Immunological therapy in persistent complex regional pain syndrome: a systematic review and narrative synthesis

Abstract

Background: Immunological pathophysiological mech-anisms 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.

Methods: Articles were screened from PubMed, Embase, Scopus, clinicaltrials.gov, 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 year. Randomised controlled trials were appraised using the Cochrane Risk of Bias (RoB2).

Results: A total of 1404 studies were yielded, and 23 articles were retrieved for full-text analysis after reviewing the titles, texts and abstracts. A narrative syn-thesis was used due to the heterogeneity of studies. The immune therapies used were glucocorticoids, thalidomide/lenalidomide, immunoglobulin, plasmapheresis, mycophenolate, anti-TNF-alpha inhibitors and epidermal growth factor receptor inhibitors. There were 16 reports of beneficial effects from non-randomised trials, case series and case reports of treatment with immunomodulating drugs or interventions. Small randomised trials of low-dose immunoglobulin, epidermal growth factor receptor inhibitors and mycophenolate suggest possible treatment benefit, but larger randomised trials of immunoglobulin and lenalidomide demonstrated no effect.
Conclusion: The emergence of novel immune therapies for persistent CRPS shows promise, but evidence based on high-quality randomised trials remains limited and does not show a positive effect.
Significance Statement: This work summarises the current use of immune-modulating therapies in man-aging 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-quality clinical trials is highlighted by the few large randomised controlled trials.