Running head: COMPLEXITIES OF SCLERODERMA 1

The Scleroderma Family of Diseases

and their Symptoms, Treatments, and Complexities

Kevin R. Hamby

DuBois Area Senior High School

COMPLEXITIES OF SCLERODERMA 2

Abstract

This paper explores the scleroderma family of diseases and their symptoms, causes, diagnostic

procedures, and treatments. It offers general information about the scleroderma (SSc) family:

localized scleroderma and systemic sclerosis and their subsequent categories. The research

explores and compares each category and exemplifies an overlap syndrome through toxic oil

syndrome (TOS). The discussion transitions to overall symptoms of SSc with a narrowed focus

concerning CREST syndrome, which connects to limited scleroderma. The paper then transitions

into the complexities of diagnosing the disorder and the unknown origins of the disease,

narrowing to some theoretical causes such as T cells Th1 and Th17 and other environmental

triggers. Furthermore, an interview with a limited systemic sclerosis patient who took part in a

failed clinical trial discusses SSc’s difficult treatment patterns. Conversely, the researcher

explores a new experimental treatment to inhibit zeste homolog 2 (EZH2) using 3-

Deazaneplanocin A (DZNep) to prevent SSc symptoms. This exploration with information about

support groups and other ways to manage SSc.

Keywords: scleroderma, CREST syndrome, management

COMPLEXITIES OF SCLERODERMA 3

The Scleroderma Family of Diseases

and their Symptoms, Treatments, and Complexities

The human immune system is an extremely complex defense system that uses the body’s

ability to recognize foreign invaders in the prevention of disease and infection. It works when

lymphocytes—white blood cells—produce immunoglobins that function as antibodies and bind

to antigens, or foreign substances that evoke an immune response. Different bacteria have

different antigens, and once the immune system learns to recognize and bind a specific antigen,

the successful lymphocyte reproduces. Upon reproduction, the cells create a hereditary line of

successful lymphocyte-antigen combinations. Therefore, the immune system has a “memory”

that aids in preventing future infections and diseases (Horton, Moran, Scrimgeour, Perry, &

Rawn, 2006). In some instances, this system malfunctions and begins to produce self-antigens

that attack the host, leading to autoimmunity disorders (Vojdani, 2014). These disorders, of

which there are over one hundred, are often-unrecognized epidemics that affect up to 50 million

Americans in the United States alone. There are discrepancies in this number because the true

number of people affected by the disorders—being unknown—are not included in some U.S.

data, according to the American Autoimmune Disease Association. Moreover, some autoimmune

disorders are naturally more rare and severe than others, resulting in more excruciating living

conditions and higher mortality rates, and others are conversely common and tolerable.

Scleroderma (acronym SSc) is one of the rare and severe disorders, affecting around 300,000

Americans—typically adult females 20-50 years old—and carrying a plethora of symptoms that

vary patient to patient. (“What is scleroderma,” n.d.; Smith, 2018). The disorder is difficult to

diagnose and has no cure, although researchers are continuously discovering new ways to

manage the disease.

COMPLEXITIES OF SCLERODERMA 4

The Disease

“Scleroderma” is merely a generalized name for a large family of diseases meaning “hard

skin,” which all have a common symptom of fibrosis, or thickening of the skin (“Scleroderma

overview,” n.d.). Fibrosis is typically a positive activity in the human body that uses collagen, a

strong, fibrous protein that is in bones, teeth, tendons, and skin. In scleroderma, however,

fibrosis becomes a negative factor when the body produces too much collagen, resulting in the

thickening and over-strengthening of the affected tissue (Horton et al., 2006; “Systemic

scleroderma,” 2015). Scleroderma and its associated fibrosis exist in two subcategories: localized

and systemic sclerosis (See Appendix A for a graphic of the disease family that supplements the

following information).

Localized scleroderma means fibrosis is only present in the epidermis, or skin. Being an

umbrella term itself, localized scleroderma has four more subcategories: morphea, linear

scleroderma, eosinophilic fasciitis, and toxin-induced syndromes. Morphea is a slowly

developing fibrosis that only affects the trunk and limbs of the patient. Some interchangeably use

morphea as another name for localized scleroderma (Starkebaum, 2018). Linear scleroderma is

more severe compared to morphea. In other words, it often occurs in childhood and results in

epidermis abnormalities on one side of the body, and abnormalities in muscles, fatty tissues, and

even the skull often go with it (“Linear scleroderma,” n.d.). Eosinophilic fasciitis (EF) is a rare

subcategory of localized scleroderma that scientists define as the swelling of the fascia—or the

tissue between the skin and over the muscle—caused by a buildup of eosinophils, a type of white

blood cell. EF can cause the skin on the trunk or limbs—excluding the phalanges—to become

swollen (Starkebaum, 2017). Toxin-induced syndromes also overlap with localized scleroderma,

with some studies showing TOS (toxic oil syndrome)—a chemically induced SSc-like syndrome
COMPLEXITIES OF SCLERODERMA 5

for example—as a related cause (Alonso-Ruiz, Zea-Mendoza, Salazar-Vallinas, Rocamora-

Ripoll, & Beltrán-Gutiérrez, 1986).

Systemic sclerosis is the other major category in scleroderma. Comparatively, it is the

more severe category of scleroderma due to fibrosis in both the epidermis and internal organs. It

has three subcategories: limited scleroderma, diffuse scleroderma, and accompanying overlap

syndromes (“Scleroderma Overview,” n.d.). Limited scleroderma, formally known as CREST

syndrome, primarily involves skin changes below the joints in the arms and leg. It can also affect

many internal organs, including but not limited to the digestive tract (“Limited Scleroderma,”

n.d.). Moreover, it progresses slowly, often leaving patients more symptomatic with time. On the

opposite end, diffuse scleroderma’s fibrosis affects the epidermis all over the body with a quick

progression, meaning the first five years are the worst, followed by remission. The effect on

internal organs is similar, but not identical. (Scleroderma Foundation, 2019). Sitting next to these

two subcategories are overlap syndromes encompassing scleroderma and other autoimmune

diseases. These autoimmune diseases, such as lupus, can function as precursors to SSc. Overall,

knowing each member of the scleroderma family is important when considering the effect of the

disease and management techniques.

Symptoms

Scleroderma comes with an array of symptoms that range from some minor ailments,

such as hair loss, to extremes such as gastroparesis, or the paralysis and accompanying

dysfunction of the digestive system. CREST syndrome, otherwise known as limited scleroderma,

is a former acronym used to describe that type of the disease. Regardless, it describes symptoms

that encompass the entire disease family (internal symptoms do not apply to localized

scleroderma). The “C” stands for calcinosis, which occurs in damaged tissues where otherwise
COMPLEXITIES OF SCLERODERMA 6

normal calcium metabolism is present. Recurrences can result in skin damage, the formation of

scar tissue, and the presence of calcium deposits, which are essentially kidney stones in your

fingers (“Scleroderma overview,” n.d.; Starkebaum, 2018). Following the acronym, the “R”

stands for Raynaud’s phenomenon. Limited scleroderma’s first symptom is most often

Raynaud’s, with symptoms arising up to ten years prior to any other symptoms (“Scleroderma

Overview,” n.d.). When exposed to the cold, affected individuals will often notice a painful

sensation in the phalanges. This issue results from constricted blood flow that is a part of the

phenomenon, which classifies SSc as a microvascular disease. Moreover, overlap syndromes go

with the phenomenon, such as lupus, and can show the presence of SSc in overlap syndromes.

The “E” stands for esophageal dysfunction. This symptom is quite common, often resulting in a

“lazy esophagus” that makes swallowing difficult and causes acid reflux (more commonly

known as heartburn). The next letter, “S,” stands for sclerodactyly, meaning the skin of the

finger and toes experiences fibrosis. This can make articulation difficult in some circumstances.

The last letter of CREST, “T,” stands for telangiectasia, which is the creation of red spots on the

skin because of burst capillaries (“Scleroderma Overview,” n.d.). Other general symptoms of

scleroderma may include respiratory issues, joint pain, heart problems, and renal issues—all

these symptoms result from fibrosis and tissue scarring (Starkebaum, 2018) (See Appendix B for

pictures of clinical CREST syndrome symptoms).

To fully understand the struggle many SSc patients endure, I spoke with a ten-year

limited systemic sclerosis patient. He described the beginning of the disease: “When I was in the

military, I often woke up with muscle soreness even when I hadn’t exercised for weeks. I knew

this wasn’t normal, so I saw a doctor who was unable to pinpoint the problem.” As the disease

unknowingly progressed, he began to experience stomach irritation because of fibrosis and

COMPLEXITIES OF SCLERODERMA 7

attempted diet changes to alleviate the problem. Later, he “was diagnosed with limited systemic

sclerosis based on [his] symptoms,” of which he had three out of five in relation to CREST

syndrome. In reflection, the interviewee noted he had Raynaud’s five years prior to diagnosis but

dismissed it as something that was normal. He “considers Raynaud’s the beginning of the disease

for many people” (R. Hamby, personal communication, March 15, 2019).

Causes and Diagnosing

Scleroderma is a widely unknown autoimmune disorder with an origin that has eluded

scientists. However, many studies point towards environmental factors as a trigger for a genetic

precursor and/or predisposition. For example, a potential cause is silica because it is a T cell

adjuvant, which is a substance that enhances a body’s immune response. The affected T cells,

Th17 and Th1, begin an inflammatory process that results in widespread fibrosis (Walecka,

Roszkiewicz, & Malewska, 2017). Furthermore, organic compounds and solvents, which bind

covalently and react with thiol, amino, and hydroxyl groups, can cause an onset of the disease by

changing the body’s immunogenicity. Other factors, such as exposure to heavy metals, smoking,

drug use, and chemotherapy, all have some correlation to the illness (Vojdani, 2014). However,

it is still unknown if these factors are causes or mere aggravators of an already present disease.

Diagnosing scleroderma is not a straightforward process. Typically, an ANA test

(antinuclear antibody) finds antibodies that attack the nucleus of healthy cells by taking blood

samples. The downside of the ANA test is the results can often be incorrect in diagnosing

autoimmune diseases. This can occur because of age, medications, or simply the presence of

autoantibodies (Weselman, 2017). If the ANA test is not correct or does not diagnose properly,

the presence of Raynaud’s can be an indicator in select cases, and in most instances, the doctor

diagnoses the individual on symptoms, primarily epidermal fibrosis. (“Scleroderma Overview,”

COMPLEXITIES OF SCLERODERMA 8

n.d.). Moreover, these tests can be crucial in diagnosing symptom progression. For example,

anti-topoisomerase antibodies are specific to diffuse scleroderma, and anti-centromere antibodies

are specific to limited scleroderma. Each type of scleroderma associate to different symptom

progressions. There is a multitude of antibodies beyond the exemplified ones that can point to

more specific symptoms such as renal (kidney) failure (“Scleroderma Antibodies,” n.d.).

Treatment and Remedies

Being such a large and complicated disease with a large array of symptoms, scleroderma

has no cure, but a line of experimental medications and new treatments are being developed. A

recent study conducted by researchers at the University of Michigan may lead to the start of a

treatment for SSc victims. Zeste homolog 2 (EZH2), an epigenetic (gene) regulator, is a key

factor in determining the development of fibrosis and the irregular formation of new blood

vessels—angiogenesis. In SSc patients, EZH2 levels measured at an elevated level in skin

fibroblasts and endothelial cells, which produce collagen and are in the linings of blood vessels,

respectively. The research found the inhibition of EZH2 using 3-Deazaneplanocin A (DZNep)

ended fibrosis in vitro (in lab tests) and in vivo (in living organisms). Specifically, DZNep

reduced genes promoting fibrosis in fibroblasts, constrained the migration of affected fibroblasts,

and restored normal angiogenesis in endothelial cells. The researchers concluded “targeting

EZH2 or EZH2-regulated genes might be of therapeutic potential” in the management of

scleroderma (Tsou et al., 2019). As hopeful as this new experiment seems, it does not necessarily

translate to successful human trials. In vivo and in vitro trials are quite common in experiments,

but side effects often counteract any positive effects in human trials.

Experimental medications and clinical trials occur often to try to pinpoint successful

treatments in scleroderma. To understand what patients go through when taking part in trials, I
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once again interviewed the individual with limited systemic sclerosis. He has taken part in many

experimental trials and has tried various medications. He further spoke about one that stood out:

“I had to go [receive the medication Macitentan for the treatment of digital ulcers] once a month

for one and a half years. The trial ended early because it made little progress and was

unsuccessful.” Due to past failures in clinical trials, the interviewee has tried other management

routes: “I have taken medications unapproved by the FDA to alleviate my symptoms. Through

this and with conversations with other scleroderma patients, I learned my medication is not

successful in many other individuals” (R. Hamby, personal communication, March 15, 2019).

As represented by the interview, clinical studies and medicinal trials are not always

effective, and they often work on a patient-patient basis. Therefore, the best way to live with

scleroderma is to use medications that give symptom relief and to make lifestyle changes.

Medications, for example, may dilate blood vessels to relieve Raynaud’s or suppress the immune

system. Therapy most regularly manages general pain, and patients should stay active, avoid

smoking and drug use, manage acid reflux (heartburn), and protect themselves from the cold. For

those who are struggling, support groups are common, and conferences often take place to

inform patients about new developments in research, such as the Scleroderma Foundation’s

National Patient Symposium.

Conclusions

Autoimmune diseases affect millions annually. Some are more known, and others

unknown. Scleroderma is one of the unknown: it is a large, complex disease encompassing a

family of symptoms that differ from patient to patient. Hard to diagnose, clinically identifying

SSc is difficult when ANA tests may give false positives, but symptoms like Raynaud’s are often

precursors years before diagnosis. After an official diagnosis, SSc is manageable using new
COMPLEXITIES OF SCLERODERMA 10

discoveries in the management of fibrosis and lifestyle changes, but it can be emotionally

draining on the affected individual. Luckily, there is a multitude of support groups and

advancements made every day with the hope that it will one day have a cure and give relief to

those who have suffered.

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References

5 Various Symptoms of Scleroderma. (n.d.). Retrieved March 21, 2019, from

http://www.findarthritistreatment.com/various-symptoms-of-scleroderma/

Alonso-Ruiz, A., MD, Zea-Mendoza, A. C., MD, Salazar-Vallinas, J. M., MD, Rocamora-Ripoll,

A., MD, & Beltrán-Gutiérrez, J., MD. (1986). Toxic oil syndrome: A syndrome with

features overlapping those of various forms of scleroderma (3rd ed., Vol. 15, Seminars in

arthritis and rheumatism, pp. 200-212) (United States of America, National Institutes of

Health, U.S. National Library of Medicine). Retrieved from

https://www.ncbi.nlm.nih.gov/pubmed/3961509

American Autoimmune Related Diseases Association (n.d.). Autoimmune Disease Statistics.

Retrieved March 16, 2019, from https://www.aarda.org/NEWS-

INFORMATION/STATISTICS/#1488234345468-3bf2d325-1052

Clinical Example: CREST syndrome with scleroderma, telangiectasias and subcutaneous

calcification. (n.d.). Retrieved March 21, 2019, from http://www.e-

hand.com/img/14522.htm

Dictionary by Merriam-Webster: America's most-trusted online dictionary. (n.d.). Retrieved

March 18, 2019, from https://www.merriam-webster.com/

Horton, H. R., Moran, L. A., Scrimgeour, K. G., Perry, M. D., & Rawn, J. D. (2006). Principles

of Biochemistry (4th ed.) (G. Carlson, Ed.). Upper Saddle River, NJ: Prentice Hall.

Lepas, P. (2014, November 15). Tips to Manage Acid Reflux Now. Retrieved March 21, 2019,

from http://ivanarcangel.blogspot.com/2014/11/tips-to-manage-acid-reflux-now.html
COMPLEXITIES OF SCLERODERMA 12

Limited Scleroderma. (n.d.). Retrieved from https://www.mayoclinic.org/diseases-

conditions/crest-syndrome/symptoms-causes/syc-20355535?p=1

Sclerodactyly in Systemic Scleroderma. (2010, December). Retrieved March 21, 2019, from

http://doctorsgates.blogspot.com/2010/12/sclerodactyly-in-systemic-scleroderma.html

Scleroderma Antibodies and Clinical Relevance. (n.d.). Retrieved March 10, 2019, from

https://sclerodermainfo.org/faq/scleroderma-antibodies/

Scleroderma Foundation. (2019). Systemic Sclerosis: Diffuse and Limited [Pamphlet]. Danvers,

MA: Author.

Scleroderma Overview. (n.d.). Retrieved February 28, 2019, from

https://sclerodermainfo.org/guide/overview/

Smith, Y. (2018, August 23). What is Scleroderma? Retrieved March 22, 2019, from

http://www.news-medical.net/health/what-is-scleroderma.aspx

Starkebaum, G. A., MD. (2017, February 8). Eosinophilic Fasciitis (United States of America,

National Institutes of Health, U.S. National Library of Medicine) (D. Zieve MD & B.

Conaway, Eds.). Retrieved March 5, 2019, from

https://medlineplus.gov/ency/article/000447.htm

Starkebaum, G. A., MD. (2018, April 12). Scleroderma (United States of America, National

Institutes of Health, U.S. National Library of Medicine) (D. Zieve MD & B. Conaway,

Eds.). Retrieved March 3, 2019, from https://medlineplus.gov/ency/article/000429.htm

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Tsou, P., Campbell, P., Amin, M. A., Coit, P., Miller, S., Fox, D. A., . . . Sawalha, A. H. (2019,

February 26). Inhibition of EZH2 prevents fibrosis and restores normal angiogenesis in

scleroderma (L. Steinman, Ed.). Retrieved March 10, 2019, from

https://www.pnas.org/content/116/9/3695

United States of America, National Institutes of Health, Genetic and Rare Diseases Information

Center. (n.d.). Linear scleroderma. Retrieved March 11, 2019, from

https://rarediseases.info.nih.gov/diseases/9513/linear-scleroderma

United States of America, National Institutes of Health, U.S. National Library of Medicine.

(2019, April 12). Systemic Scleroderma. Retrieved March 10, 2019, from

https://ghr.nlm.nih.gov/condition/systemic-scleroderma

Vojdani, A. (2014). Autoimmune Diseases. A Potential Link between Environmental Triggers

and Autoimmunity, 2014, 1-18. doi:10.1155/2014/437231

Walecka, I., Roszkiewicz, M., & Malewska, A. (2017, July 14). Potential occupational and

environmental factors in SSc onset. Retrieved March 12, 2019, from

http://www.aaem.pl/Potential-occupational-and-environmental-factors-in-SSc-

onset,75894,0,2.html

Weselman, K., MD. (2017, March). Antinuclear Antibodies (ANA). Retrieved March 10, 2019,

from https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-

Conditions/Antinuclear-Antibodies-ANA

What is scleroderma? (n.d.). Retrieved March 12, 2019, from

http://www.scleroderma.org/site/PageNavigator/patients_whatis.html#.XI54Q3dFx9B
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Appendix A

Note: Many people mistakenly use “systemic scleroderma” interchangeably with “systemic

sclerosis.”
COMPLEXITIES OF SCLERODERMA 15

Appendix B

Figure 1B: Calcinosis in SSc patient’s fingers

Figure 2B: Raynaud’s Phenomenon

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Appendix B (Continued)

Figure 3B: Acid Reflux Resulting from Esophageal Dysfunction

Figure 4B: SSc Patient with Sclerodactyly

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Appendix B (Continued)

Figure 5B: SSc Patient with Telangiectasia on the Lips