Connective Tissue Diseases in Childhood: An Approach to the Diagnosis and Classification

1. Lupus disorders

(a) Systemic lupus erythematosus (SLE)

(b) Mixed connective tissue disease (MCTD)

(i) Cardiac

(ii) Noncardiac

(d) Cutaneous lupus erythematosus

(i) Discoid

(ii) Subcutaneous

(e) Drug-induced LE

2. Idiopathic inflammatory myositis

(a) Juvenile dermatomyositis

(b) Polymyositis

(d) Others (orbital and other localised forms)

3. Scleroderma disorders

(a) Systemic sclerosis

(i) Progressive/widespread

(ii) Limited (previously CREST)

(b) Localised scleroderma

(i) Linear scleroderma

(ii) En coup de sabre/facial/Parry–Romberg syndrome

(iii) Morphoea

(iv) Mixed forms

(v) Subcutaneous/pan-sclerotic morphoea

(i) Eosinophilic fasciitis

(ii) Scleroedema

(iii) Sclero-myxoedema

4. Overlap syndromes

(a) Patients who have clinical features satisfying a full diagnosis for more than one CTD and or rheumatic disorder, for example

(b) Scleroderma and JIA or scleroderma and JDM

5. Undifferentiated CTDs

(a) Often mild to moderate connective tissue disease or disorder but episodic not widespread or fulfilling enough criteria for definite diagnosis, e.g. lupus-like disorders

(b) Usually with accompanying immunological abnormalities such as positive ANA and mild elevation of inflammatory markers. May evolve to more definable CTDs over time or often resolve

Clinical History Taking in CTDs

A detailed and accurate clinical history is critical for the diagnosis of CTDs. Symptoms may be very non-specific, gradually increasing in severity and accumulating across systems. Symptoms include prolonged low-grade fever, fatigue, myalgias, weakness, loss of appetite and lymphadenopathy. Symptoms may also point to significant, apparently isolated, organ involvement such as headaches with hypertension, due to renal disease or CNS inflammation, or seizures. Common systems involved are the skin and mucous membranes and musculoskeletal system but also often cardiopulmonary, gastrointestinal, renal and the central nervous system. A CTD should be suspected when constitutional signs and symptoms occur along with dysfunction or disorder in more than one system. The clinical history helps to discriminate between the different CTDs (Tables 24.2 and 24.3)

Table 24.2

Clinical disease comparators between key CTDs

Disease	Skin/subcutaneous tissue	Muscles	Joints	Laboratory tests	Radiology
SLE	Butterfly facial rash, photosensitive eruptions, vasculitis lesions, acrocyanosis	Often present but mild or subclinical and disappears with treatment	Common and usually symmetrical small and large joint nondeforming but painful	Marked elevation of ESR but not CRP unless coexistent infection ANA+, ENA+ (Sm Ro, La RNP RibP) dsDNA, C3/C4, often markedly abnormal ACL and b2GPI Ab’s and lupus A/C	MRI for brain imaging in neuropsychiatric syndromes or symptoms. PET scans may be more specific or sensitive in available centres Occasionally CT chest imaging for suspected interstitial lung disease Plain X-rays/MRI of bones/joints for suspected avascular necrosis
JDM	Extensor surface erythematous scaling rash (Gottron’s) can be photosensitive and widespread	Dominant feature with proximal weakness and myalgia of the hips, shoulder, trunk and neck and myalgias	Mild symmetric involvement particularly alters in disease in 50 %	ANA positive in some with low titre Myositis-specific or myositis-associated antibodies	MRI of proximal muscle for disease staging, determining site of biopsy or discriminating active disease from other weaknesses (steroid atrophy or disuse)
Systemic sclerosis	Widespread symmetric thinning of the dermis, induration of subcutaneous layers of the skin	Frequently involved with myalgia and generalised weakness	Slowly progressive symmetrical deforming arthritis particularly the hands	Many ANA positive ENA: PM-SCL70, anti-centromere	For staging lung and cardiac status. CT chest essential MRI of muscles and joints may be useful. Echocardiography for pulmonary hypertension or angiography
Localised scleroderma	Linear or oval patches of diseased skin Hyper- and hypopigmentation and scar-like appearance Subcutaneous fascial tissue often profoundly and deeply involved	Myositis common early Atrophy and contracture of the underlying muscle commonly	When joints are crossed, they are usually very abnormal Synovitis contributes to cartilage erosion and damage Contracture osteopenia commonly	May be ANA positive but rarely any other specific antibodies seen	Plain X-rays may prove depth of disease, and bone and joint pathology MRI of affected areas can show active fasciitis and myositis or severity of sclerosis

Most children are well prior to the onset of their CTD but occasionally may have a history of infections in early childhood. Family history is often negative, but patients with SLE may have family members with SLE or other autoimmune diseases such as hypothyroidism, idiopathic thrombocytopenic purpura (ITP) or abnormal immune serology.

Table 24.3

A guide to history taking for recognition of CTDs in childhood

History	Key elements	Comments
Demographic	Age	CTDs occur at all ages but are very uncommon in infancy. SLE and systemic sclerosis are more frequent in teenagers
	Gender	Female gender is much commoner in SLE (in older children) and systemic sclerosis
	Race	Black African, Southeast Asian, Australian aboriginal and Polynesian ethnic origin at higher risk for SLE and greater severity in SLE and systemic sclerosis
Presenting illness	Fever	Often persistent and low grade
	Joint symptoms	Pain, stiffness, swelling and loss of motion. Common in all CTDs. Swelling usually modest, early morning pain and stiffness common but also post-activity
	Fatigue	Often profound especially in SLE and JDM
	Skin/mucosal changes (see Table 24.4)	Many general and disease-specific rashes (heliotrope eyelid, Gottron’s papules, etc.) Mucosal inflammation and ulceration. Peripheral changes such as Raynaud’s phenomenon and acrocyanosis
	Myalgia and weakness	Common in all CTDs but dominant especially proximally in inflammatory myositis
	Neuropsychological	Headaches and altered mood common in CTDs may be labelled as non-specific or behavioural. More rarely seizures and neuropathies
	Cardiovascular	Fatigue and dyspnoea on exertion with tachycardia
	ADLs	Major disturbance of eating, toileting, play, school, family activities and sleep
Past medical history	Growth and developmental delay	CTDs often under-recognised or expected when occurring in infants and toddlers
Past medical history	Previous infections, immune disorder	More at risk of CTDs. Possibly Cytomegalovirus, Parvovirus, hepatitis C and Epstein-Barr virus
Medication history	Previous immunisations, NSAID or steroid use	Onset often temporally linked to recent immunisation but link unproven. Non-specific use of NSAID steroid often with partial response or steroid side effects such as myopathy and weakness
	Exposure to immunostimulatory agents causing drug induced SLE or vasculitis syndromes	Antihypertensives (procainamide, hydralazine and quinidine), anticonvulsants/antipsychotics (phenytoin, chlorpromazine), antiacne agents (minocycline), anti-TNF agents (infliximab) and anti-TB (isoniazid)
Family history	Rheumatic or autoimmune disorders	Common in SLE-type disorders to have similar issues in first-degree relatives
Family history	Specifically SLE, ITP, Sjögren’s, rheumatoid arthritis and ANA+	Usually when patient has SLE-type disorder, rare in other disorders

Individual Systems Review

Skin and Mucous Membranes

Skin disease or rashes occur in most of the CTDs. Some are specific to a disease, whilst others may occur in many diseases (Table 24.4). Classically the ‘butterfly’ rash of SLE and the eyelid/facial rash of JDM are photosensitive. Hair loss (patchy or diffuse) occurs commonly in SLE, but also in JDM and can be widespread. Mouth ulcers occur commonly in SLE and typically the ulcers are painless and are seen on hard palate. Fingertip ulceration occurs in systemic sclerosis (SSc) and may progress to gangrene. Patients with JDM may have ulcers on knuckles, elbows or other pressure points secondary to vasculopathy. Oral and ocular dryness are the dominant symptoms of Sjögren’s syndrome though this is a rare condition in childhood. Skin tightening and contractures of the fingers are seen in scleroderma and MCTD, whilst large joint contractures occur in dermatomyositis.

Table 24.4

Dermatological features seen in individual CTDs

SLE	Photosensitive (‘butterfly’) rash
	Alopecia (can be severe)
	Mouth ulcers
	Livedo reticularis
	Raynaud’s phenomenon/acrocyanosis
	Vasculitis lesions on hands
	Petechia/purpura
	Panniculitis
Systemic sclerosis	Shiny tight skin with contractures
	Atrophy of dermis
	Alopecia (mild)
	Induration of subcutaneous layers
	Digital pitting/ulceration
	Telangiectasia
	Raynaud’s/acrocyanosis often severe
	Calcinosis
Localised scleroderma	Bands or patches of abnormal skin/subcutaneous tissue and other subjacent tissues (muscle, bone, vascular or neurological)
	Dermis is thinned and waxy with loss of adnexae
	Hyper- or hypopigmented areas within lesions
	Induration of subcutaneous tissues (fasciitis) with atrophy of fatty tissues
	Vascular dilatation/dysplasia in skin
JDM	Facial/eyelid rash (‘heliotrope’) with periorbital oedema
	Erythematous/scaly plaques (Gottron’s papules) over extensor surfaces especially hands
	Periungual erythema and vessel abnormality
	Shawl or V sign erythroderma (photosensitive)
	Calcinosis later in disease
	Peripheral and facial oedema (anasarca)

Raynaud’s Phenomenon

This occurs commonly in SSc and SLE. When Raynaud’s phenomenon occurs in patients with underlying CTD, it can progress to ulceration, scarring or gangrene. Thus a history of persistent fingertip discoloration and the development of digital ulceration should always be sought [5].

Musculoskeletal System

Musculoskeletal complaints are very common in all CTDs and can be due to the general effect of the CTD or specific co-occurrence of inflammatory arthritis. Features of inflammatory arthritis like morning stiffness, pain and restricted movements are seen in CTDs but swelling is usually subtle. A detailed history includes the pattern of arthritis, i.e. the number of joints, upper/lower extremity distribution, large/small joints, symmetrical/asymmetrical, or persistent and progressive deformities. Any major change in a child’s gait may suggest myopathy or active arthritis, joint damage or even complications of treatment (e.g. avascular necrosis secondary to steroids). A history of proximal muscle weakness of arms and legs would suggest inflammatory myositis/JDM.

Cardiopulmonary System

A pleural effusion is perhaps the most common manifestation presenting as orthopnoea, dyspnoea and chest pains. A history of the chest pain getting worse on lying down or with a deep breath may suggest a pericardial effusion. Slowly progressive respiratory symptoms are consistent with interstitial lung disease (ILD). Dyspnoea may also be due to trunk muscle weakness due to myositis. A history of significant fever accompanying respiratory distress may suggest lupus pneumonitis or a secondary pneumonia.

Gastrointestinal System

Gastrointestinal (GI) features are often missed in CTDs. Mucosal telangiectasias, reduced mouth opening due to skin tightening, swallowing difficulties and gastro-oesophageal reflux are seen in patients with SSc. Alteration in bowel habit, with either constipation or diarrhoea, may reflect bacterial overgrowth or colonic dysmotility in SSc patients. Abdominal pain and/or GI bleeding though rare may be caused by mesenteric ischaemia secondary to vasculopathic change in JDM or SLE or HSP.

Central Nervous System

SLE can be associated with involvement of the peripheral, central and autonomic nervous system. An important point is that neuropsychiatric features (including cognitive impairment and psychiatric disturbance) can occur not only as a primary manifestation of connective tissue disease but also due to a secondary cause, for example, as a result of hypertension, uraemia, infection and coagulation problems or as a result of drug treatment, especially with corticosteroids. Paraesthesia can occur in patients with connective tissue disease and can have many causes, for example, peripheral neuropathy or drug side effects. Table 24.5 describes some of the more common neuropsychiatric manifestations to be looked for in history and examination.

Table 24.5

Neuropsychological features seen in CTDs (predominantly SLE)

System	Feature	Comments
Central nervous system	Acute stroke syndromes	Due to vasculitis or ischaemia, occasionally haemorrhage. Antiphospholipid antibodies predispose
	Acute confusional states/psychosis	Meningoencephalitis due to vasculitis, high-dose steroids or steroid withdrawal
	Seizures	Vasculitis and ischaemia, any type of seizure possible
	Mood	May be subtle or moderately severe due to chronic inflammation or inflammatory cytokine effect or steroid use
	Movement disorders	Chorea/athetoid or dyskinesia due to thalamic inflammation especially with APL Ab’s or anti-ribosomal P Ab’s
	Severe headache/meningism	Due to meningeal irritation or general effect of inflammation/vasculitis
	Demyelination	Multiple neurological abnormalities at different levels usually CNS and PNS
	Acute paralysis/weakness	Transverse myelitis with bowel and bladder dysfunction
	Visual disturbance	Optic neuritis or retinal vasculitis or haemorrhage
Peripheral nervous system	Cranial nerve palsies	Rare usually part of mono-neuritis multiplex
	Polyneuropathy	Multiple nerves inflamed with sensory and motor issues in patients with severe/complex disease
	Autonomic neuropathies	Rare but profound disturbance of CVS control usually deep midbrain inflammation/demyelination

Renal

A history of proteinuria, frank haematuria, oliguria, pedal oedema and sudden weight gain all indicate renal involvement. Severe or progressively increasing headaches (and irritability in a young infant) may be due to renal origin hypertension. Renal disease is commonly seen in SLE and SSc.

Ocular

A detailed ocular history is important both in the early stages of diagnosis and subsequently whilst on treatment to monitor drug side effects. A history of acute or subacute visual loss, blurring of vision, recent squint, conjunctival inflammation and pain, flashes/floaters and ocular dryness should be sought. Visual loss can be seen in SLE especially and may be due to vasculitis or thrombosis of vessels with antiphospholipid (APL) syndrome or side effects of drugs (cataracts or glaucoma).

Clinical Examination

General Examination

Assessment of the patients’ growth parameters, nutritional status, pubertal status and vital signs should be done. Detailed assessment of the temperature chart is important. SLE and vasculitic disorders may present with significant fever, whereas JDM and SSc may present with low-grade pyrexias. Pallor is seen often either due to anaemia secondary to chronic inflammation or haemolysis. The presence of icterus (due to liver dysfunction or haemolysis) and lymphadenopathy (mild but common in SLE) should also be sought. Subsequently a detailed examination should be conducted to assess for specific system involvement.

Skin and Mucous Membranes

The skin and mucous membranes are very often reflective of the underlying CTD. On the face the classical photosensitive butterfly rash in SLE is seen over the malar region and the chin with sparing of nasolabial folds (Fig. 24.1). Pathognomonic rashes of JDM include a facial rash often over the cheeks with heliotrope eyelid discoloration and periorbital oedema, rash over the neck and upper back (so-called shawl sign) and erythematous desquamation of the extensor aspects of the hands (Gottron’s papules), elbows and knees and the periungual areas (Figs. 24.2, 24.3 and 24.4). Cutaneous ulcerations at the corner of the eyelids, axilla and over elbows may be seen in severe cases of JDM. Nailfold capillary changes are often seen when examined with microscopy reflecting significant vasculopathy (Fig. 24.5a, b). Dystrophic calcinosis in many layers of the skin and subcutaneous tissues as well as changes of lipodystrophy is quite common in more severe JDM (Figs. 24.6 and 24.7).

Fig. 24.1

A 11-year-old girl with typical malar rash of SLE

Fig. 24.2

A 11-year-old girl with JDM with widespread hyperpigmented eyelid forehead and facial rash periorbital ulceration evolving

Fig. 24.3

Classical Gottron’s papules on the hands of a 5-year-old boy with JDM

Fig. 24.4

Classical shawl-type rash in 12-year-old boy with JDM

Fig. 24.5

(a) Periungual nailfold capillary changes with vasculopathy haemorrhage typical of JDM in an 8-year-old boy. (b) Normal nailfolds in 10-year-old boy

Fig. 24.6

Popliteal fossa calcification in subcutaneous tissue and muscle in an 11-year-old girl with initially mild but untreated JDM

Fig. 24.7

Hip bursa calcification and ‘milk of calcium’ (in the same girl as Fig. 24.6) 5 years later at age 16

Annular erythema or discoid lesions may be seen particularly on the face (Fig. 24.8) in more restricted forms of SLE such as subacute cutaneous lupus erythematosus (SCLE). Hyperaemia, petechial rashes and relatively painless ulcers of oral mucosa, particularly on the hard palate, are very typical of SLE.

Fig. 24.8

Facial discoid lupus in a 13-year-old boy

Raynaud’s phenomenon is very common in SSc but often present in SLE, though not necessarily witnessed during examination. It can be provoked with cold immersion but children often do not tolerate this. Parents will often bring photographs demonstrating the phenomenon. It may be associated with visible persistent acrocyanosis of hands and feet during the clinical examination. Thinning of the hair or generalised alopecia is common in all CTDs and may be the presenting symptom. Livedo reticularis is often seen in SLE but also some forms of JDM and if severe may be a pointer towards the presence of antiphospholipid antibodies or syndrome (APS). Purpuric rashes and splinter haemorrhages and vasculitic ulcers may also be seen.

Cutaneous abnormalities in scleroderma usually evolve from early initial oedematous induration to subsequently sclerosis of the subcutaneous tissue layers with thinning and atrophy of the dermis. Skin disease in SSc is first noted in the fingers and feet (sclerodactyly) and the face and then progresses proximally in the diffuse form of SSc or remains distal in the limited SSc (Fig. 24.9a, b). Sclerodactyly can be seen in different CTDs, but sclerosis seen proximal to the metacarpophalangeal joints is the major classification criterion for the SSc.

Fig. 24.9

(a) Hands of 14-year-old girl with systemic sclerosis showing sclerodactyly. (b) The same girl’s face showing tight shiny immobile skin

Scleroderma-type skin changes occur in conditions other than SSc such as generalised morphoea or localised scleroderma, eosinophilic fasciitis and rare genetic, metabolic and toxicity disorders. Close examination looking for telangiectasias, digital pitting, ulcers and terminal resorption (Fig. 24.10), gangrene and calcinosis in suspected SSc is important. Similar digital ulcers can be seen in SLE and rarely in JDM.