Progentec Diagnostics, Inc., and Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City.
DB Analytics, LLC, Dallas, Texas.
Arthritis Rheumatol. 2023 May;75(5):723-735. doi: 10.1002/art.42389. Epub 2023 Mar 6.
Systemic lupus erythematosus (SLE) is marked by immune dysregulation linked to varied clinical disease activity. Using a unique longitudinal cohort of SLE patients, this study sought to identify optimal immune mediators informing an empirically refined flare risk index (FRI) reflecting altered immunity prior to clinical disease flare.
Thirty-seven SLE-associated plasma mediators were evaluated by microfluidic immunoassay in 46 samples obtained in SLE patients with an imminent clinical disease flare (preflare) and 53 samples obtained in SLE patients without a flare over a corresponding period (pre-nonflare). SLE patients were selected from a unique longitudinal cohort of 106 patients with classified SLE (meeting the American College of Rheumatology 1997 revised criteria for SLE or the Systemic Lupus International Collaborating Clinics 2012 revised criteria for SLE). Autoantibody specificities, hybrid SLE Disease Activity Index (hSLEDAI) scores, clinical features, and medication usage were also compared at preflare (mean ± SD 111 ± 47 days prior to flare) versus pre-nonflare (99 ± 21 days prior to nonflare) time points. Variable importance was determined by random forest analysis with logistic regression subsequently applied to determine the optimal number and type of analytes informing a refined FRI.
Preflare versus pre-nonflare differences were not associated with demographics, autoantibody specificities, hSLEDAI scores, clinical features, nor medication usage. Forward selection and backward elimination of mediators ranked by variable importance resulted in 17 plasma mediator candidates differentiating preflare from pre-nonflare visits. A final combination of 11 mediators best informed a newly refined FRI, which achieved a maximum sensitivity of 97% and maximum specificity of 98% after applying decision curve analysis to define low, medium, and high FRI scores.
We verified altered immune mediators associated with imminent disease flare, and a subset of these mediators improved the FRI to identify SLE patients at risk of imminent flare. This molecularly informed, proactive management approach could be critical in prospective clinical trials and the clinical management of lupus.
系统性红斑狼疮（SLE）的特征是免疫失调，与各种临床疾病活动有关。本研究使用 SLE 患者的独特纵向队列，旨在确定最佳的免疫介质，以反映临床疾病发作前免疫改变的经验性改良发作风险指数（FRI）。
通过微流控免疫分析评估了 46 例 SLE 患者即将发生临床疾病发作（预发作）和 53 例 SLE 患者在相应时间段内无发作（预非发作）时的 37 种 SLE 相关血浆介质。SLE 患者选自 106 例分类 SLE 患者的独特纵向队列（符合美国风湿病学会 1997 年修订的 SLE 标准或系统性红斑狼疮国际协作临床 2012 年修订的 SLE 标准）。还比较了预发作（在发作前 111 ± 47 天）与预非发作（在非发作前 99 ± 21 天）时的自身抗体特异性、混合性 SLE 疾病活动指数（hSLEDAI）评分、临床特征和药物使用情况。随机森林分析确定了变量的重要性，随后应用逻辑回归确定了告知改良 FRI 的最佳分析物数量和类型。
预发作与预非发作的差异与人口统计学、自身抗体特异性、hSLEDAI 评分、临床特征或药物使用无关。根据变量重要性进行前向选择和后向消除中介物，结果有 17 种血浆介质区分了预发作和预非发作。最后，11 种介质的组合最佳地告知了新的改良 FRI，该组合通过应用决策曲线分析定义低、中、高 FRI 评分后，实现了 97%的最大敏感性和 98%的最大特异性。
我们验证了与即将发生的疾病发作相关的改变的免疫介质，其中一些介质改善了 FRI，以识别即将发生发作的 SLE 患者。这种基于分子的、主动的管理方法在前瞻性临床试验和狼疮的临床管理中可能至关重要。
