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Skin biomarkers associated with complex regional pain syndrome (CRPS) Type I: a systematic review

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Abstract

Despite increasing research, the pathophysiology of Complex Regional Pain Syndrome (CRPS) remains poorly understood. Due to its easy accessibility, the skin represents an ideal approach to gain a better understanding of the underlying processes. We conducted a systematic review of original studies investigating potential biomarkers cutaneous biomarkers in CRPS. Original articles with a minimum level IV of evidence were screened using the following databases: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and Web of Science Core Collection. Quality assessment was performed using the Methodological Index for Non-Randomized Studies criteria. A total of 11 studies exploring cutaneous biomarkers in 299 CRPS Type I patients were included. The biomarkers identified revealed implications of the following pathophysiological processes: inflammation via interleukins and TNF-a, vascular dysregulation (ET-1/NOx disturbances and hypoxia—high lactate), small fiber neuropathy and hypersensitivity. In terms of skin morphology, evidence suggests: neurite loss, increased expression and disturbed migration of mast cells, as well as an increased expression of α1-adrenoceptors on keratinocytes. The data supporting hypersensitivity had a high risk of bias on quality assessment. The current review has emphasized the current state of knowledge regarding the cutaneous biomarkers in patients suffering from CRPS Type I. Our results serve as a basis for future developments of techniques that would either facilitate diagnosis or may represent therapeutic targets. Trial registration PROSPERO: CRD42020203405. Level of evidence: IV (Systematic Review).

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References

  1. Brunner F (2017) Complex regional pain syndrome. Z Rheumatol 76:335–347. https://doi.org/10.1007/s00393-017-0299-z

    Article  CAS  PubMed  Google Scholar 

  2. Moseley GL (2007) Reconceptualising pain according to modern pain science. Phys Ther Rev 12:169–178. https://doi.org/10.1179/108331907X223010

    Article  Google Scholar 

  3. Iolascon G, Sire A, Moretti A, Gimigliano F (2015) Complex regional pain syndrome (CRPS) type I: historical perspective and critical issues. Clin Cases Miner Bone Metab 12:4–10. https://doi.org/10.11138/ccmbm/2015.12.3s.004

    Article  PubMed  Google Scholar 

  4. Bean DJ, Johnson MH, Kydd RR (2014) The outcome of complex regional pain syndrome type 1: a systematic review. J pain 15:677–690. https://doi.org/10.1016/j.jpain.2014.01.500

    Article  PubMed  Google Scholar 

  5. Marinus J, Moseley GL, Birklein F et al (2011) Clinical features and pathophysiology of complex regional pain syndrome. Lancet Neurol 10:637–648. https://doi.org/10.1016/S1474-4422(11)70106-5

    Article  PubMed  PubMed Central  Google Scholar 

  6. Packham T, Holly J (2018) Mechanism-specific rehabilitation management of complex regional pain syndrome: proposed recommendations from evidence synthesis. J hand Ther Off J Am Soc Hand Ther 31:238–249. https://doi.org/10.1016/j.jht.2018.01.007

    Article  Google Scholar 

  7. Birklein F, Weber M, Neundörfer B (2000) Increased skin lactate in complex regional pain syndrome: evidence for tissue hypoxia? Neurology 55:1213–1215. https://doi.org/10.1212/wnl.55.8.1213

    Article  CAS  PubMed  Google Scholar 

  8. Page MJ, McKenzie JE, Bossuyt PM et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. https://doi.org/10.1136/bmj.n71

    Article  PubMed  PubMed Central  Google Scholar 

  9. Slim K, Nini E, Forestier D et al (2003) Methodological index for non-randomized studies (Minors): development and validation of a new instrument. ANZ J Surg. https://doi.org/10.1046/j.1445-2197.2003.02748.x

    Article  PubMed  Google Scholar 

  10. Li X, Kenter K, Newman A, O’Brien S (2014) Allergy/hypersensitivity reactions as a predisposing factor to complex regional pain syndrome I in orthopedic patients. Orthopedics 37:e286–e291. https://doi.org/10.3928/01477447-20140225-62

    Article  PubMed  Google Scholar 

  11. Agten CA, Kobe A, Barnaure I et al (2020) MRI of complex regional pain syndrome in the foot. Eur J Radiol 129:109044. https://doi.org/10.1016/j.ejrad.2020.109044

    Article  PubMed  Google Scholar 

  12. Finch PM, Drummond ES, Dawson LF et al (2014) Up-regulation of cutaneous α1-adrenoceptors in complex regional pain syndrome type I. Pain Med 15:1945–1956. https://doi.org/10.1111/pme.12548

    Article  PubMed  Google Scholar 

  13. Groeneweg JG, Huygen FJPM, Heijmans-Antonissen C et al (2006) Increased endothelin-1 and diminished nitric oxide levels in blister fluids of patients with intermediate cold type complex regional pain syndrome type 1. BMC Musculoskelet Disord 7:91. https://doi.org/10.1186/1471-2474-7-91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Huygen FJPM, Ramdhani N, van Toorenenbergen A et al (2004) Mast cells are involved in inflammatory reactions during Complex Regional Pain Syndrome type 1. Immunol Lett 91:147–154. https://doi.org/10.1016/j.imlet.2003.11.013

    Article  CAS  PubMed  Google Scholar 

  15. Krämer HH, Eberle T, Uçeyler N et al (2011) TNF-α in CRPS and “normal” trauma—significant differences between tissue and serum. Pain 152:285–290. https://doi.org/10.1016/j.pain.2010.09.024

    Article  CAS  PubMed  Google Scholar 

  16. Morellini N, Finch PM, Goebel A, Drummond PD (2018) Dermal nerve fibre and mast cell density, and proximity of mast cells to nerve fibres in the skin of patients with complex regional pain syndrome. Pain 159:2021–2029. https://doi.org/10.1097/j.pain.0000000000001304

    Article  PubMed  Google Scholar 

  17. Oaklander AL, Rissmiller JG, Gelman LB et al (2006) Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy). Pain 120:235–243. https://doi.org/10.1016/j.pain.2005.09.036

    Article  PubMed  Google Scholar 

  18. Wesseldijk F, Huygen FJ, Heijmans-Antonissen C et al (2008) Tumor necrosis factor-alpha and interleukin-6 are not correlated with the characteristics of Complex Regional Pain Syndrome type 1 in 66 patients. Eur J Pain 12:716–721. https://doi.org/10.1016/j.ejpain.2007.10.010

    Article  CAS  PubMed  Google Scholar 

  19. Lenz M, Uçeyler N, Frettlöh J et al (2013) Local cytokine changes in complex regional pain syndrome type I (CRPS I) resolve after 6 months. Pain 154:2142–2149. https://doi.org/10.1016/j.pain.2013.06.039

    Article  CAS  PubMed  Google Scholar 

  20. Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 62:e1–e34. https://doi.org/10.1016/j.jclinepi.2009.06.006

    Article  PubMed  Google Scholar 

  21. Birklein F, Ajit SK, Goebel A et al (2018) Complex regional pain syndrome—phenotypic characteristics and potential biomarkers. Nat Rev Neurol 14:272–284. https://doi.org/10.1038/nrneurol.2018.20

    Article  PubMed  PubMed Central  Google Scholar 

  22. Chatterjea D, Martinov T (2015) Mast cells: versatile gatekeepers of pain. Mol Immunol 63:38–44. https://doi.org/10.1016/j.molimm.2014.03.001

    Article  CAS  PubMed  Google Scholar 

  23. Gupta K, Harvima IT (2018) Mast cell–neural interactions contribute to pain and itch. Immunol Rev 282:168–187. https://doi.org/10.1111/imr.12622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hovaguimian A, Gibbons CH (2011) Diagnosis and treatment of pain in small-fiber neuropathy. Curr Pain Headache Rep 15:193–200. https://doi.org/10.1007/s11916-011-0181-7

    Article  PubMed  PubMed Central  Google Scholar 

  25. Drummond ES, Dawson LF, Finch PM et al (2014) Increased expression of cutaneous α1-adrenoceptors after chronic constriction injury in rats. J Pain 15:188–196. https://doi.org/10.1016/j.jpain.2013.10.010

    Article  CAS  PubMed  Google Scholar 

  26. Derry S, Bell RF, Straube S et al (2019) Pregabalin for neuropathic pain in adults. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD007076.pub3

    Article  PubMed  PubMed Central  Google Scholar 

  27. Misidou C, Papagoras C (2019) complex regional pain syndrome: an update. Mediterr J Rheumatol 30:16–25. https://doi.org/10.31138/mjr.30.1.16

    Article  PubMed  PubMed Central  Google Scholar 

  28. Huygen FJPM, Niehof S, Zijlstra FJ et al (2004) Successful treatment of CRPS 1 with anti-TNF. J Pain Symptom Manag 27:101–103

    Article  Google Scholar 

  29. de Rooij A (2010) Genetic and epidemiological aspect of Complex Regional Pain Syndrome

  30. Kim YO, Kim IJ, Yoon MH (2015) Antiallodynic effect through spinal endothelin-B receptor antagonism in rat models of complex regional pain syndrome. Neurosci Lett 584:45–49. https://doi.org/10.1016/j.neulet.2014.10.005

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Physical Medicine and Rheumatology, Balgrist University Hospital, University of Zürich, 8008, Zürich, Switzerland

    Diana Andronic & Florian Brunner

  2. Department of Orthopaedics, Balgrist University Hospital, Forchstrasse 340, Zurich, Switzerland

    Octavian Andronic & Martin C. Berli

  3. Center of Experimental Rheumatology, University of Zurich, Balgrist Campus, Zurich, Switzerland

    Astrid Juengel

  4. Department of Rheumatology, Center of Experimental Rheumatology, University Hospital of Zurich, Zurich, Switzerland

    Oliver Distler

Authors
  1. Diana Andronic
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  2. Octavian Andronic
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  3. Astrid Juengel
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  4. Martin C. Berli
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  5. Oliver Distler
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  6. Florian Brunner
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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by DA, OA and FB. The first draft of the manuscript was written by DA and all authors commented and edited previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Diana Andronic.

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Andronic, D., Andronic, O., Juengel, A. et al. Skin biomarkers associated with complex regional pain syndrome (CRPS) Type I: a systematic review. Rheumatol Int 42, 937–947 (2022). https://doi.org/10.1007/s00296-021-05061-5

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  • DOI: https://doi.org/10.1007/s00296-021-05061-5

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