VIENNA, Austria-A series of lectures presented Friday at the Annual European Congress of Rheumatology of the European League Against Rheumatism (EULAR) addressed the issue of tuberculosis (TB) reactivation in the setting of tumor-necrosis factor-alpha (TNF-α) inhibition. Steffen Stenger, MD, PhD, principal investigator at the Institute for Clinical Microbiology, Immunology, and Hygiene at the University of Erlangen-Nürnberg in Germany, detailed the possible contributions of TNF-α in the suppression of TB infection.
Dr. Stenger cited evidence for the role of TNF-α in four critical processes: programmed cell death, or apoptosis, of alveolar macrophages; TNF-α-stimulated production by macrophages of nitric oxide (NO) radicals, which destroy the bacterial cell wall; migration of immature dendritic cells to lymph nodes; and the production of selectins, cell adhesion molecules (CAMs), and cytokines in vascular endothelium that are required for transendothelial migration to sites of infection
Inhibition of these mechanisms by TNF-α blockade is thought to result in the breakdown of TB granulomas, resulting in the reactivation of infection. It has, therefore, become standard practice to screen patients for latent TB before initiation of therapy. However, questions persist about whether there is an increased incidence of TB in RA patients in the absence of anti-TNF-α therapy and about the effectiveness of screening and prophylaxis for TB. Several epidemiologic studies presented here examined these questions.
Swedish cohorts demonstrate increased incidence of TB in RA
Johan Askling, MD, PhD, researcher in the clinical epidemiology unit of the department of medicine at the Karolinska Institute in Stockholm, Sweden, presented analyses data from Swedish cohorts that demonstrate a 2-fold increased risk of hospitalization for TB among patients with RA, independent of the use of anti-TNF-α drugs. TNF-α inhibitors, however, increase the incidence of TB another 4-fold.1
Lars Klareskog, MD, PhD, a study author and professor of rheumatology at the Karolinska Institute, tells CIAOMed that "the effect is not that dramatic, but it's still clearly, very clinically relevant, and we have to continue to screen."
"The results are similar to those obtained from analysis of a Spanish cohort," Sir Ravinder Maini, FRCP, FRCP(E), FMedSci, emeritus professor of rheumatology and former director of The Kennedy Institute of Rheumatology at the Imperial College, University of London in England, tells CIAOMed, but comments that "the Swedish data had the right controls to really answer the question."
Screening effective, but vigilance still required
Data was also presented on the effectiveness of screening for latent TB prior to initiation of anti-TNF-α therapy. John L. Perez, MD, scientist at Abbott Laboratories in Parsippany, New Jersey, presented data from trials of adalimumab indicating that the rate of TB among unscreened patients was reduced from 13 cases per 1000 patient/years to 0.8 cases.2
There is a high rate of false negatives when screening for TB, notes Kevin Winthrop, MD, clinical associate professor at the Oregon Health Sciences University in Portland, Oregon. Assessment of a patient's history is critical, he says, and risk factors such as foreign birth, extended living abroad, previous contact with infected individuals, jail, and homelessness should be cause for concern. "Screening may not be enough," Dr. Klareskog points out. "Screening procedures are necessary, they are beneficial, but they don't exclude that TB cases may occur anyway."
This is of great concern, particularly because reactivation of TB in patients on TNF-α inhibitors can lead to extremely severe extrapulmonary and even systemic manifestations. Results of a survey of Dutch rheumatologists presented by Alfonso Abigaël den Broeder, MD, rheumatologist at Sint Maartenskliniek in Nijmegen, The Netherlands, revealed that of 5338 treatments with TNF-α blocking agents reported, 16 cases of TB infection were identified. Six of these were pulmonary, four were extrapulmonary, and there was a combined presentation in five cases.3 Three of these cases were fatal. Even after prophylaxis with isoniazid, vigilance is warranted, as two patients in this cohort had positive skin tests and were treated for 6 months, but still developed active TB.
Mycobacterium TB is the most common bacterial infection worldwide, with 90% of infections resulting in the formation of granulomas in lung parenchymal tissue that persist indefinitely. This allows for the reactivation of latent infections in cases where a patient becomes immunocompromised, such as during treatment with a TNF-α inhibitor.
References:
- Askling J, Fored CM, Brandt L, et al. Risk of tuberculosis in rheumatoid arthritis and following anti-TNF treatment. Preliminary results of an ongoing Swedish monitoring programme of biologics in RA. Presented at: Annual European Congress of Rheumatology of EULAR; June 8-11, 2005; Vienna, Austria. Abstract OP0097.
- Perez JL, Kupper H, Spencer-Green GT. Presented at: the 6th EULAR Annual European Congress of Rheumatology. Impact of screening for latent Tb prior to initiating anti-TNF therapy in North America and Europe. Presented at: Annual European Congress of Rheumatology of EULAR; June 8-11, 2005; Vienna, Austria. Abstract OP0093.
- den Broeder AA, Vonkeman H, Creemers MCW, De Jong E, Van de Laar MA. Characteristics of tuberculosis during anti-TNF treatment in RA patients in the Netherlands and influence of pre-treatment screening and treatment. Presented at: Annual European Congress of Rheumatology of EULAR; June 8-11, 2005; Vienna, Austria. Abstract OP0081.