Diagnosing and Treating Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still's Disease as Part of the Still's Disease Continuum.

Aim: We have summarised the existing evidence supporting the concept that systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) are part of the same Still's disease spectrum. Methods: A PubMed/Embase database search was conducted using specific search strings and free text words to screen for relevant articles. The search was limited to studies in humans, published up to June 2023, in English-language. Summary: sJIA and AOSD are rare autoinflammatory disorders that have similar pathophysiological and clinical features. The clinical presentations of sJIA and AOSD are highly variable, with differential diagnoses that include a broad range of malignancies, infectious diseases, and autoimmune disorders, which contribute to delays in diagnosis. Several sets of classification exist to help diagnose patients in clinical practice; the International League of Associations for Rheumatology criteria for sJIA and the Yamaguchi and Fautrel criteria for AOSD are the most-used criteria. The therapeutic strategy for Still's disease aims to relieve signs and symptoms, prevent irreversible joint damage and potentially life-threatening complications, and avoid deleterious side effects of treatment. Recently, targeted therapies such as interleukin (IL)-1 and IL-6 inhibitors have become available for the treatment of sJIA and AOSD. While these biologics were originally largely reserved for patients in whom non-steroidal anti-inflammatory drugs, corticosteroids and conventional synthetic disease-modifying anti-rheumatic drugs had failed, they are increasingly used earlier in the treatment paradigm. Among IL-1 inhibitors, canakinumab is the only biologic approved in the US for the treatment of both sJIA and AOSD.

New insights on multigenic autoinflammatory diseases.

Autoinflammatory diseases are disorders of the innate immune system, which can be either monogenic due to a specific genetic mutation or complex multigenic due to the involvement of multiple genes. The aim of this review is to explore and summarize the recent advances in pathogenesis, diagnosis, and management of genetically complex autoinflammatory diseases, such as Schnitzler's syndrome; adult-onset Still's disease; synovitis, acne, pustulosis, hyperostosis, osteitis syndrome/chronic recurrent multifocal osteomyelitis/chronic non-bacterial osteomyelitis; Adamantiades-Behçet's disease; Yao syndrome; and periodic fever with aphthous stomatitis, pharyngitis, and adenitis syndrome. The PubMed database was screened for relevant articles using free text words and specific search strings. The search was limited to English-language articles, reporting the results of studies in humans, published through March 2021. Evidence from literature suggest that these rare multigenic autoinflammatory diseases can present with different clinical features and the diagnosis of these diseases can be challenging due to a combination of nonspecific manifestations that can be seen in a variety of other conditions. Diagnostic delays and disease complications may occur due to low disease awareness and the lack of pathognomonic markers. The pathogeneses of these diseases are complex and in some cases precise pathogenesis is not clearly understood. Conventional treatments are commonly used for the management of these conditions, but biologics have shown promising results. Biologics targeting proinflammatory cytokines including IL-1, IL-6, TNF-α, IL-17A and IL-18 have been shown to ameliorate signs and symptoms of different multigenic autoinflammatory diseases.

Clinical Burden and Unmet Need in Recurrent Pericarditis: A Systematic Literature Review.

Inflammation of the pericardium (pericarditis) is characterized by excruciating chest pain. This systematic literature review summarizes clinical, humanistic, and economic burdens in acute, especially recurrent, pericarditis, with a secondary aim of understanding United States treatment patterns and outcomes. Short-term clinical burden is well characterized, but long-term data are limited. Some studies report healthcare resource utilization and economic impact; none measure health-related quality-of-life. Pericarditis is associated with infrequent but potentially life-threatening complications, including cardiac tamponade (weighted average: 12.7% across 10 studies), constrictive pericarditis (1.84%; 9 studies), and pericardial effusion (54.7%; 16 studies). There are no approved pericarditis treatments; treatment guidelines, when available, are inconsistent on treatment course or duration. Most recommend first-line use of conventional treatments, for example, nonsteroidal antiinflammatory drugs with or without colchicine; however, 15-30% of patients experience recurrence. Second-line therapy may involve conventional therapies plus long-term utilization of corticosteroids, despite safety issues and the difficulty of tapering or discontinuation. Other exploratory therapies (eg, azathioprine, immunoglobulin, methotrexate, anakinra) present steroid-sparing options, but none are supported by robust clinical evidence, and some present tolerability challenges that may impact adherence. Pericardiectomy is occasionally pursued in treatment-refractory patients, although data are limited. This lack of an evidence-based treatment pathway for patients with recurrent disease is reflected in readmission rates, for example, 12.2% at 30 days in 1 US study. Patients with continued recurrence and inadequate treatment response need approved, safe, accessible treatments to resolve pericarditis symptoms and reduce recurrence risk without excessive treatment burden.

Expansion of Phenotypic and Genotypic Spectrum in Yao Syndrome: A Case Series.

OBJECTIVES: Yao syndrome (YAOS; OMIM 617321) was formerly termed nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-associated autoinflammatory disease. This study sought to report novel findings related to this disease. METHODS: A medical records review analysis of a case series was conducted, and all patients fulfilled the diagnostic criteria for YAOS and underwent comprehensive diagnostic workups, including molecular genotyping of blood specimens for periodic fever syndromes and NOD2-associated disease. RESULTS: A total of 11 patients with YAOS were analyzed, and all were Whites with a median age of 25.9 years at disease onset. All patients shared the similar autoinflammatory phenotype of YAOS. Among the 11 patients, we identified 7 patients who had the known phenotype of YAOS, as well as recurring and brief eyelid swelling with or without eyelid discoloration or conjunctivitis. Molecular analysis of blood cells using periodic fever gene panel has identified the presence of NOD2 variants in all 11 patients. Apart from the known YAOS-associated common NOD2 genotype, 5 novel and unknown significance NOD2 variants were identified in patients who presented with typical phenotype of YAOS. CONCLUSIONS: This study provides novel clinical and molecular data for YAOS and supports the expansion of the phenotypic and genotypic spectrum of the disease.

Role of non-invasive multimodality imaging in autoimmune pericarditis.

Systemic autoimmune diseases are an important cause of pericardial involvement and contribute to up to ∼22% cases of pericarditis with a known aetiology. The underlying mechanism for pericardial involvement varies with each systemic disease and leads to a poor understanding of its management. Multimodality imaging establishes the diagnosis and determines the type and extent of pericardial involvement. In this review, we elaborate upon various pericardial syndromes associated with different systemic autoimmune and autoinflammatory diseases and the multitude of imaging modalities that can be used to further characterize autoimmune pericardial involvement. Lastly, these forms of pericarditis have a greater likelihood of recurrence, and clinicians need to understand their unique treatment approaches to improve patient outcomes.

US Database Study of Clinical Burden and Unmet Need in Recurrent Pericarditis.

Background Patients with recurrent pericarditis (RP) may develop complications, multiple recurrences, or inadequate treatment response. This study aimed to characterize disease burden and unmet needs in RP. Methods and Results This retrospective US database analysis included newly diagnosed patients with RP with ≥24 months of continuous history following their first pericarditis episode. RP was defined as ≥2 pericarditis episodes ≥28 days apart. Some patients had ≥2 recurrences, while others had a single recurrence with a serious complication, ie, constrictive pericarditis, cardiac tamponade, or a large pericardial effusion with pericardiocentesis/pericardial window. Among these patients with multiple recurrences and/or complications, some had features relating to treatment history, including long-term corticosteroid use (corticosteroids started within 30 days of flare, continuing ≥90 consecutive days) or inadequate treatment response (pericarditis recurring despite corticosteroids and/or colchicine, or other drugs [excluding NSAIDs] within 30 days of flare, or prior pericardiectomy). Patients (N=2096) had hypertension (60%), cardiomegaly (9%), congestive heart failure (17%), atrial fibrillation (16%), autoimmune diseases (18%), diabetes mellitus (21%), renal disease (20%), anxiety (21%), and depression (14%). Complications included pericardial effusion (50%), cardiac tamponade (9%), and constrictive pericarditis (4%). Pharmacotherapy included colchicine (51%), NSAIDs (40%), and corticosteroids (30%), often in combination. This study estimates 37 000 US patients with RP; incidence was 6.0/100 000/year (95% CI, 5.6‒6.3), and prevalence was 11.2/100 000 (95% CI, 10.6‒11.7). Conclusions Patients with RP may have multiple recurrences and/or complications, often because of inadequate treatment response and persistent underlying disease. Corticosteroid use is frequent despite known side-effect risks, potentially exacerbated by prevalent comorbidities. Substantial clinical burden and lack of effective treatments underscore the high unmet need.

The transcriptome of rabbit conjunctiva in dry eye disease: Large-scale changes and similarity to the human dry eye.

The pathophysiology of dry eye disease (DED) remains largely unknown, accounting in part for the lack of successful treatments. We explored the pathophysiology of DED using a rabbit model of chronic DED induced with 3 weekly injections of Concanavalin A into the periorbital lacrimal glands. The transcriptome of full-thickness's conjunctival tissue from rabbits with DED and from normal controls was determined using microarrays and, as needed, confirmatory real-time polymerase chain reactions. Results were subjected to bioinformatic analysis. DED induced large-scale changes in gene transcription involving 5,184 genes (22% of the total). Differentially expressed genes could be segregated into: functional modules and clusters; altered pathways; functionally linked genes; and groups of individual genes of known or suspected pathophysiological relevance to DED. A common feature of these subgroups is the breadth and magnitude of the changes that encompass ocular immunology and essentially all aspects of cell biology. Prominent changes concerned innate and adaptive immune responses; ocular surface inflammation; at least 25 significantly altered signaling pathways; a large number of chemokines; cell cycle; and apoptosis. Comparison of our findings to the limited extant transcriptomic data from DED patients associated with either Sjogren's syndrome or non-Sjogren's etiologies revealed a significant correlation between human and rabbit DED transcriptomes. Our data, establishing the large-scale transcriptomic changes of DED and their potential similarity to the human, underscore the enormous complexity of DED; establish a robust animal model of DED; will help expand our understanding of its pathophysiology; and could guide the development of successful therapeutic strategies.

Adult-onset Still's disease in focus: Clinical manifestations, diagnosis, treatment, and unmet needs in the era of targeted therapies.

BACKGROUND: Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology, characterized by a clinical triad of high spiking fever, arthralgia (± arthritis), and evanescent skin rash. Management of AOSD poses several challenges, including difficulty in diagnosis and limited therapeutic options. In this review, we examined whether AOSD and systemic juvenile idiopathic arthritis (SJIA) represent a continuum of the same disease. We also explored the latest available evidence related to prevalence, clinical and laboratory manifestations, complications, diagnostic challenges, novel biomarkers, and treatment options in the era of biologics and identified the unmet needs of patients with AOSD. METHODS: A comprehensive systematic literature search was performed in the Embase and MEDLINE (via PubMed) literature databases. The search was limited to human studies published in English from inception up to March 2020. Additionally, abstracts presented at various conferences were screened and hand searches were performed. Publications were processed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: A total of 123 publications were identified through the literature search, majority of which were case series and retrospective observational studies. AOSD and SJIA are widely considered part of the same disease spectrum owing to similarities in their clinical and biological features. The clinical presentation of AOSD is highly variable, accompanied by a broad spectrum of disease manifestations. Recent evidence suggests that the AOSD disease course can be classified into two distinct categories: "systemic" and "articular." Furthermore, AOSD patients may experience various life-threatening complications, such as macrophage activation syndrome - reported in as high as 23% of AOSD patients and considered to be the most severe complication characterized by a high mortality rate. The ambiguity in presentation and lack of serologic markers make the diagnosis of AOSD difficult, often leading to a delay in diagnosis. Given these limitations, the Yamaguchi and Fautrel criteria are the most widely used diagnostic tools in clinical practice. It has been observed that a clinical diagnosis of AOSD is generally reached by exclusion while investigating a patient with fever of unknown origin. Recent advances have demonstrated a major role of proinflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-18, and IL-37, and other biomarkers in the pathogenesis and management of AOSD. Owing to the rarity of the disease, there are very limited clinical trials evaluating management strategies for AOSD. The current AOSD treatment paradigm includes non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids initially, conventional synthetic disease-modifying anti-rheumatic drugs in steroid-refractory patients, and biologics in those resistant to conventional treatment. Only a few country-specific guidelines for the management of AOSD have been published, and a treat-to-target approach, as previously recommended for SJIA, is still lacking. Canakinumab is the only FDA-approved biologic for the treatment of AOSD. CONCLUSION: Emerging evidence supports that AOSD and SJIA represent a continuum of the same disease entity. Despite advancements in the understanding of AOSD, it continues to pose a substantial burden on patients and the healthcare systems, and substantial unmet needs exist across key domains such as the pathway to diagnosis, use of biomarkers in clinical practice, and standardized treatment strategies. Further research and collaboration is crucial for optimizing the diagnosis and management of AOSD patients.

Burden of Recurrent Pericarditis on Health-Related Quality of Life.

The extent to which recurrences of pericarditis episodes impact patients' health-related quality of life (HRQOL) remains poorly understood. This study aimed to evaluate HRQOL and work productivity in patients with recurrent pericarditis (RP). Adult patients from a centralized recruitment database for the rilonacept Phase 2/3 clinical trials were invited to participate in a survey. Inclusion criteria were confirmed RP diagnosis and ≥1 recurrence within the previous 12 months. The 11-Point Pain Numeric Rating Scale, Patient Global Impression of Pericarditis Severity, Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health v1.2, PROMIS Short Form Sleep Disturbance 8b, Work Productivity and Activity Impairment v2.0, and customized questions about fear and economic impact were used. In total, 83 patients (55% female, average age = 49.3 years) completed the survey. The median time since pericarditis diagnosis was 3.0 years at the time of survey completion; 49% experienced ≥3 recurrences in the previous 12 months. Forty percent had an emergency room visit, and 25% were hospitalized for their most recent recurrence. Sixty-six percent of participants rated the symptoms of their last recurrence as severe. The mean value for worst pericarditis pain (0 to 10 scale) during the most recent recurrence was 6.1. The average T-scores for PROMIS physical and mental health were 37.6 and 42.8, respectively, compared with 50 in the general population. Participants reported 50% of overall work impairment and 62% of activity impairment due to RP. In conclusion, patients with RP experienced a high number of recurrences with severe symptoms that substantially reduced their HRQOL and work productivity.

Pericarditis in Systemic Rheumatologic Diseases.

PURPOSE OF REVIEW: We review the epidemiology, pathophysiology, and management of pericarditis most commonly complicating autoimmune and autoinflammatory conditions. RECENT FINDINGS: Typically, pericarditis occurs in the context of a systemic flare of the underlying disease but infrequently, it is the presenting manifestation requiring a high index of suspicion to unravel the indolent cause. Pericardial involvement in rheumatic diseases encompasses a clinical spectrum to include acute, recurrent and incessant pericarditis, constrictive pericarditis, asymptomatic pericardial effusion, and pericardial tamponade. Direct evidence on the pathophysiology of pericarditis in the context of rheumatic diseases is scant. It is theorized that immune perturbations within pericardial tissue result from the underlying central immunopathology of the respective autoimmune or autoinflammatory disease. Pericarditis management depends on acuity, the underlying cause and epidemiological features such as patient's immune status and geographic prevalence of infections such as tuberculosis. Immunosuppressive medications including biologics such as interleukin 1 blockers emerge as possible steroid sparing agents for pericarditis treatment.

Multimodality imaging in patients with post-cardiac injury syndrome.

This review article is focused on the role of echocardiography, cardiac CT and cardiac magnetic resonance (CMR) imaging in diagnosing and managing patients with post-cardiac injury syndrome (PCIS). Clinically, the spectrum of pericardial diseases under PCIS varies not only in form and severity of presentation but also in the timing varying from weeks to months, thus making it difficult to diagnose. Pericarditis developing after recent or remote myocardial infarction, cardiac surgery or ablation if left untreated or under-treated could worsen into complicated pericarditis which can lead to decreased quality of life and increased morbidity. Colchicine in combination with other anti-inflammatory agents (non-steroidal anti-inflammatory drugs) is proven to prevent and treat acute pericarditis as well as its relapses under various scenarios. Imaging modalities such as echocardiography, CT and CMR play a pivotal role in diagnosing PCIS especially in difficult cases or when clinical suspicion is low. Echocardiography is the tool of choice for emergent bedside evaluation for cardiac tamponade and to electively study the haemodynamics impact of constrictive pericarditis. CT can provide information on pericardial thickening, calcification, effusions and lead perforations. CMR can provide pericardial tissue characterisation, haemodynamics changes and guide long-term treatment course with anti-inflammatory agents. It is important to be familiar with the indications as well as findings from these multimodality imaging tools for clinical decision-making.

Somatic mosaicism in adult-onset TNF receptor-associated periodic syndrome (TRAPS).

BACKGROUND: Somatic mosaicism is to date an uncommon finding in genetic autoinflammatory syndromes such as Cryopyrin-associated periodic syndrome, Blau syndrome, and TNF receptor-associated periodic syndrome (TRAPS). However, somatic mosaicism may be particularly important in adult-onset or atypical phenotypes of these conditions. Herein, we report a unique adult-onset TRAPS patient presenting with intermittent daily fever for 3 weeks, rash, peritonitis, and lymphadenopathy, who was found with hematopoietic mosaicism involving different white blood cell populations. METHODS: Patient's lymphocyte genomic DNA was initially analyzed by periodic fever seven-gene next-generation sequencing panel. Genomic DNAs extracted from patient's hair roots, buccal swab, and subpopulations of white blood cells were subsequently examined on the identified TNFRSF1A variant using Sanger sequencing. RESULTS: A de novo mosaic missense variant, c.265 T>C(p.Phe89Leu), in the TNFRSF1A gene was found in the patient's buccal swab, B cells, neutrophils, and NK cells but not detected in monocytes, T cells, and hair roots. CONCLUSION: These data provide additional information about somatic mosaicism in autoinflammatory conditions and provide new insights regarding cellular players that are indispensable for the phenotypic expression of TRAPS.

Myalgia and Arthralgia Immune-related Adverse Events (irAEs) in Patients With Genitourinary Malignancies Treated With Immune Checkpoint Inhibitors.

BACKGROUND: Myalgia and arthralgia immune-related adverse events (irAEs) in patients treated with checkpoint inhibitors (CPIs) present a clinical challenge. We describe the clinical characteristics and treatment of myalgia and arthralgia irAEs in CPI-treated patients with genitourinary (GU) malignancies. PATIENTS AND METHODS: Patients with GU malignancies who were treated with CPIs and developed myalgia and arthralgia irAEs that resulted in interruption or discontinuation of CPI therapy were reviewed. Patient-, disease-, and irAE-related data were collected and analyzed. RESULTS: Twenty-one patients were identified. Eighteen (86%) had renal cell carcinoma; 3 (14%) had urothelial carcinoma. The majority (71%) were male; the median age at diagnosis was 56 years (range, 36-78 years). CPI therapy included anti-programmed death-ligand 1 (29%), anti-programmed cell death protein 1 (48%), and combined programmed cell death protein 1/cytotoxic T-lymphocyte-associated protein 4 antibodies (24%). The median time from CPI initiation to myalgia and arthralgia irAE was 5.1 months (range, 0.23-50.5 months). All patients were treated with prednisone with a median initial dose of 40 mg/d (range, 10-90 mg/d) for a median duration of 64 weeks (range, 3-242 weeks). Treatment with methotrexate (14%), infliximab (14%), tocilizumab (10%), gabapentin (10%), and etanercept (5%) was also required in some patients. Six (29%) patients restarted CPI therapy following symptom improvement, 3 (15%) switched to a subsequent therapy, and 12 (55%) patients had an ongoing sustained response to therapy (median, 14.5 months; range, 3-55 months) despite no subsequent anti-cancer therapy. CONCLUSION: Myalgia and arthralgia irAEs in CPI-treated patients with GU malignancies vary in timing of presentation, severity, and treatment. Multidisciplinary teams that include a rheumatologist are critical for optimal management. Durable response to CPIs can be maintained even after therapy discontinuation.

Quantitative assessment of pericardial delayed hyperenhancement helps identify patients with ongoing recurrences of pericarditis.

Objectives: Recurrences of pericarditis (RP) are often difficult to diagnose due to lack of clinical signs and symptoms during subsequent episodes. We aimed to investigate the value of quantitative assessment of pericardial delayed hyperenhancement (DHE) in diagnosing ongoing recurrences of pericarditis. Methods: Quantitative DHE was measured in 200 patients with established diagnosis of RP using cardiac MRI. Conventional clinical criteria for diagnosis of pericarditis were ≥2 of the following: chest pain, pericardial rub, ECG changes and new or worsening pericardial effusion. Results: A total of 67 (34%) patients were identified as having ongoing episode of recurrence at the time of DHE measurements. In multivariable analysis, chest pain (OR: 10.9, p<0.001) and higher DHE (OR: 1.32, p<0.001) were associated with ongoing recurrence of RP. Addition of DHE to conventional clinical criteria significantly increased the ability to diagnose ongoing recurrence (net reclassification improvement (NRI): 0.80, p<0.001; integrated discrimination improvement (IDI): 0.12, p<0.001). Among 150 patients with history of RP who presented with chest pain, higher DHE was still independently associated with ongoing recurrence (OR: 1.28, p<0.001), showed incremental value over clinical criteria (NRI: 0.76, p<0.001; IDI: 0.13, p<0.001) and demonstrated a sensitivity of 70% and specificity of 74%. Conclusion: Among patients with RP, quantitative DHE provided incremental information to diagnose ongoing recurrences over conventional clinical criteria of pericarditis. Quantitative DHE demonstrated acceptable test characteristics to diagnose ongoing recurrence even in RP patients presenting with chest pain.

Complicated Pericarditis: Understanding Risk Factors and Pathophysiology to Inform Imaging and Treatment.

Most patients with acute pericarditis have a benign course and a good prognosis. However, a minority of patients develop complicated pericarditis, and the care of these patients is the focus of this review. Specifically, we address risk factors, multimodality imaging, pathophysiology, and novel treatments. The authors conclude that: 1) early high-dose corticosteroids, a lack of colchicine, and an elevated high-sensitivity C-reactive protein are associated with the development of complicated pericarditis; 2) in select cases, cardiovascular magnetic resonance imaging may aid in the assessment of pericardial inflammation and constriction; 3) given phenotypic similarities between recurrent idiopathic pericarditis and periodic fever syndromes, disorders of the inflammasome may contribute to relapsing attacks; and 4) therapies that target the inflammasome may lead to more durable remission and resolution. Finally, regarding future investigations, the authors discuss the potential of cardiovascular magnetic resonance to inform treatment duration and the need to compare steroid-sparing treatments to pericardiectomy.

Janus kinase inhibitors in autoimmune diseases.

Biological therapies directed at proinflammatory cytokines have irrevocably changed the landscape of treatment of rheumatoid arthritis (RA) and other autoimmune diseases. With the advances in our knowledge in cytokine signalling, the question emerges whether targeting intracellular signalling might also be a safe and efficacious strategy. Janus kinases or Jaks are critical for a large family of cytokines and the first Jak inhibitors has been approved by the FDA. It is therefore timely to consider this new category of drugs and reflect on their potential roles, present and future, in the treatment of RA and related disorders.