Introduction

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disorder in which autoantibodies form immune complexes. SLE is a relatively rare disease with 2 English studies estimating the prevalence at 26.5 cases per 100,000. The disease is much more common in women (around 10:1) and Afro-Caribbeans, commonly presenting between the ages of 20 and 40.

The cause of SLE is unknown however there are many predisposing factors and triggers linked to the disease i.e. Epstein Barr virus, family history and medications (isoniazid and hydralazine). Pathophysiology is unclear but it is thought to be due to defective apoptotic body clearance leading to immune system activation, causing inflammation.

The treatment of SLE largely relies upon steroids and immunosuppressants alongside simple analgesia. The increased use of biologic agents has greatly improved prognosis and symptom remission.

Epidemiology

  • Incidence: 5.00 cases per 100,000 person-years
  • Peak incidence: 30-40 years
  • Sex ratio: more common in females 10:1
Condition Relative
incidence
Rheumatoid arthritis8.00
Systemic lupus erythematosus1
Sjogren's syndrome1.00
Systemic sclerosis0.40
Mixed connective tissue disease0.04
<1 1-5 6+ 16+ 30+ 40+ 50+ 60+ 70+ 80+

Aetiology

SLE aetiology is influenced by a huge number of factors, it is closely linked to genetics but also environmental, hormonal and epigenetic factors. Usually, a combination of these factors leads to a break in self-tolerance and in turn, an inappropriate immune response to endogenous nuclear antigens.
  • Genetic factors genome-wide association studies have led to the discovery of many more genes implicated in SLE.
    • Most of these genes are associated with inflammatory responses and tissue and DNA repair.
    • Human leukocyte antigen alleles have also been indicated in SLE, in particular HLA- DRB1 and a predisposition to SLE.
  • Environmental factors there are a vast array of environmental links to SLE.
    • Some factors include: Epstein Barr virus, UV light, viruses and arguably most important medications.
    • Drug-induced lupus is well established with various drug types linked to the disease and is likely linked with genetic and epigenetic factors to cause SLE.
  • Hormonal factors this has mostly been studied in rodent models but the addition of oestrogen or prolactin was linked to the production of mature autoreactive B cells and is likely closely linked to why SLE is much more prevalent in women.

Pathophysiology

The autoimmune pathophysiology of SLE is complex and involves numerous cells and inflammatory response pathways. It is characterised by an autoimmune response to nuclear antigens and thought to be linked with a defect in apoptotic body clearance.
  • Trigger event (UV/ virus/ bacteria) induces apoptosis → apoptotic bodies are ingested by dendritic cells due to infective clearance → Immune complexes are presented by dendritic cells → T cell activation → activation of B cells → release of cytokines such as IL-10 and 21 → inflammatory response

In healthy individuals, immune complexes are cleared by Fc and complement receptors, however, these complexes are not effectively cleared in patients with SLE which leads to tissue deposition, inflammatory response and damage by the above mechanism.

Clinical features

SLE is a variable disease which mimics many other illnesses. Symptoms are commonly unspecific and unpredictable. The variability of the disease makes it a common differential diagnosis. Features can include:

The percentages show the frequency of symptoms at onset.
  • Malar/ butterfly rash
    • A fixed erythematous rash of the cheek bones that spares the nasolabial folds.
  • Photosensitivity (80%)
  • Arthralgia (77%)
  • Constitutional (53%)
  • Arthritis (44%)
  • Mouth ulcers (35%)
  • Alopecia (30%)
    • Non-scarring
  • Discoid erythematosus (25%)
    • Erythematous raised patches with scaling and follicular plugging.
  • Lymphadenopathy (16%)
  • Livedo reticularis (14%)
    • Mottled reticular patterned skin rash of purple discolouration.

Other symptoms can be organ-specific caused by active inflammation these tend to develop within 5 years of diagnosis, such as:
  • Renal (38%)
  • Respiratory
    • Pleuritis (16%)
    • Pneumonitis
    • Pulmonary emboli
  • Cardiovascular
    • Pericarditis (13%)
    • Raynaud's phenomenon (33%)
    • Endocarditis
    • Atherosclerosis
  • Neuropsychiatric (24%)
    • Headache or migraine
    • Seizures
    • Psychosis

SLE can also be associated with other autoimmune conditions such as anti-phospholipid syndrome (20-30%), Sjogren's disease (17.5%) and autoimmune thyroid disease (7.5%).

These lists are not conclusive and symptoms can vary, however, this lists some symptoms commonly seen.

Investigations

These investigations are recommended by BMJ best practice (updated April 2020) and when combined with clinical evidence can be diagnostic.

  • Minimum required tests for suspected illness are in bold.

TestResult
FBC Normochromic normocytic anaemia is common alongside leucopenia and thrombocytopenia. Crucial for detection of haematological abnormalities used in diagnostic criteria.
ESR and CRP ESR should be raised with a normal CRP. If CRP raised think infection or arthritis. Again, this is not part of diagnostic criteria it is crucial in the exclusion of differential causes.
Anti-nuclear antibody A positive result is 95% sensitive but very non-specific without clinical features. Arguably the most important test due to the significance in all diagnostic criteria.
Anti-dsDNA antibody titresPresence of this antibody is highly specific for SLE but only present in 70% of disease.
Anti-smith antibodyThe most specific but only present in 30-40% of disease. The presence of these antibodies is diagnostic.

Complement (C3 and C4)
Decreased levels of complement show active disease and are usually associated with flares.
Urea and electrolytesWill be deranged in lupus nephritis disease showing proteinuria and haematuria.

Diagnosis

Diagnosis of SLE can be complex, the varied symptoms alongside the overlap of other connective tissue diseases make specific diagnosis difficult. Thus the diagnosis of SLE requires a combination of symptoms, examination findings and diagnostic investigations as mentioned above. With the absence of specific diagnostic combining clinical experience and judgement with research inclusion criteria such as The American College of Rheumatology Classification system 1997 which uses 11 criteria of which 4 or more are required for diagnosis (these do not need to be present at the same time). Systemic Lupus International Collaborating Clinic Index (SLICC) more recent criteria can be combined but specificity and sensitivity vary for each.
  • Malar rash
  • Discoid lupus
  • Photosensitivity
  • Non-erosive arthritis involving 2+ peripheral joints
  • Oral or nasopharyngeal ulcers
  • Pleuritis or pericarditis
  • Renal involvement
  • Seizures or psychosis
  • Haematological disorder:
    • Haemolytic anaemia
    • Leukopenia
    • Lymphopenia
    • Thrombocytopenia.
  • Immunological disorder:
    • Anti-DNA antibody
    • Anti-Sm
    • Antiphospholipid antibodies.
  • Positive anti-nuclear antibody ( this is key in both SLICC and the updated EULAR/ ACR criteria).

However, these criteria have previously been criticised for not identifying patients early in disease and new criteria are emerging over time, for example, EULAR and ACR have combined in 2019 to produce an updated set of criteria but how the use of these in diagnostic practice is yet to be seen.

Differential diagnosis

Differential diagnoses are vast and depend hugely on the presenting complaint of the patient, however, SLE is can be difficult to differentiate from other connective tissue diseases in its early stages and therefore should be considered, such as:
  • Rheumatoid arthritis
    • This disease is very common if joint involvement is the predominant symptom exclude this disease first.
  • Sjogren's disease
    • Doesn't need to be mutually exclusive of SLE and therefore the overlap can be associated with SLE, however if dry eyes and mouth are the primary concern then this should be excluded.
  • Scleroderma
    • Similar prevalence to SLE however, if skin involvement is the major complaint exclude this disease first.
  • Mixed connective tissue disease
    • Defined as a condition where there overlap is overlap between 2 or more connective tissue disorders. This, therefore, means it is not mutually exclusive to SLE but can co-exist. By testing for the presence of raised anti-U1-ribonucleoprotein antibody, this should exclude this diagnosis.
  • Anti-phospholipid syndrome

Other diagnoses should be considered dependent on the presenting symptoms and the test results, these could include but are not limited to:
  • Infection
  • Lymphoma
  • Goodpasture's disease
  • Glomerulonephritis

Management

Management for SLE is again quite varied and specific to each patient depending on their symptoms, however, The European League Against Rheumatism produced guidelines in 2019. These aim to give a rough stepwise approach to the management of non-renal SLE when simple analgesia or non-steroidal drugs are not effective, dependent on the severity and disease activity at the time and is set out below. The principal management for symptoms and flares relies on the effective use of steroids. Those with mild symptoms and good control will generally be managed in primary care settings, however, once flares become more frequent or severe the rarity of the disease means it is usually managed in a secondary care setting.
  • All patients should receive hydroxychloroquine at all times, and the only drug continued throughout remission.
  • In mild SLE patients should receive
    • Oral or intramuscular glucocorticoids . These will provide rapid symptom relief but should be limited in their use and at a low dose wherever possible.
    • If these drugs are not sufficient immunosuppressant drugs should be considered such as methotrexate or azathioprine. The choice of medication should be dependent on manifestation and patient factors.
  • In moderate SLE:
    • The above still applies but IV glucocorticoids should be considered and immunosuppressants should be 1st line treatment. Calcineurin inhibitors and mycophenolate mofetil should also be considered as immunosuppressants.
    • Again, if the symptoms are not responding to the above biologic agents such as belimumab should be discussed.
  • Finally in severe cases, the above should all be considered but cyclophosphamide and rituximab could also be used.

Alongside these interventions, patient education and lifestyle factors should be advised and encouraged to help reduce symptom burden.



Complications

Complications associated with SLE are again broad and hospital admissions for those with SLE are around 0.69 admissions per patient-year. Common complications of SLE include infection, lupus nephritis, osteoporosis, atherosclerosis and malignancy.
  • Infection
    • Accounts for between 20-55% of all deaths in SLE patients,
    • The underlying susceptibility could already be present due to the dysregulation of the immune system but is likely compounded by treatments.
  • Lupus nephritis (LN)
    • A common condition within SLE affecting up to 60% of patients, usually within the first 5-years from the onset.
    • It is more closely associated with positive anti-dsDNA SLE and can be a severe and life-threatening complication.
    • Characterised by a typical nephritic picture with peripheral oedema and haematuria but can be present before symptoms present.
    • LN can be classified into 6 stages of disease dependent on biopsy results.
  • Atherosclerosis
    • Comparative to age-matched control patients SLE sufferers have an increased risk of coronary heart disease of between 2.3-7.5.
    • Particularly prevalent in patients with associated antiphospholipid syndrome.
  • Osteoporosis
    • Likely linked to both complications such as early menopause and uncontrolled disease activity but also disease prevention and treatment factors such as reduced sun exposure and glucocorticoids.
  • Malignancies
    • Particularly haematological, cervical or lung are particularly common in SLE patients
    • May be accounted for by immunosuppressive therapy and disease pathology.

Pregnancy can also be complicated by SLE, in particular, those with comorbid antiphospholipid syndrome are at high risk of death, recurrent miscarriage and other obstetric complications.

Prognosis

The prognosis of SLE is now very good. On the other hand, patients that develop renal involvement suffer from poorer prognosis.
  • 5-year survival rate around 90% and 15-year at 80%.
  • Prolonged and complete remission rate (5 years without clinical or laboratory evidence of disease without treatment) lags behind
  • 10-20% of patients in tertiary centres will not respond to immunosuppressive therapies.