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Systemic Lupus Erythematosus 1. Describe the epidemiology of SLE including genetic predisposition. The spectrum of connective tissue diseases… SLE is one a family of chronic overlapping autoimmune diseases. The other chronic autoimmune connective tissue diseases available in the range are… • Rheumatoid arthritis (RA). • Systemic sclerosis. • Polymyositis. • Dermatomyositis. • Sjögren’s syndrome. SLE is a very rare disease. Typically, a GP with 10,000 patients will only get about 3 cases of SLE – this makes SLE about 100 times less common than RA. The diagnosis of SLE is very difficult to make if the characteristic malar rash is not present, it requires a lot of investigations (described later), and accurate interpretation of the results. The epidemiology of SLE… • SLE is a chronic autoimmune disease that has a male:female ratio of 1:9. • The disease normally presents in patients aged between 15-40 years. • There is an increased incidence of the disease in Afro-Caribbean, Asian, and Chinese populations. • The prevalence of the disease varies greatly from place to place. Generally, the prevalence is somewhere between 4-280 per 100,000 people. • The disease principally affects the joints and the skin, though the lungs and kidneys may be affected, as may the blood (indicated by haematology investigations).

There are genetic associations with SLE… – Multiple genes are implicated (involved). – It is often associated with a complement deficiency. – HLA B8, DR2, and DR3 are also involved.

2. To be able to describe the clinical features of SLE. The clinical

features of SLE (the clinical features depend on the organ(s) affected)…


of the disease (these are not specific to SLE – they can occur with a number of medical conditions): • Often patients complain of malaise, fatigue, fever, and weight loss. • Lymphadenopathy (swelling of the lymph glands) is also a common sign. Specific features of SLE: • The butterfly (malar) rash is the most obvious characteristic, and is effectively diagnostic. Patients with the rash can be diagnosed with SLE with some certainty. • Alopecia (hair loss), and arthralgia (severe pain in a joint without swelling or the other common signs of arthritis). • Raynaud’s phenomenon (this is a condition of unknown origin in which the arteries of the fingers are unduly reactive and enter spasm (angiospasm or vasospasm) when the hands are cold. This produces attacks of pallor, numbness, and discomfort in the fingers). Other features that may be associated with SLE… • Inflammation may occur in the kidneys, CNS, heart, and lungs.

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SLE may be associated with accelerated atherosclerosis. Anti-phospholipid (antibody) syndrome – an autoimmune disease in which the presence of antibody against phospholipid is associated with a tendency to thrombosis. Vasculitis (more often known as angiitis) – this is the patchy inflammation of the walls of blood vessels. In SLE, the most commonly affected vessels are the small vessels of the head, and the feet.

3. To understand the means by which SLE is diagnosed.

Diagnosis of SLE… The 1982 ARA criteria are used to diagnose SLE. SLE can be diagnosed if 4 out of the 11 criteria below are present… • Malar rash. • Discoid rash. This is a rash that occurs in discoid lupus erythematosus (DLE) which is basically a milder form of SLE. • Photosensitivity. • Oral ulcers. • Arthritis. • Serositis (inflammation of a serous membrane, such as the lining of the thoracic cavity (pleura)). In SLE, serositis causes either pleuritis and/or pericarditis. • Renal disorders may be present and can be diagnosed with many tests. For example, proteinuria can be diagnosed by taking urine samples for 24 hours. If more than 0.5g of protein is passed, proteinuria can be diagnosed. • Neurological disorders such as seizures or psychosis may be present. • Haematological disorders may occur. • Immunologic disorders such as anti-dsDNA antibodies may be present. • A titre may reveal a raised antinuclear antibody level. 4. Understand principles underlying pathogenesis of SLE. Pathogenesis of SLE… •

The adjacent diagram shows the pathogenesis of SLE. As has been explained later, it can be crudely described as a “hoover deficiency” as there is a failure to clear the immune complexes that form as a result of the immune cells reacting with the nuclear antigens. There is also a failure to clear the nuclear antigens that are expressed on the cell surface, and this also contributes to the pathogenesis of SLE.

Basically, an uncontrolled network of cytokines leads to the production of autoimmune antibodies which then form immune complexes with immune cells which are the causative factors in SLE. Patients who go on to develop SLE are people who are poor at clearing the apoptotic material that is generated in a normal immune response.

Pathophysiology of SLE (autoantibody formation)…  The adjacent figure describes the pathophysiology of SLE.  The flow diagram illustrates how the autoantibodies are formed which are key factors in the disease.

 Note that the process begins with the abnormal clearance of apoptotic cell material – in most people the normal response would be the clearance of the apoptotic material by macrophages etc.  Remember: SLE patients are poor at clearing apoptotic material.

Diagnosis Laboratory tests in SLE…  Antinuclear antibodies (ANAs) are important in SLE.  Testing for ANAs involves a serum sample being taken from the patient and seeing if the ANAs present bind to cellular nuclei in a certain pattern (see diagram below).  ANAs are present in more than 95% of SLE patients. Testing for ANAs is useful. Though it is a relatively non-specific test, the pattern of staining is important. There are four staining patterns… 1. Homogenous – this is where the ANAs present bind to DNA (the double-stranded helix). This type of staining is characteristic in SLE. 2. Speckled – here the ANAs bind to Ro*, La*, Sm*, and RNPs. This type of staining is characteristic in SLE, but may be due to other syndromes as well as SLE, and it is possible to have this pattern of staining in patients who do not have SLE. 3. Nucleolar – here the ANAs bind to topoisomerase – this is characteristic of scleroderma. 4. Centromere – this pattern of staining is characteristic of limited cutaneous scleroderma. * Ro, La, and Sm are nuclear ribonucleoproteins (which are important in RNA processing). Antinuclear antibody staining patterns… The adjacent diagram shows what you may see with antinuclear staining… A. Shows chromosomal staining – this is staining of the DNA and associated histones. This is homogenous staining. B. Shows staining of nuclear matrix proteins – this is staining of RNPs and matrix-DNA for example. This is speckled staining. C. Shows staining of the cytoplasm – here staining is of the RNPs and also cytoplasmic enzymes. This is cytoplasmic staining. Testing for Anti-dsDNA and Sm (a nuclear ribonucleoprotein) offers a more specific test, but a less sensitive test as anti-dsDNA is present in about 60% of SLE patients, with Sm present in only 20% of SLE patients.

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Testing for Anti-Ro and/or La is very important in the diagnosis and prognosis of SLE. The presence of these nuclear ribonucleoproteins are associated with congenital heart failure, especially so in women of child-bearing age. This means that the presence of the nuclear ribonucleoproteins in a pregnant woman could result in the child (foetus) suffering from congenital heart failure. Anti-Ro and/or La are found in about 30% of SLE patients, but may also occur in patients with the following…  Subacute cutaneous lupus erythematosus (DLE).  Neonatal lupus syndrome and also Sjögren’s syndrome.

Testing for anti-cardiolipin (antibody) syndrome.

antibodies is relevant as it is associated with anti-phospholipid

They occur in about 40% of SLE patients, and they are antibodies which form and act on negatively charged phospholipids – the complexes formed between the antibody and phospholipid is associated with thrombosis.

Renal-related tests which may also suggest presence of SLE… • • •

Proteinuria (the presence of abnormally high levels of protein in the urine) may lead to protein loss (and even deficiency in severe cases). Therefore, the patient may have a low serum albumin level, for example. Haematuria (the passage of blood in the urine). This may be as a result of kidney inflammation which is commonly caused by SLE. Active urinary sediment is very important as it is will offer a poor prognosis for the patient. It is the presence of clumps of red and white blood cells in the urine. It probably occurs with severe inflammation of the kidneys associated with SLE.

Haematological-related tests which may also point to SLE… • • • •

Lymphopaenia – a decrease in the number of lymphocytes (a type of white blood cell) in the blood which occurs in a number of diseases. SLE also seems to be associated with normochromic anaemia. It is also associated with autoimmune haemolytic anaemia (AIHA). Leukopaenia (a reduction in the number of white blood cells in the blood) and thrombocytopenia are associated with SLE. The leukopenia arises as autoantibodies destroy the bodies own blood cells. A raised ESR is diagnostic also.

Other related tests which may suggest SLE is present… • A raised urea and creatinine level can be indicative. The levels rise due to renal failure. • There is an increased complement consumption which leads to a low serum complement. • Anti-cardiolipin antibodies are important (and have already been described). • The presence of β1-glycoproteins may also be associated with SLE.

Assessing the severity of SLE is important… In SLE, it is important to assess the severity of the disease as it affects the course of treatment administered. The most important assessments are… 1. Identifying the pattern of organ involvement. 2. Monitoring function of the affected organs… – Renal: the blood pressure is monitored (an uncontrolled blood pressure in young people leads to a poor prognosis for the patient as renal failure will be advanced if this occurs), urea and electrolyte levels are recorded, as is the urine sediment. – Heart and lungs: echocardiography is performed to monitor the heart for any changes, and lung function testing is important for the patient as progression of the disease may lead to the patient becoming short of breath. – The skin should be assessed for the advancing of the rash. – The eyes should also be assessed for visual problems that are common with autoimmune inflammatory diseases (such as conjunctivitis in reactive arthritis). – The blood (haematological) tests are important to pick up on several problems with the organs (such as proteinuria with renal failure), and also blood disorders such as normochromic anaemia.

3. Identifying the pattern of autoantibodies expressed is important to identify episodes of SLE flaring, and also various other problems that may occur… – Anti-dsDNA, anti-Sm, and anti-C1q are important as they predispose to renal disease. – Anti-cardiolipin antibodies are important as they predispose to thrombosis. The signs of SLE disease activity… In SLE, it is important to try and pre-empt severe attacks. The main way in which you can do this is by identifying patterns of antibodies expressed. Disease flare can be indicated by… • Clinical features, such as… – Weight loss, general tiredness (fatigue) and malaise. – Alopecia (which is often the earliest sign of disease flare). – The sudden appearance of the characteristic lupus rash. • Laboratory markers, such as… – A raised ESR. – A decreased serum complement due to increased complement consumption. – An increased anti-dsDNA and anti-C1q can be indicative. – Other antibodies and CRP markers are poor indicators of SLE flares. – Note that any one above markers may indicate SLE flare – i.e. not all of these markers need to be present to show SLE flares. 5. To understand the basic principles involved in the treatment of SLE.

Treatment of SLE… The treatment of SLE involves the severity of the disease to be assessed (based on the above criteria), and then classified into one of the following three categories:

1. Mild – this is where a joint is affected with or without skin involvement. 2. Moderate – this is where there is joint dysfunction with the inflammation of other organs (for example pleuritis, pericarditis, and mild nephritis).

3. Severe – this is where there is all of the above with severe inflammation of the vital organs, for example… – There is severe nephritis. – CNS disease. – Pulmonary disease. – Cardiac involvement. – Autoimmune haemolytic anaemia (AIHA) – which requires blood transfusion treatment, thrombocytopenia, and TTP (whatever that is). N.B. Drug therapy is devised and administered depending on the severity of the disease.

Treatment of mild SLE disease 1. Paracetamol and possibly an NSAID may be given. It is important to monitor renal function when using these drugs for long-term therapy due to toxicity. 2. Hydroxycholoroquine has been shown to be effective in cases of arthropathy, cutaneous manifestations (rashes), and also mild disease activity. 3. Topical corticosteroids may be used (such as hydrocortisone cream or ointment) to treat any rashes or underlying joint dysfunction.

Treatment of mild to moderate SLE disease

The following treatment may be needed if there is failure of effect of hydroxychloroquine and/or the NSAIDs administered. The following treatment may also be used if organ- or life-threatening disease occurs.

• Corticosteroids – A high initial dose is administered to suppress the disease activity (typically a dose such as 0.5-1.5mg/kg/day – this is a very high steroid dose). – Intravenous methyl-prednisolone may be given (typically a dose of 0.5-1.0g three times a day every 24 hours). – In many cases where long-term corticosteroid therapy is required, an initial oral dose of steroid is given for the first four weeks. The dose is then reduced slowly over the next 2-3 months until the dose is down to 10mg per day. Finally, this 10mg per day dose is reduced by 1mg per month (i.e. for the next month the dose would be 0.9mg per day, the following month 0.8mg per day).

Treatment of moderate to severe SLE disease • Azathioprine – This drug is often used in autoimmune conditions when corticosteroid therapy alone has – – – –

failed. It can be used in moderate to severe cases of SLE, and again, a very high initial dose is used to control the disease activity (typically 2.5mg/kg/day). This drug is an effective steroid sparing agent, and so will enhance corticosteroid therapy. In about 20% of patients, the drug causes neutropenia (a decrease in the number of neutrophils in the blood). Importantly, it can also cause bone marrow suppression (and this occurs in about 3/1,000 patients taking the drug). As a result of this BM suppression, patients should be warned to report immediately any evidence of infection, unexpected bruising or bleeding, or any other manifestations of bone marrow suppression. Monitoring (full blood counts) must be carried out throughout the duration of treatment. It must be carried out at least weekly for the first 8 weeks of therapy, and then at least every 3 months thereafter.

Cyclophosphamide… – This drug is used if there is severe organ involvement – it is an ankylating drug. – It has a pronounced effect on lymphocytes, and so can be used as an immunosuppressant – therefore its use in SLE is clear.

– It can be given as intravenous pulses or in an oral preparation. – Important toxic effects caused by using this drug include nausea, vomiting, bone marrow depression, and also haemorrhagic cystitis.

– Cyclophosphamide is an inactive drug (a pro-drug) until it is metabolised to the active form by the liver.

– A urinary metabolite of cyclophosphamide, called acrolein, is responsible for causing the haemorrhagic cystitis, and can be reduced by an increased fluid intake following administration of the drug. Novel Treatment of severe disease: 1. Mycophenolate mofetil  Reversible inhibitor of inosine monophosphate dehydrogenase  Rate-limiting enzyme in de novo purine synthesis  Lymphocytes – dependent upon de novo purine synthesis 2. Rituximab  Anti-CD20 mAb therapy  Leads to depletion of B cells  Effective in lupus nephritis

The prognosis and survival of SLE… SLE is a life-threatening disease, but early diagnosis and effective treatment can offer the patient a good long-term prognosis. • The 15-year survival rate if the patient has no nephritis is 85%, in patients who do have nephritis; the rate is reduced to 60%. • However, the prognosis is further worsened if the patient is black, male, and has a low socioeconomic status.

Treatment of SLE in pregnant women Prednisolone and Azathioprine can be used in pregnant mothers. •

Cyclophosphamide can be used in life-threatening complications, and so is really a lastresort treatment.

In the case of anti-phospholipid syndrome developing… • Low dose aspirin can be used for its thrombolytic properties. However, aspirin is a very toxic drug, and so it can cause complications for the foetus. • Sub-cutaneous heparin can be used if aspirin is not potent enough. If the mother is already in the second trimester, then warfarin should be used. • In episodes of thrombosis, warfarin INR* 3.5-4.5 is used. *The therapeutic dose of warfarin needs a careful balance between giving too little, leaving unwanted coagulation unchecked, and giving too much thereby causing haemorrhage. Therapy is complicated not only because the effect of a particular dose is seen 2 days after giving it, but also because of numerous conditions that modify sensitivity to warfarin, including interactions with other drugs. The effect of warfarin is monitored by measuring PT (you don’t need to know what this is at this stage), which is expressed as an INR (International Normalised Ratio).

The following slides are a case history. Hopefully you will be able to read the slides and understand what is going on. If you can, you know all that you need to know at this stage…

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