Dermatology

Limited cutaneous systemic sclerosis (Scleroderma, CREST syndrome)

Are You Confident of the Diagnosis?

What you should be alert for in the history

Scleroderma is a broad term used to denote a subset of fibrosing disorders. Scleroderma has been further subclassified into localized scleroderma (morphea), limited cutaneous systemic sclerosis (previously CREST syndrome, standing for calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) and diffuse cutaneous systemic sclerosis. Patients with limited cutaneous systemic sclerosis (LSScl) have sclerosis limited to distal extremities (ie, below the elbows and knees) and face. This differentiates them from patients with diffuse cutaneous systemic sclerosis, who present with proximal (above the knee and elbow) skin thickening.

Although patients in each subset of disease share many comorbidities, patients with limited cutaneous systemic sclerosis have a better prognosis than patients with diffuse cutaneous systemic sclerosis and are less likely to suffer from renal crisis. However, patients with limited cutaneous systemic sclerosis are more likely to suffer from isolated pulmonary artery hypertension (PAH ,ie, pulmonary hypertension not associated with interstitial lung disease [ILD] or left heart failure) than patients with diffuse cutaneous systemic sclerosis, and are at high risk of developing ILD.

Patients with early limited cutaneous systemic sclerosis may present with swollen erythematous hands and Raynaud’s phenomenon. Unfortunately, these findings are not specific to systemic sclerosis, making early diagnosis difficult. Later in the course of disease patients with LSScl form sclerodactyly and sclerosis proximal to their metacarpophalangeal joints (MCPs), digital tip ulcerations, cutaneous calcinosis, a decrease in their oral aperture, and telangiectasias. Patients with LSScl are also at risk for ILD, isolated PAH, gastric esophageal reflux, and sclerosis of the gastrointestinal (GI) tract and the myocardium.

Patients with LSScl usually report that their Raynaud’s phenomenon began years prior to development of additional symptoms. They commonly report symptoms of gastroesophageal reflux. Their friends and family comment that they look younger secondary to the loss of peri-oral wrinkles. They may have noticed that their oral aperture has decreased over time. It is important to elicit symptoms of commonly associated comorbidities by performing a comprehensive review of systems, with emphasis on GI and cardiopulmonary systems.

Characteristic findings on physical examination

Physical examination of a patient with limited systemic sclerosis may reveal matte-like telangiectasias, sclerosis of the peri-oral skin with a decrease in the oral aperture, sclerosis of the skin distal to the elbows and knees with pigmentary abnormalities, Raynaud’s phenomenon with digital pulp ulceration or pitting (Figure 1), nail fold capillary changes (capillary loop dilation, hemorrhage, or capillary drop-out), and cutaneous calcinosis.

Figure 1.

Note digital ulceration indicative of limited cutaneous systemic sclerosis.

Expected results of diagnostic studies

Diagnosis of limited cutaneous systemic sclerosis is based on disease pattern recognition. Histopathology is not required for diagnosis, and does not differentiate morphea from limited cutaneous systemic sclerosis or from diffuse cutaneous systemic sclerosis. The majority of patients with limited cutaneous systemic sclerosis will have positive anti-nuclear-antibodies. Forty percent to 90% of patients with limited cutaneous systemic sclerosis will have positive anti-centromere antibodies.

Although anti-topoisomerase antibodies (otherwise known as anti-Scl-70 antibodies) are more commonly seen in patients with diffuse cutaneous systemic sclerosis, they can be seen in up to 25% of patients with limited cutaneous systemic sclerosis. Presence of anti-topoisomerase antibodies is a poor prognostic sign, with an increased risk of severe ILD and heart and kidney involvement. Patients with limited cutaneous systemic sclerosis should have normal thyroid tests and no evidence of monoclonal gammopathy on serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP).

Diagnosis confirmation

The differential diagnosis of limited cutaneous systemic sclerosis includes diffuse cutaneous systemic sclerosis, generalized morphea, scleromyxedema, nephrogenic systemic fibrosis, eosinophilic fasciitis, and graft-versus-host disease. As stated previously, the physical examination finding that differentiates diffuse cutaneous systemic sclerosis from limited cutaneous systemic sclerosis is sclerosis of the skin proximal to the elbows and knees.

Generalized morphea can be difficult to differentiate from limited cutaneous systemic sclerosis. Patients with generalized morphea should not have symmetric sclerodactyly, should not have secondary Raynaud’s phenomenon or digital pulp loss, and should not have nail fold capillary changes. Up to 75% of patients with generalized morphea will have a positive antinuclear antibody (ANA), and up to 12% will have anti-centromere antibodies. Therefore, auto-antibody profiles alone do not differentiate these two disease subsets.

Patients with scleromyxedema can present with induration of their face and hands, Raynaud’s phenomenon and esophageal dysmotility, requiring a high index of suspicion for differentiation from limited cutaneous systemic sclerosis. Patients with scleromyxedema present with sheets of waxy papules that often form linear arrays, and more pronounced involvement of their foreheads, resulting in leonine facies. Patients with limited cutaneous systemic sclerosis have not been described as having these cutaneous findings.

Patients with scleromyxedema do not present with telangiectasias or calcinosis, which are common findings in limited cutaneous systemic sclerosis. Patients with scleromyxedema almost always have an associated monoclonal gammopathy, usually with IgG lambda light chains. Limited cutaneous systemic sclerosis and scleromyxedema can also be differentiated on histopathologic examination based on the diffuse infiltration of mucin seen in scleromyxedema.

Nephrogenic systemic fibrosis (NSF) is a rare fibrosing disorder occurring in patients with renal failure who are exposed to gadolinium during a time of inflammation or acidosis. These patients present days to months after gadolinium exposure with progressive, painful induration of the skin most commonly on the upper and lower extremities and characteristic brown scleral plaques. Involvement of the trunk and periocular regions have also been described. The plaques are ill defined and have intervening islands of sparing. Patients with NSF have a characteristic history (renal failure and gadolinium exposure), no Raynaud’s phenomenon, no nail fold capillary changes, and no telangiectasias.

Patients with eosinophilic fasciitis (EF) present with induration and erythema of the extremities, classically after a strenuous activity, and a peripheral eosinophilia. Patients with EF do not have sclerodactyly, facial involvement, telangiectasias, nail fold capillary changes, or Raynaud’s phenomenon.

Patients with sclerodermoid graft-versus-host disease will have a history of prior bone marrow or stem cell transplant.

Who is at Risk for Developing this Disease?

As in most autoimmune diseases, limited cutaneous systemic sclerosis is predominantly diagnosed in females. This predominance is most striking during the child-bearing years. African-Americans have approximately twice the prevalence of disease when compared with whites. Patients with limited cutaneous systemic sclerosis are usually diagnosed between the ages of 30 and 50 years.

Patients with limited cutaneous systemic sclerosis are more likely than their age- and sex-matched peers to have family members with systemic sclerosis and other autoimmune diseases. A strikingly high prevalence of diffuse cutaneous systemic sclerosis has been described in Choctaw Native Americans in Oklahoma. No such clustering has been discovered for limited cutaneous systemic sclerosis.

What is the Cause of the Disease?

Etiology

The etiology of systemic sclerosis remains a mystery. It is thought that patients who develop the disease have an underlying genetic predisposition and are then exposed to something in the environment that triggers disease presentation.

Pathophysiology

Patients with systemic sclerosis have endothelial injury early in the course of their disease. This endothelial injury upregulates cellular adhesion molecules, which promote migration of immune cells into the dermis. These cells produce pro-inflammatory and pro-fibrotic cytokines such as Il-6 and TGF-beta that activate fibroblasts.Fibroblasts increase their collagen production, and matrix metalloproteinases (enzymes that usually break down collagen) are decreased.This ultimately results in increased collagen production and decreased collagen destruction.

Systemic Implications and Complications

Patients with limited cutaneous systemic sclerosis may experience myriad systemic complications. They are most at risk for esophageal dysmotility (67%), ILD (37%), and isolated PAH (31%). Screening recommendations are based on expert opinion.

At initial presentation, patients with limited cutaneous systemic sclerosis need a thorough cardiopulmonary review of symptoms. All patients should have pulmonary function tests (PFTs) with diffusion capacity for carbon dioxide (DLCO) measurement, transthoracic echocardiogram (TTE) with Doppler, and an electrocardiogram. Patients with symptoms of ILD (dry cough, shortness of breath, etc) should also have a baseline high-resolution computed tomography (HRCT) of their lungs. Further work-up depends on the results of screening tests.

Asymptomatic patients with restrictive patterns on their PFTs (decreased lung volumes, FVC < 80% predicted, reduced DLCO) need further evaluation with HRCT and pulmonary consultation. Patients with isolated low DLCOs (ie, in the setting of otherwise normal PFTs) need to be further evaluated for both PAH and ILD with HRCT and TTE, respectively. HRCT is very sensitive for ILD. TTE is not a sensitive test for mild to moderate PAH (ie, estimated pulmonary artery pressures<45mmHg). Therefore, if a patient has an isolated low DLCO, no evidence of ILD, and your index of suspicion for PAH is high, they should undergo a right heart catheterization for more definitive evaluation of PAH.

Similarly, patients with high estimated pulmonary artery pressures (>45mmHg) also require right heart catheterization for definitive diagnosis.Patients with confirmed pulmonary hypertension need to be evaluated for secondary causes (ILD, left heart failure) and should see a pulmonologist who specializes in the care of patients with pulmonary hypertension. Asymptomatic patients with normal PFTs, DLCO, and TTE with Doppler should have these tests repeated annually.

Although patients with limited cutaneous systemic sclerosis are at low risk of renal crisis, monitoring is still recommended given the high morbidity and mortality of renal crisis. Monitoring should include regular blood pressure monitoring (both at home and in clinic), complete blood counts, creatinine and urinalysis (assessing for hematuria and proteinuria).

Renal crisis is defined as new-onset systolic blood pressure (SBP) greater than 140mmHg or diastolic blood pressure (DBP) of greater than 90mmHg, or a rise in SBP of 30mmHg or a rise in DBP of 20mmHg as well as one of five additional criteria (increased serum creatinine by 50% over baseline, dipstick proteinuria of 2+ or greater, thrombocytopenia of 100,000 or less, or evidence of hemolysis).

Renal crisis may be precipitated by corticosteroids, and thus these medications should be avoided in patients with limited cutaneous systemic sclerosis. Patients with renal crisis need to be admitted to an inpatient ward and treated with angiotensin-converting enzyme (ACE) inhibitors (preferably captopril). Treatment with these agents has dramatically improved the morbidity and mortality associated with renal crisis.

Treatment Options

Table I. Treatment options for limited cutaneous systemic sclerosis

Table I.

Treatment options for limited cutaneous systemic sclerosis
Medical Treatment Physical Modalities
Systemic Symptoms (fatigue, arthralgias, arthritis): Hydroxychloroquine 6.5mg/kg/day Physical therapy to prevent joint contractures. Occupational therapy to help with activities of daily living if needed.
Skin symptoms(pruritus, induration)
Topical steroids
UV
Raynaud’s Phenomenon: Cold avoidance/clothing layers
Nifedipine Warming gloves
Sildenafil Stop smoking
Severe systemic involvement (ILD, GI involvement):
Referral to rheumatologist
Referral to pulmonologist if evidence of ILD
Referral to gastroenterologist for help with motility disorders, bacterial overgrowth, reflux
PAH:
Referral to pulmonologist with subspecialty in treatment of PAH

Optimal Therapeutic Approach for this Disease

There is little data to guide treatment decisions for patients with limited cutaneous systemic sclerosis (Table I). The majority of the data are in the treatment of isolated PAH and digital ulceration from severe Raynaud’s phenomenon – both beyond the scope of typical dermatology practice. ILD remains difficult to treat as well. Most importantly, there are no studies that assess the role of immunosuppressive therapy in prevention of systemic complications.

I usually begin with a frank discussion with my patients. We discuss the risks of immunosuppression and the fact that there are unknown benefits. For those patients with systemic symptoms of fatigue and arthralgia, I recommend a trial of hydroxychloroquine. There is no data to support the use of hydroxychloroquine in patients with limited cutaneous systemic sclerosis, but hydroxychloroquine has proven beneficial in other autoimmune connective tissue diseases and has a relatively benign side effect profile.

Hydroxychloroquine should be dosed at 6.5mg/kg/day of ideal body weight. Patients should be counseled about the risk of cutaneous blue-grey pigmentation and retinopathy. Patients should have a baseline visual field examination within the first 3 months of hydroxycholorquine therapy, and every 6 months thereafter. hydroxychloroquine is usually not effective until taken for at least 2 to 3 months. If the patient does not feel better after 3 months of hydroxychloroquine, I suggest we consider stopping the medication.

Patients with Raynaud’s phenomenon should be counseled on cold avoidance, clothing layering, and smoking cessation. Patients with severe Raynaud’s phenomenon may benefit from dihydropiridine calcium antagonists such as nifedipine and felodipine, or cGMP phosphodiesterase inhibitors such as sildenafil. Nifedipine can be started at 30mg by mouth daily and slowly titrated up every week or two, until Raynaud's phenomenon improves or side effects prohibit further increases.

Felodipine has higher vascular specificity for peripheral vasculature, and therefore is a good option as well. Felodipine can be initiated at 2.5mg by mouth twice a day and slowly titrated up, similarly to nifedipine. Sildenafil, a cGMP phosphodiesterase inhibitor, has provided patients some relief at a dose of 50mg by mouth 3 times a day. Patients should also be counseled on the risk of hypotension with either of these classes of medications.

Patients with Raynaud’s phenomenon may also benefit from the addition of serotonin re-uptake inhibitors (SSRIs) to their regimen. SSRIs deplete platelet serotonin and therefore inhibit aggregation. I usually add fluoxetine at a dose of 20mg by mouth daily to a vasodilating medication. Patients with digital ulcerations from Raynaud’s phenomenon may also be treated with bosentan and intravenous prostacyclin.

Physicians specializing in the treatment of PAH have the most experience with these medications, and I therefore refer my patients to pulmonology for these treatments. Botulinum toxin injections have also recently been used to heal ulcerations caused by vasoconstriction and may prove to be a useful therapy in the future.

For the skin manifestations of limited cutaneous systemic fibrosis, I recommend topical steroids. The steroids help with the pruritus and may lead to some lesional thinning. Most patients with limited cutaneous systemic sclerosis do not have explosive skin involvement like their diffuse cutaneous systemic sclerosis counterparts, and I therefore generally avoid systemic immunosuppression for skin manifestations in these patients. Studies assessing skin response to systemic immunosuppression have been carried out in patients with diffuse cutaneous systemic sclerosis, and to date no form of systemic immunosuppression has resulted in significant clinical improvement.

For patients who have explosive disease, or significant sclerosis causing contractions, I do offer phototherapy. UVA1 has the most evidence supporting its use in fibrosing disorders. However, UVA1 light sources are rare in the United States. There are case series and studies supporting the use of psoralen-UVA (PUVA), broadband UVA, and narrow-band UVB (NB-UVB) in localized scleroderma (morphea) and systemic sclerosis. I offer my patients a trial of NB-UVB 3 times weekly for 3 months to involved areas. We discuss that there are no trials assessing the efficacy of NB-UVB in patients with limited cutaneous systemic sclerosis.

I choose NB-UVB over PUVA and broadband UVA because it does not require systemic medication, and the patient requires less time in the phototherapy unit, which minimizes risk and physical discomfort for this yet unstudied therapy.

I recommend that patients obtain physical therapy and occupational therapy to prevent contractures and to help them manage their activities of daily living if they have contractures.

Patient Management

As discussed previously, all patients with limited cutaneous systemic sclerosis should have annual PFTs with DLCOs and TTEs with Doppler to screen for ILD and PAH. New cardiopulmonary symptoms should be carefully evaluated. If patients have evidence of ILD, a pulmonary consult is warranted. If they have evidence of isolated PAH, evaluation by a pulmonologist who specializes in pulmonary hypertension is necessary. Monitoring for renal crisis includes regular blood pressure monitoring (both at home and in clinic), complete blood counts, creatinine and urinalysis (assessing for hematuria and proteinuria) at clinical follow-up.

If the patient is treating their skin with topical steroids, careful assessment for epidermal atrophy needs to be performed at each appointment, with cessation of topical steroids if atrophy occurs.

If a patient with limited cutaneous systemic sclerosis develops skin thickening or induration of their proximal extremities or trunk, they then meet criteria for diffuse cutaneous systemic sclerosis. I consider the use of systemic immunosuppression for skin thickening in patients with diffuse cutaneous systemic sclerosis, after a frank discussion of the risks and the unknown benefits.

Unusual Clinical Scenarios to Consider in Patient Management

The diagnosis of early systemic sclerosis is difficult, as patients may present with only Raynaud’s phenomenon and swollen hands. The differential then includes mixed connective tissue disease (if they have high-titer U1 RNP [ribonucleoproteins]antibodies) or undifferentiated connective tissue disease. Patients with autoimmune connective tissue disease need to be counseled on the role of pattern recognition in diagnosis, and expect that their diagnosis may change over time.

Overlap syndromes present particular diagnostic challenges. Patients with polymyositis/systemic sclerosis overlap have been described with the typical features of systemic sclerosis in addition to polymyositis, dermatomyositis, and Sjogren’s syndrome. Overlap features of rheumatoid arthritis have also been described in patients with systemic sclerosis.

What is the Evidence?

Abraham, DJ, Krieg, T, Distler, J, Distler, O. "Overview of the pathogenesis of systemic sclerosis". Rheumatology. vol. 48. 2009. pp. 3.

(This article provides a clear and succinct review of what is understood and yet unknown about the pathophysiology of systemic sclerosis. The authors highlight the interplay between microvascular damage, immunologic mediators, fibroblasts, and the epithelium.)

Gabrielli, A, Avvedimento, EV, Krieg, T. "Scleroderma". N Engl J Med. vol. 360. 2009. pp. 1989.

(This article is an in-depth review of systemic sclerosis. The authors discuss the known epidemiology, genetic, and environmental factors in disease progression, and the pathophysiology of disease development, and also highlight future treatment targets.)

Latsi, PI, Wells, AU. "Evaluation and management of alveolitis and interstitial lung disease in scleroderma". Curr Opin Rheum. vol. 15. 2003. pp. 748.

(This paper reviews the available evidence on screening for ILD in patients with systemic sclerosis including pulmonary function testing (PFTs), bronchoalveolar lavage, and HRCT. The authors highlight prognostic features that may drive early therapy (deterioration, severe disease, autoantibody status and disease duration) and review the data on early therapy. They conclude that PFTs and HRCTs are pivotal for screening and monitoring of ILD in systemic sclerosis and highlight the lack of data on treatment.)

Proudman, SM, Stevens, WM, Sahhar, J, Celermajer, D. "PAH in systemic sclerosis: the need for early detection and treatment". Int Med J.. vol. 37. 2007. pp. 485.

(This paper reviews the definition and classification of PAH, as well as the pathogenesis and prevalence of PAH in systemic sclerosis. The authors highlight the risk factors associated with PAH in systemic sclerosis and the current evidence on treatment options. They discuss the need for early detection of PAH for improved patient outcomes and review appropriate screening practices including pulmonary function tests and transthoracic echography, as well as the limitations of both.)

Lambova. "New lines in therapy of Raynaud’s phenomenon". Rheumatol Int. vol. 29. 2009. pp. 355.

(This review is an exhaustive list of the treatment options for Raynaud's phenomenon (with the exception of botulinum toxin), in conjunction with supporting trial information. It is a wonderful reference for practice purposes.)

Quillinan, NP, Denton, CP. "Disease-modifying treatment in systemic sclerosis: current status". Curr Opin Rheum. vol. 21. 2009. pp. 636.

(This review summarizes treatment options by class (ie, immunomodulatory, antifibrotic, biologic) and the studies of their use in systemic sclerosis. )

Kreuter, A, Hyun, J, Stucker, M, Sommer, A, Altmeyer, P, Gambichler, T. "A randomized controlled study of low-dose UVA1, medium-dose UVA1, and narrowband UVB phototherapy in the treatment of localized scleroderma". J Am Acad Dermatol. vol. 54. 2006. pp. 440.

(This is a prospective randomized trial comparing low-dose UVA1, medium-dose UVA1 and narrowband UVB (NBUVB) in the treatment of localized scleroderma (morphea). A total of 64 patients were treated: 27 with low-dose UVA1, 18 with medium-dose UVA1, 19 with NBUVB. Outcome measures included change in skin score, change in visual analog scale, change in histopathologic score, change in 20Hz ultrasound measurement. All three treatments had statistically significant changes in the outcome measures, with medium-dose UVA1 being the most effective.)

Morita, A, Kobayashi, K, Isomura, I, Tsuji, T, Krutmann, J. "Ultraviolet A1 (340-400 nm) phototherapy for scleroderma in systemic sclerosis". J Am Acad Dermatol. vol. 43. 2000. pp. 670.

(This is a small pilot study of four subjects with systemic sclerosis. Treatment was localized to the forearms. All four subjects had improvement of their skin scores, increased range of motion, and change in histology with treatment.)

El-Mofty, M, Mostafa, W, El-Darouty, M, Bosseila, M, Nada, H, Yousef, R. "Different low doses of broad-band UVA in the treatment of morphea and systemic sclerosis". Photodermatol Photoimmunol Photomed. vol. 20. 2004. pp. 148-56.

(This is a small prospective randomized trial of 15 patients with systemic sclerosis who were randomly assigned treatment with 5, 10, or 20J/cm2 of UVA, with cumulative doses of 100, 200 or 400J/cm2, respectively. The outcome measure was changed based on visual and palpation inspection. The authors did not assess for statistically significant changes within treatment groups. They report that treatment of systemic sclerosis with broad-band UVA at all three doses resulted in equivalent clinical outcomes.)

Brenner, M, Herzinger, T, Berking, C, Plewig, G, Degitz, K. "Phototherapy and photochemotherapy of sclerosing skin disease". Photodermatol Photoimmunol Photomed. vol. 21. 2005. pp. 157-65.

(This article reviews phototherapy modalities, side effects, and the studies to date in subjects with systemic sclerosis.)
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