The study confirms and expands the known safety profile of Adalimumab and reports no additional safety risk of laboratory abnormalities, hepatitis B reactivation and pregnancy outcomes.

Tumor necrosis factor inhibitors (TNFi or anti-TNFs) have significantly contributed in improving the clinical outcomes of rheumatoid arthritis (RA), however, safety has always been a concern. Various severe infectious event (SIE) have been reported in patients using biologics. Different risk minimization activities, such as vaccinations and latent tuberculosis (TB) infection (LTBI) screening and prophylaxis are used to mitigate the infection risk. Recently, many other adverse events (AEs) have become a focus of interest including viral reactivation, vaccination response, laboratory abnormalities and pregnancy outcomes. This study focused on above-emerging events using comprehensive data from global Adalimumab clinical trials in RA.

Rationale behind the research:

This research has been carried out to account for adverse effects, and safety concerns associated with anti-TNF use in RA patients.

Objective:

To update adverse events (AEs) of particular interest from global Adalimumab clinical trials in RA patients.

Study outcomes:

• Study outcome measures were adverse effects associated with influenza vaccination, laboratory abnormalities including Hb count, overall infections like active tuberculosis, hepatitis B, etc. and adverse effects on the pregnancy of women exposed to anti-TNF inhibitors like Adalimumab

Time Points: Baseline and 6 months

Outcomes

Baseline: No significant baseline differences were observed between the groups.

Study outcomes:

• Incidence rates of serious infections includes pneumonia (0.7E/100 PYs), cellulitis (0.3E/100 PYs), bacterial arthritis and sepsis (0.2E/100 PYs each)  {Fig1}
• Incidence rate for tuberculosis was 0.3 events/100 patient-years {Fig1}
  

Fig 1: Incidence rates of serious infections in women patients with RA (Events/ 100 patient years)

• Incidence rates for opportunistic infection was <0.1E/100 Pys for oesophageal candidiasis and for coccidiomycosis, cytomegalovirus infection and Mycobacterium avium complex infection it was <0.1E/100 Pys.
• There were no considerable laboratory abnormalities seen with Adalimumab-plus-methotrexate in comparison to placebo-plus-methotrexate
• AE related to influenza were observed in 5% of vaccinated patients vs. 14% of patients not vaccinated during the study
• Relative risk of significant congenital disabilities and spontaneous abortions in Adalimumab-exposed women was similar between unexposed women with RA and healthy women {Fig 2 &3}

Fig 2: Incidence rates of major birth defects in pregnant women with RA exposed to adalimumab

Fig 3: Pregnancy outcome (live birth rates) associated with adalimumab exposure in pregnant women with RA

Anti-TNF therapy has always been a matter of concern as they are associated with an increased risk of infections. The spectrum of infections reported in this study possess similarity with those reported with other anti-TNFs in both randomized clinical trials and registries. There is no change found in the types of infections over a period.

The opportunistic infections include a variety of possible bacterial, mycobacterial, fungal, viral and parasitic agents which may be challenging from a diagnostic perspective. Recently, there has been a considerable interest in herpes zoster infections. The overall rate of HZ with Adalimumab was low and similar to reported rates in registries and a large claims database. It is suggested that anti-TNF therapies usage may not put patients at higher risk of HZ. However, still there is a need of the risk-benefit assessment for vaccination before starting biological therapy.

Overall, the impact of Adalimumab on haemoglobin and lipid parameters implicated no new safety signals about MTX-monotherapy, in both early and long-standing RA. There is a great importance of monitoring lipid changes owing to the probability of an increased risk of cardiovascular events in RA. It is recommended that RA patients should be vaccinated with non-live agents, even if their treatment with anti-TNF therapy is ongoing.

However, awareness of vaccination among RA patients appears to be low, since only a minority of patients with RA starting Adalimumab receive influenza vaccination. Patients who received this vaccine were presented with fewer influenza-related adverse effects over an average of 5.6 years of follow-up, compared with patients not receiving the vaccine.

Like other anti-TNFs, Adalimumab is classified as pregnancy category B (no documented human toxicity) by the US Food and Drug Administration. The safety of Adalimumab in pregnancy has been reported in a reproductive animal study. The animal study has revealed no evidence of fetal harm on administration with Adalimumab, but only a small number of Adalimumab-exposed human pregnancies have been published to date. The OTIS registry reported neither specific pattern of defects in Adalimumab-exposed infants during prenatal development nor adverse pregnancy outcomes.