Baseline RANKL:OPG ratio and markers of bone and cartilage degradation predict annual radiological progression over 11 years in rheumatoid arthritis.
OBJECTIVE
To determine to what extent baseline measurements of the ratio receptor activator of nuclear factor-kappaB ligand (RANKL):osteoprotegerin (OPG) and C-terminal cross linking of type-I and type-II (CTX-I and CTX-II), in addition to traditional markers of disease severity, could predict annual radiological progression.


METHODS
A cohort of 155 patients with early, active, untreated rheumatoid arthritis (RA) who participated in the Combination Therapy in Early Rheumatoid Arthritis trial (COBRA trial) was followed up for 11 years. Urine was sampled at baseline and after 3 months from the start of treatment and analysed for CTX-I and CTX-II. Baseline serum samples were analysed for RANKL and OPG. Available traditional markers of disease severity included baseline measurements of erythrocyte sedimentation rate, rheumatoid factor and baseline radiological damage. A digital database of frequent radiographs was available, scored according to the Sharp/van der Heijde method. Individual annual progression rates were calculated and used as outcome variable. Multiple linear regression analyses identified the strongest predictors of annual radiological progression.


RESULTS
In multivariable analyses the RANKL:OPG ratio and CTX-I or CTX-II proved to be independent predictors of annual radiological damage over 11 years. The prediction of annual radiological progression was strongest when the RANKL:OPG ratio and CTX-I or CTX-II were evaluated in the same model (36-39% explained variance). Adding the effect of treatment at 3 months to the baseline models improved the predictive ability of the models up to 44-46%.


CONCLUSIONS
Unfavourable baseline levels of the RANKL:OPG ratio as well as CTX-I and CTX-II in patients with early, active, untreated RA are strong independent predictors of rapid and persistent damage progression over the 11-year follow-up. Early improvement in bone markers by treatment predicts a better outcome.
VU University Medical Center, Department of Rheumatology, De Boelelaan 1117, Amsterdam, The Netherlands. l.vantuyl@vumc.nl
Lilian H D
LH
van Tuyl
Alexandre E
AE
Voskuyl
Maarten
M
Boers
Piet
P
Geusens
Robert B M
RB
Landewé
Ben A C
BA
Dijkmans
Willem F
WF
Lems
D000328:Adult; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001862:Bone Resorption / Q000209:etiology; D002357:Cartilage Diseases / Q000209:etiology; D024042:Collagen Type I; D024043:Collagen Type II / Q000652:urine; D018450:Disease Progression; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D053244:Osteoprotegerin / Q000097:blood*; D010446:Peptide Fragments / Q000652:urine; D010455:Peptides; D011347:Procollagen / Q000652:urine; D011379:Prognosis; D053245:RANK Ligand / Q000097:blood*
D018501:Antirheumatic Agents; D015415:Biomarkers; D024042:Collagen Type I; D024043:Collagen Type II; D053244:Osteoprotegerin; D010446:Peptide Fragments; D010455:Peptides; D011347:Procollagen; D053245:RANK Ligand; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C543437:collagen II C-telopeptide; C052929:collagen type I trimeric cross-linked peptide