ARTICLE
Systemic scleroderma (SSc) is a connective tissue disease of unclear
pathogenesis. It is characterized by induration and thickening of the
skin, Raynaud's phenomenon and involvement of the inner organs. The incidence
is about 4 to 12 per million [1], with women affected 3 to 5 times as
frequently as men. Systemic scleroderma rarely appears in children. Only
1.5% of all SSc patients are younger than 10 years and 7.2% are between
10 and 19 years [1].
We must differentiate between systemic scleroderma and localized scleroderma
(morphea, sclerodermie en coup de sabre), so-called overlap syndromes
(mixed connective tissue disease) and pseudosclerodermas such as amyloid
degeneration, vinyl chloride and trichloroethylene disease, paraneoplastic
syndrome and Werner's syndrome [2, 3]. The diagnosis is based primarily
on clinical criteria, especially in view of the fact that in many patients,
the typical circulating autoantibodies are not detectable. In such cases,
new diagnostic possibilities are provided by nailfold capillaroscopy and
fluorescence video microscopy using intravenous sodium fluorescein [4-6].
We would like to present one of the rare cases of juvenile systemic
scleroderma in a boy recently treated by us and then describe the new
diagnostic possibilities.
Case study
Our patient first came to our hospital at the age of 16 years because
of cyanosis and numbness of the fingers following exposure to cold. These
symptoms had been recurring for 2 to
3 years. He is still attending school and does not smoke. About 3 weeks
before his first visit the patient suffered from mycoplasmal pneumonia
and 4 months earlier, from brief difficulty in swallowing, probably as
a result of pharyngitis. There was no dyspnea, no substantial trouble
with exertion (the boy actively participates in sports), no arthritis
and no digestive problems. A physical examination showed him to be slightly
dystrophic but in good general health. His weight was 39 kg (below the
third percentile according to Tanner's percentile curves), height 163
cm (10th percentile), with a target parameter of 168 cm (3rd percentile).
The boy had a very narrow face, a hint of microstomia, and a tight, cool
skin with little subcutaneous fat tissue. The ends of the 2nd and left
3rd fingers were livid and there were pitting necroses on almost all of
the fingertips (Fig. 1).
Skin flexibility was limited in the area of the distal phalanges. There
was neither clinical nor radiological evidence of calcinosis. Pulses were
clearly palpable at the hands and feet. Otherwise, there was normal internal
and neurological status.
Laboratory results
Serum electrophoresis revealed a hyper-gamma-globulinemia (1.81 g/dl)
with an elevation of the three immunoglobulin fractions IgG (913 mg/dl),
IgA (375 mg/dl) and IgM (412 mg/dl). Although no cryoglobulins were detected,
there was a markedly elevated cold agglutinin titer (1:1024). Routine
laboratory parameters as well as C3 and C4 complement,
angiotensin-converting enzyme and plasma renin activity, BSR and CRP were
all in the normal range. Apart from an elevated titer for Mycoplasma
antibodies all of the blood tests for possible infections were negative.
In the immunopathological tests, we were able to find antibodies against
keratin, smooth muscles and nuclear membranes, but no ANA, ENA and ACA.
Sweat test, chromosome analysis and stool and urine examinations were
normal.
Diagnostic results
X-rays of the hands, abdominal sonography, ECG, echocardiograms and
barium swallow were all normal. Repeated X-rays of the thorax continued
to show increased, discrete markings for a long time after the mycoplasmal
pneumonia. In addition, two whole-body plethysmographic lung function
tests consistently showed a restrictive ventilation disorder, with a total
lung capacity of 3.3 l (69% of the norm), a vital capacity of 2.5 l (66%
of the norm) and an intrathoracic gas volume of 1.8 l (75% of the norm).
The carbon monoxide diffusion test revealed a mild diffusion disorder
with a reduction of the transfer factor to 70% of the norm.
Capillaroscopy
In comparison to normal findings (Fig.
2A), our patient showed clear signs of microangiopathy, with a
non-homogeneous distribution of dilated capillaries, capillary rarefaction
and microhemorrhages (Fig. 2B).
Local exposure of the nailfold of the left third finger to cold caused
a pathological lengthening of the so-called stasis time in the capillaries
to 62 seconds (physiological stasis times in healthy individuals range
from 0 to maximum 10 s). After the intravenous injection of 0.025 ml/kg
sodium fluorescein, the video microscope recording of the capillaries
showed an increased local dye leakage at the peak of the capillary loop
in the shape of a pointed cap (Fig.
3B; normal findings Fig.
3A).
We were able to diagnose systemic scleroderma on the basis of the clinical
findings and supplementary examinations. After subsequent therapy with
pentoxifylline (2 x 400 mg/day), avoidance of exposure to cold, and lymphatic
drainage, the attacks of Raynaud's phenomenon became milder and less frequent.
Subjectively, finger mobility increased, but this improvement could not
be quantified by a decrease of stasis time in local cold exposure tests.
Discussion
A diagnosis of systemic scleroderma is usually made on the basis of
typical clinical symptoms (Table
I). In order to make a more exact classification possible, the
American Rheumatism Association has worked out specific criteria, all
of which are met by our patient. An examination of almost 800 patients
showed these criteria to have a specificity rate of 98% and a sensitivity
of 97% [7]. Our patient's hyper-gamma globulinemia is just as consistent
with systemic scleroderma as the elevated titer for cold agglutinins,
which is found in 25% of all patients [2]. In our case, however, the cold
agglutinins could also be increased because of the recent bout of mycoplasmal
pneumonia. The corresponding tests have yet to be performed.
The restrictive ventilation disorder, limited diffusion capacity and
the increased markings in the chest X-rays indicate that there is early
pulmonary fibrosis.
Although antinuclear antibodies are detectable in up to 90% of all cases
[1], usually with a "spotty" or "nuclear" immunofluorescence pattern,
their absence in our patient does not rule out this diagnosis. Anticentromeric
antibodies are found in 12-43% of all SSc patients and the highly specific
anti-Scl-70 antibodies in approximately 50% [3].
Recently, the microscopic evaluation of the nailfold capillaries in
vivo has proven to be a useful diagnostic tool [4, 6]. Like our patient,
more than 90% of all systemic scleroderma patients have pronounced dilatation
to the point of megacapillaries, as well as capillary rarefaction, a loss
of capillary loops, and irregular courses of the capillaries. The extent
of these changes does not correlated with the involvement of the inner
organs [8]. However, they are detectable even in early stages of the disease
and make it possible to distinguish between patients with idiopathic Raynaud's
syndrome and patients with Raynaud's phenomenon who will go on to develop
systemic scleroderma [9]. Kenik et al. [5] have shown that it is
possible to correctly classify the various collagenoses solely on the
basis of typical changes in the nailfold capillaries. Children with localized
scleroderma do not exhibit any capillary changes [6].
Other capillary damage in patients with systemic scleroderma can be
visualized with capillary angiography using intravenous sodium fluorescein
[4, 10]. This method reveals a pathological leakage of dye at the peak
of the capillary loop in the shape of a cone or as a cloud of dye at quite
a distance from the capillary. We were able to see this leakage in our
patient, too. Such findings could make an early diagnosis possible in
patients with suspected collagenosis without any other morphological changes
in the capillaries [10].
The etiology and pathophysiology of systemic scleroderma remain the
subject of controversy. Lately, numerous data have been gathered which
suggest a primary vascular or immunological disorder which then leads
to a secondary fibrosis typical for this disease [11]. The early changes
in capillary morphology described above [10] and the detection of an endotheliotoxic
factor in the serum of scleroderma patients [12-14] are consistent with
a primary microangiopathy [15, 16].
Haustein [17] gives an up-to-date, thorough
overview of the therapeutic possibilities. With children and teenagers
in particular, the outlook for success must be weighed carefully against
the expected side effects because treatment may be life-long. Aside from
hypotonia, pentoxifylline has relatively few side effects and leads to
vasodilatation as well as a direct inhibition of collagen metabolism [18].
For this reason we use this drug with our patients and have already observed
a subjective improvement of Raynaud symptoms. With increasing involvement
of the inner organs, especially in the case of pulmonary fibrosis, treatment
with D-penicillamine seems indicated [1]. This substance inhibits cross-linking
of the collagen, so it remains soluble for longer, and it also has an
immunosuppressive and cytostatic effect. A very slow increase of the dosage
over a period of months is advisable in order to reduce side effects such
as kidney damage, hematological damage, neuropathies, and autoimmune reactions
[1].
By means of nailfold capillaroscopy we are already able to detect typical
changes at an early stage. These take the form of capillary rarefaction,
megacapillaries and microhemorrhages, and deviations from the hairpin-shaped
morphology of the nailfold capillaries seen in healthy individuals [1,
19].
Fluorescence video microscopy represents an important addition to the
functional diagnostic methods at our disposal. It allows us to observe
the influx and efflux of the small molecules of the dye (sodium fluorescein)
as well as their distribution and transcapillary diffusion in the nailfold
capillaries. The research group around Bollinger in Zurich [9, 12, 13]
was able to prove that there is a pathological increase in sodium fluorescein
dye leakage at the apex of the capillaries in SSc patients. This phenomenon
is a pars pro toto indication of a pathological increase in permeability
for low-molecular weight plasma components.
These morphological and functional disorders are associated with changes
in the perfusion of the capillary segments in question, as shown by high-resolution
capillaroscopy. Besides capillaries with unhindered flow, we also found
extended periods of stasis in the flow of erythrocytes. The distribution
of perfusion was not homogenous to the point that some capillaries were
not perfused at all.
Manual lymphatic drainage can have a lasting therapeutic effect because
it causes a decongestion of the tissue, reactivation of the transport
processes in the lymph capillaries and, in the case of whole-body lymphatic
drainage, a suction effect on the periphery which contributes to a decrease
in edema and can thus stop the pathological changes in the connective
tissue. Manual lymphatic drainage should be continued even after acute
signs of inflammation have subsided in order to support the reestablishment
of physiological conditions in the microcirculatory system.
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