{"doi":"10.1002/ajh.27132","title":"Siltuximab administration results in spurious <scp>IL</scp>‐6 elevation in peripheral blood","abstract":"Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder involving a cytokine storm-driven inflammatory syndrome.1 Interleukin-6 (IL-6) has been implicated in disease pathogenesis and therapies that target IL-6 show efficacy in a portion of iMCD patients.1 Tocilizumab, a monoclonal antibody that targets the IL-6 receptor, was approved to treat iMCD in Japan.1 Siltuximab, a monoclonal antibody that directly targets IL-6, was shown to have a 34% response in the phase II clinical trial and is the only drug approved to treat iMCD in the United States, European Union, and most regions of the world.1 International, consensus treatment guidelines recommend siltuximab first-line,1 but it is not effective in all patients, and predictors of response to siltuximab are still under investigation.2 C-reactive protein (CRP), which is elevated in iMCD and one of the minor diagnostic criteria, is also an established biomarker of IL-6 activity,3 and the normalization of CRP is thought to indicate clinical benefit.1 Further, the open-label, dose-finding phase I study of siltuximab (NCT00412321) found sustained suppression of CRP after administration3 and a post hoc analysis of the phase II siltuximab trial found that CRP normalized a median of 2.0 months post-siltuximab.3 Notably, despite IL-6 being the therapeutic target of siltuximab, IL-6 measurements are not recommended as an indicator of response. Treatment guidelines for iMCD include anecdotal reports that IL-6-directed therapy can cause spurious elevation of serum IL-6.1 However, there is concern that these artificial increases could cause physicians to erroneously infer treatment failure as the potential for siltuximab to cause spuriously elevated IL-6 is not widely known. Indeed, we are aware of physicians who have interpreted increased IL-6 values after siltuximab administration to indicate disease progression, despite disease control. In fact, a direct quote from a physician in medical records of the ACCELERATE natural history registry of Castleman disease (CD) (NCT02817997) stated that based on a patient's “rising IL-6 she appears to have progressed on siltuximab.” We used the ACCELERATE registry to evaluate circulating IL-6 values before and after siltuximab administration, irrespective of response. We also examined the time between the final siltuximab dose and normalization of IL-6 values. Additionally, we compared changes in IL-6 values after siltuximab administration to changes in CRP after siltuximab administration to assess whether increased IL-6 values reflected progressive disease activity. Lastly, we analyzed longitudinal serum IL-6 values in patient samples from the siltuximab phase II clinical trial. To understand the effect of siltuximab administration on IL-6 values, we analyzed IL-6 values before and after siltuximab initiation. Forty-two patients from the ACCELERATE natural history registry were found in February 2023 to have circulating IL-6 values quantified at least once before and after initiating siltuximab and lymph node histopathology consistent with CD. The breakdown by gender was 50% male (n = 21) and 50% female (n = 21), and the mean age was 41.5 years. IL-6 values were extracted directly from medical records. Though they were quantified for clinical purposes using multiple different assays, IL-6 measurements were typically performed using sandwich Enzyme-Linked Immuno-Sorbant Assays (ELISA) or Luminex bead-based assays.4 Since IL-6 values were quantified using different assays, we standardized IL-6 values relative to the upper limits of normal for the assay to adjust for differences between assays, log10 transformed them, and presented the results in standardized IL-6 units. We used a paired t-test to detect a difference in log10 transformed IL-6 values pre- and post-siltuximab. When IL-6 was measured multiple times before or after siltuximab administration, we selected the peak value for analysis. For IL-6 values reported to be below","journal":"American Journal of Hematology","year":2023,"id":345182,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9662,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":295573,"name":"Sheila K. Pierson","orcid":"0000-0002-3736-1411","position":1,"is_corresponding":false},{"id":1044252,"name":"Mateo Sarmiento Bustamante","orcid":"0009-0002-6774-2714","position":2,"is_corresponding":false},{"id":821294,"name":"Joshua D. Brandstadter","orcid":"0000-0003-0652-5791","position":3,"is_corresponding":false},{"id":61737,"name":"Frits van Rhee","orcid":"0000-0001-9959-1282","position":4,"is_corresponding":false},{"id":295575,"name":"David C. Fajgenbaum","orcid":"0000-0002-7367-8184","position":5,"is_corresponding":false},{"id":1044253,"name":"Natalie Mango","orcid":"0009-0003-1718-0490","position":0,"is_corresponding":true}],"reference_count":6,"raw_metadata":null,"created_at":"2026-07-19T01:11:39.484741Z","pmid":"37867418","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}