IntroductionAlthough rare, juvenile-onset lupus (JSLE) causes significant morbidity and even mortality in children. It is a complex illness. It can present with such a variety of symptoms and signs that it can mimic many common paediatric conditions. This means diagnosis is often difficult to make and there are frequently significant delays in attaining specialist care. Much is inferred about the disease from adultonset lupus. However, children are not mini-adults - their normal growth, development and evolving immune system affect the disease presentation and complicate its diagnosis and management.
What is so special about JSLE?• Severity of the disease - JSLE has a more severe disease presentation than lupus in adults, with a higher incidence of major organ involvement and a more aggressive course. Paediatric patients are more likely to die in the acute phase of the illness compared to adults who more commonly die of disease complications. However, JSLE patients will also have longer disease duration than their adult counterparts and so have a higher chance of developing complications.
• Additional management challenges - Longer exposure time and reexposure to carcinogenic or gonadal-toxic agents are of particular importance to patients with JSLE. Handling and bioavailability of potent immune-modulating drugs differs between adults and children. Side effects of drugs used in the management of JSLE can be particularly problematic in adolescents with JSLE. JSLE can have a dramatic impact on a child’s education, social development and, indeed, their whole family.
How common is JSLE?• There are no robust incident data for JSLE in the UK. Data from different ethnic populations from around the world put the incidence between 0.5 and 6 per 100,000.
• Approximately 15-20% of patients with lupus will present in childhood or adolescence.
• The female predominance of lupus found in adults is less apparent in JSLE. While the overall female to male ratio in JSLE is approximately 4.5:1, this difference is even less marked pre-pubertally.
• Children of any age can develop JSLE, although it is extremely rare before the age of 5 years.
Challenges of diagnosing JSLE• Clinical manifestations of JSLE are extremely variable, from a relatively mild disease characterised by facial rash, joint pains and fatigue to a severe life threatening illness.
• These non-specific features, that could underlie a myriad of paediatric conditions, can make it a major diagnostic conundrum. Knowledge and experience of the spectrum of paediatric and adolescent disease is important as well as recognition of when features merit further investigation.
• Some symptoms of JSLE may present a long time before other symptoms. Patients may have already been diagnosed with another condition such as chronic fatigue, juvenile idiopathic arthritis, and idiopathic thrombocytopenia. Only careful monitoring and re-evaluation will enable the diagnosis of JSLE to be made.
• Although the diagnostic criteria used in JSLE are the same as those used in adult-onset lupus, they must be used with caution in JSLE to avoid over- or under-diagnosis.
What features could indicate JSLE?• Constitutional – Tiredness, fatigue, lethargy and malaise are very common in JSLE. An associated anaemia may be contributory. Fever and anorexia are typically present while poor weight gain and delayed growth suggest long standing illness.
• Cutaneous manifestations – The characteristic facial butterfly rash is present in only about half of patients with JSLE and even then may not be diagnostic. It is often faint and typically spares the naso-labial folds. Sun exposure can, but does not always, precipitate systemic and cutaneous features of JSLE. Unlike adult-onset disease, discoid lupus is very unusual in JSLE. Raynaud’s phenomenon, nailfold capillary abnormalities and livedo reticularis are all common and may precede other manifestations of lupus. While raising the clinician’s suspicion of JSLE they are not diagnostic. A patient with JSLE often complains of hair thinning when brushing or clumps of hair on their pillow in the morning.
• Musculoskeletal – Arthritis and arthralgia occur in approximately two thirds of patients at presentation. Symptoms, often symmetrical involving the small joints of the hands, can be transient and fluctuating with minimal objective signs on examination. Any joint may be affected. Myalgia and myositis do occur, typically in the acute sick patient, and raise the possibility of a mixed connective tissue disorder.
Major organ involvementThis must be actively sought and excluded. Renal, neuropsychiatric and haematological involvement occurs more frequently in JSLE.
• Neuropsychiatric lupus, a cause of debilitating long term morbidity in JSLE, can be very difficult to diagnose and can manifest in a vast range of presentations including headache, depression, severe anxiety, aseptic meningitis, seizures, psychosis, visual disturbance or visual loss.
• Nephritis is much more common at diagnosis in JSLE than in adults. Proteinuria in an early morning urine or mild hypertension may be the only initial manifestations of significant renal involvement. However, patients may also present with severe hypertension, nephritic syndrome or acute renal failure.
• As with adult-onset lupus, JSLE can affect any organ system in many different ways. Cardiopulmonary manifestations are increasingly recognised in JSLE.
Making a diagnosis of JSLE• The diagnosis is made from a constellation of clinical and laboratory features.
• A low index of suspicion must be maintained, particularly in a patient with varying signs and symptoms affecting several organ systems, who is not responding to usual therapies, is clinically deteriorating or in whom constitutional symptoms are prevalent.
What investigations should be carried out if JSLE is suspected?In any child who is acutely ill in whom JSLE is suspected, an emergency referral to hospital should be made to a paediatric rheumatologist or experienced paediatrician for multi-system investigation and assessment.
In a child less acutely ill, a number of investigations may be very helpful in accumulating diagnostic evidence but should not delay referral if clinically indicated. They can also be useful in monitoring disease activity. All of these tests and more would be carried out during comprehensive assessment.
• Haematology – Anaemia is common and a Coomb’s positive haemolytic anaemia and thrombocytopenia are twice as common in JSLE. Lymphocytopenia is very common and can help in monitoring disease activity.
• Acute phase proteins - Disparity in these can help in assessing disease activity reflected in a high ESR and low CRP. Elevated CRP should raise concern of inter-current infection. Both these bio-markers may be raised for other reasons which should also be considered.
• Autoantibodies – Antinuclear antibodies (ANA), the hallmark of adult lupus, are also present in JSLE but are non-specific. They must be interpreted in the context of clinical features. It is very rare that ANAs are negative in JSLE although they may be so early on in the disease presentation. There are a wide spectrum of encapsulated nuclear antibodies (ENAs) that may be present in JSLE including anti-double stranded DNA (dsDNA) and anti-Sm antibodies. The titre of anti-dsDNA antibodies is helpful in monitoring disease activity.
• Complement – C4 and particularly C3 levels are often low in active JSLE and, therefore, routinely measured.
• Renal function and urinalysis – Blood pressure measurement and urinalysis are important in the assessment of all children with suspected JSLE. Proteinuria, haematuria or cellular casts should be followed up with an early morning urine albumin-creatinine ratio. Normal renal function does not preclude active lupus nephritis.
Interpretation of investigations and differential diagnoses• As with adult-onset disease, there is no one diagnostic test for JSLE. All routine tests to aid the diagnosis (and long term monitoring of disease activity) are non-specific. They must be interpreted in the context of the clinical features and other bio-markers.
• The differential diagnosis of JSLE is extensive and includes infection, malignant disease, other auto-inflammatory conditions and any specific organassociated disease. The ability to diagnose JSLE correctly, particularly in the adolescent, may be very challenging and require great clinical acumen.
Appropriate speed and referral pathway• All children who are systemically unwell, have signs of major organ involvement, are clinically deteriorating or are not responding to existing therapy should be referred as an emergency for further investigation and assessment.
• Any child suspected of having JSLE should be discussed with or referred to a paediatrician or paediatric rheumatologist as soon as possible.
Access of specialist services – ARMA Guidelines• Early diagnosis and access to specialist services can significantly improve outcome and reduce the risk of life-threatening events. Patients, unfortunately, frequently attend numerous appointments and specialists before a diagnosis is finally made.
• Recently published ARMA guidelines stipulate that GPs should have access to specialist units where assessment can be made by a multi-disciplinary team led by a paediatric rheumatologist. Each local District General Hospital should have a nominated paediatrician with knowledge of JSLE, access to and regular communication with regional specialist centres to whom they can refer on where appropriate. Emergency services should, therefore, be available for specialised connective tissue disease advice.
Management of patients with JSLEThere is significant paucity of evidence for therapeutic intervention specific to JSLE. Much is inferred from case series or adult studies where the disease characteristics vary. There is now an impetus from national and international collaborations to perform randomised controlled trials in JSLE.
• Immuno-suppressive therapies - Medications currently used to treat JSLE include: hydroxychloroquine; azathioprine or methotrexate for mild/moderate disease; mycophenolate mofetil or intravenous cyclophosphamide for severe disease or major organ involvement and, more recently, biologic therapies such as rituximab. Regular blood monitoring is important.
• Treatment of intercurrent infection - Patients with JSLE have an abnormal immune response as part of their disease process and all of the therapeutic agents used are associated with immuno-suppression. Any sign of infection must be actively investigated and aggressively treated.
• Sunblock - The highest factor sunblock is important, even on cloudy days.
• Multi-disciplinary care - Patients with JSLE should receive multidisciplinary care from professionals trained to address the diverse and complex issues of a chronic paediatric multi-system disease. This input is vital to address their considerable needs and concerns.
Integration of patient care in JSLEIntegration of care across primary, secondary and tertiary services is vital to improving outcome and to support children and adolescents with JSLE and their families. Patients with JSLE will require long term follow up. Travelling distances to tertiary services may be long and very disruptive to the child’s education and for the family. Patients with mild disease or who are well controlled should have the opportunity to have shared care locally.
UK-wide network of care for JSLEThere are few long term outcome data on patients diagnosed with JSLE. The UK JSLE Study Group is a multi-centre, multi-disciplinary collaborative network comprising representatives from nearly all the major paediatric centres in the UK providing specialist care of patients with JSLE. It has established a UK-wide cohort of patients with JSLE to improve the knowledge base of the disease. It has set standards for the assessment, diagnosis and on-going monitoring of patients with JSLE. In partnership with LUPUS UK it is developing patient and parental information specific to JSLE and is actively pursuing a clinical trials agenda in JSLE.
Dr Michael W Beresford
Senior Lecturer (Clinical) in Paediatric Medicine
Institute of Child Health
University of Liverpool
Royal Liverpool Children’s Hospital
Liverpool L12 2AP