Discoid lupus erythematosus is a chronic inflammatory condition in which the pathogenesis and the role of cell-mediated immunity remains unclear. Currently, the most effective treatments for severe disease are thalidomide, methotrexate, and cyclosporin, although the evidence for this is limited. Efalizumab is a monoclonal antibody directed against CD11a, the α-subunit of the leukocyte-functioning antigen 1, with a current license for use in psoriasis. Because discoid lupus erythematosus is known to be predominantly T-cell mediated, our aim was to use efalizumab as a T-cell modulator in patients with recalcitrant disease.
Thirteen patients received efalizumab, with treatment responses varying from good to excellent in 12 of 13 patients. There was a significant reduction in the cutaneous lupus activity and severity score (CLASS) score after therapy with efalizumab (P = .002).
We have presented efalizumab as a novel alternative treatment for patients with difficult discoid lupus erythematosus. The response to treatment in 12 patients was very encouraging, with the mean time to response being 5.5 weeks. However, patient numbers were small, and many remain in the early stages of therapy. A prospective randomized study with a long-term follow-up is required, especially in light of recent findings to evaluate both the effectiveness and safety profile of this monoclonal antibody.
Discoid lupus erythematosus (DLE) is a chronic scarring condition with a predominantly lymphocytic histological picture. A mixed helper T cell lymphocyte profile, TH1/TH2, is seen with the role of autoantibodies remaining unclear. Most T cells express 1a-like antigens and the γδ T-cell receptor, with the ubiquitous presence of CD4+, CD8+, and HLA-DR+ in all types of cutaneous lupus erythematosus.1 Current treatments include antimalarial agents as well as a range of immunosuppressants, many of which have significant systemic adverse effects. Of these treatments, thalidomide, methotrexate, and cyclosporin appear to be the most effective,2 although the evidence for this is limited. In those situations in which clinical trial data exist, the overall response to therapy appears to be approximately 60%.
More recently, the potential role of biological therapies has been considered, with a number of cases reported in the literature showing good cutaneous response in patients with lupus. Fautrel et al3 described resolution of subacute cutaneous lupus erythematosus in a patient with rheumatoid arthritis who was treated with etanercept. A further study, which looked at tumor necrosis factor (TNF) blockade in systemic lupus erythematosus (SLE), demonstrated an overall decline in disease activity in all patients treated with infliximab.4 Efalizumab is a monoclonal antibody directed against CD11a, the α-subunit of the leukocyte-functioning antigen 1 (LFA-1), with a current license for use in psoriasis.5 Our aim was to use this T-cell modulator in patients with DLE to assess their response to treatment.
A retrospective review was conducted of 13 patients who had received efalizumab for severe recalcitrant DLE at the Department of Dermatology, Leeds General Infirmary, Leeds, England. All 13 patients had had severe DLE, which had failed to respond to a wide range of systemic therapies including steroids (intravenous and oral), antimalarial agents, dapsone, oral gold, azathioprine, methotrexate, and cyclosporin as well as repeated inpatient stays. Case notes were extensively reviewed to assess the course and outcome of treatment.
All patients were treated with efalizumab, 1 mg/kg subcutaneously once per week, with an initialization dose of 0.7 mg/kg. Before treatment was commenced, full blood cell count, routine biochemical analysis, and chest radiography were performed. During treatment, full blood cell count was performed monthly for the first 3 months and then once every 3 months. Routine biochemistry was performed once every 6 months.
As well as a general assessment of the patients' clinical response to treatment, an objective assessment of therapeutic response using the cutaneous lupus activity and severity score (CLASS) was undertaken but without the scarring element. This is a validated scoring system used in the Leeds Connective Tissue Clinic to assess lupus severity. It is derived from the Psoriasis Area and Severity Index score, with measures of erythema, plaque elevation, and scaling assessed on a scale of 0 to 3, with a possible cumulative score of 0 to 9, and with disease extent scored from 1 to 5 in each affected area. The scores are then added together to produce a final result.6 Statistical analyses were performed with SPSS for Windows version 11.0 (SPSS Inc, Chicago, Illinois) using the Wilcoxon signed rank test for nonparametric paired values. P < .05 was considered significant.
Table 1 summarizes the salient features of the cohort of patients. The case series consisted of 9 women and 4 men, all with severe recalcitrant DLE. The age range was 32 to 66 years, and the main sites affected were the face and scalp. Of the 13 patients, 9 had a positive antinuclear antibody (ANA) test result, and 1 patient with a negative ANA test result had a positive result for extractable nuclear antigens. All 13 patients had had a wide range of systemic immunosuppression as well as recurrent courses of intravenous steroids and repeated inpatient stays. Despite this, their disease had progressed relentlessly.
Patient 1 had a good response within 4 weeks of starting efalizumab therapy. Two months later, however, she noticed some lesions recurring, and acitretin was added to her treatment. For the past 12 months, her condition has been maintained with efalizumab and mepacrine with a small dose of prednisolone (7.5 mg/d). It should be emphasized that prednisolone and mepacrine were not able to control her condition before efalizumab was added to her treatment (Figure, A and C). Patient 2 had an excellent response within 2 months of treatment, although her efalizumab dose was increased from 1 mg/kg to 1.25 mg/kg owing to a mild flare. Nine months after starting treatment, she developed superficial facial erosions, which responded well to fluocinolone acetonide ointment. At this time, her efalizumab treatment was discontinued for 1 month. Currently, her condition is maintained with efalizumab therapy, 75 mg/wk, and dapsone therapy, 50 mg/d. Again, it should be emphasized that this dose of dapsone had been used previously without success in this patient (Figure, B and D).
Clinical photographs before (A and C) and 6 months after (B and D) treatment with efalizumab.
Table 2 records the outcome to response to efalizumab in all 13 patients. The mean time to treatment response in patients was 5.5 weeks (Table 2). The mean treatment duration in all patients who received efalizumab was 14.1 months. The overall response to treatment in 11 of 13 patients was very good to excellent. The CLASS score was significantly reduced after therapy in 12 patients (P = .002). In 6 of 13 patients, the ANA titer improved after therapy. Although some adverse effects were experienced, this necessitated the cessation of treatment in only 1 patient (Table 3). Apart from patient 4, all patients currently receive efalizumab therapy, either alone or in conjunction with other therapies.
The pathologic nature of DLE remains poorly understood. In conjunction with the genetic and UV-mediated element, the general consensus is that it is a T-cell–mediated condition in which the role of autoantibodies remains unclear. Tissue damage occurs secondary to immune deposition in the skin with a resultant inflammatory response. The role of cytokines within this response is currently of much interest with recent reports suggesting that activated memory T cells, possibly clonally stimulated, may specifically target skin appendage cells.7
Of these cytokines, TNF-α is well recognized in its role as an important proinflammatory mediator with pleiotropic properties.
Meijer et al8 looked at cytokine profiles including TNF-α in 3 patients with SLE observed over 10 years. They demonstrated highly elevated levels of TNF-α in active as well as inactive periods of disease. In 2004, Aringer et al4 went on to report on an open-label study, which looked at the safety and efficacy of TNF-α blockade in SLE. The authors studied 6 patients with moderately active SLE who were given infliximab in addition to immunosuppression with either azathioprine or methotrexate. Although antibodies to double-stranded DNA and cardiolipin were increased in 4 patients, this was not associated with a decrease in complement, vascular events, or with flares of their condition. In all patients, disease activity declined during therapy.
However, TNF blockade has so far been treated with caution owing to reports of induction and, rarely, symptoms of lupus associated with use. In both rheumatoid arthritis and Crohn disease, TNF blockade has been reported to lead to the formation of antinuclear antibodies in 30% to 40% of patients and to the formation of autoantibodies to double-stranded DNA in approximately 15% of patients. Anticardiolipin antibodies have also been observed.3,9 Aside from this, there are also a number of reports in which patients have developed cutaneous and systemic features of lupus, with resolution occurring on cessation of therapy.10,11
Given these potential difficulties of the use of anti-TNF agents and the presumed T-cell pathogenesis of cutaneous lupus, we decided to use efalizumab for our patients. Efalizumab is a monoclonal antibody to the CD11 α-chain of LFA-1. In psoriasis it blocks the interaction of LFA-1 on the T cell with the intercellular adhesion molecule on the antigen-presenting cell. This interaction is important in the initial activation of T cells, in the adhesion of T cells to endothelial cells in the blood vessel wall, and, finally, in the migration of T cells to the site of inflammation.12 We suspect that efalizumab acts on similar T-cell–mediated targets in lupus. So far, its only licensed use is in the treatment of psoriasis with anecdotal reports in the treatment of granuloma annulare,13 dermatomyositis,14 and more recently, severe atopic dermatitis.15
Adverse effects of efalizumab include headache and/or flulike symptoms, arthralgia, thrombocytopenia, a transient pruritic eruption, and flares of psoriasis on discontinuation of treatment. In our case series of patients, there was an acute infective flare of lupus in 1 patient, superficial erosions in 2 patients, which was treated by temporary cessation of efalizumab therapy, and a symptomatic drug rash. Although arthralgia is a known adverse effect, 5 of the 12 patients in our case series have experienced such symptoms during their treatment with efalizumab. This quickly resolved with a short course of oral steroids in 2 patients, and in 2 others, the arthralgia had been an ongoing problem even before efalizumab therapy was started. In the remaining patient, the arthralgia has been severe and has warranted other systemic therapies. Since our case series of patients have been treated, there has also been a reported case of efalizumab-induced subacute cutaneous lupus erythematosus. This occurred in a woman aged 65 years, who was being treated with efalizumab for her oral and cutaneous lichen planus. Eight weeks after treatment, she developed a papulosquamous rash, which on biopsy was confirmed to be lupus. Her ANA test result was also positive, with an ANA titer of 1:160. Eleven weeks after the discontinuation of efalizumab therapy, her rash had cleared and her ANA titer had decreased to 1:80.16 Clearly, this is of concern and highlights the need for continued surveillance of patients who are receiving efalizumab therapy.
In conclusion, we have presented efalizumab as a novel alternative treatment for patients with difficult DLE. The response to treatment in 12 patients has been very encouraging, with the mean time to response being 5.5 weeks. Interestingly, in 6 of 13 patients, there was also a fall in the ANA titer. Although this may reflect an improvement in the disease activity, it may also suggest that efalizumab is also involved in some form of B-cell regulation in conjunction with its T-cell modulatory properties.
We do, however, acknowledge the limitations of our study. It is retrospective with a small number of patients, many of whom remain in the early stages of therapy. A prospective randomized study with long-term follow-up is required, especially in light of recent findings, to evaluate both the effectiveness and safety profile of this monoclonal antibody, which we hope to carry out in the future.
Correspondence: Naila Usmani, MBChB, MRCP, Leeds General Infirmary, Great George St, Leeds LS1 3EX, England (email@example.com).
Financial Disclosure: Dr Goodfield has served as a consultant for Schering Plough, Novartis, and Leo; has received honoraria from Serono, Schering Plough, Wyett, and Leo; has given expert testimony for Novartis; and has received grants from Serono. Dr Usmani has received grants from Serono.
Accepted for Publication: March 15, 2007.
Author Contributions: Dr Usmani had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Goodfield. Acquisition of data: Goodfield. Analysis and interpretation of data: Usmani. Drafting of the manuscript: Usmani and Goodfield. Critical revision of the manuscript for important intellectual content: Goodfield. Administrative, technical, and material support: Usmani and Goodfield. Study supervision: Goodfield.
Funding/Support: This study was supported in part by Serono, who provided the patients with efalizumab.
Role of the Sponsor: The sponsor had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; or in the preparation of the manuscript, review, or approval of the manuscript.
Usmani N, Goodfield M. Efalizumab in the Treatment of Discoid Lupus Erythematosus. Arch Dermatol. 2007;143(7):873-877. doi:10.1001/archderm.143.7.873