseases, and/or other irAEs, as well as patient preferences will all shape the discussions around ICI-IA management.

Corticosteroid-resistant immune-related adverse events: a systematic review.

Immune checkpoint inhibitor (ICI) treatment has become an important therapeutic option for various cancer types. Although the treatment is effective, ICI can overstimulate the patient's immune system, leading to potentially severe immune-related adverse events (irAEs), including hepatitis, colitis, pneumonitis and myocarditis. The initial mainstay of treatments includes the administration of corticosteroids. There is little evidence how to treat steroid-resistant (sr) irAEs. It is mainly based on small case series or single case reports. This systematic review summarizes available evidence about sr-irAEs. We conducted a systematic literature search in PubMed. Additionally, we included European Society for Medical Oncology, Society for Immunotherapy of Cancer, National Comprehensive Cancer Network and American Society of Clinical Oncology Guidelines for irAEs in our assessment. The study population of all selected publications had to include patients with cancer who developed hepatitis, colitis, pneumonitis or myocarditis during or after an immunotherapy treatment and for whom corticosteroid therapy was not sufficient. Our literature search was not restricted to any specific cancer diagnosis. Case reports were also included. There is limited data regarding life-threatening sr-irAEs of colon/liver/lung/heart and the majority of publications are single case reports. Most publications investigated sr colitis (n=26), followed by hepatitis (n=21), pneumonitis (n=17) and myocarditis (n=15). There is most data for mycophenolate mofetil (MMF) to treat sr hepatitis and for infliximab, followed by vedolizumab, to treat sr colitis. Regarding sr pneumonitis there is most data for MMF and intravenous immunoglobulins (IVIG) while data regarding infliximab are conflicting. In sr myocarditis, most evidence is available for the use of abatacept or anti-thymocyte globulin (ATG) (both with or without MMF) or ruxolitinib with abatacept. This review highlights the need for prompt recognition and treatment of sr hepatitis, colitis, pneumonitis and myocarditis. Guideline recommendations for sr situations are not defined precisely. Based on our search, we recommend-as first line treatment-(1) MMF for sr hepatitis, (2) infliximab for sr colitis, followed by vedolizumab, (3) MMF and IVIG for sr pneumonitis and (4) abatacept or ATG (both with or without MMF) or ruxolitinib with abatacept for sr myocarditis. These additional immunosuppressive agents should be initiated promptly if there is no sufficient response to corticosteroids within 3 days.

Immune checkpoint inhibitor therapy in patients with cancer and pre-existing systemic sclerosis.

OBJECTIVE: Immune checkpoint inhibitor (ICI) therapies have dramatically improved outcomes in multiple cancers. ICI's mechanism of action involves immune system activation to augment anti-tumor immunity. Patients with pre-existing autoimmune diseases, such as systemic sclerosis (SSc), were excluded from initial ICI clinical trials due to concern that such immune system activation could precipitate an autoimmune disease flare or new, severe immune related adverse events (irAE). In the present study, we report our experience with ICIs in patients with pre-existing SSc. METHODS: Patients with SSc who received ICI therapy for cancer were identified from the Johns Hopkins Scleroderma Center Research Registry. Through chart review and prespecified definitions, we identified whether patients experienced worsening SSc activity or new irAEs. SSc disease activity worsening was pre-defined as an increase in modified Rodnan skin score (mRSS), new scleroderma renal crisis, progression of interstitial lung disease (ILD) on CT scan, increased Raynaud's phenomenon frequency or severity, new pulmonary hypertension, or myositis flare. IrAEs also included active inflammatory arthritis and dermatitis. RESULTS: Eight patients with SSc who received ICI therapy for cancer were included. Overall, SSc symptoms remained stable during and after ICI therapy. None of the patients with long-standing sine or limited cutaneous SSc (lcSSc) had progressive skin thickening after ICI therapy. One patient, who was early in his diffuse cutaneous SSc (dcSSc) disease course, experienced worsening skin thickening and renal crisis. Three patients (38 %) experienced a total of five irAEs (grade 2: diarrhea, mucositis and dermatitis; grade 3: pneumonitis, and grade 4: nephritis). The patient with grade 4 nephritis developed scleroderma renal crisis and immune checkpoint related nephritis simultaneously. There were no deaths due to irAEs. CONCLUSION: In this study, ICI therapy was well tolerated in patients with longstanding, sine or lcSSc. IrAE were common but generally manageable. Patients with early, active SSc may be at greater risk from ICI therapy, but more research is needed.

Defining D-irAEs: consensus-based disease definitions for the diagnosis of dermatologic adverse events from immune checkpoint inhibitor therapy.

With an increasing number of patients eligible for immune checkpoint inhibitors, the incidence of immune-related adverse events (irAEs) is on the rise. Dermatologic immune-related adverse events (D-irAEs) are the most common and earliest to manifest, often with important downstream consequences for the patient. Current guidelines lack clarity in terms of diagnostic criteria for D-irAEs. The goal of this project is to better define D-irAE for the purposes of identification, diagnosis, and future study of this important group of diseases.The objectives of this project were to develop consensus guidance for an approach to D-irAEs including disease definitions and severity grading. Knowing that consensus among oncologists, dermatologists, and irAE subspecialists would be critical for usability, we formed a Dermatologic irAE Disease Definition Panel. The panel was composed of 34 experts, including oncologists, dermatologists, a rheumatologist, and an allergist/immunologist from 22 institutions across the USA and internationally. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two virtual meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness, and accuracy on 9-point scales in electronic surveys and provided free text comments. A working group aggregated survey responses and incorporated them into revised definitions. Consensus was based on numeric ratings using the RAND/UCLA Appropriateness Method with prespecified definitions.Following revisions based on panelist feedback, all items received consensus in the second round of ratings. Consensus definitions were achieved for 10 core D-irAE diagnoses: ICI-vitiligo, ICI-lichen planus, ICI-psoriasis, ICI-exanthem, ICI-bullous pemphigoid, ICI-Grover's, ICI-eczematous, ICI-eruptive atypical squamous proliferation, ICI-pruritus without rash, and ICI-erosive mucocutaneous. A standard evaluation for D-irAE was also found to reach consensus, with disease-specific exceptions detailed when necessary. Each disorder's description includes further details on disease subtypes, symptoms, supportive exam findings, and three levels of diagnostic certainty (definite, probable, and possible).These consensus-driven disease definitions standardize D-irAE classification in a useable framework for multiple disciplines and will be the foundation for future work. Given consensus on their accuracy and usability from a representative panel group, we anticipate that they can be used broadly across clinical and research settings.