Clinical and Health Affairs
Toward the Early Diagnosis of Systemic Sclerosis
Warning Signs the Practitioner Needs to Recognize
By Jerry A. Molitor, M.D., Ph.D.
Abstract
Systemic sclerosis, or scleroderma, is a rare condition that first presents with symptoms common to many other diseases. Because of this, diagnosing it can be difficult and take time. This article describes warning signs of possible incipient scleroderma as well as tests that can help the primary care provider identify this serious autoimmune disorder.
Among the challenges busy primary care practitioners face is knowing when to suspect a possible rare diagnosis among the many common ones seen each day. Systemic sclerosis (SSc), or scleroderma, is a condition that presents such a challenge. Scleroderma, which is Greek for “hard skin,” refers to a spectrum of disorders that carry the common histologic hallmark of excessive collagen deposition in the skin. There are two forms of SSc: diffuse cutaneous SSc and limited cutaneous SSc, also known as CREST, which is an acronym for calcinosis, Raynaud’s, esophageal dysmotility, sclerodactyly, and telangiectasias. Diffuse cutaneous SSc refers to the disease when it presents with significant thickening and irritation of the skin over most of the body. Limited cutaneous SSc refers to disease in patients with skin thickening limited to the face, hands, feet, and/or distal forearms and legs. This form of scleroderma always spares the more proximal extremities and trunk.
With an estimated prevalence of approximately 250 cases per 1 million population1 and an annual incidence of approximately 20 new cases per million population,2 SSc is a very rare disease. It has been estimated that the average primary care provider may see only one or two cases in a lifetime. Both because it is so rare and because the initial symptoms are common ones, SSc can be difficult to diagnose. In many cases, the diagnosis is made after a year or more of progressive disease manifestations and after several referrals to different specialists including orthopedic hand surgeons, cardiologists, vascular surgeons, and pulmonary specialists.
Treatment of SSc is complex and tends to be based on the organ systems involved and the patient’s most predominant problems. Although there are few universally agreed-upon treatment guidelines for the disease, treatments aimed at several manifestations of SSc (eg, gastroesophageal reflux disease or GERD, renal crisis, and pulmonary hypertension) have improved greatly in recent years.3,4 There has been evidence of improved overall survival as well.5 For those reasons, early diagnosis has become increasingly important. In addition, it allows patients to participate in trials of potential new protocols when they are most likely to qualify for them.
This article describes symptoms that physicians should consider as warning signs of SSc, tests useful for further differentiating SSc from other diseases, and clues to look for on the physical exam.
Warning Signs
Primary care providers should be aware that a number of symptoms and conditions are possible signs of early SSc.
- Raynaud’s Phenomenon
The most frequent initiating symptom of limited cutaneous SSc is Raynaud’s phenomenon (RP). A common condition, RP is estimated to occur in approximately 10% of females and a much smaller percentage of males. Its hallmark is the development of cyanosis of the hands, sometimes with associated pallor, usually in response to exposure to cold or stress. (A common trigger is driving on a cold morning.) With idiopathic RP, there typically is a reactive hyperemia on rewarming. So how does a physician identify the small percentage of patients with RP for whom it is an initial manifestation of SSc or a related autoimmune connective tissue disease such as systemic lupus erythematosus or dermatomyositis?
A major clue is mid-life onset of the phenomenon. Most idiopathic RP starts in adolescence and is characterized by brief, intermittent attacks during the winter with exposure to particularly severe cold. By contrast, SSc-associated RP often has a severe and sudden mid- or late-life onset, with numerous daily attacks that may last for 20 minutes or more. These attacks may occur year round and with only minimal temperature changes or emotional stressors. In addition, scleroderma-associated RP may occur in the feet, nose, or ears, which is quite rare in idiopathic RP. Most important, because patients with SSc-associated RP are at risk for developing digital ulcers and gangrene, any patient who exhibits these characteristics of severe digital ischemia should be assumed to have an underlying systemic disorder. The most likely diagnosis is one of the ANA-positive connective tissue diseases including SSc.
- Hand Edema
Many patients with early diffuse cutaneous SSc present with painful hands and hand swelling that obscures normal visualization of veins and tendons over the dorsum of the hands. Notably, these patients do not have anasarca, and swelling is almost always limited to the hands and forearms and sometimes to the feet and distal calves. They typically have morning stiffness lasting longer than 30 minutes, a sign of inflammation that is also seen in early rheumatoid arthritis and other forms of inflammatory arthritis.
- Bilateral Carpal Tunnel Syndrome
Bilateral carpal tunnel syndrome may accompany hand swelling and stiffness in patients with SSc and is the presenting complaint in a substantial number of patients with SSc, particularly those with diffuse cutaneous SSc. Alert primary care providers, neurologists, and hand surgeons have made provisional diagnoses of scleroderma in this situation. Even when repetitive use may be a contributing factor, the presence of significant contralateral features in the less-used hand may be a sign of SSc, especially if there is hand swelling and no evidence of thyroid disease.
- Gastroesophageal Reflux (GERD)
A condition common in the general population, GERD is a nearly universal feature of patients with both limited cutaneous SSc and diffuse cutaneous SSc. It is present in more than 90% of all SSc cases.
GERD usually develops early in the disease process and may progress at a faster pace than it does in the general population. Often, the patient can clearly identify when it started. On the other hand, a substantial percentage of SSc-associated GERD is asymptomatic, or presents atypically, for example with a cough. Newly diagnosed GERD, especially if accompanied by dysphagia and/or if it occurs with other symptoms of SSc, is a warning sign of SSc. Patients with SSc-associated GERD benefit from aggressive treatment with proton pump inhibitors, often requiring twice-daily treatment.
- Dyspnea/Fatigue/Decreased Exercise Tolerance
These symptoms are, of course, among the most common ones that any clinician encounters, and they can indicate many things. Most patients with early SSc describe fatigue, sometimes even crushing fatigue, with a fairly abrupt onset. Athletes and other physically active patients may be able to quantify a loss of exercise tolerance, which makes this symptom more credible and more worrisome. Those individuals who are not very physically active but become unable to climb a flight of stairs without stopping should also be viewed as having potentially significant dyspnea. Fatigue in association with morning stiffness is highly suggestive of underlying inflammation.
- Severe Hypertension
Severe hypertension in an individual with one or more of the previously mentioned features is highly concerning for possible scleroderma-related renal crisis. This accelerated form of hypertension may result in loss of renal function, congestive heart failure, cardiac arrhythmias, myocardial infarction, seizures, stroke, and death within weeks if unrecognized and untreated.
Testing and Physical Exam
Although there is no definitive test for SSc, a number of tests can help indicate whether a patient with one or more of the above-mentioned symptoms needs to be referred for further evaluation. Any patient who has developed two or more of such concerns over a relatively short period of time should be considered at high risk for SSc and be tested and referred for evaluation by a rheumatologist.
The following tests are simple to do and provide helpful information:
- Nailfold Capillaroscopy
This is an easily learned technique for detection of microscopically visible nailbed telangiectasias, which, when found in several distinct nailbeds in an individual with mid- to late-life onset of RP, are highly suggestive of SSc, dermatomyositis, or other autoimmune connective tissue diseases.6 A small amount of K-Y jelly is applied to the patient’s cuticle to diminish refraction of light. The nailbed can then be examined with 10x to 20x magnification through an ophthalmoscope at close range. The presence of multiple dilated capillary loops and/or tortuous telangiectasias and the presence of areas of obliterated capillaries may indicate SSc or dermatomyositis and should prompt a referral for further evaluation.
- Laboratory Tests
The ANA is an important screening test for connective tissue diseases such as SSc and systemic lupus erythematosus. It is warranted for individuals with diffuse hand swelling or carpal tunnel syndrome and accompanying complaints of hand stiffness or pain. The ANA test is positive in 95% of SSc cases. Many SSc patients will test positive for anti-topoisomerase antibodies or anti-centromere antibodies. These tests are quite specific but relatively insensitive for diffuse cutaneous SSc and limited cutaneous SSc, respectively.
Since early diffuse hand swelling and stiffness are seen in both RA and SSc, and RA is by far the more common diagnosis, both the rheumatoid factor and the anti-CCP (cyclic citrullinated peptide) assays are useful for trying to distinguish RA from SSc during the initial evaluation. The relatively new anti-CCP assay is the more sensitive and specific of the two tests and is positive in approximately 70% of RA cases; it is also highly specific for RA. Erythrocyte sedimentation rate and c-reactive protein are both nonspecific tests for inflammation; but when either surpasses the upper limits of normal, there is an increased likelihood of underlying RA, SSc, or other connective tissue disease.
In patients with a significantly elevated blood pressure and any of the above features, one should suspect possible scleroderma-related renal crisis. Of particular concern are patients who test positive for elevated creatinine combined with microscopic proteinuria. Such patients should be immediately referred to a rheumatologist or nephrologist skilled in caring for patients with SSc renal crisis. These patients benefit from ACE inhibitors, even when their creatinine is significantly elevated, and may require urgent or emergent hospitalization. The goal is to control their blood pressure before seizures, stroke, or MI occur.
- Barium Esophagram (or Esophageal Manometry)
Esophageal manometry is highly sensitive for the detection of esophageal dysmotility, which distinguishes SSc and dermatomyositis-associated GERD from idiopathic GERD. Barium esophagram, however, is nearly as sensitive for dysmotility, also detects strictures or masses, is easily performed at most institutions, and is relatively well-tolerated by patients, making it a good screening test for early SSc-associated GERD.
- Pulmonary Function
Patients with diffuse cutaneous SSc in particular may experience decreased exercise tolerance with or without perceived dyspnea early in disease; but any patient with these features may benefit from a pulmonary function evaluation. Lung volumes or DLCO below the predicted range should prompt an immediate pulmonary evaluation. If any other features are present, the patient should receive a serologic evaluation and rheumatologic referral as well. Most patients with early SSc-associated lung disease will have interstitial lung disease, which may respond to treatment with cyclophosphamide or immunosuppressant drugs such as azathioprine or mycophenolate mofetil. A substantial proportion of SSc patients will develop pulmonary hypertension, usually later in the course of the disease. A growing list of drugs is available for treating pulmonary hypertension.
- The Physical Exam
The last, but certainly not the least important, part of diagnosing SSc is a careful physical exam. The onset of SSC can be quite variable; however, the most severely affected patients may have detectable sclerodactyly, RP, and basilar velcro lung crackles. Patients with diffuse cutaneous SSc who have severe inflammation often have prominent, palpable, and sometimes audible tendon “rubs” reminiscent of knee crepitance but much more notable. These can be detected over extensor surfaces of major joints by palpation and/or auscultation.
Patients who have any of these exam findings or test results in the presence of one or more of the warning signs should be referred to a rheumatologist for consideration of an SSc diagnosis.
Conclusion
Suspecting SSc early in its course is a challenge that “favors the prepared mind,” in the words of Louis Pasteur. Primary care physicians who are aware of the warning signs of the disease and initiate early testing and referral will be able to help patients get the earliest possible diagnosis and the best possible treatment at a time when it is most likely to be effective.MM
Jerry Molitor is associate professor of medicine in the division of rheumatic and autoimmune diseases at the University of Minnesota. He also directs the university’s scleroderma clinic.
References
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