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Long-term safety – part 1/2

Table 1: Adverse events conclusively shown to be associated with the anti-TNF therapy Adverse event

Non-serious upper respiratory tract infections

Serious rare infections: Legionella pneumophila,

Listeria monocytogenes, Salmonella sp., Pneumocystis


Hepatitis B reactivation Herpes zoster reactivation

Non-melanoma skin cancer Lymphoma

Neurological adverse events: central and peripheral demyelinisation

Hepatotoxicity Thrombocytopenia

Aggravation of psoriasis and pustulosis palmo-plantaris

Lupus-like syndrome 21,35

41–43 44


21,32,47– 50

51,52 53,54

55,56 57–59


Reference Comments OR 1.05-1.339

7–9 10–12

Incidence is greatest during the first months of therapy.10

Adjusted IRR 4.6 (95% CI 1.8-11.9).11 The risk

is higher for infliximab and adalimumab than for etanercept

Highest rates with adalimumab or infliximab than with etanercept

Incidence is higher for infliximab and adalimumab (7.9–15.1/1000 patient-years) than for etanercept (5.6–13.3/1000 patient-years)

however, the observed increase may be due to the overall increased incidence of NMSC in rheumatoid arthritis45

OR 1.2–1.8,47

SIR 1.3–2.2. Risk is higher with infliximab (SIR 2.3–5.6) and adalimumab (SIR 2.3–7.1) than with etanercept (SIR 0.4–1.8)21

Incidence is low. All anti-TNFs seem to be able to induce neurological adverse events. Atypical clinical symptoms. Non-reversible in approximately 50% of cases

Strongest association with Infliximab. Rarely severe and usually reversible

Overall incidence of 4.3%56 –

– IRR=incidence rate ratio; OR=odds ratio; SIR=standardised incidence ratio

danger of cumulative immunosuppression? If yes, is this reversible after cessation of treatment? What is the risk of unpredictable and unexpected AEs over time? Which drug(s) provide(s) the highest benefit for the long-term management of patients?

In this chapter, we will address these questions by reviewing currently available evidence for the four approved biologics (adalimumab, etanercept, infliximab and ustekinumab).

Safety of biological agents across different indications

Combined analyses of the data from clinical studies, open-label extension studies and the registries have consistently identified the safety profile for the anti-TNF agents (Tables 1 and 2). By far the greatest contribution to these analyses comes from rheumatology, followed by gastroenterology. Safety information for ustekinumab can be derived from dermatology and rheumatology. The overall safety profile of the anti-TNF agents is excellent. The risk of AEs is only marginally increased compared to either the conventional therapies or to the background

population.3 Anti-TNFs have been linked

to the risk of infection, in particular, from intracellular bacteria causing tuberculosis, legionellosis and listeriosis. Anti-TNF agents may reactivate latent viral infections such as hepatitis B, herpes zoster or cytomegalovirus, but not HIV or hepatitis C. The overall risk of cancer is not increased, but there is a safety signal regarding non-melanoma skin cancer (NMSC) and lymphoma (see Table 1). Cardiac safety is excellent except for the contraindication for the patients with advanced cardiac insufficiency where an increased mortality has been observed.4–6 An important message from the described safety analyses is that the AEs of anti-TNF agents are not cumulative. Some AEs occur within months of initiation of therapy (for example, severe infections) and some occur randomly throughout the whole period of therapy.7–12

Assessment of safety of biologics for psoriasis

Not all AEs listed in Tables 1 and 2 have been consistently observed in patients with psoriasis or psoriatic arthritis. There is, however, no reason to believe that the safety profile of the anti-TNFa

Table 2: Casuistic reports of adverse events to be associated with the anti-TNF therapy20 Adverse event

Opportunistic infections:

histoplasmosis, coccidioidomycosis, aspergillosis, pneumocystis, listeriosis, nocardiosis

CMV reactivation

JC virus reactivation (progressive multifocal leukoencephalopathy)

Aspergillosis and other deep fungal infections Malignant melanoma Heart insufficiency

Autoimmune disorders: lupus erythematosus, alopecia areata, vitiligo, lichenoid eruptions

drugs in psoriasis is radically different to that documented for the rheumatological patients. In fact, direct comparison of the safety profiles for the same drugs across different indications suggests a generally lower rate of AEs in psoriasis compared to patients with either rheumatoid arthritis or inflammatory bowel disease.1

There may, however, be

important differences in the risk for particular side-effects in patients with different diseases. For example, the cases of hepatosplenic lymphoma after anti-TNFa have almost entirely been documented for the patients with inflammatory bowel disease.13

Safety profile of biologics in placebo- controlled clinical trials

While the determination of the efficacy of a drug in clinical trials is straightforward, the assessment of its safety may be very difficult. The ideal method for the assessment of safety would be by comparing the incidence and types of AE occurring in the group treated with the drug to the group receiving placebo. Although such analyses are routinely done during all phases of clinical trial, the validity of the results is often insufficient due to a number of factors. First, safety is rarely a primary endpoint in clinical trials and the studies are therefore underpowered with respect to the proper assessment of the frequency of AEs. Second, due to ethical reasons, the placebo-controlled phase of the trial is time limited and rarely exceeds six months, which means that those rare occasions of cumulative toxicity will not be captured. Third, the population in clinical trials does not always reflect the real-life situation, where patients may present with numerous comorbidities.

The most comprehensive analysis of 21

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