Caroline Gordon: Emeritus Professor of Rheumatology at University of Birmingham and Honorary Consultant Rheumatologist, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK
Lead author: BSR guideline for the management of systemic lupus erythematosus in adults.
Background: why lupus needs specialist care – it is a cause of premature death
Systemic lupus erythematosus (SLE or lupus for short) is a multisystem, autoimmune disease that may develop at any age from about 18 months to 80 years. It affected nearly 1 in 1000 of the population in the UK in 2012 and is most common in women in the reproductive age group. It affects women of African descent more severely and at a younger age, often in their 20s compared with women of European origin in whom it may not present till after the age of 40. It is often not considered as a diagnosis in men but can cause serious disease, possibly because it is diagnosed late in the disease course. Kidney involvement, lupus nephritis, occurs in about 30% of UK lupus patients, especially those of African origin, and was found to cause end-stage renal disease in 20% of these patients managed in a UK lupus specialist centre. Patients with lupus nephritis died at a mean age of 40.3 years with an average of 7.5 years between the diagnosis of lupus nephritis and death. Despite treatment at another lupus specialist centre, another study published in 2015 showed a 2-fold increased risk of death and a risk of premature death in women and men with lupus in general, with a mean age of death of 53.7 years between 1989 and 2010. Most lupus patients die from infection or cardiovascular disease rather than active lupus disease in the UK. During life, lupus causes considerable morbidity as it may present with a variety of clinical symptoms and signs that progress slowly or in some cases rapidly, causing the accumulation of chronic damage if not promptly diagnosed, appropriately treated and regularly monitored.
Management of lupus
The British Society of Rheumatology (BSR) published a NICE-accredited guideline for the management of systemic lupus erythematosus in adults in 2018 to optimise management and to improve the outcome of this variable and potentially life-threatening disease. Both the executive summary and the full guideline are available open access online for reference. The guideline covers the diagnosis, assessment, and monitoring of lupus and the treatment of mild, moderate and severe active lupus disease and is based on an extensive literature review up to June 2015. The target audience is anyone involved in the care of adult lupus patients and includes rheumatologists and other clinicians such as nephrologists, immunologists, dermatologists, emergency medicine specialists, GPs, trainees in these specialties, clinical nurse specialists and other allied health professionals
Clinical features of lupus and diagnosis
The diagnosis of lupus requires a combination of relevant clinical features and at least one immunological abnormality (as discussed below) according to the BSR guideline for lupus. Diagnosing lupus can be challenging as lupus causes a large variety of clinical features affecting any system in the body with a wide differential diagnosis and expert advice is required to confirm the diagnosis (see below). Delays in diagnosis are common with studies suggesting it takes a mean of 5-8 years from onset which is a serious concern. The commonest symptom is fatigue which is non-specific and the best known are skin rashes often associated with photosensitivity, hair loss and inflammatory arthritis in about 60-80% of cases. Kidney and neurological involvement are associated with the greatest risk of chronic damage and death and require prompt specialist assessment and treatment. Constitutional features, cardio-respiratory, gastrointestinal and liver involvement may occur in up to 60% of patients. These features are often not recognised as being associated with lupus, and must be distinguished from infection, drug side-effects and other conditions including cancer so they require multidisciplinary care by specialists with experience of managing lupus. Ophthalmic involvement, other than dry eyes, is rare but potentially sight-threatening and requires urgent referral to an ophthalmologist experienced in autoimmune disease.
Causes of lupus and immunological features
Lupus is caused predominantly by the formation of immune complexes involving autoantibodies that induce complement activation that results in inflammation and that can affect any organ but most often affects the skin, joints, pleura and kidneys. Thrombosis associated with antiphospholipid antibodies may contribute to disease manifestations in some patients. Environmental triggers for autoantibody formation and clinical flares include infection, UV light, hormones such as oestrogen, and cigarette smoking that act on genetic predisposition. Drug-induced lupus is most often caused by tetracyclines but isoniazid, sulphonamides, propylthiouracil, hydralazine, procainamide, phenytoin and anti-TNF therapy are other well recognised triggers. Drug-induced lupus usually resolves over one year after withdrawal of the offending drug.
An autoantibody screen should be requested in anyone in whom there is a clinical suspicion of lupus. Most patients are ANA positive (<95%). If ANA is negative, there is a low clinical probability of the patient having SLE however a minority have anti-double stranded (ds)DNA or anti-Ro antibody positivity without ANA. ANA tests are not specific for the diagnosis of lupus and may occur in a variety of other autoimmune rheumatic conditions, viral infections such as infectious mononucleosis and occasionally in patients with cancer. The ANA test can become negative in treated patients and the results can vary with different assays. Anti-dsDNA and anti-Sm antibodies are very specific for lupus but are only present in about 60% and 25% of lupus patients respectively. Anti-dsDNA antibodies rise and complement C3 and C4 levels fall with active disease and are useful in monitoring disease as well as diagnosis. Anti-Ro and anti-La antibodies are associated with photosensitive rashes, Sjögren’s syndrome and neonatal lupus syndrome including congenital complete heart block in babies. Anti-RNP antibodies occur in lupus and mixed connective tissue disease. Antiphospholipid antibodies are associated with an increased risk of arterial/venous thrombosis and adverse pregnancy outcomes. In active lupus CRP is usually low despite raised ESR (and viscosity) but CRP rises in infection or with lupus effusions.
Organisation of care for SLE patients
Patients suspected of suffering from lupus should be referred by their GP to a physician with experience of managing lupus so that they can assess the clinical features and arrange necessary investigations to confirm the diagnosis which may require skin and/or kidney biopsies. They should assess disease activity, distinguish pre-existing chronic damage and co-morbidity and then provide advice on treatment and prevention of future flares. Further monitoring of both lupus, its complications and side effects of therapy will be required. Thrombotic manifestations will require anticoagulation and involvement of haematologists.
Mild disease activity is clinically stable lupus with no organ-threatening involvement. It is treated with sunscreen, hydroxychloroquine, methotrexate and low-dose oral corticosteroids if local measures fail. Patients with moderate disease activity have more serious inflammatory lupus manifestations requiring immunosuppression with the addition of drugs such as azathioprine, mycophenolate mofetil, calcineurin inhibitors and higher doses of corticosteroids to induce disease control and then lower doses for maintenance therapy. Severe disease is defined as organ or life-threatening and requires the most intense immunosuppression usually with high-dose corticosteroids initially and mycophenolate mofetil or cyclophosphamide. With an increase in disease activity (termed lupus flare) it can be helpful to consider the likely triggers such as exposure to sunlight, concurrent or recent infection, hormonal changes, and any recent drug change as this will guide further investigation, current treatment change and future monitoring. Fatigue can be difficult to manage and may be due to lupus, anaemia for other reasons (often iron-deficiency), hypothyroidism or associated with physical decondition and/or coexisting chronic pain or fibromyalgia in up to 30% of patients. It requires careful assessment and management with appropriate drug therapy, physiotherapy advice and sometimes psychological support.
The aim of lupus treatment is to achieve a low level of disease activity if not remission using hydroxychloroquine, immunosuppressants and the minimum amount of corticosteroids, in order to reduce accumulating damage from active inflammatory disease and its treatment. It is important to consider adherence to treatment and to ensure that patients are seen regularly so that therapy can be optimised to promote disease control and to prevent complications and premature death. Managing lupus patients with immunosuppressive therapies can be challenging due to the risk of infection, attribution of cytopenias to lupus or cytotoxic drugs, and the constant need to distinguish disease activity from damage and co-morbid conditions. Shared care agreements with GPs may be arranged once patients are stable on established drug therapy. SLE patients should have access to a multi-disciplinary team including rheumatologists, nephrologists, dermatologists, haematologists, cardiologists, chest physicians, neurologists, obstetricians, nurse specialists, physiotherapists, as well as psychologists, podiatrists and occupational therapists, all of whom should work as part of collaborative clinical network involving regional and national specialist centres, local hospitals and GPs.
Treatment of SLE patients
In 2011, belimumab became the first drug to be licensed for the treatment of active lupus for over 50 years. The only other licensed drugs for lupus are prednisolone and hydroxychloroquine but immunosuppressants are used off-license in lupus by physicians experienced in their use. The supporting evidence is reviewed in the BSR guideline for the management of SLE which divides the treatment of lupus in to three sections covering mild, moderate and severe lupus. For advice about the use of drugs in pregnant lupus patients there is a separate BSR guideline on the use of drugs in rheumatic diseases in pregnancy and breastfeeding.
Mild lupus should be managed with hydroxychloroquine and/or methotrexate and high factor sunscreen as these therapies reduce the need for corticosteroids. Topical preparations, intra-articular injections and oral prednisolone may be needed. Short courses of non-steroidal anti-inflammatory drugs may be considered for symptomatic benefit but they are contraindicated in patients with renal disease and have a high risk of side effects.
The management of moderate lupus requires specialist advice and usually involves immunosuppressive, steroid-sparing drugs such as azathioprine, mycophenolate mofetil, calcineurin inhibitors (ciclosporin and tacrolimus) or methotrexate with corticosteroids, in addition to hydroxychloroquine and avoidance of UV radiation. Corticosteroid use may include intramuscular or intravenous doses of methylprednisolone to reduce the need for oral prednisolone. Patients that are refractory to these drugs need discussion with and often referral to a recognised regional or national specialist lupus centre. The biologic drugs belimumab and rituximab should only be used if the patients meet the appropriate criteria for these drugs. NICE guidance for the use of belimumab in active autoantibody-positive SLE in adults was published in 2016 (https://www.nice.org.uk/guidance/TA397) and the interim clinical commissioning policy statement for rituximab in adult SLE patients was published by NHS England in 2013 (http://www.england.nhs.uk/wp-content/upSOAds/2013/09/a13-psa.pdf).
Lupus nephritis and neuropsychiatric lupus are examples of severe lupus disease. Such organ or life-threatening conditions should be managed by a lupus specialist with intensive immunosuppression followed by prolonged maintenance therapy to prevent relapse. Intravenous methylprednisolone and/or high dose oral prednisolone are used to induce remission with mycophenolate mofetil or cyclophosphamide, followed by steroid reduction over several months. If patients fail conventional immunosuppressive drugs due to inefficacy or intolerance belimumab and rituximab should be used as discussed above. Intravenous immunoglobulin and plasmapheresis are rarely used.
Management should ensure regular use of factor 50 sunscreen and sun avoidance, adequate vitamin D3 intake given the inability to synthesise vitamin D without UV light exposure, weight control, exercise, not smoking and other measures to reduce risk factors for infection, atherosclerosis and osteoporosis including vaccinations and monitoring of cholesterol, blood pressure and bone mineral density as lupus patients are at increased risk of these complications. Routine cancer screening and advice on contraception are also important and should not be neglected. Pre-pregnancy counselling should be provided so that pregnancy is planned and occurs when lupus has been well controlled for at least 6 months and the patient is on appropriate treatment for conception. This will ensure the best outcome for mother and baby as there are often increased risks associated with pregnancy in lupus patients.
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