History of Scleroderma

The first account of a person with scleroderma may have been described by Hippocrats when he wrote about an Athenian patient whose skin could not be raised in folds because it was so hard.1 In modern times, the earliest description of the condition is attributed to Carlo Curzio, an Italian doctor, who reported in 1753 the case of a 17-year-old girl with severe skin thickening, particularly involving the neck. The term scleroderma was first coined by the Milanese physician Giovambattista Fantonetti in 1836, with the first cases reported in the United States by physician Abraham B. Arnold in 1869.2 

Scleroderma is an umbrella term for a heterogeneous group of rheumatic disorders; it includes several fibrosing conditions with varying features and management. Derived from the Greek words skleros meaning “hard” and derma for “skin,” scleroderma has skin thickening as the common and defining manifestation.3 It is a chronic connective tissue and autoimmune disorder that has immune dysfunction, vasculopathy, tissue fibrosis, and inflammation as the main underlying pathologic processes. 

Localized scleroderma

When the disease is restricted to the skin, it is called localized scleroderma. On occasion, lesions will be deep enough to affect fascia, muscles, and bone. Depending on the morphology of the skin lesions, localized scleroderma is further classified as4:

  • Circumscribed or plaque morphea. This condition is characterized by a single or a few thickened skin patches or plaques that typically give a hard and shiny appearance. In the early stages, a characteristic purple ring can be seen around the plaque.
  • Generalized morphea. Generalized morphea is defined as patches of skin involvement in more than 2 areas of the body, such as on the trunk, legs, and head. These plaques of thick, tight skin can coalesce.
  • Linear scleroderma. Appearing as a single band of taught, thickened skin affecting the trunk, head, or extremities, this condition most frequently occurs in children and adolescents. It may be referred to as en coup de sabre because of its resemblance to a sabre wound.

Systemic Scleroderma or Sclerosis

When scleroderma involves internal organs as well, it is called systemic sclerosis or systemic scleroderma. Systemic scleroderma can affect almost any organ but particularly impacts the abdominal organs, lungs, and heart, as well as blood vessels, joints, and muscles. It can present as5:

  • Limited scleroderma. With this most frequent form of scleroderma, skin and internal organ involvement is limited. A limited subset of scleroderma patients can show features consistent with the CREST syndrome:
    • Calcinosis: calcium deposits in tissues and skin
    • Raynaud’s phenomenon: fingers and toes numb and discolored when exposed to cold, due to vasospasm; occurs in over 95% of patients with systemic sclerosis3 
    • Esophageal dysmotility: dysfunction of the esophagus leading to acid reflux
    • Sclerodactyly: skin thickening of the fingers
    • Telangiectasias: dilated blood vessels, visible as “spider veins” on the skin
  • Diffuse scleroderma. Diffuse scleroderma is characterized by the involvement of large swathes of skin and extensive organ damage. When vital organs, such as the lungs and heart, become affected, it becomes life threatening.
  • Sine sclerosis. Presenting with systemic features of the disease and involving various organs, but with no skin fibrosis, this form of the condition is called sine sclerosis.

Epidemiology

Globally, the incidence rate of scleroderma ranges from 8 to 56 new cases per 1 million people per year. The United States represents the high side of that range. Incidence rates have been found to be lower in South America and Asia. Concerning prevalence of scleroderma, most estimates indicate 38 to 341 total cases per 1 million globally. Scleroderma is up to 8 to 9 times more common in women than men.6 

Increased awareness and early detection of the disease, improved data capture, and changing classification criteria may account for the differences in incidence and prevalence rates between reports.6

Etiology and Risk Factors

There is no clear-cut cause of scleroderma that has been identified. Its occurrence is attributed to a host of factors ranging from genetic to external. 

The proposed pathogenetic pathway begins with repetitive injury to endothelial and epithelial cells. Chemical mediators released from these injured cells activate local immune and inflammatory processes, including the recruitment of fibroblasts which develop into myofibroblasts. Myofibroblasts in turn start producing excessive collagen and are responsible for the fibrosis.7

This pathogenesis correlates well with an association of scleroderma with a human leukocyte antigen (HLA) complex of genes that are intricately connected with the functioning of the immune system. Nonetheless, links to non-HLA genes have been detected as well. As such, the genetic biomarkers that determine a predisposition to scleroderma have not been fully established.7

The main identified risk factors associated with the development of scleroderma8 are:

  • Age. Risk appears to peak between ages 45 and 64.
  • Sex. Women are clearly more susceptible, with female:male prevalence ratios ranging from 3:1 to 8:1.
  • Geography and ethnicity. The condition is more prevalent in North America and Australia vs Europe or Asia. Among Americans, it is more common in Black individuals than in White individuals.
  • Family history. Positive family history increases risk.
  • Environmental exposure. Environmental or occupational exposure to several substances has been associated with a risk of developing scleroderma. Substances include organic solvents, silica, and heavy metals, including zinc, cadmium, and palladium.
  • Vitamin D. Insufficient vitamin D can be a risk factor.

Prognosis

Internal organ involvement makes systemic scleroderma a life-threatening condition. If unchecked, it can lead to serious complications, such as heart failure, interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), and renal crisis. Cardiopulmonary deterioration and failure are the chief mechanisms of death.

Systemic sclerosis with multi-organ involvement has a pooled standardized mortality ratio of 2.3 to 3.5. From the point of diagnosis, the cumulative survival rate at 5 years is 75%; at 10 years, 62.5%. Compared with their peers, patients have a life expectancy reduced by 16 to 34 years.6 For people with localized scleroderma, life expectancy is normal.

While scleroderma is more common in women, it is associated with increased mortality in men.9 More research into this association is needed due to the relatively small study numbers of male patients. Some established predictors of mortality in scleroderma are6:

  • Old age
  • Male gender
  • Diffuse scleroderma
  • Lung involvement
  • Heart failure
  • Renal crisis

Scleroderma Diagnosis & Presentation

Physical Examination Findings

Because skin involvement makes scleroderma essentially a clinical diagnosis, a thorough and proper physical examination is essential.

In this regard, the classification criteria devised by the combined committee of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR)—the 2013 ACR/EULAR criteria and 2016 update—provide a critical road map.10,11 The criteria provide not only a basis to classify the disease, but also hint at what to look for during the physical examination.

An important element of the physical examination would be to assess the extent, location, and pattern of skin thickening. As described earlier, this would inform whether the patient has circumscribed or generalized morphea, or linear scleroderma. 

Assessing skin thickening of the fingers is particularly significant. If it involves both hands and extends proximal to the metacarpophalangeal joints, this sign alone is sufficient to diagnose scleroderma.10 Thickening of the skin of the fingers and toes, called sclerodactyly, is considered a characteristic sign of scleroderma, with the sclerosed hand and fingers bent inward to give a “claw-like” appearance.3

Examination of the fingers would include checking for fingertip ulcers or pitting scars and eliciting a history of Raynaud’s phenomenon. Abnormal nailfold capillaries and telangiectasias should be checked as well.

Further, any signs and symptoms suggesting involvement of internal organs would point to systemic sclerosis; for example, heartburn, dyspnea, cough, and easy fatigability. Where systemic sclerosis is suspected, the physical examination would look for signs indicating involvement of commonly affected organ systems.

Diagnostic Workup

Laboratory Testing 

  • Complete blood count
  • Liver function tests
  • Renal function tests
  • Urinalysis
  • Electrocardiogram and MRI. Cardiac involvement can predispose to conduction defects and arrhythmias.5
  • Nailfold capillaroscopy. Looks for vascular anomalies, such as angiogenesis, architectural disorganization, giant capillaries, or loss of capillaries.5
  • Screening for antinuclear antibodies. Screens for the main 3 auto-antibodies related to scleroderma: anti-centromere, anti–topoisomerase I (anti-Scl-70), and anti-RNA polymerase III.10
  • NT-proBNP testing. Assesses heart failure.5
  • Esophageal manometry. Assists in the assessment of gastroesophageal reflux disease (GERD).5
  • Diffusing capacity of the lung for carbon monoxide (DLCO) and spirometry. Assesses severity of ILD.5

Imaging Studies

  • Hand x-ray
  • Upper gastrointestinal endoscopy
  • High-resolution computed tomography (HRCT) of the chest. Helps to detect and characterize interstitial changes in ILD.5
  • Transthoracic echocardiography. Measures pulmonary arterial systolic pressure, which if greater than 40 mm Hg at rest points toward PAH

The following tests are useful to monitor disease progression and are advised to be performed yearly:

  • NT-proBNP testing
  • Spirometry and DLCO
  • Transthoracic echocardiography

Differential Diagnosis

Scleroderma is more a syndrome than a disease—a collection of clinical characteristics that can vary highly from person to person. Because of this and the fact that it can affect a wide range of organs giving rise to a multitude of symptoms, it can mimic many other diseases and fibrosing conditions. Furthermore, cutaneous fibrosis is a clinical feature shared by many other medical disorders.1

Several conditions should be kept in mind in the differential diagnosis when evaluating for scleroderma1,3:

  • Sclerederma. A sclerotic skin disease that is more common in women, it causes a nonpitting induration of the skin on the upper and mid-back, chest, neck, face, and arms. In contrast to scleroderma, it does not affect the hands and feet. Raynaud’s phenomenon is absent and it and involvement of internal organs is absent.
  • Scleromyxedema. This condition is a rare primary cutaneous mucinosis. Mucin deposition in the skin gives rise to papules and a characteristic “cobblestone” appearance. It affects the face, neck, trunk, and extremities, including hands and fingers. It can involve internal organs.
  • Eosinophilic fasciitis. Eosinophilic fasciitis has a tendency to involve the trunk and extremities while sparing the hands and feet. The condition causes skin thickening similar to scleroderma. Raynaud phenomenon is absent and systemic complications are rare. A full-thickness skin biopsy is usually diagnostic.
  • Graft-vs-host disease (GVHD). GVHD occurs as a late complication of bone marrow transplantation. It can cause cutaneous fibrosis similar to scleroderma.
  • Nephrogenic systemic fibrosis. Nephrogenic systemic fibrosis is the name given to a condition causing skin fibrosis and systemic organ involvement during end-stage renal disease. It has been linked to the use of gadolinium-based contrast agents. Raynaud’s phenomenon is absent.
  • Diabetic cheiroarthropathy. Diabetic cheiroarthropathy is a complication of uncontrolled diabetes mellitus. Due to its tendency to cause induration and thickening of the skin of the hands and fingers, it may present as pseudoscleroderma. However, nailfold capillaroscopy is normal and there is no Raynaud’s phenomenon.

When encountered with conditions mimicking scleroderma, the following features would point to a diagnosis of scleroderma over other fibrosing conditions12:

  • Typical skin involvement pattern with a predilection for acral regions, ie, extremities and digits; sclerodactyly is a classic sign of scleroderma.
  • Raynaud’s phenomenon occurs in most cases.
  • A particular nailfold capillary pattern as revealed on capillaroscopy.
  • Antibodies typically associated with scleroderma, as described above.
  • A certain pattern of organ involvement, as discussed earlier.

Scleroderma Management

Nonpharmacologic

Since there is no curative treatment for scleroderma, nonpharmacologic therapies aimed at support and rehabilitation of patients have an important role to play. There are many such therapies. Some examples are given below13:

  • Physical therapy/physiotherapy to improve joint flexibility, hand grip strength, and muscle tautness
  • Occupational therapy to enhance functional capacity
  • Nursing support for patients with severe systemic sclerosis who cannot take care of themselves
  • Psychological therapy to promote emotional well-being
  • Nutrition therapy to ensure an adequate diet
  • Oral/dental hygiene therapy to maintain a healthy mouth

Pharmacologic

Pharmacologic therapy in scleroderma is aimed at symptomatic improvement. There is no curative drug therapy for the condition. Under such circumstances, the goals of pharmacotherapy in scleroderma are to3:

  • Address symptoms as they relate to each affected organ
  • Slow disease progression
  • Prevent or delay the onset of complications

In 2016, EULAR presented its guideline recommendations for the treatment of scleroderma based on the updated evidence. Some of the key recommendations are as follows11:

Table 2. Pharmacologic Management of Scleroderma

PathologyPharmacotherapy
Localized sclerodermaTopical corticosteroidsSystemic corticosteroidsMethotrexatePhototherapy
Cutaneous sclerosisMethotrexateCyclophosphamide
Internal organ fibrosisMethotrexateCyclophosphamide
Raynaud’s phenomenonCalcium channel antagonists (dihydropyridine derivatives), such as nifedipinePDE-5 inhibitors, such as sildenafilIloprost
Fingertip lesionsIloprostPDE-5 inhibitors, such as sildenafilEndothelin receptor antagonist, such as bosentan
Pulmonary arterial hypertensionEndothelin receptor antagonist, such as bosentanPDE -5 inhibitors, such as sildenafilRiociguat
Scleroderma renal crisisACE inhibitors
Gastrointestinal manifestationsProton pump inhibitorsProkinetic agentsAntibiotics, such as quinolones, amoxicillin + clavulanic acid, metronidazole
Inflammatory manifestations, such as arthritis and myositisSystemic corticosteroidsMethotrexate
Potential treatments under investigationTyrosine kinase inhibitors, such as nintedanibTGF‑β inhibitors, such as fresolimumabAnti-interleukin-13, such as tralokinumabHuman CTLA4, such as abataceptCannabinoids

ACE, angiotensin-converting enzyme; CTLA4, cytotoxic T-lymphocyte-associated antigen 4; PDE, phosphodiesterase; TGF, transforming growth factor. 

Monitoring for side effects, adverse effects, drug-drug interactions

Once pharmacotherapy is instituted it needs meticulous monitoring, including via laboratory testing, to keep an eye on medication side effects, adverse effects, and drug-drug interactions. Some key points to consider are3,11,14:

  • Beta-blockers worsen Raynaud’s phenomenon, even if used as eye drops.
  • Glucocorticoids increase the risk of scleroderma renal crisis. Kidney function and blood pressure should be monitored when using glucocorticoids.
  • Bosentan is metabolized by the liver cytochrome enzyme system and is its inducer; hence, drug and food interactions are possible with its use. Of note, sildenafil is metabolized by the same enzyme system and has reduced effectiveness when used with bosentan.
  • Nifedipine, a dihydropyridine calcium channel blocker, is associated with adverse effects such as hypotension, peripheral edema, constipation, and GERD.
  • Adverse effects associated with methotrexate are liver toxicity, teratogenicity, and pancytopenia. A low dose of methotrexate is usually used in scleroderma compared with its use in other inflammatory conditions such as rheumatoid arthritis.

Comorbidities

Scleroderma can be complicated by the presence of comorbidities. Comorbidities add to the morbidity and mortality of scleroderma. Therefore, when managing patients with scleroderma, it is imperative to not only attempt to treat the condition itself but any comorbidity as well.

A wide range of diseases can occur at the same time as scleroderma. Some of the more frequent are diabetes mellitus, dyslipidemia, hypertension, chronic obstructive pulmonary disease (COPD), and heart disease.15
It has been found that depression requiring treatment is more prevalent in patients with diffuse scleroderma compared with rheumatoid arthritis, another common connective tissue and immune disorder.15

Complications

Skin

Complications in scleroderma are directly related to the extent of disease progression and internal organ involvement. An interprofessional and multidisciplinary approach is required to prevent and manage complications. A system-wide summary of notable complications3,5:

  • Esthetic deformity
  • Sclerodactyly of the hands leading to physical disability

Gastrointestinal

  • Limited mouth opening and dryness (microstomia and xerostomia) causing eating and dental hygiene problems
  • Esophageal involvement with difficult or painful swallowing
  • GERD, which can in turn cause esophageal strictures and Barrett’s esophagus
  • Intestinal involvement can cause diarrhea or constipation

Pulmonary

  • Pulmonary arterial hypertension and right heart failure
  • Interstitial lung disease; advanced lung disease may necessitate lung transplantation

Cardiac

  • Heart involvement, such as myocardial fibrosis, coronary disease, heart failure, and valvular complications
  • Conduction defects and arrhythmias

Renal

  • Scleroderma renal crisis

Musculoskeletal

  • Tendinopathy
  • Joint contractures
  • Arthritis

Patient Education

There is no known cure for scleroderma. However, extensive research is ongoing across the globe to find a cure. Current treatments are aimed at relieving symptoms and preventing complications.

The main treatment method is through medications. Patients should know that drug therapy is aimed at relieving symptoms and preventing complications. There are drugs to soften the skin, improve Raynaud’s phenomenon, and address the problems arising from the involvement of internal organs. Other therapies including physiotherapy, occupational therapy, and psychological therapy have an important role to play.

There are several steps that can be taken to improve fitness and well-being:

  • Stopping smoking is important. It will help both Raynaud’s phenomenon and lung health.
  • Avoiding exposure to cold, including washing hands with cold water.
  • Regular exercise will prevent contractures and improve overall fitness.
  • A healthy diet is essential. Smaller meals help with heartburn.
  • Joining a support group can promote emotional well-being.

References

  1. Morgan ND, Hummers LK. Scleroderma mimickers. Curr Treatm Opt Rheumatol. 2016;2(1):69-84. doi:10.1007/s40674-016-0038-7 
  2. Benedek TG, Rodnan GP. The early history and nomenclature of scleroderma and of its differentiation from sclerema neonatorum and scleroedema. Semin Arthritis Rheum. 1982;12(1):52-67. doi: 10.1016/0049-0172(82)90023-3
  3. Odonwodo A, Badri T, Hariz A. Scleroderma. In: StatPearls [Internet]. StatPearls Publishing; August 9, 2021. https://www.ncbi.nlm.nih.gov/books/NBK537335/
  4. Careta MF, Romiti R. Localized scleroderma: clinical spectrum and therapeutic update. An Bras Dermatol. 2015;90(1):62-73. doi:10.1590/abd1806-4841.20152890
  5. Sobolewski P, Maślińska M, Wieczorek M, et al. Systemic sclerosis–multidisciplinary disease: clinical features and treatment. Reumatologia. 2019;57(4):221-233. doi:10.5114/reum.2019.87619
  6. Ingegnoli F, Ughi N, Mihai C. Update on the epidemiology, risk factors, and disease outcomes of systemic sclerosis. Best Pract Res Clin Rheumatol. 2018;32(2):223-240. doi:10.1016/j.berh.2018.08.005
  7. Khanna D, Tashkin DP, Denton CP, Renzoni EA, Desai SR, Varga J. Etiology, risk factors, and biomarkers in systemic sclerosis with interstitial lung disease. Am J Respir Crit Care Med. 2020;201(6):650-660. doi:10.1164/rccm.201903-0563CI
  8. Abbot S, Bossingham D, Proudman S, de Costa C, Ho-Huynh A. Risk factors for the development of systemic sclerosis: a systematic review of the literature. Rheumatol Adv Pract. 2018;2(2):rky041. doi:10.1093/rap/rky041
  9. Freire M, Rivera A, Sopeña B; RESCLE Investigators, Autoimmune Diseases Study Group (GEAS). Clinical and epidemiological differences between men and women with systemic sclerosis: a study in a Spanish systemic sclerosis cohort and literature review. Clin Exp Rheumatol. 2017;35(4)(Suppl 106):89-97. PMID: 28980905
  10. van den Hoogen F, Khanna D, Fransen J, et al. 2013 Classification criteria for systemic sclerosis: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2013;72(11):1747-1755. doi:10.1136/annrheumdis-2013-204424 
  11. Kowal-Bielecka O, Fransen J, Avouac J, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017;76(8):1327-1339. doi:10.1136/annrheumdis-2016-209909
  12. Varjú C, Kumánovics G, Czirják L, Matucci-Cerinic M, Minier T. Sclerodermalike syndromes: great imitators. Clin Dermatol. 2020;38(2):235-249. doi:10.1016/j.clindermatol.2019.10.010
  13. Willems LM, Vriezekolk JE, Schouffoer AA, et al. Effectiveness of nonpharmacologic interventions in systemic sclerosis: a systematic review. Arthritis Care Res (Hoboken). 2015;67(10):1426-1439. doi:10.1002/acr.22595
  14. Lee JJ, Pope JE. Diagnosis and management of systemic sclerosis: a practical approach. Drugs. 2016;76(2):203-213. doi:10.1007/s40265-015-0491-x
  15. Panopoulos S, Tektonidou M, Drosos AA, et al. Prevalence of comorbidities in systemic sclerosis versus rheumatoid arthritis: a comparative, multicenter, matched-cohort study. Arthritis Res Ther. 2018;20(1):267. doi:10.1186/s13075-018-1771-0