Interferon pathway lupus risk alleles modulate risk of death from acute COVID-19.

Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR = 29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in antiviral immunity.

Novel mutation in the NRLP3 manifesting as an intermediate phenotype of cryopyrinopathies.

Cryopyrin-associated periodic syndromes (CAPS) are a group of autoinflammatory diseases associated with NLRP3 gain of function mutations. CAPS associated mutations are found predominantly in exon 3. The objective of this study is to describe a new variant on NRLP3 gene and its phenotype. Case report description of a new NRLP3 pathogenic variant and literature case-based search through INFEVERS database. A 21-year old male who presented multiple tonic-clonic seizures on his 3rd day of life. At age 2, he had recurrent central facial palsy, high fever (40 °C), painful and persistent oral ulcers, abdominal pain, nausea and vomiting, and delayed neuropsychomotor development, with polyarthritis in wrists and knees. Over the years, several symptoms were observed: livedo reticularis, Raynaud's phenomenon, positive pathergy test, heat allodynia, extremely painful genital ulcers, and sporadic conjunctivitis. Laboratory studies revealed persistently elevated inflammatory markers and serum amyloid protein A (30 µg/l). The genetic panel for autoinflammatory diseases revealed heterozygous mutation in the NLRP3, (c.2068G > C, p.E690Q) with 0% of frequency in the general population. The patient denies rash and did not have frontal bossing or patellar overgrowth. We found a positive familial history on mother and brother, who carried the same mutation. The patient was started on canakinumab which controlled his symptoms. Currently, 241 missense variants in the NLRP3 have been described. We presented a new mutation in exon 3 of the NRLP3 gene in a patient that fulfills clinical criteria for CAPS who had complete clinical response to Canakinumab, supporting the idea that this mutation is pathogenic.

Type I interferon in rheumatic diseases.

The type I interferon pathway has been implicated in the pathogenesis of a number of rheumatic diseases, including systemic lupus erythematosus, Sjögren syndrome, myositis, systemic sclerosis, and rheumatoid arthritis. In normal immune responses, type I interferons have a critical role in the defence against viruses, yet in many rheumatic diseases, large subgroups of patients demonstrate persistent activation of the type I interferon pathway. Genetic variations in type I interferon-related genes are risk factors for some rheumatic diseases, and can explain some of the heterogeneity in type I interferon responses seen between patients within a given disease. Inappropriate activation of the immune response via Toll-like receptors and other nucleic acid sensors also contributes to the dysregulation of the type I interferon pathway in a number of rheumatic diseases. Theoretically, differences in type I interferon activity between patients might predict response to immune-based therapies, as has been demonstrated for rheumatoid arthritis. A number of type I interferon and type I interferon pathway blocking therapies are currently in clinical trials, the results of which are promising thus far. This Review provides an overview of the many ways in which the type I interferon system affects rheumatic diseases.

Patient-provider discordance between global assessments of disease activity in rheumatoid arthritis: a comprehensive clinical evaluation.

BACKGROUND: Discordance between patients with rheumatoid arthritis (RA) and their rheumatology health care providers is a common and important problem. The objective of this study was to perform a comprehensive clinical evaluation of patient-provider discordance in RA. METHODS: A cross-sectional observational study was conducted of consecutive RA patients in a regional practice with an absolute difference of ≥ 25 points between patient and provider global assessments (possible points, 0-100). Data were collected for disease activity measures, clinical characteristics, comorbidities, and medications. In a prospective substudy, participants completed patient-reported outcome measures and underwent ultrasonographic assessment of synovial inflammation. Differences between the discordant and concordant groups were tested using χ2 and rank sum tests. Multivariable logistic regression was used to develop a clinical model of discordance. RESULTS: Patient-provider discordance affected 114 (32.5%) of 350 consecutive patients. Of the total population, 103 patients (29.5%) rated disease activity higher than their providers (i.e., 'positive' discordance); only 11 (3.1%) rated disease activity lower than their providers and were excluded from further analysis. Positive discordance correlated with negative rheumatoid factor and anticyclic citrullinated peptide antibodies, lack of joint erosions, presence of comorbid fibromyalgia or depression, and use of opioids, antidepressants, or anxiolytics, or fibromyalgia medications. In the prospective study, the group with positive discordance was distinguished by higher pain intensity, neuropathic type pain, chronic widespread pain and associated polysymptomatic distress, and limited functional health status. Depression was found to be an important mediator of positive discordance in low disease activity whereas the widespread pain index was an important mediator of positive discordance in moderate-to-high disease activity states. Ultrasonography scores did not reveal significant differences in synovial inflammation between discordant and concordant groups. CONCLUSIONS: The findings provide a deeper understanding of patient-provider discordance than previously known. New insights from this study include the evidence that positive discordance is not associated with unrecognized joint inflammation by ultrasonography and that depression and fibromyalgia appear to play distinct roles in determining positive discordance. Further work is necessary to develop a comprehensive framework for patient-centered evaluation and management of RA and associated comorbidities in patients in the scenario of patient-provider discordance.

Rilonacept maintains long-term inflammatory remission in patients with deficiency of the IL-1 receptor antagonist.

BACKGROUND: Deficiency of IL-1 receptor antagonist (DIRA) is a rare autoinflammatory disease that presents with life-threatening systemic inflammation, aseptic multifocal osteomyelitis, and pustulosis responsive to IL-1-blocking treatment. This study was performed (a) to investigate rilonacept, a long-acting IL-1 inhibitor, in maintaining anakinra-induced inflammatory remission in DIRA patients, (b) to determine doses needed to maintain remission, and (c) to evaluate the safety and pharmacokinetics of rilonacept in young children (<12 years). METHODS: Six mutation-positive DIRA patients (children, ages 3-6 years), treated with daily anakinra, were enrolled into an open-label pilot study of subcutaneous rilonacept for 24 months. Clinical symptoms and inflammatory blood parameters were measured at all visits. A loading dose (4.4 mg/kg) was administered, followed by once weekly injections (2.2 mg/kg) for 12 months. Dose escalation (4.4 mg/kg) was allowed if inflammatory remission was not maintained. Subjects in remission at 12 months continued rilonacept for an additional 12 months. RESULTS: Five of six patients required dose escalation for findings of micropustules. Following dose escalation, all patients were in remission on weekly rilonacept administration, with stable laboratory parameters for the entire study period of 24 months. All children are growing at normal rates and have normal heights and weights. Quality of life improved while on rilonacept. No serious adverse events were reported. CONCLUSION: Rilonacept was found to maintain inflammatory remission in DIRA patients. The once weekly injection was well tolerated and correlated with increased quality of life, most likely related to the lack of daily injections. TRIAL REGISTRATION: ClinicalTrials.gov NCT01801449. FUNDING: NIH, NIAMS, and NIAID.