Systemic sclerosis is also known as scleroderma. It is one of the most fatal of the autoimmune disorders. It affects up to 75,000 people in the United States each year[mfn]Mayes MD. Scleroderma epidemiology. Rheum Dis Clin North Am. 2003;29(2):239-54.[/mfn].  An early and accurate diagnosis can be challenging due to the way the disease presents and its rare nature. The objective of this article is to provide a comprehensive overview to aid in the understanding of systemic sclerosis. It includes recommendations for its diagnosis and management, as well as a discussion on the future hope for this disease.

[Note: the term systemic sclerosis and scleroderma will be used interchangeably in this article.]

What is systemic sclerosis?

Systemic sclerosis is a rheumatic autoimmune disorder that affects the skin and internal organs. It is a complex disease driven by inflammation and fibrosis (scarring of tissue). This leads to severe damage and failure of multiple organs including,

• the skin
• joints
• tendons
• the gastrointestinal tract
• lungs
• heart
• blood vessels and
• kidneys[mfn]Sierra-Sepulveda A, Esquinca-Gonzalez A, Benavides-Suarez SA, Sordo-Lima DE, Caballero-Islas AE, Cabral-Castaneda AR, et al. Systemic Sclerosis Pathogenesis and Emerging Therapies, beyond the Fibroblast. Biomed Res Int. 2019;2019:4569826[/mfn]

Although scleroderma is rare, it is considered one of the most life-threatening rheumatic diseases.

What are the two main types of systemic sclerosis?

There are two main types of systemic sclerosis: limited and diffuse. They are defined by the extent of skin involved.

• Limited systemic sclerosis

Limited is the milder form of skin involvement. It is characterized by fibrosis below the elbows and knees. Generally, limited systemic sclerosis causes less severe fibrosis of internal organs than the more severe form.

• Diffuse systemic sclerosis

In diffuse form, fibrosis affects larger areas of skin including the torso, upper arms, and legs. It often involves internal organs. Diffuse systemic sclerosis can have damaging and harmful effects on the lungs, heart, and kidneys. If not treated promptly, it can lead to poor outcomes[mfn]LeRoy EC, Medsger TA, Jr. Criteria for the classification of early systemic sclerosis. J Rheumatol. 2001;28(7):1573-6.[/mfn], [mfn]Shah AA, Wigley FM. My approach to the treatment of scleroderma. Mayo Clin Proc. 2013;88(4):377-93.[/mfn].

What is the underlying cause of scleroderma?

This disease is characterized by immune system activation, vasculopathy, and widespread tissue fibrosis. However, its pathogenesis is still unclear.

ADD_THIS_TEXT
 

The most accepted working hypothesis suggests that a triggering event occurs that causes activation of specific cells of the immune system and extracellular matrix (ECM). These findings are the defining features of connective tissue disease.

The chronic activation of immune cells, inflammatory mediators, and components of the ECM, including fibroblasts, can lead to fibrosis, organ damage, and even loss of organ function[mfn]Katsumoto TR, Whitfield ML, Connolly MK. The pathogenesis of systemic sclerosis. Annu Rev Pathol. 2011;6:509-37[/mfn], [mfn]Asano Y. Systemic sclerosis. J Dermatol. 2018;45(2):128-38.[/mfn], [mfn]Jimenez SA. Role of endothelial to mesenchymal transition in the pathogenesis of the vascular alterations in systemic sclerosis. ISRN Rheumatol. 2013;2013:835948.[/mfn], [mfn]Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007;117(3):557-67.[/mfn].

What other factors contribute to systemic sclerosis?

As mentioned, the exact cause of the disorder is unknown. It is widely accepted that the interaction of several factors leads to the disease [5], including:

• abnormal immune activity,
• genetic predisposition
• and potential environmental triggers

Scleroderma can present at any age. However, it is typically found in people between the ages of 20 and 50 years [1]. Seventy-five percent or more of patients with the disorder are female, suggesting that gender plays a role[mfn]Peoples C, Medsger TA, Jr., Lucas M, Rosario BL, Feghali-Bostwick CA. Gender differences in systemic sclerosis: relationship to clinical features, serologic status, and outcomes. J Scleroderma Relat Disord. 2016;1(2):177-240.[/mfn].

What are the symptoms of systemic sclerosis?

The symptoms of systemic sclerosis can be similar to other autoimmune diseases. This can make accurate diagnosis challenging.

Early clinical signs of the condition can be varied, but often include Raynaud’s phenomenon and gastroesophageal reflux disease (GERD)[mfn]Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017;390(10103):1685-99.[/mfn]. Other early symptoms include inflammatory skin disease, puffy and swollen fingers, musculoskeletal inflammation, and/or fatigue [mfn]Bellando-Randone SG, S.; Marco Matucci-Cerinic, M. Very Early Diagnosis of Systemic Sclerosis. Polish Archives of Internal Medicine. 2012;122:18-23.[/mfn].

Later in the disease course, some patients present with end-organ manifestations, such as pulmonary arterial hypertension [mfn]Domsic RT, Nihtyanova SI, Wisniewski SR, Fine MJ, Lucas M, Kwoh CK, et al. Derivation and validation of a prediction rule for two-year mortality in early diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 2014;66(6):1616-24.[/mfn], [mfn]Cavagna L, Codullo V, Ghio S, Scire CA, Guzzafame E, Scelsi L, et al. Undiagnosed connective tissue diseases: High prevalence in pulmonary arterial hypertension patients. Medicine (Baltimore). 2016;95(39):e4827.[/mfn]. Lung fibrosis is a common complication of systemic sclerosis. Up to 50% of patients develop interstitial lung disease (ILD). It is the most common cause of mortality in patients [mfn]Tackling systemic sclerosis from all angles. The Lancet Rheumatology. 2020;2(3):e121.[/mfn].

What is the prognosis of systemic sclerosis?

The disorder has both physical and emotional effects on patients living with this condition. It can cause significant disability, disfiguration, and reduced life expectancy [4],[mfn]Debois AC, Cacoub P. Systemic sclerosis: An update in 2016. Autoimmun Rev. 2016;15(5):417-26.[/mfn]. Patients often experience a reduced quality of life, complicated by the uncertainty of outcome and development of potentially lethal manifestations.

The prognosis depends on the type, the time of diagnosis, and treatment. With limited disease, a patient’s condition can be stable for years. However, the diffuse form can be fatal if not treated promptly. This is especially true for those who present with pulmonary hypertension, despite currently available treatment options.

Systemic sclerosis is among the most fatal autoimmune disorders. One in four patients dies within eight years of diagnosis, demonstrating the importance of early diagnosis and prompt treatment[mfn]Hao Y, Hudson M, Baron M, Carreira P, Stevens W, Rabusa C, et al. Early Mortality in a Multinational Systemic Sclerosis Inception Cohort. Arthritis Rheumatol. 2017;69(5):1067-77.[/mfn]. 

How is scleroderma diagnosed?

Scleroderma is an uncommon disease for most physicians. It is usually diagnosed by a rheumatologist.

Once the disorder is suspected, patients are often assessed by ACR/EULAR (American College of Rheumatology/European League Against Rheumatism) OR VEDOSS (Very Early Diagnosis of Systemic Sclerosis) criteria. As systemic sclerosis presents with heterogeneous clinical manifestations, not all patients diagnosed will fulfill these criteria[mfn]Saketkoo LA, Magnus JH, Doyle MK. The Primary Care Physician in the Early Diagnosis of Systemic Sclerosis: The Cornerstone of Recognition and Hope. American Journal of the Medical Sciences. 2014;347(1):54-63.[/mfn].

• Tests to diagnose and screen for organ involvement

Tests are ordered to confirm diagnosis and screen for internal organ involvement, including:

• Blood tests to detect levels of antibodies
• Pulmonary function tests
• Electrocardiogram
• Echocardiogram
• Kidney function tests
• Gastrointestinal tests

Though gastrointestinal tract involvement is not part of the classification criteria, it is often affected in systemic sclerosis. As such, screening for esophageal disease can be helpful for diagnosis and management.

Additional tests for patients diagnosed with systemic sclerosis

It is recommended that patients diagnosed with systemic sclerosis be considered for pulmonary function tests. This is because lung fibrosis is a common complication of the disease.

These tests evaluate lung restriction and reduction in diffusion capacity and can allow the initiation of proper therapies. Other tests for heart and lung screening include:

• Echocardiogram and brain natriuretic peptide (BNP) for pulmonary hypertension
• High-resolution computed tomography (HRCT) of the chest for diagnosis of ILD
• Right heart catheterization (RHC) for diagnosis of pulmonary hypertension

Early diagnosis of scleroderma is critical

Early diagnosis and screening are critical for the management of the disease. Cases can be misdiagnosed, especially in cases with mild or no skin manifestations.

The disease cannot be cured. However, it is treatable in its early stages.

Primary care physicians often play an important role in recognizing initial symptoms of systemic sclerosis and referring their patients to specialists with expertise in treating the disease, such as rheumatologists.

Delays in referring patients to rheumatologic care, especially for those with moderate-to-severe cases, can be detrimental. Such cases can progress to irreversible end-organ damage that may have been prevented or delayed by early diagnosis and intervention [mfn]Guiducci S, Bellando-Randone S, Matucci-Cerinic M. A New Way of Thinking about Systemic Sclerosis: The Opportunity for a Very Early Diagnosis. Isr Med Assoc J. 2016;18(3-4):141-3.[/mfn].

What treatments are available for systemic sclerosis?

Available treatments can help improve pain, various disease manifestations, and improve the quality of life for patients with systemic sclerosis. However, there is currently no cure for this chronic disease.

Current approaches to managing systemic sclerosis are organ-specific. They are aimed at responding to the damage driven by inflammation and fibrosis, and not the underlying mechanisms of the disease [2], [mfn]Kowal-Bielecka O, Fransen J, Avouac J, Becker M, Kulak A, Allanore Y, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017;76(8):1327-39.[/mfn], [mfn]Smith V, Scire CA, Talarico R, Airo P, Alexander T, Allanore Y, et al. Systemic sclerosis: state of the art on clinical practice guidelines. RMD Open. 2018;4(Suppl 1):e000782.[/mfn].

• Current Treatment Options: Summary

The following table outlines the current treatment options. [2], [mfn]Eldoma M, Pope J. The contemporary management of systemic sclerosis. Expert Rev Clin Immunol. 2018;14(7):573-82.[/mfn].

Organ System	Clinical Manifestation	Example Treatments
Skin	Scleroderma	-Immunosuppressive therapies (IST) e.g. methotrexate
Musculoskeletal	Inflammatory arthritis	-IST e.g. methotrexate
Renal	Scleroderma renal crisis	-Angiotensin-converting enzyme inhibitors
Gastrointestinal	Gastroesophageal reflux disease (GERD)	-Lifestyle modifications -Proton-pump inhibitors
Peripheral vascular	Raynaud’s phenomenon Digital ulcers Critical ischemia	-Calcium channel blockers -Phosphodiesterase 5 inhibitors -Angiotensin II receptor blockers -Endothelin receptor antagonists
Pulmonary	Interstitial lung disease (ILD) Pulmonary arterial hypertension (PAH)	-Immunosuppressive treatment e.g. mycophenolate mofetil, cyclophosphamide -Tyrosine kinase inhibitor -Endothelin receptor antagonists -Phosphodiesterase 5 inhibitors -Prostacyclin analogs -Soluble guanylate cyclase agonists
Cardiovascular	Heart failure Inflammatory cardiac disease	-Drug therapies e.g. angiotensin-converting enzyme inhibitors and diuretics -IST e.g. corticosteroids and/or cyclophosphamide

 

What are other treatments for clinical manifestations of systemic sclerosis?

Clinical manifestations, such as joint contractures, may require physical and occupational therapy to prevent disability. Other ancillary services may be indicated based on clinical features, such as:

• Lymphedema clinic for edema
• Wound care for digital ulcers
• Dietary services for malnutrition
• Pulmonary rehabilitation for pulmonary disease

For patients with rapidly progressive disease at risk for organ failure, hematopoietic stem cell transplantation (HSCT) can be considered, but should only be done at high volume expert centers [19].

As previously mentioned, patients with systemic sclerosis should be referred to specialists, like rheumatologists who are experienced in treating the complex clinical manifestations of this disease. Often, rheumatologists will work together with primary care physicians and other specialists to ensure comprehensive care of the patient [4], [mfn]Denton CP, Hughes M, Gak N, Vila J, Buch MH, Chakravarty K, et al. BSR and BHPR guideline for the treatment of systemic sclerosis. Rheumatology (Oxford). 2016;55(10):1906-10.[/mfn]. For example, management of gastrointestinal manifestations can be achieved through coordinating care between a gastroenterologist and rheumatologist[mfn]Sakkas LI, Simopoulou T, Daoussis D, Liossis SN, Potamianos S. Intestinal Involvement in Systemic Sclerosis: A Clinical Review. Dig Dis Sci. 2018;63(4):834-44.[/mfn].

Treating systemic sclerosis requires a thoughtful approach carefully tailored to each patient. A new physician resource, www.totalssc.com, addresses the complexity of systemic sclerosis which is helpful for understanding the needs of patients living with this devastating disease.

What is the future hope for the treatment of systemic sclerosis?

Systemic sclerosis is a complex disease with many different clinical manifestations. Currently, the only FDA-approved therapy is a tyrosine kinase inhibitor. It slows the decline of pulmonary function in adults with ILD-associated with systemic sclerosis.

Treatments used today only address clinical manifestations and not the underlying drivers of the disease demonstrating a large unmet need.

Research on the treatment of systemic sclerosis is fundamental to improving outcomes for patients. Considerable progress has been made in the understanding of the pathogenesis of this disease in recent years which has led to the development of novel therapeutic candidates.

• Therapy that targets the endocannabinoid system

For example, one therapy in development targets the endocannabinoid system (ECS), which is a regulator of inflammation and fibrosis [mfn]Gonzalez-Mariscal I, Krzysik-Walker SM, Doyle ME, Liu QR, Cimbro R, Santa-Cruz Calvo S, et al. Human CB1 Receptor Isoforms, present in Hepatocytes and beta-cells, are Involved in Regulating Metabolism. Sci Rep. 2016;6:33302.[/mfn]. Research has shown that targeting the cannabinoid receptor type 2 (CB₂) on immune cells can reduce inflammation and limit fibrosis. This is a novel approach and if approved could be the first therapy that targets underlying drivers of systemic sclerosis as opposed to its clinical manifestations.

• Antifibrotic therapy

Antifibrotic therapy to treat ILD-associated systemic sclerosis is being actively studied as an add-on to immunosuppressive therapy. Studies have shown that the underlying mechanisms of idiopathic pulmonary fibrosis (IPF) may be similar to those contributing to fibrosis in systemic sclerosis which has led to the investigation of its use in ILD-associated systemic sclerosis [mfn]Volkmann ER, Tashkin DP. Treatment of Systemic Sclerosis-related Interstitial Lung Disease: A Review of Existing and Emerging Therapies. Ann Am Thorac Soc. 2016;13(11):2045-56.[/mfn].

Currently, there are several drug candidates in Phase 3 trials, which is significant given the low incidence of this disease. This indicates that there is growing interest in developing new treatments for systemic sclerosis, providing hope to those affected by the disease.

In addition to a community rheumatologist, what resources are available to patients with scleroderma?

• The Scleroderma Foundation

The Scleroderma Foundation is a national non-profit organization that supports patients and their families, promotes public awareness and education. It also supports research to improve treatment and eventually find a cure for systemic sclerosis.

This foundation offers many tools and resources for new and current patients and their families, including

• support programs
• peer counseling
• physician referrals
• educational information.

“The Scleroderma Foundation is proud to be the leading scleroderma patient advocacy organization in the US and the largest one globally,” said Robert Riggs, chief executive officer of the Scleroderma Foundation. “With a network of 19 chapters and 150 support groups around the country, the Scleroderma Foundation is a trusted source of medically-vetted information and community connection.”

• Scleroderma Specialty Centers

Scleroderma specialty centers specialize in the care of patients with systemic sclerosis and related conditions. Physicians at these centers seek to learn more about systemic sclerosis and the best treatment approaches.

Oftentimes, a scleroderma center can help coordinate treatment services for patients in addition to providing access to clinical research opportunities.

Related content:
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What Will Healthcare Look Like in a Post-COVID-19 World? (Part 1)

References

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1. Mayes MD. Scleroderma epidemiology. Rheum Dis Clin North Am. 2003;29(2):239-54.
2. Sierra-Sepulveda A, Esquinca-Gonzalez A, Benavides-Suarez SA, Sordo-Lima DE, Caballero-Islas AE, Cabral-Castaneda AR, et al. Systemic Sclerosis Pathogenesis and Emerging Therapies, beyond the Fibroblast. Biomed Res Int. 2019;2019:4569826.
3. LeRoy EC, Medsger TA, Jr. Criteria for the classification of early systemic sclerosis. J Rheumatol. 2001;28(7):1573-6.
4. Shah AA, Wigley FM. My approach to the treatment of scleroderma. Mayo Clin Proc. 2013;88(4):377-93.
5. Katsumoto TR, Whitfield ML, Connolly MK. The pathogenesis of systemic sclerosis. Annu Rev Pathol. 2011;6:509-37.
6. Asano Y. Systemic sclerosis. J Dermatol. 2018;45(2):128-38.
7. Jimenez SA. Role of endothelial to mesenchymal transition in the pathogenesis of the vascular alterations in systemic sclerosis. ISRN Rheumatol. 2013;2013:835948.
8. Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007;117(3):557-67.
9. Peoples C, Medsger TA, Jr., Lucas M, Rosario BL, Feghali-Bostwick CA. Gender differences in systemic sclerosis: relationship to clinical features, serologic status and outcomes. J Scleroderma Relat Disord. 2016;1(2):177-240.
10. Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017;390(10103):1685-99.
11. Bellando-Randone SG, S.; Marco Matucci-Cerinic, M. Very Early Diagnosis of Systemic Sclerosis. Polish Archives of Internal Medicine. 2012;122:18-23.
12. Domsic RT, Nihtyanova SI, Wisniewski SR, Fine MJ, Lucas M, Kwoh CK, et al. Derivation and validation of a prediction rule for two-year mortality in early diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 2014;66(6):1616-24.
13. Cavagna L, Codullo V, Ghio S, Scire CA, Guzzafame E, Scelsi L, et al. Undiagnosed connective tissue diseases: High prevalence in pulmonary arterial hypertension patients. Medicine (Baltimore). 2016;95(39):e4827.
14. Tackling systemic sclerosis from all angles. The Lancet Rheumatology. 2020;2(3):e121.
15. Debois AC, Cacoub P. Systemic sclerosis: An update in 2016. Autoimmun Rev. 2016;15(5):417-26.
16. Hao Y, Hudson M, Baron M, Carreira P, Stevens W, Rabusa C, et al. Early Mortality in a Multinational Systemic Sclerosis Inception Cohort. Arthritis Rheumatol. 2017;69(5):1067-77.
17. Saketkoo LA, Magnus JH, Doyle MK. The Primary Care Physician in the Early Diagnosis of Systemic Sclerosis: The Cornerstone of Recognition and Hope. American Journal of the Medical Sciences. 2014;347(1):54-63.
18. Guiducci S, Bellando-Randone S, Matucci-Cerinic M. A New Way of Thinking about Systemic Sclerosis: The Opportunity for a Very Early Diagnosis. Isr Med Assoc J. 2016;18(3-4):141-3.
19. Kowal-Bielecka O, Fransen J, Avouac J, Becker M, Kulak A, Allanore Y, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017;76(8):1327-39.
20. Smith V, Scire CA, Talarico R, Airo P, Alexander T, Allanore Y, et al. Systemic sclerosis: state of the art on clinical practice guidelines. RMD Open. 2018;4(Suppl 1):e000782.
21. Eldoma M, Pope J. The contemporary management of systemic sclerosis. Expert Rev Clin Immunol. 2018;14(7):573-82.
22. Denton CP, Hughes M, Gak N, Vila J, Buch MH, Chakravarty K, et al. BSR and BHPR guideline for the treatment of systemic sclerosis. Rheumatology (Oxford). 2016;55(10):1906-10.
23. Sakkas LI, Simopoulou T, Daoussis D, Liossis SN, Potamianos S. Intestinal Involvement in Systemic Sclerosis: A Clinical Review. Dig Dis Sci. 2018;63(4):834-44.
24. Gonzalez-Mariscal I, Krzysik-Walker SM, Doyle ME, Liu QR, Cimbro R, Santa-Cruz Calvo S, et al. Human CB1 Receptor Isoforms, present in Hepatocytes and beta-cells, are Involved in Regulating Metabolism. Sci Rep. 2016;6:33302.
25. Volkmann ER, Tashkin DP. Treatment of Systemic Sclerosis-related Interstitial Lung Disease: A Review of Existing and Emerging Therapies. Ann Am Thorac Soc. 2016;13(11):2045-56.