Systemic lupus erythematosus (SLE) is a complex autoimmune-mediated connective tissue disease that affects multiple organs and body systems (Petri et al, 2012; Gouliemos et al, 2018; Basta et al, 2020). Its aetiology remains unclear however environmental factors, immune system dysregulation and viral susceptibility may be possible triggers (Mantovani Cardoso et al, 2020; Oliver, 2020). SLE is characterised by the production of a range of autoantibodies with associated immune complex formation and deposition. Inflammation ensues, resulting in tissue and eventually organ damage (Lam and Petri, 2005). Its onset can be insidious with diverse clinical presentations such as arthritis, skin lesions, Raynaud's phenomenon, alopecia, fatigue, cognitive impairment and nephritis (Murphy and Isenberg, 2013). The clinical course of the disease is variable and unpredictable between individuals, with episodic flares and remissions (Bertsias et al, 2013).
The incidence and prevalence of SLE varies worldwide. In 2017, North America had the highest reported estimates of incidence (23.2 per 100 000) and prevalence (241 per 100 000), with people of African ancestry having the highest incidence and prevalence of the disease compared with Caucasians, who had the lowest (Rees et al, 2017). Between 1973 and 2006 incidence rates in the Asia-Pacific region were recorded as being between 0.9 and 3.1 with prevalence rates ranging from 4.3 to 45.3 per 100 000 (Jakes et al, 2012). Arab Americans were found to have higher incidence rates compared with African Americans and non-Arab Caucasians (Housey et al, 2015). In the UK, Rees et al (2016) found a decline in SLE incidence between 1999 and 2012 of 1.8%, but reported an increase in prevalence from 64.9 to 97.04 per 100 000 within the same time frame.
SLE affects females of childbearing age more than age-matched males, with a female to male ratio ranging between 8:1 and 15:1 (Lu et al, 2010). This female predominance could be attributed to female sex hormones triggering the autoimmune system in a genetically predisposed individual, resulting in the modification and survival of reactive B cells (Renau and Isenberg, 2012). Although these factors are relevant to the pathology of SLE, hormonal factors alone are most likely insufficient to identify the source of the disease (Lu et al, 2010). Genetic studies report 25% monozygotic twin concordance compared with 2% concordance in dizygotic twins, proving a link between genetic susceptibility and pathogenesis (Sullivan, 2000). Variations between phenotypes are seen between the sexes. Cardiovascular comorbidities, renal involvement and pulmonary fibrosis manifest more in men (Riveros Frutos et al, 2017), while mucocutaneous and musculoskeletal symptoms are more common in women (Murphy and Isenberg, 2013).
Despite major advances in SLE treatments and medication regimens, mortality rates remain high compared with the general population. It is well documented that cardiovascular comorbidities from accelerated atherosclerosis lead to high rates of myocardial infarction and stroke in SLE patients (Manzi et al, 1997; Bessant et al, 2004; Hak et al, 2009; Santos et al, 2012). Strikingly, premenopausal female patients have a 50-fold increased risk of a major cardiovascular event compared with sex- and age-matched controls (Manzi et al, 1997; 1999).
SLE patients also have a higher risk of developing liver, lung and thyroid malignancies, and non-Hodgkin's lymphoma (Thong and Olsen, 2017). Along with infection due to long-term immunosuppression, lupus nephritis also remains a major cause of death for these patients, with a 4.7 increase in mortality for SLE patients with renal disease (Lee et al, 2016; Stojan and Petri, 2018).
Clinical assessment
Due to the complexity and heterogeneity of the disease, SLE demands a meticulous history, extensive physical examination and specific laboratory assessments. Common constitutional symptoms include fever, malaise, myalgia and fatigue, which can also be attributable to other autoimmune diseases, infections or malignancy, so diligence is required to rule out possible differentials. Up to 90% of patients will suffer from musculoskeletal involvement (Kuhn et al, 2015). The most commonly occurring joint manifestations are symmetrical non-erosive arthritis and arthralgia typically affecting, but not limited to, the small joints of the hands and wrists (Lam and Petri, 2005). This joint destruction in the absence of erosive disease is termed Jaccoud arthropathy (Kuhn et al, 2015). A full joint examination should be undertaken, observing the functional movement or limitation of each joint, palpating for tenderness, and noting swelling or bogginess along joint margins.
Assessment of the patient's skin is paramount. A malar rash is the most widely recognised skin lesion in SLE patients. Most commonly known as the ‘butterfly rash’, it occurs on the face in a butterfly distribution across the cheeks sparing the nasal folds and is usually triggered by sun exposure. Cutaneous lupus is a distinct entity and a subtype of SLE (Figure 1). It occurs in up to 85% of patients and can be classified into acute, subacute and chronic (Thong and Olsen, 2017). In the acute phase, skin manifestations present as erythematosus papules, which develop into papulosquamous or annular lesions. Chronic cutaneous lupus lesions present as erythematous papules in discoid form. These often become hyperkeratotic with scarring and associated atrophy, causing alopecia if there are lesions present on the scalp (Lam and Petri, 2005; Kuhn et al, 2015). Oral and genital ulcerations can be present and quite distressing for patients. Other skin manifestations include bullous lesions, telangiectasia, urticaria, panniculitis and Raynaud's phenomenon (Lam and Petri, 2005).
Around half of SLE patients will develop renal involvement (Bertsias et al, 2012). Lupus nephritis is a glomerular nephritis diagnosed mainly by proteinuria, increased levels of serum creatinine, haematuria and/or pyuria (Lam and Petri, 2005; Kuhn et al, 2015). Dipstick urinalysis is a cost-effective test to detect proteinuria or haematuria with an immediate result. It can also show the presence of infection. Renal biopsy is helpful and definitive in ascertaining degree of involvement and classification of disease, and assists clinicians in treatment choices. Urine sent for protein–creatinine ratio can offer a more detailed assessment of renal function. A 24-hour urine collection to examine protein and creatinine clearance can also be helpful, but depends on patient compliance for collection.
Neurologic manifestations such as headache, anxiety and depression occur in 15-50% of patients and are often non-specific and difficult to assess (Kuhn et al, 2015). Other signs of central nervous system involvement include seizures, stroke, transverse myelitis and peripheral neuropathy. Psychiatric symptoms can involve psychosis and cognitive dysfunction. Diagnosis of neurological involvement can be aided by magnetic resonance imaging or cerebrospinal fluid assessment via a spinal tap.
Assessment of gastrointestinal symptoms should be undertaken to check for oral ulceration, dyspepsia, inflammatory bowel disease, anorexia/weight loss or oesophageal dysmotility (Wheeler, 2010). Serositis, an inflammation of the pleura, peritoneum or pericardium, is a common manifestation in SLE, along with gastrointestinal complications. Assessment for pleural effusions must be carried out if the patient describes pleuritic-type chest pain. The clinician will listen for a pleural friction rub, or decreased breath sounds on auscultation, or dullness on percussion. Pericarditis can be diagnosed by electrocardiogram or by hearing a pericardial rub on auscultation. An echocardiogram can be ordered if there is a clinical suspicion of pericardial effusion.
Other respiratory complications include fibrosis, pneumonitis and pulmonary hypertension. If antiphospholipid antibodies are present in the blood it may predispose the patient to thromboemboli, therefore one must suspect pulmonary embolus if a patient presents with acute dyspnoea. Infection or viral illness should be ruled out where patients present with pyrexia, cough or dyspnoea. Chest radiography, bronchiolar lavage and pulmonary function tests can aid the physician if there is clinical suspicion of lung manifestations.
Laboratory findings
Circulating autoantibodies are the main serologic feature of SLE. More than 200 autoantibodies have been linked with the disease (Choi and Fritzler, 2019), but the most commonly tested are: antinuclear antibodies (ANA), anti-Sm antibodies, anti-RNP, double-stranded DNA, antiphospholipid antibodies, anti-Ro/SSA and anti-La/SSB. ANA positivity is present in up to 95% of SLE patients (Azevedo et al, 2014), but also in 26% of the general population (Raj et al, 2013).
ANA titre does not correlate with disease activity and its power as a prognostic or predictive indicator is limited (Kuhn et al, 2015; Thong and Olsen, 2017). Some studies claim the predictive power of ANA positivity can be increased if testing is performed in conjunction with other biomarkers, such as ‘interferon signatures’, as part of an autoimmune patient profile (Li et al, 2010; Arriens et al, 2017). Production of autoantibodies leads to the formation and deposition of immune complexes that activate the complement system. The complement cascade comprises 20 proteins that defend against infection and clear damaged cells from the host but, when triggered, can promote inflammation and cause injury (Robinson et al, 2011). C3 and C4 are the most commonly tested complement proteins and a blood test should be undertaken to monitor SLE disease activity.
Complete blood counts are important at presentation and have a valued role in disease monitoring and identification of complications. Anaemia of chronic disease and haemolytic anaemia can be common findings. Other haematologic abnormalities include leukopenia, lymphopenia and thrombocytopenia. These can be as a result of medication side-effects or, again, due to autoantibodies against cell surface antigens. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) tests may be helpful. A high ESR may be indicative of active disease, whereas CRP is usually only marginally elevated in the absence of serositis or inflammatory arthritis (Kuhn et al, 2015).
Classification criteria
Criteria for the classification of SLE published by the Systemic Lupus International Collaborating Clinics (Petri et al, 2012)—known as the SLICC criteria—improved on prior criteria by including skin lesions, neuropsychiatric manifestations, and serology in the calculation. The working group declared histology-confirmed nephritis, compatible with the disease, sufficient to meet the criteria if serology was positive.
In 2019, the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) updated and revised the 2012 criteria to enable classification of patients with early disease and include expert consensus in the methodological recommendations. These criteria, when tested in their validation cohort, achieved 96.1% sensitivity and 93.4% specificity (Aringer et al, 2019).
Treatment
The EULAR treatment guidelines for SLE published in 2008 achieved widespread acceptance and clinical support at that time (Bertsias et al, 2008). Since then, many studies have been published on new management strategies, new goals of treatment and alternative steroid-sparing agents, prompting EULAR to call for a revision. The 2019 EULAR update of recommendations for the management of SLE offers a more comprehensive overview of treatment and discusses immunosuppressive treatments with biological medications for each manifestation (Fanouriakis et al, 2019). This guideline proposes four overarching principles and 33 recommendations categorised into four themes: the goals of treatment, treatment, manifestations, and comorbidities. Treatments should be aimed at reducing flares, achieving and maintaining remission, symptom relief, and is dependent on the system or organs affected.
According to Fanouriakis et al (2019), irrespective of phenotype, hydroxychloroquine (HCQ) should be considered in every patient unless contraindicated. It is effective in maintaining remission and reduces flares (Ruiz-Irastorza and Khamashta, 2008). Female SLE patients are advised to continue its use in pregnancy; research has shown that HCQ prevents neonatal heart block in infants of mothers with SLE who test positive for Ro/SSA and La/SSB antibodies. Clinicians must ensure that patients undertake regular ophthalmological examinations if on long-term HCQ treatment because there is a risk of retinal toxicity, resulting in irreversible bull's-eye maculopathy. Therapeutic benefit can take up to 6 months, so some patients may require additional oral anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (NSAIDs) or oral glucocorticoids.
Oral glucocorticoids are often used to treat a disease flare. They are potent anti-inflammatory agents, and should be used only if clinically indicated and prescribed at the lowest dose to achieve maximum effect for the shortest period. Long-term use of glucocorticoids increases the risk of infections, cardiovascular events, osteoporosis, weight gain and glaucoma (Cowan, 2018), so clinicians must use careful clinical judgement in the dose and duration of prescriptions. Glucocorticoids are also prescribed to treat skin manifestations in SLE. Where patients are unable to wean off steroids, immunosuppressive treatments such as methotrexate, azathioprine, cyclosporine or mycophenolate mofetil are recommended (Fanouriakis et al, 2019).
Rituximab, an anti-CD20 monoclonal antibody, and belimumab, an anti-BAFF [B-cell activating factor] monoclonal antibody, are B-cell-targeted biologic medications currently used in clinical practice in the treatment of SLE (Murphy and Isenberg, 2019). EULAR recommends the use of rituximab in patients with refractory or organ-threatening disease (Fanouriakis et al, 2019). Currently, in both Ireland and the UK, rituximab is available only off-label to treat SLE and is therefore used in patients with refractory disease, at the discretion of the specialist clinician (Fanouriakis et al, 2019; NHS England, 2020).
More recently, calcineurin inhibitors (voclosporin) and other biologic medications targeting CD19, the interferon pathway, interleukins and the JAK-STAT signalling pathway have shown promising results in recent studies, having met end points in phase II and III clinical trials (Murphy and Isenberg, 2020). JAK inhibitors are currently used widely in rheumatology in the treatment of rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, and could offer another option for treating SLE.
Management
Patient education is paramount for SLE patients to enable self-management. Educated patients are better equipped with problem-solving and decision-making skills, and are more active in self-care. The management of SLE should be based on a shared decision-making process between the informed patient and their physician/nurse (van Vollenhoven et al, 2014). Holistic care of the patient commands an awareness of their needs. SLE patients' most desired outcomes include flare reduction, resumption of normal work and social activities, reduction of pharmacological side-effects, maintaining emotional wellbeing and prevention of organ damage (McElhone et al, 2010; Ng et al, 2018).
Review by a rheumatology specialist nurse to educate patients on their disease, medications, prognosis, and to offer continued support, is vital in achieving patient-desired outcomes. Specialist nurses at a minimum can improve patient wellbeing by merely taking the time to listen to their fears and concerns, try to understand the impact of SLE from a psychological and psychosocial perspective, and guide patients towards self-help groups or counsellors to help with coping strategies. Regular disease assessment and routine monitoring can be done by specialist trained nurses expert in multi-system examination. When monitoring disease activity, nurses must be alert to adverse drug effects, disease complications and for the presence of comorbidities.
Several disease assessment tools have been published to help researchers classify responses to medications in clinical trials and to aid disease monitoring in the clinical setting. The British Isles Lupus Assessment Group (BILAG) 2004 index (Isenberg et al, 2005) is a comprehensive tool that takes nine organ systems into consideration. Items are scored through subjective assessment and objectively through laboratory findings (Murphy and Isenberg, 2019). Results are graded alphabetically A to E, depending on extent of disease activity on the basis of a physician's intention to treat (Yee et al, 2010). Other composite measurement tools include the SLE Disease Activity Index 2000 (SLEDAI 2K), the Systemic Lupus Activity Measure (SLAM) and the European Consensus Lupus Activity Measurements (ECLAM) (Ward et al, 2000; Romero-Diaz et al, 2011). It is advisable to use the same standardised tool at each visit to enable accurate assessment of disease activity over time.
Health promotion is crucial to any management programme. Vaccination advice, particularly against influenza, pneumococci and COVID-19, should be given to all SLE patients, with particular attention to infusion schedules in the case of patients taking rituximab. They should be advised against live vaccinations (if receiving second-line immunosuppression treatment) (O'Neill and Isenberg, 2006), to stop smoking, and to wear protective clothing and apply sun protection factor 50 and higher. Supplementation with vitamin D might be necessary due to the lack of sun exposure and may be beneficial to disease outcomes. Those who have had treatment with glucocorticoids should be educated on bone health and fracture prevention strategies.
Patients who suffer oral ulcers should be advised to maintain good oral hygiene, and use mouthwash and lip balms frequently. Dietary intervention, such as regular snacking and taking softer food during oral flares, can help alleviate painful chewing. Triggers for Raynaud's phenomenon should be identified and advice given in relieving symptoms, such as wearing gloves and using heat packs. Alopecia or receding hairlines can be traumatic for the individual. Psychological support may be necessary for these patients and the clinician should explore the options of scarfs, hats or a wig to help patients feel less self-conscious.
SLE patients who engage in regular exercise find an improvement in fatigue levels, sleeping patterns and general wellbeing (Ayán and Martín, 2007; Larsen et al, 2018). Tailored exercise programmes delivered by a physiotherapist who can pace and grade activities might be necessary for patients with complex comorbidities or respiratory complications. Recognition of hypertension in SLE patients is vital to identify the risk of stroke, coronary disease and heart failure, so regular blood pressure measurement, and weight and cholesterol monitoring should be performed.
Repeated flares and frequent hospital/general practice visits can have a negative impact on a patient's quality of life. Restrictions on family planning and complications during pregnancy can also have a huge impact on patients and their partner's emotional and psychological wellbeing. All women of childbearing age should therefore be offered reproductive counselling. Antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin antibodies and anti-beta 2 glycoprotein 1) are present in 30-40% of patients and should be measured, especially if a thromboembolic event or pregnancy loss is reported. Teratogenic medications should be discontinued if patients express a desire to conceive. Conception is recommended after 6 months of disease quiescence to improve foetal and maternal outcomes (Thong and Olsen, 2017). Maternal anti-Ro and anti-La antibodies should also be checked to mitigate the risk of neonatal lupus and congenital heart block in the newborn. Flares of the disease can occur at any time during pregnancy and can mimic the symptoms of pre-eclampsia, so all pregnancies in women with SLE require close observation from the rheumatologist and the obstetric team.
SLE and COVID-19
COVID-19 is a systemic infectious disease, primarily of the respiratory system caused by the SARS-CoV-2 virus, which was classified as a global pandemic by the World Health Organization in March 2020 (Cucinotta and Vanelli, 2020). Initial reports demonstrated high morbidity in older adults with co-existing illnesses (Colaneri et al, 2020). Reassuringly, there appears to be little correlation between the incidence of many underlying autoimmune diseases and severe complications, including mortality associated with COVID-19 (Horisberger et al, 2020).
Due to the use of immunosuppressant therapies, hypercoagulability and SLE-related organ damage, SLE patients (more so black and Asian individuals) are considered a vulnerable cohort for COVID-19 infection (Mason et al, 2020; Spihlman et al, 2020). Some case studies have reported a possible increase in morbidity, albeit low, in some SLE patient cohorts, possibly due to pre-existing risk factors such as long-term glucocorticoid exposure and pre-existing respiratory disease (Ramirez et al, 2020; Wallace et al, 2021). Data collected by the COVID-19 Global Rheumatology Alliance (C19-GRA) demonstrated that rheumatic patients taking prednisolone 10 mg a day or higher were at increased risk of hospitalisation due to COVID-19 (Gianfrancesco et al, 2020).
The pandemic has had a substantial impact on SLE patients. As a result of numerous lockdowns, many could only be reviewed virtually or by phone. Those who required face-to-face review were often anxious and reluctant to attend a hospital where COVID-19 patients were managed. This, coupled with an imposed restriction on outdoor activities for many, resulted in an increase in psychosocial stressors (Rathi et al, 2021). Compliance with additional public health advice, such as cocooning and social distancing, is vital for SLE patients as COVID-19 continues. Treatment advice for SLE patients during the pandemic was to continue their usual medications, unless advised otherwise by their rheumatology team.
Due to the rapidly infectious nature of COVID-19 and the public health need to report data urgently, study designs involving high-quality randomised controlled trials in SLE patients are lacking. HCQ, the gold standard treatment for SLE, was initially proposed as a treatment for COVID-19 based on its antiviral mechanisms (Sinha and Balayla, 2020), however studies examining efficacy and potential prophylactic properties have yielded varying results (Jorge, 2021; Joshi et al, 2021; Kashour et al, 2021; Kumar et al, 2021).
Rituximab, due to its method of action, can compromise vaccine efficacy while potentially increasing the risk of infection. Recent evidence that has emerged suggesting that rituximab is an independent risk factor for COVID-19 severity (Avouac et al, 2021). ACR, EULAR and the National Institute for Health and Care Excellence (NICE) have advised clinicians to consider disrupting or prolonging treatment schedules to mitigate infection risk and allow for B-cell re-population in individuals prior to vaccination in the absence of life-threatening disease (Landewé et al, 2020; NICE, 2021; Curtis et al, 2021). As a consequence, some SLE patients required maintenance glucocorticoid dosing to control flaring disease, potentially increasing infection risk. These patients required education regarding the timing of COVID-19 vaccination and B-cell depletion/re-population kinetics and extra support to maintain disease control, while waiting for vaccination. Evidence has been published suggesting that delaying rituximab treatment in other B-cell driven diseases could be more harmful in the long term (Baker et al, 2020a; 2020b; Giovannoni, 2020).
Conclusion
SLE is a multifactorial complex disease. Patients require multidisciplinary input to achieve disease control and maintain quality of life. When diagnosed early and offered the education and support they require many patients are able to self-manage. As time progresses understanding of the disease improves among clinicians. For those whose disease is refractory many new treatment options are finally on the horizon, such as calcineurin inhibitors, anti-CD19/CD20 humanised monoclonal antibodies, interleukin targeted-agents and JAK inhibitors.
KEY POINTS
- Systemic lupus erythematosus (SLE) is a complex disease with varying manifestations, comorbidities and treatments
- Initial assessment should be done by a trained clinician expert in history taking and advanced physical examination
- Disease monitoring should be done by a trained clinician and involve the use of a disease-specific assessment tool at each visit to observe disease progression over time
- Medications to treat SLE can predispose patients to contracting infections and viruses, including COVID-19
CPD reflective questions
- Can systemic lupus erythematosus (SLE) disease-specific assessment criteria generated to aid classification in clinical trials be used in clinical practice with confidence?
- How can nurses improve on SLE patient education?
- Should rheumatology centres have a combined rheumatology–cardiology clinic to manage cardiovascular risk in premenopausal females?