While close to 75% of SCLE lesions can be managed with conventional topical and systemic therapies, one quarter are refractory to these treatments. The authors of the current study suggest that expression of TNF-a in refractory lesions may indicate a role for TNF blockers in their treatment, although the use of these agents in lupus is still controversial. This class of drugs has been used widely in rheumatoid arthritis (RA) and Crohn disease, and has been linked to the appearance of antinuclear antibodies (ANA) and transient lupus-like syndrome in some patients.
In the present study, expression of TNF-a in refractory lesional and nonlesional skin biopsies from four SCLE patients was analyzed in situ using an immunohistochemical approach. At the time of biopsy, these patients were being treated with systemic medications such as antimalarial agents, immunosuppressive drugs, and/or thalidomide. As controls, expression of TNF-a was also assessed in cutaneous lesions of patients with other inflammatory and neoplastic skin diseases.
"We observed that lesional skin of SCLE patients was characterized by an increased expression of TNF-a when compared with normal skin obtained from the same patient and with a small group of [controls with] inflammatory and neoplastic skin conditions," conclude the researchers, led by Sandra Zampieri, PhD, at the University of Padova in Padova, Italy.
The authors observed that TNF-a was localized to the epidermal compartment of the SCLE patients, suggesting that keratinocytes are the major source of this cytokine during the cutaneous inflammatory process.They also found that serum levels of TNF-a were associated with disease activity, but that there was no correlation between the levels of TNF-a in the blood and the levels of expression in skin tissue.
"These findings support the hypothesis that TNF-a is locally produced by keratinocytes and could not have leaked from the patients' circulation into inflammatory lesions, binding to the TNF receptors locally," the authors write. "The tissue localization of TNF-a may represent a potential therapeutic target, providing a new perspective in the treatment of refractory skin lesions in SCLE."
Other options besides TNF blockers should be tried first in refractory SCLE
At this juncture, second-line agents for patients with recalcitrant subacute or discoid lesions who are antimalarial resistant can include dapsone, azathioprine, and methotrexate (MTX), says Andrew G. Franks Jr, a professor of dermatology and director of the connective tissue section at New York University School of Medicine in New York City. "More recently, thalidomide has been introduced as useful in recalcitrant subacute lupus," he says.
"If you had a patient who wasn't having florid systemic disease and go through the algorithm, having tried antimalarials, dapsone, azathioprine and methotrexate, and the patients have also failed thalidomide, then we may try retinoids, mycophenolate mofetil, cyclosporine, or tacrolimus," Dr. Franks suggests. "If one were to use anti-TNF agents, it might possibly be in patients that have other indications for their use, such as [those] who have overlap syndrome, but it is not a treatment that I would gravitate to right away, unless you have already followed the algorithm or it is part of a study protocol," he says. "We don't have enough information yet, and it should not be done cavalierly," he tells CIAOMed.
According to Dr. Franks, it is important to weigh both the risks and the benefits of TNF blockade in this setting. "TNF-a at the tissue site is proinflammatory, so [with inhibitors] you may get improvements in the skin, but you risk systemic upregulation with increased autoantibody production," he points out. "You have to look at the effects of TNF-a from the tissue versus its effects globally before making a decision on the use of these agents in SCLE."
Reference
- Zampieri S, Alaibac M, Iaccarino L, et al. TNF-a is expressed in refractory skin lesions from subacute cutaneous lupus erythematosus patients. Ann Rheum Dis. August 11, 2005. [Epub ahead of print]