Joint Inflammation In Patients Research Articles

Ultrasound of the forefeet besides the hands in patients at risk for rheumatoid arthritis: is it worth the effort? A longitudinal cohort study.

Ultrasound (US) can detect subclinical joint-inflammation in patients with clinically suspect arthralgia (CSA), which is valuable as predictor for rheumatoid arthritis (RA) development. In most research protocols both hands and forefeet are scanned, but it is unclear if US of the forefeet has additional value for predicting RA, especially since synovial hypertrophy in MTP-joints of healthy individuals is also common. To explore the possibility to omit scanning of the forefeet we determined if US of the forefeet is of additional predictive value for RA-development in CSA patients. CSA patients of two independent cohorts underwent US of the hands and forefeet. We analyzed the association between RA-development and US-positivity for the full US-protocol, the full US-protocol with correction for Gray Scale(GS)-findings in the forefeet of healthy and the protocol without-forefeet. In total, 298 CSA patients were studied. In patients with a positive US, subclinical joint-inflammation was mostly present in the hands (90-86%). Only 10-14% of patients had subclinical joint-inflammation solely in the forefeet. US-positivity was associated with inflammatory arthritis development in both cohorts, with HRs 2.6(95%CI 0.9-7.5) and 3.1(95%CI 1.5-6.4) for the full protocol, 3.1(95%CI 1.3-7.7) and 2.7(95%CI 1.3-5.4) for the full US-protocol with correction, and 3.1(95%CI 1.4-6.9) and 2.8(95%CI 1.4-5.6) without the forefeet. AUROCs were equal across both cohorts. The forefeet can be omitted when US is used for the prediction of RA-development in CSA patients. This is due to the finding that subclinical joint-inflammation in the forefeet without concomitant inflammation in the hands is infrequent.

Subclinical joint inflammation in rheumatoid arthritis: comparing thermal and ultrasound imaging at the metacarpophalangeal joint

BackgroundWhile ultrasound and MRI are both superior to clinical examination in the detection of joint inflammation, there is presently a lack of data whether thermography may be similarly useful in the assessment of joint inflammation in patients with RA. Our study aims to evaluate the use of thermography in detecting subclinical joint inflammation at clinically quiescent (non-tender and non-swollen) metacarpophalangeal joints (MCPJs) in patients with rheumatoid arthritis (RA). The outcomes from thermography in our study will be compared with ultrasonography (which is a more established imaging tool used for joint inflammation assessment in RA).MethodsThe minimum (Tmin), average (Tavg) and maximum (Tmax) temperatures at the 10 MCPJs of each patient were summed to obtain the Total Tmin, Total Tavg and Total Tmax, respectively. Ultrasound grey-scale (GS) and power Doppler (PD) joint inflammation (scored semi-quantitatively, 0–3) at the 10 MCPJs were summed up to derive the respective TGS and TPD scores per patient. Pearson’s correlation and simple linear regression were respectively used to assess correlation and characterize relationships between thermographic parameters (Total Tmin, Total Tavg and Total Tmax) and ultrasound imaging parameters (TGS, TPD and the number of joint(s) with PD ≥ 1 or GS ≥ 2).ResultsIn this cross-sectional study, 420 clinically non-swollen and non-tender MCPJs from 42 RA patients were examined. All thermographic parameters (Total Tmin, Total Tavg and Total Tmax) correlated significantly (P-values ranging from 0.001 to 0.0012) with TGS score (correlation coefficient ranging from 0.421 to 0.430), TPD score (correlation coefficient ranging from 0.383 to 0.424), and the number of joint(s) with PD ≥ 1 or GS ≥ 2 (correlation coefficient ranging from 0.447 to 0.465). Similarly, simple linear regression demonstrated a statistically significant relationship (P-values ranging from 0.001 to 0.005) between all thermographic parameters (Total Tmin, Total Tavg and Total Tmax) and ultrasound imaging parameters (TPD and TGS).ConclusionFor the first time, thermographic temperatures were shown to correlate with ultrasound-detected joint inflammation at clinically quiescent MCPJs. The use of thermography in the detection of subclinical joint inflammation in RA appears promising and warrants further investigation.

Pain sensitisation and joint inflammation in patients with active rheumatoid arthritis

IntroductionDespite better therapies and strategies, many people with rheumatoid arthritis (RA) have persistent pain, often from abnormal pain processing, now termed nociplastic pain. However, RA patients with fibromyalgia (FM), a...

To treat or not to treat? Current attitudes on treatment aimed at modifying the disease burden in clinically suspect arthralgia: a survey among participants of the TREAT EARLIER trial and healthcare professionals

ObjectivesWhile awaiting therapies accomplishing rheumatoid arthritis (RA)-prevention in individuals at-risk, recent evidence supports that a 1-year methotrexate treatment may lead to sustained reduction in disease burden and subclinical joint inflammation...

Effect of Radiosynovectomy with Rhenium-188 in the Treatment of Knee Joint Inflammation in Patients with Hemophilia

Background: One of the effective methods to control chronic hemophilic synovitis is radiosynovectomy. Rhenium-188 is a new radionuclide, and its half-life is 0.7 day. This study aimed to investigate the effect of radiosynovectomy with Rhenium-188 on the knee joint of hemophilic patients.
 Methods: Thirty patients with hemophilic synovitis of the knee visited in the orthopedic clinic in 2019 and 2020, entered the study. They all had at least two bleeding per month; in the supine position with slight knee flexion, after local sterilization, 550 to 750 MBq Rhenium-188 was injected into the knee. A splint was installed for five days. The demographic characteristics, radiography, articular line tenderness, joint line tenderness, flexion and extension restrictions, and joint volume characteristics were evaluated before and six months after injection.
 Results: The amount of monthly injected factors (VIII and IX) 6 months after injection was decreased from 5260.2±1836 units to 3870.83±1106 units (p<0.001). The radiographic classification has not changed within six months. The average knee pain score decreased from 7.3±1.2 to 2.3±1.1, after six months (p<0.001), and knee flexion increased from 84.6±26.22 to 114±21.58 degrees (p<0.001). None of the patients have experienced complications such as skin necrosis or joint infection. All patients have reported that the pain increases 24 hr after the injection were manageable.
 Conclusion: The use of Rhenium-188 radiopharmaceutical in radiosynovectomy of 30 hemophilic patients’ knees is effective in reducing pain, tenderness of the joint line, and the number of bleeding episodes, and it improved knee range of motion in the short term (6 months).

Drivers of heterogeneity in synovial fibroblasts in rheumatoid arthritis

Inflammation of non-barrier immunologically quiescent tissues is associated with a massive influx of blood-borne innate and adaptive immune cells. Cues from the latter are likely to alter and expand activated states of the resident cells. However, local communications between immigrant and resident cell types in human inflammatory disease remain poorly understood. Here, we explored drivers of fibroblast-like synoviocyte (FLS) heterogeneity in inflamed joints of patients with rheumatoid arthritis using paired single-cell RNA and ATAC sequencing, multiplexed imaging and spatial transcriptomics along with in vitro modeling of cell-extrinsic factor signaling. These analyses suggest that local exposures to myeloid and T cell-derived cytokines, TNF, IFN-γ, IL-1β or lack thereof, drive four distinct FLS states some of which closely resemble fibroblast states in other disease-affected tissues including skin and colon. Our results highlight a role for concurrent, spatially distributed cytokine signaling within the inflamed synovium.

Ultrasound Hand and Wrist Findings in Children with Systemic Lupus Erythematosus.

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that can involve any organ system. SLE typically affects the musculoskeletal system to varying degrees, and patients are frequently most prone to have pain in the hand joints. The study aims to assess by ultrasound the presence of joint inflammation in patients with juvenile Systemic Lupus Erythematosus (JSLE) not complaining of painful joints of the hand and wrist (asymptomatic) and compare the findings with those in JSLE patients complaining of painful hand and wrist joints (symptomatic) and in healthy controls. This was a cross-sectional case control study on 37 JSLE patients. Thirty were asymptomatic for joint complaints. Ultrasound examined wrists and joints of both hands, 11 joints in each hand, to assess synovial hypertrophy, effusion and pathological vascularization (using power Doppler) (PD), and were given a score of 0-3. Patients were compared with 8 healthy controls. Ultrasound abnormalities (synovial hypertrophy and increased vascularity) were detected in 22/30 of the asymptomatic patients (73.3%) and in all 7 symptomatic patients (100%). In asymptomatic children, 29 joints were affected (4.4% of all joints), compared to 13 joints in the symptomatic patients (8.4% of all joints). Synovitis score was mild or moderate (1 or 2) in both symptomatic and asymptomatic patients, with all showing increased vascularity. In the control group, 5 joints (2.8% of all joints) showed synovial hypertrophy but no increased vascularity. Increased vascularity (PD more than 0) is a more reliable indicator of inflammation than synovial hypertrophy, which may be detected in healthy individuals.

Regulatory Fibroblast-Like Synoviocytes Cell Membrane Coated Nanoparticles:A Novel Targeted Therapy for Rheumatoid Arthritis.

Fibroblast-like synoviocytes (FLS) are the main cell component in the inflamed joints of patients with rheumatoid arthritis (RA). FLS intimately interact with infiltrating T cells. Fibroblasts have potent inhibitory effects on T cells, leading to the resolution of inflammation and immune tolerance. However, this "regulatory" phenotype is defect in RA, and FLS in RA instead act as "proinflammatory" phenotype mediating inflammation perpetuation. Signals that orchestrate fibroblast heterogeneity remain unclear. Here, it is demonstrated that different cytokines can induce distinct phenotypes of FLS. Interferon-gamma (IFN-γ) is pivotal in inducing the regulatory phenotype of FLS (which is termed FLSreg ) characterized by high expressions of several inhibitory molecules. Rapamycin enhances the effect of IFN-γ on FLS. Based on the characteristics of FLSreg , a novel biomimetic therapeutic strategy for RA is designed by coating cell membrane derived from FLSreg induced by IFN-γ and rapamycin on nanoparticles, which is called FIRN. FIRN show good efficacy, stability, and inflammatory joint targeting ability in an RA mouse model. The findings clarify how fibroblast phenotypes are modulated in the inflammatory microenvironment and provide insights into novel therapeutic designs for autoimmune diseases based on regulatory fibroblasts.

NRF2/Itaconate Axis Regulates Metabolism and Inflammatory Properties of T Cells in Children with JIA.

CD4+ T cells critically contribute to the initiation and perturbation of inflammation. When CD4+ T cells enter inflamed tissues, they adapt to hypoxia and oxidative stress conditions, and to a reduction in nutrients. We aimed to investigate how this distinct environment regulates T cell responses within the inflamed joints of patients with childhood rheumatism (JIA) by analyzing the behavior of NRF2-the key regulator of the anti-oxidative stress response-and its signaling pathways. Flow cytometry and quantitative RT-PCR were used to perform metabolic profiling of T cells and to measure the production of inflammatory cytokines. Loss of function analyses were carried out by means of siRNA transfection experiments. NRF2 activation was induced by treatment with 4-octyl-Itaconate (4-OI). Flow cytometry analyses revealed a high metabolic status in CD4+ T cells taken from synovial fluid (SF) with greater mitochondrial mass, and increased glucose and fatty acid uptake. This resulted in a heightened oxidative status of SF CD4+ T cells. Despite raised ROS levels, expression of NRF2 and its target gene NQO1 were lower in CD4+ T cells from SF than in those from blood. Indeed, NRF2 activation of CD4+ T cells downregulated oxidative stress markers, altered the metabolic phenotype and reduced secretion of IFN-γ. NRF2 could be a potential regulator in CD4+ T cells during chronic inflammation and could instigate a drift toward disease progression or regression, depending on the inflammatory environment.

Assessment of inflammation in patients with rheumatoid arthritis using thermography and machine learning: a fast and automated technique

ObjectivesSensitive detection of joint inflammation in rheumatoid arthritis (RA) is crucial to the success of the treat-to-target strategy. In this study, we characterise a novel machine learning-based computational method to...

Preclinical evaluation and pilot clinical study of [18F]AlF-NOTA-FAPI-04 for PET imaging of rheumatoid arthritis.

Fibroblast-like synoviocytes (FLSs) are key effector cells in the inflamed joints of patients with rheumatoid arthritis (RA). Previous studies have suggested that fibroblast activation protein (FAP) is highly expressed in RA-derived FLSs and is a specific marker of activated RA FLSs. In this study, we developed aluminum-[18F]-labeled 1,4,7-triazacyclononane-N,N',N″-triacetic acid-conjugated FAP inhibitor 04 ([18F]AlF-NOTA-FAPI-04) to image RA-FLSs in vitro and arthritic joints in collagen-induced arthritis (CIA) mice and RA patients. RA FLSs and NIH3T3 cells transfected with FAP were used to perform in vitro-binding studies. Biodistribution was conducted in normal DBA1 mice. Collagen-induced arthritis (CIA) models with different arthritis scores were subjected to [18F]AlF-NOTA-FAPI-04 and 18F-FDG PET imaging. Histological examinations were performed to evaluate FAP expression and Cy3 dye-labeled FAPI-04(Cy3-FAPI-04) uptake. Blocking studies with excess unlabeled FAPI-04 in CIA mice and NIH3T3 xenografts in immunocompromised mice were used to evaluate the binding specificity of [18F]AlF-NOTA-FAPI-04. Additionally, [18F]AlF-NOTA-FAPI-04 PET imaging was performed on two RA patients. The binding of [18F]AlF-NOTA-FAPI-04 increased significantly in RA FLSs and NIH3T3 cells overexpressing FAP compared to their parental controls (FAP-GFP-NIH3T3 vs. GFP-NIH3T3, 2.40 ± 0.078 vs. 0.297 ± 0.05% AD/105 cells; RA FLSs vs. OA FLSs, 1.54 ± 0.064 vs. 0.343 ± 0.056% AD/105 cells). Compared to 18F-FDG imaging, [18F]AlF-NOTA-FAPI-04 showed high uptake in inflamed joints in the early stage of arthritis, which was positively correlated with the arthritic scores (Pearson r=0.834, P<0.001). In addition, the binding of [18F]AlF-NOTA-FAPI-04 to cells with high FAP expression and the uptake of [18F]AlF-NOTA-FAPI-04 in arthritic joints both could be blocked by excessive unlabeled FAPI-04. Fluorescent staining showed that the intensity of Cy3-FAPI-04 binding to FAP increased accordingly as the expression of FAP protein increased in cells and tissue sections. Furthermore, the uptake of [18F]AlF-NOTA-FAPI-04 in FAP-GFP-NIH3T3 xenografts was significantly higher than that in GFP-NIH3T3 xenograft (35.44 ± 4.27 vs 7.92 ± 1.83% ID/mL). Finally, [18F]AlF-NOTA-FAPI-04 PET/CT imaging in RA patients revealed nonphysiologically high tracer uptake in the synovium of arthritic joints. [18F]AlF-NOTA-FAPI-04 is a promising radiotracer for imaging RA FLSs and could potentially complement the current noninvasive diagnostic parameters.

Effect of Baihu and Guizhi decoction in acute gouty arthritis: study protocol for a randomized controlled trial

BackgroundThe prevalence rates of gout worldwide have increased annually. Acute gouty arthritis (AGA) accounts for a large proportion of gout patients and causes severe physical and mental pain in patients. Controlling the occurrence and development of gout inflammation is the first step in the treatment of gout. The main treatment drugs in gout are non-steroid anti-inflammatory drugs (NSAIDs), colchicine, and glucocorticoids, but these treatments have many adverse reactions which limit their clinical application. Baihu and Guizhi decoction (BHGZ) is one of the classic prescriptions in the Synopsis of the Golden Chamber and is a good prescription for AGA. Previous clinical studies have shown that BHGZ confers a strong benefit for treating AGA. However, the literature shows a lack of high-quality RCT research on BHGZ with respect to AGA. Therefore, in this study, we use a randomized, double-blind, controlled study with a placebo to evaluate the clinical efficacy and safety of BHGZ on the AGA of moist heat arthralgia spasm syndrome.MethodsThis study is a randomized, double-blind, controlled clinical trial. A total of 102 adult participants with AGA of moist heat arthralgia spasm syndrome will be enrolled, with balanced treatment allocation (1:1). The experimental intervention will be BHGZ plus the low-dose colchicine, and the control intervention will be placebo plus the low-dose colchicine for 10 days. To study the clinical efficacy (including VAS score; joint tenderness, joint swelling, joint movement disorder; TCM evidence efficacy score) and the changes of inflammatory indexes. At the same time, the improvement of joint inflammation in patients with AGA will be observed from musculoskeletal ultrasound imaging, and the safety evaluation will be carried out.DiscussionThis study will be the first placebo-controlled RCT to assess whether BHGZ plus low-dose colchicine have beneficial effects on changing reducing inflammation of joints for patients with AGA of moist heat arthralgia spasm syndrome. The results of this trial will help to provide evidence-based recommendations for clinicians.Trial registrationChinese Clinical Trials Register ChiCTR1900024974. Registered on 5 August 2019

Synergistic effect of Bruton's tyrosine kinase and TNF-α in the regulation of rheumatoid arthritis and underlying mechanisms.

The presence of Bruton's tyrosine kinase (BTK) in macrophages has been recommended as a promising therapeutic target for rheumatoid arthritis (RA). In addition, activated macrophages in the inflamed joints of patients with RA can also produce a plethora of cytokines, such as TNF-α. The aim of the present study was to investigate the potential role of BTK and TNF-α in the regulation of RA. The results demonstrated that higher levels of BTK and TNF-α were observed in macrophages in inflamed RA joints compared with those in normal joint tissues. Subsequently, the role of BTK and TNF-α in the regulation of cellular process in inflammatory macrophages was analyzed. It was demonstrated that aberrant expression of BTK and TNF-α in inflammatory macrophages can lead to higher cell proliferation rates. Once the expression of BTK or TNF-α was restricted by using short interfering (si)RNAs (siBTK or siTNF-α), the activity of inflammatory macrophages was significantly downregulated. Of note, when the expression of BTK and TNF-α was simultaneously decreased, the proliferation rate of inflammatory macrophages was inhibited to the greatest extent. Subsequently, the underlying mechanisms through which BTK and TNF-α can regulate RA were investigated. The results demonstrated that BTK mainly regulated the ERK/JNK pathway, while TNF-α mainly affected the inactive rhomboid protein 2/B-cell-activating factor pathway. Finally, animal experiments demonstrated that simultaneous silencing of both BTK and TNF-α can significantly alleviate the symptoms associated with RA.

A Worthwhile Measurement of Early Vigilance and Therapeutic Monitor in Axial Spondyloarthritis: A Literature Review of Quantitative Sacroiliac Scintigraphy

Background: Back pain a common cause for hospital visits. Nuclear skeletal scintigraphy, at a high sensitivity, provides a functional imaging for detecting bone diseases. Sacroiliitis is an inflammation of the sacroiliac joint. Bone scan with quantitative sacroiliac scintigraphy (QSS) has been a useful inflammation indicator for sacroiliac joints. However, QSS has been ignored in the rehabilitation practice. Objective: To present the background, mechanisms, and current clinical applications of bone scan with QSS in spondyloarthropathy (SpA). Methods: The authors performed a literature review of QSS through database searching of MEDLINE, Embase, CINAHL, HaPI, Cochrane Review, and citation mining. Studies were included if they had QSS in the methodology performed in adult patients with various diseases. Any articles, including the authors’, that can be performed in a clinical setting were enrolled. Articles explicitly referencing QSS were retained for screening. Results: QSS appearance of SpA, including ankylosing spondylitis, may give rise to early detection. The specificity of sacroiliitis based on QSS increases from 73% to 97%. After investigating the relationship between serum C-reactive protein and sacroiliac joint inflammation in patients with SpA, there appeared to be a significant difference between serum C-reactive protein in serum and in sacroiliac ratio (particularly the middle part of the both joints), indicating a systemic inflammatory response to flair-up of SpA, for example, serum C-reactive protein as an indicator of inflammation. Sacroiliitis also occurs in post-streptococcal reactive arthritis. The involvement of sacroiliac joints in the development of post-streptococcal reactive arthritis had been demonstrated a significant correlation between anti-streptolysin O titres and QSS in patients with post-streptococcal reactive arthritis. Lower extremity periostitis acts as a human model in the study of bottom-up processing for periostitis-induced sacroiliac pain. The use of QSS can also monitor sacroiliac joint dysfunction before and after laser therapy. Improvements of the sacroiliac joint after convalescing of foot periostitis have been reported. Conclusions: Bone scan using QSS is a good screening measurement in scintigraphy rehabilitation for early detection of SpA and raises awareness of physicians toward the next step of diagnosis.

OP0300 USE OF THERMOGRAPHY OF HANDS AND MACHINE LEARNING TO QUANTIFY JOINT INFLAMMATION AND ESTIMATE DAS28, CDAI, SDAI IN PATIENTS WITH RHEUMATOID ARTHRITIS

Background:Disease activity scores such as DAS28, CDAI and SDAI are used in the follow-up of patients with rheumatoid arthritis (RA). These scores include variables obtained on physical examination such as the tender joint count (TJC) and the swollen joint count (SJC). In telematic consultations, it is not possible to determine these variables by physical joint assessment. Therefore, it is necessary to develop new tools that allow detecting joint inflammation in places close to the patient. Thermography is a safe and fast technique that measures heat through infrared imaging. Inflammation of the joints causes an increase in temperature and can therefore be detect by thermography. Machine learning methods are highly accurate in analyzing medical images automatically.Objectives:To develop an algorithm that, based on thermographic images of hands and machine learning, learn to quantify joint inflammation in patients with RA and estimate the DAS28, CDAI, SDAI by including the patient global health (PGH).Methods:Multicenter observational study conducted in the rheumatology and radiology service of two hospitals. Patients with RA, psoriatic arthritis (PA), undifferentiated arthritis (UA) and arthritis of hands secondary to other diseases (SA) that attended the follow-up visits were recruited. Companions of patients and healthcare professionals were also recruited as healthy subjects (HS). In all cases, a thermographic image of the hands was taken using a Flir One Pro or a Thermal Expert TE-Q1 camera connected to a smartphone. Ultrasound (US) of both hands was performed in patients with RA, PA, UA and SA. The degree of synovial hypertrophy (SH) and power doppler (PD) was assessed for each joint (score from 0 to 3). Machine learning was used to quantify joint inflammation (SH+PD) from the thermal images using US as ground truth. RA patients whose thermal image was taken with the Thermal Expert TE-Q1 camera were used to evaluate the performance (test dataset). The other participants were used as training dataset. The TJC, SJC, PGH, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were also assessed in the test dataset. A linear regression was used to estimate the DAS28, CDAI and SDAI with the resultant joint inflammation quantification from the thermal images and the PGH. Performance was evaluated by means of Pearson’s correlation coefficient. The study was approved by the Clinical Ethics and Research Committee of both centers.Results:The total number of recruited subjects was 521 (422 for the training and 99 for the testing dataset). In the training dataset, the thermography of 296 patients was taken with the Flir One Pro (163 RA, 17 PA, 22 UA, 12 SA and 82 HS) and 126 with the Thermal Expert TE-Q1 camera (6 RA without clinical data, 20 PA, 7 UA, 23 SA and 70 HS).We found higher correlations between joint inflammation variables (US and SJC) and thermography (0.48, p&lt;0.01 for US and 0.48, p&lt;0.01 for SJC) than between joint inflammation variables (US and SJC) and the PGH (0.29, p&lt;0.01 for US and 0.35, p&lt;0.01 for SJC). Thermography did not show statistically significant correlation with the PGH (0.14, p=0.164). The linear regression of thermography and the PGH showed strong correlation with the DAS28 (0.73, p&lt;0.01), CDAI (0.84, p&lt;0.01) and SDAI (0.82, p&lt;0.01).Conclusion:Thermography of hands and machine learning can effectively quantify joint inflammation and can be used in combination with the PGH to estimate disease activity scores. These results open an opportunity to develop tools that facilitate telematic consultations in patients with RA.

The Observational Study of Reduction in Inflammatory Markers and Simultaneous Reduction in Joint Inflammation in Patients of Rheumatoid Arthritis Treated by Leech Therapy

The sense of pain in arthritis carries the highest stigma among the sufferers as well as the treating physicians.It makes the life miserable for the patients along with the disability the disease rheumatoid arthritis causes,which can be correlated to Aamvata in Ayurveda.There are the conventional treatment options whichare available in the form of shodhana and shanmana. Besides NSAID.s and corticosteroids in modernmedicine rendering many side effects Ayurveda offers drugless healing art in the form of jaloukavacharanalso known as leech therapy which is known for the anti-inflammatory and analgesic, anesthetic actionsof leech salivary gland secretions. Hence, a protocol was designed for the doctoral research on “Study ofinflammatory markers in patients of Rheumatoid Arthritis treated by leech therapy”, for the assessment ofsubjective parameters of pain, swelling, redness, tenderness, loss of function of joints assessed by standardcriterion, and objective parameters like CRP and ESR before and after leech therapy for 10 sittings onalternate days. Observations were taken on day 0 and day 21, and follow up taken on day 30 and day 45.Statistical tests were applied which revealed significant results of anti-inflammatory effect of leech therapyon CRP(relative change 23.54%),with p value =0.0001,than ESR(relative change 10.30). Leech therapy wasfound to be having highly significant effect on pain score (relative change 57.62%), followed by tendernessscore(relative change 72%) and followed by significant increase in walking effect (relative change 56.67%).There was statistically significant improvement in other subjective parameters of assessment like swellingon ankle(relative change by 11.73).,knee joint(relative change 10.29),redness(relative change25%),walkingeffect(relative change 72%),rise in local temperature(relative change 61.90%) withp value,0.0001.with corelatable clinical improvement.

Selective Increment of Synovial Soluble TYRO3 Correlates with Disease Severity and Joint Inflammation in Patients with Rheumatoid Arthritis.

Objective To investigate the role of TAM receptors in rheumatoid arthritis (RA) by determining synovial tissue TAM receptor expression, synovial fluid levels of soluble TAM receptors, and the relationship between soluble TAM receptors, joint inflammation and disease activity. Methods TAM receptor expression was determined by immunohistochemistry on the synovium from RA and osteoarthritis (OA) patients. Soluble (s) Tyro3, sAxl, sMer, and their ligand Gas6 were measured by ELISA in the synovial fluid of RA (n = 28) and OA (n = 12) patients and cytokine levels by multiplex immunoassay in RA samples. Correlation analyses were performed among sTAM receptors with local cytokine levels; systemic disease parameters like erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), and anticyclic citrullinated peptide antibodies (ACPA); and disease activity scores (DAS28-ESR) in RA patients. Results TAM receptors were expressed on different locations in the synovial tissue (lining, sublining, and blood vessels), and a similar expression pattern was observed in RA and OA patients. Synovial fluid sTyro3 and sMer were significantly enhanced in RA compared to OA patients, whereas no significant differences in sAxl and Gas6 levels were found. In RA samples, sTyro3 levels, but not sMer, correlated positively with proinflammatory local cytokines and the systemic factor erythrocyte sedimentation rate. Moreover, stratification analysis showed high sTyro3 levels positively correlated with higher DAS28-ESR and in RF and ACPA double positive RA patients. Conclusion sTyro3 in the synovial fluid of RA patients correlates with local inflammatory molecules and systemic disease activity. These findings suggest that the reduced negative control of cell activation by TAM receptors due to their shedding in the synovial fluid, mainly sTyro3, favoring joint inflammation in RA patients.

Association of a Type 2-Polarized T Cell Phenotype With Methotrexate Nonresponse in Patients With Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease mediated through complex immunologic pathways. Among RA patients receiving low-dose methotrexate (MTX) monotherapy, approximately one-half exhibit a meaningful clinical response within the first 6 months of starting treatment. Whether baseline immune phenotypes differ between subsequent MTX responders and nonresponders is unknown. This study utilized comprehensive T cell immunophenotyping to identify specific immunologic pathways associated with MTX-nonresponsive joint inflammation in patients with RA. In total, 32 patients with recent-onset RA were treated with MTX therapy. After 6 months, 15 patients were categorized as responders and 17 as nonresponders. Comprehensive blood T cell immunophenotyping, using multiparameter immunofluorescence flow cytometry analyses, was performed at baseline and following 6 months of treatment. Baseline measures of disease activity (Disease Activity Score in 28 joints [DAS28], C-reactive protein level, and erythrocyte sedimentation rate) did not differ between MTX responders and nonresponders following MTX treatment. Frequencies of CD4+ and CD8+ T cells were skewed to favor higher CD4:CD8 T cell ratios in MTX responders compared to nonresponders (P < 0.05). The proportion of inducible costimulator-expressing Treg cells was significantly greater among MTX nonresponders. Interleukin-13 (IL-13)-producing, but not interferon-γ- or IL-17-producing, CD4+ effector memory T (Tem) cells were significantly more frequent in MTX nonresponders (P < 0.05). The ratio of IL-13+:IL-17+ Tem cells among CD4+ Tem cells was 1.9-fold higher in MTX nonresponders compared to responders (P < 0.05). Both the CD4:CD8 T cell ratio and the frequency of IL-13+CD4+ Tem cells correlated with changes in the DAS28 score following MTX treatment, whereas T cell expression of immune checkpoint inhibitor markers (CTLA-4, programmed death 1, and T cell immunoglobulin and mucin domain-containing protein 3) did not differ between MTX responders and nonresponders. We observed a bias toward type 2-polarized T cell inflammatory responses in the peripheral blood of MTX-nonresponsive RA patients. Targeting the IL-13+CD4+ T cell pathway could be a new therapeutic strategy in RA patients whose disease remains resistant to MTX.

Diagnostic Value of Optical Spectral Transmission in Rheumatoid Arthritis: Associations with Clinical Characteristics and Comparison with Joint Ultrasonography.

To examine the value of optical spectral transmission (OST) in detecting joint inflammation in patients with rheumatoid arthritis (RA) and to evaluate whether OST correlates with certain patient characteristics. OST measurements were performed in the metacarpophalangeal, proximal intraphalangeal, and wrist joints of 168 patients with RA and 114 controls. OST difference between the 2 groups was statistically examined and subsequently controlled for the effect of possible confounding factors. Diagnostic OST performance was tested by receiver-operating characteristics. Moreover, associations of OST with clinical and serological activity markers (patient group), joint ultrasound (US; patient subgroup) and various anthropometric and epidemiologic parameters (patient and control group) were evaluated by Spearman correlation coefficient and a generalized linear statistical adjustment model. OST was significantly higher in the RA group than in the control group, even after adjustment for confounding factors (1.89; 95% CI 0.709-3.070, padj = 0.002). Taking US as a reference, area under the curve for all 1251 joints simultaneously was 0.67 (95% CI 0.631-0.709). In the patient group, correlation and adjustment analyses showed associations of OST with various disease activity markers [28-joint count Disease Activity Score (rho 0.313), swollen joint counts (rho 0.361), C-reactive protein (rho 0.389); all, padj = 0.001], age (rho 0.276, p < 0.001), and osteoarthritis (p = 0.022). Moreover, OST associated with a power Doppler US score (rho 0.442; p = 0.001) and a greyscale US score (rho 0.591; p < 0.001). In both groups males had significantly higher OST values than females and OST associated moderately weakly with body mass index (rho patients 0.316, rho controls 0.24; all, p < 0.001). Patients with RA showed higher OST values in comparison to controls. Moreover, OST associated with clinical, US, and laboratory disease activity markers.

Interleukin-17 in rheumatoid arthritis: Trials and tribulations.

Interleukin-17A (IL-17A) is a pro-inflammatory cytokine with well-characterized biological effects on stromal cell activation, angiogenesis, and osteoclastogenesis. The presence of this cytokine in the inflamed joints of patients with rheumatoid arthritis (RA), together with compelling data from in vitro and experimental arthritis models demonstrating its pro-inflammatory effects, made this cytokine a strong candidate for therapeutic targeting. Clinical trials, however, have shown relatively modest success in RA as compared with other indications. Guided by recent insights in IL-17 biology, this review aims to explore possible reasons for the limited clinical efficacy of IL-17A blockade in RA, and what we can learn from these results going forward.