Preventing herpes zoster in immunocompromised patients: Current concepts.

Herpes zoster (HZ) incidence is much higher in immunocompromised individuals than in immunocompetent individuals. HZ also occurs at a younger age and is often more severe in immunocompromised persons. Preventive strategies center around the recombinant zoster vaccine (RZV), which is approved for immunocompromised adults age 19 and older. Identifying those at greatest risk is critical. For those considering vaccination, evidence gaps regarding vaccine efficacy, toxicity, length of protection, and potential effects on underlying conditions may complicate shared and informed decision-making. Recent data have filled some of these gaps, with several societies issuing recommendations regarding vaccination. Remaining gaps are currently addressed by expert opinion.

A scoping review of vasculitis as an immune-related adverse event from checkpoint inhibitor therapy of cancer: Unraveling the complexities at the intersection of immunology and vascular pathology.

BACKGROUND/PURPOSE: Vasculitis as an immune-related adverse event (irAE) from checkpoint inhibitor therapy (ICI) to treat cancer is a rare clinical event, and little is known regarding its nosology, clinical manifestations, or response to treatment and outcomes. METHODS: To address these gaps, we used the Preferred Reporting Items for Systemic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) framework to further define this complication. Two independent PUBMED searches in September and November of 2022 revealed 127 publications with 37 excluded from title by relevance, 43 excluded by article type, and 23 excluded due to lack of biopsy results, or biopsy negative for vasculitis. Twenty-nine documented cases from 24 publications were included for final analysis. Basic demographics, ICI details, timing of onset of vasculitis symptoms, irAE treatment and outcomes were collected. The vasculitides were classified using 2022 ACR/EULAR Vasculitis Classification Criteria as well as 2012 Revised Chapel-Hill Nomenclature. Adaptations from Naidoo et al. 2023 [1] consensus definitions for irAEs were used and efforts were made to classify steroid-responsive versus unresponsive irAEs. RESULTS: Of the 29 cases reviewed, the average age of patients was 62.1 ± 11.0, composed of 58.6 % (n = 17) male and 41.3 % (n = 12) female. Prominent cancer types were lung cancer (41.4 %; n = 12), melanoma (41.4 %; n = 12), and renal cancer (10.3 %; n = 3), with majority being stage 4 (75.9 %, n = 22) and stage 3 (10.3 %, n = 3). Only 8 cases met the ACR/EULAR criteria, and by Chapel-Hill Nomenclature, approximately a third were small-vessel vasculitis (31.0 %; n = 9) with n = 4 positive for ANCA. Most biopsies were taken from the skin (37.9 %, n = 11) and kidney (24.1 %, n = 7). Patients were either treated with single (65.5 %, n = 19), dual (17.2 %; n = 5), or sequential (17.2 %; n = 5) ICI regimen which included anti-PD-1 therapy in all but one case, with mean of 8.7 ± 10.5 cycles received. Mean time to onset of symptoms from start of ICI was 7.2 ± 7.8 months, with 55.2 % occurring >3 months since the initial immunotherapy. Vasculitis treatment included glucocorticoids in 96 % of cases and immunotherapy was often discontinued (44.8 %; n = 13). Clinical improvement of irAE was documented in 86.2 % (n = 25). Data were missing in terms of fate of ICI (34.5 %; n = 10) and tumor outcomes (41.4 %; n = 12). Cancer progressed in 20.7 % (n = 6), stable in 34.5 % (n = 10) cases, and 6 patients died of all-causes. CONCLUSION: Vasculitis as an irAE appears clinically heterogeneous and rare. Among reported cases with adequate documentation, vasculitis is of delayed onset following the initiation of immunotherapy. Outcomes of ICI-vasculitis were generally favorable, responding to glucocorticoids and immunotherapy withdrawal. There is an urgent need for more standardized reporting of rare irAEs such as vasculitis to clarify clinical risks, classification, relationship to immunotherapy and outcomes.

Imaging in Rheumatic Immune-related Adverse Events.

Since their introduction, immune checkpoint inhibitors have revolutionized cancer treatment by harnessing the body's own immune system as a defense against tumor growth. The downside of activating the immune system is the development of immune-related adverse events (irAEs), which mimic autoimmune disease of various organ systems. The musculoskeletal system is an uncommon, but substantial one for patients and can lead to long-term pain and disability that affects their quality of life. This review summarizes recent literature on imaging forms utilized for diagnosis and assessing treatment response in rheumatic irAEs.

Mechanistic insights into bone remodelling dysregulation by human viral pathogens.

Bone-related diseases (osteopathologies) associated with human virus infections have increased around the globe. Recent findings have highlighted the intricate interplay between viral infection, the host immune system and the bone remodelling process. Viral infections can disrupt bone homeostasis, contributing to conditions such as arthritis and soft tissue calcifications. Osteopathologies can occur after arbovirus infections such as chikungunya virus, dengue virus and Zika virus, as well as respiratory viruses, such as severe acute respiratory syndrome coronavirus 2 and enteroviruses such as Coxsackievirus B. Here we explore how human viruses dysregulate bone homeostasis, detailing viral factors, molecular mechanisms, host immune response changes and bone remodelling that ultimately result in osteopathologies. We highlight model systems and technologies to advance mechanistic understanding of viral-mediated bone alterations. Finally, we propose potential prophylactic and therapeutic strategies, introduce 'osteovirology' as a research field highlighting the underestimated roles of viruses in bone-related diseases, and discuss research avenues for further investigation.

Risk factors for severe COVID-19 among patients with systemic lupus erythematosus: a real-world analysis of a large representative US administrative claims database, 2020-2021.

OBJECTIVES: To identify risk factors for progression to severe COVID-19 and estimate the odds of severe COVID-19 associated with vaccination among patients with systemic lupus erythematosus (SLE). METHODS: This retrospective cohort study identified adults with SLE in the Merative™ MarketScan® Databases. Patients were continuously enrolled the year before 1 April 2020 (baseline) and had a COVID-19 diagnosis between 1 April 2020 and the earliest of death, enrolment end or 31 December 2021. Severe COVID-19 was defined as hospitalisation with a COVID-19 diagnosis. Demographics on 1 April 2020, baseline comorbidities, corticosteroid use ≤30 days before COVID-19 diagnosis and other SLE medication use ≤6 months before COVID-19 diagnosis were assessed. Vaccination was identified by claims for a COVID-19 vaccine or vaccine administration. Backward stepwise logistic regression estimated odds of progression to severe COVID-19 associated with patient characteristics and vaccination. RESULTS: Among 2890 patients with SLE with COVID-19, 500 (16.4%) had a COVID-19-related hospitalisation. Significant risk factors for progression to severe COVID-19 included rituximab (OR (95% CI) 2.92 (1.67 to 5.12)), renal failure (2.15 (95% CI 1.56 to 2.97)), Medicaid (vs Commercial; 2.01 (95% CI 1.58 to 2.57)), complicated hypertension (1.96 (95% CI 1.38 to 2.77)) and time of infection, among others. Vaccination had a significant protective effect (0.68(95% CI 0.54 to 0.87)) among all patients with SLE with COVID-19, but the effect was not significant among those with prior use of belimumab, rituximab or corticosteroids. CONCLUSIONS: Certain chronic comorbidities and SLE medications increase the odds of progression to severe COVID-19 among patients with SLE, but vaccination confers significant protection. Vaccine effectiveness may be attenuated by SLE treatments. Protective measures such as pre-exposure prophylaxis and booster vaccines should be encouraged among patients with SLE.

Learning Needs of Patients with Cancer and a Pre-Existing Autoimmune Disease Who Are Candidates to Receive Immune Checkpoint Inhibitors.

Patients with pre-existing autoimmune disorders and cancer considering immune checkpoint inhibitors (ICIs) need to receive balanced information about the benefits and risk of developing immune-related adverse events (irAEs) and flare-ups of their autoimmune disease. To assess the learning needs of patients with cancer and pre-existing autoimmune disease regarding ICI treatment, we interviewed 29 patients with autoimmune disease and cancer from a comprehensive cancer center, of whom 20 had received ICI and 9 were candidates to receive ICI at a US Cancer Center. In-depth semi-structured interviews were conducted from August 2021 and January 2022. Interviewee's opinions and preferences about content and information delivery methods were collected. We recorded and transcribed interviews and analyzed them using thematic analysis. Half of the participants were female, and their median (SD) age was 62.9 (±10.9) years. The identified health information needs included the following: (1) information on irAEs and autoimmune disease flare-ups; (2) benefits of ICI; (3) ICI mechanism in the context of autoimmune disease; (4) management of flare-ups; (5) reasons for stopping or modifying cancer or autoimmune disease treatment; (6) likelihood of autoimmune disease progression or organ damage; and (7) lifestyle changes that could help avoid irAEs. Patients who had received ICI and those who had not yet received treatment reported similar needs, although patients who had received ICI had more questions about cancer treatment modifications. Patients also expressed the need to better understand when to contact their provider and how to share information with multiple providers. Most patients wanted to receive information in visual formats for review at home and at their own pace. Patients expressed interest in having educational tools to facilitate shared decision-making with their physicians, and they identified several areas of health information concerning therapy with ICI. They also highlighted the importance of communication among their various providers.

Physician Views on the Provision of Information on Immune Checkpoint Inhibitor Therapy to Patients with Cancer and Pre-Existing Autoimmune Disease: A Qualitative Study.

Immune checkpoint inhibitors (ICIs) have improved cancer outcomes but can cause severe immune-related adverse events (irAEs) and flares of autoimmune conditions in cancer patients with pre-existing autoimmune disease. The objective of this study was to identify the information physicians perceived as most useful for these patients when discussing treatment initiation with ICIs. Twenty physicians at a cancer institution with experience in the treatment of irAEs were interviewed. Qualitative thematic analysis was performed to organize and interpret data. The physicians were 11 medical oncologists and 9 non-oncology specialists. The following themes were identified: (1) current methods used by physicians to provide information to patients and delivery options; (2) factors to make decisions about whether or not to start ICIs in patients who have cancer and pre-existing autoimmune conditions; (3) learning points for patients to understand; (4) preferences for the delivery of ICI information; and (5) barriers to the implementation of ICI information in clinics. Regarding points to discuss with patients, physicians agreed that the benefits of ICIs, the probability of irAEs, and risks of underlying autoimmune condition flares with the use of ICIs were most important. Non-oncologists were additionally concerned about how ICIs affect the autoimmune disease (e.g., impact on disease activity, need for changes in medications for the autoimmune disease, and monitoring of autoimmune conditions).

Schnitzler syndrome.

A woman in her late 40s with a history of psoriatic arthritis presented to us with fever, migratory rash, cervical and axillary lymphadenopathy, and generalised myalgia. Her symptoms did not improve with steroids and her inflammatory markers were in the range of 200 mg/dL for C-reactive protein, erythrocyte sedimentation rate of 71 mm/hour and ferritin of 4000 ng/mL. Infectious workup was negative. Haematological malignancy and autoimmune conditions were among the top differentials, and she was eventually diagnosed with Schnitzler syndrome. A multidisciplinary team consisting of internal medicine, rheumatology, infectious disease and haematology-oncology specialists was involved in the care of this patient. We highlight the diagnostic schema that was followed for this rare and unique constellation of symptoms.

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.

2022 American College of Rheumatology Guideline for Vaccinations in Patients With Rheumatic and Musculoskeletal Diseases.

OBJECTIVE: To provide evidence-based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs). METHODS: This guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review for the PICO questions, graded the quality of evidence, and produced an evidence report. An expert Voting Panel reviewed the evidence and formulated recommendations. The panel included adult and pediatric rheumatology providers, infectious diseases specialists, and patient representatives. Consensus required ≥70% agreement on both the direction and strength of each recommendation. RESULTS: This guideline includes expanded indications for some vaccines in patients with RMDs, as well as guidance on whether to hold immunosuppressive medications or delay vaccination to maximize vaccine immunogenicity and efficacy. Safe approaches to the use of live attenuated vaccines in patients taking immunosuppressive medications are also addressed. Most recommendations are conditional and had low quality of supporting evidence. CONCLUSION: Application of these recommendations should consider patients' individual risk for vaccine-preventable illness and for disease flares, particularly if immunosuppressive medications are held for vaccination. Shared decision-making with patients is encouraged in clinical settings.

2022 American College of Rheumatology Guideline for Vaccinations in Patients With Rheumatic and Musculoskeletal Diseases.

OBJECTIVE: To provide evidence-based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs). METHODS: This guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review for the PICO questions, graded the quality of evidence, and produced an evidence report. An expert Voting Panel reviewed the evidence and formulated recommendations. The panel included adult and pediatric rheumatology providers, infectious diseases specialists, and patient representatives. Consensus required ≥70% agreement on both the direction and strength of each recommendation. RESULTS: This guideline includes expanded indications for some vaccines in patients with RMDs, as well as guidance on whether to hold immunosuppressive medications or delay vaccination to maximize vaccine immunogenicity and efficacy. Safe approaches to the use of live attenuated vaccines in patients taking immunosuppressive medications are also addressed. Most recommendations are conditional and had low quality of supporting evidence. CONCLUSION: Application of these recommendations should consider patients' individual risk for vaccine-preventable illness and for disease flares, particularly if immunosuppressive medications are held for vaccination. Shared decision-making with patients is encouraged in clinical settings.

Identification of outcome domains in immune checkpoint inhibitor-induced inflammatory arthritis and polymyalgia rheumatica: A scoping review by the OMERACT irAE working group.

INTRODUCTION: Immune checkpoint inhibitors (ICI), increasingly used cancer therapeutics, can cause off-target inflammatory effects called immune-related adverse events (irAEs), including ICI-induced inflammatory arthritis (ICI-induced IA) and polymyalgia rheumatica (ICI-induced PMR). There are no validated classification criteria or outcome measures for these conditions, and adaptation of treatment recommendations from corresponding rheumatic diseases may not be appropriate. We summarized clinical descriptors of ICI-induced IA and ICI-induced PMR and aggregated domains used for these conditions in order to inform the development of a core set of outcome domains. METHODS: As the initial step of the core domain set generation process, we systemically searched Medline (Pubmed), EMBASE, Cochrane, and CINHL through March 2021 to identify all studies that provide both clinical descriptions and domains relevant to ICI-induced IA and ICI-induced PMR. Domains were mapped to core areas, such as pathophysiological manifestations, life impact, resource use, and longevity/survival, as suggested by the OMERACT 2.1 Filter. RESULTS: We identified 69 publications, over a third of which utilized non-specific diagnoses of "arthritis," "arthralgia," and/or "PMR". Other publications provided the number, the distribution and/or names of specific joints affected, while others labeled the irAE as the corresponding rheumatic disease, such as rheumatoid arthritis or spondyloarthritis. Most distinct domains mapped to the pathophysiology/manifestations core area (24 domains), such as signs/symptoms (13 domains), labs (6 domains), and imaging (5 domains), with harm domains of adverse effects from irAE treatment and fear of irAE treatment decreasing ICI efficacy. Forty-three publications also referenced irAE treatment and 35 subsequent response, as well as 32 tumor response. CONCLUSION: There is considerable heterogeneity in the domains used to clinically characterize ICI-induced IA and ICI-induced PMR. There were several domains mapped to the pathophysiologic manifestations core area, although several publications highlighted domains evenly distributed among the other core areas of life impact, longevity/survival and resource use.

American College of Rheumatology Guidance for COVID-19 Vaccination in Patients With Rheumatic and Musculoskeletal Diseases: Version 5.

OBJECTIVE: To provide guidance to rheumatology providers on the use of COVID-19 vaccines for patients with rheumatic and musculoskeletal diseases (RMDs). METHODS: A task force was assembled that included 9 rheumatologists/immunologists, 2 infectious diseases specialists, and 2 public health physicians. After agreeing on scoping questions, an evidence report was created that summarized the published literature and publicly available data regarding COVID-19 vaccine efficacy and safety, as well as literature for other vaccines in RMD patients. Task force members rated their agreement with draft consensus statements on a 9-point numerical scoring system, using a modified Delphi process and the RAND/University of California Los Angeles Appropriateness Method, with refinement and iteration over 2 sessions. Consensus was determined based on the distribution of ratings. RESULTS: Despite a paucity of direct evidence, statements were developed by the task force and agreed upon with consensus to provide guidance for use of the COVID-19 vaccines, including supplemental/booster dosing, in RMD patients and to offer recommendations regarding the use and timing of immunomodulatory therapies around the time of vaccination. CONCLUSION: These guidance statements are intended to provide direction to rheumatology health care providers on how to best use COVID-19 vaccines and to facilitate implementation of vaccination strategies for RMD patients.

Immune checkpoint inhibitor induced myocarditis, myasthenia gravis, and myositis: A single-center case series.

BACKGROUND: Immune checkpoint inhibitors can result in overlap syndrome comprised of myasthenia gravis, myositis and myocarditis. However, the mortality predictors have not been clearly delineated. METHODS: We examined the characteristics of 11 patients diagnosed with overlap syndrome at Cleveland Clinic. All the available clinical, diagnostic, biochemical and disease specific factors were examined. Clinical predictors of increased mortality were using student t-test for parametric data and Wilcoxon-signed rank testing for nonparametric data. RESULTS: Seven patients out of eleven patients were alive during the analysis. Our study did confirm that troponins were indicator of early demise. However, study showed that elevated creatinine, BUN, and decreased hemoglobin were also observed in patients who met early demise. Unlike previously published studies, elevated NT Pro-BNP and reduced left ventricular ejection fraction were not a seen in this study. However, there were higher incidence of electrical abnormalities in deceased patients when compared to alive. CONCLUSION: Our study is first to examine various clinical parameters of overlap syndrome that might be predictive of mortality. This study confirms troponin as possible predictor and adds elevated creatinine, BUN and reduced hemoglobin as possible early biomarkers in deceased patients. The analysis showed that reduced LVEF was not a seen in deceased patients.

Long COVID and rheumatology: Clinical, diagnostic, and therapeutic implications.

As of this writing, it is estimated that there have been nearly 600 million cases of coronavirus disease 2019 (COVID-19) around the world with over six million deaths. While shocking, these figures do not fully illustrate the morbidity associated with this disease. It is also estimated that between 10% and 30% of those who survive COVID-19 develop persistent symptoms after the acute infection has passed. These individuals, who most often experienced initial infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) considered mild to moderate in severity, often display a broad array of symptoms. Collectively, this disorder or syndrome is now referred to as Long COVID (among other designations), and it represents a national/international health crisis. The most frequently reported symptoms associated with Long COVID include chronic fatigue with post exertional features, neurocognitive dysfunction, breathlessness, and somatic pain. Long COVID can range in severity from mild to severely debilitating, with resultant loss of quality of life and productivity. For now, there are many unanswered questions surrounding Long COVID: how can it be best defined, what is needed for accurate diagnosis, what is causing it, and how should it be best managed. How rheumatologists will engage in the Long COVID pandemic is another question; at the minimum, we will be called upon to evaluate and manage our own patients with immune-mediated inflammatory diseases who have developed it. This review focuses on addressing the disease essentials, providing both declarative and procedural knowledge to prepare rheumatologists for how to address Long COVID: understanding its origins, its current case definitions, epidemiology, pathobiology and clinical manifestations. Finally, it will provide an outline on how to clinically approach patients with possible Long COVID and initiate treatment and/or guide them on how to best manage it.

Outpatient Management of COVID-19: A Primer for the Dermatologist.

Purpose of Review: To summarize diagnostic and therapeutic management of COVID-19 in the outpatient setting for dermatologists. Recent Findings: Paxlovid (nirmatrelvir-ritonavir) is the preferred treatment in patients with mild symptoms at high risk of progression to severe SARS-CoV2 infection. Additional options include monoclonal antibodies (bebtelovimab), remdesivir, and molnupiravir. Summary: Dermatologists need to be aware of recent developments in diagnostic and therapeutic management of COVID-19 in the outpatient setting, as their patients may rely on dermatologists to provide advice, particularly in cases where treatments for dermatological disease may impact the risk of COVID-19 and/or vaccine efficacy. Supplementary Information: The online version contains supplementary material available at 10.1007/s13671-022-00368-3.