Case Reports

The Clinical Pathophysiology of Chronic Systemic Sclerosis

Fed Pract. 2018 May;35(5):36-43

References

1. Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum. 1998;41(5):778-799.

2. Silman AG. Scleroderma. In: Epidemiology of the Rheumatic Diseases. 2nd ed. Silman AJ, Hochberg MC, eds. Oxford, UK: Oxford University Press. 1993:chap 8.

3. Chung L, Krishnan E, Chakravarty EF. Hospitalizations and mortality in systemic sclerosis: results from the Nationwide Inpatient Sample. Rheumatology (Oxford). 2007;46(12):1808-1813.

4. Hinchcliff M, Varga J. Systemic sclerosis/scleroderma: a treatable multisystem disease. Am Fam Physician. 2008;78(8):961-968.

5. Tyndall AJ, Bannert B, Vonk M, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis. 2010;69(10):1809-1815.

6. Piga M, Casula L, Sanna S, et al. Population-based analysis of hospitalizations for patients with systemic sclerosis in a West-European region over the period 2001-2012. Rheumatol Int. 2016;36(1):73-81.

7. Giuggioli D, Manfredi A, Colaci M, Lumetti F, Ferri C. Osteomyelitis complicating scleroderma digital ulcers. Clin Rheumatol. 2013;32(5):623-627.

8. Schiopu E, Impens AJ, Phillips K. Digital ischemia in scleroderma spectrum of diseases. Int J Rheumatol. 2010;2010:923743.

9. Hassoun PM. Therapies for scleroderma-related pulmonary arterial hypertension. Expert Rev Respir Med. 2009;3(2):187-196.

10. Giacomelli R, Liakouli V, Berardicurti O, et al. Interstitial lung disease in systemic sclerosis: current and future treatment. Rheumatol Int. 2017;37(6):853-863.

11. McLaughlin V, Humbert M, Coghlan G, Nash P, Steen V. Pulmonary arterial hypertension: the most devastating vascular complication of systemic sclerosis. Rheumatology (Oxford). 2009; (suppl 3):iii25-iii31.

12. Gigante A, Barbano B, Granata G, et al. Evaluation of estimated glomerular filtration rate and clinical variables in systemic sclerosis patients. Clin Nephrol. 2016;85(6):326-331.

13. Bose N, Chiesa-Vottero A, Chatterjee S. Scleroderma renal crisis. Semin Arthritis Rheum. 2015;44(6):687-694.

14. Woodworth TG, Suliman YA, Furst DE, Clements P. Scleroderma renal crisis and renal involvement in systemic sclerosis. Nat Rev Nephrol. 2016;12(11):678-691.

15. Mouthon L, Bérezné A, Bussone G, Noël LH, Villiger PM, Guillevin L. Scleroderma renal crisis: a rare but severe complication of systemic sclerosis. Clin Rev Allergy Immunol. 2011;40(2):84-91.

16. Champion HC. The heart in scleroderma. Rheum Dis Clin North Am. 2008;34(1):181-90.

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Renal Involvement

Renal involvement in patients with SSc can have profound effects on QOL. Even without clinical renal involvement, glomerular filtration rate (GFR) usually decreases with the progression of vascular damage correlated with age and disease duration.¹² Patients with a history of digital ulcers, like Mr. P, usually have a lower GFR than that of patients without digital ulcers.¹² Monitoring renal function is vital in caring for these patients, because SRC occurs in 2% to 15% of all patients with SSc.^13,14

Scleroderma renal crisis is generally defined as an abruptly elevated BP (> 140/90 mm Hgor > 30 mm Hg rise from baseline) with acute renal failure (elevated SCr) and decreased urine output.¹⁴ Given the rarity of SSc in the population, diagnosis of SRC requires high clinical suspicion. In the case of Mr. P, a workup involving serum analysis, urinalysis, and renal biopsy allowed for a definitive diagnosis. A renal biopsy can show microangiopathic hemolytic anemia and confirm SRC, although it may not be necessary in patients with known SSc presenting with new hypertension, rising creatinine, and unremarkable urine sediment on microscopy.^14,15

Although an acute SRC can be difficult to predict, monitoring renal function and attention to key factors can assist in discovering this SSc complication. Scleroderma renal crisis usually occurs within the first 4 years of SSc diagnosis, often paralleling rapid progression of skin thickening and tightening with higher rates in both African Americans and males.^13,14 Additional predictive factors include diffuse skin involvement, rapid progression of skin involvement, positive anti-RNA polymerase III antibodies, new anemia, new cardiac events (eg, pericardial effusion, pericarditis, left ventricular insufficiency), CHF, tendon friction rubs, arthritis, and recent (within 3 months) high-dose glucocorticoid use.^4,13-15

The presentation of SRC can be nonspecific, often resembling findings related to acute kidney injury. Patients may report malaise, fatigue, fever, headache, seizure, blurred vision, or dyspnea.¹³ Clinical parametersto examine include systolic BP > 140 mm Hgand/or diastolic BP > 90 mm Hg (or an abrupt rise of > 30 or > 20, respectively), SCr increase by 50%+ or > 120% of the upper normal limit, proteinuria at 2+, high protein:creatinine ratio, hematuria > 2+ or > 10 red blood cells (RBCs), platelets < 100,000/mm³, and hypertensive encephalopathy.¹³ Mr. P presented with fatigue, dyspnea, an abrupt rise in BP (156/96 mm Hg), foamy urine, bilateral lower extremity edema (3.9 g/dL albumin), 2+ RBCs, and a SCr of 2.46 mg/dL on admission (a 205% increase from his last baseline of 1.2 mg/dL).

Treatments have had a large impact on the mortality rates of SRC. Following the introduction of ACE inhibitors, mortality from SRC has decreased from 76% to < 10% over recent decades.¹³ In addition to improving survival, these medications also have improved hospitalization outcomes for these patients.³ Captopril is often the medication of choice given its rapid onset and short duration of action relative to other medications in the same class, such as benazepril, enalapril, fosinopril, lisinopril, quinapril, and ramipril.^4,13 Current clinical trials are assessing the specific renal benefits of endothelin-1 receptor antagonists, which often are used for pulmonary and skin involvement.¹⁴ For patients presenting with acute SRC and uremia, dialysis may be necessary (typically predicted by elevated NT-proBNP serum levels), while the decision for transplantation may be indicated at least 2 years after SRC onset and resolution.^4,13-15

Once the acute crisis resolves, it is important to discuss prognosis with patients. The 1-, 2-, 3-, 5-, and 10-year survival rates are 82%, 74%, 71%, 59%, and 47%, respectively; however, when looking at only male patients at 10 years, the survival rate is 17%.¹³ Prevention of SRC can be addressed with daily BP checks and advising patients to seek medical care if they notice a consecutive 2-day abrupt rise.¹³

Cardiac Involvement

Systemic sclerosis has significant effects on patients’ heart function. The introduction of ACE inhibitors has shifted mortality in SSc patients from predominantly SRC to cardiac causes.⁶ Cardiac involvement can occur through a range of processes, including abnormal cardiac conduction, CHF, diastolic dysfunction, mitral valve nodular thickening, and pericardial effusion.³ Even though patients often present with skin findings, an initial cardiac workup is crucial to understanding disease progression and patient prognosis. The severity of the cutaneous manifestations often predicts the degree of diastolic dysfunction.¹⁶

Clinical evidence of cardiac involvement is seen in 20% to 25% of patients with SSc and is associated with a 70% mortality at 5 years when symptoms are evident.¹⁶ Additionally, right ventricular dysfunction at presentation is the strongest marker for all-mortality prognosis, representing the degree of pulmonary involvement, and includes findings such as progressive shortness of breath and systemic edema.⁹

Given the increasing survival of patients with SSc, cardiac involvement is becoming more evident and prominent. Direct treatments for cardiac manifestations are based on the causative feature, namely, focusing on pulmonary and renal involvement, which can be assessed with periodic echocardiograms evaluating left ventricular EF.