Interferon trial results

I am delighted to say that the interferon alpha 2b in Behçet’s disease (BD) trial (trial registration number ISRCTN 36354474; EudraCT 2004-004301-18) is now published (www.ncbi.nlm.nih.gov/pubmed/25269831), and I am allowed to pass the results on to you. I thank you all for your patience, particularly those who enrolled in the trial and made it possible. I also thank the Society for additional financial assistance with the trial, which was funded by the Moulton Trust.

The consultants involved in the care of patients with Behcet’s disease in the trial were Sue Lightman (Consultant Ophthalmologist), Hilary Longhurst (Consultant Physician), Robert Moots (Consultant Physician), Miles Stanford (Consultant Ophthalmologist) and Dorian Haskard (Consultant Physician). Particular thanks go to Professor William Lynn, who helped us manage the interferon-α-2b, and to Dr Virginia Calder for the immunology work. Additionally, special thanks go to Dr Oren Tomkins for his invaluable help in all aspects of the work and to Georgina Seaman who audited all the trial data. Dr Colin Barnes and Professor Richard Powell managed the trial committees, and I thank them for their help and support throughout.

The use of interferon-α-2a and interferon-α-2b has been reported previously in BD in a randomised study as well as in small case series. In some studies, interferon-α has been used continuously, but in others a short course of the drug appears to induce prolonged disease remission allowing discontinuation of all medication without relapse. The mechanism of interferon in BD is unknown, but in some patients treated for hepatitis B infection, regulatory T cells (Tregs) are induced.

This trial aimed to answer the question of whether a 6-month course of interferon-α-2b would reduce the amount of corticosteroid needed to control the disease at 1 year, and if so was this effect still seen at 3 years. We chose to use interferon-α-2b as both interferon-α-2a and 2b had already been shown to be effective and interferon-α-2b was available in a pegylated form, which meant that it could be given once a week rather than three times a week. It also has the advantage of being much cheaper than interferon-α-2a and so would be more likely to be available to patients in resource poor countries where BD is prevalent. Patients with BD requiring to take systemic therapy of all types were enrolled and randomised to either continue on their treatment or to add pegylated interferon-α-2b given once weekly to their treatment for 26 weeks and then to stop the interferon-α-2b. Both groups of patients were followed over the next 3 years with quality of life questionnaires and clinical examination of disease activity. If the disease relapsed, we tried to manage the relapse in a standardised manner with a treatment regimen appropriate to whether the relapse was graded as mild, moderate or severe. Of course, if you needed a different type of treatment we always did what was best for you. Some of you also took part in two other linked studies that were run in parallel. One was to look at the immune cells in the blood and see if we could observe the effect of interferon-α-2b on these and if changes correlated with the effect of the interferon to see how it worked. The other study was to look at cardiovascular effects of the interferon, and these results will be reported separately very soon now that the main trial paper has been published.

 

Trial results

The study was a multicentre, randomised, controlled, parallel-group, single-masked clinical trial of peginterferon-α-2b in BD patients on systemic treatment. Patients were randomly assigned in a 1:1 ratio to one of two treatment groups and were stratified in blocks according to centre, disease duration (<3 years or ³3 years) and presence of ocular involvement. Stratification according to disease duration was based on an increased risk of ocular involvement among patients with disease >3 years because higher treatment doses are frequently required for sight-threatening disease. In all, 72 patients were included. The addition of peginterferon-α-2b to the drug regimen of the whole group of BD patients did not significantly reduce their corticosteroid dose required at 1 year.

However, in those on corticosteroids at baseline post hoc analysis demonstrated that the addition of peginterferon-α-2b did result in a significant reduction in corticosteroid dose with a significantly improved quality of life and a trend to reduce other required immunosuppressive agents. This effect was seen at 1 year and associated with a rise in Tregs suggesting a possible mode of action for interferon in those on corticosteroids at baseline.

There was no difference in the relapse rates recorded between the two groups. There was no significant difference in the quality of life scores at the primary endpoint of 12 months, although there was a tendency for the interferon-treated group to have better scores throughout the trial, and at 36 months this difference was statistically significant. Higher fatigue scores were observed in the standard treatment arm, although this was not statistically significant. Additionally, there was a non-significant trend for less use of second-line immunosuppressive agents, less use of biological drugs and a decreased severe relapse rate in the peginterferon-treated group at 1 year that was less apparent at 3 years. Response was unaffected by the duration of disease, location (ocular or systemic), age or gender, and there was no difference between the two groups in the serious adverse events that occurred.

We are very excited by these findings! BD is heterogeneous with different phenotypes, so a heterogeneous response to therapies could be anticipated. A major role in pathogenesis is suggested for Th1 and Th2 immune cells and more recently for Th17 immune cells in the blood. Individual susceptibility seems to be modulated by genetic variants in genes codifying these cytokines. Th1 and Th17 cells are thought to be involved in active disease phases, whereas Th2 cells affect the development or severity of the disease. Th17 responses were controlled by Tregs in rheumatoid arthritis (RA) patients treated successfully with infliximab, and anti-TNF therapy was found to induce Tregs in RA patients. In ocular fluids, infliximab also inhibited Th17 differentiation by CD4+ immune cells. This suggests that Tregs are able to modulate Th17 responses and therefore can decrease inflammatory activity in disease settings. IL-17 is also thought to coordinate the cross-talk between lymphocytes and neutrophils in BD, so the related cytokines could be potential targets for therapy.

Others have suggested that interferon only works when corticosteroids and other immunosuppressive agents have been discontinued, as its effect is mitigated by these agents. We did not confirm this in our study; indeed, those on minimal systemic therapy did not have any benefit from the addition of peginterferon-α-2b, at least in the parameters we measured. The mode of action of interferon may depend on the dose used, as at very high doses, such as those used in treating melanoma, an immunostimulatory mechanism has been suggested, although others have also found an increase in Tregs. Tregs control immune responses to self-antigens and can modulate the effect of many immune cells by blocking proliferation, differentiation and effector functions. In addition to the potentiating effect on Tregs, there was a concomitant decrease in the percentages of Th17 cells in the paired blood specimens that were obtained at all time points. Th17 cells have been proposed as effector cells in active BD, and their down-regulation by interferon-α could be a reflection of the up-regulation of Tregs, although this requires further study.

Interferon-α has been used in BD patients since the mid-1980s, and there is no consensus about the ideal dose or duration of treatment. Anti-TNF drugs, particularly infliximab, are also very effective in rapidly resolving inflammatory episodes. A group of us led by Professor Robert Moots have recently been successful in obtaining funding to run a clinical trial comparing interferon alpha and infliximab in BD, which should start in 2015. These are exciting times, and we hope these studies will translate into better treatment strategies for successful treatment of you the patient with BD.

Sue Lightman