25th February 2025

Systemic lupus erythematosus (SLE)

Overview of SLE

SLE is a heterogenous multisystem autoimmune (AI) disease resulting in immune complex deposition in various organs. Diagnosis requires clinical findings combined with serology, particularly antinuclear antibodies (ANA).

Women are more commonly affected than men, at a ratio of around 10:1, and onset is usually between puberty and menopause. Certain ethnic groups are at higher risk, including people of African-Caribbean origin and from South America.

Clinical features of SLE

SLE can affect multiple organs and also often causes constitutional symptoms such as fever, fatigue and weight loss.

The revised American College of Rheumatology classification criteria, commonly used for diagnosis, can be remembered using the mnemonic SOAP BRAIN MD as follows:

Table 1 Diagnostic features in SLE

Other respiratory manifestations can occur, including pulmonary fibrosis or hypertension, and shrinking lung syndrome. This is characterised by increased dyspnoea, diaphragmatic elevation and decreased lung volumes on CXR, and restrictive pulmonary function tests with no parenchymal lung disease. This can be treated with steroids.

Investigations in SLE

Full blood count can show decreased white blood cells, lymphocytes or platelets. ESR increases with disease activity, whereas CRP classically does not, and so a raised CRP suggests another cause for symptoms such as infection.

Antinuclear antibodies are the hallmark of serological diagnosis of SLE, although can be nonspecific. Around 10% of healthy individuals will have low-titre ANA positivity, which is of no consequence if not accompanied by relevant clinical features (Box 1). Conversely, there can be very rare cases of ANA-negative SLE, although this occurs in less than 5% of cases. Other autoantibodies may be found and are correlated with specific clinical features (Table 2).

Additionally, reduced levels of C3 and C4 are common in SLE, and often correlate with increased disease activity. Furthermore, hereditary deficiencies of the classical complement pathway (C1q, C1r, C1s, C2, C4) can cause SLE.

Table 2 Autoantibodies in SLE and their associated clinical features.

Box 1 ANA testing and significance

Management of SLE

Conservative measures such as wearing sun cream, preventing sun exposure, staying hydrated and regular exercise are very important.

Pharmacological treatment may include the following:

• Glucocorticoids can help in achieving remission and treating flares. 
• Hydroxychloroquine is used as a disease-modifying agent to prevent flares, maintain remission, and is particularly useful to treat joint symptoms and malar rash. It is generally well tolerated and does not require blood monitoring. Retinal toxicity is a rare but important side effect, and patients should have ophthalmology review 5 yearly and stop taking the drug straight away if any visual symptoms develop.
• Mycophenolate mofetil (MMF) is an immunosuppressive agent which helps to prevent flares, and is particularly effective in lupus nephritis.
• Azathioprine is another immunosuppressive drug which is effective in the management of SLE. It is generally less commonly used than MMF. However, it is safe to use throughout pregnancy and, therefore, is commonly seen in this cohort. Thiopurine methyltransferase enzyme should be tested prior to initiation, as those with a low level of this are at higher risk of side effects.
• Cyclophosphamide is used in severe flares that do not respond to conventional therapy, particularly with lupus nephritis. It has side effects, including haemorrhagic cystitis and risk of developing transitional cell carcinoma of the bladder if used long-term. Mesna is given concomitantly to prevent bladder irritation. 
• Rituximab is an anti-CD20 monoclonal antibody that has recently started to be used in SLE for patients who do not respond to conventional treatments. It depletes B cells, which are key inflammatory mediators in SLE. Serum sickness, a type III hypersensitivity reaction which causes fever, maculopapular rash and arthralgia, can occur 7-10 days following administration, and first-dose infusion reactions with fevers are not uncommon. Progressive multifocal leukoencephalopathy (PML) is the most important side effect to be aware of, although this is extremely rare. This is a progressive and often fatal demyelinating disease caused by reactivation of the JC virus.
• Belimumab is a recently approved monoclonal antibody against B-cell activating factor (BAFF), a B-cell differentiation factor. This has been shown to decrease severe flares and decrease cumulative steroid exposure.

Lupus nephritis

Renal involvement is common in SLE, and onset is usually early in the disease. This can be the first presenting feature or may occasionally occur without any systemic features of SLE. Lupus nephritis is usually associated with increased mortality. Patients generally present with proteinuria, with or without deranged renal function on blood tests. Renal biopsy is the gold standard for diagnosis, and lupus nephritis can be classified histologically into 6 distinct subtypes, which are summarised below.

Table 3 Histopathological classification of lupus nephritis

Drug-induced lupus erythematosus (DILE)

Multiple drugs have been shown to cause DILE. The most common include:

Drug-induced lupus usually occurs in patients at older ages than SLE, and renal, neurological and skin features are rare. Common presenting features include arthritis, fever, serositis and myalgia. TNF alpha-induced lupus-like syndrome (TAILS), however, commonly presents with skin involvement.

ANA is commonly positive in DILE, and anti-histone antibodies are seen more frequently in drug-induced lupus than in idiopathic SLE. Other antibodies, such as anti-Sm and anti DsDNA are occasionally seen.

Treatment is to remove the causative drug.

References

• Clunie GPR, Wilkinson N, Nikiphorou E, Deepak Jadon. Oxford handbook of rheumatology. Oxford: Oxford University Press; 2018.
• Bloch DB. Measurement and clinical significance of antinuclear antibodies[Internet]. Shmerling RH, Ramirez Curtis M, editors. UptoDate. 2021 [cited 2022 Jun 10]. Available from: https://www.uptodate.com/contents/measurement-and-clinical-significance-of-antinuclear-antibodies
• Anders H-J, Saxena R, Zhao M, Parodis I, Salmon JE, Mohan C. Lupus nephritis. Nature Reviews Disease Primers [Internet]. 2020 Jan 23 [cited 2022 Jun 10];6(1):1–25. Available from: https://www.nature.com/articles/s41572-019-0141-9
• Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, Ramsey-Goldman R, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Annals of the rheumatic diseases [Internet]. 2019 [cited 2022 Feb 22];78(9):1151–9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31383717
• Kaul A, Gordon C, Crow MK, Touma Z, Urowitz MB, van Vollenhoven R, et al. Systemic lupus erythematosus. Nature Reviews Disease Primers [Internet]. 2016 Jun 16 [cited 2022 Feb 11];2(1). Available from: https://www.nature.com/articles/nrdp201639
• Williams VL, Cohen PR. TNF alpha antagonist-induced lupus-like syndrome: report and review of the literature with implications for treatment with alternative TNF alpha antagonists. International Journal of Dermatology. 2011 Apr 20;50(5):619–25
• Tan EM, Feltkamp TE, Smolen JS, Butcher B, Dawkins R, Fritzler MJ, et al. Range of antinuclear antibodies in “healthy” individuals. Arthritis and Rheumatism [Internet]. 1997 Sep 1 [cited 2022 Jan 28];40(9):1601–11. Available from: https://pubmed.ncbi.nlm.nih.gov/9324014