Systemic sclerosis (SSc) is a chronic systemic disease characterized
by fibrosis of skin and internal organs,microangiopathy
and autoimmune disturbances. Though
scleroderma is a chronic disease, it can present to emergency with
symptoms unless treated aggressively can result in death of the patient.
ACUTE SCLERODERMA RENAL CRISIS (SRC )
Scleroderma renal crisis develops in
approximately 10% – 15% of patients.(1)It is characterized by:
Acute onset of renal
Abrupt onset of moderate to marked hypertension (some patients
A urine sediment that is usually normal or reveals only mild
proteinuria with few cells or casts
also characterized by microangiopathic haemolytic anemia and thrombocytopenia.
Congestive heart failure and pericardial effusions are common.(3)
Around 80% of the renal crisis occur in patients with
diffuse systemic sclerosis within the 4-5 years of disease. Other risk factors are
recent use of high dose steroids and presence of anti-RNA polymerase III antibody.
ACE inhibitors is the treatment of choice for
scleroderma renal crisis.ACE inhibitors are of value even in normotensive renal
crisis.Continuation of ACE inhibitors in patients on dialytic support often
leads to enough renal recovery to permit dialysis discontinuation after 6-18
Control of hypertension can stabilize or even improve renal
function in 55% to 70% of cases, if
begun before marked irreversible vascular injury has occurred.(3)
Nevertheless, the mortality is high and a poor outcome is common.(4) Patients
who fail to respond to ACE inhibitor may still respond to potent vasodilators
such as minoxidil along with beta blockers and diuretics. Patients
with severe scleroderma renal crisis have a component of myocarditis and
ventricular stiffness. Hence maintenance of blood volume is essential.
The improvement in renal function can continue for up to 2
years. Allograft survival is lower compared with that of transplant recipients
thrombocytopenic purpura (TTP), is a rare but potentially lethal condition. 5
The diagnosis is made clinically and is classically characterized by a pentad
of thrombocytopenia, microangiopathic hemolytic anemia, transient neurological
symptoms, renal dysfunction, and fever.Basic pathogenesis is presence of large
von Willebrand factor(vWF) multimers
ascribed to deficiency of the vWF-cleaving protease (ADAMTS13) enzyme 6.The vWF cleaving protease done by
activity-based assay, is normal in SRC
and ADAMTS13 level is low
One of the main organs involved in scleroderma
is the heart. Involvement of the heart can generally be divided into
direct myocardial effects and the indirect effect of other organ involvement .
Direct myocardial disease includes myocarditis, cardiac failure, cardiac
fibrosis, coronary artery disease, conduction system abnormalities, and
RIGHT HEART FAILURE AND PAH
failure is most commonly the result of pulmonary hypertension. Pulmonary
hypertension is a common manifestation of scleroderma and a poor prognostic
PAH results from restricted flow through the
pulmonary arterial circulation leading to increased pulmonary vascular
resistance and right heart failure.
PAH in the
context of pulmonary fibrosis is of
moderate degree and has slow
progression.PAH occurs due to increase in resistance in pulmonary vasculature.PAH
in SSc patients with minimal or no pulmonary fibrosis is a severe complication,
and it results from narrowing of small
of PAH include dyspnea on exertion, fatigue, chest pain, dizziness,
palpitations, and edema at the lower extremities. On examination, a loud
pulmonary component of the second heart sound, gallop, and pan-systolic murmur
of tricuspid regurgitation may be found, along with features of right heart
failure in advanced cases7.
Chest X-ray and
ECG may show signs suggestive of PAH, mainly in advanced stages, such as an enlarged pulmonary artery,
attenuation of peripheral pulmonary vascular markings (in chest X-ray), and
peaked P wave
? 2.5 mm in leads II, III and Avf7,8. If PAH is suspected, Doppler echocardiography is recommended.7,8
PAH is defined as mean PAP > 25 mmHg at rest, > 30 mmHg during exercise,
or systolic pulmonary pressure > 40 mmHg on echocardiography. Clues to
diagnosis of PAH could be an elevated TR velocity jet above 2.8 m/s, or a dilated right
ventricle or atrium9. Carbon
monoxide diffusing capacity(DLC0) is also used in the diagnostic approach when
PAH is suspected and reduced DLCO is a marker of pulmonary vascular disease . Of
note, it is associated with poor prognosis.
the treatment,all patients suspected to
have PAH after noninvasive evaluation should undergo right heart catheterization.
It is the gold standard for diagnosing PAH, and allows for the measurement of
the transpulmonary gradient (PAP mean wedge).It was found to be significantly elevated only in
PAH patients, but not in patients whose pulmonary hypertension was due to
increased cardiac output, left heart myocardial or valvular disease8,10.Pulmonary
vascular resistence is a more reliable
diagnostic parameter for PAH , which
reflects the influence of transpulmonary gradient and cardiac output and is
only elevated if the vascular obstruction occurs within the precapillary
pulmonary circulation. However, PVR can also be elevated in patients with left
ventricular heart disease or valve disease 26. However, PAH is a
diagnosis of exclusion. In the absence of thromboembolism,lung disease, valve
or left ventricular pathology, the
diagnosis of PAH requires both a mean PAP > 25 mmHg and a PVR > 3 Wood
units with a pulmonary capillary wedge pressure < 15 mmHg 8,10. TREATMENT SSc-associated PAH previously had a poor prognosis with a one-year survival rate of 45%. Poor survival has significantly increased with modern treatments such as prostanoids, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. Drugs used in PAH 1) Prostanoids a)Epoprostenol: Starting dose of infusion is 1-2 ng/kg per minute, gradually increased up to 25-40 ng/kg per minute b) Treprostinil: given as a continuous subcutaneous or intravenous infusion in patients with PAH from functional class II, III and IV Dose:1.25 ng/kg per minute 2).Endothelin receptor antagonists a)Bosentan: It is indicated for PAH functional classes II, III and IV. Dose: 62.5 mg bid for 4 weeks before titration up to 125-250 mg bid b) Ambrisentan: Dose: 2.5-10 mg Ambrisentan in combination with tadalafil reduces the risks of disease progression and hospitalization for worsening PAH and improves exercise ability. 3)PDE inhibitors a) Sildenafil: Dose:20mg tid b) Tadalafil: Dose:40mg OD CORONARY VASCULATURE AND MYOCARDIAL PERFUSION The hyperactivation of the immune system and systemic inflammation lead to premature atherosclerosis. Myocardial infarction has been described in SSc patients with normal coronary arteries. Vasospasm of the small coronary arteries and arterioles ( myocardial Raynaud's phenomenon) is considered to be involved in the early scleroderma-related ischemic myocardial changes with subsequent ischemia reperfusion injury and the development of structural vascular changes. PERICARDIAL DISEASE Asymptomatic pericardial effusions usually occur in scleroderma11. Moreover, there also have been large effusions causing tamponade and can even occur prior to skin involvement and the diagnosis of scleroderma12,13. Pulmonary hypertension in scleroderma can present as pericardial effusions14. TREATMENT Therapy may include NSAIDs. Corticosteroids are considered to be of limited benefit.Immunosuppressors may be indicated if profound inflammation is present. Pericardiocentesis is indicated in cases of life-threatening tamponade. CONDUCTION SYSTEM DISEASE Arrhythmias and conduction abnormalities are probably due to conduction system 15,16 and myocardial fibrosis17. Supraventricular arrhythmias occurs in 2/3rd of SSc patients18. Hence,Holter monitoring is recommended in patients with symptoms of light headedness, palpitations,dizziness, or syncope. TREATMENT AICD implantation is recommended in patients with inducible ventricular tachycardia or reduced LVEF. INTERSTITIAL LUNG DISEASE End stage lung disease secondary to ILD, leads to > 50% of SSc-related deaths 19.
The standard method for the noninvasive
diagnosis of SSc-ILD is HRCT.The HRCT pattern seen in SSc patients is generally nonspecific
interstitial pneumonia 20, with a greater proportion of ground-glass
opacities and a lower degree of coarse reticulation . However, a usual
interstitial pneumonia pattern can also be seen . Reversibility of HRCT changes
is rare 21.
Dl,CO is reduced in almost all patients
22 and correlates with the
extent of lung disease on HRCT 23. Although FVC and Dl,CO are both identified as adverse prognostic markers 24,25,
a declining Dl,CO is the single most
significant marker of poor outcome 10.
mofetil,cyclophosphamide and rituximab if used in appropriate doses stops the
progression of ILD.26,27,28Once patient reaches ESLD, pulmonary
rehabilitation and lung transplantation are the treatment options.
Peripheral vascular involvement occurs in
almost all patients who have systemic sclerosis (SSc).Digital
ischemia can result in digital ulcers, digital pitting 29, and
Digital ischemia in SSc can be
so severe due to abnormalities of neuroendothelial control mechanism,
structural abnormalities of the microvasculature and intravascular factors, including a
procoagulant tendency and oxidative stress 30.
SSc has been suggested to be
primarily a vascular disease31.32.
If macrovascular disease is increased in
SSc, it may be due to atheromatous disease or from the disease process itself.Possibility
of proximal vessel disease should always be considered in SSc patients with severe digital ischemia.
Although the main contributor
to disease pathogenesis is a noninflammatory microangiopathy in most patients
who have SSc-related peripheral vascular disease, other possibilities should
always be considered,such as
(1) concomitant proximal vessel disease
(2) vasculitis, which is unusual in SSc 33,34
(3) thrombotic disease as part of a concomitant
APS, which is rare 35.Prolonged discolouration of the digit and increased
pain are the main symptoms of critical ischemia.Peripheral pulses must be
checked if any evidence of critical ischemia is seen.Absence of one or more peripheral pulses suggests a proximal vessel
problem, which demands more investigation.
1) Doppler ultrasound
If the distal pulses are
difficult to feel, then Doppler ultrasound will establish whether significant
large vessel disease is likely which requires angiography.
A plain radiograph of the
affected digit will show underlying
calcinosis or osteomyelitis.
4)Nailfold capillaroscopy assess
Thermography gives an indirect
assessment of small and large vessel function.
6) Conventional MRI and CT angiography assess
large vessel structure.
of cold,stress, nicotine, caffeine, and sympathomimetic decongestants are nonpharmacologic elements to prevent or avoid
exacerbating Raynaud’s phenomenon. Cigarette smoking is a risk factor for
severity of digital ischaemia. 36
1)Calcium channel blockers
They are considered first-line treatment in SSc-related
Treatment with slow release nifedipine (30-180mg daily) may
decrease the frequency or severity of attacks.
2)Phosphodiesterase type 5 inhibitors
Sildenafil and tadalafil has been proven
to be effective in RCTs in preventing new onset ulcers and healing the existing
Bosentan is also found effective in
preventing new onset ulcers in patients with scleroderma.
(carbaprostacyclin, given parenterally at 0.5-2 ng/kg/minute), is a potent
vasodilator.37It acts very
rapidly and helps in healing ulcers by improving the microcirculation.
It has been shown to improve digital perfusion in
patients with resistant Raynaud’s phenomenon.
The most common form of surgery is debridement
of necrotic or infected tissue.But if osteomyelitis is established, amputation
may be necessary.
If patients have proximal arterial
disease, angioplasty may be indicated. Finally, if an area of calcinosis is
underlying a nonhealing ulcer, it has to be debulked.
A temporary sympathetic block
could be considered if patients remain in severe pain.38
Antral Vascular Ectasia):
Mucosal telangiectasias are the most common
source of bleeding.
The appearance of GAVE in
gastroendoscopy is uniqueand is known as
“watermelon stomach”. GAVE can precede SSc diagnosis.39 It is estimated
that the prevalence of GAVE ranges from 5.7% to 14% of SSc patients.40,41
GAVE can sometimes manifest itself as GI bleeding, although pernicious anemia,
achlorhydria is more common.
Sclerotherapy,bipolar cautery,laser ablation and heat probe are
available for the treatment of GAVE.
The small intestine is the second most commonly
involved portion of GI tract during SSc, following the esophagus. Small intestine
function is impaired in 40% of SSc patients.42 Small intestine
hypomotility is the primary abnormality and may lead to pseudo-obstruction and
bacterial overgrowth, which is the main cause of malnutrition in SSc patients.
Additionally, pneumatosis cystoides intestinalis (PCI) may occur but is a rare
Small intestine pseudo-obstruction:
intestinal hypomotility because may provoke luminal dilatation and overt
pseudo-obstructions.Radiological evidence of distended bowel loops and
air-fluid levels in erect position is an important diagnostic marker of this
pathological condition. Acute episodes can last only a few hours, but in the
most severe cases intestinal loops are chronically distended and air-fluid
levels are invariably detected.
A more characteristic sign is a ‘hide-bound’ appearance produced by closely packed valvulae
due to excessive collagen deposition.
The initial treatment should include bowel rest, intravenous fluid
infusion and electrolyte correction.
Octreotide has also been shown to be effective.43
Neostigmine can lead to rapid colon decompression.
If neostigmine and octreotide treatments are not effective,then
colonoscopic decompression is the
treatment of choice.
Pneumocystis cystoides intestinalis
intestinalis is a benign idiopathic condition in which multiple thin-walled
cysts develop in the submucosa or subserosa of the colon. Usually, this form
has no associated symptoms, and the cysts may be found incidentally through
radiography or endoscopy.
intestinalis may be complicated by pneumoperitoneum.Generally,
the prognosis of PCI is good.