Nonstandard and adjunctive medical therapies for systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is an acute and chronic autoimmune inflammatory disease that affects women predominantly. Peak incidence occurs during the reproductive years, and sex, sex hormones, and fertility influence disease pathogenesis, treatment options, and therapeutic decisions. Initial SLE disease manifestations in more than 50% of patients include constitutional symptoms, arthritis, and cutaneous disease. Progressive, cumulative disease activity and damage eventually produce renal, cardiopulmonary, or neuropsychiatric involvement in more than 50% of patients, although constitutional symptoms, arthritis, and cutaneous disease remain the most common SLE disease manifestations(1-3). Standard medical therapy for active lupus includes nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, hydroxychloroquine, azathioprine, or cyclophosphamide, alone or in combination(4-15). Although standard SLE management is relatively safe and successful, lupus patients may have recalcitrant or recurrent symptoms, may wish to avoid potential treatment side effects, or may develop intolerable adverse or toxic effects necessitating discontinuation of treatment(16-18). In a review of cytotoxic therapy use in lupus patients, 40–50% of cytotoxic courses (azathioprine, cyclophosphamide, or methotrexate) were terminated because of side effects, lack of efficacy, or patient preference(18). Persistent symptoms of lupus activity and adverse effects of standard therapy have led to the continued search for SLE treatments that offer a therapeutic advantage. These nonstandard treatments must be efficacious, provide an additive or synergistic benefit, or encompass untreated or recalcitrant lupus disease, yet have little additional toxicity. Several potential nonstandard or adjunctive SLE treatments have been identified; however, it must be emphasized that the majority of these potential treatments have not been compared to standard treatments in randomized, blinded trials. Hence, acceptance of these treatments has likely been impaired by the success of standard therapies, the lack of comparative data, unfamiliarity with or novelty of the agent or manipulation, concern for additional toxicities, availability of the treatment, or expense. The use of many of these agents has been reported in conjunction with standard treatments for refractory lupus disease activity, for unusual disease manifestations, or as less toxic therapy than traditional agents. Nevertheless, reports of successful nonstandard or adjunctive SLE therapies broaden the therapeutic armamentarium, facilitate individualization of treatment regimens, and provide therapeutic options to those patients unresponsive to or intolerant of standard lupus management. In a recent review of guidelines for the management of SLE(1), only 5 traditional agents and 1 nonstandard agent were listed as primary treatment for SLE disease manifestations. In the present review, additional nonstandard or adjunctive SLE treatments published in peer-reviewed medical literature and, in most cases, readily available to the clinical rheumatologist have been accumulated. These additional treatments can be categorized into oral and parenteral immunosuppressives, biologic agents and manipulations, hormonal therapies, and SLE miscellaneous and symptom-specific treatments. There are several exciting new biologic agents and manipulations, such as monoclonal antibodies, B cell tolerization, stem cell transplantation, and immunoadsorption; however, the relative absence of published, peer-reviewed data in the medical literature (exclusive of abstracts) as well as their availability to the practicing rheumatologist preclude their use and extensive review in the present article. The reader is referred to current reviews for a discussion of their status and use(4-7). Therefore, in this review, the medical evidence, treatment data, SLE indications, dosing, and side effects for more than 20 nonstandard and adjunctive SLE therapies published in peer-reviewed medical literature are described and approaches to their utilization are considered. Oral immunosuppressives that have potential usefulness as nonstandard or adjunctive therapies include methotrexate and lymphocyte-specific drugs such as cyclosporine, mycophenolate mofetil, tacrolimus, and cladribine. Parenteral immunosuppressives include intravenous immunoglobulin (IVIG) or antithymocyte globulin (ATG). The use of these and other immunosuppressive agents in the management of SLE is described below and summarized in Table 1. Sulfasalazine, though efficacious in some studies, has been reported to induce lupus manifestations(19, 20), whereas gold(21), thalidomide(22), and retinoic acids have been reserved primarily for treatment of recalcitrant cutaneous disease and are reviewed elsewhere(23). Methotrexate (MTX) is an antagonist of folate metabolism that reduces DNA synthesis and lymphocyte proliferation and function(24). Its use in SLE has been evaluated in several open-label studies(24-30) documenting response rates of 50–70% in the treatment of skin rash, arthritis, pleurisy, proteinuria, or steroid-sparing effects. In a series of 16 SLE cases treated with MTX, improvement was noted in 57% with symptoms of arthritis, rash, serositis, fatigue, and renal disease, and facilitation of a reduction in required steroid dosage was observed(29). In 5 patients with active SLE (3 with renal disease), MTX at dosages of 5–20 mg/week improved renal function and reduced proteinuria, suppressed autoantibodies, decreased arthralgias, and also facilitated corticosteroid tapering. MTX was used in combination with steroids, antimalarial drugs, and azathioprine(27). In a 2-year open-label trial, 12 patients with active lupus were treated with 5–15 mg/week. Eight patients had marked reduction in arthritis as the primary outcome measure; however, 3 patients had to discontinue MTX because of hepatitis, nausea, and mucositis, respectively. No significant changes in serologic measures of lupus disease activity were seen(28). MTX administration to 22 patients with active SLE (excluding renal and central nervous system [CNS] disease) produced a significant reduction in global SLE disease activity measures, and steroid reduction was facilitated without marked MTX side effects. Two patients did develop a mild, transient hepatitis. Erythrocyte sedimentation rate (ESR) was reduced, but no other serologic measures of lupus disease activity were altered. Dosages ranged from 7.5 to 15 mg/week. Lupus patients treated with MTX may develop significant hepatitis or gastrointestinal (GI) side effects, particularly when MTX is used in combination with diuretics or NSAIDs(26). A recent double-blind, placebo-controlled trial of MTX in mild to moderate lupus confirmed its efficacy in the treatment of musculoskeletal and cutaneous lupus, although 70% of patients reported dyspepsia(24). Therefore, MTX may be used as a nonstandard or adjunctive treatment of mild to moderate SLE disease activity, particularly arthritis, with modest success and a definite risk of side effects, mainly dyspepsia and transaminitis. A new therapeutic approach to CNS lupus, which utilizes MTX with intrathecal dexamethasone, has been proposed(31). Cyclosporine has multiple immunosuppressive actions, but it is particularly effective in blocking T cell IL-2 production and IL-2 receptor expression, thereby suppressing immune responses(16). Cyclosporine is effective in reducing SLE disease activity as evidenced by improvements in arthralgias, proteinuria, and steroid dose but had little effect on anti-DNA antibodies, complement levels, or glomerular filtration rates(32-39). A significant reduction in proteinuria and preservation of renal function over 48–64 months has been documented (33, 34), including a biopsy-proven reduction in glomerular disease activity indices (DAI)(33). In comparing microemulsion cyclosporine to corticosteroids and cyclophosphamide in pediatric lupus nephritis in an open, randomized study, cyclosporine was as effective as cyclophosphamide in reducing heavy proteinuria without significant changes in renal function, liver function, or lipid profile(35). A recent report(40) has further supported and extended the use of cyclosporine for membranous lupus nephritis with promising results. However, these potential benefits must be balanced against the potential for nephrotoxicity, dose-dependent reductions in renal function, and the development of hypertension(32-39). Cyclosporine dosages ranged from 3 to 10 mg/kg/day; however, side effects of hypertrichosis, hypertension, and gum hypertrophy were relatively common in all studies(32-39). Therefore, in SLE patients with progressive arthritis or renal disease and heavy proteinuria, cyclosporine is a valid nonstandard therapy, although hypertrichosis in a predominantly female population, hypertension, and nephrotoxicity remain significant concerns. Mycophenolate mofetil is hydrolyzed to mycophenolic acid, which selectively and reversibly blocks lymphocyte inosine monophosphate dehydrogenase, thereby inhibiting purine synthesis, lymphocyte proliferation, and T cell dependent antibody responses. This agent has been used extensively in preventing renal allograft transplant rejection with little toxicity, although nausea, vomiting, and diarrhea are common side effects(16). Large-scale studies in lupus patients have not been conducted, but its beneficial effects in preventing and reducing autoimmune disease in murine lupus are well documented(41-43). Emerging evidence has demonstrated a beneficial effect of mycophenolate mofetil in cyclophosphamide-resistant lupus nephritis(44-48) as well as other disease manifestations, although proteinuria may not be significantly reduced(48). In an evaluation of 12 SLE patients with relapsing or cyclophosphamide-resistant lupus nephritis, combination mycophenolate mofetil and corticosteroid therapy significantly reduced proteinuria and creatinine and, in some patients, improved hypocomplementemia and elevated anti-DNA(44). In a preliminary report of 22 patients with active SLE unresponsive to high-dose glucocorticoids, mycophenolate mofetil (2000 mg/day) significantly improved SLE disease activity index (SLEDAI) score, reduced corticosteroid dose, and induced serologic improvement(48). Typical reported dosages have been 500–1000 mg twice a day. Mycophenolate mofetil has potential efficacy as a nonstandard or adjunctive agent to azathioprine or cyclophosphamide in the treatment of SLE and lupus nephritis, although its long-term benefit remains to be proven. Currently, there is a therapeutic trial comparing mycophenolate mofetil to cyclophosphamide therapy in the treatment of class IV lupus nephritis(49). [Note added in proof: A recent published investigation has demonstrated that the combination of mycophenolate mofetil and prednisolone is as effective as a regimen of cyclophosphamide and prednisolone followed by azathioprine and prednisolone for the treatment of diffuse proliferative lupus nephritis. Eighty-one percent of the 21 patients treated with mycophenolate mofetil and prednisolone had a complete remission as defined by the study parameters. Improvements in the degree of proteinuria and the serum albumin and creatinine concentrations were similar in the 2 groups. Chan TM, Li FK, Tang CSO, Wong RWS, Fang GX, Ji YL, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. N Engl J Med 2000;343:1156–62.] Tacrolimus (FK506) suppresses immune reactivity by blocking T cell activation and cytokine response(16). Tacrolimus has been used successfully in the treatment of lupus as documented by a case report of 3 patients resistant to cyclophosphamide or cyclosporine treatment(50). Briefly, tacrolimus reduced arthralgias, pleurisy, and renal disease and was well tolerated without significant side effects in this very limited series of patients. The potential for nephrotoxicity remains a concern and renal function should be closely monitored(16). 2-chloro-2'-deoxyadeno- sine (cladribine) has been used successfully in a limited number of SLE patients(51-54). This purine analog is immunosuppressive by inhibiting T cell function(16) and its administration to SLE patients reduced disease activity. In a pilot study to determine safety and tolerability, cladribine administration produced a peripheral lymphocytopenia and a reduction in proteinuria, particularly when given as a 7-day continuous intravenous infusion(51), although in 2 additional reported cases it had questionable efficacy and was rescued by mycophenolate mofetil treatment(52). Infections appear to be a common complication of cladribine administration(51, 52). Vincristine, a vinca alkaloid, interferes with microtubule assembly and inhibits cell proliferation(16). Its limited use in SLE patients with thrombocytopenia(55, 56) suggests that is it is a well tolerated adjunctive or nonstandard therapy, particularly for this lupus manifestation. Zileuton, a 5-lipoxygenase inhibitor, was evaluated in 40 SLE patients with constitutional, articular, and cutaneous manifestations at a dose of 600 mg 4 times per day in an 8-week randomized, double-blind, placebo-controlled trial. Systemic Lupus Activity Measure (SLAM) score improved significantly although there was no significant improvement in subscores. Moreover, zileuton's role in lupus nephritis or cerebritis was not defined(57). Nevertheless, zileuton was well tolerated, suggesting a role for its use as adjunctive or nonstandard therapy in mild to moderate SLE. A recent reexamination of chloroquine in SLE was reported in a double-blind, placebo-controlled trial and it was shown to prevent disease reactivation and facilitate steroid tapering(58). Accordingly a revisitation of quinacrine, traditionally used as an adjunctive or synergistic agent to antimalarial therapy, is appropriate. Quinacrine has an established record of efficacy in the treatment of SLE(59, 60) with a relatively rapid onset of action, but its adverse side effects, which include dermatitis, GI symptoms, and a chance of aplastic anemia, discourage its widespread use(59). IVIG has traditionally been used in immunoglobulin deficiency disorders and with corticosteroids in the treatment of idiopathic thrombocytopenia purpura. Although the exact mechanism of action is obscure, it has been postulated that IVIG modulates immune complex deposition, anti-DNA antibodies, or anti-idiotype interactions(16, 61). In an open-label trial of 12 patients with disease refractory to standard treatment(62), IVIG (0.4 g/kg/day for 5 consecutive days over 6–24 months) significantly reduced disease activity (measured by an unvalidated scoring instrument), ESR, and proteinuria. Case reports(63-65) also suggest efficacy of IVIG in the treatment of SLE. Adverse side effects such as nausea, flushing, and musculoskeletal pain are uncommon, and renal failure has been rarely reported(66). Opportunistic infections have not been reported with its administration. It is apparently efficacious and relatively nontoxic, although the main prohibitions to its more widespread use are cost and availability(61). In a report of patients with refractory SLE, T lymphocyte depletion was achieved using combination intravenous ATG and peroral azathioprine or cyclosporine(67). This treatment produced prompt and prolonged improvement of autoimmune hemolytic anemia, arthritis, cutaneous disease, and nephritis, but, in this limited number of patients, its administration was associated with infection. In a separate case report(68), severe SLE responded to ATG and cyclosporine but was also complicated by infection. Adverse side effects may also include anaphylaxis or serum sickness(16). Its usefulness is likely limited to severe, recalcitrant SLE disease activity. The improved understanding of the pathogenesis of SLE has led to specific molecular and biologic agents and manipulations directly targeting SLE immune complex formation and T and B cell function. However, reports of human administration of many of these immunobiologic treatments have not yet been published in peer-reviewed medical literature (exclusive of scientific meeting abstracts), although their potential usefulness and status are reviewed on an annual basis(4-6). However, the use of these agents and manipulations in SLE remains primarily experimental in nature, is restricted to tertiary care institutions and the most severe cases of SLE, is unavailable, or is prohibitively expensive for practical application. These approaches (Table 2) include monoclonal antibodies, B cell tolerization, stem cell transplantation, immunoadsorption, and plasmapheresis. Current research initiatives and novel therapeutic trials in lupus are summarized in alternative sources(49). Several antibody manipulations directed against cytokines and T lymphocyte molecules including, but not limited to, IL-6, IL-10, IFNγ, ICAM, and LFA-1 have been shown to alter the disease course of murine lupus(69). Similar studies in human SLE have not been as successful or have not reached peer-reviewed publication status. Nevertheless, there is, for example, abnormal expression of CD40 ligand on SLE lymphocytes(70) and this has led to the development of monoclonal antibody therapy directed at this target. Murine lupus has responded beneficially to this treatment(71) and published clinical studies will likely be forthcoming. LJP 394 is a novel immunomodulating B cell tolerizing agent administered as an intravenous or bolus injection(72) that has been shown to delay murine lupus disease progression(73). The safety of its administration has been demonstrated and it has been shown to reduce anti-DNA antibodies in 2 patients, although transient increases in some complement split products were noted(73). Its efficacy in the treatment of SLE appears promising but remains to be shown in peer-reviewed literature. Human bone marrow transplantation and stem cell transplantation in the treatment of SLE has been used successfully and resolves SLE disease activity(74-78). Recently there has been a focus on autologous stem cell transplantation. However, the prohibitive expense and the potential morbidity and mortality associated with bone marrow or stem cell transplantation restrict this treatment, at the current time, to the most severely ill SLE patients. Immunoadsorption using dextran sulfate cellulose columns removes pathogenic antibodies. In an open-label clinical study of 19 patients, an average of 4 apheresis treatments significantly reduced SLEDAI disease activity by approximately 60%(79) and may have provided a steroid-sparing effect. No major clinical complications have been observed, although this nondrug therapy remains controversial because of its novelty and availability. Plasmapheresis remains a therapeutic option for the treatment of severe, life-threatening SLE despite studies that show that plasmapheresis in addition to the standard regimen of corticosteroids and cyclophosphamide does not improve clinical outcome(80, 81) and that plasmapheresis increases the occurrence of life-threatening bacterial and viral infections compared with standard therapy alone(82). Nevertheless, there are reports that plasmapheresis, usually synchronized with standard immunosuppressive therapy, is efficacious in some patients(84-87). The female preponderance of autoimmune disease and the sexual differences in immune response have been attributed to hormonal differences between men and women. This is most evident in SLE and has resulted in a number of investigations of hormonal immunotherapy. Efficacy in treating SLE disease activity has been observed but not demonstrated in large-scale studies(88-90). The use of hormonal agonists and antagonists in SLE is described below and summarized in Table 3. Dehydroepiandrosterone (DHEA) is a weak androgenic steroid precursor of testosterone that appears to inhibit cytokine production(16). Its use in SLE is well documented and reviewed(91-97). Successful treatment of active SLE by DHEA, 200 mg/day, was initially suggested in an open-label, uncontrolled examination of 10 female lupus patients. After 3–6 months of treatment, global lupus scores were decreased, prednisone requirements were reduced, and proteinuria was lowered in 2 of 3 patients(91). In a double-blind, placebo-controlled, randomized clinical trial of 3 months duration, DHEA decreased global lupus disease activity, lupus flares, and concurrent prednisone administration. DHEA did not significantly change laboratory measures of disease activity but did increase serum concentrations of DHEA, DHEA sulfate, and testosterone; however, these hormone concentrations did not correlate with or predict a clinical response(92, 93). DHEA was administered concomitantly with corticosteroids and hydroxychloroquine. Moreover, DHEA has been successful in reducing difficult-to-treat lupus symptoms such as overall well-being, fatigue, and lack of energy(91). In a prospective, open-label, uncontrolled longitudinal study of 50 female lupus patients, DHEA, at doses of 50–200 mg/day, was associated with improvement in several lupus global disease activity scores, a reduction in prednisone dosage, and an increase in serum testosterone concentrations that was sustained over the entire treatment period. However, 58% of patients discontinued DHEA within the 12-month treatment period because of lack of efficacy or androgenic side effects(93). DHEA is relatively well tolerated, but the development of acne and hypertrichosis may preclude its widespread use in a predominantly female population. Its effects on lupus nephritis or cerebritis have not been clearly established. Another androgenic steroid, danazol, has demonstrated effects in SLE, particularly in association with treatment of thrombocytopenia(98-104). Other beneficial effects include reduction in arthralgias and rashes; however, again, androgenic side effects in a predominantly female population preclude its widespread use. Perhaps lower doses of either DHEA or danazol in conjunction with other agents would be most efficacious, although this remains to be proven. The beneficial effects of DHEA and danazol are in contrast to effects of the anabolic steroid 19-nortestosterone, which is relatively devoid of androgenic properties. This steroid did not improve and even worsened lupus disease activity(105). A relationship between prolactin, autoantibodies, and active autoimmune disease has been established and reviewed(106-109). Bromocriptine is a dopamine agonist that suppresses secretion of the immunostimulatory pituitary hormone prolactin(110) and may act directly on B cells to suppress antibody production(111). In case reports(112-114) and an open-label, uncontrolled investigation(115), bromocriptine has been shown to suppress global measures of SLE disease activity, as well as rash and arthralgias, while facilitating reduction in corticosteroid use. Bromocriptine had the added benefit of reducing fatigue and lupus headaches and was associated with decreased anti-DNA antibodies and a reduction in cholesterol(115). Its effects on the difficult-to-treat symptom of fatigue have also been documented in the post-polio syndrome(116). Bromocriptine in SLE studies was used at doses of 1.25–7.5 mg/day and benefit was independent of pretreatment serum prolactin concentrations (i.e., bromocriptine helped patients with normal or high prolactin levels). Therapeutic responses appeared optimal at serum prolactin concentrations < 3 ng/ml. Bromocriptine was used successfully in combination with hydroxychloroquine, corticosteroids, and NSAIDs. Side effects included nasal stuffiness and increased dreaming. The benefits of bromocriptine administration to SLE patients have recently been confirmed in a double-blind, randomized, placebo-controlled study of 66 SLE patients. Patients were treated at a fixed dosage of 2.5 mg of bromocriptine daily without regard for prolactin concentrations. Mean serum prolactin concentrations were significantly reduced during bromocriptine administration. Bromocriptine was administered concomitantly with corticosteroids, antimalarial agents, or cytotoxic drugs. Over a 12-month study period, the SLEDAI score was significantly reduced at 5 months of treatment and the mean number of lupus flares/patient/month was significantly reduced. Twenty-two percent of patients left the study because of side effects not directly attributable to bromocriptine(117). In a preliminary report comparing bromocriptine to hydroxychloroquine, bromocriptine was as efficacious as hydroxychloroquine in suppressing non–organ-threatening SLE(118); however, its efficacy in the treatment of lupus nephritis or cerebritis has not been established. Although its use in lupus pregnancy has not been defined, bromocriptine has been used extensively in pregnant patients without teratogenic effects(110) and, therefore, may be an agent available for use in the pregnant lupus patient, who has high prolactin levels in the presence of active lupus(119). Traditional concepts have suggested that female sex hormones are immunostimulatory and exacerbate SLE(89-91), but recent evidence has suggested that estrogen may be immunosuppressive, particularly to T cell function(120, 121). Although the estrogen receptor blocker tamoxifen has been clearly successful in modifying models of murine SLE(122, 123), a limited trial of tamoxifen in 11 SLE patients showed no effect on lupus disease activity and exacerbated activity in 2 patients(124), possibly because of agonistic effects on lymphocyte function(125, 126) or the blockade of estrogenic immunosuppressive effects(120, 121). In contrast, administration of norgestrel/ethinyl estradiol, a combination progesterone/estrogen contraceptive, has been shown to have efficacy in treating cyclical acute cutaneous lupus rashes in a limited number of cases(127). Clearly, estrogen and progesterone have immunomodulatory effects(128); however, their specific effects on lupus disease activity are not clearly established. Moreover, estrogen increases secretion of the immunostimulatory hormone prolactin, demonstrating the need for further delineation of hormonal effects and their use in immunotherapy. Recent reviews of oral contraceptive use in SLE emphasize the absence of controlled trials demonstrating exacerbations of SLE disease activity associated with hormone administration, the efficacy and potential benefits of oral contraceptive use in stable or inactive SLE, and the risk of exacerbating renal disease or hypercoagulability, especially in the setting of antiphospholipid antibodies(129, 130). Many of the aforementioned confounding problems will be answered by the ongoing National Institutes of Health–funded SELENA (Safety of Estrogens in Lupus Erythematosus: National Assessment) trial(49). In the persistent pursuit of hormonal immunotherapy, the effects of a gonadotropin-releasing hormone (GnRH) agonist (buserelin) have been examined in SLE patients. GnRH agonists down-regulate gonadotropin secretion in such a way that a reversible “medical oophorectomy” is induced, markedly reducing serum estradiol levels(16, 131). In an open-label case report of 6 normally menstruating SLE patients treated with buserelin 200 μg/day subcutaneously, a marked reduction in plasma 17-β estradiol was documented at 6 weeks of treatment. No significant side effects were noted with the exception of hot flashes. Four of 6 patients experienced clinical and serologic improvement, which included reductions in fatigue, arthralgias, rash, proteinuria, anti-dsDNA antibodies, and corticosteroid dose, and improvements in hypocomplementemia. Buserelin was administered concomitantly with corticosteroids, antimalarial drugs, and azathioprine(131). Although long-term suppression of estrogens may lead to osteoporosis(16), this effect can be counteracted by the use of calcitonin or alendronate. In contrast, lueprorelin, a gonadotropic releasing hormone analog, which increases follicle-stimulating hormone (FSH), luteinizing hormone (LH), and serum estrogen, has been reported to exacerbate lupus nephritis(132), as have ovulation induction regimens(133-135). Cyproterone, a synthetic hydroxyprogesterone derivative that possesses antigonadotropic properties, also suppresses ovulation and depresses ovarian estrogen secretion, thereby acting as an oral contraceptive(16). In an open-label, uncontrolled trial of 7 female patients with moderately active SLE, oral cyproterone was administered at a daily dose of 50 mg either continuously or discontinuously(136). Over 27-months study duration, no significant side effects were recorded. The number of clinical exacerbations was lower during the treatment compared with the pretreatment period, in association with a striking reduction in mucositis. A steroid-sparing effect was noted, and this occurred without a change in serologic parameters of lupus disease activity. A significant reduction in the estradiol:testosterone ratio was observed during the treatment period(136). Hence, anti-gonadotropic treatment may be effective treatment for active lupus, although the absence of additional trials and the availability of other agents have limited their use as nonstandard or adjunctive treatment of active SLE. Utilization of these agents will likely be limited to recalcitrant or cyclical disease, as further study is required to understand the role of sex steroids in active SLE. A number of miscellaneous and symptom-specific therapies (Table 4) have been identified that may prove to be useful adjuncts to standard therapy, especially in certain clinical situations. For example, lupus nephritis is accompanied by hypertension in two thirds of diffuse proliferative nephritis and one third of membranous nephritis. Moreover, in patients with SLE, hypertension is a potent independent risk factor for adverse renal outcomes(137). Although several antihypertensive regimens are effective in controlling hypertension and, thereby, retarding progressive deterioration in renal function, there is evidence that angiotensin-converting enzyme inhibitors (ACEI) may be a preferred therapy, based on available data(138-140). In the B/W mouse model of SLE, both enalapril and captopril have been shown to reduce disease activity and delay mortality in comparison with other agents. Captopril was slightly more effective than enalapril in improving murine lupus outcome, possibly because of the reducing action of the sulfhydryl group(141, 142). In an open-label, uncontrolled study examining ACEI-based treatment of hypertension in association with lupus renal disease, captopril controlled blood pressure and improved renal function (increased glomerular filtration rate) in more than 50% of patients (n = 14). Treatment was initiated with a dose of 12.5–25 mg/day and dose was titrated to a reduction of diastolic blood pressure <95 mm Hg (maximum captopril dose of 150 mg/day). Moreover, proteinuria was significantly reduced. If necessary, furosemide or metoprolol was added to achieve the necessary control(138). These anecdotal reports suggest that ACEI may provide benefit to patients with lupus nephritis(138-140); a comparison with benefits that may be provided by other antihypertensives is not available. Additional nonstandard or adjunctive therapies that have been considered for use in the treatment of lupus nephritis include pharmacologic manipulations of prostaglandins. This may be achieved through thromboxane inhibition(143-145), cyclooxygenase 2 (COX-2) inhibition(146), or dietary modification(147-154). In the case of thromboxane inhibition, experimental inhibitors have been shown to benefit human lupus nephritis(143-145) but have not been used widely. In relation to the probable pathogenic role of prostaglandins in SLE, high levels of COX-2 are present in mouse and human lupus kidneys and murine models of lupus nephritis have been suppressed by use of COX-2 inhibitors (reviewed in ref. 146). However, the potential risk for nephrotoxicity and the absence of clinical data in SLE preclude the use of COX-2 inhibitors for any indication other than arthritis at this juncture. A recent report of thrombosis inpatients with antiphospholipid antibodies and selective COX-2 inhibition has raised additional concerns about manipulations of prostaglandins in lupus(147). The potential role of prostaglandins in lupus pathogenesis is further emphasized by studies of dietary manipulation of fatty acids, which have been shown to have dramatic effect on experimental lupus(148-150). The successful extension into clinical practice has been not fully realized(151-155), although a benefit on dyslipidemia has been reported(155) and its subsequent potential impact on cardiovascular disease in SLE must be considered(156-159). Similarly, recent reports of elevated homocysteine in SLE patients as a risk factor for accelerated atherosclerosis(160) have identified another cardiovascular risk factor that could also be potentially modified by dietary intervention(161). Several unrelated nonstandard or adjunctive therapies for special situations exist: UVA-1 ultraviolet phototherapy for cutaneous and systemic disease(162-166), an extensive list of therapies such as retinoids or thalidomide for recalcitrant cutaneous disease(23), dimethylsulfoxide (DMSO) for cystitis(167), lobenzarit or aminoglutethimide administration for systemic disease activity(168, 169), valproic acid/clonidine(170) or bromocriptine(171) treatment for lupus-associated movement disorders, granulocyte–macrophage colony-stimulating factor (GM-CSF) therapy for recurrent infections(172), and administration of fresh frozen plasma (FFP) for complement-deficient SLE patients(173). These reports (Table 4) provide some guidance for atypical and difficult cases as well as insight into the pathogenic mechanisms of this heterogeneous disease. Standard lupus therapy is successful and well established, and it should be used as the primary regimen in most SLE patients. More than 20 additional agents are available for use as nonstandard or adjunctive therapy for individualizing treatment regimens, avoiding potential toxic side effects of traditional therapy, and approaching persistent disease activity (Figure 1). Many of these agents have been used in combination with traditional agents and should be considered as additional or adjunctive therapies to control recalcitrant lupus disease activity. Moreover, the diagnosis and treatment of widely disparate comorbidities, such as fibromyalgia or antiphospholipid antibody syndrome, are also crucial to the successful treatment of lupus patients. Utilization of nonstandard therapies such as mycophenolate, cyclosporine, or IVIG, addition of relatively safe adjunctive treatments such as DHEA or bromocriptine, control of hypertension with ACEIs if indicated, and modification of cardiovascular risk factors may further improve lupus disease activity and long-term outcome. The nonstandard and adjunctive SLE therapies in this review broaden the therapeutic armamentarium and facilitate individualization of treatment regimens to the variable and heterogeneous disease course of SLE. Standard and nonstandard adjunctive therapies for constitutional and organ-specific disease manifestations in systemic lupus erythematosus (SLE). Conventional therapies are listed in the top row and should be tried initially; nonstandard or adjunctive therapies are listed in the second row and could be considered for addition to or instead of standard SLE therapy. CNS = central nervous system; DHEA = dehydroepiandrosterone; NSAID = nonsteroidal anti-inflammatory drug; IVIG = intravenous immunoglobulin. * Severe, diffuse organ system involvement could be considered or referred for bone marrow transplant, autologous bone marrow transplant, or plasmapheresis/immunosuppressive pulse synchronization with their attendant risks. This work was generously supported by the Lupus Foundation of Mississippi.