Inflammation functions as a key mediator in the link between ACPA and erosion development: an association study in Clinically Suspect Arthralgia

Brinck, Robin M. ten; Toes, René E. M.; Mil, A.H.M. van der Helm-van

doi:10.1186/s13075-018-1574-3

Cited by 12 publications

(10 citation statements)

References 18 publications

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“…Even though MRI-detected erosions were not associated with RA development, higher erosion scores were present in ACPA-positive compared to ACPAnegative patients, which is similar to our previous finding in the same cohort (7). In our view, these data suggest that the presence of subclinical inflammation in ACPA-positive arthralgia is mediating the development of erosions.…”

Section: Discussionsupporting

confidence: 89%

Do magnetic resonance imaging-detected erosions predict progression to rheumatoid arthritis in patients presenting with clinically suspect arthralgia? A longitudinal study

Wouters

Matthijssen

Boeters

et al. 2020

Scandinavian Journal of Rheumatology

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Objective: Radiographic joint erosions are a hallmark of rheumatoid arthritis (RA). Magnetic resonance imaging (MRI) is more sensitive than radiographs in detecting erosions. It is unknown whether MRI-detected erosions are predictive for RA development in patients with clinically suspect arthralgia (CSA). Therefore, we investigated the prognostic value of MRI-detected erosions, defined as any MRI erosion, or MRI erosion characteristics that were recently identified as specific for RA in patients with evident arthritis. Method: Patients presenting with CSA (n = 490) underwent contrast-enhanced 1.5 T MRI of the wrist, metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joints. MRIs were scored according to the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring system (RAMRIS). Presence of any MRI erosion (present in < 5% of symptomfree controls) and RA-specific erosion characteristics as identified previously (grade ≥ 2 erosions, erosions in MTP5, erosions in MTP1 if aged < 40 years) were studied with clinically apparent inflammatory arthritis development as outcome. Analyses were corrected for age and MRI-detected subclinical inflammation. Results: Erosions were present in 20%. Presence of any MRI erosion was not associated with arthritis development [multivariable analysis hazard ratio (HR) 0.97 (95% confidence interval 0.59-1.59)]. The different RA-specific erosion characteristics were not predictive [grade ≥ 2 HR 1.05 (0.33-3.34), erosions in MTP5 HR 1.08 (0.47-2.48), and MTP1 if aged < 40 years HR 1.11 (0.26-4.70)]. Erosion scores were higher in anti-citrullinated protein antibody (ACPA)positive than in ACPA-negative patients (median 2.0 vs 1.0, p = 0.002), and related to more subclinical inflammation. Within both subgroups, MRI erosions were not predictive. Conclusions: MRI-detected erosions in hands and feet were not predictive for inflammatory arthritis development. Therefore, evaluating MRI for erosions in addition to subclinical inflammation does not provide added clinical value in CSA.

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Section: Discussionsupporting

confidence: 89%

Do magnetic resonance imaging-detected erosions predict progression to rheumatoid arthritis in patients presenting with clinically suspect arthralgia? A longitudinal study

Wouters

Matthijssen

Boeters

et al. 2020

Scandinavian Journal of Rheumatology

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“…Earlier studies have demonstrated that inhibition of interleukin-8 interferes with osteoclastogenesis and thus prevents osteolysis (32,33). Moreover, ACPAs are only associated with higher erosion scores in the clinically suspect arthralgia stage of RA when concomitant inflammation is present, indicating that inflammation functions as a key mediator in the link between ACPAs and erosion development (34). Since there is strong evidence that erosive disease and systemic BMD loss in RA have common pathways in their pathogenesis (35,36), these results might also suggest an indirect association between ACPAs and bone loss via inflammation.…”

Section: Discussionmentioning

confidence: 99%

Association Between Bone Mineral Density and Autoantibodies in Patients With Rheumatoid Arthritis

Amkreutz

Moel

Theander

et al. 2021

Arthritis & Rheumatology

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Objective. Autoantibodies, such as anti-citrullinated protein antibodies (ACPAs), have been described as inducing bone loss in rheumatoid arthritis (RA), which can also be reflected by bone mineral density (BMD). We therefore examined the association between osteoporosis and autoantibodies in two independent RA cohorts.Methods. Dual x-ray absorptiometry (DXA) of the lumbar spine and left hip was performed in 408 Dutch patients with early RA during 5 years of follow-up and in 198 Swedish patients with early RA during 10 years of follow-up. The longitudinal effect of ACPAs and other autoantibodies on several BMD measures was assessed using generalized estimating equations.Results. In the Dutch cohort, significantly lower BMD at baseline was observed in ACPA-positive patients compared to ACPA-negative patients, with an estimated marginal mean BMD in the left hip of 0.92 g/cm 2 (95% confidence interval [95% CI] 0.91-0.93) versus 0.95 g/cm 2 (95% CI 0.93-0.97) (P = 0.01). In line with this, significantly lower Z scores at baseline were noted in the ACPA-positive group compared to the ACPA-negative group (estimated marginal mean Z score in the left hip of 0.18 [95% CI 0.08-0.29] versus 0.48 [95% CI 0.33-0.63]) (P < 0.01). However, despite clear differences at baseline, ACPA positivity was not associated with greater decrease in absolute BMD or Z scores over time. Furthermore, there was no association between BMD and higher levels of ACPAs or other autoantibodies (rheumatoid factor and anti-carbamylated protein antibodies). In the Swedish cohort, ACPA-positive patients tended to have a higher prevalence of osteopenia at baseline (P = 0.04), but again, ACPA positivity was not associated with an increased prevalence of osteopenia or osteoporosis over time.Conclusion. The presence of ACPAs is associated with significantly lower BMD at baseline, but not with greater BMD loss over time in treated RA patients. These results suggest that ACPAs alone do not appear to contribute to bone loss after disease onset when disease activity is well-managed.

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“…The presence of ACPAs and their binding to citrullinated targets within the inflamed synovium is associated with disease severity and enhanced tissue injury in RA patients and murine models of RA. [37][38][39][40][41] In addition, the generation of ACPAs in the early development phases of RA has a strong predictive value for the progression to full-blown disease. 42,43 However, we previously demonstrated that a small subset of ACPAs, derived from single chain variable fragment (scFv) libraries containing the immune repertoire of RA patients, 44 exhibit strong therapeutic activity in CAIA and CIA mouse models of IA.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases

Chirivi¹,

Rosmalen²,

Linden³

et al. 2020

Cell Mol Immunol

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Excessive release of neutrophil extracellular traps (NETs) is associated with disease severity and contributes to tissue injury, followed by severe organ damage. Pharmacological or genetic inhibition of NET release reduces pathology in multiple inflammatory disease models, indicating that NETs are potential therapeutic targets. Here, we demonstrate using a preclinical basket approach that our therapeutic anti-citrullinated protein antibody (tACPA) has broad therapeutic potential. Treatment with tACPA prevents disease symptoms in various mouse models with plausible NET-mediated pathology, including inflammatory arthritis (IA), pulmonary fibrosis, inflammatory bowel disease and sepsis. We show that citrulline residues in the N-termini of histones 2A and 4 are specific targets for therapeutic intervention, whereas antibodies against other N-terminal post-translational histone modifications have no therapeutic effects. Because citrullinated histones are generated during NET release, we investigated the ability of tACPA to inhibit NET formation. tACPA suppressed NET release from human neutrophils triggered with physiologically relevant human diseaserelated stimuli. Moreover, tACPA diminished NET release and potentially initiated NET uptake by macrophages in vivo, which was associated with reduced tissue damage in the joints of a chronic arthritis mouse model of IA. To our knowledge, we are the first to describe an antibody with NET-inhibiting properties and thereby propose tACPA as a drug candidate for NET-mediated inflammatory diseases, as it eliminates the noxious triggers that lead to continued inflammation and tissue damage in a multidimensional manner.

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Inflammation functions as a key mediator in the link between ACPA and erosion development: an association study in Clinically Suspect Arthralgia

Cited by 12 publications

References 18 publications

Do magnetic resonance imaging-detected erosions predict progression to rheumatoid arthritis in patients presenting with clinically suspect arthralgia? A longitudinal study

Do magnetic resonance imaging-detected erosions predict progression to rheumatoid arthritis in patients presenting with clinically suspect arthralgia? A longitudinal study

Association Between Bone Mineral Density and Autoantibodies in Patients With Rheumatoid Arthritis

Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases

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