Epidemiology

SLE, although uncommon, is not a rare condition. In UK studies the prevalence is approximately 1 in 4000 individuals, but there is a marked female preponderance with a female : male ratio of 9–13 : 1, meaning that SLE affects approximately 1 in 2000 females in the UK. There are also differences in prevalence according to ethnic background. Compared with white Caucasians, the prevalence is approximately 2–3 times higher in Asians from the Indian subcontinent and 5–10 times higher in Africans and African Caribbeans. SLE can present at any age from childhood through to older adulthood. The peak age at onset is in the late third – early fourth decade of life, with a second peak in the sixth decade.

Aetiology

The cause of lupus remains unclear, but there is a strong genetic predisposition with first-degree family members being 50 times more likely to develop the disease than the background population. Additional factors known to cause or influence the development of lupus include ultraviolet (UV) light exposure, female sex hormones and certain drugs, e.g. chlorpromazine, hydralazine and isoniazid. It is known that anti-double-stranded DNA antibodies are directly toxic to the kidney, but it is not certain what role, if any, is played by the numerous other autoantibodies produced in SLE.

Clinical features

The symptoms and signs of SLE are diverse, but, as indicated in Table 17.1, inflammation is the predominant pathology associated with many of the key clinical features. Non-specific constitutional upset characterized by malaise, low-grade fever, fatigue and unexplained weight loss are common in SLE. More specific inflammatory features include a malar or ‘butterfly’ rash, which is often light sensitive, and other cutaneous lesions including alopecia, mucosal ulceration and digital vascular changes such as nail-edge infarcts and splinter haemorrhages. Arthritis (small joint symmetrical polyarthritis) is also a common presenting feature. The arthritis is non-erosive, but in some cases ligamentous laxity can result in deformities similar to those seen in rheumatoid arthritis (RA) (Jaccoud’s arthropathy; Fig. 17.2). In contrast to RA, however, these deformities are reducible. Importantly, SLE is also associated with inflammation in other organ systems, including serositis, nephritis and involvement of the central nervous system. Renal disease is often asymptomatic and can affect up to 25% of patients, although a higher occurrence is noted in African Caribbean, Chinese and Indo-Asian patients. Careful clinical assessment and regular urine examination is, therefore, necessary. A wide range of neuropsychiatric presentations have been described. Currently, the classification of SLE is based on a combination of clinical and laboratory investigations, and patients should have 4 of 11 criteria to confirm the classification of SLE (Box 17.1). However, it is important to remember that these criteria cannot be used as diagnostic criteria: they may assist in defining the spectrum of possible features but must be interpreted with common sense and clinical judgement and expertise.

FIGURE 17.2 Jaccoud’s arthropathy in a patient with systemic lupus erythematosus. There are swan neck deformities on several digits (A). These are, however, fully reducible and the patient is still able to make a complete fist (B). This deformity is a result of ligamentous laxity rather that joint subluxation

Thrombosis represents an important cause of clinical manifestations in lupus. The propensity to thrombosis is related to the presence of antiphospholipid antibodies, which reflect a pro-coagulant state. In addition, blood vessel inflammation can impair the normal anticoagulant properties of the endothelium. As a result, patients with SLE are at increased risk of venous thrombo-embolism, arterial thrombosis and adverse pregnancy outcomes (see antiphospholipid syndrome).

Up to 50% of patients with SLE also describe Raynaud’s phenomenon, although this is usually less severe and less likely to cause digital ulceration compared with that in patients with scleroderma. Typical skin changes include scarring or fibrosis, and a subgroup of patients with SLE present with discoid lupus lesions (Fig. 17.3), which are often discrete areas, associated with scaling, hypo- or hyper-pigmentation and loss of associated skin appendages. If discoid lesions occur on the scalp, this results in scarring alopecia.

FIGURE 17.3 (A) Actively inflamed discoid lupus eruption on the light-exposed skin of the cheek and bridge of nose. (B) Even after successful treatment there is still residual atrophy and depigmentation of the affected area

Other complications

Infection is a common complication in patients with SLE. Active disease is associated with complement consumption, relative hyposplenism, neutropenia and lymphopenia. In addition to low absolute counts, leucocyte function is also impaired. In addition, drugs such as corticosteroids and immunosuppressive agents increase the propensity to infection. It is also not unusual for infection to coexist with a flare-up of the underlying inflammatory disease and, therefore, sepsis needs to be considered carefully in most clinical settings. SLE is associated with an accelerated onset of atherosclerosis. The early development of atherosclerosis coupled with the increased thrombotic risk seen in SLE means that atherosclerosis should be considered in the differential diagnosis of relevant presentations, e.g. acute chest pain, acute focal neurological event.

Laboratory abnormalities

Simple investigations can be extremely informative in patients with SLE. Anaemia may be present due to chronic disease, but haemolytic anaemia (positive Coombs’ test) may also occur. Leucopenia, in particular lymphopenia, is characteristic and thrombocytopenia can occur either as a chronic, stable, low platelet count or as an acute profound thrombocytopenia, which is associated with bruising and bleeding complications. Urine abnormalities may be detected on dipstick (haematuria, pyuria and proteinuria). Any such abnormality requires further investigation to exclude infection or significant renal involvement. Patients can have significant glomerulonephritis requiring immunosuppressive therapy even when the serum creatinine level is within normal limits and, therefore, persistent microscopic haematuria/proteinuria usually requires a renal biopsy to determine further management. Serologically, patients with active lupus often have reduced C3 or C4 complement concentrations due to immune complex-driven consumption. Hypocomplementaemia may also be due to an underlying hereditary complement deficiency, which itself is a risk factor for developing SLE. ANA testing is positive in more than 90% of patients with SLE; however, the titre does not reflect underlying disease activity. In contrast, antibodies to double-stranded DNA (dsDNA) are highly specific for SLE, although they may be positive in only 60% of all cases. In some patients, the titres of dsDNA antibodies do reflect underlying disease activity and in such cases rising titre may portend a future flare of clinical disease.

Clinical course and prognosis

SLE classically runs a relapsing and remitting course. With treatment, initial clinical manifestations are often suppressed; however, as treatment is tapered a further flare can occur. Certain triggers for flares can sometimes be recognized, such as psychosocial stress, intercurrent infection, UV light exposure or exposure to exogenous oestrogens. Although a clinical flare-up is often associated with recurrence of the previous clinical features, it is not unusual for new clinical features to develop or for a flare-up to be characterized by an entirely new organ/system involvement. Obviously, because the disease and its treatment can cause chronic morbidity, additional complications can also mimic a flare of the disease. For example, a patient with SLE presenting with acute chest pain may have an inflammatory serositis such as pericarditis. However, acute chest pain may also be caused by a pulmonary embolus, acute myocardial infarction or bacterial pneumonia, all of which are more common in patients with SLE.

The long-term survival for patients with SLE has improved considerably over the past 50 years. In the 1950s the 5-year mortality rate was 50%. Currently the 10-year survival rate is greater than 85% in most series. There is increased mortality in patients of African Caribbean or African American background. Mortality is also higher in patients who have renal or pulmonary involvement, as well as in patients with thrombocytopenia.

Management of systemic lupus erythematosus

The aim is to make a clear diagnosis and to determine the extent of involvement. It is also important to determine whether specific clinical features can be attributed to inflammation, thrombosis or other disease mechanisms, as well as to exclude specific complications such as infection. For mild non-life-threatening disease, topical therapies, non-steroidal anti-inflammatory drugs (NSAIDs) and general lifestyle advice, such as avoidance of sun exposure, may be sufficient. For mild-to-moderate disease, anti-malarial drugs (hydroxychloroquine or chloroquine phosphate), methotrexate, leflunomide, azathioprine and/or low-dose corticosteroids are frequently used. In patients with significant organ involvement, e.g. proliferative glomerulonephritis, severe neuropsychiatric involvement or uncontrolled generalized disease, immunosuppressive drugs, such as cyclophosphamide or mycophenolate mofetil, are indicated. Because of the risks of long-term toxicity from cyclophosphamide, most patients are switched to maintenance azathioprine or mycophenolate following successful initial disease control. More recently, novel therapies, such as anti-CD20 monoclonal antibodies, have shown limited efficacy in refractory disease. In addition to these therapies, other specific agents to control symptoms and/or to prevent complications are commonly required (Table 17.2). These therapies include anticonvulsants, anticoagulants, antihypertensives, lipid-lowering drugs and bone protective agents.

Table 17.2 Examples of drugs commonly used in the management of patients with systemic lupus erythematosus, including the indication and disease process being treated

Background

The antiphospholipid syndrome (APS) is defined as a clinical syndrome characterized by a tendency to recurrent thrombosis (arterial or venous) and/or pregnancy morbidity associated with persistently raised levels of antibodies to phospholipid-related proteins.

Antiphospholipid antibodies have been formally studied and delineated as recently as the early 1980s. However, an associated test for the lupus anticoagulant (LAC) was described in the early 1950s. This functional test is an in vitro assay in which a phospholipid-dependent coagulation test is prolonged (e.g. activated partial thromboplastin time, Russell’s viper venom test, etc.). This prolongation cannot be corrected by the addition of normal plasma (which excludes a clotting factor deficiency). In contrast, however, adding phospholipid in excess to the mixture will normalize the test. Although the in vitro phenomenon is that of prolongation of a clotting time, the lupus anticoagulant test actually reflects a prothrombotic tendency. It was first described in the context of SLE, but the lupus anticoagulant can also be observed in patients who do not have SLE.

Clinical features (Table 17.3)

Vascular thrombosis

Thrombosis associated with APS can occur in any part of the circulation. The most important thrombotic complications include deep vein thrombosis and pulmonary embolism as well as stroke (Fig. 17.4), myocardial infarction and retinal artery occlusion. Untreated, there is a high risk of recurrent thrombotic events and, indeed, a careful clinical history may reveal previous unexplained thrombotic episodes in the distant past. Patients with APS can experience thrombosis on the venous and arterial side of the circulation, although it is more common for recurrent thrombosis to occur on the same side of the circulation as the previous thrombosis.

Table 17.3 Summary of the Sapporo criteria for the classification of antiphospholipid syndrome

FIGURE 17.4 Magnetic resonance image of the brain in a patient with systemic lupus erythematosus and secondary antiphospholipid syndrome. The scan demonstrates significant cerebral atrophy as well as several areas of infarction from previous thrombotic episodes (strokes)

Other clinical features

Approximately one-third of patients with APS have thrombocytopenia, which is usually a chronic stable thrombocytopenia (50–150 × 10⁹/l). In addition, about 15% also have a Coombs-positive haemolytic anaemia. Cutaneous features associated with APS include livedo reticularis (Fig. 17.5), superficial thrombophlebitis and chronic leg ulcers. On careful screening, patients with APS frequently have thickening of cardiac valves, and 20–30% may have clinical evidence of mitral valve prolapse. In the central nervous system, clinical syndromes such as transverse myelitis, chorea and migraine may occur. It is, however, unclear whether these are primarily thrombotic in nature or whether they represent a separate pathogenic mechanism. Occasionally patients can present with thrombosis in multiple vascular beds. This ‘catastrophic’ antiphospholipid syndrome is difficult to recognize clinically and is associated with a high mortality rate.

FIGURE 17.5 Livedo reticularis rash in a patient with antiphospholipid syndrome. The rash has a bluish purple reticular pattern, which does not improve in a warm environment

Classification

The initial descriptions of APS occurred in the context of SLE. APS may also be a complicating feature of other autoimmune diseases, such as rheumatoid arthritis and Sjögren syndrome. In this context the term secondary APS is usually employed. The majority of patients with APS do not have any other systemic autoimmune condition, and these are described as having primary APS.

Management

APS is only one cause of recurrent thrombosis or miscarriage. Careful evaluation should, therefore, be undertaken to identify other causes of thrombosis, e.g. Factor V Leiden, protein C and protein S deficiencies. Similarly, for recurrent miscarriage other causes, e.g. hormonal, anatomical and chromosomal causes, should be actively excluded. APS will constitute anything from 5% to 30% of such cases.