The frequency of anti-β2-glycoprotein I antibodies is low and these antibodies are associated with pulmonary hypertension in mixed connective tissue disease

Abstract

The objective of this study is to evaluate the prevalence of antiphospholipid antibodies, mainly anti-β₂-glycoprotein I (anti-β₂-GPI), and their possible clinical and laboratory relevance in mixed connective tissue disease (MCTD). This study included 39 consecutive patients with MCTD (Kasukawa’s criteria) from January, 2005, to March, 2007, and compared them with 21 age- and sex-matched healthy controls. IgG and IgM anticardiolipin (aCL) and anti-β₂-GPI were measured by ELISA. Lupus anticoagulant (LA) was detected by functional coagulation tests. Medium to high titres of aCL and anti-β₂-GPI antibodies were found in sera from four (10.2%) MCTD patients. One of these patients was found to be positive for IgM aCL, IgM anti-β₂-GPI and LA antibodies simultaneously. Additionally, this patient had a previous history of foetal loss in the second trimester and new-onset pulmonary arterial hypertension (PAH). The other three patients had none of the manifestations of antiphospholipid syndrome (APS) or PAH. The mean value of IgG anti-β₂-GPI was higher among those MCTD patients with PAH than in the group without PAH (34.2 ± 46.8 vs 12.3 ± 9.1, P = 0.018). None of the controls were positive for antiphospholipid antibodies. High to moderate titres of anti-β₂-GPI as well as APS were rare in MCTD, and these antibodies may be correlated with the development of PAH in these patients.

Keywords

anti-β2-glycoprotein I antibody anticardiolipin antiphospholipid antibody lupus anticoagulant mixed connective tissue disease

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References

1 Hughes GRV . Thrombosis. Abortion, cerebral disease, and lupus anticoagulant. Br Med J 1983; 287: 1088–1089.

2 Miyakis S Lockshin MD Atsumi T . International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295–306.

3 Sharp GC Irwin WS Tan EM Gould RG Holman HR . Mixed connective tissue disease: an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med 1972; 52: 148–158.

4 Miyata M Suzuki K Sakuma F . Anticardiolipin antibodies are associated with pulmonary hypertension in patients with mixed connective tissue disease or systemic lupus erythematosus. Int Arch Allergy Immunol 1993; 100: 351–354.

5 Doria A Ruffatti A Calligaro A . Antiphospholipid antibody in mixed connective tissue disease. Clin Rheumatol 1992; 11: 48–50.

6 Mendonça LL Amengual O Atsumi T Khamashta MA Hugues GRV . Most anticardiolipin antibodis in mixed connective tissue disease are beta2-glycoprotein independent. J Rheumatol 1998; 25: 189–190.

7 Komatireddy GR Wang GS Sharp GC Hoffman RW . Antiphospholipid antibodies among anti-U1-70kDa autoantibody positive patients with mixed connective tissue disease. J Rheumatol 1997; 24: 319–322.

8 Somers E Magder LS Petri M . Antiphospholipid antibodies and incidence of venous thrombosis in a cohort of patients with systemic lupus erythematosus. J Rheumatol 2002; 29: 2531–2536.

9 Wahl DG Guilhermin F de Maistre E Perret-Guillaume C Lecompete T Thibaut G . Risk of venous thrombosis related to antiphospholipid antibodies in systemic lupus erythematosus – a meta-analysis. Lupus 1997; 6: 467–473.

10.

10 Miyata M Kida S Kanno T . Pulmonary hypertension in MCTD: report of two cases with anticardiolipin antibody. Clin Rheumatol 1992; 11: 195–201.

11.

11 Vegh J Szodoray P Kappelmayer J . Clinical and immunoserological characteristics of mixed connective tissue disease associated with pulmonary arterial hypertension. Scand J Immunol 2006; 64: 69–76.

12.

12 Kasukawa R Tojo T Miyawaki S . Preliminary diagnostic criteria for classification of mixed connective tissue disease. In: R Kasukawa GC Sharp , (eds), Mixed connective tissue disease and antinuclear antiodies. Amsterdam: Elsevier; 1987. pp. 41–47.

13.

13 Harris EN Pierangeli S . The Anticardiolipin ELISA test. Clin Immunol Newsl 1991; 11: 33–44.

14.

14 Wisloff F Jacobsen EM Liestol S . Laboratory diagnosis of the antiphospholipid syndrome. Thromb Res 2002; 108: 263–271.

15.

15 Hoffman RW Rettenmaier LJ Takeda Y . Human autoantibodies against the 70kd polypeptide of U1 small nuclear RNP are associated with HLA-DR4 among connective tissue disease patients. Arthritis Rheum 1990; 35: 94–101.

16.

16 Kurata N Tan EM . Identification of antibody to nuclear acidic antigens by counterimmunoelectrophoresis. Arthritis Rheum 1976; 19: 574–580.

17.

17 Elkon KB Culhane L . Partial immunochemical characterization of the Ro and La proteins using antibodies from patients with the sicca syndrome and lupus erythematosus. J Immunol 1984; 132: 2350–2356.

18.

18 Tan EM Peebles C . Quantitation of antibodies to Sm antigen and nuclear ribonucleoprotein by hemagglutination. In: NR Rose H Friedman , (eds), Manual of clinical immunology. 2nd ed. Washington: American Society of Microbiology; 1980. pp. 866–870.

19.

19 Wahl DG Guilhermin F de Maistre E Perret-Guillaume C Lecompete T Thibaut G . Meta-analisis of the risk of venous thrombosis in individuals with antiphospholipid antibodies without underlying autoimmune disease or previous thrombosis. Lupus 1998; 7: 15–22.

20.

20 Amengual O Atsumi T Khamashta MA Koike T Hughes GRV . Specificity of ELISA for antibody beta-2glycoprotein I in patients with antiphospholipid syndrome. Br J Rheumatol 1996; 35: 1239–1243.

21.

21 Asherson RA Cervera R . Pulmonary hypertension, antiphospholipid antibodies, and syndromes. Clin Rev Allergy Immunol 2007; 32: 153–158.

22.

22 Stojanovich L . Pulmonary manifestations in antiphospholipid syndrome. Autoimmun Rev 2006; 5: 344–348.

23.

23 Espinosa G Cervera R Font J Asherson RA . The lung in the antiphospholipid syndrome. Ann Rheum Dis 2002; 61: 195–198.