The BBC has reported that “some popular treatments for rheumatoid arthritis could increase the risk of the painful condition shingles”. The news website said a German study suggests that TNF-alpha inhibitors, which are used to slow the disease’s progression, could make some patients vulnerable. The authors of the article advise that this adverse effect be monitored.

This large study of people with rheumatoid arthritis (RA) found more cases of shingles in those treated with TNF-alpha inhibitor drugs than in those treated with conventional drugs. However, as these drugs are only used in people who have not responded to conventional treatments, the patients typically have more severe disease. As such, it is difficult to tell whether the increased rate of shingles is due to these drugs or to the advanced form of the patient’s disease and effects on their immune system of having extensive, intense treatments. As the authors say, further research will be needed to confirm this.

The authors’ advice to doctors to be aware of the risk of shingles in TNF-alpha inhibitor treatments for RA seems reasonable. TNF-alpha inhibitors are prescribed only by specialists, are known to have risks and their use should be carefully monitored.

Where did the story come from?

Dr Anja Strangfeld and colleagues from the German Rheumatism Research Centre and Charité University Medicine carried out this research. The work was funded by grants from Essex Pharma, Wyeth Pharma, Amgen, Abbott, Hoffman-LaRoche and Bristol-Myers Squib. The study was published in the peer-reviewed Journal of the American Medical Association .

What kind of scientific study was this?

This cohort study investigated whether therapy drugs for RA increased the rate of shingles (herpes zoster) in people with arthritis. Shingles is a painful rash that develops through reactivation of the chickenpox virus, which lies dormant inside people’s bodies following chickenpox infection. Any person who has previously had chickenpox may develop shingles at some point, although it most often occurs in the elderly and those with compromised immune systems or chronic illnesses.

The TNF-alpha inhibitor drugs adalimumab, infliximab and etanercept work by inhibiting tumour necrosis factor (TNF) alpha, a molecule involved in the immune response. They are used to treat severe RA when other treatments have failed. They are also used to treat other diseases including inflammatory bowel disease and psoriatic arthritis. There has been some evidence from previous trials that TNF-alpha inhibitor drugs may increase the risk of bacterial infections, but little is known about their effects on viral infections.

This study aimed to investigate whether these drugs also increase the risk of reactivation of the virus herpes zoster, which causes shingles.

This study used a group of people from an ongoing German prospective cohort study. This nationwide study, called RABBIT or the German biologics register, began in 2001 and aims to investigate the safety of biological agents, such as TNF-alpha inhibitors, in the treatment of RA. The researchers identified all patients who were started on the drugs adalimumab, infliximab or etanercept between 2001 and 2006. For a comparison group, they identified people who were taking another type of RA drug: disease modifying anti-rheumatic drugs (DMARDs). DMARDs are the main treatments used in RA to slow disease progression. These people had to have tried one of the DMARDs and were switching to another DMARD.

Rheumatologists collected data from all 5,040 patients at the beginning of the study and at three, six, 12, 18, 24, 30 and 36 months. Information was collected on disease activity (tender and swollen joints, morning stiffness and blood markers of disease activity), adverse effects of treatment (graded as mild, moderate or severe), other medications used and other current medical conditions. Patients also completed questionnaires on their level of functioning. In their analyses, the researchers looked at whether TNF-alpha inhibitors were associated with an increased risk of shingles.

What were the results of the study?

Compared with the controls (1,774 patients), patients taking the TNF-alpha inhibitors (3,266 patients) had significantly higher RA disease activity, poorer functioning, had tried more previous treatments with DMARDs and steroids, had suffered from RA for a longer time, and were more likely to be positive for rheumatoid factor. Rheumatoid factor is an autoimmune antibody (one that is targeted against the body’s own tissues) that is often found in RA and can indicate that the disease is likely to be more active.

During follow-up there were 86 cases of herpes zoster in 82 patients. Of those cases, 18 were considered serious. In total, 62 of these cases occurred in the TNF-alpha inhibitor treated group and 24 cases occurred in the control groups, which was a statistically significant difference. When the researchers looked at how many instances of herpes zoster there were for each individual TNF-alpha drug, more cases were found in those taking adalimumab and infliximab than etanercept. Calculated incidence rates per 1,000 patient years were 11.1 for use of adalimumab and infliximab, 8.9 for etanercept and 5.6 for conventional DMARD drugs.

The researchers took into account other factors associated with shingles. They found that risk increased with age, greater disease activity, poorer functioning and higher dose used of glucocorticoid drugs.

What interpretations did the researchers draw from these results?

The researchers conclude that treatment with the TNF-alpha inhibitors adalimumab and infliximab may be associated with an increased risk of shingles, but further study is required to confirm this association.

What does the NHS Knowledge Service make of this study?

This study has strengths in that it followed a large number of people with RA and reliably collected extensive patient information at a number of follow-up sessions over three years. Although it has demonstrated a higher rate of shingles in patients taking the TNF-alpha inhibitors, particularly adalimumab and infliximab, it is difficult to say that the drugs themselves were the cause of the shingles. This is because of the significant differences between those taking TNF-alpha inhibitors and the controls taking conventional DMARD drugs.

Patients with RA, like those with other immune disorders and inflammatory musculoskeletal conditions, are at an increased risk of shingles compared with the general population. As TNF-alpha inhibitor drugs are only used in people who have not responded to other drug treatments, those being treated typically have a more severe stage of disease. Although the researchers attempted to adjust their statistical analyses to take these differences into account, the effects may not have been fully countered.

As such, it is difficult to say whether the higher rate of shingles in these people was due to the drugs they were taking or the advanced form of their disease and the effect on their immune system of having extensive, intense treatments. In addition, as this was an observational study and the patients were not randomly allocated to which treatment they were given, there is the possibility that other factors that differed between the groups affected the results.

Another important limitation of the study is the small number of shingles cases relative to the total number in the study, which reduces the reliability of any statistical comparisons. Additionally, the multiple testing and subgroup analyses increase the risk of chance findings.

The authors advise that doctors should be aware of the risk of shingles in patients receiving TNF-alpha inhibitor treatments for RA, and this seems reasonable. The drugs are prescribed only by specialists, are known to have risks and their use should always be carefully monitored.