Fig. 30.1
The scleroderma patterns in systemic sclerosis are characterised by progressive loss of capillaries. In an early pattern, there is a prevalence of giant capillaries without loss of capillaries. In the active pattern, there are giants combined with abnormal individual morphologies, combined with a lowered density (lowered density defined as less than six capillaries per linear mm). In the late pattern, there is a loss of capillaries combined with abnormal shapes. Of note, the late scleroderma pattern has been linked with worse disease manifestations. A late scleroderma pattern (On behalf of the EULAR study group on microcirculation in Rheumatic diseases. Pathologic nailfold capillary changes (arrows). Courtesy of V Smith, I Foedvari, M cutolo)
A prospective study in adults with Raynaud’s syndrome, without other features of connective tissue disease, identified specific nailfold capillary changes and autoantibodies as independent predictors of progression to systemic sclerosis [15]. Such large-scale prospective studies are lacking in children with Raynaud’s syndrome. There are currently no guidelines on how to investigate children and young people with Raynaud’s syndrome, which prognostic markers suggest progression to the development of a connective tissue disease and how frequently children should be assessed to identify early evolution of systemic disease. The Pediatric Rheumatology European Society (PReS) working group for systemic sclerosis is working on it. Raynaud’s syndrome is reported as the first sign of disease in 61–70 % of patients with JSSc [16]. In follow-up studies of JSSc, the prevalence of Raynaud’s increases to 72–84 % [1, 16] and approaches nearly 100 % by adulthood.
The occurrence of oedema of the fingers, tightening of the skin and development of sclerodactyly marks the development of JSSc (Picture 30.1). The capillary changes have several phases of development too based on the progressive loss of capillaries, inherent to the disease [17] (Picture 30.2. late capillary changes). The late pattern is characterised by the presence of extreme loss of capillaries associated with the presence of abnormal shapes (neoangiogenesis). The mean time from the early to the active pattern is 28 ± 20 months and from the early to the late pattern 36 ± 29 months (adult data).
Picture 30.1
Patient with sclerodactyly and ulceration on the fingertip
Picture 30.2
Capillaroscopy picture of a 12-year-old girl with Raynaud’s phenomenon with anti-centromere antibodies. In the capillaroscopy she has giant capillaries and capillary loss (Picture courtesy of Francesca Ingegnoli, Division of Rheumatology, University of Milan)
The rate of internal organ involvement often mirrors the advancing skin disease and capillary changes as seen on the nailfolds. The skin involvement in JSSc is of two main subtypes, limited and diffuse [18]. The diffuse cutaneous subtype is defined with truncal and acral skin involvement, tendon friction rub, early interstitial lung disease, oliguric renal failure, diffuse gastrointestinal disease and myocardial involvement. The absence of anti-centromere antibody and the presence of anti-topoisomerase antibody in around 30 % of patients are characteristic, as are the nailfold capillary changes.
The limited subtype has skin involvement on the hands, face, feet and forearms and significantly late incidence of pulmonary hypertension, with or without interstitial lung disease, trigeminal neuralgia, skin calcification and telangiectasias. These patients have a high prevalence of anti-centromere antibodies.
According to the largest pediatric case collection of 153 patients [16], around 90 % had the diffuse subtype. The mean age at disease onset was 8.1 years. 120 of the 153 patients were female. At diagnosis 75 % had Raynaud’s, 19 % had digital infarcts and 28 % digital pitting. This data is based on a cross-sectional survey with no standardised assessment of the organ involvement. In 36 of 146 patients, abnormal capillaroscopy was reported. Ten percent had dyspnoea and 5 % abnormal high-resolution CT of the lung. One patient had pulmonary hypertension. Two patients had heart failure. The gastrointestinal system involvement ranged from dysphasia in 10 %, 8 % with gastro-oesophageal reflux and 2 % diarrhoea. Eighteen percent of patients reported weight loss. None had renal crisis and only 1 % hypertension. Arthritis occurred in 26 %. This pattern differed from the adult early diffuse disease with lower prevalence of the main organ system development.
The second large cohort of JSSc patients has been described by Foeldvari et al. [1]. The main differences in the organ involvement in the two large pediatric cohorts are the higher rate of cardiovascular (44 % versus 28.8) and in the central nervous system involvement (16 % versus 3 %) in the cohort described by Foeldvari et al. [1]. In the cohort of Martini et al., there is a higher rate of muscular involvement, 24.2 % [16]. The comparative features of both the pediatric JSSc cohorts are tabulated in Table 30.1.
Table 30.1
Comparative features of two JSSc cohorts
Organ involvement | Foeldvari et al. n = 135 (%) | Martini et al. n = 153 (%) |
|---|---|---|
Skin | 135 (100) | 116 (75.8)a |
Joints | 106 (79) | 97 (63.5) |
GI tract | 88 (65) | 106 (69) |
Only oesophagus | 63 (47) | 47 (31) |
Pulmonary | 68 (50) | 64 (41.8) |
Cardiovascular | 60 (44) | 44 (28.8) |
CNS | 21 (16) | 4 (3) |
Renal | 17 (13) | 15 (9.8) |
Muscular | 13 (10) | 37 (24.2) |
Raynaud’s | 97 (72) | 128 (83.7) |
Calcinosis | 36 (27) | 28 (18.3) |
Sjögren’s syndrome | 7 (5) | ? |
CREST | 1 | ? |
Complications
The survival of the children in the two cohorts reported above was better than the comparable adult diffuse scleroderma patient population. The 5-year survival is between 92 and 95 %, and the highest mortality was in the first 2–5 years of the disease. Most patients who died had multisystem organ involvement. Patients with fatal outcome had a higher rate of cardiovascular, pulmonary, renal and central nervous system involvement. The mean disease duration till death in these patients was 2 years. Interestingly the female/male ratio was 1:1 [16].
In the cohort described by Martini et al., 15 of the 123 patients died. Most of the patients (n = 10) had cardiac problems, two had pulmonary arterial hypertension, two renal involvement, two respiratory insufficiency and one sepsis [19]. The time interval until diagnosis was 8.8 months in patients who died as compared to 23 months in the survivors. The patients with a fatal outcome had a higher rate of pulmonary, gastrointestinal and cardiac involvement.
Differential Diagnosis
In scleroderma-like disorders, the distribution and characteristics of skin involvement seem to be “atypical” as compared to classic SSc, and the acral skin involvement is usually missing. Exposure to certain chemicals or drugs may also suggest the presence of a scleroderma-like disease. These exposures are less frequent in children as compared to the adult population. Lack of Raynaud’s phenomenon, scleroderma-specific antinuclear antibodies, scleroderma capillary pattern on nailfold capillaroscopy and typical internal organ manifestations may also indicate the presence of a scleroderma-like disorder. For a definitive diagnosis, skin biopsy is almost always required.
Scleroderma-like disorders include diseases with mucin deposition (scleromyxoedema, scleroedema, etc.). Some disorders show papular-nodular skin changes with or without dermal deposition of materials (amyloid, mucin deposition, fibroblastic rheumatism, etc.). Diseases with monoclonal gammopathy (scleromyxoedema, POEMS syndrome, myeloma with scleroderma-like skin changes) also belong to the large group of scleroderma-like diseases. Some disorders are characterised by eosinophilia (diffuse fasciitis with eosinophilia, eosinophilia-myalgia syndrome, toxic oil syndrome), metabolic/biochemical abnormalities (insulin-dependent diabetes mellitus (IDDM), nephrogenic fibrosing dermopathy) and endocrine abnormalities (POEMS syndrome, hypo-/hyperthyroidism with mucin deposition, diabetes). Chronic graft-versus-host disease (cGVHD) may also show scleroderma-like skin changes.
Scleroderma-like disorders can be induced by drugs or chemicals (eosinophilia-myalgia syndrome, toxic oil syndrome, vinyl chloride disease, cytostatic/appetite suppressant, etc.) and also by physical injury (trauma, vibration stress, radiation injury). Inherited progeroid syndromes with early ageing (Werner’s syndrome, adult progeria, etc.) and a large heterogeneous group of hereditary disorders with either skin thickening (porphyria, phenylketonuria) or skin atrophy/tightening (restrictive dermopathy, scleroatrophic and keratotic dermatosis of the limbs, etc.) should also be taken into consideration in the differential diagnosis of scleroderma-like disorders. These categories are not mutually exclusive, because the remarkably different scleroderma-like diseases show overlapping features.
Approach to the Diagnosis
The diagnosis of JSSc is clinical, based on the typical skin involvement, the occurrence of Raynaud’s phenomenon and the classical nailfold capillary changes. There are patients who have no primary skin involvement, only “classical” internal organ involvement. To classify these patients as systemic sclerosis, the new adult classification system may be helpful [20].
The assessment of the organ involvement in children is more difficult, because several assessment methods, which are routinely used in adults with SSc, are not validated in the pediatric population. Most items, which need to be assessed, are well summarised in the preliminary disease severity score for juvenile systemic sclerosis [21]. This score reflects more damage than disease activity.
The modified Rodnan skin score, a validated tool to assess skin disease in adult systemic scleroderma patients, needs adaptation, if applied in children, because the subcutaneous tissue has a different consistency at younger age [22]. The score describes the “hardness of the skin”. This score consists of an evaluation of patient’s skin thickness rated by clinical palpation using a 0–3 scale (0 = normal skin, 1 = mild thickness, 2 = moderate thickness, 3 = severe thickness with inability to pinch the skin into a fold) for each of the 17 surface anatomic areas of the body. The total score is 51.
The definition of the “normal nailfold capillaroscopy pattern” is not fully developed for children. Children show an increase in the number of capillaries during the normal process of growth and development. Tortuous capillaries may occur in healthy children. An avascular picture is a characteristic of JSSc [23–26].
The 6-min walk test, a pivotal measure to assess cardiopulmonary function in the adult scleroderma patient, is also not validated for pediatric use. Two important studies showed different normal values for children in different ethnic populations; the Chinese patients [27] had a significantly higher value than the UK patients [28]. A current not yet published study from Foeldvari et al. [29] in a Caucasian population in Hamburg, Germany, shows similar values for the 6-min walk test as the UK patients. The Childhood Myositis Assessment Scale (CMAS) is also not validated in JSSc. Joint contractures influence the muscle strength and the cardiopulmonary fitness tests. In the assessment of the pulmonary involvement, the cooperation of the patient is needed, which can be difficult in the younger ones. None of the measures are validated in childhood JSSc according to the OMERACT criteria [30].
Management
There are no pediatric recommendations or pediatric controlled studies that can be used to direct the management of JSSc. There is the inception cohort protocol for the prospective evaluation of the patients (www.juvenile-scleroderma.com), where 6 monthly clinical evaluation is suggested including skin scoring, joint count, evaluation by examination of all organ systems, DLCO and FVC, cardiac echo every 6 months and evaluation of blood pressure every 3 months. A high-resolution computerised tomography (HRCT) is done at the baseline and at signs of clinical deterioration. A right heart catheterisation should be performed with features of pulmonary hypertension and before starting targeted treatment for pulmonary hypertension.
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