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.
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
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.
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.
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.
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.
History
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).
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.
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).
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
The following investigations may be helpful in JIA.
Blood tests
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.
Imaging
Management
The goals of JIA management are as follows:
1. Switch off inflammation, hence preventing permanent joint damage.
5. Treat complications and extra-articular manifestations.
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.
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.
Corticosteroids
Systemic use
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
Etanercept (ETN) (recombinant p75 soluble tumour necrosis factor receptor (sTNFR): Fc fusion protein)
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.
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.
Sequence of drugs/agents
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:
2 Provide analgesia and treat stiffness
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).
