{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T18:43:02Z","timestamp":1772995382859,"version":"3.50.1"},"reference-count":72,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T00:00:00Z","timestamp":1762473600000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T00:00:00Z","timestamp":1761955200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Pain"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immunological pathophysiological mechanisms have been postulated in Complex Regional Pain Syndrome (CRPS).Clinical features suggest abnormal immune activation, supported in laboratory studies. The purpose of this review is to systematically review the effects of therapies that can modulate the immune system in persistent CRPS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Articles were screened from PubMed, Embase, Scopus,\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">clinicaltrials.gov<\/jats:ext-link>\n                      , ISRCTN databases and Web of Science for articles, studies and conference abstracts in CRPS and immune therapies from inception up to April 2024. Titles and abstracts were screened, followed by reading the full text and reference lists to determine the final articles for analysis. Studies were restricted to adults and a duration of disease greater than 1\u2009year. Randomised controlled trials were appraised using the Cochrane Risk of Bias (RoB2).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 1404 studies were yielded, and 23 articles were retrieved for full\u2010text analysis after reviewing the titles, texts and abstracts. A narrative synthesis was used due to the heterogeneity of studies. The immune therapies used were glucocorticoids, thalidomide\/lenalidomide, immunoglobulin, plasmapheresis, mycophenolate, anti\u2010TNF\u2010alpha inhibitors and epidermal growth factor receptor inhibitors. There were 16 reports of beneficial effects from non\u2010randomised trials, case series and case reports of treatment with immunomodulating drugs or interventions. Small randomised trials of low\u2010dose immunoglobulin, epidermal growth factor receptor inhibitors and mycophenolate suggest possible treatment benefit, but larger randomised trials of immunoglobulin and lenalidomide demonstrated no effect.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The emergence of novel immune therapies for persistent CRPS shows promise, but evidence based on high\u2010quality randomised trials remains limited and does not show a positive effect.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>This work summarises the current use of immune\u2010modulating therapies in managing patients with persistent Complex Regional Pain Syndrome (CRPS). It complements the current interest in immunological approaches to pain management with the increasing role of immune mechanisms in both pain and CRPS. While promise has been shown in small case reports and cohort studies, the need for high\u2010quality clinical trials is highlighted by the few large randomised controlled trials.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejp.70156","type":"journal-article","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T09:00:17Z","timestamp":1762506017000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunological Therapy in Persistent Complex Regional Pain Syndrome: A Systematic Review and Narrative Synthesis"],"prefix":"10.1002","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9524-3130","authenticated-orcid":false,"given":"David","family":"Pang","sequence":"first","affiliation":[{"name":"Pain Management Centre Guy's and St Thomas' NHS Foundation Trust  London UK"},{"name":"Pain Research Institute, Institute of Life Course and Medical Sciences University of Liverpool, Clinical Sciences Centre  Liverpool UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Royds","sequence":"additional","affiliation":[{"name":"Pain Management Centre Guy's and St Thomas' NHS Foundation Trust  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Goebel","sequence":"additional","affiliation":[{"name":"Pain Research Institute, Institute of Life Course and Medical Sciences University of Liverpool, Clinical Sciences Centre  Liverpool UK"},{"name":"Department of Pain Medicine Walton Centre NHS Foundation Trust  Liverpool UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,11,7]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"383","article-title":"Plasma Exchange Therapy in Patients With Complex Regional Pain Syndrome","volume":"18","author":"Aradillas E.","year":"2015","journal-title":"Pain Physician"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/pm\/pnv002"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2018.20"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/2049463719893399"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejp.572"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(21)00023-6"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.1"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbspin.2017.03.009"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.RHU.0000062620.10630.21"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001662"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1177\/1744806918799127"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2006.09.008"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000008736"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/papr.12078"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001280"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2014.09.022"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/papr.12070"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/pm\/pnw147"},{"key":"e_1_2_7_20_1","unstructured":"European Medicines Agency.2022.\u201cOrphan Designation.\u201dhttps:\/\/www.ema.europa.eu\/en\/glossary\/orphan\u2010designation."},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(24)00076-0"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-152-3-201002020-00006"},{"key":"e_1_2_7_23_1","unstructured":"Goebel A. 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