Review Treatment of Cutaneous Lupus Erythematosus MARTI J. ROTHE* and FRANCISCO A. KERDEL** *Division of Dermatology, University of Connecticut Health Center, Farmington, Connecticut; **Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, Miami, Florida, USA The mainstays of treatment of cutaneous lupus erythematosus (LE) are topical and intralesional steroids, sunscreen, and the antimalarials. However, the practitioner is often faced with the challenge of cutaneous disease unresponsive to these conventional measures. We present our approach to the management of cutaneous LE and review the literature regarding therapy of refractory disease.
Key Words: Antimalarials Retinoids Dapsone Clofazamine Gold
Introduction
often determines the response to therapy. Lesions on the palms and soles and on cutane~uslmu~~~~.i junctions (i.e. vermillion border or eyelids) may be resistant to conventional therapy. The recognition of SCLE as a distinct clinical entity is of utmost importance. While approximately 5007o of these patients meet the ARA criteria for SLE, their disease often follows a more benign course 3. SCLE shows striking photosensitivity and does not produce scarring unless accompanied by DLE lesions. Acute lupus may or may not present with cutaneous manifestations. The therapy for ALE is often determined by the of systemic involvement. Since not infrequently patients with ALE are treated for renal, hematologic or central nervous system involvement with high doses of systemic corticosteroids and immunosuppressive agents, the cutaneous manifestations not only are of secondary consideration but usually respond to these therapeutic interventions.
The patient presenting with a dermatosis clinically consistent with discoid lupus erythematosus (DLE), subacute cutaneous LE or acute systemic LE (ALE) warrants biopsy confirmation of the diagnosis and evaluation for systemic disease. Assessment for American Rheumatism Association (ARA) criteria’ is made and laboratory investigations, including tests for antinuclear antibodies (ANA), anti-double-stranded DNA antibodies, anti-Ro antibodies, anti-La antibodies, C3, C4 and CH50, complete blood’count (CBC) plt, blood urea
nitrogen/creatinine (BUN/Cr) and urinalysis,
are
per-
formed. Although the initial evaluation for all clinical forms of lupus is similar, it is important to classify the condition into the aforementioned subgroups (DLE, SCLE, ALE), since this will have therapeutic as well as prognostic implications. It is also important to note the presence or absence of certain other cutaneous manifestations of such as vasculitis, which while not specific may accompany the disease and may necessitate
different therapeutic approach. DLE is probably the most common cutaneous manifestation of LE. Therapeutically, the extent of disease and sites of involvement are important. Approximately 25% of patients with systemic LE (SLE) will develop DLE during their disease Fewer than 10% of cases where patients present initially with DLE alone will evolve into although this may be an overestimation. Studies have shown that those patients with disseminated particularly below the neck, are more to develop SLE~. The site of DLE lesions
Conventional therapy
a
Limited and
non-disfiguring disease is best managed with intralesional and topical steroids and sunscreen. More generalized disease. and limited disease unresponsive to local measures necessitate systemic antimalarials are generally considered the treat’
ment of
choice.
Intralesional and steroids I’ntralesional steroids of various strengths and concentrations have enjoyed tremendous popularity in the treatment of cutaneous lupus. Patients with limited disease, particularly those with a few DLE lesions, often to intralesional triamcinolone acetonide in
Correspondence: Francisco A. Kerdel, M.D., University of Miami School of Medicine, P.O. Box 016250 (R-250), Miami, Florida 33101, USA.
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concentrations of 10-20 mg/ml. The volume injected depends on the size of the lesion, but it is customary to inject not more than 1 ml per lesion. If the number of lesions or the size of the lesions requires large volumes of the steroid suspension ( > 6 ml), then the addition of other therapeutic agents should be considered. In order to minimize side effects, lesions should not be injected more frequently than once each month. The treatment of DLE lesions with intralesional steroids, while effective, is often difficult. Scarring with the development of telangiectasias is the natural progression of the disease. However, chronic steroid usage can also produce similar effects. Telangiectasias often give the lesion an erythematous appearance, which can confuse the physician as to the activity of the disease. It is therefore helpful to elicit the presence of tenderness and hyperemia (warmth) of the lesions, since these two signs often accompany increased disease activity. Some patients may also present with flare-up of their systemic disease as well as their cutaneous lesions. It is important to recognize these signs, since systemic corticosteroid therapy may be warranted. The introduction of superpotent fluorinated steroids for topical use has allowed some patients to be treated without intralesional steroids. These agents, applied twice daily, can be extremely effective in early lesions. Intralesional and topical steroids have the same unwanted side effects of atrophy and telangiectasias. It is therefore imperative for the physician to determine whether the lesion is active (requiring therapy) and when therapy should be stopped. Failure to discontinue the treatment will result in atrophy and possibly breakdown of the skin, precisely what the treatment is attempting to avoid.
Sunscreen Sunscreens probably represent the most important factor in the treatment of cutaneous lupus, irrespective of type or severity. Patients should be instructed to introduce use of sunscreens with a sun protection factor of 15 or higher into their daily routine, avoid peak periods of sun exposure from 10 am to 3 pm, and wear protective clothing and broad-rimmed hats when outdoors. The action spectrum of photosensitivity in LE has been considered to be of the UVB (280-320 nm) wavelength; however, recent studies show that both UVB and UVA (320-400 nm) may induce lesions of LE in phototested patients’. Thus, the use of more broadspectrum sunscreens should be instituted; sunscreens containing butyl methoxydibenzoylmethane may be very useful in this respect. It is well known that UVA can penetrate window glass and, therefore, the daily application of sunscreen is important because of considerable ultraviolet exposure during travel by car.
Antimalarials The antimalarials most commonly used in the treatment of cutaneous lupus are those derived from 4-aminoquinoline. Currently, hydroxychloroquine is widely used, although chloroquine and quinacrine are occasionally employed. These compounds are effective in approximately ’71?-l~f#~J~ of patients with cutaneous LE 6-8. Recent data also suggest that antimalarials may also prevent lupus flares in both cutaneous and systemic disease 9. The mechanism of action is unknown, although there is significant in vitro work suggesting a broad biological activity!°. Antimalarials have one important drawback: ocular toxicity. In this respect, they can produce three main side effects: (1) blurring of vision, due to reversible lateral rectus paralysis, (2) ’haloes around white lights’, due to corneal deposits, and (3) retinopathy. The blurring of vision is a rare occurrence, usually dose dependent and entirely reversible. It infrequently requires discontinuation of the drug. Corneal deposits, although relatively common with chloroquine ~lfl-~~~1~ of patients), are infrequently seen in patients on hydrt~xyehlorc~quine$’. Again, this side effect is reversible and seldom requires discontinuation of therapy. The incidence of retinopathy is unknown, although there are about 300 cases reported in the world’s literature&dquo;. This side effect can be seen with both chloroquine and hydroxychloroquine. Some authors suggest that the risk of developing retinopathy with hydroxychloroquine is less, but no supportive data for this exist. Quinacrine is not associated with retinopathy. The importance of retinopathy stems from its progressive course, which can eventuate in visual loss and irreversible blindness. Even though early studies suggested that retinopathy was related to the cumulative dose of antimalarials 12, more recent work has shown that it is the daily dose that determines the risk of developing this complication. This risk can thus be decreased if the dose of chloroquine does not exceed 250 mg/day (4 mg/kg/day) and if the dose of hydroxychloroquine does not exceed 4t10 mg/day (6.5 mg/kg/day) 6, 11,12. While these doses are relatively safe, they represent the maximum daily dose and therefore, whenever possible, a decreased dosage should be attempted. The symptoms of retinopathy include night blindness, tunnel vision, decreased visual acuity, and scotoma formation. Unfortunately, however, by the time the symptoms develop, retinopathy is well established and irreversible damage cannot be avoided. Retinopathy can nevertheless be prevented by the performance of ophthalmological evaluations before and during therapy ~ ~. Most ophthalmologists recommend a screening examination and subsequent examinations every 4-6 months &dquo;. It has been noticed that retinopathy is
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preceded by a premaculopathy stage; ocular changes are reversible at this point upon discontinuation of the drug. While there is argument as to the best screening test for these patients (absence of foveal reflex, macular dazzle testing, electro-oculograms, electroretinogram), visual field testing is the most practical and currently is probably the most widely used examination 1 I. Formal visual field testing may be supplemented with home self-testing with an AMSLER grid&dquo;’ 13. Early retinal changes produce so-called relative scotomas (blurred areas), which can be best detected by visual field testing with red
Iight&dquo;.
If the medicine is discontinued at this stage, the evolution towards absolute scotomas and visual loss can be prevented. Quinacrine does not produce ocular toxicity, but may cause hemolysis in glucose-6-phosphate dehydrogenasedeficient individuals’°. Rarely, aplastic anemia has been reported 10. Quinacrine also causes a yellowish discoloration in most patients, limiting its use to patients of darker complexion. The dose of quinacrine is 100 mg/day and it can be added to either hydroxychloroquine or chloroquine in patients with unresponsive disease. In addition to baseline ophthalmologic examinations, laboratory screening, including liver function tests, BUN/Cr and CBC plt, should be performed and followed every 3-6 months during antimalarial therapy.
Treatment of antimalarial-resistant disease
variety of treatment options exists for cutaneous disease resistant to conventional local and systemic ther-
especially beneficial in the treatment of hypertrophic DLE 15,16. Optimal dosage ranges are approximately ~.5-l.~l m~lkglday. Clinical response has been noted generally within 2-4 weeks of treatment. Shornick et al. noted that their patients suffered striking and rapid relapse upon discontinuation of isotretinoin 14. Significant side effects of retinoid therapy include teratogenicity, mucocutaneous changes of xerosis, cheilitis, epistaxis, alopecia, and alterations of serum lipid profile. Adequate contraception must be taken by isotretinoin-treated women during therapy and for 1 month after therapy is discontinued. Etretinate has a prolonged half-life and therefore should be avoided in women of childbearing potential. While acitretin appears to have a shorter half-life, its teratogenetic effects post therapy are under investigation and it should therefore also be avoided in women of childbearing potential. Prolonged therapy with retinoids may be complicated by skeletal hyperostoses. Laboratory parameters, including beta-HCG in women, lipid profile, liver function tests and CBC plt, are measured at baseline and every month of therapy. Thus, while the retinoids have been reported as quite effective in the treatment of cutaneous lupus, their use is limited by side effects and possibly by the need for chronic treatment to sustain a therapeutic response. Additionally, while reports in the literature emphasize the therapeutic successes, in practice there are many patients who fail to respond to retinoid therapy. been
A
Dapsone
apy : retinoids, dapsone (DDS), vitamin E, clofazimine, thalidomide and oral gold. As well, treatment with immunosuppressive and immunomodulating agents,
including conventional cytotoxics (methotrexate, cyclophosphamide, azathioprine), pulse methylprednisolone, cy~Ic~spc~rine, alpha-interferon, and extracorporeal photochemotherapy may be considered. Finally, surgical modalities may play a role in the treatment of inactive lesions of DLE. Literature suggesting treatment efficacy is limited to. either case reports or reports of open clinical trials. Both side-effect profile and relative efficacy in the treatment of formes of cutaneous LE are important considerations in the selection of these
.
systemic therapies. Retinoids The retinoids
(isotretinoin, etretinate
and its
metabolite, acitretin), best known for the and
psoriasis, have
been used with
major
treatment of
excellent chronic malar rash of SCLE and the SLE 14-19. DLE, They have acne
DDS is often utilized in dermatology for the treatment of neutrophilic dermatoses such. as leukocytoc1astic vasculitis and dermatitis herpetiformis. In this fashion, DDS has proven effective in dre treatment of the bullous eruption of lupus and vasculitis associated with lupus 20. Additionally, there have been reports of DDS°s efficacy in the treatment of annular SCLE21. 22. However, there has been only a fair response to DDS in the treatment of chronic DLE, with improvement in one-quarter to onethird, ~f patients &dquo;, 24. The authors of one open trial suggest greater efficacy when DDS is used in combination with hydroxychloroquine. Dosage of DDS in one open trial was 100 Common adverse reactions to DDS include dizziness, depression and minor psychiatric disturbances. Significant side effects of DDS include hemolysis, methemoglobinemia, agranulocytosis, leukopenia, and a reversible peripheral neuropathy. A baseline G6PD and CBC should be obtained prior to initiation of therapy. Folate supplementation may be beneficial in the management of low-grade hemolysis associated with chronic
an
response rate of ~~-1£~Q~~ in the literature for
treatment.
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Vitamin E
Vitamin E or tocopherol has been advocated as a nontoxic therapeutic modality in the treatment of cutaneous LE with optimal doses of d,alpha-tocopheryl acetate or succinate ranging from 800 to 2000 IU/day. Ayres and Mihan reported on seven patients with DLE treated with oral vitamin E. Only two patients failed to show an excellent response; notably they were receiving only 300 IU/day and also were treated with topical steroids rather than the topical vitamin E received by the other five
day may be required. Likewise, reduced doses may be helpful in combination with antimalarials 33 . Unfortunately, not only is thalidomide a potent teratogen, it also may frequently induce irreversible peri-
pheral neuropathy, which is dependent neither on dose nor on duration of therapy. Nerve conduction studies should be performed prior to initiation of thalidomide and at intervals during therapy. Reversible side effects include sleepiness, headache, constipation, xerosis and weight gain. Oral gold
patients 25 . Ayres and Mihan reviewed the results of numerous previous open trials of vitamin E for DLE and SCLE 25. In general, trials have shown only a fair response for low doses of vitamin E and only a fair response for hypertrophic disease. Treatment with adequate dosages, particularly for superficial disease of recent onset, showed marked improvement. It is important to note that the use of vitamin E in lupus is controversial and not universally
accepted. Vitamin E-induced increases in cardiac muscle tone and in glycogen storage warrant dosage adjustments in patients with hypertension and diabetes, with an initial dose of 100 IU/day and gradual increases as tolerated, with monitoring of blood pressure and blood glucose. Side effects of vitamin E are negligible’.
A fair response was seen in chronic severe DLE treated with an average dose of 3 mg b.i.d. of oral gold for 1 year in an open trial of 23 patients 31 . There was complete remission in four patients and ’improvement’ in another 15 patients. The best response was seen in patients with
rosacea-like lupus. While thick plaques were responsive, more verrucous plaques were not. Side effects included loose stool, nausea and vomiting, sore mouth and tongue, pruritus and rash. While the only significant laboratory abnormality was reversible proteinuria in one patient, the prescription of oral gold should include baseline and monthly urinalysis, BUN/Cr and CBC plt.
Immunosuppressive and immunomodulatory therapy The use of cytotoxic agents in the treatment of cutaneous LE should preferably be restricted to the concomitant treatment of systemic disease. In one open trial of nine patients, more than 50% of patients with either SCLE or DLE showed an excellent response and one-third of patients showed a moderate response to treatment with 50-200 mg/day of cyclophosphamide35. Pulse cyclophosphamide is efficacious in the treatment of lupus nephritis and cerebritis 36. Callen favors the use of azathioprine over methotrexate, cyclophosphamide and chlorambucil, noting response within 1-2 months in DLE and S~LE~’. In an open trial, six patients with treatment-resistant cutaneous LE (four SCLE, two DLE) were treated with azathioprine 100-150 mg/day. Four patients showed an excellent response, but one patient discontinued therapy due to pancreatitis. Azathioprine therapy proved to be
Clofazimine Clofazimine is an important antilepromatous agent that has shown some promise in the treatment of SCLE 26 and DLE27-29. An open trial in the treatment of DLE showed clinical remissions in 17 of 26 patients over a 3-6-month period of treatment. A dose of 100 mg/day is
optimal. Clofazimine has minimal side effects, such as nausea and xerosis. Most remarkable is its characteristic deposition in subcutaneous fat, which evokes a pinkish discoloration of the skin. The pinkish discoloration appears to be dose related, as does occasional hyperpigmentation of discoid plaques. The subcutaneous deposition appears to have a therapeutic advantage, in that clinical remission was evident in six patients several months after discontinuation of the drug~.
steroids sparing~. Two patients with SCLE had rapid clearance of cutaneous disease with pulse methylprednisolone 39. Oral cyclosporine has not been effective therapy for cuta-
Thalidomide
Thalidomide is also an antilepromatous agent utilized to suppress the immunologic reaction of erythema nodosum leprosum. At doses of 100-200 mg/day thalidomide has impressive efficacy within several weeks in the treatment of DLE and SCLE, with hypertrophic LE showing a less favorable response’o~&dquo;. Relapse may occur upon abrupt discontinuation and maintenance doses of 25-50 mg/
neous
LE 40. Caution should be exercised
as
the
use
of
cyclosporine may be associated with compromised renal function in patients with pre-existing lupus nephritis. A recent experimental advance in the treatment of DLE and SCLE is with the
use
of the immunomoduLow or intermediate
lating agent interferon-alpha 2a 41. 354
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doses (18-45 million units per week) for 4-8 weeks resulted in complete clearing in four patients and marked improvement in two patients with DLE. High doses (100-200 million units per week) for 12 weeks resulted in complete clearing in one patient and marked improvement in another patient with SCLE. Relapse was seen after discontinuation. Side effects included flu-like symptoms, fever and elevated liver function test levels in two patients. More recently, low-dose intralesional interferon-alpha led to significant improvement in one patient with chronic DLE 42. Finally, the use of extracorporeal photochemotherapy in SLE seems encouraging. This therapy is currently used predominantly for cutaneous ’~’-~ell lymphoma but has been tried, with success, in other autoimmune disorders. In a recent report of 10 patients with SLE treated with extracorporeal photochemotherapy, seven patients seemed to improve, with the skin showing significant beneficial response~.
Surgery Modest benefits have been reported from the surgical treatment of DLE. Modalities including skin grafting44, dermabrasion 45 and argon laser have been utilized. The theoretical risk for exacerbation of DLE from the trauma of surgery has prompted to recommend the prescription of antimalarials or steroids prior to the
surgical procedure to diminish
.
Conclusion The cutaneous manifestations of lupus erythematosus can frequently be controlled with the combination of sunscreens and t~pi~al,~intral~s~onal corticosteroids. In those patients with extensive or unresponsive disease, antimalarials can be witch safety, as long as the patients are monitored by an ophthalmologist. While there is little evidence to indicate greater efficacy of any particular antimalarial over another, hydroxychloroquine has gained popularity over chloroquine because of its possible decreased ocular toxicity. It is clear that the risk of antimalarial can be reduced if the dose of chloroquine does not exceed 4.0 mg/kg/day and the dose of doer not exceed 6.5 mg/kg/day. does not rctmopathy and the average daily dose is 100 mg/day. The use of other agent for cutaneous lupus is less well studied and most of the evidence comes from open unblinded studies. DDS appears to be effective in bullous lupus and in some patients with DLE and SCLE. Clofazimine seems to be effective in DLE and SCLE, with the advantage of being a very safe agent; unfortunately it is associated with cutaneous discoloration, which some patients may find intolerable. Thalidomide,
while effective, is a potent teratogen and may produce an irreversible peripheral neuropathy. Oral gold may be effective but requires further study. Retinoids are the drugs of choice in hypertrophic cutaneous lupus but may also be useful in DLE and SCLE. Their use is restricted by their teratogenicity and other cutaneous and systemic side effects. The effectiveness of vitamin E in cutaneous lupus remains controversial. Alpha interferon, while promising, will probably be of little value because of the high doses required to control the disease and the side effects accompanying these large doses. Immunosuppressive agents, while effective in cutaneous lupus, should be reserved for patients with intractable disease or those with associated systemic complications.
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(Received 24 April 1992) (Accepted 4 August 1992)
Key Words: Antimalarials Retinoids Dapsone Clofazamine Gold
Introduction
often determines the response to therapy. Lesions on the palms and soles and on cutane~uslmu~~~~.i junctions (i.e. vermillion border or eyelids) may be resistant to conventional therapy. The recognition of SCLE as a distinct clinical entity is of utmost importance. While approximately 5007o of these patients meet the ARA criteria for SLE, their disease often follows a more benign course 3. SCLE shows striking photosensitivity and does not produce scarring unless accompanied by DLE lesions. Acute lupus may or may not present with cutaneous manifestations. The therapy for ALE is often determined by the of systemic involvement. Since not infrequently patients with ALE are treated for renal, hematologic or central nervous system involvement with high doses of systemic corticosteroids and immunosuppressive agents, the cutaneous manifestations not only are of secondary consideration but usually respond to these therapeutic interventions.
The patient presenting with a dermatosis clinically consistent with discoid lupus erythematosus (DLE), subacute cutaneous LE or acute systemic LE (ALE) warrants biopsy confirmation of the diagnosis and evaluation for systemic disease. Assessment for American Rheumatism Association (ARA) criteria’ is made and laboratory investigations, including tests for antinuclear antibodies (ANA), anti-double-stranded DNA antibodies, anti-Ro antibodies, anti-La antibodies, C3, C4 and CH50, complete blood’count (CBC) plt, blood urea
nitrogen/creatinine (BUN/Cr) and urinalysis,
are
per-
formed. Although the initial evaluation for all clinical forms of lupus is similar, it is important to classify the condition into the aforementioned subgroups (DLE, SCLE, ALE), since this will have therapeutic as well as prognostic implications. It is also important to note the presence or absence of certain other cutaneous manifestations of such as vasculitis, which while not specific may accompany the disease and may necessitate
different therapeutic approach. DLE is probably the most common cutaneous manifestation of LE. Therapeutically, the extent of disease and sites of involvement are important. Approximately 25% of patients with systemic LE (SLE) will develop DLE during their disease Fewer than 10% of cases where patients present initially with DLE alone will evolve into although this may be an overestimation. Studies have shown that those patients with disseminated particularly below the neck, are more to develop SLE~. The site of DLE lesions
Conventional therapy
a
Limited and
non-disfiguring disease is best managed with intralesional and topical steroids and sunscreen. More generalized disease. and limited disease unresponsive to local measures necessitate systemic antimalarials are generally considered the treat’
ment of
choice.
Intralesional and steroids I’ntralesional steroids of various strengths and concentrations have enjoyed tremendous popularity in the treatment of cutaneous lupus. Patients with limited disease, particularly those with a few DLE lesions, often to intralesional triamcinolone acetonide in
Correspondence: Francisco A. Kerdel, M.D., University of Miami School of Medicine, P.O. Box 016250 (R-250), Miami, Florida 33101, USA.
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concentrations of 10-20 mg/ml. The volume injected depends on the size of the lesion, but it is customary to inject not more than 1 ml per lesion. If the number of lesions or the size of the lesions requires large volumes of the steroid suspension ( > 6 ml), then the addition of other therapeutic agents should be considered. In order to minimize side effects, lesions should not be injected more frequently than once each month. The treatment of DLE lesions with intralesional steroids, while effective, is often difficult. Scarring with the development of telangiectasias is the natural progression of the disease. However, chronic steroid usage can also produce similar effects. Telangiectasias often give the lesion an erythematous appearance, which can confuse the physician as to the activity of the disease. It is therefore helpful to elicit the presence of tenderness and hyperemia (warmth) of the lesions, since these two signs often accompany increased disease activity. Some patients may also present with flare-up of their systemic disease as well as their cutaneous lesions. It is important to recognize these signs, since systemic corticosteroid therapy may be warranted. The introduction of superpotent fluorinated steroids for topical use has allowed some patients to be treated without intralesional steroids. These agents, applied twice daily, can be extremely effective in early lesions. Intralesional and topical steroids have the same unwanted side effects of atrophy and telangiectasias. It is therefore imperative for the physician to determine whether the lesion is active (requiring therapy) and when therapy should be stopped. Failure to discontinue the treatment will result in atrophy and possibly breakdown of the skin, precisely what the treatment is attempting to avoid.
Sunscreen Sunscreens probably represent the most important factor in the treatment of cutaneous lupus, irrespective of type or severity. Patients should be instructed to introduce use of sunscreens with a sun protection factor of 15 or higher into their daily routine, avoid peak periods of sun exposure from 10 am to 3 pm, and wear protective clothing and broad-rimmed hats when outdoors. The action spectrum of photosensitivity in LE has been considered to be of the UVB (280-320 nm) wavelength; however, recent studies show that both UVB and UVA (320-400 nm) may induce lesions of LE in phototested patients’. Thus, the use of more broadspectrum sunscreens should be instituted; sunscreens containing butyl methoxydibenzoylmethane may be very useful in this respect. It is well known that UVA can penetrate window glass and, therefore, the daily application of sunscreen is important because of considerable ultraviolet exposure during travel by car.
Antimalarials The antimalarials most commonly used in the treatment of cutaneous lupus are those derived from 4-aminoquinoline. Currently, hydroxychloroquine is widely used, although chloroquine and quinacrine are occasionally employed. These compounds are effective in approximately ’71?-l~f#~J~ of patients with cutaneous LE 6-8. Recent data also suggest that antimalarials may also prevent lupus flares in both cutaneous and systemic disease 9. The mechanism of action is unknown, although there is significant in vitro work suggesting a broad biological activity!°. Antimalarials have one important drawback: ocular toxicity. In this respect, they can produce three main side effects: (1) blurring of vision, due to reversible lateral rectus paralysis, (2) ’haloes around white lights’, due to corneal deposits, and (3) retinopathy. The blurring of vision is a rare occurrence, usually dose dependent and entirely reversible. It infrequently requires discontinuation of the drug. Corneal deposits, although relatively common with chloroquine ~lfl-~~~1~ of patients), are infrequently seen in patients on hydrt~xyehlorc~quine$’. Again, this side effect is reversible and seldom requires discontinuation of therapy. The incidence of retinopathy is unknown, although there are about 300 cases reported in the world’s literature&dquo;. This side effect can be seen with both chloroquine and hydroxychloroquine. Some authors suggest that the risk of developing retinopathy with hydroxychloroquine is less, but no supportive data for this exist. Quinacrine is not associated with retinopathy. The importance of retinopathy stems from its progressive course, which can eventuate in visual loss and irreversible blindness. Even though early studies suggested that retinopathy was related to the cumulative dose of antimalarials 12, more recent work has shown that it is the daily dose that determines the risk of developing this complication. This risk can thus be decreased if the dose of chloroquine does not exceed 250 mg/day (4 mg/kg/day) and if the dose of hydroxychloroquine does not exceed 4t10 mg/day (6.5 mg/kg/day) 6, 11,12. While these doses are relatively safe, they represent the maximum daily dose and therefore, whenever possible, a decreased dosage should be attempted. The symptoms of retinopathy include night blindness, tunnel vision, decreased visual acuity, and scotoma formation. Unfortunately, however, by the time the symptoms develop, retinopathy is well established and irreversible damage cannot be avoided. Retinopathy can nevertheless be prevented by the performance of ophthalmological evaluations before and during therapy ~ ~. Most ophthalmologists recommend a screening examination and subsequent examinations every 4-6 months &dquo;. It has been noticed that retinopathy is
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preceded by a premaculopathy stage; ocular changes are reversible at this point upon discontinuation of the drug. While there is argument as to the best screening test for these patients (absence of foveal reflex, macular dazzle testing, electro-oculograms, electroretinogram), visual field testing is the most practical and currently is probably the most widely used examination 1 I. Formal visual field testing may be supplemented with home self-testing with an AMSLER grid&dquo;’ 13. Early retinal changes produce so-called relative scotomas (blurred areas), which can be best detected by visual field testing with red
Iight&dquo;.
If the medicine is discontinued at this stage, the evolution towards absolute scotomas and visual loss can be prevented. Quinacrine does not produce ocular toxicity, but may cause hemolysis in glucose-6-phosphate dehydrogenasedeficient individuals’°. Rarely, aplastic anemia has been reported 10. Quinacrine also causes a yellowish discoloration in most patients, limiting its use to patients of darker complexion. The dose of quinacrine is 100 mg/day and it can be added to either hydroxychloroquine or chloroquine in patients with unresponsive disease. In addition to baseline ophthalmologic examinations, laboratory screening, including liver function tests, BUN/Cr and CBC plt, should be performed and followed every 3-6 months during antimalarial therapy.
Treatment of antimalarial-resistant disease
variety of treatment options exists for cutaneous disease resistant to conventional local and systemic ther-
especially beneficial in the treatment of hypertrophic DLE 15,16. Optimal dosage ranges are approximately ~.5-l.~l m~lkglday. Clinical response has been noted generally within 2-4 weeks of treatment. Shornick et al. noted that their patients suffered striking and rapid relapse upon discontinuation of isotretinoin 14. Significant side effects of retinoid therapy include teratogenicity, mucocutaneous changes of xerosis, cheilitis, epistaxis, alopecia, and alterations of serum lipid profile. Adequate contraception must be taken by isotretinoin-treated women during therapy and for 1 month after therapy is discontinued. Etretinate has a prolonged half-life and therefore should be avoided in women of childbearing potential. While acitretin appears to have a shorter half-life, its teratogenetic effects post therapy are under investigation and it should therefore also be avoided in women of childbearing potential. Prolonged therapy with retinoids may be complicated by skeletal hyperostoses. Laboratory parameters, including beta-HCG in women, lipid profile, liver function tests and CBC plt, are measured at baseline and every month of therapy. Thus, while the retinoids have been reported as quite effective in the treatment of cutaneous lupus, their use is limited by side effects and possibly by the need for chronic treatment to sustain a therapeutic response. Additionally, while reports in the literature emphasize the therapeutic successes, in practice there are many patients who fail to respond to retinoid therapy. been
A
Dapsone
apy : retinoids, dapsone (DDS), vitamin E, clofazimine, thalidomide and oral gold. As well, treatment with immunosuppressive and immunomodulating agents,
including conventional cytotoxics (methotrexate, cyclophosphamide, azathioprine), pulse methylprednisolone, cy~Ic~spc~rine, alpha-interferon, and extracorporeal photochemotherapy may be considered. Finally, surgical modalities may play a role in the treatment of inactive lesions of DLE. Literature suggesting treatment efficacy is limited to. either case reports or reports of open clinical trials. Both side-effect profile and relative efficacy in the treatment of formes of cutaneous LE are important considerations in the selection of these
.
systemic therapies. Retinoids The retinoids
(isotretinoin, etretinate
and its
metabolite, acitretin), best known for the and
psoriasis, have
been used with
major
treatment of
excellent chronic malar rash of SCLE and the SLE 14-19. DLE, They have acne
DDS is often utilized in dermatology for the treatment of neutrophilic dermatoses such. as leukocytoc1astic vasculitis and dermatitis herpetiformis. In this fashion, DDS has proven effective in dre treatment of the bullous eruption of lupus and vasculitis associated with lupus 20. Additionally, there have been reports of DDS°s efficacy in the treatment of annular SCLE21. 22. However, there has been only a fair response to DDS in the treatment of chronic DLE, with improvement in one-quarter to onethird, ~f patients &dquo;, 24. The authors of one open trial suggest greater efficacy when DDS is used in combination with hydroxychloroquine. Dosage of DDS in one open trial was 100 Common adverse reactions to DDS include dizziness, depression and minor psychiatric disturbances. Significant side effects of DDS include hemolysis, methemoglobinemia, agranulocytosis, leukopenia, and a reversible peripheral neuropathy. A baseline G6PD and CBC should be obtained prior to initiation of therapy. Folate supplementation may be beneficial in the management of low-grade hemolysis associated with chronic
an
response rate of ~~-1£~Q~~ in the literature for
treatment.
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Vitamin E
Vitamin E or tocopherol has been advocated as a nontoxic therapeutic modality in the treatment of cutaneous LE with optimal doses of d,alpha-tocopheryl acetate or succinate ranging from 800 to 2000 IU/day. Ayres and Mihan reported on seven patients with DLE treated with oral vitamin E. Only two patients failed to show an excellent response; notably they were receiving only 300 IU/day and also were treated with topical steroids rather than the topical vitamin E received by the other five
day may be required. Likewise, reduced doses may be helpful in combination with antimalarials 33 . Unfortunately, not only is thalidomide a potent teratogen, it also may frequently induce irreversible peri-
pheral neuropathy, which is dependent neither on dose nor on duration of therapy. Nerve conduction studies should be performed prior to initiation of thalidomide and at intervals during therapy. Reversible side effects include sleepiness, headache, constipation, xerosis and weight gain. Oral gold
patients 25 . Ayres and Mihan reviewed the results of numerous previous open trials of vitamin E for DLE and SCLE 25. In general, trials have shown only a fair response for low doses of vitamin E and only a fair response for hypertrophic disease. Treatment with adequate dosages, particularly for superficial disease of recent onset, showed marked improvement. It is important to note that the use of vitamin E in lupus is controversial and not universally
accepted. Vitamin E-induced increases in cardiac muscle tone and in glycogen storage warrant dosage adjustments in patients with hypertension and diabetes, with an initial dose of 100 IU/day and gradual increases as tolerated, with monitoring of blood pressure and blood glucose. Side effects of vitamin E are negligible’.
A fair response was seen in chronic severe DLE treated with an average dose of 3 mg b.i.d. of oral gold for 1 year in an open trial of 23 patients 31 . There was complete remission in four patients and ’improvement’ in another 15 patients. The best response was seen in patients with
rosacea-like lupus. While thick plaques were responsive, more verrucous plaques were not. Side effects included loose stool, nausea and vomiting, sore mouth and tongue, pruritus and rash. While the only significant laboratory abnormality was reversible proteinuria in one patient, the prescription of oral gold should include baseline and monthly urinalysis, BUN/Cr and CBC plt.
Immunosuppressive and immunomodulatory therapy The use of cytotoxic agents in the treatment of cutaneous LE should preferably be restricted to the concomitant treatment of systemic disease. In one open trial of nine patients, more than 50% of patients with either SCLE or DLE showed an excellent response and one-third of patients showed a moderate response to treatment with 50-200 mg/day of cyclophosphamide35. Pulse cyclophosphamide is efficacious in the treatment of lupus nephritis and cerebritis 36. Callen favors the use of azathioprine over methotrexate, cyclophosphamide and chlorambucil, noting response within 1-2 months in DLE and S~LE~’. In an open trial, six patients with treatment-resistant cutaneous LE (four SCLE, two DLE) were treated with azathioprine 100-150 mg/day. Four patients showed an excellent response, but one patient discontinued therapy due to pancreatitis. Azathioprine therapy proved to be
Clofazimine Clofazimine is an important antilepromatous agent that has shown some promise in the treatment of SCLE 26 and DLE27-29. An open trial in the treatment of DLE showed clinical remissions in 17 of 26 patients over a 3-6-month period of treatment. A dose of 100 mg/day is
optimal. Clofazimine has minimal side effects, such as nausea and xerosis. Most remarkable is its characteristic deposition in subcutaneous fat, which evokes a pinkish discoloration of the skin. The pinkish discoloration appears to be dose related, as does occasional hyperpigmentation of discoid plaques. The subcutaneous deposition appears to have a therapeutic advantage, in that clinical remission was evident in six patients several months after discontinuation of the drug~.
steroids sparing~. Two patients with SCLE had rapid clearance of cutaneous disease with pulse methylprednisolone 39. Oral cyclosporine has not been effective therapy for cuta-
Thalidomide
Thalidomide is also an antilepromatous agent utilized to suppress the immunologic reaction of erythema nodosum leprosum. At doses of 100-200 mg/day thalidomide has impressive efficacy within several weeks in the treatment of DLE and SCLE, with hypertrophic LE showing a less favorable response’o~&dquo;. Relapse may occur upon abrupt discontinuation and maintenance doses of 25-50 mg/
neous
LE 40. Caution should be exercised
as
the
use
of
cyclosporine may be associated with compromised renal function in patients with pre-existing lupus nephritis. A recent experimental advance in the treatment of DLE and SCLE is with the
use
of the immunomoduLow or intermediate
lating agent interferon-alpha 2a 41. 354
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doses (18-45 million units per week) for 4-8 weeks resulted in complete clearing in four patients and marked improvement in two patients with DLE. High doses (100-200 million units per week) for 12 weeks resulted in complete clearing in one patient and marked improvement in another patient with SCLE. Relapse was seen after discontinuation. Side effects included flu-like symptoms, fever and elevated liver function test levels in two patients. More recently, low-dose intralesional interferon-alpha led to significant improvement in one patient with chronic DLE 42. Finally, the use of extracorporeal photochemotherapy in SLE seems encouraging. This therapy is currently used predominantly for cutaneous ’~’-~ell lymphoma but has been tried, with success, in other autoimmune disorders. In a recent report of 10 patients with SLE treated with extracorporeal photochemotherapy, seven patients seemed to improve, with the skin showing significant beneficial response~.
Surgery Modest benefits have been reported from the surgical treatment of DLE. Modalities including skin grafting44, dermabrasion 45 and argon laser have been utilized. The theoretical risk for exacerbation of DLE from the trauma of surgery has prompted to recommend the prescription of antimalarials or steroids prior to the
surgical procedure to diminish
.
Conclusion The cutaneous manifestations of lupus erythematosus can frequently be controlled with the combination of sunscreens and t~pi~al,~intral~s~onal corticosteroids. In those patients with extensive or unresponsive disease, antimalarials can be witch safety, as long as the patients are monitored by an ophthalmologist. While there is little evidence to indicate greater efficacy of any particular antimalarial over another, hydroxychloroquine has gained popularity over chloroquine because of its possible decreased ocular toxicity. It is clear that the risk of antimalarial can be reduced if the dose of chloroquine does not exceed 4.0 mg/kg/day and the dose of doer not exceed 6.5 mg/kg/day. does not rctmopathy and the average daily dose is 100 mg/day. The use of other agent for cutaneous lupus is less well studied and most of the evidence comes from open unblinded studies. DDS appears to be effective in bullous lupus and in some patients with DLE and SCLE. Clofazimine seems to be effective in DLE and SCLE, with the advantage of being a very safe agent; unfortunately it is associated with cutaneous discoloration, which some patients may find intolerable. Thalidomide,
while effective, is a potent teratogen and may produce an irreversible peripheral neuropathy. Oral gold may be effective but requires further study. Retinoids are the drugs of choice in hypertrophic cutaneous lupus but may also be useful in DLE and SCLE. Their use is restricted by their teratogenicity and other cutaneous and systemic side effects. The effectiveness of vitamin E in cutaneous lupus remains controversial. Alpha interferon, while promising, will probably be of little value because of the high doses required to control the disease and the side effects accompanying these large doses. Immunosuppressive agents, while effective in cutaneous lupus, should be reserved for patients with intractable disease or those with associated systemic complications.
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(Received 24 April 1992) (Accepted 4 August 1992)
