NEWS & VIEWS limb OA were excluded even though these are important causes of pain and disability. Three details from the OA burden studies were unexpected, raising questions about the validity of the models. First, the perverse finding that inclusion of BMI reduced prevalence estimates. Second, the decision not to define joint replacement surgery as remission, even though the overwhelming majority of patients have marke dly reduced symptoms after such surgery. Finally, the finding that prevalence peaked at age 50 years for knee OA, a finding that is unlikely to be accurate. Geographical variation might be explained by the nature of the available publications. Whereas the hip OA model differences between regions are (relatively) evenly distributed, in the knee OA model there seem to be three outliers with high prevalence: Asia Pacific, Oceania and the Middle East–North Africa regions. The spinal pain methodology was updated, including new case definitions and disease weights for low back pain, and included neck pain for the first time. This methodology is major progress for any attempt to quantify global ill health, although the dramatic increase in the DALY ranking of low back pain (105th in 2004, 6th in 2010) highlights the vulnerability of modelling. Heterogeneity in pain severity and impact, and in personal and cultural meaning of spinal pain, makes any assessment of burden difficult, as does its episodic nature with wide variation in frequency and duration of attacks. The contribution to YLD of spinal pain is huge, with back pain alone the greatest single contributor. Given the link between physical inactivity, obes ity and back pain, it was unexpected to see Western Europe with the highest prevalence and North America one of the lowest. The WHO GBD study is a welcome, rigorous attempt to understand threats to global health. The musculoskeletal modelling methodology continues to evolve. Although this evolution makes temporal compari sons difficult, we can expect increasingly valid and reliable estimates and more coherent disorder subgroups. The investigators acknowledge the difficulty of defining and quantifying burden. The narrow base of disease-weight estimates means that cultural variations in understanding and evaluation of disability are excluded from the outputs. As the leading cause of global disability, the economic and social impact of musculoskeletal disorders—on individuals, families, carers, employers, health and care services, and the state—is large and important, but outside the scope of these studies.2–9 450 | AUGUST 2014 | VOLUME 10
The study raises questions about disease surveillance of noncommunicable diseases and the need for consensus and standardization of case definitions in prevalence studies. A more challenging question is whether extrapolation from such studies, however rigorous, can ever provide sufficiently robust data for global estimates. While the eventual goal should be prevalence calculations based on extraction and linkage of routine health and care data, an intermediate solution should be high-quality national health surveys, performed at regular, rationally derived intervals, using WHO-agreed methodologies. Lord Kelvin said “...when you can measure what you are speaking about, and express it in numbers, you know something about it; but when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind...” So if global musculoskeletal health is to be improved, measurement is required to stimulate action by the public health community and policy makers, to allocate appropriate resources, to model outcomes of interventions and to measure progress against goals. Action begins with measurement, but measurement should not be seen as an end in itself. The scale of musculoskeletal disease burden is such that a public health approach is now required. Arthritis Research UK, 41 Portland Place, London W1B 1QH, UK (B.E., A.S.). Correspondence to: A.S. [email protected] Acknowledgements The authors acknowledge the helpful contribution of J. Oliver in the analysis of the data from the publications reviewed.
Competing interests The authors declare no competing interests. 1.
The World Health Organization. Health transition. The World Health Organization [online], http://www.who.int/trade/glossary/ story050/en/ (2014). 2. Cross, M. et al. The global burden of rheumatoid arthritis: estimates from the Global Burden of Disease 2010 study. Ann. Rheum. Dis. http://dx.doi.org/10.1136/ annrheumdis-2013-204627. 3. Smith E. et al. The global burden of gout: estimates from the Global Burden of Disease 2010 study. Ann. Rheum. Dis. http:// dx.doi.org/10.1136/annrheumdis-2013204647. 4. Hoy, D. et al. The global burden of neck pain: estimates from the Global Burden of Disease 2010 study. Ann. Rheum. Dis. http:// dx.doi.org/10.1136/annrheumdis-2013204431. 5. Cross, M. et al. The global burden of hip and knee osteoarthritis: estimates from the Global Burden of Disease 2010 study. Ann. Rheum. Dis. http://dx.doi.org/10.1136/ annrheumdis-2013-204763. 6. Hoy, D. et al. The global burden of low back pain: estimates from the Global Burden of Disease 2010 study. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis2013-204428. 7. Driscoll, T. et al. The global burden of occupationally related low back pain: estimates from the Global Burden of Disease 2010 study. Ann. Rheum. Dis. http://dx.doi.org/10.1136/ annrheumdis-2013-204631. 8. Sànchez-Riera, L. et al. The global burden attributable to low bone mineral density. Ann. Rheum. Dis. http://dx.doi.org/10.1136/ annrheumdis-2013-204320. 9. Smith, E. et al. The global burden of other musculoskeletal disorders: estimates from the Global Burden of Disease 2010 study. Ann. Rheum. Dis. http://dx.doi.org/10.1136/ annrheumdis-2013-204680. 10. Ellis, B. and Silman, A. Raising the profile of musculoskeletal disorders with governments. Rheumatology (Oxford) 52, 1929–1930 (2013).
IMAGING
Diagnostic value of ultrasonography in Sjögren’s syndrome Andreas V. Goules and Athanasios G. Tzioufas
Salivary gland ultrasonography is a promising tool for the evaluation of Sjögren’s syndrome. Cumulative data suggest that ultrasonography is comparable with older imaging modalities such as sialography and scintigraphy. However, certain issues remain to be addressed before it can be integrated into current or future classification systems. Goules, A. V. & Tzioufas, A. G. Nat. Rev. Rheumatol. 10, 450–452 (2014); published online 3 June 2014; doi:10.1038/nrrheum.2014.86
Sjögren’s syndrome is a chronic systemic autoimmune disorder affecting mainly the exocrine salivary glands. A constellation of
symptoms and signs related to dryness are required for classification and diagnosis of these patients. For many years, different www.nature.com/nrrheum
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS sets of criteria had been tested, but in 2002 the scientific community reached an agreement on classification by proposing the American–European Consens us Group (AECG) classification criteria.1 This set of criteria included imaging techniques such as parotid sialography and salivary gland scintigraphy to enable diagnosis. The experi ence with these existing tests is that they cannot be easily used in everyday clinical practice, or in clinical trials and epidemio logical studies. Having proven their ability to discriminate between normal and diseased salivary glands, imaging of exocrine glands has substantially improved and refined with use of more-sophisticated modalities such as MRI, MRI sialography and ultrasono graphy. A new set of classification criteria for Sjögren’s syndrome was proposed by the ACR in 2012.2 These criteria rely only on objective parameters, ignoring the important patients’ complaints related to dryness that would lead them to seek expert help. Recent clinical data highlight the need to incorporate salivary gland ultrasonography (SGUS) into the current classification systems for Sjögren’s syndrome and open the discussion for new revised classification criteria for the condition. Towards this direction, Cornec et al.,3 recruited 101 patients with suspected Sjögren’s syndrome who were referred for evaluation mainly because of mucosal dry ness and laboratory findings of autoimmune abnormalities. Almost half of the patients were diagnosed with Sjögren’s syndrome and the other half with other connective tissue disorders, according to expert opinion that was used as a gold standard. The two groups were compared on the basis of sicca symptoms, items of the ACR criteria—including the ocular staining score (OSS), the focus score and the presence of anti-SSA/SSB ant ibody or rheumatoid factor (RF) and antinuclear antibody (ANA) positivity— and anti-SSA/SSB antibody positivity alone. The diagnostic performance of the ACR criteria and the SGUS score—defined as the highest grade among the four major salivary glands, based on a 0–4 scoring scale for echogenicity—was assessed. Sensitivity and specificity of the ACR criteria was 64.4% and 91.1%, respectively, whereas it was 60.0% and 87.5%, respectively, for a SGUS score ≥2. The addition of SGUS score to the ACR criteria increased sensitivity to 84.4% without substantially affecting specificity (a slight decrease to 89.3%). The authors concluded that the introduction of SGUS into the core set of the ACR criteria could
further improve the diagnostic value of this particular classification system. In this study,3 a focus score ≥1, a SGUS score ≥2 and the addition of using the combined positivity of RF and ANA to anti-SSA/ SSB antibody positivity as classification criteria were found to enable the discrimination between patients with and without Sjögren’s syndrome despite similar symptoms between the two groups. Interestingly, the OSS showed low sensitivity and specificity (55.6% and 58.9%, respectively) in contrast with the addition of RF and ANA positivity, which increased sensitivity from 53.3% to 60.0% compared with the presence of anti-SSA/SSB antibody alone. A focus score ≥1 had the highest sensit ivity and specificity among the objective parameters of this study.
‘‘
…the introduction of SGUS into the core set of the ACR criteria could further improve the diagnostic value…
’’
At this point, we feel it is important to underline the necessity of retaining biopsy of the minor labial salivary gland during diagnosis; although an invasive method, this approach is a confirmatory diagnostic tool in clinical practice and a means to exclude other entities that cause dryness, including lymphoma. Considering that IgG4-related syndrome also affects the parotid glands frequently, this overlap in symptoms further supports biopsy as a method to ensure the correct diagnosis of Sjögren’s syndrome.4 The inability of the OSS to display high sensitivity and specificity raises concerns about the nature of the new ACR criteria that incorporates this score. Indeed, the ACR criteria were also found to exhibit low sensitivity probably because the dominating symptoms related to dryness were not taken into account despite their ability to differentiate patients with and without Sjögren’s syndrome. Furthermore, the fact that the ACR classification system omits the subjective complaints of the disease seems to restrict the role of the expert to performing objective confirmatory tests for every referred patient. However, the rheumatologist will re-evaluate and conceptualize each patient in the context of both clinical and laboratory terms to set a diagnosis or recruit patients for research purposes. Therefore, it seems more useful for a classification system to include the subjective component of dryness along with objective
NATURE REVIEWS | RHEUMATOLOGY
criteria that will encompass the specific nature of Sjögren’s syndrome as opposed to the ACR criteria currently in place. 4 Moreover, the addition of RF and ANA positivity to anti-SSA/SSB antibody positivity in the classification criteria (as proposed by the serological item in the ACR criteria), provides further evidence to reconsider the serological criterion of the AECG criteria or future classification systems.5 The use of SGUS as a distinct diagnostic procedure seemed to improve sensitivity of the ACR criteria. In a previous study, this group (after using the same methodology) showed that SGUS score could also improve the diagnostic performance of the AECG criteria by increasing sensitivity from 77.9% to 87.0% and slightly decreasing specificity from 98.7% to 96.1%.6 Similarly, Milic et al.7 supported the idea that ultrasonography could replace the current imaging modality of sialoscintigraphy included in the AECG criteria. Furthermore, ultrasonography has been found to exhibit high diagnostic accuracy in detecting glandular structural lesions, comparable to that of scintigraphy and even salivary gland biopsy.8,9 Recently, Theander and colleagues10 concluded that SGUS could identify typical patients with Sjögren’s syndrome as well as patients at high risk of developing lymphoma. However, the ultrasonographical parameters tested in these studies differ. Among echogenicity, homogenicity, blood flow and glandular size, echogenicity has been found to better reflect the underlying pathology, although variability exists when characterizing the different approaches in terms of grading and scoring. Intriguingly, no data are available to compare patients with Sjögren’s syndrome with individuals with symptoms of dryness because of other inflammatory conditions such as hepatitisC-related sialadenitis, sarcoidosis, the newly described IgG4-related syndrome and MALT (mucosa-associated lymphoid tissue) lymphoma. Conclusively, SGUS is an inexpensive and noninvasive method and is well tolerated by patients; however, it is highly dependent on the subjective perception and interpretation of the examiner. Future studies should, therefore, focus on recruiting a large number of patients from different centres to achieve consensus regarding the proposal of grading and scoring systems and to investigate whether SGUS can discriminate between Sjögren’s syndrome and other entities affecting the exocrine glands. The fact that SGUS can be easily performed VOLUME 10 | AUGUST 2014 | 451
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS in clinical practice and carries the same, if not better, diagnostic accuracy compared with scintigraphy or sialography, certainly favours the discussion about replacing the imaging techniques recommended in the current or future classification systems of Sjögren’s syndrome. Department of Pathophysiology, School of Medicine, National University of AthensGreece, 75 Micras Asias Street, 11527 Athens, Greece (A.V.G., A.G.T.). Correspondence to: A.G.T. [email protected] Competing interests The authors declare no competing interests. 1.
Vitali, C. et al. Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the AmericanEuropean Consensus Group. Ann. Rheum. Dis. 61, 554–558 (2002). 2. Shiboski, S. C. et al. American College of Rheumatology classification criteria for Sjögren’s syndrome: a data-driven, expert consensus approach in the Sjögren’s International Collaborative Clinical Alliance cohort. Arthritis Care Res. (Hoboken) 64, 475–487 (2013). 3. Cornec, D. et al. Salivary gland ultrasonography improves the diagnostic performance of the 2012 American College of Rheumatology classification criteria for Sjögren’s syndrome. Rheumatology (Oxford) http://dx.doi.org/10.1093/rheumatology/ keu037. 4. Goules, A. V., Tzioufas, A. G. & Moutsopoulos, H. M. Classification criteria of Sjögren’s syndrome. J. Autoimmun. 48–49, 42–45 (2014). 5. Baldini, C., Talarico, R., Luciano, N., Tavoni, A. & Bombardieri, S. Are the revised AmericanEuropean Consensus Criteria too stringent for primary Sjögren’s syndrome (pSS)? The experience on a large monocentric cohort of pSS patients. Ann. Rheum. Dis. 69 (Suppl. 3), 391 (2010). 6. Cornec, D. et al. Contribution of salivary gland ultrasonography to the diagnosis of Sjögren’s syndrome: toward new diagnostic criteria? Arthritis Rheum. 65, 216–225 (2013). 7. Milic, V. et al. Ultrasonography of major salivary glands could be an alternative tool to sialoscintigraphy in the American-European classification criteria for primary Sjögren’s syndrome. Rheumatology (Oxford) 51, 1081–1085 (2012). 8. Milic, V. D. et al. Diagnostic value of salivary gland ultrasonographic scoring system in primary Sjögren’s syndrome: a comparison with scintigraphy and biopsy. J. Rheumatol. 36, 1495–1500 (2009). 9. Salaffi, F. et al. Ultrasonography of salivary glands in primary Sjögren’s syndrome: a comparison with contrast sialography and scintigraphy. Rheumatology (Oxford) 47, 1244–1249 (2008). 10. Theander, E. & Mandl, T. Primary Sjögren’s syndrome: The diagnostic and prognostic value of salivary gland ultrasonography using a simplified scoring system. Arthritis Care Res. (Hoboken) http://dx.doi.org/10.1002/ acr.22264.
452 | AUGUST 2014 | VOLUME 10
AUTOIMMUNITY
Regulatory B cells—IL-35 and IL-21 regulate the regulators Thomas F. Tedder and Warren J. Leonard
IL-21 regulates the activity and number of IL-10-producing regulatory B cells (B10 cells) that modulate immune responses and limit diverse autoimmune diseases. A new study demonstrates that IL-35 has a similar function. Identifying regulatory circuits that control B10-cell function in vivo might open the door to future treatments for autoimmune diseases. Tedder, T. F. & Leonard, W. J. Nat. Rev. Rheumatol. 10, 452–453 (2014); published online 17 June 2014; doi:10.1038/nrrheum.2014.95
A subset of regulatory B cells (BREG cells) that can express IL-10, known as B10 cells, has been identified in humans and mice.1 The production of IL-10, a potent regulatory cytokine,2 is central to the ability of these cells to maintain tolerance to self-antigens, as well as to suppress inflammation, autoimmune disease and both innate and antigen-specific adaptive immune responses. Wang et al.3 now report an advance in our understanding of the physiological signals controlling BREG cells, showing that IL-35 induces IL-10 production and expands the number of B10 cells with the ability to suppress autoimmune disease. B10 cells are rare in naive mice (1–3% of splenic B cells) and in humans (
The study raises questions about disease surveillance of noncommunicable diseases and the need for consensus and standardization of case definitions in prevalence studies. A more challenging question is whether extrapolation from such studies, however rigorous, can ever provide sufficiently robust data for global estimates. While the eventual goal should be prevalence calculations based on extraction and linkage of routine health and care data, an intermediate solution should be high-quality national health surveys, performed at regular, rationally derived intervals, using WHO-agreed methodologies. Lord Kelvin said “...when you can measure what you are speaking about, and express it in numbers, you know something about it; but when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind...” So if global musculoskeletal health is to be improved, measurement is required to stimulate action by the public health community and policy makers, to allocate appropriate resources, to model outcomes of interventions and to measure progress against goals. Action begins with measurement, but measurement should not be seen as an end in itself. The scale of musculoskeletal disease burden is such that a public health approach is now required. Arthritis Research UK, 41 Portland Place, London W1B 1QH, UK (B.E., A.S.). Correspondence to: A.S. [email protected] Acknowledgements The authors acknowledge the helpful contribution of J. Oliver in the analysis of the data from the publications reviewed.
Competing interests The authors declare no competing interests. 1.
The World Health Organization. Health transition. The World Health Organization [online], http://www.who.int/trade/glossary/ story050/en/ (2014). 2. Cross, M. et al. The global burden of rheumatoid arthritis: estimates from the Global Burden of Disease 2010 study. Ann. Rheum. Dis. http://dx.doi.org/10.1136/ annrheumdis-2013-204627. 3. Smith E. et al. The global burden of gout: estimates from the Global Burden of Disease 2010 study. Ann. Rheum. Dis. http:// dx.doi.org/10.1136/annrheumdis-2013204647. 4. Hoy, D. et al. The global burden of neck pain: estimates from the Global Burden of Disease 2010 study. Ann. Rheum. Dis. http:// dx.doi.org/10.1136/annrheumdis-2013204431. 5. Cross, M. et al. The global burden of hip and knee osteoarthritis: estimates from the Global Burden of Disease 2010 study. Ann. Rheum. Dis. http://dx.doi.org/10.1136/ annrheumdis-2013-204763. 6. Hoy, D. et al. The global burden of low back pain: estimates from the Global Burden of Disease 2010 study. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis2013-204428. 7. Driscoll, T. et al. The global burden of occupationally related low back pain: estimates from the Global Burden of Disease 2010 study. Ann. Rheum. Dis. http://dx.doi.org/10.1136/ annrheumdis-2013-204631. 8. Sànchez-Riera, L. et al. The global burden attributable to low bone mineral density. Ann. Rheum. Dis. http://dx.doi.org/10.1136/ annrheumdis-2013-204320. 9. Smith, E. et al. The global burden of other musculoskeletal disorders: estimates from the Global Burden of Disease 2010 study. Ann. Rheum. Dis. http://dx.doi.org/10.1136/ annrheumdis-2013-204680. 10. Ellis, B. and Silman, A. Raising the profile of musculoskeletal disorders with governments. Rheumatology (Oxford) 52, 1929–1930 (2013).
IMAGING
Diagnostic value of ultrasonography in Sjögren’s syndrome Andreas V. Goules and Athanasios G. Tzioufas
Salivary gland ultrasonography is a promising tool for the evaluation of Sjögren’s syndrome. Cumulative data suggest that ultrasonography is comparable with older imaging modalities such as sialography and scintigraphy. However, certain issues remain to be addressed before it can be integrated into current or future classification systems. Goules, A. V. & Tzioufas, A. G. Nat. Rev. Rheumatol. 10, 450–452 (2014); published online 3 June 2014; doi:10.1038/nrrheum.2014.86
Sjögren’s syndrome is a chronic systemic autoimmune disorder affecting mainly the exocrine salivary glands. A constellation of
symptoms and signs related to dryness are required for classification and diagnosis of these patients. For many years, different www.nature.com/nrrheum
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS sets of criteria had been tested, but in 2002 the scientific community reached an agreement on classification by proposing the American–European Consens us Group (AECG) classification criteria.1 This set of criteria included imaging techniques such as parotid sialography and salivary gland scintigraphy to enable diagnosis. The experi ence with these existing tests is that they cannot be easily used in everyday clinical practice, or in clinical trials and epidemio logical studies. Having proven their ability to discriminate between normal and diseased salivary glands, imaging of exocrine glands has substantially improved and refined with use of more-sophisticated modalities such as MRI, MRI sialography and ultrasono graphy. A new set of classification criteria for Sjögren’s syndrome was proposed by the ACR in 2012.2 These criteria rely only on objective parameters, ignoring the important patients’ complaints related to dryness that would lead them to seek expert help. Recent clinical data highlight the need to incorporate salivary gland ultrasonography (SGUS) into the current classification systems for Sjögren’s syndrome and open the discussion for new revised classification criteria for the condition. Towards this direction, Cornec et al.,3 recruited 101 patients with suspected Sjögren’s syndrome who were referred for evaluation mainly because of mucosal dry ness and laboratory findings of autoimmune abnormalities. Almost half of the patients were diagnosed with Sjögren’s syndrome and the other half with other connective tissue disorders, according to expert opinion that was used as a gold standard. The two groups were compared on the basis of sicca symptoms, items of the ACR criteria—including the ocular staining score (OSS), the focus score and the presence of anti-SSA/SSB ant ibody or rheumatoid factor (RF) and antinuclear antibody (ANA) positivity— and anti-SSA/SSB antibody positivity alone. The diagnostic performance of the ACR criteria and the SGUS score—defined as the highest grade among the four major salivary glands, based on a 0–4 scoring scale for echogenicity—was assessed. Sensitivity and specificity of the ACR criteria was 64.4% and 91.1%, respectively, whereas it was 60.0% and 87.5%, respectively, for a SGUS score ≥2. The addition of SGUS score to the ACR criteria increased sensitivity to 84.4% without substantially affecting specificity (a slight decrease to 89.3%). The authors concluded that the introduction of SGUS into the core set of the ACR criteria could
further improve the diagnostic value of this particular classification system. In this study,3 a focus score ≥1, a SGUS score ≥2 and the addition of using the combined positivity of RF and ANA to anti-SSA/ SSB antibody positivity as classification criteria were found to enable the discrimination between patients with and without Sjögren’s syndrome despite similar symptoms between the two groups. Interestingly, the OSS showed low sensitivity and specificity (55.6% and 58.9%, respectively) in contrast with the addition of RF and ANA positivity, which increased sensitivity from 53.3% to 60.0% compared with the presence of anti-SSA/SSB antibody alone. A focus score ≥1 had the highest sensit ivity and specificity among the objective parameters of this study.
‘‘
…the introduction of SGUS into the core set of the ACR criteria could further improve the diagnostic value…
’’
At this point, we feel it is important to underline the necessity of retaining biopsy of the minor labial salivary gland during diagnosis; although an invasive method, this approach is a confirmatory diagnostic tool in clinical practice and a means to exclude other entities that cause dryness, including lymphoma. Considering that IgG4-related syndrome also affects the parotid glands frequently, this overlap in symptoms further supports biopsy as a method to ensure the correct diagnosis of Sjögren’s syndrome.4 The inability of the OSS to display high sensitivity and specificity raises concerns about the nature of the new ACR criteria that incorporates this score. Indeed, the ACR criteria were also found to exhibit low sensitivity probably because the dominating symptoms related to dryness were not taken into account despite their ability to differentiate patients with and without Sjögren’s syndrome. Furthermore, the fact that the ACR classification system omits the subjective complaints of the disease seems to restrict the role of the expert to performing objective confirmatory tests for every referred patient. However, the rheumatologist will re-evaluate and conceptualize each patient in the context of both clinical and laboratory terms to set a diagnosis or recruit patients for research purposes. Therefore, it seems more useful for a classification system to include the subjective component of dryness along with objective
NATURE REVIEWS | RHEUMATOLOGY
criteria that will encompass the specific nature of Sjögren’s syndrome as opposed to the ACR criteria currently in place. 4 Moreover, the addition of RF and ANA positivity to anti-SSA/SSB antibody positivity in the classification criteria (as proposed by the serological item in the ACR criteria), provides further evidence to reconsider the serological criterion of the AECG criteria or future classification systems.5 The use of SGUS as a distinct diagnostic procedure seemed to improve sensitivity of the ACR criteria. In a previous study, this group (after using the same methodology) showed that SGUS score could also improve the diagnostic performance of the AECG criteria by increasing sensitivity from 77.9% to 87.0% and slightly decreasing specificity from 98.7% to 96.1%.6 Similarly, Milic et al.7 supported the idea that ultrasonography could replace the current imaging modality of sialoscintigraphy included in the AECG criteria. Furthermore, ultrasonography has been found to exhibit high diagnostic accuracy in detecting glandular structural lesions, comparable to that of scintigraphy and even salivary gland biopsy.8,9 Recently, Theander and colleagues10 concluded that SGUS could identify typical patients with Sjögren’s syndrome as well as patients at high risk of developing lymphoma. However, the ultrasonographical parameters tested in these studies differ. Among echogenicity, homogenicity, blood flow and glandular size, echogenicity has been found to better reflect the underlying pathology, although variability exists when characterizing the different approaches in terms of grading and scoring. Intriguingly, no data are available to compare patients with Sjögren’s syndrome with individuals with symptoms of dryness because of other inflammatory conditions such as hepatitisC-related sialadenitis, sarcoidosis, the newly described IgG4-related syndrome and MALT (mucosa-associated lymphoid tissue) lymphoma. Conclusively, SGUS is an inexpensive and noninvasive method and is well tolerated by patients; however, it is highly dependent on the subjective perception and interpretation of the examiner. Future studies should, therefore, focus on recruiting a large number of patients from different centres to achieve consensus regarding the proposal of grading and scoring systems and to investigate whether SGUS can discriminate between Sjögren’s syndrome and other entities affecting the exocrine glands. The fact that SGUS can be easily performed VOLUME 10 | AUGUST 2014 | 451
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS in clinical practice and carries the same, if not better, diagnostic accuracy compared with scintigraphy or sialography, certainly favours the discussion about replacing the imaging techniques recommended in the current or future classification systems of Sjögren’s syndrome. Department of Pathophysiology, School of Medicine, National University of AthensGreece, 75 Micras Asias Street, 11527 Athens, Greece (A.V.G., A.G.T.). Correspondence to: A.G.T. [email protected] Competing interests The authors declare no competing interests. 1.
Vitali, C. et al. Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the AmericanEuropean Consensus Group. Ann. Rheum. Dis. 61, 554–558 (2002). 2. Shiboski, S. C. et al. American College of Rheumatology classification criteria for Sjögren’s syndrome: a data-driven, expert consensus approach in the Sjögren’s International Collaborative Clinical Alliance cohort. Arthritis Care Res. (Hoboken) 64, 475–487 (2013). 3. Cornec, D. et al. Salivary gland ultrasonography improves the diagnostic performance of the 2012 American College of Rheumatology classification criteria for Sjögren’s syndrome. Rheumatology (Oxford) http://dx.doi.org/10.1093/rheumatology/ keu037. 4. Goules, A. V., Tzioufas, A. G. & Moutsopoulos, H. M. Classification criteria of Sjögren’s syndrome. J. Autoimmun. 48–49, 42–45 (2014). 5. Baldini, C., Talarico, R., Luciano, N., Tavoni, A. & Bombardieri, S. Are the revised AmericanEuropean Consensus Criteria too stringent for primary Sjögren’s syndrome (pSS)? The experience on a large monocentric cohort of pSS patients. Ann. Rheum. Dis. 69 (Suppl. 3), 391 (2010). 6. Cornec, D. et al. Contribution of salivary gland ultrasonography to the diagnosis of Sjögren’s syndrome: toward new diagnostic criteria? Arthritis Rheum. 65, 216–225 (2013). 7. Milic, V. et al. Ultrasonography of major salivary glands could be an alternative tool to sialoscintigraphy in the American-European classification criteria for primary Sjögren’s syndrome. Rheumatology (Oxford) 51, 1081–1085 (2012). 8. Milic, V. D. et al. Diagnostic value of salivary gland ultrasonographic scoring system in primary Sjögren’s syndrome: a comparison with scintigraphy and biopsy. J. Rheumatol. 36, 1495–1500 (2009). 9. Salaffi, F. et al. Ultrasonography of salivary glands in primary Sjögren’s syndrome: a comparison with contrast sialography and scintigraphy. Rheumatology (Oxford) 47, 1244–1249 (2008). 10. Theander, E. & Mandl, T. Primary Sjögren’s syndrome: The diagnostic and prognostic value of salivary gland ultrasonography using a simplified scoring system. Arthritis Care Res. (Hoboken) http://dx.doi.org/10.1002/ acr.22264.
452 | AUGUST 2014 | VOLUME 10
AUTOIMMUNITY
Regulatory B cells—IL-35 and IL-21 regulate the regulators Thomas F. Tedder and Warren J. Leonard
IL-21 regulates the activity and number of IL-10-producing regulatory B cells (B10 cells) that modulate immune responses and limit diverse autoimmune diseases. A new study demonstrates that IL-35 has a similar function. Identifying regulatory circuits that control B10-cell function in vivo might open the door to future treatments for autoimmune diseases. Tedder, T. F. & Leonard, W. J. Nat. Rev. Rheumatol. 10, 452–453 (2014); published online 17 June 2014; doi:10.1038/nrrheum.2014.95
A subset of regulatory B cells (BREG cells) that can express IL-10, known as B10 cells, has been identified in humans and mice.1 The production of IL-10, a potent regulatory cytokine,2 is central to the ability of these cells to maintain tolerance to self-antigens, as well as to suppress inflammation, autoimmune disease and both innate and antigen-specific adaptive immune responses. Wang et al.3 now report an advance in our understanding of the physiological signals controlling BREG cells, showing that IL-35 induces IL-10 production and expands the number of B10 cells with the ability to suppress autoimmune disease. B10 cells are rare in naive mice (1–3% of splenic B cells) and in humans (
