Chiara Bazzani

TNF-α Antagonist Survival Rate in a Cohort of Rheumatoid Arthritis Patients Observed under Conditions of Standard Clinical Practice

A cohort of rheumatoid arthritis (RA) patients in the Lombardy Rheumatology Network (LOHREN) registry and receiving anti‐TNF therapy was evaluated after 6, 12, 24, and 36 months. Of the 1114 patients in the registry 1064 met the clinical criteria for inclusion with 519 receiving infliximab, 303 adalimumab, and 242 etanercept. The therapeutic survival curve of these patients showed that the likelihood of continuing anti‐TNF therapy was 78.8% after 12 months, 65.2% after 24 months, and 52.9% after 36 months, with a risk of dropout similar for inefficacy and adverse events. There were 405 anti‐TNF therapy discontinuations (38.1%): 180 (16.9%) due to inefficacy, 194 (18.2%) adverse events, and 31 (2.9%) other reasons. Four deaths (2 septicemia, 1 postinfective cerebritis, 1 heart failure) were considered to be related to anti‐TNF therapy. Of the discontinuations, 219 (54.1%) occurred within the first 12 months: 110 due to adverse events, 89 inefficacy, and 20 due to other reasons. After 36 months, the likelihood of survival on etanercept (62.5%) was significantly greater than the likelihood of survival on infliximab (49.1%) or adalimumab (53.6%). A higher risk of therapy discontinuations due to adverse events was associated with increasing age, a corticosteroid >5 mg/day, a high erythrocyte sedimentation rate (ESR), a higher risk of therapy discontinuations due to inefficacy was associated with the previous use of ≥4 disease‐modifying antirheumatic drugs (DMARDs) and a high ESR. Comorbidities, increasing DAS28 values and co‐therapy with methotrexate were associated with a lower risk of discontinuation.

Tumour necrosis factor antagonist therapy and cancer development: Analysis of the LORHEN registry

OBJECTIVE The objective was to compare cancer risk in a RA cohort population treated with TNF antagonists, and identify the characteristics of the patients at higher risk. METHODS The study involved 1114 RA patients treated with anti-TNF agents after failing to respond to traditional DMARDs, 1064 of whom were evaluable for adverse events over an average observational period of 23.32 months. The relative cancer risks (expressed as hazard ratios) in the anti-TNF treated patients were estimated using univariate and multivariate analyses. The rate of cancer in this cohort was compared with that in the general population using data from the Varese and Milan Cancer Report. RESULTS There were 18 incident cases (1.7%), 4 of which involved lymphomas. Comparison with the general population showed that the overall cancer risk was similar, but the risk of lymphoma was about five times higher in the RA patients treated with a biological agent. Higher RR were found in males (HR 4.95, 95% CI 1.97-12.48; p=0.001) and patients aged >65 years (HR 2.72, 95% CI 1.08-6.84; p=0.034); combined therapy with methotrexate seemed to be protective (HR 0.31, 95% CI 0.11-0.87; p=0.026). CONCLUSION The overall cancer risk in RA patients treated with anti-TNF seemed to be similar to that in the general population in the same geographical area, but the risk of haematological cancer was significantly greater. The demographic and clinical factors associated with a higher risk of cancer in our cohort were male gender and an age of >65 years.

Use of Tumor Necrosis Factor-α-blocking Agents in Hepatitis B Virus-positive Patients: Reports of 3 Cases and Review of the Literature

Objective. To evaluate the development of hepatitis B virus (HBV) infection in patients receiving tumor necrosis factor-α-blocking agents (TNFBA), and to evaluate whether lamivudine (LAM) prophylaxis can reduce the risk of viral reactivation in inactive HBsAg carriers. Methods. Local experience and published reports were reviewed. Patients with HBV infection were classified as having chronic HBV hepatitis, or being inactive HBsAg carriers or occult carriers. Results. Three patients in our series and 24 patients in the literature were identified: 2 had active HBV-associated disease, 23 were inactive HBsAg carriers, and 2 occult carriers. When exposed to TNFBA, HBsAg-inactive carriers pretreated with LAM had lower risk of having detectable HBV-DNA (p = 0.02) or viral reactivation (p = 0.046) than those without LAM prophylaxis. In 3 patients who discontinued TNFBA, LAM prophylaxis was also discontinued 10–12 months thereafter without hepatitis flares. Two cases of reactivation in occult carriers (HBsAg-negative, anti-HBs+, anti-HBc+) were described in the literature. Conclusion. TNFBA should be avoided in patients with active HBV replication and should be used with caution in inactive HBsAg carriers. In these patients, the risk of viral reactivation seems to be high, but it might be reduced by prophylactic LAM, which should probably be given for a long time when TNFBA are discontinued (e.g., 12 mo). Potential occult carriers might carry a low, but not negligible, risk of viral reactivation. They should therefore be monitored with particular care.

Lupus and the antiphospholipid syndrome in pregnancy and obstetrics: clinical characteristics, diagnosis, pathogenesis, and treatment.

The antiphospholipid syndrome (APS) in pregnancy is associated with repeated miscarriages and fetal loss. Other complications of pregnancy such as preeclampsia and placental insufficiency are also frequently reported during pregnancy in APS. The pathogenesis of pregnancy failures in APS is related to both the thrombophilic effect of antiphospholipid antibodies and also to different mechanisms including a direct effect of antibodies on trophoblast differentiation and invasion. Although optimal pharmacologic treatment is essential to achieve a successful outcome in APS pregnancy, the standard APS pharmacologic treatment alone may not be sufficient. A good obstetric outcome is the result of careful obstetric monitoring, proper delivery timing, and skillful neonatal care. A multidisciplinary team (obstetricians, rheumatologists, and neonatologists) and the progress in neonatal intensive care are as important as drugs in achieving a good obstetric outcome and to reduce the possible consequences of premature delivery.

Predicting response to anti-TNF treatment in rheumatoid arthritis patients

OBJECTIVE To identify the clinical factors predicting failure or a good clinical response in the cohort of RA patients entered in the Lombardy Rheumatology Network (LORHEN) registry after 3 years of treatment with anti-TNF agents. METHODS We studied the patients who had received anti-TNF agents and been followed up for a minimum of 6 months. Disease activity at baseline and after 6 months was assessed using the DAS28, and response was evaluated according to the EULAR improvement criteria. RESULTS 1005 patients (55.72 years) were included in the analysis. at baseline the DAS-28 was 5.91+/-0.95 and a HAQ score was 1.46+/-0.61. At mean of 14.57 months, 29.9% of the patients achieved a DAS-28 of <or=2.6 (remission). A higher RR for remission was associated with male gender (AHR 1.51, 95% CI 1.14-2.00; p: 0.004) and a lower RR for remission with: prior treatment with >3 DMARDs (AHR 0.077, 95% CI 0.58-1.03; p: 0.074), a high ESR (AHR 0.86, 95% CI 0.81-0.92; p: 0.000), Steinbrockers functional class III/IV (AHR 0.66, 95% CI 0.48-0.90; p: 0.010), a high TJC (AHR 0.97, 95% CI 0.94-0.99; p: 0.011). A 12-month EULAR non-response was observed in 153/821 (18.6%) associated with a higher baseline HAQ score (AOR 1.51, 95% CI 1.03-2.20, p: 0.033), prior treatment with >3 DMARDs (AOR 1.76, 95% CI 1.09-2.85; p: 0.021) and corticosteroid >5 mg/day (AOR 2.05, 95% CI 1.06-3.97; p: 0.034). CONCLUSION We found that only a minority of patients with long-standing RA treated with anti-TNF agents achieve a good clinical response or remission.

Anti-TNFα therapy in a cohort of rheumatoid arthritis patients: Clinical outcomes

OBJECTIVE To assess the effectiveness of anti-TNFalpha agents by analysing the principal clinical outcomes in patients with active rheumatoid arthritis (RA). METHODS 1010 patients who received no clinical benefit from previous treatment with methotrexate and/or other DMARDs, were subsequently treated with one or more of the anti-TNFalpha agents. RESULTS After the first six months of anti-TNFalpha therapy, 29% of the patients showed a good and 47% a moderate European League Against Rheumatism (EULAR) response, and this positive result was maintained after two years of follow-up. Their median Disease Activity Score based on the erythrocyte sedimentation rate and the evaluation of 28 joints (DAS28) decreased from 5.94 at baseline to 4 after six months (p<0.001; Delta 1.94), and further significant responses were also observed after 12, 18 and 24 months; their median 36-month DAS28 score reflected mild disease activity. The median Health Assessment Questionnaire (HAQ) score fell from 1.34 at baseline to 1 after six months of therapy (Delta 0.34; p<0.05), and a further significant reduction was observed during the second and third year of follow up. CONCLUSIONS Especially when combined with DMARDs, anti-TNFalpha drugs can induce a good clinical response regardless of the particular molecule used, whereas their combination with steroids does not seem to improve disease outcomes at any time during follow-up.

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.

Pregnancy in autoimmune rheumatic diseases: the importance of counselling for old and new challenges.

Rheumatic diseases can affect women during their childbearing age. Therefore, physicians should introduce a discussion with the patients about pregnancy and its problems. Lupus pregnancies can be successful, even in patients with renal disease, when planned in remission state; the use of low dose aspirin was shown to be an independent predictor of good outcome, so it can be suggested as a preventive measure. Pregnancies in women with Antiphospholipid Syndrome can fail even if properly treated, especially when associated with a systemic autoimmune disease, a history of both thrombosis and pregnancy morbidity, and a triple positivity of antiphospholipid antibody assays. Women with systemic sclerosis have generally a good obstetric outcome, except for an increase rate of preterm deliveries. Severe disease complications were sometimes reported, but their relationship with gestation is not clear yet. Although data on human pregnancy are still preliminary, anti-TNF agents are classified as non teratogens in contrast to methotrexate and leflunomide. So women affected by aggressive chronic arthritis may be treated with anti-TNF in the pre-conceptional period, discontinuing the drug as soon as pregnancy starts. In order to increase maternal compliance and cope with difficult cases, a multidisciplinary team (rheumatologists/internists, obstetricians and neonatologists) should take care of patients during pregnancy.

Cardiological features in idiopathic inflammatory myopathies.

Idiopathic inflammatory myopathies (IIMs) represent a heterogeneous group of autoimmune systemic diseases characterized by chronic muscle weakness and inflammatory cell infiltrates in skeletal muscle. The most frequent IIMs, such as adult-onset polymyositis and dermatomyositis, display a wide range of clinical manifestations other than myositis, including skin changes, Raynauds phenomenon and interstitial lung disease. Cardiac involvement is now well recognized as a clinically important manifestation in patients with polymyositis or dermatomyositis, although its actual frequency is still uncertain. Cardiovascular complications represent one of the most frequent causes of death in myositis, apart from cancer and lung involvement. Despite the fact that clinical manifestations are relatively rare, asymptomatic cardiovascular features are frequently reported in patients with polydermatomyositis and dermatomyositis. They are characterized by isolated electrocardiographic changes, valve disease, coronary vasculitis, ischemic abnormalities, heart failure and myocarditis. Chronic inflammation producing myocyte degeneration, tissues fibrosis and vascular alterations can explain the majority of reported cardiac features in myositic patients. Although previous works reported an association between heart involvement and some myositis-specific autoantibodies (namely anti-signal recognition particle), electrocardiography, echocardiography and, where necessary, heart magnetic resonance remain the mainstay for diagnosing and monitoring myocardial inflammation in these diseases. Anyway, a complete multiorgan assessment and a careful analysis of autoantibodies should be performed in every patient in order to define any possible distinct disease entities with different prognosis within the spectrum of IIMs.

Efficacy and safety of rituximab with and without methotrexate in the treatment of rheumatoid arthritis patients: Results from the GISEA register

INTRODUCTION Rituximab (RTX) is a monoclonal anti-CD20 antibody approved for the treatment of rheumatoid arthritis (RA) in association with methotrexate (MTX). OBJECTIVES To evaluate the efficacy and safety of RTX-MTX combination therapy compared with RTX alone in the treatment of RA. METHODS We analyzed data from a prospective cohort study, the Italian biologic register GISEA, to investigate the efficacy and safety of rituximab. Moreover, the adverse events (AE) and the causes of discontinuation therapy were analyzed. RESULTS We identified 338 RA patients, 162 treated with RTX and 176 with RTX-MTX. After 52 and 104 weeks of therapy the disease activity score in 28 joints and the Health Assessment Questionnaire Score were available in 168 patients (78 with RTX-MTX and 60 with RTX alone), showing significant reduction without differences among the two groups. AE were reported in 142 patients (42%), for a total of 368 recorded side effects. The majority (90.5%) of AE were mild to moderate in severity. Comparable percentages of severe AE were reported in the 2 groups (9.9% for RTX alone and 9.3% for RTX+MTX). A poor disease control was observed in 14.2% and 13.5% of patients treated with RTX+MTX and RTX, respectively; while 12 patients (4.5% in RTX+MTX, and 2.5% in RTX group) suspended therapy for AE. CONCLUSIONS RTX showed a good efficacy and safety profile in the real-life management of RA patients regardless of the association with MTX.