sclrodermae

Systemic Scleroderma
Definition and etiology
Scleroderma, or systemic sclerosis (SSc), is a chronic multisystem autoimmune disease characterized by a vasculopathy, diffuse fibrosis of skin and various internal organs, and immune abnormalities. The clinical manifestations of this disease are extremely heterogeneous and depend on the presence and degree of various internal organ involvement
Classification
There are two major forms of scleroderma, localized scleroderma and systemic scleroderma (sclerosis). Diffuse (dcSSc) and limited (lcSSc) scleroderma are the two main types of systemic sclerosis
Localized Scleroderma
The more common form of the disease, localized scleroderma, only affects the skin without any internal organ involvement. It often appears in the form of waxy patches (morphea, Localized scleroderma can be disfiguring and sometimes requires systemic therapy to control disease activity.
Localized Scleroderma (Localized cutaneous fibrosis)
• Limited or generalized morphea: Circumscribed patches of sclerosis
• Linear scleroderma: Linear lesions seen in childhood
• En coup de sabre: Linear lesions of the scalp or face
Systemic Scleroderma (Cutaneous and noncutaneous involvement)
• Limited cutaneous systemic sclerosis (lcSSc), formerly called CREST syndrome (calcinosis of the digits, Raynaud s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias)
• Diffuse cutaneous systemic sclerosis (dcSSc): Sclerosis of proximal extremities, trunk, and face
• Systemic sclerosis sine scleroderma (ssSSc): Organ fibrosis only; no skin thickening
In limited disease (formerly called CREST [calcinosis, Raynaud s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias] syndrome), skin tightening is confined to the fingers, hands, and forearms distal to the elbows, with or without tightening of skin of the feet and of the legs distal to the knees. Proximal extremities and the trunk are not involved. In diffuse disease or diffuse cutaneous systemic sclerosis (dcSSc), the skin of the proximal extremities and trunk is also involved. Both dcSSc and lcSSc are associated with internal organ involvement; however, patients with dcSSc are at greater risk for clinically significant major organ dysfunction

Diffuse Cutaneous Systemic Sclerosis (dcSSc)
• Onset of Raynaud s within 1 year of onset of skin changes (puffy or hidebound skin)
• Truncal and acral skin involvement
• Presence of tendon friction rubs
• Early and significant incidence of interstitial lung disease, oliguric renal failure, diffuse gastrointestinal disease, and myocardial involvement
• Absence of anticentromere antibodies
• Nailfold capillary dilation and capillary destruction
• Antitopoisomerase antibodies (30% of patients)
Limited Cutaneous Systemic Sclerosis (LcSSc)
• Raynaud s phenomenon for years (occasionally decades)
• Skin involvement limited to hands, face, feet, and forearms (acral) or absent
• A significant late incidence of pulmonary hypertension, with or without interstitial lung disease, trigeminal neuralgia, skin calcifications, telangiectasias
• A high incidence of anticentromere antibodies (70%-80%)
• Dilated nailfold capillary loops, usually without capillary dropout
Epidemiology
Systemic scleroderma is a rare disorder, with an annual incidence in the United States of about 20 cases per 1 million adults. Several studies have estimated the prevalence of systemic sclerosis in the United States to be around 240 cases per 1 million adul
Age- and gender-adjusted mortality rates for patients with dcSSc are approximately five to eight times greater than those of the general population
Survival, which is strongly dependent on the degree of internal organ involvement, has improved over the past few decades due to the advent of newer classes of drugs. The average 10-year survival rate is now 70% to 80%
Diffuse disease has a variable disease course, but it still carries a relatively poor prognosis
Progressive pulmonary fibrosis, pulmonary hypertension, severe gastrointestinal involvement, and scleroderma heart disease are the main causes of death. Limited disease has a relatively better prognosis except when pulmonary hypertension develops as a late complication.
Pathophysiology and pathogenesis
Scleroderma is characterized by immune system activation, endothelial dysfunction, and enhanced fibroblast activity, The earliest stage in the development of the scleroderma lesion is endothelial cell activation and vascular damage, the precise inciting events of which are unknown
The endothelium contributes to the regulation of the contraction and relaxation of vascular smooth muscle cells through the production and release of endothelium-derived vasoactive substances including prostacyclin (prostaglandin]
Vascular injury occurs before clinically evident fibrosis, platelet-derived growth factor (PDGF) and the beta chemokines monocyte chemoattractant protein (MCP)-1 and MCP-3. There may be a sequential interplay between these growth factors as the disease develops
Major Clinical Manifestations of Systemic Sclerosis
Cutaneous
• Diffuse edema of hands and feet (early stages)
• Progressive skin tightening
• Sclerodactyly
• Calcinosis
• Telangiectasias
• Digital ulcers and pits
• Contractures
• Hyperpigmentation, hypopigmentation, salt and pepper skin
• Characteristic facies
Vascular
• Raynaud s phenomenon
• Nailfold capillary changes
• Digital ischemia and ulcers
• Vasculitic leg ulcers (rare)
Pulmonary
• Interstitial lung disease, including alveolitis and interstitial fibrosis
• Pulmonary hypertension
• Recurrent aspiration pneumonitis caused by esophageal reflux and dysmotility
• Chest wall restriction (decreased thoracic compliance)
• Respiratory muscle weakness
Cardiac
• Cardiomyopathy (systolic and diastolic dysfunction): Congestive heart failure
• Conduction defects
Musculoskeletal and Rheumatologic
• Arthralgia
• Tendon friction rubs (relatively specific for diffuse scleroderma)
• Inflammatory arthritis, erosive arthropathy (rare)
• Myopathy, myositis
Renal
• Scleroderma renal crisis (hypertension, renal failure MAHA
Gastrointestinal
• Gastroesophageal reflux
• Esophageal dysmotility, aperistaltic esophagus
• Esophageal stricture
• Adenocarcinoma arising in Barrett s esophagus (occasionally)
• Watermelon stomach (gastric antral vascular ectasias [GAVE]): Iron-deficiency anemia
• Decreased peristalsis throughout the GI tract, leading to bloating, early satiety, stasis, and pseudo-obstruction
• Bacterial overgrowth and malabsorptive diarrhea, alternating diarrhea and constipation
• Megacolon (rare)
Endocrine
• Hypothyroidism
Neurologic
• Carpal tunnel syndrome
• Trigeminal neuralgia
Raynaud s phenomenon is present in most patients with systemic sclerosis and is often the earliest manifestation of disease
Diagnosis
American College of Rheumatology Diagnostic Criteria for Systemic Sclerosis
Major Criterion
• Proximal sclerodermatous skin changes (proximal to the metacarpophalangeal joints)
Minor Criteria*

• Sclerodactyly
• Digital pitting scars of fingertips or loss of substance of the distal finger pads
• Bibasilar pulmonary fibrosis
A complete blood count, complete metabolic panel, muscle enzymes, thyroid function test, and urinalysis are indicated in all patients. Serologic testing for autoantibodies can be helpful in diagnosing and classifying PSS
Once the diagnosis has been established, the clinician must determine whether the disease is diffuse or limited, based on the extent of skin tightening. The initial evaluation on the physical examination should include a skin score
endoscopy and esophageal manometry (although in practice these invasive studies are often not routinely performed unless there is a reason to suspect esophageal stricture, Barrett s esophagus, or adenocarcinoma). Pulmonary function studies, including spirometry for forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLCO), may suggest the presence of interstitial lung disease (ILD), when both FVC and DLCO are reduced. Chest radiography and high-resolution computed tomography of the chest may suggest the presence of ILD and help differentiate active alveolitis (ground-glass opacification) from established pulmonary fibrosis (coarse reticulation and honeycombing)

Differential Diagnosis of Systemic Sclerosis
Mixed connective tissue disease
Graft-versus-host disease
Nephrogenic systemic fibrosis (formerly known as nephrogenic fibrosing dermopathy)
Diabetic scleredema
Diffuse fasciitis with eosinophilia (Shulman s syndrome)
Toxic oil syndrome
Eosinophilia-myalgia syndrome
Lichen sclerosus et atrophicus
Sclerodermiform acrodermatitis chronica atrophicans (Lyme disease)
Scleromyxedema (lichen myxedematosus) associated with paraproteinemia
Drugs and toxins (l-tryptophan, bleomycin, pentazocine, carbidopa, vinyl chloride, silica)

Treatment
person with scleroderma can take many steps to better manage the disease.
Exercise
Regular exercise not only helps improve overall physical and spiritual well-being but it also helps keep the joints flexible and improves circulation
Skin Protection
Taking proper precautions and care of the skin can be beneficial for symptoms of Raynaud s phenomenon and for the dry, thick patches of skin that result from localized scleroderma. During the colder months, patients should dress appropriately. Keeping the body warm and protected from the cold weather with a hat, gloves
Diet
Aside from eating healthy foods to get the proper amounts of vitamins and nutrients, it is important to eat foods that do not aggravate existing stomach problems. Patients should avoid excess alcohol use, smoking, and foods that cause heartburn. Water or another liquid helps soften food further. High-fiber foods decrease constipation
Dental Care
For patients with scleroderma who also have Sj?gren s syndrome, proper dental care is essential. Sj?gren s syndrome increases the risk of developing cavities and tooth decay.

Assessment of disease activity and treatment
Institution of therapy is predicated on proper assessment of disease activity and organ involvement. The extent of skin thickening is useful for assessing overall disease activity, disease subset (lcSSc or dcSSc), prognosis, and risk of internal organ involvement
Patients with Raynaud s phenomenon are advised to stop smoking, avoid cold exposure, wear warm clothing and gloves, and avoid vasoconstrictive substances (clonidine, sympathomimetics, cocaine, ergot alkaloids). Various pharmacologic agents are aimed at reversing digital vasospasm. The dihydropyridine calcium channel blockers (amlodipine and long-acting preparations of nifedipine) are first-line agents, For patients who do not respond to calcium channel blockers, other drugs such as topical nitrates, and ?-adrenergic blockers (such as prazosin or tamsulosin) may be tried.
The role of antiplatelet and anticoagulant therapy is unclear, although in the absence of contraindications, most experts would recommend low dose aspirin to patients with Raynaud s phenomenon. Phosphodiesterase-5 (PDE5) inhibitors like sildenafil, tadalafil or vardenafil, have been found to be particularly useful in ameliorating refractory digital ischemia and ulceration,
Because of its anticollagen and immune-modulating effects, d-penicillamine has been used in patients with dcSSc in an effort to slow skin fibrosis
Cyclophosphamide may be beneficial in patients with interstitial lung disease associated with scleroderma. Multiple uncontrolled studies had suggested that cyclophosphamide mig Methotrexate has been shown to improve skin scores, but the effects were modest. Corticosteroids may be useful in the treatment of myositis and alveolitis, but their use is limited by the observation that high doses can precipitate renal CRASIS
Gastroesophageal reflux usually responds to proton pump inhibitors, and motility disorders are treated with prokinetic agents such as metoclopramide and domperidone
Angiotensin-converting enzyme inhibitors should be used at the first sign of renal crisis (severe hypertension, renal failure, and microangiopathic hemolytic anemia). Their early use is critical in preserving renal function
Hypoxia from pulmonary hypertension is treated with oxygen. Epoprostenol is an intravenous prostacyclin analogue delivered by continuous central infusion
Future directions
The central role of TGF-? in inducing endothelial damage and fibroblast activation has led investigators to target this molecule as a promising site for future therapies. Indeed, anti–TGF-? drugs and other cytokine-based therapies could theoretically provide true disease modification
Although no cure has been found for scleroderma, the disease is often slowly progressive and manageable, and people who have it can lead healthy and productive lives
Summary
• The initial presentation in most scleroderma patients is Raynaud s phenomenon.
• Nailfold capillary microscopy can help differentiate primary Raynaud s phenomenon from that secondary to an underlying connective tissue disease.
• Although not specific, ANA has high sensitivity in scleroderma (60%-80%) and is useful as a screening test.
• Limited and diffuse diseases have different disease courses and prognoses. The nature and extent of organ system involvement also determine the prognosis.
• Therapeutic modalities now include ACE inhibitors for scleroderma renal crisis; parenteral prostanoids, oral endothelin receptor antagonists, and PDE5 inhibitors for pulmonary hypertension; cyclophosphamide for interstitial lung disease in early scleroderma; and octreotide for intestinal pseudo-obstruction