Serum cartilage biomarkers in late rheumatoid arthritis Marcadores séricos de cartilagem na artrite reumatóide avançada

June 6, 2017 | Autor: Carlos Gayer | Categoria: Rheumatoid Arthritis, P-glycoprotein
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Serum cartilage biomarkers in late rheumatoid arthritis

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ORIGINAL ARTICLE

Serum cartilage biomarkers in late rheumatoid arthritis Marcadores séricos de cartilagem na artrite reumatóide avançada Morton Aaron Scheinberg1, Geraldo da Rocha Castelar Pinheiro2, Carlos Augusto Ferreira de Andrade3, Carlos Roberto Gayer4, Marsen Garcia Pinto Coelho5, Sérgio Miranda Freire6

ABSTRACT Objectives: To evaluate the clinical value of two new cartilage serum markers in patients with rheumatoid arthritis of long duration. Methods: One hundred and forty patients followed for an average period of twelve years were evaluated for the presence of human cartilage glycoprotein-39 and cartilage serum oligomeric matrix protein and the respective coefficient correlation between markers and disease activity score. Results: The mean values of cartilage serum oligomeric matrix protein and human cartilage glycoprotein-39 were respectively 9 ± 6 ug/ml and 36 ± 16 mg/ ml (p > 0,001) when compared to controls. A positive correlation was observed between disease activity score and the cartilage biomarkers (r = 0,67 for human cartilage glycoprotein-39 and r = 0,83 for cartilage serum oligomeric matrix protein. Conclusion: This study shows in a inequivocal form that patients with rheumatoid arthritis of long duration show higher values of serum biochemical markers of cartilage metabolism and a positive correlation with disease activity score. Keywords: Arthritis rheumatoid; Biological makers/analysis; Cartilage/metabolism

RESUMO Objetivos: Avaliar o valor clínico de dois novos marcadores séricos de cartilagem em pacientes com artrite reumatóide crônica. Métodos: Cento e quarenta pacientes foram seguidos por um período médio de 12 anos e avaliados para a presença de glicoproteína-39 de cartilagem humana e para matrix de proteína oligomérica sérica e seu respectivo coeficiente de correlação entre os marcadores e um escore de atividade da doença. Resultados: Os valores médios da matrix de proteína oligomérica sérica e

glicoproteína-39 de cartilagem humana foram, respectivamente, 9 ± 6 ug/ml e 36 ± 16 ug/ml (p > 0,001) quando comparados aos controles. Uma correlação positiva foi observada entre os escores de atividade da doença e os biomarcadores (r = 0,67 para a glicoproteína-39 de cartilagem humana e r = 0,83 para a matrix de proteína oligomérica sérica). Conclusão: O presente estudo mostra de maneira inequívoca que pacientes com artrite reumatóide de longa duração mostram valores séricos mais elevados de marcadores bioquímicos do metabolismo da cartilagem e uma correlação positiva com o escore de atividade da doença. Descritores: Artrite reumatóide; Marcadores biológicos/análise; Cartilagem/metabolismo

INTRODUCTION Rheumatoid arthritis (RA) is a chronic disease clinically leading to joint destruction as a consequence of a destructive inflammatory process(1-2). Besides serum rheumatoid factor early predictors of joint destruction in recent onset rheumatoid arthritis are few including HLA DRB1, cartilage biomarkers and the novel anti-cyclic citrullinated peptide antibody(3-5). In the present report we looked into a large number of patients with rheumatoid arthritis of long duration and the serum levels of two cartilage biochemical markers, YKLK-40 (also known as human cartilage glycoprotein-39) and cartilage serum oligomeric matrix protein (COMP) in an attempt to determine if patients with higher disease activity score (DAS) correlate with the serum levels of cartilage markers.

Study carried out at University Hospital from the Universidade Estadual do Rio de Janeiro, UERJ, Rio de Janeiro, (RJ) and Hospital Israelita Albert Einstein, São Paulo (SP), Brazil. 1

PhD, Boston University; Post doctorate degree from the Universidade de São Paulo – USP; MD; Researcher in Rheumatology and Immunology at the Instituto Israelita de Ensino e Pesquisa Albert Einstein – IIEP; Scientific director of the Hospital Abreu Sodré - AACD, São Paulo (SP), Brazil.

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Adjunct Professor, Universidade Estadual do Rio de Janeiro - UERJ, Rio de Janeiro (RJ), Brazil.

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Adjunct Professor, Universidade Estadual do Rio de Janeiro - UERJ, Rio de Janeiro (RJ), Brazil.

4

Adjunct Professor, Universidade Estadual do Rio de Janeiro - UERJ, Rio de Janeiro (RJ), Brazil.

5

Adjunct Professor, Universidade Estadual do Rio de Janeiro - UERJ, Rio de Janeiro (RJ), Brazil.

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Adjunct Professor, Universidade Estadual do Rio de Janeiro - UERJ, Rio de Janeiro (RJ), Brazil. Corresponding author: Morton Aaron Scheinberg - Av. Albert Einstein, 627 - Morumbi - CEP 5651-901 - São Paulo (SP), Brazil - Tel.: 11 3747 3209 - e-mail: [email protected] Received on December 2, 2005 - Accepted on February 20, 2006

einstein. 2006; 4(1):1-3

Scheinberg MA, Pinheiro GRC, Andrade CAF, Gayer CR, Coelho MGP, Freire SM

METHODS Patients Hundred forty patients with long standing rheumatoid arthritis according to the ACR criteria attending the outpatient clinic of the University Hospital from the State University of Rio de Janeiro and Hospital Israelita Albert Einstein of São Paulo were studied: 128 women and 12 men with a mean age of 53 years and a mean duration of 12 years (table 1). The DAS was evaluated by the method of van der Heidje D and co-workers(6). According to the Eular criteria none of our patients were in remission or/and burned out disease (DAS less than 1). The drugs employed in the treatment of these patients are shown on table 2.

Table 3. Serum levels of COMP and YKL-40 ug/ml COMP mg/ml YKL-40

Correlation (DAS)

9+/-6 36+/-16

1.2+/-3 0.3+/-0.2

r=0.83 r=0.67

120 100 80 60 40 20

Patients

Controls

140 12.0 53 2.5–7.0 3–15

50 – 42.0 – 0.2–0.8

0 0

1

2

3

4

5

6

7

8

9

7

8

9

DAS Figure 1. Correlation between DAS and COMP (r = 0,83) DAS vs COMP

6 5

Table 2. Patient therapy Number of Patients

Azathioprime Sulfasalazine Chloroquine Methotrexate Anagelsic drugs Seroids NSAIDS Gold salts

8 4 26 50 17 39 42 3

Laboratory analysis The laboratory parameters used were COMP YKL-40 and C reactive protein performed as previously described (7-8). Statistical Analysis Spearman’s rank test and a linear multiple regression analysis were employed in our study. RESULTS Both cartilage markers were significantly elevated in patients with RA of long duration, when compared to a control population. The mean values of COMP and YKL-40 were respectively 9 + 6 and 36 + 16 (p > 0,001) (table 3). The scattered of COMP and YKL plotted agonist DAS are shown on figures 1 and 2. A positive correlation were observed between DAS and both cartilage biomarkers (r = 0,83 for COMP) and (r = 0,67 por YKL-40).

4 YK L-40

Medication

einstein. 2006; 4(1):1-3

Controls

DAS vs YK L-40

Table 1. Characteristics of patients and controls Number Disease duration (years) Mean age Disease activity CRP (mg/dl)

RA

140

YK L-40

2

3 2 1 0

0

1

2

3

4

5 6 DAS Figure 2. Correlation between DAS and YKL-40 (r = 0,67)

DISCUSSION Our study shows that serum cartilage markers are elevated in patients with RA of long duration. Also both markers point to a strong correlation between DAS and biologic markers of cartilage turnover. The identification of blood markers that could identify patients with rheumatoid arthritis of the destructive type is important since now we have various new forms of therapy that could avoid joint destruction and functional impairment. Cartilage markers have been evaluated in patients with early onset RA and suggested to be a good predictor of aggressive disease even though correlation with inflammatory markers are somewhat controversial in some reports(9-12). Our study we believe is the first one looking in a large number of patients with elevated DAS. The correlation observed between cartilage markers and DAS confirms the notion that both YKL-40 and COMP are

Serum cartilage biomarkers in late rheumatoid arthritis

good markers of outcome assessment and in some way similar to other proposed ones such as bone erosions, synovium activation and genetic susceptibility markers. In fact, treatment with DMARDs and biologicals are also shown to induce clinical response associated with reduction of the serum level of these markers in sera(13-14). We have not attempted to look at correlations between inflammatory markers YKL-40 and COMP serum levels since in previous publications using the same patient population in disease of long duration we did not find a very good correlation between sedimentation rate, C reactive protein and DAS(15). In summary, in a population of patients with RA of long duration serum cartilage markers appear to reflect severe disease and maybe helpful as a routine tool in clinical practice where new therapeutic measures are gradually taking place in the treatment of rheumatoid arthritis(16).

CONCLUSION This study shows in a inequivocal form that patients with RA of long duration show higher values of serum biochemical markers of cartilage metabolism and a positive correlation with DAS. REFERENCES

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4. Kroot EJ, de Jong BA, van Leeuwen MA, Swinkels H, van den Hoogen FH, van t Hof M et al. The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent onset rheumatoid arthritis. Arthritis Rheum. 2000;43(8):1831-5. 5. Pinheiro GC, Scheinberg MA, Aparecida da Silva M, Maciel S. Anti cyclic citrullinated peptide antibodies in advanced rheumatoid arthritis. Ann Intern Med. 2003;139(3):234-5. 6. van der Heijde DM, van t Hof M, van Riel PL, van de Putte LB. Development of a disease activity score based on judgment in clinical practice by rheumatologists. J Rheumatol. 1993;20(3):579-81. 7. Maciel SB, Scheinberg MA. Serum chondrex values in knee osteoarthritis (OA). The effect of arthroscopy. Clin Rheumatol. 2000;19(1):76-7. 8. Scheinberg MA, Maciel S. Increased serum levels of cartilage oligomeric matrix protein and human cartilage glycoprotein-39 in marathon runners [abstract]. Arthritis Rheum. 2001;44(6):817. 9. Forslind K, Eberhardt E, Jonsson A, Saxne T.Increased serum concentrations of cartilage oligomeric matrix protein. A prognostic marker in early rheumatoid arthritis. Br J Rheumatol. 1992;31(9):593-8. 10. Matsumoto T, Tsurumoto T. Serum YKL-40 levels in rheumatoid arthritis: correlations between clinical and laboratory parameters. Clin Exp Rheumatol. 2001;19(6):655-60. 11. Johansen JS, Kirwan JR, Price PA, Sharif M. Serum YKL-40 concentrations in patients with early rheumatoid arthritis: relation to joint destruction. Scand J Rheumatol. 2001;30(5):297-304. 12. Peltomaa R, Paimela L, Harvey S, Helve T, Leirisalo-Repo M. Increased level of YKL-40 in sera from patients with early rheumatoid arthritis: a new marker for disease activity. Rheumatol Int. 2001;20(5):192-6. 13. Den Broeder AA, Joosten LA, Saxne T, Heinegard D, Fenner H, Miltenburg AM et al. Long term anti-tumour necrosis factor alpha monotherapy in rheumatoid arthritis: effect on radiological course and prognostic value of markers of cartilage turnover and endothelial activation. Ann Rheum Dis. 2002;61(4):311-8.

1. Scheinberg MA. The pathogenesis of rheumatoid arthritis and the immune response. Semin Arthritis Rheum. 1983;13(1 Suppl 1):99-101.

14. Charles PJ, Maini RN, Serum YKL-40, a chondrocyte derived protein, is reduced by infliximab (anti TNF) therapy in patients with rheumatoid arthritis [abstract]. Arthritis Rheum. 1999;42 (2):236.

2. Pap T, Gay R, Gays S. Mechanisms of joint destruction In: Firestein GS, Panayi GS, Wolheim F, eds. Rheumatoid arthritis. New frontiers in pathogenesis and treatment. Oxford: Oxford University Press; 2000. p.189-99.

15. Pinheiro GR, Andrade CA, Gayer CR, Coelho MS, Scheinberg MA. Serum vascular endothelial growth factor in late rheumatoid arthritis.Clin Exp Rheumatol. 2001;19(6):721-3.

3. Nakamura RM. Progress in the use of biochemical and biologic markers for evaluation of rheumatoid arthritis. J Clin Lab Anal. 2000;14(6):305-13.

16. Wollheim FA. TNF inhibition as therapy for rheumatoid arthritis. Expert Opin Investig Drugs. 2002;11(7):947-3.

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