Systemic Sclerosis/Scleroderma: A Treatable Multisystem Disease MONIQUE HINCHCLIFF, MD, and JOHN VARGA, MD Northwestern University, Feinberg School of Medicine, Chicago, Illinois Systemic sclerosis (systemic scleroderma) is a chronic connective tissue disease of unknown etiology that causes wide- spread microvascular damage and excessive deposition of collagen in the skin and internal organs. Raynaud phenome- non and scleroderma (hardening of the skin) are hallmarks of the disease. The typical patient is a young or middle-age woman with a history of Raynaud phenomenon who presents with skin induration and internal organ dysfunction. Clinical evaluation and laboratory testing, along with pulmonary function testing, Doppler echocardiography, and high-resolution computed tomography of the chest, establish the diagnosis and detect visceral involvement. Patients with systemic sclerosis can be classified into two distinct clinical subsets with different patterns of skin and internal organ involvement, autoantibody production, and survival. Prognosis is determined by the degree of internal organ involvement. Although no disease-modifying therapy has been proven effective, complications of systemic sclerosis are treatable, and interventions for organ-specific manifestations have improved substantially. Medications (e.g., cal- cium channel blockers and angiotensin-II receptor blockers for Raynaud phenomenon, appropriate treatments for gastroesophageal reflux disease) and lifestyle modifications can help prevent complications, such as digital ulcers and Barrett esophagus. Endothelin-1 receptor blockers and phosphodiesterase-5 inhibitors improve pulmonary arte- rial hypertension. The risk of renal damage from scleroderma renal crisis can be lessened by early detection, prompt initiation of angiotensin-converting enzyme inhibitor therapy, and avoidance of high-dose corticosteroids. Optimal patient care includes an integrated, multidisciplinary approach to promptly and effectively recognize, evaluate, and manage complications and limit end-organ dysfunction. (Am Fam Physician. 2008;78(8):961-968, 969. Copyright © 2008 American Academy of Family Physicians.) ▲ Patient information: ystemic sclerosis (systemic sclero- Table 1 includes the clinical features of lim- A handout on sclero- derma) is a connective tissue disease ited and diffuse cutaneous systemic sclerosis, derma, written by Uma 3,4 Jayaraman, MD, AFP Edit- associated with autoimmunity, vas- and Table 2 presents the clinical associa- ing Fellow, is provided on culopathy, and fibrosis. The annual tions between subtypes and autoantibodies. page 969. Sincidence is estimated to be 10 to 20 cases per The limited cutaneous subset is diagnosed 1 million persons,1 whereas the prevalence when skin thickening is limited to areas dis- The online version 2 of this article is four to 253 cases per 1 million persons. tal to the elbows and knees. CREST (calcino- includes supple- Raynaud phenomenon and scleroderma sis cutis, Raynaud phenomenon, esophageal mental content at http:// (hardening of the skin) are the clinical hall- dysfunction, sclerodactyly, telangiectasia) www.aafp.org/afp. marks of the disease. Pulmonary fibrosis syndrome is a variant of limited cutane- and pulmonary arterial hypertension are the ous systemic sclerosis. Systemic sclerosis leading causes of death.3 sine scleroderma is a less common subset (approximately 5 percent of patients with Epidemiology and Classification systemic sclerosis) that is associated with the Patients who have systemic sclerosis can be characteristic internal organ manifestations classified into distinct clinical subsets with of the disease without skin thickening. different patterns of skin and internal organ Localized forms of scleroderma, such as involvement, autoantibody production, and linear scleroderma and morphea, primarily patient survival.4 The most common sub- affect children and, in contrast to systemic sets are limited cutaneous (approximately sclerosis, are not associated with Raynaud 60 percent of patients with systemic sclero- phenomenon or significant internal organ sis) and diffuse cutaneous (approximately manifestations. Scleroderma mimics are 35 percent of patients with systemic sclerosis). uncommon conditions that are associated Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright © 2008 American Academy of Family Physicians. For the private, noncommercial use of one individual user of the Web site. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests. SORT: KEy RECOMMENDATIONS FOR PRACTICE Evidence Clinical recommendation rating References Patients with significant internal organ involvement are often asymptomatic until the late stages of systemic C 11, 12 sclerosis; therefore, routine monitoring for underlying disease is essential after the initial diagnosis. Doppler echocardiography, pulmonary function testing, and high-resolution computed tomography of the C 7, 8 chest should be performed at diagnosis of systemic sclerosis and at regular intervals thereafter. Treating active interstitial lung disease with oral cyclophosphamide (Cytoxan) for one year modestly improves B 25, 27 lung function, dyspnea, skin thickening, and health-related quality of life in patients with systemic sclerosis. Initiation and continuation of angiotensin-converting enzyme inhibitors are recommended in patients with B 11, 16 scleroderma renal crisis, even in the presence of elevated creatinine levels. A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease- oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp. org/afpsort.xml. with skin induration, but lack Raynaud phe- Table 1. Distinguishing Clinical Features of Limited nomenon, internal organ involvement, and Cutaneous and Diffuse Cutaneous Systemic Sclerosis autoantibodies. Other diseases, such as mixed or undifferentiated connective tissue disease Feature Limited cutaneous Diffuse cutaneous and overlap syndrome, should be considered before establishing a diagnosis (Table 3 ). Skin fibrosis Areas distal to the elbows Areas proximal or and knees; may affect distal to the elbows the face and knees; may Clinical Presentation affect the face A systemic sclerosis diagnosis is based on Typical form of lung Pulmonary arterial Interstitial lung disease clinical findings, which have substantial het- involvement hypertension erogeneity and varying manifestations. The Characteristic Severe gastroesophageal Scleroderma renal classic clinical presentation is a young or visceral organ reflux disease and crisis involvement Raynaud phenomenon middle-age woman with Raynaud phenome- Physical examination Telangiectasia, calcinosis Tendon friction rubs, non and skin changes accompanied by mus- findings cutis, sclerodactyly, digital pigment changes culoskeletal discomfort and gastrointestinal ischemic complications symptoms. Table 4 summarizes the systemic manifestations of the disease. RAYNAUD PHENOMENON Cold-induced Raynaud phenomenon is the Table 2. Clinical Associations Between Systemic Sclerosis most common manifestation of systemic Subtypes and Scleroderma-Specific Autoantibodies sclerosis, occurring in more than 95 percent of patients. Patients’ fingers may change from Subtype (percentage with Autoantibody subtype and autoantibody) Clinical associations white (vasospasm) to blue-purple (ischemia) to red (hyperemia); this is precipitated by Antinuclear antibody Limited cutaneous and Pulmonary arterial exposure to cold temperature or emotional diffuse cutaneous hypertension stress. Idiopathic or primary Raynaud phe- (95 percent [nucleolar Interstitial lung pattern is most specific]) disease nomenon typically occurs in female adoles- Anticentromere Limited cutaneous Pulmonary arterial cents, and is not associated with ischemic antibody (60 to 80 percent) hypertension complications. In contrast, secondary Ray- Diffuse cutaneous Digital ulcerations or naud phenomenon tends to occur later in (2 to 5 percent) digital loss life and often leads to tissue damage. Table 5 Antitopoisomerase-1 Diffuse cutaneous Rapidly progressive presents the characteristics of primary and antibody (anti-Scl-70) (20 to 40 percent) skin thickening secondary Raynaud phenomenon. Physical Scleroderma renal crisis findings of secondary Raynaud phenom- Pulmonary fibrosis enon include cyanosis and signs of ischemic damage to the fingers, such as digital pitting Information from references 3 and 4. (Figure 1A), visible capillaries on the nail bed, ischemic ulcerations (Figure 1B), and 962 American Family Physician www.aafp.org/afp Volume 78, Number 8 ◆ October 15, 2008 Systemic Sclerosis/Scleroderma Table 3. Scleroderma Spectrum Disorders Disorder Variants Diffuse cutaneous — B1 and B2). With disease progression, ulcerations over systemic sclerosis joints and flexion contractures of the fingers, wrists, and Limited cutaneous CREST syndrome systemic sclerosis elbows may occur. Systemic sclerosis — sine scleroderma MUscULOskeletAL MANifestAtiONS Localized Linear scleroderma Musculoskeletal involvement is common in early sys- scleroderma En coup de sabre temic sclerosis and often prompts patients to seek medi- Morphea cal evaluation. Puffy hands with arthralgia and myalgia Generalized may lead to difficulty making a fist. Palpable or audible Plaque friction rubs may be noted over the