While a number of systemic medications have been reported to be of benefit to SCLE patients, by far those having the highest safety/benefit ratios are the aminoquinoline antimalarial agents. There is general agreement that 70-80% of SCLE patients will respond to single agent or combination anti-malarial therapy. The three agents most frequently prescribed in the USA for SCLE patients are hydroxychloroquine sulfate (Plaquenil [Sanofi-Synthelabo]), chloroquine phosphate (Aralen [Sanofi-Synthelabo]), and quinacrine (currently available in the USA only as a compounded formulation of the dihydrochloride salt which must be encapsulated). In general, hydroxychloroquine is best tolerated with the least side effects.
Therapy with hydroxychloroquine alone should be tried initially starting at 6.5mg/kg/day in two divided doses (approximately 400mg/day for the average size person). Hydroxychloroquine reaches steady state levels in 6-8 weeks and its full clinical efficacy cannot be judged before then. Its full clinical effects can take even longer. If there is no significant improvement by 2-3 months, quinacrine 100mg/day can be added to the hydroxychloroquine (Toubi et al., 2000; Chung and Hann, 1997; Lipsker et al., 1995; Feldmann et al., 1994). If the response is inadequate after 4-6 weeks of combined hydroxychloroquine and quinacrine therapy, chloroquine 250 mg/day can be substituted for the hydroxychloroquine in this combination as an occasional cutaneous LE patient will respond better to chloroquine than hydro-xychloroquine. (Hydroxychloroquine and chloro-quine should not be used concurrently because of enhanced risk of retinopathy.) Once disease activity is controlled, the hydroxychloroquine can be decreased to 200mg/day for maintenance. Most authorities recommend a treatment period of 1-2 years to fully suppress cutaneous LE activity. As noted previously there is evidence that cigarette smoking through a unknown mechanisms can interfere with efficacy of antimalarials in cutaneous LE.
It should also be realized that the aminoquino-line antimalarials, especially hydroxychloroquine, are being increasingly recognized to have a salutary effect on the extracutaneous manifestations of SLE (Canadian Hydroxychloroquine Study Group, 1991; Molad et al., 2002). Thus, the malaise, fatigue, and arthralgia that SCLE patients can experience can respond to antimalar-ials that have been given to control SCLE skin disease activity. As with the cutaneous LE disease activity, the musculoskeletal manifestations of SCLE patients will take several months to be fully impacted after starting antimalarials.
When using either hydroxychloroquine or chloroquine, ophthalmological moniotoring is required to minimize the risk of retinal toxicity (quinacrine is not retinopathic). A baseline oph-thalmological evaluation should be obtained before starting antimalarial therapy to document any pre-existing changes that might subsequently attributed to the medication. The frequency with which patients are subsequently monitored has been debated. The most recent set of guidelines published by the American Academy of Ophthalmologists in April, 2002 suggests that this should be repeated at 6-12 month intervals while the patient is undergoing therapy (Marmor et al., 2002). This evaluation should, at minimum, include a funduscopic exam, visual field testing (including central fields with a red object), and visual acuity testing. Use of the self-administered Amsler Grid at home to detect the earliest evidence of visual field defects has become popular. Retinal changes can become irreversible if not detected early. It has been suggested that the risk of retinal toxicity is minimized when the total daily dose of hydro-xychloroquine does not exceed 6.5mg/kg/day (3.5mg/kg/day for chloroquine). There does not appear to be an upper limit on the "safe" total lifetime dose of these drugs if these daily maximum dosing recommendations are not exceeded.
Periodic assessments of hematological and hepatic function are carried out by most dermatologists during the hydroxychloroquine and chloroquine therapy to identify the occasional patient who will suffer an idiosyncratic reaction. However, it should be noted that when using hydroxychloroquine for SLE, the American College of Rheumatology guidelines indicate that no such routine hematologic monitoring is necessary (American College of Rheumatology Ad Hoc Committee on Clinical Guidelines, 1996). It should be noted that full-dose hydroxychloroquine or chloroquine therapy in an individual having sub-clinical porphyria cutanea tarda can produce an acute hepatotoxic reaction that it can produce symptoms simulating an acute surgical abdomen. Quinacrine hydrochloride is more likely to induce hemolysis in glucose-6-phosphate dehydrogenase-deficient patients than is hydroxychloroquine or chloroquine and routine hematologic monitoring should be carried out with this agent. Neuro-toxicity and muscular toxicity (including cardio-toxicity) can occur with the aminoquinoline antimalarials but was much more of a problem in the past when much higher daily doses of these drugs were used.
Antimalarial agents can induce a number of dermatological changes. All can cause a blue-black pigmentation of the skin (particularly in the sun exposed areas), palatal mucosa, nails, and pretibial surfaces. They can also rarely cause bleaching of lightly pigmented hair, although this is rare with currently recommended daily doses. Quinacrine frequently causes diffuse yellowing of the skin, sclera, and bodily secretions that is fully reversible on discontinuation of the drug. On occasion, quinacrine produces a lichenoid drug reaction that can be the harbinger of severe bone marrow tox-icity if the drug is must not discontinued (Wallace, 1989). The lichenoid drug eruptions that can be produced by all of the aminoquinoline antimalar-ials can at time simulate the appearance of cutaneous LE lesions, including SCLE, resulting in a highly confusing clinical setting (Geraminejad et al., 2004).
Dapsone (diaminodiphenylsulfone) has been reported in small numbers of cases to be of benefit to SCLE within a few weeks after starting therapy (Holtman et al., 1990; Fenton and Black, 1986; McCormack et al., 1984). Dose of 50-200 mg/day are typically required but even higher doses might be needed. Hematological, renal, and hepatic tox-icity can occur with this drug and thus careful monitoring is required. Unfortunately, in SCLE patients personally treated by the author Dapsone has been of only moderate to marginal benefit.
Isotretinoin (Accutane) at approximately 1 mg/kg/ day and acitretin (Soriatane) at 25-50 mg/day have been shown to significantly improve cutaneous LE including SCLE lesions (Furner, 1990). The great potential for teratogenic effects with the retinoids makes it imperative that fertile females use contraceptive techniques according to guidelines set forth specifically for patients on retinoids. A common dose-related side effect is mucocutaneous dryness. It is advisable to have patients use sunscreens judiciously while being treated with these agents to minimize their tendency to aggravate photosensitivity. Drug-induced hepatitis and hypertriglyceridemia can occur with these agents and requires periodic laboratory evaluation. Occasionally, these drugs can also induce bony changes consistent with the diffuse idiopathic skeletal hyperostosis (DISH) syndrome. Hair loss and peeling of the hands and feet are seen more often with acitretin. Cutaneous LE disease activity tends to recur quickly after discontinuing systemic retinoids. This plus their high rates of adverse reactions limit the clinical utility of systemic retinoids in the management of long-term skin disorders such as cutaneous LE.
Thalidomide 50-200 mg/day can be very effective for active SCLE (Volc-Platzer and Wolff, 1983; Naafs et al., 1982) but due to its side effects is generally limited to use in difficult, refractory cutaneous LE patients. Its clinical benefit can be seen as early as 2 weeks, however cutaneous LE disease activity typically relapses 2-3 months after discontinuing the drug.
The severe teratogenicity of thalidomide is well known and has limited the frequency with which it is prescribed. Additionally, a predominately sensory peripheral neuropathy has been described to occur in 10-25% of treated cutaneous LE patients even with low doses as much as 50-100 mg/daily. Since thalidomide works quickly in SCLE, it is possible to treat recalcitrant patients with short courses of thalidomide (8-16 weeks) to minimize toxicity. To prevent flares after discontinuation of thalidomide, antimalarial therapy can be administered concomitantly with thalidomide and continued after thalidomide is withdrawn. Other side effects include secondary amenorrhea and induction of a hypercoagulable state, especially in the setting of antiphospholipid antibody production. Thalidomide's mechanism of action is unclear, however many have suggested TNF-a inhibition.
Oral gold (auranofin [Ridaura]) therapy has been successfully used in cutaneous LE patients whose disease is resistant to the less toxic forms of therapy (Dalziel et al., 1986). Generally, parenteral forms of gold (aurothiomalate and aurothioglu-cose) have been more efficacious for most indications than the oral form of gold. However, the parenteral forms of gold previously available in the US have been supplanted by other drugs having less mucocutaneous, hematological, renal, and pulmonary toxicity.
Crovoto reported the successful use of clofazimine (Lamprene) in a patient with annular SCLE in 1981 (Mackey and Barnes, 1974). He used a dose of 100 mg/day and noted clearing of the lesions within a few weeks. At this dosage clofazimine is generally well tolerated, though gastrointestinal intolerance can be a problem. At higher doses, clofazimine has rarely been reported to precipitate in mesenteric arteries, resulting in major abdominal catastrophes such as splenic infarction. A pink-brown-black skin pigmentation develops in most patients on long-term clofazimine therapy. This pigmentation resolves over months to years after discontinuing the drug. Similar discoloration of bodily secretions also frequently occurs. Clofazimine is currently not available in the USA.
Several other agents have been suggested anecdo-tally to be of benefit in SCLE. Those include cefuroxime axetil (Rudnicka et al., 2000), statins (Namazi, 2004), pulsed by laser (Gupta and Roberts, 1999), and recombinant interferon-a 2a (Nicolas and Thivolet, 1989; Nicolas et al., 1990). However, interferon-a therapy has also been associated with the precipitation of SCLE. The author has no personal experience with any of these agents in SCLE.
7.10. Systemic corticosteroids and other immunosuppressive agents
Systemic corticosteroids and other immunosuppres-sive/cytotoxic agents (methotrexate, azathioprine, mycophenolate mofetil, cyclophosphamide, etc) are reserved for patients with more severe SCLE that have failed to respond to the less toxic forms of therapy discussed above. A patient may occasionally be encountered whose disease is so severe that these more potent agents may be used earlier in the disease course, even before the patient is given a complete trial of the less toxic agents, or before the less toxic agents (i.e., hydroxychloroquine) reach steady state levels. It should be remembered that long-term systemic corticosteroid usage in LE patients carries a high risk of complications such as avascular bone necrosis and premature atherosclerosis. Thus, when treating only or predominately the cutaneous manifestations of LE every effort should be made to avoid long-term use of systemic corticosteroids.
Methylprednisolone given in pulse doses (1 g intravenously slowly [approximately 4h] daily for 3 consecutive days) has been reported to provide improvement in SCLE patients with systemic LE. Anecdotally, methotrexate, azathioprine, and cyclophosphamide have been suggested to be of benefit in refractory SCLE. Due to the potential for severe immunosuppression, bone marrow and mucous membrane toxicity, hepatotoxicity, and opportunistic malignancies, these agents should be reserved for patients with severe disease and used only as a last resort in patients with severe cutaneous LE alone.
Although drug combinations have long been frowned upon by the USA Food and Drug Administration, various combinations of the above systemic anti-inflammatory and immuno-suppressive agents have routinely been employed by rheumatologists in diseases such as rheumatoid arthritis. The rationale for such combined ''chemotherapy-like'' approaches to non-malignant inflammatory musculoskeletal disease has been to provide additive or synergistic clinical efficacy by employing combinations of drugs that act through different mechanisms while minimizing toxicity by limiting daily dosage maxima of individual drugs. The downside is that adverse reactions developing during combination therapy can be difficult to ascribed to a specific agent.
Except for the above comments concerning combination antimalarial therapy, USA dermatologists have traditionally not been very creative in employing combination of therapeutic agents for the management of rheumatic skin diseases such as SCLE. There is published data suggesting that the following drugs can be used concurrently with hydroxychloroquine safely and effectively in other rheumatic disease settings: sulfasalazine, met-hotrexate, gold, azathioprine. The author has personally observed this to be the case for dapsone as well. In addition, the following combinations of other anti-rheumatic drugs have safely been employed concurrently with hydroxychloroquine: sulfasalazine + methotrexate, sulfasalazine + gold, and methotrexate + azathioprine. Perhaps dermatologists have missed opportunities by not more systematically examining such combinations for efficacy in difficult cutaneous LE patients including SCLE.
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