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Emily Mathews Marker: Dr. Shane Clarke January 2005 Word count: 1,885 How to diagnose and manage SLE confidently and competently. SLE (Systemic Lupus Erythematosus) is a chronic, multisystem inflammatory disease the specific cause of which is unknown. It can affect any, or indeed every, system and organ of the body. Its manifestations and course are highly variable between individuals, meaning that its diagnosis is a complex and often confusing one. This essay will present the tools currently available to the physician in the diagnosis of SLE and those useful for separating it from its differential diagnoses. The various treatment options for this disease will also be discussed. The Diagnosis The correct diagnosis is important for several reasons, not least of which is to avoid the risks of inappropriate treatment but also to avoid psychological harm from being incorrectly informed of a diagnosis of a serious chronic disease and possibly economical disadvantage too, in the form of not being able to obtain life insurance. Hence it is important for the physician to be confident when informing the patient of a diagnosis of SLE that this is indeed the correct diagnosis. Despite advances in serology, the time between onset of symptoms and diagnosis in patients with SLE is still variable and often delayed (Maddison, 2002). The diagnosis of SLE is made on a balance between clinical features and laboratory tests: Clinical features SLE is a multi-system disease and so its effects are wide ranging. Most features are due to the consequences of vasculitis and they are summarised in the following table: System Clinical features General Fever Malaise Fatigue Skin Malar (butterfly) rash Photosensitivity Purpura Urticaria Respiratory Serositis: Pleurisy (+/- effusion) Restrictive lung defect (rare) Musculoskeletal Arthritis Aseptic necrosis of hip (rare) Myopathy Nervous Fits Hemiplegia Psychosis Cranial nerve lesions Cardiovascular Serositis: Pericarditis Endocarditis Aortic valve lesions Gastrointestinal Abdominal pain Mouth ulcers Renal Glomerulonephritis Others Raynaud’s phenomenon The most common presenting feature in SLE is arthritis. Fatigue and general malaise, as well as mouth ulcers are also common presenting symptoms. Although, obviously, not everyone who presents with these symptoms has SLE, there are characteristics of the features which can lead on to a suspicion of SLE. For example (Belilos & Carsons, 1995), the arthritis seen in SLE is very similar to the pattern of rheumatoid arthritis: small joints of the hands and feet as well as the ankles, knees and wrists are most often involved. Patients also usually experience the stiffness and ‘gelling’ of rheumatoid arthritis. However, on examination, joints usually display a less impressive synovitis and any deformity will usually be reducible (Jaccoud’s arthropathy). Additionally, and again in contrast to rheumatoid, the arthritis seen in SLE in typically non-erosive. The malar or ‘butterfly’ rash is often the sign most associated with SLE. In fact this is only present as a presenting feature in 30 % of patients. Equally, Raynaud’s phenomenon is not at all specific for SLE, being found in a whole host of other diseases as well as standing alone in some cases (emedicine.com). Differential diagnosis In addition to the fact that SLE manifestations are so varied there are other reasons, which make diagnosis complex. SLE is often seen as a disease of women of a childbearing age. This is, in fact, the group amongst whom it is most commonly seen, but this knowledge can also lead to a reduced index of suspicion in diagnosis in males, children and the elderly. Mostly importantly, perhaps, there are a number of conditions that can mimic SLE. These are shown in the following table along with distinguishing features of each one: Table taken from Maddison 2002. Rheumatoid arthritis can often be confused as SLE and vice versa because the commonest presentation in both is arthritis. A careful history, examination and serology should normally distinguish one from the other but this is also confused by what are known as the ‘overlap syndromes’ and also by undifferentiated connective tissue disease (UCTD). A patient is said to have an overlap syndrome when they fulfil criteria for more than one connective tissue disease, the most commonest overlap in SLE are with systemic sclerosis and/or polymyositis or rheumatoid arthritis; ‘Rhupus’ patients (Maddison, 2002). In contrast to the overlap syndromes, UCTD is said to occur in patients who have clinical and laboratory features of a connective tissue disease but who do not fulfil the criteria of any one disease. UCTD has no formal definition but it is important to consider as a diagnosis because although many patients remain in the same state (often symptoms including arthritis, cutaneous involvement and fatigue but rarely with major organ involvement), some people will go on to develop full blown SLE. Another differential diagnosis that should not be ignored, especially since it is entirely treatable, is that of drug-induced lupus. The presenting features are very similar to SLE but these patients tend to have less CNS or renal involvement. Drugs that can cause this syndrome include procainamide, hydralazine, chlorpromazine, methyldopa and isoniazid (Belilos & Carsons, 1995). The treatment is simply to discontinue these medications. Investigations There are several laboratory tests available to be used as diagnostic aids in SLE. The commonest performed is a test for the presence of ANA (anti-nuclear antibody). 98% of people with active SLE are ANA positive (Maddison, 2002), however, because of its presence in other diseases such as rheumatoid arthritis and in 15% of the normal population, the results of an ANA investigation should only be considered when a full clinical picture has been ascertained. The most specific test for SLE is a test for anti-dsDNA antibodies (those that bind double- stranded DNA) although only 50 % (Kumar & Clark, 2002) of patients with active SLE will be anti-dsDNA positive. A full blood count usually shows a lymphopenia, leucopenia, anaemia and/or thrombocytopenia. The ESR will be raised in proportion to disease activity while CRP is usually normal. Other tests that will be positive in a certain proportion of patients include (Kumar & Clark, 2002; Maddison, 2002): Rheumatoid factor, anticardiolipin antibodies and antibodies to various RNA-binding proteins such as La or Ro. A further test that has reduced in its popularity since the advent of readily available serology is the lupus-band test (Maddison, 2002). In SLE, granular deposits of immunoglobulin and complement are laid down in a ‘band’ between the dermis and epidermis in lesional and non- lesional skin. The lupus-band test is a histological test that looks for this lupus-specific sign. Only 50% of people with SLE will have this ‘banding’ and because serology is far easier to carry out, the use of this test has been reduced to only those patients who have atypical serology and/or clinical signs. In 1997, the American College of Rheumatology (ACR) published its updated criteria for the classification of SLE (Hochberg, 1997). These are as follows: 1. Malar rash 2. Discoid rash 3. Photosensitivity 4. Oral ulcers 5. Non-erosive arthritis 6. Serositis: pleurisy or pericarditis 7. Proteinuria >0.5g/24hrs or casts 8. Neurological: seizures or psychosis 9. Haematological: haemolysis/leucopenia/lymphopenia or thrombocytopenia 10. Immunological: anti-DNA or anti-Sm or antiphospholipid antibodies 11. Positive ANA They claim that the presence of 4 or more of these criteria is 96% sensitive and 96% specific for SLE. The criteria are designed as a means of standardising patient populations for the purpose of research (Maddison, 2002) and there has been criticism of their use as a diagnostic tool. Direct criticism of the content of the criteria has occurred. For example, it has been said that the revised criteria lack a definition of the durations involved in serological testing (Piette, 1998). Further evidence against the use of these criteria as diagnostic exists in the form of a paper by Levin et al. which reports that 50% of their patients with lupus do not conform to the criteria (Levin et al. 1982). SLE is a highly variable disease, both in course and manifestations, making it’s diagnosis very complex and one that is based on a detailed history, clinical exam and investigations. These should all be tailored towards the individual patients and all results should be taken in context with all other information available. The Management Patient education One of the most important aspects in managing SLE, especially in newly diagnosed SLE, is that of patient education. The patient should know all the possible outcomes of having SLE and that often many cases of SLE are mild. They should know how to help themselves, such as wearing sunscreen for most months of the year and, for women, avoiding oestrogen- containing contraceptive pills. Drug treatment in SLE The aims of treatment in SLE are not only to control the disease itself but also to control co- existent diseases such as diabetes or hypertension and to manage the results of the disease such as end-stage renal failure, and the side effects of drugs. There are a number of drugs available for use in the treatment of SLE. Again, treatment is individualised to the patient’s ‘own’ SLE. Besides the use of anti-inflammatories (steroidal and non-steroidal) and painkillers for treating symptoms such as those from the arthritis in SLE, the following drugs are used to attempt to control the disease itself: Drug Manifestation of SLE best treated Azathioprine Treats a wide range of manifestations but most data on efficacy comes from studies done on patients with lupus nephritis. Cyclophosphamide Considered standard treatment for SLE with major organ involvement. Still debate on optimal administration protocol (Mosca et al. 2001). Hydroxychloroquine Mainly used to control articular and cutaneous manifestations, but also for fatigue and serositis. Recently shown to be beneficial on the lipid profile of lupus patients (Mosca et al. 2001) Methotrexate Articular and cutaneous manifestations shown to respond best to methotrexate (Ruiz-Irastorza et al. 2001), but methotrexate is only indicated for these symptoms after non-responsiveness to steroids and antimalarials. Thalidomide Thalidomide has the potential to treat resistant cutaneous manifestations of this disease but side effects can restrict its long-term use (Ruiz-Irastorza et al. 2001). Intravenous Fever, arthritis and thrombocytopenia have been shown to respond immunoglobulins well to human intravenous immunoglobulins (Ruiz-Irastorza et al. 2001). The use of drugs within the management of SLE is dependent upon the patients individual needs and should be balanced with the side-effects of these drugs, especially considering that many patients will be on these drugs for long periods of time. Another consideration when choosing a drug or drugs is the need for monitoring. For example both azathioprine and methotrexate require regular blood tests to confirm that there is no toxic effects. New therapies such as immunoablative therapy, autologous marrow stem cell transplantation are currently being developed. A phase I study combining these therapies showed promising results (Traynor et al. 2000). Gene therapy for SLE has also been tried in mice (Xiaojing et al. 2004). Systemic lupus erythematosus is a multi-system inflammatory disease that affects most of the different tissues and systems of the body. Its manifestations vary highly between individuals. This means that the diagnosis of SLE is far from routine and the physician must use all of the tools at his disposal in concert to correctly diagnose patients as near to the time of presentation as possible. This essay cannot specifically answer the question of how to diagnose SLE purely because each case is so different. This fact also applies to the management of SLE patients – each is different and treatment is different for each. References Belilos E and Carsons SE, 1995. Systemic Lupus Erythematosus: Recognition and Management by the Primary Care Physician. Primary Care Update Ob/Gyns. 2, 80- 84 Hochberg MC, 1997. Updating the American College of Rheumatology revised criteria for the classification of Systemic Lupus Erythematosus. Arthritis and Rheumatism, 40, 1725-1734 Kumar P and Clark M, Editors, 2002. Clinical Medicine 5th ed. Saunders. P557-560 Levin DL, Roenigk HH, Caro WA & Lyons M, 1982. Histologic, immunofluorescent and antinuclear antibody findings in PUVA-treated patients. Journal of the American Academy of Dermatology, 6, 328-333 Maddison PJ, 2002. Is it SLE? Best Practice & Research Clinical Rheumatology. 16, 167-180 Mosca M, Ruiz-Irastorza G, Khamashta MA & Hughes GRV, 2001. Treatment of Systemic Lupus Erythematosus. International Immunopharmacology. 1, 1065-1075 Piette JC, 1998. Updating the American College of Rheumatology revised criteria for the classification of Systemic Lupus Erythematosus: comment on the letter by Hochberg. Arthritis and Rheumatism, 41, 751 Ruiz-Irastorza G, Khamashta MA, Castellino G & Hughes GRV, 2001. Systemic Lupus Erythematosus. Lancet, 357, 1027-1032 Traynor AE, Schroeder J, Rosa RM et al. 2000. Treatment of severe systemic lupus erythematosus with high-dose chemotherapy and haematopoietic stem-cell transplantation: a phase I study. Lancet. 356, 701-707 Xiaojing Y, Tong Z, Juan L & Xiao X, 2004. AAV-mediated gene therapy for systemic lupus erythematosus (SLE). Molecular Therapy 9, 16.
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