Hubert Marotte

The association between periodontal disease and joint destruction in rheumatoid arthritis extends the link between the HLA-DR shared epitope and severity of bone destruction

Objective: To evaluate a possible association between wrist and periodontal destruction in rheumatoid arthritis, and between periodontal destruction, dry mouth, and labial salivary gland biopsy and the contribution of genetic factors (the shared epitope (SE) and IL1B (+3954) or TNFA (−238 or −308) gene polymorphisms). Methods: 147 patients with rheumatoid arthritis were enrolled. Periodontal damage was defined according to the Hugoson and Jordan criteria on panoramic dental x rays. Typing for the SE and cytokine polymorphisms was undertaken by enzyme linked oligosorbent assay. Odds ratios (OR), relative risk (RR), and χ2 values were calculated to quantify associations. Results: An association was observed between wrist and periodontal bone destruction (χ2u200a=u200a11.82; p<0.001): 63 patients had both wrist and periodontal destruction, 31 had wrist destruction alone, 20 had periodontal destruction alone, and 33 had no destruction at either site. An association was seen between a positive labial salivary gland biopsy and periodontal bone destruction (RRu200a=u200a2.73 (95% CI, 1.35 to 5.51), p<0.01, nu200a=u200a41) or wrist bone destruction (RRu200a=u200a4.52 (1.96 to 10.45), p<0.001, nu200a=u200a41). The SE was associated with wrist bone destruction (ORu200a=u200a2.5 (1.16 to 5.42), p<0.05) and periodontal bone destruction (ORu200a=u200a2.2 (1.04 to 4.84), p<0.05). No association was found between the selected cytokine polymorphisms and bone destruction. Conclusions: A strong association was found between wrist and periodontal bone destruction. The destruction risk was further increased in patients with sicca syndrome. The SE appears to be a severity genetic marker for both wrist and periodontal bone destruction.

A 1-year case-control study in patients with rheumatoid arthritis indicates prevention of loss of bone mineral density in both responders and nonresponders to infliximab

The goal of the present study was to record changes in bone mineral density (BMD) and markers of bone turnover in patients with rheumatoid arthritis (RA) who were treated with methotrexate combined (or not combined) with infliximab. Included were 90 patients with RA who required anti-TNF-α therapy with infliximab because of persistent active disease despite treatment with methotrexate. The historical control group included 99 patients with RA who were treated with methotrexate at a time when anti-TNF-α treatment was not yet available. Lumbar and femoral neck BMD was measured using dual energy X-ray absorptiometry at baseline and 1 year later. Osteocalcin, C-terminal cross-linked telopeptide of type I collagen, parathyroid hormone and 25-hydroxycholecalciferol were measured in plasma at baseline and 1 year later. At 1 year BMD had decreased in the control group at spine (P < 0.01) and femoral neck (P < 0.001). In contrast, BMD at spine and femoral neck did not change after 1 year of infliximab treatment. At the same time point, no change in bone remodelling markers was observed. No association was observed between clinical response and changes in BMD, indicating that even those who did not respond clinically did not lose bone over a 1-year period. These data confirm the BMD decrease observed in RA patients treated with methotrexate alone. This bone loss was prevented by infliximab therapy. Importantly, this beneficial effect was also observed in apparent nonresponders.

Circulating tumour necrosis factor-α bioactivity in rheumatoid arthritis patients treated with infliximab: link to clinical response

Our objective was to clarify the heterogeneity in response to infliximab treatment in rheumatoid arthritis (RA); to this end, a bioassay was designed to explore the contribution of circulating tumour necrosis factor (TNF)-α bioactivity and its possible link to response. The bioassay is based on the induction of IL-6 and osteoprotegerin (OPG) production by synoviocytes in response to TNF-α. RA synoviocytes were cultured with TNF-α (5 ng/ml) and 42 RA plasma samples collected just before starting therapy. Levels of IL-6 and OPG were measured in supernatants. In 20 of the patients, plasma samples collected before and 4 hours after the first and the ninth infusions were tested in the same way. Plasma concentrations of TNF-α and p55 and p75 soluble receptors were measured using ELISA. TNF-α induced IL-6 and OPG production by synoviocytes, which was further increased with patient plasma dilutions and inhibited by infliximab. With plasma samples obtained before the first infusion, the IL-6-induced production was greater in patients with a good clinical response than in the poor responders (44.4 ± 23.3 ng/ml versus 27.4 ± 20.9 ng/ml; P = 0.05). This high circulating TNF-α bioactivity was strongly inhibited with the first infliximab infusion. The difference between IL-6 levels induced with plasma samples obtained before and 4 hours after the first infusion was greater in patients with a good clinical response (40.0 ± 23.7 ng/ml versus 3.4 ± 10.0 ng/ml; P = 0.001). Similar findings were obtained for OPG production (7.0 ± 6.2 ng/ml versus 0.0 ± 3.0 ng/ml; P < 0.05). Levels of circulating TNF-α bioactivity were predictive of clinical response to TNF-α inhibition, confirming a key role for TNF-α in these RA patients.

Effects of infliximab therapy on biological markers of synovium activity and cartilage breakdown in patients with rheumatoid arthritis

BACKGROUNDnDefining the remission criteria of rheumatoid arthritis (RA) remains a critical issue. Markers of synovium activity, urinary glucosyl-galactosyl-pyridinoline (Glc-Gal-PYD) and of cartilage destruction, urinary C-terminal crosslinking telopeptide of type II collagen (CTX-II) have been shown to reflect disease activity and joint damage progression in RA.nnnMETHODSnThe prospective study cohort comprised 66 RA patients treated with infliximab and methotrexate and 76 healthy controls. Measurements of urinary Glc-Gal-PYD and CTX-II were performed at baseline and at 1 year of infliximab therapy.nnnRESULTSnAt baseline, urinary Glc-Gal-PYD and CTX-II levels were increased in patients with RA and correlated with modified Sharp scores and progression of joint damage. Patients with more progressive joint destruction had higher Glc-Gly-PYD and CTX-II baseline levels.nnnCONCLUSIONnThese markers reflected bone erosion evolution and might be useful for treatment monitoring and evaluation of RA. Markers remained high even in clinical responders after infliximab, suggesting persistence of synovitis.

Nitrated type III collagen as a biological marker of nitric oxide-mediated synovial tissue metabolism in osteoarthritis

OBJECTIVESnNitric oxide (NO) is a major mediator of joint tissue inflammation and damage in osteoarthritis (OA) and mediates the nitration of tyrosine (Y*) residues in proteins. We investigated the nitration of type III collagen, a major constituent of synovial membrane, in knee OA.nnnMETHODSnA polyclonal antibody directed against the nitrated QY*DSY*DVKSG sequence from type III collagen N-telopeptide was generated. Synovial tissues from patients with knee OA (n=4) and rheumatoid arthritis (RA, n=4) were analyzed by immunohistochemistry for IIINys. Serum IIINys levels were measured by enzyme-linked immunosorbent assay in 87 patients with painful knee OA (mean age: 63.0+/-8.0 years, Kellgren-Lawrence score II-III) and in 40 sex and age-matched healthy controls.nnnRESULTSnCompetition experiments using various nitrated and un-nitrated type III collagen and derived sequences, showed that the antibody was highly specific for the nitrated IIINys sequence. High IIINys immunoreactivity was detected in the synovial tissues from all patients with OA and RA with a preferential localization in the intimal layer. Serum IIINys levels were on average 1.5-fold higher (P<0.0001) in patients with knee OA than in healthy controls and significantly correlated with C-reactive protein values (r=0.40, P<0.005).nnnCONCLUSIONSnNitration of tyrosine residues of type III collagen N-telopeptide is increased in the synovial tissue of patients with knee OA. Measurements of serum IIINys level may be useful for the clinical investigation of oxidative-related alterations of synovial tissue metabolism in OA.

Circulating nitrated N-telopeptide of type III collagen (IIINys) as a biochemical marker of oxidative-related synovial tissue metabolism in rheumatoid arthritis

Synovial tissue inflammation plays a major role in mediating joint damage in rheumatoid arthritis (RA).1 An important mediator of inflammation is nitric oxide (NO)2 which is produced by different cells in joint tissues including synoviocytes.3 NO leads to nitration of tyrosine residues producing the post-translational modified nitrotyrosine (Y*).4 Increased immunoreactivity against nitrotyrosine has been shown in synovial tissue from patients with RA although the nature of the proteins and amino acid sequences involved has not been characterised.5 6nnWe generated a polyclonal antibody directed against the synthetic sequence QY*DSY*DVKSG (IIINys) from the …

Severe periodontal disease associated with severe rheumatoid arthritis is a predictive factor for clinical infliximab response

Background Prediction of tumour necrosis factor α (TNFα) response remains a huge challenge. Recently, a bad dental hygiene was described to be associated with a poor response to TNFα blockers in 20 rheumatoid arthritis (RA) patients. Previously, the authors reported an association between dental bone loss and joint damage in established 147 RA. Here, the authors investigated association between severe periodontal disease (PD) with or without joint damage and response to infliximab in RA patients. Methods All 101 RA patients enrolled in the study had typical clinical and biological features of severe RA. Their mean (SD) age was 50.6 (15.5) years. Patients were predominantly women (77.2%) with mean disease duration of 12.3 (9.8) years, and 81.2% were RF positive. Most patients had active disease with a disease activity score-28 (DAS28) at 5.1 (1.12) despite methotrexate treatment. They all were treated with infliximab according to the usual regimen in association with methotrexate. American College of Rheumatology 20 response was evaluated at 6 months and DAS28 improvement was calculated. Severe PD was defined by a periodontal bone destruction according to the Hugoson and Jordan criteria by an alveolar bone loss with a horizontal alveolysis over one third of the normal bone height. Joint damage was defined according to the Larsen wrist x-ray score with a right Larsen wrist score ≥2. χ2 test and non-parametric test were performed. Results Among our population, 62 patients had severe PD and 73 patients had joint damage. An association between severe PD and joint damage was observed (χ2 test=3.9; p<0.05). However, only 48 patients had destruction at both wrist and periondotal sites while 16 had no destruction at these two sites; 23 had only wrist destruction; and 14 had only periodontal destruction. At 6 months, 71 patients reached the ACR20 response criteria. No association between PD severity or joint damage and ACR20 response was observed. Then, the authors compared DAS28 improvement according to PD severity. Likewise, DAS28 improvement was similar in RA patients with severe PD (median (25th–75th quartile)) at 1.85 (0.59–3.07)) compared to RA patients without severe PD (1.63 (1.01–2.68); not significant). Similarly, DAS28 improvement was equal according to the joint damage status (1.85 (1.05–3.11)) in RA patients with joint damage compared to RA patients without joint damage (1.53 (0.11–2.79); not significant). Conclusion These results suggested no association between severe periodontal disease and response to infliximab. RA severity markers are not predictor to infliximab response.

93 SERUM DICKKOPF-1 (DKK-1) LEVELS ARE INCREASED IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS, BUT DECREASED IN PATIENTS WITH KNEE OSTEOARTHRITIS AND ARE ASSOCIATED WITH CARTILAGE AND SYNOVIAL TISSUE TURNOVER

significant correlation has been observed between radiological damage index and COMP levels, with a Pearson correlation index of 0.45 (95%CI: 0.32−0.64, p = 0.018). Conclusions: We observed increased serum COMP levels in patients with symptomatic radiological hand OA. Higher serum COMP levels seems to correlate to more aggressive and severe disease, in terms of pain (VAS values) and radiologic damage (Kellgren and Lawrence index).