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Rare connective tissue diseases in childhood
SYMPOSIUM: CONNECTIVE TISSUE AND BONES
Rare connective tissue diseases in childhood
heading under which autoimmune diseases affecting collagen with particular blood vessel abnormalities are grouped together. Over-riding headings are confusing where diseases such as systemic lupus erythematosus are so multi-organ and multitissue in nature that the more precise individual disease label may be more satisfactory as diseases may seem to have very little in common with other disorders under the same broad heading. Few, if any of these disorders have specific diagnostic tests and the diagnoses are made from a combination of clinical pattern recognition, with serological and genetic testing having to be interpreted in each case. The rarity of these disorders necessitates specialist and even sub-specialist referral for diagnoses and management as outcomes are linked to the level of experience of teams involved in the care of these conditions. The majority of these disorders produce chronic and often life-long difficulties requiring a holistic and multi-disciplinary team approach and the help of information from specific patient organizations.
Eileen Baildam
Abstract Connective tissue disorders can be primary genetic conditions such as EhlerseDanlos syndrome or Marfan’s syndrome leading to increased stretchiness of tissues with hypermobility as a common feature. The term connective tissue disease is used as an overarching category with varied autoimmune conditions such as systemic lupus erythematosus, juvenile dermatomyositis and scleroderma included. They are all frequently multi-system and multi-organ and require early recognition and referral for specialist assessment and treatment. These conditions have major morbidity and even mortality risks if not treated promptly and aggressively. Diagnoses are made primarily on the basis of pattern recognition.
Heritable connective tissue disorders 1) Marfan syndrome caused by mutations of the fibrillin-1 (FBN1) gene on chromosome 15 encoding for the glycoprotein fibrillin with clinical effects, in particular the vasculopathy, mediated through the transforming growth factor-beta signalling pathway. There is a clinical phenotype with diagnosis based on a defined set of criteria, the Ghent criteriae, with aortic root dilatation and ectopia lentis (with superior dislocation of the lens) as the two cardinal signs. There is now a new systemic calculator score of clinical features available on the Marfans Foundation website.
Keywords connective tissue disorder; EhlerseDanlos syndrome; homocystinuria; hypermobility; juvenile dermatomyositis; juvenile localized scleroderma and systemic sclerosis; juvenile SLE; Marfan’s syndrome; Raynaud’s phenomenon
The term connective tissue disease is mysterious and unhelpful in equal measure and not necessarily meaningful to patients or clinicians as the disorders covered by the term are so numerous and diverse. However it is in clinical use and understanding is therefore required. One definition is that a connective tissue disease is any disorder primarily involving the connective tissues of the body and this therefore could be used to cover many disorders of bone, joints, skin, blood vessels. Connective tissue is then defined as tissue that provides a support structure for the body with an extensive extracellular matrix composed of two major structural protein molecules, collagen and elastin as well as proteoglycans and glycoproteins. Elastin is the major component of ligaments and skin. Disorders of connective tissues can be inherited when they are called heritable connective tissue disorders. These are present from birth but may not be recognized for years some only causing complications decades later. Conditions such as Marfan’s syndrome directly affect the structural strength of tissues as they are formed; while others (such as homocystinuria) are caused a biochemical defect leading to accumulation of metabolites in the tissues with subsequent cumulative vascular damage. Diseases of connective tissues on the other hand are inflammatory and autoimmune and may be caused by a combination of genetic predisposition and an environmental trigger. For example some cases of SLE are caused by known genetic mutations in the complement pathways predisposing to poor control of inflammatory responses. Collagen vascular disease is an alternative
Calculation of systemic score Clinical manifestations of MFS in other organ systems were critically evaluated for their specificity and diagnostic utility based or expert opinion and the available literature. Several of the “minor” criteria from the old Ghent nosology were eliminated, but the most selective systemic features were included in the “systemic score”.
Eileen Baildam MBChB MCRGP FRCP FRCPCH is Consultant Paediatric Rheumatologist at Alder Hey Children’s Foundation NHS Trust, Liverpool, UK. Conflicts of interest: none.
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Feature
Value
Click to include
Wrist AND thumb sign Wrist OR thumb sign Pectus carinatum deformity Pectus excavatum or chest asymmetry Hindfoot deformity Plain flat foot Spontaneous pneumothorax Dural ectasia Protucio acetabulae Scoliosis or thoracolumbar kyphosis
þ þ þ þ
3 1 2 1
þ þ þ þ þ þ
2 1 2 2 2 1
(continued on next page)
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3) Osteogenesis imperfecta (brittle bone disease) e caused by insufficient production of normal collagen to produce healthy, strong bones. There are four types (primarily type I the mildest type and type II is the most severe and usually fatal.) The majority of cases are caused by a dominant mutation to type 1 collagen (COL1A1 or COL1A2) genes. Other types are caused by mutations of the cartilageassociated protein (CRTAP) gene or the LEPRE1 gene. This type of mutation is inherited in a recessive manner. 4) Stickler syndrome is associated with a COL2A1, COL 11A1, COL11A2 mutations and may result in a distinctive facial appearance, eye abnormalities flat cornea, high myopia, a high risk of retinal detachment, cataracts and glaucoma, hearing loss, and joint problems with combinations of stiff joints and over-flexible joints and cleft palate abnormalities. 5) Alport syndrome with defects in collagen (type IV) found in the renal basement membrane, inner ear and eyes leading to glomerulonephritis, hearing loss, and eye disease, respectively. 6) Congenital contractural arachnodactyly, also know as Beal’s syndrome, has similar fibrillin gene mutations to Marfan’s syndrome but has characteristic contractures of hip, knee, elbows and ankle joint and a crumpled appearance of the top of the ear. Aortic root problems and mitral valve regurgitation only occur occasionally. 7) Homocystinuria is caused by a homozygous or compound heterozygous mutation in the gene encoding cystathionine betasynthase on chromosome 21q22. This leads to a deficiency in cystathionine synthetase. There is an accumulation of homocysteine, serine and methionine as well as possible defects in collagen cross-linking. Patients with Type 1 homocystinuria have a similar phenotype to patients with Marfan’s syndrome with tall stature, long limbs, peripheral retinal detachment and ectopia lentis (this time with inferior displacement of the lens). Affected individuals are fair skinned with fair hair. Hypotonia is present but joints are usually stiff rather than hypermobile. Progressive mental retardation and progressive severe osteoporosis are characteristic and there is a risk of thromboembolic events. Treatment includes methionine restriction and treatment with pyridoxine.
(continued ) Feature
Value
Click to include
Reduced elbow extension Three of five facial features Skin striae Severe myopia Mitral valve prolapse Reduced upper segment/ lower segment & increased arm span/height
þ þ þ þ þ þ
1 1 1 1 1 0
Open to calculate
A score of 7 is considered a positive systemic score. From the Marfan’s organization website.
Management Treatment with angiotensin II receptor I blockade (ATI antagonists) such as losartan can be used to block the dysregulation of TGF beta. ACE inhibitors and beta-blockers may be helpful but aortic root surgery may be required when the aortic diameter at the sinus of Valsalva is more than 5 cm. 2) EhlerseDanlos syndrome with mutations in the collagen genes leading to defects in type I or type III collagen leading to stretching in the collagen at different sites depending on the exact mutation. Hypermobile type EhlerseDanlos syndrome: stretchy velvety skin, lax ligaments, hypermobile joints, are seen in the most common type, the Hypermobility type. In this mild subtype there is such an overlap with benign hypermobility and the normal childhood variants of flexibility that caution must be exercised in mislabelling essentially normal children as having a “disorder” with the subsequent potentially unhelpful psychological consequences of such a label. TNXB genetic mutations may be found but more usually clinical diagnoses are made. This area needs particular care as it is possible to assign an incorrect label that may be difficult to adjust later.
Systemic autoimmune connective tissue disorders IN childhood Vascular type EhlerseDanlos syndrome: Associated with mutations in COL3A1 leading to arterial, intestinal, uterine fragility and rupture, characteristic facies with thin lips and philtrum, small chin, thin translucent skin and easy bruising and dystrophic scars.
Juvenile systemic lupus erythematosus (jSLE) Juvenile dermatomyositis (jDMS) and polymyositis Juvenile idiopathic arthritis (JIA) with positive rheumatoid factor (RF) €gren’s syndrome Primary Sjo Mixed connective-tissue disease (MCTD) or overlap connective tissue disease Systemic sclerosis in childhood (jSSc) Localized scleroderma (jLS) in childhood Incidences in childhood jSLE 0.5e0.6 per 100,000 F:M 4.5:1 jDMS 0.4 per 100,000 F:M 3e5:1 jSSc rare 1:1,000,000 F:M 3:1 jLS incidence 0.8 per 100,000, prevalence by 18 yrs 50 per 100,000 F:M 2.5:1 These diseases are included under the term classic collagen vascular diseases or autoimmune connective tissue diseases.
Classic type EhlerseDanlos syndrome: Associated with mutations in COL5A1 and COL5A2. Cases have a combination of joint hypermobility, skin fragility and hyperextensibility, widened atrophic tissue paper or cigarette paper scars are typical and aortic root dilatation may occur. Kyphoscoliotic type EhlerseDanlos syndrome Progressive scoliosis is present from birth or within the first year of life. Scleral fragility and rupture of the globe of the eye may occur. Severe muscle hypotonia present at birth with generalized joint laxity and friable hyperextensible skin. POLD1 gene mutations are associated with this phenotype.
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However, they all are really better considered as complex autoimmune inflammatory diseases with genetic components, cellular and humoral dysregulation, some with environmental triggers and with complex inter-relationships such that some patients have features of all of the conditions below at once. Most of the conditions below are associated with Raynaud’s phenomenon in some patients, positive antinuclear antibodies ANA’s, skin involvement, arthritis, general debility and tiredness and most are progressive without treatment. They all require immunosuppressive therapy to obtain states of clinical remission and this therapy is usually required on a long-term basis. These include steroids, disease modifying anti-rheumatic drugs (DMARDS) such as methotrexate and hydroxychloroquine, possible cyclophosphamide and biologic treatment. In childhood they all can affect growth and development and quality of life and some are life-threatening. Many are associated with an increased long-term risk of cardiovascular disease. Vasculitis can also be associated with connective tissue diseases €gren’s syndrome, systemic sclerosis, in pre-existing SLE, primary Sjo relapsing polychondritis, primary anti-phospholipid syndrome, juvenile dermatomyositis, mixed connective tissue disease. Vasculitis occurring in any of these situations suggests a more severe disease severity and need for stepping up to aggressive treatments.
Systemic sclerosis and localized scleroderma JIA and JIA associated uveitis Juvenile dermatomyositis and polymyositis Mixed connective tissue disease Autoimmune hepatitis €gren’s syndrome Primary Sjo Short lived positivity in viral infections and in some neoplasias such as acute lymphoblastic leukaemia and lymphoma. Positive ANAs can be seen in between 3 and 15% of healthy individuals Juvenile systemic lupus erythematosus (jSLE) SLE is a multi-system, episodic, autoimmune disease affecting all organs including the connective tissues of skin and joints and blood vessels and identified by the presence of antinuclear antibodies especially antibodies to native (double-stranded) DNA (dsDNA). Some patients have genetic mutations such as C1q deficiencies, some have photosensitive disease triggers. Diagnosis is made on the basis of the American College of Rheumatology (ACR) criteria which (Table below), although developed for research in adult disease, also help in the diagnosis in childhood. It is helpful in demonstrating the range of systems usually involved. However most types of named disorders affecting most organs can be seen in SLE, truly a disease with a thousand faces. The BILAG score (British Isles Lupus Assessment Group) 2004 index is educational in outlining the range of complications and organ disease as well as validated in assessing the actual disease severity. The SLEDAI 2000 Disease Activity Index contains a shorter list of activity measures and the SLICC/ ACR Damage Index (Paediatric) is used to score permanent disease related damage. Presenting features of jSLE are often non-specific constitutional symptoms of headache, tiredness, malaise and weight loss with arthralgia or arthritis, rashes (especially a malar rash) and mouth or nasal ulcers. Temperatures, serositis, lymphadenopathy and hepatosplenomegaly are common. Renal involvement is common in jSLE occurring in between 20 and 82% depending on the length of the study follow-up. Early diagnosis and rapid commencement of treatment can literally be life-saving as the rate of progression is very rapid in some cases where renal failure, severe macrophage activation or major lung, cardiac or brain disease can prove fatal. In addition there are long-term risks from thromboembolic phenomenon especially in patients with anti-phospholipid syndrome as well as from accelerated cardiovascular disease in the longer term. Raynaud’s phenome€gren’s disease and vasculitis can also occur. non, secondary Sjo Treatment nearly always requires steroid use (often in high dose at initial diagnosis and with disease flares), hydroxychloroquine and total sunblock. In addition DMARD therapy with mycophenolate mofetil, azathioprine, methotrexate, ciclosporin and infliximab are used with cyclophosphamide reserved for life threatening situations. Anti-B cell therapies are in trials with rituximab used as step up therapy and for long-term maintenance especially in non-compliant teenagers. New drug therapies are being used SLE (and starting in trials in jSLE) including belimumab, ocrelizumab, epratuzimab and atacicept. Anti-phospholipid treatments are needed. Intensive treatment of refractory lupus may include plasma-exchange and even
Raynaud’s phenomenon Definition: a triphasic response to cold trigger or stress. Initial vasospastic phase with white fingers, toes and or nose tips. During this phase the digits often feel numb, may become stiff with decreased fine coordination. Secondly, a cyanotic phase as the haemoglobin in the vasospastic blood vessels deoxygenates. Thirdly, a vasodilatory red phase with increased blood flow making the area hot, red and painful with tingling. Primary Raynaud’s phenomenon is common and occurs in 15% of normal school aged children. It is more common in girls than boys (18% versus 12%) and more common with older teenagers. Investigations and treatment depend on the severity of the episodes. Investigations include FBC, thyroid function, antinuclear antibody and possible capillaroscopy, and cold challenge tests. Secondary Raynaud’s phenomenon occurs in association with: Systemic sclerosis Systemic lupus erythematosus Mixed connective tissue disease Overlap connective tissue disease Secondary to drug treatments such as beta-blockers, sumatriptan, decongestants, the contraceptive pill, ACE inhibitors and clonidine. Drug misuse such as with amphetamines and cocaine Raynaud’s phenomenon needs to be differentiated from chilblains (episodic colour change after exposure to cold with cold injury leading to tissue damage manifesting as an inflammatory response with painful erythematous/violaceous nodules often with cracked skin. Acrocyanosis is a common, painless vasospastic disorders leading to coldness and bluish discolouration of the hands and feet but without the triphasic colour responses. Positive antinuclear antibodies (ANAs) can be associated with: SLE and drug-induced lupus
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Juvenile dermatomyositis and polymyositis (jDM and PM) JDM is also a multi-system disorder with widespread but patchy inflammation in muscles and skin rashes with arthritis commonly seen, but where small blood vessel vasculopathy is now thought by many to be the primary pathology. The clinical presentation may be insidious and is often missed in children until quite profound weakness is present. Again systemic symptoms may occur with fever, malaise, poor appetite, poor energy levels, weight loss and irritability. Rashes can take many forms but typically seen is the violaceous heliotrope rash on the eyelids, periorbital oedema, a malar rash with perioral sparing, Gottron’s papules over extensor surfaces especially of the fingers. In severe cases widespread oedema and tissue ulceration can occur. Nail fold capillary changes and hypertrophy of the cuticle are important diagnostic clues. Polyarticular arthritis, and myalgia can occur but muscle weakness starting proximally and extending to involve most muscle groups occurs in most patients. This weakness can include weakness in swallow with risks of aspiration, dysphonia, and dyspnoea. In the long term calcinosis of skin and subcutaneous tissues is related both to the severity of the disease subtype and to delay in adequate treatment establishing disease control. Similarly lipoatrophy and lipodystrophy can occur. Early diagnosis and rapid commencement of treatment can again be life-saving as the rate of progression can be rapid in some cases, severe macrophage activation can occur and systemic vasculitis affecting for example brain and gut blood vessels can create serious presentations. Interstitial pneumonitis can occur denovo and aspiration pneumonia can create serious outcomes. Helpful ways of quantifying muscle strength and function to assess response to treatment include the Childhood Myositis Assessment Scale (CMAS) and the Manual Muscle Testing 8 Standard Scoring System (Oxford and Kendal). MRI scanning of muscles with gadolinium enhancement or with special sequences is the accepted modality of muscle diagnosis. However, muscle biopsy is still recommended with the intention of excluding metabolic myopathies as well as for enhancing the understanding of disease subtypes. Increasingly myositis specific and myositis associated antibodies are recognized in jDMS associated with specific disease phenotypes and these may help to direct treatment in the future. Treatment nearly always requires steroid therapy, methotrexate, hydroxychloroquine and sunblock. Unresponsive disease may need intravenous immunoglobulins. Cyclophosphamide is used for life-threatening and ulcerative disease. Ciclosporin helps in cases with macrophage activation syndrome. Treatments with anti-TNF drugs especially intravenous infliximab may be helpful. Mycophenolate mofetil, tacrolimus ointment and rituximab are all helpful in individual cases.
haematopoietic stem cell transplantation. The complexity of this disease requires urgent referral for management by paediatric rheumatologists with expertise. ACR revised criteria for classification of SLE Criteria
Definition
Malar rash
Fixed erythema, flat or raised, over malar eminences, tending to spare nasolabial folds Erythematous raised patches of adherent keratotic scaling and follicular plugging. Atrophic scarring may be seen in older lesions Skin rash as a result of unusual reaction to sunlight Oral and nasopharyngeal ulcers, usually painless, observed by a physician Non-erosive arthritis involving 2 or more peripheral joints, characterized by tenderness, swelling or effusion Pleuritis- pleuritic pain, rub heard or pleural effusion or, Pericarditis-documented by ECG or rub or pericardial effusion Persistent proteinuria >0.5 g/day or >3þ, or Cellular casts: red cell, haemoglobin, granular, tubular or mixed Seizures or Psychosis in the absence of offending drugs or metabolic derangement (e.g. uraemia, ketoacidosis, electrolyte imbalance) Haemolytic anaemia with reticulocytes, or Leucopenia <4000 per mm3 on 2 or more occasions, or Lymphopenia <1500 per mm3 on 2 or more occasions, or Thrombocytopenia <100,000 per mm3 in the absence of offending drugs Anti- DNA antibody, or Anti-Sm antibody, or Anti-phospholipid antibodies C Abnormal anticardiolipin antibody C Positive lupus anticoagulant C False positive for syphilis for >6 months Abnormal titre of ANA at any point in absence of drugs known to be associated with drug-induced lupus.
Discoid lupus
Photosensitivity Oral and nasal ulceration Non-erosive arthritis Serositis
Nephritis
Neurological
Haematological
Immunological
Antinuclear antibody
€gren’s syndrome can occur alone as primary Sjo €gren’s synSjo drome in childhood but more usually occurs in association with scleroderma, systemic lupus erythematosus or mixed connective €gren’s syndrome. In childhood a tissue disease as secondary Sjo chronic parotitis is the usual presentation. It is associated with a chronic, slowly progressing inability to secrete saliva and tears.
If four or more of these 11 items are positive either simultaneously or cumulatively the patient can be said to have SLE. ~ ez, D., & Urowitz, M. B. (2002). Systemic Gladman, D. D., Iban lupus erythematosus disease activity index 2000. The Journal of Rheumatology, 29(2), 288e91. Lupus nephritis is classified according to the 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) working group revision published in 2004.
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Mixed connective-tissue disease (MCTD) is a disorder in which features of various connective-tissue diseases (CTDs) such as
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systemic lupus erythematosus (SLE); systemic sclerosis (SSc); dermatomyositis (DM); polymoyositis (PM); polyarticular or €gren’s syndrome can rheumatoid arthritis and, occasionally, Sjo coexist and overlap. The course of the disease is chronic and usually milder than with other primary CTDs. In some cases, MCTD is considered an intermediate stage of a disease that eventually becomes either SLE or systemic sclerosis. Anti- RNP positivity is a hall mark of this disease.
scleroderma can affect the quality of life. It is difficult to distinguish active from inactive disease and long-term treatment is often necessary. In a cohort of children and young people with jLS from London, photographs of 65 patients were analyzed by Adobe Illustrator and overlain on a master file where many similarities between the areas affected and Blaschko’s lines were found suggesting a possible skin mosaicism as part of the jLS pathogenesis with the inflammation and fibrosis occurring in the mosaic affected skin only. This is still only a theory of causation. Isolated congenital cases of jLS have been reported. SSc is a chronic progressive disorder of unknown aetiology characterized by the excess synthesis and deposition of collagen (both types I and III) and other extracellular matrix components in a variety of tissues and organs. There are associated vascular abnormalities and autoimmunity. This subsequent damage may eventually be life-threatening. Juvenile systemic sclerosis (JSSc) is characterized by Raynaud’s phenomenon, skin changes of thickening and oedema termed sclerodermatous change and widespread abnormalities of the blood vessel walls and internal organs such as kidney, heart, lungs and the gut. SSc is a generalized body disorder whereas localized scleroderma is confined to a single or multiple sites but with normal tissue between and without distant internal organ involvement. There are proposed PRES classifications for juvenile systemic sclerosis/jSSc although these have yet to be validated. The two main subtypes of SSc are termed limited cutaneous disease and diffuse cutaneous disease (these confusing terms describe the skin involvement and should not be read as suggesting that SSc is limited only to the skin). This brave attempt at a separate paediatric classification is unfortunate as it is likely that SSc is really a spectrum from childhood to adult disease and that different classifications are more likely to delay successful transition. The limited cutaneous type of SSc has skin changes confined to the more distal arms and legs as well as the neck and face but with truncal sparing. This type was called the CREST syndrome previously and the acronym still reminds of the associated calcinosis, Raynaud’s phenomenon, oesophageal involvement and telangiectasia. However serious interstitial lung disease and pulmonary fibrosis with or without pulmonary hypertension can also occur in this subtype. In the diffuse cutaneous type of SSc skin involvement extends onto the upper arms and trunk and internal organ disease such as renal involvement is more severe. Childhood disease is more often diffuse in nature and there is a significant mortality especially from pulmonary and cardiac causes and often in the first 3e5 years after onset requiring urgent diagnosis, assessment and treatment. The 1980 ACR classification criteria for adult systemic sclerosis (SSc) lacked sensitivity for diagnosing early SSc and limited cutaneous SSc, often delaying treatment. Therefore these have just been updated in 2013 by consensus methodology. In the new criteria thickening in the skin of the fingers extending proximal from the metacarpophalangeal joints allows the patient to be classified as having SSc. If proximal skin thickening is absent, seven additive weighted items apply: skin thickening of fingers distal to the MCP joints, fingertip lesions, telangiectasia, abnormal nail fold capillaries, interstitial lung disease or
Polyarticular JIA with positive RF or childhood onset rheumatoid arthritis can also coexist with other connective tissue disease and strictly all JIA could possibly be termed an autoimmune connective tissue disease. Scleroderma in childhood A spectrum of conditions is covered by the term scleroderma with presentations, complications and outcomes so different from each other that it is questionable whether they should be spoken about together. The terminology is particularly confusing for non-experts and the classifications have not been validated in children. The term scleroderma simply means “hard skin” and it is thickening or hardening of the skin that links the two main disease subtypes in the classification: systemic sclerosis (SSc) or juvenile systemic sclerosis (jSSc) and localized scleroderma/juvenile localized scleroderma (jLS). Under these two headings are many different phenotypes varying from a mild skin disorder in localized superficial morphea, through to potentially disfiguring and disabling linear scleroderma or linear morphea to the generalized life-threatening systemic illnesses seen in systemic sclerosis. There has been a real explosion in the last 5e10 years in scleroderma research, especially into systemic sclerosis and the main pathogenic cells (T and B cells) fibroblasts and endothelial cells and their cytokine interactions are quite well worked out now. This has given rise to the classical triad of pathological alterations found in SSc: i) progressive cutaneous and visceral fibrosis, ii) a functional and structural vasculopathy, iii) immunological abnormalities. A better recent understanding of the molecular and cellular mechanisms of LS has lead to evaluation of new treatments that modify profibrotic cytokines such as TGF b and IL4. Other treatments affect factors regulating the assembly and deposition of extracellular matrix components. Others such as IL12 and IFN gamma restore Th1/Th2 immune balance. IFN gamma acts by directly inhibiting collagen synthesis and restoring immune balance. The pathology within localized lesions has similarities to SSc and there is an acceptance of a link between diseases in this spectrum. However, there is no evidence of progression from one type to another but it is more likely that the some diseases under this heading have an inherent deepening and worsening as part of their disease course while others remain as more superficial diseases primarily affecting the skin. Juvenile localized scleroderma (jLS) causes inflammation in the skin and underlying tissues leading to fibrosis. Long-term morbidity occurs from loss of function, disfigurement and deformity. Although only rarely life-threatening localized scleroderma can be disfiguring and disabling as the full thickness of tissues can be affected from skin to deep tissues including brain and bone underlying the lesions. Both types of
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Other conditions associated with stiff SKIN
pulmonary arterial hypertension, Raynaud’s phenomenon, and SSc-related autoantibodies. Isolated jSSc is one of the rarest connective tissue diseases and again needs to be treated by teams with expertise in paediatric scleroderma. A BPSU study reported an annual incidence rate of 0.27 per million children under the age of 16 years (Herrick and Baildam). It is much more common to have sclerodermatous features as part of an overlap syndrome in childhood disease. Significant localized scleroderma is still rare affecting 3.4 per million children although the milder forms of simple morphea patches are much more common. The Mayo Clinic classification is still used although there are proposed PRES classification for localized scleroderma/morphea. The types of localized scleroderma include: Morphea Circumscribed (superficial/deep) Generalized, guttate Pansclerotic/profunda Mixed morphea Linear scleroderma Linear scleroderma of trunk/limbs Linear scleroderma of face, neck and/or scalp including ‘en coup de sabre’ and hemifacial atrophy (Parry Romberg syndrome) In association with localized scleroderma the following can occur: Eye lesions Uveitis (either for directly overlying facial lesions or distant to the inflammation and therefore ophthalmology screening is required). Optic neuritis and optic atrophy have been reported. Eyelid changes Changes in eyelash colour, changes in colour of the iris. Neurological symptoms including seizures, cranial nerve palsies, headaches, irritability, neuro-psychiatric problems and learning difficulties from deep brain lesions including vasculitis and direct brain inflammation. MRI scan changes can be single, multiple, enhancing or calcific. Brain biopsies have shown inflammatory brain changes. Scalp lesions associated with waxy alopecia in the en coup de sabre distribution. This may be amenable to surgical removal by plastic surgeons once the disease is quiescent. Contractures of joints occurs if overlying skin and deep tissues are affected by the lesions. Arthritis both locally and of distant joints also occurs. Local impairment of bone and joint growth can lead to severe limb deformities with very large limb length discrepancies occurring. The temporomandibular joint may be affected and contribute to major facial asymmetry. Dental problems can be significant in facial lesions with gum retraction and severe non-alignment requiring complex orthodontic work. Raynaud’s phenomenon and cardiopulmonary, renal and gastrointestinal disease does not occur in localized disease. The natural history is not defined and there are no long-term cohort studies of outcome either on or off treatment. There are several recent studies of the efficacy of corticosteroids and methotrexate with mycophenolate mofetil and biological treatments used in individual unresponsive cases.
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Systemic sclerosis. Localized scleroderma. Graft versus host disease. Nephrogenic fibrosing dermopathy induced by gadolinium enhanced MRI scans when used in patients with renal impairment. Chemical induced scleroderma like disease e.g. from polyvinyl chloride, bleomycin, toxic-oil syndrome. Localized idiopathic fibroses. The stiff skin syndrome caused by fibrillin gene defects Pseudosclerodermas Phenylketonuria- a minority of PKU patients develop sclerodermatous skin lesions resembling morphoea, often symmetrical and poorly defined. Disorders of premature ageing such as progeria and Werner’s syndrome Scleromyxedema e with popular cutaneous lesions and induration of the underlying subcutaneous tissues. Lesions mainly on the face, neck, trunk and hands. Histology e a dense acid mucopolysaccharide deposits and fibrohistiocytic infiltrate Scleredema-with stiff skin and induration of the face, neck, shoulders, chest and proximal parts of the limbs, following beta- haemolytic streptococcal infections. Dupuytren’s contractures Gardener’s syndrome e intra-abdominal fibrosis associated with multiple colonic polyps and osteomas Diabetic cheiroarthropathy in juvenile-onset diabetes leading to short stature, tightening of the skin and soft tissues and figure contractures. Porphyria cutanea tarda some patients develop plaque like lesions similar to localized scleroderma and others like discoid lupus. A
FURTHER READING Baildam EM, Ennis H, Foster H, et al. Influence of childhood scleroderma on physical function and quality of life. J Rheumatol 2011; 38: 167e73. Ennis H, Herrick A, Baildam E, Richards H. Childrens’ and parents’ beliefs about childhood onset scleroderma are influenced by child age and physical function impairment. Rheumatology July 2011. ~ez D, Urowitz MB. Systemic lupus erythematosus Gladman DD, Iban disease activity index 2000. J Rheumatol 2002; 29: 288e91. Gutierrez-Suarez R, Ruperto N, Gastaldi R, et al. A proposal for a pediatric version of the systemic lupus international collaborating Clinics/American college of rheumatology damage index based on the analysis of 1,015 patients with juvenile-onset systemic lupus erythematosus. Arthritis Rheum 2006; 54: 2989e96. Herrick AL, Baildam EM. Capillaroscopy in juvenile connective tissue diseases, chapter 18. In: Atlas of capillaroscopy in rheumatic diseases. Elsevier, 2010. Herrick AL, Ennis H, Bhushan M, Silman A, Baildam EM. Incidence of childhood scleroderma in the UK and Ireland. Arthritis Care Res (Hoboken) 2010; 62: 213e8.
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Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725. Jones GT, Herrick AL, Woodham SE, Baildam EM, Macfarlane GJ, Silman AJ. Occurrence of Raynaud’s phenomenon in children ages 12-15 years: prevalence and association with other common symptoms. Arthritis Rheum 2003; 48: 3518e21. Foster Helen, Brogan Paul, eds. Oxford specialist handbooks in paediatrics paediatric rheumatology 2012. Cassidy James, Petty Ross, Laxer Ronald, Lindsley Carol, eds. Textbook of pediatric rheumatology 2013 (check the current list of authors). van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M. 2013 classification criteria for systemic sclerosis: an American College of
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Rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis 2013; 72: 1747e55. Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004; 15: 241e50. Yee C, Cresswell L, Farewell V, et al. Numerical scoring for the BILAG-2004 index. Rheumatology (Oxford England) 2010; 49: 1665e9. Zulian F, Vallongo C, Woo P, et al. Localized scleroderma in childhood is not just a skin disease. Arthritis Rheum 2005; 52: 2873e81. Zulian F. Systemic sclerosis and localized scleroderma in childhood. Rheum Dis Clin North Am 2008; 34: 239e55.
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Rare connective tissue diseases in childhood
heading under which autoimmune diseases affecting collagen with particular blood vessel abnormalities are grouped together. Over-riding headings are confusing where diseases such as systemic lupus erythematosus are so multi-organ and multitissue in nature that the more precise individual disease label may be more satisfactory as diseases may seem to have very little in common with other disorders under the same broad heading. Few, if any of these disorders have specific diagnostic tests and the diagnoses are made from a combination of clinical pattern recognition, with serological and genetic testing having to be interpreted in each case. The rarity of these disorders necessitates specialist and even sub-specialist referral for diagnoses and management as outcomes are linked to the level of experience of teams involved in the care of these conditions. The majority of these disorders produce chronic and often life-long difficulties requiring a holistic and multi-disciplinary team approach and the help of information from specific patient organizations.
Eileen Baildam
Abstract Connective tissue disorders can be primary genetic conditions such as EhlerseDanlos syndrome or Marfan’s syndrome leading to increased stretchiness of tissues with hypermobility as a common feature. The term connective tissue disease is used as an overarching category with varied autoimmune conditions such as systemic lupus erythematosus, juvenile dermatomyositis and scleroderma included. They are all frequently multi-system and multi-organ and require early recognition and referral for specialist assessment and treatment. These conditions have major morbidity and even mortality risks if not treated promptly and aggressively. Diagnoses are made primarily on the basis of pattern recognition.
Heritable connective tissue disorders 1) Marfan syndrome caused by mutations of the fibrillin-1 (FBN1) gene on chromosome 15 encoding for the glycoprotein fibrillin with clinical effects, in particular the vasculopathy, mediated through the transforming growth factor-beta signalling pathway. There is a clinical phenotype with diagnosis based on a defined set of criteria, the Ghent criteriae, with aortic root dilatation and ectopia lentis (with superior dislocation of the lens) as the two cardinal signs. There is now a new systemic calculator score of clinical features available on the Marfans Foundation website.
Keywords connective tissue disorder; EhlerseDanlos syndrome; homocystinuria; hypermobility; juvenile dermatomyositis; juvenile localized scleroderma and systemic sclerosis; juvenile SLE; Marfan’s syndrome; Raynaud’s phenomenon
The term connective tissue disease is mysterious and unhelpful in equal measure and not necessarily meaningful to patients or clinicians as the disorders covered by the term are so numerous and diverse. However it is in clinical use and understanding is therefore required. One definition is that a connective tissue disease is any disorder primarily involving the connective tissues of the body and this therefore could be used to cover many disorders of bone, joints, skin, blood vessels. Connective tissue is then defined as tissue that provides a support structure for the body with an extensive extracellular matrix composed of two major structural protein molecules, collagen and elastin as well as proteoglycans and glycoproteins. Elastin is the major component of ligaments and skin. Disorders of connective tissues can be inherited when they are called heritable connective tissue disorders. These are present from birth but may not be recognized for years some only causing complications decades later. Conditions such as Marfan’s syndrome directly affect the structural strength of tissues as they are formed; while others (such as homocystinuria) are caused a biochemical defect leading to accumulation of metabolites in the tissues with subsequent cumulative vascular damage. Diseases of connective tissues on the other hand are inflammatory and autoimmune and may be caused by a combination of genetic predisposition and an environmental trigger. For example some cases of SLE are caused by known genetic mutations in the complement pathways predisposing to poor control of inflammatory responses. Collagen vascular disease is an alternative
Calculation of systemic score Clinical manifestations of MFS in other organ systems were critically evaluated for their specificity and diagnostic utility based or expert opinion and the available literature. Several of the “minor” criteria from the old Ghent nosology were eliminated, but the most selective systemic features were included in the “systemic score”.
Eileen Baildam MBChB MCRGP FRCP FRCPCH is Consultant Paediatric Rheumatologist at Alder Hey Children’s Foundation NHS Trust, Liverpool, UK. Conflicts of interest: none.
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Feature
Value
Click to include
Wrist AND thumb sign Wrist OR thumb sign Pectus carinatum deformity Pectus excavatum or chest asymmetry Hindfoot deformity Plain flat foot Spontaneous pneumothorax Dural ectasia Protucio acetabulae Scoliosis or thoracolumbar kyphosis
þ þ þ þ
3 1 2 1
þ þ þ þ þ þ
2 1 2 2 2 1
(continued on next page)
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3) Osteogenesis imperfecta (brittle bone disease) e caused by insufficient production of normal collagen to produce healthy, strong bones. There are four types (primarily type I the mildest type and type II is the most severe and usually fatal.) The majority of cases are caused by a dominant mutation to type 1 collagen (COL1A1 or COL1A2) genes. Other types are caused by mutations of the cartilageassociated protein (CRTAP) gene or the LEPRE1 gene. This type of mutation is inherited in a recessive manner. 4) Stickler syndrome is associated with a COL2A1, COL 11A1, COL11A2 mutations and may result in a distinctive facial appearance, eye abnormalities flat cornea, high myopia, a high risk of retinal detachment, cataracts and glaucoma, hearing loss, and joint problems with combinations of stiff joints and over-flexible joints and cleft palate abnormalities. 5) Alport syndrome with defects in collagen (type IV) found in the renal basement membrane, inner ear and eyes leading to glomerulonephritis, hearing loss, and eye disease, respectively. 6) Congenital contractural arachnodactyly, also know as Beal’s syndrome, has similar fibrillin gene mutations to Marfan’s syndrome but has characteristic contractures of hip, knee, elbows and ankle joint and a crumpled appearance of the top of the ear. Aortic root problems and mitral valve regurgitation only occur occasionally. 7) Homocystinuria is caused by a homozygous or compound heterozygous mutation in the gene encoding cystathionine betasynthase on chromosome 21q22. This leads to a deficiency in cystathionine synthetase. There is an accumulation of homocysteine, serine and methionine as well as possible defects in collagen cross-linking. Patients with Type 1 homocystinuria have a similar phenotype to patients with Marfan’s syndrome with tall stature, long limbs, peripheral retinal detachment and ectopia lentis (this time with inferior displacement of the lens). Affected individuals are fair skinned with fair hair. Hypotonia is present but joints are usually stiff rather than hypermobile. Progressive mental retardation and progressive severe osteoporosis are characteristic and there is a risk of thromboembolic events. Treatment includes methionine restriction and treatment with pyridoxine.
(continued ) Feature
Value
Click to include
Reduced elbow extension Three of five facial features Skin striae Severe myopia Mitral valve prolapse Reduced upper segment/ lower segment & increased arm span/height
þ þ þ þ þ þ
1 1 1 1 1 0
Open to calculate
A score of 7 is considered a positive systemic score. From the Marfan’s organization website.
Management Treatment with angiotensin II receptor I blockade (ATI antagonists) such as losartan can be used to block the dysregulation of TGF beta. ACE inhibitors and beta-blockers may be helpful but aortic root surgery may be required when the aortic diameter at the sinus of Valsalva is more than 5 cm. 2) EhlerseDanlos syndrome with mutations in the collagen genes leading to defects in type I or type III collagen leading to stretching in the collagen at different sites depending on the exact mutation. Hypermobile type EhlerseDanlos syndrome: stretchy velvety skin, lax ligaments, hypermobile joints, are seen in the most common type, the Hypermobility type. In this mild subtype there is such an overlap with benign hypermobility and the normal childhood variants of flexibility that caution must be exercised in mislabelling essentially normal children as having a “disorder” with the subsequent potentially unhelpful psychological consequences of such a label. TNXB genetic mutations may be found but more usually clinical diagnoses are made. This area needs particular care as it is possible to assign an incorrect label that may be difficult to adjust later.
Systemic autoimmune connective tissue disorders IN childhood Vascular type EhlerseDanlos syndrome: Associated with mutations in COL3A1 leading to arterial, intestinal, uterine fragility and rupture, characteristic facies with thin lips and philtrum, small chin, thin translucent skin and easy bruising and dystrophic scars.
Juvenile systemic lupus erythematosus (jSLE) Juvenile dermatomyositis (jDMS) and polymyositis Juvenile idiopathic arthritis (JIA) with positive rheumatoid factor (RF) €gren’s syndrome Primary Sjo Mixed connective-tissue disease (MCTD) or overlap connective tissue disease Systemic sclerosis in childhood (jSSc) Localized scleroderma (jLS) in childhood Incidences in childhood jSLE 0.5e0.6 per 100,000 F:M 4.5:1 jDMS 0.4 per 100,000 F:M 3e5:1 jSSc rare 1:1,000,000 F:M 3:1 jLS incidence 0.8 per 100,000, prevalence by 18 yrs 50 per 100,000 F:M 2.5:1 These diseases are included under the term classic collagen vascular diseases or autoimmune connective tissue diseases.
Classic type EhlerseDanlos syndrome: Associated with mutations in COL5A1 and COL5A2. Cases have a combination of joint hypermobility, skin fragility and hyperextensibility, widened atrophic tissue paper or cigarette paper scars are typical and aortic root dilatation may occur. Kyphoscoliotic type EhlerseDanlos syndrome Progressive scoliosis is present from birth or within the first year of life. Scleral fragility and rupture of the globe of the eye may occur. Severe muscle hypotonia present at birth with generalized joint laxity and friable hyperextensible skin. POLD1 gene mutations are associated with this phenotype.
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However, they all are really better considered as complex autoimmune inflammatory diseases with genetic components, cellular and humoral dysregulation, some with environmental triggers and with complex inter-relationships such that some patients have features of all of the conditions below at once. Most of the conditions below are associated with Raynaud’s phenomenon in some patients, positive antinuclear antibodies ANA’s, skin involvement, arthritis, general debility and tiredness and most are progressive without treatment. They all require immunosuppressive therapy to obtain states of clinical remission and this therapy is usually required on a long-term basis. These include steroids, disease modifying anti-rheumatic drugs (DMARDS) such as methotrexate and hydroxychloroquine, possible cyclophosphamide and biologic treatment. In childhood they all can affect growth and development and quality of life and some are life-threatening. Many are associated with an increased long-term risk of cardiovascular disease. Vasculitis can also be associated with connective tissue diseases €gren’s syndrome, systemic sclerosis, in pre-existing SLE, primary Sjo relapsing polychondritis, primary anti-phospholipid syndrome, juvenile dermatomyositis, mixed connective tissue disease. Vasculitis occurring in any of these situations suggests a more severe disease severity and need for stepping up to aggressive treatments.
Systemic sclerosis and localized scleroderma JIA and JIA associated uveitis Juvenile dermatomyositis and polymyositis Mixed connective tissue disease Autoimmune hepatitis €gren’s syndrome Primary Sjo Short lived positivity in viral infections and in some neoplasias such as acute lymphoblastic leukaemia and lymphoma. Positive ANAs can be seen in between 3 and 15% of healthy individuals Juvenile systemic lupus erythematosus (jSLE) SLE is a multi-system, episodic, autoimmune disease affecting all organs including the connective tissues of skin and joints and blood vessels and identified by the presence of antinuclear antibodies especially antibodies to native (double-stranded) DNA (dsDNA). Some patients have genetic mutations such as C1q deficiencies, some have photosensitive disease triggers. Diagnosis is made on the basis of the American College of Rheumatology (ACR) criteria which (Table below), although developed for research in adult disease, also help in the diagnosis in childhood. It is helpful in demonstrating the range of systems usually involved. However most types of named disorders affecting most organs can be seen in SLE, truly a disease with a thousand faces. The BILAG score (British Isles Lupus Assessment Group) 2004 index is educational in outlining the range of complications and organ disease as well as validated in assessing the actual disease severity. The SLEDAI 2000 Disease Activity Index contains a shorter list of activity measures and the SLICC/ ACR Damage Index (Paediatric) is used to score permanent disease related damage. Presenting features of jSLE are often non-specific constitutional symptoms of headache, tiredness, malaise and weight loss with arthralgia or arthritis, rashes (especially a malar rash) and mouth or nasal ulcers. Temperatures, serositis, lymphadenopathy and hepatosplenomegaly are common. Renal involvement is common in jSLE occurring in between 20 and 82% depending on the length of the study follow-up. Early diagnosis and rapid commencement of treatment can literally be life-saving as the rate of progression is very rapid in some cases where renal failure, severe macrophage activation or major lung, cardiac or brain disease can prove fatal. In addition there are long-term risks from thromboembolic phenomenon especially in patients with anti-phospholipid syndrome as well as from accelerated cardiovascular disease in the longer term. Raynaud’s phenome€gren’s disease and vasculitis can also occur. non, secondary Sjo Treatment nearly always requires steroid use (often in high dose at initial diagnosis and with disease flares), hydroxychloroquine and total sunblock. In addition DMARD therapy with mycophenolate mofetil, azathioprine, methotrexate, ciclosporin and infliximab are used with cyclophosphamide reserved for life threatening situations. Anti-B cell therapies are in trials with rituximab used as step up therapy and for long-term maintenance especially in non-compliant teenagers. New drug therapies are being used SLE (and starting in trials in jSLE) including belimumab, ocrelizumab, epratuzimab and atacicept. Anti-phospholipid treatments are needed. Intensive treatment of refractory lupus may include plasma-exchange and even
Raynaud’s phenomenon Definition: a triphasic response to cold trigger or stress. Initial vasospastic phase with white fingers, toes and or nose tips. During this phase the digits often feel numb, may become stiff with decreased fine coordination. Secondly, a cyanotic phase as the haemoglobin in the vasospastic blood vessels deoxygenates. Thirdly, a vasodilatory red phase with increased blood flow making the area hot, red and painful with tingling. Primary Raynaud’s phenomenon is common and occurs in 15% of normal school aged children. It is more common in girls than boys (18% versus 12%) and more common with older teenagers. Investigations and treatment depend on the severity of the episodes. Investigations include FBC, thyroid function, antinuclear antibody and possible capillaroscopy, and cold challenge tests. Secondary Raynaud’s phenomenon occurs in association with: Systemic sclerosis Systemic lupus erythematosus Mixed connective tissue disease Overlap connective tissue disease Secondary to drug treatments such as beta-blockers, sumatriptan, decongestants, the contraceptive pill, ACE inhibitors and clonidine. Drug misuse such as with amphetamines and cocaine Raynaud’s phenomenon needs to be differentiated from chilblains (episodic colour change after exposure to cold with cold injury leading to tissue damage manifesting as an inflammatory response with painful erythematous/violaceous nodules often with cracked skin. Acrocyanosis is a common, painless vasospastic disorders leading to coldness and bluish discolouration of the hands and feet but without the triphasic colour responses. Positive antinuclear antibodies (ANAs) can be associated with: SLE and drug-induced lupus
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Juvenile dermatomyositis and polymyositis (jDM and PM) JDM is also a multi-system disorder with widespread but patchy inflammation in muscles and skin rashes with arthritis commonly seen, but where small blood vessel vasculopathy is now thought by many to be the primary pathology. The clinical presentation may be insidious and is often missed in children until quite profound weakness is present. Again systemic symptoms may occur with fever, malaise, poor appetite, poor energy levels, weight loss and irritability. Rashes can take many forms but typically seen is the violaceous heliotrope rash on the eyelids, periorbital oedema, a malar rash with perioral sparing, Gottron’s papules over extensor surfaces especially of the fingers. In severe cases widespread oedema and tissue ulceration can occur. Nail fold capillary changes and hypertrophy of the cuticle are important diagnostic clues. Polyarticular arthritis, and myalgia can occur but muscle weakness starting proximally and extending to involve most muscle groups occurs in most patients. This weakness can include weakness in swallow with risks of aspiration, dysphonia, and dyspnoea. In the long term calcinosis of skin and subcutaneous tissues is related both to the severity of the disease subtype and to delay in adequate treatment establishing disease control. Similarly lipoatrophy and lipodystrophy can occur. Early diagnosis and rapid commencement of treatment can again be life-saving as the rate of progression can be rapid in some cases, severe macrophage activation can occur and systemic vasculitis affecting for example brain and gut blood vessels can create serious presentations. Interstitial pneumonitis can occur denovo and aspiration pneumonia can create serious outcomes. Helpful ways of quantifying muscle strength and function to assess response to treatment include the Childhood Myositis Assessment Scale (CMAS) and the Manual Muscle Testing 8 Standard Scoring System (Oxford and Kendal). MRI scanning of muscles with gadolinium enhancement or with special sequences is the accepted modality of muscle diagnosis. However, muscle biopsy is still recommended with the intention of excluding metabolic myopathies as well as for enhancing the understanding of disease subtypes. Increasingly myositis specific and myositis associated antibodies are recognized in jDMS associated with specific disease phenotypes and these may help to direct treatment in the future. Treatment nearly always requires steroid therapy, methotrexate, hydroxychloroquine and sunblock. Unresponsive disease may need intravenous immunoglobulins. Cyclophosphamide is used for life-threatening and ulcerative disease. Ciclosporin helps in cases with macrophage activation syndrome. Treatments with anti-TNF drugs especially intravenous infliximab may be helpful. Mycophenolate mofetil, tacrolimus ointment and rituximab are all helpful in individual cases.
haematopoietic stem cell transplantation. The complexity of this disease requires urgent referral for management by paediatric rheumatologists with expertise. ACR revised criteria for classification of SLE Criteria
Definition
Malar rash
Fixed erythema, flat or raised, over malar eminences, tending to spare nasolabial folds Erythematous raised patches of adherent keratotic scaling and follicular plugging. Atrophic scarring may be seen in older lesions Skin rash as a result of unusual reaction to sunlight Oral and nasopharyngeal ulcers, usually painless, observed by a physician Non-erosive arthritis involving 2 or more peripheral joints, characterized by tenderness, swelling or effusion Pleuritis- pleuritic pain, rub heard or pleural effusion or, Pericarditis-documented by ECG or rub or pericardial effusion Persistent proteinuria >0.5 g/day or >3þ, or Cellular casts: red cell, haemoglobin, granular, tubular or mixed Seizures or Psychosis in the absence of offending drugs or metabolic derangement (e.g. uraemia, ketoacidosis, electrolyte imbalance) Haemolytic anaemia with reticulocytes, or Leucopenia <4000 per mm3 on 2 or more occasions, or Lymphopenia <1500 per mm3 on 2 or more occasions, or Thrombocytopenia <100,000 per mm3 in the absence of offending drugs Anti- DNA antibody, or Anti-Sm antibody, or Anti-phospholipid antibodies C Abnormal anticardiolipin antibody C Positive lupus anticoagulant C False positive for syphilis for >6 months Abnormal titre of ANA at any point in absence of drugs known to be associated with drug-induced lupus.
Discoid lupus
Photosensitivity Oral and nasal ulceration Non-erosive arthritis Serositis
Nephritis
Neurological
Haematological
Immunological
Antinuclear antibody
€gren’s syndrome can occur alone as primary Sjo €gren’s synSjo drome in childhood but more usually occurs in association with scleroderma, systemic lupus erythematosus or mixed connective €gren’s syndrome. In childhood a tissue disease as secondary Sjo chronic parotitis is the usual presentation. It is associated with a chronic, slowly progressing inability to secrete saliva and tears.
If four or more of these 11 items are positive either simultaneously or cumulatively the patient can be said to have SLE. ~ ez, D., & Urowitz, M. B. (2002). Systemic Gladman, D. D., Iban lupus erythematosus disease activity index 2000. The Journal of Rheumatology, 29(2), 288e91. Lupus nephritis is classified according to the 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) working group revision published in 2004.
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Mixed connective-tissue disease (MCTD) is a disorder in which features of various connective-tissue diseases (CTDs) such as
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systemic lupus erythematosus (SLE); systemic sclerosis (SSc); dermatomyositis (DM); polymoyositis (PM); polyarticular or €gren’s syndrome can rheumatoid arthritis and, occasionally, Sjo coexist and overlap. The course of the disease is chronic and usually milder than with other primary CTDs. In some cases, MCTD is considered an intermediate stage of a disease that eventually becomes either SLE or systemic sclerosis. Anti- RNP positivity is a hall mark of this disease.
scleroderma can affect the quality of life. It is difficult to distinguish active from inactive disease and long-term treatment is often necessary. In a cohort of children and young people with jLS from London, photographs of 65 patients were analyzed by Adobe Illustrator and overlain on a master file where many similarities between the areas affected and Blaschko’s lines were found suggesting a possible skin mosaicism as part of the jLS pathogenesis with the inflammation and fibrosis occurring in the mosaic affected skin only. This is still only a theory of causation. Isolated congenital cases of jLS have been reported. SSc is a chronic progressive disorder of unknown aetiology characterized by the excess synthesis and deposition of collagen (both types I and III) and other extracellular matrix components in a variety of tissues and organs. There are associated vascular abnormalities and autoimmunity. This subsequent damage may eventually be life-threatening. Juvenile systemic sclerosis (JSSc) is characterized by Raynaud’s phenomenon, skin changes of thickening and oedema termed sclerodermatous change and widespread abnormalities of the blood vessel walls and internal organs such as kidney, heart, lungs and the gut. SSc is a generalized body disorder whereas localized scleroderma is confined to a single or multiple sites but with normal tissue between and without distant internal organ involvement. There are proposed PRES classifications for juvenile systemic sclerosis/jSSc although these have yet to be validated. The two main subtypes of SSc are termed limited cutaneous disease and diffuse cutaneous disease (these confusing terms describe the skin involvement and should not be read as suggesting that SSc is limited only to the skin). This brave attempt at a separate paediatric classification is unfortunate as it is likely that SSc is really a spectrum from childhood to adult disease and that different classifications are more likely to delay successful transition. The limited cutaneous type of SSc has skin changes confined to the more distal arms and legs as well as the neck and face but with truncal sparing. This type was called the CREST syndrome previously and the acronym still reminds of the associated calcinosis, Raynaud’s phenomenon, oesophageal involvement and telangiectasia. However serious interstitial lung disease and pulmonary fibrosis with or without pulmonary hypertension can also occur in this subtype. In the diffuse cutaneous type of SSc skin involvement extends onto the upper arms and trunk and internal organ disease such as renal involvement is more severe. Childhood disease is more often diffuse in nature and there is a significant mortality especially from pulmonary and cardiac causes and often in the first 3e5 years after onset requiring urgent diagnosis, assessment and treatment. The 1980 ACR classification criteria for adult systemic sclerosis (SSc) lacked sensitivity for diagnosing early SSc and limited cutaneous SSc, often delaying treatment. Therefore these have just been updated in 2013 by consensus methodology. In the new criteria thickening in the skin of the fingers extending proximal from the metacarpophalangeal joints allows the patient to be classified as having SSc. If proximal skin thickening is absent, seven additive weighted items apply: skin thickening of fingers distal to the MCP joints, fingertip lesions, telangiectasia, abnormal nail fold capillaries, interstitial lung disease or
Polyarticular JIA with positive RF or childhood onset rheumatoid arthritis can also coexist with other connective tissue disease and strictly all JIA could possibly be termed an autoimmune connective tissue disease. Scleroderma in childhood A spectrum of conditions is covered by the term scleroderma with presentations, complications and outcomes so different from each other that it is questionable whether they should be spoken about together. The terminology is particularly confusing for non-experts and the classifications have not been validated in children. The term scleroderma simply means “hard skin” and it is thickening or hardening of the skin that links the two main disease subtypes in the classification: systemic sclerosis (SSc) or juvenile systemic sclerosis (jSSc) and localized scleroderma/juvenile localized scleroderma (jLS). Under these two headings are many different phenotypes varying from a mild skin disorder in localized superficial morphea, through to potentially disfiguring and disabling linear scleroderma or linear morphea to the generalized life-threatening systemic illnesses seen in systemic sclerosis. There has been a real explosion in the last 5e10 years in scleroderma research, especially into systemic sclerosis and the main pathogenic cells (T and B cells) fibroblasts and endothelial cells and their cytokine interactions are quite well worked out now. This has given rise to the classical triad of pathological alterations found in SSc: i) progressive cutaneous and visceral fibrosis, ii) a functional and structural vasculopathy, iii) immunological abnormalities. A better recent understanding of the molecular and cellular mechanisms of LS has lead to evaluation of new treatments that modify profibrotic cytokines such as TGF b and IL4. Other treatments affect factors regulating the assembly and deposition of extracellular matrix components. Others such as IL12 and IFN gamma restore Th1/Th2 immune balance. IFN gamma acts by directly inhibiting collagen synthesis and restoring immune balance. The pathology within localized lesions has similarities to SSc and there is an acceptance of a link between diseases in this spectrum. However, there is no evidence of progression from one type to another but it is more likely that the some diseases under this heading have an inherent deepening and worsening as part of their disease course while others remain as more superficial diseases primarily affecting the skin. Juvenile localized scleroderma (jLS) causes inflammation in the skin and underlying tissues leading to fibrosis. Long-term morbidity occurs from loss of function, disfigurement and deformity. Although only rarely life-threatening localized scleroderma can be disfiguring and disabling as the full thickness of tissues can be affected from skin to deep tissues including brain and bone underlying the lesions. Both types of
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Other conditions associated with stiff SKIN
pulmonary arterial hypertension, Raynaud’s phenomenon, and SSc-related autoantibodies. Isolated jSSc is one of the rarest connective tissue diseases and again needs to be treated by teams with expertise in paediatric scleroderma. A BPSU study reported an annual incidence rate of 0.27 per million children under the age of 16 years (Herrick and Baildam). It is much more common to have sclerodermatous features as part of an overlap syndrome in childhood disease. Significant localized scleroderma is still rare affecting 3.4 per million children although the milder forms of simple morphea patches are much more common. The Mayo Clinic classification is still used although there are proposed PRES classification for localized scleroderma/morphea. The types of localized scleroderma include: Morphea Circumscribed (superficial/deep) Generalized, guttate Pansclerotic/profunda Mixed morphea Linear scleroderma Linear scleroderma of trunk/limbs Linear scleroderma of face, neck and/or scalp including ‘en coup de sabre’ and hemifacial atrophy (Parry Romberg syndrome) In association with localized scleroderma the following can occur: Eye lesions Uveitis (either for directly overlying facial lesions or distant to the inflammation and therefore ophthalmology screening is required). Optic neuritis and optic atrophy have been reported. Eyelid changes Changes in eyelash colour, changes in colour of the iris. Neurological symptoms including seizures, cranial nerve palsies, headaches, irritability, neuro-psychiatric problems and learning difficulties from deep brain lesions including vasculitis and direct brain inflammation. MRI scan changes can be single, multiple, enhancing or calcific. Brain biopsies have shown inflammatory brain changes. Scalp lesions associated with waxy alopecia in the en coup de sabre distribution. This may be amenable to surgical removal by plastic surgeons once the disease is quiescent. Contractures of joints occurs if overlying skin and deep tissues are affected by the lesions. Arthritis both locally and of distant joints also occurs. Local impairment of bone and joint growth can lead to severe limb deformities with very large limb length discrepancies occurring. The temporomandibular joint may be affected and contribute to major facial asymmetry. Dental problems can be significant in facial lesions with gum retraction and severe non-alignment requiring complex orthodontic work. Raynaud’s phenomenon and cardiopulmonary, renal and gastrointestinal disease does not occur in localized disease. The natural history is not defined and there are no long-term cohort studies of outcome either on or off treatment. There are several recent studies of the efficacy of corticosteroids and methotrexate with mycophenolate mofetil and biological treatments used in individual unresponsive cases.
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Systemic sclerosis. Localized scleroderma. Graft versus host disease. Nephrogenic fibrosing dermopathy induced by gadolinium enhanced MRI scans when used in patients with renal impairment. Chemical induced scleroderma like disease e.g. from polyvinyl chloride, bleomycin, toxic-oil syndrome. Localized idiopathic fibroses. The stiff skin syndrome caused by fibrillin gene defects Pseudosclerodermas Phenylketonuria- a minority of PKU patients develop sclerodermatous skin lesions resembling morphoea, often symmetrical and poorly defined. Disorders of premature ageing such as progeria and Werner’s syndrome Scleromyxedema e with popular cutaneous lesions and induration of the underlying subcutaneous tissues. Lesions mainly on the face, neck, trunk and hands. Histology e a dense acid mucopolysaccharide deposits and fibrohistiocytic infiltrate Scleredema-with stiff skin and induration of the face, neck, shoulders, chest and proximal parts of the limbs, following beta- haemolytic streptococcal infections. Dupuytren’s contractures Gardener’s syndrome e intra-abdominal fibrosis associated with multiple colonic polyps and osteomas Diabetic cheiroarthropathy in juvenile-onset diabetes leading to short stature, tightening of the skin and soft tissues and figure contractures. Porphyria cutanea tarda some patients develop plaque like lesions similar to localized scleroderma and others like discoid lupus. A
FURTHER READING Baildam EM, Ennis H, Foster H, et al. Influence of childhood scleroderma on physical function and quality of life. J Rheumatol 2011; 38: 167e73. Ennis H, Herrick A, Baildam E, Richards H. Childrens’ and parents’ beliefs about childhood onset scleroderma are influenced by child age and physical function impairment. Rheumatology July 2011. ~ez D, Urowitz MB. Systemic lupus erythematosus Gladman DD, Iban disease activity index 2000. J Rheumatol 2002; 29: 288e91. Gutierrez-Suarez R, Ruperto N, Gastaldi R, et al. A proposal for a pediatric version of the systemic lupus international collaborating Clinics/American college of rheumatology damage index based on the analysis of 1,015 patients with juvenile-onset systemic lupus erythematosus. Arthritis Rheum 2006; 54: 2989e96. Herrick AL, Baildam EM. Capillaroscopy in juvenile connective tissue diseases, chapter 18. In: Atlas of capillaroscopy in rheumatic diseases. Elsevier, 2010. Herrick AL, Ennis H, Bhushan M, Silman A, Baildam EM. Incidence of childhood scleroderma in the UK and Ireland. Arthritis Care Res (Hoboken) 2010; 62: 213e8.
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Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725. Jones GT, Herrick AL, Woodham SE, Baildam EM, Macfarlane GJ, Silman AJ. Occurrence of Raynaud’s phenomenon in children ages 12-15 years: prevalence and association with other common symptoms. Arthritis Rheum 2003; 48: 3518e21. Foster Helen, Brogan Paul, eds. Oxford specialist handbooks in paediatrics paediatric rheumatology 2012. Cassidy James, Petty Ross, Laxer Ronald, Lindsley Carol, eds. Textbook of pediatric rheumatology 2013 (check the current list of authors). van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M. 2013 classification criteria for systemic sclerosis: an American College of
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Rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis 2013; 72: 1747e55. Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004; 15: 241e50. Yee C, Cresswell L, Farewell V, et al. Numerical scoring for the BILAG-2004 index. Rheumatology (Oxford England) 2010; 49: 1665e9. Zulian F, Vallongo C, Woo P, et al. Localized scleroderma in childhood is not just a skin disease. Arthritis Rheum 2005; 52: 2873e81. Zulian F. Systemic sclerosis and localized scleroderma in childhood. Rheum Dis Clin North Am 2008; 34: 239e55.
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