NEW YORK, NY—CIAOMed's "Virtual Roundtable" of lupus experts identified drugs borrowed from other areas of rheumatology as the most important recent advances in treatment of systemic lupus erythematosus (SLE) and emphasized the need for reliable biomarkers as the major rate-limiting factor in SLE clinical research.
The roundtable participants were:
- Tak Mao Chan, MD, FRCP, professor of medicine at the University of Hong Kong's Queen Mary Hospital, in Pokfulam, Hong Kong
- Mary K. Crow, MD, Benjamin M. Rosen Chair in immunology and inflammation research, professor of medicine, and director of the rheumatology research and autoimmunity and inflammation research program at the Hospital for Special Surgery, in New York City
- Christopher J. Edwards, BSc, FRCP, MD, consultant rheumatologist and honorary senior lecturer at the Southampton Lupus Clinic and the department of rheumatology at Southampton University Hospitals, in the United Kingdom
- Joan T. Merrill, MD, medical director at the Lupus Foundation of America and head of the clinical pharmacology research program at the Oklahoma Medical Research Foundation, in Oklahoma City
How might the care of SLE be different by the end of 2007?
Dr. Edwards predicted more use of mycophenolate mofetil (MMF; CellCept®, Roche Pharmaceuticals) and rituximab, less use of corticosteroids, and lower doses of cyclophosphamide IV for severe SLE. He also expects a greater emphasis on the early prediction of prognosis and treatment response.
Dr. Merrill pointed out that most of the treatments discussed by the panel involves off-label use. "This is because there have been no new drugs approved for lupus in almost 40 years," she said. "The standard of care is unfortunately quite empiric and is not supported by the level of evidence-based medicine that we wish we had."
Dr. Merrill expects increased use of newer agents used to treat rheumatoid arthritis (RA), such as MMF and leflunomide (Arava®, Aventis Pharmaceuticals, Inc), because these drugs provide options for moderate-to-severely ill SLE patients who either do not respond to or cannot tolerate other immunosuppressants, such as methotrexate, azathioprine, or cyclophosphamide.
"There is already sporadic use of the B-cell depleting agent rituximab [Rituxan®, Genentech/Biogen Idec] around the country, usually in severely ill patients," Dr. Merrill said. "Since both rituximab and abatacept [Orencia®, Bristol-Myers Squibb Co] are on the market and recently approved for RA, it seems likely that these agents will be increasingly tried in lupus patients when other options are exhausted. Both of these treatments are currently being studied in ongoing clinical trials with lupus patients. The trend to studying agents for lupus in a more comprehensive and timely manner after approvals for RA will be greatly appreciated by our community."
Within the coming years, Dr. Chan also foresees increasing attention to anti-B lymphocyte antibodies, including anti-CD20, anti-CD22, anti-BLyS; to atacicept (ZymoGenetics, Inc), a treatment targeting activation of immune cells (CTLA4Ig); to anticytokine treatment; and to immunomodulators such as edratide (Teva Pharmaceutical Industries, Ltd).
What does the future hold for SLE care?
There are a number of new therapies available and in development," Dr. Edwards said. "These new options improve our chances of treating individuals with the most severe lupus. There are also opportunities to reduce serious side effects of current drug regimes. This is particularly true for the use of MMF in lupus nephritis. The trend to lower-dose corticosteriods and less aggressive IV pulse cyclophosphamide regimes, such as that championed by St Thomas' Hospital, in London, is also vital."
Dr. Crow commented "In parallel to the success of TNF-inhibition in rheumatoid arthritis, I am looking forward to seeing data on inhibition of cytokine pathways, particularly those involving IL-6 and interferon-alpha, in SLE."
Dr. Chan expects increasing adoption of MMF and corticosteroids as primary therapies to have a major impact on SLE outcomes. "The most significant step forward over the past decade has been the increasing use of MMF in place of cyclophosphamide [CTX] in the treatment of active severe lupus. The data to date show that when combined with corticosteroid, MMF has equal [in Chinese patients] or superior [in US patients of African or Hispanic origin] efficacy in inducing remission in patients with active severe proliferative lupus nephritis. Practically all the studies have demonstrated reduced adverse outcomes with MMF compared to CTX, and these include infections, neutropenia, amenorrhea, alopecia. MMF treatment is also associated with better quality-of-life scores in patients. Something which might not have been readily visible from the published data is the practical ease of treatment with MMF, which obviates the need for hospital admission to receive the IV CTX pulses."
Nobody expects a magic bullet, however. Dr. Merrill said, "The heterogeneity of lupus means that it is unlikely that any one treatment currently on the horizon will be optimal for all patients. Now that drug development is becoming more globalized, there is hope that more than one agent will become available through ongoing clinical trials to improve the choices we have available today, which are limited by restricted effectiveness and significant toxicities." She added, "It seems possible that with better biomarkers to characterize the aspects of immune imbalance, which are either shared or unique in different people with lupus, individualized cocktails of targeted therapies could some day be devised to improve immune equilibrium in these patients."
In the meantime, Dr. Merrill suggests that it might be reasonably safe to combine treatments that target central immune components with others that target more peripheral structures specific to certain subsets of lupus. "One example might be to use a B-cell-targeted treatment combined with one that targets a specific subset of autoantibodies, particularly those that are thought to be pathogenic, but might not necessarily be depleted in a timely manner with a given B-cell therapy."
Need for SLE biomarkers more urgent than ever
Biomarkers, which Dr. Merrill described as "useful biologic tests developed as guideposts to enhance the understanding of illness, help select optimal treatments for individual patients, optimize dosing of treatments, and predict [and thereby prevent] treatment toxicities," remain target needs under hot pursuit by SLE researchers.
"No ailment is more in need of objective, clarifying markers than lupus, the prototypic heterogenous, waxing, waning, clinically unpredictable disease," Dr. Merrill said. She noted that a number of promising new biomarkers are being studied, including measurements for specialized immune cell activation states, such as CD27 (high) plasma cells, upregulation of BAFF, activated circulating endothelial cells, and the interferon-α inducible gene expression pattern. Also being studied are other potentially helpful biomarkers with new techniques for the quantification of circulating products of inflammation, such as soluble VCAM-1, soluble BAFF, and complement activation products, which have recently become quantifiable as cell-bound markers for disease activity.
Dr. Crow is encouraged by progress in measuring activation of the type I interferon pathway as a potential biomarker in SLE. "Longitudinal studies of lupus patients are in progress that will compare interferon-alpha expression to clinical measures of disease activity," she said.
Cell-surface molecules are on Dr. Chan's short list of promising SLE biomarkers. These include erythrocyte-bound C4d (increased in active SLE), erythrocyte complement receptor-1 level (reduced in SLE patients), platelet-bound C4d (highly specific for SLE and correlates with activity), B-cell CD27 expression (correlates with active SLE), and lymphocyte P-glycoprotein expression (correlates with disease activity and steroid responsiveness). He believes circulating molecules might serve as biomarkers of activity, including antinucleosome antibodies, soluble adhesion molecules, and soluble cytokine receptors; potential urinary biomarkers include urinary cytokines (IL-6, MCP-1) and urine sediment mRNA expression of inflammatory mediators.
Both Drs. Crow and Merrill emphasized the need for large, well-designed studies to validate all prospective SLE biomarkers.
"I suppose the newest thing is that a collaborative group…has submitted a concept proposal for lupus biomarker development to the Foundation for the National Institutes of Health [FNIH] Biomarkers Consortium. The concept proposal has been approved and the next step for the group is to submit a full proposal for possible support from the FNIH," said Dr. Merrill.
That group undertaking this enormous initiative has been launched by clinical investigators, scientists, government agencies, including researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the Food and Drug Administration (FDA), and voluntary patient organizations, known as the Lupus Biomarkers Working Group.
Dr. Merrill described other issues: "The main unanswered questions involve difficulties in unraveling the tangled, overlapping immune disorders which characterize this multifactorial disease. Strategic approaches are needed in order to solve the puzzle of which biomarkers best characterize disease exacerbations and remissions in individual lupus patients, who might share some but not all of the pathology found in other patients."
The strategic approach Dr. Merrill described requires researchers to amass carefully collected biologic materials from a large cohort of patients that allows stratification of both symptoms and biologic profiles, with sufficient power to identify and validate biomarkers. "Not only should this collection contain specimens which have been precisely [and reproducibly] collected and stored, but equal care must go into the clinical characterization of the patients. And many more of these samples are needed than have ever before been collected," she said.
"During the pilot phase of this [collaborative] initiative, significant financial and administrative support was provided by NIAMS and the Lupus Foundation of America. IBM volunteered staff and infrastructure to develop a database and central server for the project, the goal of which is to expand into a comprehensive, international collection within the next few years, suitable for biomarker studies applicable even to the more rare [and most life-threatening] manifestations of lupus," Dr. Merrill said. "The potential to break the codes that unify and separate different patients with this disease gives rise to a realistic expectation that clinical trials can be better designed, patients more rationally selected for the testing of targeted biologic agents, outcomes more accurately measured, and the time and costs of getting a new treatment approved and on the market markedly decreased."
Although Dr. Edwards agreed that there is little help with practical day-to-day management of SLE, he pointed to an encouraging recent study. "The key is to find markers or, more likely, combinations of markers that allow the future prognosis of patients or their response to particular therapy," he said. "I like the approach of Capuano and colleagues1 who identified ratios of cytokines present in renal biopsies that predicted response to cyclophosphamide in individuals with lupus nephritis."
Reference
1. Capuano A, Costanzi S, Peluso G, et al. Hepatocyte growth factor and transforming growth factor β1 ratio at baseline can predict early response to cyclophosphamide in systemic lupus erythematosus nephritis. Arthritis Rheum. 2006;54:3633-3639.
