الفهرس 
Review of LiteratureOnly 14 pages are availabe for public view
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Abstract
SSc is an autoimmune disease with a complex pathogenesis leading to diffuse microangiopathy and tissue fibrosis. Skin involvement is one of the major clinical features of SSc due to an abnormal collagen dermal deposition. The evolution of SSc skin involvement is characterized by three phases in temporal sequence: edematous, fibrotic, and atrophic (Albano et al., 2020).
The modified Rodnan skin score (mRSS) is a quick, noninvasive clinical assessment that correlates with histological grading of skin fibrosis. However, it lacks the sensitivity to differentiate between clinically indistinguishable pathological phases such as inflammatory edema vs. established fibrosis (Flower et al., 2021).
High frequency (≥18MHz) ultrasound (HFU) with high spatial resolution may visualize the epidermis, dermis, and hypodermis, precisely measure skin thickness, as well as assess skin edema, fibrosis, and atrophy. HFU is subject to sampling artifacts and incompleteness, so its validity is disputed (Lettieri et al., 2020).
The aim of this study was to evaluate the role of HFUS of skin in assessment of early changes in skin thickness and echogenicity in patients with SSc.
Our study is a cross-sectional, observational study involving homogenous groups consisting of 23 SSc patients and 21 healthy age and sex matched controls.
Patients who fulfilled the 2013 ACR/EULAR Classification Criteria for SSc (Van Den Hoogen et al., 2013).
All patients were subjected to the following:
Full history taking and through clinical examination (both general and musculoskeletal) and subjected to basic lab tests as ESR, CRP, CBC.
Skin involvement was assessed using the mRSS, by palpation of 17 skin regions (face, anterior chest, abdomen and bilateral upper arms, forearms, hand dorsa, fingers, thighs, legs and dorsa of the feet) and was scored on a 0 - 3 categorical scale (maximum = 51).
Skin HFU: Skin thickness and echogencity were assessed in both patients and controls by high frequency US Linear array transducer 6-18 MHz and E-Zaote My Lab Six machine for assessment of skin thickness and echogenicity at 5 areas previously assessed by modified Rodnan skin score in both patients and control (Khanna et al., 2017). All subjects were examined at five anatomical sites— the area in-between dorsal metacarpophalangeal joints of second and third fingers of the right hand (area1), the dorsal skin of the proximal phalanx of the right second finger (area2), the dorsal skin of the right forearm 3 cm proximal to the wrist (area 3), the skin of the right leg 12 cm proximal to the ankle joint (area 4) and the sternum 2 cm distal to the upper part of the manubrium (area 5).
The patient’s skin echogenicity of each site was compared with site matched normal skin in healthy controls and classified as; normal, hypoechogenic and hyperechogenic.
Nail fold capillary microscopy was performed for all SSc patients as a confirmatory diagnostic tool.
In the our study, all cases (100%) had positive Raynaud’s phenomenon. 13 patients (56.5%) had dyspnea, 4 patients (17.4%) had leathery crepitations, 3 (13%) had hypertension, 12 (52.2%) had dysphagia, 18 patients (78.3%) had reflux and mRSS was 24.83±6.30 (22.0 – 29.0).
All the 23 SSc cases (100%) had positive nail fold capillary criteria of SSc at disease onset. HRCT was indicated in 17 cases and revealed that 11 patients (64.7%) had ILD, 10 patients had ground-glass opacity whereas only one patient (5.9%) had honeycombing.
Regarding patient serology our study reported that anti-Scl70 was positive in 78.3% of the studied cases (known to be more common in dcSSc), ANA in 73.9% of the studied cases.
In our work, US measured dermal thickness showed statistically significant higher values in cases compared to controls.
In our study, zero mRSS was detected at abdomen, thigh, arm, dorsum of feet and dorsum of hand in some patients with SSc.We compared US skin thickness at dorsum of hand in SSc patients with zero mRSS with US dermal thickness at dorsum of hand in age and sex matched controls.This revealed highly statistically significant higher dermal thickness in cases compared to controls, a finding that reflects the value of HFUS to detect even subclinical increase of dermal thickness in early stages of the disease hence its superiority to mRSS.
In our study we used the ROC curve to test the diagnostic performance of HFUS in SSc. There was reliable sensitivity for US dermal thickness at area 1 both longitudinal (95.7%) and transverse (86.96%) and at area 2 longitudinal (95.65%) and transverse (100%) (at cut off values of >1, >1.1, >1.2, and >1 respectively) in differentiating normal from pathologic skin thickness. Moreover, negative predictive value for US skin thickness at area 1 longitudinal and transverse was 90% and 76.9% respectively, and at area 2 was 92.3% and 100% respectively, reflecting the reliability of US measured dermal thickness at area 1 and 2 (distal upper extremity) as a screening tool that differentiates normal from scleroderma skin at the previously mentioned cut off values.
In our study we tested the value of HFUS detected skin echogenicity and compared them as regards measured skin thickness at different areas, first in patients with disease duration <5 years. Despite statistical insignificant US dermal thickness difference, 9 out of 11 patients had higher skin thickness (both longitudinal and transverse) with skin hypoechogenicity in area 1 compared to SSc patients with other echogenicity. Similar findings were recorded at area 2 (5 out of 11 patients had higher skin thickness with skin hypoechogenicity). These findings indicate predominance of hypoechogenicity associating increase dermal thickness at distal upper extremities (area 1 and 2) within first 5 years of the disease. This may reflect reliability of US measured skin thickness and echogenicity to determine active skin affection especially at early stages of the disease.
On the other hand, we compared different US detected skin echogenicity at different areas as regards US dermal thickness in SSc patients with disease duration >5 years. Despite statistical insignificance, there were 9 out of 12 SSc patients at area 2, 7 out of 12 patients at area 3, and 10 out of 12 patients at area 5 showing lower US dermal thickness (longitudinal and transverse) associated with hyperechogenicity at late stages of disease. This and the previous finding reveal the reliable role of US combined dermal thickness and echogenicity in determination of the stage of the disease, with increased skin thickness and decreased echogenicity occurring early and during skin disease activity due to edema; and decrease skin thickness and increased echogenicity occurring late with skin atrophy. Hence, emphasizing the value of serial HFUS in monitoring skin disease activity and changes in terms of thickness and echogenicity during follow up of SSc patients..
In our study no significant correlation was detected between US dermal thickness (at different areas and total area) and mRSS, which may be explained by the fact that skin thickness was measured precisely by US at only 5 areas out of the 17 areas of mRSS and only in the dominant side. Moreover, mRSS is subjective and clinician dependent and inferior to US in detecting preclinical skin changes.
The relation between US skin thickness and disease stage was confirmed in our study where significantly higher values of US skin thickness were recorded at areas 1 in longitudinal, areas 2, 3, 5 and total skin thickness in longitudinal and transverse, in patients with disease duration < 5 years, i.e., early active disease compared to those with disease duration > 5 years.
In our study we utilized ESR, CRP and Hb% (reflecting anemia with active chronic disease) as parameters of SSc disease activity. We recorded significant negative correlation between Hb% and transverse dermal thickness at abdomen. On other hand there was significant negative correlation between ESR and US dermal thickness at area 3, area 4, area 5, and total dermal thickness and significant negative correlation between CRP and US dermal thickness at area 5 (both longitudinal and transverse). These surprising findings may be explained by the fact that 11 out of 23 SSc patients had IPF and active disease (with increase ESR, CRP) requiring steroids and immunosuppressive therapy that can dramatically influence skin edema consequently skin thickness decreasing it even before affecting ESR or CRP.
However, in patients with subclinical skin changes (mRSS zero at hand dorsum and at arm) there was statistically significant positive correlation between US dermal thickness and ESR (at arm) and CRP (at hand dorsum).