Osteoarthritis year in review 2019: biomarkers (biochemical markers)

Journal Pre-proof Osteoarthritis year in review 2019: biomarkers (biochemical markers) W.E. van Spil, PhD., M.D., I.A. Szilagyi, MSc. PII:

S1063-4584(19)31294-4

DOI:

https://doi.org/10.1016/j.joca.2019.11.007

Reference:

YJOCA 4565

To appear in:

Osteoarthritis and Cartilage

Received Date: 7 August 2019 Revised Date:

4 November 2019

Accepted Date: 11 November 2019

Please cite this article as: van Spil WE, Szilagyi IA, Osteoarthritis year in review 2019: biomarkers (biochemical markers), Osteoarthritis and Cartilage, https://doi.org/10.1016/j.joca.2019.11.007. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

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Osteoarthritis year in review 2019: biomarkers (biochemical markers)

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W.E. van Spil, PhD., M.D. 1*, I.A. Szilagyi, MSc.2

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1. University Medical Center Utrecht, Department of Rheumatology & Clinical Immunology, P.O. Box

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85500, 3508 GA, Utrecht, the Netherlands; tel. +31 88 75 50549; fax. +31 88 75 556 39; email

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[email protected].

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2. Department of General Practice, Erasmus University Medical Center, Rotterdam, the Netherlands;

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email [email protected].

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* Corresponding author.

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Running headline: year in review 2019: biochemical markers

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Word count: 3784.

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Abstract

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Objective: to provide an insightful summary of studies on biochemical markers for osteoarthritis (OA).

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Design: two investigators systematically searched the electronic PubMed database for clinical studies into

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soluble biochemical markers for OA in humans that were published between 01-03-2018 and 01-03-2019.

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Data from selected publications were systematically extracted and tabulated and were summarized in a

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narrative review.

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Results: Out of 1,279 publications, 124 fulfilled all selection criteria and were selected for data extraction.

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The majority were around knee OA, cross-sectional in design, relatively small, and/or focused on one or a

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few biochemical markers. Among the intervention studies, relatively many were on non-pharmacological

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interventions, used clinical outcomes and/or were rather short. Some leads that were provided by this

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year’s studies pertained to less conventional inflammatory mediators, oxidative stress, acidosis,

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angiogenesis and/or autoantibody formation.

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Conclusions: this year’s biochemical marker studies did provide potential leads for therapeutic targets or

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other biochemical marker applications that require robust and strategic follow-up research to be validated.

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Keywords (3-6): biomarkers, osteoarthritis, diagnosis, prognosis, trial, review.

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Introduction

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The huge and ever increasing burden of osteoarthritis (OA) is obvious (1). Yet, current diagnostic

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approaches have their limitations and conservative treatment options typically are modestly effective.

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Numerous efforts are undertaken to improve this situation, including attempts to identify and validate

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biochemical markers for the OA disease process. Biochemical markers could help diagnose OA at an

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earlier stage and distinguish between OA subgroups or phenotypes (i.e. be diagnostic), identify people at

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high risk of developing OA or people with OA that are anticipated to progress relatively rapidly (i.e. be

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predictive), monitor disease progression and response to interventions (i.e. reflect disease burden,

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intervention, safety), and/or understand the pathobiological mechanisms behind OA and identify

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therapeutic targets (2). As such, successful biochemical markers would have a range of possible

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applications and hold big potential for benefitting the OA field.

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Over the past years, challenges on the way to having successful biochemical markers have become

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obvious, a number of which were also discussed in previous year reviews in this series (3-6). First,

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biochemical markers might lack specificity to joint tissues and to particular joints. Second, assays might

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need improvement in sensitivity and specificity to the marker of interest. Third, the complexity of the OA

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pathobiology is not in line with the common approach of measuring one or a limited number of

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biochemical markers. Fourth, there is a need to integrate biochemical marker panels with intervention

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studies.

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In this year’s review we will summarize publications with original data on soluble biochemical markers

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for OA in human clinical studies. In doing so, we will follow-up on this year’s progress in the field and

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provide directions for future research.

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Method

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Titles and abstracts in the electronic PubMed database were searched for publications on clinical studies

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into soluble biochemical markers for OA in humans that were published between 01-03-2018 and 01-03-

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2019, using search terms relating to OA, biomarkers, blood, urine, and/or synovial fluid (SF) (see

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Appendix for search terms).

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The thus identified publications were then stepwise selected by two independent investigators. First,

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publications were required to be in English and present original work (i.e., no reviews, conference

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proceedings, etc.). Second, publications had to present data on humans with OA. Animal or in vitro

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studies were not selected for further review. Third, studies should present data on soluble biochemical

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markers in blood, urine and/or SF. The markers should relate to matrix metabolism, inflammation and/or

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other pathobiological processes within joints. Genetic markers, essential elements, vitamins, glucose and

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cholesterol were considered outside the scope of this review. Differences between the publications that

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were selected by the two investigators were discussed until consensus was reached.

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Data from the final selection of publications were extracted and tabulated. Studies were categorized as

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either observational-cross sectional, observational-longitudinal or intervention study. Some were also

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selected for more extensive discussion according to the insights of the two investigators.

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The selection process was performed using the Rayyan QCRI platform for systematic reviews, available

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at https://rayyan.qcri.org/ (7).

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Results

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PubMed search and selection of relevant publications

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The stepwise selection of potentially relevant publications is shown in Figure 1. 35 Studies were selected

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differently between investigators. All differences were resolved after discussing them.

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[ Suggested position Figure 1 ]

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Data extraction

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Extracted data are shown in Tables 1-3. The vast majority of studies were about the knee (N=89). Others

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were about knee and hip (N=6), hand (N=6), temporomandibular joint (TMJ) (N=4), knee and hand

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(N=2), hip (N=2), multiple joints/generalized (N=2), ankle (N=1) or lumbar spine (N=1). Eleven

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publications did not specify the OA joint(s). For six publications, only abstracts were available.

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Eighty-four publications were categorized as observational - cross-sectional, 10 as observational –

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longitudinal, 28 as intervention study, and one was categorized for both cross-sectional and longitudinal

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observational data from different cohorts. Many, but not all intervention studies were randomized clinical

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trials.

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[ Suggested position Tables 1-3 ]

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Newly studied immunoassays and markers

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New immunoassays for measuring type II collagen markers were presented. He et al. introduced an

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immunoassay to measure a cathepsin K-generated neoepitope of collagen type 10 (Col10neo) (8). The

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neoepitope appeared to be localized to the pericellular matrix of chondrocytes and its presence was

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extended and more prominent in superficial fibrillation in advanced cartilage degradation. Plasma

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Col10neo levels were higher in knee OA patients than in rheumatoid arthritis (RA) patients or healthy

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controls. Among knee OA patients, Col10neo levels tended to increase with every Kellgren & Lawrence

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(KL) grade, but not to a statistically significant extent. More people had KL grade 3 or 4 changes in their

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most painful knee within the highest tertile of Col10neo levels though. Luo et al. presented the PRO-C2

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immunoassay to assess the type IIB splice variant of the N-terminal propeptide of type II collagen

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(PIIBNP) (9). Serum levels of the type IIA and IIB splice variants were not correlated in OA, RA or

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healthy adult and pediatric samples. Furthermore, serum PIIBNP levels were higher in OA patients with

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KL grades 0 or 1 as compared to KL grades 2-4.

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Maly et al. studied TSP (thrombospondin-) 4 in serum of knee OA patients and controls (10). TSP4 binds

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collagen in articular cartilage and, as opposed to COMP (cartilage oligomeric matrix protein), is not

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expressed in the growth plate. The authors found that levels of total and pentameric TSP4 levels were not

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increased in OA, but specific fragments were.

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Specificity for particular joints

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Virtually all studies focused on one particular joint and those that did focus on multiple joints did not

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compare associations with biochemical markers between them. Kisand et al. did compare between the

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tibiofemoral and patellofemoral compartments (TFJ and PFJ, respectively) of the knee in 60 middle-aged

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people of whom some reported knee symptoms, while others did not (11). Among a spectrum of 60

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cytokines, chemokines and growth factors in plasma, associations with radiographic OA were different

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between compartments. Radiographic OA was associated with cholesterol-related PCSK9, anti-

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angiogenic IP-10 in the TFJ, but with cytokines of the MMP/TIMP (tissue inhibitor of metalloproteinase)

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system and angiogenesis in the PFJ and with BMI and leptin in both. As was to be expected for this

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middle-aged cohort, radiographic OA grades were relatively low and represented osteophytes more than

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joint space narrowing (JSN). Also, isolated OA in the PFJ and OA in the lateral TFJ were somewhat

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underrepresented. Validation of these findings in a larger cohort with a larger range of OA grades and

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predominantly affected joint compartments would, therefore, be of great value.

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Applications in intervention studies

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Biochemical markers were used to study the response to a wide range of interventions. The majority

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reported on relatively short follow-up periods, small cohorts, and/or clinical outcomes as opposed to

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imaging outcomes. None of the publications included data on the current major potential disease-

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modifying OA drugs, such as sprifermin (12) and lorecivivint (SM04690) (13).

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In some intervention studies, biochemical markers suggested treatment effects that were not in line with

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clinical and/or imaging outcomes. One might wonder whether this indicates that currently used clinical

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and imaging outcomes might not always suffice to show potential treatment effects. Alternatively, this

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might indicate that the pathobiological pathways under study were not clinically relevant or that other

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study characteristics, such as follow-up period or the study population, were suboptimal.

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The COLKOA trial failed to demonstrate efficacy of colchicine over placebo for reducing pain and

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synovitis and improving function at 16 weeks in 109 persons with symptomatic knee OA (14).

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Nevertheless, hsCRP (high-sensitivity C-reactive protein) in serum and CTXI (C-terminal cross-linked

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telopeptide of type I collagen) in SF were statistically significantly reduced in the colchicine arm only.

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Mean levels of IL (interleukin-) 6, IL8, TNFα (tumour necrosis factor α), CD (cluster of differentiation-)

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14 and IL18 in SF were reduced in the colchicine arm as well, but not statistically significantly as

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compared to baseline and the placebo arm. The decrease in hsCRP might confirm the anticipated anti-

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inflammatory effect of colchicine in knee OA patients. The interpretation of the decrease in CTXI in SF is

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not straightforward though; CTXI was not associated with the KL grade or with any of the other markers,

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while significant correlations did exist between IL6, IL8, TNFα, CD14 and IL18 in SF, cartilage loss

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and synovitis on MRI, and/or urinary CTXII (C-terminal cross-linked telopeptide of type II collagen).

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Kloppenburg et al. published on the lack of efficacy of the anti-IL1α/β dual variable domain

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immunoglobulin lutikizumab (ABT-981) on clinical and imaging outcomes in 132 people with erosive

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hand OA in a 26-week phase trial (15). Levels of IL1α, IL1β, hsCRP and C1M (type I collagen degraded

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by matrix metalloproteinase) in serum were reduced in the lutikizumab arm though. Moreover, C3M (type

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III collagen degraded by matrix metalloproteinase), CRPM (neoepitope of C-reactive protein, derived

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from protease degradation) and CTXI showed a tendency to improve more in the lutikizumab arm,

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although less robustly. Data on HA (hyaluronic acid), PIIANP (IIA splice variant of N-terminal

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propeptide of type II collagen) and CTXII did not suggest a treatment effect.

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Including biochemical markers in intervention studies can also help identify or confirm new therapeutic

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targets. Sun et al. studied PACAP (pituitary adenylate cyclase-activating polypeptide) levels in the SF

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and serum of knee OA patients and controls (16). PACAP levels in SF, but not in serum were increased in 9 of 28

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patients as compared to controls. Among patients, PACAP levels in SF were inversely associated with KL

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grade, self-reported pain and function, and SF levels of Il1β and MMP (matrix metalloproteinase-) 3.

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PACAP levels increased at 8 weeks after three intra-articular injections of hyaluronic acid.

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Wide spectrum biochemical marker measurements

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Some studies used metabolomics, proteomics or lipidomics approaches and/or non-traditional statistical

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analysis methods. These novel approaches sometimes provided results that would not have become clear

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from traditionally designed studies.

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Two studies assessed plasma metabolites in knee OA patients at the time of knee replacement from the

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Newfoundland Osteoarthritis Study and healthy controls from the Complex Diseases in the

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Newfoundland population: Environment and Genetics study. Hu et al. studied 153 cases and 236 controls

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and employed an evolutionary algorithm and network analysis to identify (combinations of) metabolites

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associated with the presence of OA (17). This way, out of 186 metabolites, arginine, C16, C18:1,

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isoleucine, nitrotyrosine, ornithine, taurine, threonine and tyrosine were found most frequently appearing

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in the best models. Moreover, they identified taurine, arginine, threonine and ornithine as key metabolites

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of the OA pathobiology in that they acted as hubs and bottlenecks in the network analysis. These findings

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confirm and extend on previous studies and the authors hypothesized that ornithine might relate to

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inflammation associated with oxidative stress and that nitrotyrosine is linked to oxidative damage and

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aging. Rockel et al. focused on lysophosphatidylcholine (lysoPC) and phosphatidylcholine (PC) in 152

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cases and 194 controls (18). They found a signature of 32 metabolites that individually had sufficient

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power to classify cases versus healthy participants. Moreover, they found that their models performed the

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best in males over age 50 (fair power), which might indicate differences in the OA pathobiology between

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sexes. Adding other markers to the dataset, e.g. amino acids or cytokines, might improve model

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performance.

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Another, pilot study determined 1233 metabolites in SF of 5 OA patients, 3 RA patients and 5 controls

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(joints, demographics and disease characteristics not specified) (19). Co-regulated metabolites that were

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upregulated in OA compared to healthy SF mapped to disease processes including chondroitin sulfate

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degradation, arginine and proline metabolism and nitric oxide metabolism. Receiver operating

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characteristic (ROC) analysis identified 35 metabolites as potential OA markers, with an area under the

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ROC curve >0.9. These included phosphatidylcholine, lysophosphatidylcholine, ceramides, myristate

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derivatives and carnitine derivatives.

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The relationship between obesity and OA was analyzed via an untargeted metabolomics approach (20) in

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14 obese and 14 non-obese knee OA patients (OKOA and NOKOA patients, respectively) and 15 controls

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without radiographic OA. According to metabolic pathway analyses, 32 different pathways for patients

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versus controls and 16 different pathways for OKOA versus NOKOA patients could be affected by the

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differences in metabolite levels. Glycerolipid, nitrogen, glycerophospholipid, glycine, serine and

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threonine metabolism, tryptophan metabolism, and fatty acid biosynthesis were the most affected

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pathways for both comparisons. Altogether, these results suggest that OA is characterized by

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inflammation, higher oxidative stress and acidosis, all the more in obese individuals.

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Tsuno et al. performed a proteomic analysis of serum-derived exosomes (21). It is the first report to

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compare protein profiles of serum exosomes among patients with OA (joint unspecified), patients with

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RA and healthy donors. They found that cathepsin F levels were increased, while Ig alpha-2 chain C

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region levels were decreased only in OA patients as compared to healthy controls. The exact involvement

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of cathepsins in the pathobiology of OA might, therefore, need further research.

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One study looked into serum profiles of lipid metabolism-related compounds and arterial stiffness in 70

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end-stage knee and hip OA patients and 82 age-matched controls (22). Acylcarnitine levels appeared to be

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decreased in the OA patients. Moreover, medium and long-chain acylcarnitines showed independent

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associations with radiographic OA severity and arterial stiffness. These findings indicate that

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acylcarnitines might be involved in the association between OA and cardiovascular disease. Another

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study followed a lipidomics approach to assess 22 omega-6 hydroxy or epoxy metabolites (oxylipins) in

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SF from 58 participants with knee OA and 44 controls (23). Prostaglandin D2, 11,12-

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dihydroxyeicosatrienoic acid (DHET) and 14,15-DHET levels were statistically significantly higher in

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OA versus controls. In a subset of people with unilateral knee OA for whom SF samples for both knees

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were available, 11,12- DHET and 14,15-DHET, but not prostaglandin D2 levels were higher in the

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affected knee. Synovial fluid levels of 11,12-, 14,15-, and 8,9-DHET, but not prostaglandin D2 were

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positively associated with radiographic knee OA progression over 3.3 years. NSAIDs appeared to

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decrease 16-HETE and 20-HETE levels. All analyses were adjusted for age, sex, BMI and use of

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NSAIDs.

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Subgroups, phenotypes

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Research into sex differences and the effects of hormones on OA was encouraged in a previous review in

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this series (5). In the aforementioned study of Kisand et al., they assessed 60 cytokines, chemokines and

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growth factors in plasma from 60 middle-aged people of whom 35 were female and 25 were male (11).

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They found that global radiographic knee OA was associated with multiple angiogenesis-related

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cytokines and leptin in women, but predominantly with cytokines of tissue-remodeling and injury in men 12 of 28

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and with CXCL10/IP-10 (C-X-C motif chemokine 10/interferon gamma-induced protein 10) in both

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sexes.

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A number of studies showed data on subgroups that might be of relevance for OA management. In a

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study by Azukizawa et al., 42 women with knee pain showed improved physical function when they

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participated in an exercise trial, with 12 weekly, supervised exercise sessions, follow-up by 12 weeks of

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home exercises (24). Serum PIICP (C-terminal propeptide of type II collagen) levels had increased at 8

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weeks, urinary CTXII levels decreased at 24 weeks, urinary C2C (cleavage product of type II collagen by

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collagenases) levels decreased at 12 weeks, and serum COMP levels increased at 24 weeks. Biochemical

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marker changes were also compared between pre-OA and OA groups based on radiographic findings (KL

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grade ≤1 vs. ≥2, respectively) and it appeared that the changes in PIICP and CTXII levels only occurred

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in the pre-OA subgroup and the change in COMP levels occurred in both. These data might suggest that

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exercise is particularly beneficial in early-stage, symptomatic OA, although it should be pointed out that

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the authors did not adjust for differences in age and baseline marker levels between subgroups.

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Karsdal et al. studied biomarker profiles in serum of 47 cases of type 2 rapidly progressive OA (RPOA)

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who had been treated with tanezumab and compared these to 69 controls without joint safety events (25).

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They distinguished between limited and chronic NSAID users and between time points of sample

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collection versus the RPOA event (baseline, ≤3 months prior, >3 months prior). It appeared that in limited

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NSAID users, the phenotype for type 2 RPOA was one of high cartilage degradation and synovial

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inflammation (C2M and C3M) in the upper range of what is observed in non-OA subjects. The predictive

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biomarkers changed over time to biomarkers of bone metabolism (N-terminal propeptide of type I

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collagen/PINP, CTXI, osteocalcin). In chronic NSAID users, low levels of bone signaling and connective

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tissue turnover (sclerostin, MMP9) were associated with increased odds of RPOA, which changed over 13 of 28

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time to markers of bone and connective tissue degradation (cross-linked telopeptide of type I

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collagen/ICTP, CTXI).

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One interesting pilot study found evidence for IgG isotype autoantibodies against TSP4, COMP and

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CLEC3A (C-type lectin domain family 3 member A) in OA (joint unspecified) (26). The serum of 9/10

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OA patients but only 1/10 healthy donors exhibited IgG isotype antibodies against TSP4, COMP and/or

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CLEC3A. The authors suggested that these data represent a OA subgroup that might benefit from

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immunosuppressive treatment.

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Favero et al. compared fetuin-A levels in SF of symptomatic knee OA patients with either no calcium

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crystals, calcium pyrophosphate crystals or basic calcium phosphate crystals in the SF (27). It appeared

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that fetuin-A levels were higher in both groups with crystals as compared to the group without. The

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authors hypothesized that the observed crystals may have developed because fetuin-A is less able to form

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complexes in OA.

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A number of studies compared between OA subgroups with and without particular comorbidities, such as

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metabolic syndrome, type 2 diabetes mellitus (DM2), and hyperuricemia. Dong et al. found that leptin

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levels were higher and adiponectin levels were lower in plasma and SF from female knee OA patients

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with metabolic syndrome as compared to those without, independent of BMI (28). Arellano Perez Vertti

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et al. showed an association between DM2 and knee OA, also persisting after covariate adjustments, and

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found higher COMP levels in SF from people with both knee OA and DM2 as compared to those with

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either knee OA or DM2 alone (29). Surprisingly, BMI was not different between people with and without

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knee OA. Glycemic control was less in people with both DM2 and knee OA as compared to those with

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DM2 only. Likewise, Luo et al. (30) found that the MMP1, -7, -8, -9, -10 and -12 levels in SF and MMP1 14 of 28

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and -7 levels in serum were higher in people with both DM2 and knee OA as compared to those with knee

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OA alone and healthy controls. People with only DM2 were not included. Data on the association

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between uric acid and OA progression have been conflicting so far (5). Kim et al. this time studied the

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association between serum uric acid levels and OA (joint unspecified) in 5842 subjects from the

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KNHANES VII-1 2016 cohort study. They observed lower uric acid levels in people with OA among the

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cohort as a whole, but higher levels in women with OA versus women without OA and similar levels in

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men with OA versus men without OA. All differences disappeared after adjusting for covariates (31).

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As was indicated in a previous year review, there is evidence that sleep disturbance in people with OA is

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related to pain and depression (3). Heffner et al. assessed serum levels of IL6 and TNFα at rest and at 5

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time points over 90 minutes upon pain in response to electrical stimulation to the ankle in 16 knee OA

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patients before and after cognitive-behavioral therapy for insomnia and compared these to 14 patients

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without treatment (32). After 8 weeks, insomnia scores were lower in people that received treatment as

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compared to those who did not. In the group as a whole, insomnia had improved for 12 and had not for

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the 18 others. IL6 levels were lower at rest and during the first 40 minutes upon pain stimulation in

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insomnia improvers as compared to non-improvers. Serum TNFα levels decreased in response to pain in

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the insomnia improvers, but remained stable in non-improvers. Overall IL6 and TNFα levels over the 90-

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minute period were not statistically significantly different between improvers and non-improvers.

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No studies employed biochemical marker data with the goal of selecting one or more particular patient

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subsets to participate.

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Discussion

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This year’s review was again able to show that potential biochemical markers for OA are still considered

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of interest by the scientific community, as a considerable number of studies on them have been published

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over the last year. They helped gain better understanding of the pathobiological mechanisms involved in

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the OA process and how interventions might be able to interfere with these. Data from the reviewed

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studies more or less consistently suggest roles for somewhat less conventional inflammatory mediators,

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oxidative stress, acidic media, angiogenesis and/or autoantibody formation (also see Figure 2).

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[ Suggested position Figure 2 ]

320 321

Strategic and robust follow-up research is needed to validate findings from these studies, that were now

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often set up as pilots. Future cohort studies with this purpose had best specify the joints of interest, take

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into account potential confounders, have larger sample sizes, perform standardized sample collection,

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provide data on individual structural OA features as opposed to global scores, and (also) include data on

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earlier OA stages as opposed to end-stage OA at the time of joint replacement. When validated, these

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findings in cohort studies might be an appropriate motive for more fundamental research into the

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molecular mechanisms behind them and ways to intervene with these.

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The Foundation for the National Institutes of Health Biomarkers Consortium aims to facilitate drug

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development with biomarkers in OA and other diseases (33). Over the last year, biochemical markers

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were used as secondary or exploratory outcomes in intervention studies. A considerable number of these

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were relatively small and short studies into untargeted, non-pharmacological interventions, such as

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balneotherapy and spa therapy. Biochemical marker data from the recent and current phase II and III trials

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of potential disease-modifying agents were not available though. Biochemical marker data on the effects

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of these agents might help to learn even more about the working mechanisms of the agents and, vice

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versa, about the biochemical markers themselves.

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Biochemical markers were relatively infrequently used to investigate the existence of OA subgroups,

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heterogeneity or phenotypes. This may come from limitations of the available datasets, with respect to

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sample size, number of markers and lack of data on other potentially relevant OA characteristics. To

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make any subgrouping primarily based on biochemical markers useful, it should be combined with (other)

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clinical and structural outcomes to show its impact on patients and maybe treatment. One relevant

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initiative in this field is the ongoing public-private IMI-APPROACH consortium. It aims to identify and

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validate different phenotypes of progressive knee OA in a longitudinal cohort using existing and newly-

345

developed biomarkers (34).

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Concluding, this year has provided us with many new data on biochemical markers for OA and their

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implications. A strategic continuation of these lines in well-designed studies is now needed to make the

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field actually move forward.

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Acknowledgements

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None.

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Contributions

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Both authors contributed to acquisition, analysis and interpretation of data and to drafting and revising the

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manuscript. They both provided final approval of the version to be submitted.

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Role of the funding source

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The funding source did not have any influence on study design, collection, analysis and interpretation of

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data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.

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Competing interests

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W.E. van Spil received funding from Osteoarthritis Research Society International (OARSI) for travel

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and accommodation to attend the OARSI 2019 world conference. He also received funding from The

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Innovative Medicines Initiative Joint Undertaking under grant agreement No. 115770, resources of which

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are composed of financial contribution from the European Union’s Seventh Framework programme

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(FP7/2007-2013) and EFPIA (European Federation of Pharmaceutical Industries and Associations)

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companies’ in-kind contribution. I.A. Szilagyi has no competing interests to declare.

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Appendix

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Search term that was used for selecting potentially relevant publications in PubMed:

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("osteoarthritis"[MeSH Terms] OR "osteoarthritis" [TIAB] OR "arthrosis"[TIAB]) AND ("blood"[TIAB]

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OR "serum"[TIAB] OR "plasma"[TIAB] OR "urine"[TIAB] OR "urinary"[TIAB] OR “synovial

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fluid”[TIAB] OR “SF”[TIAB] OR biomarker*[TIAB] OR marker*[TIAB])

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References

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468

Cartilage. 2018;26:S272-S3.

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469

Table and figure legends

470

Figure 1 Flow diagram of the stepwise selection process of relevant publications.

471

Figure 2 Overview of biochemical marker areas. All areas probably are interrelated and overlapping. For

472

details on the individual markers, please see the tables and main text. Abbrevations: AGNx1 =

473

ADAMTS-degraded aggrecan; ANG = angiopoietin; C3M = collagen type III degraded by matrix

474

metalloproteinase; CLEC3A = C-type lectin domain family 3 member A; Coll2-1NO2 = nitrated epitope

475

of the α-helical region of type II collagen; COL3-ADAMTS (collagen type III cleavage product derived

476

from ADAMTS; COMP = cartilage oligomeric matrix protein; CTXII = C-terminal cross-linked

477

telopeptide of collagen type II; CXCL10 = C-X-C motif chemokine 10; FGF = fibroblast growth factor;

478

HGF = hepatic growth factor, hsCRP = high sensitivity C-reactive protein; IL = interleukin; IFN =

479

interferon; MCP = monocyte chemoattractant protein; PDGF = platelet-derived growth factor; PIIANP,

480

PIIBNP = N-terminal propeptide of type II collagen, splice variants IIA and IIB, respectively; TNF =

481

tumour necrosis factor; TSP = thrombospondin.

482

Table 1 Extracted data from observational, cross-sectional studies.

483

Table 2 Extracted data from observational, longitudinal studies.

484

Table 3 Extracted data from intervention studies.

485

Tables 1-3 Common abbreviations: ACL = anterior cruciate ligament; ACR = American College of

486

Rheumatology criteria; AUC = area under the curve; C1M, C2M, C3M = collagen degraded by matrix

487

metalloproteinase, type I, II and III, respectively; CD = cluster of differentiation; COMP = cartilage

488

oligomeric matrix protein; (hs)CRP = (high sensitivity) C-reactive protein; CRPM = neoepitope of C-

489

reactive protein, derived from protease degradation; CS846 = chondroitin sulphate 846; CTXI, CTXII =

490

C-terminal cross-linked telopeptide of collagen, type I and II, respectively; FA = fatty acids; HA =

491

hyaluronic acid; IFN = interferon; IL = interleukin; JSN= radiographic joint space narrowing; JSW =

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492

radiographic joint space width; KOOS = Knee injury and osteoarthritis outcome Score; KL = Kellgren &

493

Lawrence grade; MMP = matrix metalloproteinase; MOAKS = MRI osteoarthritis knee score; NTXI = N-

494

terminal cross-linked telopeptide of type I collagen; PIINP, PIIANP, PIIBNP = N-terminal propeptide of

495

type II collagen, and splice variants IIA and IIB, respectively; PIICP = C-terminal propeptide of type II

496

collagen; PRP = platelet-rich plasma; ROA = radiographic osteoarthritis; SF = synovial fluid; TGF =

497

transforming growth factor; TNF = tumour necrosis factor; VAS = visual analogue score; WOMAC =

498

Western Ontario and McMaster Universities osteoarthritis index; YKL-40 = 40 kDa heparin- and chitin-

499

binding glycoprotein. Less common abbreviations are explained in the table.

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Author Anderson

Year Joint 2018 knee

Source SF

Marker 50 metabolites (amino acids, saccharides, nucleotides and soluble lipids)

Subjects 10 OA, 14 RA

OA parameter(s)

Arellano Perez Vertti Atar

2019 knee

SF

COMP

2018 knee, hand

serum

Bai Barker

2019 knee 2019 knee

serum serum

Bay-Jensen

2018 knee

serum

Brown

2018 knee

SF

periostin

9 OA, 9 RA

No difference between OA vs. RA

Carlson

2018 unspecified

SF

1233 metabolites

5 OA, 3 RA vs. 5 controls

Distinct metabolomic profiles and clusters of co-regulated metabolites. For OA, co-regulated metabolites that were upregulated compared to healthy included chondroitin sulfate degradation, arginine and proline metabolism, and nitric oxide metabolism.

Chandran

2019 knee and hip serum

COMP, hyaluronan, adiponectin, 201 OA, 77 PsA vs. 76 controls adipsin, resistin, hepatocyte growth factor (HGF), insulin, leptin, CRP, IL1β, IL6, IL8, TNFα, monocyte chemoattractant protein-1 (MCP1), nerve growth factor (NGF)

Pairwise comparisons: resistin lower, HGF lower, IL6 higher, IL8 lower, IL1β higher, insulin lower, leptin higher, MCP1 lower, NGF higher, hyaluronan higher in OA vs. controls. Resistin lower, HGF lower, CRP lower, IL6 lower, Il8 lower, insulin lower, leptin higher, MCP1 lower, NGF higher, TNFα lower, COMP lower, hyaluronan higher in OA vs. PsA.

Chen

2018 knee

serum

25 amino acids and 4 biogenic amines, CRP

CRP, leucine, arginine, valine, isoleucine, tryptophan, alanine,lysine, Alanine, γ-aminobutyric acid and 4-hydroxy-L-proline were creatine, tyrosine and 4-hydroxy-L-proline higher in OA vs. controls. considered important markers, based on VIP value. Validated Glutamine, phenylalanine, serine,proline,γ-aminobutyric acid, creatinine, in other 30 OA patients and 30 controls. dimethylglycine,taurine, asparagine, aminobutyric acid, acetyl-carnitine and citrulline lower in OA vs. controls.

Chiba

2018 knee

serum

MMP3

Clair

2019 knee

SF

Conway

2018 unspecified

plasma

Deveza

2018 knee

serum

Dong

2018 knee

plasma, SF adipokines and leptin receptor

Dou

2019 knee

serum

92 DM (diabetes mellitus)-OA, 29 OA, 110 control endothelin-1 89 OA, 50 controls cartilage thickness, VAS, WOMAC, Duruöz hand index IL17 595 OA, 576 controls cytokine spectrum 29 OA pain, reported physical function, muscle strength COL3-ADAMTS (collagen type 261 OA pain (VAS, WOMAC and III cleavage product derived Lequesne), KL from ADAMTS), C3M, AGNx1 (ADAMTS-degraded aggrecan)

32 OA vs. 35 controls

1278 volunteers of whom 389 KOOS pain, KL KL2 or higher and 28 chondrocalcinosis (CC) 10 cytokines, chemokines, 41 knees with meniscal injury growth factors vs. 41 contralateral knees without sGPVI (glycoprotein VI) 23 OA, 53 controls, 27 gout flare, 41 intercritical gout MMP3, HA, Coll2-1NO2 600 participants from OAI (also KL, WOMAC, MOAKS (nitrated epitope of the α-helical included in the FNIH Hoffa and effusion synovitis region of type II collagen) biomarkers Consortium)

COMP, MMP3, CRP, Coll2-1 (epitope of the α-helical region of type II collagen)

43 OA with metabolic syndrome (MetS), 37 OA without MetS ? OA, ? controls

VAS, JSN

Association(s) Metabolites of glycolysis and the TCA cycle and taurine increaed in OA compared to RA. Metabolic pathways that differ: glycolysis, aminoacid biosynthesis and taurine and hypotaurine metabolism.

Remark(s)

SF COMP increased in DM-OA vs. OA and in DM-OA vs. DM-control. Endothelin-1 increased in OA vs. controls. No correlations with cartilage thickness or questionnaires IL17 increased in OA vs. controls. IL1β, IL4, IL5, IL12, IL13, IFNγ correlated with pain and physical function. No correlations with muscle strength. COL3-ADAMTS: inverse association with pain scores. COL3-ADAMTS, Association AGNx1 with symptomatic vs. asymptomatic C3M inversely associated and AGNx1 positively associated with RKOA only after adjusting for age. symptomatic RKOA vs asymptomatic RKOA.

Increased subintimal staining in synovial biopsies in RA, not in OA.

COMP, resistin, MCP-1 and NGF were independently associated with PsA vs. OA.

MMPs higher with CC and higher KL grade, no association with KOOS pain IL6, MCP1, MIP1β, MMP3 higher in injured knee. MCP1, MIP1β, VEGF higher with high grade vs. low grade cartilage lesions. TIMP1 lower, MMP3-TIMP1 ratio higher with synovitis. sGPVI similar between OA and controls. sGPVI higher in gout flare vs. OA. HA and MMP3 positive association with effusion-synovitis at baseline.

Leptin increased and adiponectin decreased in OA with MetS vs. OA without MetS, independent of BMI.

All female.

COMP increased in OA vs. controls. COMP positive correlation with VAS and JSN. The combination of miR-338-3p, COMP, and CS-846 demonstrated higher diagnostic value.

Abstract only.

Elshabrawy

2018 knee, hip

plasma, SF IL11

40 OA SF, 35 OA plasma, 40 RA SF, 40 RA plasma, 35 control plasma

SF IL11 increased in RA vs. OA, SF IL11 similar in OA vs. control, plasma IL11 similar in RA, OA and controls

Author Fadda

Year Joint 2018 knee

Source SF, serum

Marker pleiotrophin

Subjects 40 OA, 35 RA, 20 controls

OA parameter(s) Association(s) disease duration, WOMAC, SF similar in OA vs. OA. Serum similar between RA, OA and controls. KL No associations of serum and SF levels with OA parameters.

Favero

2019 knee

SF

fetuin-A, IL6, IL8

8 OA with CCP, 8 OA with BCP, 8 OA without crystals

KL

Fioravanti

2018 hand

serum

resistin, visfatin, adiponectin

47 erosive OA (EHOA), 47 nonerosive OA (NEHOA), 21 controls

Fioravanti

2018 hand

serum

CRP, MPO (myeloperoxidase)

80 EHOA, 55 NEHOA, 25 controls

Franz

2018 knee

SF, serum

Galicia

2018 knee

plasma

24 OA, 11 meniscopathy, 34 ACL rupture 105 OA, 35 controls

Georgiev

2018 knee

serum

8-isoprostane F2α, 3nitrotyrosine lubricin, IL2, IL4, IL6, IL8, IL10, VEGF, IFNγ, IL1α, IL1β, MCP1, EGF (epidermal growth factor), TNFα COMP, MMP3, Coll2-1 (epitope of the α-helical region of type II collagen), CRP

Gómez

2018 knee

SF

sCD14, sCD163, CCL2 83 OA (chemokine (CeC motif)-ligand2)

Guan

2019 knee

SF

α-MSH (α-melanocytestimulating hormone)

105 OA, 98 controls

Gundogdu

2018 knee

serum

adropin, TNFα, CRP

60 OA, 30 controls

Han

2019 knee

SF

MMP1, MMP9, IL6, IL1β

205 OA

Hartjen

2018 knee

SF

surfactant proteins A, B, C, D

10 OA, 10 RA, 10 controls

He

2019 knee

plasma

col10neo (collagen type X neoepitope)

C4P study: 253 OA, NYU study: 142 OA, 34 RA, 20 controls

Horta-Baas

2019 unspecified

PB

CRP

Huang

2018 knee

SF

Hu

2018 knee

plasma

56 OA, 31 controls

220 OA, 88 fibromyalgia, 322 RA, 69 spondylarthritis (SpA) DKK1 (Dickkopf-related protein 22 OA, 208 knee injury, 9 1), FRZB (frizzled-related controls protein), GREM1 (gremlin 1) 186 metabolites including 90 glyceropho-spholipids, 40 acylcarnitines (1freecarnitine), 21 amino acids, 19 biogenic amines, 15 sphingolipids, 1 hexose (above 90% is glucose)

153 OA, 236 controls

disease duration, Kallman score

Lequesne, WOMAC, VAS pain, HAQ-DI, disease duration, generalized vs. localized OA, KL grade, WORMS

Remark(s) SF levels higher than plasma levels.

Fetuin-A higher in CCP/BCP vs. no crystals. No assocation fetuin-A with No association fetuin-A with IL6 or IL8. KL grade. IL6 higher in BCP vs. no crystals. IL8 no differences. Resistin higher in EHOA and NEHOA vs. controls. Visfatin higher in EHOA vs. NEHOA and controls. Adiponectin no differences. Resistin higher in generalized vs lone HOA. Visfatin en adiponectin similar.

More generalized OA in EHOA vs. NEHOA.

CRP no differences. MPO higher in EHOA vs. NEHOA and in EHOA and NEHOA vs. controls. MPO negative association with disease duration, positive association with Kallman. 3-nitrotyrosine and 8-isoprostane F2α no differences.

No association CRP with MPO.

Majority of samples under detection limits.

IL6, IL8, VEGF, IL1β, MCP1, EGF, and TNFα higher and lubricin lower in OA vs. controls

Knee OA patients at the time of joint replacement. IL1β and TNFα negative associations with lubricin.

COMP, MMP3 and CRP higher in OA vs. control. COMP positive association with disease duration. CRP positive association with with VAS and WOMAC. MMP3 higher in generalized vs. localized OA. COMP, MMP3 and CRP higher in Kl2/3 vs. KL1. COMP positive association with WORMS.

KOOS, WOMAC. Macrophage subsets, total leukocytes.

sCD163 and sCD14 not associated with KOOS or WOMAC. sCD14 positive association with total macrophages/SFL and CD14-CD16 macrophages/SFL ratio. CCL2 positive assocation with CD14-CD16 macrophages/total macrophage ratio. KL, WOMAC, IL6, TNFα, α-MSH negative association with KL grade and WOMAC. No difference Abstract only. COMP, MMP3 between OA vs. controls. α-MSH negative association with IL6, TNFα, COMP and MMP3. KL, white blood cell count, Adropin decreased, TNFα increased, CRP similar in OA vs. controls. Adropin negative association with TNFα. blood neutrophilAdropin negative association, TNFα positive association KL grade. lymphocyte ratio Adropin negative association, TNFα no association WBC and NLR. PAR-2 SNPs (single MMP-1, MMP-9, IL-6, and IL-1 increased in particular PAR-2 SNP nucleotide polymorphisms) mutants

KL

End-stage OA.

Surfactant proteins A, B, C, D increased in OA/RA vs. controls, except surfactant protein B in OA vs. controls. C4P study: Col10neo increased in OA vs. RA and controls. Highest tertile of Col10neo more KL3-4, no differences between individual KL grades. NYU study: Col10neo increased in OA vs. RA and controls. CRP increased in RA vs. OA, similar in OA vs. SpA and fibromyalgia. FRZB decreased, DKK1 and GREM1 similar in OA vs. control, GREM increased in recent injury vs. control and old injury

There are 9 metabolites that appear within the 20 most common ones on all three rounds of analyses: arginine, C16, C18:1, isoleucine, nitrotyrosine, ornithine, taurine, threonine, and tyrosine.

Taurine, arginine, threonine, andornithine were identified as hubs and bottlenecks of the network.

Author Ishii

Year Joint 2018 unspecified

Source SF, serum

Marker ADAM17, ICAM1, TNFα

Subjects 23 RA, 16 OA and 7 controls

OA parameter(s)

Şimşek Kaya

2018 TMJ

SF

chemerin

Joseph

2018 knee

serum, urine

Kisand

2018 knee

plasma

60 markers

60 OA

Kim

2018 unspecified

serum

uric acid

669 OA, 5173 controls (KNHANES VII-1 2016)

Kosek

2018 knee

CSF, serum, SF

TNF, IFNγ, IL1β, IL2, IL4, IL6, 40 OA, 40 controls IL8, IL10, IL12p70, IL13, MCP1 (also called CCL2)

Kodama

2018 hand

serum

MMP3, CRP

1546 participants (ROAD study)

Kropáčková

2018 hand

serum

CLU (clusterin), CRP

135 OA, 53 controls

AUSCAN, VAS pain, US synovitis, US osteophytes

CLU decreased in OA vs controls and in erosive vs non-erosive OA. CLU No association between CRP and CLU. negative association with AUSCAN and VAS pain in erosive hand OA. CRP similar between erosive and non-erosive OA.No association with US synovitis, US osteophytes, and disease duration.

Laavola

2018 knee

SF

IL6

100 OA

radiographic Ahlbäck classification, SF MMP1 and MMP3

IL6 increased in Ahlbäck 4-5 vs. 1-3. IL6 positive associations with MMP1 and MMP3.

Legrand

2018 knee

plasma

glucosepane

Glucosepane increased in OA, RA, non-RA vs. control and in advanced OA vs. early OA, RA, non-RA and control.

Li

2018 knee

plasma, SF eotaxin-1

28 early OA, 38 advanced OA (TKP), 35 RA, 32 non-RA inflammatory disease, 29 control 143 OA, 135 controls

Liu

2018 unspecified

SF, serum

Luo

2019 knee

SF, serum

Luo

2018 knee

serum

PIIANP, PIIBNP

145 OA, controls

Maghbooli

2019 knee

serum

2019 knee 2018 knee, hip

serum serum

36 OA, 54 controls without or mild OA 13 OA, 5 controls 126 OA

KL

Maly Mears

CTRP3 (complement-C1q TNFrelated protein 3) TSP4 (thrombospondin-4) IL6

No correlation PIIANP and PIIBNP. PIIBNP increased in controls (KL0/1) compared to OA (KL2/3/4). CTRP3 decreased in OA vs. controls.

OARSI scoring system WOMAC, alternate Healthy Eating Index-2010 (AHEI2010), body composition

Specific degradation products increased in OA vs. controls. IL6 negative correlation with AHEI-2010. AHEI-2010 negative, Older overweight and obese African-American women. WOMAC physical function positive, and body composition no predictor of IL6.

Naqvi

2019 knee

serum

resistin

32 OA, 32 controls

51 internal derangement (ID), 9 OA sHA, sCOMP, sMMP3, uCTXII 141 OA

Association(s) Serum ADAM17 increased in RA vs. OA and controls. SF ADAM17 increased in RA vs. OA. Chemerin increased in OA vs ID.

Remark(s)

sHA, sMMP and sCOMP positive associations with T2 lateral femur, lateral tibia, and all regions averaged. uCTXII positive associations with T2 patella. sHA, sMMP positive associations with meniscal damage. radiographic OA, global, in IP-10, leptin, PDGF-BB, ANG1, RANTES, TIMP4 associated with TFJ and in PFJ global OA. PCSK9, IP-10 leptin associated with OA in TFJ. TIMP4, vWF2, sE-selectin, leptin associated with PFJ. Serum uric acid level lower in OA vs. control.

VAS, KOOS

CSF MCP1 and IL8 higher in OA vs controls. SF IL6, IL8, IFNγ higher in OA vs controls. Serum IL8 lower, IL6 and MCP1 similar in OA vs controls. CSF IL6 and IL8 inversely associated with symptoms, SF IL6 and IL8 positively associated with symptoms. MMP3 and CRP higher in OA vs. controls, disappearing after adjusting for covariates.

Differences between men and women.

In women, serum uric acid level higher in OA vs controls, disappearing after adjusting for covariates. In men, no differences. MCP1 and IL8 higher in CSF than serum. MCP1 correlated across CSF, serum and SF in women, but not men. SF IL8 positive association with pain in women, not in men. Associations with CRP only in men, not in women. MMP3 positive association with age and higher in men vs women.

At the time of joint replacement. No association serum and SF IL6.

WOMAC, KL, MMP3, IL6 SF and plasma eotaxin-1 increased in OA vs. controls. SF eotaxinPlasma eotaxin-1 levels higher than SF levels. 1 positive association KL grade, WOMAC, MMP3 and IL6. Plasma eotaxin-1 no associations. osteopontin 68 RA serum, 46 OA serum, 11 SF and serum osteopontin increased in RA vs. OA RA SF, 9 OA SF MMP1, MMP7, MMP8, MMP9, 30 OA without DM2 (OA), 20 ACR The expression of MMP-1, -7, -8, -9, -10 and -12 in SF in DM-OA group MMP10, MMP12 OA with DM2 (DM-OA), 5 were significantly higher than in OA group and healthy control. The controls expression of MMP-1 and -7 in serum were highest in DM-OA group.

Resistin similar in OA vs. controls.

Postmenopausal women.

Author Ngarmukos

Year Joint 2018 knee

Source Marker plasma, SF HSP70 (heat shock protein 70)

Subjects 72 OA, 30 controls

Nowicka-Stążka Ok

2018 knee 2018 TMJ

SF urine

15 OA, 38 RA 31 OA, 36 controls

Okura Oppl Otsubo

2019 knee 2018 hip 2018 knee

SF serum serum

QUDA (Quinaldic acid) PYD (pyridinoline), DPD (deoxypyridinoline), CTXI, CTXII Rspo2 (R-spondin 2) ferritin, transferrin soluble folate receptorβ (sFRβ)

Pengas

2018 knee

SF, serum

GAG, MMP3

8 subjects, 40 yrs after meniscectomy, operated knee vs. nonoperated knee

Rosshirt

2018 knee

SF, IFNγ, IL2, IL4, IL6, IL10, peripheral IL17A, TNFα blood (PB)

Rockel

2018 knee

plasma

Ruan

2018 knee

serum

Ruan

2019 knee

serum

Ruthard

2018 unspecified

Sanchez Senol

52 OA 940 AO, 940 controls 29 OA, 41 controls, 27 RA.

55 OA

OA parameter(s) KL

Association(s) Plasma and SF Hsp70 positive correlations with KL. QUDA increased in OA vs. RA. PYD and DPD increased in OA vs. controls.

Remark(s) Plasma Hsp70 associated with SF Hsp70. SF Hsp70 3-fold higher than paired plasma Hsp70. Abstract only.

KL

Rspo2 increased up to KL3, decreased at KL 4. Rspo2 higher in females vs. males. Ferritin and transferrin saturation decreased in OA vs. controls sFRβ increased in OA vs. controls. sFRβ increased in RA vs. OA and controls. KL, Ahlbäck grade, quality SF MMP3 positive asscociation, SF GAG negative association with KL SF and serum MMPs associated in operated knee, not in nonoperated knee of life (QoL) and Ahlback grade. Final model for QoL 40 years post-meniscectomy included age at meniscectomy, GAG 40 years post-meniscectomy, change in GAG from baseline and MMP3 level 40 years post-meniscectomy. IFNγ, IL2, IL10 increased in SF vs. PB.

End-stage OA.

metabolites, metabolite groups 152 OA, 194 controls (NFOAS) [(lysoPC, diacylPC(PCaa), acylalkylPC(PCae)] MMP13, adiponectin, TNFα, IL- 149 OA (AHOA study) KL 8 and IL-18

OA vs. control classification using metabolite levels was strongest in older males, resulting in a signature of 32 metabolites that individually had power to classify OA vs controls. MMP13 positive association KL. Adiponectin negative association with MMP13. TNFα, IL8 and IL18 positive associations with MMP13.

End-stage OA.

141 OA (AHOA study)

serum

S100A8/S100A, MMP3, MMP10, MMP13 IgG isotype autoantibodies

S100A8/S100A9 positive association knee symptoms, cartilage defects and MMPs. More often IgG isotype autoantibodies against TSP4, COMP, and CLEC3A (C-type lectin domain family 3 member A) in OA vs. controls.

2018 knee 2019 knee

serum serum

osteomodulin, fibulin3 metabolomics

6 OA, 6 controls 14 obese OA (OKOA), 28 nonobese OA (NOKOA), 15 controls

Osteomodulin decreased, fibulin-3 increased in OA vs. controls. 21 different metabolites in OA vs. controls and 15 different metabolites for OKOA vs. NOKOA. Glycerolipid, nitrogen, glycerophospholipid, glycine, serine and threonine metabolism, tryptophan metabolism, and fatty acid biosynthesis most affected pathways.

Sharma Sun

2018 knee 2019 unspecified

serum, SF serum

PTX3 (pentraxin 3), CRP IgG

Suyasa

2018 lumbar

serum

CRP, IL6

Serum and SF PTX3 and CRP decreased in OA vs. RA. The combination of specific glycans with different branching patterns distinguished OA from RA. Specifically, N-glycans with bisecting structures differentiate OA and RA. A high level of plasma IL-6 and hs-CRP are risk factors for symptomatic Postmenopausal women. lumbar OA in estrogen deficiency postmenopausal women.

Tsuno

2018 unspecified

serum

proteomics

30 OA, 30 active RA Discovery: 8 RA, 19 OA, 20 controls. Validation: 36 RA, 20 OA, 20 controls 44 symptomatic OA and estrogen deficiency, 44 asymptomatic OA 10 OA, 12 active RA (aRA), 11 inactive RA (iRA), 10 controls

Thorson

2019 knee, hip

plasma

lubricin, MMP1, -2, -9, -13, TIMP1 (tissue inhibitor of metalloproteinase), VEGF (vascular endothelial growth factor)

10 OA, 10 RA, 10 controls

80 OA, 31 controls

KL

WOMAC, KL, MRI

In aRA, iRA and OA, 24, 5 and 7 spots showed approximately ≥ ±1.3fold intensity differences vs. controls, respectively. Cathepsin F increased, Ig alpha-2 chain C region decreased in OA vs. controls. Lubricin and tissue factor decreased in OA vs. controls. VEGF increased, End-stage OA. MMP2 decreased post TJA vs. pre TJA. Pre and post TJA MMP9 increased, MMP13 decreased in OA vs. controls. TIMP, VEGF similar between OA vs. controls.

Author Tilinca

Year Joint 2019 knee, hip

Source serum

Marker fibrinogen, CRP, TNFα, IL6

Subjects OA parameter(s) 71 normal weight OA, 74 obese OA

Remark(s) End-stage OA.

Tootsi

2018 knee, hip

serum

metabolomics, CRP

70 OA, 82 controls

End-stage OA.

Valverde-Franco Van de Vyver

2018 knee 2018 knee

SF, serum SF

adipsin 13 OA, 13 controls saturated FAs (SFA), 23 OA, 6 controls monounsaturated FAs (MUFA), omega-3 and omega-6 polyunsaturated FAs (n-3 PUFAs and n-6 PUFAs)

Wang

2018 knee

SF, serum

IL34

182 OA, 69 controls

Wan Xiong

2018 knee 2019 TMJ

serum SF

IL17 leptin, IL6

74 OA, 79 controls KL 12 displaced disc with reduction (DDR), 13 displaced disc without reduction (DDNR), 13 OA, 7 controls

IL17 increased in OA vs. controls. IL17 positive association KL. Leptin increased in OA vs. DDR, DDNR and controls. IL6 higher in OA, DDR and DDNR vs. controls. No correlation between leptin and IL6.

Xiong Xu

2019 TMJ 2018 knee

SF serum

leptin sAxl/sMer/sTyro3

16 OA, 7 controls 100 OA, 306 RA, 120 controls

Zhang Zheng Zhou Özler

2018 2018 2018 2018

serum serum serum SF

350 OA, 350 controls 20 OA, 20 controls ? OA, ? controls KL, WOMAC 29 late OA (LOA), 28 early OA (EOA), 30 controls

Zou

2018 knee

SF, serum

MUTYH (MYH glycosylase) CTXIII TNFα ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs), serglycin activin A

Leptin increased in OA vs. controls. sMer and sTyro3 decreased in OA vs. RA and controls. sAxl not different. MUTYH increased in OA vs. controls. CTXIII increased in OA vs. controls TNFα increased with KL and WOMAC. Abstract only. ADAMTS4 and serglycin increased in LOA vs. EOA and control groups.

Zou

2019 ankle

SF, serum

ghrelin, MMP3, TNFα

97 OA, 95 controls

unspecified knee knee knee

210 OA, 150 controls

Association(s) Preoperative TNFα and CRP increased, IL6 and fibrinogen similar in obese vs. normal weight. Postoperative IL6 higher in obese vs. normal weight. arterial stiffness (pulse wave Acylcarnitines decreased, CRP increased in OA vs. controls. Medium-and analysis), KL long-chain acylcarnitines positive associations with arterial stiffness and KL. SF and serum adipsin levels increased in OA vs. controls n-6/n-3 ratio lower in OA vs. controls. Arachidonic acid (n-6 PUFA) decreased in OA, tetracosadienoic acid and nervonic acid (MUFAs) increased in OA vs. controls.

KL, WOMAC

* Also in observational - longitudinal table End-stage OA.

Serum IL34 similar between OA vs. control. Serum IL34 no association Kl and WOMAC. SF IL34 positive association with WOMAC and KL.

KL

Activin A in serum and SF increased in OA vs. controls and positive association KL. Modified KL, VAS, Serum ghrelin similar between ankle PTOA patients and controls. SF American Ortho-pedic Foot ghrelin negatively association with progression KL, VAS, MMP3 and and Ankle Society’s TNFα. SF ghrelin positive association AOFAS. (AOFAS)

Posttraumatic OA.

Author Chu

Year Joint 2018 knee

Source serum

Dai

2018 knee

serum

Marker Subjects C1,2C (carboxy terminus of 16 OA the 3/4 length piece produced by collagenase cleavage of type I and II collagen), CS846 CRP 276 OAI / 971 Framingham

Driban

2018 knee

serum

CRP

54 AKOA (accelerated knee OA), 54 NKOA (normal knee OA), 54 controls

Jacobs

2018 knee

urine

CTXII, CTXIα

600 OA

Karsdal

2019 knee, hip serum

OA parameter(s) tibiofemoral cartilage thickness on MRI

Follow-up 5 yrs

Association(s) Change in C1,2C upon mechanical stimulation inversely associated with cartilage loss at full, anterior and exterior tibial regions. CS846 positively associated with loss.

Remark(s)

incident symptomatic radiographic OA

4 yrs OAI / 9.5 yrs Framingham 48 mnths

CRP positive association with incident OA.

CRP higher with fiber intake <21 g/d vs. > 21 g/d. No radiographic OA at baseline. AKOA is KL3 or 4 within 48 months. NKOA is KL 1 or 2 within 48 months.

2 yrs

Greater increase in CTXII and CTXIα in obese+depressed vs. obese+non-depressed and non-obese In limited NSAID users, RPOA type-2 high C2M and C3M. In Tanezumab-treated patients. chronic NSAID users, low SOST or MMP-9. Over time the chronic NSAID phenotypes changed to a more destructive profile with higher MMP9, ICTP, CTXI.

CTXI, total OC 56 OA (osteocalcin), PINP, SOST (sclerostin), Dkk1, ICTP, C1M, MMP9, C2M, PIIANP, COMP, C3M, VEGF, IL6, CRP, PINP:total OC, CTXI:total OC

rapidly progressive OA type 2

CRP CCL2 (C-C Motif Chemokine Ligand 2)

incident clinical OA 10 yrs presence ROA, 5 yrs progression ROA, medial JSN ROA, MROA (MRI5 yrs defined OA), MRI effusion-synovitis

Konstari 2019 knee Longobardi 2018 knee

serum serum

Roemer

2019 knee

SF, serum IL6, IL8, IL10, TNF, IFNɣ in serum and SF; IL-12p70 in serum

113 serum, 81 SF acute ACL injury

Saberi

2018 hip

4548 OA

incident ROA

10 yrs

Valdes

2018 knee

serum, CRP, uCTXII urine SF, plasma 22 omega-6 lipids (arachidonic acid, linoleic acid, and 20 oxylipins)

58 OA, 44 controls

KL

3.25 yrs

ValverdeFranco

2018 knee

SF

175 OA

MRI tibiofemoral cartilage volume

48 mnths

adipsin

4953 OA 168 OA

10 months

CRP no major role in predicting AKOA. Large amount of unexplained variance (69%) of the CART (classification and regression tree) analysis.

CRP did not predict incident OA. CCL2 positive association presence and progression ROA or medial JSN. Markers at 2 years postinjury weakly associated with ROA or MROA at 5 years postinjury (AUC max. 0.69). Positive association IL8 and effusion-synovitis, no other associations. CRP included in the basic prediction model. uCTXII poor predictor of incident ROA (AUC=0,67). SF prostaglandin D2, 11,12-DHET, and 14,15-DHET increased in OA vs. controls. SF 11,12-DHET and 14,15-DHET higher in affected versus unaffected knees of people with unilateral OA. Plasma 8,9-DHET increased in OA vs. controls. 11,12-DHET, 14,15-DHET, and 8,9-DHET positive association with KL progression. Adipsin associated with greater cartilage volume loss in the lateral * Also in observational - cross-sectional compartment, not in the medial or medial + lateral compartments. table

Author Azukizawa

Year Joint 2018 knee

Source serum, urine

Basu

2018 knee

serum

Marker Subjects sPIICP, uCTXII, uC2C 42 (carboxy terminus of the 3/4 length piece produced by collagenase cleavage of type II collagen), sCOMP 24 markers of inflammation 17

Chen

2019 knee

SF

proteome

30

Costa-Cavalcanti 2019 knee

plasma

CRP

21

Cornish

2018 knee

serum

Dallari

2018 knee

SF

Dehghani

2018 knee

serum

Du

2019 knee

Gálvez

Intervention supervised exercise, weekly, 12 wks

Outcome(s) Follow-up Association(s) timed up and go test (TUG), 3- 24 wks sPIINP increased at 8 weeks, uCTXII decreased at 28 minute walk test (3MWT), 30 weeks, uC2C decreased at 12 weeks, sCOMP second chair stand test (CST), increased at 24 weeks. Japanese knee OA measure

Remark(s) All women. TUG, 3MWT and CST all improved at 12 weeks. sPIINP and uCTXII changes only in KL 0 or 1 subset.

strawberry 50 g/day vs. placebo for 12 ICOAP (Intermittent and 12 wks weeks Constant OA Pain) autologous PRP, intra-articularly, Lequesne Functional Index, KL 9 mnths monthly, three times in the knee alone vs. in both the knee and pes anserinus complex auriculotherapy vs. sham, weekly, 5 times 6 wks

hsTNFα, sTNF-R2, 4-hydroxy-2-nonenal and conjugated dienes all decreased. Transthyretin, matrilin and complement 5 increased in both groups. At least two-fold concentration decreases in APOA1, MMP, IGKC, HPT, and TRFE in knee+pes anserinus complex group only. CRP stable and not different between groups.

CRP, IL1β, IL6, s100 A8/A9 18 (S100 calcium-binding protein A8 and A9, respectively), TNFα, COMP

creatin monohydrate 20 g/d for one week, KOOS, isometric thigh strength 12 wks 5 g/d for 11 weeks vs. placebo

No effect on inflammation markers, COMP or KOOS. Thigh strength in 0 degress decreased, other strength measures stable, no difference between groups.

MMP1, MMP13, TIMP1, 100 IL1β, IL6, IL8, TNFα, PGE2 (prostaglandin E2) 80 resistin, TNFα

HA alone vs. HA+polynucleotides (PN), intra-articular, three times, every week

WOMAC pain and function, KSS (knee society score)

2 wks (at 3rd gift)

garlic 2 dd 1000 mg vs. placebo tablets

VAS pain

12 wks

No differences in markers between groups. Some improvements in pain at later time points in HA+PN vs. HA group. Overweight, obese women only. Resistin and pain decreased in garlic group vs, baseline, not in placebo group. TNFα changed in none.

plasma

TNFα, IL1β, IL6, IL10, IL13, MMP3, MMP13, MCP1 (monocyte chemoattractant protein-1)

63

freeze-dried whole blueberry powder, 40 g daily vs. placebo

WOMAC, gait and balance

8 and 16 wks

2018 knee

serum

IL8, TGFβ

35

balneotherapy with mud, 10 days

Heffner

2018 knee

blood

IL6, TNFα

30

cognitive-behavioral therapy for insomnia, 6 weeks

10 days knee flexion and extension, WOMAC, health-related quality of life WOMAC, KPS (Knee Pain 6 wks Scale)

Huang

2018 knee

plasma

366 IL17A, IL1β, TNFα, RANKL (receptor activator of nuclear factor kappa-Β ligand), IL6, IFNγ, HGF (hepatocyte growth factor), ICAM1 (intercellular adhesion molecule 1), OPN (osteopontin), PD-ECGF (platelet-derived endothelial cell growth factor), VEGF (vascular endothelial growth factor), PDGF (platelet derived growth factor), IGF1 (insuline-like growth factor 1) and TGFβ

PRP (2-14 ml) or placebo

clinical arthritis score; MRI damaged area, joint inflammation and synovial proliferation; Karnofsky performance status

8 wks

Cross-over design. Pain ICOAP not reported. SF total protein concentrations in both groups decreased after the second PRP injection(s). Elderly.

Improvements in WOMAC and gait and balance in blueberry over placebo group. No changes in biomarkers. Increasing trend IL13, decreasing trend MCP1 in the blueberry group. Decrease IL8 and TGFβ. Improvement of all clinical outcomes. Improved physical functioning, decline in knee pain Patients with insomnia. during transfer activities, attenuated increase IL6 and less decrease in TNFα across the pain testing session in those whose insomnia improved. Clinical and imaging outcomes improved in PRP over placebo group. IL17A, IL1β, TNFα, RANKL, IL6 and IFNγ decreased after PRP treatment compared with placebo. HGF, ICAM1, OPN, PD-ECGF, VEGF, PDGF, IGF1 and TGFβ increased after PRP treatment.

Author Huang

Jayabalan Karaarslan

Year Joint 2018 knee

Source Marker Subjects plasma LBP (lipopolysaccharide 431 binding protein), sTLR4 (soluble Toll-like receptor 4), IL6 2019 knee serum COMP, TNFα, NPY 27 (neuropeptide Y) 2018 generaliz plasma ADMA (asymmetric 80 ed dimethylarginine), Larginine, L-arginine/ADMA ratio

Kim

2018 knee

serum, urine

163 sCTXI, sC1M, sC2M, sC3M, sCS846, sMMP3, sPIIANP, sCOMP, uCTXII

Klocke

2018 knee

urine, serum

uCTXII, uNTXI, sCOMP, sHA, sYKL40, sPIIANP

Kloppenburg

2019 hand

urine, serum

sCRP, sIL1α, sIL1β, sC1M, 132 sC3M, sCRPM, sCTXI, sHA, sPIIANP, uCTXII

Leung

2018 knee

Mahler

80

Intervention doxycycline 100 mg vs. placebo

Outcome(s) Follow-up Association(s) radiographic JSN, uCTXII, total 16 months Plasma LBP associated with JSN, sTLR4 associated WOMAC with uCTXII change, IL6 associated with WOMAC change (disappeared after adjusting for confounders).

continuous 45 min walking exercise vs. 3 times 15 min walking exercise spa hospital vs. locomotor system disease VAS pain, patient, and ambulatory clinics + 15 days home physician global assessment; exercises HAQ; and WOMAC intra-articular TissueGene-C (TG-C, cell IKDC (International Knee and gene teraphy) vs. placebo Documentation Committee), VAS pain, WOMAC, KOOS, radiographic JSW, MRI: WORMS, bone area, cartilage thickness triamcinolon 40 mg + 4 ml 1% lignocaine radiographic JSN and OP, intra-articularly WOMAC pain

45 mins 1 mnth

COMP increases in continuous exercise, stable in intermittent. TNFα and NPY stable in both. L-arginine and L-arginine/ADMA ratio increased in spa group. ADMA decreased in clinics group. All clinical outcomes improved in spa vs. clinics group.

Remark(s) Obese women aged 45-64 years with unilateral radiographic knee OA.

Two-phase sequential design.

52 wks

KL3. No differences in biomarkers between TG-C and placebo. Improved IKDC, VAS, WOMAC, KOOS in TG-C vs. placebo. No difference in radiographic JSW, WORMS, cartilage thickness and bone area.

3 wks

uCTXII decreased after injection, others similar. Baseline and change uCTXII positive association with JSN, no association with OP or pain. IL1α, IL1β, hsCRP, C1M decreased. sC3M, sCRPM, Erosive hand OA. sCTXI decreased, but less robustly. sHA, sPIIANP, uCTXII similar. No clinical or structural efficacy.

lutikizumab vs. placebo

AUSCAN pain, swollen and 26 wks tender joint counts, MRI (OMERACT/HOAMRIS), radiography (Verbruggen-Veys, OARSI atlas, modified KL)

SF, urine SF IL6, SF IL8, SF TNFα, 109 SF CD14, SF IL18, SF CTXI, uCTXII, SF CTXII, s hsCRP

colchicine 2 dd 0.5 mg vs. placebo

WOMAC, pain Likert, patient global assessment, physical function, OARSI-OMERACT response, quality of life

16 wks

Decrease hsCRP and SF CTXII, no other differences between groups.

2019 knee

serum

CRP

55

low-dose radiation therapy, 1 Gr, six times in two weeks vs. sham

OMERACT-OARSI response, pain, function, patient global assessment, US inflammation, MRI inflammation

3 mnths

No differences in CRP or clinical outcomes.

Majeed

2019 knee

serum

CRP

48

Boswellia serrata extract vs. placebo

WOMAC, physician global 4 mnths assessment, 6 minute walk test, VAS, EQ5D, radiographic JSW and OP

CRP decrease in extract group vs. stable in placebo group. Improvement in all clinical outcomes in extract group vs stable in placebo group. Increase JSW and decrease OP in extract group vs. decrease JSW and increase OP in placebo group.

Marouf

2018 knee

serum

TNFα, IL1β, IL6, hsCRP, C3, C4

110

meloxicam 15 mg per day and either 500 mg per day resveratrol or placebo

ACR, KOOS, WOMAC, VAS pain

Minten

2018 hand

serum

CRP

56

Migliore

2018 knee

serum

CRP

187 OA

low-dose radiation therapy (6 × 1 Gy in 2 OMERACT-OARSI 3 mnths weeks) or sham (6 × 0 Gy in 2 weeks) responders, AUSCAN pain and function, SF36, effusion, synovial thickening and power Doppler signal on US high molecular weight HA (1,500-2,000 WOMAC, VAS pain 12 mnths kDa), single intra-articular injection

Time-dependent decrease in pain in resveratrol group. Decrease of TNFα, IL1β, IL6, hsCRP, C3, C4 compared with placebo. No difference in CRP or clinical and US outcomes Pain ≥5 (range 0-10) and nonbetween groups. responding to conservative therapy.

90 days

WOMAC and VAS pain improved.

Abstract only. No data on CRP in abstract.

Author Navarro

Year Joint 2019 knee

Source Marker serum 20 proteins

Subjects 189

Intervention Outcome(s) glucosamine hydrochloride (GH) 500 mg + chondroitin sulphate (CS) 1200 mg vs. celecoxib 1 dd 200 mg

Strath

2019 knee

serum

leptin, IFNγ, IL6, TNFα, 21 CRP, TBARS (thiobarbituric acid reactive substances)

low-carbohydrate diet (LCD), low-fat diet KOOS, brief pain inventory (LFD) vs. usual diet (CTRL) (BPI), temporal summation, timed walk, repeated chair stands, quality of life, depression

Sun

2019 knee

serum, SF

PACAP (pituitary adenylate 101 OA, 62 cyclase-activating control polypeptide), IL1β, MMP3

HA, 3 ml, weekly, three times

Wang

2019 knee

serum

CTXII, YKL40

Zheng

2018 knee

serum

CRP, IL6, IL8, IL10, 200 resistin, leptin, adiponectin, adipsin, apelin-36

ACR, KL, numeric pain scale (NPS), revised Oxford Knee Score (OKS), American Knee Society Score (AKSS)

90 OA and 50 GS (glucosamine sulphate) 500 mg WOMAC, KL controls (N=29), diacerein 50 mg (N=29) vs. GS 500 mg + diacerein 50 mg (N=32), twice daily

vitamin D3 1.25 mg, monthly vs. placebo ACR, VAS

Follow-up Association(s) 6 mnths All proteins except WNT16 decreased after GH+CS, about half increased after celecoxib. IL6 decreased after GH+CS. CCL20, CSF3, WNT16 increased after celecoxib, but not anymore after controlling for multiple testing. 12 wks In LCD group improvements in pain interference, quality of life, pain intensity, chair stands, TBARS and leptin. No changes in LFD and CTRL group. Change in TBARS correlated with change in pain intensity following temporal summation. Trend suggesting a relation between change in TBARS and pain intensity associated with the chair stand test. 8 wks

9 wks

24 mths

Remark(s) Abstract only.

Change in weight was related to the change in leptin between groups.

SF PACAP level but not serum decreased in OA patients vs. controls. SF PACAP negative association with KL and NPS, positive association with AKSS and OKS. SF PACAP negative associations with IL1β and MMP3. SF PACAP incremental trend after HA injection. CTXII and YKL40 increased in OA vs. controls. CTXII and YKL40 positive associations with KL. CTXII and YKL40 before treatment positive associations with WOMAC. CTXII and YKL40 decreased with treatment. CTXII positive association with YKL40 and WOMAC during treatment. No differences in CTXII and YKL40 between treatment arms. No change in marker levels over 2 years.

Vitamin D deficient patients.

Total

1,279 hits

English? 29 excluded Original data? 251 excluded Human ? 247 excluded OA? 278 excluded Clinical ?

d 118 excluded

Soluble marker? 232 excluded Soluble biochemical markers in body fluids of people with OA 124 hits

Inflammation

Obesity, metabolic

hsCRP, IL6, IL1β, IFNγ, syndrome Leptin, adiponectin, TNFα, endothelin, clusterin, MCP1, etc.

insulin, ghrelin, HGF, uric acid, etc.

Oxidative stress Nitrotyrosine, Coll2-1NO2, etc.

Cartilage matrix CTXII, COMP,

Angiogenesis

Col10neo, PIIANP,

CXCL10, FGF1/2, PDGF-

PIIBNP (PRO-C2),

AA/BB, ANG1, etc.

AGNx1, activin, etc.

Crystal formation Fetuin-A.

Synovial matrix Col3-ADAMTS,

Autoimmunity

C3M, etc.

IgG autoantibodies against TSP4, COMP

Bone matrix

and CLEC3A.

Pyridinolin,

Sensitisation

deoxypyridinolin, etc.

Neurotrophic growth factor. Amino acid metabolism

Carbohydrate metabolism

Taurine, hypotaurine,

Glycolysis, citric acid cycle, etc.

arginine, proline, etc. Fatty acid metabolism Acylcarnitines, glycerolipids, etc.