Short summary

Different aspects of psoriatic arthritis and spondyloarthritis. We investigate the value of biomarkers for cartilage metabolism, the innate immunsystem, inflammation and epigenetic changes for early diagnosis, clinical phenotype, disease activity and treatment response in cohorts of patients with psoriatic arthritis and spondyloarthritis.

Rationale

Spondyloarthritis (SpA) and psoriatic arthritis (PsA) are chronic inflammatory diseases primarily targeting the axial skeleton and entheses, but also the synovium and more rarely extra-skeletal sites as well. If left untreated, spinal and peripheral joint deformities may develop due to cartilage and bone destructive processes along with progressive new bone formation throughout the spine and in peripheral joints. The etiology is unknown but both genetic and environmental triggers seem to be implicated.

A number of biomarkers have been investigated in patients with SpA and PsA. Most of them are related to connective tissue, bone or the immune response to these diseases. The biomarkers have both been tested as gene variants within associated genes, such as interleukin-13 (IL-13) and TNF-alpha, and as circulating protein markers, including immune markers such as IL-12, IL-17, IL-2, IL-10, IL-13, focusing on the T-helper cell 17 response, growth factors, such as vascular endothelial grow factor (VEGF), metalloproteinases (MMP), collagen markers and other. Association for citrullinated and carbonylated proteins has also been tested because these are found associated with rheumatoid arthritis.

Circulating nucleic acids, both DNA and RNA, are new biomarkers tested in many diseases. Circulating DNA is probably associated with cell degradation and inflammation and is thus a nonspecific marker for many diseases. In recent years, the focus has been on microRNA as a diagnostic tool in a number of different diseases and there are few studies of these markers in SpA and PsA. MicroRNAs are short pieces of RNA that have been shown to be stable and avoid degradation, both because they are bound to exosomes and maybe also because they are bound to protein. However, they are found in all types of cells in full blood, so sample handling is of great importance for interpreting these markers. MicroRNAs are thought to be epigenetic changes that regulate protein expression for a wide variety of genes.

In this study we investigate the pathophysiological background for the development of structural lesion in spine and in peripheral joints in patients with SpA and PsA by studies of cartilage metabolism and the immune system.

Description of the cohort

This is a case-control study of patients with X-ray or MRI verified axial SpA according to the ASAS criteria, age 18-63 years (n=110), disease duration 6.5 (5.4-7.5) years and PsA patients fulfilling the CASPAR criteria, age 21-53 years (n=101), disease duration 6.8 (5.7-7.9) years. Patients attending the Rheumatology outpatient clinics at Esbjerg, Vejle Hospital and Odense University Hospital, Denmark were recruited in November 2011 through February 2014 (33-120 patients per center).

Data and biological material

BMI, gender, age, smoking habits, current and previous treatment, HLA-B27 status and disease scorings were recorded. Standard hospital laboratory tests were carried out including haemoglobin, white bold cell count, platelet count, ALAT, creatinine, sodium, potassium, albumin, urate and CRP. Personal data, clinical data and standard hospital laboratory tests were collected in DANBIO, the national Danish registry of patients with rheumatologically diseases.

Non-fasting blood samples were collected in plain tubes from patient populations at 9-16 AM. They were allowed to clot for 30-120 minutes and then centrifuged for 12 minutes at 2.200 g. Serum and DNA samples are kept frozen at -80°C. Urine samples were collected and stored at -80°C. Blood, DNA and urine are stored in a biobank at Odense University Hospital.

Collaborating researchers and departments

Department of Immunology, Neastved Hospital.

• Consultant Ole Birger Vesterager Pedersen, Ph.d.

Cancer and Inflammation Research, Department of Molecular Medicine, University of Southern Denmark, Odense.

• Professor Grith Lykke Sørensen, MD.
• Professor Uffe Holmskov, MD.

Department of Epidemiology, Biostatistics and Biodemography, University of Southern Denmark, Odense.

• Cand.scient Ph.d. Lene Christiansen, Ph.d.
• Professor Qihua Tan, Ph.d.

Department of Internal Medicine, Lillebaelt Hospital, Vejle.

• Consultant Anne Friesgaard Christensen, Ph.d.
• Consultant Anne Gitte Loft, MD.

Department of Rheumatology, Esbjerg Hospital, Esbjerg.

• Consultant Leif Ejstrup.

Publications associated with the project

PhD Thesis: Spondyloarthritis and psoriatric arthritis. Aspects of cartilage metabolism and innate immune defence in relation to clinical phenotype and disease activity. 2014.

Publications in international peer reviewed journals:

Surfactant protein-D, a potential mediator of inflammation in axial spondyloarthritis.

Munk HL, Fakih D, Christiansen L, Tan Q, Christensen AF, Ejstrup L, Loft AG, Junker K, Kyvik KO, Jounblat R, Holmskov U, Sorensen GL, Junker P.

Rheumatology (Oxford). 2018 Oct 1;57(10):1861-1865. doi: 10.1093/rheumatology/key187.

PMID: 29982797

Type I and III collagen turnover is increased in axial spondyloarthritis and psoriatic arthritis. Associations with disease activity and diagnostic capacity.

Gudmann NS, Siebuhr AS, Christensen AF, Ejstrup L, Sørensen GL, Loft AG, Karsdal MA, Bay-Jensen AC, Munk HL, Junker P.

Clin Exp Rheumatol. 2017 Jul-Aug;35(4):653-659. Epub 2017 Feb 24

PMID: 28240584

No diagnostic utility of antibody patterns against Klebsiella pneumoniae capsular serotypes in patients with axial spondyloarthritis vs. patients with non-specific low back pain: a cross-sectional study.

Hermansen LT, Loft AG, Christiansen AA, Munk HL, Gilbert L, Jurik AG, Arnbak B, Manniche C, Weber U, Østergaard M, Pedersen SJ, Barington T, Junker P, Hørslev-Petersen K, Hendricks O. Scand J Rheumatol. 2017 Jul;46(4):296-302. doi: 10.1080/03009742.2016.1205659. Epub 2016 Sep 7.

PMID: 27600931

Chondrocyte activity is increased in psoriatic arthritis and axial spondyloarthritis.

Gudmann NS, Munk HL, Christensen AF, Ejstrup L, Sørensen GL, Loft AG, Karsdal MA, Bay-Jensen AC, He Y, Siebuhr AS, Junker P.

Arthritis Res Ther. 2016 Jun 16;18(1):141. doi: 10.1186/s13075-016-1040-z.

PMID: 27306080

Cartilage collagen type II seromarker patterns in axial spondyloarthritis and psoriatic arthritis: associations with disease activity, smoking and HLA-B27.

Munk HL, Gudmann NS, Christensen AF, Ejstrup L, Sorensen GL, Loft AG, Bay-Jensen AC, Siebuhr AS, Junker P.

Rheumatol Int. 2016 Apr;36(4):541-9. doi: 10.1007/s00296-015-3397-8.

PMID: 26620690