Recognition and management of systemic lupus erythematosus · ˜l Systemic lupus erythematosus 14 Prescriber March 2019 prescriber.co.u and divided lupus features into clinical and

Prescriber March 2019 ❚ 13prescriber.co.uk

DRUG REVIEW ■

Systemic lupus erythematosus (SLE) is a complex chronic autoimmune rheumatic disease with a broad spectrum of

clinical presentations encompassing almost all organs and systems. It most commonly affects younger women during their reproductive years. However, in Europeans, SLE is increasingly recognised after the age of 40 years.1 The disease is character-ised by the production of numerous antibodies to nuclear com-ponents resulting in the formation and deposition of immune complexes, which leads to tissue damage and inflammation.2

Primary care physicians often have to deal with the initial presentation of this systemic disease. Therefore, it is important to recognise the variability of presentations in order to expedite diagnosis, referral and treatment. There is no diagnostic test for SLE. A positive antinuclear antibody (ANA) test is invariably present in patients with SLE. A number of other autoantibod-ies are routinely measured either for diagnostic purposes or because their presence is strongly associated with particular clinical profiles. Thus, anti-dsDNA and anti-Sm antibodies are virtually diagnostic of SLE. In contrast, anti-Ro antibodies are linked to photosensitivity, concomitant Sjögren syndrome and the neonatal lupus syndrome. The latter syndrome consists of a facial rash, which disappears spontaneously, and a form of heart block, which can be detected from approximately week 22 of pregnancy. Therefore, pregnant patients with anti-Ro antibodies should be referred to a specialist obstetrician. Anti-phospholipid antibodies are linked to venous and arterial thrombosis and miscarriage. Anti-dsDNA antibodies, especially at high levels, are strongly linked to lupus nephritis. The precise diagnosis of SLE relies upon clinical judgment, which is invariably influenced by one of two sets of classifica-tion criteria. The revised criteria of the American College of Rheumatology (ACR) are shown in Table 1.3 To fulfil the SLE classification, four of these criteria need to be present, though not simultaneously. In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) proposed a new set of criteria

Recognition and management of systemic lupus erythematosus LILIANA R SANTOS, SERENA FASANO AND DAVID A ISENBERG

Early recognition of the signs and symptoms of systemic lupus erythematosus (SLE) is important in order to expedite diagnosis, referral and treatment. This article discusses the wide spectrum of clinical manifestations of SLE, the treatment options available and the GP’s role in management.

SPL

Figure 1. Bilateral malar erythema ‘butterfly rash’ typical of acute cutaneous lupus

■ DRUG REVIEW l Systemic lupus erythematosus

14 ❚ Prescriber March 2019 prescriber.co.uk

and divided lupus features into clinical and immunological (see Table 1).4 Again, four criteria must be present, with at least one each from these two groups of features. A key difference is that the SLICC criteria also recognise that histologically confirmed lupus nephritis may be a dominant feature, and in this situation allow for only three criteria to be present.

Patient groups most susceptible The aetiopathology of SLE remains unknown. It is clearly a multifactorial disease in which genetic, epigenetic, hormonal and environmental factors play important roles.5-6 These fac-tors lead to a break in immunological tolerance manifested by immune responses against endogenous nuclear antigens. The risk of developing SLE is increased about 20-fold in first-degree relatives of affected patients. The emergence of genome-wide association studies (GWAS) has improved our understanding of the disease, especially in terms of its genetic

susceptibility. More than 60 SLE-associated loci predisposing to disease susceptibility have been identified.7 The proposed genes participate in different immunological pathways, namely immune complex handling, B cell signalling, regulation of apop-tosis, and antigen processing and presentation. SLE risk may also be influenced by epigenetic effects. The most well studied type of epigenetic factor is DNA methylation, which has also provided important insights into the pathophysiology of SLE.7,8 Inhibiting DNA methylation in CD4+ T cells induces autoreactiv-ity, and these autoreactive cells promote B cell activation and consequent autoantibody production.7 Most recently, there is a growing body of evidence that the transcription factor enhanc-ers play important roles in triggering SLE disease activity via epigenetic mechanisms.8

Moreover, the interaction of hormonal and environmental factors modifies this genetic susceptibility and the clinical expression of the disease. For instance, approximately 90% of

1982 revised ACR criteria for classification of SLE3 SLICC classification system4

Clinical criteria Clinical criteria

Must meet 4 of 11 criteria • Malar rash• Discoid rash• Photosensitivity• Oral ulcers• Arthritis• Serositis: a) pleuritis; b) pericarditis• Renal disorder: a) proteinuria >0.5g/24h or 3+,

persistently; b) cellular cast• Neurological disorder: a) seizures; b) psychosis (excluding

other causes, eg drugs)• Haematological disorder: a) haemolytic anaemia with

reticulocytosis ; b) leukopenia or <4000/mm3 on 2 or more occasions); c) lymphopenia or <1500/mm3 on two or more occasions); d) thrombocytopenia (<100,000/mm3)

• Immunological disorders: a) positive lupus erythematous cell; b) raised anti-native DNA antibody binding; c) anti-Sm antibody; d) false-positive serological test for syphilis, present for at least six months

Must meet 4 criteria (including 1 clinical and 1 immunological)• Acute cutaneous lupus (1 or more of the following): a)

malar rash; b) bullous lupus; c) maculopapular rash; d) photosensitive rash

• Chronic cutaneous lupus (1 or more of the following): a) classic discoid (localised vs generalised); b) hypertrophic lupus; c) lupus panniculitis; d) mucosal lupus; e) lupus erythematous tumidus; f) chilblains lupus; g) discoid lupus/lichen planus overlap

• Oral or nasal ulcers• Non-scarring alopecia• Synovitis OR tendonitis: 2 or more joints; 1 morning

stiffness• Serositis: a) pleural; b) pericardial• Renal: a) urine protein-to-creatinine ratio with more than

500mg protein/24 h; b) red blood cell casts• Neurological disorder (1 or more of the following):

a) seizures; b) psychosis; c) mononeuritis multiplex; d) myelitis; e) neuropathy; f) acute confusional state

• Haematological disorder: a) haemolytic anaemia; b) leukopenia (<4000/mm3 at least once); c) lymphopenia (<1000/mm3 at least once); d) thrombocytopenia (<100,000/mm3)

Immunological criteria Immunological criteria

Abnormal titre of ANA a) ANA above reference range; b) anti-dsDNA above reference range; c) anti-Sm; d) antiphospholipid antibody positivity; e) low complement; f) direct Coombs (in absence of haemolytic anaemia)

Key: ANA = antinuclear antibody; dsDNA = double-stranded DNA

Table 1. Diagnostic criteria for systemic lupus erythematosus (SLE): 1982 revised American College of Rheumatology (ACR) criteria for the classification of SLE and the Systemic Lupus International Collaborating Clinics (SLICC) classification system3,4


Systemic lupus erythematosus l DRUG REVIEW ■

SLE patients are women and multiple studies have shown that oestrogens affect immune function. Environmental factors such as UV light, chemical agents, drugs and infection may function as triggers for SLE or lupus flare.9 One example in particular is the association between cigarette smoking and SLE incidence, with decreasing risk five years after stopping smoking.10

The underlying mechanism in SLE involves the failure of phagocytes to remove apoptotic material efficiently from dying cells. This failure leads to immune system activation following the unusual exposure of nuclear antigens to antigen-presenting cells and subsequent triggering of B and T cells. The disease is thus the consequence of the failure of cellular ‘waste disposal’. The final result is the production of pathogenic autoantibodies.9

Signs and symptomsSLE shows a wide spectrum of clinical manifestations and many patients initially develop only non-specific constitutional symptoms (eg fatigue, weight loss and fever). This heterogene-ity makes diagnosis, assessment and monitoring a challeng-ing process. The disease is also prone to relapses resulting in flares of disease activity, therefore the occurrence of new signs or symptoms must be carefully evaluated. The diversity and approximate cumulative prevalence of lupus features is shown in Figure 2. Lupus nephritis and central nervous system involvement are the major causes of morbidity and mortality rates in SLE.9

Mucocutaneous disease Cutaneous manifestations occur in most patients with SLE. The skin manifestations include lupus specific and lupus non-spe-cific lesions. The former is divided in acute, subacute or chronic lesions. A typical lesion of acute cutaneous lupus is the bilateral malar erythema with sparing of the nasolabial fold area (see Figure 1). This ‘butterfly rash’ is usually transient, photosensi-tive and resolves without scarring. Subacute cutaneous lupus may have a papulosquamous presentation or an annular aspect, often sparing the midfacial skin. The sides of the face, neck, upper chest, upper back, shoulders, and extensor surfaces of the arms are commonly involved.9 Discoid lupus erythematous (DLE) is the most common form. The discoid lesions are erythemato-sus plaques covered by adherent scales that extend into dilated hair follicles. Generalised DLE is the term used when lesions are present both above and below the neck.9

Non-specific cutaneous lesions include photosensitivity, cutaneous vasculitis, urticarial vasculitis, livedo reticularis, Raynaud’s phenomenon, periungual telangiectasias, erythema multiforme and calcinosis. Non-scarring alopecia, oral and nasal ulcers are included in the ACR and SLICC criteria for clas-sification of SLE. The recurrent crops of oral ulcers are usually painless.

Musculoskeletal manifestationsMusculoskeletal manifestations range from arthralgia and morning stiffness to arthritis. The most characteristic artic-ular manifestation of SLE is a non-deforming, non-erosive

and symmetrical arthritis, particularly affecting the hand and knee joints. These non-erosive, reducible joint subluxations are called Jaccoud’s arthropathy, which occurs in less than 5% of SLE patients. Deformities in the hands lead to ulnar drift at metacarpophalangeal joints, swan neck and Boutonniere deformities, and hyperextension at the interphalangeal joint of the thumb that closely resembles that seen in rheumatoid arthritis. A true erosive arthritis occurs in about 3–5% of SLE patients. The condition is sometimes referred to as ‘rhupus’.9

Radiologically <5% of patients with SLE have erosions, but evaluation by ultrasound reveals a broad spectrum of changes that also involve anatomic structures not recognised by X-rays, including entheses and tendons.11 Another important clinical concern is avascular necrosis, which can also cause joint pain and needs to be considered in patients on corticosteroids.

Renal manifestationsRenal involvement is the most important factor influencing prog-nosis in SLE. Lupus is known to affect all renal compartments including glomeruli, tubules, interstitium and blood vessels. The most widely used classification of lupus nephritis is the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification.12 This divides lupus nephritis into six main subtypes of which the most worrying are type III (focal proliferative disease), type IV (diffuse proliferative disease) and type V (membranous disease).9 For a detailed assessment and monitoring of renal disease activity, urinalysis (to look for both protein and blood) and urine sediment (to look for hyaline granular casts, leukocyte and/or erythrocyte casts and dysmorphic erythrocytes) are under-taken. A 24-hour collection to measure protein is less often used than previously as it is often incomplete and patients do not like carrying the required bottles when they have to travel long distances to hospital. In preference, the urine protein/creatinine ratio, based on a single sample given on arrival at the clinic, is now widely used. Renal biopsy performed under ultrasound is important, providing evidence for prognosis and the rationale for treatment. Hypertension in SLE patients is often a feature of renal dis-ease. It must be well controlled to help ensure a good outcome.9

Cardiac manifestationsThe heart is affected in around 30% of SLE patients and any part of the heart can be involved, notably the pericardium, myocar-dium, the conduction system, the valves and coronary arteries. Pericarditis is included in the ACR and SLICC diagnostic criteria for systemic lupus. Valvular pathology can occur in SLE. Libman-Sacks endocarditis most commonly affects the mitral valve. A high incidence of acute cardiovascular events is increas-ingly recognised as a cause of mortality. Female SLE patients between the ages of 35 and 44 years are 50 times more likely to have a myocardial infarction. This coronary disease is not fully explained by traditional risk factors;13 however, it is asso-ciated with several SLE-related risk factors including disease duration, disease activity and severity, autoantibody positivity



and exposure to drugs such as corticosteroids.12 Lipid control, hypertension control, exercise and smoking cessation are of prime importance.

Pulmonary manifestationsPulmonary manifestations of SLE include pleuritic, interstitial lung disease, shrinking lung syndrome, alveolar haemorrhage and thromboembolic disease. Chest pain, cough, shortness of breath and fever may all be presenting features of pleuritis, which is the most common pulmonary problem. Pleural effusion is usually bilateral and scanty but can be massive. As there are numerous other causes of pleural effusion, a thoracentesis is a helpful diagnostic tool. Pleural fluid in lupus pleuritis is exudative. Interstitial lung disease occurs in 3–13% of SLE patients.

The typical pattern on high-resolution computed tomography scan is of non-specific interstitial pneumonitis. Pulmonary function tests will show a restrictive pattern with a decreased diffusing capacity of the lungs for carbon monoxide (DLCO). Diffuse alveolar haemorrhage is a rare but life-threatening complication of SLE that can result from capillaritis. An acute decrease in haemoglobin in the presence of non-specific diffuse ground glass or patchy opacities on CT scan should prompt con-cern for haemorrhage. Bronchoscopy will show an increase in blood and hemosiderin-laden macrophages on serial aliquots.

Neuropsychiatric manifestationsNeuropsychiatric manifestations are included in the ACR and SLICC criteria for classification of SLE, with seizures and psy-chosis being well recognised.3,4 A working committee of the

Figure 2. Approximate cumulative prevalence of systemic lupus erythematosus (SLE) clinical manifestations

Dermatological Butterfly rash - 40%Maculopapular eruption - 35%Discoid lupus - 20%Relapsing nodular nonsuppurative panniculitis <5%

Dermatological (non-specific)Alopecia - 70%Vasculitic skin lesions - 40%Purpuric lesions - 40%Livedo reticulares - 20%

CardiopulmonaryPulmonary function abnormalities - 85%Shortness of breath - 40%Pleurisy - 35%Pleural effusion - 25%Cardiomegaly - 20%Pericarditis - 15%Cardiomyopathy - 10%Lupus pneumonitis - 5%Interstitial fibrosis - 5%Myocardial infarction - 5%

MusculoskeletalArthralgia/arthritis - 90%Myalgia - 50%Tenosynovitis - 20%Myositis - 5%

CerebralMigraine - 40%Seizures - 20%Depression - 10%Hemiplegia - 10%Cranial nerve lesions - 10%Cerebellar signs - 5%Psychosis - 2%Meningitis – 1%

RenalProteinuria - 60%Reduced 24-hour creatinine clearance - 35%Casts - 30%Serum albumin <35g/L - 30%Serum creatinine >25µmol/L - 30%Haematuria - 10%

GastrointestinalAnorexia - 40%Abdominal pain - 30%Hepatomegaly - 25%Nausea - 15%Splenomegaly - 10%Vomiting <10%Diarrhoea <10%Ascites < 10%

HaematologicalLymphopenia - 80%Anaemia of chronic disease - 75%Leukopenia - 60%Anaemia (iron-deficiency) - 30%Thrombocytopenia - 25%Autoimmune haemolytic anaemia - 15%Circulating anticoagulants - 15%



ACR provided the definition of 19 neuropsychiatric syndromes, divided into central, peripheral and autonomic components. It defined the diagnostic criteria and the workup to ascertain each neuropsychiatric feature; it also listed the exclusion criteria, aimed at excluding events not directly related to SLE. The fre-quency of neuropsychiatric SLE has been hard to define, due to variation in symptomatology, definition of disease, and difficulty in determining whether the disease is directly attributable to underlying lupus (see Figure 2). Several pathogenic mechanisms have been suggested, including cerebral vasculitis, the consequence of thrombosis linked to antiphospholipid antibodies, antibodies that bind directly to antigens in the CNS, and antibodies that cross react with elements in the nervous system. As an example of the last of these four mechanisms, some antibodies to DNA actu-ally recognise a peptide and the amino-acid sequence is also present in N-methyl-D-aspartate receptors in the amygdala and hippocampus. However, for an antibody mechanism to be viable there must also be a decrease in blood-brain barrier function to allow them access to the CNS.9

Cerebrovascular events are reported in 4.5% of patients with SLE, with strokes and transient ischaemic attacks (TIAs) being the most frequent types of cerebrovascular manifesta-tions.14

First- and second-line treatment optionsAims of SLE treatment include preventing organ damage and optimising health-related quality of life by controlling disease activity and minimising co-morbidities and drug toxicity, and therefore ensuring long-term survival.13 Non-adherence to treat-ment is a major cause of lupus flares. For appropriate man-agement, the disease activity can be broadly categorised as mild, moderate or severe. The main treatment options in SLE management are shown in Figure 3. Glucocorticoids remain the cornerstone of SLE treatment.

Mild diseaseThe term mild disease includes patients with stable disease without life-threatening organ involvement. Clinical manifesta-tions include fatigue, malar rash, diffuse alopecia, mouth ulcers and a platelet count of 50–149 x 109/L.1

In the treatment of mild SLE, the European League Against Rheumatism (EULAR) recommend that antimalarials and/or glucocorticoids are beneficial. Sunscreen is helpful in patients with skin manifestations, therefore the GP should encourage their utilisation.15 Hydroxychloroquine is known to have a central role in the long-term treatment of all SLE patients. The Lupus in Minority Populations: Nature versus Nurture (LUMINA) trial provided evi-dence of a decrease in flares and prolonged life in patients treated with hydroxychloroquine.16 The mechanism of action of antimalarials in SLE has not yet been entirely clarified. Hydroxychloroquine seems to induce the modulation of the innate immune response, increasing the lysosomal pH in macrophages and other antigen-presenting cells, thus inter-fering with endosomal toll-like receptor activation and with

antigen processing required to stimulate CD4+ T cells.9,17

Hydroxychloroquine has also shown favourable metabolic prop-erties in terms of glucose control and lipid levels, and may reduce thrombotic complications.18

It is compatible with preg-nancy and breast-feeding. Hydroxychloroquine is typically well tolerated at the rec-ommended dose of <5mg per kg real body weight to minimise toxicity.19 The most common side-effects are gastrointestinal disorders and skin rashes. Although rare, there is an increased risk of hydroxychloroquine retinopathy with increases in the cumulative dose. Hydroxychloroquine may cause retinal toxic-ity with visual changes or loss of vision.20 The risk of toxicity increases in those aged 60 years or older taking high doses for more than five years, or in those with renal disease or a pre-existing maculopathy, which is a contraindication to its use. Thus, an ophthalmology review at five years is generally recommended, and this screening should include dilated fun-dal examination and automated visual field testing. Whether screening is needed prior to/around the start of this therapy is not universally agreed. Although not licensed for SLE treatment, methotrexate 7.5–15mg per week can be used in order to control inflammatory arthritis and lupus skin rashes.1

Moderate diseasePatients with moderate disease have more serious manifes-tations including fever, lupus-related rash covering up to 2/9 body surface area, cutaneous vasculitis, alopecia with scale inflammation, arthritis, pleurisy, pericarditis, hepatitis and a platelet count of 25–49 x 109/L.1

In patients with moderate SLE or in patients not able to reduce steroids to below 10mg daily, immunosuppressive agents such as azathioprine, mycophenolate mofetil and methotrexate should be considered. A high cumulative dose of steroids is associated with side-effects such as cataracts, hypertension, osteoporosis, diabetes, infections and athero-sclerosis.9

Azathioprine (approximately 2–3mg/kg daily) is used for inducing disease remission in SLE patients with mucocutane-ous, serositis or haematological manifestations. It is also used as maintenance therapy after cyclophosphamide in severe SLE manifestations.21Azathioprine is a synthetic purine analogue that is rapidly metabolised in the liver and red blood cells to 6-mercaptopurine, which blocks intracellular purine synthesis resulting in a reduction in B and T cell activity. As a result, the most common side-effect of azathioprine is bone morrow suppression. Individuals who are homozygous or heterozygous for thiopurine S-methyltransferase (TPMT) polymorphisms may have an increased risk of severe myelotoxicity when receiving azathioprine. There is no general consensus as to whether determining TPMT activity is cost-effective. Some authors sug-gest that TPMT activity levels should be tested before azathio-prine is prescribed.22 Others believe that starting a thiopurine drug at a low dose and simply checking the blood count after a week could identify individuals who have very low or absent enzymatic activity (≤1%). However, more cost-effectiveness



studies are necessary.9 Other well recognised side-effects of azathioprine include nausea, vomiting, diarrhoea and abnormal liver enzymes.9

If allopurinol is being co-prescribed, the dose of azathioprine should be reduced by 50–75%. Allopurinol increases the blood levels of azathioprine by blocking the xanthine oxidase enzyme, which metabolises 6-mercaptopurine to inactive metabolites. Methotrexate is an antifolate drug that can inhibit enzymes involved in purine synthesis. It is used as a steroid-sparing agent or in non-responsive patients with arthritis and skin disease.1,9

Mycophenolate mofetil (2–3g daily) is metabolised in the liver to the active metabolite mycophenolic acid, which inhib-its inosine monophosphate dehydrogenase, the enzyme that controls the de novo pathway of purine synthesis, resulting in a reduction of B and T cell proliferation. It is used in cases of moderate to severe SLE, for inducing disease remission or as maintenance therapy after cyclophosphamide.

Severe diseaseSevere disease is defined as organ or life threatening and reflects the most serious form of systemic disease. Typical manifestations include rash involving more than 2/9 body surface area, myositis, severe pleurisy and/or pericarditis with effusion, ascites, enteritis, myelopathy, psychosis, acute confusion, optic neuritis and a platelet count <25 x 109/L.1

More prolonged steroid use and intensive immunosuppressive therapy is generally reserved for patients with involvement of vital organs. Cyclophosphamide is an alkylating agent that interferes with DNA integrity causing cell death in highly proliferative tissues (bone marrow, gastrointestinal tract and the reproductive sys-tem). It is often used in SLE patients with severe cerebral and renal involvement. Cyclophosphamide-based regimens have shown long-term efficacy in SLE nephritis,23,24 but this drug may cause infertility and bone marrow suppression. Encouragingly, the Euro-Lupus Nephritis trial reported that a shorter treatment protocol of six pulses of 500mg cyclophosphamide (each infu-sion two weeks apart) is as effective and safer than the stand-ard high-dose regimen in induction therapy of lupus nephritis25 and does not cause an increased risk of infertility. However, in short- and medium-term trials, mycophenolate mofetil has demonstrated at least similar efficacy compared with pulsed cyclophosphamide and has a more favourable tox-icity profile. In addition, mycophenolate mofetil seems to be more effective in African or Hispanic patients and in those with membranous glomerulonephritis. For maintenance treatment, mycophenolate mofetil has been shown to be superior to aza-thioprine in maintaining a renal response to treatment and in preventing relapse in patients with lupus nephritis who had a response to induction therapy.26 Maintenance therapy aims for the lowest glucocorticoid dosage needed to control disease. If an SLE patient does not respond to conventional immuno-suppressive drugs, there are biological drug options available.1 Belimumab (10mg/kg every four weeks), a monoclonal antibody that blocks a B cell activating factor known as BLyS, is the first targeted biological agent for SLE. Since 2012, it has been used for patients with antibody-positive SLE who have active skin and joint disease despite treatment with conventional drugs. Trials assessing its effectiveness in other lupus manifesta-tions are ongoing. In 2016, NICE recommended belimumab as an option as add-on treatment in active autoantibody-positive adult SLE patients with serological disease activity and a Safety of Estrogen in Lupus National Assessment - Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score of ≥10 despite standard treatment (TA397). In addition, off-label use of rituximab, a chimeric anti-CD20 monoclonal antibody that transiently depletes B cells, has also been recommended when conventional therapies have proved ineffective. Rituximab has been used for nearly 20 years and many open-label studies strongly support its clinical efficacy in inducing remission in SLE patients.27 Despite the encouraging results from non-randomised studies, the two double-blind trials that assessed the efficacy of rituximab in patients with active SLE (EXPLORER and LUNAR trials) failed to reach their primary endpoints.28,29 However, the concomitant use of high doses of glucocorticoids and immunosuppressive therapies used in both studies made it difficult to show any benefit for rituximab. Furthermore, the recently published EULAR and ACR recom-mendations on induction therapy in lupus nephritis support the off-label use of rituximab as a second-line regimen in SLE patients who are refractory to conventional immunosuppressive

Severe SLE(eg nephritis/platelet count <25 x 109/L)

Oral steroids (usually start with 40–60mg daily. Reduce rapidly)plusMycophenolate mofetil/IV cyclophosphamide/rituximab/belimumab (for skin and joint disease only in serologically active patients)

Moderate SLE(eg arthritis/pleuritis/pericarditis/platelet count 25–49 x 109/L)

Oral steroids (often start with 20–40mg dailyReduce to 5–7.5mg daily as soon as possible)plusImmunosuppressive drugs (eg azathioprine, methotrexate, mycophenolate mofetil)If the above do not work consider:• Rituximab • Belimumab (for skin and joint disease only in serologically

active patients)

Mild SLE(eg arthralgia/low-grade arthritis/minor skin rash/fatigue)

HydroxychloroquineNSAIDs (if renal function is normal)Local steroids

Figure 3. Management of mild, moderate and severe systemic lupus erythermatosus (SLE)



treatment.30,31 In 2016, NHS England approved the use of rituxi-mab for SLE. There is also increasing interest in the notion that rituximab followed by mycophenolate or azathioprine could be used at the time of lupus diagnosis, replacing oral steroids (which cause many side-effects) altogether. Unfortunately, a major clinical trial, RITUXILUP, which aimed to confirm the value of early B cell depletion, was stopped due to poor recruitment.

Drugs in developmentBiological agents targeting type I interferons (IFNs) are cur-rently in clinical trials. Sifalimumab met its endpoints in a pla-cebo-controlled phase 2B trial, as did anifrolumab, which blocks all types of type I IFNs and which is now in pivotal phase 3 tri-als. Rontalizumab, however, did not meet endpoints in a phase 2 trial, but exploratory analyses suggested improvements in some patient subgroups. These emerging data suggest that the therapeutic approach of type I IFN blockade holds promise. Blockade of other pathways, such as T cell co-stimulation, IL-6 and IFN alpha, have been shown to have efficacy in some SLE patients.32 Exciting new possibilities include atacicept, which blocks two B cell-activating factors (BlyS and APRIL). Among other approaches, the use of Fcγ II receptor blockers and blocking the JAK-STAT signalling pathway are being closely considered.

The GP’s role in management SLE is a heterogenous disease that can fluctuate in severity over time. Close links between primary and secondary care are essential in managing patients with SLE. The GP has a pivotal role in the recognition of disease manifestations/flares, monitoring disease activity and excluding other differential diag-noses. The GP also has a role in monitoring the toxicity and efficacy of immunosuppressive drugs, improving adherence to medication and in managing infections and vaccinations. In particular, live viral vaccines should be avoided in those on 10mg daily prednisolone or more, or in those taking immuno-suppressive drugs. Live attenuated vaccinations (eg herpes zoster) should be given before starting a disease-modifying antirheumatic drug (DMARD) or a biological agent. Inactivated vaccines (eg pneu-mococcal, influenza, hepatitis B) should be given based on age and risk. If the patient starts a biological drug, the vaccination schedule should be discussed with the consultant rheumatol-ogist.9 Guidance about vaccination changes regularly, so GPs are recommended to consult their local and/or national guid-ance when vaccinations are needed in immunocompromised patients. In the UK, the Green Book is very helpful and updated regularly by Public Health England. Patients with lupus benefit from a discussion about contra-ception and the challenges of pregnancy. This could be done by the GP or the local rheumatologist. Since oestrogen is clearly a factor in the development of lupus, low-dose or progesto-gen-only contraceptive pills are advisable to avoid pregnancy. Although controversial, most authorities agree that pregnancy in lupus patients is not often associated with flare of the condi-

tion provided the patient is well-controlled at the time of concep-tion. A particular concern is patients with active renal disease whose management during pregnancy demands careful moni-toring in secondary care. Some medications notably steroids, hydroxychloroquine and azathioprine are relatively safe to take during pregnancy but other immunosuppressives, notably meth-otrexate, mycophenolate and in particular cyclophosphamide, need to be avoided for a minimum of three months prior to conception. Long-term primary care providers deal with the responsibil-ity of coronary artery disease risk factor modification, diabetes and osteoporosis screening in patients with SLE. With regard to managing cardiovascular risk, the GP may also help in the promotion of lifestyle changes, the identification of additional atherosclerosis risk factors, and measuring and maintaining normal blood pressure, especially in those patients on long-term higher dose steroids and those with renal organ damage. Concerning vitamin D deficiency, recent evidence shows that vitamin D plays an important role in the pathogenesis and pro-gression of SLE. Moreover, vitamin D supplementation seems to ameliorate inflammatory and haemostatic markers and can improve clinical course.33

SLE has an impact on many aspects of patients’ health, so a multidisciplinary team including the GP, rheumatologist and other specialists must co-operate to optimise the follow-up of SLE patients.9

References1. Gordon C, et al. The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults. Rheumatology 2018;57(1):e1–e45.2. Rahman A, Isenberg A. Systemic lupus erythematosus. N Engl J Med 2008;358:929–39.3. Tan EM, et al. The 1982 revised criteria for the classification of sys-temic lupus erythematosus. Arthritis Rheum 1982;25:1271–7.4. Petri M, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64(8):2677–86.5. Mok CC, Lau CS. Pathogenesis of systemic lupus erythematosus. J Clin Pathol 2003;56(7):481–90.6. Wahren-Herlenius M, Domer T. Immunopathogenic mechanisms of systemic autoimmune disease. Lancet 2013;381:819–31.7. Niewold TB. Advances in lupus genetics. Curr Opin Rheumatol 2015;27(5):440–7.8. Weeding E, Sawalha AH. Deoxyribonucleic acid methylation in sys-temic lupus erythematosus: implications for future clinical practice. Front Immunol 2018;9:875.9. Fasano S, Isenberg D. Systemic lupus erythematosus and the role of the GP. Prescriber 2015;26(20):31–5.10. Speyer CB, Costenbader KH. Cigarette smoking and the patho-genesis of systemic lupus erythematosus. Expert Rev Clin Immunol 2018;14(6):481–7. 11. Ruano CA, et al. Ultrasound detects subclinical joint inflamma-tion in the hands and wrists of patients with systemic lupus ery-thematosus without musculoskeletal symptoms. Lupus Sci Med 2017;4(1):e000184. 12. Weening JJ, et al. The classification of glomerulonephritis in systemic lupus erytehmatosus revisited. J Am Soc Nephrol 2004;15(2):241–50.



13. Esdaile JM, et al. Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythemato-sus. Arthritis Rheum 2001;44(10):2331–7.14. Hanly JG, et al. Cerebrovascular events in systemic lupus erythe-matosus: results from an international inception cohort study. Arthritis Care Res 2018;70(10):1478–87.15. Bertsias G, et al. EULAR recommendations for the management of systemic lupus erythematosus. Report of a task force of the EULAR standing committee for international clinical studies including therapeu-tics. Ann Rheum Dis 2008;67(2):195–205.16. Alarcon GS, et al. Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (LUMINA L). Ann Rheum Dis 2007;66(9): 1168–72.17. Fox RI. Mechanism of action of hydroxychloroquine as an antirheu-matic drug. Semin Arthritis Rheum 1993;23(2, Suppl 1):82–91.18. Petri M. Hydroxychloroquine use in the Baltimore Lupus Cohort: effects on lipids, glucose and thrombosis. Lupus 1996;5(Suppl. 1):S16–S22.19. Jain S, et al. 2017 ACR/ARHP Annual Meeting Abstract Supplement. Arthritis Rheumatol 2017;69(Suppl 10):1–4426.20. Marmor MF, et al. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology 2011;118(2):415–22.21. Abu-Shakra M, Shoenfeld Y. Azathioprine therapy for patients with systemic lupus erythematosus. Lupus 2001;10(3):152–3.22. Gauba V, et al. Thiopurine methyltransferase screening before aza-thioprine therapy. Br J Ophthalmol 2006;90(7):923–4.23. Boumpas DT, et al. Controlled trial of pulse methylprednisolone ver-sus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 1992;340(8822):741–5.24. Contreras G, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004;350:971–80.25. Appel GB, et al. Mycophenolate mofetil versus cyclophospha-mide for induction treatment of lupus nephritis. J Am Soc Nephrol 2009;20(5):1103–12.26. Dooley MA, et al. Mycophenolate versus azathioprine as main-tenance therapy for lupus nephritis. N Engl J Med 2011;365(20): 1886–95.27. Murray E, Perry M. Off-label use of rituximab in systemic lupus ery-thematosus: a systematic review. Clin Rheumatol 2010;29(7):707–16.28. Merrill JT, et al. Efficacy and safety of rituximab in moderate-ly-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 2010;62(1):222–33.29. Rovin BH, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 2012;64(4):1215–26.30. Hahn BH, et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res 2012;64(6):797–808.31. Bertsias GK, et al. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the man-agement of adult and paediatric lupus nephritis. Ann Rheum Dis 2012;71(11):1771–82.32. Fattah Z, Isenberg DA. Recent developments in the treatment of patients with systemic lupus erythematosus: focusing on biologic ther-apies. Expert Opin Biol Ther 2014;14(3):311–26.33. Hassanalilou T, et al. Role of vitamin D deficiency in systemic lupus erythematosus incidence and aggravation. Autoimmunity Highlights

2018;9:1. DOI: https://doi.org/10.1007/s13317-017-0101-x

Declaration of interestsProfessor Isenberg is supported by the National Institutes of Health Research, University College London Hospital, Biomedical Research Centre.

Liliana R Santos is an Internal Medicine Registrar at Santa Maria Hospital – CHLN, Lisbon, Portugal; Serena Fasano is a Rheumatology Consultant at the University of Campania ‘Luigi Vanvitelli’, Naples, Italy; and David A Isenberg is Professor of Rheumatology at the Centre for Rheumatology, Division of Medicine, University College London

Documents

Recognition and management of systemic lupus erythematosus · ˜l Systemic lupus erythematosus 14 Prescriber March 2019 prescriber.co.u and divided lupus features into clinical and