Repeat serological testing for anti-citrullinated peptide antibody after commencement of therapy is not helpful in patients with seronegative rheumatoid arthritis.

AIM: To Investigate the prevalence of seroconversion to ACPA after commencement of triple disease-modifying anti-rheumatic drug (DMARD) treat-to-target therapy. BACKGROUND: Anti-citrullinated peptide antibody (ACPA) and rheumatoid factor (RF) define 'seropositive' rheumatoid arthritis (RA). Both predict unfavourable disease course, development of extra-articular features and treatment outcomes. We investigated the prevalence of seroconversion to ACPA after commencement of triple disease-modifying anti-rheumatic drug (DMARD) treat-to-target therapy. METHODS: DMARD-naïve patients with RA according to the 1987 American College of Rheumatology criteria and disease duration of <96 weeks were enrolled. RF and ACPA levels were recorded at baseline and sequentially during triple DMARD therapy. RESULTS: A total of 368 patients were followed for a median of 272 weeks. Of 154 patients seronegative for ACPA at recruitment, 10 (6.5%) seroconverted at some point. Nine of these were positive for RF at baseline and baseline RF titre was predictive of seroconversion. Four (2.6%) patients remained seropositive. No patients seroconverted from negative to positive for both RF and ACPA. Median time to seroconversion for ACPA was 29 months. CONCLUSION: Persistent seroconversion of ACPA from negative to positive after diagnosis in patients with RA is uncommon. ACPA and RF double negative patients are highly unlikely to ever develop ACPA positivity with a risk <1%. It is therefore unlikely to be helpful or cost effective to perform serial ACPA measurements in patients with seronegative RA after commencement of a treat-to-target strategy.

Modifiable Lifestyle Factors Associated With Response to Treatment in Early Rheumatoid Arthritis.

OBJECTIVE: We aimed to evaluate the associations between response to algorithm-directed treat-to-target conventional synthetic disease-modifying antirheumatic drug therapy and potentially modifiable lifestyle factors, including dietary fish oil supplementation, body mass index (BMI), and smoking history in a rheumatoid arthritis (RA) inception cohort. METHODS: Patients with RA with a duration of less than 12 months were reviewed every 3 to 6 weeks to adjust therapy according to disease response. All patients received advice to take fish oil supplements, and omega-3 status was measured as plasma levels of eicosapentaenoic acid (EPA). Lifestyle factors and other variables potentially prognostic for 28-joint Disease Activity Score (DAS28) remission and DAS28 low disease activity (LDA) at the 12-month visit were included in multivariable logistic regression models. RESULTS: Of 300 participants, 57.7% reached DAS28 LDA, and 43.7% were in DAS28 remission at 1 year. Increase in plasma EPA was associated with an increase in the odds of being in LDA (adjusted odds ratio [OR] = 1.27; P < 0.0001) and remission (adjusted OR = 1.21; P < 0.001). There was some evidence that the effect of BMI on LDA might be modified by smoking history. An increase in BMI was associated with a decrease in the odds of being in LDA in current and former smokers but had no impact on LDA in patients who had never smoked. There were no meaningful associations between BMI or smoking history and remission. CONCLUSION: Omega-3 status, BMI, and smoking history are potential predictors of outcome in early RA. The possibility of an effect modification by smoking on the predictive value of BMI merits further investigation.

Quantitation of total and free teriflunomide (A77 1726) in human plasma by LC-MS/MS.

The clinical activity of leflunomide, a drug used in the treatment of rheumatoid arthritis, is due to its active metabolite, teriflunomide. In vitro studies indicate that at least 99% of teriflunomide is expected to be protein bound in human plasma in vivo, leaving<1% in the unbound or 'free' state for clinical activity. To examine details of the relationships between leflunomide dosing and patient response, it is necessary to have an assay that is sufficiently sensitive to measure the minor fraction of free teriflunomide in patient samples. Therefore, we aimed to develop and validate an LC-MS/MS method for the measurement of teriflunomide, and use it to determine the total and free teriflunomide concentration in patients with rheumatoid arthritis. Teriflunomide and its deuterated internal standard were extracted from human plasma and separated using a reversed phase method with a C18 column. Detection was conducted with an API 3000 LC-MS/MS System by monitoring selected ions in negative ion MRM. Optimal detection occurred at m/z 269.1/160.0 (teriflunomide) and m/z 273.1/164.0 (teriflunomide-D4). Over a linear range of 5-500 µg/L, the inter-batch precision ranged from 1.9 to 8.8% and accuracy from -8.4 to 8.0%. The intra- and inter-batch assay precision for quality control samples ranged from 2.1-5.4% and 5.7-7.1% respectively. The procedure was applied to assess total and free plasma concentrations of teriflunomide in patients with rheumatoid arthritis. Free teriflunomide was approximately 0.11% of total teriflunomide, and there was a significant correlation (r2=0.724) between free and total teriflunomide concentrations. A validated, accurate and sensitive method was developed and successfully applied for the measurement of total and free teriflunomide concentration in human plasma samples. This method has been shown to be reproducible and sensitive and can be applied to clinical samples.

Fish oil and rheumatoid arthritis: past, present and future.

Meta- and mega-analysis of randomised controlled trials indicate reduction in tender joint counts and decreased use of non-steroidal anti-inflammatory drugs with fish-oil supplementation in long-standing rheumatoid arthritis (RA). Since non-steroidal anti-inflammatory drugs confer cardiovascular risk and there is increased cardiovascular mortality in RA, an additional benefit of fish oil in RA may be reduced cardiovascular risk via direct mechanisms and decreased non-steroidal anti-inflammatory drug use. Potential mechanisms for anti-inflammatory effects of fish oil include inhibition of inflammatory mediators (eicosanoids and cytokines), and provision of substrates for synthesis of lipid suppressors of inflammation (resolvins). Future studies need progress in clinical trial design and need to shift from long-standing disease to examination of recent-onset RA. We are addressing these issues in a current randomised controlled trial of fish oil in recent-onset RA, where the aim is to intervene before joint damage has occurred. Unlike previous studies, the trial occurs on a background of drug regimens determined by an algorithm that is responsive to disease activity and drug intolerance. This allows drug use to be an outcome measure whereas in previous trial designs, clinical need to alter drug use was a 'problem'. Despite evidence for efficacy and plausible biological mechanisms, the limited clinical use of fish oil indicates there are barriers to its use. These probably include the pharmaceutical dominance of RA therapies and the perception that fish oil has relatively modest effects. However, when collateral benefits of fish oil are included within efficacy, the argument for its adjunctive use in RA is strong.

A case of longitudinally extensive transverse myelitis (LETM): neuromyelitis optica.

Neuromyelitis optica (NMO), characterised by longitudinally extensive transverse myelitis (LETM), was previously thought to be a variant of multiple sclerosis. Transverse myelitis may be a manifestation of autoimmune connective tissue diseases and NMO is now recognised to be a humorally mediated autoimmune disease. We present a case of NMO associated with non-organ-specific autoantibodies and the absence of the characteristic NMO-IgG antibody. Our case provides an opportunity to review the diagnostic criteria of NMO and its distinction from other autoimmune and demyelinating conditions. We report successful treatment with plasmapheresis and rituximab in NMO-IgG-negative relapsing disease.

Digital vasculitis: a late complication of anti-tumour necrosis factor alpha therapy.

Anti-tumour necrosis factor alpha therapy has led to significant advancement in the treatment of rheumatological disease. Rarely, anti-TNFalpha antagonists have been associated with vasculitis, predominantly cutaneous leukocytoclastic vasculitis. We present the first case of angiographically-confirmed digital vasculitis occurring as a late complication of etanercept therapy. Our case adds to the limited repertoire of case reports of anti-TNFalpha induced vasculitis and highlights the potential risk of this serious complication occurring up to several years after initiation of these agents.

Eosinophilic fasciitis as a paraneoplastic phenomenon associated with metastatic colorectal carcinoma.

A 72-year-old man presented with erythema and induration of his calves and forearms. He had a past history of stage 1 colorectal carcinoma, treated with resection and primary anastamosis 4 years earlier. A diagnosis of eosinophilic fasciitis was made based on the characteristic clinical appearance, peripheral blood eosinophilia and a skin biopsy. There was no improvement in the condition following treatment with prednisolone or methotrexate. One year later, abnormal liver function studies were noted, and an abdominal computed tomography scan and subsequent needle biopsy of the liver confirmed a neoplastic lesion in the liver consistent with a metastatic colorectal carcinoma. Systemic chemotherapy with oxaliplatin, 5-fluorouracil and capecitabine was commenced, and resulted in partial remission of the colorectal carcinoma. Simultaneously, the indurations of the forearms and calves also improved, suggesting that the eosinophilic fasciitis was a paraneoplastic phenomenon.

The role of fats in the lifecycle stages. Adulthood--prevention: rheumatoid arthritis.

There is evidence for preventive and therapeutic effects of dietary omega-3 fats in rheumatoid arthritis. While doses of up to several grams per day of fish-derived fatty acids may be necessary for therapeutic effects in long-standing rheumatoid arthritis, much lower doses should provide benefits to reduce the mortality from cardiovascular disease in this inflammatory disorder.