- Email: [email protected]
15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics
G Model PRP-51811; No. of Pages 8
ARTICLE IN PRESS Pathology – Research and Practice xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.com/locate/prp
Review
15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics V. Krenn a,∗ , G. Perino b , W. Rüther c , V.T. Krenn a , M. Huber d , T. Hügle e , A. Najm f , S. Müller a , F. Boettner b , F. Pessler g,h , W. Waldstein i , J. Kriegsmann a,j , R. Casadonte j , T. Häupl k , S. Wienert l , M.G. Krukemeyer m , S. Sesselmann n , S. Sunitsch o , R. Tikhilov p , L. Morawietz q a
MVZ-Zentrum für Histologie, Zytologie und Molekulare Diagnostik, Trier, Germany Department of Pathology and Laboratory Medicine, Hospital for Special Surgery, New York, USA c Klinik und Poliklinik für Orthopädie, Universitätsklinikum Hamburg-Eppendorf, Germany d Pathologisch-bakteriologisches Institut, Otto Wagner Spital, Vienna, Austria e Hôpital Orthopédique, Lausanne, Switzerland f Rhumatologie, Centre hospital-universitaire de Nantes, France g TWINCORE, Zentrum für Experimentelle und Klinische Infektionsforschung GmbH, Hannover, Germany h Helmholtz-Zentrum für Infektionsforschung, Braunschweig, Germany i Medizinische Universität Wien, AKH-Wien, Universitätsklinik für Orthopädie, Vienna, Austria j Proteopath GmbH, Trier, Germany k Med. Klinik, Rheumatologie und Klinische Immunologie (Charité),Berlin, Germany l VMscope-Berlin, Germany m Paracelsus-Kliniken Deutschland, Osnabrück, Germany n Orthopädische Universitätsklinik Erlangen, Erlangen, Germany o Medizinische Universität Graz – Institut für Pathologie, Austria p Vreden Russian Scientific Research Institute of Traumatology and Orthopedics, Saint Petersburg, Russia q MVZ Fürstenberg-Karree, Berlin, Germany b
a r t i c l e
i n f o
Article history: Received 30 March 2017 Accepted 11 May 2017 Keywords: Synovitis score Synovitis Rheumatoid arthritis Arthrosis Semiquantitative evaluation Immunohistochemistry Risk stratification
a b s t r a c t The histopathological synovitis score evaluates the immunological and inflammatory changes of synovitis in a graduated manner generally customary for diagnostic histopathological scores. The score results from semiquantitative evaluation of the width of the synovial surface cell layer, the cell density of the stroma and the density of the inflammatory infiltration into 4 semiquantitative levels (normal 0, mild 1, moderate 2, severe 3). The addition of these values results in a final score of 0–9 out of 9. On the basis of this summation the condition is divided into low-grade synovitis and high-grade synovitis: A synovitis score of 1 to ≤ 4 is called low-grade synovitis (arthrosis-associated/OA synovitis, posttraumatic synovitis, meniscopathy-associated synovitis and synovitis with haemochromatosis). A synovitis score of ≥ 5 to 9 is called high-grade synovitis (rheumatoid arthritis, psoriatic arthritis, Lyme arthritis, postinfection/reactive arthritis and peripheral arthritis with Bechterew’s disease). By means of the synovitis score it is therefore possible to distinguish between degenerative/posttraumatic diseases (low-grade synovitis) and inflammatory rheumatic diseases (high-grade synovitis) with a sensitivity of 61.7% and a specificity of 96.1%. The diagnostic accuracy according to ROC analysis (AUC: 0.8–0.9) is good. Since the first publication (2002) and an associated subsequent publication (2006), the synovitis score has nationally and internationally been accepted for histopathological assessment of the synovitis. In a PubMed data analysis (status: 14.02.2017), the following citation rates according to Cited by PubMed Central articles resulted for the two synovitis score publications: For DOI: 10.1078/0344-0338-5710261 there were 29 Cited by PubMed Central articles and for the second extended publication DOI:10.1111/j.13652559.2006.02508 there were 44 Cited by PubMed Central articles. Therefore a total of 73 PubMed citations are observed over a period of 15 years, which demonstrates an international acceptance of the score. This synovitis score provides for the first time a diagnostic, standardised and reproducible histopathological evaluation method enabling a contribution to the differential diagnosis of chronic inflammatory
∗ Corresponding author at: MVZ Zentrum für Histologie, Zytologie und Molekulare Diagnostik, Max-Planck-Straße. E-mail address: [email protected] (V. Krenn). http://dx.doi.org/10.1016/j.prp.2017.05.005 0344-0338/© 2017 Elsevier GmbH. All rights reserved.
Please cite this article in press as: V. Krenn, et al., 15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.05.005
G Model
ARTICLE IN PRESS
PRP-51811; No. of Pages 8
V. Krenn et al. / Pathology – Research and Practice xxx (2017) xxx–xxx
2
general joint diseases. This is particularly the case by incorporation into the joint pathology algorithm. To specify the synovitis score an immunohistochemical determination of various inflammation-relevant CD antigens is proposed to enable a risk stratification of high-grade synovitis (e.g.: progression risk and sensitivity for biologicals). © 2017 Elsevier GmbH. All rights reserved.
Contents 1. 2.
3.
4. 5.
Pathogenesis of rheumatoid arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Classification criteria of rheumatoid arthritis, histopathological synovitis diagnostics and differential diagnosis of synovial diseases . . . . . . . . . . . . . 00 2.1. Synovitis score as a standardised histopathological evaluation method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.2. Histopathological criteria of the synovitis score . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.3. Dual stratification by means of the synovitis score: low-grade/high-grade synovitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.4. Diagnostic discrimination of the synovitis score . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 National and international acceptance of the synovitis score for the histopathological assessment of the synovialis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1. Evaluation of the synovitis score in PubMed according to the cited by PubMed central articles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.2. Synovitis score in online databanks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.3. Publicising and correct use of the synovitis score by IAP tutorials (Internationale Akademie für Pathologie, Deutsche Abteilung, e.V., Bonn) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.4. Synovial pathology algorithm and synovitis score: comprehensive diagnostic and pathogenetic context . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.5. Synovial diagnostics in orthopaedics, orthopaedic rheumatology and joint endoprosthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.6. Synovial diagnostics in rheumatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Molecular validation of the synovitis score . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.1. Immunohistochemical synovitis score: biologics sensitivity, risk stratification, synovial inflammation regression under medicamentous treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.2. Digital quantification software for synovitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.3. Molecular methods of synovitis typing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conflict of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1. Pathogenesis of rheumatoid arthritis Rheumatoid arthritis (RA) is the most frequent inflammatory systemic connective tissue disease with a predominantly symmetric manifestation at the peripheral, small joints of the upper extremities. Extraarticular manifestations exist in the bursa, synovial sheathes, in the subepidermal tissue, in the eyes, in the pleura and the internal organs [19]. Pathogenetically, the underlying cause of rheumatoid arthritis of RA lies in a chronic, destructive synovitis which is largely based on a dysregulation of the B lymphocyte and T lymphocyte response as well as fibroblast and macrophage activation [17,20,24]. Current data indicate an expansion of deregulated synovial T and B lymphocytes [17]. In RA, primary synovitis with secondary cartilage damage is observed, by contrast, in arthrosis (osteoarthrosis, OA) a secondary synovitis is present with primary cartilage damage [25,26]. 2. Classification criteria of rheumatoid arthritis, histopathological synovitis diagnostics and differential diagnosis of synovial diseases A synovial biopsy is not necessary for diagnosis and classification of RA according to the internationally applicable ACR criteria 2010 [15,19,23], this clinically weighted classification being based on clinical, seroimmunological, sonographic and radiological criteria. In the event of incomplete classification of rheumatic joint disease or clinically unclear arthritis and arthritis-like diseases, a synovial biopsy can make a significant diagnostic contribution [4,13]. It is to be said generally that a histopathological differential diagnosis of “synovitis” is a comprehensive differential diagnosis and includes not only the differential diagnosis of inflammatory diseases [2,4,8,11,16,21,22]. This inflammatory, non-inflammatory,
infectious, metabolic and neoplastic diagnosis spectrum is combined in the joint pathology algorithm (Diagram 1) [8], which illustrates the diagnostic position of the synovitis score. 2.1. Synovitis score as a standardised histopathological evaluation method The fact that in inflammatory (e.g. Rheumatoid arthritis; RA) and non-inflammatory (e.g. osteoarthrosis; OA) joint diseases histopathological differences in the severity of the synovitis occur was regarded as knowledge based on histopathological diagnostic “everyday experience”. Histopathological scores in this regard have been developed since 1976 and focussed on evaluating the local activity diagnosis of the RA [12,16]. The synovitis score [6,7], however, provides for the first time a diagnostic, standardised and reproducible histopathological evaluation method which allows a contribution to the differential diagnosis of chronic inflammatory general joint diseases [8]. This is particularly the case by incorporation into the joint pathology algorithm [8] (Diagram 1). 2.2. Histopathological criteria of the synovitis score The synovitis score evaluates the immunological and inflammatory tissue changes of synovitis in a graduated manner generally customary for diagnostic histopathological scores [6,7]. This score [6,7] represents a semiquantitative, additive evaluation method (additive score), which by specifying three compartments of synovitis (surface cell layer, stroma cells and inflammatory infiltration) is based on a graduated, semiquantitative evaluation of the width of the surface cell layer, the cell density of the stroma and the density of the inflammatory infiltration (absent, mildly, moderately and
Please cite this article in press as: V. Krenn, et al., 15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.05.005
G Model
ARTICLE IN PRESS
PRP-51811; No. of Pages 8
V. Krenn et al. / Pathology – Research and Practice xxx (2017) xxx–xxx
3
Synovial pathology algorithm Non -inflammatory
Inflammatory
Benign tumours PVNS (Pigmented Villonodular Synovis) Lipoma Haemangioma/Angiodysplasia Synovial chondromatosis
Malign tumours Synovial sarcoma Ewing sarcoma
Granulomatous
Infecons Mycobateria Mycoses, Brucellosis Rare infecons with granuloma formaon
Immunologic/metabolicand storage diseases Macrophages/Granulomaformaon
Bacterial synovis Low-grade infecon: Low virulent bacteria High-grade infecon: High virulent bacteria
Crystal-induced
Non-granulomatous Foreign body reacon Condion aer intraarcular injecon
Synovialis-Score ≤ 4 Low-Grade Synovis
Arthrosis-associated synovis Lymphoplasmacyc-type Detritus-type Posraumac synovis Meniscopathy synovis Haemochromatosis
Gout Acute Chronic tophus
CPPA
Calcareous deposits Calcium phosphate Calcium carbonate
Synovialis-Score ≥ 5 High-Grade Synovis
Rheumatoid arthris Lyme arthris (Borreliosis) Reacve arthris Psoriac arthris Ankylosing spondylis (Arthris in distal joints)
Diagram 1. Synovial pathology algorithm modified according to [8] with integration of low-grade (blue background) and high-grade synovitis (orange background). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
severely changed). Only the criterion of width of the surface cell layer is a quantitative criterion and consists of direct counting of the synovial surface cells. In order to ensure a good reproducibility of the synovitis score, characteristic microphotographs were published to illustrate all of the criteria [6,7]. The three different compartments of synovitis are each evaluated on four levels from 0 to 3 points, resulting in a final score from 0/9 to 9/9. There are additionally two criteria which are independent of this semiquantitative evaluation, the surface cell layer ulceration (3 points) and the detection of intrasynovial rheumatoid necrosis. Intrasynovial rheumatoid necrosis (Fig. 1) are a morphological equivalent of an RA, the maximum points of 9/9 are being given here [8]. 2.3. Dual stratification by means of the synovitis score: low-grade/high-grade synovitis In the first published version of the synovitis score [6], a numerical summation was proposed as the score result; in the second, extended published version of the synovitis score [7] a classification into low-grade synovitis and high-grade synovitis based on this numerical summation was specified (Fig. 2). A synovitis score of 1 to ≤ 4 is called low-grade synovitis (Fig. 2a), a synovitis score of ≥ 5 to 9 is called high-grade synovitis (Fig. 2b) [7]. The diagnosis of low-grade synovitis is associated (Diagram 1) with a non-inflammatory or mildly inflammatory joint disease/arthropathy (arthrosis-associated synovitis, posttraumatic synovitis, meniscopathy-associated synovitis and synovitis with
Fig. 1. Rheumatoid granuloma Rheumatoid necrosis in the fibrous tissue of a bursa wall with central, so-called land map-like necrosis and histiocytic peripheral palisading (HE staining, original magnification about 400×).
haemochromatosis). The histopathological classification of a highgrade synovitis leads to the diagnoses: Rheumatoid arthritis, psoriatic arthritis, Lyme arthritis, reactive arthritis and peripheral arthritis with Bechterew’s disease (Diagram 1). The synovitis score does not allow subspecifying of the synovitis within the group of low-grade synovitis and high-grade synovitis (Diagram 1). The
Please cite this article in press as: V. Krenn, et al., 15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.05.005
G Model PRP-51811; No. of Pages 8 4
ARTICLE IN PRESS V. Krenn et al. / Pathology – Research and Practice xxx (2017) xxx–xxx
Fig. 2. Low-grade and high-grade synovitis: 2a: Low-grade synovitis (3/9); in OA: According to the synovitis score there is a slight widening of the surface cell layer (1), a slightly increased cell density of the synovial stroma (1), and a mild inflammatory leukocytic (mononuclear) infiltration (1) in blue (synovitis score: 3/9). 2b: High-grade synovitis (7/9) in RA with moderate widening of the surface cell layer (2), moderate cell density of the synovial stroma (2), severe leukocytic, plasma cell-rich inflammatory infiltration (3) (HE staining, original magnification about 200×). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
sensitivity and specificity and the inter- and intraobserver reproducibility are adequate [6,7] and therefore ensure reproducible, histopathological synovitis diagnostics [7]. Using the synovitis score it is therefore possible to distinguish between degenerative/posttraumatic diseases (low-grade synovitis) and inflammatory rheumatic diseases (high-grade synovitis) with a sensitivity of 61.7% and a specificity of 96.1% [7]. The diagnostic accuracy according to the ROC analysis (AUC: 0.8–0.9) is good [14]. 2.4. Diagnostic discrimination of the synovitis score The diagnostic discrimination of the synovitis score and of each of its individual components was investigated with the receiver operating characteristic (ROC) curve analysis [14]. The area under the ROC curve (AUC) corresponds to the diagnostic accuracy of a test (AUC 0.50 − 0.75 = average, 0.75–0.92 = good, 0.92–0.97 = very good, 0.97–1.00 = excellent). The synovitis score had AUCs ranging from 0.8–0.9 in the differentiations between inflammatory (e.g. RA) and degenerative (e.g. OA) arthropathies and an AUC of 0.87–0.98 in the demarcation of degenerative arthropathies from normal tissue. A multicategorical ROC analysis showed that: 1) The components of stroma density and width of the surface cell layer contribute much more to the diagnostic discrimination of the score than the infiltration component and that 2) Combining the individual components to give the complete score synergistically increases the general diagnostic accuracy several-fold [14]. 3. National and international acceptance of the synovitis score for the histopathological assessment of the synovialis 3.1. Evaluation of the synovitis score in PubMed according to the cited by PubMed central articles In a PubMed analysis (status: 12.02.2017), the following citation rates according to the criterion Cited by PubMed Central articles resulted for the two synovitis score publications: For DOI: 10.1078/0344-0338-5710261 there were 29 Cited by PubMed Central articles and for the second extended publication DOI:10.1111/ j.1365-2559.2006.02508 there were 44 Cited by PubMed Central articles. There is therefore a total of 73 PubMed citations were observed over a period of 15 years (Diagram 2a and b). In these 73 PubMed-cited publications the synovitis score was used in various non-experimental, clinical and experimental studies (Diagram 2c). In these studies the synovitis was evaluated by the synovitis score. Generally, in all 73 publications there is a direct and sta-
tistically confirmed agreement between the synovitis scores and various clinical, imaging, histological, immunohistochemical and functional parameters of joint diseases [12,21]. 3.2. Synovitis score in online databanks The synovitis score can also be found in the following online databanks: Wikibooks: https://de.wikibooks.org/wiki/Pathologie: Gelenke, Wikipedia: https://de.wikipedia.org/wiki/SynovialitisPathologisch: https://pathologisch.de/index.php/ Score, arbeitshilfen/arbeitshilfen-sonstige/krenn-score-synovialitis, DocCheck Medical Services: http://flexikon.doccheck.com/de/ Synovitis, LinkFang: http://www.linkfang.de/wiki/SynovialitisScore 3.3. Publicising and correct use of the synovitis score by IAP tutorials (Internationale Akademie für Pathologie, Deutsche Abteilung, e.V., Bonn) New IAP seminars have been implemented by the author (V.K.) for publicising and using the synovitis score as a new diagnostic score for pathology (Rheumapathology, Inflammatory and neoplastic joint diseases and Orthopaedic pathology). These 15 IAP seminars have been held 9 x as a half-day and 6 x as a full day event since 2006. About 2–4 joint pathological cases which demonstrate the synovitis score as an important diagnostic principle have been presented and discussed at each seminar. 3.4. Synovial pathology algorithm and synovitis score: comprehensive diagnostic and pathogenetic context The histopathological differential diagnoses of joint diseases according to the synovial pathology algorithm [8] are presented in the extended algorithm (Diagram 1). An important diagnostic constituent is the diagnostic, dichotomous classification of joint diseases by the synovitis score into low-grade and high-grade synovitis. By this means and by the synovial pathology algorithm diagnosis of synovial diseases in a comprehensive diagnostic and pathogenetic context is possible. 3.5. Synovial diagnostics in orthopaedics, orthopaedic rheumatology and joint endoprosthetics Patients with RA and OA might require surgical interventions which includes synovialectomy especially in cases which can-
Please cite this article in press as: V. Krenn, et al., 15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.05.005
G Model PRP-51811; No. of Pages 8
ARTICLE IN PRESS V. Krenn et al. / Pathology – Research and Practice xxx (2017) xxx–xxx
5
Diagram 2. Synovitis score citations in PubMed (Cited by PubMed Central articles, status: 14.02.2017) shown according to the citation location (country of origin) with respect to the two synovitis score publications 2002 (a) and 2006 (b) and according to the context of the contents (c) here of the two publications (2002 and 2006).
not be influenced by medicaments, and joint replacements when advanced joint degeneration is observed. The histopathological assessment of the synovial section can follow the joint pathology algorithm (Diagram 1). The task of synovial diagnostics is that at the time of the surgical intervention the diagnosis of the joint disease (e.g. OA, RA) is often unknown and an evaluation of the synovium provides information regarding the inflammatory activity of the disease at the time of the surgical intervention. This is highly relevant asthe survival of a joint endoprosthesis is also influenced by the underlying disease [2]. The relevance of synovialectomy section diagnostics therefore lies not only in the evaluation of the inflammatory activity by means of the synovitis score. Taking the joint pathology algorithm into
account the histopathological evaluation of synovitis may exclude infectious synovitis, a pigmented villonodular synovitis and crystal arthropathy which all have a direct impact on the survival of joint endoprostheses [2,5,9]. 3.6. Synovial diagnostics in rheumatology Although new and more efficient methods of synovial biopsy (Fig. 4) have been developed in recent years [3], histopathological diagnostics of RA are not a constituent of the primary diagnostics. The international classification criteria [19] are based on clinical, serological and imaging criteria and are therefore nonhistopathological. With the exception of differential diagnosis of
Please cite this article in press as: V. Krenn, et al., 15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.05.005
G Model PRP-51811; No. of Pages 8 6
ARTICLE IN PRESS V. Krenn et al. / Pathology – Research and Practice xxx (2017) xxx–xxx
5. Prospects 5.1. Immunohistochemical synovitis score: biologics sensitivity, risk stratification, synovial inflammation regression under medicamentous treatment Since it has been possible to demonstrate a CD68, CD3, CD15 and CD20 reduction after biologics therapy and a high Ki67, IL7R, IL18rap, CXCL11 and IL18 expression in non-responders to biologics [1], these markers can be employed in combination with the synovitis score in the sense of an immunohistochemical synovitis score. This might subspecify forms of a high-grade synovitis and might provide further information regarding the possibility of eventual regression of synovial inflammation. The immunohistochemical determination of various CD antigens is recommended for immunohistochemical validation of a possible regression of the synovial inflammation with e.g. biologics therapy. 5.2. Digital quantification software for synovitis Fig. 3. Ki67 inflammation quantifier High-grade synovitis, synovitis score (8/9). Determination of the proliferation fraction by means of quantification software (Ki67 Inflammation Quantifier, VMscope Berlin). Proliferation fraction Ki67: 14.42% with a total of 846 quantified cells, synovial surface cell layer and subsynovial stroma. The high proliferation fraction is possibly associated with a high local synovial destruction or with a progressive course of the disease. Shown in the so-called Ki67 Inflammation Quantifier mode, VMscope Berlin, negative cells are bordered in green, positive cells, Ki67-positive, are bordered in red. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
a rheumatic nodule, histopathological synovial diagnostics is of importance chiefly in the case of arthritis in large joints. From the point of view of the rheumatologist, a synovial biopsy is appropriate for “rheumatologically unclear arthritis”, especially of large joints, where the histopathological assessment can make an important diagnostic contribution [4]. 4. Molecular validation of the synovitis score Stratification by means of the synovitis score into normal tissue, low-grade synovitis and high-grade synovitis shows statistically significantly divergent gene expression profiles of degenerative and inflammatory rheumatic joint diseases in a molecular analysis. Secreted phosphoprotein 1 (SPPA) has been identified as a significantly highly regulated gene in RA (high-grade synovitis), which is associated with T lymphocyte activation and apoptosis processes [18]. The extent to which this marker could also be used in histopathological diagnostics has currently not yet been validated.
Through newly developed digital quantification software for synovial inflammatory reactions, specific software has been developed for CD15 [5], Ki67 and for CD3: CD15 Quantifier, Ki-67 Inflammation Quantifier, S. Müller, Histopathologische Klassifikation der Synovialis bei dysfunktioneller Endoprothese des oberen Sprunggelenks. Diss. Medizinische Fakultät Charité – Universitätsmedizin Berlin 2016. URN: urn:nbn:de:kobv:188-fudissthesis 000000101571-6 (see Fig. 3) and CD3 Quantifier (VM-Scope Berlin, Germany) which could objectify cell quantifications (e.g. regression of synovial inflammation), and assist in the development of a diagnostic, digital pathology in the field of rheumatic pathology and orthopaedic pathology. 5.3. Molecular methods of synovitis typing At the miRNA expression level different expression patterns of miR-146a, miR-155 and miR33 have been found in low-grade and high-grade synovitis [11], and divergent patterns likewise exist at the protein level [10]. In the MALDI method (matrix-assisted laser desorption/ionisation) the so-called analyte is ionised by means of laser bombardment [10]. This usually takes place via a matrix in which the analytes are embedded. The laser bombardment causes the matrix to vaporise explosively and the molecules to be investigated are fragmented kinetically. An ionisation of the analyte usually takes place at the same time. The ions formed in this way are accelerated in an electric field and detected. A distinction is made between MALDI profiling and MALDI imaging. By means of MALDI imaging mass spectrometry it has been possible to detect calgranulin, defensin and thymosin in the subsynovial compartment by
Fig. 4. Retrograde synovial biopsy in the knee under local anaesthetic. The instrument (Retroforce, Karl Storz GmbH, Tuttlingen, Germany) is inserted into the joint cavity, opened and withdrawn.
Please cite this article in press as: V. Krenn, et al., 15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.05.005
G Model PRP-51811; No. of Pages 8
ARTICLE IN PRESS V. Krenn et al. / Pathology – Research and Practice xxx (2017) xxx–xxx
7
Fig. 5. Hematoxylin and eosin staining (a) and MALDI-images (b- f) of synovial tissue of a patient with Rheumatoid arthritis. The paraffin sections were deparaffinated, trypsinated and spayed with a matrix solution for crystallization of peptides. Subsequently, the tissue was analysed by MALDI-imaging mass spectrometry in a Rapiflex (Bruker Daltonik, Bremen) mass spectrometer. Each area of the tissue was analysed allowing exact localization of various peptides in different compartments of the tissue. The peptide abundance is expressed by a chromatic scale color code indicating the highest (white) and lowest (blue) intensity color in the bar. We detected predictive peptides for Calgizzarin (m/z 771.4), Calgranulin (m/z 1271.7), Histone H2A (m/z 944.5), Histone H4 (m/z 1325.7), Histone H3 like (m/z 788.5). All scale bars are 2 mm (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
analysis of synovitis [10], and specific patterns exist in high-grade synovitis (Fig. 5). Since with this method possibly functionally relevant proteins can be shown for the first time in pathogenetic tissues (so-called in situ proteomics), it is to be expected that biomarkers of RA will be identified [10] which can enable a risk stratification of high-grade synovitis (e.g. progression risk and biologic sensitivity). This could be a new basis for highly differentiated synovitis diagnostics.
Conflict of interests Regardless of a possible conflict of interests, this scientific paper is independent and product-neutral.
References [1] A. Abdalmula, L.M. Dooley, C. Kaufman, et al., Immunoselected STRO-3+ mesenchymal precursor cells reduce inflammation and improve clinical outcomes in a large animal model of monoarthritis, Cell Res. Ther. 8 (February (1)) (2017) 22, http://dx.doi.org/10.1186/s13287-016-0460-7, PMID:28173831. [2] V. Badot, C. Galant, A. Nzeusseu Toukap, et al., Gene expression profiling in the synovium identifies a predictive signature of absence of response to adalimumab therapy in rheumatoid arthritis, Arthritis Res. Ther. 11 (2) (2009) R57, PMID: 19389237. [3] B. Fink, I. Berger, C. Siegmüller, et al., Recurring synovitis as a possible reason for aseptic loosening of knee endoprostheses in patients with rheumatoid arthritis, J. Bone Joint Surg. Br. 83 (May (4)) (2001) 604–608, PMID: 11380140. [4] T. Hügle, G. Gashi, M. Wiewiorski, et al., Development of a new device for synovial biopsies, Surg Innov. 22 (October (5)) (2015) 496–499. [5] M. Jakobs, L. Morawietz, H. Rothschenk, et al., Synovitis score: value of histopathological diagnostics in unclear arthritis. Case reports from rheumatological pathological practice, Z. Rheumatol. 66 (December (8)) (2007) 706–712, German. [6] B. Kölbel, S. Wienert, J. Dimitriadis, et al., CD15 focus score for diagnostics of periprosthetic joint infections: neutrophilic granulocytes quantification mode and the development of morphometric Software (CD15 quantifier), Z. Rheumatol. 74 (September (7)) (2015) 622–630. [7] V. Krenn, L. Morawietz, T. Häupl, et al., Grading of chronic synovitis- a histopathological grading system for molecular and diagnostic pathology, Pathol. Res. Pract. 198 (5) (2002) 317–325, PMID: 12092767.
[8] V. Krenn, L. Morawietz, G.R. Burmester, et al., Synovitis score: discrimination between chronic low-grade and high-grade synovitis, Histopathology 49 (October (4)) (2006) 358–364, PMID: 16978198. [9] V. Krenn, L. Morawietz, A. König, et al., Differential diagnosis of chronic synovitis, Pathologe 27 (November (6)) (2006) 402–408, Review. German. PMID: 17031677. [10] J. Kriegsmann, M. Kriegsmann, R. Casadonte, MALDI TOF imaging mass spectrometry in clinical pathology: a valuable tool for cancer diagnostics (review), Int. J. Oncol. 46 (March (3)) (2015) 893–906, Review. [11] T.M. Kriegsmann, et al., Expression of miR-146a, miR-155, and miR-223 in formalin-fixed paraffin-embedded synovial tissues of patients with rheumatoid arthritis and osteoarthritis, Virchows Arch. 469 (July (1)) (2016) 93–100, http://dx.doi.org/10.1007/s00428-016-1939-4, PMID:2707919. [12] F. Koizumi, H. Matsuno, K. Wakaki, et al., Synovitis in rheumatoid arthritis: scoring of characteristic histopathological features, Pathol. Int. 49 (April (4)) (1999) 298–304, PMID:1036584. [13] A. Najm, C. Orr, M.F. Heymann, et al., Success rate and utility of ultrasound-guided synovial biopsies in clinical practice, J. Rheumatol. 43 (December (12)) (2016) 2113–2119. [14] F. Pessler, L. Dai, C. Diaz-Torne, et al., The synovitis of non-inflammatory orthopaedic arthropathies: a quantitative histological and immunohistochemical analysis, Ann. Rheum. Dis. 67 (August (8)) (2008) 1184–1187, PMID:18203762. [15] F. Pessler, A. Ogdie, C. Diaz-Torne, et al., Subintimal Ki-67 as a synovial tissue biomarker for inflammatory arthropathies, Ann. Rheum. Dis. 67 (February (2)) (2008) 162–167, PMID:17613556. [16] W. Püschel, G. Geiler, P.Z. Stiehl, The value of synovial biopsies in the diagnosis of rheumatoid arthritis and in estimating local inflammatory activity, Rheumatol 35 (July–August(7–8)) (1976) 278–285, German. PMID:96107. [17] D.A. Rao, M.F. Gurish, J.L. Marshall, et al., Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis, Nature 542 (February (7639)) (2017) 110–114, http://dx.doi.org/10.1038/nature20810. [18] E. Slansky, J. Li, T. Häupl, et al., Quantitative determination of the diagnostic accuracy of the synovitis score and its components, Histopathology 57 (September (3)) (2010) 436–443. [19] J.S. Smolen, F.C. Breedveld, G.R. Burmester, et al., Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force, Ann. Rheum. Dis. 75 (January (1)) (2016) 3–15. [20] S. Söder, T. Aigner, Osteoarthritis. Etiology, typing, staging and histological grading, Pathologe 32 (May (3)) (2011) 183–192, Review. German. PMID:2149975. [21] S.E. Sweeney, G.S. Firestein, Rheumatoid arthritis: regulation of synovial inflammation, Int. J. Biochem. Cell Biol. 36 (March (3)) (2004) 372–378, Review. PMID: 14687914. [22] U. Ungethuem, T. Haeupl, H. Witt, et al., Molecular signatures and new candidates to target the pathogenesis of rheumatoid arthritis, Physiol. Genom. 42 (November A(4)) (2010) 267–282.
Please cite this article in press as: V. Krenn, et al., 15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.05.005
G Model PRP-51811; No. of Pages 8 8
ARTICLE IN PRESS V. Krenn et al. / Pathology – Research and Practice xxx (2017) xxx–xxx
[23] M.P. van der Linden, R. Knevel, T.W. Huizinga, et al., Classification of rheumatoid arthritis: comparison of the 1987 american college of rheumatology criteria and the 2010 american college of Rheumatology/European league against rheumatism criteria, Arthritis Rheum. 63 (January (1)) (2011) 37–42. [24] M.G. van de Sande, D.L. Baeten, Immunopathology of synovitis: from histology to molecular pathways, Rheumatology (Oxford) 55 (April (4)) (2016) 599–606, PMID: 26359330.
[25] W. Waldstein, G. Perino, S.T. Jawetz, et al., Does intraarticular inflammation predict biomechanical cartilage properties? Clin. Orthop. Relat. Res. 472 (July (7)) (2014) 2177–2184. [26] J. Zustin, T. Aigner, Osteoarthritis–histopathologic diagnosis: typing, grading, and staging, Orthopade 38 (June (6)) (2009) 491–500, Review. German. PMID: 1951709.
Please cite this article in press as: V. Krenn, et al., 15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.05.005
ARTICLE IN PRESS Pathology – Research and Practice xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.com/locate/prp
Review
15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics V. Krenn a,∗ , G. Perino b , W. Rüther c , V.T. Krenn a , M. Huber d , T. Hügle e , A. Najm f , S. Müller a , F. Boettner b , F. Pessler g,h , W. Waldstein i , J. Kriegsmann a,j , R. Casadonte j , T. Häupl k , S. Wienert l , M.G. Krukemeyer m , S. Sesselmann n , S. Sunitsch o , R. Tikhilov p , L. Morawietz q a
MVZ-Zentrum für Histologie, Zytologie und Molekulare Diagnostik, Trier, Germany Department of Pathology and Laboratory Medicine, Hospital for Special Surgery, New York, USA c Klinik und Poliklinik für Orthopädie, Universitätsklinikum Hamburg-Eppendorf, Germany d Pathologisch-bakteriologisches Institut, Otto Wagner Spital, Vienna, Austria e Hôpital Orthopédique, Lausanne, Switzerland f Rhumatologie, Centre hospital-universitaire de Nantes, France g TWINCORE, Zentrum für Experimentelle und Klinische Infektionsforschung GmbH, Hannover, Germany h Helmholtz-Zentrum für Infektionsforschung, Braunschweig, Germany i Medizinische Universität Wien, AKH-Wien, Universitätsklinik für Orthopädie, Vienna, Austria j Proteopath GmbH, Trier, Germany k Med. Klinik, Rheumatologie und Klinische Immunologie (Charité),Berlin, Germany l VMscope-Berlin, Germany m Paracelsus-Kliniken Deutschland, Osnabrück, Germany n Orthopädische Universitätsklinik Erlangen, Erlangen, Germany o Medizinische Universität Graz – Institut für Pathologie, Austria p Vreden Russian Scientific Research Institute of Traumatology and Orthopedics, Saint Petersburg, Russia q MVZ Fürstenberg-Karree, Berlin, Germany b
a r t i c l e
i n f o
Article history: Received 30 March 2017 Accepted 11 May 2017 Keywords: Synovitis score Synovitis Rheumatoid arthritis Arthrosis Semiquantitative evaluation Immunohistochemistry Risk stratification
a b s t r a c t The histopathological synovitis score evaluates the immunological and inflammatory changes of synovitis in a graduated manner generally customary for diagnostic histopathological scores. The score results from semiquantitative evaluation of the width of the synovial surface cell layer, the cell density of the stroma and the density of the inflammatory infiltration into 4 semiquantitative levels (normal 0, mild 1, moderate 2, severe 3). The addition of these values results in a final score of 0–9 out of 9. On the basis of this summation the condition is divided into low-grade synovitis and high-grade synovitis: A synovitis score of 1 to ≤ 4 is called low-grade synovitis (arthrosis-associated/OA synovitis, posttraumatic synovitis, meniscopathy-associated synovitis and synovitis with haemochromatosis). A synovitis score of ≥ 5 to 9 is called high-grade synovitis (rheumatoid arthritis, psoriatic arthritis, Lyme arthritis, postinfection/reactive arthritis and peripheral arthritis with Bechterew’s disease). By means of the synovitis score it is therefore possible to distinguish between degenerative/posttraumatic diseases (low-grade synovitis) and inflammatory rheumatic diseases (high-grade synovitis) with a sensitivity of 61.7% and a specificity of 96.1%. The diagnostic accuracy according to ROC analysis (AUC: 0.8–0.9) is good. Since the first publication (2002) and an associated subsequent publication (2006), the synovitis score has nationally and internationally been accepted for histopathological assessment of the synovitis. In a PubMed data analysis (status: 14.02.2017), the following citation rates according to Cited by PubMed Central articles resulted for the two synovitis score publications: For DOI: 10.1078/0344-0338-5710261 there were 29 Cited by PubMed Central articles and for the second extended publication DOI:10.1111/j.13652559.2006.02508 there were 44 Cited by PubMed Central articles. Therefore a total of 73 PubMed citations are observed over a period of 15 years, which demonstrates an international acceptance of the score. This synovitis score provides for the first time a diagnostic, standardised and reproducible histopathological evaluation method enabling a contribution to the differential diagnosis of chronic inflammatory
∗ Corresponding author at: MVZ Zentrum für Histologie, Zytologie und Molekulare Diagnostik, Max-Planck-Straße. E-mail address: [email protected] (V. Krenn). http://dx.doi.org/10.1016/j.prp.2017.05.005 0344-0338/© 2017 Elsevier GmbH. All rights reserved.
Please cite this article in press as: V. Krenn, et al., 15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.05.005
G Model
ARTICLE IN PRESS
PRP-51811; No. of Pages 8
V. Krenn et al. / Pathology – Research and Practice xxx (2017) xxx–xxx
2
general joint diseases. This is particularly the case by incorporation into the joint pathology algorithm. To specify the synovitis score an immunohistochemical determination of various inflammation-relevant CD antigens is proposed to enable a risk stratification of high-grade synovitis (e.g.: progression risk and sensitivity for biologicals). © 2017 Elsevier GmbH. All rights reserved.
Contents 1. 2.
3.
4. 5.
Pathogenesis of rheumatoid arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Classification criteria of rheumatoid arthritis, histopathological synovitis diagnostics and differential diagnosis of synovial diseases . . . . . . . . . . . . . 00 2.1. Synovitis score as a standardised histopathological evaluation method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.2. Histopathological criteria of the synovitis score . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.3. Dual stratification by means of the synovitis score: low-grade/high-grade synovitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.4. Diagnostic discrimination of the synovitis score . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 National and international acceptance of the synovitis score for the histopathological assessment of the synovialis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1. Evaluation of the synovitis score in PubMed according to the cited by PubMed central articles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.2. Synovitis score in online databanks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.3. Publicising and correct use of the synovitis score by IAP tutorials (Internationale Akademie für Pathologie, Deutsche Abteilung, e.V., Bonn) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.4. Synovial pathology algorithm and synovitis score: comprehensive diagnostic and pathogenetic context . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.5. Synovial diagnostics in orthopaedics, orthopaedic rheumatology and joint endoprosthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.6. Synovial diagnostics in rheumatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Molecular validation of the synovitis score . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.1. Immunohistochemical synovitis score: biologics sensitivity, risk stratification, synovial inflammation regression under medicamentous treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.2. Digital quantification software for synovitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.3. Molecular methods of synovitis typing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conflict of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1. Pathogenesis of rheumatoid arthritis Rheumatoid arthritis (RA) is the most frequent inflammatory systemic connective tissue disease with a predominantly symmetric manifestation at the peripheral, small joints of the upper extremities. Extraarticular manifestations exist in the bursa, synovial sheathes, in the subepidermal tissue, in the eyes, in the pleura and the internal organs [19]. Pathogenetically, the underlying cause of rheumatoid arthritis of RA lies in a chronic, destructive synovitis which is largely based on a dysregulation of the B lymphocyte and T lymphocyte response as well as fibroblast and macrophage activation [17,20,24]. Current data indicate an expansion of deregulated synovial T and B lymphocytes [17]. In RA, primary synovitis with secondary cartilage damage is observed, by contrast, in arthrosis (osteoarthrosis, OA) a secondary synovitis is present with primary cartilage damage [25,26]. 2. Classification criteria of rheumatoid arthritis, histopathological synovitis diagnostics and differential diagnosis of synovial diseases A synovial biopsy is not necessary for diagnosis and classification of RA according to the internationally applicable ACR criteria 2010 [15,19,23], this clinically weighted classification being based on clinical, seroimmunological, sonographic and radiological criteria. In the event of incomplete classification of rheumatic joint disease or clinically unclear arthritis and arthritis-like diseases, a synovial biopsy can make a significant diagnostic contribution [4,13]. It is to be said generally that a histopathological differential diagnosis of “synovitis” is a comprehensive differential diagnosis and includes not only the differential diagnosis of inflammatory diseases [2,4,8,11,16,21,22]. This inflammatory, non-inflammatory,
infectious, metabolic and neoplastic diagnosis spectrum is combined in the joint pathology algorithm (Diagram 1) [8], which illustrates the diagnostic position of the synovitis score. 2.1. Synovitis score as a standardised histopathological evaluation method The fact that in inflammatory (e.g. Rheumatoid arthritis; RA) and non-inflammatory (e.g. osteoarthrosis; OA) joint diseases histopathological differences in the severity of the synovitis occur was regarded as knowledge based on histopathological diagnostic “everyday experience”. Histopathological scores in this regard have been developed since 1976 and focussed on evaluating the local activity diagnosis of the RA [12,16]. The synovitis score [6,7], however, provides for the first time a diagnostic, standardised and reproducible histopathological evaluation method which allows a contribution to the differential diagnosis of chronic inflammatory general joint diseases [8]. This is particularly the case by incorporation into the joint pathology algorithm [8] (Diagram 1). 2.2. Histopathological criteria of the synovitis score The synovitis score evaluates the immunological and inflammatory tissue changes of synovitis in a graduated manner generally customary for diagnostic histopathological scores [6,7]. This score [6,7] represents a semiquantitative, additive evaluation method (additive score), which by specifying three compartments of synovitis (surface cell layer, stroma cells and inflammatory infiltration) is based on a graduated, semiquantitative evaluation of the width of the surface cell layer, the cell density of the stroma and the density of the inflammatory infiltration (absent, mildly, moderately and
Please cite this article in press as: V. Krenn, et al., 15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.05.005
G Model
ARTICLE IN PRESS
PRP-51811; No. of Pages 8
V. Krenn et al. / Pathology – Research and Practice xxx (2017) xxx–xxx
3
Synovial pathology algorithm Non -inflammatory
Inflammatory
Benign tumours PVNS (Pigmented Villonodular Synovis) Lipoma Haemangioma/Angiodysplasia Synovial chondromatosis
Malign tumours Synovial sarcoma Ewing sarcoma
Granulomatous
Infecons Mycobateria Mycoses, Brucellosis Rare infecons with granuloma formaon
Immunologic/metabolicand storage diseases Macrophages/Granulomaformaon
Bacterial synovis Low-grade infecon: Low virulent bacteria High-grade infecon: High virulent bacteria
Crystal-induced
Non-granulomatous Foreign body reacon Condion aer intraarcular injecon
Synovialis-Score ≤ 4 Low-Grade Synovis
Arthrosis-associated synovis Lymphoplasmacyc-type Detritus-type Posraumac synovis Meniscopathy synovis Haemochromatosis
Gout Acute Chronic tophus
CPPA
Calcareous deposits Calcium phosphate Calcium carbonate
Synovialis-Score ≥ 5 High-Grade Synovis
Rheumatoid arthris Lyme arthris (Borreliosis) Reacve arthris Psoriac arthris Ankylosing spondylis (Arthris in distal joints)
Diagram 1. Synovial pathology algorithm modified according to [8] with integration of low-grade (blue background) and high-grade synovitis (orange background). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
severely changed). Only the criterion of width of the surface cell layer is a quantitative criterion and consists of direct counting of the synovial surface cells. In order to ensure a good reproducibility of the synovitis score, characteristic microphotographs were published to illustrate all of the criteria [6,7]. The three different compartments of synovitis are each evaluated on four levels from 0 to 3 points, resulting in a final score from 0/9 to 9/9. There are additionally two criteria which are independent of this semiquantitative evaluation, the surface cell layer ulceration (3 points) and the detection of intrasynovial rheumatoid necrosis. Intrasynovial rheumatoid necrosis (Fig. 1) are a morphological equivalent of an RA, the maximum points of 9/9 are being given here [8]. 2.3. Dual stratification by means of the synovitis score: low-grade/high-grade synovitis In the first published version of the synovitis score [6], a numerical summation was proposed as the score result; in the second, extended published version of the synovitis score [7] a classification into low-grade synovitis and high-grade synovitis based on this numerical summation was specified (Fig. 2). A synovitis score of 1 to ≤ 4 is called low-grade synovitis (Fig. 2a), a synovitis score of ≥ 5 to 9 is called high-grade synovitis (Fig. 2b) [7]. The diagnosis of low-grade synovitis is associated (Diagram 1) with a non-inflammatory or mildly inflammatory joint disease/arthropathy (arthrosis-associated synovitis, posttraumatic synovitis, meniscopathy-associated synovitis and synovitis with
Fig. 1. Rheumatoid granuloma Rheumatoid necrosis in the fibrous tissue of a bursa wall with central, so-called land map-like necrosis and histiocytic peripheral palisading (HE staining, original magnification about 400×).
haemochromatosis). The histopathological classification of a highgrade synovitis leads to the diagnoses: Rheumatoid arthritis, psoriatic arthritis, Lyme arthritis, reactive arthritis and peripheral arthritis with Bechterew’s disease (Diagram 1). The synovitis score does not allow subspecifying of the synovitis within the group of low-grade synovitis and high-grade synovitis (Diagram 1). The
Please cite this article in press as: V. Krenn, et al., 15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.05.005
G Model PRP-51811; No. of Pages 8 4
ARTICLE IN PRESS V. Krenn et al. / Pathology – Research and Practice xxx (2017) xxx–xxx
Fig. 2. Low-grade and high-grade synovitis: 2a: Low-grade synovitis (3/9); in OA: According to the synovitis score there is a slight widening of the surface cell layer (1), a slightly increased cell density of the synovial stroma (1), and a mild inflammatory leukocytic (mononuclear) infiltration (1) in blue (synovitis score: 3/9). 2b: High-grade synovitis (7/9) in RA with moderate widening of the surface cell layer (2), moderate cell density of the synovial stroma (2), severe leukocytic, plasma cell-rich inflammatory infiltration (3) (HE staining, original magnification about 200×). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
sensitivity and specificity and the inter- and intraobserver reproducibility are adequate [6,7] and therefore ensure reproducible, histopathological synovitis diagnostics [7]. Using the synovitis score it is therefore possible to distinguish between degenerative/posttraumatic diseases (low-grade synovitis) and inflammatory rheumatic diseases (high-grade synovitis) with a sensitivity of 61.7% and a specificity of 96.1% [7]. The diagnostic accuracy according to the ROC analysis (AUC: 0.8–0.9) is good [14]. 2.4. Diagnostic discrimination of the synovitis score The diagnostic discrimination of the synovitis score and of each of its individual components was investigated with the receiver operating characteristic (ROC) curve analysis [14]. The area under the ROC curve (AUC) corresponds to the diagnostic accuracy of a test (AUC 0.50 − 0.75 = average, 0.75–0.92 = good, 0.92–0.97 = very good, 0.97–1.00 = excellent). The synovitis score had AUCs ranging from 0.8–0.9 in the differentiations between inflammatory (e.g. RA) and degenerative (e.g. OA) arthropathies and an AUC of 0.87–0.98 in the demarcation of degenerative arthropathies from normal tissue. A multicategorical ROC analysis showed that: 1) The components of stroma density and width of the surface cell layer contribute much more to the diagnostic discrimination of the score than the infiltration component and that 2) Combining the individual components to give the complete score synergistically increases the general diagnostic accuracy several-fold [14]. 3. National and international acceptance of the synovitis score for the histopathological assessment of the synovialis 3.1. Evaluation of the synovitis score in PubMed according to the cited by PubMed central articles In a PubMed analysis (status: 12.02.2017), the following citation rates according to the criterion Cited by PubMed Central articles resulted for the two synovitis score publications: For DOI: 10.1078/0344-0338-5710261 there were 29 Cited by PubMed Central articles and for the second extended publication DOI:10.1111/ j.1365-2559.2006.02508 there were 44 Cited by PubMed Central articles. There is therefore a total of 73 PubMed citations were observed over a period of 15 years (Diagram 2a and b). In these 73 PubMed-cited publications the synovitis score was used in various non-experimental, clinical and experimental studies (Diagram 2c). In these studies the synovitis was evaluated by the synovitis score. Generally, in all 73 publications there is a direct and sta-
tistically confirmed agreement between the synovitis scores and various clinical, imaging, histological, immunohistochemical and functional parameters of joint diseases [12,21]. 3.2. Synovitis score in online databanks The synovitis score can also be found in the following online databanks: Wikibooks: https://de.wikibooks.org/wiki/Pathologie: Gelenke, Wikipedia: https://de.wikipedia.org/wiki/SynovialitisPathologisch: https://pathologisch.de/index.php/ Score, arbeitshilfen/arbeitshilfen-sonstige/krenn-score-synovialitis, DocCheck Medical Services: http://flexikon.doccheck.com/de/ Synovitis, LinkFang: http://www.linkfang.de/wiki/SynovialitisScore 3.3. Publicising and correct use of the synovitis score by IAP tutorials (Internationale Akademie für Pathologie, Deutsche Abteilung, e.V., Bonn) New IAP seminars have been implemented by the author (V.K.) for publicising and using the synovitis score as a new diagnostic score for pathology (Rheumapathology, Inflammatory and neoplastic joint diseases and Orthopaedic pathology). These 15 IAP seminars have been held 9 x as a half-day and 6 x as a full day event since 2006. About 2–4 joint pathological cases which demonstrate the synovitis score as an important diagnostic principle have been presented and discussed at each seminar. 3.4. Synovial pathology algorithm and synovitis score: comprehensive diagnostic and pathogenetic context The histopathological differential diagnoses of joint diseases according to the synovial pathology algorithm [8] are presented in the extended algorithm (Diagram 1). An important diagnostic constituent is the diagnostic, dichotomous classification of joint diseases by the synovitis score into low-grade and high-grade synovitis. By this means and by the synovial pathology algorithm diagnosis of synovial diseases in a comprehensive diagnostic and pathogenetic context is possible. 3.5. Synovial diagnostics in orthopaedics, orthopaedic rheumatology and joint endoprosthetics Patients with RA and OA might require surgical interventions which includes synovialectomy especially in cases which can-
Please cite this article in press as: V. Krenn, et al., 15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.05.005
G Model PRP-51811; No. of Pages 8
ARTICLE IN PRESS V. Krenn et al. / Pathology – Research and Practice xxx (2017) xxx–xxx
5
Diagram 2. Synovitis score citations in PubMed (Cited by PubMed Central articles, status: 14.02.2017) shown according to the citation location (country of origin) with respect to the two synovitis score publications 2002 (a) and 2006 (b) and according to the context of the contents (c) here of the two publications (2002 and 2006).
not be influenced by medicaments, and joint replacements when advanced joint degeneration is observed. The histopathological assessment of the synovial section can follow the joint pathology algorithm (Diagram 1). The task of synovial diagnostics is that at the time of the surgical intervention the diagnosis of the joint disease (e.g. OA, RA) is often unknown and an evaluation of the synovium provides information regarding the inflammatory activity of the disease at the time of the surgical intervention. This is highly relevant asthe survival of a joint endoprosthesis is also influenced by the underlying disease [2]. The relevance of synovialectomy section diagnostics therefore lies not only in the evaluation of the inflammatory activity by means of the synovitis score. Taking the joint pathology algorithm into
account the histopathological evaluation of synovitis may exclude infectious synovitis, a pigmented villonodular synovitis and crystal arthropathy which all have a direct impact on the survival of joint endoprostheses [2,5,9]. 3.6. Synovial diagnostics in rheumatology Although new and more efficient methods of synovial biopsy (Fig. 4) have been developed in recent years [3], histopathological diagnostics of RA are not a constituent of the primary diagnostics. The international classification criteria [19] are based on clinical, serological and imaging criteria and are therefore nonhistopathological. With the exception of differential diagnosis of
Please cite this article in press as: V. Krenn, et al., 15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.05.005
G Model PRP-51811; No. of Pages 8 6
ARTICLE IN PRESS V. Krenn et al. / Pathology – Research and Practice xxx (2017) xxx–xxx
5. Prospects 5.1. Immunohistochemical synovitis score: biologics sensitivity, risk stratification, synovial inflammation regression under medicamentous treatment Since it has been possible to demonstrate a CD68, CD3, CD15 and CD20 reduction after biologics therapy and a high Ki67, IL7R, IL18rap, CXCL11 and IL18 expression in non-responders to biologics [1], these markers can be employed in combination with the synovitis score in the sense of an immunohistochemical synovitis score. This might subspecify forms of a high-grade synovitis and might provide further information regarding the possibility of eventual regression of synovial inflammation. The immunohistochemical determination of various CD antigens is recommended for immunohistochemical validation of a possible regression of the synovial inflammation with e.g. biologics therapy. 5.2. Digital quantification software for synovitis Fig. 3. Ki67 inflammation quantifier High-grade synovitis, synovitis score (8/9). Determination of the proliferation fraction by means of quantification software (Ki67 Inflammation Quantifier, VMscope Berlin). Proliferation fraction Ki67: 14.42% with a total of 846 quantified cells, synovial surface cell layer and subsynovial stroma. The high proliferation fraction is possibly associated with a high local synovial destruction or with a progressive course of the disease. Shown in the so-called Ki67 Inflammation Quantifier mode, VMscope Berlin, negative cells are bordered in green, positive cells, Ki67-positive, are bordered in red. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
a rheumatic nodule, histopathological synovial diagnostics is of importance chiefly in the case of arthritis in large joints. From the point of view of the rheumatologist, a synovial biopsy is appropriate for “rheumatologically unclear arthritis”, especially of large joints, where the histopathological assessment can make an important diagnostic contribution [4]. 4. Molecular validation of the synovitis score Stratification by means of the synovitis score into normal tissue, low-grade synovitis and high-grade synovitis shows statistically significantly divergent gene expression profiles of degenerative and inflammatory rheumatic joint diseases in a molecular analysis. Secreted phosphoprotein 1 (SPPA) has been identified as a significantly highly regulated gene in RA (high-grade synovitis), which is associated with T lymphocyte activation and apoptosis processes [18]. The extent to which this marker could also be used in histopathological diagnostics has currently not yet been validated.
Through newly developed digital quantification software for synovial inflammatory reactions, specific software has been developed for CD15 [5], Ki67 and for CD3: CD15 Quantifier, Ki-67 Inflammation Quantifier, S. Müller, Histopathologische Klassifikation der Synovialis bei dysfunktioneller Endoprothese des oberen Sprunggelenks. Diss. Medizinische Fakultät Charité – Universitätsmedizin Berlin 2016. URN: urn:nbn:de:kobv:188-fudissthesis 000000101571-6 (see Fig. 3) and CD3 Quantifier (VM-Scope Berlin, Germany) which could objectify cell quantifications (e.g. regression of synovial inflammation), and assist in the development of a diagnostic, digital pathology in the field of rheumatic pathology and orthopaedic pathology. 5.3. Molecular methods of synovitis typing At the miRNA expression level different expression patterns of miR-146a, miR-155 and miR33 have been found in low-grade and high-grade synovitis [11], and divergent patterns likewise exist at the protein level [10]. In the MALDI method (matrix-assisted laser desorption/ionisation) the so-called analyte is ionised by means of laser bombardment [10]. This usually takes place via a matrix in which the analytes are embedded. The laser bombardment causes the matrix to vaporise explosively and the molecules to be investigated are fragmented kinetically. An ionisation of the analyte usually takes place at the same time. The ions formed in this way are accelerated in an electric field and detected. A distinction is made between MALDI profiling and MALDI imaging. By means of MALDI imaging mass spectrometry it has been possible to detect calgranulin, defensin and thymosin in the subsynovial compartment by
Fig. 4. Retrograde synovial biopsy in the knee under local anaesthetic. The instrument (Retroforce, Karl Storz GmbH, Tuttlingen, Germany) is inserted into the joint cavity, opened and withdrawn.
Please cite this article in press as: V. Krenn, et al., 15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.05.005
G Model PRP-51811; No. of Pages 8
ARTICLE IN PRESS V. Krenn et al. / Pathology – Research and Practice xxx (2017) xxx–xxx
7
Fig. 5. Hematoxylin and eosin staining (a) and MALDI-images (b- f) of synovial tissue of a patient with Rheumatoid arthritis. The paraffin sections were deparaffinated, trypsinated and spayed with a matrix solution for crystallization of peptides. Subsequently, the tissue was analysed by MALDI-imaging mass spectrometry in a Rapiflex (Bruker Daltonik, Bremen) mass spectrometer. Each area of the tissue was analysed allowing exact localization of various peptides in different compartments of the tissue. The peptide abundance is expressed by a chromatic scale color code indicating the highest (white) and lowest (blue) intensity color in the bar. We detected predictive peptides for Calgizzarin (m/z 771.4), Calgranulin (m/z 1271.7), Histone H2A (m/z 944.5), Histone H4 (m/z 1325.7), Histone H3 like (m/z 788.5). All scale bars are 2 mm (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
analysis of synovitis [10], and specific patterns exist in high-grade synovitis (Fig. 5). Since with this method possibly functionally relevant proteins can be shown for the first time in pathogenetic tissues (so-called in situ proteomics), it is to be expected that biomarkers of RA will be identified [10] which can enable a risk stratification of high-grade synovitis (e.g. progression risk and biologic sensitivity). This could be a new basis for highly differentiated synovitis diagnostics.
Conflict of interests Regardless of a possible conflict of interests, this scientific paper is independent and product-neutral.
References [1] A. Abdalmula, L.M. Dooley, C. Kaufman, et al., Immunoselected STRO-3+ mesenchymal precursor cells reduce inflammation and improve clinical outcomes in a large animal model of monoarthritis, Cell Res. Ther. 8 (February (1)) (2017) 22, http://dx.doi.org/10.1186/s13287-016-0460-7, PMID:28173831. [2] V. Badot, C. Galant, A. Nzeusseu Toukap, et al., Gene expression profiling in the synovium identifies a predictive signature of absence of response to adalimumab therapy in rheumatoid arthritis, Arthritis Res. Ther. 11 (2) (2009) R57, PMID: 19389237. [3] B. Fink, I. Berger, C. Siegmüller, et al., Recurring synovitis as a possible reason for aseptic loosening of knee endoprostheses in patients with rheumatoid arthritis, J. Bone Joint Surg. Br. 83 (May (4)) (2001) 604–608, PMID: 11380140. [4] T. Hügle, G. Gashi, M. Wiewiorski, et al., Development of a new device for synovial biopsies, Surg Innov. 22 (October (5)) (2015) 496–499. [5] M. Jakobs, L. Morawietz, H. Rothschenk, et al., Synovitis score: value of histopathological diagnostics in unclear arthritis. Case reports from rheumatological pathological practice, Z. Rheumatol. 66 (December (8)) (2007) 706–712, German. [6] B. Kölbel, S. Wienert, J. Dimitriadis, et al., CD15 focus score for diagnostics of periprosthetic joint infections: neutrophilic granulocytes quantification mode and the development of morphometric Software (CD15 quantifier), Z. Rheumatol. 74 (September (7)) (2015) 622–630. [7] V. Krenn, L. Morawietz, T. Häupl, et al., Grading of chronic synovitis- a histopathological grading system for molecular and diagnostic pathology, Pathol. Res. Pract. 198 (5) (2002) 317–325, PMID: 12092767.
[8] V. Krenn, L. Morawietz, G.R. Burmester, et al., Synovitis score: discrimination between chronic low-grade and high-grade synovitis, Histopathology 49 (October (4)) (2006) 358–364, PMID: 16978198. [9] V. Krenn, L. Morawietz, A. König, et al., Differential diagnosis of chronic synovitis, Pathologe 27 (November (6)) (2006) 402–408, Review. German. PMID: 17031677. [10] J. Kriegsmann, M. Kriegsmann, R. Casadonte, MALDI TOF imaging mass spectrometry in clinical pathology: a valuable tool for cancer diagnostics (review), Int. J. Oncol. 46 (March (3)) (2015) 893–906, Review. [11] T.M. Kriegsmann, et al., Expression of miR-146a, miR-155, and miR-223 in formalin-fixed paraffin-embedded synovial tissues of patients with rheumatoid arthritis and osteoarthritis, Virchows Arch. 469 (July (1)) (2016) 93–100, http://dx.doi.org/10.1007/s00428-016-1939-4, PMID:2707919. [12] F. Koizumi, H. Matsuno, K. Wakaki, et al., Synovitis in rheumatoid arthritis: scoring of characteristic histopathological features, Pathol. Int. 49 (April (4)) (1999) 298–304, PMID:1036584. [13] A. Najm, C. Orr, M.F. Heymann, et al., Success rate and utility of ultrasound-guided synovial biopsies in clinical practice, J. Rheumatol. 43 (December (12)) (2016) 2113–2119. [14] F. Pessler, L. Dai, C. Diaz-Torne, et al., The synovitis of non-inflammatory orthopaedic arthropathies: a quantitative histological and immunohistochemical analysis, Ann. Rheum. Dis. 67 (August (8)) (2008) 1184–1187, PMID:18203762. [15] F. Pessler, A. Ogdie, C. Diaz-Torne, et al., Subintimal Ki-67 as a synovial tissue biomarker for inflammatory arthropathies, Ann. Rheum. Dis. 67 (February (2)) (2008) 162–167, PMID:17613556. [16] W. Püschel, G. Geiler, P.Z. Stiehl, The value of synovial biopsies in the diagnosis of rheumatoid arthritis and in estimating local inflammatory activity, Rheumatol 35 (July–August(7–8)) (1976) 278–285, German. PMID:96107. [17] D.A. Rao, M.F. Gurish, J.L. Marshall, et al., Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis, Nature 542 (February (7639)) (2017) 110–114, http://dx.doi.org/10.1038/nature20810. [18] E. Slansky, J. Li, T. Häupl, et al., Quantitative determination of the diagnostic accuracy of the synovitis score and its components, Histopathology 57 (September (3)) (2010) 436–443. [19] J.S. Smolen, F.C. Breedveld, G.R. Burmester, et al., Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force, Ann. Rheum. Dis. 75 (January (1)) (2016) 3–15. [20] S. Söder, T. Aigner, Osteoarthritis. Etiology, typing, staging and histological grading, Pathologe 32 (May (3)) (2011) 183–192, Review. German. PMID:2149975. [21] S.E. Sweeney, G.S. Firestein, Rheumatoid arthritis: regulation of synovial inflammation, Int. J. Biochem. Cell Biol. 36 (March (3)) (2004) 372–378, Review. PMID: 14687914. [22] U. Ungethuem, T. Haeupl, H. Witt, et al., Molecular signatures and new candidates to target the pathogenesis of rheumatoid arthritis, Physiol. Genom. 42 (November A(4)) (2010) 267–282.
Please cite this article in press as: V. Krenn, et al., 15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.05.005
G Model PRP-51811; No. of Pages 8 8
ARTICLE IN PRESS V. Krenn et al. / Pathology – Research and Practice xxx (2017) xxx–xxx
[23] M.P. van der Linden, R. Knevel, T.W. Huizinga, et al., Classification of rheumatoid arthritis: comparison of the 1987 american college of rheumatology criteria and the 2010 american college of Rheumatology/European league against rheumatism criteria, Arthritis Rheum. 63 (January (1)) (2011) 37–42. [24] M.G. van de Sande, D.L. Baeten, Immunopathology of synovitis: from histology to molecular pathways, Rheumatology (Oxford) 55 (April (4)) (2016) 599–606, PMID: 26359330.
[25] W. Waldstein, G. Perino, S.T. Jawetz, et al., Does intraarticular inflammation predict biomechanical cartilage properties? Clin. Orthop. Relat. Res. 472 (July (7)) (2014) 2177–2184. [26] J. Zustin, T. Aigner, Osteoarthritis–histopathologic diagnosis: typing, grading, and staging, Orthopade 38 (June (6)) (2009) 491–500, Review. German. PMID: 1951709.
Please cite this article in press as: V. Krenn, et al., 15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.05.005