Lee Pace
Rheumatology Paper
Introduction
In recent years great advances have been made in the treatment of rheumatoid arthritis.
Most notably, the used of anti-TNF-a agents are becoming a central aspect of treatment
of several patients with this disease. In particular, patients with severe, erosive disease
who have not responded or not appropriately responded to treatment with other agents
such as methotrexate, sulfasalazine and hydroxychloroquine have benefited greatly from
the anti-TNF agents infliximab, etanercept and adalimumab. Also, patients with Crohn’s
disease (infliximab), psoriatic arthritis and ankylosing spondylitis (etanercept) have
benefited from this treatment. Many patients have enjoyed a complete resolution of
symptoms while many more have enjoyed a significant decrease in symptoms that has
allowed them to return to their prior level of functioning. Like any medicine, however,
there are associated side effects that the clinician must be aware of and monitor for
during treatment with these agents. These adverse effects include injection site reactions,
new onset multiple sclerosis, drug induced lupus and a possible increased risk of
lymphoma. In addition, there have been a lot of questions about the possible increased
risk of serious bacterial infections from anti-TNF agents, most notably tuberculosis. A
brief discussion of this aspect of anti-TNF therapy will be the subject of discussion for
this paper.
Mechanism of action
The agents infliximab, adalimumab and etanercept operate to block TNF-a via two
different mechanisms. Infliximab is a chimeric IgG monoclonal antibody comprising a
human Fc portion and murine Fv. Adalimumab is also an IgG monoclonal antibody but it
is entirely human in origin. Etanercept is a dimer of the p75 component of the human
TNF receptor fused to human IgG Fc (1). Infliximab and Adalimumab are capable of
binding both soluble and membrane bound forms of TNF-a. Etanercept can only bind the
soluble form of TNF-a. Etanercept also binds TNF-b or lymphotoxin-a (LT-a). The two
antibodies do not bind LT-a (2).
Risk of serious bacterial infections
TNF-a plays a central role in the pathophysiology of inflammation and is key in
inflammatory diseases and infection. Some of its key functions include inducing immune
cells to produce other pro-inflammatory cytokines, influencing the maturation of various
inflammatory cells, promoting the expression of adhesion molecules and thus causing a
flux of cells into areas of inflammation, and it induces the release of proteolytic enzymes.
TNF-a also induces apoptosis of infected cells in granuloma forming infections,
tuberculosis in particular. This is thought to be a key factor in containing TB and
preventing widespread dissemination of the disease (2).
Several studies have looked at the risk of serious bacterial infections in patients receiving
anti-TNF therapy, not including tuberculosis. A recent review article citing multiple
clinical trials including the STAR and ACCENT II trials suggested that there was no
increased risk of infection in patients receiving anti-TNF therapy vs. placebo (1).
In contrast, a prospective study published in 2003 looked at the rate of serious infection
in RA patients in the two years prior to starting anti-TNF therapy and during TNF
therapy for a three year period. A serious infection was defined as one that required
hospitalization and/or intravenous antibiotics. There were a total of 60 patients treated
with either etanercept (36) or infliximab (28). There were a total of 11 (18.3%) serious
infections in the group. This corresponded to an incidence of 0.181 per anti-TNF
treatment year vs 0.008 in the two years preceding treatment. The authors cited a rate of
serious infection approximately twice as high as those studies reported in several efficacy
studies and postmarketing surveys (3).
In addition to these studies, there are several case reports in the literature documenting
various severe bacterial infections in patients receiving anti-TNF therapy. A few
examples include a 52 year old woman with seropostive RA who developed
pneumococcal meningitis (4), a 12 year old girl with JRA with multifocal septic arthritis
and osteomyelitis (5), and a 54 year old woman with seropositive RA with Listeria
associated septic arthritis (6). Although these are case reports and large generalizations
cannot be extrapolated from them, they can serve as data for more studies in the future to
help determine the exact risk of certain infections in different types of patients receiving
anti-TNF therapy. At this point, however, it is safe to recommend that clinicians should
exercise a high index of suspicion in patients receiving anti-TNF therapy who present
with even equivocal signs of possible infection. Due to the devastating potential of
infection in people on these drugs, clinicians should not hesitate to order the appropriate
tests and radiologic studies to rule out an infection and be aggressive in starting antibiotic
therapy.
Risk of Tuberculosis
The increased risk of tuberculosis has received a lot of attention in people taking antiTNF agents. As mentioned earlier, TNF-a plays a key role in inducing granuloma
formation by triggering Mycobacterium tuberculosis - infected macrophage apoptosis (2).
This is the human body’s major defense mechanism against tuberculosis. Several studies
have shown that people taking anti-TNF medications have an increased risk of this
disease and that the disease has a higher tendency to be disseminated in these patients.
This is in addition to the already increased risk of infection that people have with various
inflammatory diseases, RA in particular (1). The review article cited earlier summarized
the BIOBADASER database that was created in Spain by the Spanish Society of
Rheumatology in 2000. This database was able to record all patients in Spain with
rheumatologic diseases who were receiving anti-TNF treatment. As of February 2002,
there were 1540 registered patients. The majority of patients (86%) were treated with
infliximab. There were seventeen cases of TB among people treated with infliximab. Of
these patients, 65% have extrapulmonary TB compared with 25% in community
population controls. The estimated risk ratio for TB in RA patients treated with
infliximab in this study was 11.7 (95% CI 9.5 to 14.6). The small number of patients
treated with etanercept precluded determining its effect on patients in this study (1).
More recently, a study in Sweden sought to determine the amount of increased risk of TB
in their population of RA patients treated with anti-TNF agents. Sweden has a much
lower rate of TB than Spain (5 vs 20 per 100,000). The authors sought to see if these
agents had a similar effect on RA patients from a low risk population. 5 separate cohorts
were set up. 3 cohorts were with patients who had RA and 2 were from the general
population. Of the three RA cohorts, one cohort was made up of patients with RA who
were treated with etanercept or infliximab. The other cohorts were of any RA patients
who were hospitalized because of their RA and of any newly diagnosed (<1 year) patients
with RA. These patients’ charts were then retrospectively reviewed looking for the
incidence of TB among them. No routine or specific search for radiologic TB lesions
was done, nor was there any routine recording of a history of TB. Performance of a PPD
test was uncommon among these patients. After statistical analysis, it was found that
patients with RA who were not treated with anti-TNF agents had relative risk of TB of
1.6 (95% CI 1.3 to 1.9) compared to the general population. This corresponded to a 60%
increased risk of TB in RA patients. Furthermore, it was found that RA patients treated
with anto-TNF agents had a 4-fold increased risk of TB vs. RA patients not treated with
an anti-TNF agent (relative risk 4.0, 95% CI 1.3 to 12). Based on these results, the
authors concluded that anti-TNF treatment does significantly increase the risk of TB even
in a low risk population (7).
Based on these studies, it is recommended that all patients who are to begin treatment
with any anti-TNF agent undertake proper screening for TB. The American Thoracic
Society and the Centers for Disease Control recommend PPD placement on all patients
prior to initiation of treatment. A chest radiograph should be obtained if certain risk
factors are present such as recent exposure to the infection or travel to a high risk area.
Patients with active or latent TB must complete a course of antibiotic therapy before they
can start anti-TNF treatment (1).
Conclusions
Anti-TNF agents have revolutionized the field of Rheumatology in recent years. Patients
with non responsive RA and AS as well as patients with Crohn’s and psoriasis have
benefited immensely from these drugs. Like any medicine, there are side effects that
must be monitored for and dealt with as they arise. In the case of anti-TNF agents, the
increased risk of infection, most notably TB, is significant and must be treated seriously.
The benefits of treatment easily outweigh the risks and with proper screening and clinical
suspicion, this risk can be dealt with effectively and provide patients with suppression of
their disease process.
References
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