- CIGB-814, an altered peptide ligand derived from human heat-shock protein 60, decreases anti-cyclic citrullinated peptides antibodies in patients with rheumatoid arthritis. [Journal Article]
- CRClin Rheumatol 2018 Nov 10
- Rheumatoid arthritis (RA) is a chronic T cell-mediated autoimmune disease. Serum autoantibodies against cyclic citrullinated peptides (anti-CCP) are significant markers for diagnosis and prognosis of...
Rheumatoid arthritis (RA) is a chronic T cell-mediated autoimmune disease. Serum autoantibodies against cyclic citrullinated peptides (anti-CCP) are significant markers for diagnosis and prognosis of this disease. Induction of immune tolerance as therapeutic approach for RA constitutes a current research focal point. In this sense, we carried out a phase I clinical trial in RA patients with a new therapeutic candidate (called CIGB-814); which induced mechanisms associated with restoration of peripheral tolerance in preclinical studies. CIGB 814 is an altered peptide ligand (APL), derived from a CD4+ T cell epitope of human heat-shock protein 60 (HSP60), an autoantigen involved in the pathogenesis of RA. Twenty patients with moderate disease activity were included in this open label trial. Sequential dose-escalation of 1, 2.5 and 5 mg of CIGB-814 was studied. Consecutive groups of six, five, and nine patients received a subcutaneous dose weekly of the peptide during the first month and one dose monthly during the next 5 months. The peptide was well tolerated and reduced disease activity. Here, we reported the quantification of anti-CCP antibodies during the treatment with this APL and in the follow-up stage. Anti-CCP antibodies were quantified in the plasma from patients by a commercial enzyme immunoassay at baseline (T0) and at weeks 28 and 48. Results showed that CIGB-814 induced a significant reduction of anti-CCP antibodies. In addition, this decrease correlated with clinical improvement in patients assessed by Disease Activity Score in 28 joints (DAS28) criteria. These findings reinforce the therapeutic potential of CIGB-814.
- Feline histoplasmosis presenting with bone and joint involvement: clinical and diagnostic findings in 25 cats. [Journal Article]
- JFJ Feline Med Surg 2018 Nov 08; :1098612X18806706
- CONCLUSIONS: Inflammatory arthritis is common in cats with histoplasmosis, with lameness a common presenting complaint. Organisms are found in synovial fluid cytology in most cases. If not, appropriate additional diagnostics must be pursued.
- Multidisciplinary dentistry for transitional care patients. [Journal Article]
- QIQuintessence Int 2018; 49(10):855-861
- A growing patient population is adolescents and young adults who have had one or more serious medical problems and are aging into adulthood. This group of patients has unique medical needs, which has...
A growing patient population is adolescents and young adults who have had one or more serious medical problems and are aging into adulthood. This group of patients has unique medical needs, which has resulted in the development of a specialized area of medicine: transitional care medicine. The case reviews of two of these patients are described. Patient 1 was a 23-year-old man with hereditary pancreatitis. His genetic condition resulted in the need for pancreatic splenectomy and removal of part of his small bowel, resulting in insulin-dependent diabetes and malnutrition. These complex clinical issues and the challenges of chronic pain were further complicated by severe anxiety disorder and substance abuse. He presented to the University of Rochester Medical Center's Complex Care Center (CCC), an interdisciplinary clinic that provides care for adults with pediatric onset conditions, staffed with both dentists and physicians, with acute pain from a grossly decayed premolar tooth. His blood glucose measured > 500 mg/dL and he was experiencing an acute episode of anxiety. With the expertise and experience of center staff his care needs could be met. Patient 2 was a 32-year-old woman with chronic juvenile rheumatoid arthritis, drug-associated lupus, and mental health problems including depression. This condition requires her to be managed with broad spectrum immunosuppression to prevent joint inflammation that results in significant joint destruction and bone loss. She presented to the CCC with an abscessed molar tooth, which prevented her from receiving her required immunotherapy, IV tocilizamab. While monitored by on-site physicians, a center dentist could safely proceed with the extraction. These cases illustrate that, as the population of transitional care patients grows, general dentists can learn to work on-site with physicians and allied health per-sonnel to meet the need.
- In vivo imaging of activated macrophages by 18F-FEDAC, a TSPO targeting PET ligand, in the use of biologic disease-modifying anti-rheumatic drugs (bDMARDs). [Journal Article]
- BBBiochem Biophys Res Commun 2018 Nov 17; 506(1):216-222
- Rheumatoid arthritis (RA) is a chronic disease with systemic inflammation resulting in destruction of multiple articular cartilages and bones. Activated macrophage plays a pivotal role during the dis...
Rheumatoid arthritis (RA) is a chronic disease with systemic inflammation resulting in destruction of multiple articular cartilages and bones. Activated macrophage plays a pivotal role during the disease course and has been one of main targets to inhibit inflammatory reaction of RA by using biological disease-modifying anti-rheumatic drugs (bDMARDs). 18F-FEDAC is one of PET imaging agents targeting TSPO, which is overexpressed in activated macrophages. The aim of this study was to evaluate the roles of 18F-FEDAC PET as an in vivo imaging of activated macrophages on etanercept (ETN), a TNF-antagonist as one of bDMARDs in collagen induced arthritis mice. In RAW 264.7 cells, the expressions of TSPO as well as iNOS and infiltrated nucleus of NF-κB were induced by activation with lipopolysaccharide and interferon-gamma. TSPO expression was slightly attenuated by ETN treatment, not by methotrexate (MTX) as a cytotoxic agent. However, cell uptake of 18F-FEDAC did not show significant changes according to both of the treatments. Similarly in CIA mice, 18F-FEDAC uptake in inflamed paws on PET imaging did not show significant changes during both of the treatments, contrary to the uptake decrease of 18F-FDG, a glucose analog to reflect metabolic or active inflammatory activity. Interestingly, when we divided joints according to the degree of 18F-FEDAC uptake before ETN treatment, the joints of high 18F-FEDAC uptake showed better response to ETN than the joints with low 18F-FEDAC uptakes. In case of 18F-FDG, there was no such kinds of patterns. We can speculate that 18F-FEDAC PET imaging may identify activated macrophage-induced arthritis because that 18F-FEDAC can reflect activated macrophages, which is the therapeutic target of ETN by TNF antagonistic effect. Thus, in vivo imaging using 18F-FEDAC may be used as a predictor of therapeutic effects among those kinds of bDMARDs having anti-inflammatory actions to inhibit activated macrophage.
- Arthroscopic repair of glenoid rim fractures: a ligamentotaxis surgical technique. [Journal Article]
- MSMusculoskelet Surg 2018; 102(Suppl 1):41-48
- CONCLUSIONS: Acute antero-inferior glenoid rim fractures are uncommon but they are increasing in over 55 years population (frequently associated with cuff tear). Correct classification and treatment are necessary to achieve good results. The X-ray assessment includes the Neer's trauma series and the CT study with PICO measurement of glenoid fragment size. Wrong treatment can lead to chronic instability, degenerative joint disease and poor results. The arthroscopic repair with ligamentotaxis is a good solution and permits the treatment of the associated rotator cuff tear. Arthroscopic technique imposes a long learning curve. CT can be used to confirm the anatomic reduction and the healing of the fracture but since it uses X-rays it must be reserved to comminuted fractures.
- Pro-inflammatory cytokines: The link between obesity and osteoarthritis. [Review]
- CGCytokine Growth Factor Rev 2018 Oct 11
- Osteoarthritis (OA), characterized by joint malfunction and chronic disability, is the most common form of arthritis. Clinical and animal experiments reveal that age-related OA is associated with man...
Osteoarthritis (OA), characterized by joint malfunction and chronic disability, is the most common form of arthritis. Clinical and animal experiments reveal that age-related OA is associated with many factors such as age, sex, trauma, and obesity. One of the most influential and modifiable risk factors is obesity. Obesity not only increases mechanical stress on the tibiofemoral cartilage, but also leads to a higher prevalence of OA in non-weight-bearing areas. There is a link between obesity and inflammation. Adipose tissues play a crucial role in this context because they are the major source of cytokines, chemokines, and metabolically-active mediators named adipokines. The adipokines, including adiponectin and leptin, have been demonstrated to regulate inflammatory immune responses in cartilage. Obese people and animals show a higher level of serum tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL)-1β and IL-6, all of which are produced by macrophages derived from adipose tissue. These pro-inflammatory cytokines regulate the proliferation and apoptosis of adipocytes, promote lipolysis, inhibit lipid synthesis and decrease blood lipids through autocrine and paracrine mechanisms. Elevated levels of TNF-α, IL-1 and IL-6 have been found in the synovial fluid, synovial membrane, subchondral bone and cartilage of OA patients, confirming their important roles in OA pathogenesis. TNF-α, IL-6 and IL-1 are the factors released by fat to negatively regulate cartilage directly. Moreover, TNF-α, IL-1 and IL-6 can induce the production of other cytokines, matrix metalloproteinases (MMPs) and prostaglandins and inhibit the synthesis of proteoglycans and type II collagen; thus, they play a pivotal role in cartilage matrix degradation and bone resorption in OA. Activated chondrocytes also produce MMP-1, MMP-3, MMP-13, and aggrecanase 1 and 2 (ADAMTS-4, ADAMTS-5). In addition, IL-1, TNF-α and IL-6 may cause OA indirectly by regulating release of adiponectin and leptin from adipocytes. In this review, we first summarize the relationship between obesity and inflammation. Then we summarize the roles of IL-1, TNF-α and IL-6 in OA. We further discuss how IL-1, TNF-α and IL-6 regulate the communication between fat and OA, and their pathological roles in obesity-related OA. Lastly, we discuss the possibility of using the pro-inflammatory signaling pathway as a therapeutic target to develop drugs for obesity-related OA.
- Diarylheptanoid, a constituent isolated from methanol extract of Alpinia officinarum attenuates TNF-α level in Freund's complete adjuvant-induced arthritis in rats. [Journal Article]
- JEJ Ethnopharmacol 2018 Oct 15; 229:233-245
- CONCLUSIONS: 5-HPH may exhibit its anti-arthritic potential via inhibition of elevated oxido-inflammatory markers thus restoring the elevated hyperalgesia, allodynia and reducing destruction in synovial membrane and cartilage. Therefore, 5-HPH is a potential moiety bearing antioxidant and with anti-inflammatory properties to inhibit FCA-induced arthritis in rats. The results of the present investigation should enable the design of potent small-molecule inhibitors that inactivate TNF-α with high affinity and specificity.
- Tyro3/Axl/Mertk-deficient mice develop bone marrow edema which is an early pathological marker in rheumatoid arthritis. [Journal Article]
- PlosPLoS One 2018; 13(10):e0205902
- Rheumatoid arthritis is an auto-immune disease of the synovial joints, hallmarked by chronic inflammation and subsequent progressive tissue destruction. TYRO3, AXL and MER (gene name Mertk) (TAM) rec...
Rheumatoid arthritis is an auto-immune disease of the synovial joints, hallmarked by chronic inflammation and subsequent progressive tissue destruction. TYRO3, AXL and MER (gene name Mertk) (TAM) receptors are part of a negative feedback signaling system in the immune reaction and mediate efferocytosis thereby tempering the inflammatory process. We have shown that Axl-/- and Mertk-/- mice develop more severe arthritis whereas activating these receptors by overexpressing their ligands Pros1 and Gas6 ameliorates arthritis. Mice genetically ablated for the three genes of the TAM receptor family Tyro3/Axl/Mertk (TAM triple knock-out or TKO) have been described to spontaneously develop macroscopic signs of arthritis. In this study we aimed to analyze arthritis development in TAM TKO mice histologically to determine the extent and sequence of pathological changes in the joint. Ankle joints of three different age groups, adolescence (14 weeks), mature adult (34 weeks) and middle-age (52 weeks), of TAM TKO or wild-type mice were examined macroscopically, histologically and immunohistochemically. Surprisingly, until the age of 52 weeks, none of the mice examined developed spontaneous macroscopic signs of arthritis. There was no synovial inflammation nor any signs of damage to the cartilage or bone. However, bone marrow edema was observed in TAM TKO mice in the two latter age groups. The infiltrate in the bone marrow was characterized by both myeloid cells and lymphocytes. This study showed that TAM TKO mice developed a pre-stage (pre-clinical phase) of arthritis marked by bone marrow edema.
- Polyphyllin I Ameliorates Collagen-Induced Arthritis by Suppressing the Inflammation Response in Macrophages Through the NF-κB Pathway. [Journal Article]
- FIFront Immunol 2018; 9:2091
- Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder, characterized by an increased number of M1-like macrophages in the joints. Polyphyllin I (PPI), one of the main components in ...
Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder, characterized by an increased number of M1-like macrophages in the joints. Polyphyllin I (PPI), one of the main components in the Rhizoma of Paris polyphyllin, displays a selective inhibitory effect on various tumor cells. Here we sought to investigate the anti-rheumatoid arthritis effects and mechanisms of PPI on macrophages in vivo and in vitro. Materials and Methods: In vitro, primary bone marrow-derived macrophages (BMMs) and peritoneal elucidated macrophages (PEMs) were stimulated by lipopolysaccharide (LPS) and Interferon (IFN)-γ and then treated with PPI. We determined the degree of activation of IKKα/β and p65, two key mediators of the NF-κB-mediated inflammatory pathway, by measuring their phosphorylated forms by Western blot. The p65 nuclear localization was detected by immunofluorescent staining. Further, a NF-κB-linked luciferase reporter plasmid, as well as those expressing key mediators of the Toll-like receptor 4 pathway, such as myeloid differentiation primary response 88 (MYD88), interleukin-1 receptor (IL-1R) associated kinase (IRAK)-1, TNF receptor associated factors (TRAF)-6, Transforming growth factor-b-activated kinase 1 (TAK1) and p65, were used to identify the mechanism by which PPI achieves its inhibitory effects on macrophage-mediated inflammation. Moreover, a NF-κB inhibitor, p65-targeted siRNAs, and a p65 plasmid were further used to validate the anti-inflammatory mechanism of PPI. In vivo, PPI (1 mg/kg) was administered intragastrically one time a day for 7 weeks starting on the 42nd day after the first immunization with collagen in a collagen-induced arthritis (CIA) mouse model. Micro-computed Tomography scanning, histological examination, F4/80 and iNOS double immunofluorescent staining and CD4 immunohistochemical staining were performed to determine the effect of PPI treatment on joint structure and inflammation in this model. Results: PPI reduced the inflammatory cytokines production of PEMs stimulated by LPS/IFN-γ, inhibited the phosphorylation of IKKα/β and p65, and prevented p65 nuclear localization. The NF-κB luciferase assay showed that the target of PPI was closely related to the NF-κB pathway. Moreover, NF-κB inhibition, siRNA-mediated knockdown of p65, and p65 overexpression eliminated PPI's inhibitory effect. In addition, PPI attenuated the bone erosion and synovitis, as well as M1-like macrophage and T cell infiltration, in the ankle joint of the CIA model. Conclusion: PPI demonstrated effective amelioration of synovial inflammation in the ankle joint of CIA mice while suppressing NF-κB-mediated production of pro-inflammatory effectors in activated macrophages.
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- Spontaneous Septic Arthritis of Canine Elbows: Twenty-One Cases. [Journal Article]
- VCVet Comp Orthop Traumatol 2018; 31(6):488-493
- CONCLUSIONS: Septic arthritis, even in the absence of pyrexia, should be considered as a major differential diagnosis in middle aged, large breed dogs, with pre-existing elbow arthritis, that suffer an acute onset lameness, with elbow joint effusion and discomfort. Antibiotic therapy alone was effective for treatment with high initial response rates. Chronic lameness post-treatment was common, and a high rate of recurrence was seen with 3/12 dogs suffering more than one episode.