Systemic lupus erythematosus: causes and manifestations

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● Rheumatology

Systemic lupus erythematosus: causes and manifestations

Laura Barcia-Sixto, Registrar in Internal Medicine Department, University Hospital Complex of Pontevedra, Spain; David Isenberg, Academic Director of Rheumatology, Division of Medicine, University College, London

Little is known about the precise aetiology of systemic lupus erythematosus, but treatment should be individualised according to predominant symptoms, organ involvement, response to previous therapy and disease activity and severity.
Systemic lupus erythematosus (SLE) is a chronic multisystemic autoimmune disease with a highly heterogeneous pattern of clinical and serological manifestations. It can affect all organs and systems and affects nearly 1 in 1000 in the UK.1 Although SLE is much more common in female patients, its diagnosis, treatment and management remains the same for male patients.
The improvement in patient survival – 50% four year survival in 1950; 85% 15 year survival in 2019 – is probably due to multiple factors, including earlier disease recognition with more sensitive diagnostic tests and improved treatment.2
Despite the improvement in outcome, patients with SLE still have mortality rates two to five times higher than the general population.3,4
Immunology Interactions between susceptibility genes, hormonal influences (90% of SLE patients are female) and environmental factors result in abnormal immune responses, resulting in autoantibody production and consequent dysregulation of the

inflammatory response, leading to induction and maintenance of the disease. Autoantibodies may be present for a several years before the first clinical symptom appears.
Genetic factors In the last decade, with the development of genome-wide association study technology, more than 80 loci with common variants have been shown to have a confirmed association with SLE. One of the chromosome regions having the strongest association with SLE is the human leucocyte antigen (HLA) locus, especially the class region containing HLA-DRB1,-DQA1 and -DQB1. There are also associations of some of these loci with specific clinical and serological features.2
There is a higher prevalence of SLE in the African-Caribbean population living in Europe and North America, compared with the Caucasian population (approximately 5:1).2
Environmental influences The importance of the environment has been suggested by epidemiological studies.5 Infections, for example, can modulate the immune system protecting against autoimmunity, but can also trigger the disease. Other reported environmental triggers are ultraviolet light, smoking and silica. Medications implicated in druginduced lupus include hydralazine, d-penicillamine, minocycline, lithium and TNF alpha-blocking agents.2
Predictors The most useful laboratory tests to predict a SLE flare (particularly lupus

nephritis) are an increasing serum level of anti-DNA antibodies and a fall in complement levels (especially C3). High levels of antibodies to complement C1q are also associated with activity of lupus nephritis.
However, not all patients with these serologic markers have active disease, and these markers do not necessarily predict disease exacerbation.
In any year approximately 50–60% of patients will experience a flare, with 10% of this group experiencing a severe flare. The leading causes of death in the first decade of disease are systemic disease activity, renal failure, infections and thromboembolic events. Subsequently, atherosclerosis and cancer become more common causes of death.
Organ dysfunction SLE can affect every organ and system in the body, and during the flares more than one organ is usually affected (see Table 1).
Disease activity is categorised into mild forms, moderate and severe. Mild disease forms are clinically stable with no life-threatening organ involvement, mainly manifesting as arthritis or mucocutaneous lesions. Patients with moderate disease activity have more serious manifestations, such as cutaneous vasculitis or pericarditis, and severe disease activity is defined as organ- or life-threatening.1
Treatment aims Nonpharmacological and preventive intervention Several nonpharmacological measures and other medical interventions are important in the comprehensive

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management of SLE, in addition to the specific medication regimens.7 Sun protection. Exposure to ultraviolet (UV) light may exacerbate or induce systemic manifestations of SLE. Patients should therefore avoid exposure to direct or reflected sunlight and other sources of UV light. Sunscreens that block both UVA and UVB and have a sun protection factor (SPF) ≥55 are suggested. Smoking cessation. Smoking has been associated with more active disease.8 Smoking increases the already higher risk of accelerated atherosclerosis in those with SLE. There is also evidence to suggest that smoking diminishes the efficacy of hydroxychloroquine.9 Immunisations. Patients should receive appropriate immunisations prior to the institution of corticosteroids (>10mg/day) or immunosuppressive therapies. Vitamin D. The majority of patients with SLE have low serum levels of 25-hydroxyvitamin D (calcifediol), probably due to avoidance of sun exposure and/or use of sunscreen products. Vitamin D levels should be monitored periodically and patients with low vitamin D levels should be treated with supplemental vitamin D. This measure is important to help counter the increased risk of osteoporosis associated with corticosteroid use.10,11 Treating comorbid conditions. Cardiovascular risk factors and cardiovascular disease, pulmonary hypertension and antiphospholipid syndrome, as well as osteopenia or osteoporosis, are among the comorbid conditions that can be treated and for which screening tests need to be performed. Modifiable risk factors, such as hypertension and hyperlipidaemia, should be identified and concurrently managed.
Pharmacological therapies The choice of therapy for SLE is highly individualised and depends on the predominant symptoms, organ


Prevalence Manifestation

1. Systemic: Fatigue, malaise, fever, anorexia
2. Musculoskeletal: Arthralgias/myalgias Non-erosive polyarthritis Hand deformities Myopathy/myositis Ischaemic necrosis of bone
3. Cutaneous: Photosensitivity Malar rash Oral ulcers Alopecia Discoid/vasculitis rash Other
4. Haematological: Anaemia (chronic disease) Leukopenia Lymphopenia Thrombocytopenia Lymphadenopathy Splenomegaly Haemolytic anaemia
5. Neurological: Cognitive disorder Mood disorder Headache Seizures Mono-, polyneuropathy Stroke, transient ischemic attack Acute confused state or movement disorder Aseptic meningitis, myelopathy

95% 95% 60% 10% 25/5% 15%
80% 70% 50% 40% 40% 20% 15%
85% 70% 65% 50% 15% 15% 15% 10%
60% 50% 40% 25% 20% 15% 10%

6. Cardiopulmonary: Pleurisy, pericarditis, effusions Myocarditis, endocarditis Lupus pneumonitis Coronary artery disease Interstitial fibrosis Pulmonary hypertension, acute respiratory distress syndrome, haemorrhage Shrinking lung syndrome
7. Renal: Proteinuria ≥500mg/24h, cellular casts Nephrotic syndrome Endstage renal disease
8. Gastrointestinal: Nonspecific (nausea, mild pain, diarrhoea) Abnormal liver enzymes Vasculitis
9. Thrombosis: Venous Arterial
10. Ocular Sicca syndrome Conjunctivitis, episcleritis Vasculitis

60% 30–50%
10% 10% 10% 5% <5%
30–50% 30–50%
25% 5–10%
40% 30%
40% 5%
15% 10% 5%
15% 15% 10% 5%

Table 1. Clinical manifestations of cumulative systemic lupus erythematosus and prevalence over the entire course of disease. Adapted from ‘Systemic Lupus Erythematosus’ Harrison’s Principles of Internal Medicine, 20th edition6

involvement, response to previous therapy, and disease activity/severity.7 Antimalarial drugs, notably hydroxychloroquine, can help to manage a variety of SLE manifestations, particularly fatigue, arthralgia and even renal disease. It helps to prevent lupus flare and to keep steroid dosage to a minimum.

Corticosteroids modify genomic and non-genomic pathways; the latter being activated at higher dosages leading to immunosuppression. The dose and route of administration of these drugs varies according to the organ(s) affected and disease severity. Some patients do not respond sufficiently to corticosteroids agents, and in many

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manifestations of SLE (eg, severe thrombocytopenia, renal disease and haemolytic anaemia) a combination with an immunosuppressive drug is more effective.
Long-term damage and increased mortality are established complications of glucocorticoids (GCs). There is a direct linear correlation between increasing dose of GCs with sideeffects, the most important of which are increased infection risk, diabetes, high blood pressure and osteoporosis.
Conventional immunosuppressive drugs12 Azathioprine (AZA) is a purine analogue drug that acts at the level of DNA replication and can block the de novo pathway of purine synthesis.
The limited toxicity of AZA (it can be used in pregnant patients, unlike mycophenolate and cyclophosphamide) has been related to the presence of a genetic polymorphism that limits activity of the thiopurine methyltransferase enzyme. Serious adverse events can occur in homozygous patients. Mycophenolate (MMF) inhibits DNA synthesis by decreasing the synthesis of guanine and, therefore, lymphocytic proliferation. This drug has a selective action in the lymphocytes with less haematological toxicity.
MMF is effective in refractory haematological and dermatological manifestations. Cyclophosphamide. For 30 years, until the late 1990s, the gold standard
Key points
• Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that affects nearly 1 in 1000 people in the UK1
• It is more common in female patients
• There is a higher prevalence of SLE In the African-Caribbean population living in Europe and North America
• New steroid-sparing therapies are needed in order to treat disease activity and minimise accumulative and high-dose steroid exposure

induction therapy for severe lupus nephritis (LN) consisted of GCs with cyclophosphamide.
Studies in the 1980s established that cyclophosphamide-containing regimens were more effective than corticosteroids alone when treating LN. It was also used to treat myositis and gastrointestinal and pulmonary manifestations.1 The original higher doses (1g/m2 monthly for six months, followed by 1g/m2 every three months for two years) have been replaced by the Eurolupus regimen (six fortnightly pulses at a fixed dose of 500mg), that is effective with fewer side-effects. Calcineurin inhibitors. Tacrolimus and ciclosporin, via inhibition of calcineurin, inhibit the production of cytokines and lymphocyte proliferation, especially T helper cells. They are used for the induction of the treatment in LN and to reduce the use and side-effects of corticosteroids.
Biological therapy To date, the most logical and widely used biological option in SLE has been B cell depletion, achieved by direct B cell elimination or inhibition of B cell survival agents. Rituximab is a humanised monoclonal antibody against CD20 and was the first biologic to be used in the treatment of SLE in 2000.13,14
In the UK, rituximab is currently widely used off-licence (although approved by NHS England) to treat SLE. In many open-label studies, rituximab has shown efficacy in treating a wide variety of different features, such as fatigue, skin, arthritis, serositis and renal disease. It is generally safe and well tolerated when used either alone or in combination. However, patients must be carefully monitored for their immunoglobulin levels, which tend to fall with repeated use.
Side-effects include infusion reactions (fever, bronchospasm, rash and hypotension), which usually settle once the infusion has been stopped.
Rituximab may be used as an

add-on therapy to induction regimens, for refractory disease or as a steroid-sparing agent. It has been used successfully at the time of diagnosis in SLE for both, renal and non-renal diseases. Belimumab is a human monoclonal antibody that binds to BLyS (also known as BAFF, B cell activating factor), an important B cell stimulator protein.1 Levels of BLyS are elevated in some patients with SLE, and it may play a role in the pathogenesis of lupus by promoting the formation and survival of memory B cells and plasmablasts making autoantibodies.
The US Food and Drug Administration approved Belimumab in 2011 for treatment of mild to moderate SLE affecting the skin and joints.
Complete remission, partial remission and flare avoidance Studies on remission in SLE have used various definitions, including absence of clinical and serological activity, serological activity but clinically quiescent, and whether these states are achieved on or off treatments.
Up to 30–50% of patients may achieve low disease activity (defined as mild activity on hydroxychloroquine with or without the use of low-dose glucocorticoids); less than 10% experience remissions.6
It is useful to follow tests that indicate the status of organ involvement known to be present during SLE flares. These might include urinalysis for haematuria and proteinuria, haemoglobin levels, platelet counts, and serum levels of creatinine or albumin.
Conclusion SLE is a chronic multisystemic autoimmune disease with a heterogeneous pattern of clinical and serological manifestation.
The pathogenesis of SLE is the result of interactions between genes, hormones and the environment, but its precise aetiology is mostly unknown. The choice of therapy

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should be individualised and depends on the predominant symptoms, organ involvement, response to previous therapy, and disease activity and severity. Biological treatments have an important corticosteroid-sparing effect, but no biological drug apart from belimumab has currently been approved in the UK for the treatment of SLE.
Declaration of interests Professor Isenberg has received honoraria from Merck Serono, Pfizer, GlaxoSmithKline, ImmuPharma, UCB, Celgene and Eli Lilly.
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3. Borchers AT, Keen CL, Shoenfeld Y, Gershwin ME. Surviving the butterfly and the wolf: mortality trends in systemic lupus erythematosus. Autoimmun Rev 2004;3:423–53. 4. Singh RR, Yen EY. SLE mortality remains disproportionately high, despite improvements over the last decade. Lupus 2018;27:1577–81. 5. Lewis MJ, Jawad AS. The effect of ethnicity and genetic ancestry on the epidemiology, clinical features and outcome of systemic lupus erythematosus. Rheumatology (Oxford) 2017;56(suppl 1):i66–i77. 6. Bevra HH. Systemic Lupus Erythematosus. In: Harrison’s Principles of Internal Medicine. 20th edition. J. Larry Jameson JL, Fauci AS, Kasper DL, et al, eds. New York, NY: McGraw-Hill, 2020. 7. Lee CH, Ishimori ML, Wallace DJ. Principles of therapy, local measures and NSAIDs. In: Wallace D, Hahn B, eds. Dubois’ Lupus Erythematosus and Related Syndromes. 9th Ed. Oxford: Elsevier, 2018;640–9. 8. Ghaussy NO, Sibbitt W Jr, Bankhurst AD, Qualls CR. Cigarette smoking and disease activity in systemic lupus erythematosus. J

Rheumatol 2003;30:1215–21. 9. Chasset F, Francès C, Barete S, et al. Influence of smoking on the efficacy of antimalarials in cutaneous lupus: a meta-analysis of the literature. J Am Acad Dermatol 2015;72:634–9. 10. Zonana-Nacach A, Barr SG, Magder LS, Petri M. Damage in systemic lupus erythematosus and its association with corticosteroids. Arthritis Rheum 2000;43:1801–8. 11. Velo-García A, Ntatsaki E, Isenberg D. The safety of pharmacological treatment options for lupus nephritis. Expert Opin Drug Saf 2016;13:1041–54. 12. Litrin I, Dvorkina O, Ginzler EM. Immunosuppressive Drug Therapy. In: Wallace D, Hahn B, eds. Dubois’ Lupus Erythematosus and Related Syndromes. 9th Edn. Oxford: Elsevier;689–701. 13. Aguiar R, Araujo C, Martins-Coelho G, Isenberg D. Use of Rituximab in Systemic Lupus Erythematosus: A Single Center Experience over 14 years. Arthritis Care Res 2017;69:257–62. 14. Gladman DD, Urowitz MB, Rahman P, et al. Accrual of organ damage over time in systemic lupus erythematous. J Rheumatol 2003;301:1955–9.

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Systemic lupus erythematosus: causes and manifestations