Systemic sclerosis (SSc) is a chronic systemic disease characterizedby fibrosis of skin and internal organs,microangiopathyand autoimmune disturbances. Though scleroderma is a chronic disease, it can present to emergency withsymptoms unless treated aggressively can result in death of the patient. RENAL EMERGENCIESACUTE SCLERODERMA RENAL CRISIS (SRC )Scleroderma renal crisis develops inapproximately 10% – 15% of patients.(1)It is characterized by:· Acute onset of renalfailure· Abrupt onset of moderate to marked hypertension (some patientsremain normotensive)(2)· A urine sediment that is usually normal or reveals only mildproteinuria with few cells or castsSRC isalso 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 withdiffuse systemic sclerosis within the 4-5 years of disease.
Other risk factors arerecent use of high dose steroids and presence of anti-RNA polymerase III antibody.Treatment ACE inhibitors is the treatment of choice forscleroderma renal crisis.ACE inhibitors are of value even in normotensive renalcrisis.Continuation of ACE inhibitors in patients on dialytic support oftenleads to enough renal recovery to permit dialysis discontinuation after 6-18months. Control of hypertension can stabilize or even improve renalfunction in 55% to 70% of cases, ifbegun before marked irreversible vascular injury has occurred.(3)Nevertheless, the mortality is high and a poor outcome is common.(4) Patientswho fail to respond to ACE inhibitor may still respond to potent vasodilatorssuch as minoxidil along with beta blockers and diuretics. Patientswith severe scleroderma renal crisis have a component of myocarditis andventricular stiffness.
Hence maintenance of blood volume is essential.The improvement in renal function can continue for up to 2years. Allograft survival is lower compared with that of transplant recipientswithout scleroderma. Differential DiagnosisThromboticthrombocytopenic purpura (TTP), is a rare but potentially lethal condition. 5The diagnosis is made clinically and is classically characterized by a pentadof thrombocytopenia, microangiopathic hemolytic anemia, transient neurologicalsymptoms, renal dysfunction, and fever.
Basic pathogenesis is presence of largevon Willebrand factor(vWF) multimers ascribed to deficiency of the vWF-cleaving protease (ADAMTS13) enzyme 6.The vWF cleaving protease done byactivity-based assay, is normal in SRCand ADAMTS13 level is lowin TTP. Cardiopulmonary causes One of the major organs involved in sclerodermais the heart.
Involvement of the heart can generally be divided intodirect myocardial effects and the indirect effect of other organ involvement .Direct myocardial disease includes myocarditis, cardiac failure, cardiacfibrosis, coronary artery disease, conduction system abnormalities, andpericardial disease. RIGHT HEART FAILURE AND PAHRight heartfailure is most commonly the result of pulmonary hypertension. Pulmonaryhypertension is a common manifestation of scleroderma and a poor prognosticsign.
PAH results from restricted flow through thepulmonary arterial circulation leading to increased pulmonary vascularresistance and right heart failure. PAH in thecontext of pulmonary fibrosis is ofmoderate degree and has slowprogression.PAH occurs due to increase in resistance in pulmonary vasculature.PAHin SSc patients with minimal or no pulmonary fibrosis is a severe complication,and it results from narrowing of smallpulmonary arteries.Clinical signsof PAH include dyspnea on exertion, fatigue, chest pain, dizziness,palpitations, and edema at the lower extremities.
On examination, a loudpulmonary component of the second heart sound, gallop, and pan-systolic murmurof tricuspid regurgitation may be found, along with features of right heartfailure in advanced cases7. Chest X-ray andelectrocardiogram 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), andpeaked P wave? 2.5 mm in leads II, III and Avf7,8. If PAH is suspected, atransthoracic Doppler echocardiography is recommended.7,8 PAH isdefined as mean PAP > 25 mmHg at rest, > 30 mmHg during exercise, orsystolic pulmonary pressure > 40 mmHg on echocardiography. Clues todiagnosis of PAH can be an elevated TR velocity jet above 2.8 m/s, or a dilated rightventricle or atrium9. Reducedcarbon monoxide diffusing capacity is a marker of pulmonary vascular diseaseand is standardly used in the diagnostic approach when PAH is suspected.
Ofnote, it is associated with poor prognosis. Before startingthe treatment,all patients suspected tohave PAH after noninvasive evaluation should undergo right heart catheterization.This method is the gold standard for diagnosing PAH, and allows for themeasurement of the transpulmonary gradient (PAP mean wedge).It was found to be significantly elevated only inPAH patients, but not in patients whose pulmonary hypertension was due toincreased cardiac output, left heart myocardial or valvular disease8,10.Pulmonaryvascular resistence is a more reliablediagnostic parameter for PAH , whichreflects the influence of transpulmonary gradient and cardiac output and isonly elevated if the vascular obstruction occurs within the precapillarypulmonary circulation.
However, PVR can also be elevated in patients with valvedisease or left ventricular heart disease26. Consequently, PAH is adiagnosis of exclusion. In the absence of lung disease, thromboembolism, leftventricular or valve pathology, the diagnosis of PAH requires both a mean PAPmore than 25 mmHg and a PVR more than 3Wood units with a pulmonary capillary wedge pressure < 15 mmHg 8,10.TREATMENTSSc-associated PAH historically had a poor prognosis with aone-year survival rate of 45%. Poor survival has significantly increased withmodern treatments such as prostanoids, endothelin receptor antagonists, andphosphodiesterase-5 inhibitors.
Drugs used in PAH1) Prostanoidsa)Epoprostenol: Starting dose of infusionis 1-2 ng/kg per minute, gradually increased up to 25-40 ng/kg per minute b) Treprostinil: given as a continuous subcutaneous or intravenousinfusion in patients with PAH from functional class II, III and IVDose:1.25 ng/kg per minute2).Endothelin receptor antagonistsa)Bosentan: It is indicated for PAH functional classes II, III andIV.Dose: 62.5 mg bid for 4 weeks before titration up to 125-250 mgbidb) Ambrisentan: Dose: 2.
5-10 mgAmbrisentan in combination with tadalafil reduces the risks ofdisease progression and hospitalization for worsening PAH and improves exerciseability. 3)PDE inhibitorsa) Sildenafil: Dose:20mg tidb) Tadalafil: Dose:40mg ODCORONARY VASCULATURE AND MYOCARDIAL PERFUSIONThehyperactivation of the immune system and systemic inflammation lead topremature atherosclerosis and earlier occurrence of its clinicalmanifestations. Myocardialinfarction has been described in SSc patients with unaltered coronary arteries.Vasospasm of the small coronary arteries and arterioles (the so-called myocardialRaynaud’s phenomenon) is considered to be involved in the earlyscleroderma-related ischemic myocardial changes with subsequent ischemiareperfusion injury and the development of structural vascularalterations.
PERICARDIAL DISEASEAsymptomatic pericardialeffusions commonly occur in scleroderma11.Moreover, there also have been large effusions causing tamponade and can evenoccur prior to skin thickening and the diagnosis of scleroderma12,13.Pericardial effusions may be thepresenting feature of pulmonary hypertension in scleroderma14.TREATMENT Therapy may include NSAIDs.
Corticosteroidsare considered to be of limited benefit.Immunosuppressors may be indicated ifprofound inflammation is evident. Pericardiocentesis is indicated in cases of life-threateningtamponade.CONDUCTION SYSTEM DISEASEArrhythmias andconduction abnormalities are probably the result from conduction systemfibrosis15,16 and myocardial fibrosis17. Supraventriculararrhythmias occurs in two thirds of SScpatients18. Hence,Holtermonitoring is recommended in patients with symptoms of palpitations, light headedness,dizziness, or syncope.
TREATMENTAICDimplantation is recommended in patients with inducible ventricular tachycardiaor reduced LVEF.INTERSTITIAL LUNG DISEASEEnd stage lungdisease secondary to ILD, accounts for > 50% of SSc-related deaths 19. The standard method for the noninvasivediagnosis of SSc-ILD is HRCT.The HRCT pattern seen in SSc patients is generally nonspecificinterstitial pneumonia 20, with a greater proportion of ground-glassopacities and a lower degree of coarse reticulation . However, a usualinterstitial pneumonia pattern can also be seen .
Reversibility of HRCT changesis rare 21. Pulmonary functiontests Dl,CO is reduced in almost all patientswith other PFT abnormalities 22 and correlates with the extent oflung 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 mostsignificant marker of poor outcome 10.
TREATMENTMycophenolatemofetil,cyclophosphamide and rituximab if used in appropriate doses halts theprogression of ILD.26,27,28Once the patient reached ESLD, pulmonaryrehabilitation and lung transplantation are the treatments which can be offered. IMPENDING GANGRENEPeripheral vascular involvement occurs inalmost all patients who have systemic sclerosis (SSc).Digitalischemia can result in digital ulcers, digital pitting 29, andsometimes gangrene.Digital ischemia in SSc can beso severe due to abnormalities of neuroendothelial control mechanism,structural abnormalities of the microvasculature and intravascular factors, including aprocoagulant tendency and oxidative stress 30.SSc has been suggested to beprimarily a vascular disease31.
32. If macrovascular disease is increased inSSc, it may be from the SSc disease process or because of atheromatous disease.Possibility of proximalvessel disease should always be considered in patients who have SSc and severedigital ischemia. DIAGNOSISAlthough the main contributorto disease pathogenesis is a noninflammatory microangiopathy in most patientswho have SSc-related peripheral vascular disease, other possibilities shouldalways be considered,such as (1) concomitant proximal vessel disease (2) vasculitis, which is unusual in SSc 33,34 (3) thrombotic disease as part of aconcomitant antiphospholipid syndrome, which is rare 35.Permanent discolouration of the digit andincreased pain are the main symptoms of critical ischemia.If any evidence ofcritical ischemia is seen, the distal pulses must be checked.Absence of one or more peripheral pulses suggests a proximalvessel problem, which demands further investigation. INVESTIGATIONS1) Doppler ultrasoundIf the peripheral pulses aredifficult to feel, then Doppler ultrasound will establish whether significantlarge vessel disease is likely requiring angiography.
2)X rayA plain radiograph of theaffected digit may show underlying calcinosis or osteomyelitis.4)Nailfold capillaroscopy assessmicrovascular structure. 5)Thermography gives an indirectassessment of small and large vessel function.6) Conventional MRI and CT angiography assesslarge vessel structure.
MANAGEMENTGeneralMeasuresAvoidanceof cold,stress, nicotine, caffeine, and sympathomimetic decongestants are nonpharmacologic elements to prevent or avoidexacerbating RP. Cigarette smoking is a risk factor for severity ofdigital ischaemia. 36 1)Calcium channel blockersThey are considered first-line treatment in SSc-relatedRaynaud’s phenomenon.Treatment with slow release nifedipine (30-180mg daily) maydecrease the frequency or severity of attacks.
2)Phosphodiesterase type 5 inhibitors Sildenafil and tadalafil has been provento be effective in RCTs in preventing new onset ulcers and healing the existingulcers. 3)Endothelin-1 receptorantagonistsBosentan is also found effective inpreventing new onset ulcers in patients with scleroderma. 4)Prostacyclinanalogs: Iloprost(carbaprostacyclin, given parenterally at 0.5-2 ng/kg/minute), is a potentvasodilator.
37This drug actsvery rapidly and helps in ulcer healing by improving the microcirculation.5)Botulinum toxin Botulinum toxin has been shown to improve digitalperfusion in patients with resistant Raynaud’s phenomenon. 6)SurgeryThe most common form of surgery isdebridement of infected or necrotic tissue. But once osteomyelitis is established,amputation may be necessary.If patients have proximal arterialdisease, angioplasty may be indicated. Finally, if an area of calcinosis isunderlying a nonhealing ulcer, it has to be debulked.
7)Lumbar sympathectomyA temporary sympathetic blockcould be considered if patients remain in severe pain.38 GICOMPLICATIONS GAVE(GastricAntral Vascular Ectasia):Mucosal telangiectasias are the most commonsource of bleeding.The appearance of GAVE undergastroendoscopy observation is unique known as “watermelon stomach”. GAVE canprecede an SSc diagnosis.39 It is estimated that the prevalence ofGAVE ranges from 5.
7% to 14% of SSc patients.40,41 GAVE cansometimes manifest itself as severe GI bleeding, although achlorhydria,pernicious anemia is more common. TreatmentBipolar cautery, heat probe, sclerotherapy and laser ablation areavailable for the treatment of GAVE.
SMALLBOWELThe small intestine is the second most commonlyinvolved portion of GI tract during SSc, following the esophagus. Smallintestine function is compromised in 40% of SSc patients.42 Smallintestine hypomotility is the primary abnormality and may lead to pseudo-obstructionand bacterial overgrowth, which is the major cause of malnutrition in SScpatients. Additionally, pneumatosis cystoides intestinalis (PCI) may occur butis a rare condition.Small intestine pseudo-obstruction: Smallintestinal hypomotility because may provoke luminal dilatation and overtpseudo-obstructions.Radiological evidence of distended bowel loops andair-fluid levels in the upright position is an important diagnostic marker ofthis pathological condition. Acute episodes can last only a few hours, but inthe most severe cases intestinal loops are chronically distended and air-fluidlevels are invariably detected.
A more characteristic sign is a ‘hide-bound’ appearance produced by closely packed valvulaeresulting from excessive collagen deposition. TreatmentThe initial treatment for this condition should include bowelrest, intravenous fluid infusion and electrolyte correction. Octreotide has also been shown to be effective.43Neostigmine 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 Primary pneumatosisintestinalis is a benign idiopathic condition in which multiple thin-walledcysts develop in the submucosa or subserosa of the colon. Usually, this formhas no associated symptoms, and the cysts may be found incidentally throughradiography or endoscopy. Pneumatosisintestinalis may be complicated by pneumoperitoneum.Generally,the prognosis of PCI is good.