Tumor necrosis factor-α inhibitor-related autoimmune disorders.

Biotechnological monoclonal antibodies and receptor antagonists capable of targeting specific inflammatory actors, such as cytokines, cytokines receptors, co-stimulatory molecules or leukocyte populations, have emerged as an alternative to conventional therapies for treating systemic inflammatory diseases with immune pathogenesis. However, there is no doubt that, with a frequency that is not exceptionally high but also not negligible, immunotherapies can favour the development of systemic and organ-specific immune-mediated disorders. It has become increasingly evident that interference with a specific immune pathway may favour the activation of opposing compensatory signalling, which may exacerbate underlying subclinical disorders or cause immune-mediated diseases completely different from the underlying disease. The 'compensatory immunological switch' has emerged primarily in patients treated with tumor necrosis factor (TNF) -α inhibitors, the first biological drugs approved for treating systemic inflammatory diseases with immune pathogenesis. In this Review, we describe the clinical features and predisposing factors of the main TNF-α inhibitor-related autoimmune disorders, organising them into subclinical serological autoimmunity, autoimmune disorders other than those for which TNF-α inhibitors are indicated, and paradoxical reactions. We also discuss the underlying pathogenetic mechanisms and precautions for use in the therapeutic management of these patients. Better understanding of the complex phenomenon of the 'compensatory immunological switch', which TNF-α inhibitors and other biological drugs might trigger, can help not only appropriately managing immune-mediated disorders, but also better interpreting the heterogeneity of the pathogenetic mechanisms underlying certain chronic inflammatory conditions that, although different from each other, are arbitrarily placed in the context of overly generic nosological entities.

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.

Efficacy and safety of anti-tumour necrosis factor in elderly patients with rheumatoid arthritis: an observational study.

This study aims to compare the efficacy and safety of anti-TNF agents in elderly (aged >or=65 years) and younger patients (aged 18-65 years) with active RA. The study involved 1,114 RA patients treated with anti-TNF drugs and followed-up for >6 months by LORHEN group, who were divided into two cohorts on the basis of their age (311 aged >or=65 and 803 aged <65 years) in order to evaluate 3-year outcomes and treatment discontinuations. Drug effectiveness was assessed by disease activity (DAS28 and EULAR response), functional status (HAQ) and serological parameters (ESR) at baseline and during anti-TNFalpha therapy; safety was evaluated on the basis of drug discontinuation rates. At baseline, the elderly patients showed greater disease activity (DAS28, ESR) and loss of joint function (HAQ, functional class; p < 0.05). During therapy, clinical and laboratory parameters (DAS28, ESR) improved in both groups without any statistically significant difference between them, whereas the difference in HAQ remained after 36 months of treatment (p < 0.05). Anti-TNFalpha therapy was discontinued by 123 of the elderly (42%) and 282 of the younger patients (36.6%) because of loss of efficacy (17.4% vs. 16.7%), severe adverse events (21.8% vs. 16.9%) or other reasons (2.7% vs. 3%). The number of adverse events was significantly higher in the elderly patients (p < 0.05). Anti-TNFalpha treatment reduced disease activity and led to functional improvement in both groups, although the baseline difference in HAQ remained statistically significant at the end of the follow-up. The elderly patients experienced more infective events.

Serious infections during anti-TNFalpha treatment in rheumatoid arthritis patients.

The objective was to estimate the incidence of serious infections in the patients treated with anti-TNFalpha agents for rheumatoid arthritis (RA) recorded in the Lombardy Rheumatology Network (LORHEN) registry. The study inclusion criteria were met by 1064 of the 1114 patients with long-standing RA, 519 treated with infliximab, 303 with adalimumab, and 242 with etanercept; their mean age was 55.8 years and the mean duration of RA 9.4 years. Seventy-three patients (6.9%) experienced a total of 74 serious infections, an incidence rate for all treatment courses of 35.9 per 1000 patient-years (95% confidence interval [95% CI] 27.66-44.13). Most were lower respiratory tract (34.2%) or skin and soft tissue infections (20.5%). Of the 1064 patients, the 790 treated with anti-TNFalpha after March 2002 underwent screening tests for LTBI; five patients developed active tuberculosis. Three patients died of septic shock. The type of anti-TNFalpha agent did not seem to affect the incidence or site of the infections. Both univariate and multivariate analyses identified age at the start of anti-TNFalpha treatment (p=0.008), baseline erythrocyte sedimentation rate ([ESR] p=0.014), and the concomitant use of corticosteroids (p=0.029) as significant predictors of infections. There was no statistically significant difference in risk between the anti-TNFalpha agents.

Treatment of rheumatoid arthritis with anti-TNF-alpha agents: a reappraisal.

It has been found that tumour necrosis factor(TNF)-alpha plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA), and the development of drugs targeting this molecule has extended the therapeutical approaches to RA patients. A number of observational studies of large patient series have also been published over the last few years, many of which have been based on national registries designed to monitor the efficacy and safety of anti-TNF agents, and allow healthcare institutions to control expenditure. Registry data can also help in identifying clinical and laboratory findings capable of predicting response. It has been suggested that the percentage of responding patients is lower in everyday clinical practice than that observed in RCTs, possibly because of patient selection, the use of a washout period before inclusion (which may artificially increase disease activity), and differences in doses, co-morbidities and adherence to therapy. A number of safety concerns have been raised since the introduction of anti-TNF agents, and they are now contraindicated in patients with advanced heart failure; however, the most widely debated current issues regard infections and neoplastic diseases. Moreover, the marketing of new and expensive biological agents has made strictly necessary to create systems capable of monitoring their safety and effectiveness in everyday practice, including the use of longitudinal observational studies. As the first published registry of anti-TNFalpha-treated patients in Italy, Lombardy Rheumatology Network (LORHEN) is already making its contribution in this direction.

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 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), Steinbrocker's 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.