Written by: Leah Rooney, MB BCH BAO MRCPI, Rheumatology SPR St Vincent’s University Hospital, Anne-Barbara Mongey, MD DCH MRCPI, Consultant Rheumatologist, St. Vincent’s University Hospital.
Systemic Lupus Erythematous (SLE) is an autoimmune disease with a worldwide prevalence of 50- 100/100,000. It is a heterogenous disease where manifestations can range from mild disease involving skin and joints to life-threatening organ involvement. It has a significant female predominance with a female:male ratio of almost 10:1. Its prevalence is 3-4 times higher in people of African, Asian and Hispanic ancestry and they tend to develop a more severe disease phenotype. The peak age of disease onset is younger in females than in males and often in childbearing years.
SLE is a chronic disease which is characterised by the production of autoantibodies and deposition of complement, leading to systemic inflammation. Although the pathogenesis of the disease is not fully understood, genetic factors, environmental risks and hormonal influences likely all play a role. Over 30 genetic loci have been associated with SLE, smoking, ultraviolet light and viral infections have been identified as environmental triggers and the female predominance suggests hormones may play a part.
Autoantibodies associated with SLE
Antinuclear antibodies (ANA) are a hallmark of SLE. They are useful as a screening test since they are positive in >98% of cases and therefore have a high sensitivity for the diagnosis of SLE. However, they have poor specificity, particularly a low titre, since up to 30% of the healthy population have a positive ANA. ANAs can represent reactivity to a number of different antigens such as double stranded DNA and a variety of extractable antigens (ENA) which can be assessed using ELISAs and other assays. Antibodies to these antigens have greater specificity for the connective tissue diseases, including SLE, although their presence alone is insufficient to make a diagnosis. Double stranded DNA (dsDNA) antibodies have a high specificity for SLE but are only present in 30% of patients.
dsDNA antibodies are associated with more severe disease, particularly lupus nephritis. Their titres often correlate with disease activity and in those patients can be helpful into monitoring disease activity. Anti-Smith antibody occurs in 20% and is specific to SLE and in particular for renal involvement. Anti-Ro (SS-A) antibody is present in 30% and Anti-La (SS-B) in 15% of SLE patients, although they are also associated with Sjogren’s syndrome. Anti-Ro antibody is associated with the development of neonatal lupus, which is manifested by the development of congenital heart block and/or rash in the newborn, a result of transplacental crossing of the anti-Ro antibody into the foetal circulation. Antiphospholipid antibodies, which include antibodies to cardiolipin, β2 glycoprotein- 1and the lupus anticoagulant, occur in 30% of patients with SLE and are associated with the development of arterial and/or venous thrombosis, vasculopathy and foetal loss. A diagnosis of secondary anti-phospholipid syndrome is made when these antibodies are present in moderate or high titer (> 99th percentile) on 2 or more occasions, at least 12 weeks apart, in a SLE patient who develops one of these clinical manifestations. It is advisable that patients with SLE who are considering pregnancy be assessed for both the anti-phospholipid and anti-Ro antibodies.
The diagnosis of SLE requires a combination of clinical manifestations and immunologic/ laboratory abnormalities. The SLICC (Systemic Lupus International Collaborating Clinics) criteria was published in 2012 and currently it is widely used for the classification of SLE and can also be used to aid in the diagnosis of SLE in the clinical setting. For classification, a person needs to fulfil 4 or more criteria: at least one clinical and one immunologic criterion, or anyone with biopsy proven lupus nephritis with positive ANA or dsDNA (table 1).
SLE can affect almost any organ in the body. Its manifestations can range from mild cutaneous and/ or joint disease to life-threatening renal, pulmonary, neurologic, or haematologic involvement.
It most commonly affects the skin and/or joints and was first described as a dermatological condition. Cutaneous lupus can present acutely as a malar rash which is a photosensitive, erythematous rash across the cheeks, chin and nose; as subacute lupus which can resemble psoriasis or annular lesions, or as discoid lupus which is a chronic form of cutaneous lupus manifested by plaques with scarring on sun exposed areas.
The majority of patients with discoid lupus do not have other systemic manifestations.
Musculoskeletal involvement or myalgia occur in up to 95% of cases. Arthritis, and arthralgias typically affect small joints of hands and wrists and pain tends to be disproportionate to the degree of joint swelling. Jaccoud-type arthropathy can also occur with SLE. This can look like rheumatoid arthritis (RA) with ulnar deviation, MCP joint subluxation and swanneck deformities, however, unlike in RA, the deformities are reducible as they are caused by ligament, tendon and joint capsule laxity and not by joint damage (image 1).
The kidney is the most common visceral organ to be affected in SLE and is clinically involved in 50% of cases. Lupus nephritis is an immune complex glomerulonephropathy where immune complexes are formed by antibodies binding to intrarenal autoantigens. Immune complexes activate endothelial and mesangial cells and the complement system, driving inflammation. The presentation of lupus nephritis is variable. Asymptomatic proteinuria is the most common but it can also present with hypertension, nephritic syndrome, nephrotic syndrome or rapid renal failure with rapidly progressive glomerulonephritis. Urinalysis and quantifying proteinuria are important in the diagnostic work-up and in disease monitoring. Renal biopsy is used to diagnose and classify lupus nephritis and to asses for activity vs chronicity. The presence of interstitial disease is associated with a worse prognosis. Early diagnosis and initiation of treatment is important to optimise prognosis and preserve renal function.
The clinical features of CNS lupus are very heterogenous; they can be diffuse: acute confusion, cognitive impairment, headache, aseptic meningitis and psychiatric disease with psychosis or anxiety/depression, or focal: stroke/TIA, seizures, demyelination and transverse myelopathy. CNS lupus likely results from cerebrovascular endothelial dysfunction, disrupting the blood-brain barrier, allowing immune cells, cytokines and antibodies into the CNS. Twenty different autoantibodies in the serum and CSF have been identified in patients with CNS lupus, and anti-cardiolipin antibody is the most commonly associated. 1,2
Haematologic abnormalities are common in SLE and are part of the classification criteria. All three blood cell lines can be affected with leucopenia (lymphopenia more common than neutropenia), thrombocytopenia, autoimmune haemolytic anaemia and anaemia of chronic disease. The degree of lymphopenia can be associated with disease activity.
The most common pulmonary and cardiac manifestations in SLE is serositis – pericarditis/pleuritis with or without effusion, with patients presenting with pleuritic chest pain and sometimes associated dyspnoea. Other forms of pulmonary disease are uncommon, although patients can develop pneumonitis, chronic interstitial lung disease and rarely pulmonary hypertension without underlying parenchymal disease. Shrinking lung syndrome is rare, presenting with progressive dyspnoea, elevated diaphragm on imaging and reduced lung volumes and restrictive pattern on pulmonary function tests. 3
TREATMENT OF SLE
Immunosuppressive drugs. The treatment of SLE depends on the disease severity and organ involvement. Hydroxychloroquine, an antimalarial agent, is recommended for all patients with SLE, unless contraindicated. Long term studies have demonstrated the clear benefit of hydroxychloroquine in reducing morbidity and mortality in SLE. It is used as the initial treatment of cutaneous and joint disease. Methotrexate is useful in patients with more severe joint disease.
Steroids are frequently used in the treatment of SLE. Their dose and mode of administration is determined by the disease severity and by organ involvement. High dose steroids are used initially for treatment of acute active lupus nephritis, pneumonitis, cerebritis or transverse myelitis, severe thrombocytopenia or haemolytic anaemia because of their quick onset of action. However, given their significant long term side effects patients are also commenced on immunosuppressive agents in order to allow tapering of steroids as soon as possible.
Cyclophosphamide or mycophenolate mofetil are the agents most frequently used to treat severe disease. Mycophenolate is associated with less toxicity than cyclophosphamide and it can be used for both induction and maintenance treatment; it is generally preferred for women of child bearing age who wish to become pregnant in the future given that cyclophosphamide can cause infertility. However, mycophenolate is teratogenic and therefore needs to be discontinued prior to a woman planning pregnancy; patients can be switched to azathioprine which is generally considered to be safe throughout pregnancy.
For renal disease, mycophenolate or azathioprine can then be used for maintaining remission. 4
Biologic drugs in SLE
B cell targeted treatments are effective in SLE. Belimumab targets B cell activating factor and inhibits mature B cells. It has been demonstrated to be effective in the treatment of mild to moderate SLE and as an addon therapy for the treatment of lupus nephritis. Rituximab is a monoclonal antibody which targets CD20, a B cell specific antigen. Although clinical trials of rituximab for the treatment of SLE did not achieve their primary endpoint, it is used in the clinical setting for SLE, including lupus nephritis, when other immunosuppressive therapies have not been effective. It is given by intravenous infusion and causes B cell depletion lasting 6-12 months. Obintuzumab which also targets CD 20, has been shown in the NOBILITY study, to improve renal outcomes, when added to the standard care for treatment of lupus nephritis. Similarly, Voclosporin, a calcineurin inhibitor, and Anifrolumab, which targets interferon, have also been approved as adjunct treatments for lupus nephritis. 4
Lupus in pregnancy
Pregnancy in women with SLE is associated with increased maternal and foetal risks, including preterm birth, preeclampsia, foetal loss and SLE flares. The risk factors for adverse pregnancy outcomes include: active disease, lupus nephritis, low complement, dsDNA antibodies and antiphospholipid antibodies. Detailed pre-pregnancy planning with rheumatology and obstetrics is essential to ensure disease is optimally controlled and prescribed medications are safe in pregnancy. 5
Hydroxychloroquine is commonly continued throughout pregnancy in SLE patients. Azathioprine and calcineurin inhibitors are also considered safe in pregnancy (although there have been no prospective controlled trials to prove this). Glucocorticoids can be used to treat lupus flares if required, although their dose should be minimised. Patients at risk of pre-eclampsia, especially those with lupus nephritis and those with antiphospholipid antibodies, are generally prescribed aspirin. Patients with secondary antiphospholipid syndrome, particularly those with a history of foetal loss, are generally treated with a combination of aspirin and heparin. 6
Anti-Ro antibodies can cross the placenta and result in neonatal lupus manifesting as congenital heart block and/or neonatal cutaneous lupus. The presence of these antibodies in the mother is associated with a 2-3% risk of congenital heart block; when this occurs, the risk is 12-20% in subsequent pregnancies. This risk is reduced with hydroxychloroquine treatment. Patients with anti-Ro antibodies who become pregnant need to be monitored in a high-risk obstetrical unit with weekly foetal echocardiograms during their second and third trimesters. Neonatal cutaneous lupus will resolve once the maternal anti-Ro antibody leaves the neonatal circulation but the heart block can be permanent.
Drug induced lupus
Drug-induced lupus refers to the development of a lupus like syndrome following exposure to a causative drug. Unlike SLE, it affects males and females equally. The classic autoantibodies present in drug-induced lupus is anti-histone antibodies.
Drug-induced lupus can manifest in 3 different phenotypes: systemic disease, subacute cutaneous lupus and cutaneous vasculitis. The systemic disease typically presents with arthralgia, myalgia, serositis and constitutional symptoms. Drug-induced subacute cutaneous disease presents with similar findings to acute cutaneous SLE and this diagnosis is considered in individuals who develop cutaneous lupus over the age of 50.
Procainamide and hydralazine are drugs with the highest risk of developing drug-induced lupus, however these drugs are now infrequently prescribed. Isoniazid, methyldopa, minocycline and anti-TNF agents are also associated with drug induced lupus, and although they have a lower risk, they are more commonly prescribed and therefore seen more.
It is generally accepted that anti-nuclear antibodies need to be present to diagnose drug-induced lupus although their presence alone is not sufficient to make the diagnosis. The autoantibody profile associated with drug-induced lupus is more restrictive compared with the vast multitude of autoantibodies seen in idiopathic SLE. Anti-histone antibodies occur most frequently. Antibodies to double-stranded dsDNA are uncommon in drug-induced lupus but they have been reported to develop in patients treated with TNF-α inhibitors, sulphasalazine, and minocycline.
A temporal association between the ingestion of an agent and the development of the lupus-like features is required to make the diagnosis. Unlike drug hypersensitivity, it generally requires weeks to months of exposure to an agent before drug-induced lupus develops. Remission of the clinical features with a decrease in the autoantibody titres should occur following withdrawal of the offending agent. Recurrence of the syndrome following reintroduction of the agent would provide confirmatory evidence for an association but this is seldom done in clinical practice. Many patients will develop anti-nuclear antibodies while taking certain medications but the majority do not develop a lupus-like syndrome. Hence, the development of a positive ANA in the absence of other clinical features is insufficient for the diagnosis of drug induced lupus and should not be a reason to discontinue the medication.
The mainstay treatment of drug induced lupus is to discontinue the offending drug. In patients with more severe signs and symptoms, such as serositis, a short course of steroids can be used. 7
SLE, like other chronic inflammatory diseases, is associated with accelerated atherosclerosis and cardiovascular events are a leading cause of mortality. Effective treatment of active lupus reduces this risk and management of traditional cardiovascular risk factors, such as hypertension and smoking, is particularly important.
SLE is an autoimmune disease where manifestations can range from mild disease to life threatening organ involvement.
Treatment of lupus depends on disease severity and organ manifestations and almost all patients are prescribed hydroxychloroquine.
SLE frequently presents in females in childbearing years and is associated with increased maternal and foetal risks.
Cardiovascular disease is a leading cause of mortality in SLE and management of cardiovascular risk factors is important.
References available on request
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