Letter to the Editor
Tuberculosis and TNFα antagonists – What are we missing?
Tuberculose e antagonistas do FNTα – onde estamos a falhar?
C. Ribeiroa,, A.M. Correiab, R. Duartec,d
a Centro Hospitalar de Vila Nova de Gaia, Vila Nova de Gaia, Portugal
b Public Health Department, Administração Regional de Saúde do Norte, Porto, Portugal
c Centro de Referência Regional para a Tuberculose Multirresistente da Região de Saúde do Norte, Vila Nova de Gaia, Portugal
d Centro de Diagnóstico Pneumológico de Vila Nova de Gaia, Vila Nova de Gaia, Portugal
Dear Editor,

In 2012 Portugal had a tuberculosis incidence of 21.6/100,000 inhabitants (2286 new cases, 942 of which were reported in the northern region).1 A recent retrospective study in Portugal identified, from 2001 to 2012, 25 cases of tuberculosis out of 765 patients under anti-TNFα (297/100,000 patient-years).2

Treatment with tumor necrosis factor antagonists (anti-TNFα) is associated with an elevated risk for development of tuberculosis mostly due to reactivation of latent tuberculosis infection. Since 2006, national guidelines advise tuberculosis screening for all candidates for anti-TNFα therapy including chest X ray, tuberculin skin test (TST) and Interferon-Gamma Release Assay (IGRA) and treatment should be offered to every patient with evidence of LTBI, provided major toxicity is excluded.3

Worldwide, the application of tuberculosis screening guidelines in these patients has been related to a decrease of tuberculosis within this group.4,5

In order to understand the pitfalls that can still lead to the development of tuberculosis in these patients, we reviewed all cases of tuberculosis between 03/2010 and 02/2012 in Portugal's northern region, identifying those who developed the disease while on anti-TNF-α therapy. In this region there are both clinical notification of all tuberculosis cases and laboratory notification of confirmed cases (which allowed for the identification of all patients). Demographic, epidemiological and clinical data was obtained by consulting epidemiological research studies and clinical records.

In the period studied, 1834 cases of tuberculosis were diagnosed in the region, five of which were receiving anti-TNF-α therapy (Table 1).

Table 1.

Patient data.

Gender  Male  Male  Male  Male  Male 
Age  49  57  53  33  37 
Disease  Ulcerative colitis  Crohn's disease  Crohn's disease  Crohn's disease  Crohn's disease 
Disease duration (years)  15  30  26  13 
Previous TB or previous contact with TB patients  Absent  Absent  Absent  Absent  Absent 
Other high risk condition for TB  Absent  Absent  Absent  Absent  Absent 
Other immunossupressors  CorticosteroidsAzathioprine  Azathioprine  CorticosteroidsAzathioprine 
TB screeningTSTIGRA  Not performedNot performed  0Not performed  8Not performed  0Not performed  Not performedNot performed 
LTBI treatment  None  None  Isoniazid – suspended for hepatic toxicity  None  None 
Anti-TNFα therapy  Infliximab  Adalimumab  Infliximab  Infliximab  Adalimumab 
Time on anti-TNF α (months)  24  13 
Site of disease  Disseminated  Pulmonary, Lymphatic  Pulmonary  Pulmonary  Pulmonary, Pleural 
TB treatment duration (months)  12  10  12 
Outcome  Cured  Cured  Cured  Cured  Cured 

All these 5 cases had intestinal disease (4 had Crohn's disease) of an average duration of 18.2 years (minimum 7 maximum 30). None of the patients had known exposure to tuberculosis, 3 patients underwent screening with TST but IGRA was never used. One patient was diagnosed with latent infection based on a TST of 8mm induration and started isoniazid but it was suspended 15 days later due to liver toxicity and anti-TNF-α was started. Patients developed tuberculosis between 3 and 24 months on therapy.

In none of the cases was screening performed according to the published guidelines, it was either absent or incomplete. Even though they represent a small fraction of TB diagnosis, the incidence in this group is significantly higher2 and a methodical screening and follow up while on biological therapy should be our goal. This is particularly important in a country like ours which has an intermediate incidence of TB.

The fact that all TB cases occurred in patients being treated for inflammatory bowel disorders may represent a lack of awareness of tuberculosis and of the guidelines by the clinicians treating these patients.

R. Duarte,A. Diniz
Programa Nacional de Luta Contra a Tuberculose
Ponto da Situação Epidemiológica e de Desempenho,
C. Abreu,F. Magro,J. Santos-Antunes,A. Pilão,E. Rodrigues-Pinto,J. Bernardes
Tuberculosis in anti-TNF-α treated patients remains a problem in countries with an intermediate incidence: analysis of 25 patients matched with a control population
J Crohns Colitis, 7 (2013), pp. e486-e492 http://dx.doi.org/10.1016/j.crohns.2013.03.004
J.E. Fonseca,H. Lucas,H. Canhão,R. Duarte,M. José Santos,M. Villar
Recommendations for the diagnosis and treatment of latent and active tuberculosis in inflammatory joint diseases candidates for therapy with tumor necrosis factor alpha inhibitors – March 2008 update
Rev Port Pneumol, XIV (2008), pp. 271-283
L. Carmona,J.J. Gomez-Reino,V. Rodriguez-Valverde,D. Montero,E. Pascual-Goméz,E.M. Mola
Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists
Arthritis Rheum, 52 (2005), pp. 1766-1772 http://dx.doi.org/10.1002/art.21043
F. Nacci,M. Matucci-Cerinic
Tuberculosis and other infections in the anti-tumour necrosis factor-alpha (anti-TNF-a) era
Best Pract. Res. Clin. Rheumatol., 25 (2011), pp. 375-388 http://dx.doi.org/10.1016/j.berh.2011.06.001
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