TNF antagonist therapy has dramatically altered the therapeutic landscape in rheumatology. However, TNF antagonists are thought to be associated with AEs that, in a small percentage of patients, may reflect the same immunomodulatory properties mediating efficacy. These could be infections, including TB and opportunistic infections, or AEs resulting from inappropriate immune/inflammatory cell activity, such as lymphoma, autoimmune, and demyelinating diseases.
For this adalimumab safety report, two sources of information were used: the RA clinical trial safety database and US spontaneous postmarketing reports. From these sources, the rates of clinical trial SAEs and postmarketing AEs were found to be low and stable over time.
The increased risk for serious infection in patients with RA may be partly attributable to alterations in immunoregulation that accompany RA.33
However, additional risk factors include increased age, disease severity, comorbid illnesses (such as diabetes mellitus), and the use of corticosteroids or other immunosuppressive medications.18
Published cohort studies have tried to elucidate the risk of serious infection among infliximab treated and etanercept treated patients. Phillips et al34
found no difference in rates of infection before and after exposure to etanercept, while Kroesen et al12
demonstrated an increase in the rate of serious infection from 0.008 events/year before therapy with infliximab and etanercept, to 0.181 events/year after TNF antagonist therapy exposure. The British Society of Rheumatology Biologics Register estimated the incidence rate of serious infections with the use of biologic agents to be 5.0–6.5/100 PYs, with no significant differences between adalimumab, etanercept, and infliximab.35
The rates of serious infections in adalimumab treated patients from the adalimumab clinical trial safety database were 4.9/100 PYs on 31 August 2002, and 5.1/100 PYs on 15 April 2005. These rates fall within the range of serious infection rates observed for the general RA population naive to TNF antagonists (fig 1).17,28
The stability of the adalimumab rate over time shows that, as OLE experience accrued in the years following RCT exposure, serious infections did not become more frequent. These data also suggest that the administration of adalimumab in clinical trials did not increase the rate of serious infections beyond that expected without adalimumab. Nonetheless, the risk for serious infections with anti‐TNF therapy should be discussed with patients, especially those on concomitant immunosuppressive medications and those who have predisposing comorbid illnesses.
TNF plays a role in host defence against Mycobacterium tuberculosis
by mediating granuloma homeostasis and containment of latent disease.36
Cases of TB have been documented in patients treated with TNF blockade with etanercept, infliximab, and adalimumab.37
It is believed that most such cases are a result of reactivation of LTB. Accordingly, the labels of all three TNF antagonists carry a warning regarding the increased risk of TB, and the Centers for Disease Control (CDC) recommend all patients be screened for TB prior to initiating anti‐TNF therapy.38
During the first 534 PYs of adalimumab exposure in clinical trials, screening for TB was not required and seven TB cases were reported, all in Europe (1.3/100 PYs). After routine TB screening was introduced in adalimumab clinical trials, the rate of TB was 0.33/100 PYs in Europe as of April 2005. This 75% decrease in the overall rate of TB in clinical trials in Europe may underestimate the true effectiveness of screening because several of the postscreening cases could have been detected by more stringent screening criteria. The incidence in North America is lower, with four cases representing a rate of 0.08/100 PYs. In this regard, the CDC recommends that induration
5 mm diameter be considered a positive PPD result in immunosuppressed patients, such as those with RA.38
The importance of applying a high level of vigilance, conducting careful histories, and initiating prophylactic TB treatment for LTB prior to anti‐TNF therapy cannot be overemphasised. The duration of treatment for LTB needed before TNF antagonist therapy can be safely administered is uncertain because of a lack of published data that could guide clinical decisions.
Opportunistic infections have been reported with the use of all three TNF antagonists.37
They include histoplasmosis, listeriosis, pulmonary aspergillosis, and Pneumocystis carinii
pneumonia. In the adalimumab clinical trial safety database as of April 2005, four cases of histoplasmosis (0.03/100 PYs) were seen, all in endemic areas. In the US postmarketing database, opportunistic infections had an overall rate of 0.06/100 PYs and included infections from nine different organisms. These results confirm that opportunistic infections can occur in patients receiving adalimumab, but they appear to be infrequent and involve a variety of organisms.
Both the present analysis of adalimumab and previous studies of other TNF antagonists have found no association between TNF antagonist therapy and non‐lymphomatous cancers. Several reports show that, in the absence of TNF antagonists, the risk for lymphoma in patients with RA is more than double that of the general population (table 3).29,30,31,32
Risk factors thought to be associated with this increased rate of lymphoma are the severity and duration of the disease. A case‐control study of RA patients found that the odds ratio for lymphoma was increased approximately 5‐ or 25‐fold for patients whose RA disease activity over time was moderate or high, respectively.32
Most patients in adalimumab clinical trials had moderately to severely active RA at study entry, which increased their risks for lymphoma. The SIR of 3.19 for lymphoma in adalimumab treated patients is consistent with that expected in RA patients naive to TNF antagonists. During a March 2003 FDA advisory meeting, the lymphoma SIR reported in RA clinical trials was 6.35 for infliximab and 3.47 for etanercept.39
Given the unprecedented efficacy of TNF antagonists compared with traditional DMARDs in controlling RA disease activity, what remains to be seen with long term observations is whether or not anti‐TNF therapy can actually lower the risk for lymphoma in RA.
Demyelinating disease was seen infrequently with adalimumab, both in clinical trials and in US postmarketing reports. Some cases occurred in patients with evidence of neurologic symptoms prior to initiation of adalimumab therapy. This indicates that caution is warranted when initiating the use of anti‐TNF therapy in patients with symptoms suggestive of pre‐existing central nervous system disease.14
Analyses of safety data from adalimumab global clinical trials and US postmarketing reports show that adalimumab therapy is generally safe and well tolerated in patients with RA. There were no new safety signals that suggest a considerable difference compared with other TNF antagonists. Furthermore, the rates of serious infections and lymphoma for patients treated with adalimumab appear to be similar to those reported for the general RA population, as well as for patients treated with etanercept or infliximab. As with any anti‐TNF agent, it would be prudent for physicians and patients alike to remain vigilant in monitoring for serious and opportunistic infections, as well as lymphoma. Overall, the relatively low rates of occurrence of these SAEs with adalimumab therapy do not appear to outweigh the substantial clinical benefits adalimumab offers the RA population.