13.3 Arthritis and connective tissue disorders

Chronic inflammatory arthritis and connective tissue disorders are associated with immune dysregulation and may affect many systems, involving joints, skin and internal organs. Although the exact aetiology of most of these disorders remains unknown, it is believed that they may be the result of interaction between genetic and environmental factors.

Box 13.3.1 lists some of the important forms of chronic arthritis and connective tissue disorders of childhood.

Frequency

The chronic arthritis and connective tissue disorders in childhood are generally uncommon. The most common type of chronic arthritis is juvenile idiopathic arthritis (JIA). The prevalence is estimated to be 1 in 1000, although the condition may be even more common. Other causes of arthralgia or musculoskeletal pains are seen far more often, such as pain related to mechanical disorders, ligamentous laxity or joint hypermobility.

Arthritis in children

Arthritis is inflammation of, or related to, a joint and symptoms of arthritis may include:

• pain

• heat

• swelling

• deformity or loss of range of motion

• stiffness, particularly early morning

• loss of function

• occasionally erythema.

In the evaluation of the acute onset of joint inflammation, infection or trauma must be considered. Infection may occur as primary septic arthritis or extension of infection from a nearby focus of osteomyelitis into the joint space (see Chapter 12.2). Meningococcal septicaemia and Haemophilus influenzae type b meningitis may be complicated by septic arthritis, or by sterile reactive arthritis. Where trauma is suspected with joint swelling, both accidental and non-accidental injury must always be considered. Inflammation in a joint may also result from bleeding into the joint in haemophilia (see Chapter 16.2), from chloroma associated with neoplastic disease, or rarely from foreign-body penetration.

Juvenile idiopathic arthritis

Persistent or chronic arthritis in the absence of any other associated diagnosis or disorder, in a young person under 16 years of age, is diagnosed as JIA. The term ‘juvenile’ refers to the onset of this disorder, and arthritis commonly persists into adulthood.

In 1996, efforts to harmonize research and clinical care in juvenile forms of chronic arthritis resulted in the development of an international classification system, which is now widely recognized. The most recent revision of this classification is detailed in Box 13.3.1. The three main broad clinical presentations are:

• oligoarthritis

• polyarthritis

• systemic arthritis.

Oligoarthritis

Oligoarthritis, defined as four or fewer joints involved during the first 6 months after onset of symptoms, is the commonest form of JIA, accounting for over 60% of cases. Most children present between 1 and 4 years of age, girls twice as frequently as boys. Knees are affected most commonly, followed by ankle (and subtalar) joints, wrists and elbows. Hip disease is rare, and a child presenting with isolated hip involvement must be investigated carefully for disorders such as septic arthritis or osteomyelitis and, in the appropriate age groups, avascular necrosis of the femoral head (Perthes disease) and slipped femoral capital epiphysis (see Chapter 8.1).

There is usually no systemic disturbance in oligoarthritis. Radiographs may show soft tissue swelling, effusions and widening of the joint space, but erosions are rare. Where treatment has been delayed, epiphyseal overgrowth and lengthening of the involved limb is common. Untreated children ultimately develop erosive disease, whereas growth plate involvement may result in arrest of linear growth and limb deformity (Fig. 13.3.1A,B). More than 70% have a positive serological test for antinuclear antibody (ANA), and rheumatoid factor is usually negative. Oligoarthritis onset has the greatest association with anterior uveitis (see below), which if untreated can cause blindness. Approximately 25% of patients with oligoarthritis will develop progressive polyarthritis after the first 6 months, and are classified as having extended oligoarthritis.

Fig. 13.3.1 A 15-year-old girl with oligoarthritis-onset form of juvenile idiopathic arthritis from age 5 years, largely untreated. (A) Marked flexion deformity and overgrowth of the left leg. (B) Response to multiple joint injections, methotrexate and intensive physiotherapy for 12 months.

Clinical example

Tianna, 2 years old, had an 8-week history of a painful left knee that was stiff in the mornings and became progressively more swollen. The orthopaedic team performed arthroscopic drainage of the knee joint and gave antibiotics with little improvement in her knee. The synovial fluid showed more than 20 000 white blood cells but was negative on culture. The histopathology report of a synovial biopsy showed synovial hypertrophy with ‘non-specific’ inflammation.

Rheumatology review noted a knee effusion, synovial thickening and 15° flexion deformity with significant quadriceps wasting. Tianna also had mild (asymptomatic) swelling of her left ankle that had gone unnoticed. Investigations revealed an erythrocyte sedimentation rate (ESR) of 41 mm/h and a positive ANA titre of 1 : 160. Ophthalmological review revealed evidence of cells and flare in the anterior chamber of Tianna’s left eye, consistent with chronic iridocyclitis. The diagnosis was juvenile idiopathic arthritis of the oligoarthritis type with uveitis.

Tianna was treated with a non-steroidal anti-inflammatory drug (NSAID), aspiration of involved joints, with intra-articular injection of long-acting corticosteroid (triamcinolone) and regular physiotherapy. Within 3 weeks all signs of her arthritis had resolved and her range of motion was near normal. Her eye disease responded rapidly to topical steroids and mydriatics, although it recurred several times over the next 2 years. The arthritis recurred twice in the following few years, requiring further corticosteroid injections with further excellent response. By 10 years of age, Tianna’s arthritis and uveitis had been in remission off all treatment for over 2 years.

Polyarthritis

Polyarthritis, defined as involvement of five or more joints in the first 6 months of disease, accounts for about 25% of JIA cases. Girls are affected twice as often as boys. Onset is most common between the ages of 2 and 4 years, but can be at any age.

Asymmetrical large and small joint involvement is usual. Hip disease may occur, particularly later. Untreated polyarthritis may cause severe disability, joint deformities, asymmetrical overgrowth (particularly knees) and undergrowth (temporomandibular joint and mandible; Fig. 13.3.2), destruction, ankylosis (especially the wrist and cervical spine) and considerable muscle wasting.

Fig. 13.3.2 A 14-year-old girl with severe mandibular deformity due to asymmetrical right-sided temporomandibular joint involvement causing failure of growth of the right ramus.

Only a small subgroup is rheumatoid factor-positive, usually adolescent females with a symmetrical small and large joint arthritis (see below). Tests for ANA are positive in 30–40%, and uveitis may also occur, mandating screening, although not as commonly as with oligoarthritis. Radiographs are similar to those in oligoarthritis, but radiological progression is more frequent.

Systemic arthritis

Systemic arthritis (formerly called Still’s disease) may present at any age in childhood, although rarely in the first year. Adults may rarely develop a similar ‘adult-onset Still’s disease’. Presentation is classically with systemic symptoms and extra-articular manifestations, and affected children may not develop joint disease for many months, making diagnosis difficult.

Systemic arthritis affects both sexes equally and accounts for about 10% of cases of JIA. The initial presentation is often with daily or twice-daily spiking fevers, usually above 39 °C, returning to normal between spikes. Affected children are very irritable and movement appears painful, although joints may not appear inflamed. A classical evanescent rash, usually salmon-pink macules, may occur on the upper trunk, arms and thighs associated with fever, a warm bath or scratching the skin (Koebner phenomenon) (Fig. 13.3.3). Notably, in some individuals, particularly darker-skinned children, the rash may be more urticarial and papular.

Fig. 13.3.3 Typical salmon-pink macular rash of systemic onset form of juvenile idiopathic arthritis in a 10-year-old boy.

Other features include generalized lymphadenopathy, hepatosplenomegaly, serositis causing abdominal pain (peritonitis), pleuritis and pericarditis. Pericardial effusions may result in cardiogenic shock in young children.

Early systemic arthritis mimics infection and malignancy, and diagnosis may be difficult, especially when there is no joint involvement. Haematological features include anaemia, leukocytosis, thrombocytosis, and markedly raised acute-phase reactants.

Both large and small joint involvement occurs. About half of children with arthritis respond relatively well to treatment and eventually remit within a few years. In others, the course is of relentless polyarthritis, often initially with persistent fever and rash. Occasionally children die from infections or macrophage activation syndrome. In the era before methotrexate and other cytotoxics, systemic amyloidosis could cause fatal multisystem failure. In recent years, biological agents that inhibit interleukin (IL)-1, IL-6 or tumour necrosis factor (TNF)-α have been used increasingly in severe disease.

Clinical example

Andrew, aged 3 years, had been unwell for 4 weeks with a daily high-spiking fever and a widespread rash that was worse with fever or if he scratched himself. He had not responded to several courses of antibiotics. He presented to the emergency department with chest pain and difficulty breathing. He was unwell, dyspnoeic, febrile to 39.5 °C and had a widespread, erythematous, macular rash. He had generalized lymphadenopathy and mild hepatosplenomegaly. His heart sounds were muffled and his peripheral pulses weak.

Andrew’s haemoglobin was 89 g/L, white cell count 29 000/mm³, platelets 829 000/mm³ and ESR 131 mm/h. Tests for ANA and rheumatoid factor were negative, as were multiple blood cultures. He had cardiomegaly on chest X-ray and a moderate pericardial effusion on echocardiography.

A diagnosis was made of JIA of the systemic arthritis type. Andrew had minimal response to NSAIDs and developed a widespread polyarthritis of both small and large joints. He was given intravenous pulse (high-dose) methylprednisolone for 3 days followed by oral steroids, with a dramatic improvement in his fever, rash and joint swelling. His pericarditis resolved within a week. He was commenced on low-dose methotrexate (15 mg/m²) as a ‘steroid-sparing agent’, but relapsed whenever steroids were tapered.

Six months later Andrew’s polyarthritis deteriorated, with only a transient response to methylprednisolone. He was started on the biological agent etanercept (anti-TNF) subcutaneously twice weekly, with a moderate improvement over 6 months. The etanercept therapy was switched to anakinra (an IL-1 receptor antagonist), used for several years with methotrexate. He improved markedly and was eventually weaned successfully off all medication.

Other forms of juvenile idiopathic arthritis

Arthritis in association with other connective tissue diseases or conditions associated with immune dysregulation

Chronic or episodic arthritis may be seen in other connective tissue disorders such as systemic lupus erythematosus (SLE), juvenile dermatomyositis, sarcoidosis, vasculitides (e.g. polyarteritis nodosa), and scleroderma (both localized and systemic). Furthermore, velocardiofacial and Down syndrome, as well as some specific immune deficiency disorders, may feature chronic inflammatory arthritis. Cystic fibrosis and other suppurative lung diseases may develop inflammatory arthropathy, possibly due to immune complex deposition. Hypertrophic pulmonary osteoarthropathy (HPOA) associated with congenital cyanotic heart disease or severe cystic fibrosis involves large joints symmetrically, closely resembling inflammatory arthritis.

Eye disease in juvenile arthritis

Inflammatory disease of the uveal tract (uveitis or iridocyclitis) can complicate most forms of JIA, and is an important cause of acquired paediatric eye disease and blindness in developed countries. Young girls with oligoarthritis who are ANA-positive are at highest risk, whereas young boys may be more refractory to treatment (Fig. 13.3.4).

Fig. 13.3.4 Abnormal right eye of a 5-year-old boy with juvenile idiopathic arthritis and chronic silent anterior uveitis, showing an irregular fixed pupil and early cataract formation.

Acute anterior uveitis presents as unilateral painful red eye with photophobia and reduced vision. Chronic anterior uveitis, however, is painless and usually goes unnoticed, so slit-lamp examination by an ophthalmologist at diagnosis and in follow-up is essential. Treatment is with mydriatics and topical steroid preparations. Untreated eye disease may lead to severe impairment of vision due to band keratopathy and adhesions of the iris (synechiae). Glaucoma and cataracts may also occur due to persistent inflammation.

A granulomatous pan-uveitis or posterior uveitis may occur in paediatric sarcoidosis, which is rare.

Investigation of chronic arthritis in childhood

Pathology and laboratory findings

Useful initial investigations are listed in Box 13.3.2. Common findings on investigation in a child with one of the arthritis or connective tissue disorders are: