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)

 (c) Neonatal lupus erythematosus (NLE)

  (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

 (c) Myositis in overlap syndromes

 (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

 (c) Scleroderma-like disorders

  (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


Skin/subcutaneous tissue



Laboratory tests



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


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


Key elements




CTDs occur at all ages but are very uncommon in infancy. SLE and systemic sclerosis are more frequent in teenagers


Female gender is much commoner in SLE (in older children) and systemic sclerosis


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


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


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


Headaches and altered mood common in CTDs may be labelled as non-specific or behavioural. More rarely seizures and neuropathies


Fatigue and dyspnoea on exertion with tachycardia


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

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

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


Photosensitive (‘butterfly’) rash

Alopecia (can be severe)

Mouth ulcers

Livedo reticularis

Raynaud’s phenomenon/acrocyanosis

Vasculitis lesions on hands



Systemic sclerosis

Shiny tight skin with contractures

Atrophy of dermis

Alopecia (mild)

Induration of subcutaneous layers

Digital pitting/ulceration


Raynaud’s/acrocyanosis often severe


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


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)




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


Vasculitis and ischaemia, any type of seizure possible


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


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


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


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.


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.
Oct 25, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Connective Tissue Diseases in Childhood: An Approach to the Diagnosis and Classification

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