Conservative Management
ARTHRITIS, ARTHRALGIA, AND MYALGIA
Arthritis, arthralgia, and myalgia are the most common manifestations of SLE. Severity ranges from mild to disabling. For patients with mild symptoms, administration of analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), or salicylates may provide adequate relief, although none of these is as effective as glucocorticoids. 1, 2, 3
Nonacetylated salicylates are useful because they inhibit prostaglandin synthesis less than acetylated salicylates and NSAIDs and, therefore, are associated with a relatively low incidence of gastrointestinal symptoms and bleeding. They usually do not impair platelet function. Therapeutic range (approximately 150 to 200 mg/dl) can be assessed by measuring serum salicylate levels.
The use of standard NSAIDs that inhibit both cyclooxygenase-1 and -2 (COX-1 and -2), or NSAIDs that are more specific inhibitors of COX-2, requires special caution in patients with SLE. Several agents (ibuprofen, tolmetin, sulindac, rofecoxib) can cause aseptic meningitis. 4, 5 Through their effects on renal prostaglandins, all NSAIDs can reduce glomerular filtration rates and renal blood flow, especially in patients who have clinical or subclinical nephritis, who are taking diuretics, or who have congestive heart failure or cirrhosis. Although sulindac is least likely to have this effect, it does occur; serum creatinine levels should be monitored after introduction of any salicylate or NSAID. Hyperkalemia and interstitial nephritis are uncommon side effects of NSAIDs. Salt retention secondary to NSAID use may elevate blood pressure and cause pedal edema; NSAIDs may reduce the efficacy of furosemide and thiazide diuretics. Gastrointestinal toxicity with ulcer symptoms, perforation, or bleeding can develop at any time during therapy. Protection from gastrointestinal adverse events has not been studied in patients with SLE, but the prevalence of this problem is lower in individuals treated with NSAIDs that inhibit COX-2 more than COX-1, at least for the first year of therapy. 4, 6 Finally, patients with SLE have a higher incidence of hepatotoxicity than other patients taking standard NSAIDs 4 ; hepatotoxicity is usually manifested as transaminitis without permanent hepatic damage. In summary, SLE patients treated with NSAIDs should be monitored regularly for renal, gastrointestinal, and hepatic side effects.
Concomitant use of glucocorticoids and NSAIDs that strongly inhibit COX-1 substantially increases the risk of gastrointestinal bleeding. Use of such NSAIDs with or without glucocorticoids may require addition of gastroprotective therapies—either proton pump inhibitors such as omeprazole or the prostaglandin analogue misoprostol. 7 Glucocorticoids also increase clearance of salicylates; lowering glucocorticoid doses may be accompanied by increases in serum salicylate levels.
In many SLE patients, musculoskeletal symptoms are not well controlled by salicylate or NSAID therapy. A trial of antimalarial drugs may be useful in such individuals, or as initial therapy in patients with prominent arthralgia or arthritis. 8, 9 Antimalarials are discussed later with the treatment of cutaneous manifestations. Hydroxychloroquine is the preferred antimalarial agent in the United States (chloroquine may be more effective but has a higher incidence of retinal toxicity; quinacrine is often effective but, rarely, can cause aplastic anemia). The usual dose of hydroxychloroquine for SLE patients with arthritis is 400 mg daily. If response does not occur within 6 months, the patient can be considered a nonresponder and the drug stopped. If hydroxychloroquine is used for more than 6 months or chloroquine is used for more than 3 months, regular examination by an ophthalmologist for retinal damage is mandatory. If antimalarials are effective, the maintenance dose should be reduced periodically if possible, or the drug should be withdrawn when a patient is doing well, because the retinal toxicity is cumulative.
Some patients with arthritis or arthralgia do not benefit from NSAIDs or salicylates, with or without antimalarials. Administration of dihydroandrosterone (DHEA), 100 to 200 mg daily, lowers activity of SLE in some patients, including arthritis and arthralgias. 10 A recent study has suggested that 200 mg/day is more effective than lower doses. 11 Acne is a side effect in 10 to 30 percent of patients; the potential adverse effects of elevated serum levels of testosterone, which occurs in all women treated with DHEA in these doses, is unknown.
Methotrexate (MTX) in weekly oral or parenteral doses of 10 to 20 mg may also be considered, because there are reports of its efficacy in lupus arthritis. 12 Recent uncontrolled studies of leflunomide treatment in patients with SLE have suggested that disease activity, including arthritis, is reduced. 13 However, none of these interventions is as reliable as glucocorticoid therapy in suppressing lupus arthritis and arthralgia. If quality of life is seriously impaired by joint pain, the physician should consider institution of low-dose glucocorticoids, not to exceed 15 mg each morning. Rare patients require high-dose glucocorticoids or even cytotoxic drugs. Such interventions should be avoided if possible. In fact, if arthritis is the major manifestation of disease that compels the physician to choose high-dose immunosuppressive treatments, it may be preferable to use around-the-clock non-narcotic or narcotic analgesics to control pain, rather than risk the life-threatening side effects of immunosuppression.
Pain that persists in one or two joints may be due to ischemic necrosis of bone or, rarely, to septic arthritis. Ischemic necrosis of bone can be associated with warmth and swelling in continguous joints; it should be ruled out in patients with a small number of persistently inflamed or painful joints (especially knees, hips, shoulders, wrists, or ankles) who do not have additional evidence of active SLE before these patients are treated for lupus arthritis.
CUTANEOUS LUPUS
As many as 70 percent of patients with SLE are photosensitive. 14 Flares of SLE can be caused by ultraviolet (UV) light, infrared light, heat, or rarely, fluorescent light. Some patients are sensitive to UVB (290 to 320 nm), some to UVA (320 to 400 nm), and some to both. Photosensitive patients should minimize their exposure by wearing protective clothing, using tinted glass in car windows, avoiding direct sun exposure, and applying sunscreens. Most topical sunscreens are creams, oils, lotions, or gels that physically block or scatter UVB light; contain UV light-blocking chemicals such as para-aminobenzoic acid (PABA) and its esters, benzophenones, salicylates, anthranilates, and cinnamates; or both. 15 All absorb UVB light; UVA is absorbed partially by benzophenones and anthranilates. The sun protection factor (SPF) is the ratio of the time required for UVB to produce erythema when sunscreen is worn compared to the time required to produce the same degree of erythema in unprotected skin. SPFs range from 2 to 50; lupus patients should use preparations with an SPF of 15 or higher. The agents should be reapplied after toweling or sweating.
Table 76-1 lists some available high-protection sunscreens that are free of PABA; there is a relatively high prevalence of contact dermatitis to PABS. Patients should begin with preparations that block UVA and UVB. Sunscreens can be locally irritating (especially those that contain PABA); patients may need to try several preparations to find one that is not irritating, drying, or staining and that stays on well. Cosmetic preparations of concealing makeup that cover disfiguring lesions and also contain products that block UV light are also listed in Table 76-1. Local glucocorticoids, including topical creams and ointments and injections into severe skin lesions, are also helpful in lupus dermatitis. 15, 16 Patients with disfiguring (discoid) or extensive lesions should be seen by a dermatologist, because management of severe lupus dermatitis can be difficult. Because topical steroids, especially fluorinated preparations, can cause skin atrophy, depigmentation, telangiectasia, and fragility, care should be taken to choose the correct preparations for the involved area. Facial lesions should be treated with low- to medium-potency nonfluorinated preparations (hydrocortisone, desonide); trunk and arm lesions with medium-potency fluorinated preparations (betamethasone valerate, triamcinolone acetonide); and scalp lesions with medium-potency preparations administered as lotions. Hypertrophic lesions elsewhere and disabling lesions on the palms and soles should be treated with high-potency topical glucocorticoids (betamethasone dipropionate, clobetasol). 15, 16 Continuous use of high-potency creams should be limited to 2 weeks, if possible, after which time less-potent preparations should be substituted for a brief time, or topical steroid therapy could be stopped altogether. Because skin lesions often worsen when topical therapies are discontinued, additional strategies may be required.
An alternative to topical steroids is topical tacrolimus, which is FDA-approved for contact dermatitis. Tacrolimus inhibits T cell activation locally. Use of 0.1% cream on lesions twice a day for 3 weeks has been repeated in open trials as effective in some patients for molar SLE rash, discoid lupus, and subacute cutaneous lupus. 16, 16a
Antimalarial agents are useful in many patients with lupus dermatitis, whether the lesions are those of SLE, subacute cutaneous lupus, or discoid lupus. 8, 16, 17, 18, 19 Antimalarials have multiple sunblocking, anti-inflammatory, and immunosuppressive effects. They may be immunosuppressive as a result of binding to lysosomal cell membranes, where they alter pH with subsequent impairment of protein process to peptides, assembly of the α- and β-chains of HLA class II molecules, and of transport of mature class II molecules containing peptides to the surfaces of antigen-presenting cells (APC). Thus, T cell activation is impaired. In addition, antimalarials reduce the release of interleukin 1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α) from monocytes and macrophages, and of IL-2 and interferon-γ (IFN-γ) from T cells. They also bind melanin and serve as sunscreens, and they have antiplatelet and cholesterol-lowering effects. All these properties may be beneficial to patients with SLE.
A controlled trial of hydroxychloroquine in patients with stable lupus showed that replacement of the antimalarial agent with placebo resulted in a significant increase in flare-ups, some of which were serious. 9 In addition, multiple open studies of hundreds of patients with discoid lupus erythematosus (LE), SLE, or subacute cutaneous LE have reported that 60 to 90 percent of patients with cutaneous lupus have good to excellent responses to antimalarials. 8, 16 Higher doses of each agent give earlier responses, and a larger proportion of patients improve. (Higher doses are more toxic.) Responses to chloroquine and quinacrine are usually demonstrable within 1 to 3 months; responses to hydroxychloroquine may require 3 to 6 months. Antimalarials may be steroid sparing. Recommended initial doses of antimalarials are as follows: hydroxychloroquine, 400 mg daily; chloroquine phosphate, 500 mg daily; and quinacrine, 100 mg daily. Higher doses can be given for brief periods (2 to 4 weeks). After disease is well controlled, the drugs can be slowly tapered. Daily doses can be reduced, or the drug can be given less frequently (e.g., a few days each week). The combination of hydroxychloroquine (or chloroquine) and quinacrine is probably synergistic and can be used in patients refractory to single-drug therapy.
Toxicities of these agents are important but infrequent in comparison with other agents used to treat SLE. 8 Retinal damage is the most important; it can occur in up to 10 percent of patients receiving chronic chloroquine therapy but in less than 5 percent of those receiving hydroxychloroquine. Regular ophthalmologic examinations with appropriate special testing can identify retinal changes early. If changes occur, antimalarial therapy should be stopped or the daily dose decreased. This strategy substantially lowers the incidence of clinically important retinal toxicity. Other significant adverse events associated with all the antimalarials include gastrointestinal disturbances (nausea, diarrhea, weight loss), rashes, peripheral neuropathies, and myopathies of skeletal and cardiac muscles. Quinacrine is associated with aplastic anemia, especially in patients who experience an antecedent lichen planus-like rash. 8 Pigment changes are common with quinacrine (usually a yellow discoloration of skin). They occur less frequently with chloroquine and hydroxychloroquine, which can cause depigmentation, hyperpigmentation, and blue-black discoloration of skin, nails, and mucous membranes. If neuropathies or myopathies develop, antimalarials should be discontinued; skin changes are usually tolerated by patients (in the case of quinacrine, any dermatitis other than pigment changes or lupus dermatitis should cause the physician to discontinue treatment). The use of antimalarials during pregnancy is controversial, with conflicting reports of fetal damage and of good outcomes; most reports indicate no adverse effects on the fetus. 18 Use of antimalarial agents in lupus is reviewed in Table 76-2.
For individuals with lupus rash resistant to antimalarials and other conservative strategies, systemic therapy with retinoids such as isotretinoin or topical therapy with tretinoin have been beneficial. 16, 17 Initial doses of 1 mg/kg divided into two daily doses are recommended; within a few weeks response occurs and the dose should be tapered. Discontinuing the therapy is often followed by flare of skin lesions. Systemic retinoids are teratogenic, cause cheilitis in most patients, and elevate cholesterol and triglyceride levels in some. Patients resistant to antimalarials and retinoids may require systemic glucocorticoids, which improve lupus skin lesions of any type.
Additional treatments, which should be considered experimental for dermatologic lupus because there are no controlled prospective trials, include dapsone, thalidomide, and tacrolimus (FK506). 16, 19, 20, 21, 22 Dapsone has been used in discoid lupus, urticarial vasculitis, and bullous LE lesions with some success. The recommended initial dose is 50 mg daily; that can be increased to 100 mg daily for a few weeks if needed. Dapsone has significant hematologic toxicities (including methemoglobinemia, sulfhemoglobinemia, hemolytic anemia, and aplastic anemia) as well as exfoliative dermatitis, acute tubular necrosis, peripheral neuropathy, and hepatotoxicity. It can occasionally worsen the rashes of LE. Many experts have reported success with thalidomide therapy in approximately 50 percent of individuals with refractory skin lesions of SLE or subacute cutaneous lupus (as well as for other manifestations of active lupus including refractory aphthous-type mouth ulcers). 20, 21 Low doses (e.g., 50 mg twice a day) may be effective and are reported to be substantially less toxic than higher doses. Adverse effects include, most importantly, teratogenesis, so use of thalidomide in the United States is severely restricted and is provided only after contact with and screening by the manufacturer. Fertility control must be maintained. Other side effects may include peripheral neuropathy, neutropenia, hypertension, bradycardia, and seizures, along with drowsiness, dizziness, diarrhea, and fever. Topical tacrolimus (FK506) interferes with cutaneous T cell function: The preparation is approved in the United States for treatment of atopic dermatitis, at 0.03 or 0.1 percent concentrations applied twice a day. There are a few reports of efficacy in refractory cutaneous lupus. 22
Some steroid-resistant cases of lupus dermatitis have improved when treated with cytotoxic drugs such as asazathioprine or MTX. 16, 17 I have found MTX particularly useful in this situation; I begin doses of 10 mg/week and escalate the dose every few weeks if needed (as for management of patients with rheumatoid arthritis [RA]), then taper slowly if efficacious. Folic acid supplementation is recommended. Side effects of these cytotoxic drugs include bone marrow suppression (particularly leukopenia), hepatotoxicity, increased infections (including herpes zoster), nausea and diarrhea, and aphthous stomatitis.
FATIGUE AND SYSTEMIC COMPLAINTS
Fatigue is common in patients with SLE and may be the major disabling complaint. It reflects multiple problems, including depression, sleep deprivation, and fibromyalgia, as well as disease activity. 23, 24 Some patients are improved by treatment of any of these aspects, with glucocorticoids and antimalarials sometimes suppressing this manifestation, at least in part. Complaints of fatigue should be approached sympathetically, with recommendations for increased rest periods and flexibility in working hours when possible. Fever and weight loss, if mild, can be managed with the conservative approaches outlined in the preceding paragraphs. When severe, systemic glucocorticoid therapy is necessary.
SEROSITIS
Episodes of chest and abdominal pain may be secondary to lupus serositis. In some patients, complaints respond to salicylates, NSAIDs (indomethacin may be best), antimalarial therapies, or to low doses of systemic glucocorticoids, such as 15 mg/day. 1 In others, systemic glucocorticoids must be given in high doses to achieve disease control.
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