Scleroderma

Scleroderma is a rare autoimmune disease characterized by thick and tightening skin. It produces an accumulation of scar tissue and causes damage to organs such as the heart, lungs, kidneys and stomach. In some aspects it has similarities with lupus and rheumatoid arthritis. Autoimmune diseases (those in which the body attacks itself) are becoming more frequent.

Scleroderma is frequent among middle-aged women between 30 and 50, although it can occur at any age. Currently, the exact causes of scleroderma are unknown. However, it is known that besides its relation to the immune system, it’s also connected to microcirculatory disorders and perivascular inflammatory infiltrates, which are related to immune activation, antibody production and an excessive presence of fibroblasts (cells responsible for synthesizing other cells that form the connective tissue). Among the factors that originate these processes, current research points to an influence of genetic inheritance and environment, more specifically, the exposure to toxic agents, oxidative stress and free radicals.

Types of Scleroderma

There are different types of scleroderma that present different prognoses. However, all these different types can be classified into two large groups:

Localized Scleroderma

Is characterized by affecting only the skin, without the occurrence of Raynaud’s phenomenon, resulting in a better prognosis. “Localized scleroderma (LoS), which classically presents benign and self-limited evolution and is confined to the skin and/or underlying tissues. Localized scleroderma or morphea is a chronic connective tissue disease of unknown etiology. Several types of morphea exist and each has different clinical manifestations and levels of connective tissue involvement. Morphea is characterized by skin thickening with increased quantities of collagen in the indurative lesion. This entity is subdivided into linear scleroderma, plaque morphea, deep morphea, bullous morphea, and generalized morphea. Each one of these subtypes may affect the face with varying intensity. LoS is the most common subtype of scleroderma in childhood. LoS categories are not mutually exclusive, since different subtypes may occur associated in the same patient.”¹

“It is the most common form of scleroderma, occurs generally in young adults, and has a predominance in the female sex. In morphea, the lesions are usually limited to the skin and subcutaneous fatty tissue, but they can extend over muscular fascia, muscle tissue, tendons, joint synovia, and even bone marrow. Other symptoms such as arthralgia, synovitis, and infrequent ipsilateral uveitis, or even Raynaud’s phenomenon, sometimes accompany skin involvement. Visceral involvement, affecting pulmonary function or esophageal motility, is generally considered an attribute of systemic sclerosis and is rare in patients with morphea. Therefore, prognosis of patients with morphea is usually good. Histopathologic examination reveals different degrees of collagenization of the dermis and extension of fibrous tissue into the subcutaneous fat, musculature, fascia, and, rarely, late in the course of the disease, into the bone marrow. However, depth of infiltration by collagen bundles is expected mainly in the deep and generalized types of morphea. Autoimmune abnormalities of localized scleroderma have been well recognized during the past two decades, and recently this disease has been considered to have an autoimmune background because of the high frequency of antinuclear antibodies encountered.”²

“The incidence of LoS is around 0.3 to 3 cases per 100.000 inhabitants/year. It affects commonly Caucasian women, with a women/men ratio of 2–4/1, a similar prevalence in children and adults with a peak in the fifth decade of life in adults, whereas 90% of children are diagnosed between 2 and 14 years of age.

Etiology of LoS is unknown, even if the probable trigger is a vascular injury that culminates in increased collagen production and decreased collagen destruction.

Plaque morphea lesions have an initial inflammatory (or active) stage of erythematous to lilaceous dusky patches or plaques; over time, the center becomes white and sclerotic, and the borders take on a characteristic ‘lilaceous ring.’ When the active stage ends, white sclerotic plaques with postinflammatory hyperpigmentation may be found. […]

Plaque morphea is the most common presentation in adults, unlike the linear morphea that is more common in children and it often presents with fibrosis of underlying tissues up to bone. The subcutaneous tissue and the muscular fascia are targeted by the deep morphea. Finally, the generalized and the bullous morphea are rare clinical entities.

Though LoS is known as a dermatologic disease, it has also been reported in literature the possibility of visceral involvement, in the case of overlap with other autoimmune diseases or as possible evolution towards a systemic form; the latter possibility was described anecdotally in pediatric cases.

Despite distinct clinical entities, SSc and LoS present analogue histopathological findings; furthermore, the presence of autoantibodies or Raynaud’s phenomenon (RP) could be reported also in LoS. In this perspective they might represent two extremities of the same spectrum of disease.”³

Systemic Scleroderma

Besides presenting a cutaneous affection, it causes visceral damage and thus, a worse prognosis.

“SSc (Systemic Sclerosis) is a multisystemic, autoimmune disease affecting small arteries, microvessels and fibroblasts resulting in vascular obliteration, collagen accumulation and scarring (fibrosis) of skin and internal organs. This leads to hidebound skin and damage of gastrointestinal tract, lungs, heart and kidneys. The serological specifity of the disease is the presence of antinuclear antibodies (ANAs) which are directed mainly against cell nuclear enzymes, like DNA topoisomerase -1 (anti -Topo I) and RNA polymerases, as well as centromeric proteins, anticentromere antibodies, ACA).”⁴

“In general, systemic sclerosis (SSc) is an autoimmune disease of the connective tissue, clinically characterized by dermal thickening due to the accumulation of connective tissue and may involve other organs. The etiology of this disease is multifactorial and is caused by the interaction of alterations in the immune response, excessive extracellular matrix remodeling and the presence of proliferative vasculopathy, all this under genetic and environmental influence. SSc has an estimated prevalence of 10 cases per 100 000 inhabitants, which is why it is considered a rare disease, with an incidence of 4-8 cases per 10 000 inhabitants, affecting mostly women with an average age of 45 years. SSc is characterized by fibrosis that causes the thickening and hardening of the skin and other tissues. It starts with an endothelial injury and a subsequent imbalance of its repair, generating a cascade of proinflammatory events and hyperactivation of fibroblasts that constitute abnormal extracellular matrix clusters in different tissues and degrees, and almost always affecting the gastrointestinal tract, lung, kidney, heart and skin. In addition, it is associated with mortality when it manifests with interstitial lung disease and pulmonary arterial hypertension. This skin condition causes lesions ranging from digital ulcers (DU) to facial atrophy, which are susceptible to management by plastic surgery. With this in mind and considering the difficulties that could arise regarding medical and surgical management of skin lesions, hand involvement and facial alteration, this work describes the results of a detailed literature review, presenting the best therapeutic options for these patients from the point of view of plastic surgery.”⁵

“Although systemic sclerosis is uncommon, it has a high morbidity and mortality. Improved understanding of systemic sclerosis has allowed better management of the disease, including improved classification and more systematic assessment and follow-up. Additionally, treatments for specific complications have emerged and a growing evidence base supports the use of immune suppression for the treatment of skin and lung fibrosis. Some manifestations of the disease, such as scleroderma renal crisis, pulmonary arterial hypertension, digital ulceration, and gastro-oesophageal reflux, are now treatable. However, the burden of non-lethal complications associated with systemic sclerosis is substantial and is likely to become more of a challenge.”⁶

Symptoms

The symptoms of scleroderma vary from person to person, depending on the severity and type. Some of the possible symptoms are:

• Progressive tightness of the skin: this is the most common sign of scleroderma. During a variable number of years, the affected person will show hardening of the skin. This hardening occurs especially in the hands (sclerodactyly), accompanied by Raynaud’s phenomenon.
• The phenomenon of Raynaud: it is a vascular disorder characterized by a lack or reduction of blood supply to the fingers (ischemia) in an episodic way. It manifests an alteration of the color of the hands after exposure to cold and redness after exposure to heat.
• “Raynaud’s phenomenon is highly localized and affects the arterial inflow of specific skin areas such as fingers, toes, and tips of the nose and ears. These sites are distinct from other skin areas in that they have specialized structural and functional features for thermoregulation. They have a high density of arteriovenous anastomoses, which bypass capillaries and provide direct connections between arterioles and venules. Arteriovenous anastomoses therefore do not contribute to capillary blood flow, which provides essential nutritional support to the skin, but instead function as thermoregulatory structures. During exposure to cold, arteriovenous anastomoses remain predominantly closed, whereas they are fully dilated during the elimination of heat. Cold-induced cutaneous vasoconstriction is mediated by a reflex increase in sympathetic constrictor nerve activity and local cold-induced amplification of the sympathetic response.”⁷
• Numbness of the fingers and toes: this sign constitutes an exaggerated response to cold, causing numbness or pain accompanied by changes in color.
• Problems of the digestive system: the gastrointestinal issues affect mainly the esophagus. However, any part of the digestive tract may suffer alterations. “The gastrointestinal tract is one of the main systems involved in SSc patients causing significant morbidity and even mortality. There is no single objective measure to assess the extent and severity of GI involvement in SSc patients. A multidisciplinary approach with a rheumatologist, gastroenterologist, and sometimes a nutritionist is mandatory in all patients with severe gastrointestinal involvement. The management of GIT involvement in SSc remains empirical and symptom-driven. Data regarding the influence of immunomodulatory therapy on GIT involvement are scarce. Well-designed and high-powered prospective studies are needed to determine the effect of immunosuppressive treatment on the onset of GI tract disease, especially in early SSc.”⁸
• Pulmonary complications: patients with scleroderma have a difficulty breathing. Also, in general, they suffer a gradual deterioration of lung function as a result of fibrosis. This is the main cause of death in these patients.
• Cardiac issues: this situation occurs rarely and manifests itself mainly in the form of arrhythmias and angina-type chest pain. “Systemic sclerosis (SSc) can cause a wide variety of cardiac abnormalities, including microvascular coronary artery disease (with resultant myocardial ischemia), myocardial fibrosis, left ventricular (LV) systolic dysfunction, LV diastolic dysfunction, pericardial disease, and conduction abnormalities (including bradyarrhythmias and tachyarrhythmias). In addition, cardiac involvement in SSc can be primary (i.e. direct cardiac involvement) or secondary to pulmonary arterial hypertension (PAH), interstitial lung disease (ILD), or kidney disease, all of which are potential complications of SSc. Clinically evident cardiac involvement in SSc is associated with an increased risk of death; therefore, understanding the cardiac manifestations of SSc is critically important.
  Pathophysiologic aspects of cardiac manifestations of SSc, especially direct myocardial involvement, have been reviewed in detail elsewhere. Therefore, the present review will focus on the latest data on epidemiology of SSc-induced heart disease, current and emerging tools for the detection and monitoring of cardiac involvement in SSc, and evaluation and treatment of patients with SSc who have known or suspected cardiac manifestations.”⁹
• Malfunction of the kidneys: when it affects the kidney, it’s called nephropathy (any disease that affects the kidney), and appears during the first years of the disease.

Other symptoms of this disease include joint pain, hair loss, dry cough and wheezing (sound made by air passing through congested airways).

If you suspect that you may have scleroderma, you should see a doctor to perform medical tests. For diagnosis, your doctor can request a blood test (to detect the presence of antibodies), a capillaroscopy (allows visualization of the microscopic vessels of the skin) and/or a cutaneous biopsy (consists of taking a piece of skin to analyze it under a microscope).

Currently, there is no allopathic treatment (based on medications) that can cure the disease. Because it is a heterogeneous condition that can present diverse symptoms, treatment must be adapted to each patient individually. There are certain symptoms that can be treated with immunosuppressive medication in more severe cases. These symptomatic treatments are key to improve the prognosis of the disease.

Treatment can also be complemented with non-medicated care. An example is physiotherapy, which helps maintain joint mobility. Because the skin becomes fragile, it will be necessary to protect it from the cold and the sun. It is recommended to apply moisturizers adapted to the needs of your skin.

Some other simple measures can be put into practice to attenuate the symptoms. These measures would be aimed at improving general health of the patient, such as smoking cessation, doing physical exercise on a regular basis (walking or swimming) and a healthy diet in order to maintain an ideal weight.

References:

(1) Careta, M. F., & Romiti, R. (2015). Localized scleroderma: clinical spectrum and therapeutic update. Anais brasileiros de dermatologia, 90(1), 62-73. Available online at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323700/

(2) Horger, M., Fierlbeck, G., Kuemmerle-Deschner, J., Tzaribachev, N., Wehrmann, M., Claussen, C. D., & Fritz, J. (2008). MRI findings in deep and generalized morphea (localized scleroderma). American Journal of Roentgenology, 190(1), 32-39. Available online at https://www.ajronline.org/doi/pdf/10.2214/AJR.07.2163

(3) Dilia, G., Michele, C., Emanuele, C., Amelia, S., Federica, L., & Clodoveo, F. (2018). From localized scleroderma to systemic sclerosis: coexistence or possible evolution. Dermatology research and practice, 2018. Available online at https://www.hindawi.com/journals/drp/2018/1284687/

(4) Vlachoyiannopoulos, D. P. G. (2001). Systemic sclerosis (scleroderma). liver, 2, 3. Available online at https://www.orpha.net/data/patho/GB/uk-SSc.pdf

(5) Rodríguez-Franco, K., Miranda-Díaz, A. J., Hoyos-Restrepo, J. D., & Meléndez, G. L. (2018). Systemic scleroderma: An approach from plastic surgery. Revista de la Facultad de Medicina, 66(2), 237-245. Available online at http://www.scielo.org.co/pdf/rfmun/v66n2/0120-0011-rfmun-66-02-00237.pdf

(6) Denton, C. P., & Khanna, D. (2017). Systemic sclerosis. The Lancet, 390(10103), 1685-1699. Available online at https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(17)30933-9.pdf

(7) Wigley, F. M., & Flavahan, N. A. (2016). Raynaud’s phenomenon. New England Journal of Medicine, 375(6), 556-565. Available online at https://www.mfprac.com/web2018/07literature/literature/Rheumatology/RaynaudsPhenomenon_Wigley.pdf

(8) Braun-Moscovici, Y., Brun, R., & Braun, M. (2016). Systemic Sclerosis and the Gastrointestinal Tract—Clinical Approach. Rambam Maimonides medical journal, 7(4). Available online at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101005/

(9) Desai, C. S., Lee, D. C., & Shah, S. J. (2011). Systemic sclerosis and the heart: current diagnosis and management. Current opinion in rheumatology, 23(6), 545. Available online at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678364/