Damage to the peripheral nervous system in rheumatoid arthritis: a review of current data, diagnostic criteria, and therapeutic strategies

Aim of the review — to summarize current data on the pathogenesis, clinical manifestations, diagnosis, and treatment of peripheral neuropathy in patients with rheumatoid arthritis.

Peripheral neuropathy (PN) is a common complication of rheumatoid arthritis (RA), significantly impairing patients’ quality of life and leading to disability. This article provides an overview of current data on the pathogenesis, clinical manifestations, diagnosis, and treatment of PN in RA. Mechanisms involved in the pathogenesis of PN include vasculitis, autoimmune responses, neurogenic inflammation, and nerve compression. Clinical manifestations of PN are diverse and include sensory, motor, and autonomic disorders. Diagnosis involves clinical examination, electroneuromyography, ultrasound, magnetic resonance imaging (MRI), and nerve biopsy. MRI, including magnetic resonance neurography, functional MRI, and MRI spectroscopy, allows visualization of affected nerves, assessment of their structure and function, as well as detection of brain changes associated with pain. Treatment of PN in RA includes control of the underlying disease with disease-modifying antirheumatic drugs (DMARDs) and biologic therapy, as well as symptomatic treatment of neurological manifestations. In cases of vasculitic neuropathy, more aggressive therapy with high doses of glucocorticoids and/or cytotoxic drugs may be required. Conservative methods and surgical intervention are used to treat compressive neuropathies. Additional therapy includes drugs affecting neurotransmitters, B vitamins, and α-lipoic acid. In recent years, data have emerged on the effectiveness of palmitoylethanolamide and pterostilbene in the treatment of PN in RA, but further research is needed to confirm their efficacy and safety. Despite the progress made in understanding PN in RA, questions remain that require further study, including the development of more effective treatments and the identification of predictors of the development of neuropathy.

Contribution:
Makhmutova B.K. — development of the concept and structure of the review, analysis of literature on the topic, writing of review sections, editing of the text;
Orynbaeva A.M. — collection and analysis of data, interpretation of results, writing of review sections;
Pernebay A.N. — critical analysis of literature, formulation of conclusions, participation in the discussion of results, editing of the text;
Grigolashvili M.A. — collection and analysis of data, participation in the discussion of results;
Otarbaeva M.B. — analysis of literature, writing of review sections, editing of the text;
Battakova Sh.B. — analysis of data, participation in the discussion of results.
All co-authors are responsible for the integrity of all parts of the manuscript and approval of its final version.

Acknowledgements. The study had no sponsorship.

Conflict of interest. The authors declare no conflict of interest.

Received: September 22, 2024
Accepted: January 28, 2025
Published: April 30, 2025

1. Rajeshwari B., Kumar S. Rheumatoid neuropathy: a brief overview. Cureus. 2023; 15(1): e34127. https://doi.org/10.7759/cureus.34127

2. Li Y., Jiang L., Zhang Z., Li H., Jiang L., Wang L., et al. Clinical characteristics of rheumatoid arthritis patients with peripheral neuropathy and potential related risk factors. Clin. Rheumatol. 2019; 38(8): 2099–107. https://doi.org/10.1007/s10067-019-04521-5

3. Castelli G., Desai K.M., Cantone R.E. Peripheral neuropathy: evaluation and differential diagnosis. Am. Fam. Physician. 2020; 102(12): 732–9.

4. Venetsanopoulou A.I., Alamanos Y., Voulgari P.V., Drosos A.A. Epidemiology and risk factors for rheumatoid arthritis development. Mediterr. J. Rheumatol. 2023; 34(3): 404–13. https://doi.org/10.31138/mjr.301223.eaf

5. GBD 2021 Rheumatoid Arthritis Collaborators. Global, regional, and national burden of rheumatoid arthritis, 1990–2020, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021. Lancet Rheumatol. 2023; 5(10): e594–610. https://doi.org/10.1016/S2665-9913(23)00161-3

6. López‐López C.O., Montes Castillo M.D.L.L., Soto‐Fajardo R.C., Sandoval‐García L.F., Loyola‐Sánchez A., Burgos‐Vargas R., et al. Peripheral neuropathies in rheumatic diseases: More diverse and frequent than expected. A cross‐sectional study. Int. J. Rheum. Dis. 2020; 23(2): 226–32. https://doi.org/10.1111/1756-185x.13755

7. Kaeley N., Ahmad S., Pathania M., Kakkar R. Prevalence and patterns of peripheral neuropathy in patients of rheumatoid arthritis. J. Family Med. Prim. Care. 2019; 8(1): 22–6. https://doi.org/10.4103/jfmpc.jfmpc_260_18

8. Sim M.K., Kim D.Y., Yoon J., Park D.H., Kim Y.G. Assessment of peripheral neuropathy in patients with rheumatoid arthritis who complain of neurologic symptoms. Ann. Rehabil. Med. 2014; 38(2): 249–55. https://doi.org/10.5535/arm.2014.38.2.249

9. Varshney M., Ray S., Reddy M., Chatterjee D., Chakravarty K., Bhatia V., et al. A neurological complication in rheumatoid arthritis – a scenario of catastrophic proportions. Ann. Indian Acad. Neurol. 2023; 26(4): 560–3. https://doi.org/10.4103/aian.aian_94_23

10. Biswas M., Chatterjee A., Ghosh S.K., Dasgupta S., Ghosh K., Ganguly P.K. Prevalence, types, clinical associations, and determinants of peripheral neuropathy in rheumatoid patients. Ann. Indian Acad. Neurol. 2011; 14(3): 194–7. https://doi.org/10.4103/0972-2327.85893

11. Beachy N., Satkowiak K., Gwathmey K.G. Vasculitic neuropathies. Semin. Neurol. 2019; 39(5): 608–19. https://doi.org/10.1055/s-0039-1688990

12. Jin L., Liu Y. Clinical manifestations, pathogenesis, diagnosis and treatment of peripheral neuropathies in connective tissue diseases: more diverse and frequent in different subtypes than expected. Diagnostics (Basel). 2021; 11(11): 1956. https://doi.org/10.3390/diagnostics11111956

13. Tulbă D., Popescu B.O., Manole E., Băicuș C. Immune axonal neuropathies associated with systemic autoimmune rheumatic diseases. Front. Pharmacol. 2021; 12: 610585. https://doi.org/10.3389/fphar.2021.610585

14. Imamura M., Mukaino A., Takamatsu K., Tsuboi H., Higuchi O., Nakamura H., et al. Ganglionic acetylcholine receptor antibodies and autonomic dysfunction in autoimmune rheumatic diseases. Int. J. Mol. Sci. 2020; 21(4): 1332. https://doi.org/10.3390/ijms21041332

15. Dede B.T., Oğuz M., Bulut B., Bagcıer F., Aytekin E. Carpal tunnel syndrome evaluation with ultrasound in rheumatoid arthritis patients. ARP Rheumatol. 2023; 2(4): 330–7.

16. De Souza J.M., Trevisan T.J., Sepresse S.R., Londe A.C., França Júnior M.C., Appenzeller S. Peripheral neuropathy in systemic autoimmune rheumatic diseases – diagnosis and treatment. Pharmaceuticals (Basel). 2023; 16(4): 587. https://doi.org/10.3390/ph16040587

17. Tanemoto M., Hisahara S., Hirose B., Ikeda K., Matsushita T., Suzuki S., et al. Severe mononeuritis multiplex due to rheumatoid vasculitis in rheumatoid arthritis in sustained clinical remission for decades. Intern. Med. 2020; 59(6): 705–10. https://doi.org/10.2169/internalmedicine.3866-19

18. Boyd C.J., Singh N.P., Robin J.X., Sharma S. Compression neuropathies of the upper extremity: a review. Surgeries. 2021; 2(3): 320–34. https://doi.org/10.3390/surgeries2030032

19. Shesternya N.A., Ivannikov S.V., Zharova T.A., Makarova E.V., Tarasov D.A., Ulianova O.S. The myths and mythical views in traumatology and orthopedics. Sechenovskii vestnik. 2022; (1-2): 47–51. (in Russian)

20. Jahan K., Begum N., Ferdousi S. Autonomic neuropathy in Rheumatoid Arthritis: Relationship with seropositivity of Rheumatoid factor and disease activity. J. Bangladesh Soc. Physiol. 2021; 16(2): 70–6. https://doi.org/10.3329/jbsp.v16i2.57566

21. de Araújo Pereira F., de Almeida Lourenço M., de Assis M.R. Evaluation of peripheral neuropathy in lower limbs of patients with rheumatoid arthritis and its relation to fall risk. Adv. Rheumatol. 2022; 62(1): 9. https://doi.org/10.1186/s42358-022-00238-3

22. Gutiérrez J., Sandoval H., Pérez-Neri I., Arauz A., López-Hernández J.C., Pineda C. Advances in imaging technologies for the assessment of peripheral neuropathies in rheumatoid arthritis. Rheumatol. Int. 2021; 41(3): 519–28. https://doi.org/10.1007/s00296-020-04780-5

23. Minhas A.S., Oliver R. Magnetic resonance imaging basics. Adv. Exp. Med. Biol. 2022; 1380: 47–82. https://doi.org/10.1007/978-3-031-03873-0_3

24. Kollmer J., Bendszus M. Magnetic resonance neurography: improved diagnosis of peripheral neuropathies. Neurotherapeutics. 2021; 18(4): 2368–83. https://doi.org/10.1007/s13311-021-01166-8

25. Ku V., Cox C., Mikeska A., MacKay B. Magnetic resonance neurography for evaluation of peripheral nerves. J. Brachial Plex. Peripher. Nerve Inj. 2021; 16(1): e17–23. https://doi.org/10.1055/s-0041-1729176

26. Noguerol T.M., Barousse R. Update in the evaluation of peripheral nerves by MRI, from morphological to functional neurography. Radiología (Engl. Ed.). 2020; 62(2): 90–101. https://doi.org/10.1016/j.rx.2019.06.005

27. Martín-Noguerol T., Montesinos P., Hassankhani A., Bencardino D.A., Barousse R., Luna A. Technical update on MR neurography. Semin. Musculoskelet. Radiol. 2022; 26(2): 93–104. https://doi.org/10.1055/s-0042-1742753

28. Phukan P., Barman B., Chengappa N.K., Lynser D., Paul S., Nune A., et al. Diffusion tensor imaging analysis of rheumatoid arthritis patients with neuropsychiatric features to determine the alteration of white matter integrity due to vascular events. Clin. Rheumatol. 2022; 41(10): 3169–77. https://doi.org/10.1007/s10067-022-06262-4

29. Eajazi A., Weinschenk C., Chhabra A. Imaging biomarkers of peripheral nerves: focus on magnetic resonance neurography and ultrasonography. Semin. Musculoskelet. Radiol. 2024; 28(1): 92–102. https://doi.org/10.1055/s-0043-1776427

30. Pérez-Neri I., González-Aguilar A., Sandoval H., Pineda C., Ríos C. Therapeutic potential of ultrasound neuromodulation in decreasing neuropathic pain: clinical and experimental evidence. Curr. Neuropharmacol. 2021; 19(3): 334–48. https://doi.org/10.2174/1570159x18666200720175253

31. Dou Z., Yang L. The application of functional magnetic resonance imaging in neuropathic pain. In: Medical Imaging: Principles and Applications. IntechOpen, UK; 2019.

32. Yang Y.C., Zeng K., Wang W., Gong Z.G., Chen Y.L., Cheng J.M., et al. The changes of brain function after spinal manipulation therapy in patients with chronic low back pain: A rest BOLD fMRI Study. Neuropsychiatr. Dis. Treat. 2022; 18: 187–99. https://doi.org/10.2147/ndt.s339762

33. Loh A., Gwun D., Chow C.T., Boutet A., Tasserie J., Germann J., et al. Probing responses to deep brain stimulation with functional magnetic resonance imaging. Brain Stimul. 2022; 15(3): 683–94. https://doi.org/10.1016/j.brs.2022.03.009

34. Scripcariu V., Sava A., Furnica C., Poroch V., Tomaziu-Todosia M., Chistol R.O., et al. Magnetic resonance imaging in assessing chemotherapy-induced peripheral neuropathy: systematic review. BRAIN. Broad Research in Artificial Intelligence and Neuroscience. 2023; 14(4): 417–39.

35. Mills E.P., Keay K.A., Henderson L.A. Brainstem pain-modulation circuitry and its plasticity in neuropathic pain: insights from human brain imaging investigations. Front. Pain Res. (Lausanne). 2021; 2: 705345. https://doi.org/10.3389/fpain.2021.705345

36. Yeh C.H., Caswell K., Pandiri S., Sair H., Lukkahatai N., Campbell C.M., et al. Dynamic brain activity following auricular point acupressure in chemotherapy-induced neuropathy: a pilot longitudinal functional magnetic resonance imaging study. Glob. Adv. Health Med. 2020; 9: 2164956120906092.

37. Islam J., Rahman M.T., Kc E., Park Y.S. Deciphering the functional role of insular cortex stratification in trigeminal neuropathic pain. J. Headache Pain. 2024; 25(1): 76. https://doi.org/10.1186/s10194-024-01784-5

38. Boland E.G., Selvarajah D., Hunter M., Ezaydi Y., Tesfaye S., Ahmedzai S.H., et al. Central pain processing in chronic chemotherapy-induced peripheral neuropathy: a functional magnetic resonance imaging study. PLoS One. 2014; 9(5): e96474. https://doi.org/10.1371/journal.pone.0096474

39. Gross F., Üçeyler N. Mechanisms of small nerve fiber pathology. Neurosci. Lett. 2020; 737: 135316. https://doi.org/10.1016/j.neulet.2020.135316

40. Bhatt R.R., Gupta A., Mayer E.A., Zeltzer L.K. Chronic pain in children: structural and resting-state functional brain imaging within a developmental perspective. Pediatr. Res. 2020; 88(6): 840–9. https://doi.org/10.1038/s41390-019-0689-9

41. Yin Y., He S., Xu J., You W., Li Q., Long J., et al. The neuro-pathophysiology of temporomandibular disorders-related pain: a systematic review of structural and functional MRI studies. J. Headache Pain. 2020; 21(1): 78. https://doi.org/10.1186/s10194-020-01131-4

42. Trouvin A.P., Attal N., Perrot S. Assessing central sensitization with quantitative sensory testing in inflammatory rheumatic diseases: a systematic review. Joint Bone Spine. 2022; 89(5): 105399. https://doi.org/10.1016/j.jbspin.2022.105399

43. Coffey C.M., Richter M.D., Crowson C.S., Koster M.J., Warrington K.J., Ytterberg S.R., et al. Rituximab therapy for systemic rheumatoid vasculitis: indications, outcomes, and adverse events. J. Rheumatol. 2020; 47(4): 518–23. https://doi.org/10.3899/jrheum.181397

44. Ding Y., Zhang L., Zeng H., Liu S. Clinical analysis of 46 rheumatoid arthritis patients with peripheral neuropathy. Zhonghua Nei Ke Za Zhi. 2021; 60(3): 222–6. https://doi.org/10.3760/cma.j.cn112138-20201118-00950 (in Chinese)

45. Cohen J.C., Lewis R.A. Rituximab for chronic inflammatory demyelinating polyneuropathy-A potential therapeutic option. Muscle Nerve. 2020; 61(5): 549–51. https://doi.org/10.1002/mus.26871

46. Parisi S., Ditto M.C., Borrelli R., Fusaro E. Efficacy of a fixed combination of palmitoylethanolamide and acetyl-l-carnitine (PEA+ALC FC) in the treatment of neuropathies secondary to rheumatic diseases. Minerva Med. 2021; 112(4): 492–9. https://doi.org/10.23736/s0026-4806.21.07486-3

47. Amin A., Akhtar M.F., Saleem A., et al. Pterostilbene improves CFA-induced arthritis and peripheral neuropathy through modulation of oxidative stress, inflammatory cytokines and neurotransmitters in Wistar rats. Inflammopharmacology. 2022; 30(6): 2285–300. https://doi.org/10.1007/s10787-022-01069-w

48. Arshad M., Younus R., Ali A., Hassan S. (2023). Effect of combined neuromuscular electrical stimulation and disease-modifying antirheumatic drug therapy versus disease-modifying antirheumatic drug therapy alone on enhancing gait and reducing fall risks in patients with rheumatoid arthritis and peripheral neuropathy. J. Health Rehabil. Res. https://doi.org/10.61919/jhrr.v3i2.103