Circulating surfactant protein -D is low and correlates negatively with systemic inflammation in early, untreated rheumatoid arthritis.
BACKGROUND
Surfactant protein D (SP-D) is a collectin with immuno-regulatory functions, which may depend on oligomerization. Anti-microbial and anti-inflammatory properties have been attributed to multimeric SP-D variants, while trimeric subunits per se have been suggested to enhance inflammation. Previously, we reported low circulating SP-D in early rheumatoid arthritis (RA), and the present investigation aims to extend these data by serial SP-D serum measurements, studies on synovial fluid, SP-D size distribution and genotyping in patients with early RA.


METHODS
One-hundred-and-sixty disease-modifying antirheumatic drug (DMARD) naïve RA patients with disease duration less than six months were studied prospectively for four years (CIMESTRA (Ciclosporine, Methotrexate, Steroid in RA) trial) including disease activity measures (C-reactive protein, joint counts and Health Assessment Questionnaire (HAQ) score), autoantibodies, x-ray findings and SP-D. SP-D was quantified by enzyme-linked immunosorbent assay (ELISA) and molecular size distribution was assessed by gel filtration chromatography. Further, SP-D Met11Thr single nucleotide polymorphism (SNP) analysis was performed.


RESULTS
Serum SP-D was significantly lower in RA patients at baseline compared with healthy controls (P < 0.001). SP-D increased slightly during follow-up (P < 0.001), but was still subnormal at four years after adjustment for confounders (P < 0.001). SP-D in synovial fluid was up to 2.5-fold lower than in serum. While multimeric variants were detected in serum, SP-D in synovial fluid comprised trimeric subunits only. There were no significant associations between genotype distribution and SP-D. Baseline SP-D was inversely associated to CRP and HAQ score. A similar relationship was observed regarding temporal changes in SP-D and CRP (zero to four years). SP-D was not associated to x-ray findings.


CONCLUSIONS
This study confirms that circulating SP-D is persistently subnormal in early and untreated RA despite a favourable therapeutic response obtained during four years of follow-up. SP-D correlated negatively to disease activity measures, but was not correlated with x-ray progression or SP-D genotype. These observations suggest that SP-D is implicated in RA pathogenesis at the protein level. The exclusive presence of trimeric SP-D in affected joints may contribute to the maintenance of joint inflammation.


BACKGROUND
(j.nr NCT00209859).
Christensen
Anne Friesgaard
AF
Department of Rheumatology, Odense University Hospital, Sdr, Boulevard 29, DK-5000 Odense C, Denmark. a.friesgaard@gmail.com
Sørensen
Grith Lykke
GL
Hørslev-Petersen
Kim
K
Holmskov
Uffe
U
Lindegaard
Hanne Merete
HM
Junker
Kirsten
K
Hetland
Merete Lund
ML
Stengaard-Pedersen
Kristian
K
Jacobsen
Søren
S
Lottenburger
Tine
T
Ellingsen
Torkell
T
Andersen
Lis Smedegaard
LS
Hansen
Ib
I
Skjødt
Henrik
H
Pedersen
Jens Kristian
JK
Lauridsen
Ulrik Birk
UB
Svendsen
Anders
A
Tarp
Ulrik
U
Pødenphant
Jan
J
Vestergaard
Aage
A
Jurik
Anne Grethe
AG
Østergaard
Mikkel
M
Junker
Peter
P
D000293:Adolescent; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000235:genetics / Q000503:physiopathology; D001175:Arthrography; D005260:Female; D005838:Genotype; D006304:Health Status; D006801:Humans; D008297:Male; D008668:Metallothionein / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D037663:Pulmonary Surfactant-Associated Protein D / Q000097:blood*; D012016:Reference Values; D011795:Surveys and Questionnaires; D055815:Young Adult
C491053:MT2A protein, human; D037663:Pulmonary Surfactant-Associated Protein D; D008668:Metallothionein