64 research outputs found
JAK/STAT Activation: A General Mechanism for Bone Development, Homeostasis, and Regeneration
The Janus kinase (JAK) signal transducer and activator of transcription (STAT) signaling pathway serves as an important downstream mediator for a variety of cytokines, hormones, and growth factors. Emerging evidence suggests JAK/STAT signaling pathway plays an important role in bone development, metabolism, and healing. In this light, pro-inflammatory cytokines are now clearly implicated in these processes as they can perturb normal bone remodeling through their action on osteoclasts and osteoblasts at both intra- and extra-articular skeletal sites. Here, we summarize the role of JAK/STAT pathway on development, homeostasis, and regeneration based on skeletal phenotype of individual JAK and STAT gene knockout models and selective inhibition of components of the JAK/STAT signaling including influences of JAK inhibition in osteoclasts, osteoblasts, and osteocytes
Impact of Janus Kinase Inhibition with Tofacitinib on Fundamental Processes of Bone Healing
Both inflammatory diseases like rheumatoid arthritis (RA) and anti-inflammatory treatment of RA with glucocorticoids (GCs) or non-steroidal anti-inflammatory drugs (NSAIDs) negatively influence bone metabolism and fracture healing. Janus kinase (JAK) inhibition with tofacitinib has been demonstrated to act as a potent anti-inflammatory therapeutic agent in the treatment of RA, but its impact on the fundamental processes of bone regeneration is currently controversially discussed and at least in part elusive. Therefore, in this study, we aimed to examine the effects of tofacitinib on processes of bone healing focusing on recruitment of human mesenchymal stromal cells (hMSCs) into the inflammatory microenvironment of the fracture gap, chondrogenesis, osteogenesis and osteoclastogenesis. We performed our analyses under conditions of reduced oxygen availability in order to mimic the in vivo situation of the fracture gap most optimal. We demonstrate that tofacitinib dose-dependently promotes the recruitment of hMSCs under hypoxia but inhibits recruitment of hMSCs under normoxia. With regard to the chondrogenic differentiation of hMSCs, we demonstrate that tofacitinib does not inhibit survival at therapeutically relevant doses of 10-100 nM. Moreover, tofacitinib dose-dependently enhances osteogenic differentiation of hMSCs and reduces osteoclast differentiation and activity. We conclude from our data that tofacitinib may influence bone healing by promotion of hMSC recruitment into the hypoxic microenvironment of the fracture gap but does not interfere with the cartilaginous phase of the soft callus phase of fracture healing process. We assume that tofacitinib may promote bone formation and reduce bone resorption, which could in part explain the positive impact of tofacitinib on bone erosions in RA. Thus, we hypothesize that it will be unnecessary to stop this medication in case of fracture and suggest that positive effects on osteoporosis are likely
Fluorescence optical imaging for treatment monitoring in patients with early and active rheumatoid arthritis in a 1-year follow-up period
BACKGROUND:
Fluorescence optical imaging (FOI) enables visualization of inflammation in the hands in rheumatic joint diseases with currently a lack of long-term follow-up studies.
OBJECTIVE:
To investigate FOI for treatment monitoring in a homogenous cohort of patients with early (disease duration â3.2) RA over a period of 12âmonths.
METHODS:
Thirty-five RA patients (24 (68.6%) females, mean age 53.3âyears (SD 13.6)) were investigated clinically by DAS28, tender joint count (TJC) and swollen joint count (SJC) and by FOI in phases 1-3 and PrimaVistaMode (PVM) before therapy change and after 12âmonths. The FOI activity score (FOIAS) was calculated based on individual joint scores from 0 to 3 in 30 joints per patient, adding up to a sum score (0-90).
RESULTS:
We found a statistically significant reduction of FOIAS in phase 1 from baseline (median 5.0, IQR 24.96) to follow-up (median 1.0, IQR 4.0) in all patients (pâ=â0.0045), both in responders and non-responders according to EULAR response criteria by DAS28. Statistically significant reductions over 12âmonths were found for median DAS28(ESR) 5.61 to 3.31, TJC 7.0 to 1.0, and SJC 5.0 to 1.0 (each pâ<â 0.001). No statistically significant correlations were detected between the FOIAS change in phase 1 and DAS28(ESR), TJC, or SJC. Correlations between the other phases and clinical outcomes were weak to moderate.
CONCLUSION:
Reduced early enhancement in FOI phase 1 can be observed in clinically responding and non-responding early RA patients under treatment. Regarding potential marker performance, FOI probably shows a reduction of inflammation more objectively
a pilot study
Background Utilising fluorescence optical imaging (FOI), the distribution of
an intravenously applied colouring agent indocyanine green (ICG) can be
analysed with the potential to identify malperfusion by little to no tissue
enhancement. Systemic sclerosis (SSc) is characterised by the presence of
digital ulcers reflecting progressive vasculopathy. The objective was to
investigate the potential of FOI in the detection of disturbed
microcirculation in the hands and fingers of patients with SSc and to link FOI
findings to clinical signs of ischemia such as digital ulcers and pitting
scars. Methods In this cross-sectional study, 63 patients with SSc and 26
healthy subjects were examined. FOI was performed in all 89 individuals and
compared to clinical data and capillaroscopic findings assembled for the SSc
cohort. Results Healthy subjects showed initial ICG signals in their
fingertips in 93.6%, SSc patients in 78.5% (limited SSc) and 43.2% (diffuse
SSc). Moreover, in SSc patients, FOI findings were significantly associated
with a late capillaroscopic pattern, disseminated SSc features, a diffuse SSc
subtype, and the presence of digital ulcers or pitting scars. Intra- and
inter-reader reliability for FOI amounted to Îșâ=â0.786 and Îșâ=â0.834,
respectively. Conclusions FOI is able to detect areas of reduced
microcirculation in patients with SSc with high association to capillaroscopic
findings. The results pave the way for future FOI investigations into its role
in the prediction of complications due to an impaired acral perfusion
Reliability Exercise for the Polymyalgia Rheumatica Classification Criteria Study: The Oranjewoud Ultrasound Substudy
Objective. A study supported by the EULAR and the ACR being conducted to establish classification criteria for polymyalgia rheumatica (PMR) will include ultrasound examination of the shoulders and hips. Ultrasound (US) depicts glenohumeral joint effusion, biceps tenosynovitis, subdeltoid bursitis, hip joint synovitis, and trochanteric bursitis in PMR. These findings may aid in distinguishing PMR from other diseases. The purpose of this study was to assess standards and US interreader agreement of participants in the PMR classification criteria study.
Methods. Sixteen physicians in four groups examined shoulders and hips of 4 patients and 4 healthy adults with ultrasound. Overall agreement and interobserver agreement were calculated. Results. The overall agreement (OA) between groups was 87%. The OA for healthy shoulders was 88.8%, for healthy hips 100%, for shoulders with pathology 85.2%, and 74.3% for hips with pathology, respectively. Conclusion. There was a high degree of agreement found for the examination of healthy shoulders and pathologic hips. Agreement was moderate for pathologic shoulders and perfect for healthy hips. US of shoulder and hips performed by different examiners is a reliable and feasible tool for assessment of PMR related disease pathology and can be incorporated into a classification criteria study
Monitoring of patients with rheumatoid arthritis by indocyanine green (ICG)-enhanced fluorescence optical imaging treated with anti-TNFα therapy
Background: Fluorescence optical imaging (FOI) enables visualisation of inflammation in both hands in rheumatoid arthritis (RA).
Objective: To investigate the usefulness of FOI in treatment monitoring under anti-TNF alpha therapy with certolizumab pegol (CZP) in patients with RA in comparison to clinical and laboratory outcome parameters.
Methods: CZP-naive patients with RA were eligible for this open-label study with an observational period of 52 weeks. Disease activity was monitored by the clinical score DAS28, tender/swollen joint count (TJC-28/SJC-28) and laboratory outcomes for systemic inflammation (CRP and ESR). FOI results were analysed in three different phases (P1-3) and PrimaVistaMode (PVM) by the FOI activity score (FOIAS).
Results: Twenty-eight RA patients (median age 52.5 years, 26 females, thirteen with a history of other biologic therapy) were included. DAS28 (CRP) decreased from moderate disease activity at baseline (median 4.6, IQR 1.8) to low disease activity at week (w)52 (median 2.7, IQR 2.1; p < 0.001). Statistically significant decreases could also be demonstrated for SJC-28 and TJC-28. CRP/ESR were reduced numerically from baseline to w52. FOIAS in P1 (early phase) showed a continuous decrease of enhancement during the course of treatment period: from baseline (median 1.5, IQR 9.3) over w6 (median 1.0, IQR 3.0; p= 0.069), w12 (median 0.5, IQR 3.0; p = 0.171), w24 (n = 27 , median 0.0, IQR 3.0; p = 0.004), until w52 (n= 18, median 0.0, IQR 2.8; p = 0.091), which could not be presented for FOIAS in P2, P3 and PVM.
Conclusion: FOI in P1 appears to be a valuable tool for fast and easy monitoring of treatment response to certolizumab in a clinical setting
a comparative study with ultrasonography
Background Valid detection of arthritis is essential in differential diagnosis
of joint pain. Indocyanin green (ICG)-enhanced fluorescence optical imaging
(FOI) is a new imaging method that visualizes inflammation in wrist and finger
joints. Objectives of this study were to compare FOI with ultrasonography (US,
by gray-scale (GS) and power Doppler (PD)) and clinical examination (CE) and
to estimate the predictive power of FOI for discrimination between
inflammatory and non-inflammatory juvenile joint diseases. Methods FOI and
GSUS/PDUS were performed in both hands of 76 patients with joint pain (53 with
juvenile idiopathic arthritis (JIA), 23 with non-inflammatory joint diseases).
Inflammation was graded by a semiquantitative score (grades 0â3) for each
imaging method. Joints were defined clinically active if swollen or tender
with limited range of motion. Sensitivity and specificity of FOI in three
phases dependent on ICG enhancement (P1âP3) were analyzed with CE and
GSUS/PDUS as reference. Results For JIA patients, FOI had an overall
sensitivity of 67.3%/72.0% and a specificity of 65.0%/58.8% with GSUS/PDUS as
reference; specificity was highest in P3 (GSUS 94.3%/PDUS 91.7%). FOI was more
sensitive for detecting clinically active joints than GSUS/PDUS (75.2% vs
57.3%/32.5%). In patients with non-inflammatory joint diseases both FOI and US
showed positive (i.e., pathological) findings (25% and 14% of joints). The
predictive value for discrimination between inflammatory and non-inflammatory
joint diseases was 0.79 for FOI and 0.80/0.85 for GSUS/PDUS. Conclusions
Dependent on the phase evaluated, FOI had moderate to good agreement with CE
and US. Both imaging methods revealed limitations and should be interpreted
cautiously. FOI may provide an additional diagnostic method in pediatric
rheumatology. Trial registration Deutsches Register Klinischer Studien
DRKS00012572. Registered 31 July 2017
Four-dimensional computed tomography detects dynamic three-dimensional pathologies of the wrist in patients with calcium pyrophosphate deposition disease
ObjectivesCrystal deposits in ligaments of the wrist are typical findings in patients with calcium pyrophosphate deposition (CPPD) disease. CPPD crystals trigger inflammation and ultimately result in ligament tears with scapholunate (SL) advanced collapse (SLAC). This study aimed to investigate carpal instabilities in patients with CPPD using four-dimensional computed tomography (4D-CT) of the wrist.MethodsThis IRB-approved prospective feasibility study investigated patients with CPPD of the hand. All patients underwent a static 3D-CT and two dynamic 4D-CT in ulnar- and radial abduction and in supination and pronation movements to analyze instabilities of the SL region and of the distal radioulnar joint (DRUJ). Two independent readers scored the images for the presence of SL ligament and triangular fibrocartilage complex (TFCC) calcifications. Furthermore, the readers assessed the dynamic images for SL and DRUJ instabilities. Descriptive analyses were performed. Inter-rater reliability was assessed using Cohenâs kappa (Îș).ResultsNine patients were included. SL ligament calcifications and instabilities were found in all patients. Of these, dynamic SL instability was detected in 77.8% of the patients, while 22.2% had a SLAC wrist. TFCC calcifications were found in 87.5% of the patients. Four patients had DRUJ instability (50%). No patient showed DRUJ instability without the presence of TFCC calcifications. Agreement between readers for calcifications was excellent (Îșâ=â1) and almost perfect (Îșâ=â0.89) for instabilities.ConclusionThis study provides the first evidence of relevant dynamic carpal instability in CPPD patients using advanced imaging techniques with 4D-CT, offering unique insights into wrist biomechanics
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