Does anti-tumor necrosis factor-α therapy affect risk of serious infection and cancer in patients with rheumatoid arthritis?: a review of longterm data

Given the important role tumor necrosis factor-α (TNF-α) antagonists play in managing rheumatoid arthritis and the concern for safety during longterm therapy, we reviewed the latest evidence regarding longterm risk of infection and malignancy with TNF-α antagonists. Our objective was to provide clinicians with information that can be used to counsel and monitor patients who may be candidates for biologic therapy for rheumatoid arthritis (RA). Risk is examined in the context of background infection and malignancy rates in RA. Randomized controlled trial (RCT) data and observational studies summarizing the risk of infection and/or malignancy in RA and specific risks associated with the use of anti-TNF-α biologic agents (adalimumab, infliximab, and etanercept) were identified through a PubMed search. Overall, patients with RA appear to have an approximately 2-fold increased risk of serious infection compared to the general population and non-RA controls, irrespective of TNF-α antagonist use. Although data on infection rates with TNF-α antagonist use are contradictory, caution is merited. Recent analyses suggest that the risk of infection is highest within the first year. Regarding malignancy risk, RCT and observational data are also conflicting; how ever, caution is warranted regarding lymphoproliferative cancers in children and adolescents.     

Plasmapheresis therapy in combination with TNF-α inhibitor and DMARDs: A multitarget method for the treatment of rheumatoid arthritis

Objective: To evaluate the effects of a multitarget method involving plasmapheresis therapy combined with tumor necrosis factor (TNF)-α inhibitor and disease-modifying antirheumatic drugs (DMARDs) on disease activity parameters in the treatment of active rheumatoid arthritis (RA).

Methods: Sixty-five patients with active RA were divided into two groups according to the treatment administered: the plasmapheresis combination therapy group (Plasmapheresis combination group; 38 cases), in which patients received plasmapheresis therapy along with a TNF-α inhibitor (recombinant human tumor necrosis factor-Fc; rhTNFR:Fc; Etanercept biosimilars) and DMARDs, and a TNF-α inhibitor therapy group (biological agent group; 27 cases), in which patients received a TNF-α inhibitor and DMARDs. Clinical parameters were measured before and at 4 and 24 weeks after treatment.

Results: ACR20, ACR50, and ACR70 responses at week 4 were achieved in 84.2%, 78.9%, and 60.5% of the patients in the plasmapheresis combination group, respectively, and 74.1%, 55.6%, and 29.6% of the patients in the biological agent group, respectively. The ACR50 and ACR70 response rates were superior in the former than the latter group (p?p?Conclusions: The multitarget method combining plasmapheresis, TNF-α inhibitor, and DMARDs for RA therapy was superior to the combination of TNF-α inhibitor for reducing disease activity parameters in patients with active RA.     

TNF-α inhibitors and tocilizumab do not influence hepatic steatosis in patients with rheumatoid arthritis

AIM: To investigate the influence, if any, of tumor necrosis factor(TNF)-α inihibitors and Tocilizumab, on hepatic steatosis(HS) in rheumatoid arthritis(RA) patients in the light of the known role of TNF-α and interleukin-6, which are key-cytokines in the pathogenesis of RA, in inducing HS in general population.METHODS: We retrospectively reviewed the clinical charts of 36 RA patients, out of whom 12 had been treated with Methotrexate(MTX), 12 with TNF inhibitors ± MTX and 12 with Tocilizumab ± MTX. The 3 subgroups of patients matched each other for sex, age, body mass index, metabolic syndrome(MS) and other risk factors for atherosclerosis. At baseline and after 12 mo each patient underwent an abdominal ultrasonog-raphy for the assessment of presence of HS and the evaluation of its grade.RESULTS: No difference was detected either in the prevalence of HS or in that of its distinct grades between the 3 groups of patients at baseline. After 12 mo, the HS grade unchanged in 20 patients(7 subjects treated with MTX, 7 with TNF-α inhibitors ± MTX and 6 Tocilizumab ± MTX); increased in 12 patients(4 subjects treated with MTX, 4 TNF-α blockers ± MTX and 4 Tocilizumab ± MTX); decreased in 4(1 treated with MTX, 1 with anti-TNF-α + MTX and 2 with TCZ ± MTX(P = 0.75). No correlation was found between getting remission or low disease activity and the course of either MS or HS.CONCLUSION: We failed to detect any influence of MTX ± TNF-α inhibitors or Tocilizumab in reducing MS and HS. A prospective study is needed to clarify the topic.     

Anti-TNFα therapy in rheumatoid arthritis and autoimmunity

The aim of the study was to evaluate a panel of autoantibodies in patients affected by rheumatoid arthritis (RA) treated with anti-TNF blockers, and to consider a different autoantibody induction effect by infliximab and etanercept; and in addition to evaluate in these cases a relationship between antinuclear antibody (ANA) titre and both C-reactive protein (CRP) and Blys levels. Fifty-four patients (8 men, 46 women, mean age 51.4 years, mean duration of disease 13.6 years) affected by refractory RA were treated with anti-TNF blockers for 12 consecutive months; 43 patients were given infliximab and 11 etanercept. At baseline and every 4 months a panel of autoantibodies consisting of rheumatoid factor, antinuclear, anti-double-stranded DNA, anti-ENA, anti-mitochondrial, anti-thyroid and anti-neutrophil cytoplasmic antibodies (ANCA) was tested. At the same time CRP level was measured. Blys level was determined at baseline and after 1 year in five cases that developed a strong positivity for ANA during infliximab therapy. In 41 cases (95.3%) treated with infliximab, ANA were detected on at least one occasion, and in almost half of these cases the titre was very high, equal to or higher than 1:1.280. On the other hand, patients treated with etanercept presented ANA positivity in a lower percentage of cases and at a low titre. No correlation was found between ANA titre and CRP level; Blys level did not present a constant trend in patients who developed a very high positivity for ANA. Anti-double-stranded DNA, anti-thyroid or ANCA were found only in a few patients, in the absence of a clinical picture indicative of systemic lupus erythematosus, autoimmune thyroiditis or ANCA-associated vasculitis. A different incidence of ANA positivity was found in infliximab- and etanercept-treated RA patients; this finding might be due to the partially different method of inhibition of TNF between the two drugs. Both CRP and Blys do not seem to participate in this phenomenon. Other autoantibodies were detected in a few patients, but no case of onset of new autoimmune disorders was observed.     

Combination therapy with cyclosporine A and anti-TNF-α agents in the treatment of rheumatoid arthritis and concomitant hepatitis C virus infection

We describe two cases of rheumatoid arthritis (RA) patients and concomitant hepatitis C virus infection (HCV), treated with cyclosporine A (CsA) and anti-TNF-α agents. SGOT/SGPT and HCV-RNA serum levels remained unchanged longer than 1 year of treatment. No side effects were registered. We suggest that combination therapy with CsA and TNF-α blockers should be considered safe and well-tolerated in the treatment of HCV-positive RA patients.     

Comment on “Tumor necrosis factor-α antagonist therapy for concomitant rheumatoid arthritis and hepatitis C virus infection: a case series study”

Clinical Rheumatology -     

Carotid ultrasound in the cardiovascular risk stratification of patients with rheumatoid arthritis: when and for whom?

Adequate stratification of cardiovascular (CV) risk is one of the major points of interest in the management of patients with rheumatoid arthritis (RA). A task force of the European League Against Rheumatism has proposed to adapt CV risk management calculated in RA patients according to the systematic coronary risk evaluation (SCORE) function by application of a multiplier factor of 1.5 in those patients with two of the following three criteria: disease duration >10 years, rheumatoid factor (RF) or anticyclic citrullinated peptide (anti-CCP) antibody positivity, and presence of severe extra-articular manifestations. However, a major concern when using the modified SCORE is to know whether the effect of chronic inflammation on the CV risk of RA patients can be fully determined using this tool. As increased carotid intima-media thickness (IMT) and carotid plaques have been proved to predict the development of CV events in RA, the authors suggest performing carotid ultrasound when SCORE does not yield results indicating high CV risk in RA patients with extra-articular manifestations, RF or anti-CCP positivity as well as in patients with 10 years disease duration or longer. The presence of abnormal carotid IMT (>0.90 mm) or carotid plaques would lead to these patients being considered as having high CV risk regardless of the results derived from the modified SCORE.     

Dose tapering of biologic agents in patients with rheumatoid arthritis—results from a cohort study in Germany

Clinical Rheumatology - To assess the association of demographic and clinical factors with the clinical decision of tapering biologic disease modifying antirheumatic drugs (bDMARDs) in patients...     

Catalase and PPARγ2 genotype and risk of rheumatoid arthritis in Koreans

Catalase (CAT) and peroxisome proliferator activated receptor-γ2 (PPARγ2) are important regulators of oxidative stress and inflammation, and may contribute to the development of rheumatoid arthritis (RA). We investigated the association between CAT and PPARγ2 genotypes and risk and severity of RA using 474 cases and 400 controls. Genotyping for the −262C→T polymorphism of CAT and the Pro12Ala polymorphism of PPARγ2 was performed by PCR-RFLP analysis. Severity of RA was assessed by the anatomical stage according to Steinbrocker, and a Korean language version of a Health Assessment Questionnaire (KHAQ). No association was observed between CAT and PPARγ2 genotypes and risk of RA. Our results suggest that genetic polymorphisms of CAT and PPARγ2 do not play a significant role in the susceptibility to RA among Koreans.     

Reduction of plasma IL-6 but not TNF-α by methotrexate in patients with early rheumatoid arthritis: a potential biomarker for radiographic progression

Objective

To determine the effect of methotrexate (MTX) on plasma levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α and to investigate their associations with clinical and radiographic responses in patients with early rheumatoid arthritis (RA).

Methods

Sixty-two untreated RA patients with the disease duration of ≤36 months in whom MTX was initiated were consecutively identified in our prospective RA cohort and included in this study. Concomitant use of prednisolone and synthetic disease-modifying anti-rheumatic drugs with MTX was allowed, but patients who used biological agents were excluded. Plasma IL-6 and TNF-α levels were measured at the time of diagnosis (baseline) and 1 year later. The relationships of the clinical and radiographic data with plasma levels of IL-6 and TNF-α were analyzed.

Results

The median age of the patients was 57 years, 49 patients were female, and the median disease duration was 3 months. Forty-six (74.2 %) patients were anti-cyclic citrullinated protein antibody-positive. Serum C-reactive protein (CRP), plasma IL-6, and DAS28 decreased significantly (p <0.001) after MTX treatment, but plasma TNF-α did not. Radiographic progression was significantly correlated with disease activity score and plasma IL-6 levels but not with CRP or TNF-α after MTX treatment. Patients with plasma IL-6 level above 4.03 pg/ml showed clinically relevant radiographic progression with a sensitivity of 91.7 % and a specificity of 88.0 %.

Conclusion

In this early RA cohort, we demonstrated a significant (p <0.001) reduction of plasma IL-6, but not TNF-α, during MTX treatment. The post-treatment IL-6 level was a strong indicator of radiographic progression.