Microalbuminuria: is it a predictor of ischaemic heart disease in rheumatoid arthritis?

SIR, We read with interest the article by Kitas and Erb [1],where an interesting parallel is drawn between rheumatoid arthritis(RA) and type-2 diabetes (T2D) with respect to ischaemic heartdisease (IHD). The association between RA and IHD, as with T2D,is clearly important, yet in the     

Does early rheumatoid arthritis exist?

The 'life cycle' of established rheumatoid arthritis can be divided into four phases. The first is the period leading up to the onset of arthritis. The second is the period during which persistence or remission is determined. The third is the evolution into a specific form of inflammatory arthritis, and the fourth is the outcome/severity of that arthritis. In some patients, these four phases follow in rapid succession; however, in other patients, the time course is prolonged over several months or years. This chapter explores the hypothesis that these four phases are distinct in the majority of patients, and that different genetic and environmental factors influence the various phases. It investigates the suggestion that a defect in the hypothalamic-pituitary-adrenal axis may underlie the persistence of inflammatory arthritis. It suggests that the term 'early rheumatoid arthritis' is not appropriate and that patients either have established rheumatoid arthritis or an undifferentiated inflammatory arthritis.     

Is there a rationale to using leflunomide in early rheumatoid arthritis?

The efficacy of leflunomide in the treatment of early rheumatoid arthritis (RA) patients might be attributed to the fact that it acts at several levels, including the anti-inflammatory and anti-destructive pathways. This is in addition to its inhibition of the L-dihydro-orotate dehydrogenase (DHOH) enzyme and pyrimidine de novo synthesis which decreases cell proliferation and more specifically early activated CD4+ T cells, as well as monocyte interaction with T cells leading to cytokine and anticytokine production. Recent studies clearly indicate the rationale of an early administration of leflunomide in RA patients, particularly in the light of the results of previously reported clinical studies showing its rapid onset of action when compared to other DMARDs. The early efficacy and safety of leflunomide in patients with early RA is sustained over a long period, and the long-term safety profile of leflunomide does not seem to be different from that observed in phase III trials.     

Are imaging techniques necessary for defining remission in rheumatoid arthritis?

Accurate assessment of inflammatory activity in rheumatoid arthritis (RA) is essential to evaluate response to therapy and disease remission. RA remission has been classically assessed by clinical and laboratory parameters. However, subclinical synovitis may explain progression of joint damage in spite of apparent clinical remission in RA patients. Imaging techniques, such as magnetic resonance imaging and high-resolution ultrasonography (US) with Doppler technique, provide a sensitive measure and monitoring of joint inflammatory activity and a more accurate assessment of RA remission than clinical evaluation which may contribute to make optimal treatment decisions. Within the last decade, an increasing number of rheumatologists have progressively incorporated musculoskeletal US as a valuable diagnostic tool in their clinical practice. This technique facilitates the scanning of all peripheral joints as many times as required at the time of consultation.     

Magnetic resonance imaging of the knee: a tool for prediction of joint damage in early rheumatoid arthritis?

OBJECTIVE: To evaluate the usefulness of magnetic resonance imaging (MRI) in predicting destructive rheumatoid arthritis (RA) in the knee joint, and to compare this method with clinical examination and conventional radiography (CR). METHODS: Clinical evaluations of the knee joint, followed by MRI and CR examinations were performed in 30 patients with early RA. The MRI examination included evaluation of inflammation using a synovitis score and evaluation of destruction with an erosion score. The first examinations were performed within 14 months from disease onset. Twenty-eight patients were re-examined after 1 year, and 23 patients after 3 years. 'Disease activity score' (DAS), using a 28 joints score (DAS28); health assessment questionnaire (HAQ); rheumatoid factor (RF); and C-reactive protein (CRP) were also analysed. RESULTS: At baseline, MRI found synovitis in 29 patients, of whom 18 also had clinical synovitis. At baseline five patients had 17 MRI erosions, whereas on CR two patients had one erosion each. After 1 year 17 of 35 and after 3 years 28 of 55 MRI erosions were detected also on CR. In only one case CR showed an erosion that was not visible on MRI. The MRI synovitis score (reflecting the extent of the synovitis) at baseline correlated significantly with the number of erosions on MRI both at year 1 and 3, and with the number of erosions on CR at 3 years. In logistic multiple regression analyses the MRI-synovitis score proved to be the best independent predictor of erosiveness. CONCLUSION: MRI was superior to clinical examination and CR in detecting erosions. MRI synovitis score was the best independent predictor of erosiveness in the knee joint in patients with early RA.     

Is the disease course of rheumatoid arthritis becoming milder?: Time trends since 1985 in an inception cohort of early rheumatoid arthritis

Objective

Based on comparisons of short‐term cohort studies or cross‐sectional samples of patients from different calendar times, it has been suggested that present patients with rheumatoid arthritis (RA) have a milder disease course compared with that of patients in past decades. This study was undertaken to investigate whether the course of disease activity and functional disability in patients with RA has become milder over the past several years.

Methods

We used the Nijmegen inception cohort of early RA, which included all patients with newly diagnosed RA who had attended the department of rheumatology at Radboud University Nijmegen Medical Centre since 1985. Patients were assessed for disease activity by the Disease Activity Score in 28 joints (DAS28) every 3 months and for functional disability by the Health Assessment Questionnaire (HAQ) disability index (DI) every 6 months. Within the total cohort, 4 subcohorts were defined, based on the date of inclusion of the patients (1985–1990, 1990–1995, 1995–2000, 2000–2005). To investigate whether the course of disease activity and functional disability (over time) was different between the subcohorts, longitudinal regression analysis (linear mixed models) was used, with the DAS28 and HAQ DI over time as outcome variables, respectively, and subcohort as the independent variable, correcting for baseline demographic and clinical characteristics. The treatment strategy was compared between the subcohorts.

Results

The DAS28 at baseline and over the first 5 years of disease was lower in the more recent subcohorts. The HAQ DI did not show improvement but instead a trend toward worsening functional disability. Using longitudinal regression it was shown that disease activity improved early in the disease course and stabilized thereafter, and that this improvement was greater in patients in the more recent subcohorts and in patients with a higher baseline DAS28. Initially, the HAQ DI also improved but stabilized thereafter, and this initial improvement was less pronounced in patients in the more recent subcohorts and was greater for patients with a higher baseline HAQ DI. The treatment strategy was more aggressive in the more recent subcohorts, as shown by a shorter duration from diagnosis to the start of treatment with prednisone or disease‐modifying antirheumatic drugs (DMARDs), and a greater prevalence of DMARD therapy.

Conclusion

The course of disease activity in RA patients has become milder in more recent years. The reason for this improving trend remains to be elucidated, although the trend coincides with a more aggressive treatment strategy.

     

Is early rheumatoid arthritis the same disease process as late rheumatoid arthritis?

Thoughts on treatment for the early control of synovitis have stimulated research on pathobiological events at the site of inflammation in patients with early rheumatoid arthritis. Several studies have thus been conducted to examine synovial biopsy samples at various stages of the disease. The most important conclusion from these studies is that all features of chronic synovial inflammation can be observed in so-called early rheumatoid arthritis. This suggests that no arguments exist for the effect of therapeutic intervention on synovitis varying in different phases of rheumatoid arthritis. In end-stage rheumatoid arthritis, factors that are secondary to the disease may contribute to the perpetuation of synovial inflammation. Mutations in key regulatory genes could play a role in the autonomous progression of the disease. In addition, it is conceivable that the release of bone and cartilage fragments might elicit an inflammatory response in patients with destructive rheumatoid arthritis.     

Is thiopurine methyltransferase genetic polymorphism a major factor for withdrawal of azathioprine in rheumatoid arthritis patients?

OBJECTIVE: To determine whether the presence of thiopurine methyltransferase (TPMT) alleles associated with reduced or absent activity of thiopurine methyltransferase is a major factor for withdrawal of azathioprine (AZA) in rheumatoid arthritis (RA) patients. METHODS: The TPMT genotype, including the variable number of tandem repeats (VNTR) pattern in the 5' untranslated region, was analysed in 111 patients with long-standing RA. Azathioprine (AZA) therapy was used in 40 patients (36%) as a disease-modifying anti-rheumatic drug. RESULTS: Seven out of 111 RA patients (6.3%) were carriers of a mutant allele, TPMT3A (G(460)-->A, A(719)-->G) being the mutant allele observed most frequently. In the group of 40 AZA-treated patients, therapy was discontinued in six patients because of side-effects and in 26 patients because of lack of efficacy. Three patients presented moderate side-effects and were homozygous for the wild-type TPMT allele, whereas the remaining three patients, who developed gastrointestinal effects with severe nausea and vomiting, were TPMT3A carriers. CONCLUSION: In this observational study, the absence of response, probably due to the low-dose scheme used, was the major cause of AZA withdrawal in our series of RA patients. TPMT genotyping may allow the use of high doses of AZA in patients with normal TPMT alleles to improve the efficacy of this immunosuppressive drug. Our data support the relationship between gastrointestinal intolerance and thiopurine metabolic imbalance.     

B cells: a fundamental role in the pathogenesis of rheumatoid arthritis?

The role of T cells in the pathogenesis of RA is well established, whereas to date the precise contribution of B cells is less well defined. B cells have many potential key roles: they can act as antigen-presenting cells, secrete pro-inflammatory cytokines (including tumour necrosis factor-alpha), produce rheumatoid factor (RF) and other autoantibodies and activate T cells. B cells act as antigen-presenting cells by processing and presenting antigenic peptides to T cells, which become activated, proliferate and exert pro-inflammatory activities. RF may also play a role in perpetuating B-cell activation and antigen presentation to T cells, thus leading to sustained production of RF. This, combined with RF immune-complex-mediated complement activation, may contribute to the sustained inflammatory response. Studies have shown that the use of an anti-CD20 monoclonal antibody in RA depletes circulating B cells, resulting in improvement in disease activity for up to 1 yr. It is thus evident that B cells play a central role in the pathophysiology of RA and therefore merit further investigation as a therapeutic target.