QuestionSBA
QuestionChoice
The patient’s presentation suggests a case of drug-induced lupus. Common causes of drug induced lupus include isoniazid (used for TB), procainamide, hydralazine, minocycline and phenytoin.
10017266
a
Active pulmonary tuberculosis
QuestionChoice
Trigeminal neuralgia is typically treated with carbamazapine, which can rarely cause drug-induced lupus but not as commonly as isoniazid.
10017268
c
Trigeminal neuralgia
QuestionChoice
The anti-histone antibodies and joint pain point towards drug-induced lupus.
10017270
e
Pulmonary Fibrosis
QuestionChoice
The anti-histone antibodies and joint pain are suggestive of drug-induced lupus.
10017267
b
Metastatic breast cancer
QuestionChoice
Atrial fibrillation can be treated in a variety of ways, none of which are likely to cause drug-induced lupus.
10017269
d
Atrial fibrillation
QuestionComment
good question, shame I shat the bed on it 
38831
User
subscriber
Melanosis coli
QuestionComment
Gutted not to take all 3 points on this one
61436
User
subscriber
Gabriel Magalhaes
Concept
Chapter
# Summary

Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease that may cause a wide variety of symptoms and affect major organs. It is more common in women and people of Afro-Caribbean heritage. Common signs and symptoms include rashes, hair loss, mouth ulcers, arthralgia and fatigue. Renal, cardiac and central nervous system involvement is common. Initial investigations include urinalysis, full blood count and auto-antibodies (e.g. anti-nuclear, anti-DNA and anti-Smith antibodies). First-line medical management is commonly with hydroxychloroquine, which may be escalated to immunosuppressants such as prednisolone, methotrexate, or biologic agents (e.g. rituximab). Patients should be regularly monitored to assess disease activity and organ involvement, as well as side effects of treatment and comorbidities.

# Definition

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that may affect a wide variety of organs. The clinical course is commonly a relapsing-remitting one, with intermittent flares of disease activity.

# Epidemiology

- Prevalence in the UK is approximately 1 in 1000
- SLE is nine times more common in women than men
- It is most common in people of Afro-Caribbean and South Asian descent
- Mean age at diagnosis is 49 years

# Aetiology

- The pathogenesis of SLE is complex, involving multiple autoantibodies leading to immune complex formation and deposition
- There is a genetic contribution with many genetic risk factors identified 
- Proposed environmental risk factors include:
- Smoking
- Ultraviolet light
- Silica exposure
- Epstein-Barr virus
- Flares of SLE may be triggered by:
- Oestrogen exposure (e.g. pregnancy, the combined oral contraceptive pill)
- Infections
- Emotional stress
- Physical stress e.g. surgery, injury
- Excessive ultraviolet light exposure

# Classification

The 2019 EULAR/ACR classification is used for diagnosis - patients need to have positive antinuclear antibodies (ANA) and score 10 or more with at least one clinical criterion:


| **Clinical Domain** | **Criteria** | **Points** |
|-------------------------|---------------------------------------------------|---------- | 
| Constitutional | Fever > 38 degrees | 2 |
| Haematologic | Leukopenia | 3 |
| | Thrombocytopenia | 4 |
| | Autoimmune haemolysis | 4 |
| Neuropsychiatric | Delirium | 2 |
| | Psychosis | 3 |
| | Seizure (generalised or focal) | 5 |
| Mucocutaneous | Non-scarring alopecia | 2 |
| | Oral ulcers | 2 |
| | Subacute cutaneous or discoid lupus | 4 |
| | Acute cutaneous lupus | 6 |
| Serosal | Pleural or pericardial effusion | 5 |
| | Acute pericarditis | 6 |
| Musculoskeletal | Joint involvement (at least 2) | 6 |
| Renal | Proteinuria > 0.5 g/24 hours | 4 |
| | Class II or V lupus nephritis on biopsy | 8 |
| | Class III or IV lupus nephritis on biopsy | 10 |
| **Immunological Domain**| | |
| Antiphospholipid antibodies | Anti-cardiolipin, _2 glycoprotein I, or lupus anticoagulant | 2 |
| Complement proteins | Low C3 *or* low C4 | 3 |
| | Low C3 *and* low C4 | 4 |
| SLE-specific antibodies | Anti-dsDNA or anti_Smith | 6 |


# Signs and Symptoms

## Systemic manifestations

- Fevers
- Fatigue
- Weight loss
- Myalgia
- Malaise

## Dermatological manifestations

[lightgallery] [lightgallery1] 

- 80% of patients have skin involvement
- Photosensitivity is common
- The classic malar rash appears as butterfly-shaped erythema across the cheeks, sparing the naso-labial folds
- A discoid rash consists of indurated hyperpigmented plaques in sun-exposed areas, that may occur without systemic features
- Livedo reticularis
- A variety of other rashes may occur e.g. maculopapular, bullous, annular, urticarial or hypertrophic rashes
- Nonscarring diffuse alopecia
- Raynaud's phenomenon
- Cutaneous vasculitis may manifest as splinter haemorrhages and/or purpura

## Musculoskeletal manifestations

- Generalised arthralgia, often with early morning stiffness, is common
- A non-erosive symmetrical polyarthritis often affects the knees, wrists, shoulders and hands
- A minority of patients develop a non-erosive arthropathy (**Jaccoud's arthropathy**) that may mimic rheumatoid arthritis deformities
- Complications of chronic steroid treatment may be seen, including osteonecrosis, insufficiency fractures and tendinopathies

## Renal manifestations

- The majority of patients develop renal disease, with approximately 4% progressing to end-stage renal disease
- Lupus nephritis varies in severity and may be asymptomatic, or present with nephritic or nephrotic syndrome
- Presenting features include hypertension, frothy urine and peripheral oedema
- Renal involvement is classified based on histology as below:

| Class | Classification | Description |
|-----------|-----------------------------------|-----------------------------------------------------------------------------------------------|
| I | Minimal Mesangial Glomerulonephritis | Normal appearance under light microscopy; mesangial deposits on electron microscopy or immunofluorescence|
| II | Mesangial Proliferative Lupus Nephritis | Mesangial hypercellularity and immune deposits on light microscopy |
| III | Focal Lupus Nephritis | Involvement of less than 50% of glomeruli with thickened capillary loops and subendothelial immune complexes |
| IV | Diffuse Lupus Nephritis | Involvement of more than 50% of glomeruli, rapidly progressive glomerulonephritis may be present |
| V | Membranous Nephritis | Diffuse basement membrane thickening with proteinuria; nephrotic syndrome may develop |
| VI | Advanced Sclerosing Lupus Nephritis | > 90% of glomeruli are sclerotic; usually progresses to end-stage renal disease |


## Cardiovascular manifestations

- Pericarditis is the most common cardiac feature of SLE, presenting with chest pain, dyspnoea, tachycardia and a pericardial rub may be heard on auscultation
- Pericardial effusions are also common although the risk of tamponade is low
- Myocarditis is rare and may present with arrhythmias and heart failure
- Libman-Sacks endocarditis refers to the formation of non-infective vegetations that usually form on the mitral and aortic valves
- There is a significantly increased risk of adverse cardiovascular events such as myocardial infarction 

## Respiratory manifestations

- Pleurisy is very common (where there is inflammation of the pleura, typically presenting with sharp chest pain exacerbated by vigorous inhalation or expiration)
- Pleural effusion
- Patients with antiphospholipid antibodies are at increased risk of pulmonary emboli
- Rarer pulmonary manifestations include:
- Acute lupus pneumonitis
- Pulmonary hypertension
- Chronic interstitial pneumonitis
- Obliterative bronchiolitis
- Pulmonary vasculitis
- Alveolar haemorrhage
- Patients on immunosuppressive treatments are at increased risk of opportunistic infections

## Neurological manifestations

- Up to 80% of patients develop neuropsychiatric involvement 
- Seizures are the most common features (either generalised or local)
- There is a significantly increased risk of stroke, which is contributed to by:
- Antiphospholipid syndrome
- Hypertension
- Accelerated atherosclerosis
- Embolisms from Libman-Sacks endocarditis
- Thrombocytopaenia
- Cerebral vasculitis
- Psychosis 
- Delirium
- Cognitive impairment (although usually not severe enough to result in dementia)
- Increased rates of depression and anxiety
- Headaches
- Peripheral neuropathy (most commonly a sensorimotor polyneuropathy)

## Haematological manifestations

- Anaemia may occur due to chronic disease, medications or haemolysis
- Leukopaenia and thrombocytopaenia are also common 
- Reactive lymphadenopathy and splenomegaly may be present, particularly in active disease
- Antiphospholipid syndrome occurs in around 20% of patients (although higher numbers have antibodies without complications)

## Gastrointestinal (GI) manifestations

- Mouth ulcers are common and may be painful
- A protein-losing enteropathy may be seen
- Ascites may occur secondary to peritonitis or hypoalbuminaemia due to enteropathy or nephrotic syndrome
- Pancreatitis
- Splenic infarction
- Hypoadrenalism
- Hepatomegaly, hepatitis or cirrhosis may be seen
- Vasculitis affecting the GI tract may cause colitis, mucosal ulceration, mesenteric ischaemia or oesophageal dysmotility
- Antiphospholipid syndrome may cause Budd-Chiari syndrome or thrombosis of intestinal vessels

# Differential Diagnosis

- **Drug-induced lupus** presents similarly to SLE, commonly with systemic upset, a non-erosive arthritis and serositis
- It occurs due to chronic use of triggering medications
- These include procainamide, hydralazine, isoniazid, quinidine and methyldopa
- Symptoms improve after withdrawal of the causative drug
- Rashes, renal disease and neurological involvement are rare
- Anti-histone antibodies are positive but anti-dsDNA and anti-Sm are negative
- **Subacute cutaneous lupus** may be associated with SLE but is often seen in isolation or in association with other diseases such as Sjogren's syndrome or rheumatoid arthritis
- Patients present with a widespread non-scarring papulosquamous rash
- There are annular plaques which coalesce
- It is photosensitive and typically affects the neck, upper trunk and arms
- There may be associated features of alopecia, livedo reticularis and mouth ulcers
- It may also be drug induced (e.g. due to thiazides, terbinafine or calcium channel blockers)
- Patients are often anti-Ro positive
- **Discoid lupus** also only affects the skin and is the commonest form of cutaneous lupus
- Patients develop scaly plaques on the face and scalp which may become generalised in a minority of cases
- It may be asymptomatic or itchy/sore
- Atrophic scarring of the skin and scarring alopecia is common
- ANA is usually negative unlike in SLE
- **Rheumatoid arthritis** may present with similar features of systemic symptoms, cardiac and pulmonary involvement
- However the polyarthritis seen in rheumatoid arthritis is typically erosive and deforming
- Mouth ulcers, rashes and alopecia are suggestive of SLE
- **Sarcoidosis** also shares systemic features such as fevers, weight loss and fatigue
- Rashes include erythema nodosum and lupus pernio (red/purple plaques and nodules on the face)
- Neurological, pulmonary, cardiac and GI involvement is also seen
- **Rosacea** may mimic the classic malar rash of SLE and is also photosensitive
- However pustules are common which are not seen in SLE
- Systemic involvement is not seen

# Investigations

**Bedside tests:**

- **Blood pressure** to monitor for hypertension 
- **Urine dip** for proteinuria or haematuria
- **Urinary protein:creatinine ratio** may be useful to quantify proteinuria
- **Urine microscopy** looking for casts
- **ECG** in suspected cardiac involvement

**Blood tests:**

- **Full blood count** looking for anaemia, leukopenia and thrombocytopaenia
- **U&Es** to screen for renal impairment due to lupus nephritis
- **Liver function tests** are usually normal; hypoalbuminaemia may be seen due to GI or renal involvement
- **ESR** is usually high; **CRP** may be normal or mildly raised
- **Clotting screen** may show paradoxical prolongation of the APTT if there are anti-phospholipid antibodies present
- **Complement** (**C3** and **C4**) may be low in active disease
- **Antinuclear antibody (ANA)** is almost always positive 
- Results may be given as a titre (i.e.how much serum can be diluted and still test positive)
- A titre of 1:160 or higher is considered positive
- The pattern of staining may also be described - classically this is **speckled** in SLE
- **Anti-double stranded DNA (anti-dsDNA) antibodies** are highly specific for SLE
- T hey correlate with disease activity, especially lupus nephritis
- **Anti-Smith (anti-Sm) antibodies** are found in fewer patients but are also highly specific
- **Antiphospholipid antibodies** should be tested for in all patients
- **Anti-histone antibodies** are found in both SLE and drug-induced lupus and so should be sent in patients on causative medications
- **Anti-Ro** and **anti-La antibodies** are not specific to SLE but may be positive
- They are associated with neonatal lupus syndrome in babies born to mothers with these antibodies
- **Anti-RNP antibodies** may be positive in SLE but are non-specific; if found alone positivity suggests mixed connective tissue disease
- **Creatine kinase** to screen for associated myositis
- **Vitamin D** as patients avoiding sun exposure are at increased risk of deficiency
- **Thyroid function** as thyroid disease often coexists with SLE and symptoms may overlap (e.g. fatigue)
- **Immunoglobulins** prior to starting immunosuppressive medications that may lead to immunoglobulin deficiency 
- **Direct Coombs' test** to screen for autoimmune haemolytic anaemia

**Imaging:**

- **Chest X-ray** in all patients as a baseline and to screen for pulmonary involvement
- **CT chest** may be required for more detailed assessment of lung involvement; **CT pulmonary angiography** is required in suspected pulmonary embolism
- **Ultrasound of the kidney, ureters and bladder (KUB)** to exclude other causes of renal impairment e.g. obstruction
- **X-rays of affected joints** looking for arthritis and fractures 
- Joint space narrowing is uncommon
- Soft tissue swelling and periarticular osteoporosis may be seen
- **Ultrasound of affected joints** may show signs of inflammation e.g. tenosynovitis
- **CT** or (preferably) **MRI** brain if cerebral lupus is suspected
- **Echocardiogram** may show pericarditis, heart failure, pericardial effusion or pulmonary hypertension

**Special tests:**

- **Renal biopsy** is the key diagnostic test for lupus nephritis and is important for classification
- **Skin biopsy** may be useful for the diagnosis of dermatological manifestations
- **Pulmonary function tests** if there 
- **Pleural tap** if there is an effusion present - the majority of cases are exudative
- **Neurophysiology testing** in suspected peripheral neuropathy

# Management

**Conservative management:**

- Patients with suspected SLE should all be referred to specialist services for confirmation of the diagnosis and ongoing management
- All patients require regular follow up
- 1-3 monthly follow up is appropriate for patients with active disease
- Stable patients can be followed up every 6-12 months
- Patient counselling and education, with signposting to resources and support
- Advise on sun protection e.g. using sunscreen, limiting exposure and covering skin
- Avoid triggers such as oestrogen-containing contraceptives
- Optimise cardiovascular health with regular exercise, smoking cessation and a balanced diet
- Ensure patients are up to date with vaccinations

**Medical management:**

- All patients should be treated with hydroxychloroquine
- Steroids are also commonly used e.g. oral prednisolone; high-dose IV methylprednisolone is often required for acute severe disease (e.g. renal or neuropsychiatric lupus)
- Use of steroid-sparing agents is very important to minimise the long-term effects of prolonged steroid use - options include methotrexate and azathioprine
- Patients with severe or refractory disease may be considered for biologic agents such as belimumab or rituximab
- Topical agents may be used in addition to systemic treatment for skin disease e.g. topical glucocorticoids or calcineurin inhibitors
- Mycophenolate mofetil (MMF) and cyclophosphamide are commonly used for lupus nephritis, with most patients continuing on either MMF or azathioprine
- If anti-phospholipid syndrome is present, this may require additional management (see separate chapter)
- Cardiovascular risk factors such as hypertension and hyperlipidaemia may require medical treatment
- Vitamin D supplementation may be required as well as bone protection in patients on long-term steroids

# Complications

- **Medication side effects** are common
- Retinal toxicity is the main issue with hydroxychloroquine and all patients should undergo regular eye screening
- Patients on immunosuppressive treatments are at increased risk of opportunistic infections
- Reactivation of latent infections (e.g. tuberculosis, hepatitis) is also a risk and so these should be screened for prior to initiating treatment
- Other DMARDs (e.g. methotrexate) have their own extensive side effect profiles
- **End-stage renal failure** develops in approximately 20% of patients with lupus nephritis
- This may require renal replacement therapy either with dialysis or transplant
- **Accelerated atherosclerosis** leads to an increased risk of myocardial infarction, ischaemic stroke and peripheral vascular disease
- **Overlap syndromes** may develop in patients with SLE (where the criteria for multiple rheumatological diseases are met), for example
- Sjogren's syndrome
- Antiphospholipid syndrome
- Mixed connective tissue disease
- **Neonatal lupus** is a complication that arises in babies born to mothers with anti-Ro and/or anti-La antibodies
- These antibodies cross the placenta and cause a transient autoimmune syndrome 
- Manifestations include a red rash on the scalp and around the eyes, complete heart block, deranged liver function and cytopaenias
- **Other pregnancy complications** include recurrent miscarriage, pre-eclampsia, intrauterine growth restriction and preterm delivery

# Prognosis

- Patients with SLE have a 2.6x increased mortality compared to the general population 
- Although death from active lupus is rare in the UK, life expectancy is shortened to an average of 54 years
- A third of patients develop lupus nephritis and this is associated with a poorer prognosis, with a mean age of death of 40 years
- Other poor prognostic factors include:
- Black ethnicity
- Male sex
- Antiphospholipid antibodies
- Central nervous system involvement

# References

[Patient UK - systemic lupus erythematosus](https://patient.info/doctor/systemic-lupus-erythematosus-pro)

[2019 EULAR/ACR Classification Criteria for Systemic Lupus Erythematosus](https://pmc.ncbi.nlm.nih.gov/articles/PMC6827566/)

[EULAR recommendations for the management of systemic lupus erythematosus](https://ard.bmj.com/content/78/6/736)

[Management of systemic lupus erythematosus: British Society for Rheumatology guideline scope](https://academic.oup.com/rheumap/article/7/3/rkad093/7458323)

[Radiopaedia - systemic lupus erythematosus](https://radiopaedia.org/articles/systemic-lupus-erythematosus?lang=gb)

[DermNet - Systemic Lupus Erythematosus](https://dermnetnz.org/topics/systemic-lupus-erythematosus)
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An example of the typical appearance of a malar rash
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The typical appearance of raynaud's syndrome.
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Drug-induced lupus erythematosus can occur with medications like isoniazid, commonly used for treating pulmonary tuberculosis.
A 46-year-old Caucasian woman complains of fatigue and joint pain. Antibody analysis shows positive anti-histone antibodies.

Which of the following is most likely to be found in the patient’s current medical history?
a