Neuropsychiatric Manifestations in Systemic Autoimmune Diseases

Abstract

Autoimmune diseases are heterogeneous, multifactorial disorders defined by a loss of immunological tolerance to self-antigens, resulting in chronic inflammation and tissue damage. Even though the immune system dysregulation most commonly elicits physical symptoms, neuropsychiatric manifestations are frequently observed in autoimmune diseases and are associated with increased morbidity, elevated mortality, and a marked decline in health-related quality of life. Although extensively characterized in systemic lupus erythematosus (SLE) due to its epidemiological relevance and diagnostic complexity, neuropsychiatric involvement holds clinical significance across a wider spectrum of rheumatologic disorders. The frequent co-occurrence of connective tissue disorders with mood and anxiety symptoms suggests shared etiological mechanisms. The early identification of neuropsychiatric manifestations in patients with chronic autoimmune diseases represents the cornerstone of clinical management, given the substantial impact these symptoms have on individuals already burdened by debilitating conditions. We reviewed the principal neuropsychiatric manifestations associated with selected systemic autoimmune diseases: the novelty of this research lies not only in its approach to autoimmune-related neuropsychiatric symptoms but also in the special emphasis placed on the immunopathogenic mechanisms potentially responsible for these manifestations and, more significantly, on therapeutic decision-making, including an evaluation of treatment strategies targeting immune dysregulation and their potential impact on the neuropsychiatric profile, to optimize clinical outcomes and ensure patients have a comprehensive cure.

Keywords

autoimmune disease / inflammatory myopathies / myositis / neuropsychiatric manifestations / rheumatoid arthritis / systemic lupus erythematosus

References

[1] Dantzer, R. Depression and inflammation: An intricate relationship. Biol. Psychiatry 2012, 71, 4-5.

[2] Isung, J.; Williams, K.; Isomura, K.; et al. Association of primary humoral immunodeficiencies with psychiatric disorders and suicidal behavior and the role of autoimmune diseases. JAMA Psychiatry 2020, 77, 1147-1154.

[3] Kayser, M.S.; Dalmau, J. The emerging link between autoimmune disorders and neuropsychiatric disease. J. Neuropsychiatry Clin. Neurosci. 2011, 23, 90-97.

[4] Danieli, M.G.; Antonelli, E.; Gammeri, L.; et al. Intravenous immunoglobulin as a therapy for autoimmune conditions. Autoimmun. Rev. 2025, 24, 103710.

[5] Gladman, D.D.; Urowitz, M.B. The SLICC/ACR damage index: Progress report and experience in the field. Lupus 1999, 8, 632-637.

[6] Gladman, D.D.; Ibañez, D.; Urowitz, M.B. Systemic lupus erythematosus disease activity index 2000. J. Rheumatol. 2002, 29, 288-291.

[7] Sarwar, S.; Mohamed, A.S.; Rogers, S.; et al. Neuropsychiatric systemic lupus erythematosus: A 2021 update on diagnosis, management, and current challenges. Cureus 2021, 13, e17969.

[8] Tisseverasinghe, A.; Peschken, C.; Hitchon, C. Anxiety and mood disorders in systemic lupus erythematosus: Current insights and future directions. Curr. Rheumatol. Rep. 2018, 20, 85.

[9] Bertsias, G.K.; Ioannidis, J.P.; Aringer, M.; et al. EULAR recommendations for SLE with neuropsychiatric manifestations. Ann. Rheum. Dis. 2010, 69, 2074-2082.

[10] Justiz-Vaillant, A.A.; Gopaul, D.; Soodeen, S.; et al. Neuropsychiatric systemic lupus erythematosus: Molecules involved in its immunopathogenesis, clinical features, and treatment. Molecules 2024, 29, 747.

[11] Chessa, E.; Piga, M.; Perra, A.; et al. Effect of anti-P ribosomal and anti-NR2 antibodies on depression and cognitive processes in SLE: An integrated clinical and functional MRI study. Lupus Sci. Med. 2023, 10, e001005.

[12] Nikolopoulos, D.; Manolakou, T.; Polissidis, A.; et al. Microglia activation in the presence of intact blood-brain barrier and disruption of hippocampal neurogenesis via IL-6 and IL-18 mediate early diffuse neuropsychiatric lupus. Ann. Rheum. Dis. 2023, 82, 646-657.

[13] Toubi, E.; Kessel, A.; Shoenfeld, Y. High-dose intravenous immunoglobulins: An option in the treatment of systemic lupus erythematosus. Hum. Immunol. 2005, 66, 395-402.

[14] Zandman-Goddard, G.; Levy, Y.; Shoenfeld, Y. Intravenous immunoglobulin therapy and systemic lupus erythematosus. Clin. Rev. Allergy Immunol. 2005, 29, 219-228.

[15] Winder, A.; Molad, Y.; Ostfeld, I.; et al. Treatment of systemic lupus erythematosus by prolonged administration of high dose intravenous immunoglobulin: Report of 2 cases. J. Rheumatol. 1993, 20, 495-498.

[16] Cheikh, M.M.; Bahakim, A.K.; Aljabri, M.K.; et al. Neuropsychiatric lupus and lupus nephritis successfully treated with combined IVIg and rituximab: An alternative to standard of care. Case Rep. Rheumatol. 2022, 2022, 5899188.

[17] Andreasson, K.M.; Espinosa-Ortega, F.; Sandlund, H.; et al. Self-reported physical activity and fatigue and its associations to anxiety and depression in adult patients with idiopathic inflammatory myopathies. Clin. Exp. Rheumatol. 2025, 43, 230-240.

[18] Achtman, J.; Kling, M.A.; Feng, R.; et al. A cross-sectional study of untreated depression and anxiety in cutaneous lupus erythematosus and dermatomyositis. J. Am. Acad. Dermatol. 2016, 74, 377-379.

[19] Christopher-Stine, L.; Paik, J.J.; Goriounova, A.S.; et al. Patient reported physical function, mental health, and treatment patterns in dermatomyositis: Survey results from a cross-sectional study. BMC Rheumatol. 2025, 9, 23.

[20] Lodin, K.; Espinosa-Ortega, F.; Dastmalchi, M.; et al. Patient global assessment and inflammatory markers in patients with idiopathic inflammatory myopathies: A longitudinal study. Semin. Arthritis Rheum. 2024, 65, 152379.

[21] Reddy, A.; Birur, B.; Shelton, R.C.; et al. Major depressive disorder following dermatomyositis: A case linking depression with inflammation. Psychopharmacol. Bull. 2018, 48, 22-28.

[22] Goswami, R.P.; Haldar, S.N.; Chatterjee, M.; et al. Efficacy and safety of intravenous and subcutaneous immunoglobulin therapy in idiopathic inflammatory myopathy: A systematic review and meta-analysis. Autoimmun. Rev. 2022, 21, 102997.

[23] Gandiga, P.C.; Ghetie, D.; Anderson, E.; et al. Intravenous immunoglobulin in idiopathic inflammatory myopathies: A practical guide for clinical use. Curr. Rheumatol. Rep. 2023, 25, 152-168.

[24] Danieli, M.G.; Antonelli, E.; Auria, S.; et al. Low-dose intravenous immunoglobulin (IVIg) in different immune-mediated conditions. Autoimmun. Rev. 2023, 22, 103451.

[25] Rosado, S.N.; Silveira, V.; Reis, A.I.; et al. Catatonia and psychosis as manifestations of primary Sjögren’s syndrome. Eur. J. Case Rep. Intern. Med. 2018, 5, 000855.

[26] Salehi, M.; Zamiri, A.; Kim, J.; et al. Exploring the psychiatric manifestations of primary Sjögren’s syndrome: A narrative review. Int. J. Rheumatol. 2024, 2024, 5520927.

[27] Spezialetti, R.; Bluestein, H.G.; Peter, J.B.; et al. Neuropsychiatric disease in Sjögren’s syndrome: Anti-ribosomal P and anti-neuronal antibodies. Am. J. Med. 1993, 95, 153-160.

[28] Malinow, K.L.; Molina, R.; Gordon, B.; et al. Neuropsychiatric dysfunction in primary Sjögren’s syndrome. Ann. Intern. Med. 1985, 103, 344-350.

[29] Chiu, Y.H.; Lee, T.S.; Chao, E.; et al. Application of classification criteria of Sjogren syndrome in patients with sicca symptoms: Real-world experience at a medical center. J. Formos. Med. Assoc. 2020, 119, 480-487.

[30] Levite, M. Glutamate receptor antibodies in neurological diseases: Implications for autoimmune disorders. J. Neural Transm. 2014, 121, 1029-1075.

[31] Alexander, E.L.; Beall, S.S.; Gordon, B.; et al. Magnetic resonance imaging of cerebral lesions in patients with the Sjögren syndrome. Ann. Intern. Med. 1988, 108, 815-823.

[32] Alexander, E.L.; Ranzenbach, M.R.; Kumar, A.J.; et al. Anti-Ro(SS-A) autoantibodies in CNS disease associated with Sjögren’s syndrome: Clinical and neuroimaging correlates. Neurology 1994, 44, 899-908.

[33] Pelizza, L.; Bonacini, F.; Ferrari, A. Psychiatric disorder as clinical presentation of primary Sjögren’s syndrome: Two case reports. Ann. Gen. Psychiatry 2010, 9, 12.

[34] Alcázar-Hernández, J.M.; Pecci-Lloret, M.R.; Guerrero-Gironés, J. Oral Manifestations in Patients in Treatment with Antidepressants: A Systematic Review. J. Clin. Med. 2024, 13, 6945.

[35] Mura, G.; Bhat, K.M.; Pisano, A.; et al. Psychiatric symptoms and quality of life in systemic sclerosis. Clin. Pract. Epidemiol. Ment. Health 2012, 8, 30-35.

[36] Koczanowski, S.; Morrisroe, K.; Fairley, J.; et al. Role of intravenous immunoglobulins in systemic sclerosis: A systematic literature review. Semin. Arthritis Rheum. 2024, 68, 152471.

[37] McNair, S.; Hategan, A.; Bourgeois, J.A.; et al. Neuropsychiatric symptoms in scleroderma. Psychosomatics 2013, 54, 382-386.

[38] van Eeden, C.; Rezaeifar, M.; ElezzabI, M.; et al.; Severe fatigue is associated with diminished lung function and elevated Galectin-9 levels in early systemic sclerosis. Front. Immunol. 2025, 16, 1655414. https://doi.org/10.3389/fimmu.2025.1655414.

[39] Georges, C.; Chassany, O.; Toledano, C.; et al. Impact of pain in health related quality of life of patients with systemic sclerosis. Rheumatology 2006, 45, 1298-1302.

[40] Sandusky, S.B.; McGuire, L.; Smith, M.T.; et al. Fatigue: An overlooked determinant of physical function in scleroderma. Rheumatology 2009, 48, 165-169.

[41] Rubenzik, T.T.; Derk, C.T. Unmet patient needs in systemic sclerosis. J. Clin. Rheumatol. 2009, 15, 106-110.

[42] Schouffoer, A.A.; Zirkzee, E.J.; Henquet, S.M.; et al. Needs and preferences regarding health care delivery in systemic sclerosis. Clin. Rheumatol. 2011, 30, 815-824.

[43] Nacci, F.; Righi, A.; Conforti, M.L.; et al. Intravenous immunoglobulins improve function and joint involvement in systemic sclerosis: A pilot study. Ann. Rheum. Dis. 2007, 66, 977-979.

[44] Uguz, F.; Akman, C.; Kucuksarac, S.; et al. Anti-TNF-alpha therapy and mood disorders in rheumatoid arthritis. Psychiatry Clin. Neurosci. 2009, 63, 50-55.

[45] Covic, T.; Cumming, S.R.; Pallant, J.F.; et al. Depression and anxiety in rheumatoid arthritis: Comparison of DASS and HADS. BMC Psychiatry 2012, 12, 6.

[46] Joaquim, A.F.; Appenzeller, S. Cervical spine involvement in rheumatoid arthritis: A systematic review. Autoimmun. Rev. 2014, 13, 1195-1202.

[47] Isik, A.; Koca, S.S.; Ozturk, A.; et al. Anxiety and depression in rheumatoid arthritis. Clin. Rheumatol. 2007, 26, 872-878.

[48] Smith, B.W.; Zautra, A.J. Anxiety and depression effects on weekly pain in arthritis. Pain 2008, 138, 354-361.

[49] Pigłowska-Juhnke, A.; Stanisławska-Kubiak, M.; Kalmus, P.; et al. Cognitive Impairment in Rheumatoid Arthritis: The Role of Pain, Inflammation, and Multimorbidity in Neuropsychological Outcomes. Biomedicines 2025, 13, 1699.

[50] Madsen, S.G.; Danneskiold-Samsøe, B.; Stockmarr, A.; et al. Correlations between fatigue and disease factors in rheumatoid arthritis. Scand. J. Rheumatol. 2016, 45, 255-261.

[51] Albeltagy, E.S.; Elaziz, S.Y.A.; Abozaid, S.Y.; et al. IL-6, IL-17 and depression in rheumatoid arthritis. Clin. Rheumatol. 2021, 40, 895-904.

[52] Bougea, A.; Anagnostou, E.; Spandideas, N.; et al. An update of neurological manifestations of vasculitides and connective tissue diseases: A literature review. Einstein 2015, 13, 627-635.

[53] Ghinoi, A.; Zuccoli, G.; Pipitone, N.; et al. ANCA-associated vasculitis involving the central nervous system: Case report and review of the literature. Clin. Exp. Rheumatol. 2010, 28, 759-766.

[54] Berlit, P. Neuropsychiatric disease in collagen vascular diseases and vasculitis. J. Neurol. 2007, 254, II87-II 89.

[55] Van Eeden, C.; Mohazab, N.; Redmond, D.; et al. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia: PR3-versus MPO-ANCA-associated vasculitis, an exploratory cross-sectional study. Lancet Reg. Health Am. 2023, 20, 100460.

[56] Guidelli, G.M.; Tenti, S.; Pascarelli, N.A.; et al. Granulomatosis with polyangiitis and intravenous immunoglobulins: A case series and review of the literature. Autoimmun. Rev. 2015, 14, 659-664.

[57] Benavides-Villanueva, F.; Loricera, J.; Calvo-Río, V.; et al. Intravenous immunoglobulin therapy in ANCA-associated vasculitis. Eur. J. Intern. Med. 2023, 117, 78-84.

[58] Shoenfeld, Y.; Gershwin, M.E. Intravenous immunoglobulin: New indications and mechanisms of action. Clin. Rev. Allergy Immunol. 2005, 29, 165-166.

[59] Ozaki, S. ANCA-associated vasculitis: Diagnostic and therapeutic strategy. Allergol. Int. 2007, 56, 87-96.

[60] Jensen, K.Y.; Aagaard, P.; Suetta, C.; et al. High-intensity resistance training improves quality of life in myositis. Rheumatol. Int. 2024, 44, 1909-1921.