Abstract
Connective tissues diseases (CTDs) can also be diagnosed early by “external” and safe imaging methods beyond the visceral organ analysis. This study aims to explore various imaging techniques used in diagnosing CTDs. Skin impairment in systemic sclerosis (SSc) may be recognized and studied by the modified Rodnan skin score (mRSS), which has some drawbacks, whereas high-frequency ultrasound (US) seems advantageous for the early identification of skin involvement. Salivary gland involvement in Sjögren syndrome (SS) can be assessed using standard tests such as unstimulated salivary flow test, salivary gland scintigraphy or contrast sialography. However, US of the major salivary glands, as an alternative, seems a reliable method with good sensitivity and specificity for the diagnosis of SS. Both the qualitative and quantitative nailfold capillaroscopic (NVC) assessments in SSc patients affected by the Raynaud’s phenomenon (RP) may assist in making a differential diagnosis between primary and secondary RP. Microcirculatory imaging by NVC, along with the laser Doppler analysis, seems useful in the prediction of complications and prognosis in CTDs (i.e. SSc) and in monitoring therapeutic trials.
A. Utility of musculoskeletal imaging in connective tissue diseases
The autoimmune connective tissue diseases (CTDs) may have both genetic and environmental causes (influencing their epigenetic control) and are characterized as a group, by the presence of overactivity of the immune system that results in the production of autoantibodies.
The classic CTDs include:
Systemic lupus erythematosus (SLE), which can afflict every organ system.
Rheumatoid arthritis (RA), which is a systemic disorder wherein immune cells mainly attack and inflame the synovial tissue around joints, but can also affect the heart, lungs and eyes.
Systemic sclerosis (SSc), characterized by the involvement of microcirculation impairment followed by progressive fibrosis in the skin but also internal organs.
Sjögren’s syndrome (SS), which is a chronic, slowly progressing disease that mainly manifests in the inability to secrete saliva and tears. It can occur alone or with RA, SSc or SLE.
Mixed CTD (MCTD), which is a disorder wherein features of various CTDs such as SLE, SSc, dermatomyositis (DM), polymyositis (PM); anti-synthetase syndrome and, occasionally, SS syndrome can coexist and overlap.
This review aims to analyse recently emerged various imaging techniques in the diagnosis of CTDs. These techniques evaluate the involvement of superficial organs in the manifestation of CTDs such as skin, dermal microvessels and glands, over and above the “visceral” organ involvement.
We explore the utility of musculoskeletal imaging in CTDs, then analyse whether imaging of skin and salivary glands in connective tissue diseases is sufficiently addressed to be implemented in clinical practice, followed by the qualitative and quantitative assessments of the diagnostic and prognostic value of microcirculation imaging in CTDs.
The recent availability of non-invasive and safe imaging tools such as ultrasonography and videocapillaroscopy has permitted to also evaluate the “superficial” manifestation of the CTDs, such as skin, dermal microvessels, and gland involvement, beyond the “visceral” organ involvement.
In fact, CTDs such as SSc and SS are characterized from the beginning by a limited visceral involvement, and on the contrary, they express early “external” clinical signals that need to be evaluated and possibly quantified.
Therefore, today, the differential diagnosis during the early manifestation of CTDs (like the presence of Raynaud phenomenon (RP), or lymphonodal gland enlargement or increasing skin thickness and/or joint temperature) is an easier task because of the image analysis with the tools mentioned above, and in the “pocket” of an increasing number of rheumatologists. Among the most challenging CTDs that can be evaluated by the “external” imaging analysis, SSc and SS will be analysed in particular.
B. Is imaging of skin and salivary glands in connective tissues diseases sufficiently addressed to be implemented in clinical practice?
B1. Skin involvement in systemic sclerosis
One of the most promising and applicable CTDs for the skin imaging analysis is SSc. It is an autoimmune CTD characterized by a diffuse microangiopathy, autoimmunity and fibrosis of the skin and various internal organs. It is divided into systemic disease and localized scleroderma. In SSc, various lesions occur in the internal organs, whereas in localized scleroderma, the internal organs are not involved.
Cutaneous changes in the texture and appearance of the skin are the markers for disease classification and activity . The skin damage observed is related to an excessive dermal deposition of collagenous and non-collagenous extracellular matrix components because of an altered production and remodelling of tissue fibroblasts and myofibroblasts .
Skin impairment in SSc follows a course of oedema, sclerosis and atrophy. The oedematous phase is expressed by painless pitting oedema of the hands and fingers, which may also affect the feet and legs as well as the forearms. This situation usually evolves quite quickly into fibrosis, with a decrease in skin elasticity. This second phase, which may persist for many years, is characterized by hard, shiny, taut skin, adherent to the subcutis. In the atrophic phase, the skin becomes thinner and is bound to the underlying tissue .
The skin involvement in SSc plays a major diagnostic role with prognostic relevance . Indeed, the quantification of skin impairment not only allows for an assessment of disease activity but also of severity and therapy response. A correct evaluation of the skin damage is critical as the severity of the skin involvement has an inverse correlation with survival and prognosis .
B2. The analysis of the skin in systemic sclerosis
Routine clinical practice classifies the skin manifestation of this disorder into three different subsets, limited cutaneous skin involvement (lcSSc), diffuse cutaneous skin involvement (dcSSc) and limited SSc (lSSc) . The skin manifestation may be recognized and studied by the modified Rodnan skin score (mRss), the validated method to evaluate the severity of skin involvement in SSc and to distinguish, as aforementioned, patients with lcSSc from those with dcSSc or with lSSc .
Skin involvement is confined to the extremities (hands, forearms, feet, legs and face) in lcSSc, while the arms, chest, abdomen and thighs are involved in dcSSc patients. In lSSc, skin impairment is limited to the hand . The use of mRss provides an evaluation of the skin thickness and has been used as the primary outcome measure in most clinical trials, as it is feasible, reliable, valid and responsive to change in multicentre clinical trials, especially in duSSc. The original score was developed in 1979 by Rodnan et al. .
The mRss is a summation of ratings obtained from a clinical palpation of 17 skin areas (zygoma, fingers, the dorsum of the hands, forearms, arms, chest, abdomen, thighs, legs and feet) . Skin thickness is assessed by palpation and marked on a scale ranging from 0 (normal), 1 (weak), 2 (intermediate) to 3 (severe skin thickening). The total skin score is the sum of the individual skin assessments in the 17 body areas that provides scores ranging from 0 (=normal skin thickness over the total body area) to 51 (severe skin thickness in all 17 areas); the higher the score, the greater are the extent and severity of skin thickening .
Of note, mRss does have some drawbacks, i.e. it is extremely dependent on the examiner skills and therefore requires specific training and experience, it cannot differentiate between skin thickness and tightness, and has high intra- and inter-observer variability (12% and 25%, respectively). Moreover, it is unable to detect small but clinically relevant changes in skin thickness over time. Indeed, mRss tends to worsen in the early stage with some improvement in the late stage, even if the time of peak involvement remains to be clearly defined .
B3. High-frequency skin ultrasound in systemic sclerosis
However, several studies reported the utility of high-frequency skin ultrasound (US) for early identification of skin involvement in SSc patients . The use of US to assess the skin was first published in 1979 by Alexander and Miller who measured skin thickness with a 15-MHz US . Most of the other authors used a US equipped with a probe at a frequency of 10–30 MHz, as high frequencies must be used to study skin thickness to obtain a good resolution, even if it has poor penetration. This allows for a good visualization able to distinguish the epidermis, dermis and subcutaneous fat, providing a determination of thickness and a qualitative assessment of the skin, and the authors have made a comparison with the mRss, the current gold standard to study skin impairment in SSc patients ( Fig. 1 A and B).
In addition, several authors did not show any correlation between local mRss and US findings, but some showed a correlation with global mRss . US offers a range of values for dermal thickness measurement compared to the semi-quantitative mRss scale with only four integer values. Indeed, US and mRss do not measure the same properties of the skin, as mRss measures not only thickness but also texture and fixation, whereas US allows to identify different layers of skin and to measure the dermal thickness, but differentiating between oedema and fibrosis is difficult .
However, US offers several benefits in skin assessment. It is a reliable and reproducible method to assess dermal thickness with a low intra- and inter-observer variability: 4% and 8%, respectively. Moreover, the US scoring system can be a useful outcome measure, especially in clinical trials, because it allows for the early detection of skin involvement and it has been demonstrated that there is a correlation with the clinical phase and the US values of dermal thickness . Interestingly, a recent study has demonstrated a correlation between dermal thickness and peripheral blood perfusion .
Another recent study has demonstrated that high-frequency US can identify increased skin thickness and dermal involvement in patients with lcSSc, even in skin areas that showed negative result in the mRss analysis . In fact, the results showed a higher DT in lcSSc than in healthy subjects in 4/6 skin areas with normal mRss (mRss = 0), in contrast with the diagnosis of lcSSc (arm, chest and abdomen). The observations made in this study are also in agreement with previous histopathological publications in which in clinically uninvolved skin, both in lcSSc and dcSSc patients, a hyaline collagen score was present, whereas in controls and patients with lSSc, the hyalines collagen score equalled that of controls .
Additionally, these results seem to be in agreement with recent microarray gene expression studies, which suggest that clinically unaffected skin shares the peculiar gene signatures and pathology of clinically affected skin in SSc . The same authors also confirmed that US identifies an earlier skin involvement than does the mRss. Other articles demonstrated that US can identify the oedematous phase preceding palpable skin involvement in the early stage, thus allowing for an early diagnosis of a very early dcSSc . However, few studies have evaluated the sensitivity of change of US .
B4. The utility of ultrasound in systemic sclerosis
US also has some drawbacks, i.e. it necessitates an operator training to learn the correct use of the machine (e.g. setting, position of the probe and hand pressure) and, like mRss, US is more time-consuming (usually 15–20 min per patient) to evaluate the 17 points. A favourable fact for US is that the images may be saved for future reference and the enhanced sensitivity of US in the early stages of skin involvement may represent a valuable contribution to clinical assessment, especially for research on the pathogenesis and treatment of this disorder.
Recently, a few studies have demonstrated the utility of elastosonography (ES) to investigate skin impairment in scleroderma, with varying results on the correlation with US evaluation, most likely, as hypothesized by Delle Sedie et al., because of the use of different machines and software .
Elastosonography allows for the evaluation of tissue elasticity, which, as aforementioned, is decreased in SSc because of skin fibrosis, providing a colour scale that can be superimposed on the grey scale image of the US. Elastosonography has some drawbacks, i.e. it is very time consuming, operator dependent and requires specific training, similar to that for US .
Although other clinical tools have recently been proposed for the clinical quantification of skin involvement in SSc patients, including magnetic resonance imaging, optical coherence tomography, plicometer and durometry, to date only a few studies have been reported .
Ultrasound has also been used in several studies to evaluate localized scleroderma. The first was published in 1990 . It also shows the increased dermal thickness and echogenicity at the level of active lesion. The most commonly used transducer has a frequency from 6 to 20 MHz. All these studies have demonstrated a good US sensitivity in detecting and monitoring during the localized treatment of scleroderma lesions .
B5. Sjögren’s syndrome and its classification
Sjögren’s syndrome (SS) is a chronic progressive autoimmune CTD with external exocrine glands dysfunction and multiorgan involvement. It is characterized clinically by dry eyes (keratoconjunctivitissicca) and dry mouth (xerostomia) and histologically by lymphocytic infiltration and destruction of the salivary and lacrimal glands . Sjögren’s syndrome is the second most common autoimmune disease and overlapping in 15–30% of patients with other autoimmune diseases. An accurate diagnosis of SS is important since about 5% of patients can develop a mucosa-associated lymphoid tissue (MALT) B cell lymphoma . There is no gold standard test for the diagnosis of SS .
Several sets of classification criteria have been proposed for research purposes . The American–European Consensus Group (AECG) criteria published in 2002 continues to be the most widely accepted and widely used criteria for the diagnosis and classification of SS. Current AECG diagnostic criteria for SS include ocular and oral symptoms, ocular signs, salivary gland involvement determined by low unstimulated whole salivary flow rate or the presence of typical features of SS in parotid gland sialography or scintigraphy, histopathology of labial minor salivary gland biopsy (LSGB) and autoantibodies (anti-Ro/SSA or anti-La/SSB) .
Another classification criteria for SS, proposed in 2012 by the American College of Rheumatology (2012 ACR criteria), have recently been endorsed and discussed . However, all published classification criteria for SS, including 2002 AECG criteria and 2012 ACR criteria, have high specificity but low sensitivity . Even if both criteria are applied in parallel, 20% of SS patients were still unclassified .
B6. Methods of assessment of salivary gland involvement in Sjögren’s syndrome
Standard tests for the assessment of salivary gland involvement (the unstimulated salivary flow test, salivary gland scintigraphy and contrast sialography) have several disadvantages. The rate of unstimulated whole salivary flow varies considerably over time in a patient .
Sensitivity of scintigraphy is 73–80% , and specificity is quite poor as reported in several studies . The low specificity of salivary gland scintigraphy is related to the fact that decreased uptake and delayed excretion of 99mTc pertechnetate is a non-specific phenomenon. Therefore, salivary gland scintigraphy is considered not to be pathognomonic for SS . Bilaterally decreased uptake and delayed excretion may be seen in patients with other systemic CTDs, chronic recurrent sialodochoadenitis, sialodenosis and physiological ageing as well as in those with SS . Salivary scintigraphy is not widely used because of its lower specificity in comparison with other tests , limited availability and radiation exposure.
The sensitivity of contrast sialography ranged from 66% to 95% in different studies . The specificity of parotid sialography is not so good since sialographic patterns associated with SS are also seen in recurrent parotitis of childhood and in lympho-epithelial lesions not associated with SS . Thus, alternative diagnostic procedures have been evaluated and have widely replaced conventional invasive examinations in scientific research and clinical practice. Among them, US of the major salivary glands seems to be the most appropriate because it is a simple, non-invasive, inexpensive, widely available and non-irradiating method. Its reproducibility is comparable with sialography .
B7. Salivary gland ultrasound
Normal salivary gland tissue is seen by the US as a homogeneous granular structure, with echogenicity similar to that of the thyroid gland. Normal salivary gland is hyperechogenic in comparison to the surrounding structures, and blood vessels are frequently seen inside the gland parenchyma ( Fig. 2 A). In patients with SS, the heterogeneity of salivary glands is seen, with hypoechoic areas (single and grouped) surrounded by the hyperechoic regions of salivary gland tissue ( Fig. 2 B). In periods of exacerbation, an intense blood flow is registered in microvascular systems, which are typical of vessels located in the nodal hilus. The final outcome of SS is adipose tissue atrophy with decreasing volume of proliferative lymphoid tissue. The late stages of the disease are characterized by significant parenchymal fibrosis and sparse parenchymal blood flow .
B8. Reliability and limits of salivary gland ultrasound in Sjögren’s syndrome
Several studies demonstrated high reliability of the salivary gland US (SGUS) in identifying abnormalities associated with SS , comparable to sialography. These findings suggested that the SGUS could replace the sialogram in the classification criteria.
Colour Doppler (CD) findings in patients with primary SS have shown an increase in colour signal within the parenchyma and the resistive index or pulsatility index at the facial artery, which may reflect the vascular changes in the salivary glands ( Fig. 2 B). In addition, CD has proved to be useful in determining the degree of vascularization within the salivary glands which is considered a surrogate marker of glandular inflammation . Very few studies incorporated evidence from the Doppler mode in the evaluation of salivary glands in primary SS (pSS) patients . It was hypothesized that greater vascularization correlates with increased inflammation. However, CD multi-observer reliability proved to be inconclusive because of differences in sensitivity of the equipment and interpretation of artefacts .
Ultrasonographic classification criteria for pSS are still lacking. This has resulted in variable SGUS sensitivity of 43–93% and specificity of 64–100% for the diagnosis of SS . The heterogeneity of the salivary parenchyma seems to be the most reliable diagnostic criterion . The heterogeneity described in the literature denotes hypoechoic areas, lines or spots or hypoechoic areas surrounded by hyperechoic lines and/or spots resembling a reticular or honeycomb image . The highest values of sensitivity and specificity (90.0% and 95.1%, respectively) for the heterogeneity of the salivary parenchyma were obtained by Milic et al. in 2010 . Parenchymal inhomogeneity with multiple focal hypo/anechoic rounded areas was shown to be highly suggestive, in combination with other AECG criteria, for the diagnosis of pSS . The inclusion of SGUS information into the AECG criteria resulted in sensitivity increasing from 77.9% to 87% with specificity remaining almost unchanged . Moreover, the addition of SGUS data to the 2012 ACR criteria increased their sensitivity from 64.4% to 84.4% with specificity decreasing slightly from 91.1% to 89.3% .
However, only evident inhomogeneity, characterized by multiple scattered hypoechoic areolae to multiple cyst-like changes in the gland parenchyma, can be regarded as being of true diagnostic value for the disease, because mild inhomogeneity may also be present in other disorders (subjective xerostomia, acute bacterial infection, abscesses, haematoma and neoplasm, where structural changes are often unilateral). On the other hand, viral infections, chronic parotitis or sarcoidosis, limited only in the parotid glands can mimic SS changes of salivary glands .
Most published studies showed that the definition of an abnormal inhomogeneity finding, diagnostically sensitive and specific for pSS is score ≥2 (i.e. when evident hypoechoic areas are present) . This simplified approach to the recognition of normal vs. abnormal SG showed high reliability .
The reliability of SGUS within two different international groups comprising experienced and inexperienced observers was proved to be good to excellent for assessing salivary gland parenchymal inhomogeneity in pSS patients. US of salivary glands is more reliable for low scores (i.e. in identifying normal glands vs. abnormal finding) than for high scores (the quantification of the abnormalities is less precise) .
Numerous studies assessed the size of the salivary glands during SS. Milic et al. demonstrated that the patients with dryness symptoms show the enlargement of the parotid glands, while some other studies reported the decrease in the size of the glands in patients with SS as compared with the control group. Moreover, the salivary glands with heterogeneous echostructure were smaller than those with homogeneous echostructure.
To fulfil the diagnostic criteria for SS, ENA-negative patients with suspected SS should show characteristic focal lymphocytic aggregates of at least one focal score of 50 lymphocytes per 4 mm 2 of glandular tissue adjacent to normal-appearing mucous acini in a LSGB, according to the AECG .
The LSGB is an invasive procedure and can be associated with complications such as pain 7.32%, inflammation 3.66%, altered sensation 3.05% and granuloma 1.22% . It is only a moderately sensitive test, and there is no international consensus on a standard operating procedure for the surgical technique or for the histopathology reporting .
The substitution of the LSGB with an alternative non-invasive test such as SGUS would be valuable. SGUS had lower sensitivity than the SGB (62.8% versus 80.8%) but higher specificity (95.0% versus 83.8%) .
To replace the minor SGB, several groups presented updates on the use of SGUS, which included a review of over 167 publications that showed sensitivity ranging from 45.8% to 91.6% and specificity from 73.0% to 98.1% . One study tried to answer if SGUS could be the substitute for SGB in the AECG criteria. The authors constructed modified AECG criteria including SGUS instead of SGB, but the sensitivity of these criteria was lower than that of the original AECG criteria (68.8% versus 77.9%), with the same specificity (98.7%) . Then, the authors added SGUS to the AECG criteria. These modified criteria had the sensitivity much higher than the original AECG criteria (87.0% versus77.9%) and similar specificity (96.1% versus 98.7%) . Since the adjunction of SGUS in the AECG criteria resulted in much higher sensitivity, the authors proposed that, when evaluating a patient for a diagnosis of pSS, SGB should be performed only when the results of SGUS are negative .
In another study, the authors investigated the accuracy of major SGUS in predicting the LSGB histopathology finding in patients suspected of having SS. The US finding had a positive predictive value of 85% and a strikingly negative predictive value of 96% for the LSGB histopathology finding. The overall concordance between the US and the histology was 91% . The main finding of this study is the demonstration that a negative US finding (normal US finding) is highly predictive of negative LSGB histopathology (normal histology finding) in patients with sicca symptoms. Therefore, the authors suggested that in ENA-negative patients with no sonographic signs of SS, an LSGB should not be performed, unless there is an otherwise strong clinical indication for SS .
Milic et al. obtained similar results of the US compatibility with histopathological evaluation of the minor salivary glands, scintigraphy and titre of the anti-nuclear antibodies (ANA) .
One study aimed to establish a new point-scoring diagnostic system for SS based on the quantified SPECT imaging of salivary gland (SSG), and evaluate its feasibility and performance compared with 2002 AECG criteria and 2012 ACR criteria . Except for quantified SSG, the new diagnostic system included the evaluation of anti-SSA/Ro antibody and anti-SSB/La antibody , minor SGB and ocular examination according to the clinical features of SS. The new point-scoring diagnostic system could significantly improve the sensitivity for the diagnosis of SS while maintaining a high specificity .
B9. Conclusions
In conclusion, although both US and ES are interesting and promising techniques to detect and evaluate the outcome of skin impairment in SSc and localized scleroderma, further studies should be carried out before heralding them as validated measures in daily clinical practice.
SGUS could be included in the new classification criteria for SS, since this method can replace standard tests for the assessment of salivary gland involvement. SGUS has high reliability for the diagnosis of SS, comparable reproducibility and good feasibility. The heterogeneity of the salivary parenchyma is the main diagnostic criterion on SGUS, with a variable diagnostic sensitivity of 43–93% and specificity of 64–100%. The reliability of SGUS within experienced and inexperienced observers was proved to be good to excellent for assessing GS parenchymal inhomogeneity in pSS patients. The definition of an abnormal gland for pSS diagnosis is score ≥2 (I.e. when evident hypoechoic areas are present), which is proved to be reliable. It is suggested that SGUS finding of heterogeneity of the salivary parenchyma could replace the minor SGB for the diagnosis of SS, since it has positive and negative predictive values of 85% and 96%, respectively, in comparison with the histology results. With its high sensitivity and specificity, high correlation with histology results, accessibility, non-invasive characteristics, repeatability and low cost, SGUS is becoming the important imaging technique in the diagnosis of SS.
B. Is imaging of skin and salivary glands in connective tissues diseases sufficiently addressed to be implemented in clinical practice?
B1. Skin involvement in systemic sclerosis
One of the most promising and applicable CTDs for the skin imaging analysis is SSc. It is an autoimmune CTD characterized by a diffuse microangiopathy, autoimmunity and fibrosis of the skin and various internal organs. It is divided into systemic disease and localized scleroderma. In SSc, various lesions occur in the internal organs, whereas in localized scleroderma, the internal organs are not involved.
Cutaneous changes in the texture and appearance of the skin are the markers for disease classification and activity . The skin damage observed is related to an excessive dermal deposition of collagenous and non-collagenous extracellular matrix components because of an altered production and remodelling of tissue fibroblasts and myofibroblasts .
Skin impairment in SSc follows a course of oedema, sclerosis and atrophy. The oedematous phase is expressed by painless pitting oedema of the hands and fingers, which may also affect the feet and legs as well as the forearms. This situation usually evolves quite quickly into fibrosis, with a decrease in skin elasticity. This second phase, which may persist for many years, is characterized by hard, shiny, taut skin, adherent to the subcutis. In the atrophic phase, the skin becomes thinner and is bound to the underlying tissue .
The skin involvement in SSc plays a major diagnostic role with prognostic relevance . Indeed, the quantification of skin impairment not only allows for an assessment of disease activity but also of severity and therapy response. A correct evaluation of the skin damage is critical as the severity of the skin involvement has an inverse correlation with survival and prognosis .
B2. The analysis of the skin in systemic sclerosis
Routine clinical practice classifies the skin manifestation of this disorder into three different subsets, limited cutaneous skin involvement (lcSSc), diffuse cutaneous skin involvement (dcSSc) and limited SSc (lSSc) . The skin manifestation may be recognized and studied by the modified Rodnan skin score (mRss), the validated method to evaluate the severity of skin involvement in SSc and to distinguish, as aforementioned, patients with lcSSc from those with dcSSc or with lSSc .
Skin involvement is confined to the extremities (hands, forearms, feet, legs and face) in lcSSc, while the arms, chest, abdomen and thighs are involved in dcSSc patients. In lSSc, skin impairment is limited to the hand . The use of mRss provides an evaluation of the skin thickness and has been used as the primary outcome measure in most clinical trials, as it is feasible, reliable, valid and responsive to change in multicentre clinical trials, especially in duSSc. The original score was developed in 1979 by Rodnan et al. .
The mRss is a summation of ratings obtained from a clinical palpation of 17 skin areas (zygoma, fingers, the dorsum of the hands, forearms, arms, chest, abdomen, thighs, legs and feet) . Skin thickness is assessed by palpation and marked on a scale ranging from 0 (normal), 1 (weak), 2 (intermediate) to 3 (severe skin thickening). The total skin score is the sum of the individual skin assessments in the 17 body areas that provides scores ranging from 0 (=normal skin thickness over the total body area) to 51 (severe skin thickness in all 17 areas); the higher the score, the greater are the extent and severity of skin thickening .
Of note, mRss does have some drawbacks, i.e. it is extremely dependent on the examiner skills and therefore requires specific training and experience, it cannot differentiate between skin thickness and tightness, and has high intra- and inter-observer variability (12% and 25%, respectively). Moreover, it is unable to detect small but clinically relevant changes in skin thickness over time. Indeed, mRss tends to worsen in the early stage with some improvement in the late stage, even if the time of peak involvement remains to be clearly defined .
B3. High-frequency skin ultrasound in systemic sclerosis
However, several studies reported the utility of high-frequency skin ultrasound (US) for early identification of skin involvement in SSc patients . The use of US to assess the skin was first published in 1979 by Alexander and Miller who measured skin thickness with a 15-MHz US . Most of the other authors used a US equipped with a probe at a frequency of 10–30 MHz, as high frequencies must be used to study skin thickness to obtain a good resolution, even if it has poor penetration. This allows for a good visualization able to distinguish the epidermis, dermis and subcutaneous fat, providing a determination of thickness and a qualitative assessment of the skin, and the authors have made a comparison with the mRss, the current gold standard to study skin impairment in SSc patients ( Fig. 1 A and B).
In addition, several authors did not show any correlation between local mRss and US findings, but some showed a correlation with global mRss . US offers a range of values for dermal thickness measurement compared to the semi-quantitative mRss scale with only four integer values. Indeed, US and mRss do not measure the same properties of the skin, as mRss measures not only thickness but also texture and fixation, whereas US allows to identify different layers of skin and to measure the dermal thickness, but differentiating between oedema and fibrosis is difficult .
However, US offers several benefits in skin assessment. It is a reliable and reproducible method to assess dermal thickness with a low intra- and inter-observer variability: 4% and 8%, respectively. Moreover, the US scoring system can be a useful outcome measure, especially in clinical trials, because it allows for the early detection of skin involvement and it has been demonstrated that there is a correlation with the clinical phase and the US values of dermal thickness . Interestingly, a recent study has demonstrated a correlation between dermal thickness and peripheral blood perfusion .
Another recent study has demonstrated that high-frequency US can identify increased skin thickness and dermal involvement in patients with lcSSc, even in skin areas that showed negative result in the mRss analysis . In fact, the results showed a higher DT in lcSSc than in healthy subjects in 4/6 skin areas with normal mRss (mRss = 0), in contrast with the diagnosis of lcSSc (arm, chest and abdomen). The observations made in this study are also in agreement with previous histopathological publications in which in clinically uninvolved skin, both in lcSSc and dcSSc patients, a hyaline collagen score was present, whereas in controls and patients with lSSc, the hyalines collagen score equalled that of controls .
Additionally, these results seem to be in agreement with recent microarray gene expression studies, which suggest that clinically unaffected skin shares the peculiar gene signatures and pathology of clinically affected skin in SSc . The same authors also confirmed that US identifies an earlier skin involvement than does the mRss. Other articles demonstrated that US can identify the oedematous phase preceding palpable skin involvement in the early stage, thus allowing for an early diagnosis of a very early dcSSc . However, few studies have evaluated the sensitivity of change of US .
B4. The utility of ultrasound in systemic sclerosis
US also has some drawbacks, i.e. it necessitates an operator training to learn the correct use of the machine (e.g. setting, position of the probe and hand pressure) and, like mRss, US is more time-consuming (usually 15–20 min per patient) to evaluate the 17 points. A favourable fact for US is that the images may be saved for future reference and the enhanced sensitivity of US in the early stages of skin involvement may represent a valuable contribution to clinical assessment, especially for research on the pathogenesis and treatment of this disorder.
Recently, a few studies have demonstrated the utility of elastosonography (ES) to investigate skin impairment in scleroderma, with varying results on the correlation with US evaluation, most likely, as hypothesized by Delle Sedie et al., because of the use of different machines and software .
Elastosonography allows for the evaluation of tissue elasticity, which, as aforementioned, is decreased in SSc because of skin fibrosis, providing a colour scale that can be superimposed on the grey scale image of the US. Elastosonography has some drawbacks, i.e. it is very time consuming, operator dependent and requires specific training, similar to that for US .
Although other clinical tools have recently been proposed for the clinical quantification of skin involvement in SSc patients, including magnetic resonance imaging, optical coherence tomography, plicometer and durometry, to date only a few studies have been reported .
Ultrasound has also been used in several studies to evaluate localized scleroderma. The first was published in 1990 . It also shows the increased dermal thickness and echogenicity at the level of active lesion. The most commonly used transducer has a frequency from 6 to 20 MHz. All these studies have demonstrated a good US sensitivity in detecting and monitoring during the localized treatment of scleroderma lesions .
B5. Sjögren’s syndrome and its classification
Sjögren’s syndrome (SS) is a chronic progressive autoimmune CTD with external exocrine glands dysfunction and multiorgan involvement. It is characterized clinically by dry eyes (keratoconjunctivitissicca) and dry mouth (xerostomia) and histologically by lymphocytic infiltration and destruction of the salivary and lacrimal glands . Sjögren’s syndrome is the second most common autoimmune disease and overlapping in 15–30% of patients with other autoimmune diseases. An accurate diagnosis of SS is important since about 5% of patients can develop a mucosa-associated lymphoid tissue (MALT) B cell lymphoma . There is no gold standard test for the diagnosis of SS .
Several sets of classification criteria have been proposed for research purposes . The American–European Consensus Group (AECG) criteria published in 2002 continues to be the most widely accepted and widely used criteria for the diagnosis and classification of SS. Current AECG diagnostic criteria for SS include ocular and oral symptoms, ocular signs, salivary gland involvement determined by low unstimulated whole salivary flow rate or the presence of typical features of SS in parotid gland sialography or scintigraphy, histopathology of labial minor salivary gland biopsy (LSGB) and autoantibodies (anti-Ro/SSA or anti-La/SSB) .
Another classification criteria for SS, proposed in 2012 by the American College of Rheumatology (2012 ACR criteria), have recently been endorsed and discussed . However, all published classification criteria for SS, including 2002 AECG criteria and 2012 ACR criteria, have high specificity but low sensitivity . Even if both criteria are applied in parallel, 20% of SS patients were still unclassified .
B6. Methods of assessment of salivary gland involvement in Sjögren’s syndrome
Standard tests for the assessment of salivary gland involvement (the unstimulated salivary flow test, salivary gland scintigraphy and contrast sialography) have several disadvantages. The rate of unstimulated whole salivary flow varies considerably over time in a patient .
Sensitivity of scintigraphy is 73–80% , and specificity is quite poor as reported in several studies . The low specificity of salivary gland scintigraphy is related to the fact that decreased uptake and delayed excretion of 99mTc pertechnetate is a non-specific phenomenon. Therefore, salivary gland scintigraphy is considered not to be pathognomonic for SS . Bilaterally decreased uptake and delayed excretion may be seen in patients with other systemic CTDs, chronic recurrent sialodochoadenitis, sialodenosis and physiological ageing as well as in those with SS . Salivary scintigraphy is not widely used because of its lower specificity in comparison with other tests , limited availability and radiation exposure.
The sensitivity of contrast sialography ranged from 66% to 95% in different studies . The specificity of parotid sialography is not so good since sialographic patterns associated with SS are also seen in recurrent parotitis of childhood and in lympho-epithelial lesions not associated with SS . Thus, alternative diagnostic procedures have been evaluated and have widely replaced conventional invasive examinations in scientific research and clinical practice. Among them, US of the major salivary glands seems to be the most appropriate because it is a simple, non-invasive, inexpensive, widely available and non-irradiating method. Its reproducibility is comparable with sialography .
B7. Salivary gland ultrasound
Normal salivary gland tissue is seen by the US as a homogeneous granular structure, with echogenicity similar to that of the thyroid gland. Normal salivary gland is hyperechogenic in comparison to the surrounding structures, and blood vessels are frequently seen inside the gland parenchyma ( Fig. 2 A). In patients with SS, the heterogeneity of salivary glands is seen, with hypoechoic areas (single and grouped) surrounded by the hyperechoic regions of salivary gland tissue ( Fig. 2 B). In periods of exacerbation, an intense blood flow is registered in microvascular systems, which are typical of vessels located in the nodal hilus. The final outcome of SS is adipose tissue atrophy with decreasing volume of proliferative lymphoid tissue. The late stages of the disease are characterized by significant parenchymal fibrosis and sparse parenchymal blood flow .
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