THE
TREATMENT OF LOCALIZED SCLERODERMA IN CHILDHOOD
Alessandra Bruns, Claudia Gennari Lacerda,
Lúcia Stella S. de Assis Goulart, Virgínia Moça F. Trevisani
Division of Rheumatology
Universidade de Santo Amaro
(UNISA)
Contact:
Alessandra Bruns
Address: Rua Primeiro de Janeiro 450
ap.35, Vila Clementino, São Paulo – SP. CEP: 04044-060.
Phone Number: 55 – 11 –
55876174
Fax Number: 55 – 11 -
56682515
E-mail: alessandra_bruns@hotmail.com
Key Words: localized
scleroderma; childhood; treatment.
ABSTRACT
Localized scleroderma is a
connective tissue disorder of unknown etiology which causes induration and
discoloration of the skin as well as induration of subcutaneous tissue and
muscles. It is a different disease from systemic scleroderma. It is subdivided
into morphea and linear scleroderma. There are still few reports on localized
scleroderma in children. There are no studies that demonstrate a proven therapy
for localized scleroderma. Even without specific
therapy, many different types of
medications are used including corticosteroids, immunosuppressive and several
other drugs with different possible mechanisms of actions. The disease’s own
variable course and lack of standardization of outcome criteria make evaluation
of the effectiveness of these treatments challenging.
Localized scleroderma in children is
a distinct entity from systemic sclerosis due to the absence of vasospasm,
vascular lesions, and involvement of internal organs (1). It is classified into
two subtypes: morphea and linear scleroderma. Linear scleroderma includes the
typical linear lesions of localized scleroderma as well as “coup de sabre”
lesions and facial hemiatrophy (Parry-Romberg Syndrome) (2). Morphea and linear
scleroderma are clinically different, but histologically indistinguishable, and
the lesions tend to improve in a period of 2 to 3 years (3). The linear form is
frequently associated with growth deformities of the involved extremity.
Rarely, either subtype may evolve to systemic sclerosis, although linear
scleroderma can coexist with the systemic form or with another connective
tissue disorder (4).
Morphea is characterized by the presence of
one or more hardened and hypopigmented oval plaques on the face, trunk or
extremities. In the initial phase, we can identify a reddish or violet
inflammatory border. These plaques may be limited in number and size or may
become extensive (generalized morphea).
In children, the localized form of scleroderma is more
frequent than the systemic form but both of them are rare, constituting less
than 3% of rheumatic diseases in childhood.. Approximately 1.5% of all
scleroderma cases occur before 10 years of age (5,6). This illness is present
in all races and is more frequent in females (3:1). There is no significant
familial incidence, and no consistent association with HLA antigens (1,5).
Different etiological factors have
been implicated, including: 1.. trauma (6);
2. infectious agents, such as Borrelia burgdorferi (7); 3. environmental
agents, such as toxic oil (8); 4. treatment with D-penicillamine (9); 5. bone
marrow transplant (10); 6. oxygen-free radicals of endogenous and
exogenous origin (11).
The main characteristics of linear scleroderma is the presence of one or
more linear areas of involvement which affect the skin and can involve the
underlying subcutaneous tissue, muscles and even the bones (Figure 1). The extremities, the face or the scalp might
be affected. . Joint contractures, functional limitations, digit atrophy, and
cosmetic deformities are frequent complications (Figure 2). The denomination
“scleroderma en coup de sabre” is used to designate the involvement of the face
and/or the scalp and can be followed by profound tissue atrophy (Parry-Romberg
Syndrome), most prominent in small children (Figure 3).
LABS AND OUTCOME MEASURES
Labs are of
limited benefit in following the clinical course of local scleroderma. Skin
biopsy may be required to rule out similar skin lesions such as sclerodema and
eosinophilic fasciitis. There is no biochemical marker for diagnosis or serum
test that can help in the evaluation of clinical improvement. The complete
blood count is generally normal, with the exception of eosinophilia which can
occur in 25% of children with active disease. Acute phase reactants are often
normal and are not reliable in reflecting disease activity.
The most common laboratory abnormality is
the antinuclear antibody (ANA) which is present in 37% to 67% of cases. The
filamentous, homogeneous and nucleolar patterns are the most frequent
immunofluorescent patterns (1,12). Anticentromere antibodies and low titer
anti-double-stranded (denatured) DNA antibodies are occasionally noted (?SITE).
Anti-scleroderma antibodies (anti-Scl 70) are negative.
Other techniques are used to follow the response to therapy
for local and systemic scleroderma. For localized involvement, photography can
help document changes that may occur over time and in response to treatment.
TREATMENT
As for the
systemic form, there is not any pharmacological therapy proven as definitely
effective for the treatment of localized scleroderma. Studies are few in number
and mostly uncontrolled. Despite this situation, or because of this situation,
many therapeutic modalities are currently utilized for localized scleroderma,
including corticosteroids, methotrexate, D-penicillamine, Vitamins D and E,
phototherapy, and plasmapheresis. Possible new therapies include anti-TNF-
monoclonal antibodies and other biologics, as well as the use of thalidomide.
In linear scleroderma and in
generalized morphea, physical therapy and
occupational therapy play a critical therapeutic role. Their objectives
are maintaining functional ability, muscular strength and the joint range of
motion. It is essential to prevent flexion contractures. Massage of the
involved skin can be taught to the parents. It improves cutaneous elasticity
and thereby the joint movement (5).
Corticosteroids:
Oral
corticosteroids or the intravenous administration of high dose corticosteroids
(pulse therapy) are indicated for localized scleroderma in two clinical
situations. The first would be when linear scleroderma and morphea are in the
initial edematous phase. The second would be for rapidly progressive linear
scleroderma, characterized by a relatively fulminant development of cutaneous
lesions with progressive tissue atrophy, muscular loss and contractures as well
as growth delay of the involved limb (1). Corticosteroids appear to quickly
control the inflammatory component of the illness, allowing early use of adequate
physiotherapy and splinting.. Some authors advocate the maintenance of low oral
doses of corticosteroids for many years, as linear scleroderma may often have a
long period of low grade, subacute activity (5).
D-Penicillamine:
This drug has
been used since the 1980’s in the treatment of localized and systemic
scleroderma as well as for rheumatoid arthritis and JRA. Falanga & Medsger
observed improvement in the cutaneous lesions of their patients at 3 to 6
months after the onset of treatment (13). There has been no controlled
double-blind study corroborating its efficacy. The recommended dosage is
5mg/kg/day. The dose can be gradually increased according to the tolerance and
the clinical response of the patient, until the maximum of 10 mg/kg/day (14). The
side effects are a major concern and the drug appears to be utilized less now
than in the 1980’s due to those side effects.
Chan et al (15) described
the case of a twelve-year-old boy with linear scleroderma who developed over a
3 month period progressive cutaneous induration with erythema in the left lower
limb. The child was treated initially with oral prednisolone with some success
and continued to do well for the long-term on D-penicillamine and an emollient
applied topically.
Methotrexate
Methotrexate
(MTX) has been used since the mid-1980’s for rheumatoid arthritis and JRA. MTX
has multiple other indications as a second line agent in pediatric rheumatology
diseases such as dermatomyositis, SLE, vasculitis and sarcoidosis The mechanism
of action is based on its similarity with folic acid. It inhibits the
folate-dependent enzymes involved in the synthesis of ribonucleic and
deoxyribonucleic acids. The exact mechanism of action in localized scleroderma
has not been well elucidated yet (16).
Uziel et al utilized MTX (0.3 to 0.6
mg/kg/week) in the treatment of 10 patients with local scleroderma. The ten
patients,6 girls and 4 boys,,had a mean age of 6.8 years, and had an average
duration of disease of 4 years before the onset of treatment. In addition to the weekly MTX, nine of the 10
patients received intravenous methylprednisolone pulse therapy (30 mg/kg/day).
They received 3 consecutive days of the pulse initially, followed by one pulse
per month for 3 months. One patient discontinued the MTX after a month. The other nine patients obtained a good
response in 3 months. The authors concluded, despite the absence of a control
group, that the combination of MTX and pulse methyprednisolone is well
tolerated and appears to be effective in the treatment of localized scleroderma
(17). Krafchik, using slightly different
doses of MTX and intravenous pulse methylprednisolone, also noted positive
results when treating children with localized scleroderma during the acute
stage or when rapid progression of symptoms was present (12).
Vitamin D
The efficacy of
vitamin D and its analogs in the treatment of scleroderma was initially
described by Humbert et al in 11 patients with systemic sclerosis and 7 with
morphea, who showed improvement of the cutaneous disease with the use of oral
calcitriol (11). Its favorable results were corroborated by subsequent reports
that suggested the efficacy of oral calcitriol for localized scleroderma
(19,20)
Cunningham et al (21) evaluated the
effectiveness of calcipotriene ointment 0.005% (a synthetic analog of vitamin
D) in an open study of 3 months duration. The ointment was applied twice a day
to the scleroderma plaques. The authors treated 12 patients between 12 and 38
years of age with active and biopsy-proved linear scleroderma or morphea. At
the end of the study, the authors observed significant improvement of cutaneous
induration in all patients and a lack of side effects and of abnormalities in
mineral metabolism. They concluded that this drug is effective in the treatment
of localized scleroderma.
Vitamin E
Vitamin E has
been used in the treatment of localized scleroderma at a dosage of 400 mg/day.
The mechanism of action appears to be stabilization of the liposome membranes
preventing the release of hydrolytic enzymes. It also acts as antioxidant,
contributing to the inactivity of free radicals.
Eubanks et al reported two children
with linear scleroderma who showed progression of the disease during the
treatment with vitamin E (22). ??
Phototherapy
Skin irradiation with 340 to 400 nm of
ultraviolet rays A1 (UVA1) can reduce collagen deposition activity of human
fibroblasts in scleroderma lesions. This finding has led to some studies using
the phototherapy modality in localized scleroderma (23,24,25)
Kerscher et al evaluated phototherapy
therapy in 20 patients with severe linear scleroderma. The patients, 11 women
and 9 men, were between 10 and 73 years of age. Each patient was irradiated
with 20 J/cm2 UVA1 for 2 weeks. Their results suggested that low
doses of UVA can be highly effective for sclerotic plaques, even in those
patients with advanced disease and whose lesions rapidly progressed despite the
conventional treatment (25).
The experience with children is
limited. There are only two reported cases in the literature, an 8-year-old
girl and a 16-year-old boy with pansclerotic morphea. This is a variant of
localized scleroderma characterized by a rapid progression of cutaneous
fibrosis with extension to joints and fascia. Severe joint contractures and
cutaneous ulcers are common. The children received UVA1 irradiation for 6
months and 2 months, respectively. At the end of treatment, the patients showed
healing of ulcers, improvement of joint mobility and important reduction of
cutaneous sclerosis (26,27)
Kreuter et al (29) reported a study
with 19 children with morphea treated with low doses of UVA1 at 20 J/cm2, four
times a week for 10 weeks combined with topical calcipotriol (0.005%) applied
twice a day (28). The children had a mean age of 8.5 years, with a range of 3
to 13 years. At the completion of the treatment, significant improvement of the
cutaneous lesions was noted. These results indicated that the combined therapy
appears to be effective in the treatment of morphea. A controlled study is needed.
Plasmapheresis
Wash et al reported 3 patients with
localized scleroderma treated with plasmapheresis combined with prednisone for
5 months. One patient was a 5-year-old girl with severe generalized morphea and
high titers of ANA. The efficacy of this therapeutic modality was assessed by
evaluating the improvement of the cutaneous lesions and any joint limitations.
In all three cases, significant
improvement occurred after 2
months of treatment. The authors concluded that plasmapheresis can be
recommended for the treatment of severe cases of localized scleroderma
associated with high ANA titers.
New therapies
There are several
therapies that may hold promise. Anti-tumor necrosis factor treatments
(etanercept, infliximab) have been used in adult scleroderma and may be
beneficial for severe cases of localized scleroderma (31). Thalidomide has been
shown to improve SLE skin rash in multiple studies and may be useful for severe
localized scleroderma (32).
CONCLUSION
The diagnosis of
localized scleroderma is based on the history, physical examination, and often
skin biopsy. There is no specific laboratory test available. The cause of
localized scleroderma remains unknown. Many treatments are currently in use,
none evidence-based. The difficulty in evaluating the efficacy of the different
types of treatment is partly due to the low-grade, episodic course of localized
scleroderma and to the lack of standardization of outcome measures.
Corticosteroids, methotrexate, Vitamin D, and phototherapy may be beneficial.
New therapies, such as biologics and thalidomide, need to be evaluated for use
in severe cases of localized scleroderma.
REFERENCES