Scleroderma

Scleroderma
Morphea
Classification and external resources
ICD-10	L94.0-L94.1, M34
ICD-9	701.0 710.1
MedlinePlus	000429

Scleroderma, also known as systemic sclerosis, is a chronic systemic autoimmune disease characterised by hardening (sclero) of the skin (derma). In the more severe form, it also affects internal organs.^[1][2]

Limited scleroderma involves cutaneous manifestations that mainly affect the hands, arms and face. It was previously called CREST syndrome in reference to the following common manifestations:^[3] calcinosis (the deposition of calcium nodules in the skin), raynaud's phenomenon (exaggerated vasoconstriction in the hands, with fingers undergoing white-blue-red color transitions in the cold), esophageal dysfunction (leading to difficulty swallowing), sclerodactyly (skin thickening on the fingers), and telangiectasias (dilated capillaries on the face, hands and mucous membranes).

Diffuse scleroderma is rapidly progressing and affects a large area of the skin and one or more internal organs, frequently the kidneys, esophagus, heart and/or lungs. This form of scleroderma can be quite disabling. There are no treatments for scleroderma itself, but individual organ system complications are treated.^[4][5]

The prognosis is generally good for limited cutaneous scleroderma persons who escape lung complications, but is worse for those with the diffuse cutaneous disease, particularly in older age and for males. Death occurs most often from lung, heart and kidney complications. In diffuse cutaneous disease, five-year survival is 70% and 10-year survival is 55%.^[6]

The cause of scleroderma is unknown.^[1] It is an autoimmune condition, in which the body's immune system attacks healthy tissues.^[1] Strong associations with certain mutations in the HLA gene have been identified.^[7][8] Strong environment influences have also been implicated in the etiology of scleroderma.^[9][10]

Signs and symptoms

Potential signs and symptoms include:^[2][3][6]

• Cardiovascular: Raynaud's phenomenon (is the presenting symptom in 70% of affected persons, occurs in 95% of affected individuals at some time during their illness); healed pitting ulcers on the fingertips; skin and mucousal telangiectasis; palpitations, irregular heart rate and fainting due to conduction abnormalities, hypertension and congestive heart failure.
• Digestive: gastro-oesophageal reflux disease, bloating, indigestion, loss of appetite, diarrhoea alternating with constipation, sicca syndrome and its complications, loosening of teeth and hoarseness (due to acid reflux).
• Pulmonary: progressive worsening of shortness of breath, chest pain (due to pulmonary artery hypertension) and dry, persistent cough due to interstitial lung disease.
• Musculoskeletal: joint, muscle aches, loss of joint range of motion, carpal tunnel syndrome and muscle weakness.
• Genitourinary: erectile dysfunction, dyspareunia, scleroderma renal crises and kidney failure.
• Other: facial pain due to trigeminal neuralgia, hand paraesthesias, headache, stroke, fatigue, calcinosis and weight loss.

Cause

Scleroderma is caused by genetic and environmental factors.^{[7][8][9][10]} Mutations in the HLA gene seems to play a crucial role in the pathogenesis of some cases (but not all), likewise silica, aromatic and chlorinated solvents, ketones, trichloroethylene, welding fumes and white spirits exposure seems to contribute to the condition in a small proportion of affected persons.^{[7][8][9][10][11]}

Pathophysiology

It is characterised by increased synthesis of collagen (leading to the sclerosis), damage to small blood vessels, activation of T lymphocytes and production of altered connective tissues.^[12] Its proposed pathogenesis is the following:^{[13][14][15][16][17]}

• It begins with an inciting event at the level of the vasculature, probably the endothelium. The inciting event is yet to be elucidated, but may be a viral agent, oxidative stress or autoimmune. Endothelial cell damage and apoptosis ensue, leading to the vascular leakiness that manifests in early clinical stages as tissue oedema. At this stage it is predominantly a Th1 and Th17-mediated disease.
• After this the vasculature is further compromised by impaired angiogenesis and impaired vasculogenesis (fewer endothelial progenitor cells), likely related to the presence of anti-endothelin cell antibodies. Despite this impaired angiogenesis, elevated levels of pro-angiogenic growth factors like PDGF and VEGF is often seen in persons with the condition. The balance of vasodilation and vasoconstriction becomes off-balance and the net result is vasoconstriction. The damaged endothelium then serves as a point of origin for blood clot formation and further contributes to ischaemia-reperfusion injury and the generation of reactive oxygen species. These later stages are characterised by Th2 polarity.
• The damaged endothelium upregulates adhesion molecules and chemokines to attract leucocytes, which enables the development of both innate and adaptive immune responses,including loss of tolerance to various oxidised antigens, which includes topoisomerase I. B cells mature into plasma cells, which furthers the autoimmune component of the condition. T cells differentiate into various subsets, including Th2 cells, which play a vital role in tissue fibrosis. Anti–topoisomerase 1 antibodies, in turn, stimulate type I interferon production.
• Fibroblasts are recruited and activated by multiple cytokines and growth factors to generate myofibroblasts. Dysregulated transforming growth factor β (TGF-β) signalling in fibroblasts and myofibroblasts has been observed in multiple studies of scleroderma-affected individuals. Activation of fibroblasts and myofibroblasts leads to excessive deposition of collagen and other related proteins, leading to fibrosis. B cells are also implicated in this stage, IL-6 and TGF-β produced by the B cells decrease collagen degradation and increase extracellular matrix production. Endothelin signalling is also implicated in the pathophysiology of fibrosis.^[18]

Vitamin D is also implicated in the pathophysiology of the disease, for one an inverse correlation between plasma levels of vitamin D and scleroderma severity has been noted and vitamin D is known to play a crucial role in regulating (usually suppressing) the actions of the immune system.^[19]

Diagnosis

Typical scleroderma is classically defined as symmetrical skin thickening, with about 70% of cases also presenting with Raynaud's phenomenon, nail-fold capillary changes and antinuclear antibodies. Affected individuals may or may not experience systemic organ involvement. There is no single test for scleroderma that works all of the time and hence the diagnosis is often a matter of exclusion. Atypical scleroderma may show any variation of these changes without skin changes or with finger swelling only.^[20]

Laboratory testing can show antitopoisomerase antibodies, like anti-scl70 (causing a diffuse systemic form), or anticentromere antibodies (causing a limited systemic form and the CREST syndrome). Other autoantibodies can be seen, such as anti-U3 or anti-RNA polymerase.^[1]

Differential

Diseases that are often in the differential include:^[21]

• Eosinophilia, a condition in which there are too many eosinophils (a type of immune cell that attacks parasites and is involved in certain allergic reactions) in the blood.
• Eosinophilia-myalgia syndrome, a form of eosinophilia that is caused by L-tryptophan supplements.
• Eosinophilic fasciitis, a disease that affects the connective tissues surrounding skeletal muscles, bones, blood vessels and nerves in the arms and legs.
• Graft-versus-host disease, an autoimmune condition that occurs as a result of bone marrow transplants in which the old marrow attacks the new marrow.
• Mycosis fungoides, a type of cutaneous T cell lymphoma, a rare cancer that causes rashes all over the body.
• Nephrogenic systemic fibrosis, a condition usually caused by kidney failure that causes fibrosis (thickening) of the tissues.
• Primary biliary cirrhosis, an autoimmune disease of the liver.
• Primary pulmonary hypertension
• Complex regional pain syndrome

Classification

Scleroderma is characterised by the appearance of circumscribed or diffuse, hard, smooth, ivory-colored areas that are immobile and which give the appearance of hidebound skin, a disease occurring in both localised and systemic forms:^[22]

Treatment

There is no cure available for scleroderma, although relief of symptoms is often achieved. These include:^[2][23]

• Raynaud's phenomenon with vasodilators such as calcium channel blockers, alpha blockers, serotonin receptor antagonists, angiotensin II receptor inhibitors, statins, local nitrates or iloprost
• Digital ulcers with phosphodiesterase 5 inhibitors (e.g. sildenafil) or iloprost
• Prevention of new digital ulcers with bosentan
• Malnutrition, secondary to intestinal flora overgrowth with tetracycline antibiotics like tetracycline
• Alveolitis with cyclophosphamide, azathioprine with or without corticosteroids
• Pulmonary arterial hypertension with endothelin receptor antagonists, phosphodiesterase 5 inhibitors and prostanoids
• Gastrooesophageal reflux disease with antacids or prokinetics
• Kidney crises with angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists

Systemic disease-modifying treatment with immunosuppressants is also often also used.^{[7][24][25][26][27][28]} Immunosuppressants used in its treatment include: azathioprine, methotrexate, cyclophosphamide, mycophenolate, intravenous immunoglobulin, rituximab, sirolimus, alefacept and the tyrosine kinase inhibitors, imatinib, nilotinib and dasatinib.^{[7][23][24][25][26][27][28][29]} Experimental therapies currently under investigation include endothelin receptor antagonsits, tyrosine kinase inhibitors, beta-glycan peptides, halofuginone, basiliximab, alemtuzumab, abatacept and haematopoietic stem cell transplantation.^[30][31]

Immunomodulatory agents in the treatment of scleroderma
INN	Mechanism of action[32][33]	Route of administration[32]	Pregnancy category[32][34]	Major toxicities[32]
Alefacept	Monoclonal antibody to inhibit T lymphocyte activation by binding to CD2 portion of human leukocyte function antigen-3.	IM	B (US)	Malignancies, injection site reactions, blood clots, lymphopenia, hepatotoxicity and infections.
Azathioprine	Purine analogue that inhibits lymphocyte proliferation via conversion to mercaptopurine	PO, IV	D (Au)	Myelosuppression and rarely: malignancy, hepatitis, infection, hepatic sinusoidal obstruction syndrome and hypersensitivity reactions.
Cyclophosphamide	Nitrogen mustard that cross-links DNA base pairs, leading to breakages and triggering apoptosis in haematopoietic cells.	PO, IV	D (Au)	Vomiting, myelosuppression, haemorrhagic cystitis and rarely: heart failure, pulmonary fibrosis, hepatic sinusoidal obstruction syndrome, malignancy and SIADH.
Dasatinib	Tyrosine kinase inhibitor against various pro-angiogenic growth factors (including PDGF and VEGF).	PO	D (Au)	Fluid retention, myelosuppression, haemorrhage, infections, pulmonary hypertension, electrolyte anomalies and uncommonly: hepatotoxicity, heart dysfunction/failure, myocardial infarction, QT interval prolongation, renal failure and hypersensitivity.
Imatinib	As above.	PO	D (Au)	As above and rarely: GI perforation, avascaular necrosis and rhabdomyolysis.
Immunoglobulin	Immunoglobulin, modulates the immune system.	IV	N/A	Varies.
Methotrexate	Antifolate; inhibits dihydrofolate reductase.	PO, IV, IM, SC, IT	D (Au)	Myeosuppression, pulmonary toxicity, hepatotoxicity, neurotoxicity and rarely: kidney failure, hypersensitivity reactions, skin and bone necrosis and osteoporosis.
Mycophenolate	Inosine monophosphate dehydrogenase inhibitor, leading to reduced purine biosynthesis in lymphocytes.	PO, IV	D (Au)	Myelosuppression, blood clots, less commonly GI perforation/haemorrhage and rarely pancreatitis, hepatitis, aplastic anaemia and pure red cell aplasia.
Nilotinib	As per dasatinib.	PO	D (Au)	As per imatinib.
Rituximab	Monoclonal antibody against CD20 which is expressed on B lymphocytes.	IV	C (Au)	Infusion-related reactions, infection, neutropenia, reduced immunoglobulin levels, arrhythmias, less commonly anaemia, thrombocytopenia, angina, myocardial infarction, heart failure and rarely haemolytic anaemia, aplastic anaemia, serum sickness, severe skin conditions, pulmonary infiltrates, pneumonitis, cranial neuropathy (vision or hearing loss) and progressive multifocal leucoencephalopathy.
Sirolimus	mTOR inhibitor, thereby reducing cytokine-induced lymphocyte proliferation.	PO	C (Au)	Neutropenia, hypokalaemia, interstitial lung disease, pericardial effusion, pleural effusion, less commonly pulmonary haemorrhage, nephrotic syndrome and rarely hepatotoxicity and lymphoedema.
Notes: PO = Oral. IV = Intravenous. IM = Intramuscular. SC = Subcutaneous. IT = Intrathecal. The preferred pregnancy category, above, is Australian, if available. If unavailable an American one is substituted.

Prognosis

The 5-year survival rate for scleroderma is about 85%, whereas the 10-year survival rate is less than 70%.^[35] This varies according to the subtype; for instance, persons with limited skin disease have a 10-year survival rate of 71%, whereas those with diffuse skin disease have a 10-year survival rate of just 21%.^[1] The major causes of death in persons with scleroderma are: pulmonary hypertension, pulmonary fibrosis and scleroderma renal crisis.^[1] People with scleroderma are also at a heightened risk for contracting cancers (especially liver, lung, haematologic and bladder cancers) and, perhaps, cardiovascular disease.^{[36][37][38][39][40]}

Epidemiology

This disease is found worldwide and women are four to nine times more likely to develop scleroderma than men.^[1] In the United States, prevalence is estimated at 240 per million and the annual incidence of scleroderma is 19 per one million.^[1] Likewise in the US it is slightly more common in African Americans than in their white counterparts.^[1] In Germany, on the other hand, the prevalence is 1-15/100,000 and the annual incidence is 0.3-2.8/100,000.^[35] In South Australia the annual incidence is 22.8 per 1 million and the prevalence 233 per 1 million.^[41] It most commonly first presents between the ages of 20 and 50 years, although any age group can be affected and is less common in the Asian population.^[1][2][42]

Pregnancy

Scleroderma in pregnancy is a complex situation; it increases the risk to both mother and child.^[43] Overall scleroderma is associated with reduced fetal weight for gestational age.^[43] The treatment for scleroderma often includes known teratogens such as cyclophosphamide, methotrexate, mycophenolate, etc. and hence careful avoidance of such drugs during pregnancy is advised.^[43] In these cases hydroxychloroquine and low-dose corticosteroids might be used for disease control.^[43]

See also

• List of cutaneous conditions
• Congenital fascial dystrophy

External links

• Handout on Health: Scleroderma - US National Institute of Arthritis and Musculoskeletal and Skin Diseases

References

Diseases of the skin and appendages by morphology Growths Epidermal wart callus seborrheic keratosis acrochordon molluscum contagiosum actinic keratosis squamous-cell carcinoma basal-cell carcinoma Merkel cell carcinoma nevus sebaceous trichoepithelioma Pigmented Freckles lentigo melasma nevus melanoma Dermal and subcutaneous epidermal inclusion cyst hemangioma dermatofibroma (benign fibrous histiocytoma) keloid lipoma neurofibroma xanthoma Kaposi's sarcoma infantile digital fibromatosis granular cell tumor leiomyoma lymphangioma circumscriptum myxoid cyst Rashes With epidermal involvement Eczematous contact dermatitis atopic dermatitis seborrheic dermatitis stasis dermatitis lichen simplex chronicus Darier's disease glucagonoma syndrome langerhans cell histiocytosis lichen sclerosus pemphigus foliaceus Wiskott–Aldrich syndrome Zinc deficiency Scaling psoriasis tinea (corporis cruris pedis manuum faciei) pityriasis rosea secondary syphilis mycosis fungoides systemic lupus erythematosus pityriasis rubra pilaris parapsoriasis ichthyosis Blistering herpes simplex herpes zoster varicella bullous impetigo acute contact dermatitis pemphigus vulgaris bullous pemphigoid dermatitis herpetiformis porphyria cutanea tarda epidermolysis bullosa simplex Papular scabies insect bite reactions lichen planus miliaria keratosis pilaris lichen spinulosus transient acantholytic dermatosis lichen nitidus pityriasis lichenoides et varioliformis acuta Pustular acne vulgaris acne rosacea folliculitis impetigo candidiasis gonococcemia dermatophyte coccidioidomycosis subcorneal pustular dermatosis Hypopigmented tinea versicolor vitiligo pityriasis alba postinflammatory hyperpigmentation tuberous sclerosis idiopathic guttate hypomelanosis leprosy hypopigmented mycosis fungoides Without epidermal involvement Red Blanchable Erythema Generalized drug eruptions viral exanthems toxic erythema systemic lupus erythematosus Localized cellulitis abscess boil erythema nodosum carcinoid syndrome fixed drug eruption Specialized urticaria erythema (multiforme migrans gyratum repens annulare centrifugum ab igne) Nonblanchable Purpura Macular thrombocytopenic purpura actinic/solar purpura Papular disseminated intravascular coagulation vasculitis Indurated scleroderma/morphea granuloma annulare lichen sclerosis et atrophicus necrobiosis lipoidica Miscellaneous disorders Ulcers Hair telogen effluvium androgenic alopecia trichotillomania alopecia areata systemic lupus erythematosus tinea capitis loose anagen syndrome lichen planopilaris folliculitis decalvans acne keloidalis nuchae Nail onychomycosis psoriasis paronychia ingrown nail Mucous membrane Aphthous stomatitis oral candidiasis lichen planus leukoplakia pemphigus vulgaris mucous membrane pemphigoid cicatricial pemphigoid herpesvirus coxsackievirus syphilis systemic histoplasmosis squamous-cell carcinoma Index of skin Description Anatomy Physiology connective tissue Development Disease Infections by morphology Vesiculobullous Dermatitis and eczema factitial Papulosquamous Urticaria and erythema Radiation-related Pigmentation Mucinoses Keratosis, ulcer, atrophy, and necrobiosis Vasculitis Fat Neutrophilic and eosinophilic Congenital Neoplasms and cancer nevi and melanomas epidermis dermis Symptoms and signs eponymous Terminology Treatment Procedures Drugs antibiotics disinfectants emollients and protectives itch psoriasis other Wound and ulcer

Cutaneous keratosis, ulcer, atrophy, and necrobiosis (L82–L94, 700–701.5) Epidermal thickening keratoderma: Keratoderma climactericum Paraneoplastic keratoderma Acrokeratosis paraneoplastica of Bazex Aquagenic keratoderma Drug-induced keratoderma Paraneoplastic keratoderma psoriasis Keratoderma blennorrhagicum keratosis: Seborrheic keratosis Clonal seborrheic keratosis Common seborrheic keratosis Irritated seborrheic keratosis Seborrheic keratosis with squamous atypia Reticulated seborrheic keratosis Dermatosis papulosa nigra Keratosis punctata of the palmar creases other hyperkeratosis: Acanthosis nigricans Confluent and reticulated papillomatosis Callus Ichthyosis acquisita Arsenical keratosis Chronic scar keratosis Hyperkeratosis lenticularis perstans Hydrocarbon keratosis Hyperkeratosis of the nipple and areola Inverted follicular keratosis Lichenoid keratosis Multiple minute digitate hyperkeratosis PUVA keratosis Reactional keratosis Stucco keratosis Thermal keratosis Viral keratosis Warty dyskeratoma Waxy keratosis of childhood other hypertrophy: Keloid Hypertrophic scar Cutis verticis gyrata Necrobiosis/granuloma Necrobiotic/palisading Granuloma annulare Perforating Generalized Subcutaneous Granuloma annulare in HIV disease Localized granuloma annulare Patch-type granuloma annulare Necrobiosis lipoidica Annular elastolytic giant cell granuloma Granuloma multiforme Necrobiotic xanthogranuloma Palisaded neutrophilic and granulomatous dermatitis Rheumatoid nodulosis Interstitial granulomatous dermatitis/Interstitial granulomatous drug reaction Foreign body granuloma Beryllium granuloma Mercury granuloma Silica granuloma Silicone granuloma Zirconium granuloma Soot tattoo Tattoo Carbon stain Other/ungrouped eosinophilic dermatosis Granuloma faciale Dermis/ localized CTD Cutaneous lupus erythematosus chronic: Discoid Panniculitis subacute: Neonatal ungrouped: Chilblain Lupus erythematosus–lichen planus overlap syndrome Tumid Verrucous Rowell's syndrome Scleroderma/ Morphea Localized scleroderma Localized morphea Morphea–lichen sclerosus et atrophicus overlap Generalized morphea Atrophoderma of Pasini and Pierini Pansclerotic morphea Morphea profunda Linear scleroderma Atrophic/ atrophoderma Lichen sclerosus Anetoderma Schweninger–Buzzi anetoderma Jadassohn–Pellizzari anetoderma Atrophoderma of Pasini and Pierini Acrodermatitis chronica atrophicans Semicircular lipoatrophy Follicular atrophoderma Linear atrophoderma of Moulin Perforating Kyrle disease Reactive perforating collagenosis Elastosis perforans serpiginosa Perforating folliculitis Acquired perforating dermatosis Skin ulcer Pyoderma gangrenosum Other Calcinosis cutis Sclerodactyly Poikiloderma vasculare atrophicans Ainhum/Pseudo-ainhum Index of skin Description Anatomy Physiology connective tissue Development Disease Infections by morphology Vesiculobullous Dermatitis and eczema factitial Papulosquamous Urticaria and erythema Radiation-related Pigmentation Mucinoses Keratosis, ulcer, atrophy, and necrobiosis Vasculitis Fat Neutrophilic and eosinophilic Congenital Neoplasms and cancer nevi and melanomas epidermis dermis Symptoms and signs eponymous Terminology Treatment Procedures Drugs antibiotics disinfectants emollients and protectives itch psoriasis other Wound and ulcer

Systemic connective tissue disorders (M32–M36, 710) General Systemic lupus erythematosus Drug-induced SLE Libman-Sacks endocarditis Inflammatory myopathy Myositis Dermatopolymyositis Dermatomyositis/Juvenile dermatomyositis Polymyositis* Inclusion body myositis Scleroderma Systemic scleroderma Progressive systemic sclerosis CREST syndrome Overlap syndrome / Mixed connective tissue disease Other hypersensitivity/autoimmune Sjögren's syndrome Other Behçet's disease Polymyalgia rheumatica Eosinophilic fasciitis Eosinophilia–myalgia syndrome fibrillin Marfan syndrome Congenital contractural arachnodactyly Index of muscle Description Anatomy head neck arms chest and back diaphragm abdomen genital area legs Muscle tissue Physiology connective tissue Disease Myopathy Soft tissue Connective tissue Congenital abdomen muscular dystrophy Neoplasms and cancer Injury Symptoms and signs eponymous Treatment Procedures Drugs anti-inflammatory muscle relaxants