HLA DRB1* typing and cartilage oligomeric matrix protein (COMP) as predictors of joint destruction in recent-onset rheumatoid arthritis

The carriage of a characteristic sequence of amino acids at position 67- 72 in the third hypervariable region of the HLA DRB1 chain has been linked to susceptibility to rheumatoid arthritis (RA). Whether this epitope is also a predictor of more severe disease remains controversial. Cartilage oligomeric matrix protein (COMP) is a protein, the serum levels of which have been found to correlate with large joint destructive disease in previous work. In this paper, we compare DRB1* typing and serum COMP levels in a prospectively observed group of RA patients with or without early hip joint destruction. The COMP levels at study inclusion, median 11 months from onset of symptoms, were significantly higher in the patients with early hip joint destruction compared to the patients in the more benign group. There was no difference in the number of disease susceptibility-related epitopes between the groups. DRB1*04, in contrast, was found among 8/8 patients with hip destruction, but also in 5/8 more benign cases. We conclude that in this type of RA patient, COMP serum levels are more informative predictors of aggressive disease than HLA DRB1* typing.      

CNI-1493, an inhibitor of proinflammatory cytokines, retards cartilage destruction in rats with collagen induced arthritis

OBJECTIVE: To investigate if administration of CNI-1493, an inhibitor of the synthesis of proinflammatory cytokines and NO, protects against development of joint destruction in collagen induced arthritis (CIA) in rats. METHODS: In a placebo controlled experiment, CNI-1493 was given once daily intraperitoneally after onset of clinical arthritis in DA rats. Disease progression was studied by clinical scoring of arthritis, serial measurement of serum levels of COMP, and histological examination of joints. RESULTS: Clinical signs of arthritis were significantly reduced in the CNI-1493 treated group of rats in comparison with the placebo treated group. Histological examinations of paws demonstrated a significant reduction of cartilage destruction in the CNI-1493 treated group, but marked destruction of cartilage in the placebo group. Serum levels of COMP increased in the placebo group, whereas in the CNI-1493 treated group levels were low and decreased significantly during the observation time. CONCLUSIONS: Treatment with CNI-1493 provides efficient protection against synovial inflammation and cartilage destruction when used therapeutically in CIA. The protective effect against cartilage destruction can be monitored by measuring serum COMP. These observations make CNI-1493 an attractive candidate for therapeutic studies in human arthritis, and COMP an attractive serum marker for monitoring joint protective effects.     

Bone and cartilage destruction in rheumatoid arthritis

Rheumatoid arthritis is an inflammation-mediated bone disease characterized by local joint inflammation which results from systemic immune responses. It is essential to clarify the mechanisms by which inflammation elicits bone destruction for the establishment of novel therapeutic strategies. Advances in osteoimmunology, in addition to the development of a various kind of genetically-modified mice and animal models of RA, have greatly contributed to our understanding of these mechanisms. Recently, Th17 cells have been shown to contribute not only to the initiation and amplification of inflammation in RA, but also to bone destruction by enhancing osteoclast differentiation through the interaction with synovial fibroblasts. Thus, Th17-synovial fibroblasts interaction is considered to be a promising therapeutic target for RA.     

Mechanism of cartilage destruction in rheumatoid arthritis

Destruction of cartilage in rheumatoid arthritis (RA) is mediated mainly by proteinases which can degrade cartilage matrix including type II collagen and aggrecan. Of these proteinases, matrix metalloproteinases (MMP) play significant roles in RA pathology, however recent studies show that a disintegrin and metalloproteinase (ADAM) families are another candidates. These proteinases are mainly produced from synovial cells and inflammatory cells, and concentrations of these proteinases in synovial fluid are significantly higher in RA than in OA. Several proteinases have been shown to express in chondorocytes of RA and these chondrocytic proteinases are thought to mediate cartilage destruction in RA. Apoptosis which is mediated by nitric oxide (NO) is another pathway of cartilage destruction in RA.     

Pathogenesis of bone and cartilage destruction in rheumatoid arthritis

Proinflammatory cytokines, such as interleukin-1 (IL-1) and tumour necrosis factor alpha (TNFalpha), have been implicated in the dysregulation of bone and cartilage remodelling characteristic of rheumatoid arthritis (RA). With respect to bone remodelling, both of these cytokines have been shown to up-regulate the production of the receptor activator of nuclear factor-kappaB ligand, which acts to enhance osteoclastic bone resorption. TNFalpha stimulates differentiation of osteoclast progenitors into mature osteoclasts and IL-1 acts directly on osteoclasts to increase the bone-resorbing capacity of these cells. IL-1 and TNFalpha also adversely affect cartilage remodelling, although IL-1 is more potent on a molar basis. This cytokine not only increases production of factors that stimulate cartilage matrix degradation, but also inhibits the synthesis of type II collagen and proteoglycans. Enhanced understanding of the mechanisms underlying the processes of joint destruction will allow more selective and specific application of therapeutic agents that target these proinflammatory cytokines and, thus, more effective management of patients with RA and other inflammatory disorders.     

Serum concentrations of cartilage oligomeric matrix protein,fibrinogen and hyaluronan distinguish inflammation and cartilage destruction in experimental arthritis in rats

OBJECTIVES: We investigated if changes in serum/plasma fibrinogen (FIB), hyaluronan (HA) and cartilage oligomeric matrix protein (COMP) levels can be used to differentiate between inflammation and cartilage involvement during arthritis. METHODS: Collagen-induced arthritis (CIA), oil-induced arthritis (OIA) and for comparison, experimental autoimmune encephalitis (EAE) induced in DA rats were investigated. RESULTS: Elevations of FIB concentrations were apparent at days 4-7 post-immunization in both arthritis models reaching a maximum on day 20-21, i.e. before peak arthritis. Elevations of HA in both models were seen shortly before macroscopically apparent arthritis, and peaked at or just before maximal arthritis, i.e. later in CIA than in OIA. COMP levels increased only after onset of arthritis and peaked late in disease (days 34-37), being significantly higher in the more destructive CIA compared with the less destructive OIA. During EAE flares, only FIB levels increased. CONCLUSIONS: FIB is a general inflammation marker, HA appears to be a marker for synovitis and changes in COMP levels appear to reflect the cartilage destruction process.     

Corticosteroid treatment induces chondrocyte apoptosis in an experimental arthritis model and in chondrocyte cultures

OBJECT: In order to examine the mechanisms involved in steroid-induced arthropathy after intra-articular corticosteroid injection, a histological examination was performed in vivo using severe combined immunodeficiency (SCID) mice that were implanted with human articular cartilage into the back (SCID/hu model). In addition, the effect of corticosteroids on chondrocyte apoptosis was evaluated in vitro using cultured human chondrocytes. METHOD: Human articular cartilage was obtained during knee surgery and implanted subcutaneously into the backs of SCID mice. One month later, weekly injections of corticosteroid (hydrocortisone acatate: 1 mg/0.2 ml, triamcinolone acetonide: 0.2 mg/0.2 ml, dexamethasone acetate: 0.1 mg/0.2 ml) in the subcutaneous cavity around the grafted cartilage in SCID mice were initiated. After six weeks of treatment, the grafted cartilage pieces were removed from the SCID mice and examined histologically. Chondrocyte apoptosis after corticosteroid treatment was also investigated using cultured human chondrocytes. RESULT: In the corticosteroid treated, grafted articular cartilage, apoptotic chondrocytes were apparent in the superficial and middle layers of cartilage. But a reduced intensity of Safranin O staining was not remarkable. In the cultured chondrocytes, apoptotic changes were also observed after corticosteroid treatment. CONCLUSION: Corticosteroid treatment induces chondrocyte apoptosis and it may be important to understand the steroid-induced arthropathy.     

Serum cartilage oligomeric matrix protein (COMP) in rheumatoid arthritis and knee osteoarthritis

The cartilage oligometrix matrix protein (COMP) is a noncollagenous protein, a glycoprotein, the function of which is to bind to type II collagen fibres and stabilise the collagen fibre network in the articular cartilage. In the serum of the normal population the COMP level is 5 g/ml. An increased level of COMP in the synovial fluid was described in the early stage of rheumatoid arthritis (RA), whereas in advanced stages of RA, the level of COMP decreased. In this study we assessed the serum COMP level in patients with RA and knee osteoarthritis (OA) and found a correlation between the serum COMP level and other markers as well as bone mass density (BMD) changes, activity of disease, disease duration and the age of the patients. The blood was collected from 30 RA patients and 30 OA patients who constituted the control group. The serum COMP level was determined using an inhibition enzyme-linked immunosorbent assay (ELISA). The average value of the serum COMP level in RA patients was 10.4±3.6 U/l. There was a correlation between the serum COMP level and the age of RA patients (p<0.005) and disease activity score (DAS) value (p<0.01). According to correlation coefficients, the serum COMP level was independent of stage of disease, number of painful and swollen joints, duration of morning stiffness, disease duration and titre of the Waaler–Rose test. The influence of rheumatoid nodule presence on the serum COMP level was shown (p<0.05). In RA patients with erythrocyte sedimentation rate (ESR) values below 20 mm/h compared with patients with ESR values over 60 mm/h, the serum COMP level was observed to be significantly lower (p<0.05). The average value of COMP in OA patients was 10.4±2.7 U/l. No correlation was found between the serum COMP level and patients age and disease duration. There was a correlation between the serum COMP level and Western Ontario and McMaster Universities (WOMAC) index pain scale for the lower limbs (p<0.005) and T-score value of densitometry examinations (p<0.036) in OA patients. No statistical differences were found between the average serum COMP level in RA and OA patients.     

The relationship between polymorphonuclear granulocytes and cartilage destruction in rheumatoid arthritis

The pannus-cartilage junction was investigated in cases of rheumatoid joint destruction. By a histochemical method for demonstrating the presence of neutrophil granulocytes, it became obvious that these cells in some cases were found in high numbers in the immediate vicinity of the cartilage in the process of being destroyed. It is concluded that these blood-carried cells may also participate in cartilage destruction in acute phases of chronic rheumatoid disease.     

Efficacy of golimumab for preventing large joint destruction in patients with rheumatoid arthritis as determined by the ARASHI score

Objectives: The objective of this study is to investigate the inhibitory effect of golimumab on large joint destruction in patients with rheumatoid arthritis.

Methods: We recruited 45 patients with rheumatoid arthritis and evaluated the radiographic severity of large joint destruction using the assessment of rheumatoid arthritis by scoring of large joint destruction and healing in radiographic imaging (ARASHI) score. We evaluated 450 large joints including the elbow, shoulder, hip, knee, and ankle at baseline and 52 weeks after treatment with golimumab. Rapid radiographic progression (RRP) and rapid radiographic improvement (RRI) were calculated and the correlation between large joint destruction and clinical factors was analyzed.

Results: The mean age of the study population was 61.29?±?14.71 years old, and most patients (91.1%) were female. The mean disease duration was 12.6?±?12.48 years. The cohort included patients in all clinical stages of disease as defined by the Steinbroker criteria (I:7, II:10, III:9, IV:19) as well as clinical classes 2 (n?=?18), 3 (n?=?26), and 4 (n?=?1) and the mean disease activity score-CRP (DAS28-CRP) was 4.431?±?1.044. Patients were treated with methotrexate (mean dose 6.44?±?1.78?mg/week), prednisolone (PSL) (mean dose 1.078?±?1.871?mg/d), and golimumab (44.4% of 100?mg). RRP was evident in 20% of the large joints treated with golimumab, and, therefore, golimumab was effective at inhibiting large joint destruction in 80% of joints. RRI was evident in 33.3% of large joints following golimumab treatment. We also observed that EULAR response criteria significantly correlated with the ARASHI change score at 52 weeks after treatment. The total ARASHI status score significantly correlated with the Sharp–van der Heijde score, but not with the delta total sharp score. Multiple regression analyses revealed that the total ARASHI change score was only correlated with EULAR response criteria significantly.

Conclusions: Golimumab therapy was effective at inhibiting large joint destruction of RA patients who have good clinical response, including higher improvement of the shoulder and ankle joints than other large joints.     

类风湿关节炎患者血清软骨寡聚基质蛋白水平及意义的研究

目的 探讨检测软骨寡聚基质蛋白(COMP)水平对类风湿关节炎(RA)患者疾病活动性及早期软骨破坏的临床意义.方法 采用酶联免疫吸附试验(ELISA)法,检测94例RA患者及40名健康人血清中COMP的水平.同时测定RA患者的其他实验室及临床指标:类风湿因子(RF)、红细胞沉降率(ESR)、C反应蛋白(CRP)、抗环瓜氨酸肽抗体(抗CCP抗体)、压痛关节数、疼痛关节数、肿胀关节数、晨僵时间及双手X线,分析它们与COMP的相关性.结果 RA患者血清COMP水平(11.3±5.2)U/L明显高于正常对照组的(9.2±1.7)U/L;两组差异有统计学意义(p=0.017).64例RA活动期患者血清COMP水平为(14±6)U/L,30例缓解期患者为(9±4)U/L,组间比较差异有统计学意义(p=0.005).COMP水平与RA思者的ESR、CRP、晨僵时间、压痛关节数、疼痛关节数、肿胀关节数、X,线分期呈正相关(P<0.05),与年龄、病程、RF、抗CCP抗体水平、功能分级无明显关系(p＞0.05).30例RA患者完成2年放射学随访,18例COMP值大于健康者,16例X线有递增现象,2例无递增现象;而12例COMP值正常/低于健康者,有递增5例,无递增7例,两组间差异有统计学意义(p=0.013).结论 RA患者血清中COMP高水平存在提示RA疾病活动性和早期关节软骨破坏.COMP可以作为反映RA疾病急性活动程度与软骨破坏的血清学指标.     

Low serum level of COMP,a cartilage turnover marker,predicts rapid and high ACR70 response to adalimumab therapy in rheumatoid arthritis

The aim of this study was to evaluate serum biomarkers, used in clinical routine, to predict the American College of Rheumatology (ACR) response to long-term anti-TNF alpha treatment (adalimumab). Sera from 29 consecutive rheumatoid arthritis patients were analysed for anti-cyclic citrullinated peptide (anti-CCP), cartilage oligomeric matrix protein (COMP) and IgM and IgA RFs (class-specific rheumatoid factors) at the start of treatment with adalimumab and after 3, 6 and 12 months. The response to the therapy was evaluated by ACR 20, 50, 70 and by DAS 28 scores. The mean serum COMP level of the population did not change after treatment. However, patients with low serum COMP levels (<10 U/l) at baseline showed a significant (p<0.02) higher ACR70 response (>50%) within 3 months, and also at 6 months, than patients with higher COMP values (ACR70<20%). This was also reflected by significantly higher decrease in DAS score at 3 (p<0.02) and 6 months (p<0.01) treatments. The IgM RF titre decreased significantly (p=0.02) after the therapy, but the percentage of serum positivity for anti-CCP and IgA/IgM RF did not change. No significant correlation was shown between serum COMP levels and C-reactive protein/erythrocyte sedimentation rate during the follow-up. Neither were any correlations shown between ACR/DAS 28 scores and anti-CCP, Ig M/IgA RFs. Our data indicate that low (<10 U/l) serum COMP before starting anti-TNF alpha treatment predicts a rapid (within 3 months) and high ACR70 response compared to RA patients with higher COMP values. This might reflect different mechanisms in the cartilage process in the RA disease at that time of treatment with different therapeutic sensitivity to anti-TNF alpha treatment.     

Serum and synovial cartilage oligomeric matrix protein (COMP) in patients with rheumatoid arthritis and osteoarthritis

ObjectiveTo measure serum and synovial COMP levels in rheumatoid arthritis (RA) and osteoarthritis (OA) patients and to assess their correlation with clinical, laboratory and ultrasonographic parameters.MethodsTwo groups of patients were included in this study consisting of 32 patients with RA and 10 patients with knee OA. Ultrasonography of knee joints was performed and serum and synovial Cartilage oligomeric matrix protein (COMP) levels were measured using an inhibition ELISA.ResultsThe mean synovial COMP level was significantly higher in RA compared to OA patients (14.3 ± 5.19μg/mL and 9.26 ±2.42 μg/mL respectively, P< 0.01). Amongst RA patients, it was higher in those with erosions. COMP levels were higher in synovial fluid compared to serum levels in both groups (P <0.01). Amongst RA patients, synovial COMP levels showed a significant positive correlation with synovial membrane thickness on ultrasonography (P <0.001), and significant negative correlation with the cartilage thickness (P <0.001). In OA group, synovial and serum COMP level showed significant positive correlation with WOMAC index for the lower limbs (r= 0.64, P < 0.05, and r=0.92, P <0.001 respectively) and a significant negative correlation with cartilage thickness (P <0.001).ConclusionThe synovial COMP and ultrasonographic joint evaluation may be considered as markers of disease activity and cartilage destruction in both RA and OA patients.     

Functional capacity and cartilage oligomeric protein (COMP) in serum of patients with maturity-onset polyarthritis

Zusammenfassung Bei 58 von 175 Patienten mit chronischer Polyarthritis lag der Krankheitsbeginn nach dem 60. Lebensjahr. Es konnten somit 58 Patienten mit Alters-Polyarthritis mit den 117 Patienten mit Erwachsenenen-Polyarthritis bezüglich klinischer Parameter und der Funktionskapazit?t verglichen werden. Bei 104 Patienten wurde zus?tzlich das Cartilage Oligomeric Matrix Protein (COMP) im Serum bestimmt.    Neben den bekannten Unterschieden zwischen den beiden Krankheitsentit?ten – der Anteil der M?nner lag bei Alters-Polyarthritis nur gering unter dem der Frauen, die Blutsenkungsgeschwindigkeit war bei Alters-Polyarthritis erh?ht – fand sich bei Patienten mit Alters-Polyarthritis ein signifikant schlechterer funktioneller Wert gemessen am HAQ (Health Assessment Questionnaire) und ein signifikant h?herer Serum-COMP-Wert. In Korrelationsuntersuchungen konnte gezeigt werden, dass beide Parameter altersabh?ngig waren. W?hrend der HAQ auch mit den Entzündungsparametern positiv korrelierte, konnte ein solcher Zusammenhang für Serum-COMP nicht nachgewiesen werden.    Es wird daraus geschlossen, dass bezüglich der Krankheitsaktivit?t aber auch der funktionellen Kapazit?t und des COMP-Spiegels kein sicherer direkter Unterschied zwischen den Krankheitsentit?ten besteht. Die gefundenen Unterschiede k?nnten altersabh?ngig sein, insbesondere begleitende arthrotische Prozesse in gro?en Gelenken k?nnten zu h?heren COMP-Spiegeln im Alter beitragen. Eingegangen: 4. April 2001 Akzeptiert: 9. August 2001     

Role of tumour necrosis factor alpha in experimental arthritis: separate activity of interleukin 1beta in chronicity and cartilage destruction

Chronic arthritis is characterised by persistent joint inflammation and concomitant joint destruction. Using murine arthritis models and neutralising antibodies as well as cytokine specific knockout conditions, it was found that tumour necrosis factor alpha (TNFalpha) is important in early joint swelling. Membrane bound TNFalpha is sufficient to drive this aspect of inflammation as well as the acute cellular infiltrate in the synovial tissue. Interleukin 1 (IL1) is not necessarily a dominant cytokine in early joint swelling, but has a pivotal role in sustained cellular infiltration and erosive cartilage damage. TNFalpha independent IL1 production is a prominent feature in murine arthritis models. These observations provide evidence for potential uncoupling of joint inflammation and erosive changes, implying that both cytokines need to be targeted to achieve optimal treatment.     

The role of stromelysin in the cartilage destruction that accompanies inflammatory arthritis

Articular cartilage from arthritic joints of rats immunized with type II collagen is severely depleted of proteoglycans. Depletion begins within 48 hours after the onset of inflammation, prior to extensive pannus formation, and may represent a critical first step in cartilage destruction. We have immunolocalized stromelysin, an enzyme that is believed to play a major role in the pathologic degradation of proteoglycans, in the joints of rats with collagen-induced arthritis. Immunoperoxidase staining of frozen tissue sections demonstrated the presence of stromelysin in both the synovium and chondrocytes. In contrast, collagenase was localized primarily to the pannus-cartilage junction. Neither enzyme was detectable in joints from normal animals. To test the hypothesis that chondrocytes respond directly to inflammatory mediators by increasing the production of stromelysin, isolated chrondrocytes were incubated with various concentrations of interleukin-1. The culture media were also assayed for the presence of stromelysin by immunoreactivity on Western blots and by analysis of enzymatic activity on casein substrate gels. A 3-fold increase in a doublet of proteins synthesized in response to 10 units/ml of interleukin-1 was observed. These proteins also immunoreacted with the stromelysin antibody and degraded casein. Northern blotting results established that the increased levels of stromelysin were accompanied by increases in stromelysin-specific messenger RNA levels. These results suggest that stromelysin is responsible for proteoglycan degradation in early inflammatory arthritis, and that chondrocytes may play a direct role in the earliest stages of the degradation of their own matrices.