November, 2006 - CRA Journal Club Review by Dr. JERRY TENENBAUM
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The ratio of circulating osteoprotegerin to RANKL in early rheumatoid arthritis predicts later joint destruction.
Geusens PP. Landewe RB. Garnero P. Chen D. Dunstan CR. Lems WF. Stinissen P. van der Heijde DM. van der Linden S. Boers M. Journal Article. Multicenter Study. Randomized Controlled Trial] Arthritis & Rheumatism. 54(6):1772-7, 2006 Jun. |
Jerry Tenenbaum
M.D., FRCPC |
Editorial by
Dr. Jerry Tenenbaum
INTRODUCTION
It has been proposed that a mechanism of bone destruction could be dissociated from inflammation
At pannus invasion sites, find cells with specific surface markers for osteoclasts
RANKL & OPG
NORMAL BONE REMODELING: RANKL and its naturally occurring decoy receptor, OPG, play key roles
HUMAN RA & ANIMAL MODELS OF RA : RANKL and OPG play key roles (as well as in erosive PsA and multiple myeloma)
OPG & RANKL
RANKL – promotes osteoclastogenesis and osteoclast activity (induces osteoclastic bone destruction)
OPG – inhibits osteoclastogenesis and osteoclast activity (prevents binding of RANKL with receptor, RANK)
RANKL & OPG
It is the relative levels of expression of RANKL and OPG locally which regulate bone resorption
Useful to express this as a ratio
RANKL:OPG |
"PULLING RANK"
Receptor activator of nuclear factor-kappaB
literally....
New England Journal of Medicine from Feb. 2006
In Rheumatoid Arthritis...
RHEUMATOID ARTHRITIS
- Find levels of RANKL and OPG in joints and sera of RA patients (?clinical relevance)
- Inflammation and osteoclastogenesis are different processes in the joints
- Proinflammatory cytokines are major cofactors in differentiation and activation of osteoclasts
DISSOCIATION
- UNLIKELY THAT JOINT DESTRUCTION IN RA WOULD OCCUR IN ABSENCE OF INFLAMMATION
- INFLAMMATION MAY OCCUR IN ABSENCE OF JOINT DESTRUCTION
Some recent studies show this. Dissociation (infl. improves but damage occurs in some patients)
The ratio of circulating osteoprotegerin to RANKL in early rheumatoid arthritis predicts later joint destruction.
Geusens PP. Landewe RB. Garnero P. Chen D. Dunstan CR. Lems WF. Stinissen P. van der Heijde DM. van der Linden S. Boers M. Journal Article. Multicenter Study. Randomized Controlled Trial] Arthritis & Rheumatism. 54(6):1772-7, 2006 Jun
HYPOTHESIS
THERAPY has been shown in a cohort of early RA patients to influence increased levels of bone resorption markers in early RA.
Hypothesis: in patients with early untreated RA, serum OPG:RANKL at baseline (a measure of osteoclast activation) is negatively associated with progression of joint damage
Also, it is of interest to do an analysis of relationship of this ratio to parameters of inflammation
ABSTRACT:
OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disease that may result in debilitating joint deformities with destruction of bone and cartilage. Inflammation is still considered the pivotal inducer of both components of joint damage. Results of recent animal studies suggested a prominent contribution of osteoclastic bone resorption that could be dissociated from inflammation. RANKL and its natural decoy receptor, osteoprotegerin (OPG), play key roles in osteoclast activation. In a group of patients with early RA not treated with disease-modifying drugs, we tested the hypothesis that osteoclast activation, reflected by the serum OPG:RANKL ratio at baseline, is negatively associated with progression of bone damage, independent of inflammation.
METHODS: OPG and RANKL levels, together with a parameter of inflammation (first-year time-averaged erythrocyte sedimentation rate [tESR]), were measured in 92 patients with newly diagnosed early active RA who were participants in a randomized study. The tESR and the OPG:RANKL ratio were evaluated for the ability to predict 5-year radiographic progression of joint damage.
PATIENTS
- 92/155 patients with available serum at baseline (before Rx instituted) in COBRA study
- COBRA (56 week of early RA which was highly active) (SSz + MTx with early CS vs. SSz alone) with freedom to alter Rx after 56 wks and follow up for 5 years.
OUTCOME MEASURES
- Primary : radiographic progression over 5 years (hands and feet at 1 yr intervals scored by modified Sharp/van der Heijde method (0-448)by 2 readers (mean score)
- Secondary: progression rates during different time intervals (0-1year; 0-1 years; 1 to 2 years)
METHODS
- RANKL & OPG baseline levels: (blinded) by Capture ELISA with 2 Abs detecting different epitopes (OPG by commercial kit and RANKL by Amgen).
- tESR = first-year time-averaged ESR (6 equally spaced values – to incorporate effects of Rx on inflammation)
- Statistics: logistic regression analysis
PATIENTS
- AGE: 50 ± 12 YEARS
- DISEASE DURATION: 5.2 ± 4.6 MONTHS
- W:M = 59:31
- RF + : 75%
- ESR: 51 ±30 mm/hr
- HAQ score: 1.4 ± 0.7 (0-3)
- DISEASE ACTIV. SCORE: 6.1 ± 1.0 (0-9)
- SWOLLEN JT COUNT: 13 ± 8
- TENDER JT COUNT: 24 ± 12
- RADIOGRAPHIC DAMAGE (>4 Sharp units) : 44% AT BASELINE and 65% showed significant x-ray progression (>2 Sharp units/yr over 5 yrs)
RADIOGRAPHIC PROGRESSION
- Median x-ray progression was 4.1 Sharp units/yr
- X-ray progression moderately associated with baseline ESR (Spearman’s ñ=0.44, P<0.001) and more strongly associated with first-year tESR (Spearman’s p=0.50, P<0.001)
- Weakly associated with RANKL level (Spearman’s p=0.17, P=0.08) but not with OPG level.
- A stronger negative association was observed with OPG:RANKL ratio (Spearman’s ñ = -0.38, P=.001)
OTHER CORRELATIONS
- Baseline ESR correlated weakly with the baseline RANKL level(ñ=0.17. P=0.08) and the baseline OPG (ñ=0.23, P=0.017) but did not correlate with OPG:RANKL ratio (ñ=0.01, P=0.91)
- OPG:RANKL ratio did not correlate with baseline radiographic damage (ñ=-0.013, P NS)
- First-year tESR and baseline OPG:RANKL ratio seemed to add to each other’s effect on radiographic progression
 ADDITIVE EFFECT
- Radiographic progression was highest (median 26 Sharp units/year) in patients with a high first-year tESR and a low OPG:RANKL ratio
- Radiographic progression was lowest (median 1 Sharp unit/year) in patients with a low first-year tESR and a high OPG:RANKL ratio<>
5-YEAR RADIOGRAPHIC PROGRESSION (by multiple regression analysis)
- First-year tESR (â=0.38, P<0.001)
- OPG:RANKL ratio (â=0.36, P<0.001)
- Equally and independently contributed to explaining the variation in radiographic progression
- No relevant interaction between the tESR and OPG:RANKL ratio
- The effects of these 2 were independent of treatment allocation
- Adding ‘baseline damage’ to the regression model did NOT influence the relationship between the OPG:RANKL ratio and the 5-year radiographic progression
Nor
- The relationship between the tESR and 5-year progression
t:ESR + OPG:RANKL ratios in various
combinations for 5-Year
x-ray progression (>2 Sharp units/yr)
- Could discriminate patients with 5-year x-ray progression from patients with 5-year x-ray stability (shaded area)
- Positive predictive value was 0.86 and negative predictive value was 0.67
- For this optimal combination, odds ratio (OR) for x-ray progression was 12.5 (95% CI 4.3-36.0)
ALL RISK FACTORS
(multivariate analysis)
- Patients with high level of RANKL at baseline had an OR of 4.4 (1.5-13) for long-term x-ray progression (>2 Sharp units/yr)
- Patients with high level of OPG at baseline had an OR of 0.29 (0.10-0.85)
- X-ray progression score was highest in group of patients with a high level of RANKL and a low level of OPG (8 Sharp units/yr) and was lowest in the group of patients with a low level of RANKL and a high level of OPG (2 Sharp units/yr)
- Secondary Analysis: Different progression intervals as dependent variables for tESR and OPG:RANKL ratio did not change the results
DISCUSSION 1
- Inflammation (tESR)
- Osteoclast activation (circ OPG/RANKL)
Are additive on long-term radiographic progression in patients with early RA
These effects are shown in this study to be statistically partly independent
DISCUSSION 2
OPG/RANKL:
- In multiple myeloma, the ratio is 0.67
- In RA, ratio (this study) is 1.2
- In controls, ratio (this study) is 3.0
- In erosive PsA, can demonstrate migration of circulating osteoclast precursors to the inflamed synovium and to SUBCHONDRAL BONE with subsequent exposure to RANKL
DISCUSSION 3
QUESTION: Why do some patients with high degree of disease activity not develop x-ray joint damage whereas others with or without significant inflammation show rapid progression of damage?
DISCUSSION 4
One possible Answer:
Permissive levels of RANKL:
-in vitro, need enough to have TNFá-stimulated macrophages to induce osteoclastogenesis
-animal data – synergistic effect of mechanisms underlying inflammation (TNFá and RANKL) and those underlying destruction
DISCUSSION 5
Critical amounts of RANKL must be present for TNF to be able to accelerate bone destruction
OPG Rx protects against erosions in TNFá transgenic mice with arthritis
RANKL-knockout mice remain free of erosions in animal models, despite persistent inflammation
DISCUSSION 6
Osteoclasts are an important mechanism of joint destruction in RA
Osteoclasts provide an explanation for the clinically suspected partial dissociation between inflammation and joint destruction
DISCUSSION 7
- RANKL is a specific constitutive feature in a proportion of patients (and a high early level at baseline predicts a 5 year progression of damage)
- The balance between activation signals (RANKL) and protective signals (OPG) (these are genetically determinable) determines long-term outcome
DISCUSSION 8
- The pro-erosive effects of (mediators of inflammation) then superimpose on the effects of osteoclasts
DISCUSSION 9
- Existing baseline damage is an important known predictor of radiographic progression of damage
- This study found that despite this variable, OPG:RANKL ratio was predictive (ie a marker of) independently of radiographic progression
DISCUSSION 10
PROBLEM
- OPG:RANKL ratio and 5-year x—ray progression of damage is neither modified nor confounded by treatment
- This is at odds with previous study of the same cohort showing glucocorticoids as part of intensive combination therapy has inhibitory effects on 5- year x-ray progression (osteoclasts and therapeutic impact on them require further study)
DISCUSSION 11
What delivers RANKL ‘on site’?
- activated T cells
- synoviocytes
Both have been shown to secrete RANKL
DISCUSSION 12
Therapeutic agents (Mtx, SSx, Infliximab) have been shown to suppress RANK expression on peripheral blood mononuclear cells (capable of osteoclast formation)
From Abstract
RESULTS: The first-year tESR and the OPG:RANKL ratio, as measured at baseline, independently predicted 5-year radiographic progression of joint damage (both P < or = 0.001). Progression of radiographic damage was greatest in patients with a high tESR and a low OPG:RANKL ratio and was lowest in patients with a low tESR and a high OPG:RANKL ratio.
CONCLUSION: This study in patients with early untreated RA is the first to confirm the findings in animal models of arthritis, that radiographic progression of the bone component of joint destruction is dependent on both inflammation (tESR) and osteoclast activation (the OPG:RANKL ratio).
Both signals deliver pro-erosive effects
progression of joint damage and inflamation can, in part, be dissociated
THERAPEUTIC
IMPLICATIONS ???
Supress
Inflammation
Supress bone resorption |
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Learning Objectives
1. To understand an important mechanism of joint damage in rheumatoid arthritis.
2. To understand the roles of osteoprotegerin (OPG) and RANKL in the damage of bone in rheumatoid arthritis.
3. To identify the ratio of OPG/RANKL as a potential marker predicting damage in patients with early rheumatoid arthritis.
Click HERE Full Text Article (PDF)
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CRA Forum : Review by Dr. JERRY TENENBAUM
Topic: Review By Dr. Jerry Tenenbaum
