Timo Palosuo

Crossreaction between antibodies to oxidised low-density lipoprotein and to cardiolipin in systemic lupus erythematosus

Serum lipoproteins contain phospholipids and modified low-density lipoprotein (LDL) may thus act as a target for antiphospholipid antibodies. Raised concentrations of IgG antibodies against oxidised LDL were found in 47 of 61 (80%) patients with systemic lupus erythematosus (SLE). 46% of patients also had raised concentrations of IgG anticardiolipin antibodies. Binding of anticardiolipin antibodies to solid-phase cardiolipin was inhibited by oxidised LDL but not by native LDL in 16 of 21 sera from SLE patients. These observations suggest crossreactivity between antiphospholipid antibodies, which are closely associated with thrombosis in SLE, and antibodies to oxidised LDL, thus providing a possible link between thrombotic and atherosclerotic complications in SLE.

Serum androgen-anabolic hormones and the risk of rheumatoid arthritis

OBJECTIVE It has been hypothesised, mainly on the basis of indirect evidence, that low serum concentrations of androgen-anabolic hormones would play a causal part in the aetiology of rheumatoid arthritis (RA). METHODS A case-control study was nested with a Finnish cohort of 19 072 adults who had neither arthritis nor a history of it at the baseline examination during 1973–1977. Pre-illness serum specimens for the assay of testosterone and dehydroepiandrosterone sulphate (DHEAS) were available from 116 cases who had developed RA by late 1989. Three controls per each incident case were individually matched for sex, age, and municipality. RESULTS The mean testosterone concentration was 1.4 nmol/l in those 84 women who developed RA and 1.4 nmol/l in their controls; the corresponding figures for DHEAS were 5.2 μmol/l and 5.5 μmol/l, respectively. Mean testosterone concentration in the 32 male cases was 26.1 nmol/l and 26.4 nmol/l in their controls; the corresponding figures for DHEAS were 11.2 μmol/l and 10.1 μmol/l, respectively. Analysis by subgroups (rheumatoid factor positive and negative disease, premenopausal and postmenopausal women) and by hormone distributions showed no differences. CONCLUSION The findings are not in line with the contention that low concentrations of testosterone and DHEAS play a part in the aetiology of RA.

Autoantibodies binding to citrullinated telopeptide of type II collagen and to cyclic citrullinated peptides predict synergistically the development of seropositive rheumatoid arthritis

Objectives: To find out whether autoantibodies to citrullinated telopeptides of type I and II collagens and to cyclic citrullinated peptides (CCPs) predict the development of rheumatoid arthritis (RA). Methods: A case-control study (matched for sex, age and municipality) was nested within a Finnish cohort of 19072 adults who had neither arthritis nor a history of it at the baseline examination during 1973–7. 124 subjects developed RA by late 1989, and of these, 89 were positive for rheumatoid factor (RF). Preillness serum specimens were analysed for autoantibodies against arginine (A)- or citrulline (C)-containing synthetic telopeptides using a chemiluminescence method and for anti-CCPs Mark2 with an enzyme-linked immunosorbent assay method. Results: The mean levels of autoantibodies to citrulline-containing telopeptides and the C/A ratios of type I and II collagens and to CCP were higher in subjects who later developed RF-positive RA. In the highest tertiles of C/A (I), C/A (II) ratios and anti-CCPs levels, the relative risk of RF-positive RA was significantly increased. In the multifactorial model, only anti-CCPs retained its statistical significance. However, the interaction term of C/A (II) ratio and anti-CCPs proved to be statistically significant (p = 0.02). The subjects ranked into the highest tertiles of both C/A (II) ratio and anti-CCPs had an odds ratio of 20.06 (95% confidence interval, 4.37 to 92.06) of developing RF-positive RA compared with those in the lowest tertiles of these antibodies. None of the autoantibodies predicted RF-negative RA. Conclusion: Autoantibodies to citrullinated telopeptides of type I and II collagen and to CCPs exert a synergistic effect on the risk of seropositive RA.

Peptidylarginine deiminase, the arginine to citrulline converting enzyme, is frequently recognized by sera of patients with rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren syndrome

Objective: Antibodies to citrulline‐containing epitopes of filaggrin are highly specific for rheumatoid arthritis (RA). We studied whether the enzyme peptidylarginine deiminase (PAD), responsible for the post‐translational modification of peptide‐bound arginine residues to citrulline, constitutes an antigen for patients with RA. Methods: IgG antibodies to PAD were measured by enzyme‐linked immunosorbent assay (ELISA) in sera from patients with RA, systemic lupus erythematosus (SLE), primary Sjögren syndrome (pSS), multiple sclerosis (MS) and healthy controls. Results: Compared to healthy controls, raised levels of IgG antibodies to PAD were found in 50 of 57 recent‐onset RA patients (88%) and in 40 (70%) of the same 57 patients 3 years later (p<0.0001 for both comparisons). Eleven of 51 (22 %) patients with RA of long duration, 19/43 (44%) patients with SLE and 16/19 (84%) patients with pSS, but none of 20 patients with MS, had elevated anti‐PAD levels. Conclusion: The arginine–citrulline converting enzyme PAD was recognized as a new antigen against which patients with inflammatory rheumatic diseases frequently show IgG class antibodies.

Serum immunoglobulins and the risk of rheumatoid arthritis

OBJECTIVE Rheumatoid arthritis (RA) is associated with several autoantibodies that can precede the clinical disease. The immunoglobulin concentrations in serum samples before illness were studied to learn more about the immunological process before RA. METHODS A case-control study was nested within a Finnish cohort of 19 072 adults who had neither arthritis nor a history of it at the baseline examination during 1973–1977. By late 1989, 124 had developed RA, of which 89 were positive for rheumatoid factor (RF). Three controls per each incident case were individually matched for sex, age, and municipality. The concentrations of IgG, IgA, and IgM were measured from stored serum samples. RESULTS Serum IgG before illness was found to be directly proportional to the risk of RF positive RA, and a non-linear association was present between serum IgA and the risk of RF positive RA. These associations were constant between men and women and other subgroups of the study population and not confounded by serum orosomucoid concentration, level of education, smoking, alcohol intake or body mass index. As adjusted for these factors, the odds ratios (95% confidence intervals) of RF positive RA in the lowest, mid, and highest tertiles of IgG distribution were 1.00, 1.55 (0.81, 2.97), and 2.22 (1.16, 4.26), and in the tertiles of IgA 1.00, 2.23 (1.14, 4.36), and 1.78 (0.89, 3.57), respectively. The associations persisted throughout the entire observation period but were most distinct when the period to the onset of clinical RA was ≥ 10 years. IgM carried no predictive significance. None of the serum immunoglobulins predicted the development of RF negative RA. CONCLUSIONS Increased IgG levels may reflect some, at present unknown process in the early events leading to the development of RA, typically occurring ≥ 10 years before the onset of clinical disease.

Association of mannan-binding lectin deficiency with venous bypass graft occlusions in patients with coronary heart disease.

We investigated the effect of mannan-binding lectin (MBL) deficiency on the susceptibility to bypass graft occlusion in 62 patients with coronary heart disease. MBL deficiency appeared to be associated with occlusion (p = 0.0099). A high level of anti-cardiolipin IgG as well as the number of venous bypass grafts were also involved (p = 0.0018 and p = 0.0104, respectively). Since early occlusion (<5 years after surgery) of a venous bypass graft is considered to be caused by thrombosis or fibro-intimal hyperplasia superimposed by thrombosis, our finding also implies an association of MBL deficiency with thrombotic events. It remains unclear whether the previously confirmed effect of MBL deficiency in coronary disease is mediated through this possible thrombotic mechanism, or whether plaque formation is also involved in the process. Further studies are clearly warranted.

Rheumatoid factors and rheumatoid arthritis.

Rheumatoid factors (RFs) are autoantibodies which bind the Fc region of IgG (1, 2). They can be induced in experimental animals by B cell mitogens and by immunization with a variety of different antigens. Induction by the antigen-driven route has been accomplished only in secondary but not in primary immunization, suggesting that RFs arise as a response occasioned by antigenlantibody-complex rather than the antigen alone.

IgG-rheumatoid factor in seronegative rheumatoid arthritis

The occurrence of IgG-rheumatoid factor (RF) reacting with rabbit IgG was studied in the sera of:a) 1105 elderly (55-74 years) males from rural areas of Finland, which were obtained in connection with a cohort study of atherosclerotic cardiovascular diseases (population series); and ofb) 201 adult patients with definite or probable rheumatoid arthritis or non-definite arthritis, which were taken in connection with a follow-up (6-9 years) examination of a patient cohort with recent inflammatory joint disease (patient series).IgG-RF was measured with an enzyme-linked immunosorbent assay (ELISA) adopting a Δ-value (absorbance to antigen/antibody complex minus absorbance to antigen alone) for use. The Waaler-Rose test was positive in 28 cases (2.5 %) of the population series. Raised levels of IgG-RF (a Δ-value of ≥ 0.200) were found in 12 sera. Nine of these were positive in the Waaler-Rose test, and two further sera contained raised levels of IgM-RF as measured by latex test or by IgM-RF ELISA. The IgG-RF ac...