The treatment of cutaneous lesions of lupus erythematosus (LE) involves both an empiric and a scientific approach (Callen 2001). Unfortunately, there are few double- blind, placebo-controlled trials of drugs used to treat cutaneous LE (CLE). I generally approach patients with “specific” cutaneous lesions of LE (e. g., subacute CLE [SCLE], discoid LE [DLE], or lupus profundus/panniculitis) in a similar manner (Table 31.1).
Several other chapters in this text deal with individual therapies and their risks and potential uses in depth; this chapter includes an overview of my approach that encompasses most of the therapies mentioned elsewhere in this volume.
The goals of management of the patient with DLE or SCLE are to improve the patient’s appearance and to prevent the development of deforming scars, atrophy, or dyspigmentation. In addition, most patients with chronic CLE or SCLE have disease that primarily affects their skin, and they may be reassured that their prognosis is relatively benign.
A complete list of the patient’s medications will assist in the exclusion of drug- induced CLE (Bleumink et al. 2001, Bonsmann et al. 2001, Callen et al. 2001, Crowson and Magro 1997, Reed et al. 1985). Also, patients who smoke may have more severe clinical disease than nonsmokers (Gallego et al. 1999).
Cosmetic problems are often of major importance to the patient with CLE. Dys- pigmentation may follow both DLE and SCLE and may be effectively hidden by agents such as Covermark or Dermablend. Scarred lesions may be excised if they are inactive, but the possibility of reactivation resulting from manipulation exists because the Koebner phenomenon has been reported to occur in some patients with LE.
Photosensitivity is generally prevalent in patients with CLE (Lehmann et al. 1990, Millard et al. 2000). Of patients with systemic LE, 57%–73% have a history of photo- sensitivity, whereas 70%–90% of those with SCLE and 50% of those with DLE report photosensitivity. An issue in the patient with LE is whether they may also have another photosensitive eruption – polymorphous light eruption (PLE). Scandinavian investigators (Nyberg et al. 1997) suggested that 49% of patients with LE also have PLE, whereas Millard et al. (Millard et al. 2000) reported that 50% of their patients with DLE and 60%–70% of their patients with SCLE have PLE. The PLE often pre- cedes the diagnosis of CLE, but it may continue to manifest after the diagnosis. Fur- thermore, these investigators noted that CLE is a rare consequence of PLE. I observed PLE in patients who were later identified as having SCLE, but it has been my con- tention that these patients actually had SCLE from the onset of their photosensitivity.
Regardless of whether this issue is merely a matter of terminology usage, it is evident
Management of Cutaneous Lupus Erythematosus
Jeffrey P. Callen
31
that many patients with CLE are photosensitive. The action spectrum has been defined by photoprovocation testing and includes UVA, UVB, and, occasionally, visi- ble light. Phototesting does not reproduce lesions in all or even most patients, and it should be reserved for investigations or for individual circumstances in which it is necessary for worker’s compensation or other medicolegal circumstances.
Sunscreens are a cornerstone of therapy, but their importance is often forgotten as the physician manipulates the topical or systemic therapies that the patient is using.
The ideal sunscreen would have a broad spectrum and be water resistant. Unfortu- nately, no sunscreen can block all UV radiation that might exacerbate CLE; therefore, patients should also be encouraged to alter their sun-related behavior and to use sun- protective measures, including sun-protective clothing. A recent study (Stege et al.
2000) examined the capacity of three sunscreens to prevent the development of skin lesions by provocative phototesting. Although each of the three sunscreens tested pre- vented lesions, the extent to which they did so varied greatly. The sunscreen that was most effective contained octocrylene as the UVB protectant; Mexoryl SX, Mexoryl XL, and Parsol 1789 as UVA protectants; and titanium oxide. This sunscreen’s sun protec- tive factor (SPF) was 60. Their study was of only 11 patients (9 men and 2 women), of whom 8 had SCLE and 3 had DLE. This preparation is not available in the United States at the present time. Therefore, it is my recommendation that the patient apply a high SPF, broad-spectrum sunscreen daily.
Topical corticosteroids are usually prescribed for patients with CLE. An appropri- ate topical corticosteroid is selected for the area of the body being treated as well as the type of lesions that are present. Facial lesions should be treated with low- to mid-
Table 31.1. Therapy for cutaneous lupus erythematosus Standard therapy:
Thorough evaluation
Is the patient taking any drugs that might exacerbate the disease?
Is the patient a smoker?
Reassurance and education
Sunscreens, sun-protective clothing, and lifestyle alterations Topical agents – corticosteroids, retinoids
Intralesional corticosteroids
Antimalarial agents – hydroxychloroquine, chloroquine, quinacrine When standard therapy fails:
Is the patient using the therapy appropriately?
Dapsone Auranofin Thalidomide
Retinoids – isotretinoin, acitretin
Immunosuppressive/cytotoxic agents – azathioprine, methotrexate, mycophenolate mofetil, cyclosporine, other
Intravenous immune globulin
Cytokines – interferonα, chimeric CD4 monoclonal antibody Systemic corticosteroids
potency agents such as 2.5% hydrocortisone, desonide, aclomethasone, or hydrocor- tisone valerate. Lesions on the trunk and arms may be treated with mid-potency agents such as triamcinolone acetonide or betamethasone valerate. Lesions on the palms or soles and hypertrophic lesions often require superpotent corticosteroids such as clobetasol or halobetasol. Patients prefer creams over ointments; however, ointments may be more potent and are possibly more effective. For lesions on hairy areas, most patients prefer a lotion or foam. Although topical corticosteroids are effective in study settings, in the office setting they do not seem to be as effective, probably because of their expense and messiness. Last, the prescribing physician should consider the total amount of corticosteroid that the patient applies, as it is possible to cause hypothalamic-pituitary-adrenal axis suppression with use of even as little as 2 oz/day of the superpotent corticosteroids.
Several other topical agents might be of use in individual patients with CLE. How- ever, none of these agents have been tested in any systematic manner. Retinoids, specifically, tretinoin, might be effective and have primarily been used in patients with DLE and hypertrophic LE. Tazarotene (Tazorac, a topical retinoid) might also be used. Topical application of calcipotriene (Dovonex, a topical vitamin D derivative) has been reported to be effective in patients with localized scleroderma, but it might also be tried in patients with CLE. Another nonsteroidal agent that might be consid- ered in the future is tacrolimus or pimicrolimus. Finally, because it is known that sys- temically administered interferon is effective for CLE, it might be helpful to apply imiquimod to individual lesions.
Intralesional injections of corticosteroids are often effective in patients with lesions that are refractory to topical corticosteroids. Small amounts of triamcinolone acetonide may be injected with a 30-gauge needle into multiple areas. These injec- tions are often very effective in the control of lesions, but they do not prevent the development of new lesions. The potential for cutaneous atrophy or dyspigmentation similar to that seen with the disease should be discussed with the patient; however, in most cases, an experienced dermatologist is able to inject without great risk. Also, as noted with topical corticosteroids, the total dose of intralesional corticosteroids should be noted. Alternative agents for intralesional injection have not been well tested. Interferon has been successfully used when given subcutaneously, and it would be interesting to see if lower doses injected into individual lesions would be effective, without systemic ill effects.
When existing lesions are not controlled with topical agents or intralesional corti- costeroids, systemic therapy is often indicated. First-line therapy is the use of an anti- malarial drug. Antimalarials seem to work less well in patients who smoke (Jewell and McCauliffe 2000, Rahman et al. 1998). The antimalarial agent that I prefer is hydroxychloroquine sulfate (Plaquenil). This drug is used in doses of 200 mg orally once or twice per day or in a dose of less than 6.5 mg/kg per day. The onset of action of the antimalarial agents is roughly 4–8 weeks, and for this reason some physicians have advocated higher initial loading doses. Hydroxychloroquine is also of benefit to the joint symptoms and malaise that may accompany CLE. Hydroxychloroquine is less toxic but also less effective than chloroquine phosphate (Aralen), which is used in doses of 250–500 mg/day. Thus, patients who fail to fully respond to hydroxy- chloroquine may be switched to chloroquine; however, I believe that these two agents should not be used together because of concern that ophthalmologic toxicity may be
enhanced. Another antimalarial, quinacrine hydrochloride (Atabrine), may add ben- efit to either hydroxychloroquine or chloroquine and is not associated with ophthal- mologic toxicity (Feldmann et al. 1994). This agent is not readily available, but several compounding pharmacies in the United States offer it.
Antimalarial drugs may cause nausea, diarrhea, myopathy, cardiomyopathy, or psy- chosis. Cutaneous eruptions have also been reported with antimalarial drug therapy, as have hyperpigmentation,generalized or localized pruritus,lichenoid drug eruption, or hypopigmentation of the hair, nails, and mucous membranes. Hematologic toxicity may occur and may be manifest late in the course of therapy. Hematologic toxicity seems to be more common with quinacrine therapy than with use of other antimal- arials. Fortunately, the frequency of these side effects with antimalarials is relatively uncommon, with the exception of the gastrointestinal tract side effects.
Ocular toxicity, including irreversible retinopathy, has been reported with chloro- quine and hydroxychloroquine therapy but not with quinacrine use. The risk of ocu- lar changes is greater with chloroquine therapy. Ophthalmologic toxicity is probably related to the dose and duration of therapy. If detected early, these changes often do not progress if use of the drug is stopped. However, there are patients in whom the drug therapy is discontinued but the retinopathy continues. Although other ocular changes, including blurring of vision and corneal deposition of the antimalarial, occur, these are reversible on cessation of drug therapy. Ophthalmologic evaluation, preferably by a physician familiar with these agents, should be performed at baseline or shortly after initiation of therapy and then periodically (e. g., every 6–12 months).
In difficult cases, multiple other approaches have been advocated for the treatment of CLE. In general, low-dose systemic corticosteroids (<1 mg/day of prednisone or its equivalent) are rarely effective for DLE and only partially effective for SCLE lesions.
Corticosteroids are effective for the acute lesions of photosensitivity, malar rash, or vasculitic lesions that may complicate LE. The long-term use of oral or intramuscular corticosteroids for patients with cutaneous disease should be avoided.
Dapsone, given in doses of 25–200 mg daily, has been useful for patients with vas- culitic lesions that may accompany LE, SCLE lesions, bullous LE, and oral ulcerations (Neri et al. 1999). In open-label clinical trials, dapsone treatment resulted in improve- ment in some patients with DLE or SCLE; however, the level of benefit has been judged as “excellent” in only approximately 25% of patients. In contradistinction, clofazimine failed to demonstrate efficacy in all but one report (Krivanek and Paver 1980). There are several special circumstances in which dapsone may be useful. The first is bullous LE. In addition, patients with urticarial vasculitis along with SCLE lesions may benefit from the use of dapsone. In my practice, I have observed only one patient who seemed to benefit from dapsone therapy; therefore, it is the first line of therapy for only a few patients.
A variety of other antibiotics have been used for the treatment of CLE. Recently, Rudnicka et al. (Rudnicka et al. 2000) reported that use of the antibiotic cefuroxime axetil resulted in the clearing of skin lesions in three patients with SCLE at a dose of 500 mg daily. Cefuroxime axetil is a second-generation β-lactamase oral cephalo- sporin. Others must replicate this observation before it can be recommended for widespread use; however, it is a relatively benign form of treatment. Another group has reported the successful use of sulfasalazine in 8 of 11 patients (Delaporte et al.
1997). Sulfasalazine is used for inflammatory bowel disease and various arthritides.
These authors administered 2 g daily, but they noted that the minimal effective daily dose was 1.5 g. The eight patients who responded were all rapid acetylators, whereas the three who failed to respond were all slow acetylators. No serious toxicity was noted in this small open-label case series. In contrast, Lagrange et al. noted a drug eruption in five of six patients they treated with sulfasalazine, and in only two patients did they believe that there was a beneficial effect (Lagrange et al. 1998).
Auranofin (Ridura), an oral form of gold, has been used for CLE (Dalziel et al. 1986).
Complete remission occurs in a few patients, approximately 15%, whereas a partial response has been noted in about two thirds of those treated. My personal experience has been encouraging in a few patients. Auranofin is begun at a dose of 3 mg/day, and after 1 week the dose may be raised to twice daily if the patient experiences no prob- lem with nausea, diarrhea, or headache. I have treated patients with as high as 3 mg three times daily without difficulty. Monitoring with regular complete blood cell counts and urinalysis is suggested. Responsiveness may be best in patients with non- scarring forms of CLE. I have seen one patient with a lichenoid drug eruption pre- sumed to be due to auranofin use. She had been treated with auranofin for “anti- malarial-resistant” SCLE, and the dose had been raised when the eruption occurred.
Cessation of the drug led to resolution of the eruption, and control of her SCLE was achieved with aggressive sun-protection measures and chloroquine therapy.
Thalidomide has recently become more available and is being used for patients with CLE with some regularity (Atra and Sato 1993, Duong et al. 1999, Ordi-Ros et al.
2000). Its mechanism of action is believed to involve a decrease in inflammatory mediators, particularly tumor necrosis factor (TNF)-α and Fas-ligand. Open-label trials suggest that it is highly effective and may result in an increase in the lympho- cyte count and a decrease in the C-reactive protein level. Induction with 100–300 mg daily at bedtime results in improvement in 90% of the patients who can tolerate the drug. Toxicity commonly associated with thalidomide use includes drowsiness, headache, weight gain, amenorrhea, and dizziness. Drowsiness and dizziness may persist during the following day. Neuropathy, usually sensory, may limit the ability of patients to continue thalidomide therapy on a long-term basis. Neuropathy may be reversible, but there are patients whose neuropathy has progressed despite discontin- uing the drug therapy. Whether nerve conduction studies should be performed at the onset of therapy and periodically is not known. Thalidomide is a potent teratogen and, accordingly, the company has developed a program to prevent the chance of pregnancy in patients exposed to the drug. The program requires that the prescrib- ing physician and the pharmacy be registered with the company and that the patient take extra precautions in taking the drug. No more than a 1-month supply may be written for at any one time. Unfortunately, the response to thalidomide therapy is not durable in most patients; therefore, long-term, low-dose maintenance therapy may be necessary.
Rodriquez-Castellanos and coworkers (Rodriquez-Castellanos et al. 1995) treated 93 patients with CLE with oral phenytoin (up to 300 mg/day) and observed excellent results in 90%. Relapse occurred in at least one third of the patients in whom follow- up data were available, but prolonged remission of 6–12 months was noted in 33 patients. Toxicity was minimal in prevalence and severity.
Oral retinoids are effective in many patients who have failed previous less toxic therapies. Isotretinoin (Accutane) and acitretin (Soriatane) have both been used in
doses similar to those used for acne vulgaris and psoriasis, respectively (Newton et al. 1986, Ruzicka et al. 1985). The response is not durable, and after short courses the patient will still need further suppressive therapy. These agents are particularly help- ful in patients with hypertrophic lesions or those with lesions on the palms or soles.
These patients are monitored for lipid abnormalities, liver enzyme elevations, and cytopenias. In addition, these agents are teratogenic and should not be used in poten- tially pregnant women. If the clinician decides to use these agents in women of child- bearing age, pregnancy prevention counseling should take place at each visit and pregnancy prevention methods should be provided to the patient.
Several cytotoxic agents have been reported to be beneficial for the control of CLE lesions. Azathioprine has perhaps had the greatest number of reports (Callen et al.
1991), but methotrexate (Boehm et al. 1998) and mycophenolate mofetil (Pashinian et al. 1998, Goyal and Nousari 2001) have also been reported to benefit patients with
“recalcitrant” disease. We treated six patients with refractory disease, and most improved within 4–8 weeks. Continued therapy is required to maintain the remission.
Small case series or individual reports have suggested that cytarabine, cyclophos- phamide, and cyclosporine may be effective.
High-dose intravenous immune globulin was used by Lagrange et al. (Lagrange et al. 2004) in nine patients and by Genereau et al. (Genereau et al. 1999) in one patient.
One gram per kilogram per day for 2 consecutive days monthly was administered to patients who had failed multiple previous therapies. There was an excellent result in 4 of the 10 patients, but the response is short-lived. Toxicity is minimal, but this thera- py is extremely expensive.
The use of cytokine therapy has been reported. I predict that there will be addi- tional reports of newer agents that are available and are just beginning to be tested for some dermatologic indications, as well as others that are not currently on the market. Because thalidomide may be effective through its effects on TNF-α, it might be possible that infliximab or etanercept therapy might also prove to be of benefit to patients with CLE. However, at least one patient developed SCLE while taking etaner- cept (Bleumink et al. 2001). Interferon-α has been used successfully (Nicolas et al.
1990, Tebbe et al. 1992); however, all patients taking this regimen develop toxicity, and long-term remission is rarely achieved. In contrast, Prinz and colleagues (Prinz et al.
1996) used chimeric CD4 monoclonal antibody infusions in five patients with severe, refractory CLE. Long-lasting improvement was noted, with restoration of responsive- ness to conventional treatments. If other cytokines can be administered and result in the restoration of response with less toxic therapy, then perhaps we will be able to induce remission with one agent and maintain it with another.
Conclusion
In summary, patients with LE may manifest a variety of skin lesions. A thorough eval- uation of any given patient is needed before therapy. Patients may have factors that exacerbate their disease, such as light from the sun or from artificial sources, drugs, or smoking. If possible, therapy should begin with the removal of any identified exac- erbating factors and include sunscreens, protective clothing, behavioral alteration, and topical corticosteroids. Calcipotriene or retinoids may be effective in some
patients. Intralesional injection of corticosteroids and oral antimalarials are the other parts of a standard therapy program. The choice of alternative therapy is personal, and discussions of the risks and benefits should be carefully documented. Successful therapy for CLE is possible in almost all well-motivated, cooperative patients.
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