Clinical features and management of late-onset systemic lupus erythematosus

Late-onset systemic lupus erythematosus (LSLE) refers to the patient's clinical symptoms first occurring after the age of 50, accounting for about 2% ~ 20% of SLE, although the proportion is low, but due to the insidious onset of the disease, the clinical manifestations are heterogeneous, it is easy to miss and misdiagnose, and the mortality rate of LSLE is higher than SLE, so it is necessary to timely and accurate diagnosis and treatment
.

Features of clinical presentation

The clinical symptoms of SLE patients are mostly fever, arthralgia, rash, multi-organ involvement, etc.
, while the clinical manifestations of LSLE patients are insidious and atypical, less involving the skin and mucous membranes, typical skin lesions are rare, organ involvement is less, disease activity is low and the cumulative damage degree is higher, and the complication rate and mortality are high
.

Clinical presentation is heterogeneous

LSLE is less common than the mucocutaneous symptoms of SLE patients, such as zygomatic rash, discoid erythema, photosensitivity, skin vasculitis, etc.
, fever, kidney damage, nervous system and other symptoms are also uncommon, but mostly manifested as serositis, Sjogren's syndrome, thrombosis, etc
.
Elderly patients are mostly manifested as muscle weakness, serositis, cardiac damage, etc.
, while the incidence of butterfly erythema, photosensitivity, and renal damage is low
.

Myopathy has low activity and a higher degree of cumulative injury

Clinically, the disease activity index (SLEDAI-2K) of systemic lupus erythematosus was mostly used to evaluate disease activity, and the score was positively correlated
with disease activity and severity.
The results showed that LSLE patients had lower SLEDAI-2K scores than SLE, indicating that LSLE disease activity was lower and the disease progression was slow
.
The Systemic Lupus Erythematosus International Collaborative Tissue Damage Index (SDI) is used to assess the extent of SLE injury and can better predict disease prognosis
.
Patients with LSLE have a higher SDI score and more common cumulative organ damage, in which the eye, musculoskeletal system, and cardiovascular system are susceptible, and the cumulative degree of injury increases
over time.
LSLE disease activity is low but cumulative damage is higher, which may be related to a variety of factors such as aging-related
complications and drug toxicity.

Complication and mortality rates are high

LSLE is more likely to have multisystem disease, but these complications are less detectable, delaying diagnosis and treatment, resulting in higher mortality
.
The most common complication of LSLE is cardiovascular disease, but osteoporosis, malignant tumors, diabetes, and cerebrovascular accidents are also common
.
Similarly, LSLE mortality was higher than SLE (14.
3% vs.
4.
7%, P<0.
001), with vascular lesions accounting for 31.
7%, infections accounting for 31.
1%, and cancer accounting for 22.
9%.

Some scholars have also pointed out that half of the patients who died of SLE died of infection, and the other half died of ischemic cardiovascular or ischemic cerebrovascular disease
.
Relevant research results in China also show that infection is the leading cause
of death from SLE.
This difference in causes of death may be due to
differences in the level of medical services and disease activity in different regions.

Pathogenesis and related influencing factors

The pathogenesis of SLE is currently unclear, and may be related to genetic, sex hormone, immune, environmental, psychopsychological and other factors, and it is currently believed that the pathogenesis of SLE is mainly the loss of immune tolerance and the production
of autoantibodies.
 

The incidence of LSLE is also related to
the above factors.
By comparing the clinical pathogenesis characteristics of LSLE and SLE, it can be concluded that age can affect the clinical manifestations and prognosis of the disease, but the specific mechanism is not clear, and we believe that immunosenescence plays a greater role
in it.
Immunosenescence is an age-related immune dysfunction that is one of the main manifestations of the aging process and can affect various types of cells, such as neutrophils, monocytes, macrophages, natural killer (NK) cells and dendritic cells in innate immune responses, and B cells and T cells
in adaptive immune systems 。 On the one hand, immunosenescence and SLE have similarities in changes in the immune system, such as being in a state of mild inflammatory activity, decreased function of NK cells, increased memory effector T cells, decreased naïve T cells, etc.
, which make the elderly aging and SLE clinically similar, such as increased susceptibility to infection, chronic inflammation, cardiovascular disease and cancer; On the other hand, there are differences in immune system changes, some of which may lead to differences in the clinical presentation characteristics of LSLE and SLE
.

Immune cells in the innate immune system such as neutrophils, dendritic cells, NK cells, etc.
play an important role in the pathogenesis of SLE, but aging leads to a decrease in the number and/or function of these cells, making LSLE clinically atypical and disease activity low
.

Neutrophil extracellular traps (NETs) are the main source of SLE autoantigens, and impaired clearance of NETs mediates the pathogenesis of SLE, while neutrophil function decreases in the elderly and NETs release decreases
.
Plasmacytoid dendritic cells (pDCs) secrete large amounts of type I interferons, activate antigen-presenting cells of naïve T cells, and mediate immune responses
.
Among them, type I interferon is related to disease activity and severity, the percentage of circulating pDCs in the elderly decreases, and its ability to produce IFN-α also decreases
with age.
In addition, aging can lead to the redistribution of NK cell subsets, reducing their cytotoxic activity and reduced
disease activity.
Monocytes function decreases with age, their tendency to migrate decreases, and the production and release of interleukin (IL)-12 and tumor necrosis factor (TNF)-α is impaired
.

The number and function of T cells in the adaptive immune system can be reduced, which can cause insufficient activation of B cells, while B cells can have a decrease in the number of naïve cells in the aging process, an increase in oligoclonal memory B cells, a decrease in the antigen affinity of the antibodies produced, and a weakening of its functional response with age, these changes make the clinical manifestations of LSLE heterogeneous and the disease activity reduced
.

Sex hormones and environmental factors (drugs, smoking, etc.
) can also mediate the onset of
LSLE.
The lower ratio of men to women with LSLE supported the pathogenesis of LSLE.
Drug-induced provocation is more common in older adults; The older the smoker, the more susceptible they are to LSLE, and the higher
the cumulative degree of damage.

Age, sex hormones, environment and other factors are related to the incidence of LSLE, but there are few relevant literature reports to explain the specific mechanism and the reasons for atypical clinical manifestations, and it is still necessary to strengthen the research on the pathogenesis of LSLE in the future to explore the reasons for
the differences.

diagnosis

LSLE does not have clear diagnostic criteria, at present, SLE diagnostic criteria are mostly used, of which the diagnosis of SLE mostly relies on clinical manifestations and immunological indicators, among which the most commonly used and clinically important immunological indicators include antinuclear antibody (ANA), anti-double-stranded DNA (anti-ds-DNA) antibody, anti-Sm antibody, anti-nucleosome, anti-ribosomal P protein, anti-histone, anti-phospholipid antibody, etc
.
 

The immunologic performance of LSLE was also heterogeneous
.
Most literature reports that the positive rates of anti-ds-DNA antibody, anti-Sm antibody positive, anti-RNP antibody, antiphospholipid antibody, and hypocomplement in LSLE patients are lower than those in SLE patients
.
However, with the exception of hypocomplementemia, there were no significant differences in immunological measures
.
Due to the heterogeneity of clinical manifestations and immunological indexes of LSLE, clinicians need to comprehensively diagnose and diagnose diseases to reduce the occurrence of
missed diagnosis and misdiagnosis.

The diagnosis of SLE is mostly based on the 1997 American College of Rheumatology (ACR) criteria, but in order to further improve the sensitivity and specificity of SLE diagnosis, the European Union Against Rheumatism and the American College of Rheumatology (EULAR/ACR) SLE classification standard have been updated
.
It mainly includes updates on: (1) high titer of antinuclear antibody positivity as a shortlisted criterion for SLE diagnosis; (2) non-infectious fever was included in the classification criteria; (3) Each aspect takes the score
of the highest weighted item.
The sensitivity and specificity ratios of the 2019 EULAR/ACR classification standard and the 1997 ACR standard were 96%:95% and 93%:85%, and the specificity of the new classification standard has been significantly improved
.

In the new classification criteria, positive antinuclear antibody is a highly sensitive shortlisted criterion, with a sensitivity of 97.
8% when the titer ≥ 1:80, although the antinuclear antibody positivity rate can also be increased in healthy older people, indicating a threshold titer ≥1∶ 80% may not be suitable for diagnosis
in patients with LSLE.
Therefore, we believe that ANA titers
for LSLE diagnosis can be increased in older patients without strong clinical evidence.

The new classification criteria contains 7 clinical manifestations and 3 immunological indicators, and different items in each aspect have different weights, and the clinical manifestations and immunological indicators of LSLE are atypical, and whether this classification criterion can accurately diagnose late-onset patients needs further research
.
This criterion has demonstrated good sensitivity and specificity in both adult and pediatric populations, but no trials have tested the sensitivity and specificity of this criterion in older populations, and future studies
in patients with LSLE are needed.

Key points of treatment 

The treatment principle of SLE is early, personalized treatment, which delays disease progression, reduces organ damage, and improves prognosis
to the greatest extent.
In recent years, sustained remission has been considered the ultimate goal of SLE treatment, but it has been difficult to achieve
.
Common medications include corticosteroids, hydroxychloroquine, immunosuppressants, and biologics
.
Treatment of LSLE is similar to SLE therapy, but due to low disease activity and slow disease progression in older patients, the dose of the drug can be reduced
accordingly.
It is worth noting that sometimes the treatment itself can also bring damage, especially in elderly patients often have multiple diseases, and adverse reactions to treatment are more common, so the treatment of elderly patients also needs to consider the impact
of possible drug interactions and decreased liver and kidney function.
 

Patients with SLE are prone to a variety of diseases, of which cardiovascular disease is the most common
.
Recent research results show that the overall prevalence of cardiovascular events in SLE is 4%~20%, and the risk of clinical cardiovascular disease in SLE patients is increased by 2~10 times
compared with healthy people.
Patients with LSLE have a higher risk of cardiovascular disease than those with SLE, which may be related
to aging and longer exposure to classic cardiovascular risk factors (eg, hypertension, hypercholesterolemia, diabetes, menopause, etc.
).
In addition, cardiovascular disease is also the most common cause of death in patients with LSLE, so clinicians need to regularly screen for complications and adequately control them to reduce their damage
.
 

Patients with SLE are also prone to bone metabolism disorders, which can lead to bone metabolism abnormalities, increasing the risk of osteoporosis, fractures, and osteonecrosis
.
The results showed that the prevalence of osteoporosis in SLE patients was approximately 16%, and the risk of osteoporotic fractures was 2.
964-fold increased compared to age- and sex-matched
healthy people.
The increased incidence of bone metabolism abnormalities in SLE is related to age, sex, menopause, body mass index, way of life, the disease itself, and the influence of therapeutic drugs, especially glucocorticoids.

Glucocorticoids play an important role in the treatment of SLE, and are the most commonly used basic drugs for inducing remission therapy and uniformly recommended by relevant guidelines at home and abroad, but their induced osteoporosis is also an important cause
of osteoporosis secondary to SLE.
The results of the study in China show that the incidence of abnormal bone mass (including osteopenia and osteoporosis) in patients aged > 50 years is higher than that in patients aged ≤ 50 years, so preventive calcium supplementation and vitamin D are very important, and for women after menopause and men over 50 years old, according to the fracture risk assessment tool for overall risk assessment, phosphonates can be used as appropriate to reduce the adverse effects of glucocorticoids on bone metabolism
。

Hydroxychloroquine remains the treatment of choice in patients with LSLE
.
Long-term use of hydroxychloroquine can reduce disease activity, the risk of organ damage, improve blood lipids, improve survival, and be effective in the treatment of joint and mucocutaneous manifestations, but long-term use of hydroxychloroquine may cause irreversible retinopathy, and the daily dose of hydroxychloroquine > 5.
0 mg/kg significantly increases the risk of hydroxychloroquine retinopathy, and the higher the risk of older age, high body mass index, macular retinopathy, concomitant kidney disease, use of tamoxifen, and long intake of hydroxychloroquine
。

With increasing age, the elderly often have retinopathy (such as diabetic retinopathy, age-related macular degeneration, etc.
), so it is more necessary to be vigilant about hydroxychloroquine retinitivity
when using hydroxychloroquine.
A study on hydroxychloroquine retinopathy in SLE patients showed that the overall prevalence of hydroxychloroquine retinopathy was 4.
3%, the incidence of hydroxychloroquine retinopathy in patients under 45 years of age was 0.
5%, and the incidence of hydroxychloroquine retinopathy in patients aged 45~49 and 60 years and above was 4.
4% and 10.
1%, respectively
.
This indicates that the older the patient, the greater the retinal toxicity of hydroxychloroquine, so fundus examination and regular screening for retinopathy
are indicated in patients treated with hydroxychloroquine within 1 year.

Immunosuppressants reduce hormone use and prevent disease recurrence
.
In patients with refractory or relapsed SLE, immunosuppressants control disease activity and increase clinical response rates
.
Commonly used immunosuppressants include cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil, etc
.
Older patients have milder disease, and immunosuppressant use can be moderately less
.

Although a variety of biologics have been tried to treat SLE and have achieved some clinical efficacy, only belimumab has been approved by the US Food and Drug Administration (FDA) and the State Food and Drug Administration (CFDA) for the treatment of SLE
。 Belimumab can be used in extrarenal disease with poor disease control and inability to reduce the daily dose of glucocorticoids to acceptable levels (maximum 7.
5 mg/day), reduces disease activity, reduces hormone use, and has fewer adverse effects and a high clinical safety profile, including infection, allergy, headache, nausea, and infusion reactions
.
This agent
may be considered in patients with LSLE who have poor disease control.

Lifestyle modifications can help in the treatment
of LSLE.
Patients should follow the following principles: (1) avoid exposure to hazardous substances; (2) Pay attention to sun protection; (3) moderate exercise; (4) focus on mental health; (5) quit smoking; (6) Supplement vitamin D, etc
.

The treatment of LSLE should focus on the efficacy and safety of drugs, reduce the occurrence of adverse drug reactions, reduce organ damage, and pay attention to the prevention and treatment of complications to delay disease progression and improve prognosis
.
At present, most therapeutic studies are limited to adults, and few are aimed at elderly patients, and the morbidity and mortality rate of elderly patients are high, so it is necessary to study the impact of
related treatments on elderly patients.

References:

[1] HU Xiaoqian,XIA Yumin.
Clinical features and diagnosis and treatment progress of late-onset systemic lupus erythematosus[J].
Chinese Journal of Geriatrics,2022,41(8):986-991.