A Comprehensive Review on the Role of Interleukin-40 as a Biomarker for Diagnosing Inflammatory Diseases.

Progressive bone and cartilage destruction in arthritic joints leads to irreversible joint destruction and, subsequently, to functional declines and to work disability. During recent years a lot of interest has been focused on serum biomarkers in the clinic to evaluate the ongoing disease process in the cartilage and bone. New biomarkers such as osteoprotegerin or receptor activator of NF-κB ligand have been developed to describe the local bone process in affected joints. Cartilage oligomeric matrix protein in serum (sCOMP) is a biomarker for the cartilage turnover [1] and is elevated in patients with rheumatoid arthritis (RA), in patients with osteoarthritis and in patients with articular trauma. sCOMP is a valuable parameter for the assessment of therapy response in RA [2]. Elevated serum levels of sCOMP showed a significant correlation with the progression of the Larsen score within 5 years in a patient group with established RA, and sCOMP is also described as a prognostic factor in early RA [3,4]. Inflammatory synovium has been considered a potential tissue source of sCOMP since the molecule has been detected in the synovium in both RA [5,6] and osteoarthritis [6]. However, less is known of how much sCOMP the synovium produces in other inflammatory rheumatic diseases. The aim of our study was to investigate whether increased sCOMP is a specific marker for joint destruction, comparing sCOMP between patients with RA and patients with other inflammatory rheumatic diseases with less cartilage-destructive arthritis. Levels of sCOMP and serum C-reactive protein (CRP) were measured in 150 patients. Seventy-seven of the patients had seropositive erosive RA, fifteen patients had psoriatic arthritis (PsA), ten patients had reactive arthritis, twelve patients had primary Raynaud's syndrome, eleven patients had scleroderma, nine patients had systemic lupus erythematosus, seven patients had leucozytoclastic vasculitis, five patients had primary Sjogren's syndrome and four patients had CRST (calcinosis, Raynaud's syndrome, scleroderma, teleangiectasia) syndrome and primary biliary cirrhosis. Cartilage oligomeric matrix protein was measured with an ELISA according to the recommendation of the manufacturer (cut-off point, 10 U/l; AnaMar Medical AB, Uppsala, Sweden). Statistical evaluation was calculated by paired t test. Elevated sCOMP levels were detected only in patients with RA and with PsA. We found a significant difference between sCOMP in patients with RA and PsA (P = 0.01), in patients with reactive arthritis (P = 0.0001), in patients with Raynaud's syndrome (P = 0.0005), in patients with scleroderma (P = 0.003), in patients with systemic lupus erythematosus (P = 0.0002), in patients with leucozytoclastic vasculitis (P = 0.0004) and in patients with Sjogren's syndrome (P = 0.0007), but not in patients with CRST syndrome and primary biliary cirrhosis (P = 0.06) (Fig. ​(Fig.1).1). sCOMP did not differ significantly between Steinbrocker stages II–IV in RA patients. Levels of sCOMP were not significantly associated with CRP (P = 0.78). Figure 1 Serum levels of cartilage oligomeric matrix protein (COMP) in rheumatoid arthritis (RA) and other inflammatory rheumatic diseases. PsA, psoriatic arthritis; ReA, reactive arthritis; RS, Raynaud's syndrome; SCL, scleroderma; SLE, systemic lupus erythematosus; ... Cartilage oligomeric matrix protein is described as an indicator for the current extent of cartilage destruction in RA. In our patient group elevated levels of sCOMP could only be detected in patients with RA and in a few patients with PsA, but not in patients with reactive arthritis, with Raynaud's syndrome, with scleroderma, with systemic lupus erythematosus, with leucozytoclastic vasculitis or with Sjogren's syndrome. This result indicates that among these inflammatory arthritic diseases cartilage is affected only in RA. In none of the diseases was sCOMP associated with inflammation markers such as CRP. This is not in agreement with other studies where elevated cartilage oligomeric matrix protein levels were found even in patients with low clinical prognostic factors (erythrocyte sedimentation rate, CRP, rheumatoid factor, disease activity score). However, a correlation between sCOMP and the delta Larsen score over 5 years in this patient group could be demonstrated. Our results further confirm the conclusion that sCOMP levels are highly specific markers for the cartilage degradation process in RA [6,7] and are not related to a nonspecific inflammatory process in an arthritic joint.

FRI0531 AIR POLLUTANTS AND DEVELOPMENT OF INTERSTITIAL LUNG DISEASE IN PATIENTS WITH AUTOIMMUNE DISEASES

CYSTIC LUNG DISEASE IN A YOUNG MALE WITH SYSTEMIC LUPUS ERYTHEMATOSUS

Patients with chronic inflammatory rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and especially primary Sjögren's syndrome (SS), are at higher risk than the general population of developing B-cell non-Hodgkin lymphoma (NHL). Analyses of the association between various lymphoma subtypes and specific disease entities suggest that this association might be mediated by disease-specific mechanisms, as well as by mechanisms unique to lymphoma subtype. These specific associations can provide important information about abnormal B-cell stimulation in these conditions. Patients with primary SS, SLE and RA are at high risk of developing diffuse large B-cell lymphomas, a group of high-grade NHLs with remarkable heterogeneity. Patients with primary SS are at particularly high risk of developing marginal-zone B-cell lymphomas. The risk factors of lymphoma development in primary SS seem to be closely related to the underlying mechanisms of abnormal stimulation and/or impaired censoring mechanisms of B cells. In patients with RA and SLE, more intense disease activity and/or long-lasting disease might be indications of a higher risk of lymphoma development. This Review will focus on the risk of lymphoma, common and disease-specific mechanisms of B-cell lymphoma development, and on the clinical consequences of lymphoma in patients with inflammatory rheumatic diseases.

Immunologic rheumatic disorders

The relationships of HLA-DR and the newer DS (second D locus) B cell alloantigens (MB and MT) to the clinical and serologic expression of primary and secondary forms of Sjögren's syndrome (SS) were examined in 102 patients (86 whites and 16 blacks). Although HLA-DR3 was significantly increased in whites (25 of 50, 50%) and blacks (4 of 5, 80%) with primary SS compared with race-matched normal controls, it was not appreciably elevated in those with systemic lupus erythematosus (SLE)-SS, rheumatoid arthritis (RA)-SS, or connective tissue disease-SS. The MT2 specificity, however, was more strongly associated with primary SS (86% of whites and 100% of blacks) and also with SLE-SS and RA-SS compared with race-matched normal controls. Furthermore, MT2 was significantly increased in SLE-SS and RA-SS when compared with non-sicca SLE and RA controls. Although primary and secondary SS were most strongly associated with this DS specificity (MT2), the anti-Ro (SS-A) and anti-La (SS-B) antibody responses were more closely allied to DR antigens. HLA-DR3 was increased in anti-Ro positive patients, both whites and blacks, with primary SS (74%) and in total anti-Ro positive subjects (54%) compared with their anti-Ro negative counterparts (38% and 31%, respectively). Among DR3 negative patients, HLA-DR2 correlated with anti-Ro in both primary SS (83%) and in the total SS group (58%). Thus, 96% of Ro antibody positive patients with primary SS had DR3 and/or DR2, as did 80% of anti-Ro positive subjects in all categories.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective. Systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) share clinical and immunogenetic features and may occur together. We undertook this study to determine the risk of primary SS among SLE-unaffected relatives of SLE patients and whether or not primary and secondary SS tended to occur in the same families. Methods. We collected clinical and serological data on 2694 SLE patients, 7390 SLE-unaffected relatives of the SLE patients, and 1470 matched controls. Results. Of the 2694 subjects with SLE, 548 had secondary SS, while 71 of their 7390 SLE-unaffected relatives had primary SS. None of the 1470 controls had SS as defined herein (p = 5 × 10−5 compared to SLE-unaffected relatives). Of the 71 SLE-unaffected relatives with primary SS, 18 (25.3%) had an SLE-affected family member with secondary SS, while only 530 of the 7319 (7.2%) SLE-unaffected relatives without SS did so (p = 1 × 10−8). Conclusion. Among families identified for the presence of SLE, primary and secondary SS tend to occur within the same families. These results highlight the commonalities between these two forms of SS, which in fact correspond to the same disease.

We wanted to determine the prevalence of IgA and IgG antibodies against alpha-fodrin in the patients with primary and secondary Sjögren's syndrome (SS) and also to compare with anti-Ro and anti-La antibodies in the diagnosis of SS. We tested the prevalence of anti-alpha-fodrin IgA, IgG, anti-Ro, anti-La antibodies, anti-nuclear antibodies (ANA) and rheumatoid factor (RF) in naive patients with primary (n = 20) and secondary SS (n = 20) (Rheumatoid Arthritis [RA]+SS, n = 10; Systemic Lupus Erythematosus [SLE] + SS, n = 10), RA (n = 10), SLE (n = 10) and in healthy controls (n = 20). Salivary gland biopsies were performed in the patients with primary and secondary SS. In primary SS, anti-alpha-fodrin IgA, IgG, anti-Ro and anti-La antibodies were detected as 20, 10, 55 and 20% respectively. In RA + SS, anti-alpha-fodrin IgA was detected to be 10% and IgG was negative; however, anti-Ro antibodies and anti-La antibodies were found to be 40% and 20% respectively. In SLE + SS, anti-alpha-fodrin IgA was found to be 20% and IgG was found to be 10%, but anti-Ro and anti-La antibodies were found to be 90% and 20% respectively. Alpha-fodrin antibodies were not detected in RA, SLE and healthy controls. The detection of anti-alpha-fodrin antibodies by used ELISA does not give much contribution to the diagnosis of SS, and anti-Ro and anti-La are still useful serological markers in the diagnosis of SS.

Associations of Epstein-Barr virus (EBV) and autoimmune diseases have been hypothesized. We have analysed IgG antibodies to EBV nuclear antigen (EBNA)-2 in sera from Japanese patients with autoimmune systemic connective tissue diseases (CTD), exemplified by systemic lupus erythematosus (SLE), primary Sjogren's syndrome (SS), rheumatoid arthritis (RA), systemic sclerosis (SSc) and secondary SS (classical CTDs complicated with SS). An enzyme-linked immunosorbent assay (ELISA) which uses glutathione-S-transferase polypeptides fused to EBV nuclear antigen (EBNA)-2 and EBNA-1 was developed. Ratios of IgG antibody reactivity to whole IgG concentrations of sera were calculated to normalize EBNA-2 and EBNA-1 antibody levels to the hypergammaglobulinaemia that occurs in CTD. The ELISA optical density OD(450) readings of IgG antibodies to both the amino-terminal aa 1-116 of EBNA-2 and carboxyl-terminal aa 451-641 of EBNA-1 were elevated significantly in patients with SLE, primary SS, RA, SSc and secondary SS when compared to EBNA-1. The OD readings were divided by serum IgG concentrations to normalize for the hypergammaglobulinaemia. The specific levels of IgG antibodies to the amino-terminal region of EBNA-2 were elevated in patients with SLE, primary SS or RA, as well as those with secondary SS complicated with SLE or RA. The EBNA-2 amino-terminal region contains a polyproline tract and a proline-rich sequence and has considerable amino acid sequence homology with many cellular proline-rich proteins. High ratios of EBNA-2 aa 1-116 to EBNA-1 aa 451-641 IgG antibody levels which probably suggest reactivation of EBV latent infection were associated significantly with pulmonary involvement in SS patients. These results are consistent with the hypothesis that the sequence similarity between the amino-terminal region of EBNA-2 and proline-rich cellular proteins is associated with pathogenesis in a subpopulation of CTD patients, possibly by the molecular mimicry-epitope shift mechanism.

Chronic inflammatory autoimmune conditions like rheumatoid arthritis and systemic lupus erythematosus are associated with an increased risk of accelerated atherosclerosis (ATS). Very limited data are available about the incidence of ATS in patients with primary Sjogren's syndrome (PSS). Ankle brachial index (ABI) is a recognized method of detecting subclinical atherosclerosis. The objective of this study was to compare the prevalence of abnormal ABI in patients with PSS and in controls without PSS. Twenty-five PSS patients were compared with an age-, ethnicity-, and sex-matched control group. Traditional risk factors such as smoking, high blood pressure, blood sugar, lipids, and family history of atherosclerosis were assessed in both groups. Baseline clinical and laboratory features of PSS patients were recorded. ABI was measured in both groups. ABI less than 1.0 is considered abnormal. Fifty individuals (25 in each group) were studied. PSS patients and controls did not differ significantly in age, sex, and ethnicity. The prevalence of traditional cardiovascular risk factors was the same in both groups. Five out of 25 PSS patients (20%) had an ABI < 1.0 compared to one of 25 (4%) in the control group [P = 0.189 (odds ratio (OR) = 6.000 and 95% confidence interval (CI) 0.6464 to 55.692)]. Eight out of 25 PSS patients (32%) had disease duration of more than 10 years. This group of patients had a higher prevalence of low ABI compared to the individuals with lesser disease duration [P = 0.02 (OR = 16, 95% CI 1.38 to 185)]. PSS patients had a higher prevalence of low ABI, although this did not reach statistical significance. The subgroup of PSS patients with a longer duration of disease had a significantly lower ABI. This study was underpowered and a larger study is required to confirm the findings of this pilot study.

Systemic Autoimmune Diseases

Objective: Anti‐α‐fodrin autoantibody has been reported to be a highly specific and sensitive test for the diagnosis of Sjogren's syndrome (SS). The objective of our report is to investigate the sensitivity and specificity of anti‐α‐fodrin antibody in patients with SS and its correlation with clinical manifestations.Methods: Recombinant human α‐fodrin was used as envelope antigen in enzyme‐linked immunosorbent assay (ELISA) to detect the relatively specific autoantibody in sera of 42 primary SS, 24 secondary SS with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), and 40 other connective tissue diseases (CTDs) (SLE 17, RA 8, ankylosing spondylitis 5, dermatomyositis 5, systemic schlerosis 3, mixed connective tissue disease 1, Takayasu's disease 1) patients.Results: Antibodies against α‐fodrin were present in 59.5% of primary SS patients, 31.5% of secondary SS patients, 35.0% and 11.3% of other CTD patients and controls, respectively; the specificity of anti‐α‐fodrin antibody was 79.4% in patients with SS. It showed no significant difference between primary and secondary SS (P &gt; 0.05), as well as SS compared with other CTD patients (P &gt; 0.05). The positive rates of antibodies against α‐fodrin in CTD patients were significantly higher than those in non‐CTD patients and normal controls (P &lt; 0.01). The presence of anti‐α‐fodrin antibodies has no significant correlation with clinical manifestations or other autoantibodies, while the levels of sera IgG and erythrocyte sedimentation rate (ESR) are higher in α‐fodrin antibody‐positive patients (IgG: 23.2 vs. 18.6, P &lt; 0.05; ESR: 52.9 vs. 37.1, P &lt; 0.05) than α‐fodrin antibody‐negative patients. Anti‐α‐fodrin antibodies are all negative in anti‐SS antigen A and antinuclear antibody‐negative SS patients.Conclusion: The result showed a lower sensitivity and specificity for anti‐α‐fodrin antibody as a diagnostic marker of SS, compared with previous reports. Anti‐α‐fodrin antibodies had no significant association with clinical manifestations, but might be related to the sera IgG level. Antibodies against α‐fodrin played no important roles in diagnosis of antibody‐negative SS patients.

Contribution of dendritic cell immunoreceptor (DCIR) polymorphisms in susceptibility of systemic lupus erythematosus and primary Sjogren’s syndrome

Sjögren's syndrome (SS) is an autoimmune disorder characterized by dry eyes and mouth (sicca syndrome) and lymphocytic infiltration of the lacrimal and salivary glands. Abnormalities of parasympathetic neurotransmission may contribute to the glandular dysfunction. In this study, we used a functional assay to investigate autoantibody-mediated effects on parasympathetic neurotransmission and smooth muscle contraction. Serum and purified IgG were obtained from patients with primary and secondary SS and from control subjects. Contraction of isolated bladder strips in response to stimulation of M3-muscarinic receptors by a muscarinic receptor agonist, carbachol, or by endogenous acetylcholine released from postganglionic parasympathetic nerves was measured before and after the addition of patient serum or IgG. Sera from 5 of 9 patients with primary SS and from 6 of 6 patients with secondary SS inhibited carbachol-evoked bladder contraction by approximately 50%. Sera from these patients also inhibited the action of neuronally released acetylcholine at M3-muscarinic receptors. Sera from 7 of 8 healthy individuals, from patients with rheumatoid arthritis without sicca symptoms, and from patients with systemic lupus erythematosus had no effect. The anti-muscarinic receptor activity was localized in the IgG fraction, since purified IgG from patients with SS also inhibited agonist- and nerve-evoked contractions. In this preliminary study, the autoantibodies seemed to be associated with the presence of bladder symptoms and other autonomic features. Autoantibodies that act as antagonists at M3-muscarinic receptors on smooth muscle occur in a subset of patients with primary and secondary SS. Their presence in secondary SS was unexpected and provides new evidence for a common pathogenetic link between primary and secondary SS. These autoantibodies appear to contribute to sicca symptoms and may explain associated features of autonomic dysfunction in some patients.

SAT0184 Ct Scan Confirms Presence of Erosion in Systemic Lupus Erythematosous and Primary Sjogren's Syndrome as Well as Healthy Control, with Different Characteristics as Compared to Rheumatoid Arthritis: an Observational...