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 major 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
electrocardiogram may reveal 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, a
transthoracic 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 can be an elevated TR velocity jet above 2.8 m/s, or a dilated right
ventricle or atrium9. Reduced
carbon monoxide diffusing capacity is a marker of pulmonary vascular disease
and is standardly used in the diagnostic approach when PAH is suspected. Of
note, it is associated with poor prognosis.
the treatment,all patients suspected to
have PAH after noninvasive evaluation should undergo right heart catheterization.
This method 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 valve
disease or left ventricular heart disease26. Consequently, PAH is a
diagnosis of exclusion. In the absence of lung disease, thromboembolism, left
ventricular or valve pathology, the diagnosis of PAH requires both a mean PAP
more than 25 mmHg and a PVR more than 3
Wood units with a pulmonary capillary wedge pressure < 15 mmHg 8,10. TREATMENT SSc-associated PAH historically 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 and earlier occurrence of its clinical manifestations. Myocardial infarction has been described in SSc patients with unaltered coronary arteries. Vasospasm of the small coronary arteries and arterioles (the so-called 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 alterations. PERICARDIAL DISEASE Asymptomatic pericardial effusions commonly occur in scleroderma11. Moreover, there also have been large effusions causing tamponade and can even occur prior to skin thickening and the diagnosis of scleroderma12,13. Pericardial effusions may be the presenting feature of pulmonary hypertension in scleroderma14. TREATMENT Therapy may include NSAIDs. Corticosteroids are considered to be of limited benefit.Immunosuppressors may be indicated if profound inflammation is evident. Pericardiocentesis is indicated in cases of life-threatening tamponade. CONDUCTION SYSTEM DISEASE Arrhythmias and conduction abnormalities are probably the result from conduction system fibrosis15,16 and myocardial fibrosis17. Supraventricular arrhythmias occurs in two thirds of SSc patients18. Hence,Holter monitoring is recommended in patients with symptoms of palpitations, light headedness, 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, accounts for > 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
with other PFT abnormalities 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 halts the
progression of ILD.26,27,28Once the patient reached ESLD, pulmonary
rehabilitation and lung transplantation are the treatments which can be offered.
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 from the SSc disease process or because of atheromatous disease.Possibility of proximal
vessel disease should always be considered in patients who have SSc and severe
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 antiphospholipid syndrome, which is rare 35.
Permanent discolouration of the digit and
increased pain are the main symptoms of critical ischemia.If any evidence of
critical ischemia is seen, the distal pulses must be checked.Absence of one or more peripheral pulses suggests a proximal
vessel problem, which demands further investigation.
1) Doppler ultrasound
If the peripheral pulses are
difficult to feel, then Doppler ultrasound will establish whether significant
large vessel disease is likely requiring angiography.
A plain radiograph of the
affected digit may show underlying calcinosis
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 RP. 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.37This drug acts
very rapidly and helps in ulcer healing by improving the microcirculation.
Botulinum toxin has been shown to improve digital
perfusion in patients with resistant Raynaud’s phenomenon.
The most common form of surgery is
debridement of infected or necrotic tissue. But once 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 under
gastroendoscopy observation is unique known as “watermelon stomach”. GAVE can
precede an 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 severe GI bleeding, although achlorhydria,
pernicious anemia is more common.
Bipolar cautery, heat probe, sclerotherapy and laser ablation 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 compromised 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 major cause of malnutrition in SSc
patients. Additionally, pneumatosis cystoides intestinalis (PCI) may occur but
is a rare condition.
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 the upright 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
resulting from excessive collagen deposition.
The initial treatment for this condition should include bowel
rest, intravenous fluid infusion and electrolyte correction.
Octreotide has also been shown to be effective.43
Neostigmine can lead to prompt colon decompression.
If octreotide and neostigmine treatments are not effective,
however, colonoscopic decompression is normally 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.