Miller-Fisher syndrome in a patient with rheumatoid arthritis treated with adalimumab

Adalimumab is a frequently prescribed TNFα inhibitor for treatment of rheumatoid arthritis. We report on a patient who probably developed a Miller-Fisher syndrome after the second injection of adalimuma

Miller-Fisher syndrome in a patient with rheumatoid arthritis treated with adalimumab.

Adalimumab is a frequently prescribed TNFalpha inhibitor for treatment of rheumatoid arthritis. We report on a patient who probably developed a Miller-Fisher syndrome after the second injection of adalimumab

Methotrexate in chronic-recurrent calcium pyrophosphate deposition disease: no significant effect in a randomized crossover trial

Calcium pyrophosphate deposition (CPPD) may cause severe arthropathy, major joint destruction and treatment options are limited. The aim of this study was to test the therapeutic efficacy of methotrexate (MTX) in chronic or recurrent CPPD arthropathy

Pathogenic role of basic calcium phosphate crystals in destructive arthropathies.

BACKGROUND: basic calcium phosphate (BCP) crystals are commonly found in osteoarthritis (OA) and are associated with cartilage destruction. BCP crystals induce in vitro catabolic responses with the production of metalloproteases and inflammatory cytokines such as interleukin-1 (IL-1). In vivo, IL-1 production induced by BCP crystals is both dependant and independent of NLRP3 inflammasome. We aimed to clarify 1/ the role of BCP crystals in cartilage destruction and 2/ the role of IL-1 and NLRP3 inflammasome in cartilage degradation related to BCP crystals. METHODOLOGY PRINCIPAL FINDINGS: synovial membranes isolated from OA knees were analysed by alizarin Red and FTIR. Pyrogen free BCP crystals were injected into right knees of WT, NLRP3 -/-, ASC -/-, IL-1α -/- and IL-1β-/- mice and PBS was injected into left knees. To assess the role of IL-1, WT mice were treated by intra-peritoneal injections of anakinra, the IL-1Ra recombinant protein, or PBS. Articular destruction was studied at d4, d17 and d30 assessing synovial inflammation, proteoglycan loss and chondrocyte apoptosis. BCP crystals were frequently found in OA synovial membranes including low grade OA. BCP crystals injected into murine knee joints provoked synovial inflammation characterized by synovial macrophage infiltration that persisted at day 30, cartilage degradation as evidenced by loss of proteoglycan staining by Safranin-O and concomitant expression of VDIPEN epitopes, and increased chondrocyte apoptosis. BCP crystal-induced synovitis was totally independent of IL-1α and IL-1β signalling and no alterations of inflammation were observed in mice deficient for components of the NLRP3-inflammasome, IL-1α or IL-1β. Similarly, treatment with anakinra did not prevent BCP crystal effects. In vitro, BCP crystals elicited enhanced transcription of matrix degrading and pro-inflammatory genes in macrophages. CONCLUSIONS SIGNIFICANCE: intra-articular BCP crystals can elicit synovial inflammation and cartilage degradation suggesting that BCP crystals have a direct pathogenic role in OA. The effects are independent of IL-1 and NLRP3 inflammasome

OCP crystal-induced inflammation and cartilage degradation is NLRP3 inflammasome- and IL-1 independent.

<p>WT (n = 6), ASC-/- (n = 4), NLRP3-/- (n = 6), IL-1α-/- (n = 5) and IL-1β-/- (n = 6) mice were injected i.a. with OCP crystals (200 µg in 20 µl) or PBS. In a second set of experiment, anakinra, the recombinant form of IL-1Ra, or PBS were injected for 4 days (7 mice per group), the first injection being 30 min prior to OCP injection into the knee of WT (F). Ratio of isotope uptake into OCP injected knee versus PBS-injected ones was calculated at different time points (A). Synovial inflammation (B, E, F), cartilage PG loss (C, E, F) and VDIPEN immunohistochemistries (D, F) were assessed. Results are expressed as % of scores against WT (B,C,D) or in arbitrary units (E, F), and represent mean ± S.E.M. of at least n = 4 mice per group. For p values, *  =  p<0.05, **  =  p<0.01, ***  =  p<0.001.</p

OCP crystals induce macrophage expression of genes involved in inflammation and cartilage degradation.

<p>Bone marrow derived macrophages were stimulated <i>in vitro</i> with 500 µg/ml of OCP crystals for 4 hours. RNA was extracted, reverse transcribed and qRT-PCR performed using gene specific primers with Tbp, and Gapdh as reference genes. Results are expressed as the fold induction of OCP treated over unstimulated macrophages, using the mean ± S.E.M of triplicate samples.</p

OCP crystals induce cartilage degradation.

<p>C57BL/6 mice were injected with OCP crystals (OCP+) or PBS (OCP-). Knees harvested at different times (day 4, 17 and 30 n = 8 mice per group) were assessed for cartilage PGs with Safranin-O (A), aggrecan degradation via VDIPEN immunohistochemistry (B) and apoptosis (C). Since at all time points, data from PBS-injected control knees were similar, only data from PBS-injected knees at day 4 were shown in D, E, and F. Scoring of PG loss and VDIPEN staining was performed on sections, using a scale of 0 to 6 and 0 to 3, respectively (D and E). Apoptotic chondrocytes were counted per field of view (F). Results are expressed as mean ± S.E.M with significance being at * p<0.05, ** p<0.01, *** p<0.001</p

Intra-articular BCP crystals induce synovial inflammation and cartilage proteoglycan loss in mice.

<p>OCP crystals (200 µg/20 µl) were injected into right knees of C57BL/6 mice whereas 20 µl PBS was injected into the left knees (A–E). Knees were harvested at different times (day 4, 17 and 30 n = 8 mice per group). Sections were stained with fast green/iron hematoxylin (A) and the degree of inflammation was assessed at the different time points (B). Since the inflammation was very low and similar at all time points in the PBS-injected control knees, only data from PBS-injected knees at day 4 was shown in B. OCP crystal deposition in the synovial membrane was evidenced at day 30 after OCP crystals injection by Von Kossa staining (see arrows) (C). Macrophage, endothelial and PMN cells were detected using antibodies for MAC-2, ICAM, and MPO, respectively, at day 4 after OCP injection (D). Isotype controls allowed the identification of giant cells that had engulfed tissue crystal deposits (*) (D). Ratio of Tc uptake between OCP-injected (n = 8) versus PBS controls was calculated (E). Fast green/iron hematoxylin staining of knees injected with 20 µg/20 µl of HA or OCP crystal at day 4 (F). Results are expressed as mean ± S.E.M with significance being at * p<0.05, ** p<0.01, *** p<0.001.</p