Rapid identification of inflammatory arthritis and associated adverse events following immune checkpoint therapy: a machine learning approach.

Introduction: Immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA) poses a major clinical challenge to ICI therapy for cancer, with 13% of cases halting ICI therapy and ICI-IA being difficult to identify for timely referral to a rheumatologist. The objective of this study was to rapidly identify ICI-IA patients in clinical data and assess associated immune-related adverse events (irAEs) and risk factors. Methods: We conducted a retrospective study of the electronic health records (EHRs) of 89 patients who developed ICI-IA out of 2451 cancer patients who received ICI therapy at Northwestern University between March 2011 to January 2021. Logistic regression and random forest machine learning models were trained on all EHR diagnoses, labs, medications, and procedures to identify ICI-IA patients and EHR codes indicating ICI-IA. Multivariate logistic regression was then used to test associations between ICI-IA and cancer type, ICI regimen, and comorbid irAEs. Results: Logistic regression and random forest models identified ICI-IA patients with accuracies of 0.79 and 0.80, respectively. Key EHR features from the random forest model included ICI-IA relevant features (joint pain, steroid prescription, rheumatoid factor tests) and features suggesting comorbid irAEs (thyroid function tests, pruritus, triamcinolone prescription). Compared to 871 adjudicated ICI patients who did not develop arthritis, ICI-IA patients had higher odds of developing cutaneous (odds ratio [OR]=2.66; 95% Confidence Interval [CI] 1.63-4.35), endocrine (OR=2.09; 95% CI 1.15-3.80), or gastrointestinal (OR=2.88; 95% CI 1.76-4.72) irAEs adjusting for demographics, cancer type, and ICI regimen. Melanoma (OR=1.99; 95% CI 1.08-3.65) and renal cell carcinoma (OR=2.03; 95% CI 1.06-3.84) patients were more likely to develop ICI-IA compared to lung cancer patients. Patients on nivolumab+ipilimumab were more likely to develop ICI-IA compared to patients on pembrolizumab (OR=1.86; 95% CI 1.01-3.43). Discussion: Our machine learning models rapidly identified patients with ICI-IA in EHR data and elucidated clinical features indicative of comorbid irAEs. Patients with ICI-IA were significantly more likely to also develop cutaneous, endocrine, and gastrointestinal irAEs during their clinical course compared to ICI therapy patients without ICI-IA.

Financial Conflicts of Interest Among Physician Authors of ACR Appropriateness Criteria.

BACKGROUND: The accuracy and completeness of self-disclosures by authors of imaging guidelines are not well known. OBJECTIVE: The aim of this study was to assess the accuracy of financial disclosures by US authors of ACR appropriateness criteria. METHODS: We reviewed financial disclosures provided by US-based authors of all ACR-AC published in 2019, 2021 and 2023. For each US- based author, payment reports were extracted from the Open Payments Database (OPD) in the previous 36 months related to general category and research payments categories. We analyzed each author individually to determine if the reported disclosures matched results from OPD. RESULTS: A total of 633 authorships, including 333 unique authors were included from 38 ACR AC articles in 2019, with 606 authorships (387 unique authors) from 35 ACR-AC articles published in 2021, and 540 authorships (367 unique authors) from 32 ACR AC articles published in 2023. Among authors who received industry payments, failure to disclose any financial relationship was seen in 125/147 unique authors in 2019, 142/148 authors in 2021 and 95/125 unique authors in 2023. The proportion of nondisclosed total value of payments was 86.1% in 2019, 88.6% in 2021 and 56.7% in 2023. General category payments were nondisclosed in 94.1% in 2019, 89.7% in 2021 and 94.4% in 2023 by payment value. CONCLUSION: Industry payments to authors of radiology guidelines are common and frequently undisclosed.

Painful Convictions: Examining Pain Management Malpractice Claims From Incarcerated Patients, 2000-2020.

We aim to characterize the legal landscape of incarcerated patients' pain management malpractice claims and to discuss the ethical and policy implications that result. The most common rationales for lawsuits were failure to completely treat (38 [46.3%]), failure to offer (34 [41.4%]), and delay of treatment (6 [7.3%]). In cases won by defendants, the most common rationale for verdicts was no deliberate indifference occurred (74 [86.6%]). We found that incarcerated individuals were often unsuccessful in litigating claims for inadequate pain management despite several cases pointing toward treatment strategies far below what would be ethically accepted as standard of care in the community setting.

Off-Label studies on anakinra in dermatology: a review.

PURPOSE: Anakinra (Kineret®) is an interleukin-1 receptor antagonist (IL-1Ra) FDA approved for use in rheumatoid arthritis and in neonatal-onset multisystem inflammatory disease (NOMID). It has been used off-label for a variety of dermatologic conditions. A review of the available studies and cases of these off-label uses would be valuable to the dermatologist considering alternative treatments for these oftentimes poorly studied conditions. MATERIALS AND METHODS: The PubMed/MEDLINE, EMBASE, Scopus, and ClinicalTrials.gov databases were searched with the term 'anakinra.' Results were manually screened to identify published data on off-label uses of anakinra in dermatologic conditions and systemic conditions with prominent dermatologic manifestations. RESULTS: Anakinra appears to show efficacy for numerous dermatologic conditions, with the strongest evidence for hidradenitis suppurativa, Bechet's disease, Muckle-Wells syndrome, and SAPHO syndrome. Case reports and case series data are available for numerous other dermatologic conditions. CONCLUSION: Anakinra is a potential option for patients with certain difficult-to-treat dermatologic diseases, given its relatively benign adverse effect profile and its effectiveness in a wide array of conditions. Overall, anakinra appears to be a promising option in the treatment of numerous dermatologic inflammatory conditions refractory to first line therapies, but further and higher-quality data is needed to clarify its therapeutic role.

Advances in the Translational Science of Dermatitis.

The cycle of converting mechanistic insight into therapeutic interventions is called translational science. It has been relatively sluggish in atopic dermatitis (AD), but finally pathomechanisms have been identified and therapeutic targets selected and refined. From inflammatory mediators, skin barrier enhancement, itch relief, and alteration of the microbiota, several therapies have been proposed and are actively being studied for AD, suggesting an end to the drought of innovation.

Integrated genomic analyses of cutaneous T-cell lymphomas reveal the molecular bases for disease heterogeneity.

Cutaneous T-cell lymphomas (CTCLs) are a clinically heterogeneous collection of lymphomas of the skin-homing T cell. To identify molecular drivers of disease phenotypes, we assembled representative samples of CTCLs from patients with diverse disease subtypes and stages. Via DNA/RNA-sequencing, immunophenotyping, and ex vivo functional assays, we identified the landscape of putative driver genes, elucidated genetic relationships between CTCLs across disease stages, and inferred molecular subtypes in patients with stage-matched leukemic disease. Collectively, our analysis identified 86 putative driver genes, including 19 genes not previously implicated in this disease. Two mutations have never been described in any cancer. Functionally, multiple mutations augment T-cell receptor-dependent proliferation, highlighting the importance of this pathway in lymphomagenesis. To identify putative genetic causes of disease heterogeneity, we examined the distribution of driver genes across clinical cohorts. There are broad similarities across disease stages. Many driver genes are shared by mycosis fungoides (MF) and Sezary syndrome (SS). However, there are significantly more structural variants in leukemic disease, leading to highly recurrent deletions of putative tumor suppressors that are uncommon in early-stage skin-centered MF. For example, TP53 is deleted in 7% and 87% of MF and SS, respectively. In both human and mouse samples, PD1 mutations drive aggressive behavior. PD1 wild-type lymphomas show features of T-cell exhaustion. PD1 deletions are sufficient to reverse the exhaustion phenotype, promote a FOXM1-driven transcriptional signature, and predict significantly worse survival. Collectively, our findings clarify CTCL genetics and provide novel insights into pathways that drive diverse disease phenotypes.

Diagnostic contribution of contrast-enhanced 3D MR imaging of peripheral nerve pathology.

OBJECTIVE: To assess the diagnostic contribution of contrast-enhanced 3D STIR (ce3D-SS) high-resolution magnetic resonance (MR) imaging of peripheral nerve pathology relative to conventional 2D sequences. MATERIALS AND METHODS: In this IRB-approved retrospective study, two radiologists reviewed 60 MR neurography studies with nerve pathology findings. The diagnostic contribution of ce3D-SS imaging was scored on a 4-point Likert scale (1 = no additional information, 2 = supports interpretation, 3 = moderate additional information, and 4 = diagnosis not possible without ce3D-SS). Image quality, nerve visualization, and detection of nerve pathology were also assessed for both standard 2D neurography and ce3D-SS sequences utilizing a 3-point Likert scale. Descriptive statistics are reported. RESULTS: The diagnostic contribution score for ce3D-SS imaging was 2.25 for the brachial plexus, 1.50 for extremities, and 1.75 for the lumbosacral plexus. For brachial plexus, the mean consensus scores for image quality, nerve visualization, and detection of nerve pathology were 2.55, 2.5, and 2.55 for 2D and 2.35, 2.45, and 2.45 for 3D. For extremities, the mean consensus scores for image quality, nerve visualization, and detection of nerve pathology were 2.60, 2.80, and 2.70 for 2D and 1.8, 2.20, and 2.10 for 3D. For lumbosacral plexus, the mean consensus scores for image quality, nerve visualization, and detection of nerve pathology were 2.45, 2.75, and 2.65 for 2D and 2.0, 2.45, and 2.25 for 3D. CONCLUSION: Overall, our study supports the potential application of ce3D-SS imaging for MRN of the brachial plexus but suggests that 2D MRN protocols are sufficient for MRN of the extremities and lumbosacral plexus.

The Effect of Homelessness on Patient Wait Times in the Emergency Department.

BACKGROUND: Prolonged emergency department (ED) wait times could potentially lead to increased morbidity and mortality. While previous work has demonstrated disparities in wait times associated with race, information about the relationship between experiencing homelessness and ED wait times is lacking. OBJECTIVES: The purpose of this study was to explore the relationship between residence status (undomiciled vs. domiciled) and ED wait times. We hypothesized that being undomiciled would be associated with longer wait times. METHODS: We obtained data from the National Hospital Ambulatory Medical Care Survey from 2014 to 2017. We compared wait times in each triage category using t tests. We used multivariate linear regression to explore associations between residence status and wait times while controlling for other patient- and hospital-level variables. RESULTS: On average, undomiciled patients experienced significantly longer mean ED wait times than domiciled patients (53.4 vs. 38.9 min; p < 0.0001). In the multivariate model, undomiciled patients experienced significantly different wait times by 15.5 min (p = 0.0002). Undomiciled patients experienced increasingly longer waits vs. domiciled patients for the emergent and urgent triage categories (+33.5 min, p < 0.0001, and +22.7 min, p < 0.0001, respectively). CONCLUSIONS: Undomiciled patients experience longer ED wait times when compared with domiciled patients. This disparity is not explained by undomiciled patients seeking care in the ED for minor illness, because the disparity is more pronounced for urgent and emergent triage categories.

Readability of online patient education materials for juvenile dermatomyositis.

In this study, we sought to analyze the readability of online patient education materials (PEMs) related to juvenile dermatomyositis (JDM). We analyzed the top 100 Google results and using six different readability scores, found 53 PEMs which had an average grade reading level of 17.4 (graduate level). PEMs by health care providers were written at higher grade levels than those by non-health care providers. Our findings demonstrate a clear need for online JDM PEMs that are written at an appropriate reading level and can be comprehended by patients and families of all levels of health literacy.

Off-label Studies on the Use of Ruxolitinib in Dermatology.

PURPOSE: Ruxolitinib (Jakafi) is a Janus kinase 1 and 2 small molecule inhibitor that the Food and Drug Administration approved for myelofibrosis and polycythemia vera. It has been expanded to off-label treatment for a variety of dermatologic conditions, with several clinical trials ongoing. A review of available studies and cases of off-label uses was performed to guide clinicians seeking evidence on the efficacy of this Janus kinase inhibitor for dermatologic disorders. MATERIALS AND METHODS: PubMed/MEDLINE, EMBASE, Scopus, and ClinicalTrials.gov databases were searched with the term "ruxolitinib," and results were manually reviewed to identify published data on off-label uses of ruxolitinib. Studies included are structured by quality of evidence available. RESULTS: Ruxolitinib may have utility in the treatment of atopic dermatitis, psoriasis, and vitiligo, with data from open-label and randomized trials supporting efficacy of topical formulations. Evidence of utility for alopecia areata is mixed and differs depending on topical versus oral form. Evidence for numerous other conditions is available through case reports and case series. CONCLUSIONS: There is growing evidence supporting potential off-label use of oral and topical ruxolitinib for a wide range of skin conditions. There are several ongoing investigations of ruxolitinib use in dermatology that will undoubtedly better define its efficacy and appropriate use in dermatology.

Off-label studies on tofacitinib in dermatology: a review.

PURPOSE: Tofacitinib citrate is an oral Janus kinase 1/3 inhibitor approved for rheumatoid arthritis, ulcerative colitis, and active psoriatic arthritis. Tofacitinib is being increasingly used off-label for dermatological conditions, with varying efficacy across recent studies. A review of these studies will be a helpful resource for dermatologists considering the use of tofacitinib for conditions refractory to first-line therapies. MATERIALS AND METHODS: MEDLINE, Embase, CINAHL Plus, Cochrane Library, Scopus, Web of Science, Clinicaltrials.gov, and the WHO International Clinical Trials Registry Platform were all searched for articles and trials mentioning the term 'tofacitinib', then manually reviewed to identify published data on off-label uses of tofacitinib. The article was structured according to the quality of the evidence available. RESULTS: Tofacitinib appears to show strong efficacy for numerous dermatologic conditions. Randomized controlled trial data is available for atopic dermatitis, alopecia areata, and plaque psoriasis. Case report and case series data is available for numerous other dermatologic conditions. CONCLUSION: While tofacitinib has a wide array of immunoregulatory properties, making it a possible candidate for treating many dermatologic conditions refractory to other treatments, further testing is needed to better characterize its efficacy and utility moving forward, as well as its safety and adverse effect profile.

US Prescription trends of antihistamines for atopic dermatitis, 2011-2016.

Antihistamine use for primary treatment of atopic dermatitis (AD) is not recommended, but current guidelines state that sedating antihistamines are favored over non-sedating antihistamines for relief of burdensome pruritus. We analyzed the National Ambulatory Medical Care Survey data to compare use of antihistamines between dermatologists and non-dermatologists. Overall, dermatologists are more likely to prescribe sedating than non-sedating antihistamines when compared to non-dermatologists (P < .001, δabs  = 0.45). Patients under 21 years old (P = .03, δabs  = 0.10) and Black patients (P < .001, δabs  = 0.19) were also more likely to receive sedating antihistamines than non-sedating antihistamines. These findings highlight the differential prescribing practices for atopic dermatitis among physicians.

A Point-of-Care, Real-Time Artificial Intelligence System to Support Clinician Diagnosis of a Wide Range of Skin Diseases.

Dermatological diagnosis remains challenging for nonspecialists because the morphologies of primary skin lesions widely vary from patient to patient. Although previous studies have used artificial intelligence (AI) to classify lesions as benign or malignant, there have not been extensive studies examining the use of AI on identifying and categorizing a primary skin lesion's morphology. In this study, we evaluate the performance of a standalone AI tool to correctly categorize a skin lesion's morphology from a test bank of images. To provide a marker of performance, we evaluate the accuracy of primary care physicians to categorize skin lesion morphology in the same test bank of images without any aids and then with the aid of a simple visual guide. The AI system achieved an accuracy of 68% in determining the single most likely morphology from the test image bank. When the AI's top prediction was broadened to its top three most likely predictions, accuracy improved to 80%. In comparison, the diagnostic accuracy of primary care physicians was 36% without any aids and 68% with the visual guide (P < 0.001). The AI was subsequently tested on an additional set of 222 heterogeneous images of varying Fitzpatrick skin types and achieved an overall accuracy of 70% in the Fitzpatrick I-III skin type group and 68% in the Fitzpatrick IV-VI skin type group (P = 0.79). An AI is a powerful tool to assist physicians in the diagnosis of skin lesions while still requiring the user to critically consider other possible diagnoses.

Lung Cancer Survival in Patients With Autoimmune Disease.

Importance: Patients with autoimmune disease and lung cancer pose a multidisciplinary treatment challenge, particularly with the advent of immunotherapy. However, the association between autoimmune disease and lung cancer survival is largely unknown. Objective: To determine the association between autoimmune disease and lung cancer survival. Design, Setting, and Participants: Retrospective cohort study between 2003 and 2019 at a single academic medical center (Northwestern University). A query of the Northwestern Medicine Enterprise Data Warehouse identified 349 patients with lung cancer and several autoimmune diseases. Types of lung cancers included small cell, adenocarcinoma, squamous cell carcinoma, non-small cell not otherwise specified, and large cell carcinoma. Autoimmune diseases included rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, mixed connective tissue disease, myositis, and Sjögren syndrome. Inclusion criteria were biopsy-confirmed lung cancer, autoimmune diagnosis confirmed by a rheumatologist, and death or an encounter listed in the electronic medical record within 2 years of study end. A control group of patients with biopsy-proven lung cancer but without autoimmune disease was identified. Data analysis was conducted from March to July 2020. Exposure: Presence of autoimmune disease. Main Outcomes and Measures: Overall survival and progression-free survival in patients with autoimmune disease. The hypothesis was that patients with autoimmune disease would have worse progression-free survival and overall survival compared with patients in the control group. Results: Of the original 349 patients, 177 met inclusion criteria. Mean (SD) age at lung cancer diagnosis was 67.0 (10.0) years and 136 (76.8%) were women. Most common autoimmune diseases were rheumatoid arthritis (97 [54.8%]), systemic sclerosis (43 [24.3%]), and systemic lupus erythematous (15 [8.5%]). Most common lung cancers were adenocarcinoma (99 [55.9%]), squamous cell carcinoma (29 [16.4%]), and small cell lung cancer (17 [9.6%]). A total of 219 patients (mean [SD] age at diagnosis, 65.9 [4.1] years; 173 [79.0%]) were identified as having lung cancer without autoimmune disease and included in the control cohort. Compared with patients in the control group, patients with autoimmune disease experienced no difference in overall survival (log-rank P = .69). A total of 126 patients (69.5%) with autoimmune disease received standard of care vs 213 patients (97.3%) in the control group (P < .001). No individual autoimmune disease was associated with worse prognosis, even among patients with underlying interstitial lung disease. Conclusions and Relevance: Compared with institutional controls, patients with autoimmune disease experienced no difference in survival despite the fact that fewer patients in this group received standard-of-care treatment. No individual autoimmune disease was associated with worse prognosis. Future multicenter prospective trials are needed to further evaluate autoimmune disease and lung cancer survival.

The role of EGFR mutations in predicting recurrence in early and locally advanced lung adenocarcinoma following definitive therapy.

INTRODUCTION: Roughly one third of new non-small cell lung cancer (NSCLC) is diagnosed at early stages. While lobectomy can improve mortality in this group, about 30-55% of patients will experience disease recurrence. Increased investigation into the factors affecting recurrence, particularly tumor molecular genetics such as EGFR mutations, is needed. MATERIALS AND METHODS: We conducted a single-center retrospective study of 282 patients with early or locally advanced lung adenocarcinoma, with or without EGFR mutations, who underwent definitive therapy. We then assessed recurrence, stage at recurrence, time to recurrence and progression-free survival (PFS). RESULTS: We identified 142 patients with EGFR-mutated and 140 EGFR-wildtype lung adenocarcinoma. Overall progression between groups was equivalent at ~40% at 5 years; no difference in PFS was observed at any time-point. However, among those who recurred, EGFR-mutated lung cancer had increased rates of metastatic recurrence compared to EGFR-wildtype disease (97% vs 68%, p = 0.007). CONCLUSIONS: EGFR-mutated disease may be associated with a higher risk of metastatic recurrence. Molecular testing may be a promising tool for risk stratification and surveillance following definitive management for early stage disease. Future prospective, multi-center cohort studies are needed to confirm these findings and improve our understanding of how EGFR mutation contributes to prognosis and clinical outcomes.

Cellular origins and genetic landscape of cutaneous gamma delta T cell lymphomas.

Primary cutaneous γδ T cell lymphomas (PCGDTLs) represent a heterogeneous group of uncommon but aggressive cancers. Herein, we perform genome-wide DNA, RNA, and T cell receptor (TCR) sequencing on 29 cutaneous γδ lymphomas. We find that PCGDTLs are not uniformly derived from Vδ2 cells. Instead, the cell-of-origin depends on the tissue compartment from which the lymphomas are derived. Lymphomas arising from the outer layer of skin are derived from Vδ1 cells, the predominant γδ cell in the epidermis and dermis. In contrast, panniculitic lymphomas arise from Vδ2 cells, the predominant γδ T cell in the fat. We also show that TCR chain usage is non-random, suggesting common antigens for Vδ1 and Vδ2 lymphomas respectively. In addition, Vδ1 and Vδ2 PCGDTLs harbor similar genomic landscapes with potentially targetable oncogenic mutations in the JAK/STAT, MAPK, MYC, and chromatin modification pathways. Collectively, these findings suggest a paradigm for classifying, staging, and treating these diseases.

The relationship between the number of available therapeutic options and government payer (medicare part D) spending on topical drug products.

The cost of prescription drugs has increased at rates far exceeding general inflation in recent history, with topical drugs increasing at a disproportionate rate compared to other routes of administration. We assessed the relationship between net changes in the number of therapeutic options, defined as any approved drug or therapeutic equivalent on the market, and prescription topical drug spending. Drugs were divided based on the category of use through pairing of Medicare Part D Prescriber Public Use and Food and Drug Administration (FDA) approved drug products databases. Across drug classes, we modeled the log of the ratio of total spending per unit in 2015 to total spending per unit in 2011 as a linear function of net number of topical therapeutic options over this time period. Primary outcomes include total Medicaid Part D spending on topical drugs and net change in the number of available therapeutic options within each category of use. Total spending on topical drugs increased by 61%, while the number of units dispensed increased by only 18% from 2011-2015. The greatest total spending increases were in categories with few new therapeutic options, such as topical corticosteroid and antifungal medications. Each net additional therapeutic option during 2011-2015 was associated with an reduction in how much relative spending per unit increased (95% CI 2.5%-14.4%, p = 0.013). Stimulating greater competition through increasing the net number of therapeutic options within each major topical category of use may place downward pressure on topical prescription drug spending under medicare Part D.

Off-label studies on apremilast in dermatology: a review.

Purpose: Apremilast is a phosphodiesterase-4 inhibitor FDA approved for psoriatic arthritis and moderate to severe plaque psoriasis. In recent years, multiple studies have suggested other potential uses for apremilast in dermatology. A summary of these various studies will be a valuable aid to dermatologists considering apremilast for an alternative indication.Materials and methods: The PubMed/MEDLINE and ClinicalTrials.gov databases were queried with the term 'apremilast,' with results manually screened to identify published data on off-label uses of apremilast. The article was structured by the quality of evidence available.Results: Apremilast use in dermatology beyond plaque psoriasis and psoriatic arthritis is frequently described in the literature, with a mixture of positive and negative results. Randomized controlled data is available for Behçet's disease, hidradenitis suppurativa, nail/scalp/palmoplantar psoriasis, alopecia areata, and atopic dermatitis.Conclusion: The relatively safe adverse effect profile of apremilast and its broad immunomodulatory characteristics may make it a promising option in the future for patients with difficult to treat diseases in dermatology, refractory to first line therapies, but further studies will be necessary to clarify its role.