Meeting report (part 3): a survey of new SLE treatment modalities
The two-day international meeting for rheumatologists at the Karolinska Institute, Stockholm, Sweden was actually packed with oral presentations providing a lot of information on fairly all fields a rheumatologist might be interested in. Actually too much to report in a concise matter in this weblog, but I will conclude my third and fourth (to follow) part of this meeting report with a summary of the oral presentations on SLE treatment and classification of myopathies.
SLE: the ongoing search for new treatment modalities
Iva Gunarsson (photo) came with a talk that provided a survey of current treatment options for SLE and the difficulties encountered in clinical trials. Very similar to developments in the treatment of inflammatory myopathies, promising case reports on succesfull treatment with new monoclonal antibody agents like e.g. (amongst others) rituximab could not be confirmed with convincing data from double-blinded placebo controlled studies. As a result -untill the recent approval of belimumab as a new treatment modality in SLE-, for decades SLE has mainly been treated by trial-and-error making use of conventional disease modifying anti-rheumatic drugs and corticsteroids. As also was pointed out by several speakers during the EULAR 2011 meeting in London, UK, this does not necessarily mean that other biologics than belimumab that have been inevstigated in SLE are of no value in daily clinical practice. Study designs with regard to study population, disease activity definition as well as follow-up duration may have had quite some influence on the final findings in previous trials. In an era of highly advocated evidence-based medicine there may be a risk that -following suboptimal study designs- some previously tested drugs with potential have been put aside too rigourously, perhaps we will never know.
So, Iva Gunnarsson started off with emphasising the difficulties of SLE study design: 1) above all SLE is quite a heterogenous disease, 2) frequently there is background medication involved in SLE studies, and 3) the evaluation of response varies a lot when different studies are compared to each other.
In search for new treatment modalities for SLE the focus has been on cytokine antibodies, B-cell as well as T-cell targets,
As dar as cytokine antibodies concern, in the early days the effect of anti-IL-10 has been investigated in (just) 6 SLE patients . This delivered promising preliminary results in terms of a good response on both skin and joint disease. However, all developed antibodies against anti-IL-10 and what actually happened thereafter is unclear and not well documented. In more recent days anti-IL-6 treatment (using tocilizumab) was investigated in SLE patients. In SLE IL-6 is present in high levels, has a role in B-cell activity and tissue damage and in the 14 SLE patients that were treated with tocilizumab there was a decrease in disease activity and anti-dsDNA titers as well. At high doses however neutropenia and infections were observed . Thus far, no SLE/anti-IL-6 studies are known to be in planning phase. Anti-TNF treatment was also evaluated in SLE. Although like IL-6 there are high levels of circulating TNF-alpha in SLE, the treatment of SLE patients with anti-TNF is controversial given the fact that some RA patients treated with anti-TNF agents developed a lupus-like syndrome and positive ANA/anti-dsDNA tests following treatment. A pilot study investigating the effect of infliximab treatment on SLE patients with both arthritis and nephritis was however performed and showed a decrease in SLE disease activity as well a decrease in protenuria. This was accompanied by higher anti-dsDNA titers but no flares of the disease . For nephritis there was a good response of short term infliximab treatment, the arthritis component however returned and demanded extra infusions. Furthermore in longterm anti-TNF treatment severe adverse events were encountered in SLE patients (infections, deep venous thrombosis). Interferon-alpha a key cytokine in SLE, is currently investigated as an alternative treatment option for SLE. There are ongoing studies with rontalizumab and sifalimumab.
Mechanism of IFNα production in SLE
B-cell targeted treatment strategies for SLE have been investigated quite a lot. Both anti-CD20 (rituximab, ocrelizumab) and anti-CD22 (epratizumab) strategies have been studied extensively, and the same yields for anti-BAFF (belimumab) treatment. For rituximab there was the so-called EXPLORER study and also the LUNAR trial, which were both presented briefly by Gunnarsson. The EXPLORER study included moderate to severe SLE patients on background medication (immunosuppressive drugs and corticosteroids) randomised to rituximab or placebo and a follow-up of 52 weeks. No differences in primary nor secondary outcome measures were observed, which was quite unexpected following promising case reports. Only the serological outcome (anti-dsDNA and complement) was significantly better in the rituximab treatment group, but for clinical response in SLE the evidence was lacking in this study . The LUNAR trial consisted of proliferative lupus nephritis (class III/IV) patients in which rituximab or placebo was added to the standard of care treatment combined with high dose corticostreoids for 52 weeks. Again serological improvement was statistically better in the rituximab treated group, however NO difference in either primary or secondary outcome parameters could be assessed . It’s remarkable that both study designs failed to show statistically significant clinical responses in SLE whereas e.g. the French rituximab registry shows a good clinical effect in 71% of 136 SLE patients treated with rituximab . The own experiences of using rituximab in SLE patients at the Karolinska Institute were gathered from 40 rituximab treated SLE patients, the majority suffering therapy-resistant nephritis. In these patients rituximab treatment showed a significant reduction of proteinuria after one year. Despite large clinical trials failing to provide evidence of the clinically observed positive effects of rituximab treatment in SLE the question remains whether rituximab can still not have a beneficial effect in SLE treatment and whether people and/or companies are willing to design an alternative study in SLE. Epratuzumab is targeted against CD22 and modulates B-cell function without B-cell depletion (like in the anti-CD20 agents). It is currently studied in a Phase III trial in moderate to severe SLE patients and data are expected to be presented shortly. Results from EMBLEM, the phase IIb study, were promising with regard to quality of life, disease activity, reduction of corticosteroids which all showed improvements [8 (PDF file of Poster Presentation)]. Belimumab, an anti-BAFF (B-cell activating factor, also known as Blys, B-lymphocyte stimulator) antibody is “hot” nowadays, and the first drug that has actually been approved by the authorities for the treatment of moderate to severe SLE. BAFF promotes B-cell survival and differentiation. BAFF levels seem to correlate with disease activity scores in SLE. Although in the double-blind placebo controlled Phase II trial with belimumab the primary end-point at 52 weeks was not attained, a posthoc analysis excluding patients who were not serologically active at study entry noted a modest but statistically significant improvement of disease activity in SLE patients with moderate activity at study onset. The BLISS 52  and -76  trials that included serologically active SLE patients with a higher disease activity (SLEDAI >=6) and a newly defined response index then convinced both the FDA and EMEA (july 2011) to approve belimumab as a treatment modality in SLE since the SLE Responder Index (SRI) used in these studies was significantly better in the treatment arms as compared to placebo. (Writing this blog, for me this raises the question what would have happened with rituximab when it was studied in a similar study design as the BLISS-52  and -76  trials and using the SRI as outcome measurement..? It underlines the great importance of study design and especially patient selection and outcome measurement selection once again). There is still space for further improvement though, since severe SLE nephritis patients were not included in the BLISS trials, whether there are follow-up studies planned for this SLE patient category is currently unknown, both for belimumab and the other B-cell targeting therapies. The low active SLE nephritis patients showed improvement upon belimumab treatment, which seems promising.
Gunnarsson then finished up wth mentioning a couple of T-cell targeted treatments for SLE that have been or are under investigation. CD40 ligand is overexpresssed in CD4+ and CD8+ T-cells in SLE. Previous data from murine studies suggested a disease activity lowering role of anti-CD40L antibody in SLE. So far two studies of anti-CD40 ligand antibody treatment have been carried out in SLE. One showed improvement however both in the treatment and in the placebo arm, the other one was halted because of thromboembolic adverse events . Whether there are further anti-CD40L studies in the pipeline is unclear. Abatacept, a T-cell co-stimulation inhibiter which we are familiar with nowadays in treating patients with rheumatoid arthritis, has been shown to lower anti-dsDNA titers in animal SLE models and also resulted in a better outcome in animals treated with both abatacept and cyclophosphamide as compared to monotherapy with either drug alone. A randomised placebo-controlled Phase II study with abatacept in SLE patients however did not show improvement in non-renal active SLE as compared to placebo. There was however a trend of less fatigue, better quality-of-life and better quality of sleep reported by the study participants. Apart from these more subjective outcome measurements there was also a trend towards decreased anti-dsDNA titers but on the other hand there were also more serious adverse events in the abatacept treated group as compared to placebo . Also in renal active SLE patients abatacept does not seem to gain the more impressive role of the B-cell targetng agents, so taken together abatacept may not be a new player n the field of SLE treatment shortly.
What remains needed?
-a good induction therapy for severe SLE (short run) and remission maintainance therapy (long run)
-in general there remians a need for drug development in severe SLE
Where are we now?
-belimumab is the first drug apporved for use in SLE specefically
-preliminary reports showing beneficial results with epratuzumab (anti-CD22), others -amongst which are ongoing anti-IFN-alpha studies with rontalizumab and sifalimumab- are awaited…
-better study designs seem to have been developed, which raises the chances of finding statistically significant clinical responses in to be investigated new drugs for the treatment of SLE