Pretreatment evaluation of adults with systemic sclerosis (scleroderma)

INTRODUCTION — Systemic sclerosis (SSc) encompasses a spectrum of related disorders, most of which share a characteristic clinical feature of skin thickening due to an excess of collagen-containing extracellular matrix within the dermis. The simplest division of the scleroderma-related disorders is into localized and systemic forms of the disease. Localized scleroderma is generally termed "morphea" to avoid confusion with systemic disease (table 1) and is discussed separately. (See "Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults".)

SSc is further classified into major disease subsets based on the extent of skin involvement and the accompanying pattern of internal organ involvement. The principal subsets of SSc are (table 2):

●Diffuse cutaneous systemic sclerosis (dcSSc)

●Limited cutaneous systemic sclerosis (lcSSc)

●Systemic sclerosis sine scleroderma (patients with only internal organ involvement)

●Overlap syndromes (features of systemic sclerosis that coexist with elements of other rheumatic disorders)

Treatment decisions for SSc are informed by a thorough pretreatment assessment of the extent and type of organ involvement, which may also help determine whether organ dysfunction is related to potentially reversible inflammation or vasoconstriction (active disease) or due to damage that is irreversible with existing therapies (eg, fibrosis or ischemic necrosis). This topic summarizes the approach to assessing disease activity, organ involvement and damage, and residual function in adults with SSc.

Overviews of the treatment of SSc in adults and children are presented separately. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults" and "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis".)

PRETREATMENT EVALUATION

General principles — The medical history, physical examination, laboratory tests, and imaging studies that lead to an initial diagnosis of systemic sclerosis (SSc) provide much of the information necessary to determine the distribution of organ involvement and thereby guide the pretreatment assessment. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

In addition, certain autoantibodies found in SSc are associated with subsets of the disease. The presence of some of these autoantibodies may also predict the risk of future organ involvement (table 3). (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Laboratory testing'.)

An important aspect of contemporary management is careful systematic investigation to define the presence and risk of major organ-based complications at diagnosis [1]. In addition, there should be regular review during follow-up to minimize delays in diagnosis and treatment [2], especially for lung complications such as pulmonary arterial hypertension (PAH) or lung fibrosis [3]. Studies have suggested that proactive screening for complications increases ascertainment and has been associated with improved five-year survival, especially for diffuse cutaneous SSc (dcSSc) [4].

A multifaceted approach to patient evaluation is necessary in clinical practice, as this provides a much more robust picture of clinically significant manifestations. Composite activity or severity scores for diffuse and limited disease subsets have been developed and validated [5], building upon the Medsger disease severity scale [6].

Initial organ-based assessment — Assessment of the extent of skin involvement, kidney function, pulmonary function, and the presence or absence of parenchymal lung disease by high-resolution computed tomography (CT) scanning, as well as the estimation of pulmonary arterial pressure by echocardiography, is recommended for all patients who have SSc as part of the initial evaluation. For patients who present in an emergency fashion (eg, with scleroderma renal crisis), some components of the suggested assessment may need to be deferred until the patient is sufficiently stable to undergo the recommended tests and when the presence of acute changes will not compromise the assessment of established cardiac or pulmonary involvement.

Skin involvement — An assessment of the distribution and extent of skin involvement must be made prior to the start of treatment and is typically used to determine disease classification (table 2). The distribution and extent of skin involvement may also be valuable for determining prognosis [7]. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults", section on 'Risk factors for increased mortality'.)

The assessment of skin involvement includes semiquantitative estimation of skin thickness, pliability (hardness), and fixation to underlying structures (tethering). The modified Rodnan skin score (mRSS), which was developed for clinical research, is the most widely used scoring system and may be used in clinical practice to follow the course of cutaneous involvement (figure 1 and figure 2). Skin sclerosis is graded at 17 sites, with scores at each site being 0 (normal), 1 (mild thickening), 2 (moderate thickening), or 3 (severe thickening) [8]. It has been standardized for use in clinical trials and research [9].

When examining the skin, it is generally agreed that rolling skin between index finger and thumb provides the most effective way for estimating thickness of the skin in moving from grades 1 to 3. In late-stage disease, this may be hampered by tethering to underlying structures; grade 3 is completely fixed ("hide-bound"). In practice, standardization between assessors examining the same patients and use of single observers maintain the skin score selected as a valid and useful tool to assess dcSSc. Dermal thickness may be reliably estimated using an ultrasound probe [10], and other tools have been used in clinical trials, such as the durometer. No instrument has outperformed the mRSS in clinical practice.

The skin score cannot be used as a surrogate index for organ-based involvement, but it may be prognostically valuable. As an example, in one study of 134 patients with diffuse skin involvement, a skin score of 20 or more was the third most powerful predictor of mortality after cardiac and pulmonary involvement (respective odds ratios 4.2, 4.0, and 3.6) [7]. A skin score of 20 or more was also the second most powerful predictor of the development of scleroderma renal crisis. Some studies suggest that combining skin-based subsets and autoantibodies helps better define risk of major complication and is applicable in routine clinical practice [11].

The role of patient-reported skin scores is an area of interest and may be complementary to other measures of skin involvement. As an example, the coronavirus disease 2019 (COVID-19) pandemic has reduced opportunities for formal assessment of mRSS; thus, a simple patient-reported skin score has been proposed [12]. In addition, to help assess the impact of skin disease on quality of life among patients with SSc, a patient-reported outcome has been developed [13]. Further research is needed to validate these tools and help determine their utility in routine clinical practice.

Skin involvement in SSc is characterized by variable sclerosis or thickening of the skin. The hands and face are generally the first areas involved, and the hands typically show the most severe changes, especially in the early stages of disease. A more detailed discussion of the cutaneous manifestations of SSc can be found separately. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Cutaneous manifestations'.)

Kidney function — Baseline measurement and subsequent periodic monitoring of blood pressure, serum creatinine, estimated glomerular filtration rate (GFR), and an estimate of proteinuria (either from a 24-hour urine collection or a urine protein-to-creatinine ratio) allow patients who have developed, or those who may be developing, scleroderma renal crisis to be identified. A GFR of less than 60 mL/min is considered clinically significant [14]. Classification criteria for scleroderma renal crisis have been proposed to ensure that this important complication can be confidently defined [15]. A calculator (calculator 1) will calculate the GFR using data from a specific patient. (See "Assessment of kidney function".)

Pulmonary involvement — All patients with suspected SSc should be evaluated for interstitial lung disease and pulmonary hypertension, which are the most frequent types of lung involvement in patients with SSc. A more detailed discussion of the initial evaluation for lung disease in patients with SSc is presented separately (see "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)"). However, we briefly present here the following tests that should be included in the pretreatment assessment:

●Pulmonary function testing (PFT) – This should be done to assess for the presence or absence of a restrictive ventilatory defect or a decrease in the single breath diffusion capacity for carbon monoxide (DLCO).

●Radiographic imaging of the lung – High-resolution CT is preferred to a chest radiograph in SSc due to the greater sensitivity of the high-resolution CT. High-resolution CT frequently reveals interstitial lung abnormalities even in patients with normal PFT results.

●Doppler echocardiography – This is recommended for initial screening for PAH. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening", section on 'Echocardiography'.)

In selected patients with abnormal findings suggesting parenchymal lung disease, bronchoalveolar lavage (BAL) or lung biopsy may be necessary to determine whether the abnormalities are due to active inflammation or to fibrotic interstitial lung disease. While available data do not support the utility of routine BAL, it can be of value in selected cases, especially to exclude infection or other pathology [16].

High-resolution CT has been shown to accurately assess the extent of disease and to predict the histologic subtype [17]. There is a simple staging algorithm for assessing whether lung fibrosis is mild or extensive and whether it has a low or high probability of progression [18]. Although this staging system has been validated in multiple cohorts and is valuable for patients with established lung fibrosis, it is also important to consider patients with subclinical disease who may be at risk for progression. Milder cases of lung involvement with other risk factors for progression are also important to recognize, particularly since more US Food and Drug Administration (FDA)-approved drug treatments are available in the United States [19]. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)".)

Patients with symptoms suggestive of pulmonary hypertension, whose pulmonary arterial pressures cannot be estimated noninvasively (eg, those who have no tricuspid regurgitation), may need right heart catheterization to assess prognosis and to guide treatment. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening", section on 'Screening'.)

Cardiac involvement — All patients should have a screening electrocardiogram (ECG). If there is any suspicion of myocarditis or pericarditis, serum creatine kinase (CK) and troponin (either troponin I or troponin T depending upon availability), an ECG, and an echocardiogram are recommended. Cardiac magnetic resonance imaging (MRI) may provide the best tool for identifying myocardial involvement with fibrosis or inflammation, but it is not routinely used [20]. (See "Cardiac manifestations of systemic sclerosis (scleroderma)", section on 'Screening for cardiac involvement'.)

Additional testing in selected patients — The approach to additional testing in patients is largely guided by symptoms and suspected involvement of other organ systems.

Gastrointestinal involvement — Patients who have symptoms of dysphagia, constipation, diarrhea, fecal incontinence, weight loss, or evidence of malnutrition should be referred to a gastroenterologist for further evaluation. Esophageal, small bowel, colonic, and anorectal function may be affected in patients with SSc [21]. (See "Gastrointestinal manifestations of systemic sclerosis (scleroderma)".)

Musculoskeletal involvement — Assessment of joint mobility and functional abilities may be necessary to tailor appropriate physical and occupational therapy. Measurement of muscle enzymes (CK and aldolase) is recommended initially to exclude myositis. Repeat testing is needed only if symptoms or physical findings of muscle weakness develop during the course of the disease. If myositis is suspected clinically or on the basis of muscle enzymes elevated more than fourfold, then electromyography and muscle biopsy may be considered. (See "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Diagnostic approach'.)

Functional testing — It is recommended that a functional assessment tool be used in combination with the broader assessment of disease involvement to encourage a broad approach to management that may mitigate disease impact. Various assessment tools have been proposed for use in both research and clinical practice [22-24]. Scleroderma-specific functional assessment can be measured using the scleroderma health assessment questionnaire (SHAQ); the disability index has been shown to correlate with other outcome measures in clinical trial cohorts [25]. The SHAQ is one of the most widely used tools. Another tool that has been developed is the Systemic Sclerosis Impact of Disease (ScleroID), which is a patient-reported outcome tool that is meant to capture the patient's experience to help guide care [23].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Systemic sclerosis (scleroderma)".)

SUMMARY AND RECOMMENDATIONS

●General principles – Treatment decisions for systemic sclerosis (SSc) are informed by a thorough pretreatment assessment of the extent and type of organ involvement, which may also help determine whether organ dysfunction is related to potentially reversible inflammation or vasoconstriction (active disease) or due to damage that is irreversible with existing therapies (eg, fibrosis or ischemic necrosis). (See 'Introduction' above and 'General principles' above.)

●Initial organ-based assessment – Assessment of the extent of skin involvement, kidney function, pulmonary function, and the presence or absence of parenchymal lung disease by high-resolution CT scanning, as well as the estimation of pulmonary arterial pressure by echocardiography, is recommended for all patients who have SSc as part of the initial evaluation. (See 'Initial organ-based assessment' above.)

•Skin involvement – An assessment of the distribution and extent of skin involvement must be made prior to the start of treatment and is typically used to determine disease classification (table 2). The modified Rodnan skin score (mRSS) is the most widely used scoring system to follow the course of cutaneous involvement (figure 1 and figure 2). (See 'Skin involvement' above.)

•Kidney function – Baseline measurement and subsequent periodic monitoring of blood pressure, serum creatinine, estimated glomerular filtration rate (GFR), and an estimate of proteinuria (either from a 24-hour urine collection or a urine protein-to-creatinine ratio) allow patients who have developed, or those who may be developing, scleroderma renal crisis to be identified. (See 'Kidney function' above.)

•Pulmonary involvement – All patients with suspected SSc should be evaluated for interstitial lung disease and pulmonary hypertension with pulmonary function testing (PFT), radiographic imaging of the lungs, and doppler echocardiography. (See 'Pulmonary involvement' above.)

•Cardiac involvement – All patients should have a screening ECG. Further testing is guided by symptoms. (See 'Cardiac involvement' above.)

●Additional testing in selected patients – The approach to additional testing is guided by symptoms and suspected involvement of other organ systems (eg, gastrointestinal and musculoskeletal systems). (See 'Additional testing in selected patients' above.)

●Functional testing – It is recommended that a functional assessment tool be used in combination with the broader assessment of disease involvement to encourage a broad approach to management that may mitigate disease impact. (See 'Functional testing' above.)