Interstitial lung disease induced or exacerbated by TNF-targeted therapies: analysis of 122 cases.

To analyze the clinical characteristics, outcomes, and patterns of association with the different biologic agents used in all reported cases of adult patients developing interstitial lung disease (ILD) after biologic therapy. In 2006, the Study Group on Autoimmune Diseases of the Spanish Society of Internal Medicine created the BIOGEAS project. One objective was to collect data on autoimmune diseases secondary to the use of biologic agents by quarterly Medline search surveillance of reported cases. For this study, the baseline included articles published between January 1990 and March 2010, including the MeSH term "lung diseases, interstitial" as the key research term. In addition, we report an unpublished case of ILD secondary to biologic therapy. There are 122 reported cases of new-onset or exacerbation of ILD secondary to administration of biologic therapies. Biologic agents associated with ILD were overwhelmingly anti-tumor necrosis factor agents (etanercept in 58 cases and infliximab in 56) and were administered for rheumatoid arthritis in 108 (89%) patients. ILD appeared a mean of 26 weeks after initiation of biologic agents. ILD was confirmed by pulmonary biopsy in 26 cases, although a specific histopathologic description was detailed in only 20: 7 patients were classified as usual interstitial pneumonia, 6 as nonspecific interstitial pneumonia, 5 as organizing pneumonia, 1 as diffuse alveolar damage, and 1 as lymphoid interstitial pneumonia. Treatment of ILD included withdrawal of biologic agents in all cases but 1. The outcome of ILD was detailed in 52 cases. Complete resolution was reported in 21 (40%) cases, improvement or partial resolution in 13 (25%), and no resolution in 18 (35%). Fifteen (29%) patients died during the follow-up, the majority (70%) during the first 5 weeks after initiating biologic therapy. In comparison with survivors, patients who died were aged >65 years (67% vs 33%, P = 0.036), with later onset of ILD (46 weeks vs 15 weeks, P = 0.006), received immunosuppressive drugs more frequently (33% vs 8%, P = 0.036), and more often had a previous diagnosis of ILD (67% vs 29%, P = 0.025). We found that 97% of cases of ILD associated with biologic agents were associated with agents blocking tumor necrosis factor-α, a cytokine that has been implicated in the pathophysiology of pulmonary fibrosis. Strikingly, drug-induced ILD had a poor prognosis, with an overall mortality rate of around one third, rising to two thirds in patients with preexisting ILD.

Perez-Alvarez R ，Perez-de-Lis M ，Diaz-Lagares C ，Pego-Reigosa JM ，Retamozo S ，Bove A ，Brito-Zeron P ，Bosch X ，Ramos-Casals M ... -  《-》

Autoimmune diseases induced by TNF-targeted therapies.

Ramos-Casals M ，Brito-Zerón P ，Soto MJ ，Cuadrado MJ ，Khamashta MA ... -  《-》

Eternacept for the treatment of patients with rheumatoid arthritis and concurrent interstitial lung disease.

Tumour necrosis factor-α (TNF-α)-blocking agents are increasingly used in the management of refractory rheumatoid arthritis (RA). Although effective, they are associated with rare but potentially fatal adverse effects, including interstitial lung disease (ILD). In patients with pre-existing ILD, eternacept (ETN) monotherapy is often regarded as a suitable choice. Other anti-TNF-α blockers such as infliximab and adalimumab, are used in combination therapy with methotrexate (MTX) in most of the cases. We report on a case of fatal exacerbation of ILD in a patient given ETN monotherapy and review the literature on ETN-associated ILD. We report on a case of a 75-year-old male with RA who developed severe ILD after the introduction of ETN, and we undertook a literature search to identify other reports of similar cases. We then critically assessed those reports. In addition to our case, 11 other patients have been reported to have developed ILD in association with the use of ETN. Six patients had pre-existing ILD. Although four patients received MTX, eight patients developed severe ILD without MTX. Ten patients recovered after termination of ETN, although two patients died. Although ETN is often regarded as safe for patients with ILD, our case and the literature reports suggest that caution is still required.

Horai Y ，Miyamura T ，Shimada K ，Takahama S ，Minami R ，Yamamoto M ，Suematsu E ... -  《-》

Lack of adverse effect of anti-tumor necrosis factor-α biologics in treatment of rheumatoid arthritis: 5 years follow-up.

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder affecting synovial joints and many other organs. Most patients seen in clinical settings have a progressive chronic disease, with radiographic damage, frequent work disability, incremental functional declines and increased mortality rates. The introduction of the biological drugs in treatment of RA has played an important role in prevention of destructive effects of the disease but may have serious adverse effects due to their powerful inhibition of the immune system. To study the adverse effects (ADEs) of three different tumor necrosis factor α inhibitor (TNFi) drugs (infliximab, adalimumab and etanercept) in RA patients for 5 years in the south-west area of Saudi Arabia. Two groups of RA patients were included in this study: The first group included 112 patients, representing the biologics group. These patients received biological therapy plus disease modifying anti-rheumatic drugs (DMARDs): 56 patients received infliximab (IFX), 36 patients received adalimumab (ADL) and 20 patients received etanercept (ETN). The second group also included 112 patients, representing the control group: RA patients treated only with the traditional DMARDs. ADEs were classified into mild and severe. The mild ADEs which had been recorded during 5 years of follow-up in patients receiving TNFi, were onycholysis (1.8%), positive tuberculin test (1.8%) and small vessel vasculitis (1.8%). Statistically, there were insignificant differences in the mild ADEs except for upper respiratory tract infection that was significantly higher in the control group. Severe ADEs included pneumonia (1.8%) and solid tumor (1.8%) and there were no significant differences between the biologics and control groups. Also there were no significant statistical differences for the ADEs, mild or severe, between the three biologics, infliximab, adalimumab and etanercept. Occurrence of ADEs did not correlate to methotrexate dose, steroid dose or rheumatoid factor positivity. Our results indicate that the use of TNFi therapy appeared to be as safe as traditional DMARDs in treatment of rheumatoid arthritis patients and long-term follow-up with careful examination is essential to pick up any abnormal ADEs.

Dewedar AM ，Shalaby MA ，Al-Homaid S ，Mahfouz AM ，Shams OA ，Fathy A ... -  《-》

Potential risk of TNF inhibitors on the progression of interstitial lung disease in patients with rheumatoid arthritis.

Biological therapy represents important advances in alleviating rheumatoid arthritis (RA), but the effect on interstitial lung disease (ILD) has been controversial. The objective of this study was to assess the risk of such treatment for patients with ILD. Case-control cohorts. Single centre in Japan. This study included 163 patients with RA who underwent biological therapy. We assessed chest CT before initiation of biological therapy and grouped 163 patients according to the presence of ILD (with (n=58) and without pre-existing ILD (n=105)). Next, we evaluated serial changes of chest CT after treatment and visually assessed the emergence of ILD or its progression, which was referred to as an 'ILD event'. Then, we also classified the patients according to the presence of ILD events and analysed their characteristics. Tumour necrosis factor (TNF) inhibitors were administered to more patients with ILD events than those without ILD events (88% vs 60%, p<0.05), but recipients of tocilizumab or abatacept did not differ in this respect. Of 58 patients with pre-existing ILD, 14 had ILD events, and that proportion was greater than for those without pre-existing ILD (24% vs 3%, p<0.001). Of these 14 patients, all were treated with TNF inhibitors. Four patients developed generalised lung disease and two died from ILD progression. Baseline levels of KL-6 were similar in both groups, but increased in patients with ILD events. TNF inhibitors have the potential risk of ILD events, particularly for patients with pre-existing ILD, and KL-6 is a valuable surrogate marker for detecting ILD events. Our data suggest that non-TNF inhibitors are a better treatment option for these patients.

Nakashita T ，Ando K ，Kaneko N ，Takahashi K ，Motojima S ... -  《BMJ Open》