Nonsteroid Treatment of Systemic Lupus Erythematosus

Chapter 44 Nonsteroid Treatment of Systemic Lupus Erythematosus





NONSTEROIDAL ANTI-INFLAMMATORY AGENTS


Many patients with SLE can be treated initially with bed rest. Up to 80% of patients with SLE are treated at some time with nonsteroidal anti-inflammatory drugs (NSAIDs) for musculoskeletal symptoms, headaches, or inflammation of mucous membranes and serositis1 (Table 45.1). Standard anti-inflammatory agents range from aspirin, aspirin-like substances, to nonsteroidal anti-inflammatory agents. Therapeutic doses of these agents suppress inflammation by inhibiting the prostaglandin pathways and the cyclooxygenase enzymes in a selective or nonselective manner.2,3 The cyclooxygenase enzymes are labeled type 1 or type 2. Newer agents are cyclooxygenase-2 suppressants. The safety of the Cox-2 selective drugs and all other members of the class of Cox inhibitors is now questionable, subsequent to the description of increased cardiovascular complications such as acute myocardial infarction and hypertension.46


Although such agents are known to inhibit prostacyclin, an essential component of the normal clotting process,7 enhanced clotting has not been shown with these agents in SLE patients with or without coagulopathies. Nevertheless, agents are in development and currently on the market that retain the property of prostacyclin inhibition. Despite the finding that patients with SLE have a higher incidence of atherosclerotic heart disease, there are no data on the use of these drugs in SLE patients and enhanced cardiovascular risk.8,9 Despite the lack of data, it would be prudent to avoid such agents in the treatment of patients with SLE who are at cardiovascular risk. These include all patients with SLE and rheumatoid arthritis who are at risk of developing accelerated vascular disease.


Perhaps the greatest risk for SLE patients ingesting NSAIDs of both the selective and nonselective variety can be summarized as well-known renal toxic effects. Such agents lower glomerular filtration (GFR), and have significant effects on the ascending limb of the loop of Henle and the renal medulla, causing hypertension.1013 There is also an effect from sodium retention. Azotemia quickly appears in patients with GFR less than 50 mL/min. Hypertension is also a risk in patients on any NSAID, and is dose dependent for both the Cox-1 and Cox-2 selective and nonselective agents.14


Cutaneous and allergic reactions have been seen in SLE patients ingesting these agents. These reactions include hepatotoxicity. Ovulation and pregnancy have also been affected by cyclooxygenase inhibitors.15,16 In animal model knockouts for the cyclooxygenase gene, there is total infertility. There are also modest data showing that animals exposed to high levels of the Cox-2 inhibitors fail to reproduce in comparison to their unexposed littermates.


Finally, patients with SLE have a higher sensitivity to sulfur-containing drugs.17 One drug of the selective Cox-2 variety, Celecoxib, contains a sulfonamide moiety that produces an allergic reaction in many SLE patients.18 Severe allergic reactions to other NSAIDs have not occurred in SLE patients.



ANTIMALARIAL DRUGS


Some of the most effective low-toxicity agents available to SLE patients are agents of the antimalarial class, including hydroxychloroquine, chloroquine, and quinacrine. The mechanism of action of these agents remains unknown.


These agents are effective primarily as weak immunosuppressives. However, they have the added properties of lowering serum cholesterol and acting as an anticlotting agent.19 The antimalarials have immunomodulatory and anti-inflammatory properties. In vitro effects on macrophages and B cells have been described. Membrane phospholipids, phagocytosis, and the synthesis of certain cytokines have been inhibited with these agents. The secretion of interleukin-1, interleukin-6, and tumor necrosis factor-alpha is thought to be inhibited by these agents due to the effect of the drug on post-translational events. The class activity within both the primary and secondary phospholipid syndrome revolves around the inhibition of fibrinogen binding, thrombin-induced platelet responses, and platelet aggregation.20 Despite all of these effects, these drugs are generally not useful for patients with severe SLE. The antimalarial drugs are very useful in the treatment of cutaneous SLE.21 These drugs are particularly effective in the early mild to moderate systemic disease, and they are often used in conjunction with steroids or chemotherapeutic agents.22 Hydroxychloroquine is also useful as a single agent in the treatment of antiphospholipid syndrome. Hydroxychloroquine is perfectly safe to use in pregnant SLE patients.23 Chloroquine and hydroxychloroquine are useful drugs in the treatment of discoid lupus. Clofazimine has also been used in place of hydroxychloroquine.24


The major toxicity of these agents is ophthalmologic. Corneal anesthesia and deposition of pigment in the retina are primary manifestations of toxicity.25 In the United States, patients with SLE who begin on these agents should have an ophthalmologic examination every 6 months26 (see Chapter 39) Additionally, these agents should not be used in anyone with glucose 6-phosphate dehydrogenase (G6PD) deficiency, underlying liver disease, or porphyria.


Hydroxychloroquine is prescribed at 200 mg twice daily, although lower or higher doses might be used, and depend on both the size of the patient and tolerability.27 The hydroxychloroquine dose should not exceed 6.5 mg/kg/d. Chloroquine is used at concentrations of 250 mg/d and the same safety precautions apply. However, chloroquine is not routinely used at present because of the overall safety of the drugs hydroxychloroquine and quinacrine with respect to ocular toxicity. Both of these agents are often used in conjunction with quinacrine at 100 mg/d. However, Atabrine and Mepacrine, both brand names for quinacrine, are not widely available at this writing (Table 45.2).



DAPSONE


Dapsone is a sulfone drug used primarily to treat leprosy. However, it is useful in certain forms of refractory skin lupus such as bullous SLE.28 It is also particularly useful in the treatment of lupus profundus. Some patients will be allergic to the sulfone component of dapsone, and care must be used when using this drug at doses above 100 mg/d. Use of this drug can result in long-lasting remission. Dapsone has been useful in one study in the therapy of thrombocytopenia.29 Caution must be exercised in prescribing this drug to patients with G6PD deficiency. In addition, hemolytic anemia resulting from dapsone can be a problem.

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Jul 24, 2018 | Posted by in MUSCULOSKELETAL MEDICINE | Comments Off on Nonsteroid Treatment of Systemic Lupus Erythematosus
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