Martin H. Van Rijswijk

The prognostic value of anti–cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis

OBJECTIVE To study the predictive value of anticyclic citrullinated peptide antibody (anti-CCP) in patients with recent-onset rheumatoid arthritis (RA). METHODS Outcome in terms of physical disability (Health Assessment Questionnaire) and radiologic damage (modified Sharp method) over 3-year and 6-year periods was determined in an inception cohort of 273 RA patients who had had disease symptoms for <1 year at study entry. Anti-CCP titers were determined at baseline and considered positive as recently described. Their prognostic value was studied by means of multiple regression analysis, in which anti-CCP positivity, sex, age at study entry, IgM rheumatoid factor (IgM-RF) status, Disease Activity Score (DAS), HLA-DR4 status, and (in a separate group of patients) shared epitope status were used as independent variables, and radiologic damage and functional disability as dependent variables. RESULTS Patients with anti-CCP had developed significantly more severe radiologic damage after 6 years of followup. In multiple regression analysis, radiologic damage after 6 years followup was significantly predicted by IgM-RF status, radiologic score at entry, and anti-CCP status. Functional disability was significantly predicted by sex, age at entry, IgM-RF status, and DAS. CONCLUSION Our data show that in almost 70% of RA patients, anti-CCP antibody is present at the early stages of disease. Anti-CCP-positive patients developed significantly more severe radiologic damage than patients who were anti-CCP negative, although in multiple regression analysis the additional predictive value was rather moderate.

Influence of prognostic features on the final outcome in rheumatoid arthritis: a review of the literature.

Abstract The literature on prognostic features on the final outcome in RA is reviewed. It is generally agreed that female sex and a positive RF are variables indicating a poor prognosis. Long-standing increased ESR and CRP values, decreased Hb, or the appearance of subcutaneous nodules are indicators of a less favorable clinical course. No conclusions can be drawn regarding other factors due to the incomplete and heterogeneous study designs.

Acute phase proteins in the monitoring of inflammatory disorders

Summary The acute phase reaction is in most circumstances a good indicator of (local) inflammatory activity and tissue damage. CRP is a direct and quantitative measure for the acute phase reaction and due to its fast kinetics provides adequate information of the actual situation. The ESR on the contrary is in fact an indirect measure of the acute phase reaction. It does react much slower to changes of inflammatory activity and is influenced by a number of other factors. From studies on the ‘behaviour’ of CRP it has become clear that diseases may differ with regard to the extent in which they induce an acute phase response. Incidental measurement of the CRP level may add to the diagnostic procedure in selected cases, e.g. in the differentiation between a bacterial and a viral infection or between a bacterial infection and an exacerbation of diseases like SLE. In case of an extremely elevated CRP level (>100 mg/litre) the possibility of a bacterial infection should always be considered. In clinical practice CRP is particularly useful when serial measurements are performed. The course of the CRP level may be useful for the monitoring of the effect of treatment and for the early detection of postoperative complications or intercurrent infections. The relationship between CRP and the local production and effects of cytokines on the one hand, and the possible functional role of CRP in the inflammatory process on the other hand have surely added a dimension to the clinical use of CRP as a parameter of inflammatory activity.

Sexual functioning of people with rheumatoid arthritis: a multicenter study

The objective of this study is to compare men and women with rheumatoid arthritis (RA) to controls regarding sexual motivation, activity, satisfaction, and specific sexual problems, and to determine the correlation of physical aspects of the disease with sexual functioning. Questionnaire for screening sexual dysfunctions (QSD), self-constructed questionnaire on experienced distress with joints during sexual activities, arthritis impact measurements scales 2 (AIMS2), and the modified disease activity score 28 (DAS 28) were the methods used. RA patients were recruited from a registration base in three Dutch hospitals. Controls were age and sex matched healthy volunteers. A completed questionnaire was sent back by 271 patients (response 23%). Forty-seven men and 93 women were clinically examined to obtain the DAS 28. Male patients felt less sexual desire, and female patients masturbated and fantasized less than controls. Differences in satisfaction were not found. Male and female patients did not experience more sexual problems than controls. Among the women, correlations were predominantly found between age and sexual motivation and activities, among the men between physical health and sexual problems. Up to 41% of the men (4–41 depending on the joints), and up to 51% of the women (10–51 depending on the joints) have troubles with several joints during sexual activities. Medications influencing ejaculation in men correlated with distress with orgasm. Conclusions are that patients are less sexually active than controls and a considerable number of both male and female patients have trouble with their joints during sexual activities. However, patients do not differ from controls regarding sexual satisfaction. Physiological changes due to RA are apparently independent from those on psychological level. It is argued that sexual satisfaction also depends on personal and social factors. In men, physical health and disease activity are more related with sexual problems than in women.

Clinical and therapeutic aspects of AA amyloidosis

Approach to the management of AA amyloidosis complicating RA. (A) In case of proteinuria or loss of renal function a rectal biopsy or a subcutaneous fat biopsy is a suitable screening method for the detection of amyloidosis. If in any doubt, try to ascertain the diagnosis by renal biopsy. Adequate staining with alkaline Congo red and preferably immunohistochemical staining with anti-AA antibodies should be performed. Beware of renal pathology other than amyloidosis even in the presence of a positive rectal biopsy. (B) A vigorous attempt to control disease activity of the RA should be made in order to eliminate the production of SAA, an acute phase protein. The response to treatment should be monitored by serial measurements of CRP and preferably SAA

Strong inhibition of TNF-α production and inhibition of IL-8 and COX-2 mRNA expression in monocyte-derived macrophages by RWJ 67657, a p38 mitogen-activated protein kinase (MAPK) inhibitor

In inflammatory processes, the p38 mitogen-activated protein kinase (MAPK) signal transduction route regulates production and expression of cytokines and other inflammatory mediators. Tumor necrosis factor α (TNF-α) is a pivotal cytokine in rheumatoid arthritis and its production in macrophages is under control of the p38 MAPK route. Inhibition of the p38 MAPK route may inhibit production not only of TNF-α, but also of other inflammatory mediators produced by macrophages, and indirectly of inflammatory mediators by other cells induced by TNF-α stimulation. Here we investigate the effects of RWJ 67657, a p38 MAPK inhibitor, on mRNA expression and protein production of TNF-α and other inflammatory mediators, in monocyte-derived macrophages. A strong inhibition of TNF-α was seen at pharmacologically relevant concentrations of RWJ 67657, but also inhibition of mRNA expression of IL-1β, IL-8, and cyclooxygenase-2 was shown. Furthermore, it was shown that monocyte-derived macrophages have a high constitutive production of matrix metalloproteinase 9, which is not affected by p38 MAPK inhibition. The results presented here may have important implications for the treatment of rheumatoid arthritis.

Diagnostic Performance and Prognostic Value of Extravascular Retention of 123I-Labeled Serum Amyloid P Component in Systemic Amyloidosis

Serum amyloid P component (SAP) binds to amyloid. 123I-SAP scintigraphy is used to evaluate the extent and distribution of amyloid in systemic amyloidosis and has great clinical value in the detection of systemic amyloidosis. The aim of the study was to assess during scintigraphy the diagnostic performance and prognostic value of a simple parameter describing extravascular 123I-SAP retention in systemic amyloidosis. Methods: Two hundred megabecquerels of 123I-labeled human SAP was injected intravenously for scintigraphy in 20 controls and in 189 consecutive patients with systemic and localized amyloidosis. Extravascular retention of 123I-SAP was quantified from serum and urine measurements after 24 h (EVR24) and 48 h. Sensitivity and specificity were assessed, and retention was correlated with kidney, heart, liver, and nerve involvement and with survival. Results: The cutoff value representing a desired specificity of 90% of EVR24 was 50%. The associated sensitivity of EVR24 for detecting reactive systemic, immunocyte-derived (AL), and hereditary amyloidosis was 65%, 61%, and 22%, respectively, using a cutoff point of 50%. In AL amyloidosis, the EVR24 increased with the number of organs involved (from a mean of 43% for 1 organ to a mean of 81% for 4 organs). The EVR24 correlated with serum alkaline phosphatase (r = 0.63) and with creatinine clearance (r = −0.36). In AL amyloidosis, both cardiac involvement (hazard ratio, 3.9; 95% CI, 2.0–7.8) and EVR24 (hazard ratio, 2.0; 95% CI, 1.1–3.9) were independent predictors of survival. Conclusion: In AL amyloidosis, the EVR24 is strongly associated with organ involvement and with prognosis and might serve as an indicator of the body amyloid load. Quantification of SAP retention using the EVR24 has no additional value over 123I-SAP scintigraphy in the detection of systemic amyloidosis.

SAA Versus CRP Serum Levels in Different Inflammatory Conditions, Studied by Elisa Using Polyclonal Anti-AA and Monoclonal Anti-SAA Antibodies

SAA was quantified by two newly developed sandwich ELISA’s. First antibody in both assays was a purified polyclonal rabbit anti-AA (PRαAA), bound to the microtitration plate. In one assay PRαAA was also used to detect the captured SAA, but in the second a monoclonal murine anti-SAA antibody (MMαSAA) was used for this detection. The results of both assays were comparable, so for routine purposes the more convenient and standardizable second assay was preferred. We used a highly purified apo-SAA, extracted from pooled acute-phase sera, as the ultimate standard for our assays. Purity was established by SDS-PAGE, immunoblotting and amino acid analysis. To obtain our standard we finally added an exact amount to normal negative serum. With this SAA-ELISA and a comparable one for CRP, simultaneous SAA and CRP levels were measured in CAH, PBC, hepatoma’s, NSTT, M.Crohn, CTD, RA and renal allograft rejection. The SAA/CRP ratio differed among these groups, ranging from a clear SAA preponderance in renal allograft rejection to a clear CRP preponderance in liver diseases.

Monoclonal Antibody Based ELISA for Human SAA

We developed an ELISA for human SAA in which two different monoclonal antibodies (MAb) were used (Reu.86.1 and Reu.86.5) that recognized different epitopes on SAA. These MAb’s were raised against purified SAA coupled to Helix pomatia haemocyanin (by glutaraldehyde). The MAb’s reacted with isolated AA-proteins and with SAA (all major isotypes), both isolated and after reconstitution in HDL3. The MAb’s could be used in ELISA, in immunohistochemistry, and in immuno-blotting after SDS-PAGE or IEF. In ELISA one of the MAb’s was coated to the microtiterplate (Reu.86.5), while the other (Reu.86.1) was coupled to HRPO. The internal standard in the ELISA consisted either of SAA isolated from a serum pool (150 patients with CRP >100 mg/1) reconstituted into normal serum or of a reference serum sample. The lower detection limit of the assay for SAA was 5 μg/1, allowing the use in biological fluids (serum, urine, synovial fluid) and in in-vitro systems (cultured human hepatocytes). In routine serology we found an intra-assay coefficient of variation (CV) and an inter-assay CV both >10% (N=15 res. N=17). In this assay no pretreatment of testsamples was necessary and there was no interference of rheumatoid factors. The basal reference values of healthy controls had a 95% upper limit of 2.6 mg/1. This SAA-ELISA uses well defined MAb’s for the detection of SAA, which permits standardization, inter-laboratory comparability and general availability.

Amyloid Load in Fat Tissue Reflects Disease Severity and Predicts Survival in Amyloidosis

The severity of systemic amyloidosis is thought to be related to the extent of amyloid deposition. We studied whether amyloid load in fat tissue reflects disease severity and predicts survival.