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ID PMID Title PublicationDate abstract
27865760 This Month in AJP. 2017 Jan The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology.
27753734 Investigation of Nerve Conduction Studies of Carpal Tunnel Syndrome Cases With Different R 2017 Mar PURPOSE: The aim of this study was to determine whether there are electrodiagnostic differences between carpal tunnel syndrome (CTS) patients with diabetes mellitus, CTS + hypothyroidism (HT), CTS + fibromyalgia syndrome, CTS + rheumatoid arthritis (RA), and idiopathic CTS cases, by comparing nerve conduction studies. METHODS: This research examined electrophysiologic studies of 47 untreated HT + CTS, 47 diabetes mellitus + CTS, 49 RA + CTS, 52 fibromyalgia syndrome + CTS, 50 idiopathic CTS cases, and a healthy control group of 50 individuals (a total of 293 patients and 433 hands with CTS). RESULTS: There were no significant differences between the groups in terms of sex and age. There was no significant difference between the CTS groups-in terms of numbers-with mild, moderate, and severe CTS. When the CTS groups were compared with the control group, in all CTS groups on both left and right hands, there was a significant prolongation in median motor latency and median sensory latency (in the 3rd finger); also a significant decrease in median sensory velocity in the 3rd finger. In diabetes mellitus, HT, and RA groups, the median motor amplitudes in both hands were significantly decreased compared with the idiopathic group. There was a moderate significant negative correlation between disease duration and median motor amplitudes (of both right and left sides) in RA (right; P = 0.028, r = 0.761, left; P = 0.041, r = 0.694) and HT groups (right; P = 0.035, r = 0.637, left; P = 0.049, r = 0.697). CONCLUSIONS: Electrodiagnostic results showed both demyelinating injury and axonal damage in diabetes mellitus, HT, and RA patients with CTS, in these patients during treatment for CTS. Early treatment planning should include the risk factor diseases.
28734661 Systematic Literature Review and Meta-analysis of Tumor Necrosis Factor-Alpha Experienced 2017 Aug PURPOSE: The goal of this study was to compile all available evidence regarding the efficacy of tumor necrosis factor-α (TNF) inhibitors, non-TNF biologics, and tofacitinib for TNF-experienced patients who have rheumatoid arthritis (RA). METHODS: A systematic literature review of MEDLINE, EMBASE, and rheumatology conference abstracts was performed to identify observational studies and randomized controlled trials (RCTs) reporting American College of Rheumatology response rates (ACR 20/50/70) for adult patients with RA who switched from at least 1 TNF to another TNF or a non-TNF therapy. A direct random effects meta-analysis was performed to evaluate ACR 20/50/70 response rates for TNF and non-TNF therapies. Separate analyses were conducted among 3-, 6-, and 12-month observational studies and for 6-month RCTs. FINDINGS: A total of 18 observational studies and 6 RCTs were selected. Among 3-month observational studies, the percentages of ACR20/50/70 responders switching to another TNF were similar to those switching to a non-TNF biologic (ACR20, 54.5% vs 58.6%; ACR50, 33.3% vs 33.3%; and ACR70, 13.0% vs 14.6%, respectively). Among 6-month observational studies, the percentages of TNF ACR20/50/70 responders were higher than those of non-TNF responders (ACR20, 67.7% vs 50.4%; ACR50, 50.4% vs 26.6%; and ACR70, 24.9% vs 11.6%). Among 6-month RCTs, the percentages of non-TNF biologic ACR20/50/70 responders were similar to those in the 6-month non-TNF observational studies (ACR20, 50.7% vs 50.4%; ACR50, 27.5% vs 26.6%; and ACR70, 11.9% vs 11.6%). For 12-month observational studies, TNF biologic ACR20/50/70 percentages were higher than those of non-TNF therapies (ACR20, 72.2% vs 57.0%; ACR50, 42.1% vs 28.9%; and ACR70, 22.9% vs 10.0%). IMPLICATIONS: For TNF-experienced patients with RA, subsequent TNF therapy and non-TNF biologic therapy have comparable efficacy.
25865349 Quantitative characterization of metacarpal and radial bone in rheumatoid arthritis using 2017 Mar AIM: The objectives of this study were: (i) to develop a standardized method of quantifying bone mineral density (BMD) and microarchitecture in the hand and wrist bones of patients with rheumatoid arthritis (RA) using high resolution- peripheral quantitative computed tomography (HR-pQCT); (ii) to compare quantitative bone parameters between RA and post-menopausal osteopenic (PM-OP) subjects; and (iii) to correlate quantitative bone parameters at the distal radius with those at the metacarpal heads in RA subjects. METHODS: HR-pQCT imaging of the dominant hand and wrist was performed in 12 female RA patients. BMD and trabecular parameters for the 2-12% head region of the second and third metacarpals were calculated and compared between RA patients and healthy controls. Bone parameters were also calculated for 110 slices of the distal radius in RA patients and compared to data from controls and PM-OP women from a previous study. RESULTS: Compared to controls, RA patients had significantly decreased BMD, trabecular volume and number, and increased trabecular heterogeneity in the third metacarpal and distal radius. Significantly lower trabecular number and significantly higher ratio of outer annular trabecular BMD to inner trabecular BMD were observed in patients with RA, compared to patients with osteopenia (P < 0.05). Trabecular BMD in the third metacarpal and in the distal radius were significantly correlated (ρ = 0.918, P < 0.0001) in RA patients. CONCLUSION: This study established a standardized method for quantifying bone density and trabecular properties in the hand and wrist bones of RA patients using HR-pQCT. Deterioration of bone structure in RA patients was found comparable to that in osteopenic women, and trabecular bone loss near affected joints was found to be correlated with bone loss away from joints.
28450312 Long-term outcome is better when a methotrexate-based treatment strategy is combined with 2017 Aug OBJECTIVES: In the second Computer-Assisted Management in Early Rheumatoid Arthritis trial, patients had started with methotrexate and 10 mg prednisone (MTX+pred) or placebo (MTX+plac). After the trial, prednisone was tapered and stopped, if possible. The objective was to compare, during the post-trial follow-up between the two former strategy groups, initiation of the first biological disease-modifying antirheumatic drug (bDMARD), radiographic outcome and onset of glucocorticoid (GC)-related comorbidities. METHODS: Data on prednisone and bDMARD use and onset of GC-related comorbidities were collected retrospectively. Sharp/van der Heijde scoring was performed. Data were analysed using Fisher's exact and Mann-Whitney U tests. RESULTS: Of 218 patients post-trial follow-up data were available. The maximum follow-up time was 11.8 years. Fewer patients initiated a first bDMARD in the former MTX+pred compared with the former MTX+plac strategy group: 31% vs 50%, p=0.003. At the 2 year post-trial follow-up, the median erosion score was significantly lower in the former MTX+pred versus former MTX+plac strategy group: 0 (range 0-0) versus 0 (0-2), p=0.002. No significant differences between the former strategy groups in the onset of GC-related comorbidities during the post-trial follow-up were found. CONCLUSION: Addition of 10 mg prednisone daily to an MTX-based treatment strategy in early rheumatoid arthritis results in a lower initiation rate of a first bDMARD and significantly better radiographic outcomes, yet does not result in more GC-related comorbidities.
28032180 Mortality in patients with rheumatoid arthritis: a 15-year prospective cohort study. 2017 Apr The aim of this study was to investigate (a) the mortality in a clinical cohort of patients with established rheumatoid arthritis in comparison with the general Dutch population over 15 years, (b) the trend in the mortality ratio during the study period, and (c) causes of death and compare these with the general population. In 1997, a sample of 1222 patients was randomly selected from the register of a large rheumatology outpatient clinic. Their mortality and primary causes of death between 1997 and 2012 were obtained from Statistics Netherlands. The standardized mortality ratio (SMR) for all-cause mortality and the number of life-years lost in the study period, adjusted for age, sex, and calendar year, were calculated. A linear poisson regression analysis was performed to evaluate change in all-cause SMR over time. Finally, the SMRs for cause-specific mortality were calculated. The mean age of the population at baseline was 60.4 (SD 15.4) years, and 72.6% of the patients were women. The estimated SMR (95% CI) for all-cause mortality was 1.54 (1.41, 1.67) with about one life-year lost over the study period. There was a trend to decreasing SMR (2% annually, p = .07). Mortality was higher compared with the general population for circulatory system diseases, respiratory system diseases, musculoskeletal system diseases, and digestive system diseases (p < .05). The observed mortality among patients with RA was 54% higher than in the general population after adjustment for age, sex and calendar year. More than one life-year was lost over 15 years, and the mortality tended to decrease over time. The mortality was higher for cardiovascular, respiratory, musculoskeletal and digestive diseases.
27696724 Comparative Assessment of the Different American College of Rheumatology/European League A 2017 Mar OBJECTIVE: The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) have defined remission using Boolean- or index-based criteria (i.e., a Simplified Disease Activity Index [SDAI] score of ≤3.3). We undertook this study to compare definitions of remission to inform choice of end points for future rheumatoid arthritis (RA) clinical trials, and we also included in our comparison the remission criterion of a score of ≤2.8 on the Clinical Disease Activity Index (CDAI). METHODS: We performed post hoc analyses on clinical remission rates using data from 2 infliximab trials (the ASPIRE [Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset] and ATTRACT [Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy] trials) and 1 golimumab trial (the GO-FORWARD trial). We investigated stringency of the different remission definitions, their power to discriminate between active drug and comparator, and aspects of their internal and external validity. We also investigated population determinants of discriminatory power for a particular remission end point. RESULTS: In patients with early RA (the ASPIRE trial), ACR/EULAR Boolean, CDAI, and SDAI remission rates at 6-7 months were 4-6% for methotrexate (MTX) alone versus 11-14% for infliximab plus MTX. In patients with MTX-refractory active RA (the ATTRACT and GO-FORWARD trials), remission rates were ≤1% for comparator (add-on of placebo) versus 4-6% for add-on of infliximab in the ATTRACT trial and ≤3% for comparator (add-on of placebo) versus 11-13% for add-on of golimumab in the GO-FORWARD trial. Existing remission cut points of different measures were generally comparable, with the Boolean criteria being somewhat more stringent than the SDAI and CDAI criteria. Remission rates were similar across definitions, as was average statistical power (CDAI, 55.6%; Boolean, 59.9%; SDAI, 62.6%). CONCLUSION: Remission is an ambitious primary end point for RA clinical trials, to be reserved for selected scenarios based on power considerations. The ACR/EULAR definitions are interchangeable, with slightly higher stringency of Boolean criteria over index-based criteria.
28167299 1,25(OH)(2)D(3) and calcipotriol, its hypocalcemic analog, exert a long-lasting anti-infla 2017 Oct OBJECTIVES: We investigated the effects of 1,25-dihydroxy vitamin D(3) (1,25(OH)(2)D(3)), i.e. biologically active vitamin D and calcipotriol, a vitamin D analog, on growth and secretion of inflammatory mediators in synovial stromal cells (SSC) of patients with rheumatoid arthritis (RA) or osteoarthritis (OA). METHODS: Synovial stromal cells (SSC) isolated during knee prosthesis surgery from four patients with RA and four with OA were exposed to 1,25(OH)(2)D(3) or calcipotriol with or without stimulation of cells with IL-1β or TNF-α. The proliferation of cells was studied by MTT assay. Levels of cytokines were analyzed by a magnetic bead-based multiplex assay (a panel of 27 important cytokines and IL-6 alone) and RT-PCR was used to validate the concentrations of the key cytokines secreted by SSC. The vitamin D receptor (VDR) was visualized by immunofluorescence in SSC and by immunohistochemistry in the synovial tissues of three RA and three OA patients. RESULTS: We detected intense staining for VDR in the synovial lining and vascular endothelium in tissue sections from all our RA and OA patients. Both 1,25(OH)(2)D(3) and calcipotriol inhibited SSC proliferation for a prolonged time (up to 23 days with calcipotriol), but dexamethasone tended to increase SSC proliferation in a 4-day culture. 1,25(OH)(2)D(3), calcipotriol and dexamethasone reduced the secretion of most inflammatory factors. Calcipotriol and dexamethasone additively reduced the secretions of IL-6, IFN-γ, basic FGF and VEGF in TNF-α stimulated SSC. The level of IL-6 was still diminished at 10 days after exposure, emphasizing the long-term impact of calcipotriol on SSC. CONCLUSIONS: Exposure for 24-48h to 1,25(OH)(2)D(3) or calcipotriol causes a long-lasting inhibition of cell proliferation and cytokine production in SSC in vitro.
29019884 Utility of osteosclerotic lesion biopsy in diagnosis of POEMS syndrome: A case report. 2017 Oct RATIONALE: We report a case of successful diagnosis of POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome based on monoclonality that was confirmed by an osteosclerotic lesion biopsy in a patient without pathognomonic symptoms or monoclonal gammopathy, probably because of comorbidities, which included systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome. PATIENT CONCERNS: A 57-year-old woman presented with an approximately 2-year history of numbness in the toes that had gradually spread, along with muscle weakness in both arms and legs. She had been receiving immunosuppressant and corticosteroid therapy since being diagnosed with systemic lupus erythematosus and Sjögren syndrome at the age of 31 years and rheumatoid arthritis at the age of 44 years. Neurological examination revealed predominantly distal hypoesthesia and weakness in a typical stocking-and-glove pattern. Immunoelectrophoresis revealed elevated polyclonal immunoglobulin, which was attributed to her known underlying disease. DIAGNOSES: Biopsy of an osteosclerotic lesion confirmed proliferation of monoclonal plasma cells, leading to a diagnosis of POEMS syndrome. INTERVENTIONS AND OUTCOMES: Lenalidomide therapy was started after the diagnosis and the patient had a favorable outcome. LESSONS: Osteosclerotic lesion biopsy can be useful for diagnosis of POEMS syndrome in difficult cases.
27605127 Infection and revision rates following primary total knee arthroplasty in patients with rh 2017 Dec PURPOSE: This meta-analysis compared infection and revision rates in patients with rheumatoid arthritis (RA) and osteoarthritis (OA) who underwent total knee arthroplasty (TKA). Rates of superficial wound and deep periprosthetic infections were compared in the groups, as were whether revision rates associated with infectious and noninfectious causes differed in the RA and OA groups. METHODS: Studies were included in the meta-analysis if they (1) compared infection and revision rates after primary TKA in RA and OA patients; (2) directly compared superficial wound and deep periprosthetic infection rates in RA and OA patients who underwent primary TKA; and (3) reported the actual numbers of RA and OA patients who underwent TKA and developed postoperative infection and/or required revision. RESULTS: The rate of superficial wound infections after primary TKA was similar in the RA and OA groups (15/258 [5.8 %] vs. 77/1609 [4.7 %]; odds ratio [OR] 1.12, 95 % confidence interval [CI] 0.36-3.46; P = n.n.), but the deep infection rate was significantly higher in RA than in OA patients (229/7651 [3.0 %] vs. 642/68628 [0.9 %]; OR 2.04, 95 % CI 1.37-3.05; P < 0.001). The proportion of subjects who required revision resulting from infection after TKA was significantly higher in the RA than in the OA group (86/8201 [1.0 %] vs. 555/118755 [0.5 %]; OR 1.89, 95 % CI 1,34-2.66; P < 0.001), whereas the proportion of subjects requiring revision due to noninfectious causes did not differ significantly (46/594 [7.7 %] vs. 52/904 [5.7 %]; OR 1.22, 95 % CI 0.74-2.00; P = n.n.) CONCLUSION: Following primary TKA, RA patients had a significantly higher rate of deep periprosthetic infections than OA patients, but their superficial infection rates were similar. The revision rate due to infectious causes was significantly higher in RA than in OA patients, but their revision rates due to noninfectious causes did not differ. Therefore, the surgeon should fully explain to RA patients scheduled to undergo primary TKA that, compared to OA patients, they are more likely to experience a deep infection postsurgery. LEVEL OF EVIDENCE: Meta-analysis Level III.
28342152 Association of 86 bp variable number of tandem repeat (VNTR) polymorphism of interleukin- 2017 Jun Rheumatoid arthritis (RA) is a chronic, systemic disease of unknown etiology. Several studies have reported a variable number of tandem repeat (VNTR) 86 bp (rs2234663) in the intron 2 of IL1RN gene with RA risk. The present study was designed to determine the frequencies of this polymorphism in patients with RA and control subjects (CS) and its association with RA in a western Mexican population. An analytical cross-sectional study was performed, in which 350 patients with RA and 307 CS were included. The identification of IL1RN VNTR polymorphism was carried out by polymerase chain reaction (PCR), and genotypes were associated with clinical variables (DAS28 and CRP). The presence of A1/A2 genotype was associated with RA risk (p = 0.03, OR = 1.45, 95% CI = 1.02-2.05). Also, results indicate that the presence of heterozygote genotypes which include A2 was associated with RA risk (p = 0.01, OR = 1.5, 95% CI = 1.07-2.11). Patients carrier of A2/A2 genotype have a higher score of DAS28 (5.64 [4.49-6.70]). A-/A- has higher level of CRP (2.30 [0.62-9.10]) in comparison with A2/A- (1.06 [0.37-2.82]). A1/A2 genotype was associated with susceptibility to RA in a western Mexican population. The presence of the A2/A2 genotype in RA is associated with increased disease activity.
29269418 Biomarker-related risk for myocardial infarction and serious infections in patients with r 2018 Mar BACKGROUND: Rheumatoid arthritis (RA) disease activity and associated systemic inflammation has been associated with serious infection (SIEs), myocardial infarction (MI) and coronary heart disease (CHD) events based on a few registry studies or clinical trials. There are few data from large-scale population-based studies given feasibility challenges in conducting such investigations. METHODS: Multibiomarker disease activity (MBDA) test scores (n=77 641) were linked to Medicare for US patients with RA. Outcomes of interest were hospitalised pneumonia/sepsis (SIE), MI and a composite CHD outcome. The MBDA score ranges from 1 to 100 and was analysed as time-varying. Cox proportional hazards models evaluated the association between MBDA score and SIEs, MI and CHD events, controlling for potential confounders. A sensitivity analysis excluded C reactive protein (CRP) from the MBDA score. RESULTS: There were 17 433 and 16 796 patients eligible for the SIE and MI/CHD analyses, respectively. Mean (SD) age was 69 (11) years, 79% were women, 81% were white and 38% were disabled. Over 16 424 person-years of follow-up, there were 452 SIE events, 132 MIs and 181 CHD events. Higher MBDA scores were associated with SIEs (HR=1.32, 95% CI 1.23 to 1.41 per 10 unit MBDA score change). For MI/CHD events, a threshold effect was present; higher disease activity by MBDA score was associated with increased MI (HR=1.52, 95% CI 0.92 to 2.49) and CHD rates (HR=1.54, 95% CI 1.01 to 2.34, comparing scores ≥30 vs <30). Analyses of the MBDA score without CRP yielded similar results. CONCLUSION: Higher MBDA scores were associated with hospitalised infection, MI and CHD events in a large, predominantly older, US RA population.
28584187 Efficacy and safety of the biosimilar ABP 501 compared with adalimumab in patients with mo 2017 Oct OBJECTIVES: ABP 501 is a Food and Drug Administration-approved biosimilar to adalimumab; structural, functional and pharmacokinetic evaluations have shown that the two are highly similar. We report results from a phase III study comparing efficacy, safety and immunogenicity between ABP 501 and adalimumab. METHODS: In this randomised, double-blind, active comparator-controlled, 26-week equivalence study, patients with moderate to severe active rheumatoid arthritis (RA) despite methotrexate were randomised (1:1) to ABP 501 or adalimumab (40 mg) every 2 weeks. Primary endpoint was risk ratio (RR) of ACR20 between groups at week 24. Primary hypothesis that the treatments were equivalent would be confirmed if the 90% CI for RR of ACR20 at week 24 fell between 0.738 and 1.355, demonstrating that ABP 501 is similar to adalimumab. Secondary endpoints included Disease Activity Score 28-joint count-C reactive protein (DAS28-CRP). Safety was assessed via adverse events (AEs) and laboratory evaluations. Antidrug antibodies were assessed to determine immunogenicity. RESULTS: A total of 526 patients were randomised (n=264, ABP 501; n=262 adalimumab) and 494 completed the study. ACR20 response at week 24 was 74.6% (ABP 501) and 72.4% (adalimumab). At week 24, the RR of ACR20 (90% CI) between groups was 1.039 (0.954, 1.133), confirming the primary hypothesis. Changes from baseline in DAS28-CRP, ACR50 and ACR70 were similar. There were no clinically meaningful differences in AEs and laboratory abnormalities. A total of 38.3% (ABP 501) and 38.2% (adalimumab) of patients tested positive for binding antidrug antibodies. CONCLUSIONS: Results from this study demonstrate that ABP 501 is similar to adalimumab in clinical efficacy, safety and immunogenicity in patients with moderate to severe RA. TRIAL REGISTRATION NUMBER: NCT01970475; Results.
27726376 Immunogenic HLA-DR-Presented Self-Peptides Identified Directly from Clinical Samples of Sy 2017 Jan 6 Human leukocyte antigen-antigen D related (HLA-DR) molecules are highly expressed in synovial tissue (ST), the target of the immune response in chronic inflammatory forms of arthritis. Here, we used LC-MS/MS to identify HLA-DR-presented self-peptides in cells taken directly from clinical samples: ST, synovial fluid mononuclear cells (SFMC), or peripheral blood mononuclear cells (PBMC) from five patients with rheumatoid arthritis (RA) and eight with Lyme arthritis (LA). We identified 1593 non-redundant HLA-DR-presented peptides, derived from 870 source proteins. A total of 67% of the peptides identified in SFMC and 55% of those found in PBMC were found in ST, but analysis of SFMC/PBMC also revealed new antigen-presented peptides. Peptides were synthesized and examined for reactivity with the patients' PBMC. To date, three autoantigens in RA and four novel autoantigens in LA, presented in ST and/or PBMC, were shown to be targets of T- and B-cell responses in these diseases; ongoing analyses may add to this list. Thus, immunoprecipitation and LC-MS/MS can now identify hundreds of HLA-DR-presented self-peptides from individual patients' tissues or fluids with mixed cell populations. Importantly, identification of HLA-DR-presented peptides from SFMC or PBMC allows testing of more patients, including those early in the disease. Direct analysis of clinical samples facilitates identification of novel immunogenic T-cell epitopes.
27973973 Pentraxin 3 in serum and synovial fluid of patients with rheumatoid arthritis with and wit 2017 Sep OBJECTIVES: Pentraxin 3 (PTX3) is a locally produced multifunctional protein involved in inflammation, matrix deposition, and immunity. As patients with seropositive rheumatoid arthritis (RA) have a more severe disease course and higher risk of joint destruction than seronegative patients, the aim of the present study was to examine differences in PTX3 in synovial fluid (SF) (and serum) in seropositive compared to seronegative RA, and other local markers of inflammation and destruction. METHOD: Ninety-seven RA patients with knee effusion were included. Serum and SF levels of PTX3, as well as serum levels of anti-citrullinated protein antibody and rheumatoid factor of immunoglobulin A and M subclasses, and markers of inflammation and potential destruction in SF: white blood cell counts, tumour necrosis factor, interleukin-6, vascular endothelial growth factor, metalloproteinase 3, and cartilage oligomeric matrix protein, were analysed. In addition, a radiographic knee examination was performed. RESULTS: Seropositive patients had significantly higher PTX3 levels in SF than seronegative patients, whereas there was no difference for serum levels. SF-PTX3 levels correlated with disease activity and with local inflammatory markers, especially polymorphonuclear cells, and with autoantibody levels. There was no correlation between PTX3 levels in serum and SF. CONCLUSION: The correlation of disease activity and autoantibody levels with SF-PTX3 levels in antibody-positive patients suggests a role for PTX3 in the inflammatory process specifically in seropositive RA joints, and supports the hypothesis that seropositive and seronegative RA are different disease entities. Polymorphonuclear granulocytes may be an important source of PTX3 in RA SF.
27493266 Liposomal Treatment of Experimental Arthritis Can Be Monitored Noninvasively with a Radiol 2017 Jan Rheumatoid arthritis is a chronic autoimmune disorder resulting in synovial inflammation. Fibroblast activation protein (FAP) is overexpressed by fibroblastlike synoviocytes in arthritic joints. Radioimmunoimaging with an anti-FAP antibody might be used to monitor the response to therapy, thus enabling tailored therapy strategies and therapeutic outcomes. The aim of this study was to assess whether a radiolabeled anti-FAP antibody could be used to monitor the efficacy of treatment with long-circulating liposomes (LCL) containing prednisolone phosphate (PLP-LCL) in a mouse model of arthritis. METHODS: Collagen-induced arthritis (CIA) was induced in male DBA/1J mice. Mice were treated with a single injection (10 mg/kg) of PLP-LCL or empty LCL as a control. SPECT and CT images were acquired 24 h after injection of (99m)Tc-labeled succinimidyl-hydrazinonicotinamide ((99m)Tc-S-HYNIC)-conjugated anti-FAP antibody 28H1 at 2, 5, and 9 d after treatment. The uptake of (99m)Tc-S-HYNIC-28H1 in all joints was quantified and correlated with macroscopic arthritis scores. RESULTS: Treatment of CIA with PLP-LCL significantly suppressed joint swelling. At just 1 d after treatment, the macroscopic arthritis scores had decreased by 50%. Scores decreased further, to only 10% of the initial scores, at 5 and 9 d after treatment. In contrast, macroscopic arthritis scores had increased up to 600% in untreated mice at 9 d after the injection of empty LCL. (99m)Tc-S-HYNIC-28H1 uptake ranged from 1.5 percentage injected dose per gram in noninflamed joints to 22.6 percentage injected dose per gram in severely inflamed joints. The uptake of radiolabeled 28H1 in inflamed joints (percentage injected dose) correlated with the arthritis score (Spearman ρ, 0.77; P < 0.0001). Moreover, the uptake of (99m)Tc-S-HYNIC-28H1 was slightly increased at 9 d after therapy but was not seen macroscopically, indicating that SPECT/CT imaging might be more sensitive than the macroscopic arthritis scoring method. CONCLUSION: SPECT/CT imaging with (99m)Tc-S-HYNIC-28H1 specifically monitored the response to therapy, and tracer accumulation correlated with the severity of inflammation. In addition, SPECT/CT imaging was potentially more sensitive than the macroscopic arthritis scoring method. This study showed that SPECT/CT with (99m)Tc-S-HYNIC-28H1 could be used to noninvasively monitor the course of CIA in mice.
27682064 Home Environment as a Source of Life-Threatening Azole-Resistant Aspergillus fumigatus in 2017 Jan 1 A case of fatal aspergillosis due to a TR(46)/Y121F/T289A azole-resistant Aspergillus fumigatus is reported. Environmental investigations at the patient's residence led to the recovery of TR(46)/Y121F/T289A isolates, genotypically indistinguishable from the clinical isolate, supporting for the first time the direct role of household as potential source of azole-resistant invasive aspergillosis.
28597609 Transaminase Levels and Hepatic Events During Tocilizumab Treatment: Pooled Analysis of Lo 2017 Sep OBJECTIVE: To investigate liver enzyme abnormalities and hepatic adverse events (AEs) during long-term tocilizumab treatment for rheumatoid arthritis in clinical trials. METHODS: Data were pooled from patients who received intravenous tocilizumab (4, 8, or 10 mg/kg with or without disease-modifying antirheumatic drugs [DMARDs]) in phase III or IV clinical trials, long-term extensions, and a pharmacology study. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured routinely in these trials. AE rates were measured per 100 patient-years of tocilizumab exposure for this pooled analysis. RESULTS: Overall, 16,204.8 patient-years of tocilizumab exposure (mean ± SD duration of exposure 3.9 ± 2.0 years) were evaluated for 4,171 patients. ALT and AST elevations greater than the upper limit of normal (ULN) occurred in 70.6% and 59.4% of patients, respectively. ALT/AST elevations were >1-3× ULN in 59%/55% of patients, >3-5× ULN in 8.9%/3.3% of patients, and >5× ULN in 2.9%/0.9% of patients. Most elevations occurred during the first year of treatment. Single ALT/AST elevations >3× ULN occurred in 7.7%/3.6% of patients, and ≥2 consecutive elevations >3× ULN occurred in 1.9%/0.4% of patients. Elevations >3× ULN returned to normal in 80% of patients (median of 5.6 weeks to normalization). A total of 2.5% of patients withdrew from tocilizumab treatment following ALT/AST elevations. A total of 7 hepatic serious AEs (SAEs) (0.04 per 100 patient-years [95% confidence interval 0.02-0.09]) occurred in the tocilizumab studies. CONCLUSION: Transaminase elevations with tocilizumab were frequent, but rates of hepatic SAEs were low in this clinical trial data set. Regular monitoring, with dose adjustment of tocilizumab/DMARDs for persistent elevations, is recommended.
27977623 The contribution of autoantibodies to post-translationally modified proteins to inflammato 2017 Mar PURPOSE OF REVIEW: This article provides an overview of the recent findings present in the field of antimodified protein antibodies and their relevance for rheumatic disease, with a focus on rheumatoid arthritis. RECENT FINDINGS: Next to anticitrullinated protein antibodies, also other antimodified protein antibodies such as anticarbamylated protein antibodies or antiacetylated protein antibodies are emerging. Likewise, their possible pathological contributions are getting detailed attention. Their possible relation to disease, both from a clinical as well as biological perspective will be summarized. SUMMARY: Current evidence is pointing to the notion that especially a combination of antimodified protein antibodies associates best with clinical phenotype and outcome.
28779958 Efficacy of Indocyanine Green-Mediated Sonodynamic Therapy on Rheumatoid Arthritis Fibrobl 2017 Nov Sonodynamic therapy (SDT) has become a new therapeutic method because of its activation of certain sensitizers by ultrasound. Some studies have reported that indocyanine green (ICG) has the characteristics of a sonosensitizer and favorable fluorescence imaging in synovitis of early inflammatory arthritis. In this study, we aimed to investigate the cytotoxic effect of ICG-mediated SDT on MH7A cells in vitro and the potential mechanisms involved. ICG was found to be taken up mainly in cytoplasm, with maximal uptake in 4 h. Cell viability in ICG-mediated SDT (SDT-0.5 and SDT-1.0) groups decreased significantly to 73.09 ± 1.97% and 54.24 ± 4.66%, respectively; cell apoptosis increased significantly to 26.43 ± 0.91% and 45.93 ± 6.17%, respectively. Moreover, marked loss in mitochondrial membrane potential and greatly increased generation of reactive oxygen species were observed in ICG-mediated SDT groups. Interestingly, the loss in cell viability could be effectively rescued with pretreatment with the reactive oxygen species scavenger N-acetylcysteine. These results indicate that ICG-mediated SDT is cytotoxic to fibroblast-like synoviocytes and is a potential modality for targeted therapy of synovitis in rheumatoid arthritis.