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Beyond Neuropsychiatric Manifestations of Systemic Lupus Erythematosus: Focus on Post-traumatic Stress Disorder and Alexithymia

  • Systemic Lupus Erythematosus (G Tsokos, Section Editor)
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Abstract

Purpose of Review

To deepen the comprehension of the role of specific psychological conditions in the pathogenesis and in the treatment of systemic lupus erythematosus (SLE). Specifically, the present comprehensive review aims at examining the association between SLE, alexithymia (AT)—a personality construct referring to the inability to identify, describe, and express sensations, emotions, and physical state—and post-traumatic stress disorder (PTSD), to infer potential biological relationships between these psychopathological issues and disease course, and to draw up a research agenda on gray areas of these topics.

Recent Findings

Whereas several studies document the presence of neuropsychiatric symptoms in patients with SLE, psychological distress, alexithymia, and post-traumatic manifestations are usually neglected by healthcare professionals and poorly investigated in research contexts. However, the interplay of these aspects, which affect physiologic stress coping mechanisms, potentially plays an important role in SLE pathogenesis. In particular, research documents that cytokine repertoire pattern alteration and hypothalamic–pituitary–adrenal axis impairment leading to inflammation and pain represent the main links between emotional health and immunity.

Summary

AT and PTSD seem to be common in patients with SLE and account for multiple aspects of SLE-related morbidity. Furthermore, abnormal processing of stressful stimuli as hallmarks of PTSD and AT might promote neuroendocrine dysfunction and dysregulated immunity, thus contributing to the pathogenesis of SLE. A comprehensive, multidisciplinary clinical approach, based on a cooperation between immunologists, rheumatologists, neurologists, and mental health professionals, is crucial to promote patients’ global health.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. O’Neill S, Cervera R (2010) Systemic lupus erythematosus. Best Pract Res Clin Rheumatol

  2. Fava A, Petri M (2019) Systemic lupus erythematosus: diagnosis and clinical management. J Autoimmun.

  3. Govoni M, Bortoluzzi A, Padovan M, et al (2016) The diagnosis and clinical management of the neuropsychiatric manifestations of lupus. J Autoimmun.

  4. Jeltsch-David H, Muller S (2016) Autoimmunity, neuroinflammation, pathogen load: a decisive crosstalk in neuropsychiatric SLE J Autoimmun.

  5. Unterman A, Nolte JES, Boaz M, et al. Neuropsychiatric syndromes in systemic lupus erythematosus: a meta-analysis. Semin Arthritis Rheum. 2011. https://doi.org/10.1016/j.semarthrit.2010.08.001.

  6. Meszaros ZS, Perl A, Faraone S V. (2012) Psychiatric symptoms in systemic lupus erythematosus: a systematic review. J Clin Psychiatry

  7. Sloan M, Bosley M, Blane M, et al. ‘But you don’t look sick’: a qualitative analysis of the LUPUS UK online forum. Rheumatol Int. 2020. https://doi.org/10.1007/s00296-020-04726-x.

  8. Jarpa E, Babul M, Calderón J, et al. Common mental disorders and psychological distress in systemic lupus erythematosus are not associated with disease activity. Lupus. 2011. https://doi.org/10.1177/0961203310381773.

  9. Gordon C, Isenberg D, Lerstrøm K, et al. The substantial burden of systemic lupus erythematosus on the productivity and careers of patients: a European patient-driven online survey. Rheumatol (United Kingdom). 2013. https://doi.org/10.1093/rheumatology/ket300.

  10. Nielsen NM, Pedersen BV, Stenager E, et al. Stressful life-events in childhood and risk of multiple sclerosis: a Danish nationwide cohort study. Mult Scler J. 2014. https://doi.org/10.1177/1352458514528761.

  11. Shalev A, Liberzon I, Marmar C (2017) Post-traumatic stress disorder. N Engl J Med

  12. American Psychiatric Association (2013) DSM-5 diagnostic classification. In: Diagnostic and Statistical Manual of Mental Disorders

  13. Nemiah JC. Alexithymia: theoretical considerations. Psychother Psychosom. 1977. https://doi.org/10.1159/000287064.

  14. Sifneos PE. The prevalence of “Alexithymic” characteristics in psychosomatic patients. Psychother Psychosom. 1973. https://doi.org/10.1159/000286529.

  15. FeldmanHall O, Dalgleish T, Mobbs D. Alexithymia decreases altruism in real social decisions. Cortex. 2013. https://doi.org/10.1016/j.cortex.2012.10.015.

  16. Ricciardi L, Demartini B, Fotopoulou A, Edwards MJ. Alexithymia in neurological disease: a review. J Neuropsychiatr Clin Neurosci. 2015. https://doi.org/10.1176/appi.neuropsych.14070169.

  17. Wolfe F, Petri M, Alarcón GS, et al. Fibromyalgia, systemic lupus erythematosus (SLE), and evaluation of SLE activity. J Rheumatol. 2009. https://doi.org/10.3899/jrheum.080212.

  18. Zhao SS, Duffield SJ, Goodson NJ (2019) The prevalence and impact of comorbid fibromyalgia in inflammatory arthritis. Best Pract Res Clin Rheumatol

  19. Bagby RM, Taylor GJ, Parker JDA (1994) The twenty-item Toronto Alexithymia Scale: II. J Psychosom Res

  20. •• Hori H, Kim Y (2019) Inflammation and post-traumatic stress disorder. Psychiatry Clin. Neurosci. This review summarizes evidence suggestive of increased inflammation in PTSD and examines findings on possible mechanisms of inflammation in this disorder.

  21. Todarello O, Casamassima A, Daniele S, et al. Alexithymia, immunity and cervical intraepithelial neoplasia: Replication. Psychother Psychosom. 1997. https://doi.org/10.1159/000289136.

  22. Dewaraja R, Tanigawa T, Araki S, et al. Decreased cytotoxic lymphocyte counts in alexithymia. Psychother Psychosom. 1997. https://doi.org/10.1159/000289113.

  23. Corcos M, Guilbaud O, Paterniti S, et al. Correlation between serum levels of interleukin-4 and alexithymia scores in healthy female subjects: preliminary findings. Psychoneuroendocrinology. 2004. https://doi.org/10.1016/S0306-4530(03)00087-8.

  24. Pedrosa Gil F, Nickel M, Ridout N, et al. Alexithymia and interleukin variations in somatoform disorder. Neuroimmunomodulation. 2007. https://doi.org/10.1159/000112048.

  25. Guilbaud O, Corcos M, Hjalmarsson L, et al. Is there a psychoneuroimmunological pathway between alexithymia and immunity?. Immune and physiological correlates of alexithymia. Biomed Pharmacother. 2003. https://doi.org/10.1016/S0753-3322(03)00085-4.

  26. Guilbaud O, Curt F, Perrin C, et al. Decreased immune response in alexithymic women: a cross-sectional study. Biomed Pharmacother. 2009. https://doi.org/10.1016/j.biopha.2008.08.007.

  27. Passos IC, Vasconcelos-Moreno MP, Costa LG, et al. Inflammatory markers in post-traumatic stress disorder: A systematic review, meta-analysis, and meta-regression. Lancet Psychiatry. 2015. https://doi.org/10.1016/S2215-0366(15)00309-0.

  28. Pace TWW, Heim CM (2011) A short review on the psychoneuroimmunology of posttraumatic stress disorder: from risk factors to medical comorbidities. Brain Behav Immun

  29. Bessel A, Van Kolk D. The psychobiology and psychopharmacology of PTSD. Hum Psychopharmacol. 2001. https://doi.org/10.1002/hup.270.

  30. Sripada RK, King AP, Welsh RC, et al. Neural dysregulation in posttraumatic stress disorder: evidence for disrupted equilibrium between salience and default mode brain networks. Psychosom Med. 2012. https://doi.org/10.1097/PSY.0b013e318273bf33.

  31. Daskalakis NP, Cohen H, Nievergelt CM, et al (2016) New translational perspectives for blood-based biomarkers of PTSD: From glucocorticoid to immune mediators of stress susceptibility. Exp Neurol

  32. Dixon ML, De La Vega A, Mills C, et al. Heterogeneity within the frontoparietal control network and its relationship to the default and dorsal attention networks. Proc Natl Acad Sci U S A. 2018. https://doi.org/10.1073/pnas.1715766115.

  33. Jia W, Zhu H, Ni Y, et al. Disruptions of frontoparietal control network and default mode network linking the metacognitive deficits with clinical symptoms in schizophrenia. Hum Brain Mapp. 2020. https://doi.org/10.1002/hbm.24887.

  34. Putica A, Van Dam NT, Steward T, et al. Alexithymia in post-traumatic stress disorder is not just emotion numbing: Systematic review of neural evidence and clinical implications. J Affect Disord. 2021.

  35. Shipko S. Alexithymia and somatization. Psychother Psychosom. 1982. https://doi.org/10.1159/000287573.

  36. Osti RMA, Trombini G, Magnani B. Stress and distress in essential hypertension. Psychother Psychosom. 1980. https://doi.org/10.1159/000287431.

  37. Martin JB. The stress-alexithymia hypothesis: theoretical and empirical considerations. Psychother Psychosom. 1985. https://doi.org/10.1159/000287876.

  38. Lumley MA, Neely LC, Burger AJ (2007) The assessment of alexithymia in medical settings: implications for understanding and treating health problems. J Pers Assess

  39. Waller E, Scheidt CE (2006) Somatoform disorders as disorders of affect regulation: a development perspective. Int Rev Psychiatry

  40. Connelly M, Denney DR. Regulation of emotions during experimental stress in alexithymia. J Psychosom Res. 2007. https://doi.org/10.1016/j.jpsychores.2006.12.008.

  41. Barbosa F, Mota C, Patrício P, et al. The relationship between alexithymia and psychological factors in systemic lupus erythematosus. Compr Psychiatry. 2011. https://doi.org/10.1016/j.comppsych.2010.11.004.

  42. Bruni R, Serino FM, Galluzzo S, et al (2006) Alexithymia and neuroendocrine-immune response in patients with autoimmune diseases: Preliminary results on relationship between alexithymic construct and TNF-α levels. In: Annals of the New York Academy of Sciences

  43. Chimenti MS, Fonti GL, Conigliaro P, et al. Evaluation of alexithymia in patients affected by rheumatoid arthritis and psoriatic arthritis: a cross-sectional study. Medicine (Baltimore). 2019. https://doi.org/10.1097/MD.0000000000013955.

  44. Conrad R, Geiser F, Haidl G, et al. Relationship between anger and pruritus perception in patients with chronic idiopathic urticaria and psoriasis. J Eur Acad Dermatol Venereol. 2008. https://doi.org/10.1111/j.1468-3083.2008.02714.x.

  45. Sampogna F, Puig L, Spuls P, et al. Prevalence of alexithymia in patients with psoriasis and its association with disease burden: a multicentre observational study. Br J Dermatol. 2017. https://doi.org/10.1111/bjd.15243.

  46. O’Donovan A, Cohen BE, Seal KH, et al. Elevated risk for autoimmune disorders in iraq and afghanistan veterans with posttraumatic stress disorder. Biol Psychiatry. 2015. https://doi.org/10.1016/j.biopsych.2014.06.015.

  47. Kusevic Z, Civljak M, Rukavina TV, et al. The connection between alexithymia and somatic morbidity in a population of combat veterans with chronic PTSD. Acta Inform Medica. 2013. https://doi.org/10.5455/aim.2013.21.7-11.

  48. Vadacca M, Bruni R, Terminio N, et al. Alexithymia, mood states and pain experience in systemic lupus erythematosus and rheumatoid arthritis. Clin Rheumatol. 2014. https://doi.org/10.1007/s10067-014-2593-3.

  49. Barbasio C, Vagelli R, Marengo D, et al. Illness perception in systemic lupus erythematosus patients: The roles of alexithymia and depression. Compr Psychiatry. 2015. https://doi.org/10.1016/j.comppsych.2015.09.004.

  50. Barbasio C, Granieri A. Emotion regulation and mental representation of attachment in patients with systemic lupus erythematosus: A study using the adult attachment interview. J Nerv Ment Dis. 2013. https://doi.org/10.1097/NMD.0b013e318288e215.

  51. Barbosa F, Mota C, Patrício P, et al (2011) Alexithymia and clinical variables in SLE patients. Psychother Psychosom

  52. Lumley MA, Radcliffe AM, Macklem DJ, et al. Alexithymia and pain in three chronic pain samples: comparing Caucasians and African Americans. Pain Med. 2005. https://doi.org/10.1111/j.1526-4637.2005.05036.x.

  53. • Jalenques I, Rondepierre F, Mulliez A, et al (2018) Lower emotion awareness in skin-restricted lupus patients: a case-controlled study. Psychother Psychosom. This case–control study documents that even patients with skin-restricted SLE report significantly higher levels of alexhytimia and lower emotional awareness than controls.

  54. •• Roberts AL, Malspeis S, Kubzansky LD, et al. Association of trauma and posttraumatic stress disorder with incident systemic lupus erythematosus in a longitudinal cohort of women. Arthritis Rheum. 2017. https://doi.org/10.1002/art.40222This is the only prospective study examining the association of trauma exposure and PTSD symptoms with SLE incidence and unravelling a potential causative effect.

  55. Margiotta DPE, Basta F, Dolcini G, et al. The relation between, metabolic syndrome and quality of life in patients with systemic lupus erythematosus. PLoS One. 2017. https://doi.org/10.1371/journal.pone.0187645.

  56. Peralta-Ramírez MI, Pérez-Mármol JM, Castañeda-Cabestany M, et al (2018) Association between perceived level of stress, clinical characteristics and psychopathological symptoms in women with systemic lupus erythematosus. Clin Exp Rheumatol

  57. Stojanovich L, Marisavljevich D (2008) Stress as a trigger of autoimmune disease. Autoimmun Rev

  58. Stojanovich L. The catastrophic antiphospholipid syndrome in Serbia: diagnostic and management problems. Clin Rev Allergy Immunol. 2009. https://doi.org/10.1007/s12016-008-8102-1.

  59. Bortoluzzi A, Scirè CA, Bombardieri S, et al. Development and validation of a new algorithm for attribution of neuropsychiatric events in systemic lupus erythematosus. Rheumatol (United Kingdom). 2014. https://doi.org/10.1093/rheumatology/keu384.

  60. Bortoluzzi A, Fanouriakis A, Appenzeller S, et al. Validity of the Italian algorithm for the attribution of neuropsychiatric events in systemic lupus erythematosus: a retrospective multicentre international diagnostic cohort study. BMJ Open. 2017. https://doi.org/10.1136/bmjopen-2016-015546.

  61. Gutiérrez MA, Garcia ME, Rodriguez JA, et al (1998) Hypothalamic-pituitary-adrenal axis function and prolactin secretion in systemic lupus erythematosus. In: Lupus

  62. Golier JA, Schmeidler J, Legge J, Yehuda R. Twenty-four hour plasma cortisol and adrenocorticotropic hormone in Gulf War veterans: relationships to posttraumatic stress disorder and health symptoms. Biol Psychiatry. 2007. https://doi.org/10.1016/j.biopsych.2007.04.027.

  63. Sheridan J (2003) The HPA axis, SNS and immunity: a commentary. In: Brain, Behavior, and Immunity

  64. Morand EF (2018) Systemic lupus erythematosus: stress and the onset of SLE. Nat. Rev. Rheumatol.

  65. Turnbull AV, Rivier C. Regulation of the hpa axis by cytokines. Brain Behav Immun. 1995. https://doi.org/10.1006/brbi.1995.1026.

  66. Wilder RL (2002) Neuroimmunoendocrinology of the rheumatic diseases: past, present, and future. In: Annals of the New York Academy of Sciences

  67. Quintanar-Stephano A, Abarca-Rojano E, Jarillo-Luna RA, et al. Hypophysectomy and neurointermediate pituitary lobectomy decrease humoral immune responses to T-independent and T-dependent antigens. J Physiol Biochem. 2010. https://doi.org/10.1007/s13105-010-0004-z.

  68. Wiseman SJ, Bastin ME, Hamilton IF, et al. Fatigue and cognitive function in systemic lupus erythematosus: associations with white matter microstructural damage. A diffusion tensor MRI study and meta-analysis. Lupus. 2017. https://doi.org/10.1177/0961203316668417.

  69. Ramirez GA, Rocca MA, Preziosa P, et al. Quantitative MRI adds to neuropsychiatric lupus diagnostics. Rheumatology. 2020. https://doi.org/10.1093/rheumatology/keaa779.

  70. Arnaud L, Mertz P, Amoura Z, et al. Patterns of fatigue and association with disease activity and clinical manifestations in systemic lupus erythematosus. Rheumatology. 2020. https://doi.org/10.1093/rheumatology/keaa671.

  71. Monahan RC, Beaart-van de Voorde LJ, Eikenboom J, et al (2021) Fatigue in patients with systemic lupus erythematosus and neuropsychiatric symptoms is associated with anxiety and depression rather than inflammatory disease activity. Lupus 096120332110050. https://doi.org/10.1177/09612033211005014

  72. Del Pino-Sedeño T, Trujillo-Martín MM, Ruiz-Irastorza G, et al. Effectiveness of nonpharmacologic interventions for decreasing fatigue in adults with systemic lupus erythematosus: a systematic review. Arthritis Care Res. 2016. https://doi.org/10.1002/acr.22675.

  73. Fangtham M, Kasturi S, Bannuru RR, et al (2019) Non-pharmacologic therapies for systemic lupus erythematosus. Lupus

  74. Knittle K, Maes S, De Gucht V. Psychological interventions for rheumatoid arthritis: examining the role of self-regulation with a systematic review and meta-analysis of randomized controlled trials. Arthritis Care Res. 2010. https://doi.org/10.1002/acr.20251.

  75. Prothero L, Barley E, Galloway J, et al (2018) The evidence base for psychological interventions for rheumatoid arthritis: A systematic review of reviews. Int J Nurs Stud

  76. Zhang J, Wei W, Wang CM (2012) Effects of psychological interventions for patients with systemic lupus erythematosus: a systematic review and meta-analysis. Lupus

  77. Apostolidis SA, Lieberman LA, Kis-Toth K, et al. The dysregulation of cytokine networks in systemic lupus erythematosus. J Interf Cytokine Res. 2011. https://doi.org/10.1089/jir.2011.0029.

  78. Gensous N, Boizard-Moracchini A, Lazaro E, et al. Update on the cellular pathogenesis of lupus. Curr Opin Rheumatol. 2020. https://doi.org/10.1097/bor.0000000000000775.

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Authors and Affiliations

  1. Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132, Milan, Italy

    Luca Moroni, Giuseppe Alvise Ramirez, Nicola Farina, Enrica Paola Bozzolo & Lorenzo Dagna

  2. Vita-Salute San Raffaele University, Milan, Italy

    Luca Moroni, Martina Mazzetti, Giuseppe Alvise Ramirez, Nicola Farina, Simone Guerrieri, Massimo Filippi, Valentina Di Mattei & Lorenzo Dagna

  3. Clinical Health Psychology Unit, IRCCS Ospedale San Raffaele, Milan, Italy

    Martina Mazzetti & Valentina Di Mattei

  4. Neurology Unit, IRCCS Ospedale San Raffaele, Milan, Italy

    Simone Guerrieri, Lucia Moiola & Massimo Filippi

  5. Neurorehabilitation Unit, IRCCS Ospedale San Raffaele, Milan, Italy

    Massimo Filippi

  6. Neuroimaging Research Unit, Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy

    Massimo Filippi

  7. Neurophysiology Service, IRCCS Ospedale San Raffaele, Milan, Italy

    Massimo Filippi

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  1. Luca Moroni
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Contributions

Luca Moroni had the idea for the article; Luca Moroni, MM, GAR, and NF significantly contributed in literature search, data analysis, and paper drafting; EPB, SG, Lucia Moiola, MF, VDM, and LD revised it critically for important intellectual content and interpretation of the data; all authors approved the final version to be submitted and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Luca Moroni.

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Moroni, L., Mazzetti, M., Ramirez, G.A. et al. Beyond Neuropsychiatric Manifestations of Systemic Lupus Erythematosus: Focus on Post-traumatic Stress Disorder and Alexithymia. Curr Rheumatol Rep 23, 52 (2021). https://doi.org/10.1007/s11926-021-01019-5

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