Heritability patterns in hand osteoarthritis: the role of osteophytes

Abstract Introduction The objective of the present study was to assess heritability of clinical and radiographic features of hand osteoarthritis (OA) in affected patients and their siblings. Methods A convenience sample of patients with clinical and radiographic hand OA and their siblings were evaluated by examination and radiography. Radiographs were scored for hand OA features by radiographic atlas. The heritability of hand OA phenotypes was assessed for clinical and radiographic measures based on anatomic locations and radiographic characteristics. Phenotypic data were transformed to reduce non-normality, if necessary. A variance components approach was used to calculate heritability. Results One hundred and thirty-six probands with hand OA and their sibling(s) were enrolled. By anatomic location, the highest heritability was seen with involvement of the first interphalangeal joint (h 2 = 0.63, P = 0.00004), the first carpometacarpal joint (h 2 = 0.38, P = 0.01), the distal interphalangeal joints (h 2 = 0.36, P = 0.02), and the proximal interphalangeal joints (h 2 = 0.30, P = 0.03) with osteophytes. The number and severity of joints with osteophyte involvement was heritable overall (h 2 = 0.38, P = 0.008 for number and h 2 = 0.35, P = 0.01 for severity) and for all interphalangeal joints (h 2 = 0.42, P = 0.004 and h 2 = 0.33, P = 0.02). The severity of carpometacarpal joint involvement was also heritable (h 2 = 0.53, P = 0.0006). Similar results were obtained when the analysis was limited to the Caucasian sample. Conclusions In a population with clinical and radiographic hand OA and their siblings, the presence of osteophytes was the most sensitive biomarker for hand OA heritability. Significant heritability was detected for anatomic phenotypes by joint location, severity of joint involvement with osteophytes as well as for overall number and degree of hand OA involvement. These findings are in agreement with the strong genetic predisposition for hand OA reported by others. The results support phenotyping based on severity of osteophytes and a joint-specific approach. More specific phenotypes may hold greater promise in the study of genetics in hand OA

Examining Treatment Decision-Making Among Patients With Axial Spondyloarthritis: Insights From a Conjoint Analysis Survey

OBJECTIVE: The number of therapies for axial spondyloarthritis (axSpA) is increasing. Thus, it has become more challenging for patients and physicians to navigate the risk-benefit profiles of the various treatment options. In this study, we used conjoint analysis-a form of trade-off analysis that elucidates how people make complex decisions by balancing competing factors-to examine patient decision-making surrounding medication options for axSpA. METHODS: We conducted an adaptive choice-based conjoint analysis survey for patients with axSpA to assess the relative importance of medication attributes (eg, chance of symptom improvement, risk of side effects, route of administration, etc) in their decision-making. We also performed logistic regression to explore whether patient demographics and disease characteristics predicted decision-making. RESULTS: Overall, 397 patients with axSpA completed the conjoint analysis survey. Patients prioritized medication efficacy (importance score 26.8%), cost (26.3%), and route of administration (13.9%) as most important in their decision-making. These were followed by risk of lymphoma (9.5%), dosing frequency (7.2%), risk of serious infection (6.0%), tolerability of side effects (5.3%), and clinic visit and laboratory test frequency (4.8%). In regression analyses, there were few significant associations between patients\u27 treatment preferences and sociodemographic and axSpA characteristics. CONCLUSIONS: Treatment decision-making in axSpA is highly individualized, and demographics and baseline disease characteristics are poor predictors of individual preferences. This calls for the development of online shared decision-making tools for patients and providers, with the goal of selecting a treatment that is consistent with patients\u27 preferences

Report from the Hand Osteoarthritis Working Group at OMERACT 2018: Update on Core Instrument Set Development

Objective: To evaluate hand osteoarthritis tools for core instrument set development. Methods: For OMERACT 2018, a systematic literature review and advances in instrument validation were presented. Results: Visual analog and numerical rating scales were considered valuable for pain and patient’s global assessment, despite heterogeneous phrasing and missing psychometric evidence for some aspects. The Modified Intermittent and Constant Osteoarthritis Pain scale was lacking evidence. The Michigan Hand Outcomes Questionnaire had advantages above other pain/function questionnaires. The Hand Mobility in Scleroderma scale was valid, although responsiveness was questioned. Potential joint activity instruments were evaluated. Conclusion: The development of the core instrument set is progressing, and a research agenda was also developed

2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153772/1/acr24131.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153772/2/acr24131_am.pd

Macrophage fumarate hydratase restrains mtRNA-mediated interferon production

Metabolic rewiring underlies the effector functions of macrophages1-3, but the mechanisms involved remain incompletely defined. Here, using unbiased metabolomics and stable isotope-assisted tracing, we show that an inflammatory aspartate-argininosuccinate shunt is induced following lipopolysaccharide stimulation. The shunt, supported by increased argininosuccinate synthase (ASS1) expression, also leads to increased cytosolic fumarate levels and fumarate-mediated protein succination. Pharmacological inhibition and genetic ablation of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) further increases intracellular fumarate levels. Mitochondrial respiration is also suppressed and mitochondrial membrane potential increased. RNA sequencing and proteomics analyses demonstrate that there are strong inflammatory effects resulting from FH inhibition. Notably, acute FH inhibition suppresses interleukin-10 expression, which leads to increased tumour necrosis factor secretion, an effect recapitulated by fumarate esters. Moreover, FH inhibition, but not fumarate esters, increases interferon-β production through mechanisms that are driven by mitochondrial RNA (mtRNA) release and activation of the RNA sensors TLR7, RIG-I and MDA5. This effect is recapitulated endogenously when FH is suppressed following prolonged lipopolysaccharide stimulation. Furthermore, cells from patients with systemic lupus erythematosus also exhibit FH suppression, which indicates a potential pathogenic role for this process in human disease. We therefore identify a protective role for FH in maintaining appropriate macrophage cytokine and interferon responses

Safety of procuring research tissue during a clinically indicated kidney biopsy from patients with lupus: data from the Accelerating Medicines Partnership RA/SLE Network

Objectives In lupus nephritis the pathological diagnosis from tissue retrieved during kidney biopsy drives treatment and management. Despite recent approval of new drugs, complete remission rates remain well under aspirational levels, necessitating identification of new therapeutic targets by greater dissection of the pathways to tissue inflammation and injury. This study assessed the safety of kidney biopsies in patients with SLE enrolled in the Accelerating Medicines Partnership, a consortium formed to molecularly deconstruct nephritis.Methods 475 patients with SLE across 15 clinical sites in the USA consented to obtain tissue for research purposes during a clinically indicated kidney biopsy. Adverse events (AEs) were documented for 30 days following the procedure and were determined to be related or unrelated by all site investigators. Serious AEs were defined according to the National Institutes of Health reporting guidelines.Results 34 patients (7.2%) experienced a procedure-related AE: 30 with haematoma, 2 with jets, 1 with pain and 1 with an arteriovenous fistula. Eighteen (3.8%) experienced a serious AE requiring hospitalisation; four patients (0.8%) required a blood transfusion related to the kidney biopsy. At one site where the number of cores retrieved during the biopsy was recorded, the mean was 3.4 for those who experienced a related AE (n=9) and 3.07 for those who did not experience any AE (n=140). All related AEs resolved.Conclusions Procurement of research tissue should be considered feasible, accompanied by a complication risk likely no greater than that incurred for standard clinical purposes. In the quest for targeted treatments personalised based on molecular findings, enhanced diagnostics beyond histology will likely be required

Heme Iron Coordination Structure of Heme Transport Protein HutB from Vibrio Cholerae

HutB is a putative heme transport protein located in the periplasmic space in Vibrio cholerae. Here, we purified HutB and characterized its heme binding properties. An analysis of the Soret band showed that there are two types of heme binding geometries depending on the heme concentration: 404-nm species are dominant at lower concentrations of heme, and 394-nm species dominate at higher concentrations. Moreover, a mutational study revealed that either Tyr65 or Tyr198 binds heme with the help of histidine, a property shared with another V. cholerae heme transport protein, HutX, despite the absence of sequence similarity, indicating that HutB acts as a heme transport protein in the periplasm