Disease Info

Epidemiology 

The prevalence of SLE is highest in women (between 16-55 years old) and in non-white populations (African Americans, Asians, Hispanics, and Native Americans), with an estimated prevalence in adults of 30-150 per 100 000, and incidence ranges from 2.2 to 23.1 per 100 000 per year. However, children are also affected, although SLE is less common in this population, without the gender bias seen in adults, with a reported incidence of 0.3-0.9 per 100 000 children per year, and a prevalence of 3.3-24 per 100 000 children. 

Risk factors and possible causes 

SLE aetiology is multifactorial including genetic, epigenetic risk factors and environmental trigger that led to an activation of innate and adaptative immune system.  A genetic predisposition has been demonstrated in several studies where a 10-fold increased risk of SLE in monozygotic twins has been evaluated. Environmental factors as ultraviolet light exposure, infections, toxins, hormones,  smoking cigarettes, silica dust, moderate use of alcohol and different medications (penicillin, sulfa drugs, codeine, procainide, isoniazid and hydralazine) have been identified as possible risk factors for the disease. Especially hormones have been demonstrated a key role, specifically estrogen, this might explain the higher prevalence in females. Considering the underlying potential mechanism that leads to SLE, it appears that it is the result of an interplay of complex mechanism not fully understood, where there is a disturbance of immune tolerance. This involves the adaptative immune response as well as the innate immune response triggered by stimulus in a specific genetic background, leading to Interferon-I pathway activation, immune activation and autoantibody production, generation of inflammatory mediators and activation of the complement system, resulting in tissue damage. Additionally, an uncontrolled NETosis, a specific program of cellular death mediated by neutrophil, is increased and generate/trap autoantigens and aggravate inflammation.  

Common symptoms: Signs and symptoms 

SLE typically shows an extremely variable presentations, considering its possible diverse organ involvement. The symptoms might be distinguished in constitutional and organ specific. As constitutional symptoms extremely common are fatigue, presents in almost all patients, fever and weight loss. Among the organ specific manifestations, they might classify based on the organ/system involved: 

• Mucocutaneous symptoms are one of the most affected organs in the context of a multisystemic presentation, but it may be involved in an isolated way as cutaneous LE. Among this group of manifestations, the most frequently reported are the malar rash, discoid lesions, photosensitivity, subacute cutaneous LE, alopecia, panniculitis, livedo reticularis, Raynaud phenomenon, lichen planus, bullous lesions. 
• Musculoskeletal symptoms may be reported in terms of arthralgia and/or a real arthritis. Less frequently osteonecrosis-avascular necrosis of bone and myopathy may be also present. 
• Antibodies usually show as antinuclear antibodies (ANA), antidsDNA and anti-Sm, which may be present several years before the appearance of the clinical manifestation. 
• Haematology/lymphatic abnormalities are one the others key manifestations of SLE, that may be present as leukopenia, thrombocytopenia and or anaemia..  
• Thrombotic events and antiphospholipid syndrome: There are additional manifestations as thrombotic events when antiphospholipid autoantibodies are presents including anti-beta2microglobulin IgG and IgM, anti-cardiolipin IgG and IgM and lupus anticoagulant. The thrombotic events may be venous but also arterial.  
• Renal abnormalities: lupus nephritis is one of the most notable SLE manifestations that increases the morbidity and mortality of the disease. The dominant feature is proteinuria with active sediment abnormalities. In severe cases can lead to chronic renal failure. Based upon histopathologic evaluation, six different classes of lupus nephritis are distinguished, which have different therapeutic consequences. 
• Neuropsychiatric manifestations can also be present, and they include several symptoms such as headache, seizure disorder, psychosis, acute confusional state and cognitive dysfunction.  
• Gastrointestinal system may be involved although less frequently. Abdominal pain may be reported as secondary to mesenteric vasculitis and thrombosis that lead to ischemia and infarction. Additional possible manifestations may be hepatitis, pancreatitis or intestinal pseudo-obstruction. 
• Lung usually is involved later in the disease course and the most common manifestations is pleuritis followed by others more rare manifestations as pulmonary hypertension and chronic interstitial disease. 
• Cardiovascular system may be involved as valvular heart disease as Libman-sacks lesions with sterile vegetation or serositis with pericardial disease. 
• Pregnancy morbidities: Women in childbearing age should be aware of possible pregnancy complications and morbidity and this key moment of their life should be planned in order to minimize possible consequence for the mother and the newborn. Pregnancy complications and morbidities can be distinguished in delay in pursuing pregnancy, diminished ovarian reserve, increased risk of abortus, lupus flare, preterm delivery and specific direct consequences on the newborn called neonatal lupus. Neonatal lupus happens when specific antibodies of the mother, if positive anti-Ro or anti-La, cross the placental barrier and arrive in the foetal blood and can lead to several fearsome consequences that can start during the intrauterine life as the congenital heart block, or later after the delivery as anaemia or rash. However, many of these complications resolve by progressively eliminating maternal antibodies, but others that are structural persist for the entire life as congenital heart block. 
• Other manifestations: The eye might be involved in term of optic nerve, periorbita and ocular annex. The most frequent manifestation is the keratoconjunctivitis sicca, characterized by persistent eye dryness, followed by the optic neuritis and ischemic optic neuropathy and retinal vaso-occlusion that is like diabetic and hypertensive retinopathy, which then may seriously threaten visual acuity. 

There are some additional manifestations that are considered rare because reported in a low proportion of patients with SLE.
For more details see Tani C, et al. Clin Exp Rheumatol. 2022;40 Suppl 134(5):93-102.
Childhood SLE shows similar clinical manifestations but with different frequencies.  

When to see a doctor? 

If you have developed in the last months fatigue, weight loss, photosensitivity, malar rash, arthralgia/arthritis, oral ulcers, fever, ecchymosis/haemorrhagic episodes without a clear explanation, protein in the urine, seizure or thromboembolic events, probably it is better to see your doctor. Your doctors will evaluate you and wisely select reasonable tests and the workup to perform including autoimmunity. 

 Diagnosis (path/tests/differential diagnosis) 

The diagnosis is based on clinical, anamnestic as well as laboratory and immunological findings. The classification criteria of the ACR/EULAR can support diagnosis, as they list the main manifestations of SLE. However, they are explicitly not diagnostic criteria., and have been formulated for research purpose. The diagnosis as well as any differential diagnoses must be made or excluded clinically by the treating physician.
The clinical manifestations in combinations with specific blood abnormalities as presence of ANA, antidsDNA or anti-Sm, c3, c4, low white blood cells, low platelets, inflammatory index including ESR and CRP can help in formulating the correct diagnosis.
Common laboratory tests are extremely useful as cell blood count, liver and kidney function, urine analysis, complement level (c3, c4), inflammatory index (ESR and CRP) and the autoimmunity including the ANA status, antidsDNA, anti-Sm and anti-beta2glycoproteins and anticardiolipin.
In the differential diagnosis several diseases should be taken into account including infections, malignancies and the possibility of drug induced SLE.
Because of blood manifestations leukaemia and lymphoma should be considered in the differential diagnosis, as well as infections (e.g., Leishmania, EBV, Lyme diseases, brucellosis). Additionally, other possible autoimmune diseases should be considered in the differential diagnosis based on the manifestations shown by the patients and include rheumatoid arthritis, other connective-tissue diseases (e.g., polymyositis, undifferentiated connective tissue disease, mixed connective tissue disease) or antiphospholipid syndrome.
Additional instrumental test might be performed based on the clinical manifestation including chest Xray, echocardiography, brain MRI, doppler of vessel.
The kidney biopsy is the mainstream to evaluate the lupus nephritis in order to grade the class and severity of kidney involvement and choose the appropriate treatment. 

Treatments overview 

Treatment of SLE is still a challenging topic, but the steps forward of the research have led to the identification of specific therapy that target keys molecules and pathways involved in SLE.   The clinicians are helped to find the better treatment for each patient thanks to international guidelines in order to achieve the “target” of remission or low disease activity.  However, the management is not same for all the patients with SLE, and often depends on disease severity and different organ involvement. The cornerstone of the treatment in all patients is hydroxychloroquine regardless of disease manifestation, reducing the risk of flares. Corticosteroids and immunosuppressant are the other key treatments, which are chosen based on organ manifestation and disease severity. The use of corticosteroids should be preferably as short and low as possible. Immunosuppressant as methotrexate, azathioprine and cyclophosphamide are usually used, but newer biologic drugs as belimumab, rituximab and anifrolumab are becoming part of the common treatment.

Microcirculation (capillaroscopy) and SLE

Management strategy should include not only specific therapy but also a series of actions that include: 

• The ultraviolet avoidance using the sunscreen and avoiding direct sunlight 
• Promoting the cardiovascular health with weight management, smoking cessation, management of hypertension and dyslipidaemia 
• Vaccination prior to immunosuppression if it is possible in order to prevent infections (e.g., influenza, pneumococcus, papillomavirus or herpes zoster vaccination) 
• Bone health especially for patients using chronic corticosteroids in order to prevent fractures
• Management of pain 
• Reproductive health: discuss contraception and plan pregnancies in order to find the best moment for this delicate phase of the women life if desired 
• Anti-thrombotic/antiphospholipid evaluation: routinely screen for antiphospholipid autoantibody and start primary or secondary prophylaxis as appropriate

Prognosis 

The prognosis of SLE patients have been improved in the last decades, with an amelioration in the quality of life and clinical manifestations. However, despite advances in therapy, the mortality associated with SLE remains considerable with a standard mortality rate that is still more than twice as high as that of the normal population. Usually, a death in the first phase of the disease is secondary to active disease and infection, whereas later mortality is often due to organ damage, corticosteroid-mediated injury, and cardiovascular disease.
The presence of lupus nephritis or neuropsychiatric lupus unfortunately increase the mortality.
Adverse outcomes are more common in men than in women, and specific factors associated with adverse outcomes include poor adherence and attendance at clinic appointments, low income, and the presence of haemolytic anaemia and nephritis, hypertension, antiphospholipid syndrome, and low complement. 

ERN ReCONNET publications are available for consultation.

Additional info

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