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ID PMID Title PublicationDate abstract
30601046 Lateral rim mesh in primary total hip arthroplasty: a suitable option to reconstruct segme 2019 Jan AIMS: The aim of this study was to analyze the effect of a lateral rim mesh on the survival of primary total hip arthroplasty (THA) in young patients, aged 50 years or younger. PATIENTS AND METHODS: We compared a study group of 235 patients (257 hips) who received a primary THA with the use of impaction bone grafting (IBG) with an additional lateral rim mesh with a group of 306 patients (343 hips) who received IBG in the absence of a lateral rim mesh during the same period from 1988 to 2015. In the mesh group, there were 74 male and 183 female patients, with a mean age of 35 years (13 to 50). In the no-mesh group, there were 173 male and 170 female patients, with a mean age of 38 years (12.6 to 50). Cox regression analyses were performed to study the effect of a lateral rim mesh on acetabular component survival. Kaplan-Meier analyses with 95% confidence intervals (CIs) were performed to estimate the survival of the acetabular implant. RESULTS: The hazard ratio for the use of lateral rim mesh, adjusted for potential confounders, for acetabular revision for any reason was 0.50 (95% CI 0.13 to 1.93; p = 0.31) and for acetabular revision for aseptic loosening was 0.29 (95% CI 0.020 to 4.04; p = 0.35). The Kaplan-Meier analysis showed a ten-year survival for aseptic loosening of the acetabular of 98% (95% CI 95 to 100, n = 65 at risk) in the mesh group and 94% (89 to 98, n = 76 at risk) in the no-mesh group. The 15-year survival for aseptic acetabular loosening was 90% (81 to 100, n = 35 at risk) in the mesh group and 85% (77 to 94, n = 45 at risk) in the no-mesh group (p = 0.23). CONCLUSION: This study shows that the use of a lateral rim mesh in primary THA in young patients is not associated with a higher risk of revision of the acetabular component. Therefore, we consider a lateral rim mesh combined with IBG to be effective in reconstructing segmental acetabular defects in primary THA.
30575978 Pharmacokinetics, Pharmacodynamics, and Safety of E6011, a Novel Humanized Antifractalkine 2019 May E6011 is a novel humanized antifractalkine (FKN) monoclonal antibody being developed as a therapeutic target for Crohn's disease, rheumatoid arthritis, and primary biliary cholangitis. This study was a randomized, double-blind, placebo-controlled single-ascending-dose study of intravenous administration of E6011 (0.0006-10 mg/kg) in healthy Japanese adult men (n = 64). The starting dose was the minimum anticipated biological effect level (MABEL). MABEL was estimated by extrapolating results of a pharmacokinetic/pharmacodynamic (PK/PD) model relating E6011 exposure and suppression of free soluble FKN using data obtained from cynomolgus monkeys. Safety assessments consisted of monitoring and recording adverse events, laboratory tests, vital signs, intensive electrocardiograms, and chest x-rays. Blood samples to determine PK, PD (serum total FKN concentration), and serum anti-E6011 antibody were collected. Noncompartmental analysis was used to derive PK parameters. Single intravenous infusions of E6011 were safe and well tolerated in healthy subjects. Serum E6011 concentrations showed triphasic elimination. An increase in serum total FKN concentration was observed, confirming target engagement. The dose strategy for patient studies is to select regimens that will attain a minimum serum E6011 exposure of 10 μg/mL, identified as the minimum concentration needed to saturate the target-mediated elimination pathway. Model-based drug development from preclinical stage was successful in identifying dose regimens for clinical testing.
31849953 Free Fatty Acids in Bone Pathophysiology of Rheumatic Diseases. 2019 Obesity-in which free fatty acid (FFA) levels are chronically elevated-is a known risk factor for different rheumatic diseases, and obese patients are more likely to develop osteoarthritis (OA) also in non-weight-bearing joints. These findings suggest that FFA may also play a role in inflammation-related joint damage and bone loss in rheumatoid arthritis (RA) and OA. Therefore, the objective of this study was to analyze if and how FFA influence cells of bone metabolism in rheumatic diseases. When stimulated with FFA, osteoblasts from RA and OA patients secreted higher amounts of the proinflammatory cytokine interleukin (IL)-6 and the chemokines IL-8, growth-related oncogene α, and monocyte chemotactic protein 1. Receptor activator of nuclear factor kappa B ligand (RANKL), osteoprotegerin, and osteoblast differentiation markers were not influenced by FFA. Mineralization activity of osteoblasts correlated inversely with the level of FFA-induced IL-6 secretion. Expression of the Wnt signaling molecules, axin-2 and β-catenin, was not changed by palmitic acid (PA) or linoleic acid (LA), suggesting no involvement of the Wnt signaling pathway in FFA signaling for osteoblasts. On the other hand, Toll-like receptor 4 blockade significantly reduced PA-induced IL-8 secretion by osteoblasts, while blocking Toll-like receptor 2 had no effect. In osteoclasts, IL-8 secretion was enhanced by PA and LA particularly at the earliest time point of differentiation. Differences were observed between the responses of RA and OA osteoclasts. FFA might therefore represent a new molecular factor by which adipose tissue contributes to subchondral bone damage in RA and OA. In this context, their mechanisms of action appear to be dependent on inflammation and innate immune system rather than Wnt-RANKL pathways.
31610189 Dendritic cells aggregate inflammation in experimental osteoarthritis through a toll-like 2019 Dec 1 AIMS: Dendritic cells (DCs) and Toll-like receptor (TLR) participate in mediating inflammation process. However, the functional role of TLR expressed on DCs in osteoarthritis (OA) development has not been defined yet. The purpose of this study was to investigate the role and mechanism of TLR and DCs in the progression of experimental osteoarthritis (OA). MATERIALS AND METHODS: Experimental OA model was induced by iodoacetate injection. Expressions of toll-like receptors in DCs of OA mice were detected by qRT-PCR and flow cytometry. TLR agonists lipopolysaccharide (LPS) and R848 or TLR antagonist FP7 were used, and the levels of TLRs and inflammatory cytokines were examined by qRT-PCR and ELISA. KEY FINDINGS: The expression levels of TLR family members were increased in DCs derived from synovial fluid of OA mice compared with the sham mice. In vitro, OA mice-derived DCs had increased production of inflammatory cytokine after TLR agonists LPS and R848 challenge, while TLR challenges did not affect DCs maturation. Inhibition of TLR by TLR antagonist FP7 blocked TLR challenges-induced increased inflammation in DCs. In mice, administration of FP7 attenuated LPS-induced inflammatory response and OA condition. SIGNIFICANCE: Increased TLR expression in OA-derived DCs contributes to the inflammation condition and potentially acts as a therapeutic target for osteoarthritis.
30927735 α-Difluoromethylornithine suppresses inflammatory arthritis by impairing myeloid-derived 2019 Jun OBJECTIVES: The chemopreventive drug α-difluoromethylornithine (DFMO) has been shown to have an antinociceptive effect on mechanical allodynia in inflammatory arthritis by directly inhibiting ornithine decarboxylase (ODC) and decreasing polyamine production in inflammatory sites. However, little is known about the effect of DFMO on the immune system of inflammatory arthritis. Here, we investigated the effect of DFMO in a well-established collagen-induced arthritis (CIA) mouse model and explored its effect on the immune system. METHODS: The effect of DFMO on the frequency of myeloid-derived suppressor cells (MDSCs) in the spleens of CIA mice and their associations with disease severity, tissue inflammation and the levels of proinflammatory T-helper (Th) 17 cells in lymphoid tissues were investigated. The effects of DFMO on disease severity and Th17 cells were compared with those of antibody depletion of MDSCs. The arthritis severity was also evaluated by adoptive transfer of MDSCs derived from DFMO- or dH(2)O-treated mice. RESULTS: In this study, we showed that both MDSCs and Th17 cells were significantly expanded in CIA mice. Treatment by DFMO at the onset of CIA suppressed the development of arthritis and decreased the frequency of MDSCs and Th17 cells. MDSC depletion by anti-Gr-1 mAb achieved a similar result, while combination treatment of both methods did not achieve a significant difference compared to either of the single treatments. In addition, the adoptive transfer of MDSCs derived from dH(2)O-treated mice with CIA restored the arthritis severity of CIA in mice treated with anti-Gr-1 mAb, while the transfer of MDSCs from DFMO-treated mice did not have such an effect. CONCLUSIONS: Our results identified DFMO as a potential therapeutic drug for the treatment of inflammatory arthritis.
30289018 The findings of musculoskeletal ultrasonography on primary Sjögren's syndrome patients in 2019 Sep Objective: We researched the findings of musculoskeletal ultrasound sonography (MSUS) on primary Sjogren's syndrome in childhood (pSS-C) with articular manifestations. The correlation of rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) were investigated to evaluate the usefulness of MSUS on their articular prognosis. Method: The objective patients are pSS-C cases who visited our hospital complaining joint pain and/or joint swelling and for whom MSUS was performed. Result: Eight patients included 6 female and 2 male, 5 RF-positive patients and 3 ACPA- positive patients. The mean age of onset was 11.1 ± 3.0 years (352 physical joint findings and 284 MSUS findings. The number of joints found clinical articular manifestations was 58/352 joints, and arthritis detected by MSUS was 30/284 joints). In multivariate analysis, the odds ratio of clinical articular manifestations was significant high in RF-positivity (2.9, 95%CI 1.5-6.2). The odds ratio of arthritis detected by MSUS in ACPA-positivity was significant high (3.7, 95%CI 1.5-11.6), although odds ratio in RF-positivity had no statistical significance and a similar trend was seen in odds ratios of subclinical arthritis (4.9, 95%CI 1.6-18.0). Conclusion: It was indicated that MSUS is useful for pSS-C. ACPA-positive pSS-C patients have arthritis and subclinical arthritis more frequently than ACPA-negative patients.
30511817 Association of Dendritic Cell Signatures With Autoimmune Inflammation Revealed by Single-C 2019 May OBJECTIVE: To identify single-cell transcriptional signatures of dendritic cells (DCs) that are associated with autoimmunity, and determine whether those DC signatures are correlated with the clinical heterogeneity of autoimmune disease. METHODS: Blood-derived DCs were single-cell sorted from the peripheral blood of patients with rheumatoid arthritis, systemic lupus erythematosus, or type 1 diabetes as well as healthy individuals. DCs were analyzed using single-cell gene expression assays, performed immediately after isolation or after in vitro stimulation of the cells. In addition, protein expression was measured using fluorescence-activated cell sorting. RESULTS: CD1c+ conventional DCs and plasmacytoid DCs from healthy individuals exhibited diverse transcriptional signatures, while the DC transcriptional signatures in patients with autoimmune disease were altered. In particular, distinct DC clusters, characterized by up-regulation of TAP1, IRF7, and IFNAR1, were abundant in patients with systemic autoimmune disease, whereas DCs from patients with type 1 diabetes had decreased expression of the regulatory genes PTPN6, TGFB, and TYROBP. The frequency of CD1c+ conventional DCs that expressed a systemic autoimmune profile directly correlated with the extent of disease activity in patients with rheumatoid arthritis (Spearman's r = 0.60, P = 0.03). CONCLUSION: DC transcriptional signatures are altered in patients with autoimmune disease and are associated with the level of disease activity, suggesting that immune cell transcriptional profiling could improve our ability to detect and understand the heterogeneity of these diseases, and could guide treatment choices in patients with a complex autoimmune disease.
31721044 The results of 394 consecutive cases of knee joint radiation synovectomy (radiosynoviorthe 2020 Feb OBJECTIVE: The aim of this study was to assess the treatment results of (90)Y radiation synovectomy for chronic exudative synovitis of knee joints. METHODS: The retrospective data consist of 394 consecutive knee radiation synovectomies performed using 6 mCi (222 MBq) of (90)Y. The assessment included 3-point custom pain and joint mobility scale, evaluation of joint's circumference, binary joint's temperature evaluation, patellar ballottement test, indications for puncture and its volume in applicable cases. 21 cases had to be forfeited due to missing data regarding follow-up. RESULTS: The final analysis of 373 treatment procedures performed in 253 patients yielded following results-at 6 months after treatment, 80.9% of the patients reported at least partial pain relief (including 33.3% with complete pain relief), which increased to 86.7% at one year. The pain intensity decreased over time, however, the outcomes were worse in older patients. The probability of pain recurrence was 15% at 6 months, and 28% at one year. It was highest in post-traumatic synovitis, and lowest in pigmented villonodular synovitis. The circumference of the treated knee joints decreased over the course of follow-up, however, the decrease was significantly lower in older patients. The fraction of patients with full knee joint mobility increased from 34.6 to 40.6% at 6 months and 49.2% at one year. The percentage of patients that required articular puncture decreased from 62.8% at baseline to about 35.6% at 6 months, and 32.8% at one year. Positive patellar ballottement was found in 68.5% before treatment and remained at about 40-50% during the course of follow-up. The increased temperature of the joint was reported in 51.2% at baseline and decreased to 33% at 6 months and 28.3% at one year. CONCLUSIONS: (1) Radiation synovectomy is a safe and effective method of treatment in patients with exudative synovitis, however, the pain recurrence rate is significantly higher in post-traumatic exudative synovitis compared to pigmented villonodular, undifferentiated, and rheumatoid arthritis. (2) Our results suggest that older patients have worse treatment results with radiation synovectomy compared to younger patients.
31713735 Crowned dens syndrome, yet another rheumatic disease imposter. 2020 Feb OBJECTIVE: Crowned dens syndrome (CDS) is defined as acute cervical or occipital pain due to a local inflammatory reaction related to calcifications in the ligaments surrounding the odontoid process. Virtually, all previous descriptions of CDS have related to calcium pyrophosphate dehydrate (CPPD) arthropathy. METHODS: We prospectively identified a total of twenty-four consecutive inpatients with Crowned dens syndrome from January 2016 to December 2017 in our institution. RESULTS: All patients (age range 54 to 87 years, 67% females) presented with acute onset pain in the upper neck and/or occiput accompanied with extreme neck stiffness. Most patients (79%) had elevated inflammatory markers. Four patients underwent temporal artery biopsy, which was negative for arteritis in all cases, and one was subjected to lumbar puncture, which was non-contributory. Seventeen patients (71%) had known rheumatic disease on presentation: 10 patients had the diagnosis of calcium pyrophosphate dehydrate arthropathy, 3 patients had ankylosing spondylitis, 2 patients had rheumatoid arthritis, 1 patient had Behcet's disease, and 1 suffered from Familial Mediterranean Fever. In 4 more patients, crowned dens syndrome was the presenting symptom of calcium pyrophosphate dehydrate disease. All patients were treated with glucocorticoids as 0.5 mg/kg prednisone plus colchicine 0.5 mg bid resulting in dramatic improvement in both clinical (head/neck pain alleviated and cervical spinal mobility regained) and laboratory measures. CONCLUSIONS: Crowned dens syndrome should be considered, and craniocervical junction imaged in the context of acute cervical or occipital pain with stiffness and elevated inflammation markers not only in patients previously diagnosed with calcium pyrophosphate dehydrate arthropathy but also in diverse clinical settings.Key Points• This report highlights that crowned dens syndrome should be considered in various clinical setting besides calcium pyrophosphate dehydrate (CPPD) arthropathy.• Vigilance to this syndrome allows rapid treatment and may spare the patient unnecessary invasive procedures (i.e., temporal artery biopsy or lumbar puncture).
31410932 Development of an algorithm to detect methotrexate wrong frequency error using computerize 2019 Oct PURPOSE: We validated an algorithm to detect frequency errors in computerized healthcare data and estimated the incidence of these errors in an integrated healthcare system. METHODS: We applied Sentinel System analytic tools on the electronic health records of Kaiser Permanente, Northern California, January 1, 2010, through May 30, 2015,to identify rheumatoid arthritis (RA) patients with new use of methotrexate (365-day baseline period). We identified potential methotrexate frequency errors using ICD-9 code 995.20 (adverse drug event), Current Procedural Terminology (CPT) code 96409 for injection of leucovorin and prescription refill patterns. We performed chart review to confirm the frequency errors, assessed performance for detecting frequency errors, and estimated the incidence of chart-confirmed errors. RESULTS: The study included 24,529 methotrexate dispensings among 3,668 RA patients. Among these, 722 (3%) had one dispensing and 23,807 (97.1%) had ≥2 dispensings during 1-year follow-up period. We flagged 653 (2.7%) with a potential medication error (46 with one dispensing and 607 with ≥2 dispensings). We sampled 94 for chart review, and confirmed three methotrexate errors. All three confirmed frequency errors involved a first methotrexate dispensing followed by injected rescue therapy, leucovorin, (positive predictive value, 60%; 95% confidence interval [CI], 15-95%). No potential errors were found among patients with ≥2 dispensings. We estimated the frequency error incidence among one methotrexate dispensing to be 0.4% (95%CI, 0.1% to 1.2%). CONCLUSION: Rescue therapy is a specific indicator of methotrexate overdose among first methotrexate dispensings. This method is generalizable to other medications with serious adverse events treated with antidotes.
31423933 Systemic Inflammation Rapidly Induces Reversible Atrial Electrical Remodeling: The Role of 2019 Aug 20 Background Systemic inflammation is a strong predictor of atrial fibrillation. A key role for electrical remodeling is increasingly recognized, and experimental data suggest that inflammatory cytokines can directly affect connexins resulting in gap-junction dysfunction. We hypothesized that systemic inflammation, regardless of its origin, promotes atrial electric remodeling in vivo, as a result of cytokine-mediated changes in connexin expression. Methods and Results Fifty-four patients with different inflammatory diseases and elevated C-reactive protein were prospectively enrolled, and electrocardiographic P-wave dispersion indices, cytokine levels (interleukin-6, tumor necrosis factor-α, interleukin-1, interleukin-10), and connexin expression (connexin 40, connexin 43) were measured during active disease and after reducing C-reactive protein by >75%. Moreover, peripheral blood mononuclear cells and atrial tissue specimens from an additional sample of 12 patients undergoing cardiac surgery were evaluated for atrial and circulating mRNA levels of connexins. Finally, in vitro effects of interleukin-6 on connexin expression were studied in HL-1 mouse atrial myocytes. In patients with active inflammatory diseases, P-wave dispersion indices were increased but rapidly decreased within days when C-reactive protein normalizes and interleukin-6 levels decline. In inflammatory disease patients, both P-wave dispersion indices and interleukin-6 changes were inversely associated with circulating connexin levels, and a positive correlation between connexin expression in peripheral blood mononuclear cells and atrial tissue was demonstrated. Moreover, interleukin-6 significantly reduced connexin expression in HL-1 cells. Conclusions Our data suggest that regardless of specific etiology and organ localization, systemic inflammation, via interleukin-6 elevation, rapidly induces atrial electrical remodeling by down-regulating cardiac connexins. Although transient, these changes may significantly increase the risk for atrial fibrillation and related complications during active inflammatory processes.
30776053 Assessment of Price Changes of Existing Tumor Necrosis Factor Inhibitors After the Market 2019 May 1 This study uses wholesale medication acquisition costs and Medicare claims data to assess how prices of existing tumor necrosis factor inhibitors changed in response to the market entry of new tumor necrosis factor inhibitors.
30800133 Specific Inhibition of Soluble γc Receptor Attenuates Collagen-Induced Arthritis by Modul 2019 IL-17 produced by Th17 cells has been implicated in the pathogenesis of rheumatoid arthritis (RA). It is important to prevent the differentiation of Th17 cells in RA. Homodimeric soluble γc (sγc) impairs IL-2 signaling and enhances Th17 differentiation. Thus, we aimed to block the functions of sγc by inhibiting the formation of homodimeric sγc. The homodimeric form of sγc was strikingly disturbed by sγc-binding DNA aptamer. Moreover, the aptamer effectively inhibited Th17 cell differentiation and restored IL-2 and IL-15 signaling impaired by sγc with evidences of increased survival of T cells. sγc was highly expressed in SF of RA patients and increased in established CIA mice. The therapeutic effect of PEG-aptamer was tested in CIA model and its treatment alleviated arthritis pathogenesis with impaired differentiation of pathogenic Th17, NKT1, and NKT17 cells in inflamed joint. Homodimeric sγc has pathogenic roles to exacerbate RA progression with differentiation of local Th17, NKT1, and NKT17 cells. Therefore, sγc is suggested as target of a therapeutic strategy for RA.
31931912 From Peruvian mummies to living humans: first case of pulmonary tuberculosis caused by Myc 2019 Dec 1 The zoonotic potential of Mycobacterium tuberculosis complex species is well known. However, M. pinnipedii, the causative agent of tuberculosis (TB) predominantly in seals and sea lions, has never been isolated from a respiratory specimen in humans. Here we describe the first known human case of pulmonary TB caused by M. pinnipedii in a 79-year-old female patient with rheumatoid arthritis and chronic respiratory disease. The epidemiological data did not explain where the patient was exposed to M. pinnipedii, thus leaving the source of transmission unknown.
30769033 IgM(+)CD27(+) B cells possessed regulatory function and represented the main source of B c 2019 Apr Synovial inflammation is observed in patients with osteoathritis (OA) and likely contributed to its exacerbation. Regulatory B (Breg) cells are shown to suppress inflammation in various diseases, including rheumatoid arthritis (RA). To examine whether Breg cells also participated in OA, we examined the synovial fluid from OA patients, and compared with that in RA patients. In OA synovial fluid, IL-10-producing B cells were present directly ex vivo and were increased upon stimulation, indicating that B cells were a source of IL-10 directly at the affected site of OA patients. Interestingly, the frequency of IL-10(+) cells in synovial B cells was higher in OA patients than in RA patients, but the total number of IL-10(+) B cells in OA was lower than that in RA, suggesting that OA patients presented lower B cell infiltration than RA patients. Phenotypical analysis demonstrated that the IL-10(+) B cells were IgM(+) and CD27(+), but not CD24(hi) or CD38(hi). To allow functional analysis of IgM(+)CD27(+) B cells, the IgM(+)CD27(+) B cells in the blood of OA patients were examined. These blood IgM(+)CD27(+) B cells expressed more IL-10, but less CD80 and CD86 than non-IgM(+)CD27(+) B cells. Blood IgM(+)CD27(+) B cells suppressed the proliferation and IFN-γ expression of autologous T cells, and this effect could be reverted if IL-10 was inhibited. Furthermore, we found that patients with more severe OA presented lower levels of IL-10(+) B cells in the synovial fluid. Together, our study described an IgM(+)CD27(+) B cell subset in OA patients, which represented the major IL-10-secreting B cell type in the synovial fluid of OA patients and possessed regulatory function.
31071076 An integrative transcriptome analysis framework for drug efficacy and similarity reveals d 2019 May Anti-TNF agents have been in the first line of treatment of various inflammatory diseases such as Rheumatoid Arthritis and Crohn's Disease, with a number of different biologics being currently in use. A detailed analysis of their effect at transcriptome level has nevertheless been lacking. We herein present a concise analysis of an extended transcriptomics profiling of four different anti-TNF biologics upon treatment of the established hTNFTg (Tg197) mouse model of spontaneous inflammatory polyarthritis. We implement a series of computational analyses that include clustering of differentially expressed genes, functional analysis and random forest classification. Taking advantage of our detailed sample structure, we devise metrics of treatment efficiency that take into account changes in gene expression compared to both the healthy and the diseased state. Our results suggest considerable variability in the capacity of different biologics to modulate gene expression that can be attributed to treatment-specific functional pathways and differential preferences to restore over- or under-expressed genes. Early intervention appears to manage inflammation in a more efficient way but is accompanied by increased effects on a number of genes that are seemingly unrelated to the disease. Administration at an early stage is also lacking in capacity to restore healthy expression levels of under-expressed genes. We record quantifiable differences among anti-TNF biologics in their efficiency to modulate over-expressed genes related to immune and inflammatory pathways. More importantly, we find a subset of the tested substances to have quantitative advantages in addressing deregulation of under-expressed genes involved in pathways related to known RA comorbidities. Our study shows the potential of transcriptomic analyses to identify comprehensive and distinct treatment-specific gene signatures combining disease-related and unrelated genes and proposes a generalized framework for the assessment of drug efficacy, the search of biosimilars and the evaluation of the efficacy of TNF small molecule inhibitors.
30079992 Role of Anti-Fractalkine Antibody in Suppression of Joint Destruction by Inhibiting Migrat 2019 Feb OBJECTIVE: To elucidate the role of the fractalkine (FKN)/CX(3) CR1 pathway in joint destruction in rheumatoid arthritis. METHODS: We examined the effect of treatment with anti-mouse FKN (anti-mFKN) monoclonal antibody (mAb) on joint destruction and the migration of osteoclast precursors (OCPs) into the joint, using the collagen-induced arthritis (CIA) model. DBA/1 mice were immunized with bovine type II collagen to induce arthritis, and then treated with anti-mFKN mAb. Disease severity was monitored by arthritis score, and joint destruction was evaluated by soft x-ray and histologic analyses. Plasma levels of joint destruction markers were assessed by enzyme-linked immunosorbent assay. FKN expression on endothelial cells was detected by immunohistochemistry. Bone marrow-derived OCPs were labeled with fluorescein and transferred to mice with CIA, and the migration of the OCPs to the joints was then analyzed. RESULTS: Both prophylactic and therapeutic treatment with anti-mFKN mAb significantly decreased the arthritis and soft x-ray scores. Plasma levels of cartilage oligomeric matrix protein and matrix metalloproteinase 3 decreased after treatment with anti-mFKN mAb. Histologic analysis revealed that anti-mFKN mAb inhibited synovitis, pannus formation, and cartilage destruction, as well as suppressed bone damage, with a marked reduction in the number of tartrate-resistant acid phosphatase-positive osteoclasts. Anti-mFKN mAb strongly inhibited the migration of bone marrow-derived OCPs into the affected synovium. CONCLUSION: Anti-mFKN mAb notably ameliorates arthritis and joint destruction in the CIA model, as well as inhibits migration of OCPs into the synovium. These results suggest that inhibition of the FKN/CX(3) CR1 pathway could be a novel strategy for treatment of both synovitis and joint destruction in rheumatoid arthritis.
30988125 Patient Preferences for Disease-modifying Antirheumatic Drug Treatment in Rheumatoid Arthr 2020 Feb OBJECTIVE: To summarize patients' preferences for disease-modifying antirheumatic drug (DMARD) therapy in rheumatoid arthritis (RA). METHODS: We conducted a systematic review to identify English-language studies of adult patients with RA that measured patients' preferences for DMARD or health states and treatment outcomes relevant to DMARD decisions. Study quality was assessed using a published quality assessment tool. Data on the importance of treatment attributes and associations with patient characteristics were summarized across studies. RESULTS: From 7951 abstracts, we included 36 studies from a variety of countries. Most studies were in patients with established RA and were rated as medium- (n = 19) or high-quality (n = 12). The methods to elicit preferences varied, with the most common being discrete choice experiment (DCE; n = 13). Despite the heterogeneity of attributes in DCE studies, treatment benefits (disease improvement) were usually more important than both non-serious (6 of 8 studies) and serious adverse events (5 of 8), and route of administration (7 of 9). Among the non-DCE studies, some found that patients placed high importance on treatment benefits, while others (in patients with established RA) found that patients were quite risk averse. Subcutaneous therapy was often but not always preferred over intravenous therapy. Patient preferences were variable and commonly associated with the sociodemographic characteristics. CONCLUSION: Overall, the results showed that many patients place a high value on treatment benefits over other treatment attributes, including serious or minor side effects, cost, or route of administration. The variability in patient preferences highlights the need to individualize treatment choices in RA.
30806709 JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid ar 2019 Feb 1 Janus kinase (JAK)/signal transducers and activators of transcription (STATs) are a group of molecules associated with one of the major pathways through which many cytokines exert and integrate their function, and as such they are increasingly recognized as playing critical role in the pathogenesis subserving various immune-mediated diseases, including RA, PsA, SpAs, IBD, skin disorders (e.g. alopecia areata, atopic dermatitis), single-gene disorders like interferonopathies, and others. JAKs are the key initiating players of the JAK/STAT pathway. Upon binding of their respective effector molecules (cytokines, IFNs, growth factors and others) to type I and type II receptors, JAKs are activated, and through phosphorylation of themselves and of other molecules (including STATs), they mediate signal transduction to the nucleus. A class of drugs-called JAK inhibitors or JAKinibs-that block one or more JAKs has been developed in the last decade, and now numbers >20 members. Although, so far, JAK inhibitors have been marketed only for RA and PsA, these drugs have been tested in phase 2 and phase 3 clinical trials for other inflammatory conditions and beyond. In this review, we summarize the clinical data, including efficacy and safety, available for JAK inhibitors used in some immune-mediated conditions other than RA.
31863865 Development and validation of a Level A in-vitro in-vivo correlation for tofacitinib modif 2020 Apr 30 PURPOSE: To determine if a validated Level A in-vitro in-vivo correlation (IVIVC) could be achieved with the extrudable core system (ECS) osmotic tablet platform. Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis. METHODS: Fast-, medium-, and slow-release modified-release formulations of 11 mg tofacitinib ECS tablets, and one formulation of 22 mg tofacitinib ECS tablet, were manufactured. In vitro dissolution of the tofacitinib ECS tablets was performed using USP Apparatus 2 (paddles) and in vivo pharmacokinetic (PK) data were obtained from a Phase 1 study in healthy volunteers. A 5 mg immediate-release formulation tablet was included to support deconvolution of the tofacitinib ECS PK tablet data to obtain the in vivo absorption profiles. A linear, piecewise correlation and a simple linear correlation were used to build and validate two IVIVC models. RESULTS: The prediction errors (PEs) for the linear, piecewise correlation met the Food and Drug Administration's criteria for establishing a Level A IVIVC, with a maximum absolute individual internal PE of 4.6%, a maximum absolute average internal PE of 3.9%, and a maximum absolute external PE of 8.4% obtained. CONCLUSIONS: This study demonstrates that the tofacitinib ECS osmotic tablet platform can achieve a Level A IVIVC, similar to other osmotic delivery systems.