Current Rheumatology Reports (2021) 23:52

https://doi.org/10.1007/s11926-021-01019-5

SYSTEMIC LUPUS ERYTHEMATOSUS (G TSOKOS, SECTION EDITOR)

Beyond Neuropsychiatric Manifestations of Systemic Lupus

Erythematosus: Focus on Post-traumatic Stress Disorder
and Alexithymia
Luca Moroni 1,2 & Martina Mazzetti 2,3 & Giuseppe Alvise Ramirez 1,2 & Nicola Farina 1,2 & Enrica Paola Bozzolo 1 &
Simone Guerrieri 2,4 & Lucia Moiola 4 & Massimo Filippi 2,4,5,6,7 & Valentina Di Mattei 2,3 & Lorenzo Dagna 1,2

Accepted: 21 April 2021

# The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021

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 asso-
ciation 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, psycho-
logical 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.

Keywords Systemic lupus erythematosus (SLE) . Alexithymia (AT) . Post-traumatic stress disorder (PTSD) . Autoimmunity

This article is part of the Topical Collection on Systemic Lupus

Erythematosus
Introduction
* Luca Moroni
moroni.luca@hsr.it
Systemic lupus erythematosus (SLE) is an autoimmune dis-
ease with variable clinical presentation. Complement activa-
1
tion and overproduction of a wide spectrum of cytokines,
Unit of Immunology, Rheumatology, Allergy and Rare Diseases, immune complex and autoantibodies, namely antinuclear
IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy
2
(ANA) and anti-double-strand-DNA antibodies (anti-
Vita-Salute San Raffaele University, Milan, Italy dsDNA), are the immunological hallmarks of the disease [1,
3
Clinical Health Psychology Unit, IRCCS Ospedale San Raffaele, 2]. It can affect every organ and tissue, although nervous sys-
Milan, Italy tem involvement, defined as neuropsychiatric SLE (NPSLE),
4
Neurology Unit, IRCCS Ospedale San Raffaele, Milan, Italy stands as one of the most severe and challenging clinical sce-
5
Neurorehabilitation Unit, IRCCS Ospedale San Raffaele, Milan, Italy narios [3, 4] with a prevalence ranging from 14 to 75% [5].
6
Neuroimaging Research Unit, Division of Neuroscience, IRCCS Several well-known psychiatric syndromes are observed in
Ospedale San Raffaele, Milan, Italy patients with NPSLE, which vary from mild mood disorders
7
Neurophysiology Service, IRCCS Ospedale San Raffaele, or cognitive dysfunction to paroxysmal confusional states and
Milan, Italy psychosis [6]. However, alongside these overt
 52 Page 2 of 8
neuropsychiatric manifestations, different patterns of subtle
psychological suffering might be underrecognized in patients
with SLE and might not be just simple bystanders in the dis-
ease course [7–9].
Various psychological conditions such as post-traumatic
stress disorder (PTSD) and alexithymia (AT) are associated
with increased susceptibility to develop autoimmune diseases,
probably involving impaired physiological mechanisms im-
plicated in stress response [10].
Post-traumatic stress disorder (PTSD) is one of the most
prevalent psychopathological consequences of exposure to
stressful traumatic events. Its lifetime prevalence in the gen-
eral population ranges from 1.3 to 12.2%, and it represents a
debilitating psychiatric condition characterized by persistence
of intense, distressing, and fearfully avoided reactions to re-
minders of the triggering event, alteration of mood and cog-
nition, a pervasive sense of imminent threat, disturbed sleep,
and hypervigilance [11, 12].
The term alexithymia comes from the ancient Greek and
literally means “no words for emotions” [13, 14]. This per-
sonality construct refers to the inability to identify, describe,
and express sensations, emotions, and physical states, and
may lead to an altered social attachment and poor interperson-
al relationships [15]. In the general population, AT affects
approximately 10% of individuals; however, in certain psy-
chiatric and non-psychiatric conditions, its prevalence seems
to be much higher [16, 17]. Alexithymic subjects experience
chronic sympathetic hyperarousal, an excessive focus on their
body, uncomfortable physical sensations, and an increased
susceptibility to somatic symptoms [18]. Toronto
Alexithymia Scale-20 (TAS-20) is the most widely used
self-reported questionnaire for AT diagnosis [19].
The aims of the present comprehensive review of the liter-
ature are to outline associations of AT and PTSD with SLE, to
infer potential biological relationships between these emerg-
ing psychopathological issues and disease course, and to call
for specific studies on these topics.
Alexithymia, PTSD, and the Immune System
A growing body of evidence has highlighted the presence of a
significant link between AT, PTSD and immune dysfunction
[20•]. Indeed, both are associated with a variety of partially
overlapping molecular and cellular alterations in the immune
system.
Reduced cytotoxic T and NK lymphocyte counts [21, 22]
and higher levels of interleukin-4 (IL-4) [23], IL-6, IL-10, and
immunoglobulins-E (IgE) [24] have been found in
alexithymic subjects. Immune response in alexithymic pa-
tients is similar to subjects exposed to chronic stress, with
increased production of glucocorticoids [25], predominance
of depressed cell-mediated immunity and a skewed Th1/Th2
Curr Rheumatol Rep (2021) 23:52
ratio towards Th2 response [26]. On the other hand, patients
with PTSD show increased plasmatic levels of IL-6, IL-1β,
TNF-α, and IFN-γ (Fig 1) [27, 28].
From a neurobiological point-of-view, a specific cascade of
bio-behavioral alterations in emotion regulation processes oc-
cur in individuals who develop PTSD [29, 30], namely hyper-
active sympathetic nervous system and downregulation of hy-
pothalamic–pituitary–adrenal (HPA) axis [31] leading to a
chronic state of hyperarousal [20•]. Individuals with PTSD
have difficulty in evaluating and discriminating environmen-
tal stimuli and in mobilizing adequate levels of physiological
arousal. Consequently, in a compensatory effort, they tend to
“shut down” by avoiding reminders of the trauma (on a be-
havioral level) and emotional numbing (on a psychobiological
level). However, the price for the latter is a significantly de-
creased involvement in personal life [29].
The presence of a clear clinical overlap between PTSD-
related emotion numbing and alexithymia has led researchers
to investigate the neural correlates of these two conditions, in
order to clarify if they are separate constructs or manifesta-
tions of the same post-traumatic emotion-processing deficits
[32–34].
Empirical evidence documents that alexithymic character-
istics are present to a greater degree in individuals with stress-
related illnesses as compared to other patient groups and nor-
mal controls [35, 36]. The “stress-alexithymia hypothesis”
posits that specific cognitive, behavioral, and physiological
components of alexithymia may contribute to the pathogene-
sis of a stress-related disorder. Specifically, it suggests that the
combined effect of lacking emotional awareness and affective
expression (cognitive component) may result in ineffective
and/or maladaptive coping attempts (behavioral component).
This would lead, in turn, to prolonged stress exposure, which
exacerbates somato-visceral response (physiological compo-
nent), thus increasing the disease susceptibility [37] (Fig. 2).
This “emotional failure” is supposed to predispose to cer-
tain somatic diseases [38–40]. High prevalence of alexithymia
is found in patients with immune-mediated and inflammatory
diseases, particularly SLE [41], rheumatoid arthritis (RA) [42,
43], psoriasis [44, 45], and chronic spontaneous urticaria [44].
An even clearer autoimmunity-predisposing effect has
been demonstrated for stress and PTSD. For instance, patients
diagnosed with PTSD among a cohort of war veterans were
found to be at increased risk of developing Hashimoto thy-
roiditis, inflammatory bowel diseases, and RA [46]. Kusevic
and colleagues [47] also conducted a study on 127 Croatian
combat veterans with PTSD and subsequent diagnosis of so-
matic disease including autoimmune disorders and reported
AT as an independent risk factor. These results highlight a
detrimental interplay between AT and PTSD, and corroborate
the stress-alexithymia hypothesis. In fact, these two conditions
share a theoretical pathogenic basis [37] that involves the
combination of specific internal vulnerability elements with
Curr Rheumatol Rep (2021) 23:52
Fig. 1 Immunological changes in AL and PTSD. AT and PTSD share
immunological alterations with SLE pathogenesis (*), in particular
increased production of IL1β, IL4, IL6, IL10, and IFN-γ [77, 78].
Enhanced Th-2 response is a hallmark of SLE as well as decreased
persisting biomedical and disease-related factors (Fig. 2).
These points become crucial in lifelong medical conditions
such as SLE [48].
Clinical Associations Between SLE
and Alexithymia
So far, only limited studies have tried to explore the associa-
tion between AT and SLE (summarized in Table 1).
Fig. 2 The stress-alexithymia hypothesis. Stress-induced interaction
between the immune system and hypothalamic–pituitary–adrenal axis
(HPA). Alexithymia deflects physiological stress responses into
maladaptive forms, leading to HPA failure and inflammation.
Prolonged overactivation of HPA leads to cortisol dysfunction and
enhanced production of proinflammatory cytokines by lymphocytes and
Page 3 of 8 52
cytotoxicity of CD8 + T-cells. Abbreviations: CD, cluster of
differentiation; NK, natural killer; IL, interleukin; IgE, immunoglobulin
E; TNF-α, tumor necrosis factor-alpha; IFN-γ, interferon-gamma.
Microsoft Office PowerPoint 2019 was used for this artwork
Barbasio and collaborators [49] tested 100 consecutive
SLE patients for AT, depression, and illness perception along
with rheumatological evaluation to assess disease activity.
The authors found that TAS-20 scores negatively correlated
with disease duration and strongly positively correlated with
illness perception and depression. In another study, the same
author [50] found a prevalence of 17.5% of AT among SLE
patients, while 30% scored as “probable alexithymic” in TAS-
20 questionnaire [16].
In a case–control study, Barbosa and colleagues [41] found
that patients in SLE group (n=53) scored significantly higher
macrophages. Cliparts obtained in part and adapted from Servier Medical
Art. Servier Medical Art by Servier is licensed under a Creative
Commons Attribution 3.0 Unported License. Abbreviations: HPA,
hypothalamic–pituitary–adrenal axis; ACTH, adrenocorticotropin; IL,
interleukin; TNF-α, tumor necrosis factor-alpha; IFN-γ, interferon-
gamma. Microsoft Office PowerPoint 2019 was used for this artwork
 52 Page 4 of 8 Curr Rheumatol Rep (2021) 23:52

Table 1 Main studies on

association between SLE and AT Author, year Reference Topic N Study design Results
or PTSD. The article review has
been conducted among peer- Barbasio, [49] AT 100 Prospective Positive correlation of TAS-20 scores
reviewed papers published on 2015 with illness perception (r +0.40;
PubMed until December 2020. p<0.01) and depression (r +0.47;
The study selection and outcome p<0.01)
extraction were performed Barbasio, [50] AT 40 Cross-sectional Prevalence of 17.5% of AT (TAS-20
independently by three reviewers 2013 score > 60) among SLE patients and
(LM, MM, and NF). Articles 30% of “possible alexithymia”
written in languages other-than (TAS-20 score 52-60). Positive
English were excluded. correlation between AT and
Abbreviations: N, number; AT, dissociative symptoms (r=0.652,
alexithymia; TAS-20, Toronto p<0.001)
Alexithymia Scale; SLE, systemic Barbosa, [41] AT 84 Case–control Prevalence of AT (TAS-20 >60) of
lupus erythematosus; RA, 2011 50.9% in SLE group (n=53)
rheumatoid arthritis; NS, not compared with a healthy control
significant; PTSD, post-traumatic group (n=31, AT 3.2%, p < 0.001)
stress disorder; HR, hazard ratio;
CI, confidence interval Barbosa, [51] AT 94 Case–control No difference in AT proportion in SLE
2011 group (n=51) compared with patients
with chronic asthma (n=41)
Lumley, [52] AT 438 Case–control Prevalence of AT across 3 disease
2005 groups: SLE n=123, AT 25.8% (95%
CI 19.1–34.4%); RA n=155, AT
19.4% (95% CI 13.9–26.3%);
migraine n=160, AT 8.1% (95% CI
4.8–13.4%).
Bruni, 2006 [42] AT 81 Case–control TAS-20 > 51 highly prevalent in SLE
(n=27, AT 50%) and RA (n=27, AT
62%). Healthy controls n=27, AT
prevalence not given.
Vadacca, [48] AT 49 Case–control TAS-20>60 prevalence of 37.5% in SLE
2014 patients (n=25) and 44% in RA
patients (n=24), p=NS.
Jalenques, [53•] AT 210 Case–control TAS-20 scores higher in cutaneous
2018 lupus patients (n=70, mean 48.4)
compared with healthy controls
(n=140, mean 43.4), p=0.003.
Roberts, [54••] PTSD 54,763 Prospective Compared to women with no trauma
2017 (n=14,885), probable PTSD was
associated with increased risk of
developing SLE over 24 years
follow-up (HR 2.94, 95% CI
1.19–7.26). Trauma exposure,
regardless of PTSD symptoms, was
strongly associated with incident SLE
(HR 2.83, 95% CI 1.29–6.21).
O’Donovan, [46] PTSD 666,269 Retrospective Adjusted relative risk for SLE: 1.73
2015 (95% CI 1.22–2.45) compared to
subjects without psychiatric disorders.

in TAS-20 compared with the healthy control group (p <
0.001).
In another research on the same SLE population, the au-
thors found that more than half of SLE patients obtained a
TAS-20 score indicative of alexithymia [51]. It is to consider,
however, that the presence of a high proportion of patients
with SLE in complete remission (SLEDAI=0: 69.8%) is a
potential bias in these two studies.
Lumley and colleagues [52] performed a cross-sectional
study to investigate AT in three chronic pain conditions: mi-
graine (n=160), RA (n=155), and SLE (n=123). AT preva-
lence was 26% in SLE group, 19% in RA, and 8% in migraine
patients. Since the goal of the study was to compare ethnic
groups in each condition, statistics for proportion comparison
are not given for these groups, but we post-hoc calculated
confidence intervals and reported them in Table 1. TAS-20
Curr Rheumatol Rep (2021) 23:52
scores correlated significantly although rather weakly with
lupus symptoms.
Bruni and colleagues [42] also found a high prevalence of
AT in SLE and RA (50% and 62% respectively); however, a
lower cut-off for AT classification was used (TAS-20 ≥ 51
instead of 61).
In a more recent prospective case–control study by the same
group [48], SLE and RA were compared in terms of AT, mood
states, and pain experience. A different cohort of patients was
considered, excluding subjects affected by endocrinological
and psychiatric diseases. Both TAS-20 mean value and preva-
lence of AT (defined by a score of 61 or higher in the question-
naire) had a trend towards lower representation in the SLE
group compared to RA patients (mean TAS-20 61 in SLE vs.
51 in RA; AT prevalence: 44% in SLE vs. 38% in RA).
Even patients with cutaneous lupus displayed lower emo-
tion awareness in a case–control study of 70 subjects [53].
Finally, Margiotta et al. [55], in a cross-sectional study
aimed at exploring the associations between metabolic syn-
drome and quality of life in SLE patients, found that fatigue
scores measured by the Short Form-36 inventory strongly
correlated with alexithymia.
Clinical Associations Between SLE
and Post-traumatic Stress Disorder
Very scarce research has explored post-traumatic manifesta-
tions in subjects with SLE (major studies are summarized in
Table 1). Roberts and colleagues [54••], in the only prospec-
tive study on this topic, analyzed SLE incidence over 24 years
in a US longitudinal cohort of women (n=54,763). Results
show that, compared to women with no trauma, probable
PTSD was associated with increased risk of developing SLE
(HR 2.94, 95% CI 1.19–7.26). Furthermore, trauma exposure
regardless of PTSD symptoms was strongly associated with
incident SLE (HR 2.83, 95% CI 1.29–6.21). Importantly, re-
verse causation was excluded, meaning that no evidence was
found that SLE was a stressor contributing to PTSD. Despite
various covariates being considered, a potential bias of the
aforementioned study is that family history for autoimmune
or psychiatric disease is lacking in the model.
In a previous retrospective cohort study, O’Donovan [46]
studied 666,269 Iraq and Afghanistan veterans. The authors
found a twofold increased odds of autoimmune disease diag-
nosis in subjects with PTSD compared to those without any
psychiatric disorders, and 51% increased risk compared to
veterans with psychiatric disorders other than PTSD, with an
adjusted relative risk for SLE of 1.73 (95% CI 1.22–2.45) as
compared to subjects without psychiatric disorders. The me-
dian time between PTSD diagnosis and autoimmune disease
onset in that study was only 220 days, suggesting a potential
causal relationship. Nonetheless, as in Roberts’ cohort, bias
Page 5 of 8 52
risk cannot be overlooked with regard to possible environ-
mental exposures favoring both conditions.
Beyond overt PTSD, SLE patients display higher per-
ceived stress levels compared to healthy controls showing a
positive correlation with SLE activity, even after controlling
for psychopathological dimensions [56].
Stojanovich [57] conducted a study including 120 patients
with SLE who were asked to complete a questionnaire about
different stressors that preceded the onset or exacerbation of
their disease, particularly sickness or death of a family member,
financial troubles, job loss, and political instability including
Serbia bombings. Moreover, from the analysis of the Serbian
National Antiphospholipid Syndrome (APS) Registry, it was
also documented an over 4-fold higher incidence of catastroph-
ic APS (CAPS) in a population of 256 subjects, including 94
SLE patients with secondary APS. Twelve patients in the pro-
ject developed CAPS and stress was identified as a precipitating
factor in 33% of the cases [58].
Discussion and Implications for Patient
Management
Defining the clinical and pathophysiological boundaries of the
interplay between neuropsychiatric morbidity and immune-
mediated diseases such as SLE constitutes a major challenge
due to the lack of sufficient mechanistic insight into the path-
ogenesis of these disorders. This issue is even more relevant
for AT, which is characterized by impairment in translating
feelings into meaningful concepts, thus compromising the rec-
ognition of the individual’s needs by the others. Consistently,
in the setting of an ongoing debate about the definition of
neuropsychiatric SLE, attribution algorithms for classifying
neuropsychiatric events are relatively less performant in eval-
uating mood disorders [59, 60], despite their high prevalence
in patients with SLE.
The absence of specific diagnostic tools for NPSLE and a
high variability in the interpretation of cutoff scores restrict the
accuracy of current estimates of AT and PTSD prevalence in
SLE. However, clinical evidence suggests that these disorders
are disproportionately frequent in patients who have or will
develop an autoimmune disease. From a pathophysiological
standpoint, this hypothesis well fits a model where dysfunc-
tional stress processing in combination with dysregulation of
the hypothalamic–pituitary–adrenal (HPA) axis [61–63]
might synergize with abnormalities in the deployment of the
innate [64, 65] and adaptive immune responses to trigger and/
or maintain inflammation in patients with SLE [66, 67].
Somatic expression of symptoms such as fatigue relies on
neuroendocrine overactivation, and AT negatively affects this
mechanism by impairing cognitive processing of stressors
[25, 68, 69].
 52 Page 6 of 8
Fatigue is a potential subjective output of misprocessed
stress information with overactivity of brain circuits normally
devoted to monitor the global energy balance. Indeed, recent
evidence suggests tighter links between fatigue and psycho-
logical morbidity rather than between fatigue and disease ac-
tivity [70, 71]. Dissecting the relative contribution of neuro-
psychiatric and inflammatory factors in lupus morbidity
would have major implications for patient management, pos-
sibly leading to optimization of current paradigms for the use
of immunosuppressive and psychoactive drugs and
preventing unnecessary side effects.
Many experiences of Lupus Clinics around the world dem-
onstrate that a patient-centered perspective is far more effec-
tive in treating lupus patients than traditional disease-centered
protocols. Empirical research documents that the integration
of psychological and psychotherapeutic interventions, along
with other non-pharmacologic approaches (i.e., physical exer-
cise, diets, self-regulatory techniques…), in the traditional
medical care of patients with SLE produce promising results
not only in reducing anxiety, depression, and emotional dis-
tress but also in improving fatigue, pain, and functional dis-
ability [72–76]. Therefore, it would be worthwhile to focus on
the need for multidisciplinary interventions with an ultimate
outcome of preventing stress-related immune imbalances.
Methodological heterogeneity between studies, concerning
the nature of interventions and assessment instruments, makes
it difficult to draw convincing conclusions. Therefore, future
research should deepen the analysis of the efficacy of specific
non-pharmacological therapies on disease outcomes. In addi-
tion, research agenda should include the impact of AT and
PTSD on treatment compliance and quality of life, the role
of traumatic events as a second hit in SLE pathogenesis and
reclassification of fibromyalgia in light of patients’ psycho-
logical dimension.
Conclusions
PTSD and AT might be common in patients with SLE and
account for multiple aspects of SLE-related morbidity.
Furthermore, abnormal processing of stressful stimuli as hall-
marks of PTSD and AT might promote neuroendocrine dys-
function and dysregulated inflammation, thus contributing to
the pathogenesis of SLE. A comprehensive, multidisciplinary
clinical approach, based on a synergy between immunolo-
gists, rheumatologists, neurologists, and mental health profes-
sionals, may facilitate the performance of tailored effective
treatments, centered on patients’ needs.
Unlike hereditary and genetic etiological factors that cannot
be changed, many psychological and environmental factors
may be modified to enable better management of autoimmune
diseases and from our experience, the inclusion of a trained
Curr Rheumatol Rep (2021) 23:52
psychologist among the Lupus Clinic collaborators is extremely
beneficial and recommended for this purpose.
Future research should clarify the interplay between psy-
chological and biological factors in the pathogenesis of SLE
and inform the development and implementation of novel
therapeutic approaches.
Author Contribution 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 inter-
pretation of the data; all authors approved the final version to be submit-
ted 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.
Availability of data and material Not applicable
Code availability Not applicable
Declarations
Additional declarations for articles in life science journals that report the
results of studies involving humans and/or animals Not applicable
Ethics approval Not applicable
Consent to participate Not applicable
Consent for publication Not applicable
Conflict of Interest The authors declare no competing interests.
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