Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease
14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis
OBJECTIVES/OBJECTIVE:Osteoarthritis (OA) is the most common joint disease; however, the indeterminate nature of mechanisms by which OA develops has restrained advancement of therapeutic targets. TNF signalling has been implicated in the pathogenesis of OA. TNFR1 primarily mediates inflammation, whereas emerging evidences demonstrate that TNFR2 plays an anti-inflammatory and protective role in several diseases and conditions. This study aims to decipher TNFR2 signalling in chondrocytes and OA. METHODS:Biochemical copurification and proteomics screen were performed to isolate the intracellular cofactors of TNFR2 complex. Bulk and single cell RNA-seq were employed to determine 14-3-3 epsilon (14-3-3Îµ) expression in human normal and OA cartilage. Transcription factor activity screen was used to isolate the transcription factors downstream of TNFR2/14-3-3Îµ. Various cell-based assays and genetically modified mice with naturally occurring and surgically induced OA were performed to examine the importance of this pathway in chondrocytes and OA. RESULTS:Signalling molecule 14-3-3Îµ was identified as an intracellular component of TNFR2 complexes in chondrocytes in response to progranulin (PGRN), a growth factor known to protect against OA primarily through activating TNFR2. 14-3-3Îµ was downregulated in OA and its deficiency deteriorated OA. 14-3-3Îµ was required for PGRN regulation of chondrocyte metabolism. In addition, both global and chondrocyte-specific deletion of 14-3-3Îµ largely abolished PGRN's therapeutic effects against OA. Furthermore, PGRN/TNFR2/14-3-3Îµ signalled through activating extracellular signal-regulated kinase (ERK)-dependent Elk-1 while suppressing nuclear factor kappa B (NF-ÎºB) in chondrocytes. CONCLUSIONS:This study identifies 14-3-3Îµ as an inducible component of TNFR2 receptor complex in response to PGRN in chondrocytes and presents a previously unrecognised TNFR2 pathway in the pathogenesis of OA.
Current Epidemiology and Risk Factors for the Development of Hand Osteoarthritis
PURPOSE OF REVIEW/OBJECTIVE:Hand osteoarthritis (hand OA), the most common peripheral arthritis in the world, is less studied than osteoarthritis (OA) of the knee and hip. However, it is uniquely situated to offer novel insight into OA as a disease process by removing weight-bearing as a confounder of systemic disease mechanisms. Here we review the epidemiology of hand OA and key risk factors for its development. RECENT FINDINGS/RESULTS:Mounting evidence points to obesity as an important risk factor for hand OA development, with new evidence implicating a role for leptin and serum fatty acids. Disease progression in hand OA and specifically the erosive OA subtype may be associated with diabetes. New evidence supports an association between cardiovascular disease progression and symptomatic hand OA. Alcohol use may be associated with increased synovitis and erosive hand OA. Differences in ethnical distributions of hand OA have become more apparent, with a lower prevalence in Black patients compared to White patients. Novel genetic insights implicating the WNT gene pathway and IL-1Î² have led to novel potential targets in hand OA pathogenesis. Hand OA is a heterogeneous disease with many modifiable and non-modifiable risk factors that can determine disease severity and shed light on disease pathogenesis.
Methotrexate Hampers Immunogenicity to BNT162b2 mRNA COVID-19 Vaccine in Immune-Mediated Inflammatory Disease
Objective/UNASSIGNED:To investigate the humoral and cellular immune response to mRNA COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment. Methods/UNASSIGNED:Established patients at NYU Langone Health with IMID (n=51) receiving the BNT162b2 mRNA vaccination were assessed at baseline and after second immunization. Healthy subjects served as controls (n=26). IgG antibody responses to the spike protein were analyzed for humoral response. Cellular immune response to SARS-CoV-2 was further analyzed using high-parameter spectral flow cytometry. A second independent, validation cohort of controls (n=182) and patients with IMID (n=31) from Erlangen, Germany were also analyzed for humoral immune response. Results/UNASSIGNED:Although healthy subjects (n=208) and IMID patients on biologic treatments (mostly on TNF blockers, n=37) demonstrate robust antibody responses (over 90%), those patients with IMID on background methotrexate (n=45) achieve an adequate response in only 62.2% of cases. Similarly, IMID patients do not demonstrate an increase in CD8+ T cell activation after vaccination. Conclusions/UNASSIGNED:In two independent cohorts of IMID patients, methotrexate, a widely used immunomodulator for the treatment of several IMIDs, adversely affected humoral and cellular immune response to COVID-19 mRNA vaccines. Although precise cut offs for immunogenicity that correlate with vaccine efficacy are yet to be established, our findings suggest that different strategies may need to be explored in patients with IMID taking methotrexate to increase the chances of immunization efficacy against SARS-CoV-2 as has been demonstrated for augmenting immunogenicity to other viral vaccines. KEY MESSAGES/UNASSIGNED:These results suggest that patients on methotrexate may need alternate vaccination strategies such as additional doses of vaccine, dose modification of methotrexate, or even a temporary discontinuation of this drug. Further studies will be required to explore the effect of these approaches on mRNA vaccine immunogenicity.
Periostin loss-of-function protects mice from post-traumatic and age-related osteoarthritis
BACKGROUND:Elevated levels of periostin (Postn) in the cartilage and bone are associated with osteoarthritis (OA). However, it remains unknown whether Postn loss-of-function can delay or prevent the development of OA. In this study, we sought toÂ better understand the role of Postn in OA development and assessed the functional impact of Postn deficiency on post-traumatic and age-related OA in mice. METHODS:(nÂ =â€‰3) and wt mice (nÂ =â€‰3) to discover genes and pathways altered by Postn knockout. RESULTS:mice, while those related to cell-cycle and DNA-repair were enriched in wt mice. CONCLUSIONS:Postn deficiency protects against DMM-induced post-traumatic and age-related spontaneous OA. RNA-seq findings warrant further investigations toÂ better understand the mechanistic role of Postn and its potential as a therapeutic target in OA.
A low cartilage formation and repair endotype predicts radiographic progression of symptomatic knee osteoarthritis
BACKGROUND:Osteoarthritis (OA) is a disease with multiple endotypes. A hallmark of OA is loss of cartilage; however, it is evident that the rate of cartilage loss differs among patients, which may partly be attributed to differential capacity for cartilage repair. We hypothesize that a low cartilage repair endotype exists and that such endotypes are more likely to progress radiographically. The aim of this study is to examine the associations of level of cartilage formation with OA severity and radiographic OA progression. We used the blood-based marker PRO-C2, reflecting type II collagen formation, to assess levels of cartilage formation. MATERIALS AND METHODS/METHODS:The type II collagen propeptide PRO-C2 was measured in the serum/plasma of knee OA subjects from New York University (NYU, nâ€‰=â€‰106) and a subcohort of the phase III oral salmon calcitonin (sCT) trial SMC021-2301 (SMC, nâ€‰=â€‰147). Risk of radiographic medial joint space narrowing (JSN) over 24Â months was compared between quartiles (very low, low, moderate, and high) of PRO-C2. Associations were adjusted for age, gender, BMI, race, baseline pain levels, and baseline joint space width. RESULTS:In both the NYU and SMC cohorts, subjects with low PRO-C2 levels had greater JSN compared with subjects with high PRO-C2. Mean difference in JSN between subjects with very low and high levels of PRO-C2 was 0.65Â mm (pâ€‰=â€‰0.002), corresponding to a 3.4 (1.4-8.6)-fold higher risk of progression. There was no significant effect of sCT treatment, compared with placebo, on JSN over 2Â years before stratification based on baseline PRO-C2. However, there were proportionately fewer progressors in the sCT arm of the very low/low PRO-C2 group compared with the moderate/high group (Chi squaredâ€‰=â€‰6.5, pâ€‰=â€‰0.011). CONCLUSION/CONCLUSIONS:Serum/plasma level of type II collagen formation, PRO-C2, may be an objective indicator of a low cartilage repair endotype, displaying radiographic progression and superior response to a proanabolic drug. LEVEL OF EVIDENCE/METHODS:Level III post hoc exploratory analysis of one longitudinal cohort and a sub-study from one phase III clinical trial.
Colchicine and clinical trials for hand osteoarthritis [Letter]
Critical appraisal of intra-articular glucocorticoid injections for symptomatic osteoarthritis of the knee [Review]
The Hand Osteoarthritis Registry of New York University: Impacts of Gender and Obesity [Meeting Abstract]
Background/Purpose: Hand osteoarthritis (HOA) data is often obtained from large knee OA cohorts. Targeted HOA cohorts in Europe have shed light on this disease, but the etiologies and pathophysiology remain less defined than other sites of OA. Some studies suggest a metabolic role of adiposity in OA (beyond mechanical load), as evidenced by prevalent HOA in obese patients, while other reports link hormonal status to HOA pain. Our dedicated cohort of HOA patients aims to study factors that contribute to its prevalence and severity.
Method(s): From 2016 to 2020, we enrolled patients with interphalangeal (IP) OA, regardless of 1 st carpometacarpal (CMC) involvement. Patients with rheumatoid arthritis, psoriatic arthritis or lupus were excluded. Demographic and relevant history data were collected. Participants completed adapted versions of the Michigan Hand Outcomes (MHQ) and QuickDASH Outcome questionnaires to assess pain, stiffness, and function. The semi-quantitative scores were aggregated and normalized to a 0-100 scale. Hand x-rays, if available, were scored in binary fashion for joint narrowing, osteophytes, and central erosions in all 20 joints (18 IPs, 2 1st CMCs). Blood and urine were banked for future assays.
Result(s): We screened 337 patients and found 170 to be eligible and willing to enroll. The present cohort is 80.0% Caucasian and 78.8% female with an average age of 66.3+/-9.5 years (range 42-90) and BMI of 26.2+/-5.0 kg/m 2 (range 16.4-42.1). Bilateral hand x-rays, available for 149 patients, involved 10.5+/-5.1 joints with OA on average, with 102 (68.4%) having concurrent IP and CMC OA. Radiographs revealed central erosive changes in >=1 joint in 36.5% of patients, with this subset also reporting a higher number of affected joints (12.5 vs. 9.1, p=< 0.001). Patients with BMI > 30 kg/m 2 had significantly more hand pain (p=0.022) and stiffness (p=0.047) by the adapted MHQ, and more disability (p=0.025) by the QuickDASH, compared to those with BMI < 25 despite similar ages and joint burden by x-ray (Table 1). Patients reporting OA in additional sites also reported more hand pain (p=0.018) and more disability (p=0.003), though this signal could be confounded by this subgroup's advanced age (67.7 vs. 62.3 years, p=0.01). Women reported significantly more pain (p=0.035), disability (p=0.004), and a higher average number of joints affected (p=0.02) than men with similar ages and BMI. A small subgroup of likely perimenopausal women (ages 48-54) reported more pain and disability than their older counterparts, despite a lower mean BMI and fewer hand joints affected by OA. (Figure. 1). Our analyses did not reveal any association between hand symptoms and tobacco use, comorbidities, or prior hand trauma.
Conclusion(s): We have established the only registry and biorepository in North America focused on hand OA, which could enhance progress made by existing cohorts. HOA pain and disability independently associated with adiposity, and was more severe in women. We postulate that hormonal influences during the perimenopausal state may increase HOA symptoms during those years. As we run assays on stored biospecimens, we anticipate the HONEY cohort will further our understanding of HOA etiologies and pathophysiology while facilitating future clinical trials
IL1RN Polymorphism Predicts Weight Loss, Inflammatory Biomarker Changes and Knee Osteoarthritis Pain Relief after Bariatric Surgery [Meeting Abstract]
Background/Purpose: Symptomatic knee osteoarthritis (SKOA) patients with obesity who undergo bariatric surgery experience knee pain relief, though the reduced mechanical load explains only part of the improvement. A reduction in inflammatory biomarkers from adipose tissue may also impact pain. We previously identified an IL1RN haplotype (TTG; rs419598, rs315952, and rs9005) that associates with OA severity and inflammatory markers. We aimed to determine whether TTG distinguishes patients who lose more weight and have more significant decreases in inflammation with greater knee OA pain relief.
Method(s): From 2013-2019 we enrolled patients >=30 years old with BMI >=30 kg/m 2 and painful knee OA who planned surgical (sleeve gastrectomy, gastric bypass, or laparoscopic band) or medical weight loss (MWL) at Bellevue Hospital or NYU Langone Health. Patients with lupus, rheumatoid arthritis, or psoriatic arthritis were excluded. Weight-bearing knee x-rays assessed OA severity to confirm a Kellgren-Lawrence grade of at least 1 (scale 0-4). Participants completed the Knee Injury and Osteoarthritis Outcomes (KOOS) questionnaire and provided blood at baseline and 1, 3, 6, and 12 months. Patients were genotyped to determine whether they carried 1 or 2 copies of the TTG haplotype (TTG-1/2) or none (TTG-0). Sleeve was the most common weight loss intervention, therefore our analysis is focused on this surgical subset to minimize variable effects on weight and biomarkers.
Result(s): We enrolled 113 patients (95 F, 18 M) with painful knee OA prior to their weight loss intervention. The mean age, BMI, and KOOS pain at baseline were 50.3 +/- 12.0 years, 44.8 +/- 8.9 kg/m 2, and 48.4 +/- 18.2 (0-100, with 100 = no pain). Of 113 patients, 48 underwent sleeve, 20 bypass, 9 laparoscopic banding, 12 did not have the surgery, and 24 pursued medical weight loss. The 77 who completed surgery had a mean % excess weight loss (%EWL) of 51.7 after 6 months, with significant decreases in hsCRP (4.4 mg/L) and leptin (32.8 ng/dL), and mean KOOS pain improvement of 22.4 (MCID= 16.7). The corresponding changes for patients who tried various MWL regimens were modest at best. We obtained the IL1RN haplotype for 45 of the 48 sleeve patients, and found 34 (70.8%) carried the TTG-1 or TTG 2 haplotype while 11 were TTG-0 (with similar baseline age, BMI, and KOOS for the two groups). At each follow-up time point through 6 months (Figure 1), TTG-1/2 patients had more difficulty losing weight than the TTG-0 group (p< 0.005 by ANOVA), with corresponding smaller reductions in hs CRP (p=0.36) and leptin (p=0.006). TTG-1/2 carriers also reported less KOOS pain relief relative to the TTG-0 group (p=0.021), markedly at 1 and 3 months with some improvement later (Table 1). All of these findings held true when only plotting data only from the 23 patients (18 TTG-1/2, 5 TTG-0) who completed each of the followup visits.
Conclusion(s): SKOA patients with obesity achieve marked excess weight loss, reductions in inflammatory mediators, and knee pain relief with bariatric surgery. The subset of patients with the TTG-0 IL1RN haplotype demonstrated more significant and/or rapid improvement in each of these outcomes, suggesting a potential predictor of which OA patients will have a more successful response to bariatric surgery