Download Introduction

Petra England
Case Study
Introduction
Scleroderma is a rare, autoimmune connective tissue disorder of unknown aetiology.
It can have variable clinical manifestations but is mostly characterized by
symmetrical thickening and hardening of the skin. The pathogenic pathways of
scleroderma are only partially known, but the main causation of tissue thickening is
abnormal collagen deposition which can result in eventual fibrosis in the skin as well
as internal organs. (Rosenkranz, M, et al. 2006)
Scleroderma can be divided into two main subgroups: systemic and localized. The
systemic form, also known as systemic sclerosis, involves diffuse skin involvement
associated with fibrotic changes in internal organs. Although systemic sclerosis is
rare in children, with an incidence rate of approximately 0.27 per million children per
year, (Herrick AL, Ennis H, Bhushan M, et al. 2010) it is known to be one of the most
severe rheumatic conditions in pediatric practice. (Panda, S, 2010)
Diagnosis of systemic sclerosis can be quite delayed from the time of first
presenting symptom. A retrospective study (Hawley, DP, Baildam, EM, Amin, TS, et
al. 2012) on 89 patients with systemic sclerosis, including 16 with juvenile systemic
sclerosis, revealed that the median time from the first symptom to diagnosis was 7
months, with a range of 2-50 months. Raynaud's phenomenon is the first sign of the
disease in 70% of the patients, and in 10% it is complicated by peripheral ulceration.
Proximal skin hardening is the second most frequent symptom, being present in 40%
of cases. (Panda, S, 2010)
Case presentation
T is an 18 year old male who has always led a very active lifestyle. He is currently
179cm tall and 61kg, giving a BMI of 19.04. In 2010, at age 13, his parents noted
that T was experiencing peripheral discolouration in response to temperature
changes. T also had been having problems with ulceration and swelling in the ends
of his fingers since age 12. T was seen by his local medical team in Tasmania who
determined that he had sclerodactyly and facial sclerosis. He was prescribed
Sildenafil and prednisolone to manage his condition. T had been seeing his local
Rheumatologist who referred him to the Royal Children’s Hospital for further
investigation. In early 2012, T moved to QLD and was seen by Dr A, a paediatric
rheumatologist.
T has an outstanding medical history. He has never had any chest pains or
dysphasia. He does not have any history of shortness of breath or modification in his
physical activities due to his condition. T also reported that he can play a full soccer
game and that he is as fast as his team mates. He has not had any recurrent lower
respiratory tract infections and his blood pressure is within normal limits, 125/72.
Upon examination in 2012, he presented with significant facial sclerosis and red
conjunctivi. Dr A noted that he has very striking sclerosis involving all limbs but
particularly noticeable over his upper limbs and trunk. T’s sclerodactyly is still
Petra England
Case Study
significant but his ulceration had been healing well with no major infarction or
gangrene. Systemic examination of the heart, lungs and abdomen was within normal
limits clinically. A recent blood test revealed very high amounts of Antinuclear
Antibody (ANA), indicating systemic involvement of the scleroderma. The impression
at this point was that T has systemic sclerosis and needs further investigation.
Tests Requested
1. High resolution CT (HRCT) scan of the chest to investigate pulmonary fibrosis
2. Assessment of respiratory status in relation to his current condition, including
Spirometry, DLCO, and Lung Volumes
3. Cardiac investigations, including echocardiogram and ECG to check normality
and pulmonary hypertension
4. Baseline connective tissue disease screen, including immune markers
5. Bone densitometry to assess osteopenia or osteoporosis in relation to
prolonged steroid use
Initial Test Results
Table 1: T’s Test Results upon presenting to the Royal Children’s Hospital
Test
Summary of Results (2012)
HRCT
Normal and clear windows, no fibrosis seen
Complex
Lung
Function
Moderate Restrictive Pattern, indicated by:
Spirometry: FEV1 65%, FVC 60% and FEV1/FVC 93% (LLN
75%)
DLCO: Mild reduction in diffusing capacity at 82%. VA was
moderately reduced to 59%, consistent with restriction.
DLCO/VA was 132%; this high percentage indicates that there is
no true diffusing limitation.
Lung Volumes: TLC was reduced to 63%, with RV at 66%,
giving a RV/TLC of 122%. All numbers are moderately reduced,
consistent with restriction.
CPET: TV 51% and VEmax 134%, indicating lack of respiratory
reserve.
Cardiac
Investigation
ECG: Sinus Rhythm at 95 bpm; normal ECG
Echocardiogram: Normal left and right ventricular size and
function. Normal wall thickness. No outflow tract obstruction, no
Petra England
Case Study
aortic or mitral incompetence. Minimal tricuspid incompetence.
No ASD, VSD or PDA. No clinical or echocardiographic
evidence of pulmonary hypertension.
Immune
Markers
Anti Ribonucleoprotien (RNP) present -> associated with mixed
connective tissue disorders and SLE
Antiphospholipid syndrome studies and Rheumatoid factor both
negative
High antinuclear antibody (ANA) with a speckled pattern ->
associated with connective tissue disorders and SLE
Bone Density
Bone mass density is at the lower end of expected range for age
Interpretation of test results
Examination of his HRCT chest scan revealed clear windows with no evidence of
pulmonary fibrosis.
A table of standard reference ranges used in interpretation of lung function test is
attached as Table 2 in the Appendix.
Lung function testing revealed a moderate restricted pattern. (See Fig 1 in appendix)
This is evident through a moderately reduced forced expiratory volume in one
second (FEV1) of 2.29L (65% predicted) and a moderately reduced forced vital
capacity (FVC) of 2.48L (60% predicted). The FEV1/FVC ratio corrects to 93%, with
75% being the lower limit of normal for a male of T’s age and height. (Hibbert, ME,
Lannigan, A, Landau, LI, Phelan, PD, 1989) The normality of this ratio, combined
with both FEV1 and FVC reduction is indicative of a restrictive disease process.
Diffusing Capacity of CO testing showed a mild reduction in diffusing capacity
(DLCO) of 82% predicted, along with a moderate reduction in alveolar volume (VA)
of 59% predicted. (Cotes, JE, et al, 1993) The DLCO/VA (KCO) ratio corrects
diffusing capacity for the available volume for diffusing to occur in. T’s KCO corrects
to 132% of predicted, this high percentage indicates that there is no true diffusing
limitation, ruling out fibrosis and pulmonary hypertension.
Body plethysmography revealed a total lung capacity (TLC) of 3.53L, only 63%
predicted, indicating moderate restriction. T’s reserve volume (RV) was 0.84L, 66%
of predicted, giving a RV/TLC ratio of 122%. (Hibbert, ME, Lannigan, A, Landau, LI,
Phelan, PD, 1989) This ratio may be a little higher than normal due to T’s inability to
exhale maximally as his chest wall compliance is compromised due to the sclerosis.
A cardiopulmonary exercise test (CPET) was conducted (see Fig 2 in appendix) due
to T’s active lifestyle. T was made to exercise maximally on an exercise bike for a
Petra England
Case Study
minimum of 6-8 minutes, while respiratory and cardiac parameters are monitored. T
managed to cycle at >85% predicted heart rate for 6 minutes, stopping because of
sore feet due to rubbing shoes. His results were mostly normal with an increase in
maximum ventilation (VE Max) of 134% predicted and a decrease in Tidal Volume
(TV) of 51% predicted. (Hibbert, ME, Lannigan, A, Landau, LI, Phelan, PD, 1989)
This indicates a lack of respiratory reserve, consistent with restrictive lung disease.
T’s cardiac examination showed normal left and right ventricular size and function,
with no septal defects. He had no outflow obstruction and no aortic or mitral
incompetence. He has an innocent pulmonary flow murmur with no evidence of
hypertension. His ECG was normal with a sinus rhythm of 95bpm. Normal cardiology
findings indicate no cardiac involvement with in regards to T’s systemic sclerosis.
Pathology tests revealed the presence of Anti Ribonucleoprotien (RNP) and
Antinuclear antibodies (ANA) which are consistent findings in patients with systemic
sclerosis. These are present in the blood due to the inflammatory pathways
associated with sclerosis.
T’s bone density was determined to be at the lower limit of normal for a male his age
and height, this is suspected to be due to long term use of prednisolone. To combat
this, T has also been taking calcium supplements.
Dr A confirmed the diagnosis of systemic sclerosis with chest wall restriction and no
cardiac involvement. T has had his lung function tested periodically since 2012, with
the most recent test being August 2015 (See Fig 3 in appendix). A table of his lung
function parameters throughout this period can be seen below, in Graph 1;
Petra England
Case Study
T’s most recent lung function test from July 2015, shows a small decline in FEV1 and
FVC, with his total lung capacity remaining stable at 50% of predicted. He has had a
slight decline in VA with his DLCO remaining stable, making his KCO much larger on
this test date.
Management and treatment outcomes
There is no single therapy for systemic sclerosis. Initiating the use of a combination
of therapeutic strategies early in the disease course has proven to give the maximum
beneficial clinical effects. (Rosenkranz, M, et al. 2006) Therapeutic treatments for
systemic sclerosis are divided into 3 main groups; antifibrotics, anti-inflammatories,
and vasodilators.
Antifibrotic agents work against systemic sclerosis by inhibiting the formation of
certain molecular collagen crosslinks. They been used to treat systemic sclerosis for
several decades, but have questionable efficacy. In some cases, the use of
antifibrotics has resulted in skin softening and a reduction in new visceral
involvement, but due to a high incidence of adverse events they are not commonly
used in children. (Sapadin, AN, Fleischmajer, R, 2002) T was not prescribed any
antifibrotic agents.
Anti-inflammatory agents are a crucial part in the early management of systemic
sclerosis. T has been taking a course of prednisolone, a corticosteroid, since the
initial diagnosis of scleroderma. The use of aggressive therapy with glucocorticoids
may prevent interstitial fibrosis in the lungs. Once interstitial fibrosis occurs, it is
resistant to current treatment modalities and the damage is irreversible. (Pérez
Campos, D, Estévez Del Toro, M, et al, 2012) Cyclosporine is occasionally used in
combination with glucocorticoids during treatment of juvenile systemic sclerosis. This
treatment blocks the pathways for several immune activating and pro-inflammatory
cytokines that are elevated in systemic sclerosis. Currently, only small studies have
been conducted in regards to the use of cyclosporine in the long term treatment of
systemic sclerosis. Larger trials have not been performed due to concern of acute
renal crisis in patients. (Rosenkranz, M, et al. 2006)
Vasodilators are used to reduce vasospasm and improve peripheral circulation in
children who are experiencing Raynaud’s phenomenon and peripheral ulceration.
When T first presented with Raynaud’s phenomenon he was prescribed Sildenafil,
which is a selective inhibitor of cGMP-specific phosphodiesterase type 5 that
provides micro vascular and macro vascular dilation. (Fries, R, Shariat, K,
Wilmowsky, H, Böhm, M, 2005) Sildenafil has proven to be an effective, well
tolerated treatment in patients with Raynaud’s phenomenon, and is commonly used
to restore circulation in patients with peripheral circulatory problems as a
complication of systemic sclerosis.
The majority of children affected by systemic sclerosis undergo progression of skin
and internal organ involvement that often results in morbidity and mortality. Early
Petra England
Case Study
and aggressive treatment using a combination of therapies is crucial to limiting organ
damage.
Discussion
Since his diagnosis in 2010, T has adhered to his treatment consistently. His initial
presentation of peripheral discolouration in response to temperature changes was
confirmed to be Raynaud’s phenomenon, which is known to occur in >90% of
paediatric scleroderma patients. (Rosenkranz, M, et al. 2006) This, in conjunction
with peripheral ulceration, swelling, and skin thickening, indicated that a circulatory
problem was present. T also experienced the most classic symptom of scleroderma,
a type of skin tightening called sclerodactyly, which is defined as localized thickening
and tightness of the skin of the fingers or toes. Presence of facial sclerosis further
indicated that scleroderma was the underlying disease process. In response to this,
he was prescribed Sildenafil, to improve circulation, and Prednisolone, to control the
pathophysiological process, and ordered to have further testing into systemic
involvement.
In 2012, T arrived at the Royal Brisbane Children’s Hospital and testing commenced.
His first test, a high resolution chest CT, revealed clear windows and no evidence of
interstitial fibrosis. Interstitial fibrosis is a well-recognised complication of systemic
sclerosis, with it being the major cause of mortality in children with systemic
sclerosis. (Rosenkranz, M, et al. 2006) A HRCT scan may detect early fibrosis in
children before it is evident on routine chest radiographs. Currently, T has no known
interstitial pulmonary fibrosis. He will have routine chest radiography to monitor any
interstitial changes in his lungs.
Although systemic sclerosis is a multisystem disease, it is especially known to affect
the lungs. Approximately 40% of patients develop moderate to severe restrictive lung
disease, with the biggest decline in lung function happening in the first 3-5 years
since symptom onset. (Pérez Campos, D, Estévez Del Toro, M, et al, 2012) T had
full lung function testing and a cardiopulmonary exercise test (CPET) initially,
followed by several serial lung function tests throughout the last few years. Initial
spirometry revealed a moderate restricted pattern, with his FVC reduced to 2.48L,
which is only 60% of his predicted value. There was no evidence of airway
obstruction. The restriction was further confirmed during body plethysomography,
where his TLC was 3.53L, only 63% of predicted. The lower limit of normal for TLC
for T’s height and age is 4.61L, his value of 3.53L is indicative of moderate
restriction. (Hibbert, ME, Lannigan, A, Landau, LI, Phelan, PD, 1989) T also had a
small increase in his RV/TLC ratio, this can occur in restriction due to inability to
exhale maximally. In systemic sclerosis, the thickening of visceral linings can cause
submaximal complete exhalation. T’s restrictive lung disease may be more related to
chest wall issues, rather than the lung parenchyma, as his chest CT is normal and
clinically he has remained well without respiratory symptoms.
Petra England
Case Study
As T had no interstitial fibrosis, it would be expected that his diffusing capacity would
be uncompromised, given that pulmonary hypertension is not present. T’s DLCO
was 82% of predicted, although, when we correct this number for VA (KCO), it
comes up to 132% of predicted. (Cotes, JE, et al, 1993) His high KCO shows no
diffusing limitation in the space he has available for gas exchange.
T’s CPET revealed a mostly normal exercise capacity, with a slight increase in VE
Max and a decrease in TV. Even though T claims that he does not experience any
respiratory symptoms upon maximal exertion, these numbers indicate a lack of
respiratory reserve which is common in patients with moderate restriction.
T had completely normal cardiology findings, indicating no present cardiac
involvement in regards to systemic sclerosis. Pathology tests revealed the presence
of multiple proteins and antibodies that are consistently found in patients with
systemic sclerosis. These are present in the blood due to the inflammatory pathways
associated with sclerosis. T had a bone density at the lower limit of normal due to his
constant use of prednisolone. High doses of glucocorticoids are known to have
adverse effects on bone due to increasing the excretion of calcium from the body
(Ton, FN, Gunawardene, SC, Lee, H, Neer, RM, 2005), as T is taking calcium
supplements this should not cause any major issues in his future.
T is an interesting case due to his early juvenile onset of scleroderma and his
consistent adherence to all prescribed treatments. Due to the rarity of juvenile
systemic sclerosis, data regarding prognosis and outcome of children with this
disease is limited. Results from a paediatric multicentre survey revealed that
cardiopulmonary involvement was the most common cause of death, although a few
patients have experienced spontaneous remission. (Foeldvari, I, Zhavania, M, Birdi,
N, et al., 2000)
With increasing understanding of the pathogenesis of systemic sclerosis, new
strategies and therapies to target these pathways of disease progression are being
developed. (Rosenkranz, M, et al. 2006) Due to T’s strict adherence to medication,
he has managed to avoid the progression of pulmonary fibrosis. Currently, T’s
sclerosis appears to be in a stable condition, with no new symptoms arising and no
cardiac involvement. The chest wall restriction affecting his lungs has remained
relatively stable over the last 3 years and has not affected his ability to participate in
physical activities. T will need to be closely monitored throughout his life, early
identification of new organ involvement is crucial to ensure proper disease
management and to minimise the risk of future complications. The natural course of
systemic sclerosis varies from patient to patient but with T’s consistent compliance
with medications and check-ups, he will hopefully be able to live a long and happy
life.
Petra England
Case Study
References
Cotes, JE, et al, 1993, “Standardisation of the Measurement of transfer factor
(diffusion capacity). Report working party standardisation of lung function
tests, European community for steel and coal. Official statement of European
Respiratory Society,” European Resp Journal Supplement, vol. 16, pp. 41-52.
Foeldvari, I, Zhavania, M, Birdi, N, et al., 2000, “Favourable outcome in 135
children with juvenile systemic sclerosis: results of a multi-national survey,”
Rheumatology, vol. 39, no. 5, pp. 556-559.
Fries, R, Shariat, K, Wilmowsky, H, Böhm, M, 2005, “Sildenafil in the
Treatment of Raynaud’s Phenomenon Resistant to Vasodilatory Therapy”
Circulation, vol. 112, pp. 2980-2985.
Hawley, DP, Baildam, EM, Amin, TS, et al. 2012, “Access to care for children
and young people diagnosed with localized scleroderma or juvenile SSc in the
UK,” Rheumatology (Oxford), vol. 51, pp. 1235–1239.
Herrick AL, Ennis H, Bhushan M, et al. 2010, “Incidence of childhood linear
scleroderma and systemic sclerosis in the UK and Ireland,” Arthritis Care Res,
vol. 62, pp. 213–218.
Hibbert, ME, Lannigan, A, Landau, LI, Phelan, PD, 1989, “Lung Function
values from a longitudinal study of healthy children and adolescents,”
Pediatric Pulmonology, vol. 7, pp.101-109.
Panda, S, 2010, “Scleroderma in children: emerging management issues”,
Indian Journal Of Dermatology, Venereology And Leprology, vol. 76, no. 4,
pp. 348-356.
Pérez Campos, D, Estévez Del Toro, M, et al, 2012, “Are high doses of
prednisone necessary for treatment of interstitial lung disease in systemic
sclerosis?”, Reumatol Clin., vol. 8, no. 2, pp. 58-62.
Rosenkranz, M, Agle, L, Efthimiou, P, Lehman, T, 2006, 'Systemic and
localized scleroderma in children: current and future treatment options',
Paediatric Drugs, vol. 8, no. 2, pp. 85-97.
Sapadin, AN, Fleischmajer, R, 2002, “Treatment of Scleroderma,” Arch
Dermatol, vol.138, no.1, pp 99-105.
Ton, FN, Gunawardene, SC, Lee, H, Neer, RM, 2005, “Effects of low-dose
prednisone on bone metabolism,” J Bone Miner Res, vol. 20, no. 3, pp 464470.
Petra England
Case Study
Appendix
Table 2: Summary of LLN for reference values used in the Respiratory
Laboratory
Parameters Reported
Hibbert et.al(1989; Table 2)
GIRLS
BOYS
Lower 95% confidence interval
(CI) as % of mean
FEV1
<82
<82
FEV1/FVC
<80
<76
Lower and Upper 95% CI as % of
mean
TLC
<83, >121
<82, >122
RV
<63, >159
<62, <162
RV/TLC
<17, >38
<16, >36
Cotes (1993)
DLCO
KCO
+/- 25.48
+/- 27.44
<74.52, >125.48
<72.56, >127.44
+/- 23.52
+/- 23.52
<76.48, >123.52
<76.48, >123.52
Petra England
Case Study
Fig 1: T’s Initial Lung Function Test August 2012
Petra England
Case Study
Petra England
Case Study
Fig 2: T’s Cardiopulmonary Exercise test 2012
Petra England
Case Study
Fig 3: T’s most recent lung function test, August 2015