The Many Signs of Scleroderma: How to Make a Differential Diagnosis - PracticalPainManagement.com
Scleroderma, or systemic sclerosis, remains the most challenging rheumatic disease to treat and holds the highest mortality rate. This review explores the unique pathophysiology, clinical features, and therapeutic approaches to this systemic connective tissue disease.
During my near half-century of rheumatology practice, I found that scleroderma, or systemic sclerosis, to be the most challenging rheumatic disease to diagnose and manage. Its pathogenesis is less well-understood than other systemic connective tissue diseases – such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) – and this gap has impeded development of effective therapies.
Further impacting management is the fact that systemic sclerosis (SSc) presents in a variety of ways, often resulting in consultation with myriad specialists, diagnostic confusion, and treatment delays. In this review, the many presentations of SSc will be illustrated with hypothetical case examples, as a means to exploring the disease's unique pathophysiology, clinical features, and responses to therapy.
Scleroderma Symptoms and Signs
The term scleroderma, from the Greek word sklērós, meaning "hard," describes the hardened, thick skin that defines and characterizes scleroderma, a result of prolific subdermal fibrosis. When there is any internal organ involvement, the term systemic sclerosis is used and almost all patients with SSc do experience skin manifestations. Raynaud's phenomenon – decreased blood flow to the fingers or toes, often resulting in numbness, swelling, and discoloration – is often the first manifestation of scleroderma and is present in 90% of cases.1
Skin Involvement
Scleroderma can be confined to the skin, either as patches (termed morphea) or long streaks (called linear scleroderma). Telangiectasias on the face and at the nail beds are another defining feature of the skin disease and reflect its underlying vasculopathy.
Hyperpigmentation and calcific deposits are other unique, dermatologic characteristics. Systemic sclerosis has been subclassified as limited or diffuse based on the extent of skin involvement. Diffuse skin disease generally is associated with more visceral involvement, but significant pulmonary and gastrointestinal disease may be present in limited scleroderma.
Joint manifestations
Rather than inflammatory arthritis, as in RA or SLE, joint involvement in systemic sclerosis is characterized by non-inflammatory joint contractures, tendon tightness, and audible friction rubs, often with deposits of calcium around tendons and joints.
Pulmonary, Vascular, and Renal Damage
The fibrosis and vascular damage are unique to scleroderma and not present in other systemic connective tissue diseases, such as RA and SLE. This excess fibrosis and vasculopathy may develop in many internal organs and is the cause of most of the morbidity and mortality in scleroderma.
More than 80% of people diagnosed with scleroderma have pulmonary disease, either interstitial lung disease, pathologically manifested by pulmonary fibrosis, and/or pulmonary arterial hypertension – a pulmonary vascular disorder.1
Kidney disease in scleroderma is marked by vascular fibrosis and collagen excess (see Case 3 below).
Gastrointestinal
Gastrointestinal symptoms, such as dysphagia and malabsorption, are secondary to smooth muscle atrophy and gut wall fibrosis.These clinical manifestations of scleroderma are listed in Table I.
Laboratory Tests for Diagnosing Scleroderma
Autoantibodies
Despite these unique skin and systemic features, scleroderma is still classified as a systemic autoimmune disease and, as in SLE and RA, autoantibodies are present in 80% to 90% of patients.1 These autoantibodies include a positive antinuclear antibody test (ANA), often revealing a nucleolar or speckled immunofluorescence pattern, as well as more specific autoantibodies, such as against topoisomerase 1 (also termed Scl-70).
Cytokines
In lupus or rheumatoid arthritis, the immune response activates cytokines that drive inflammation at organ sites, resulting in synovitis, myocarditis, pericarditis, and glomerulonephritis. Inflammation has not been prominent in scleroderma and anti-inflammatory medications or corticosteroids are considered ineffective. The cytokines or immune mechanisms driving scleroderma have not been identified.
Research has focused instead on potential immune factors that activate fibroblasts or that may be cytotoxic to endothelial cells. Until these immune mechanisms are better understood, effective therapy for scleroderma will continue to be elusive.
More on laboratory testing in patients with suspected rheumatic disease.
Scleroderma and Hypothetical Patient Presentations
Case 1: Scleroderma Preceded by Raynaud's Phenomenon
Symptom Presentation
A 28-year-old female presents with a 3-year history of redness and discomfort in her fingers and toes, primarily when she is exposed to the cold. She thinks that she has always been sensitive to the cold, as is her mother, but now seeks medical advice since her symptoms have been more bothersome recently. She denies any other symptoms and her general physical examination is unremarkable. Her fingers and toes appear normal.
These symptoms are consistent with Raynaud's phenomenon, an exaggerated vascular reactivity to cold or other stressors. In contrast to simple cold sensitivity, Raynaud's is characterized by a biphasic color response (see Figure 1), with a demarcated area of white or red skin followed by cyanosis (blue skin). The color change after cold exposure should go away quickly on re-warming of the involved digits. Therefore, it is important to question the patient further about the color change and its duration.
Raynaud's Phenomenon: Diagnostic Signs
- biphasic color change of digits upon exposure to cold or other stressors
- not associated with another disease in 90% of cases
- most often occurs in women, age 15 to 30 years
- a family history is often present
Assessment and Diagnosis
In this case, scleroderma is the most important disease to consider since Raynaud's is present in 80% to 90% of cases and may precede other manifestations by months or years. Raynaud's is present in 20% to 40% of patients with SLE as well.
Most individuals with Raynaud's phenomenon have no associated underlying disease and the cold reactivity tends to be mild with no lasting tissue changes, as in this young, healthy woman.2 It is most common in women, aged 15 to 30 years, and there is often a family history of Raynaud's.
If a complete history and physical examination is unremarkable, laboratory testing or further referral is usually not necessary for this young, healthy patient. Approximately 5% to 10% of individuals with Raynaud's phenomenon will eventually be diagnosed with a systemic disease so patients should be periodically reevaluated, particularly if the Raynaud's symptoms worsen.2
Treatment
The most important management issues in any person with Raynaud's phenomenon is the avoidance of excess cold exposure, especially a sudden temperature drop. Initial therapy should include recommendations to avoid the cold and to take protective warming measures.
General cardiovascular exercise and periodic extremity movement, such as whirling the arms, are useful, as well as items such as chemical hand or boot warmers.
If symptoms persist, a calcium channel blocker, such as amlodipine, should be tried, and often topical nitrates are effective. Patients with digital ischemia should be referred to a vascular specialist.
Case 2: Scleroderma and Signs of Internal Organ Disease
Symptom Presentation
A 34-year-old female reports symptoms consistent with Raynaud's phenomenon for the past year. In the past month, she noticed a small, ulcerated area of skin at the tip of her fourth right finger.
In discussing her health, she reports frequent heartburn and occasional difficulty swallowing dry foods or large chunks of meat. She also describes dry skin and a sensation of tightness around her mouth, which she associates with the swallowing difficulty.
Her physical examination reveals the small, healed digital ulcer on her right index finger and taut, indurated skin around that digit but also over a number of other fingers. The skin around her mouth and cheeks also feels thick and she has difficulty opening her mouth widely.
Assessment and Diagnosis
In this patient, a number of features suggest that the Raynaud's is associated with a systemic disease, most likely scleroderma. Raynaud's symptoms have only been present for 1 year but have been severe enough to have caused tissue changes. Tight, indurated skin on the digits and face is strong evidence for scleroderma, and other dermatologic features, including hyperpigmentation and telangiectasias, should be sought out.
Appropriate laboratory testing would include a CBC, ESR or CRP, and an ANA, with a rheumatology and possibly a dermatology consultation.
The patient's skin involvement at this stage seems limited to the face and fingers but limited scleroderma can still be associated with internal organ disease. The heartburn and difficulty swallowing suggest gastrointestinal involvement. Esophageal dysfunction is common both in limited and diffuse subtypes of SSc and referral to a gastroenterologist for evaluation and possible esophageal motility studies are warranted.
Limited cutaneous SSc may also have lung involvement, which initially may be asymptomatic. This patient should therefore undergo a complete pulmonary evaluation, including pulmonary function tests (PFTs) and a chest CT scan. Her gastrointestinal evaluation demonstrated abnormal esophageal motility but her pulmonary studies detected no abnormalities.
Treatment
In this case, let's assume the gastroenterologist found abnormal esophageal motility and conservative management for her heartburn and dysphagia would begin. Therapy would include head of the bed elevation to 30 degrees and avoidance of meals and alcohol 2 hours prior to bedtime, as well as a proton pump inhibitor.
If the dysphagia does not improve, a trial of a prokinetic drug such as metoclopramide would be recommended. Such a medication might also be useful for lower intestinal dysmotility.
Preventing further skin induration and potential contractures and deformities in this patient, as well as in Case 3 below, can be challenging and there is little evidence for significant improvement with medications in the skin manifestations of scleroderma.
Since this patient has evidence of internal organ disease, most rheumatologists would begin a trial of either methotrexate or mycophenolate mofetil; limited trials have demonstrated possible benefit in skin disease and in long-term survival.5
Case 3: Diffuse Cutaneous Scleroderma and Renal Crisis
Symptom Presentation
A 52-year-old female presents with swelling of her hands and feet for the past year. She is modestly overweight with recently diagnosed type 2 diabetes and elevated blood pressure. She began a diuretic and an oral hypoglycemic medication 3 months ago with no effect on the swelling. During the past 6 weeks, she has had difficulty fully opening her fingers and has felt short of breath with limited activity.
On examination, her blood pressure was 170/90 but there were no abnormalities noted in the heart or lungs. Her hands and feet were puffy but there was no piting edema. The skin over the hands and forearms and both distal extremities felt tight and thick, and it was difficult to extend the fingers (see Figure 2). The skin on her face also felt indurated and there were vascular patches characteristic of telangiectasias around her cheeks. The musculoskeletal and neurologic examinations were otherwise unremarkable.
Assessment and Diagnosis
This patient most likely has diffuse cutaneous SSc, presenting with skin thickness and tightness involving the upper and lower extremities as well as the face. The symptoms have been slowly developing and had been attributed to the much more common co-morbidities of type 2 diabetes, weight gain, edema, and hypertension. It can be difficult for patients or healthcare providers to differentiate whether puffy extremities are a result of excess soft-tissue fluid or skin induration, and the onset of congestive heart failure could have accounted for the swelling and dyspnea.
This patient should be referred urgently to a rheumatologist who would confirm the diagnosis and coordinate an extensive evaluation for systemic involvement. Ten percent to twenty percent of patients with diffuse cutaneous SSc may present with what has been dubbed scleroderma renal crisis, manifested by difficult to control hypertension and renal failure. In this patient, the serum creatinine was normal and there was no proteinuria. Her blood pressure was quickly brought under control with more aggressive anti-hypertensive medications. She should now be sent to a pulmonologist for a complete lung evaluation.
The two main pulmonary complications of scleroderma are interstitial lung disease, present in 50% to 65% of SSc and pulmonary hypertension, present in 10% to 20%.3 These also often occur concurrently. The pulmonary evaluation in this patient would include PFTs and a high-resolution chest CT scan. Interstitial lung disease is manifested by reduced lung volume and reduced single breath diffusion capacity for carbon monoxide (DLCO), and pulmonary imaging typically reveals diffuse ground glass opacities. Pulmonary artery pressure is usually measured by echocardiography. An elevated brain natriuretic peptide or N-terminal pro-brain natriuretic peptide is suggestive of pulmonary hypertension.4
Treatment
Interstitial lung disease is the most common cause of death among patients with systemic sclerosis, with a 10-year mortality of 40%.6 If PFTs and chest CT scan are consistent with interstitial lung disease in this patient, potent immune suppressive therapy would be generally initiated.
Mycophenolate mofetil or cyclophosphamide have been the most commonly used medications but targeted biological agents, antifibrotic therapies, and autologous hematopoietic stem-cell transplantation have been used in refractory cases.
If pulmonary hypertension is present, a pulmonologist and cardiologist would direct therapy, usually consisting of a combination of vasodilator drugs.7
Medications In the Pipeline for Scleroderma, Systemic Sclerosis
Unraveling the basic disease mechanisms of systemic immune diseases has led to an array of medications that have revolutionized the treatment of rheumatoid arthritis and many other rheumatic diseases, including vasculitis and SLE. Unfortunately, the unique pathophysiologic abnormalities of fibroblast activation and vascular damage in scleroderma have not been well characterized. There has been no therapy that has significantly interfered with fibrosis in this or any other fibrosing disease.
In search of autoimmune connections to these two underlying mechanisms, investigators are studying cytokines directed at transforming growth factor and platelet derived growth factor as well as vascular endothelin growth factor.
Most studies have focused on immune biological drugs in systemic sclerosis, including rituximab, tocilizumab, and abatacept (see Table II). Nintedanib, a tyrosine kinase inhibitor, and tocilizumab, which targets the interleukin-6-pathway, are the first FDA-approved drugs for slowing the rate of pulmonary function decline in SSc.8
However, the clinical benefit of any medication in SSc has been limited. Choice of medications for SSc needs to be determined by the specific organ involvement and its individual severity. Medications that impede excess fibrosis, such as imatinib, are being tested in SSc, although not yet-widely available. Investigators are now initiating studies utilizing a combination of immune modulating medications, each with different mechanisms of action, in the treatment of SSc. Until there is a better understanding of disease mechanisms, scleroderma will continue to be the most challenging rheumatic disease with the highest mortality rate.
Last updated on: January 5, 2022
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