Rheumatology

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Chapter 16 Rheumatology

Long Cases

Juvenile idiopathic arthritis (JIA)

Major advances have occurred in the last few years regarding the understanding and the evidence base of JIA management. The escalation of chemotherapeutic agent usage and the evolution of biological therapies have transformed the outcome goals sought in JIA, where the expectation now is to be able to switch off inflammation, not just to control it. Early aggressive treatment that induces remission rapidly is now the aim.

By convention, disability, remission, structural damage and death have been the main outcome measures in arthritis. In JIA, extra-articular co-morbidities such as uveitis have also been measured as the disease outcome. There is no single measure that could represent all outcomes in JIA. Health-related quality of life (HRQOL) may be studied using various tools that have been developed to measure single outcomes, or a combination of these outcomes. These include the ‘Childhood Health Assessment Questionnaire’ (CHAQ), the Child Health Questionnaire (CHQ) and the Pediatric Quality of Life Inventory Generic Core Scales (PedsQL), to name a few. Furthermore, measurement of change may be undertaken by using internationally agreed-upon core set variables, often in the context of response to treatment. These variables include: physician global assessment of disease activity; parent/patient assessment of overall well-being; the disability index (CHAQ score); the number of joints with active arthritis; the number of joints with a limited range of movement; and a measurement of inflammation, such as the erythrocyte sedimentation rate (ESR) or C-Reactive Protein (CRP). Recently devised definitions of clinical remission, on and off medication, and minimal disease activity will assist in comparing and contrasting different treatment regimens. The American College of Rheumatology (ACR) has developed criteria that quantify improvement in at least three of six core variables, as a percentage of improvement, so the ACR Pediatric 30 criteria define an improvement of >30% in at least three of six core variables, the ACR Pedi50 criteria define an improvement of >50%, the ACR Pedi70 of >70%, and the ACR Pedi90 of >90%, respectively. The definition of a ‘flare-up’ in the disease has been based on these same criteria, with >40% worsening of two of six components, with no more than one component improving by 30%.

Biological agents have enabled the management of JIA to evolve significantly in recent years. Trials of these agents in JIA have taken place through international collaborative efforts. Children with JIA are often used as long-case subjects, as their care is multifaceted and often difficult. The candidate should be well versed in the range of available drugs and newer biological agents employed, their important adverse effects, the role of physical and supportive therapies, the associated disorders and the long-term outcomes.

Current classification of JIA

Oligoarthritis (four or fewer joints involved within the first 6 months)

The most common form of JIA, oligoarthritis is defined as arthritis affecting one to four joints during the first 6 months after onset of the disease. Approximately 45% of all JIA, this form predominantly occurs in females aged between 12 months and 5 years (peak 3 years). This group is at risk (up to 35%) of chronic uveitis, which is almost always asymptomatic, although it can occasionally result in photophobia and red eye. The untreated uveitis can result in complications such as band keratopathy, cataract and glaucoma. This is the leading cause of blindness in children in developed countries. As such, all children in this group require regular slit-lamp examination, every 3–4 months, by an ophthalmologist. ANA positivity (which occurs in about 50% of this group) is associated with the occurrence of uveitis in this group. The knees are most commonly affected, although the ankles (including the subtalar joints), wrists and elbows may also be involved. Hip involvement as the presenting joint is very rare. The arthritis is rarely erosive.

The presence of some historical or laboratory features may exclude the diagnosis of oligoarthritis. These include: (a) a positive family history of psoriasis; or (b) a positive family history of spondyloarthropathy in a first-degree relative; or (c) a positive rheumatoid factor. A favourable outcome is dependent on appropriate and timely management, which may include intra-articular steroid injection, physiotherapy and exercise, all aimed at restoring the pre-morbid joint status. Whilst NSAIDs may be used to treat symptoms and enable more intensive physical activity, DMARDs may be used to maintain the joint and prevent recurrence of inflammation. In this way, joint complications such as asymmetrical growth, subluxation or ankylosis can be avoided.

Persistent oligoarthritis

Persistent oligoarthritis is defined as affecting no more than four joints during the course of the disease. Provided that treatment has been implemented, the arthritis prognosis in this group is relatively better than other subtypes of JIA. The associated uveitis has a better prognosis when discovered by screening than by symptomatic referral.

Extended oligoarthritis

Extended oligoarthritis is defined as arthritis affecting one to four joints during the first 6 months of the disease, and a cumulative total of five joints or more after the first 6 months of the disease. Specific exclusions are as outlined above. Methotrexate (MTX) is the agent of choice for maintenance of arthritis in this group. This subtype of JIA can be quite severe and can continue into adult life.

Polyarthritis RF-negative

‘Polyarthritis RF-negative’ is defined as arthritis affecting five or more joints during the first 6 months after onset of the disease. This accounts for around 25% of JIA with female predominance, at any age. There is arthritis involving both the large and small joints of the upper and lower limbs, as well as the cervical spine and temporomandibular joints, and it may be symmetrical or asymmetrical. Uveitis may occur in approximately 10% and requires screening. ANA may be positive in over 25%. It can remit in late childhood, although continuation into adult life may also be seen. NSAIDs may be used to treat symptoms, whilst methotrexate is the agent of choice for maintenance of disease. Some patients may need higher doses of MTX, and as absorption of oral MTX may be variable and subject to first-pass metabolism by liver, parenteral administration may be required. Subcutaneous MTX is as effective as intramuscular MTX, but less painful and more likely to be adhered to.

Polyarthritis RF-positive

Polyarthritis RF-positive is defined as arthritis affecting five or more joints during the first 6 months of the disease, associated with positive rheumatoid factor tests on at least two occasions 3 months apart. This accounts for around 5–10% of JIA with female predominance and late childhood/teenage onset. Resembles adult rheumatoid arthritis, with a symmetrical polyarthritis affecting the upper (e.g. metacarpophalangeal joints most common) and lower limbs. Other features include subcutaneous nodules and early erosive changes radiologically. Untreated, it often follows a progressive course, with eventual joint destruction. Unremitting severe disease and poor functional outcome occur in over 50%. This group responds to the same drugs as for adult rheumatoid arthritis.

Systemic arthritis

1. Early onset (1–4 years; peak at 2), equal sex incidence, up to 10% of JIA.

2. Systemic symptoms: fever (typically single or double quotidian pattern with high spikes daily, occurring at similar times every day); rash (evanescent, coming and going with fever spikes; discrete salmon pink macules 2–10 mm, usually around upper trunk and axillae; show Koebner phenomenon; rarely pruritic; not purpuric); polyarticular arthritis (can be late feature).

3. Other features: lymphadenopathy, hepatosplenomegaly, serositis (pericarditis, pleuritis), and inflammatory ascites, haematological changes (anaemia, leucocytosis, macrophage activation syndrome).

4. An occasional feature is myocarditis.

5. Systemic features can precede arthritis by months. Natural evolution: systemic features followed by polyarthritis; this remains while systemic features regress.

6. Rheumatoid factor (RF) negative and usually antinuclear antibody (ANA) negative.

7. Approximately 50% remit in 2–3 years.

8. Untreated, joint destruction occurs in most cases.

9. Systemic arthritis is the only type of JIA without a specific age, gender or HLA association.

10. Most mortality from JIA is in this subgroup. Deaths can be due to infection secondary to immunosuppression, myocardial involvement or macrophage activation syndrome (MAS). MAS is a rare complication of systemic arthritis, involving increased activation of histiophagocytosis. Triggers include preceding viral illness (e.g. EBV) and additional medications (particularly NSAIDs, sulfasalazine and etanercept). Clinical findings include lymphadenopathy, hepatosplenomegaly, purpura, mucosal bleeding and multiple organ failure. Investigations may show pancytopenia, prolonged prothrombin time and partial thromboplastin time, elevated fibrin degradation products, hyperferritinaemia, hypertriglyceridaemia and low ESR. Treatment involves pulse methylprednisolone and cyclosporine A, or dexamethasone and etoposide.

11. Uveitis is rare, although ophthalmological surveillance is necessary to detect cataracts or glaucoma as complications of steroid treatment.

The ILAR classification lists three criteria that are definite: (a) documented quotidian fever for at least 2 weeks, of which at least on three consecutive days a quotidian pattern has been recorded; (b) evanescent, non-fixed erythematous rash; and (c) arthritis. There are also criteria for probable systemic disease, in the absence of arthritis—criteria (a) and (b) above, together with any two of: generalised lymph node enlargement; hepatomegaly or splenomegaly; or serositis.

Enthesitis-related arthritis (ERA)

Approximately 15% of all JIA, this predominantly occurs in males in pre-teenage years, with lower limb involvement, especially the hips and sacroiliac joints. Many show features common to spondyloarthropathies (e.g. enthesitis, decreased lumbar flexion). Involvement of the spine is uncommon in childhood. Rarely buttock pain occurs, reflecting sacroiliitis. Imaging the sacroiliac (SI) joints with MRI scan is more sensitive than plain radiolographs, and will detect inflammatory changes before cartilage and bone destruction occurs. Bone scan may be useful if there are positive findings; however, a negative result does not rule out sacroiliitis. Uveitis in this subtype may occur in 25% of cases, and usually presents as an acute red eye with pain and photophobia. This is quite different to the chronic asymptomatic uveitis that occurs in oligoarthritis or extended oligoarthritis). HLA-B27 antigen is positive in 80%; ANA- and RF-negative.

ERA is defined by (1) arthritis and enthesitis, or (2) arthritis or enthesitis, with at least two of the following: sacroiliac joint tenderness, inflammatory spinal pain, HLA-B27 positive, a family history (first- or second-degree relatives—at least one of (a) acute anterior uveitis, (b) spondyloarthopathy confirmed by a rheumatologist or (c) inflammatory bowel disease) or acute anterior uveitis.

Specific exclusions are a positive rheumatoid factor or a positive family history of psoriasis in a first-degree relative. Treatment, just as for other subtypes, must be targeted at obliteration of active synovitis or enthesitis. This may require intra-articular or peri-entheseal long-acting corticosteroid injection (e.g. triamcinolone), as well as commencement of sulphasalazine (SSZ) for maintenance and prevention of recurrence of inflammation. Methotrexate is normally used if SSZ does not achieve this, although other cytotoxics (e.g. azathioprine) may also be useful. Tumour necrosis factor-alpha (TNF-α) inhibitors have been promising and are used when earlier steps have failed. NSAIDs may be useful to treat symptoms, but they do not change structural outcomes such as erosive disease. Prolonged use of NSAIDs may have long-term health consequences (renal or cardiovascular) and should be avoided.

ERA includes patients previously known as ‘juvenile ankylosing spondylitis’. This terminology has been now updated, however, and is best avoided. The diagnosis of IBD-related arthritis does not come under JIA, as in the presence of a specific diagnosis arthritis can no longer be regarded as ‘idiopathic’. There are two forms of arthritis associated with inflammatory bowel disease (IBD): an acute polyarticular form that tends to reflect the disease activity of the coexistent IBD; and the second, more common, form that runs independently of the IBD. Extra-articular manifestations of ERA, in addition to anterior uveitis, include aortitis, aortic incompetence, muscle weakness and fever (usually low grade).

Psoriatic arthritis (JPsA)

JPsA has a female predominance and tends to occur in mid-childhood. The arthritis is frequently asymmetrical and may have oligoarticular onset, although a polyarticular course is commonly present. Dactylitis (sausage digits) is seen in younger patients and DIP joint involvement is common. The inflammation may involve tendon sheaths, and in its severe form cause ‘arthritis mutilans’, a very destructive arthropathy. There is often a family history of psoriasis. Fingernail pitting, onycholysis or other nail dystrophic changes may be seen. About half of the patients have the rash of psoriasis before the arthritis, whilst in the others the rash may present much later, or never at all. Few cases may develop both symptoms simultaneously. Uveitis can occur, and is seen in about 10% (chronic asymptomatic, as with extended oligoarthritis). Both ANA and HLA-B27 antigen may be present. Treatment of the psoriatic arthritis subtype is along similar lines as for other JIA subtypes, utilising intra-articular steroid injections for rapid control of acute inflammation, and other disease-modifying anti-rheumatic drugs (DMARDs) for maintenance of the disease and prevention of relapse. Both methotrexate and steroids may not be as efficacious in the treatment of JpsA, and the use of TNF-α inhibitor may be indicated to prevent irreversible joint damage, or to reverse erosive changes.

Undifferentiated arthritis

This group includes patients with arthritis whose presentation does not fulfil the criteria of any other specific groups. Examples include systemic arthritis in the presence of positive RF.

Presentation of a long case with JIA

The child with JIA may have a very long and complicated history. Clarity of presentation to the examiners is essential. Long cases with JIA particularly lend themselves to pictorial display. This method can be used for recording the history and allows the examiners to appreciate clearly the progress of the illness. If the candidate wishes to try this technique, it should be practised on trial cases before the exam. Figure 16.1 demonstrates an example: a 15-year-old girl with difficult-to-control polyarthritis RF-positive JIA. The diagram shows progress over a 5-year period, with arthritis activity and drugs used. Investigation results can be shown on the same diagram.

image

Figure 16.1 The 5-year history of a 15-year-old girl with difficult-to-control polyarthritis RF-positive JIA

History

The history given here includes questions regarding possible differential diagnoses, which would be relevant only in a newly presenting patient. Differentials are given after their symptoms, in parentheses. Ask about the following.

Presenting complaint

Reason for current admission.

Current symptoms

1. General health; for example, constitutional symptoms (fever, pallor, weight loss), exercise tolerance, quality of sleep.

2. Joint symptoms; for example, early morning stiffness, nocturnal discomfort/night waking, pain, tenderness, swelling, limitation of movement, problem joints (e.g. knees, hands), splints and orthoses used.

3. Level of functioning with activities of daily living (ADLs); for example, eating or pain on mastication, poor dental hygiene (limited jaw opening reflecting temporomandibular joint (TMJ) involvement), dressing, writing, walking, aids required (e.g. dressing sticks, adaptive utensils, wheelchair, computer), home modifications required (e.g. ramps, bathroom fittings), ability to attend/manage school, limitations of sporting and social activities, depression.

4. Skin rashes; for example, salmon rash of systemic JIA, malar flush (SLE), heliotrope of eyelids (dermatomyositis), psoriasis, rheumatoid nodules.

5. Chest symptoms; for example, pain from pleuritis, pericarditis.

6. Bowel symptoms; for example, diarrhoea with inflammatory bowel disease (IBD).

7. Eye problems; for example, uveitis, cataract, glaucoma.

8. Neurological symptoms; for example, seizures, drowsiness (JIA or SLE), personality change or headache with SLE.

9. Growth concerns; for example, short stature, delayed puberty, requirement for growth hormone, self-image effects.

10. Nutritional issues; for example, anorexia from drug side effects (e.g. methotrexate), cachexia persistent high inflammatory state, mechanical issues (TMJ involvement), bone mineral density (BMD) measurements (increased fracture risk with osteopenia [low bone mass for age, BMD between 1 and 2.5 SD below the mean for age and sex] or osteoporosis [BMD more than 2.5 SD below the mean for age and sex]), whether taking calcium or vitamin D supplements, muscle mass measurements.

11. Jaw involvement; for example, micrognathia, effect on self-image.

12. Drug/agent side effects; for example, steroid effects (poor height gain, obesity, myopathy), NSAIDs (GIT upset), methotrexate (leukopenia, hepatotoxicity).

Past history

Initial diagnosis (when, where, presenting symptoms, initial investigations), apparent triggers (e.g. immunisations, precedent illness), number of hospitalisations, sequence of joint involvement, development of complications and their management.

Management

Present treatment in hospital, usual treatment at home and school (including occupational and physiotherapy, exercises, sports, drugs), previous treatments used (including effects, and why stopped), side effects, monitoring of levels, compliance, use of identification bracelet, alternative therapies tried (e.g. naturopathy), elimination diets.

Social history

1. Disease impact on child; for example, school absenteeism, limitation of ADLs, self-image.

2. Impact on parents; for example, financial considerations such as the cost of home modifications, splints, wheelchairs, transport, frequent hospitalisations, drugs.

3. Impact on siblings; for example, resentment from not getting enough attention/time from parents.

4. Benefits received; for example, Child Disability Allowance, Health Care Card.

5. Social supports; for example, Arthritis Foundation of Australia; internet resources used by parents.

Family history

Arthritis, autoimmune conditions, inflammatory bowel disease, psoriasis, enthesitis, uveitis.

At the completion of presenting the history, the examiners should have a clear impression of the following:

1. The patient’s current functioning (e.g. ADLs).

2. The patient’s current (and past) treatment modalities, such as physiotherapy, drugs and alternative therapies (e.g. naturopathic) tried.

3. The social situation (e.g. the child’s expectations for the future, and the geographical situation relative to the treating hospital).

Examination

See the short case on joints in this chapter. This gives an approach to the lead-in ‘Please examine this child’s joints’, so that it covers not only signs found in JIA, but also signs indicating other diseases, such as SLE. These latter features are not usually relevant in the JIA long case, unless a diagnostic dilemma exists.

Diagnosis

Although it is the most common chronic inflammatory arthropathy in children, JIA remains a clinical diagnosis of exclusion. Some of the diseases to be excluded are enumerated above. The diagnosis has been made categorically in patients used as long-case subjects. However, the candidate may be asked which investigations would have been appropriate when the child was initially seen. Thus, a differential diagnosis is worth considering, even in established cases, if only for possible discussion purposes.

Investigations

In terms of differential diagnoses, there are too many to allow a brief but worthwhile list to be given. However, arthritis in the context of infections (e.g. EBV), neoplastic disease (leukaemia) or other connective tissue diseases (SLE, Mixed Connective Tissue Disease—MCTD) should be considered. The most appropriate investigations obviously depend on the clinical situation.

The following investigations may be helpful in JIA.

Blood tests

Haematology

1. Full blood examination may reveal normochromic normocytic anaemia, neutrophil leucocytosis or thrombocytosis. Anaemia, and low-normal platelet count ± leukopaenia may suggest the presence of leukaemia.

2. ESR/CRP: often raised; but may be normal. May be useful for ongoing disease monitoring.

Serology

1. IgM rheumatoid factor (RF): 10% seropositive. Higher IgM RF titres carry a worse prognosis as regards permanent disability, and a greater likelihood of systemic features. The presence of CCP antibodies may add specificity to a positive RF test. Very high RF titres (>1000) may suggest SLE or MCTD to be the primary diagnosis.

2. Antinuclear antibody (ANA): positive in 50%, and mainly in oligoarthritis and extended oligoarthritis subtypes. Whilst the titre of ANA does not correlate with disease severity, by convention values ≥80 are regarded positive. Very high ANA titres (>1000) may suggest that SLE or MCTD is present.

Immunology

1. Immunoglobulins: all immunoglobulin types may be elevated as a hypergammaglobulinaemia response. The presence of specific Ig deficiency can cause arthritis, although this precludes diagnosis of JIA.

2. Complement: C3 and C4 may be elevated as a part of an inflammatory response, and a low C2 may occasionally be found (associated C2 complement deficiency), although deficiency in early complements may suggest diagnosis of SLE; raised alpha-2-macroglobulin.

HLA typing

1. B27; for example, enthesitis-related arthritis especially in males 6 years and above, psoriatic arthritis, arthritis associated with IBD.

2. DR4 (polyarthritis: RF-positive).

Imaging

Plain radiography

Plain radiographs are useful in excluding other differential diagnoses such as osteomyelitis, septic arthritis, trauma and malignancy. It is not necessary to X-ray the lumbosacral region in most children with JIA, as a negative study does not exclude the absence of sacroiliac joint involvement and the radiation dose is high. Common findings on plain X-rays include:

1. Soft-tissue swelling.

2. Joint-space narrowing (only in established untreated cases).

3. Periarticular osteoporosis.

(The above three are the most common findings in RF-negative JIA.)

4. Joint erosions (development may lead to changed management), disappearing joint line, ankylosis/subluxation.

5. Leg-length discrepancy (accelerated maturation due to hyperaemia around the joint and low grade inflammation).

Orthopantomogram (OPG)

This is used to screen for TMJ involvement (condylar resorption), although direct lateral views provide better detail.

Ultrasound

Ultrasound can be useful in:

1. Effusions (especially useful assessing hips, shoulders).

2. Synovitis/tenosynovitis (increased echogenicity with inflamed tissues).

3. Acute synovitis (assessing for increased vascularity on Doppler).

4. Guiding intra-articular therapy.

Magnetic resonance imaging (MRI)—enhanced with gadolinium (gadopentetate dimeglumine)

MRI is significantly more sensitive than a conventional X-ray, being useful in demonstrating anatomy, including soft tissue and cartilage, to assess:

1. Early joint damage.

2. Positive effects of treatment before they are clinically apparent.

3. The amount of inflamed synovium (when performed with gadolinium enhancement).

4. Long-term effects in difficult-to-monitor joints (cervical spine, TMJ, hips).

Management

The goals of JIA management are as follows:

1. Switch off inflammation, hence preventing permanent joint damage.

2. Provide analgesia.

3. Maintain joint function.

4. Prevent deformities.

5. Treat complications and extra-articular manifestations.

6. Ensure optimal nutrition.

7. Rehabilitation.

8. Ensure optimal psychosocial health.

9. Educate parents/patient regarding disease.

1 Switch off inflammation

Local corticosteroid injections

Long-acting steroid preparations (e.g. triamcinolone hexacetonide) injected intra-articularly are safe, effective and useful for any joint with significant persistent inflammation. In particular, joints with flexion deformities (contractures) not responding to physiotherapy will benefit from this type of intervention. With successful treatment of joint inflammation, symptomatic treatment (e.g. NSAID treatment) may no longer be needed. Joint injections can be performed as a day case, using nitrous oxide inhalation or under conscious sedation for older children (over 8), or under general anaesthesia for younger children, for difficult-to-access joints (e.g. fingers, hips) or when multiple joints are being injected. Image intensification or ultrasound may be useful, particularly in the shoulders, hips and subtalar joints. For the TMJ, injection under CT or US guidance may be required, especially in patients with effusion or pannus evidenced on TMJ MRI. Paediatric rheumatologists are using intra-articular therapy much earlier in the treatment of JIA than previously, as there is evidence to show that this improves protection against erosions and will delay relapses. The positive effects of the steroid are noted usually within a few days, with effects usually lasting for several months. For those cases with recurrent synovitis, especially if a polyarticular course is present, simultaneous maintenance treatment (e.g. methotrexate) will be required.

NSAIDs

NSAIDs do not modify the natural history of the condition and as such should not be a part of ongoing maintenance therapy. However, they decrease pain and stiffness, as well as increasing the range of movement. Analgesic response is rapid, although the anti-inflammatory effect may take longer to commence. The average time to achieve a therapeutic response is around 1 month. Nearly all patients who are going to respond to a particular NSAID will do so within 3 months. The most common side effects are anorexia and abdominal pain, although some children may also have behavioural effects. Gastrointestinal ulceration is rarer in children than in adults; however, medications such as antacids or H2 blockers may well be required. More significant side effects can include bruising from abnormal coagulation, and pseudoporphyria skin rashes on sun-exposed areas. Probably all NSAIDs can cause pseudoporphyria rashes, although the highest relative risk and the early descriptions were with naproxen. Unfortunately, NSAIDs are unpredictable, their effectiveness being largely idiosyncratic. Around 50% of JIA children respond to their first NSAID.

NSAIDs include naproxen, diclofenac (avoid if there is a history of aspirin allergy, as there is cross-sensitivity with aspirin), ibuprofen (can be used if intolerant to other drugs in this group), indomethacin (especially enthesitis arthritis or unresponsive systemic onset patients), piroxicam, aspirin, and tolmetin sodium (not available in Australia).

With the past adverse publicity relating to salicylate usage and Reye’s syndrome, aspirin is used rarely and is not recommended. The toxicity to therapeutic efficacy ratio is low. The usual maximum dosage is 100 mg/kg per day. Starting dosage is 50–60 mg/kg per day. Use a buffered form. Monitor with salicylate levels, particularly if high doses are used (take at 2 hours post-dose, after 5 days of treatment). It is unwise to adjust the dose by any more than 10% at any time. Levels are lowered by systemic steroids (so be aware that when steroids are ceased, salicylate levels may rise acutely). Liver function tests (LFTs) should be performed before commencing treatment and regularly during treatment (for hepatic dysfunction, especially in the systemic onset group). If LFT results are abnormal initially, aspirin should be avoided.

COX-2 (cyclo-oxygenase isoenzyme 2) inhibitors

These have been used extensively in adults. They block the prostaglandins (PGs) responsible for inflammation, pain and fever, but not the PGs that protect the gastric antrum: hence, they have a lower incidence of upper GIT symptoms than the older NSAIDs. They have similar efficacy to NSAIDs. They are reserved for patients with gastrointestinal intolerance to conventional NSAIDs. Recent concern in post-licensing adult studies about an increased relative risk of cardiovascular events has led to the withdrawal of rofecoxib from the market, and caution with the use of other COX-2 inhibitors. Meloxicam, which inhibits both COX-1 and COX-2, has been used in children and found safe and effective.

Disease-modifying anti-rheumatic drugs (DMARDs)

DMARDs are those medications that reduce the rate of adverse structural outcomes such as joint erosions. These include methotrexate (MTX), leflunomide, sulphasalazine (SSZ) and hydroxychloroquine. Their use is in (but not limited to) arthritis with a polyarticular course. DMARDs are continued until such time that the underlying disease activity is sufficiently low (remission), or if intolerance to them cannot be managed.

Methotrexate (MTX)

MTX is effective in all forms of JIA, although less so in the systemic arthritis, PsA and ERA subtypes. With over 30 years of experience in its use, low-dose, once-a-week MTX is safe and reliable. Folate supplementation decreases side effects. MTX is given at a dose of 10–20 mg per square metre of surface area once a week, by an oral or parenteral (usually subcutaneous) route. Higher doses may be more effective, but this is at the expense of an unacceptable increase in toxicity; therefore they are rarely used. The parenteral route of administration is associated with fewer side effects, although the need to train someone to administer the medication, as well as the need to eliminate the cytotoxic waste, make this more cumbersome. Side effects include appetite loss, nausea and oral ulcers (lessened by treating with folate), as well as raised liver enzymes. Less commonly, a low neutrophil or platelet count is seen, whilst agranulocytosis is a very rare complication. Regular blood tests (monthly or second monthly) are performed to detect any liver impairment or marrow involvement. Long-term studies of MTX in JIA have yet to be published. Theoretical risks of carcinogenesis, infertility or interstitial lung disease have not transpired with several years of treatment. It has been shown to slow and even stop the progression of bone destruction in adults with rheumatoid arthritis. MTX has allowed remission to be achieved early in many patients.

Leflunomide

This is a pyrimidine synthesis inhibitor of dihydro-orotate dehydrogenase. It appears safe and effective, and compares favourably to MTX, both in efficacy and in having fewer side effects. It is currently being studied for use in JIA. Its side effects include diarrhoea, elevated liver enzyme levels and mucocutaneous abnormalities. Leflunomide may have teratogenic effects; and in patients of child-bearing age, effective contraception is required during and for up to 2 years after use (‘washout’ regimens are available to shorten this interval if needed).

Sulphasalazine (SSZ)

Some rheumatologists use this before MTX, particularly in ERA. The effective moiety of the drug is 5-aminosalicylic acid. A trial of at least 3 months, and usually longer, is needed to judge efficacy. Side effects include hypersensitivity reactions, hepatotoxicity and bone marrow alterations. As in adults with rheumatoid arthritis (RA), sometimes it is used in triple therapy with MTX and hydroxychloroquine (see below).

Corticosteroids

Systemic use

The use of systemic steroids may be required to achieve rapid control of disease activity and symptom control, especially in subtypes such as systemic arthritis, or where the large number of joints involved may make the intra-articular route impractical. Whilst steroids are indicated in any serious complications (such as pericardial or pleural effusions, macrophage activation syndrome or uveitis, their use is often associated with considerable side effects (e.g. Cushing’s syndrome) and therefore they are best tapered as soon as practical They also have a place as an adjunct to other therapy (e.g. in polyarthritis not responding to other drugs). Oral steroids should be taken in the morning to minimise the impact on growth. Alternate day use of steroids may not be as effective as a daily regimen, or may result in a higher relapse rate.

Pulse intravenous steroids are used when a rapid therapeutic effect of the systemic steroids is required. Examples may include pericardial or pleural effusion, or macrophage activation syndrome in systemic arthritis. The latter is a complication in systemic arthritis, or indeed any other connective tissue disease with persistently high inflammation, and if left untreated will cause multi-system failure and death. In addition to steroids, a maintenance agent, usually cyclosporine, will be required. The treatment regimen consists of IV methylprednisolone (30 mg/kg [up to 1 g maximum dose] as an infusion given over 1–2 hours for three consecutive days. Repeating this schedule a week later may be associated with less recurrence.

Biological agents

These comprise: the tumour necrosis factor-alpha (TNF-α) inhibitors etanercept, infliximab and adalimumab; the IL-1 inhibitor anakira; the IL-6 inhibitor tocilizumab; the anti-CD20 (plasma cell receptor) rituximab; and the T-cell proliferation inhibitor abatacept. With the exception of rituximab, these agents are to be used simultaneously with methotrexate. This is to improve efficacy and minimise the possibility of developing drug antibodies in the patient, which will cause tachyphylaxis. All of these agents can cause immunosuppression, and live virus vaccines should be avoided in a patient on these medications for this reason. Varicella-susceptible children should be ideally immunised 3 months before starting these agents; however, the severity of the arthritis usually does not allow any delay in starting them. TNF inhibitors can lead to reactivation of latent tuberculosis (TB), so before starting therapy with these agents, tuberculin (PPD) non-reactivity needs to be confirmed, and a screening chest X-ray is performed. If the results are positive, then treatment with isoniazid should commence a month before starting the TNF inhibitors, to avoid reactivation of latent tuberculosis. Biological agents are used in children with severe disease that is refractory to standard therapy. Most have been shown to reverse erosions and promote bone remodelling, although this is limited to the initial phases of erosive disease. They are occasionally associated with allergic reactions (infliximab), although their medium-term side effects commonly relate to a higher rate of upper respiratory tract infections (etanercept) and injection site reactions (anakinra, etanercept). Long-term safety data for use of these agents are becoming more available, with 30 cases of neoplastic disease occurring in children who received TNF inhibitors reported to the Food and Drug Administration (FDA) in the USA, during the decade from 1998 to 2008. A further potential increased risk is that of fungal infection.

Etanercept (ETN) (recombinant p75 soluble tumour necrosis factor receptor (sTNFR): Fc fusion protein)

ETN was the first anticytokine therapy used in JIA. Now a well-established therapy for JIA, it is used for patients with a treatment-resistant (failed to respond to MTX) active polyarticular course. At the time of writing (2010), it remains the only biological agent that has full US FDA and European Agency for Evaluation of Medicinal Products (EAEM) approval for use in JIA. In Australia, it is currently the only pharmaceutical benefit scheme (PBS) approved biological agent for JIA, although adalimumab and abatacept have recently received Therapeutic Goods Administration (TGA) approval. It has a response rate of 77%, although it has been found to be less successful in treating systemic arthritis. The dose in children/adolescents aged 4–17 is 0.4 mg/kg twice weekly by subcutaneous (SC) injection. Parents are trained in reconstituting the etanercept and administering the injection using the aseptic technique. Autoinjectors (as used for diabetics) can be useful, although they are currently not available for paediatric use. Injection site reactions are common, occurring in about 40%, although these resolve after a few injections. Other common adverse events include upper respiratory tract infections, rhinitis, headache, rash and gastrointestinal symptoms. It is contraindicated in sepsis. In the past few years, numerous case reports have been published about patients in whom uveitis developed after commencement of etanercept treatment, or worsened if pre-existent. Stopping this treatment for 2 weeks (washout period) and commencement of infliximab or adalimumab controlled the uveitis in most cases.

When effective, etanercept causes significant reduction in disease activity within 2 weeks of commencement, with sustained benefit as long as treatment is continued. In JIA with a polyarticular course, it controls pain and swelling, improves laboratory parameters and slows radiographic progression of the disease. The drug is named to indicate that it intercepts TNF-α, a cytokine important in the pathogenesis of RA and JIA. It is made up of two components: the extracellular ligand-binding domain of the 75kD human receptor for TNF-α, and the constant portion of human immunoglobulin (IgG1): hence the term ‘fusion protein’. There is a low serious adverse event rate. Up to 8 years continuous therapy with ETN has demonstrated no cases of opportunistic infection or malignancies.

In Australia, Medicare requirements for the funded supply of etanercept are that application must be made for an authority for specialised drug use, and that the patient must be under the care of a recognised paediatric rheumatology service. Around one third of patients achieve remission; however, relapse rate after cessation of maintenance therapy is high.

Other biological agents

• Abatacept (CTLA4-Ig) is a fusion protein made up of the extracellular domain of human CTLA4 (a second receptor for the B-cell activation antigen B7) and a fragment of the Fc portion of human IgG1 (hinge and CH2 and 3 domains), and binds human B7 (CD80/86, on antigen-presenting cells) more strongly than CD28 (on native T cells). It targets T-cell activation, and inhibits T-cell proliferation. It has been used successfully in patients who fail to respond to TNF inhibitors.

• Adalimumab also is a monoclonal anti-TNF-α antibody, but it is completely humanised, and it is given by SC injection every 2 weeks. Early studies suggest that it may be useful in the treatment of JIA with a polyarticular course. It is especially efficacious when MTX is given concurrently.

• Anakinra is a recombinant IL-1 receptor antagonist, which may be useful in recalcitrant systemic arthritis, where it has a response rate approaching 80%.

• Infliximab is a chimeric monoclonal anti-TNF-α antibody, which binds to soluble TNF-α and its precursor, neutralising their action. In Australia, it has TGA approval for use in paediatric Crohn’s disease. It may be as efficacious as etanercept in treating JIA with a polyarticular course, although head-to-head studies have not been conducted. It is given intravenously. A higher dose of infliximab, at a level of 6 mg/kg, has a better safety profile than the dose used in the initial studies (3 mg/kg); it is given at time 0, 2 and 6 weeks, then every 6–8 weeks.

• Rituximab is a chimeric monoclonal antibody that targets cells bearing CD 20 surface markers, depleting the B-cell population. It has been used in conjunction with MTX in patients who are resistant to TNF inhibitors.

• Tocilizumab is a humanised anti-interleukin-6 (IL-6) receptor antibody, which almost completely blocks transmembrane signalling of IL-6. IL-6 is the key cytokine in the pathogenesis of systemic arthritis. It appears promising in the therapy of recalcitrant systemic arthritis, used at a dose of 8 mg/kg. It leads to significant improvement in disease activity indices, and a decrease in acute phase reactants. Adverse reactions can include anaphylactoid reactions, bronchitis and gastrointestinal haemorrhage.

Autologous haemopoietic stem cell transplantation (HSCT)

This has been performed in recalcitrant systemic arthritis. Remission can occur, but there is a significant mortality rate, usually from macrophage activation syndrome (MAS). It should only be considered if all other treatment options have failed. Long-term effects are not known. Several deaths, as a complication of an HSCT for JIA, have been recorded, related to MAS; many rheumatologists would not consider the procedure because of the inherent risks.

Other therapies

Thalidomide is an immunomodulatory agent that reverses several of the cytokine dysregulation in systemic arthritis; decreasing levels of TNF-α, interleukin 1, nuclear factor KB and interleukin 6.

Monitoring disease activity

An essential component of controlling the inflammatory process is that of clinical and laboratory monitoring:

1. Clinical disease (e.g. fever, worsening joint count, worsening joint function).

2. Erythrocyte sedimentation rate.

3. MRI/X-ray showing disease progression.

4. Degree of anaemia.

Sequence of drugs/agents

The examiners may ask about your approach to the use of the drugs noted above. In all subtypes of arthritis, active synovitis almost always needs treatment with intra-articular or systemic (IV or oral) steroids to achieve rapid remission. In polyarticular course and systemic arthritis, simultaneous commencement of MTX will be necessary:

1. For life-threatening systemic arthritis, pulse corticosteroids are the agents of choice. MTX is simultaneously started as a maintenance agent, which in time will allow reduction in the amount of oral systemic steroids used (hence the term ‘steroid-sparing agent’ used for MTX). If MTX is unsuccessful, leflunomide can be tried, although if the disease severity is significant, commencement of biological agents may be indicated. Although etanercept is the only PBS-listed biological agent, others may be available by application to the hospital drug committees or local health authorities, usually if treatment with etanercept has failed.

2. For non-life-threatening and non-systemic disease, try the following sequentially:

In oligoarthritis, intra-articular corticosteroids with NSAIDs. Sometimes repetition of IAS may be required to achieve a therapeutic response. If the relapse rate is high, the addition of a DMARD (usually MTX) will be required.

The management algorithm for each type ends with biological agents, after steroids and/or MTX along the way, although biological agents may not be authorised by Medicare if their application criteria are not met (e.g. recurrent oligoarthritis).

2 Provide analgesia and treat stiffness

Pain

1. Assess severity, timing.

2. Analgesic (e.g. paracetamol).

3. Ice packs (e.g. pack of frozen peas wrapped in a moist towel) for acutely inflamed joints or hot packs (especially if there is associated stiffness) may be useful.

Morning stiffness

1. A warm bath/shower or hot packs may be helpful.

2. May be seen the morning after a particularly physical and busy day (e.g. school sport).

3. Treat with nocturnal, longer-acting, non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. dispersible piroxicam, naproxen, indomethacin), or by taking a morning dose of shorter-acting types (e.g. ibuprofen).

3 Maintain joint function

1. Physiotherapy (including hydrotherapy) to maintain the joint range of movement (ROM) (e.g. stretching), muscle strength (exercise) and gait education. Particularly useful types of activity that help joint range and strength are walking, cycling and swimming, which need to be done at least 4–5 times during the week.

2. Attention to footwear (e.g. sports shoes with a supportive arch are comfortable and often appropriate) or wearing custom-made orthotics for leg length discrepancy or deformities (e.g. genu valgus, from epiphyseal overgrowth; measure the intermalleolar distance to monitor this).

3. Even in the presence of acute synovitis, active physiotherapy is encouraged to minimise muscle wasting and to maintain joint ROM. Hydrotherapy may be particularly useful, as the warm water promotes better mobility, and the buoyancy reduces the required power to move the body.

4. Occupational therapy assistance for those with upper limb involvement, particularly for wrist and hand involvement. This assists with fine motor movement, and ADLs such as dressing, feeding and toileting, as well as for writing and use of a keyboard.

4 Prevent deformities

1. Splinting:

(a) Resting splints (for acutely inflamed joints) will promote loss of ROM and muscle wasting, and are discouraged.
(b) A corrective splint (to increase joint ROM; by serial splinting/casting, placing in optimal ROM or dynamic splinting) may be necessary at times to improve a severely deformed joint, or to prevent nocturnal ROM loss.
(c) Functional splinting (to protect joint during ADLs; e.g. ankle–foot orthoses, wrist cock-up splint).

2. Insoles and medial arch support (for hindfoot valgus).

3. Prone lying (for hip/knee contractures in particular).

4. Nocturnal traction (especially for hip pain).

5. A cervical collar (for torticollis, pain, occipito-atlanto dislocation, and before general anaesthesia requiring intubation).

6. Surgical intervention may be needed where conservative treatment has failed to prevent deformity. Possible interventions include soft-tissue releases (e.g. for fixed flexion deformities at hips or knees), stapling (e.g. of medial femoral and tibial epiphyses to correct valgus deformity), osteotomy and fusion/arthrodesis. Synovectomy (surgical or radioactive) may be occasionally needed for persistent pain and swelling (e.g. hips, knees). Total joint replacement may be offered to individuals with severely damaged joints who have an unacceptable level of pain or functional loss, although with modern treatment fewer and fewer patients will need this.

5 Treat complications

Eye involvement

All patients with JIA are at risk of uveitis, although the incidence and type of uveitis may vary between subtypes. The oligoarthritis subtype (including extended oligoarthritis, which happens to have the highest rate of positive ANA test), young age and male gender bear the highest risk for severe chronic anterior uveitis. The ERA or PsA subtypes are more commonly associated with acute anterior uveitis (painful red eye), although chronic anterior uveitis may also occur. In addition, patients who have received long-standing systemic/topical steroid treatment are at risk of steroid effects (cataracts and glaucoma).

1. Chronic uveitis: all patients need regular uveitis screening by a trained ophthalmologist; 3–4 monthly for those at higher risk, and 6–12 monthly if the risk is lower.

2. Active uveitis is usually treated with steroid eye drops and mydriatics.

3. MTX has a therapeutic effect on uveitis.

4. The anti-TNF agents infliximab and adalimumab are efficacious in controlling uveitis. Etanercept has occasionally been held responsible for exacerbation or evolvement of uveitis.

Infection

Treat with appropriate antibiotics and general supportive measures. Immunosuppressants will need to be withheld if there is active infection present, and live vaccinations (e.g. MMR, chicken pox) are to be avoided.

Amyloidosis

Fortunately, with modern aggressive treatment this complication has become extremely rare. It may present with hepatosplenomegaly, abdominal pain, diarrhoea or albuminuria, and is diagnosed by rectal or renal biopsy. Treatment is with chlorambucil. Children with severe systemic arthritis are more likely to have this complication: the overall incidence of amyloidosis in some studies in this subtype has been as high as 9%, but these rates are old and probably do not reflect current treatment cohorts.

6 Ensure optimal nutrition

Nutritional status is paramount and must not be overlooked. Active disease or TMJ involvement, as well as side effects of drug therapy (e.g. NSAIDs, MTX), can lead to suboptimal intake, inadequate energy and muscle bulk, which can negatively impact on other aspects of treatment.

7 Rehabilitation

Occupational therapy

1. School: use of adaptive pencil holder, standing desks, ramps, decreasing inter-class distances, avoiding stairs, potential for use of laptops in place of writing.

2. Home: dressing sticks and hoops, large buttons, Velcro fasteners, adaptive utensils, hand-held shower, use of computers, tape recorders (if writing difficult).

Physiotherapy

Exercise: Active/passive (including isometric exercises) to improve joint ROM, and to strengthen muscles. Also aim to improve endurance.

Family support

Social worker, parent support groups, Healthcare card, child disability allowances, disabled parking authorisation.

8 Ensure optimal psychosocial health

1. Promote as much independence as possible.

2. Encourage the child to take responsibility for management, as appropriate for age.

3. Build self-esteem.

4. Help the child deal with peer-group problems (e.g. school liaison, addressing bullying).

5. Family psychosocial support, including siblings.

9 Educate parents and patient regarding disease

1. Ensure adequate understanding by parents, patients and siblings of the disease, treatment, drug side effects, importance of compliance and prognosis.

2. Encourage contact with reputable consumer groups (e.g. Arthritis Australia) and suggest trustworthy websites.

3. Dispel myths and false beliefs (e.g. held by other, older family members) regarding JIA, drugs used and alternative therapies (unproven therapies that are popular [despite no data in existence to support their use], including glucosamine and hyaluronic acid).

Prognosis

It has been estimated that about one third of patients with JIA will still have active disease as adults, which may well interfere with their ADLs and lifestyle. This prognosis depends on the type of JIA. RF-positive patients have the worst prognosis for ongoing disease activity: these are usually females with onset as teenagers. If adequately treated, children with only a few joints involved do better than children with ongoing systemic disease or polyarthritis, although the risk of uveitis may be higher. If untreated, serious ocular damage occurs in 10–20%. In patients treated for systemic arthritis, 60–85% will go into remission; whilst up to one third may develop destructive polyarthritis. The average duration of disease activity has been reported to be 6 years. In a follow-up study of JIA patients with disease duration over 10 years, around one third had depression, related directly to disability and ongoing disease activity. Death from complications is extremely rare (less than 0.3% in North America).

Juvenile idiopathic inflammatory myopathies (JIIMs): juvenile dermatomyositis (JDM)

The IIMs of childhood are rare diseases, but are not uncommon in examination settings.

Background

Since 1975, the criteria of Bohan and Peter have been used widely. The five diagnostic criteria include:

1. Characteristic rashes. Two are pathognomonic: (a) Gottron’s papules—scaly red papular areas over the knuckles (MP) and IP joints [papules can also overlay elbows, knees and malleoli]; (b) heliotrope rash—a violaceous or purplish, with somewhat oedematous discolouration around the eyes, particularly over the eyelids (capillary telangiectasia), which may cross the nasal bridge and include the nasolabial folds. Other rashes encountered include scaly red rash on the sun-exposed areas; the face, neck and upper chest (V-sign), the shawl area (shawl sign) and over the extensor tendons, particularly of the hands (linear extensor erythema). Commonly there is an erythematous rash involving extensor surfaces (elbows, knees), which may be mistaken for psoriasis.

The other criteria, of which three out of four are required, are as follows:

2. Symmetrical proximal muscle weakness (although in practice distal muscles, as well as the oropharynx are also involved).

3. Elevated muscle-derived enzymes (creatine kinase [CK], aldolase, lactate dehydrogenase [LDH] and transaminases [AST and ALT]).

4. Muscle histopathology confirming the typical pattern of myofibre atrophy and drop out necrosis with fibre regeneration, and chronic inflammatory infiltrate involving blood vessels.

5. Electromyography (EMG) changes of inflammatory myopathy (fasciculations at rest, bizarre high-frequency discharges). EMG interpretation is dependent on appropriate placing of the electrode in areas of inflammation. Magnetic resonance imaging (MRI) is used to select the sample site (inflammatory muscle involvement causes non-uniform changes in muscle, abnormal increased signal on T2-weighted images and normal signal on T1).

Note that recently MRI has been used more often to detect skin, fascia and subcutaneous abnormalities, as well as muscle inflammation, which can be helpful in clarifying the extent of involvement in difficult cases, therefore aiding with devising a management plan. MRI is likely to replace the more painful, invasive tests of muscle biopsy and EMG, and become one of the diagnostic criteria.

JDM is an occlusive small-vessel vasculopathy, involving arterioles and capillaries. There can be very diffuse vasculitis (which may include nail-bed telangiectasia, digital ulceration, infarction of oral epithelium and gastrointestinal ulceration) and vasomotor instability. In 1997, Rider and Miller suggested a clinicopathological classification of the juvenile IIMs, listing 11 subsets in keeping with the myositis subsets recognised in adults.

The incidence of JDM is around 2–3 per million. The gender ratio varies around the world: in the UK and the USA, girls are affected more often (up to twice as often), but in India and Japan, boys are affected more often. The mean age of onset varies also: it is around 7 years in the USA and in the UK, but in the UK it has bimodal incidence, with one peak at age 2–6 and the other at age 12–13.

Susceptibility to developing JDM has been associated with several HLA alleles, including the class II major histocompatibility complex (MHC) allele HLA-DQA1∗0501, which is found in 86–92% of patients, versus 28-46% of controls. Other alleles that are more common in JDM include HLA-B8, HLA-DRB1∗0301 and HLA-DQA1∗0301.

Tumour necrosis factor-alpha (TNF-α) is an immunomodulator and proinflammatory cytokine; TNF polymorphisms are associated with several rheumatic diseases, including JDM. Polymorphisms at the TNF-308 locus are associated with a longer disease course of over 36 months, and the development of calcification. The TNF-308 allele also is associated with an increase in concentration of thrombospondin-1, an anti-angiogenic factor that may predispose to increased vascular occlusion.

Maternal microchimerism (the persistence of maternal blood cells transferred by placenta) has been found in CD4 or CD8 peripheral blood cells and in skin lesions and muscle of children with in JDM. It has been postulated that this could lead to a graft versus host reaction presenting as autoimmune disease. Maternally derived chimeric T cells demonstrate a memory response to the child’s lymphocytes.

There is no strong evidence to support the role of any environmental agent in the pathogenesis of JDM. Some of the immune responses have been elucidated: complement-mediated damage to vessels is a major mechanism, as is overexpression of adhesion molecules (e.g. intracellular adhesion molecule-1 [ICAM-1]; vascular cell adhesion molecule-1 [VCAM-1]), which belong to the immunoglobulin superfamily and recruit inflammatory cells. No specific autoantibodies are found in most patients with JIIM.

There is some evidence of involvement of type-1 interferons in JDM. Genes regulated by type-1 interferon mediate immunomodulation, upregulate MHC class I and support dendritic maturation; they also activate natural killer cells’ cytotoxic effects, and promote activated T-cell survival. The degree of gene expression of the chemokine interferon-inducible protein 10 (IP-10) and the monocyte chemoattractant protein (MCP-1) correlates with activity of the disease. However, the mechanism by which this could lead to the pathogenesis of JDM is not known.

At diagnosis, all children have weakness and rash, and are universally reported to be irritable. Anasarca (severe generalised tissue oedema) and skin ulceration are signs of severe disease and call for aggressive treatment. Most have muscle pain and fever, and 20–50% have dysphagia or hypernasality of voice, abdominal pain and/or arthritis. Soft-tissue calcification (calcinosis) is seen in 30–70% of patients eventually, in sites exposed to trauma (buttocks, knees, elbows) and seems to reflect the severity and duration of disease; it is relatively rare at diagnosis. The mechanism of calcinosis is thought to be due to damaged muscles releasing mitochondrial calcium into matrix vesicles that promote mineralisation. Calcinosis is related to hydroxyapatitie accumulation; it can occur as superficial lumps, plates along fascial planes or widespread exoskeleton distribution. Calcification can resolve spontaneously, and drain a white exudate, leaving pitted scars. Abscess formation may be seen in the muscles and become infected with Staphylococcus aureus. Calcification can persist in fibrotic muscle in sheath-like forms, impairing function. Both the skin and the muscle manifestations may be precipitated or exacerbated by sun exposure.

Gastrointestinal involvement, through muscle weakness and/or vasculitis, can lead to impaired speech from soft palate involvement, decreased oesophageal motility with impaired swallowing, oesophageal reflux, aspiration pneumonia, ulceration, perforation, haemorrhage, pneumatosis intestinalis and malabsorption.

Cardiopulmonary involvement can cause asymptomatic conduction abnormalities, widespread cardiac vasculopathy and pulmonary fibrosis. Respiratory muscle weakness can occur in around a third of patients.

A candidate could be asked what investigations may have been ordered when the patient first presented. A list of the usual diagnostic work-up is useful, after stressing the importance of clinical examination and exclusion of mimics of JDM. Investigations commonly ordered include the following: blood for muscle enzymes, ESR, CRP and autoantibodies (anti-nuclear antibodies [ANA], anti-ds-DNA, extractable nuclear antibodies including anti-Sm, anti-RNP and anti Jo-1); imaging—MRI of proximal muscles, chest X-ray; pulmonary function tests; ECG; and nail-fold capillaroscopy.

Other manifestations include the following:

1. Vasculitis involving the central nervous system (causing seizures and organic psychosis—even fatal brainstem infarction has been described).

2. Ophthalmological complications include retinopathy (retinal exudates, ‘cottonwool’ spots, optic atrophy, visual impairment), glaucoma (from steroids) and cataracts (from steroids).

3. Renal tract: renal failure secondary to myoglobinuria from muscle breakdown; ureteral (middle third) necrosis secondary to vasculopathy.

4. Reproductive system: active disease can delay menarche, interrupt menses or adversely affect pregnancy outcomes.

5. Raynaud’s phenomenon.

6. Lipodystrophy: this is a slowly progressive symmetrical loss of subcutaneous fatty tissue that typically involves the upper half of the body; mainly in females; it can be associated with acanthosis nigricans, hirsutism, hepatomegaly, hyperlipidaemia (especially hypertriglyceridaemia) and insulin-resistant diabetes mellitus; the pathophysiology is unknown.

7. Juvenile polymyositis (JPM) is identical to JDM but without the skin rash. It is exceedingly rare.

8. Amyopathic JDM is the rash without the muscle findings.

There are recognised subgroups based on the course of the disease: monocyclic (full recovery without relapse), chronic polycyclic (prolonged relapsing course), chronic continuous (persistent disease despite maintenance treatment) and ulcerative.

In recent years, a number of groups have collaborated internationally and produced accurate, reliable and validated outcome measurement tools. The three commonly used are the Childhood Health Assessment Questionnaire (CHAQ; initially developed to measure physical function in children with arthritis), Manual Muscle Testing (MMT; a score that assesses the muscle strength of seven proximal and five distal muscle groups, bilaterally; it predicts disease activity) and the Childhood Myositis Assessment Scale (CMAS; a 14-activity assessment of physical function, strength and endurance). These standardised tools allow comparisons between groups throughout the world.

History

At the completion of presenting the history, the examiners should have a clear impression of the patient’s current functioning (e.g. ADLs), current (and past) treatment modalities (such as physiotherapy, drugs and alternative therapies [e.g. naturopathic] tried) and social situation (e.g. transport issues, distance from home to treating hospital).

Ask about the following.

Presenting complaint

Reason for current admission.

Current symptoms

1. General health (e.g. fever, weight loss, nutritional status).

2. Musculoskeletal symptoms; for example, general pain or tenderness, asthaenia, muscle weakness, cramps, joint symptoms (early morning stiffness or gelling after inactivity, nocturnal discomfort, pain, tenderness, swelling, limitation of movement [contractures or calcinosis of tendon sheaths], problem joints), contractures and the requirement for serial casting.

3. Skin rashes; for example, heliotrope of eyelids, Gottron’s papules (knuckles), photosensitive rashes, scarring and atrophy.

4. Calcinosis; for example problem areas (e.g. buttocks, extensor surfaces).

5. Level of functioning with activities of daily living (ADLs); for example, speech (tongue involvement), eating (chewing difficulties from involvement of muscles of mastication), swallowing (soft palate weakness, abnormal oesophageal motility), sitting (buttock soft-tissue calcification), walking, negotiating stairs, squatting, assistance devices (e.g. adaptive utensils, wheelchair, computer) and home modifications required (e.g. ramps, bathroom fittings).

6. Gastrointestinal (GIT) symptoms: oral, upper GIT and lower GIT (e.g. ulceration, perforation, haemorrhage, malabsorption).

7. Genitourinary symptoms; for example, discoloured urine (episodes of myoglobinuria), renal impairment, ureteral involvement and interference with menstruation.

8. Eye problems; for example, visual impairment, retinopathy, glaucoma and cataracts.

9. Neuropsychiatric symptoms; for example, mood swings and depression.

10. Drug side effects; for example, steroid effects (Cushing’s syndrome, stunted linear growth, myopathy), cytotoxics (e.g. myelosuppression, opportunistic infection, hepatotoxicity [MTX], hypertension [CPA]) and IVIG (infusion-related toxicities, other IVIG complications such as aseptic meningitis, thromboembolism).

11. Other systems review; for example, cardiopulmonary symptoms, Raynaud’s phenomenon.

Past history

Initial diagnosis (when, where, presenting symptoms, initial investigations), possible triggers (e.g. infectious agents [parvovirus, enteroviruses, hepatitis B], excessive sun exposure), pattern of illness (monocyclic, chronic polycyclic, continuous), hospitalisations, the development of complications and their management.

Management

Current treatment in hospital, usual treatment at home (e.g. occupational therapy and physiotherapy, exercises, medications), previous treatments used (e.g. azathioprine, IVIG), responses to treatment, side effects, monitoring of effect, alternative therapies tried.

Social history

1. Disease impact on: (a) child (school absenteeism, limited ADLs, poor self-image); (b) parents (financial considerations: home modifications, wheelchairs, computers, transport, frequent hospitalisations, drugs); (c) siblings (rivalry).

2. Benefits received; for example, Child Disability Allowance.

3. Social supports.

Family history

Any connective tissue/autoimmune diseases.

Examination

The approach given in Table 16.1 could be used for a short case or clinic follow-up.

Table 16.1 Examination for juvenile dermatomyositis (JDM)

Initial impression
Well or unwell
Face

• Cushingoid (steroids)

• Heliotrope eyelid rash

• ‘Chipmunk’ facies (masseter atrophy)

Parameters

• Height (short from steroids)

• Weight (obese from steroids; thin from hypercatabolism or malabsorption)

Lipodystrophy (symmetrical loss of subcutaneous fatty tissue, mainly upper body; occasionally asymmetrical; usually in females; can be associated with acanthosis nigricans, hirsutism and clitoral hypertrophy) Skin Photosensitive rashes (distribution of sun exposure) Vasculitic rash Subcutaneous calcification (buttocks, elbows, knees), scars/pits of old calcinosis Atrophy Hypertrichosis (cyclosporine); Hirsutism (steroids) Upper limbs Hands

• Raynaud’s phenomenon

• Digital ulcers/scars

Nails: nail-fold capillary bed telangiectasia or periungal erythema Palms

• Anaemia (drug side effects, e.g. cytotoxics)

Knuckles

• Gottron’s papules

Elbows

• JDM rash

Blood pressure

• Elevated (e.g. steroids, nephropathy, cyclosporine); if elevated, make a point of requesting urinalysis now

Neuromuscular assessment

• Palpate muscles (tenderness)

• Range of movement of joints (active then passive); tone (contractures from sheathing of tendons)

• Power

• Reflexes

Joint assessment

• All joints of upper limbs (as for the joints short case)

Functional assessment

• Activities of daily living (e.g. writing, brushing teeth, combing hair, turning taps on or off, feeding self, carrying household objects)

Head and neck Eyes

• Conjunctival pallor

• Visual acuity

• Glaucoma (steroids)

• Cataract (steroids)

• Retinopathy (retinal ‘cottonwool’ spots; optic atrophy)

Mouth

• Inflamed mucous membrane

• Gum hyperplasia (CSA)

• Dysphonia

Cardiorespiratory Auscultate

• Praecordium

• Lung fields

Abdomen Tenderness (gastrointestinal haemorrhage/ulceration) Buttock rash Gait, lower limbs and back Neuromuscular assessment

• Full gait examination

Squat

• Proximal weakness (JDM per se; steroids)

Test for truncal weakness: get the child to do a sit-up from a lying position on the bed, or resisted head lift off the bed (truncal weakness can take quite some time to return to normal, often lagging behind limb strength improvements) Lower limbs (neurologically)

• Palpate muscles (tenderness)

• Range of movement of joints (active then passive); tone (contractures from sheathing of tendons)

• Power (Gower’s sign)

• Reflexes

Back

• Palpate for tenderness (osteoporosis)

• Examine joints

Joint assessment

• All joints of lower limbs (as per joints short case)

Functional assessment

• Activities of daily living (e.g. sitting, getting out of chair, climbing stairs)

Other Temperature chart

• Fever (intercurrent illness, from steroids/cytotoxics)

Urinalysis

• Myoglobinuria

• Proteinuria (nephropathy: JDM per se, or cytotoxics)

• Haematuria (nephropathy: JDM per se, or cytotoxics)

Stool analysis

• Blood

The following is the sequence suggested for the joint examination (for detail, see the joints short case). Inspect the distribution of joint involvement (symmetry); note swelling, loss of normal contours, angulation, deformity, redness and muscle wasting. Next, feel the joint and periarticular areas for tenderness, warmth, effusion, ‘boggy’ swelling (thickened synovium and fluid) and contractures. Range of movement (ROM) is then examined, active movement first. Test passive movement to assess for any restriction (tenosynovitis, arthropathy) or tenderness. Describe ROM by qualifying statements (restricted, very restricted or absent), stating that formal measurement of joint ROM is carried out by a goniometer in the hands of a trained person. A suggested order for a systematic examination of all the joints is as follows: hands (DIPJ, PIPJ, MCPJ), wrists, elbows, shoulders, temporomandibular joints, cervical spine, lumbar spine, hips, knees, ankles, feet (i.e. hand to head, and head to toe). A good initial position is with the child sitting in a chair, or on the side of a bed, with the hands resting on the thighs.

The easiest places on the body to visualise capillaries are the nail folds (dermatoscope or auroscope may be needed) and along the teeth/gum line. This is where the underlying pathological lesion, capillary vasculopathy, can best be assessed. The findings of capillary branching/tortuosity and dilation, areas of haemorrhage and reduced number of capillaries (<3 per millimetre) can all be seen with nail-fold capillaroscopy. Paediatric rheumatologists may use a stereomicroscope with microscopic oil to cut down on skin reflection, or simply a magnifying glass with water-soluble gel. Counting capillaries at the distal nail fold can predict disease activity, muscle strength and function, as well as skin activity.

Management

Goals of JDM management

1. Control inflammation.

2. Restore muscle strength.

3. Maintain functional abilities.

4. Prevent and treat complications.

5. Minimise treatment side effects.

6. Educate the parents and patient regarding the disease.

First-line treatment

There is a paucity of randomised controlled trials for treatment choices in JDM. Corticosteroids (CS) are needed in relatively high doses to restore muscle power as quickly as possible, whilst commencement of a maintenance agent (e.g. MTX) will allow weaning the steroids later and helps with controlling the skin rash. Physiotherapy is started as early as possible, and other allied health professionals, such as a speech therapist, may be needed to assess the aspiration risk. The use of steroids has reduced the mortality in JDM from 40% to 3%, although with modern treatment this rate is probably even lower. It is likely that residual disability and the extent of calcinosis have been diminished by CS as well (although CS can occasionally cause muscle weakness, osteoporotic fractures and avascular necrosis, which can adversely affect disability). The oral prednisolone/prednisone dosage is usually 1–3 mg/kg per day, although doses larger than 1 mg/kg are associated with far greater side effects without much additional therapeutic benefit. The aim of the treatment should be to start weaning the CS dose as soon as the patient’s clinical condition allows, to minimise side effects. Oral steroids are given as a morning dose to minimise their impact on growth, and alternate day doses must be avoided to reduce the possibility of relapse. Intravenous methylprednisolone pulses (IVMP) are used if the overall disease severity is deemed high, or if there is incomplete response to oral corticosteroids. Aggressive induction of therapy, including the use of IVMP, seems to lead to less relapsing disease, residual weakness or calcinosis. IVMP also may be useful for treating serious complications such as myocarditis or dysphagia, as well as for treating the skin manifestations. High-dose IVMP is a potent immunosuppressive agent, and meticulous attention needs to be given to the possibility of developing infections, with aggressive treatment of the same required. During the infusion, side effects may include flushing, headache, a metallic taste in the mouth and hyper/hypotension, requiring measurement of vital signs every 15 minutes.

Other drugs used may include azathioprine (AZA), cyclosporine (CSA) and cyclophosphamide (CPA). Other immunomodulating agents include intravenous immunoglobulin (IVIG), plasmapheresis and tacrolimus. The use of any of these agents may be determined by the severity of disease and its complications, or the extent of vasculitis.

Methotrexate (MTX)

MTX inhibits dihydrofolate reductase, which is needed to make DNA and some amino acids, although its exact mechanism of action is not understood. Lower doses are used in rheumatology than in oncology. MTX was originally a second-line agent used with steroids for refractory disease, but recently there has been a shift towards earlier use of MTX as a steroid-sparing agent. Benefit is apparent within 6-8 weeks after the dosage is optimised (although it can take up to 12 weeks before a positive effect is seen). The side effects include the following (mnemonic MTX):

M. Mucositis/Myelosuppression

T. Transaminase increase (i.e. hepatotoxicity)

X. X-rays warranted (chest X-ray for pneumonia [e.g. varicella pneumonia, ] or pneumonitis (exceedingly rare)/Xtra folate recommended

Other opportunistic infections can occur; for example, cutaneous herpes zoster, herpes simplex, Listeria monocytogenes meningitis and tuberculosis. Varicella fulminans may complicate treatment of patients who have not been immunised or exposed in the past. Therefore measurement of VZV antibody titres is recommended prior to commencement of CS or immunosuppressive therapy. In combination with CS, there is an increased risk of opportunistic infection. Unfortunately, not all patients will respond to the combination of steroids and MTX.

Cyclophosphamide (CPA)

Pulse IV-CPA has been used for severe disease with vasculitic predominance; for example, skin and gut ulceration, and interstitial lung disease. The side effects are as follows (mnemonic CPA):

C. Cystitis (haemorrhagic)

P. Pancytopenia

A. Activation of latent or opportunisitic infections (e.g. herpes zoster, TB, PCP)

Intravenous immunoglobulin (IVIG)

This has, presumably, multiple mechanisms of action. A regimen of 2 days’ consecutive treatment monthly leads to the peak effect after 3 months. Some units use this monthly treatment for up to a year. The response is comparable to that of pulse methylprednisolone and cyclosporine, although this is variable and depends on individual cases. Side effects include infusion-related toxicities (e.g. hypotension, fever), aseptic meningitis, and thromboembolic events caused by increased viscosity.

Azathioprine (AZA)

This is a purine analogue, metabolised to 6-mercaptopurine, which inhibits purine ribonucleotide synthesis. It can lead to complete or partial remission in up to 70% of patients when used as the second-line immunosuppressive. It has relatively fewer side effects than the other cytotoxics, although it may not be as efficacious. Measurement of thiopurine methyltransferase (TPMT) enzyme is required to assess the risk of leukopaenia. Its onset peak effect is at 3–6 months after initiating treatment. It can cause gastrointestinal upset, and bone marrow suppression with leukopenia. In combination with CS, there is an increased risk of opportunistic infection.

Cyclosporine (CSA)

A prodrug derived from fungi, CSA binds to an intracellular protein ‘cyclophilin’, which inhibits activity of a calcium-regulated enzyme, calcineurin, required for transmitting activating signals from T-cell receptors. There are several noteworthy side effects (mnemonic CSA):

C. Compromised kidneys (nephrotoxicity includes irreversible vasculopathy, interstitial fibrosis, tubular damage)

S. Secondary malignancy potential (especially lymphoproliferative)

A. Anaemia/Accelerated blood pressure (hypertension), hair growth (hypertrichosis) and gums (gingival hyperplasia)/Additional myopathy (caused by CSA per se; this can contribute to osteoporosis)

There is little published evidence to support the use of CSA in JDM, though anecdotally some paediatric rheumatologists will quote it as being effective.

Biological agents

Those already tried in JDM include the tumour necrosis factor-alpha (TNF-α) inhibitors etanercept and infliximab, and the B-cell depleter rituximab. Biological agents are increasingly being trialled in children with severe disease that is refractory to standard therapy. For more details about these agents, see the long-case section on JIA.

Prognostic predictors

Some units use second-line agents in patients with factors known to portend a worse prognosis, including those with: (a) severe disease—vasculitis and anisarca, particularly with complications of calcification, ulceration, interstitial lung disease or significant dysphagia; (b) particular myositis-specific autoantibodies (MSAs); or (c) delayed treatment.

Life-threatening disease (e.g. myocarditis, severe dysphagia)

Treatments have included pulse methylprednisolone, oral CPA, pulse IV-CPA, plasmapheresis or combination therapies (e.g. MTX + AZA; IVIG + CSA).

Extramuscular disease

1 Calcinosis

This is more common where there has been a delay in starting treatment, and in polycyclic disease, local trauma and treatment with low CS doses. All the following treatments are anecdotal and there is no evidence for their efficacy, although there is common agreement that aggressive treatment of active disease will treat or reduce calcinosis. These include: colchicine; surgical removal (some cases); diltiazem (but can induce flares of myositis); aluminium hydroxide; oral, intralesional and intravenous magnesium sulphate and magnesium lactate; pamidronate (a bisphosphonate); and lithotripsy. More recently, treatment with the biological agents infliximab (a monoclonal antibody to TNF-α) and etanercept (a soluble TNF receptor fusion protein), and the immunomodulator thalidomide (which inhibits TNF-α and IL-6 mRNA expression in peripheral blood mononuclear cells) have shown some promise in treating this complication.

2 Skin disease

Sun protection using sunscreens, and sun avoidance, are paramount to help controlling disease and prevent relapse. Hydroxychloroquine as an adjunct to MTX or other cytotoxics may be useful. Antihistamines may be needed for associated pruritus. Other agents that can improve rashes include methylprednisolone, MTX, CSA, IVIG and dapsone.

3 Osteoporosis

This is multifactorial: (a) steroid use; (b) decreased muscle bulk and mobility; (c) deposition of resorbed bone calcium in calcinosis; (d) decreased GIT calcium absorption; and (e) production of cytokines that resorb bone (during active disease). With steroid therapy, if dietary intake is inadequate, supplementation with calcium and vitamin D is recommended.

Prognosis

The mortality rate has been quoted as 3%, although this is probably lower with modern therapy and an aggressive approach. Morbidity is relatively high, especially from delay of treatment, or from medication side effects. Treatment should generally be continued for a couple of years for consolidation and maintenance, although in individual cases this may be shortened (monophasic disease in adolescents). A periungal capillary count of <3 per mm is associated with relapse if treatment is withdrawn.

Systemic lupus erythematosus (SLE)

SLE is a multi-system autoimmune disease that usually affects older children and adolescents, although rarely younger children (<9 years old) can be affected. The main problem is persistent non-specific polyclonal B-cell activation, which causes immune complexes to be deposited widely in various organs. Compared to adults with SLE, there is a change (increase) in the frequency of several aspects of SLE in children (mnemonic CHANGE):

C. Chorea

H. Hepatosplenomegaly

AN. Avascular Necrosis

G. Glomerulonephritis

E. Exclusively paediatric problems: growth abnormalities, and neonatal lupus

Paediatric SLE is a multi-faceted chronic disease both in terms of the problem list and management, and would be an ideal long case.

Background information

The incidence of SLE with paediatric onset (under 19 years), is up to 19 per 100,000 in white females, and higher in black (20–30 per 100,000) and Puerto Rican (16–36 per 100,000) females. It is 10 times more common in females. It usually becomes apparent in the second or third decade. It is more common in African Americans, Asians and Arabs. There is a genetic component, with 30% concordance in monozygotic twins, an increased susceptibility to SLE with certain HLA haplotypes (HLA-DQ loci) and deficiency of early complement components (homozygous deficiency of C1q, C1r, C1s, C4, C2). These deficiencies remain the strongest susceptibility factors to SLE yet identified.

It has been hypothesised that the cause of SLE could be failure to maintain self-tolerance, secondary to defective removal of apoptotic cells (apoptosis = programmed cell death). A common feature of the autoantigens in SLE, particularly chromatin and the phospholipids, is that they are components of the surface blebs of apoptotic cells. Condensation and fragmentation of the nucleus, plus internucleosomal cleavage of chromatin, lead to the formation of apoptotic bodies and blebs. If there is disturbed removal of apoptotic cells, these could become antigenic targets for autoantibodies. Other non-genetic factors that may increase the likelihood of developing SLE include oestrogens (androgens protect), UV light and certain medications. There is a range of medications that are definitely associated (e.g. procainamide, hydralazine), and several that are possibly associated (e.g. minocycline) with SLE.

History

Presenting complaint

Reason for current admission.

Symptoms

This is essentially an extensive systems review. The three common organ systems involved in pSLE are the skin, and the musculoskeletal and renal systems. The most common clinical features include (in approximate descending order): rash (any type), arthritis, fever, nephritis (all of these are present in over 50% at presentation), lymphadenopathy, hepatosplenomegaly, malar rash (specifically, these present in about one third at presentation), neuropsychiatric disease, gastrointestinal disease, pulmonary disease and cardiovascular disease (these last four are uncommon in pSLE). Constitutional symptoms such as fever, fatigue/malaise and weight loss are very common at presentation and with flares of disease:

1. General (anorexia, malaise, pallor, weight loss, fatigue).

2. Skin (malar rash [in 33%], purpura), mucous membrane (palate ulcers), hair loss or scalp ulceration.

3. Joints: symmetrical polyarthritis, usually non-erosive (Jaccoud type of arthritis; reversible subluxation due to tenosynovitis) may present with morning stiffness, pain and swelling.

4. Cardiovascular (Raynaud’s phenomenon, cardiac failure symptoms due to myocarditis, chest pain from serositis or, less likely, myocardial ischaemia).

5. Respiratory (recurrent chest infections, pleuritic chest pain, dyspnoea).

6. Renal (hypertension, oedema, haematuria).

7. Neuropsychiatric (headache, cerebrovascular disease, seizures, chorea, personality change, decreased school performance, depression, suicidal ideation, acute confusional state, anxiety, cognitive dysfunction, psychosis [occurs in 50% of patients with neuropsychiatric involvement]).

8. Abdominal pain (e.g. serositis, pancreatitis).

9. Menstrual abnormalties (due to SLE per se or steroids).

10. Endocrine (diabetes).

11. Drug effects (e.g. steroid effects: Cushing’s syndrome, hypertension, poor height gain, myopathy, osteoporosis (± fracture or vertebral body collapse), avascular necrosis (AVN), especially hips and knees.

Past history

Initial diagnosis (when, where, presenting symptoms, initial investigations), recognised aetiologies such as complement deficiencies, drug-induced disease (e.g. hydralazine, alpha-methyldopa, penicillamine, isoniazid, chlorpromazine), number of hospitalisations, sequence of complication developments and their management.

Management

Present treatment in hospital, usual treatment at home, previous treatments tried, side effects, compliance, use of identification bracelet.

Social history

Disease impact on child (e.g. school absenteeism, limitation of activities of daily living, impact of disease manifestations and side effects of treatment, such as malar rash, hair loss from cyclophosphamide or weight gain from steroids). Impact on family (financial considerations, such as cost of frequent hospitalisation, private health insurance), impact on siblings (e.g. sibling rivalry), benefits received (e.g. Child Disability Allowance), social supports (e.g. Lupus Association).

Understanding of disease

By child and by parents. Ask about the degree of previous education (e.g. in hospital, by local paediatrician) and contingency plans (e.g. who to contact first when the child is unwell).

Examination

The procedure outlined here would also be suitable for a short-case approach.

General observations

1. Well or unwell.

2. Pallor (anaemia; various mechanisms).

3. Cushingoid features (steroid treatment).

4. Parameters: height (e.g. short due to steroids); weight (e.g. obese due to steroids).

5. Skin rashes.

6. Joint swelling, gait problems.

7. Peripheral oedema (renal disease).

8. Posturing (e.g. hemiplegic).

9. Involuntary movements (e.g. chorea, hemiballismus, tremor, parkinsonian-like movements).

10. Respiratory distress (e.g. pneumonitis, pulmonary oedema).

11. Impression of mental state (e.g. depressed, or difficulty concentrating, with neuropsychiatric involvement).

In a short-case setting, request the following;

1. Temperature chart (fever, e.g. infection from leucopenia, steroids or cytotoxics).

2. Blood pressure (hypertension, from renal disease or steroids).

3. Urinalysis (blood, protein [renal disease]; glucose [steroids, or frank diabetes]).

After this, the systems involved are screened sequentially.

Skin, hair and mucous membrane

Thorough inspection of the skin for rashes (including: malar rash over cheeks and nasal bridge, sparing nasolabial folds, photosensitive rash, vasculitic rash [may include ulceration, nodules and palpable purpura], discoid lesions, Raynaud’s phenomenon, palmar/plantar erythema); digital ulcers; hair for alopecia, broken hairs; mucous membranes (oral and nasal) for hyperaemia and petechial rashes on the hard palate, ulcers (painless) or infection.

Joints and bones

Full joint screening examination (after enquiring if the child has pain anywhere; always get the patient to move his or her joints first [active range of movement] before passive investigation [the candidate moving the joints] and ask if any joints hurt; if this order is forgotten, the patient could be hurt). Particularly note wrists, hands, knees and feet, as these tend to be more commonly affected. Get the patient to walk normally (looking particularly for limp; avascular necrosis of the hips or knees can occur in around 10% of pSLE). Perform Trendelenberg’s test to detect proximal weakness (with unilateral or bilateral hip disease, or proximal myopathy; both can occur due to steroids). Detailed examination of any involved joints is important (but be aware of time constraints).

Neurological and eyes

Look for lateral localising signs, screening eye examination for common complications; for example, glaucoma or cataracts.

Gait and lower limbs

Full gait examination, to detect limp (e.g. from AVN of femoral head or knee due to steroids), hemiplegia, other focal deficits, cerebellar ataxia, peripheral neuropathy or proximal myopathy (steroids, SLE per se).

Upper limbs and/or cerebellar involvement

Arms held straight out in front of body (screen for chorea, tremor, monoplegic posturing). Finger–nose test (screen for cerebellar ataxia with eyes open, and for sensory neuropathy with eyes closed).

Cranial nerves

Test motor cranial nerves (mononeuritis multiplex; trigeminal neuropathy, facial nerve palsy, extraocular muscle weakness). Look for nystagmus (cerebellar involvement). If the child has focal deficits, also check the visual fields (e.g. for hemianopia). Inspect for episcleritis. Ophthalmoscopy: check for cataracts (steroids); retinal cottonwool exudates, haemorrhages.

Cardiorespiratory

Before palpating the chest, take the pulse (e.g. tachycardia or arrhythmia with myocarditis) and count the respiratory rate. Check the blood pressure (if you have not already requested this, in the short case) for narrow pulse pressure (myocarditis) or hypertension (renal involvement). Examine the praecordium (for cardiac manifestations; e.g. pericarditis, myocarditis). Examine the posterior aspect of the chest: percuss the lung fields for pleural effusion; percuss over the vertebrae for compression fractures (steroid side effect); auscultate the lung fields (e.g. for pleuritis, pneumonitis). Examine the lymph nodes (lymphadenopathy).

Abdomen

Inspect for scars (e.g. peritoneal dialysis, renal transplant, laparotomy for acute abdomen). Palpate for tenderness (serositis), hepatosplenomegaly (SLE per se) and inguinal lymphadenopathy (SLE per se). Percuss for shifting dullness if there is any peripheral oedema or pleural effusion.

Diagnosis

The diagnosis of SLE is aided by the revised 1982 American College of Rheumatology (ACR) criteria. These criteria have been validated for using in children with a sensitivity and specificity of 96 and 100%, respectively. The 1997 ACR criteria, although widely used in paediatric SLE, have not yet been formally validated. A child is said to have SLE if four or more of 11 selected criteria are present, either serially or simultaneously. Each criterion has a specific definition (refer to the standard texts). The 11 criteria are: malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal disorder, neurological disorder, haematological disorder, immunological disorder and antinuclear antibody.

Investigations

SLE is characterised by the production of autoantibodies directed against a wide range of proteins: histone, non-histone, RNA-binding, cytoplasmic and nuclear proteins. The following lists the antibodies and their approximate frequency in SLE (derived from adult data):

• Antinuclear antibodies (ANA): up to 100%.

• Anti-U1 RNP antibodies (an RNA-binding protein): 70–90%.

• Anti-DNA antibodies: 60–70%.

• Anti-cardiolipin (aCL) antibodies (antiphospholipid antibodies): 50%.

• Anti-Sm antibodies (another RNA-binding protein): 40–50%.

• Anti-Ro antibodies: 30–40%.

• Lupus anticoagulant (LAC) antibodies (antiphospholipid antibodies): 20%.

• Anti-La antibodies: 15–20%.

• Antiribosomal antibodies: 15%.

This list is given for completeness, and does not indicate clinical usefulness, which is covered below. The following investigations may be useful.

Simple screening tests

1. Haemoglobin (e.g. haemolytic anaemia; relative macrocytosis, or normocytic anaemia of chronic disease).

2. White cell count (e.g. leukopenia).

3. Platelet count (e.g. thrombocytopenia).

4. Antinuclear antibodies (ANA), directed against a number of autoantigens. This is one of the hallmarks of SLE. This is the best simple screening test. Be aware that persistently positive ANA in the absence of other objective evidence of rheumatic disease does not suggest a chronic rheumatic disease by itself. The vast majority of ANA-positive children do not have SLE. At least 10% of the normal paediatric population are positive for ANA.

5. Inflammatory markers: ESR is typically elevated in the presence of a normal CRP. If the latter is elevated, infections must be meticulously searched for.

6. Urea, creatinine, electrolytes (to assess renal function).

7. Urinalysis (for protein, blood, or cellular casts).

More specific tests for pSLE

Blood

1. Double-stranded DNA (dsDNA) antibodies (relatively specific to SLE; correlates with more severe systemic involvement, e.g. renal disease); DNA–Farr (radioimmunoassay); DNA–Crithidia titre (immunofluorescence). DNA binding is also useful. dsDNA may be useful in disease monitoring; for example, renal or CNS disease.

2. Antibodies to extractable nuclear antigens (e.g. Ro [SSA], La [SSB], Sm, RNP). Antibodies to Ro and La are associated with neonatal lupus, and occur with increased frequency in children of mothers with SLE. Antibodies to Sm are very specific for patients with SLE: they are found in about two thirds of SLE patients.

3. CH-50, C3, C4 (usually low values in active disease). C3 and C4 are useful in monitoring disease activity. Isolated deficiencies (e.g. C2) may be found.

4. Coomb’s (direct antibody) test (e.g. positive with immune-mediated anaemias).

5. Clotting profile (e.g. prolonged PTT with circulating lupus anticoagulant; paradoxically, a tendency for thrombotic events in vivo).

6. Antiphospholipid antibodies (aPL): includes anticardiolipin antibody (aCL) and lupus anticoagulant (LAC). Associated with recurrent thromboembolic events.

7. Liver function tests (raised enzymes in salicylate hepatotoxicity or active SLE).

8. Creatine phosphokinase (myositis).

Cerebrospinal fluid

No consistent CSF abnormalities are found with neurological sequelae of SLE, although pleocytosis, elevated protein level and low glucose level may occur. CSF examination helps to exclude haemorrhage and infection, but is not part of a standard assessment of a patient with SLE.

Imaging

1. Chest X-ray (e.g. pneumonitis, myocarditis).

2. Bone X-rays (e.g. vertebral collapse).

3. Neuroimaging (all but MRI scan are research tests so far):

(a) Cranial MRI scan (e.g. localised areas of vasculitis), MR angiogram, MR venogram.
(b) SPECT (single-photon-emission computerised tomography) imaging (e.g. areas of hypoperfusion; often in parietal and cerebellar lobes).
(c) NMR (nuclear magnetic resonance) spectroscopy (e.g. areas with decreased ATP [adenosine triphosphate] levels).
(d) PET (positron emission tomography) scanning (areas of hypometabolism; often in temporal and parietal lobes).
(e) Conventional cerebral angiography is not usually performed. It is usually normal in patients with neurological or psychiatric manifestations of SLE (perhaps due to the small size of the vessels affected by lupus vasculopathy), although a positive result may suggest vasculitis or anti-phospholipid syndrome.

4. Cardiac imaging: echocardiography—M-mode, two-dimensional, Doppler and/or transoesophageal (endocarditis vegetations, mural thrombi, other cardiac source for emboli).

Neurophysiological testing

1. EEG (abnormalities may occur in children with neurological sequelae of SLE, but are non-specific).

2. ECG (e.g. pericarditis, arrhythmias).

Urine

A 24-hour urine collection for creatinine clearance and protein.

Other

1. Renal biopsy is indicated if significant abnormality is detected in the urinalysis. Many children with SLE will have a renal biopsy. The vast majority of children with SLE have some form of renal disease. Various forms of glomerulonephritis (GN) can occur; for example, mesangial GN, focal and segmental proliferative GN, diffuse proliferative GN (DPGN), membranous GN and mixed patterns.

2. Pulmonary function testing (e.g. interstitial lung disease).

3. Neuropsychological assessment (for children with neurological involvement; there is some evidence that this may be the best test for CNS lupus).

Management

The treatment goals are as follows:

1. Control disease activity (prevent and suppress disease flaring) to restore health towards normal.

2. Prevent scarring of organs (e.g. kidneys, brain).

3. Minimise adverse drug side effects (e.g. Cushing’s syndrome).

In general, systemic (oral or intravenous, or a combination) steroids are used for their quick onset of action to reduce disease activity. As with the treatment for JIA, a maintenance agent will be needed to allow reduction of the steroid dose as soon as possible. This could include methotrexate, azathioprine or mycophenolate mofetil. Hydroxychloroquine is used for its beneficial effect on skin rashes, and for long-term protection against cardiovascular events.

General measures

The role of the general paediatrician (the candidate) is as a coordinator of overall care, in conjunction with a paediatric rheumatologist and other health professionals; for example, a nephrologist. The candidate should ensure that the family is appropriately educated regarding SLE, and its complications and treatment (and its side effects), and that there are adequate contingency plans in case of intercurrent illnesses or flares in disease activity. An identification bracelet should be worn (indicating whether taking steroids), and general measures such as adequate exercise and a well-balanced diet should be encouraged.

Sun exposure should be minimised, as it can cause a systemic flare and worsen the skin component. Use sun-blocking agents with a high sun-protecting factor, and protective clothing (long sleeves, hat). Photosensitive rashes, especially annular erythema, are associated with anti-Ro and anti-La antibodies.

The child should receive the normal immunisations, unless receiving cytotoxics or high-dose steroids, when live viral vaccines are avoided. Sulphonamide drugs are best avoided, as children with SLE may have severe toxic reactions to them.

Preventative management for osteoporosis may include adequate exercise, a high calcium intake and adequate doses of vitamin D.

There may well be a number of social issues, including those specifically related to adolescence. A chronic disease conflicts with the desires for independence, peer acceptance and sexual activity, and SLE can have particularly obvious physical stigmata (e.g. malar rash). Problems to be addressed can thus include low self-esteem, poor self-image, lack of compliance and even suicidal ideation.

The issue of pregnancy whilst on cytotoxics needs to be discussed with the adolescent. Although the majority of female patients can probably tolerate an oral contraceptive pill, this should only be prescribed with caution, as the pill can induce SLE, and cause hypertension, thrombosis and chronic active hepatitis. For this, combined preparations with low-dose oestrogen, or progesterone only, preparations are preferable. In addition, barrier methods should be encouraged (a condom or diaphragm with spermicidal foam). The risks of pregnancy (which can be particularly hazardous if the patient is taking cytotoxics, or has renal disease) must be discussed with the adolescent girl. She should be aware of the following:

1. The occurrence of the ‘postpartum backlash’; that is, relapse of the disease.

2. The SLE association with increased miscarriage, and neonatal lupus with congenital heart block (see later).

3. Pregnancy must be carefully planned—that is, with blood pressure, renal disease and haematological indices under control—and is best timed when in remission, or stable for over 12 months.

Steroid usage can cause amenorrhoea, without interfering with ovulation, giving the patient a false sense of security. This may lead to unprotected intercourse and an unplanned pregnancy. Male adolescents receiving cytotoxics should be informed about the availability of sperm banks.

A key to managing an adolescent is allowing the patient to self-manage their disease as much as is practicable.

Specific measures

There is some variation between different centres regarding optimal treatment, including whether to treat only clinical disease flares or to treat serological flares (e.g. rising anti-double-stranded DNA antibodies, falling complement; decreases in C4 preceding, and decreases in C3 coinciding with, disease flares), or a balance between these options. Treatment is individualised for each patient; in selected patients, serological measurements may be useful guides to timing of treatment courses. A staging system has been developed, mirroring the example of the oncologists, by the Hospital for Special Surgery in the USA. There are 10 stages of increasing severity.

Main agents used

Corticosteroids

Most children with SLE will need steroids at some stage of their management, as most children have systemic disease. Severe systemic disease (e.g. renal involvement, haematological complications, pleuritis, pericarditis) requires steroids. Steroids will rapidly bring more minor problems (e.g. fever, arthritis and myositis) under control. Severe active disease is not likely to respond to oral steroids alone, and the use of IV methyl prednisolone may be indicated. Although this treatment is often well tolerated, its use must be carefully monitored, as occasional side effects may include hypertensive crises and fatal cardiac arrhythmias.

The side effects of steroids are well known and already alluded to in the section under JIA treatment. Children generally develop Cushingoid features if they take over 0.25 mg/kg prednisolone per day for over a month. A radioreceptor assay can measure steroid activity (plasma prednisolone equivalents). Catch-up growth after cessation of treatment may not be complete, as chronic disease may also compound growth failure. Children who have had more steroids are more likely to develop more significant sepsis.

Non-steroidal anti-inflammatory drugs (NSAlDs)

This class of medications may be used to control the symptoms of disease; for example, fever or arthralgia/joint stiffness. Problems with aspirin include the risk of salicylate hepatotoxicity (if liver enzyme levels are increased twofold or threefold and persist, aspirin should be ceased), concern regarding Reye’s syndrome and possible alteration of glomerular filtration rate (GFR). Aspirin is also contraindicated in thrombocytopenia. All NSAIDs can adversely affect the GFR, so caution or avoidance in renal disease is recommended.

Hydroxychloroquine

This may be useful for skin and joint involvement. Side effects include renal and retinal toxicities (maculopathy) and gastrointestinal symptoms. Rarely, cardiomyopathy and neuromyotoxicity have been reported.

Cytotoxics

Methotrexate (MTX) is effective as a steroid-sparing agent in musculoskeletal disease. Low-dose (10–20 mg per square metre), once-a-week MTX is safe; folate supplementation decreases side effects. It is given orally, although the parenteral route has more efficacy and is associated with less toxicity. Side effects include oral ulcers, gastrointestinal and bone marrow toxicities. Regular (1–2 monthly) blood tests are performed to detect any liver impairment or marrow involvement. Long-term studies of MTX in SLE have yet to be published.

Other cytotoxics can be useful in children with uncontrolled progressive disease, or severe steroid side effects (e.g. significant growth failure), again based largely on anecdotal evidence. Agents used include oral azathioprine (AZA) or cyclophosphamide (CPA), and intravenous cyclophosphamide (IV-CPA) pulses. Mycophenolate mofetil has recently been trialled head to head against oral cyclophosphamide and found to be as effective in treating nephritis, with fewer side effects.

Short-term effects of IV-CPA pulses include bone marrow suppression and significant hyperemesis (which can be minimised, either by giving frusemide 8–12 hours after the CPA dose, or by using ondansetron, the 5-HT3 receptor antagonist). Long-term effects of IV-CPA such as risks of infertility [around 17%] and neoplasia also need consideration. Cyclosporine A (CSA) can used for class V nephritis, as an alternative to AZA or MMF. A paediatric rheumatologist should decide if, when and which cytotoxics should be used, after careful discussion of the risk–benefit profile with the family.

A major use for these agents is severe renal pSLE. These children may need prolonged treatment. The role of cytotoxics in treating extrarenal disease is less clear.

Approach to treatment of specific system involvement

Life-threatening systemic disease

Intravenous steroids pulses (IVSP), IV-CPA and plasmapheresis.

Kidneys

Renal involvement in SLE is as follows (simplified schema of WHO classification):

WHO class I Normal light microscopy

WHO class II Mesangial lupus nephritis (around 20% of cases)

WHO class III Focal proliferative glomerulonephritis (GN) (around 20% of cases)

WHO class IV Diffuse proliferative GN (just under 50% of cases)

WHO class V Membranous GN (around 10% of cases)

WHO class VI Sclerosed glomeruli

Treatment is based on renal histology. Severe renal involvement requires intensive and prolonged treatment. Steroids (high-dose oral prednisone, or pulse intravenous doses of methylprednisolone, if required) and cytotoxics as above are often needed:

• WHO class II: low-dose steroids—short course, slow taper, excellent outcome. Some nephrologists use angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blocking agents (ARBs) alone, to decrease proteinuria.

• WHO class III and IV: high-dose steroids—slow taper, add second agent after biopsy to confirm histology. Second agent: MMF, AZA or CPA. MMF and AZA are safer. Class IV usually responds to steroids. For active SLE complicated by class IV, intravenous (IV-) CPA may be indicated. One effective regimen used monthly IV-CPA for 7 months, then IV-CPA every 3 months for the next 30 months. As the CPA-related toxicity is cumulative, there is a recent trend to use only 6 once-monthly CPA pulses as induction, and concomitant use of cytotoxics for maintenance. With this treatment, many children have exhibited marked improvement in their overall well-being, including a decrease in infection, cerebritis, arthritis and emergency hospitalisation. If nephrotic syndrome occurs, AZA may be useful.

• WHO class V may well respond to low-dose steroids. Some patients require prolonged steroids, then CSA, AZA or MMF. ACE inhibitors or ARBs are used as well to decrease proteinuria. Anticoagulation may be required, due to the risk of renal vein thrombosis, and possible pulmonary embolism.

Some children have histology that demonstrates more than one pathology type; for example, WHO classes II, III, IV and V. Treatment is directed against the most serious (proliferative) component.

Biological agents (e.g. rituximab, an anti-B-cell [CD20] antibody) have been tried and reported on, in small studies, in severe treatment-resistant lupus nephritis, with some success; rituximab has also been used successfully for severe haematological involvement.

Autologous stem cell transplantation has been successful in inducing remission in severe treatment-resistant cases.

Children with significant renal disease usually manifest haematuria and proteinuria within 6 months of initial diagnosis of their SLE. Progression to chronic renal failure (CRF) is associated with class IV, persistent hypertension lasting over 4 months, abnormal urinalysis, elevated creatinine and anaemia. If CRF and then end-stage renal disease (ESRD) supervene, dialysis may be needed while awaiting renal transplantation (RTx). Lupus can recur in transplants, but only rarely.

Children who receive RTx have a better prognosis than those on dialysis (see the section on RTx in Chapter 13, Nephrology). Those children with poor prognostic factors are treated aggressively, and those with ESRD have transplants as soon as possible.

Hypertension

Thiazide diuretics and beta blockers are the first line. If there is renal disease, especially with proteinuria, an ACE inhibitor, such as captopril, is first line. Avoid drugs that can cause SLE (e.g. hydralazine, methyldopa). Second-line agents include calcium channel blockers and minoxidil. If hypertension is uncontrolled, it can aggravate vasculitis and renal disease. Hypertension will be aggravated by steroid treatment.

Cardiovascular

The main cardiovascular system morbidity in pSLE is premature atherosclerosis. The most common cardiac manifestation is pericarditis with pericardial effusion. Other forms of involvement include endocarditis and myocarditis, which can be treated with steroids. Pericarditis can respond to NSAIDs alone. Valvular heart disease can occur, in association with aPL antibodies or with non-infective endocarditis. Libman–Sacks verrucous endocarditis can occur in acutely ill children with pSLE. The most commonly affected valves in order (left two, then right two) are as follows: mitral, aortic, pulmonary, tricuspid. There is an inflammatory infiltrate first, then the formation of nodules of fibrinoid necrosis of the supporting connective tissue of the valve. Treatment may involve high-dose steroids, cytotoxics or surgery. The main cardiovascular morbidity, however, is premature atherosclerosis. The main risk factor for this is ongoing chronic inflammation of pSLE itself. Steroids could theoretically make atherosclerosis worse. Most children with SLE will develop significant dyslipidaemia, which increases their risk of atherosclerosis in later life. Antimalarials such as hydroxychloroquine have an advantage of lipid-lowering among their many effects. Input from dieticians and physiotherapists will help avoid high blood lipid levels and obesity, and will help optimise physical exercise. In North America, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) has launched the Atherosclerosis Prevention in Pediatric Lupus Erythematosis (APPLE) prospective study, assessing the role of statins in the prevention of atherosclerosis—the largest prospective study ever undertaken in pSLE.

Pulmonary

Steroids, plus antibiotics if infection is suspected. If severe pulmonary haemorrhage occurs, use pulse IV steroids and cytotoxics. In severely ill patients, multiple antibiotics, high-dose steroids and positive pressure ventilation may be required. Children with pSLE should have opportunistic infections excluded (such as herpes, Pneumocystis carinii, legionella or fungal infections) before introducing cytotoxic agents.

Neuropsychiatric SLE (NP-SLE)

In 1999, the American College of Rheumatology divided NP-SLE into 19 separate conditions. Some of the more common ones are headache, psychosis, mood disorder/depression, cognitive dysfunction, cerebrovascular disease, seizures and movement disorders. An infrequent manifestation of NP-SLE is neuropathy (cranial [more common] and peripheral). As the area is complex, treatment decisions should involve a team including psychiatrists, psychologists, neurologists and rheumatologists. In general, high-dose steroids and cytotoxics (AZA or CPA) are used. Psychotropic drugs, antidepressants and anticonvulsants may be needed as well. Analgesia can be ineffective in lupus headache. The underlying cause for the headache must be sought and that cause treated (e.g. cerebral vein thrombosis [CVT], raised intracranial pressure from CNS infection or pseudotumour cerebri, active CNS vasculitis or systemic steroids). It may be difficult to determine whether behavioural problems are secondary to having a chronic illness or secondary to NP-SLE. Aggressive treatment of NP-SLE is indicated, as this complication can be fatal. There have been no published NP-SLE treatment trials in paediatric populations. In adults, high-dose CPA with or without autologous haematopoietic stem cell transplantation has been used with success in severe life-threatening SLE with neuropsychiatric manifestations that are unresponsive to other treatment.

Joints

A combination of hydroxychloroquine and MTX is often used as maintenance treatment, whilst low-dose steroids and NSAIDs may be used to treat joint symptoms. Physiotherapy, including a personalised goal-oriented home exercise programme (HEP), is essential to maintain joint function and aerobic fitness, as well as minimising bone loss.

Skin

Avoid sun exposure wherever possible. Adopt appropriate clothing and the use of sunscreen (with a sun protection factor at least 30), topical steroids for discoid lesions, and oral agents (hydroxychloroquine, methotrexate, with or without low-dose steroids). Raynaud’s phenomenon is less common in paediatric than in adult SLE: management is by avoidance of cold exposure, appropriate clothing (e.g. insulated mittens [rather than gloves]; multiple layers of clothing; hats, hand and feet warmers) to keep extremities warm, low-dose aspirin (if there is no thrombocytopenia) and, if these are inadequate, oral nifedipine or low-dose steroids, or topical nitroglycerine paste.

Other organ system involvement

As seen above, the most common organ systems involved in pSLE are the skin, and the musculoskeletal and renal systems. However, other systems can be involved, albeit less often than in adults.

Gastrointestinal, liver and spleen involvement

Lupus associated vasculitis can manifest as an acute abdomen; abdominal pain can be due to peritoneal inflammation (serositis), pancreatitis, acute ischaemic enteritis, pseudo-obstruction or paralytic ileus; or the involvement of periappendiceal tissue can mimic appendicitis. Vasculitis is the underlying cause in 60% of patients with SLE who develop an acute abdomen. Mesenteric vasculitis or thrombosis can inflame the bowel wall and present with cramping abdominal pain and diarrhoea. Lupus enteropathy may also present as malabsorption, or protein-losing enteropathy. Hepatomegaly occurs in around 40% of patients; up to a quarter have abnormal liver function tests; this can be due to fatty liver secondary to prolonged steroid use—if the liver function tests are significantly elevated, then lupoid hepatitis may need consideration. Splenomegaly occurs in around 30%, whilst functional asplenia is common and increases predisposition to infection.

Endocrine involvement

The organ most commonly involved is the thyroid; hypothyroidism or hyperthyroidism can occur, the former more often. Up to a third of pSLE patients have anti-thyroid antibodies, and a third of these develop overt hypothyroidism. Diabetes mellitus, induced by steroids, occurs in 5–10% of pSLE patients, and usually needs insulin. Other endocrine complications include delayed puberty and irregular menstruation. Ovarian failure can occur as a complication of CPA, and is dose dependent; this is one reason why CPA is falling out of favour in this population, and is avoided wherever possible.

Antiphospholipid (aPL) antibodies

Antiphospholipid (aPL) antibodies are associated with an increased risk of thrombotic events (TE), chorea, epilepsy, migraine and avascular necrosis; the most commonly measured of these antibodies are anti-cardiolipin (aCL) antibodies (50%) and lupus anticoagulant (LAC) (25%) antibodies. The risk of thrombosis is less in the paediatric population than in adults. In aPL-positive children, arterial and venous thromboses have been reported, including deep venous thrombosis (DVT), pulmonary embolism, superior vena cava thrombosis, ischaemic stroke, transverse myelitis, retinal artery occlusion and renal artery occlusion. Persistently positive LAC is associated with the highest risk of TE.

Neonatal lupus

Adolescent girls with pSLE contemplating having children need to be fully aware that babies of mothers with SLE can develop features of SLE. Transient features are entirely due to transplacental passage of maternal antibodies, as they resolve with clearance of the antibodies. Examples include thrombocytopenia, leukopenia, hepatosplenomegaly, myocarditis, pericarditis and the photosensitive discoid skin rash. The other group of features are permanent, their aetiology being only partially explained by transplacental antibody passage. Examples include congenital complete heart block (CCHB; associated with antibodies to SSA/Ro [particularly to the 52 kD Ro polypeptide rather than the 60kD Ro] and SSB/La), endomyocardial fibroelastosis and other forms of structural heart disease. Fetuses with congestive cardiac failure, CCHB and pericardial effusions have been treated with some success by giving the mother dexamethasone.

Prognosis

Overall survival in pSLE approximates 95–100% at 5 years, and up to 86% at 10 years. Mortality rates are connected to socio-economic status and disease activity. The most common cause of death remains infection, usually associated with the use of steroids and cytotoxic agents. Other more common causes of mortality are cerebritis, pancreatitis, pulmonary haemorrhage, renal failure and myocardial infarction. The poorest prognosis is with class VI nephritis and severe CNS involvement. After the first 2 years of disease, new organs are much less likely to become involved, with the exception of the CNS.

Short Case

Joints

This is not an infrequent case. The approach given here has three basic components:

1. Thorough general inspection.

2. Systematic examination of all joints.

3. Examination for extra-articular manifestations of JIA and other diseases affecting joints, plus detection of drug side effects.

Figure 16.2 outlines the findings sought on inspection, plus those sought on assessing for extra-articular manifestations and drug side effects. A suggested order for this is: skin, hands, blood pressure, hair, eyes, mouth, neck, chest, abdomen and lower limbs neurologically, plus temperature chart, urine and stool analysis.

image image

Figure 16.2 Joint disease: extra-articular manifestations and drug side effects

Examination

The examination for each joint comprises inspection, palpation, movement (active first, as passive movements may cause distress and immediate loss of rapport with patient and examiners), measurement, and finally assessment of functional ability.

A useful initial screen, on being introduced to the patient, is to ask him or her to walk a short distance (for antalgic gait), take off a jumper or shirt (for upper limb function) and then write her or his name for you (hand function).

Although, ideally, the child should be undressed down to underwear, there are many children who can become embarrassed, particularly those approaching adolescence. Showing sensitivity to the child’s modesty will be well received by examiners and parents alike. If the child is younger and does not get embarrassed, then watching the child undress may yield valuable clues regarding involved joints. A good position for the examination is confrontation/mirroring (i.e. positioning yourself immediately opposite the child), so that you can demonstrate clearly what movements are required of the child, while using your own joints as reminders regarding normal range of movement.

The following is the sequence suggested for whichever joints are being examined. Inspect the distribution of joint involvement (symmetry), note swelling, loss of normal contours, angulation, deformity, redness and muscle wasting. Next, feel the joint and periarticular areas for tenderness, warmth, effusion, ‘boggy’ swelling (thickened synovium and fluid), enthesitis and contractures. The range of movement (ROM) is then examined, active movement first. Test passive movement, paying attention to presence of soft-tissue restriction; for example, tenosynovitis or joint loss of ROM. Remember to watch the child’s face to detect any discomfort. Any loss of ROM should be quantified by descriptive terms such as minimally, moderately or severely reduced (see the section on JIA). Finally, function (which correlates with strength) should be tested.

A suggested order for a systematic examination of all the joints is as follows: hands, wrists, elbows, shoulders, temporomandibular joints, cervical spine, lumbar spine, hips, knees, ankles, feet (i.e. hand to head, and head to toe). A good initial position is with the child sitting in a chair, or on the side of a bed, with the hands resting on the thighs.

Specific joints

Note that the normal range of movement (ROM) at each joint is given in degrees, in parentheses.

Upper limbs

Hands and wrists

Look at the dorsum first: note any skin rash or muscle wasting. Methodically inspect the wrist, followed by the metacarpophalangeal (MCP) joints, proximal and distal interphalangeal (PIP and DIP) joints, and the nails. Then have the child turn the hands over and look at the palmar aspect in the same systematic fashion. Look for palmar or periungal erythema or punctuate vasculitic rash of SLE. Check for Gottron’s papules over PIP and MCP joints. Next, palpate each joint for tenderness and effusion. Flex and extend the child’s fingers while palpating over the flexor tendon sheaths (for tenosynovitis). Check ROM (active, then passive). Normal ROM values (in degrees) are as follows:

1. Wrist: flexion (80°), extension (70°), radial deviation (20°), ulnar deviation (30°).

2. MCP joints: flexion (90°), extension (30°).

3. PIP joints: flexion (100°).

4. DIP joints: flexion (90°), extension (10°).

Note that the thumb can flex to contact the tips of the other digits, and abduct from the index finger (50°).

Now, test the hands with respect to function. Simple tests include: grip strength; write with pencil; use knife, fork, spoon, cup; hold toothbrush; undo and do up buttons; turn key.

Elbows

Inspection (rheumatoid nodules, JDM rash) and palpation are followed by checking ROM:

1. Flexion (135°).

2. Extension (0–10°).

3. Supination (90°).

4. Pronation (90°).

Note that supination and pronation should be tested with the elbow flexed (if possible) at 90°; a pencil held in the closed hand (making a fist) can simplify assessment of the position.

Functionally, check if the child can turn an (imaginary) doorknob, comb hair, hang out the washing, or answer a telephone.

Shoulders

After inspection and palpation, test ROM. It is usually easier to test younger children with play-like activities that produce the required movements that are to be tested. For example, you can tell the child:

1. ‘Put your hands above your head’ (demonstrate to the child): tests flexion (90°) and abduction (180°).

2. ‘Give yourself a hug’ (demonstrate): tests adduction (45°).

3. ‘Scratch your back’ (demonstrate): tests external rotation (45°).

4. ‘Hide your hands behind your back’ (demonstrate): tests internal rotation (55°) and extension (45°).

Functionally, several of the tests overlap with those for the elbows: comb hair, take off clothing, hang out washing, scratch near bottom (toileting function), and use a telephone.

Jaw and neck

Look at the jaw (especially for acquired micrognathia) and teeth (for malocclusion), and feel for tenderness, crepitus or clicking over the temporomandibular joints (TMJs), with the child opening and closing the mouth. Note the interdental distance (interincisor distance) and show to the examiners (if relevant) that you are aware of the importance of measuring this to follow the progress of TMJ disease. A normal child should be able to fit the three middle fingers, lined up vertically, between the upper and lower teeth. Look for asymmetric opening, and absence of translation (anterior movement of the jaw at maximal opening) with the chin moving towards the affected side.

Next examine the cervical spine: inspect, palpate and check ROM:

1. Flexion: chin touches chest (45°).

2. Extension: head touches back (50°).

3. Rotation: turning chin to be in line with shoulder (80°).

4. Lateral flexion: ear to shoulder (40°).

Thoracolumbar spine

Inspect with the child standing, and then bending forward (for scoliosis or kyphosis). Palpate for tenderness, over the spinous processes, the paraspinal and interspinous areas, and the sacroiliac joints. Check ROM:

1. Flexion: should be able to touch toes. Best assessed by Schober’s method.

2. Extension: arching back (30° at lumbar area).

3. Lateral bending (50° to each side)/flexion. This has equal contributions from the thoracic and lumbar spine.

4. Lateral rotation: most easily checked with child sitting (40° to each side). This is almost entirely thoracic.

To assess function, the child can be asked to pick an object up from the floor and to put on socks and shoes.

Schöber’s test measuring lumbar spine flexion can be performed; in older children, more than 4 cm of movement should be measured. With the child standing upright, a mark (e.g. texta) is made 5 cm below the iliac crest, in the midline, and a second mark 10 cm above the iliac crest, in the midline. The child is then asked to bend forward to touch their toes and the distance between the marks is measured. In adults, less than 5 cm indicates restriction of movement.

Sacroiliac joints

Palpate for tenderness over the joint; additionally, press the pelvis from each side towards the midline to assess for pain (pelvic work test). Another manoeuvre is the FABER test, which comprises Flexing the hip to 90°, and ABducting and Externally Rotating the hip (which is achieved by asking the child to put the foot of the affected side on the opposite knee), then simultaneously applying pressure to the medial aspect of the ipsilateral knee (push down the knee) and the contralateral anterior superior iliac spine (push down the opposite ASIS); this compresses the SI joint, by applying pressure over the ASIS; if the child feels pain in the SI area, this indicates SI joint involvement/inflammation.

Lower limbs

Examination can commence with watching the child walk (for antalgic gait), stand on each leg (for Trendelenberg’s sign) and squat (for proximal weakness or instability). Beware of ankle tenderness, which can result in asymmetric placement of feet on squatting. Kneeling will stress the knee joints by testing them under partial weight bearing.

Hips

Inspect the resting position (e.g. external rotation with active synovitis) and muscle bulk. Palpate for tenderness. Measure the true leg length (anterior superior iliac spine [ASIS] to medial malleolus of ankle). With the child lying on the back, check ROM. Flexion (120°) can be checked first with active movement. Then perform Thomas’ test for fixed flexion deformity.

Then test:

1. Internal rotation (35°).

2. External rotation (45°).

(Both of these are tested with hips at 90° flexion.)

3. Abduction (50°).

4. Adduction (30°).

Note that the pelvis should be stabilised (by one hand fixing the ASIS) when checking all these movements. Then, have the child turn over on to the abdomen and test extension (30°). Gait examination serves as a functional assessment.

Knees

Inspect, noting the quadriceps bulk. Feel for temperature and tenderness, and palpate entheses (at 10, 2 and 6 o’clock positions on the patella) and any synovial thickening or effusion. Test for the ‘bulge sign’ by ‘milking’ any joint fluid down the lateral aspect of the joint (look for a bulge medially) and then stroking upwards on the medial aspect, moving any fluid present into the suprapatellar bursa. Next, test for a patella tap. It may be appropriate to measure the muscle bulk of the thighs and calves if there appears to be a difference between the two sides: measure the circumference at a fixed distance (e.g. 5–10 cm) above the superior aspect of the patella, and at 10 cm below the tibial tuberosity. Also, if not already done, measure the leg length. ‘True leg length’ is measured from the ASIS to the medial malleolus of the ipsilateral leg.

Next, check the ROM: flexion (135°); extension (up to 10°).

Finally, check for knee stability. This should not be done if the knee is acutely inflamed, as the test will be painful and unnecessary. Test for anteroposterior movement with the knee joint flexed, with position fixed by sitting on the child’s foot. Check for the ‘Lachman sign’ signifying damage to the cruciate ligaments (if there is movement when the leg is pulled forwards, the anterior cruciate is ruptured; if there is movement when the leg is pushed backwards, the posterior cruciate is ruptured). Also check for lateral mobility with the knee fully extended, for lesions of the medial or lateral ligament; normally, there is no lateral movement. The McMurray sign is illustrated by applying external rotational movement on the knee whilst extending from 90° flexion and feeling for a click, or eliciting pain/apprehension in the joint, and signifies a meniscal tear.

Ankles and feet

Inspect for swelling, and loss of definition of the Achilles tendon (synovial thickening at the ankle joint). Palpate the ankle joint and entheses (Achilles insertion into calcaneus, metatarsal heads, plantar fascia insertion to calcaneus). Check the ROM.

1. Ankle: plantar flexion (50°); extension (dorsiflexion) (10–20°).

2. Subtalar joint: inversion (35–40°); eversion (15–20°).

3. Midtarsal (talonavicular and calcaneocuboid) joints: abduction (10°); adduction (20°). The midtarsal joint is tested by stabilising the calcaneus with one hand and moving the forefoot with the other.

4. First metatarsophalangeal (MTP) joint: plantar flexion (45°); extension (dorsiflexion) (70°). Note any crepitus or pain on moving the first metatarsal joint (may be selectively involved in spondyloarthropathies).

At the completion of the examination, summarise the positive findings, noting the number of joints involved, symmetry (symmetrical like juvenile rheumatoid arthritis, or asymmetrical like psoriatic arthritis), the activity of the disease (active with pain, redness), the functional severity (most important) and the differential diagnosis.

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