CLINICAL FEATURES OF LATE-ONSET SYSTEMIC LUPUS ERYTHEMATOSUS

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a wide range of clinical manifestations and a relapsing-remitting course. The peak incidence of SLE occurs during the reproductive years; however, it can develop at any age. Late-onset SLE, which is diagnosed at age 50 or older, accounts for approximately 20% of all SLE cases. The comparison between late-onset SLE patients and their early-onset counterparts has revealed distinct differences in clinical characteristics, comorbidities, and mortality rates. Late-onset SLE patients exhibit lower frequencies of mucocutaneous, renal, hematological, and neuropsychiatric symptoms but higher rates of serositis, peripheral polyneuropathy, cardiovascular diseases, and pulmonary involvement. Additionally, they experience a greater burden of comorbidities and increased mortality rates. Here, we review the clinical characteristics, comorbidities, and mortality of patients with late-onset SLE.

Full text

87
Review Anti-Aging Eastern Europe
© 2024 by the authors. This work is licensed under
Creative Commons Attribution 4.0 International License
https://creativecommons.org/licenses/by/4.0/
CLINICAL FEATURES OF LATE-ONSET SYSTEMIC LUPUS
ERYTHEMATOSUS
Neslihan Gokcen1 https://orcid.org/0000-0003-3022-493X
Ayse Cee1 https://orcid.org/0000-0002-3273-7969
1Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Kocaeli University, Kocaeli,
Türkiye
Received: May 3, 2024
Accepted: June 21, 2024
Corresponding author: Neslihan Gokcen E-mail: drngokcen@hotmail.com Twitter handle: @NeslihanGken7
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a wide range of clinical
manifestations and a relapsing-remitting course. The peak incidence of SLE occurs during the reproductive years;
however, it can develop at any age. Late-onset SLE, which is diagnosed at age 50 or older, accounts for approximately
20% of all SLE cases. The comparison between late-onset SLE patients and their early-onset counterparts has revealed
distinct differences in clinical characteristics, comorbidities, and mortality rates. Late-onset SLE patients exhibit lower
frequencies of mucocutaneous, renal, hematological, and neuropsychiatric symptoms but higher rates of serositis,
peripheral polyneuropathy, cardiovascular diseases, and pulmonary involvement. Additionally, they experience a
greater burden of comorbidities and increased mortality rates. Here, we review the clinical characteristics, comorbidities,
and mortality of patients with late-onset SLE.
Keywords: clinical course; comorbidity; early-onset; late-onset; mortality; systemic lupus erythematosus
How to cite: Gokcen N., Cee A. Clinical Features of Late-onset Systemic Lupus Erythematosus. Anti Aging East Eur
2024;3(2): 87-95 https://doi.org/10.56543/aaeeu.2024.3.2.05
• Late-onset SLE patients often face delayed diagnosis due to the disease’s insidious onset, atypical
clinical manifestations, comorbidities that obscure symptoms, and reluctance to diagnose SLE in
the elderly.
• Late-onset SLE patients experience less organ involvement and a more benign disease course but
exhibit higher rates of organ damage and mortality due to the prevalence of comorbidities.
Key Messages for Research and Practice

88
Introduction
Systemic lupus erythematosus (SLE) is an
archetype autoimmune disorder characterized
by a wide spectrum of clinical and laboratory
manifestations. The chronic inammation
associated with SLE affects nearly all organs and
tissues [1-3]. Epidemiologically, the characteristics
and severity of the disease vary depending on race,
gender and age. SLE mostly affects women within
the reproductive age range, typically between
15 and 44 years. The age of disease onset plays a
crucial role in determining the prognosis, with
childhood-onset SLE generally associated with a
more severe disease course [1]. Therefore, younger
age at presentation is an important component for
predicting patients at high disease activity of SLE [1].
The literature also reports the occurrence
of SLE among older individuals, termed late-
onset SLE (l-SLE). Late-onset SLE is typically
dened as SLE diagnosed at 50 years or older,
constituting approximately 20% of all SLE cases
[4-6]. However, some studies suggest using a
higher age cutoff of 65 years and older to dene
l-SLE patients [5]. Since SLE is typically considered
a disease affecting young or adult patients, the
delay in diagnosing l-SLE is signicant and has
been reported to be up to 60 months [7]. Late-
onset SLE differs from early-onset SLE (e-SLE) in
several aspects, including gender and ethnicity
prevalence, clinical manifestations, laboratory
outcomes, progression of organ damage, disease
activity and severity, prognosis, and mortality [5,7-
9]. The predominance of females in SLE decreases
with advancing age [5]. Consequently, l-SLE is
more prevalent in men [10]. Moreover, major organ
involvement, such as central nervous system and
renal involvement, is less commonly observed
in patients with l-SLE, however; serositis and
comorbidities, such as cardiovascular disease, have
been frequently documented in late-onset patients.
Consequently, higher organ damage and mortality
rates have been indicated in these patients [8-10].
Several factors have been accused of causing these
differences between late- and early-onset SLE. It is
hypothesized that immune senescence and male
predominance are contributing factors [5,9,10].
Studies have shown that l-SLE patients
exhibit an insidious onset, less severe disease, and a
milder clinical course, but face higher rates of organ
damage and increased mortality compared to e-SLE
patients [11,12]. Furthermore, the clinical features
of l-SLE differ from those of young-onset SLE
[12]. However, interestingly, studies investigating
and comparing the clinical differences between
early-onset and late-onset patients are scarce.
Hence, this narrative review aims to
comprehensively examine and synthesize studies
on the clinical characteristics of patients with late-
onset SLE.
Methods
This narrative review was conducted by
searching for peer-reviewed publications in the
PubMed/Medline database, covering the period
from January 2014 to May 2024 [13]. We searched
for publications from the past ten years, ensuring to
include older, highly regarded publications as well.
Clinical studies and systematic reviews on late-onset
SLE published in English language were included.
Case reports, editorial letters, review articles and
conference papers were excluded. The following
search terms were used for Pubmed search: (“Late-
onset systemic lupus erythematosus” [tiab] OR
“systemic lupus erythematosus” [MeSH terms]
AND (“older-onset” [tiab] OR “elderly” [MeSH
terms] OR “older” [tiab] OR “geriatric” [tiab]).
Titles and abstracts were reviewed as part of the
selection process. The detailed selection procedure
is illustrated in Figure 1. This review focuses on the
clinical characteristics of late-onset SLE. Ultimately,
35 studies were selected for inclusion in the review.
Clinical features
Constitutional features
Constitutional symptoms of SLE consist
of fever, fatigue, myalgia, lymphadenopathy,
splenomegaly, and loss of appetite and weight
[9,14]. Generally, these manifestations have
been observed in patients with active disease
and/or organ involvement [14]. Non-specic
fatigue is the most common manifestation in
SLE, often accompanying musculoskeletal and
mucocutaneous involvement [1]. A study indicated
that these symptoms ranked third among the most
common presenting complaints in l-SLE patients,
following arthritis and oral ulcers. However,
the authors found no signicant difference
in the prevalence of fever between e-SLE and
l-SLE patients [15]. Similarly, some studies have
indicated no signicant variation in constitutional
features, such as fever, fatigue, lymphadenopathy,
and weight loss, between these groups [16-18].
Moreover, a study by Riveros Frutos et al. revealed
no signicant difference in the likelihood of
presenting with fever, splenomegaly, or weight
loss between early-onset and late-onset patients.
However, the authors found that e-SLE patients
had a higher probability of lymphadenopathy [9].
In contrast, several studies have reported lower
frequencies of fever [19-23], higher rates of weight
Anti-Aging Eastern Europe, 2024, Vol 3, №2

89
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loss [18,21], and lymphadenopathy [21] in patients
with l-SLE compared to those with e-SLE. Some
authors attribute non-specic symptoms such as
arthralgia, myalgia, and fatigue to aging [24].
Musculoskeletal features
Musculoskeletal involvement has been
described in up to 90% of SLE patients. Arthritis
and arthralgia are prevalent presenting symptoms
in these patients [1]. However, although arthritis is
the most common manifestation in patients with
l-SLE, its frequency is lower compared to patients
with e-SLE [4,9,12,15,21,25-28]. Conversely, several
studies have demonstrated no signicant difference
in the prevalence of arthritis between early-onset
and late-onset SLE groups [16-18,22,23,29,30].
Among these studies, one indicated no difference
in the rates of arthritis between childhood-onset/
early-onset SLE and l-SLE patients, both at the time
of diagnosis and throughout the disease course
[24]. On the other hand, another study revealed
that l-SLE patients exhibited a lower frequency
of arthritis both at diagnosis and at the last visit
compared to e-SLE patients [31]. Interestingly, only
one study found that the rates of arthritis increased
with the age of onset [19]. In addition, erosive
arthritis has been shown to occur more often in
l-SLE [9]. Inammatory arthralgia is also a well-
documented manifestation of SLE and appears
equally common in early-onset and late-onset
patients [1,23,32]. However, a study has reported a
higher prevalence of arthralgia in l-SLE patients [31].
Mucocutaneous features
The spectrum of mucocutaneous
involvement in SLE is diverse. It includes
manifestations such as photosensitivity, malar
rash, discoid rash, various forms of cutaneous
lupus erythematosus (acute, subacute, chronic),
non-scarring alopecia, as well as oral and nasal
ulcers [1]. The literature presents conicting
results regarding the frequency of mucocutaneous
symptoms in patients with l-SLE [12,15,33]. A study
comparing the clinical features of early-onset and
late-onset cutaneous lupus erythematosus (CLE)
revealed that patients with early-onset cutaneous
lupus erythematosus exhibited a higher prevalence
of malar rash, discoid rash, photosensitivity, and
oral ulcers, whereas the late-onset group showed
a relatively lower frequency of these symptoms.
Additionally, arthritis, renal involvement, and other
immunological disorders were more frequently
observed in the early-onset group than in the late-
onset group [25]. Likewise, several studies have
shown a lower frequency of malar rash, discoid rash,
photosensitivity, and oral ulcers in l-SLE patients
than in e-SLE patients [9,12,16,17,21,26,32,34].
Curiously, some studies reported no disparity
in the presence of malar rash, discoid rash,
photosensitivity, alopecia, and oral ulcers between
the groups [4,18,23,30,35]. A comprehensive study
examining cutaneous and systemic manifestations
in l-SLE revealed distinct patterns. Acute CLE,
characterized by features such as malar rash
and photosensitivity, was notably prevalent
among e-SLE patients. Conversely, subacute CLE
manifestations like papulosquamous rash and
chronic forms, including lupus profundus and
lupus tumidus, were more frequently observed in
l-SLE compared to e-SLE. Mucosal involvement
(especially oral ulcers), hair loss (non-scarring
alopecia), and non-specic CLE features such as
Raynaud’s phenomenon were observed more
among e-SLE patients [26]. Mongkolchaiarunya
et al. documented that malar rash was prevalent
among patients with e-SLE at the time of diagnosis.
However, the authors found no signicant
differences in cutaneous manifestations between
early-onset and late-onset patients at the last
follow-up visit [31]. Conversely, Nikolopoulos et al.
reported that the frequency of malar rash in patients
with e-SLE was comparable to that in patients with
l-SLE at the time of diagnosis. However, malar rash
was observed more frequently in the e-SLE group
during the follow-up period [20]. Another study
indicated no signicant disparities in cutaneous
manifestations between the groups at the time of
diagnosis and during the 5-year follow-up visit
[35]. A meta-analysis comparing cutaneous features
in e-SLE versus l-SLE revealed a lower prevalence
of malar rash, photosensitivity, Sicca syndrome,
alopecia, and Raynaud’s phenomenon in l-SLE
patients than in e-SLE [36].
Serositis
Serositis typically manifests as inammation
of pleura, pericardium, and peritoneum, leading
to symptoms such as pleuritis, pericarditis, and
peritonitis [23,37]. Generally, higher rates of
serositis have been observed in patients with
l-SLE [8,12,15]. On the other hand, many studies
have reported no difference in serositis between
e-SLE and l-SLE [9,16,20,22,23,26,29,30,33,35].
Furthermore, a few studies have documented a
reduced occurrence of serositis in l-SLE patients
than in e-SLE patients [4,21]. A study pointed out
that serositis was common in l-SLE patients at the
time of diagnosis. However, the authors found no
signicant differences in the occurrence of serositis
between patients with e-SLE and l-SLE at the last
follow-up visit [31].

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Renal involvement
Renal involvement is among the most
common and serious manifestations of SLE,
associated with signicant morbidity and an
increased mortality rate [38]. Its occurrence
diminishes notably after the initial 5 years of
the disease [39]. Based on the literature, patients
with l-SLE are less likely to present with renal
involvement [4,8,15,19,21,30-34]. In addition, in
a prospective study, a lower frequency of renal
involvement in l-SLE patients was observed not
only at the time of diagnosis but also throughout
the follow-up period [35]. Accordingly, proteinuria,
severe proteinuria (>3500 mg), hematuria, and
pyuria are more common in e-SLE patients than in
l-SLE patients [9,23,26]. Furthermore, renal failure
is also seen more in the e-SLE group [9,16,19]. A
few studies have demonstrated comparable rates
between the groups [16,22,29]. On the other hand, a
study by Nikolopoulos et al. revealed that although
the rate of renal involvement was similar between
the groups at the time of diagnosis, lupus nephritis
became more prevalent in the e-SLE group over
time [20]. Some studies have investigated the
clinical characteristics of patients with late-onset
lupus nephritis. Therefore, class IV lupus nephritis
is the most biopsy proven renal involvement in
patients with late-onset lupus nephritis [38-40]. The
comparison of glomerulonephritis classications
in early and late-onset nephritis appears similar
[38,41]. However, Catoggio et al. found higher
rates of class IV nephritis in patients with e-SLE
compared to those with l-SLE [32]. Despite the
generally lower prevalence of renal involvement in
l-SLE, as demonstrated by numerous studies, one
study reported a higher rate of lupus nephritis in
l-SLE patients [12].
Hematological involvement
Hematologic manifestations encompass
conditions such as leucopenia (less than 4×10^9
per liter), thrombocytopenia (less than 100×10^9
per liter), lymphopenia, autoimmune hemolysis
(positive direct Coomb’s test, along with
indications of hemolysis such as reticulocytosis,
low haptoglobin, and elevated indirect bilirubin
or lactate dehydrogenase) [1,2]. According to
the literature, younger patients with SLE often
exhibit more severe hematological involvement
[19,28]. Hematological involvement, including
leukopenia, lymphopenia, thrombocytopenia,
and hemolytic anemia, is less frequent in l-SLE
patients [23,26,31,33]. In particular, leukopenia
is more commonly observed in e-SLE patients
compared to l-SLE patients [9,21,30,31]. However,
several studies have indicated no difference in
hematological manifestations between groups,
except for leukopenia, which is more prevalent in
the e-SLE group [15,17,22,24,27,29,32,35].
Neuropsychiatric involvement
This involvement includes lupus headache,
cranial neuropathy, peripheral polyneuropathy,
delirium, seizure, and psychosis characterized by
delusions and hallucinations [1,2,9,10]. Like renal
and hematological involvement, a lower rate of
central nervous system (CNS) involvement is
documented in l-SLE [4,10,21,26,33,35]. Riveros
Frutos et al. showed that lupus headache was
frequently observed in e-SLE patients, while
depression was common in l-SLE patients [9]. A
recently published meta-analysis revealed that
seizures and psychosis were less common, but
peripheral polyneuropathy was prevalent in l-SLE
patients [10,26]. On the other hand, numerous
studies have found no disparity in neuropsychiatric
involvement between e-SLE and l-SLE patients
[15,16,22,23,29,31,32].
Cardiovascular involvement
The cardiovascular disease and the
increased risk of cardiovascular mortality are
prevalent in SLE [9]. Cardiac involvement in
SLE is predominantly subclinical and includes
myocarditis, pericarditis, angina, acute myocardial
infarction, and cardiomyopathy [1,9]. Patients
with l-SLE have an increased frequency of
cardiovascular diseases [29,30,35]. A study
revealed that the occurrence of cardiovascular
comorbidities, including myocarditis, angina, acute
myocardial infarction, and cardiomyopathy, was
higher in l-SLE patients than in e-SLE patients at
the time of diagnosis [9]. Moreover, several studies
have indicated that thromboembolism, deep vein
thrombosis, and pericarditis were more frequently
observed in l-SLE patients [18,32]. Bindroo et al.
observed that pericarditis, while common, was
not statistically signicant in the l-SLE group
[15]. A study by Mongkolchaiarunya et al. found
that cardiomyopathy and lupus endocarditis
were prevalent in l-SLE patients. However, after
adjustment, this signicance was lost, indicating no
difference between the groups [31]. Furthermore,
several studies have also demonstrated no
difference in cardiovascular disease between e-SLE
and l-SLE groups [16,21,23].
Lung involvement
The occurrence of pulmonary manifestations
in SLE is rare, with the exception of serositis.
These manifestations encompass upper and lower
airway involvement (including laryngeal affection,
bronchitis, bronchiolitis, and bronchiectasis),

92
parenchymal diseases (such as interstitial lung
disease, acute lupus pneumonitis, pulmonary
brosis, and diffuse alveolar hemorrhage),
pleural diseases (including serositis and shrinking
lung syndrome), and vascular diseases (such as
pulmonary arterial hypertension, pulmonary
embolism, and acute reversible hypoxemia
syndrome) [1,42]. Serositis is discussed in detail
under the section titled ‘Serositis.’ Previous
literature has addressed that lung involvement
is more common in l-SLE, although some studies
have provided evidence to the contrary [43,44]. The
current literature also presents conicting data.
Several studies have demonstrated that pulmonary
manifestations are prevalent in l-SLE patients
[15,29,32,45]. In particular, interstitial lung disease
and pleuritis are reported more in l-SLE [15,17,32].
In addition, pulmonary thromboembolism as
a comorbid condition has been observed more
frequently in patients with l-SLE than in those with
e-SLE [9]. Notably, a meta-analysis demonstrated
that l-SLE patients had higher odds of experiencing
pulmonary manifestations, particularly interstitial
lung disease, in comparison to their younger
counterparts [45]. In a prospective study, the
authors indicated that patients with late-onset SLE
had a higher frequency of interstitial lung disease
over time compared to e-SLE patients, although
this difference was not apparent at the time of
diagnosis [31]. Nevertheless, lung ndings may
also be present upon initial diagnosis [20]. On the
other hand, some research has signied that lung
damage occurs at similar frequencies in both e-SLE
and l-SLE patients. [22,35].
Gastrointestinal involvement
Lupus patients frequently experience
gastrointestinal symptoms, with over half of these
cases resulting from adverse medication reactions
and infections. Gastrointestinal involvement in
lupus can become severe and potentially fatal if not
addressed promptly [37]. This involvement includes
medications, infections, and associated conditions
like inammatory bowel disease, celiac disease,
and mesenteric thrombosis. Moreover, it involves
oral ulcers, gastric and esophageal involvement,
hepatobiliary and pancreatic involvement, serositis,
and bowel involvement such as lupus enteritis,
pseudo-obstruction, and lupus associated protein-
losing enteropathy [37]. There is limited data on
gastrointestinal involvement in patients with
l-SLE. Riveros Frutos et al. reported that severe
liver disease, gastric and duodenal ulcers were
common comorbidities in l-SLE patients at the time
of diagnosis. However, they found no signicant
differences in the incidence of peritonitis and lupus
hepatitis between the e-SLE and l-SLE groups
[9]. Similarly, a few studies have demonstrated
comparable frequencies of gastrointestinal
involvement in both groups [15,16,29,35].
Comorbidities
Patients with SLE often experience a high
burden of comorbidities. These comorbidities
primarily result from a combination of
disease activity, disease duration, and adverse
effects of treatments [1]. Riveros Frutos et al.
comprehensively investigated the comorbidities
of e-SLE and l-SLE upon initial diagnosis. They
revealed that autoimmune thyroid disease,
severe liver disease, gastric and duodenal ulcers,
chronic obstructive pulmonary disease, diabetes
mellitus, dyslipidemia, arterial hypertension,
peripheral artery disease, ischemic heart disease,
congestive heart failure, arrhythmias, pulmonary
thromboembolism, cerebrovascular accident,
dementia, and cancer were more common in
l-SLE patients than in e-SLE patients [9]. Similarly,
several studies have reported that thyroid disease
(mainly Hashimoto’s thyroiditis), obesity, arterial
hypertension, dyslipidemia, major depression,
osteoporosis, diabetes mellitus, and valvular
heart disease are often documented among
patients with l-SLE [16,17,20,21,24,30]. A study
indicated a higher incidence of thyroid disease,
hypertension, and coronary artery disease among
l-SLE patients, but the authors found no differences
in other comorbidities such as chronic obstructive
pulmonary disease, asthma, antiphospholipid
syndrome, and diabetes mellitus between the
groups [22]. Yu et al. showed a higher cumulative
incidence of a Charlson Comorbidity Index score
≥1 in l-SLE patients compared to e-SLE patients
at initial diagnosis. Additionally, although the
incidence of comorbidities increased in all patients
during the 5-year follow-up, the greatest increase
was observed in late-onset patients [46]. Wen et al.
reported no differences in comorbidities, including
hypertension, diabetes mellitus and Sjögren’s
syndrome, upon admission between groups [29].
Medhat et al. documented the higher presence of
comorbidities and multimorbidity (comorbidities
≥ 2) in late-onset patients than in early-onset
patients [21]. Despite the generally benign disease
course of l-SLE patients, managing these patients
can be challenging due to the high prevalence of
comorbidities, likely exacerbated by aging [4,5,8,21].
Mortality
Mortality rates in SLE are elevated due
to persistent inammation, disease activity,
organ damage, and an increased burden of
comorbidities [1]. The accumulation of these
additional health conditions directly impacts
mortality rates, resulting in a higher incidence of
death among patients with l-SLE [4,9,31,46,47,48].
Anti-Aging Eastern Europe, 2024, Vol 3, №2

93
Studies have reported a lower frequency of
mucocutaneous manifestations, renal and
hematological involvement, and neuropsychiatric
symptoms in late-onset SLE patients. Conversely,
there are higher rates of serositis, peripheral
polyneuropathy, cardiovascular diseases, and
pulmonary involvement, including interstitial
lung disease and pleuritis, in late-onset SLE
patients compared to those with early-onset SLE.
Additionally, a higher presence of comorbidities
and increased all-cause mortality have been
documented in late-onset SLE patients.
FUNDING
None
CONFLICTS OF INTEREST
None declared
ACKNOWLEDGEMENT
None
In addition, Yu et al. concluded that although
advanced age alone can signicantly contribute
to higher all-cause mortality, the survival rate
for late-onset SLE patients remains signicantly
lower than that of age- and sex-matched controls
[46]. However, some studies have reported a
comparable prevalence of mortality between e-SLE
and l-SLE patients [24,33]. The causes of mortality
are variable, with SLE-related conditions being
the most frequently accused [24]. Furthermore,
infections, cardiovascular diseases, thrombosis,
and malignancies are also considered signicant
contributing factors to mortality in late-onset
patients [4,24].
Conclusion
Late-onset systemic lupus erythematosus (SLE)
patients exhibit distinct clinical characteristics
compared to younger patients (Figure 2).
Anti-Aging Eastern Europe, 2024, Vol 3, №2
Figure 2. Relative frequency of clinical features in early-onset and late-onset SLE patients (Figure created using data
from Table 7 of Reference 5)
Late-onset
SLE
Young-onset
SLE
Arthritis
21.9%-
83.1%
Arthritis
45%-92%
Oral
ulcers
6.8%-
40.3%
Oral ulcers
15.7%-
47.2%
Malar rash
36.0%-66.1%
Malar rash
18.2%-
53.5%
Photosensitivity
19.7%-64.4%
Photosensitivity
24.8%-73.5%
Discoid
rash
5.8%-
21.5%
Discoid
rash
0-17.2%
Nephritis
26.4%-56.9%
Nephritis
10.0%-49.3%
Serositis
19.1%-
32.8%
Serositis
17.7%-35.1%
Pleuritis
14.8%-
22.9%
Pleuritis
8.0%-
23.8%
Neuropsychiatric
involvement
3.8%-27.2%
Neuropsychiatric
involvement
0-26.0%
Hematological
involvement
60.5%-92.1%
Hematological
involvement
50.0%-84.4%

94
Anti-Aging Eastern Europe, 2024, Vol 3, №2
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Anti-Aging Eastern Europe, 2024, Vol 3, №2