15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics.

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.1365-2559.2006.02508 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 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).

[Fifteen years of the histopathological synovitis score : Review and further developments of a diagnostic score]. / 15 Jahre histopathologischer Synovialitis-Score : Rückblick und Weiterentwicklung eines diagnostischen Scores.

The histopathological synovitis score evaluates in a graded approach, as is largely usual for diagnostic histopathological scores, the immunological and inflammatory changes caused by synovitis. A synovitis score of between 1 and ≤ 4 is classified as low-grade (osteoarthritis-related synovitis, post-traumatic synovitis, meniscopathy-related synovitis and synovitis in hemochromatosis). Synovitis scores of between ≥ 5 and 9 are classified as high-grade synovitis (rheumatoid arthritis, psoriatic arthritis, Lyme's arthritis, post-infection/reactive arthritis and peripheral arthritis in Bechterew disease); sensitivity is 61.7% and sensitivity 96.1%. According to receiver operating characteristic (ROC) analysis (AUC: 0.8-0.9), diagnostic value is good. National and international acceptance of the synovitis score has grown since the first publication in 2002 and a related follow-up publication in 2006. PubMed data analysis (as of 11.01.2017) yielded the following citation values according to "cited by PubMed Central articles" for two publications relating to the synovitis score: there were 29 cited-by-PubMed articles for DOI: 10.1078/0344-0338-5710261 , and 44 cited-in-PubMed articles for the second publication, DOI: 10.1111/j.1365-2559.2006.02508 . This makes a total of 73 PubMed citations over a period of 15 years, thereby evidencing the score's international acceptance. Immunohistochemical determination of a number of CD antigens relevant to inflammation has been proposed to further specify the synovitis score for the purposes of risk stratification of high-grade synovitis (e.g., risk of progression and sensitivity to biological agents).

Revised histopathological consensus classification of joint implant related pathology.

This extended classification of joint implant related pathology is a practical histopathologic classification based on defined morphological criteria covering the complete spectrum of pathohistologic changes in periprosthetic tissues. These changes may occur as a consequence of endoprosthetic replacement of large joints and may lead to a reduction in the prosthesis survival rate. We describe the established consensus classification of the periprosthetic membrane, in which aseptic and septic prosthetic loosening can be subdivided into four histological types, as well as histopathological criteria for additional significant pathologies including endoprosthetic-associated arthrofibrosis, particle-induced immunological, inflammatory and toxic mechanisms (adverse reactions), and bone tissue pathologies. These characteristic tissue alterations and their relationships are summarized in the extended classification. Since particle heterogeneity in periprosthetic tissue is high and particle identification is a necessary part of diagnosis, the identification of different types of particles is described in the histopathological particle algorithm. The morphological qualities of prosthetic material particles and the demarcation between abrasion and non-abrasion endogenous particles are also summarized. This feasible classification which is based on low cost standard tissue processing and examination and on well-defined diagnostic criteria is a solid platform for the histological diagnosis of implant associated pathologies providing a stable and reproducible tool for the surgical pathologist. Since this classification is suitable for standardized histopathological diagnostics, it might also provide a useful data set for joint arthroplasty registers, particularly for registers based on so-called routine data.

[The spectrum of histomorphological findings related to joint endoprosthetics]. / Das Spektrum histopathologischer Veränderungen in endoprothetisch versorgten Gelenken.

Approximately 230,000 total hip and 170,000 knee joint endoprostheses are implanted in Germany annually of which approximately 10% (i.e. 40,000 interventions per year) are cases of revision surgery. These interventions involve removal of a previously implanted prosthesis which has resulted in complaints and replacement with a new prosthesis. There are manifold reasons for revision surgery, the most common indication being so-called endoprosthesis loosening, which is subdivided into septic and aseptic loosening. Histomorphological studies revealed that periprosthetic tissue from endoprosthesis loosening can be classified into four types (I) wear-particle induced type, (II) infectious type, (III) combined type and (IV) fibrous type. Types I and IV represent aseptic loosening and types II and III septic loosening. Recently, the topic of implant allergy has emerged. The detection of cellular, mostly perivascular lymphocytic infiltrates is discussed as being a sign of an allergic tissue reaction. It has most frequently been observed in type I periprosthetic membranes with a dense load of metal wear, which occurs with metal-on-metal bearings. Apart from endoprosthesis loosening, arthrofibrosis is another complication of joint endoprosthetics and can cause pain and impaired function. Histopathologically, arthrofibrosis can be evaluated by a three-tiered grading system. Furthermore, bone pathologies, such as ossification, osteopenia or osteomyelitis can occur as complications of joint endoprosthetics. This review gives an overview of the whole spectrum of pathological findings in joint endoprosthetics and offers a comprehensive and standardized classification system for routine histopathological diagnostics.

[Revised consensus classification. Histopathological classification of diseases associated with joint endoprostheses]. / Erweiterte Konsensusklassifikation. Histopathologische Klassifikation von Gelenkendoprothesen-assoziierten Erkrankungen.

The revised classification of the periprosthetic membrane (synovial-like interface membrane SLIM) encompasses all pathological alterations which can occur as a result of endoprosthetic replacement of major joints and lead to a reduction in durability of prostheses. This also includes the established consensus classification of SLIM by which aseptic and septic prosthetic loosening can be subdivided into four histological types and histopathological criteria for additional pathologies: endoprosthesis-associated arthrofibrosis, immunological/allergic alterations and osseous pathologies. This revision represents the foundation for the histopathological diagnostics of the total spectrum of diseases associated with joint prostheses, is a suitable basis for a standardized diagnostic procedure and etiological clarification of endoprosthesis failure and also as a data standard for endprosthesis registers, in particular for registers based on routine data (e.g. German endoprosthesis register).

Expanded human meniscus-derived cells in 3-D polymer-hyaluronan scaffolds for meniscus repair.

Treatment options for lesions of the avascular region of the meniscus using regenerative medicine approaches based on resorbable scaffolds are rare. Recent approaches using scaffold-based techniques for tissue regeneration known from cartilage repair may be a promising treatment option for meniscal tears. The aim of the study was the investigation of meniscus matrix formation of in vitro expanded human meniscus-derived cells in a three-dimensional (3-D) bioresorbable polymer graft for meniscal repair approaches. Cultivation of the human meniscus cells was performed in a resorbable scaffold material made of polyglycolic acid (PGA) and hyaluronic acid, stabilized with fibrin glue. Cell viability and distribution of human meniscus cells in PGA-hyaluronan scaffolds were evaluated by fluorescein diacetate and propidium iodide staining. Verification of typical meniscal extracellular matrix molecules like type I and type III collagen was performed histologically, immunohistochemically and by gene expression analysis. In results, 3-D scaffold-based meniscus cultures showed high cell viability over an observational period of 21 days in PGA-hyaluronan scaffolds. On the protein level, type I collagen and proteoglycans were evident. Gene expression analysis confirmed the re-expression of meniscus-specific markers in PGA-hyaluronan scaffolds. This study demonstrated that in vitro expanded human meniscus cells allow for formation of meniscal matrix components when cultured in 3-D PGA-hyaluronan scaffolds stabilized with fibrin. These results encourage scaffold-based approaches for the treatment of meniscal lesions.

[Joint endoprosthesis pathology. Histopathological diagnostics and classification]. / Gelenkendoprothesenpathologie. Histopathologische Diagnostik und Klassifikation.

Prosthesis durability has steadily increased with high 10-year rates of 88-95%. However, four pathogenetic groups of diseases can decrease prosthesis durability: (1) periprosthetic wear particle disease (aseptic loosening) (2) bacterial infection (septic loosening) (3) periprosthetic ossification, and (4) arthrofibrosis. The histopathological "extended consensus classification of periprosthetic membranes" includes four types of membranes, arthrofibrosis, and osseous diseases of endoprosthetics: The four types of neosynovia are: wear particle-induced type (type I), mean prosthesis durability (MPD) in years 12.0; infectious type (type II), MPD 2.5; combined type (type III) MPD 4.2; and indeterminate type (type IV), MPD 5.5. Arthrofibrosis can be determined in three grades: grade 1 needs clinical information to be differentiated from a type IV membrane, and grades 2 & 3 can be diagnosed histopathologically. Periprosthetic ossification, osteopenia-induced fractures, and aseptic osteonecrosis can be histopathologically diagnosed safely with clinical information. The extended consensus classification of periprosthetic membranes may be a diagnostic groundwork for a future national endoprosthesis register.

[Comparing immunohistochemical diagnosis of cancer of unknown primary with gene expression-based tumor classification]. / Vergleich immunhistologischer mit genexpressionsbasierter Diagnostik: von Karzinomen mit unbekanntem Primarius.

Five percent of cancer cases present as metastases. If the primary tumor cannot be identified after diagnostic workup, the disease is referred to as cancer of unknown primary (CUP) and is classified as C80.9 according to ICD-10. In Germany, CUP is among the ten most common causes of tumor-related death, with mortality similar to mortality in gastric or pancreatic cancer. Biopsies of the tumor manifestation are generally examined histopathologically and by immunohistochemistry (IHC). Gene expression profiling (GEP) is a new diagnostic technique that might further contribute to tumor specification.In a retrospective study, 43 CUP cases underwent central immunohistochemical review and centrally performed GEP using a classifier based on 495 genes. There was concordance between IHC, GEP and clinical picture in 54% of cases. In four cases, the combination of methods led to an unequivocal identification of the primary tumor.In conclusion, we regard detailed IHC workup and complementary GEP advisable for the purposes of targeted therapy, as well as to identify or exclude specific tumors in a CUP situation.

[Histopathological diagnosis of periprosthetic joint infection following total hip arthroplasty : use of a standardized classification system of the periprosthetic interface membrane]. / Histopathologische Diagnose der periprothetischen Gelenkinfektion nach Hüftgelenkersatz : Verwendung eines standardisierten Klassifikationssystems der periprothetischen Interface-Membranen.

BACKGROUND: The distinction between aseptic and septic loosening of a total hip arthroplasty is a diagnostic challenge. Therapy and clinical success depend on the correct diagnosis. Histopathological evaluation of the periprosthetic interface membrane is one possible diagnostic parameter; detailed analysis of tissue characteristics may reflect the cause of failure. This study evaluated the diagnostic value of a published histopathological consensus classification for the periprosthetic interface membrane in the identification of periprosthetic joint infection (PJI). METHODS: Between 2004 and 2008, a prospective analysis was performed in 106 patients who had revisions because of assumed PJI. Based on clinical presentation, radiography, and haematological screening, infection was assumed, and a joint aspiration was performed. Based on these findings, a two-stage revision was performed, with intraoperative samples for culture and histological evaluation obtained. Final diagnosis of infection was based on the interpretation of the clinical presentation and the preoperative and intraoperative findings. The basis for histopathological evaluation was the consensus classification for the periprosthetic interface membrane. Sensitivity, specificity, and accuracy were calculated for each parameter. RESULTS: In 92 patients, a positive diagnosis of PJI could be made. Histopathology yielded the highest accuracy (0.93) in identification of PJI, identifying 86 of 92 infections (69 type II, 17 type III). In 13 of the 14 noninfected hips, histopathology correlated in 13 (93%) cases (10 type I, three type IV). The accuracies of microbiological culture, C-reactive protein, and aspiration were 0.82, 0.86, and 0.54, respectively. CONCLUSION: In the diagnosis of PJI, histopathological evaluation of the periprosthetic interface membrane proved very effective. To analyse the cause of prosthesis loosening, tissue samples of the periprosthetic interface membrane should be evaluated on the basis of the consensus classification in all revision surgeries.

[Histopathologic diagnostics in endoprosthetics: periprosthetic neosynovialitis, hypersensitivity reaction, and arthrofibrosis]. / Histopathologische Diagnostik in der Endoprothetik: Periprothetische Neosynovialitis, Hypersensitivitätsreaktion und Arthrofibrose.

The durability of endoprosthetic implants of the large joints has increased over the last decades. North American studies have shown a 10-year durability of 94% for prosthetic hip implants, and European studies have shown 10-year durabilities of 88-95%. Pathologists differentiate three etiological disease patterns for the"pathology of endoprosthetics" that lead to reduction of implant durability: 1) periprosthetic particle disease (aseptic loosening), 2) infection, and 3) arthrofibrosis. Four types of neosynovitis/periprosthetic membrane have been determined in a consensus classification: particle-induced type (type I), with a mean prosthesis durability (MPD) of 12 years; infectious type (type II), MPD 2.5 years; combined type (type III), MPD 4.2 years; and indeterminate type (type IV), MPD 5.5 years. There are three histopathologic degrees of arthrofibrosis; grade 1 always needs clinical information for diagnosis, whereas grades 2 and 3 are distinct histopathologic entities.

[Value of histological work-up for synovial diseases]. / Stellenwert der histologischen Diagnostik der Synovialkrankheiten.

At times clinicians and pathologists underestimate the value and significance of histopathological diagnostics for synovial tissue. However, the most common diseases of the synovium show specific morphological hallmarks that allow an exact diagnosis. Using the synovitis score allows one to distinguish between degenerative (low-grade synovitis) and inflammatory rheumatic (high-grade synovitis) diseases. Synovial biopsies are not only especially indicated when there are atypical patterns of arthritis, clinical options have been exhausted or monarthritis of unknown origin occurs, but also in patients with known rheumatoid arthritis. Joint infections, crystal-induced arthritis or pigmented villonodular synovitis can also be diagnosed as secondary synovial diseases. Providing clinical information when submitting biopsies/tissue specimens is essential to classify even unspecific morphological changes. Immunohistochemical staining, polarization microscopy or molecular biology techniques (PCR) may be used to ensure diagnoses.

[Differential diagnosis of synovitis]. / Differenzialdiagnostik der Synovialitis.

The synovial membrane is a site where many diseases with different etiologies can become manifest. Tumors and storage diseases are some of the rare conditions, whereas crystal deposition diseases, acute bacterial infections and in particular chronic uncharacteristic synovitis are frequently encountered. The latter present a diagnostic problem, because they can barely be assigned to concrete diagnoses. This report will give an overview of the differential diagnosis of joint diseases and will focus on the so-called synovitis score as a tool for the systematic evaluation of chronic uncharacteristic synovitis, providing a possibility to differentiate between degenerative and rheumatic synovitis with a specificity of 60.5% and a sensitivity of 95.5%.

Gene expression in endoprosthesis loosening: chitinase activity for early diagnosis?

The aim of the study was to identify markers for the early diagnosis of endoprosthesis loosening, for the differentiation between wear particle-induced and septic loosening and to gather new insights into the pathogenesis of endoprosthesis loosening. Gene expression profiles were generated from five periprosthetic membranes of wear particle-induced and five of infectious (septic) type using Affymetrix HG U133A oligonucleotide microarrays. The results of selected differentially expressed genes were validated by RT-PCR (n = 30). The enzyme activity and the genotype of chitinase-1 were assessed in serum samples from 313 consecutive patients hospitalized for endoprosthesis loosening (n = 54) or for other reasons, serving as control subjects (n = 259). Eight hundred twenty-four genes were differentially expressed with a fold change greater than 2 (data sets on http://www.ncbi.nlm.nih.gov/geo/ GSE 7103). Among these were chitinase 1, CD52, calpain 3, apolipoprotein, CD18, lysyl oxidase, cathepsin D, E-cadherin, VE-cadherin, nidogen, angiopoietin 1, and thrombospondin 2. Their differential expression levels were validated by RT-PCR. The chitinase activity was significantly higher in the blood from patients with wear particle-induced prosthesis loosening (p = 0.001). However, chitinase activity as a marker for early diagnosis has a specificity of 83% and a sensitivity of 52%, due to a high variability both in the disease and in the control group.

[Synovitis score: value of histopathological diagnostics in unclear arthritis. Case reports from rheumatological pathological practice]. / Synovialitis-Score: Wertigkeit histopathologischer Diagnostik bei unklaren Arthritiden. Fallberichte aus der rheumatologisch-pathologischen Praxis.

Histopathological assessment of synovial biopsies has an established value. The value for inflammatory joint diseases without standardized rating mechanisms was, however, unknown until recently. The exemplary use of the synovitis score in four cases all including recurrent bruises of the knee joint portrays its value for diagnosis and therapy. Usage of the score includes assessing the enlargement of the lining layer, cellular density of synovial stroma and leucocyte infiltration by giving each a score of 0-3 points and adding them. Presence of high-grade synovitis (>or=4 points) in all cases displayed the reason for the joint bruises within a primarily inflammatory, rheumatoid circle. In this report we show the broad variety of uses for the synovitis score dealing with cases of Lyme arthritis, rheumatoid arthritis, seronegative monarthritis and HLA-B27-positive peripheral arthritis.

Human polymer-based cartilage grafts for the regeneration of articular cartilage defects.

The use of autologous chondrocyte implantation (ACI) and its further development combining autologous chondrocytes with bioresorbable matrices may represent a promising new technology for cartilage regeneration in orthopaedic research. Aim of our study was to evaluate the applicability of a resorbable three-dimensional polymer of pure polyglycolic acid (PGA) for the use in human cartilage tissue engineering under autologous conditions. Adult human chondrocytes were expanded in vitro using human serum and were rearranged three-dimensionally in human fibrin and PGA. The capacity of dedifferentiated chondrocytes to re-differentiate was evaluated after two weeks of tissue culture in vitro and after subcutaneous transplantation into nude mice by propidium iodide/fluorescein diacetate (PI/FDA) staining, scanning electron microscopy (SEM), gene expression analysis of typical chondrocyte marker genes and histological staining of proteoglycans and type II collagen. PI/FDA staining and SEM documented that vital human chondrocytes are evenly distributed within the polymer-based cartilage tissue engineering graft. The induction of the typical chondrocyte marker genes including cartilage oligomeric matrix protein (COMP) and cartilage link protein after two weeks of tissue culture indicates the initiation of chondrocyte re-differentiation by three-dimensional assembly in fibrin and PGA. Histological analysis of human cartilage tissue engineering grafts after 6 weeks of subcutaneous transplantation demonstrates the development of the graft towards hyaline cartilage with formation of a cartilaginous matrix comprising type II collagen and proteoglycan. These results suggest that human polymer-based cartilage tissue engineering grafts made of human chondrocytes, human fibrin and PGA are clinically suited for the regeneration of articular cartilage defects.

[Melioidosis-like disease: infection with Burkholderia cocovenenans as rare differential diagnosis for Lymphadenitis colli]. / Melioidosis-like disease: Infektion mit Burkholderia cocovenenans als seltene Differenzialdiagnose bei Lymphadenitis colli.

INTRODUCTION: Neoplasms, autimmune disorders and infectious diseases as differential diagnoses of cervical lymphadenopathies also require the consideration of rare causes. CASE REPORT: A 25-year-old patient presented for further diagnosis and treatment of a colliquating, high febrile cervical lymphadenopathy. The patient from Thailand who had been living in Germany for 8 years reported she worked as rice farmer during the 1980s. Examination showed a vast physical condition with severe weight loss, joint- and swallowing aches which did not respond to high doses of parenteral antibiotic treatment. The histology of a lymph node revealed a necrotizing lymphadenitis, lymphoma were excluded. During further complications (sepsis, splenic and intracerebral abscesses and osteomyelitis) multiple different cytologic samples from lympoid tissue, different wound lesions and bronchial secretion microscopically showed non-fermenting, gram-negative rods by 16S-rDNA-analysis identified as Burkholderia cocovenenans/gladioli. Thus a melioidosis-like disease (endemic in south east asia) was diagnosed. Responsible for the severe course with a lethal recurrence despite antibiotic treatment was the patients additional immune defect (anti-interferone-gamma-autoantibodies). SUMMARY: Travelling history informations become more and more important considering increasing long-distance travelling and worldwide migration movements. Unclear inflammatory/infectious diseases require early interdisciplinary treatment. Detailed informations for the pathologist facilitate the diagnosis.

[Histopathological diagnostics in endoprosthesis loosening]. / Histopathologische Diagnostik der Endoprothesenlockerung.

The implantation of total joint endoprostheses has become a routine procedure, being executed about 1.5 million times per year worldwide. The indications are osteoarthritis, rheumatic diseases, trauma and bone neoplasia. However, about 5-12% of patients develop pain and impaired function of the endoprosthesis within 10 years, necessitating revision surgery. During this operation, the so-called periprosthetic membrane between bone and prosthesis is removed. This connective tissue membrane has a pathogenetic impact on the loosening process and can be evaluated by histopathology. This article aims at elucidating the defined histomorphological criteria for the standardized diagnostics of periprosthetic membranes using a recently established classification system.

[Differential diagnosis of chronic synovitis]. / Differenzialdiagnostik der chronischen Synovialitis.

This review presents an algorithm for the standardised histopathological diagnostics of synovial biopsies and synovectomy specimens. In general, changes of the synovium can be inflammatory or non-inflammatory. To the latter group belong certain benign tumors such as the diffuse variant of the tenosynovial giant cell tumor, lipoma or synovial chondromatosis, additionally the rare group of storage diseases should be kept in mind. Inflammatory diseases can be discriminated into crystal-induced arthropathies such as gout and pseudogout, into granulomatous diseases such as tuberculosis, sarcoidosis and foreign-body inoculation, and into the large group of non-granulomatous synovitis. This group is by far the most common, and it often causes difficulties in assigning the histopathological findings to a concrete diagnosis. Therefore, the synovitis-score should be applied as a diagnostic device in these cases, leading to the diagnosis of a low-grade synovitis (which is associated with degenerative arthropathies) or of a high-grade synovitis (associated with rheumatic diseases), the sensitivity and specificity being 60.5% and 95.5%, respectively.

Anti-TNF effects on destructive fibroblasts depend on mechanical stress.

Joint destruction in rheumatoid arthritis (RA) starts typically at sites of mechanically stressed inserts of the synovial membrane near the cartilage/bone border. In the therapy of RA, tumour necrosis factor (TNF) antagonists have rapidly emerged as a valuable class of anti-rheumatic agents that reduce joint destruction. The aim of this study was to investigate and profile genes involved in the interaction between articular movement and anti-TNF therapy in an in vitro model. Murine LS48 cells, an established substitute for invasive RA synovial fibroblasts, were cultured, stretched and/or treated with anti-TNF-alpha antibody for 24 h. RNA was isolated and gene transcript levels were determined using U74Av2 Affymetrix GeneChips to identify transcriptional events. Positive findings were verified by polymerase chain reaction (PCR). We identified 170 differentially regulated genes, including 44 of particular interest. Gene expression fell into different functional groups that can be explained by RA pathogenesis and experimental conditions. For 21 genes of the 44 of particular interest, regulation could be confirmed by real-time PCR. Remarkably, we found structural as well as functional genes differently regulated between stretched cells, anti-TNF-treated cells, and stretched cells treated with anti-TNF antibody. Additionally, we also found a large number of genes that are apparently not related to the experimental conditions. Mechanical exertion modulates gene expression and subsequently cellular response to anti-TNF therapy. Results in exerted cells correspond to current knowledge regarding RA pathogenesis and underline the relevance of our experimental approach. Finally, the central function of the interleukin-18 system in joint destruction could be confirmed by our findings.