OBJECTIVE: Molecular medicine raised expectations for strategically targeted biologic agents in systemic lupus erythematosus (SLE), but clinical trial results have been disappointing and difficult to interpret. Most studies add investigational agents to various, often effective, standard therapy immunosuppressants used at baseline, with unknown treatment interactions. Eliminating polypharmacy in trials of active lupus remains controversial. We undertook the Biomarkers of Lupus Disease study to test withdrawal of immunosuppressants as a novel approach to rendering SLE trials interpretable. METHODS: In 41 patients with active, non-organ-threatening SLE flare (group A), temporary steroids were given while background immunosuppressants were withdrawn. Time to loss of disease suppression (time to disease flare) and safety were evaluated; standard therapy was immediately resumed when symptoms recurred. Immunologic impacts of standard therapy were studied at baseline by multiplex assay, enzyme-linked immunosorbent assay, and messenger RNA array in group A patients plus 62 additional patients donating a single sample (group B). RESULTS: Patients with lower or higher baseline disease activity had median times to flare of 71 or 45 days, respectively; 40 of 41 patients (98%) had disease flares by 6 months. All flares were treated and resolved within 6 weeks. No serious adverse events occurred from flare or infection. Type I interferon (IFN), Th17, and B lymphocyte stimulator pathways tracked together. Baseline immunosuppressants had distinct impacts on Th17 and B lymphocyte stimulator, depending on IFN signature. CONCLUSION: Trials in active, non-organ-threatening SLE can safely withdraw background treatments if patients who have disease flares are designated nonresponders and returned to standard therapy. Immunologic effects of standard therapy vary between IFN-defined subsets. These findings provide a strategy for minimizing or optimizing treatment combinations in lupus trials and clinical care.
OBJECTIVE: Molecular medicine raised expectations for strategically targeted biologic agents in systemic lupus erythematosus (SLE), but clinical trial results have been disappointing and difficult to interpret. Most studies add investigational agents to various, often effective, standard therapy immunosuppressants used at baseline, with unknown treatment interactions. Eliminating polypharmacy in trials of active lupus remains controversial. We undertook the Biomarkers of Lupus Disease study to test withdrawal of immunosuppressants as a novel approach to rendering SLE trials interpretable. METHODS: In 41 patients with active, non-organ-threatening SLE flare (group A), temporary steroids were given while background immunosuppressants were withdrawn. Time to loss of disease suppression (time to disease flare) and safety were evaluated; standard therapy was immediately resumed when symptoms recurred. Immunologic impacts of standard therapy were studied at baseline by multiplex assay, enzyme-linked immunosorbent assay, and messenger RNA array in group A patients plus 62 additional patients donating a single sample (group B). RESULTS:Patients with lower or higher baseline disease activity had median times to flare of 71 or 45 days, respectively; 40 of 41 patients (98%) had disease flares by 6 months. All flares were treated and resolved within 6 weeks. No serious adverse events occurred from flare or infection. Type I interferon (IFN), Th17, and B lymphocyte stimulator pathways tracked together. Baseline immunosuppressants had distinct impacts on Th17 and B lymphocyte stimulator, depending on IFN signature. CONCLUSION: Trials in active, non-organ-threatening SLE can safely withdraw background treatments if patients who have disease flares are designated nonresponders and returned to standard therapy. Immunologic effects of standard therapy vary between IFN-defined subsets. These findings provide a strategy for minimizing or optimizing treatment combinations in lupus trials and clinical care.
Authors: Sandra V Navarra; Renato M Guzmán; Alberto E Gallacher; Stephen Hall; Roger A Levy; Renato E Jimenez; Edmund K-M Li; Mathew Thomas; Ho-Youn Kim; Manuel G León; Coman Tanasescu; Eugeny Nasonov; Joung-Liang Lan; Lilia Pineda; Z John Zhong; William Freimuth; Michelle A Petri Journal: Lancet Date: 2011-02-04 Impact factor: 79.321
Authors: Michelle Petri; Mimi Y Kim; Kenneth C Kalunian; Jennifer Grossman; Bevra H Hahn; Lisa R Sammaritano; Michael Lockshin; Joan T Merrill; H Michael Belmont; Anca D Askanase; W Joseph McCune; Michelene Hearth-Holmes; Mary Anne Dooley; Joan Von Feldt; Alan Friedman; Mark Tan; John Davis; Mary Cronin; Betty Diamond; Meggan Mackay; Lisa Sigler; Michael Fillius; Ann Rupel; Frederick Licciardi; Jill P Buyon Journal: N Engl J Med Date: 2005-12-15 Impact factor: 91.245
Authors: Chee-Seng Yee; Vernon Farewell; David A Isenberg; Bridget Griffiths; Lee-Suan Teh; Ian N Bruce; Yasmeen Ahmad; Anisur Rahman; Athiveeraramapandian Prabu; Mohammed Akil; Neil McHugh; Christopher Edwards; David D'Cruz; Munther A Khamashta; Peter Maddison; Caroline Gordon Journal: Rheumatology (Oxford) Date: 2009-04-24 Impact factor: 7.580
Authors: Joan T Merrill; Susan Manzi; Cynthia Aranow; Anca Askanase; Ian Bruce; Eliza Chakravarty; Ben Chong; Karen Costenbader; Maria Dall'Era; Ellen Ginzler; Leslie Hanrahan; Ken Kalunian; Joseph Merola; Sandra Raymond; Brad Rovin; Amit Saxena; Victoria P Werth Journal: Lupus Sci Med Date: 2018-03-23
Authors: Edward M Vital; Joan T Merrill; Eric F Morand; Richard A Furie; Ian N Bruce; Yoshiya Tanaka; Susan Manzi; Kenneth C Kalunian; Rubana N Kalyani; Katie Streicher; Gabriel Abreu; Raj Tummala Journal: Ann Rheum Dis Date: 2022-03-25 Impact factor: 27.973