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Scleroderma

Scleroderma

Scleroderma (systemic sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor) is an autoimmune condition characterized by diffuse collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology deposition and fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans. The clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor varies from limited skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions involvement to diffuse involvement of internal organs. Diagnosis is established by a combination of physical findings and serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus. There is no curative treatment. Management options are limited and include immunosuppressive medications as well as specific organ- or symptom-directed drugs. The overall 5-year survival of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with scleroderma is about 80%.

Last updated: 2 Feb, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Contents

Overview

Definition

Scleroderma, also known as systemic sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor (SS), is an autoimmune disorder Autoimmune Disorder Septic Arthritis in which there is progressive deposition of collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology in the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions and internal organs causing tightening and fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans.

Epidemiology

  • Women are 5 times more likely to be affected than men.
  • Women more likely to present:
    • Younger
    • With limited disease
    • With pulmonary hypertension Pulmonary Hypertension Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure, which can lead to chronic progressive right heart failure. Pulmonary hypertension is grouped into 5 categories based on etiology, which include primary PAH, and PH due to cardiac disease, lung or hypoxic disease, chronic thromboembolic disease, and multifactorial or unclear etiologies. Pulmonary Hypertension
  • Peak age at presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor: 35–50 years
  • More severe in African American patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship

Etiology

  • Etiology is unknown.
  • Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics likely play a role.
  • Suspected environmental triggers Triggers Hereditary Angioedema (C1 Esterase Inhibitor Deficiency) include:
    • Infectious Infectious Febrile Infant ( cytomegalovirus Cytomegalovirus CMV is a ubiquitous double-stranded DNA virus belonging to the Herpesviridae family. CMV infections can be transmitted in bodily fluids, such as blood, saliva, urine, semen, and breast milk. The initial infection is usually asymptomatic in the immunocompetent host, or it can present with symptoms of mononucleosis. Cytomegalovirus (CMV), herpesvirus, parvovirus)
    • Environmental:
    • Drugs ( bleomycin Bleomycin A complex of related glycopeptide antibiotics from streptomyces verticillus consisting of bleomycin a2 and b2. It inhibits DNA metabolism and is used as an antineoplastic, especially for solid tumors. Antitumor Antibiotics)
    • Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma exposure Exposure ABCDE Assessment

Pathophysiology and Clinical Presentation

Pathophysiology

  • Not completely understood
  • 3 interlinked complex processes are the basis for pathogenesis:
    • Abnormal activation of both humoral and cell immunity → autoimmune disorder Autoimmune Disorder Septic Arthritis
      • Microvascular endothelial injury likely caused by anti-endothelial antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions
      • Perivascular accumulation of T and B lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes: Histology, macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation, and fibroblast precursors
      • Secretion Secretion Coagulation Studies of cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response and growth factors by inflammatory cells
    • Abnormal stimulation of fibroblast activation and proliferation within small arteries Small arteries Arteries: Histology and arterioles Arterioles The smallest divisions of the arteries located between the muscular arteries and the capillaries. Arteries: Histology 
    • Progressive deposition of collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology and other extracellular matrix Extracellular matrix A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. Hypertrophic and Keloid Scars molecules within the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions and internal organs

Clinical variants

  • Diffuse cutaneous SS: 
    • Puffy hands
    • Involves skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions proximal to the knees and elbows (trunk, neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess, and face)
    • Early and extensive involvement of internal organs in the course of the disease
    • Rapid progression with diffuse skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions thickening and lung, renal, and cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) involvement
  • Limited cutaneous SS:
    • Puffy fingers distal to metacarpophalangeal joints Metacarpophalangeal joints The articulation between a metacarpal bone and a phalanx. Examination of the Upper Limbs
    • Limited to skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions distal to elbows and knees
    • Prominent vascular symptoms:
      • Raynaud’s phenomenon
      • Telangiectasias Telangiectasias Ataxia-telangiectasia
      • Pulmonary arterial hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension ( PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration; late symptom)
    • Also referred to as CREST syndrome:
      • Calcinosis
      • Raynaud’s phenomenon
      • Esophageal dysmotility 
      • Sclerodactyly (tight skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions over digits)
      • Telangiectasias 
  • SS sine scleroderma (rare):
    • No detectable skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions involvement
    • Raynaud’s phenomenon, digital ulcers, and PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration
  • SS with overlap syndrome:
    • Symptoms of any of the other subsets
    • Overlap with other rheumatologic diseases:
      • Lupus
      • Rheumatoid arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis
      • Polymyositis Polymyositis Polymyositis (PM) is an autoimmune inflammatory myopathy caused by T cell-mediated muscle injury. The etiology of PM is unclear, but there are several genetic and environmental associations. Polymyositis is most common in middle-aged women and rarely affects children. Polymyositis
      • Sjögren’s syndrome

Clinical symptoms

Diffuse and limited cutaneous SS:

  • Constitutional symptoms Constitutional Symptoms Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis:
    • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
    • Weight loss Weight loss Decrease in existing body weight. Bariatric Surgery 
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions:
    • Swelling Swelling Inflammation with non- pitting edema Pitting edema Edema caused by excess fluid without excess colloid. Leaves “pits” due to fluid displacement when pressure is applied to the area Edema
    • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions thickening/tightening:
      • Sclerodactyly 
      • Perioral skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions → reduced mouth opening
      • Around small joints → contractures Contractures Prolonged shortening of the muscle or other soft tissue around a joint, preventing movement of the joint. Wound Healing
    • Hyper-/ hypopigmentation Hypopigmentation A condition caused by a deficiency or a loss of melanin pigmentation in the epidermis, also known as hypomelanosis. Hypopigmentation can be localized or generalized, and may result from genetic defects, trauma, inflammation, or infections. Malassezia Fungi
    • Pruritus Pruritus An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. Atopic Dermatitis (Eczema)
  • Hands:
    • Prolonged Raynaud’s phenomenon
    • Calcinosis cutis ( calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes deposition under the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions → hard bumps)
    • Digital ulceration Ulceration Corneal Abrasions, Erosion, and Ulcers
    • Gangrene Gangrene Death and putrefaction of tissue usually due to a loss of blood supply. Small Bowel Obstruction
    • Nail bed Nail bed Skin: Structure and Functions telangiectasia Telangiectasia Permanent dilation of preexisting blood vessels creating small focal red lesions, most commonly in the skin or mucous membranes. It is characterized by the prominence of skin blood vessels, such as vascular spiders. Chronic Venous Insufficiency

Diffuse forms with or without cutaneous involvement Cutaneous involvement Coccidioides/Coccidioidomycosis:

  • Gastrointestinal (90%):
    • Dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming “stuck.” Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia
    • Gastroesophageal reflux disease Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease (GERD)
    • Hoarseness Hoarseness An unnaturally deep or rough quality of voice. Parapharyngeal Abscess
    • Malabsorption Malabsorption General term for a group of malnutrition syndromes caused by failure of normal intestinal absorption of nutrients. Malabsorption and Maldigestion
    • Vascular ectasia → watermelon stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach: Anatomy
  • Pulmonary (80%):
    • Interstitial lung disease ( ILD ILD Interstitial lung diseases are a heterogeneous group of disorders characterized by the inflammation and fibrosis of lung parenchyma, especially the pulmonary connective tissue in the alveolar walls. It may be idiopathic (e.g., idiopathic pulmonary fibrosis) or secondary to connective tissue diseases, medications, malignancies, occupational exposure, or allergens. Interstitial Lung Diseases) → pulmonary fibrosis Pulmonary Fibrosis Idiopathic pulmonary fibrosis is a specific entity of the major idiopathic interstitial pneumonia classification of interstitial lung diseases. As implied by the name, the exact causes are poorly understood. Patients often present in the moderate to advanced stage with progressive dyspnea and nonproductive cough. Pulmonary Fibrosis
    • Pulmonary arterial hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension 
    • Pulmonary embolism Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. Pulmonary Embolism
  • Cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR):
    • Restrictive cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Cardiomyopathy: Overview and Types
    • Constrictive pericarditis Pericarditis Pericarditis is an inflammation of the pericardium, often with fluid accumulation. It can be caused by infection (often viral), myocardial infarction, drugs, malignancies, metabolic disorders, autoimmune disorders, or trauma. Acute, subacute, and chronic forms exist. Pericarditis
    • Arrhythmias 
  • Genitourinary:
    • Dyspareunia Dyspareunia Recurrent genital pain occurring during, before, or after sexual intercourse in either the male or the female. Primary Ovarian Insufficiency
    • Erectile dysfunction Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Erectile Dysfunction
  • Renal:
    • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
    • Chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease
    • Scleroderma renal crisis:
      • Life-threatening acute renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome
      • Malignant hypertension Malignant Hypertension Hypertensive Retinopathy
  • Musculoskeletal:
  • Neuromuscular:
  • Face of a 9-year old with scleroderma

    Perioral skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions tightening of scleroderma
    The patient is unable to close her lips Lips The lips are the soft and movable most external parts of the oral cavity. The blood supply of the lips originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy.

    Image: “Face of a 9 year-old girl with systemic sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor” by Service of Immunology and Rheumatology, Hospital de Pediatría Prof, Dr, Juan P, Garrahan, Combate de los LOS Neisseria Pozos 1881, (1245) Buenos Aires, Argentina. License: CC BY 2.0
  • Clinical presentation of scleroderma

    Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions changes noted in SS
    a and b: widespread reticulate hyperpigmentation Hyperpigmentation Excessive pigmentation of the skin, usually as a result of increased epidermal or dermal melanin pigmentation, hypermelanosis. Hyperpigmentation can be localized or generalized. The condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. Malassezia Fungi over the trunk and extremities with discrete erythematous indurated plaques over the chest wall Chest wall The chest wall consists of skin, fat, muscles, bones, and cartilage. The bony structure of the chest wall is composed of the ribs, sternum, and thoracic vertebrae. The chest wall serves as armor for the vital intrathoracic organs and provides the stability necessary for the movement of the shoulders and arms. Chest Wall: Anatomy and anterior abdomen
    c: sclerodactyly with cool periphery of all fingers

    Image: “Clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor” by Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Prannok Rd, Bangkoknoi, Bangkok, 10700, Thailand. License: CC BY 4.0
  • Gangrenous fingertips in scleroderma

    Hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand: Anatomy of a scleroderma patient (tight, shiny appearance of the palmar skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions)
    The fingertips have become gangrenous secondary to ischemia Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage because of arterial vasoconstriction Vasoconstriction The physiological narrowing of blood vessels by contraction of the vascular smooth muscle. Vascular Resistance, Flow, and Mean Arterial Pressure (Raynaud’s phenomenon).

    Image: “22312” by CDC/Dr. Sellers, Grady Hospital. License: Public Domain

Related videos

3:27
Scleroderma

Diagnosis

Physical exam

  • 1st step in evaluation
  • Look for characteristic skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions and hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand: Anatomy changes.

Laboratory studies

  • General:
    • Complete blood count ( anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types):
      • Malabsorption Malabsorption General term for a group of malnutrition syndromes caused by failure of normal intestinal absorption of nutrients. Malabsorption and Maldigestion
      • Iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements deficiency
      • GI blood loss
    • Creatine Creatine An amino acid that occurs in vertebrate tissues and in urine. In muscle tissue, creatine generally occurs as phosphocreatine. Creatine is excreted as creatinine in the urine. Acute Kidney Injury kinase: myopathy Myopathy Dermatomyositis/myositis
    • Urinalysis Urinalysis Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. Urinary Tract Infections (UTIs) in Children to assess kidney function:
    • Serum creatinine
  • Serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus:
    • Antinuclear antibody (ANA): present in 95% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
    • Anti-centromere antibody: specific for limited SS
    • Anti-topoisomerase (anti-Scl 70): 
      • Specific for diffuse SS
      • Associated with interstitial lung disease
    • Anti- RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure polymerase III:
      • Specific for diffuse SS
      • Associated with rapidly progressive skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions involvement and scleroderma renal crisis

Additional tests

  • Pulmonary function test Pulmonary function test Pulmonary function tests are a group of diagnostic procedures yielding useful, quantifiable information about the rate of the flow of air through the individual’s airways, lung capacity, and the efficiency of gas exchange in relation to time. The most commonly utilized tests include spirometry (before and after bronchodilator use), lung volumes, and quantitation of diffusing capacity for carbon monoxide (CO). The tests can be influenced by the individual’s effort/fatigue, disease state, or anatomical malformation. Pulmonary Function Tests (PFT):
    • Restrictive ventilatory defect
    • Decrease in single-breath diffusion Diffusion The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space. Diffusion, especially facilitated diffusion, is a major mechanism of biological transport. Peritoneal Dialysis and Hemodialysis capacity for carbon monoxide Carbon monoxide Carbon monoxide (CO). A poisonous colorless, odorless, tasteless gas. It combines with hemoglobin to form carboxyhemoglobin, which has no oxygen carrying capacity. The resultant oxygen deprivation causes headache, dizziness, decreased pulse and respiratory rates, unconsciousness, and death. Carbon Monoxide Poisoning
  • High-resolution chest computed tomography Chest Computed Tomography Hemothorax (CT) scan: interstitial lung abnormalities
  • Echocardiogram Echocardiogram Transposition of the Great Vessels: screening Screening Preoperative Care for PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration
  • Other studies depending on a particular organ involvement
Scleroderma ct

Chest CT scan showing lung fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans at the time of diagnosis of progressive systemic sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor

Image: “ Chest computed tomography Chest Computed Tomography Hemothorax scan” by Division of Respiratory Medicine, Mito Medical Center, University of Tsukuba, Mito, Ibaraki 310-0015, Japan. License: CC BY 3.0

Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma

  • Rarely indicated
  • Can be performed to differentiate from other diseases (e.g., eosinophilic fasciitis, scleromyxedema, amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis)

Related videos

1:56
Scleroderma
9:13
Scleroderma: Limited vs. Diffuse

Management

There is no curative treatment for SS.

Management goals

  • Minimize symptoms.
  • Delay the progression of organ-specific complications.

Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions

  • Pruritus Pruritus An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. Atopic Dermatitis (Eczema):
    • Prevent dryness (lubricating lotions; avoid drying soaps, heat Heat Inflammation).
    • Antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines
    • Low-dose prednisone Prednisone A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. Immunosuppressants
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor:
    • 1st line: methotrexate Methotrexate An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. Antimetabolite Chemotherapy or mycophenolate Mycophenolate Immunosuppressants mofetil
    • 2nd line: cyclophosphamide Cyclophosphamide Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It has been used in the treatment of lymphoma and leukemia. Its side effect, alopecia, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. Immunosuppressants
    • For refractory cases: immune globulin or rituximab Rituximab A murine-derived monoclonal antibody and antineoplastic agent that binds specifically to the cd20 antigen and is used in the treatment of leukemia; lymphoma and rheumatoid arthritis. Immunosuppressants
    • Ultraviolet A light therapy also beneficial
  • Cutaneous calcinosis:
    • Oral minocycline Minocycline A tetracycline analog, having a 7-dimethylamino and lacking the 5 methyl and hydroxyl groups, which is effective against tetracycline-resistant staphylococcus infections. Tetracyclines
    • Surgical removal of lesions in some cases
  • Telangiectasia Telangiectasia Permanent dilation of preexisting blood vessels creating small focal red lesions, most commonly in the skin or mucous membranes. It is characterized by the prominence of skin blood vessels, such as vascular spiders. Chronic Venous Insufficiency: laser therapy Laser Therapy The use of photothermal effects of lasers to coagulate, incise, vaporize, resect, dissect, or resurface tissue. Glaucoma

Other organs

  • Kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy:
    • Angiotensin-converting inhibitors
    • Avoid glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids.
  • Esophageal reflux: H2 blockers or proton- pump Pump ACES and RUSH: Resuscitation Ultrasound Protocols inhibitors
  • Raynaud’s phenomenon: 
    • Avoid cold.
    • Calcium-channel blockers Calcium-Channel Blockers A class of drugs that act by selective inhibition of calcium influx through cellular membranes. Heart Failure and Angina Medication
    • Prostacyclin Prostacyclin A prostaglandin that is a powerful vasodilator and inhibits platelet aggregation. It is biosynthesized enzymatically from prostaglandin endoperoxides in human vascular tissue. The sodium salt has been also used to treat primary pulmonary hypertension. Eicosanoids analogs
  • Pulmonary hypertension Pulmonary Hypertension Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure, which can lead to chronic progressive right heart failure. Pulmonary hypertension is grouped into 5 categories based on etiology, which include primary PAH, and PH due to cardiac disease, lung or hypoxic disease, chronic thromboembolic disease, and multifactorial or unclear etiologies. Pulmonary Hypertension: 
    • Endothelin receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors antagonist ( bosentan Bosentan Pulmonary Hypertension Drugs)
    • Phosphodiesterase inhibitors Phosphodiesterase inhibitors Phosphodiesterase (PDE) inhibitors are a group of drugs that act by inhibiting PDE enzymes. Phosphodiesterase inhibitors have various mechanisms of action depending on the subtype of PDE targeted, but their main action is increasing the amount of intracellular cAMP or cGMP, which in turn results in physiologic effects such as reducing inflammation, promoting smooth muscle relaxation, and vasodilation. Phosphodiesterase Inhibitors ( tadalafil Tadalafil A carboline derivative and phosphodiesterase 5 inhibitor that is used primarily to treat erectile dysfunction; benign prostatic hyperplasia and primary pulmonary hypertension. Phosphodiesterase Inhibitors)
    • Prostacyclin Prostacyclin A prostaglandin that is a powerful vasodilator and inhibits platelet aggregation. It is biosynthesized enzymatically from prostaglandin endoperoxides in human vascular tissue. The sodium salt has been also used to treat primary pulmonary hypertension. Eicosanoids pathway agonists ( epoprostenol Epoprostenol A prostaglandin that is a powerful vasodilator and inhibits platelet aggregation. It is biosynthesized enzymatically from prostaglandin endoperoxides in human vascular tissue. The sodium salt has been also used to treat primary pulmonary hypertension. Hemostasis)
  • Pulmonary fibrosis Pulmonary Fibrosis Idiopathic pulmonary fibrosis is a specific entity of the major idiopathic interstitial pneumonia classification of interstitial lung diseases. As implied by the name, the exact causes are poorly understood. Patients often present in the moderate to advanced stage with progressive dyspnea and nonproductive cough. Pulmonary Fibrosis: 
    • Mycophenolate Mycophenolate Immunosuppressants mofetil
    • Cyclophosphamide Cyclophosphamide Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It has been used in the treatment of lymphoma and leukemia. Its side effect, alopecia, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. Immunosuppressants

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

  • Overall 5-year survival is 80%.
  • Mortality Mortality All deaths reported in a given population. Measures of Health Status in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with scleroderma is 4 times higher than in sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria– and age-matched controls.
  • Major predictors of mortality Mortality All deaths reported in a given population. Measures of Health Status:
    • Extensive skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions involvement
    • Lung or cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) disease
    • Renal disease
    • Younger age of onset
    • African descent

Differential Diagnosis

  • Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto’s disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism: a disorder associated with decreased production of thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview and Types. One manifestation is myxedema Myxedema A condition characterized by a dry, waxy type of swelling (edema) with abnormal deposits of mucopolysaccharides in the skin and other tissues. It is caused by a deficiency of thyroid hormones. The skin becomes puffy around the eyes and on the cheeks. The face is dull and expressionless with thickened nose and lips. Edema, which produces skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions changes similar to SS with coarseness and thickening. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship also complain of fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia. Diagnosed by measuring thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy hormone and thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy-stimulating hormone levels. The treatment is based on thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy hormone replacement.
  • Diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus: an endocrine disorder caused by insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin deficiency or insulin resistance Insulin resistance Diminished effectiveness of insulin in lowering blood sugar levels: requiring the use of 200 units or more of insulin per day to prevent hyperglycemia or ketosis. Diabetes Mellitus. Long-standing diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus type 1 Type 1 Spinal Muscular Atrophy may be associated with skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions changes and sclerodactyly. Diagnosis is established by measurement of blood glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance levels. Treatment is focused on insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin replacement and blood glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance control.
  • Amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis: a disorder of extracellular tissue deposition of fibrils. Infiltration of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions can cause thickness and systemic deposition can result in symptoms very similar to those of diffuse scleroderma. Diagnosis is established by skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma. Treatment modalities depend on the type of amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis.
  • Chronic graft-versus-host disease Graft-versus-host disease The clinical entity characterized by anorexia, diarrhea, loss of hair, leukopenia, thrombocytopenia, growth retardation, and eventual death brought about by the graft vs host reaction. Transfusion Reactions: a disorder that typically follows allogeneic hematopoietic transplantation. Can be associated with scleroderma-like skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions changes. Diagnosis is established by skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma. Treatment involves steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors and immunosuppressive medications.

References

  1. Denton C.P. (2020). Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults. Retrieved January 28, 2021, from https://www.uptodate.com/contents/overview-of-the-treatment-and-prognosis-of-systemic-sclerosis-scleroderma-in-adults
  2. Denton C.P. (2019). Pathogenesis of systemic sclerosis (scleroderma). Retrieved January 28, 2021, from https://www.uptodate.com/contents/pathogenesis-of-systemic-sclerosis-scleroderma
  3. 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. Epub 2018 Sep 14. 
  4. Jimenez S.A. (2020). Scleroderma. Retrieved January 28, 2021, from https://emedicine.medscape.com/article/331864-overview
  5. Varga J. (2020). Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults. Retrieved January 28, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-systemic-sclerosis-scleroderma-in-adults
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