title: Circulating surfactant protein -D is low and correlates negatively with systemic inflammation in early, untreated rheumatoid arthritis.
abstract: 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).
authors.affiliation: Department of Rheumatology, Odense University Hospital, Sdr, Boulevard 29, DK-5000 Odense C, Denmark. a.friesgaard@gmail.com
authors.forename: Anne Friesgaard
authors.initials: AF
authors.lastname: Christensen
authors.forename: Grith Lykke
authors.initials: GL
authors.lastname: Sørensen
authors.forename: Kim
authors.initials: K
authors.lastname: Hørslev-Petersen
authors.forename: Uffe
authors.initials: U
authors.lastname: Holmskov
authors.forename: Hanne Merete
authors.initials: HM
authors.lastname: Lindegaard
authors.forename: Kirsten
authors.initials: K
authors.lastname: Junker
authors.forename: Merete Lund
authors.initials: ML
authors.lastname: Hetland
authors.forename: Kristian
authors.initials: K
authors.lastname: Stengaard-Pedersen
authors.forename: Søren
authors.initials: S
authors.lastname: Jacobsen
authors.forename: Tine
authors.initials: T
authors.lastname: Lottenburger
authors.forename: Torkell
authors.initials: T
authors.lastname: Ellingsen
authors.forename: Lis Smedegaard
authors.initials: LS
authors.lastname: Andersen
authors.forename: Ib
authors.initials: I
authors.lastname: Hansen
authors.forename: Henrik
authors.initials: H
authors.lastname: Skjødt
authors.forename: Jens Kristian
authors.initials: JK
authors.lastname: Pedersen
authors.forename: Ulrik Birk
authors.initials: UB
authors.lastname: Lauridsen
authors.forename: Anders
authors.initials: A
authors.lastname: Svendsen
authors.forename: Ulrik
authors.initials: U
authors.lastname: Tarp
authors.forename: Jan
authors.initials: J
authors.lastname: Pødenphant
authors.forename: Aage
authors.initials: A
authors.lastname: Vestergaard
authors.forename: Anne Grethe
authors.initials: AG
authors.lastname: Jurik
authors.forename: Mikkel
authors.initials: M
authors.lastname: Østergaard
authors.forename: Peter
authors.initials: P
authors.lastname: Junker
mesh_terms: 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
chemical_list: C491053:MT2A protein, human; D037663:Pulmonary Surfactant-Associated Protein D; D008668:Metallothionein