Maurizio Benucci

Rheumatoid factor positivity rather than anti-CCP positivity, a lower disability and a lower number of anti-TNF agents failed are associated with response to rituximab in rheumatoid arthritis

OBJECTIVES We explored clinical factors associated with a major response to rituximab (RTX) (e.g. ACR >/=50, and European League against Rheumatism (EULAR) moderate to good response) in patients with active long-standing RA and inadequate response to anti-TNF agents or traditional DMARDs. METHODS RTX was used in 110 RA patients in six different Italian centres. The mean disease activity score on 28 joints (DAS28) was 6.4 +/- 0.99 and the mean HAQ was 1.63 +/- 0.68 at baseline. Thirty-two patients (29.1%) underwent RTX after the failure of DMARD therapy, 37 (33.6%) had failed or were intolerant to at least two anti-TNF agents, and 41 (37.3%) had failed or were intolerant to one anti-TNF agent. Univariate and multivariate analyses were performed. RESULTS The number of previous anti-TNF agents (P = 0.043), HAQ (P = 0.023), RF positivity (P < 0.0001) and anti-cyclic citrullinated peptide (anti-CCP) positivity (P = 0.003) were associated with ACR response >or=50 between month +4 and month +6 after starting RTX by univariate analysis. Multivariate analysis confirmed that a lower HAQ, a lower number of anti-TNF agents failed before RTX and RF positivity, but not anti-CCP positivity, were the selected variables associated with an ACR response >or=50, with an accuracy of 84% of the model. Only RF positivity correlated with EULAR moderate to good response both in the univariate and in the multivariate analysis, with an accuracy of 79% of the model. CONCLUSION RF-positive rather than anti-CCP-positive RA patients with lower baseline disability and a lower number of previously failed TNF blockers may be the best candidates to RTX.

Multidisciplinary approach to fibromyalgia: What is the teaching?

Fibromyalgia (FM) is a rheumatic disease that is characterised by chronic musculoskeletal pain, stiffness, fatigue, sleep and mood disorder. FM patients demonstrate dysregulation of pain neurotransmitter function and experience a neurohormone-mediated association with sleep irregularities. There are currently no instrumental tests or specific diagnostic markers for FM, and many of the existing indicators are only significant for research purposes. Anti-depressants, non-steroidal anti-inflammatory drugs (NSAIDS), opioids, sedatives, muscle relaxants and antiepileptics have all been used to treat FM with varying results. It has been shown that interdisciplinary treatment programmes lead to greater improvements in subjective pain and function than monotherapies. Physical exercise and multimodal cognitive behavioural therapy are the most widely accepted and beneficial forms of non-pharmacological therapy.

Predictive factors of response to rituximab therapy in rheumatoid arthritis: What do we know today?

Interest in the role of B cells in the pathogenesis of rheumatoid arthritis (RA) has increased over recent years. Rituximab (RTX), a chimeric monoclonal antibody specific for human CD20 targeting B lymphocytes, has been used to treat RA patients, and its efficacy has been clearly demonstrated in controlled clinical trials and open-label observational studies. However, it is still not known which sub-group(s) of patients will respond to RTX therapy or whether there are any factors predicting a response. The aim of this review is to discuss the most important predictive factors that are so far known. It is known that the clinical response to RTX therapy is associated with lower interferons (IFN-γ) and B-cell activating factor (BAFF) levels, the Fcγ receptor III (FcγRIII) genotype, and the C/G-174 polymorphism of interleukin 6 (IL-6); that an initial non-response to RTX depends on circulating pre-plasma cell numbers at baseline and incomplete depletion; that synovial B cells are decreased but not eliminated by RTX therapy, and that a good clinical response correlates with more substantial synovial B depletion; and, finally, that a good clinical response correlates with rheumatoid factor positivity, but not anti-cyclic citrullinated peptide antibody positivity.

The CC homozygosis of the -174G>C IL-6 polymorphism predicts a lower efficacy of rituximab therapy in rheumatoid arthritis

Identification of genetic biomarkers of response to biologics in rheumatoid arthritis (RA) is a relevant issue. Being IL-6 a key cytokine for B cell survival, the interleukin-6 (IL-6) -174G>C and the IL-6 receptor (IL-6R) D358A gene polymorphisms were investigated in 158 RA patients treated with rituximab (RTX). One hundred and twenty-eight (81.0%) were RF positive and 126 (79.7%) were anti-CCP positive. Response to therapy was evaluated at the end of the sixth month after the first RTX infusion, by using both the EULAR and the ACR criteria. The possible relationship with IL-6 serum levels was also studied. By univariate analysis, lack of response by the EULAR criteria was more prevalent in RA patients with the IL-6 -174 CC genotypes (39.1%), than in the GC/GG patients (18.5%) (OR 2.83; 95%CI=1.10-7.27; p=0.031). A good response was noticed in only one patient (4.3%) with the IL-6 -174 CC genotype, while it was present in 24.4% of GG/GC cases (p=0.06). By stepwise multivariate analysis (including RA duration, baseline DAS28, baseline HAQ, RF status, anti-CCP status and IL-6 genotype as covariates), the IL-6 -174CC genotype was selected as an independent predictor of no response to RTX by both EULAR and ACR≥50 criteria, while the IL-6R polymorphism resulted as not associated. No definite association between gene polymorphisms and IL-6 serum levels was noticed. Present results suggest a possible role for IL-6 genotyping to better plan treatment with RTX in RA, and larger studies are worthwhile.

Biomarkers of good EULAR response to the B cell depletion therapy in all seropositive rheumatoid arthritis patients: Clues for the pathogenesis

Objective To find out whether a high number of auto-antibodies can increase the probability of a “good-EULAR response” and to identify the possible biomarkers of response in seropositive rheumatoid arthritis (RA) patients undergoing the B cell depletion therapy (BCDT). Patients and Methods One hundred and thirty-eight patients with long standing RA (LSRA), 75% non or poorly responsive to one or more TNFα blockers, all seropositive for at least one autoantibody (AAB) (RF-IgM, RF-IgA, RF-IgG, anti-MCV, ACPA-IgG, ACPA-IgA, ACPA-IgM) received one full course of BCDT. The major outcomes (moderate or good-EULAR response) were assessed after 6 months of therapy. The IL6 and BAFF levels were also determined. Results At a 6-month follow-up, 33 (23.9%) of the RA patients achieved a good EULAR response. Having up to 5-AABs positivity increased the chances for treatment response. After a logistic regression analysis, however, only 4 baseline factors arose as associated with a good-EULAR response: no steroid therapy (OR = 6.25), a lymphocyte count <1875/uL (OR = 10.74), a RF-IgG level >52.1 IU/ml (OR = 8.37) and BAFF levels <1011 pg/ml (OR = 7.38). When all the AABs, except for RF-IgM and ACPA-IgG, were left in the analysis, the two final predictors were no-steroid therapy and low lymphocyte count. Discussion The number of AABs increased the chances of being a “good-EULAR” responder. The only predictors, however, at the baseline of a good response in this seropositive cohort of RA patients were 2 simple variables – no steroids and lymphocyte count – and two laboratory assays – IgG-RF and BAFF.

The 158VV Fcgamma receptor 3A genotype is associated with response to rituximab in rheumatoid arthritis: results of an Italian multicentre study

Objective The polymorphism 158V/F of Fc fragment of IgG (FCGR) type 3A may influence the response to rituximab (RTX) in rheumatoid arthritis (RA). We investigated the FCG3A polymorphism in a large cohort of RA patients treated with RTX, also by considering the possible loss of response from month +4 to +6 after RTX and the presence of established predictors of response. Methods The study analysed 212 RA patients. European League Against Rheumatism (EULAR) response was evaluated at months +4 and +6 after the first RTX infusion. The FCGR3A polymorphism was analysed by PCR followed by Sanger sequencing. Results The FCGR3A genotypes were associated with EULAR response (good or moderate) at month +6 (response in 34/38 (89.5%) VV vs 70/106 (66%) VF and in 51/77 (66.2%) FF patients; p=0.01), but not at month +4 (response in 32/37 (86.5%) VV vs 69/102 (67.6%) VF and 53/73 (72.6%) FF patients; p=0.09). Loss of response was observed only in VF and FF carriers ((VV vs VF vs FF: 0/37 (0%) vs 11/102 (10.8%) vs 12/73 (16.4%); p=0.02)). Probability of response at month +6 was very high when at least two of the three following items selected by multivariate analysis were present: positive rheumatoid factor and/or anticyclic citrullinated peptide antibodies, previous treatment with ≤1 anti-tumor necrosis factor (TNF) agent, and 158VV FCGR3A genotype (p<0.0001; OR 7.9, 95% CI 4.1 to 15.1). Conclusions The 158VV FCGR3A genotype was associated with response to RTX in a large cohort of RA patients. Patient genotyping may be helpful to plan RTX treatment, and may be integrated with clinical predictors.

Treatment of rheumatic diseases in patients with HCV and HIV infection.

A wide variety of rheumatic diseases has been documented in the presence of hepatitis C virus (HCV) infection and in human immunodeficiency virus (HIV) infection. In this conditions, physicians are refrained from using corticosteroids and/or immunosuppressants agents because of the risk of favouring viral replication and the progression of the underlying viral disease. In the present review we have focused our attention on the possible role of cyclosporine A (CsA), anti-Tumour Necrosis Factor (TNF) alpha agents in the treatment of HIV or HCV infected autoimmune patients. The results drown from the literature and from our personal experience confirm the safety of CsA and anti-TNF alpha agents, in terms of viral load and liver toxicity. A limited experience also suggest that both therapies can be given in combination in rheumatoid arthritis patients without increasing the risk of adverse events.

Hypersensitivity reactions to biological agents with special emphasis on tumor necrosis factor-α antagonists

Purpose of reviewSeveral biological agents have been introduced into the drug market and more are emerging. Adverse reactions to these agents have recently been classified into five different subtypes. Some of these reactions are frequent but without consequences for the patients. Others are less frequent but potentially life-threatening, and they include allergic reactions. Recent findingsHypersensitivity reactions are well described adverse drug reactions, corresponding to the ß-type of the newly proposed classification of adverse reactions induced by biological agents. We focus our search on tumor necrosis factor-α antagonists, as they represent a dramatic improvement in the therapy of both rheumatic and inflammatory bowel diseases and because adverse reactions have been closely scrutinized. We also add cases from our own experience. We found very few properly documented allergic reactions. SummaryHypersensitivity reactions to tumor necrosis factor-α antagonists are not rare. Whether these manifestations have to be considered type β or type γ reactions is still a matter of debate. There is a need for allergological tests in vivo and in vitro.

Disease activity and antinucleosome antibodies in systemic lupus erythematosus.

Objective: To evaluate the correlation between antinucleosome antibodies and disease activity in patients with systemic lupus erythematosus (SLE). Methods: We evaluated antinucleosome antibodies (by ELISA) in 48 SLE patients. They were divided in 2 groups: positive (Group A, nr=18) and negative (Group B, nr=30). The groups were evaluated for antinucleosome antibodies and for clinical, humoral parameters (hemoglobin, blood cell count, urinanalysis, ESR, ANA, anti‐dsDNA, anticardiolipin antibodies, LAC), and ECLAM. Results: C3,C4, and hemoglobin were lower in Group A than (vs) group B (C3: 0.61±0.16 g/L vs 0.88±0.08 g/L, p<0.001; C4: 0.086±0.03 g/L vs 0.18±0.07 g/L, p<0.05; hemoglobin: 8.7±5.8 g/dL vs 12.7±1.44 g/dL; p<0.02). ECLAM was higher in group A 7.56±2.19 vs group B 4.67±1.35 (p<0.001). Urinary sediment was more altered in group A (88.8%) vs group B (33.3%; p<0.001). Conclusion: We found a correlation between antinucleosome antibodies and SLE disease activity as expressed by the higher ECLAM score in group A.

Clinical performance evaluation of a novel rapid response chemiluminescent immunoassay for the detection of autoantibodies to extractable nuclear antigens.

BACKGROUND We analyzed the performance of a novel ENA screening chemiluminescent immunoassay (CIA) and the confirmation QUANTA Flash tests. METHODS Sera (n=1079) from patients referred to a rheumatology clinic were screened by QUANTA Flash ENA7 (INOVA Diagnostics). All positive (n=89) and a matched control group (n=90) were reflexed for autoantibodies to the individual antigens. Moreover, sera from patients with systemic lupus erythematosus (SLE, n=252), systemic sclerosis (SSc, n=64), polymyositis/dermatomyositis (PM/DM, n=72), Sjögrens syndrome (SjS, n=39) as well as disease controls (n=605) were tested by ENA7 CIA and by Quanta Lite ENA6 ELISA (INOVA). RESULTS 89/1079 (8.3%) samples were ENA7 CIA positive with the following reactivity profile: RNP (36.0%), Sm (13.5%), Scl-70 (9.0%), Jo-1 (0.0%), Ro60 (44.9%), Ro52 (39.3%) and SS-B (24.7%). In the negative group, the reactivity profile was: RNP (1.1%), Sm (1.1%), Scl-70 (2.2%) and 0.0% for Jo-1, Ro60, Ro52 and SS-B. The positive/negative/total agreements (ENA7 CIA vs. confirmation assays) were 95.3%/91.5%/93.3%. The sensitivity of the ENA7 CIA was 62.3% in SLE, 54.7% in SSc, 92.3% in SjS, 50.0% in PM/DM, and 61.8% in the total systemic autoimmune rheumatic disease (SARD) population (specificity 95.0%). CONCLUSION The QUANTA Flash ENA7 CIA is a reliable screening test.