Systemic Sclerosis Diagnosis: An In-Depth Guide for Expert Automotive Technicians

Introduction

Systemic sclerosis, often referred to as scleroderma, is a rare and intricate connective tissue disorder characterized by a complex and still not fully understood pathogenesis. This condition falls under two primary categories: localized scleroderma, encompassing morphea, linear scleroderma, and scleroderma en coup de sabre, and systemic sclerosis. Systemic sclerosis is further delineated into limited systemic sclerosis, previously known as CREST syndrome (Calcinosis, Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia), and diffuse systemic sclerosis, distinguished by clinical and serological criteria. While localized scleroderma predominantly affects the skin and underlying subcutaneous tissues, systemic sclerosis is marked by systemic manifestations and the involvement of internal organs, leading to increased morbidity and mortality. The clinical presentations of scleroderma can significantly overlap with other rheumatological and immunological conditions, and the severity can fluctuate based on the timing of a Systemic Sclerosis Diagnosis.

Systemic sclerosis is a multi-system disease requiring a coordinated approach from a diverse healthcare team. This team typically includes primary care physicians, rheumatologists, gastroenterologists, cardiologists, pulmonologists, nephrologists, and dermatologists. Early and accurate systemic sclerosis diagnosis is paramount for effective management and continuous monitoring of disease progression. While there is currently no definitive cure for systemic sclerosis, treatment strategies are primarily aimed at managing affected organs and alleviating symptoms to mitigate further organ damage. This article provides a comprehensive overview of the presentation, evaluation, and management of systemic sclerosis, emphasizing the crucial role of an interprofessional healthcare team in patient care and aiding clinicians in differentiating this complex disorder from related rheumatological diseases.

Etiology of Systemic Sclerosis

The precise cause of systemic sclerosis remains elusive, but current understanding points towards a multifactorial etiology involving both genetic predispositions and environmental triggers.

Genetic Factors

Evidence for a genetic component in systemic sclerosis is supported by observations of familial clustering and the increased incidence of multiple autoimmune diseases within affected families. Genome-wide association studies have identified the major histocompatibility complex (MHC) region as a significant genetic contributor to systemic sclerosis, similar to other autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis. Specific human leukocyte antigens (HLA), including HLA DRB1*1104, DQA1*0501, and DQB1*0301, have long been associated with systemic sclerosis. Furthermore, non-HLA loci like PTPN22, NLRP1, STAT4, and IRF5 have also been implicated in the development of systemic sclerosis.

Environmental Factors

Various environmental factors have been linked to the onset of systemic sclerosis. These include infectious agents such as Cytomegalovirus (CMV), Epstein-Barr virus, and parvovirus B19. Exposure to silica dust is another recognized risk factor, along with less frequently cited exposures to organic solvents like toluene, xylene, trichloroethylene, and polyvinyl chloride. It’s important to note that cigarette smoking has not been definitively established as a risk factor for systemic sclerosis.

It’s also worth mentioning scleroderma-like disorders, which, while distinct from systemic sclerosis based on clinical, histopathological, and laboratory findings, can be triggered by environmental exposures. Examples include toxic oil syndrome caused by contaminated rapeseed cooking oil and eosinophilia-myalgia syndrome linked to L-tryptophan. Certain medications, such as bleomycin and cocaine, have also been associated with scleroderma-like illnesses.

Epidemiology of Systemic Sclerosis

The rarity of systemic sclerosis contributes to limited epidemiological data. Reported incidence and prevalence rates vary depending on geographical location, diagnostic criteria, and methods of data collection. Globally, prevalence rates are estimated to range from 38 to 341 cases per million adults, while annual incidence rates vary from 8 to 56 new cases per million adults.

In the United States, a study estimated an incidence of 19.3 new cases per million adults annually, with a prevalence of 242 cases per million adults in the Detroit area between 1989 and 1991. Another study in Quebec in 2003 reported a prevalence of 443 cases per million adults. Interestingly, prevalence rates tend to be higher in the United States and Australia compared to Europe and Asia, particularly Japan and Taiwan. Notably, the Choctaw Native American population in Oklahoma exhibits the highest reported prevalence of systemic sclerosis at 660 cases per million adults, highlighting significant geographical variations.

Systemic sclerosis shows a marked female predominance, with a female-to-male ratio of approximately 5:1. Women typically develop the condition at a younger age than men. The peak age of onset is between 45 and 54 years for African-American females and 55 and 64 years for European-American females. Systemic sclerosis is rare in children and teenagers under 15 years of age. Onset between 15 and 24 years is also uncommon, with an incidence of 21.2 per million in African-American females and 11.16 per million in European-American females. Individuals of African ancestry are at a higher risk of developing systemic sclerosis, often experiencing earlier disease onset and more severe manifestations.

Pathophysiology of Systemic Sclerosis

The pathophysiology of systemic sclerosis is complex and not fully elucidated. The disease is characterized by three major pathological hallmarks: vascular injury, autoimmunity, and tissue fibrosis. Variations in the contribution of these factors in individual patients are thought to account for the different clinical phenotypes of systemic sclerosis. Various triggers, including viruses, environmental exposures, autoantibodies, proteolytic enzymes, and inflammatory cytokines, can initiate the initial vascular insult in systemic sclerosis. This initial injury to the vasculature leads to endothelial cell activation, overexpression of adhesion molecules, and subsequent activation of platelets and thrombotic and fibrinolytic cascades.

Activated endothelial cells release endothelin-1 (ET-1), a potent vasoconstrictor, and promote leukocyte adhesion, vascular smooth muscle cell proliferation, and fibroblast activation. These activated endothelial cells can also undergo transdifferentiation into mesenchymal cells exhibiting functional abnormalities, such as impaired responsiveness to vasodilators, including nitric oxide and prostacyclins. In addition, activated platelets release thromboxane-A2, platelet-derived growth factor, and transforming growth factor-β (TGF-β), as well as activate thrombin, contributing to coagulation, thrombosis, vasoconstriction, and fibroblast activation. The initial vascular insult ultimately leads to tissue hypoxia. Patients with systemic sclerosis exhibit impaired compensatory vascular repair mechanisms, widespread microangiopathy, microvasculature loss, and diminished angiogenesis, all contributing to chronic tissue hypoxia and oxidative stress.

Immune dysregulation and inflammation are central to the pathogenesis of systemic sclerosis, involving both the innate and adaptive immune systems. Activated T cells are prominent in both tissue and peripheral blood of systemic sclerosis patients. An imbalance in type 1 and type 2 helper T cells (Th1/Th2) cytokines, with a predominant Th2 profile, is observed. This Th2 skewing promotes fibrosis through enhanced collagen synthesis and myofibroblast transdifferentiation, driven by pro-fibrotic cytokines such as TGF-β, interleukins (ILs) 4, 5, and 13, and a reduction in anti-fibrotic cytokines like interferon-γ.

Activated macrophages, monocytes, and dendritic cells further exacerbate vascular injury and fibrosis by activating T- and B cells and producing pro-fibrotic and pro-inflammatory cytokines. Humoral autoimmunity and the presence of autoantibodies are hallmarks of systemic sclerosis, present in nearly all patients. Activated B cells produce these autoantibodies, which are considered directly pathogenic and serve as crucial diagnostic markers for the disease. Specific autoantibody profiles are associated with distinct disease phenotypes within systemic sclerosis. Vascular injury and inflammation resulting from autoimmunity contribute to tissue fibrosis through mesenchymal cell activation and differentiation. This process leads to irreversible extracellular matrix accumulation, uncontrolled fibroblast activation, persistent myofibroblasts, an increase in the microvascular pericyte compartment, and pathological epithelial-mesenchymal transition.

Histopathology of Systemic Sclerosis

The histopathological features of systemic sclerosis are characterized by noninflammatory proliferative or obliterative vasculopathy followed by interstitial or vascular fibrosis. Early in the disease, perivascular inflammatory infiltrates of CD4+ T lymphocytes may be present but are often absent in long-standing cases. The vasculopathy is marked by bland intimal proliferation, thickening of the basement membrane, capillary rarefaction, loss of vascular endothelial cadherin, platelet aggregation, and microthrombi formation. Vasculitis or immune complex deposition is rare. In later stages, extensive perivascular fibrosis, progressive luminal occlusion, and tissue fibrosis become prominent.

In early systemic sclerosis, dermal edema in the skin is evident, with perivascular inflammatory infiltrates predominantly composed of T lymphocytes and monocytes. Dermal fibrosis becomes the dominant feature as the disease progresses. Histopathological examination typically reveals a loss of dermal capillaries and skin appendages, such as hair follicles, sweat glands, and sebaceous glands. Marked dermal expansion, characterized by dense collagen and hyaluronic acid accumulation, is also observed, along with a loss of dermal lymphatics and the subcutaneous adipose layer.

Pulmonary involvement is common in systemic sclerosis and mirrors the skin’s pathology. Early pulmonary involvement is characterized by inflammatory changes, progressing to fibrosis and vascular damage. Initial inflammatory changes affect the alveolar walls, with infiltration by lymphocytes, macrophages, and plasma cells. Nonspecific interstitial pneumonitis is the most frequent pulmonary manifestation, exhibiting a relatively uniform distribution of fibrosis with interstitial inflammation and type II pneumocyte hyperplasia. Usual interstitial pneumonia, another pattern, is characterized by patchy fibrosis with fibroblastic foci and is associated with a poorer prognosis. Pulmonary arterial hypertension (PAH) develops due to vasculopathy and loss of pulmonary microvasculature secondary to progressive pulmonary fibrosis.

Renal involvement in systemic sclerosis is less frequent. Chronic ischemic changes are commonly observed, but glomerulonephritis is uncommon unless there is an overlapping syndrome. Scleroderma renal crisis, a rare but life-threatening complication, is associated with changes resembling thrombotic microangiopathy or malignant hypertension. Histologically, onion skinning, characterized by intimal proliferation and reduplication of the elastic lamina with luminal narrowing of small interlobular and arcuate renal arteries, is a hallmark finding in scleroderma renal crisis.

Fibrosis is the predominant pathological feature in systemic sclerosis, extending beyond the skin to affect various organs, including the gastrointestinal tract (from mouth to rectum), thyroid gland, salivary glands, and penile blood vessels. Inflammatory myositis can occur alone or in overlap syndromes. Cardiac involvement may lead to constrictive pericarditis, pericardial fibrosis or effusions, and patchy myocardial fibrosis.

History and Physical Examination for Systemic Sclerosis Diagnosis

Systemic sclerosis is a complex, multi-system disorder with highly variable clinical presentations. Diffuse cutaneous systemic sclerosis typically presents with more severe symptoms and higher mortality compared to limited cutaneous systemic sclerosis, often involving internal organs more extensively and severely. Systemic sclerosis also tends to be more severe in males, African Americans, and individuals with later onset of the disease.

Raynaud Phenomenon

Raynaud phenomenon is an early and highly prevalent manifestation, observed in over 95% of patients with systemic sclerosis. It involves vasospasms triggered by cold exposure, leading to triphasic color changes, typically in the digits, particularly of the upper extremities. These color changes can also occur in the ears, nose, or tongue. The sequence typically includes initial pallor (white discoloration), followed by cyanosis (bluish appearance due to ischemia), and finally, rubor (red discoloration due to reactive hyperemia). Not all patients experience all three phases. Raynaud phenomenon can precede visceral involvement by years, especially in limited cutaneous systemic sclerosis. In diffuse cutaneous systemic sclerosis, Raynaud phenomenon may occur concurrently with or shortly after skin changes. Primary Raynaud phenomenon, occurring in the absence of underlying systemic sclerosis or connective tissue disease, affects up to 15% of the general population, predominantly women, with early onset, symmetrical mild symptoms, normal nailfold capillaries, negative antinuclear antibodies, and a benign course without ischemic complications. Secondary Raynaud, as seen in systemic sclerosis, can lead to severe complications.

Image: Bilateral Signs of Raynaud Phenomenon in a Patient’s Hands. Demonstrating triphasic color changes in the digits, indicative of Raynaud Phenomenon.

In systemic sclerosis, Raynaud phenomenon is complicated by underlying non-vasculitic vasculopathy characterized by intimal hyperplasia and fibrosis. Abnormal vasomotor control regulation also contributes to loss of vessel flexibility. Consequently, digital manifestations like pitting, ulcers, and tissue loss are frequent, leading to digital ischemia and dry gangrene, potentially requiring autoamputation. Secondary infections are common complications. Nailfold capillary examination in systemic sclerosis reveals characteristic abnormalities, such as capillary dilation, hemorrhages, and dropout.

Cutaneous Manifestations

Skin involvement is the most overt feature of systemic sclerosis, present in almost all patients, with varying degrees of severity. Systemic sclerosis classification into limited and diffuse cutaneous subtypes is based on the extent of skin involvement. Limited cutaneous systemic sclerosis involves skin thickening distal to elbows and knees, typically sparing the trunk, while diffuse cutaneous systemic sclerosis involves skin proximal to elbows, knees, and/or the trunk. Facial involvement can occur in both subtypes.

The initial “puffy finger phase” is characterized by inflammation and non-pitting edema of the hands, lasting several months. Patients often report pruritus, burning pain, and erythema. Edema can compress underlying structures, leading to compression neuropathies like carpal tunnel syndrome. Loss of skin appendages contributes to dry and uncomfortable skin. Subsequently, skin thickening and fibrosis develop during the fibrotic phase.

During the prolonged fibrotic phase, skin fibrosis and thickening begin distally at the metacarpophalangeal joints (sclerodactyly) and progress proximally. The thick, leather-like skin and fibrosis of deeper subcutaneous structures cause permanent contractures and reduced peripheral joint mobility. Further loss of skin appendages and subcutaneous adipose tissue (lipodystrophy) may occur. Facial involvement results in a small oral aperture (fish-mouth or masked facies).

Image: Pursed Mouth in a Female Patient With Scleroderma. Showing the characteristic pursed mouth appearance due to cutaneous manifestations of scleroderma.

Skin ulcers may develop at trauma sites, such as extensor surfaces of metacarpophalangeal, interphalangeal, or elbow joints. A salt-and-pepper appearance, with depigmented areas among normally pigmented skin, may be observed. The final skin-softening phase can occur years after initial presentation, where skin, especially on the trunk and upper arms, softens and may appear clinically normal, though subcutaneous tissue remains fibrotic.

Telangiectasias, due to capillary dilatation, are common on hands, face, mucosal surfaces, and occasionally the trunk. They blanch on pressure and may increase over time, associated with increased PAH risk. Subcutaneous calcinosis, more frequent in limited cutaneous systemic sclerosis and anti-centromere antibody-positive patients, results from localized calcium hydroxyapatite deposits in subcutaneous tissue, typically over trauma-prone areas like finger pads and elbow extensor surfaces, predisposing to skin ulceration and secondary infection.

Musculoskeletal Manifestations

Musculoskeletal manifestations are prevalent in almost all systemic sclerosis patients. Arthralgia and myalgia are common. Inflammatory arthritis with true synovitis, resembling rheumatoid arthritis, may affect metacarpophalangeal, proximal interphalangeal, wrist, and ankle joints. Erosions are uncommon but can occur, especially with periarticular calcinosis. Large joint involvement is rare but can occur in diffuse cutaneous systemic sclerosis. Overlap with rheumatoid arthritis occurs in up to 5% of cases.

Distal bone resorption and osteolysis are seen in late diffuse cutaneous systemic sclerosis. Hand joint contractures are common, but large joint contractures are rare. Tendon friction rubs, due to tendon sheath inflammation, edema, and fibrosis, occur in up to 30% of cases, particularly in diffuse cutaneous systemic sclerosis, and are associated with poor prognosis. Muscle involvement or myopathy in systemic sclerosis is multifactorial. About 10% of patients develop inflammatory myopathy similar to polymyositis, with rapid proximal muscle weakness, elevated muscle enzymes, and inflammatory myositis on biopsy. Decreased muscle strength can also result from malnutrition or deconditioning due to joint disease and skin fibrosis.

Direct muscle involvement in systemic sclerosis can cause fibrosing myopathy, characterized by muscle fibrosis and atrophy. These patients may have mildly elevated muscle enzymes, and muscle biopsy reveals fibrosis and atrophy with minimal inflammation. Unlike inflammatory myopathies, they usually do not respond to anti-inflammatory agents. Myopathy in systemic sclerosis is associated with a poor prognosis overall.

Gastrointestinal Manifestations

Gastrointestinal involvement is almost universal in both diffuse and limited cutaneous systemic sclerosis, with symptoms ranging from mild to severe and affecting any part of the gastrointestinal tract. Oropharyngeal involvement includes perioral skin tightening, reduced oral aperture, periodontitis, and gingivitis. Dry mouth is common due to salivary gland fibrosis secondary to systemic sclerosis or inflammatory infiltrates from secondary Sjögren syndrome. Esophageal dysmotility, mainly due to fibrosis affecting the distal two-thirds of the esophagus, frequently causes dysphagia and heartburn, affecting up to 90% of patients.

The lower esophageal sphincter becomes hypotonic, worsening reflux symptoms. Complications of esophageal dysmotility include esophagitis, esophageal strictures, Barrett’s esophagus, and bleeding. Gastric involvement may manifest as delayed gastric emptying (gastroparesis), leading to early satiety, bloating, nausea, vomiting, and anorexia, potentially causing malnutrition and weight loss.

Gastric antral vascular ectasia (“watermelon stomach”) results from gastric telangiectasias and can cause occult or massive gastrointestinal bleeding. Intestinal dysmotility can lead to diarrhea, constipation, and small intestinal bacterial overgrowth. Mucosal telangiectasias can cause occult gastrointestinal bleeding. Intestinal dysmotility can lead to pseudo-obstruction. Wide-mouthed diverticula due to intestinal mucosal muscular atrophy are unique to systemic sclerosis. Reduced anal sphincter tone can result in rectal prolapse and incontinence. Hepatic involvement is not typical, although primary biliary cirrhosis has been reported in some cases.

Pulmonary Manifestations

Pulmonary disease is the leading cause of mortality in systemic sclerosis. Characteristic pulmonary involvement includes interstitial lung disease and/or PAH. Rarer manifestations include pleuritis, obstructive airway disease, aspiration pneumonia, pulmonary hemorrhage, and cryptogenic organizing pneumonia. Pulmonary disease ranges from asymptomatic to progressive respiratory failure.

Interstitial lung disease, manifesting as bibasilar pulmonary fibrosis, is more prevalent and severe in diffuse cutaneous systemic sclerosis, African Americans, males, and anti–topoisomerase I antibody-positive individuals. Clinically significant interstitial lung disease is present in about 50% of systemic sclerosis cases, though it may be asymptomatic. Postmortem studies show interstitial lung disease in approximately 80% of systemic sclerosis patients. Interstitial lung disease usually develops within the first 4 to 5 years after systemic sclerosis diagnosis. Nonspecific interstitial pneumonitis is more common than usual interstitial pneumonia, but mixed patterns occur. Symptoms include dyspnea, fatigue, and later, a non-productive cough.

Pulmonary function tests show a restrictive pattern with decreased lung volumes and FEV1/FVC ratio. Diffusing capacity for carbon monoxide (DLCO) may be reduced, partly due to pulmonary vascular disease. High-resolution computed tomography (HRCT) of the chest is highly sensitive, especially early in the disease, showing increased subpleural lung attenuations in bilateral posterior basal areas. Ground-glass opacities may indicate alveolitis, with other findings including honeycombing, traction bronchiectasis, and interlobular septal thickening.

PAH is another common pulmonary manifestation, ranging from asymptomatic to severe PAH with right heart failure. Typically, PAH develops late in the disease course, often more than 10 years after systemic sclerosis diagnosis. It can affect 30% to 50% of individuals with systemic sclerosis, more commonly in limited cutaneous systemic sclerosis. Risk factors include older age at diagnosis, multiple telangiectasias, and anti–U3-RNP antibodies. Symptoms include dyspnea initially, then chest pain, lower extremity swelling, lightheadedness, and syncope as the disease progresses. An accentuated “P component” of the second heart sound (S2) may be audible.

Pulmonary function tests show isolated reduction in diffusion capacity. NT-proBNP levels in blood may be elevated. Echocardiography may show elevated peak right ventricular systolic pressure. Right heart catheterization is needed to confirm PAH and exclude other causes, with diagnosis confirmed by mean pulmonary arterial pressure ≥25 mm Hg and normal pulmonary capillary wedge pressure.

Cardiac Manifestations

Cardiac manifestations include pericarditis, pericardial effusion, dilated cardiomyopathy, and arrhythmias. Left ventricular diastolic dysfunction can occur secondary to PAH. Cardiac involvement is associated with increased infection risk and poor prognosis. Pericardial effusions are usually small and exudative, with tamponade being rare. Pericardial effusions are more common in diffuse cutaneous systemic sclerosis and predict scleroderma renal crisis. Dilated cardiomyopathy results from patchy myocardial fibrosis. Fibrosis within conduction pathways can cause arrhythmias, with premature ventricular contractions being most common, but heart block, intraventricular conduction delays, and supraventricular tachycardia have also been reported.

Renal Manifestations

Renal manifestations in systemic sclerosis are exemplified by scleroderma renal crisis, historically almost always fatal and the primary cause of mortality before ACE inhibitors. Scleroderma renal crisis occurs in approximately 10% of systemic sclerosis patients, predominantly in diffuse cutaneous systemic sclerosis, typically within three years of systemic sclerosis diagnosis. Risk factors include African-American race, pericardial effusion, tendon friction rubs, new-onset anemia, diffuse cutaneous systemic sclerosis, anti-RNA polymerase III antibody, and high-dose (or chronic low-dose) corticosteroids. Poor outcome indicators include male gender, older age at onset, and serum creatinine >3 mg/dL.

Scleroderma renal crisis pathology mainly involves vasculopathy, similar to vascular changes in other affected organs, rather than glomerulonephritis. Clinically, it presents with new-onset hypertension or malignant hypertension, often with renal insufficiency. Microangiopathy can cause hemolytic anemia and thrombocytopenia. Proteinuria may occur, and microscopic hematuria is often mild.

Other Manifestations

Other manifestations include hypothyroidism in up to 15% of patients, especially with limited cutaneous systemic sclerosis, often due to thyroid gland fibrosis. Autoimmune thyroid diseases like Hashimoto thyroiditis and Graves disease are more common in systemic sclerosis patients. They also have higher risk of other autoimmune conditions, such as primary biliary cirrhosis and secondary Sjögren syndrome. Thrombocytopenia has also been observed.

Overlap syndromes are common in systemic sclerosis, involving rheumatoid arthritis and polymyositis. Patients also have increased risk of psychological disorders like depression, affecting up to 50%. Systemic sclerosis sine scleroderma is a variant with internal organ manifestations, particularly pulmonary and gastrointestinal, without skin thickening. These patients typically have Raynaud phenomenon, abnormal nailfold capillary exam, and positive antinuclear antibodies.

Classification Criteria for Systemic Sclerosis Diagnosis

In 2013, the American College of Rheumatology and the European League Against Rheumatism (ACR/EULAR) published updated classification criteria for systemic sclerosis, improving sensitivity and specificity over the 1980 criteria. Primarily for clinical study inclusion, these criteria can be cautiously applied in clinical settings. A scoring system is used, with a score of 9 or higher indicating classification as systemic sclerosis.

• Bilateral skin thickening proximal to metacarpophalangeal joints: 9 points
• Skin thickening of fingers (only higher score counted):
  • Between distal and proximal interphalangeal joints: 4 points
  • Puffy fingers: 2 points
• Fingertip lesions (only higher score counted):
  • Fingertip pitting scars: 3 points
  • Digital tip ulcers: 2 points
• Telangiectasia: 2 points
• Abnormal nailfold capillaries: 2 points
• Raynaud phenomenon: 3 points
• Lung disease (maximum score of 2 points):
  • Interstitial Lung Disease (ILD): 2 points
  • Pulmonary Arterial Hypertension (PAH): 2 points
• Positive systemic sclerosis-specific antibodies (anti-centromere, anti–Scl–70, anti–RNA polymerase III): 3 points

Evaluation and Diagnostic Tests for Systemic Sclerosis

Systemic sclerosis diagnosis is primarily clinical. Early detection, assessment of disease extent, and ongoing surveillance for internal organ manifestations are crucial for effective management.

Clinical Evaluation

Skin thickness assessment uses the modified Rodnan skin score (mRSS), ranging from 0 (uninvolved) to 3 (severe thickening). Monitoring changes in mRSS over time is prognostically significant. Nailfold capillary examination is indicated in all patients with Raynaud phenomenon and suspected systemic sclerosis. Comprehensive physical examination targeting multiple organ systems is conducted at each visit to detect organ involvement. Regular blood pressure monitoring, in-clinic and at home, is recommended, especially in recent diffuse cutaneous systemic sclerosis diagnoses, new-onset hypertension, or worsening hypertension, as it may signal scleroderma renal crisis.

Autoantibody Tests

Autoantibodies are essential diagnostic tools, providing predictive insights into disease phenotype and prognosis. Antinuclear antibodies (ANA), detected by direct immunofluorescence, are positive in over 90% of systemic sclerosis cases. Negative ANA warrants ruling out other diagnoses before confirming systemic sclerosis. Specific autoantibodies, positive in 60% to 70% of cases, offer greater diagnostic specificity. These mutually exclusive antibodies can appear months to years before clinical onset.

• Anti-centromere antibody (ACA): Targets centromere antigens (CENP -B, -A, -C, D), predominantly in limited cutaneous systemic sclerosis, but can occur in diffuse cutaneous systemic sclerosis, Sjögren syndrome, and systemic lupus erythematosus. Associated with increased PAH risk, limited cutaneous involvement, lower interstitial lung disease risk, and better survival.
• Anti-topoisomerase I (Scl-70) antibody: Targets DNA helicase topoisomerase I, predominantly in diffuse cutaneous systemic sclerosis, rarely in limited cutaneous systemic sclerosis. Associated with higher risk of diffuse cutaneous involvement, interstitial lung disease, and cardiac involvement.
• Anti-RNA polymerase III antibody (RNAP III): Targets eukaryotic RNA polymerase III, particularly associated with diffuse cutaneous systemic sclerosis. Linked to rapidly progressing, aggressive diffuse skin involvement, poor cutaneous outcomes, and scleroderma renal crisis. Associated with lower risk of interstitial lung disease and PAH. Some studies suggest association with malignancies in systemic sclerosis patients.
• Anti–U3-RNP (fibrillarin) antibody: More prevalent in African Americans, associated with overall poor prognosis in systemic sclerosis. Correlates with increased internal organ involvement, diffuse cutaneous manifestations, interstitial lung disease, PAH, scleroderma renal crisis, myositis/myopathy, and cardiac complications.
• Other autoantibodies:
  • Anti-Th/To antibodies: Associated with limited skin disease.
  • Anti–PM/Scl antibodies: Associated with limited skin disease and overlap syndrome, predisposing to inflammatory myositis and interstitial lung disease.
  • Anti–U1-RNP antibodies: More prevalent in African Americans, associated with overlap syndrome and mixed connective tissue disease. Linked to limited cutaneous involvement and increased risk of inflammatory arthritis, myositis, lupus skin rashes, and lupus nephritis.
  • Anti-Ku antibodies: Associated with overlap syndrome in systemic sclerosis, linked to more inflammatory arthritis and myositis.

Laboratory Evaluation

Complete blood count to assess for anemia, which can be multifactorial, should be performed. Renal function and 24-hour urine protein or urine protein:creatinine ratio should be closely monitored. Inflammatory markers typically have limited diagnostic significance, but notable elevations may indicate active inflammatory myopathy or inflammatory arthritis. Muscle enzymes, including creatine kinase and aldolase, may be elevated, especially with inflammatory myopathy.

Ancillary and Radiographic Evaluation

Extremity X-rays can reveal calcinosis and distal phalangeal loss. Periarticular erosions are rare, but periarticular osteopenia can be seen. Musculoskeletal ultrasound can show tenosynovitis. Electromyography/nernerve conduction velocity testing is the initial choice for suspected muscle involvement. Abnormal results may warrant muscle biopsy. High-resolution CT (HRCT) scan is the preferred imaging for interstitial lung disease, detecting subtle findings not visible on chest x-ray.

Pulmonary function tests, including spirometry, lung volumes, and diffusion capacity, can detect restrictive patterns in interstitial lung disease early. Lung biopsy is rarely needed unless other diagnostic concerns exist. Transthoracic echocardiography is initially performed for suspected PAH, followed by right heart catheterization to confirm diagnosis and exclude other etiologies. Electrocardiography and Holter monitoring are useful for detecting arrhythmias.

Pericardial effusions are well visualized on transthoracic echocardiography. Cardiac MRI may be needed for suspected myocardial involvement. For suspected esophageal and upper gastrointestinal involvement, upper gastrointestinal endoscopy, esophageal manometry, barium swallow studies, and 24-hour pH probe can be used. Dilated esophagus with excessive air on CT scan suggests esophageal dysmotility.

Treatment and Management of Systemic Sclerosis

No definitive cure or universally effective disease-modifying agent exists for systemic sclerosis. Management focuses on treating affected organ systems. Early systemic sclerosis diagnosis is crucial for better outcomes. Clinical evaluation, identification of affected organs, and monitoring disease progression are critical for treatment efficacy. Treatment goals are holistic, aiming to optimize quality of life and prevent organ damage. Patient education, regular exercise, healthy lifestyle, and emotional support are important.

Several agents have been investigated for systemic sclerosis manifestations, but limited large randomized controlled trials affect their efficacy. Immunosuppressive agents frequently used include cyclophosphamide (for lung and skin disease), mycophenolate mofetil (for lung and skin disease), methotrexate (MTX; for skin disease, inflammatory arthritis, and myositis), azathioprine (for skin and lung disease, and myositis), and hydroxychloroquine (HCQ; for skin disease).

Cyclosporine (for skin disease), infliximab (for inflammatory arthritis), and rituximab (for skin and lung disease) have limited data. Corticosteroids are generally avoided due to scleroderma renal crisis risk. High-dose and long-term low-to-moderate-dose corticosteroids are associated with scleroderma renal crisis. They should only be considered in refractory inflammatory myositis, inflammatory arthritis, or active inflammatory alveolitis, at the lowest possible dose for the shortest duration.

Specific Therapies

Raynaud Phenomenon

Raynaud phenomenon treatment aims to prevent digital ischemia and ulcers. Conservative management is key: keep extremities and body warm, avoid smoking and stress, eliminate sympathomimetic medications. Switch from β-blockers if possible.

Vasodilator therapy is effective. Dihydropyridine calcium channel blockers like nifedipine (30-120 mg/d) or amlodipine (5-20 mg/d) are first-line agents. Vasodilators like pentoxifylline, nitroglycerin, and phosphodiesterase inhibitors such as sildenafil (20 mg once to 3 times daily) can be considered. Prostacyclin analogs (iloprost) and endothelin receptor antagonists (bosentan) are used for refractory cases with digital ischemic ulcers. Iloprost is typically infused for 3 to 5 days at 0.5 to 2 ng/kg/min. Bosentan is started at 62.5 mg twice daily for 4 weeks, increased to 125 mg twice daily. Sympathectomy may be considered in refractory cases. Botulinum toxin injections have shown limited efficacy in small studies. Vasodilator pumps may be used for patients intolerant to vasodilator therapies. Effective wound care is essential for digital ulcers.

Skin Disease

Immunosuppressive agents for sclerodactyly include MTX, HCQ, mycophenolate mofetil, and cyclophosphamide. MTX is usually 15 to 25 mg per week orally or subcutaneously. Systemic glucocorticoids are often given concurrently, such as IV methylprednisolone (30 mg/kg/d for 3 days per month) or oral prednisone (1 mg/kg/d). MTX treatment duration is often 1 to 2 years, tapered after 6 to 12 months of inactivity (2.5 mg reduction every 2 to 4 weeks). Relapses may occur after cessation. IV methylprednisolone is typically stopped after 3 to 4 months of symptom resolution. Oral prednisone is tapered slowly over 3 to 4 months. Mycophenolate mofetil is often preferred for moderate-to-severe skin thickening (1 g twice daily, max 1.5 g twice daily), continued for 6 to 12 months post-symptom resolution, then tapered. Cyclophosphamide is recommended for patients refractory to MTX or mycophenolate mofetil, or with progressive disease.

Antihistamines and topical moisturizers help with pruritus. Topical corticosteroids, vitamin D analogs, and tacrolimus can be used for limited skin disease. Laser therapy can be considered for telangiectasias for cosmetic purposes. No effective medical treatment for calcinosis exists; surgical debulking may provide relief in severe cases.

Musculoskeletal Involvement

Mild arthralgias often do not require treatment or respond to NSAIDs. Low-dose glucocorticoids (≤15 mg/d) can be used for inflammatory arthritis. Antitumor necrosis factor agents can be used in refractory severe inflammatory arthritis.

Physical and occupational therapy are crucial for preventing contractures. Inflammatory myositis management is similar to polymyositis, but high-dose corticosteroids should be avoided. Immunosuppressive agents like MTX and azathioprine are effective. Noninflammatory myopathy is challenging to treat; physical therapy and exercises are more beneficial than immunosuppressants.

Pulmonary Involvement

Pulmonary involvement is the leading cause of mortality, requiring interprofessional involvement. Early detection of interstitial lung disease is crucial. Cyclophosphamide has shown benefit for up to 18 months, but efficacy diminishes by 24 months. Cyclophosphamide followed by azathioprine for maintenance therapy has shown some benefit in small studies. Mycophenolate mofetil (1.5-3 g daily in 2 divided doses) has shown benefits for systemic sclerosis-related interstitial lung disease. Lung transplantation may be necessary for select individuals. Nintedanib, a tyrosine kinase inhibitor, was FDA-approved in 2019 for systemic sclerosis-related interstitial lung disease, slowing pulmonary function decline. Stem cell transplants and antifibrotic agents are also being investigated.

For PAH, when no contraindication exists, supplemental oxygen, diuretics, and anticoagulation are recommended, along with patient education, healthy lifestyle, and exercise as tolerated. Calcium channel blockers are generally ineffective. Nifedipine, amlodipine, and extended-release diltiazem can be titrated up to maximum tolerated dosages over weeks. Vasodilator therapy is recommended, including phosphodiesterase-5 inhibitors (tadalafil 40 mg daily, sildenafil 20 mg orally 3 times daily), endothelin receptor antagonists (bosentan 62.5-125 mg twice daily, sitaxsentan, ambrisentan, or macitentan), and/or prostacyclin analogs (epoprostenol, treprostinil, beraprost, and iloprost 2.5-5 μg inhaled 6-9 times daily). Prostacyclin therapy is considered most effective, but all these agents improve hemodynamics and quality of life. Combination therapy may be needed for patients not improving on monotherapy or with severe PAH.

Cardiac Involvement

Arrhythmias are managed with antiarrhythmic agents and sometimes pacemaker placement. No evidence currently supports immunosuppressants or vasodilators for scleroderma-related cardiac involvement.

Gastrointestinal Involvement

Exercise may improve oral aperture. Good dental hygiene is essential to prevent caries and cavities due to sicca symptoms. Sugar-free lozenges and secretagogues like pilocarpine or cevimeline can alleviate dry mouth. For heartburn and gastroesophageal reflux, lifestyle and dietary adjustments are recommended, such as elevating the head of the bed, avoiding late and large meals, spicy foods, and opting for small, frequent meals. NSAIDs should be avoided. Proton pump inhibitors are preferred over H2 blockers, with high doses permissible, especially for erosive esophagitis. Combination of proton pump inhibitors and H2 blockers may be considered in severe cases.

Motility agents like metoclopramide and proton pump inhibitors may benefit gastroparesis. Laser coagulation is a viable option for bleeding due to gastric antral vascular ectasia. Small intestinal bacterial overgrowth may require rotational antibiotics.

Scleroderma Renal Crisis

ACE inhibitors are the sole effective treatment for scleroderma renal crisis, initiated at the earliest signs at the maximum tolerated dose. Captopril is preferred due to dosing flexibility. No data support angiotensin receptor blockers or renin inhibitors. Renal function may initially decline, but ACE inhibitor continuation is crucial. Renal function can improve markedly over months to years, potentially allowing dialysis discontinuation. Prophylactic ACE inhibitors are not recommended as they do not prevent scleroderma renal crisis and are associated with increased morbidity and mortality.

Differential Diagnosis of Systemic Sclerosis

Systemic sclerosis diagnosis is primarily clinical, but several other diseases can mimic it and should be considered in the differential diagnosis.

Eosinophilic Fasciitis

Eosinophilic fasciitis is characterized by eosinophilic inflammation of deep fascia, causing thickening and woody induration of upper and lower extremities, excluding hands and feet. Raynaud phenomenon is absent, and nailfold capillary examination is typically normal. Antinuclear antibodies and specific autoantibodies are usually negative. Patients may develop contractures similar to systemic sclerosis. Eosinophilic fasciitis may be associated with underlying malignancies. Skin biopsy shows eosinophilic infiltrates in deep fascia.

Scleromyxedema

Scleromyxedema is usually seen in patients with monoclonal gammopathy or multiple myeloma, characterized by papular waxy lesions on face, neck, extremities, and fingers. Patients may also have seizures and dementia. Raynaud phenomenon is absent, and nailfold capillary examination is typically normal. Antinuclear antibodies and specific autoantibodies are usually negative. Skin biopsy shows dermal fibrosis with perivascular inflammation and mucin and fibrocyte deposition, not typical in systemic sclerosis.

Scleredema

Scleredema can be associated with diabetes mellitus, monoclonal gammopathy, fatigue, infections, and malignancies. Characterized by doughy, indurated skin on neck, back, and face, typically sparing digits. Raynaud phenomenon is absent, and nailfold capillary examination is usually normal. Antinuclear antibodies and specific autoantibodies are generally negative. Skin biopsy shows dermal fibrosis without perivascular inflammation and mucin deposition.

Nephrogenic Systemic Fibrosis

Nephrogenic systemic fibrosis is rare, seen in end-stage renal disease patients after gadolinium contrast exposure. Characterized by cobblestone-like nodular plaques on extremities, trunk, hands, and feet, sparing face. Raynaud phenomenon is absent, and nailfold capillary examination is typically normal. Antinuclear antibodies and specific autoantibodies are generally negative. Skin biopsy shows dermal and epidermal fibrosis without perivascular inflammation, with mucin and fibrocyte deposition.

Eosinophilia Myalgia Syndrome

This syndrome was an epidemic linked to L-tryptophan use, causing severe myalgias, visceral involvement, and elevated CK levels.

Toxic Oil Syndrome

This syndrome was an epidemic in Spain linked to adulterated rapeseed oil consumption, causing livedo reticularis, pulmonary infiltrates, and elevated creatine kinase levels.

Prognosis of Systemic Sclerosis

Systemic sclerosis is associated with high mortality, having the highest case-specific mortality among collagen vascular disorders. Previously, scleroderma renal crisis was the most common cause of death before ACE inhibitors. ACE inhibitor use and increased awareness have significantly reduced scleroderma renal crisis-related mortality. Currently, pulmonary disease is the most common cause of mortality in systemic sclerosis patients.

Over the past 30 years, systemic sclerosis prognosis has improved, with 5-year survival rates reaching up to 80%. However, advanced PAH patients have less than 50% 2-year survival rate. Systemic sclerosis-related PAH prognosis is poorer than idiopathic PAH.

Before ACE inhibitors, 1-year survival rate for scleroderma renal crisis was <15%. With increased awareness and ACE inhibitors, 1-year survival in scleroderma renal crisis has improved to >85%. Systemic sclerosis patients also have increased malignancy risk, particularly lung cancer, and esophageal adenocarcinoma risk in cases with chronic gastroesophageal reflux leading to Barrett esophagus.

Prognostic Factors and Associations

• African-American race: Early disease onset, severe disease, interstitial lung disease, and scleroderma renal crisis.
• Late age of diagnosis: PAH and poor outcomes after scleroderma renal crisis.
• Diffuse cutaneous systemic sclerosis: Diffuse skin disease, large joint inflammatory arthritis, tendon friction rubs, joint contractures, distal bone osteolysis, scleroderma renal crisis, interstitial lung disease, and pericardial effusion.
• Limited cutaneous systemic sclerosis: Limited skin disease, calcinosis, PAH, and hypothyroidism.
• Multiple telangiectasias: PAH.
• Pericardial effusion: Scleroderma renal crisis.
• Tendon friction rubs: Scleroderma renal crisis and poor overall prognosis.
• New-onset anemia: Scleroderma renal crisis.
• Corticosteroid use: Scleroderma renal crisis.
• Anti-centromere antibody: Limited cutaneous systemic sclerosis and PAH; lower interstitial lung disease risk.
• Anti–Scl-70 antibody: Diffuse cutaneous systemic sclerosis, interstitial lung disease, and cardiac involvement.
• Anti-RNA polymerase III antibody: Rapidly progressing, aggressive diffuse skin involvement, poor cutaneous outcomes, scleroderma renal crisis, and malignancies; lower interstitial lung disease and PAH risk.

Complications of Systemic Sclerosis

Systemic sclerosis is associated with various complications primarily from end-organ damage due to fibrosis. Digital ischemia can lead to gangrene, necessitating amputation. Gastrointestinal complications can cause malnutrition. Pulmonary involvement is the primary cause of morbidity, leading to irreversible pulmonary fibrosis. Scleroderma renal crisis can cause permanent renal damage, although ACE inhibitors often lead to renal function recovery.

Deterrence and Patient Education for Systemic Sclerosis

Patient education is crucial for disease management, including lifestyle adjustments. Raynaud phenomenon patients should be educated on maintaining warmth, avoiding cold exposure, vasoconstrictive agents, and digital trauma. Systemic sclerosis patients should quit smoking and avoid secondhand smoke. Home blood pressure monitoring aids in early scleroderma renal crisis detection.

Enhancing Healthcare Team Outcomes in Systemic Sclerosis

Systemic scleroderma causes significant morbidity and disability. A collaborative interprofessional healthcare team approach is essential, including primary care physicians, rheumatologists, gastroenterologists, cardiologists, pulmonologists, nephrologists, and dermatologists. Nurses and pharmacists are critical for patient care. Pharmacists ensure patients avoid vasoconstricting medications and educate on blood pressure medication adherence. Nursing staff are essential for patient education, monitoring, and care coordination. Patient education on managing systemic sclerosis manifestations is vital for preventing long-term morbidity.

Review Questions

Figure

Alt text: Clinical presentation of Raynaud’s Phenomenon in a male patient exhibiting triphasic color changes in his fingers, a key diagnostic indicator for systemic sclerosis.

Figure

Alt text: Facial manifestation of systemic sclerosis in a female patient, demonstrating the characteristic pursed mouth appearance due to skin tightening.

References

[List of references as provided in the original article]

Disclosure: Rotimi Adigun declares no relevant financial relationships with ineligible companies.

Disclosure: Amandeep Goyal declares no relevant financial relationships with ineligible companies.

Disclosure: Anis Hariz declares no relevant financial relationships with ineligible companies.