Chapter 51 Specialized Treatment Approaches and Niche Therapies for Lupus Subsets

Treatment of Patients with Systemic Lupus Erythematosus and End-Stage Renal Disease

Incidence and Prevalence

Patients with end-stage renal disease (ESRD) from chronic systemic lupus erythematosus (SLE) represent 1.5% to 2.0% of all patients on dialysis in the United States and 1% of all patients with lupus.¹^–³ Between 3000 and 4000 patients with lupus are dialyzed annually, which represents 1000 new patients a year, of whom 10% succumb annually. ESRD is more prevalent among patients with lupus who are African Americans, noncompliant, on Medicaid, and underinsured. Because patients with SLE are surviving longer, the incidence of ESRD is increasing. Between 1982 and 1995, the number of patients with ESRD increased from 1.16 to 3.08 cases per million person years, and again to 4.9 cases per million person years in 2004. Patients with SLE who develop renal failure have improved mental well-being but worse physical functioning and general health, compared with patients with lupus but are not in renal failure.

Uremia and Its Reversibility

Uremia was the major cause of death in patients with SLE until the 1960s when dialysis became available. Up to 20% of all patients with SLE developed ESRD in the 1970s and 1980s, and the rate has decreased to less than 10% since that time.⁴^–⁶ Uremia and dialysis are both associated with a decrease in the systemic activity and decreased steroid requirements of SLE in many, but not all, patients. Most disease flares occur during the first year of dialysis. It has been speculated that the toxic effects of uremia on the immune system are responsible for its ameliorative effects on extrarenal disease. The first few months on dialysis appear to be critical. A high mortality rate is observed (approximately 30% to 50%), but many of those who survive either discontinue dialysis or become candidates for transplantation. Patients under 21 years of age have the highest reversibility rates.

Prognosis of End-Stage Renal Disease

The 5-year patient survival rate of those on dialysis has improved from 50% to 70% in the 1970s to 90% in Western Europe at the present time.^7,⁸ Poorer outcomes are noted in men, those with lower levels of socioeconomic attainment, and African-American women. Most deaths are related to infection and vascular access complications, as well as to thrombotic events in patients with antiphospholipid antibodies.

Hemodialysis versus Peritoneal Dialysis

The success of hemodialysis in ameliorating disease activity may result from its ability to remove circulating pathogenic immune complexes, complement, and other factors.⁹^–¹¹ Hemodialysis also has antiinflammatory effects, decreases T-helper lymphocyte levels, and diminishes mitogenic responsiveness. There are a few case reports of new-onset SLE and successful pregnancies in patients with SLE who are on hemodialysis.

Several studies have documented more reactivation of SLE, higher anti–double stranded DNA (anti-dsDNA) levels, more thrombocytopenia, lower albumin levels, and higher steroid and erythropoietin requirements with peritoneal dialysis. In one large study, peritoneal dialysis was associated with poorer survival and more serositis, cytopenias, and serologic activity when compared with hemodialysis. Switching to it from hemodialysis could reactivate lupus. In a gender-matched, controlled study comparing nondiabetic patients with lupus on peritoneal dialysis with those who did not have SLE, the patients with lupus had a higher infection rate. Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores are higher in patients with lupus on peritoneal dialysis than in those on hemodialysis.

The experience of the author of this chapter is that hemodialysis is preferable to peritoneal dialysis, barring extenuating or unusual circumstances.

Transplantation

Prevalence

Patients with lupus account for 3% of all renal transplantations in the United States.¹²^–¹⁴ Perhaps as a result of medical co-morbidities, patients with lupus and ESRD are less likely than others to be transplanted. Nevertheless, 772 of 32,644 patients who received a kidney transplant in the United States between 1987 and 1994 had lupus nephritis, and 2882 transplant procedures were performed on patients with lupus nephritis between 1995 and 2002; this figure included 254 children.

Graft and Patient Survival

Renal allografts have been performed on a wide scale since 1975. In the 1970s, 2-year graft survival averaged 50%, and now 5-year graft survival averages 70% to 80%.¹⁵^–¹⁶ These survival averages are approximately 10% lower than those in nonlupus controls. Improved outcomes are related to the introduction of cyclosporine, sirolimus, tacrolimus, mycophenolate, newer antibiotics, and more effective antihypertensive interventions. Allograft rejection in patients with SLE is greater among smokers, indigent populations, recipients of cadaveric (versus related donor) kidneys, patients with antiphospholipid antibodies, low serum complement levels, and human leukocyte antigen (HLA) mismatches. Premature cardiovascular disease is common.¹⁷ Outcomes among pediatric populations are similar to those in adults.

Serologic Features and Disease Recurrence

Patients undergoing transplantation may have persistent elevations of antinuclear antibody and anti-DNA antibody titers, as well as reduced complement levels. These serologic abnormalities are of little importance and do not affect the outcome of the graft.¹⁸^–²⁰ Up to one half of transplanted patients with lupus nephritis who undergo biopsy have some evidence for recurrent disease activity, although the activity is usually mild (e.g., mesangial, membranous) and rarely threatens the graft. Isolated case reports of disease recurrence suggest that a disproportionate number of these patients had undergone peritoneal dialysis or had active disease at the time of transplantation. Extrarenal lupus activity is usually quiescent after renal transplantation. One case of de novo SLE in a patient who underwent renal transplantation has appeared.

In conclusion, to achieve the optimal transplant environment, patients should be in remission, be on hemodialysis or no dialysis, and receive an allograft from a living, related donor (Box 51-1).

Box 51-1

Dialysis and Transplantation in Systemic Lupus Erythematosus

1. In up to 10% of patients, systemic lupus erythematosus (SLE) evolves to end-stage renal disease. Their 5-year survival with optimal care is 80% to 90%.

2. Hemodialysis has theoretical advantages over peritoneal dialysis and is associated with fewer infections and, perhaps, less lupus activity.

3. The majority of patients with lupus have disease activity improve if uremic before treatment.

4. Graft survival for patients with SLE in the United States at 1 year is less than the 93.9% national average and is usually in the 80% to 90% range.

5. Transplantation is most successful if lupus is not active at the time of surgery.

6. Patients with a history of antiphospholipid antibody–related events have a poor outcome.

Pregnancy

According to the National Transplantation Pregnancy Registry, 60 pregnancies were reported among 38 patients with lupus.²¹ Although many of the pregnancies were complicated by preeclampsia and hypertension, 77% were successful.

Laser Therapy

Carbon dioxide lasers have been used to treat discoid lupus lesions and telangiectasias. These lesions can be vaporized, but cellular alterations in nonvaporized cells that are several hundred micrometers away may be responsible for decreased disease activity.²² Argon lasers also have been used for atrophic facial scars and telangiectasias, although flares have been reported with its use.²³

Apheresis and Related Technologies

Lymphocyte Depletion: Thoracic Duct Drainage, Lymphocytapheresis, and Total Lymphoid Irradiation

Evidence has suggested that the lymphocytic actions of alkylating agents, corticosteroids, and radiation were responsible for ameliorating certain disease states, which has led to investigations of the roles of thoracic-duct drainage, total-lymphoid irradiation, and lymphocytapheresis in rheumatic diseases.^24,²⁵ Lymphoid tissue occupies up to 3% of the total body weight; this includes 1% lymphocytes, or 10¹² lymphocytes per 70 kg. Lymphocytes are widely distributed and consist of both long-lived and short-lived populations. T cells make up roughly 90% of the lymphocytes in the thoracic duct lymph, 65% in the peripheral blood, 75% in the mesentery, and 25% in the spleen; most of these are long-lived lymphocytes. Therefore thoracic duct drainage and localized radiation remove lymphocyte populations in a different manner differently from lymphapheresis. Pioneered by researchers at the University of California at Los Angeles in the early 1970s, cannulation of the thoracic duct, followed by the removal of billions of lymphocytes, clearly improved disease activity in patients with SLE. The procedure is not practical for clinical use, however, because it is technically difficult, expensive, frequently complicated by infection, and can only be performed once.

One study has demonstrated that lymphocytapheresis can be safely performed along with plasma exchange in patients with SLE. Adacolumn is a membrane that adsorbs granulocytes and monocytes. In pilot studies, it appears to be well tolerated and not associated with an increased infection rate; however, the studies do not adequately address efficacy.²⁶

Between 1980 and 1997, a total of 17 patients with lupus nephritis and nephrotic syndrome refractory to conventional drug therapy received 2000 rad of total lymphoid irradiation over a 4- to 6-week period at Stanford University.²⁷ Clinical responses were achieved within 3 months and sometimes persisted for years. At follow-up ranging from 12 to 79 months, seven patients were off corticosteroids and without nephrosis. However, one patient died, one ultimately required long-term dialysis, and four developed neutropenia; one developed thrombocytopenia, three developed bacterial sepsis, and four developed herpes zoster. T-helper populations (i.e., CD4+ cells) decreased, and selective B-cell deficits were observed. The survival rate at 7.5 years was identical to that of a historical control group treated with steroids and immunosuppressive agents, with an equal prevalence of serious complications. In a long-term follow-up on these patients in 2002, 6 of 21 patients had died, and 4 developed cancer; 57% were dialyzed, and 33% had developed opportunistic infections. Other groups reported similar findings on a smaller scale.

Total lymphoid irradiation and thoracic duct drainage have no place in the management of patients with SLE, and no online lymphocyte depletion method has been shown to be safe and effective in managing lupus.

Photopheresis

In extracorporeal photochemotherapy, commonly known as photopheresis, leukocytes obtained at apheresis are treated with ultraviolet A (UVA) irradiation after the patient has received a photoactivatable drug, 8-methoxypsoralen.²⁸ Leukocytes reinfused into the patient can function but have diminished responses. Although only 5% of a patient’s total circulating lymphocytes are treated, photopheresis is clearly beneficial for treating cutaneous T-cell lymphomas. The literature in lupus is limited to numerous case reports, mostly for cutaneous lupus, and convey modest, if any, benefit.

Plasmapheresis and Plasma Exchange

Basic Science and Clinical Rationale

Apheresis refers to the removal of a blood component (e.g., red-blood cells, lymphocytes, leukocytes, platelets, plasma) by centrifugation or a membrane cell separator, with return of the other components to the patient.^24,²⁹ Removing 1 L of plasma decreases plasma proteins by 1 g/dL; however, because of compartmental equilibration and protein synthesis, 2.5 L of plasma must be exchanged weekly to decrease protein levels. In the intravascular space, 50% of the total immunoglobulin G (IgG) and 67% of the total immunoglobulin M (IgM) are found. Nine exchanges of 40 mL/kg over a 3-week period leave only 5% of the native plasma. The removal rate of plasma proteins and components depends on charge, solubility, avidity to other plasma proteins, configuration, synthesis, and uptake rates. In immunologic disorders, the recovery of immunoglobulin levels can be slowed by the concurrent use of immunosuppressive agents. If none is used, then antibodies rebound, or the tendency of certain antibody levels to rise rapidly above their prepheresis baseline after initially decreasing, is observed; this rebound often correlates with a disease flare. Plasma is usually replaced with a combination of albumin, salt, and water. Certain complications of lupus (e.g., thrombotic thrombocytopenic purpura) necessitate the use of fresh-frozen plasma replacement, because a plasma factor is deficient. When performed by personnel at experienced blood banks or dialysis facilities, plasmapheresis is usually safe; serious complications (e.g., hypotension, arrhythmia, infection) occur less than 3% of the time in this group of sick patients. The reader is referred to detailed reviews of the subject.

The major goals of apheresis in patients with SLE are to remove circulating immune complexes and immune reactants (e.g., free antibody, complement components), alter the equilibrium between free and bound complexes, and restore reticuloendothelial phagocytic function without altering proliferative responses to mitogens or lymphocyte subpopulation percentages.

Clinical Studies in Systemic Lupus Erythematosus

The use of plasmapheresis was reported first by Jones and colleagues in 1976.³⁰ Follow-up observations concluded that patients who are the most seriously ill and have the highest levels of circulating immune complexes respond the best.³¹ Patients who are treated concomitantly with plasmapheresis, prednisone, and cyclophosphamide do better than those who are treated with prednisone and azathioprine, and those who are on prednisone alone may become worse. The procedure is well tolerated in children and pregnant women with SLE.

Lupus Nephritis

Promising case reports and case series led to a National Institutes of Health (NIH)-sponsored multicenter study in which 86 patients with recent-onset proliferative nephritis received oral cyclophosphamide and prednisone, with or without plasmapheresis.³² Both groups improved, and no differences in the outcomes were noted. Numerous methodologic flaws minimize the value of this study, however.³³ Of the 27 patients with nephrotic syndrome that was resistant to a minimum 3-month trial of steroids and cytotoxic drugs, 10 patients were randomized to continue their therapy, and plasmapheresis was added in 17 of the patients. After 2 years, the apheresis group had statistically improved outcomes that could not be predicted in advance by any of the 30 variables used.³⁴

Antiphospholipid Syndrome and Congenital Heart Block

Interest has focused on the removal of anticardiolipin antibody and the lupus anticoagulant by plasmapheresis during pregnancy or in patients who have experienced recurrent thromboembolic episodes.³⁵ Results have been mixed. Plasmapheresis is safe during pregnancy and can be used weekly for the temporary removal of anticardiolipin. It is especially helpful if large amounts of the IgM isotype are present. The apheretic removal of anti–Sjögren syndrome antigen A (anti-SSA/Ro) in mothers whose fetuses show signs of congenital heart block has been reported, but no conclusions can be made from the small numbers of patients in published studies.³⁶

Other Potential Indications

The usefulness of plasmapheresis for cryoglobulinemia, thrombotic thrombocytopenic purpura, pulmonary hemorrhage, central nervous system vasculitis, neuromyelitis optica, and hyperviscosity syndrome complicating SLE is compelling, but the literature has been limited to case series.³⁷ (The reader is referred to sections of this monograph dealing with these complications.)

Pulse Synchronization Therapy

A group in Germany devised an innovative approach for the treatment of seriously ill patients with SLE.³⁸ It involves deliberately inducing antibody rebound with plasmapheresis, followed by high-dose intravenous cyclophosphamide to eliminate the increased numbers of malignant clones. Their pulse synchronization technique has resulted in some successes with long-term, treatment-free remissions. However, pulse synchronization did not work using conventional cyclophosphamide doses, neither for lupus nephritis nor for the disease in general; although higher doses of cyclophosphamide may be more effective, such therapy carries much greater risks as well.

Membrane Technologies

Membrane technologies have enabled selective plasmapheresis to be performed.³⁹ Membranes that remove cryoproteins, anti–single stranded DNA (anti-ssDNA) IgG containing circulating immune complexes, and anti-dsDNA by immune adsorption have been developed. Unfortunately, membranes activate complement and may present additional risks of hemolysis. Some approaches, such as a complement 1q (C1q) column immunoadsorption, have shown promising clinical effects in early trials.

Summary

At this time, plasmapheresis should be used only for patients with renal disease that is resistant to corticosteroid and cytotoxic drug therapy, specific disease subsets in which its efficacy is established (e.g., those with hyperviscosity syndrome, cryoglobulinemia, or thrombotic thrombocytopenic purpura), and those with acute, life-threatening complications of SLE—in each instance in combination with corticosteroids and cytotoxic therapy (Box 51-2).⁴⁰

Box 51-2

Indications for Apheresis in Systemic Lupus Erythematosus

1. Clear-cut evidence that apheresis can be lifesaving when steroids and immunosuppressive agents fail:

Thrombotic thrombocytopenic purpura

Cryoglobulinemia

Neuromyelitis optica

Pulmonary hemorrhage

Hyperviscosity syndrome

2. Relative indication—severe organ-threatening disease unresponsive to steroids and immune suppressives, especially central nervous system vasculitis

3. Investigational—antiphospholipid syndrome, anti–Sjögren syndrome antigen A (anti-Ro/SSA) removal in pregnancy

4. Not indicated

Mild to moderate non–organ-threatening systemic lupus erythematosus (SLE)

Lymphocyte depletion

Photopheresis

Ultraviolet UVA-1 IRRadiation

A group in Louisiana and another in Germany have reported modest beneficial effects of the longer wavelengths of UVA-1 irradiation (340 nm to 400 nm) in open-label, double-blind, placebo-controlled, and long-term follow-up studies.^41,⁴² Disease activity indices, cutaneous lesions, and anti-dsDNA levels improved. No side effects were reported. UVA-1 photons may promote DNA repair, cell-mediated immunity, and apoptosis and reduce B-cell function, leading to antiinflammatory effects. Cold UVA-1 light may be marginally beneficial in selected patients with SLE.

Should Radiation Therapy Be Avoided?

Although the in vitro intrinsic cell radiosensitivity of patients with SLE is normal, anecdotal reports of disease flares in patients undergoing radiation therapy for cancers are widespread.⁴³^–⁴⁵ On the other hand, a definitive matched-controlled, prospective evaluation of 61 patients with collagen vascular disorders failed to find an increased incidence of reactions, compared with the nonautoimmune group; this finding has been supported by a smaller survey. Radiation therapy is often inappropriately denied to patients with lupus, who have uniformly tolerated treatments well at the University of Toronto.

Patients with scleroderma seem to tolerate radiation therapy poorly with accelerated cutaneous and systemic fibrosis, and radiation issues with rheumatoid arthritis and other autoimmune diseases have been reviewed.

In summary, unless a patient has lupus with a scleroderma crossover, radiation therapy is infrequently associated with any complications. The author of this text has advised his patients who need radiation therapy to undergo it; these patients have not experienced any problems.

Niche Therapies for Lupus Subsets

Antileprosy Drugs

Dapsone

Dapsone, or 4,4-diaminodiphenylsulfone, interferes with folate metabolism and inhibits para-aminobenzoic acid. It also blocks the alternate pathway of complement activation and neutrophil cytotoxicity.^46,⁴⁷ Small series have reported that dapsone, which has been used in the treatment of lupus since 1978, can ameliorate vasculitis, bullae, urticaria, oral ulcerations, thrombocytopenia, lupus panniculitis, and subacute cutaneous lupus. Dapsone may be steroid-sparing and can be effective in lupus resistant to chloroquine. In the largest study to date, dapsone was given to 33 patients with chronic cutaneous lupus erythematosus (LE)—8 had excellent results and 8 had fair results, but 17 (52%) of the patients had no response. Its use is limited by its toxicity, which includes sulfhemoglobinemia and methemoglobinemia, a dose-related hemolytic anemia, a dapsone-hypersensitivity syndrome, sulfa-related complications, and aplastic anemia.

All patients treated with dapsone should undergo baseline glucose-6-phosphate dehydrogenase levels determination; the drug should not be administered to individuals with low levels. Complete blood counts should be performed every 2 weeks for the first 3 months and then every 2 months thereafter. Dapsone should be started at a dose of 25 mg twice daily and eventually raised to 100 mg daily. Dapsone also interacts with all oxidant drugs, such as phenacetin and macrodantin. Concurrent administration of 800 U of vitamin E daily may decrease the degree of dapsone-induced hemolysis.

In the author’s opinion, dapsone has a place in the management of severe bullous lupus or lupus profundus for patients who cannot tolerate corticosteroids or antimalarial medications.

Thalidomide and Lenalidomide

Thalidomide (Thalidomid, Celegene), also known as α-phthalimidoglutarimide, is a highly teratogenic drug with antileprosy and antilupus effects.^48,⁴⁹ It has no influence on the complement system, but it can stabilize lysosomal membranes, reduce tumor necrosis factor (TNF) activity, antagonize prostaglandin, inhibit neutrophil chemotaxis and angiogenesis, and alter cellular and humeral immunity. Thalidomide inhibits ultraviolet B (UVB)-induced mouse keratinocyte apoptosis in both TNF-dependent and TNF-independent pathways, as well as UVB-induced erythema.

Since its initial use in Mexico in the 1970s, over 20 publications involving hundreds of patients with SLE have shown the following:

a. Between 60% and 70% efficacy is achieved in treating chronic cutaneous, hypertrophic lupus and lupus profundus in doses of 100 mg a day for induction and less for maintenance.

b. Significant irreversible polyneuropathic symptoms are observed in patients receiving doses greater than 100 mg (used for myeloma and myelodysplastic syndrome) along with unacceptable thrombotic risks.

c. Efficacy diminishes rapidly upon discontinuation of the agent.

Thalidomide is available in the United States from physicians who have registered with the Celgene Corporation and comply with stringent monitoring requirements of the System for Thalidomide Education and Prescribing Safety (STEPS) program. Lenalidomide (Revlamid, Celgene) was introduced in 2006 for myeloma and myelodysplastic syndrome as a more potent derivative of thalidomide and is being studied in clinical trials for cutaneous lupus.⁵⁰

Clofazimine

Clofazimine (Lamprene, Novartis) has antileprosy, antibacterial, and antimalarial activity.⁵¹ It is sequestered in macrophages, stabilizes lysosomal enzymes, and stimulates the production of reactive oxidants. Modestly effective for cutaneous lupus in therapeutic doses of 300 mg/day, it produces quinacrine-like pigment stains. Initially approved by the U.S. Food and Drug Administration (FDA) for Mycobacterium avium associated with human immunodeficiency virus, it was removed from the market in the United States in 2005 but is available from various international sources and as a compassionate-use intervention.

Novel Immune Suppressive Agents

Most immune-suppressive agents occasionally used to manage SLE are reviewed in Chapter 50. A few additional agents deserve mention here.

Immunophylins: Tacrolimus and Rapamycin

Immunophylins block interleukin (IL)-2, cell-stimulated T-cell proliferation. Cyclosporin, topical tacrolimus, and pinecrolimus are discussed in Chapters 24 and 50.

Tacrolimus (Prograf, FK-506) has been reviewed in several large case series and small controlled trials for proliferative and membranous lupus nephritis.⁵²^–⁵⁴ In doses of 0.05 mg/kg/day, it has independent ameliorative effects that are not as robust as with mycophenolate (although they can be combined), but it compares favorably with cyclophosphamide when added to corticosteroids. This agent is used when mycophenolate, cyclophosphamide, or azathioprine has either failed or is poorly tolerated.

Rapamycin (Sirolimus, Rapamune, Wyeth-Ayerst) was approved in the United States for renal transplant rejection prevention in 1999. It regulates mitochondrial transmembrane potential and calcium fluxing, and cell–mammalian target of rapamycin (mTOR) signaling, prolongs survival in lupus-prone MRL/lpr mice, and reverses T-regulator (Treg) cell depletion.⁵⁵ It has been well tolerated by patients with lupus with renal allografts. A phase II clinical trial is in progress.

Antimetabolites

Mizoribine (4-carbamoyl-1-b-D-ribofuranosylimidazolium) is an oral purine-antagonist immune suppressive similar to azathioprine.⁵⁶ It is the only immune suppressive approved for the treatment of lupus nephritis in Japan. Doses of 100 to 300 mg/day of this nucleoside of the imidazole class have been suggested in several studies to be effective for lupus nephritis in children and as a steroid-sparing vehicle, but no controlled trials have been published.⁵⁶ It has also been studied in rheumatoid arthritis and renal transplantation.

Fludarabine is a purine antimetabolite that was studied at the NIH, but the study was terminated early as a result of a high rate of bone marrow suppression. The nucleoside analog 2-chlordeoxyadenosine (2-CdA, cladribine) was given to patients with proliferative nephritis at the NIH with disappointing results. Cytarabine has been observed in case reports. These agents do not play a role in SLE.⁵⁷^–⁵⁹

Gold

For practitioners in the 1940s and 1950s, there was no clear-cut classification distinction between rheumatoid arthritis and SLE, and gold was used not infrequently (and sometimes inadvertently) to treat lupus.⁵⁷^–⁶⁰ A few case series have documented modest effects of oral and parenteral gold in ameliorating musculoskeletal and cutaneous manifestations of SLE.⁶⁰

Antilymphocyte Globulin

Because antilymphocyte globulin is an immunosuppressive, it has been experimentally tried in a number of patients with SLE and is part of some ongoing stem cell protocols. Treatment has usually been combined with steroids and other agents. Fever, as well as local and hematologic reactions, has been frequent. Results are generally equivocal. In the largest and only controlled study,⁶¹ nine patients given antilymphocyte globulin, azathioprine, and prednisone did no better than those in a prednisone-only treated group.

Beta Carotene and Retinoids

Beta carotene and retinoids are related compounds that may have antilupus actions because of their sun-blocking and antioxidant activities that enhance natural killer–cell activity and mitogenic responsiveness.^62,⁶³ Beta carotene is a vitamin A derivative that has been used to treat polymorphous light eruption, erythrohepatic protoporphyria, and discoid lupus erythematosus (DLE) with modest results at best. Retinoids inhibit collagenase, prostaglandin E2, and rheumatoid synovial proliferation, and they interfere with intracellular binding proteins and interact with kinases, such as cyclic adenosine monophosphate (cAMP). In addition, epidermal antibodies can be altered, and an effect on epidermal cell differentiation may be observed. Three retinoids have been evaluated in cutaneous lupus: (1) isotretinoin (13-cis-retinoic acid), formerly known as Accutane (Roche Laboratories); (2) etretinate (Tegison, Roche Laboratories), which is no longer available; and (3) the aromatic retinoid acitretin (Soriatene, Roche Laboratories). Isotretinoin is very effective for refractory subacute cutaneous lupus. It is initiated in doses of 40 mg twice daily and tapered rapidly over several weeks. Unfortunately, its results are rarely sustained, and it may be used as a bridge therapy until other agents become effective. Patients notice increased photosensitivity, arthralgias, and dryness. Because it can induce depression and is teratogenic, a monitoring program for registrants has been mandated by the FDA. An aromatic retinoid, acitretin, is primarily used to manage psoriasis. A literature review documented its efficacy for chronic cutaneous and subacute cutaneous lupus in eight publications, especially with the concomitant use of extra sunscreen.

In summary, patients unable to tolerate or who are nonresponsive to corticosteroids or antimalarial medications may benefit from short courses of isotretinoin or acitretin. However, these drugs are poorly tolerated, potentially toxic, and not intended for long-term use.

Miscellaneous Hormonal Interventions

The use of contraceptive and other menses-altering or menses-regulating hormones is discussed in Chapter 38.

Danazol

Danazol (Danocrine, Sanofi) is an impeded androgen whose effects in patients with SLE are unclear.⁶⁴^–⁶⁶ It may decrease Fc-receptor expression and platelet-associated IgG, can reverse protein S deficiency, and may also have a hormonal downregulating action. Danazol displaces steroids by binding to steroid-binding globulin, which frees the latter compound. Its most promising use so far is for the treatment of idiopathic thrombocytopenia purpura (ITP), in which a 67% response rate and steroid-sparing effects are observed; after an initial response, low doses can be administered as maintenance therapy. Unfortunately, the therapeutic dose (up to 800 to 1200 mg daily) greatly exceeds the dose that is well tolerated (no more than 400 mg a day). Isolated cases of cutaneous disease, autoimmune hemolytic anemia, cytopenias, and red-cell aplasias have responded to this agent as well.

In summary, danazol is useful for refractory ITP and possibly hemolytic anemias in patients with SLE as a niche therapy after steroids, rituximab, immunosuppressive agents, and intravenous immunoglobulins (IVIGs) have been used.

Testosterones

In 1948, Lamb ⁶⁷ gave androgens to five patients with lupus, but the results showed no significant improvement. In 1950, Dubois and others⁶⁸ treated several female patients with massive doses of testosterone, both orally and intramuscularly, using as much as 500 to 1000 mg/day for as long as 5 weeks without benefit. After a 30-year hiatus, interest in androgen therapy has resurfaced. Once again, several published trials failed to demonstrate any effect of this hormone.⁶⁹

Dehydroepiandrosterone

Dehydroepiandrosterone (DHEA) is a steroid precursor of androgens and, to a lesser extent, estrogens. It is produced in the adrenal gland, and its levels decline with age. DHEA increases IL-2, soluble-adhesion molecules, and interferon (IFN) while downregulating IL-4, IL-5, and IL-6. Although DHEA is available over the counter as a “dietary supplement,” a quality control review of 16 preparations showed that 0% to 150% of what was claimed on the label was actually in the product. Advocates claim that these preparations increase growth-hormone levels and improve bone density, fatigue, libido, and cognitive dysfunction.

Early studies at Stanford University showed that doses of 100 to 200 mg/day (two to three times the available over-the-counter dose) achieved favorable effects in mild to moderate lupus in an open-label study, in a double-blind trial, and at long-term follow-up.^70,⁷¹ In patients with severe SLE, bone density improved, but disease activity changes were not statistically significant. Several pivotal trials were ultimately performed. A double-blind, randomized, placebo-controlled trial of 191 female patients with lupus suggested that it was steroid sparing in individuals with a SLEDAI score greater than 2, which was a post-hoc finding. In another trial, 381 patients given 200 mg daily or placebo noted significant improvements in myalgias, oral stomatitis, and serum C3 complement. In a Taiwanese study, 120 women randomized to DHEA versus placebo showed decreased flare rates and improved patient global assessment. IL-10 synthesis was suppressed. The drug was well tolerated with mild acne and hirsutism being common but rarely requiring drug discontinuation. Suggestions that the drug might improve bone mineralization in steroid-dependent patients with lupus led to a controlled trial that failed to reach its primary endpoint. The FDA Advisory Board recommended against recommending approval of DHEA for the treatment of lupus because it objected to a post-hoc analysis by the pharmaceutical company and noted that the drug did not improve sedimentation rate, SLEDAI scores, or anti-DNA. Since the advisory board’s vote, subsequent and better-designed studies showed that DHEA had no effect on fatigue, well-being, or biomarkers for atherosclerosis or bone demineralization.⁷² DHEA probably has no place in the management of SLE.

Bromocriptine

Prolactin appears to have proinflammatory effects, and its levels are elevated in SLE. Interest has centered on the use of prolactin suppression with bromocriptine in SLE.⁷³ Two small controlled studies showed slight, if any, benefit.

Gamma Globulin and Intravenous Immunoglobulin

Hypogammaglobulinemia with recurrent infections is a rare event in SLE, and the use of intramuscular gamma globulin to prevent infection in lupus is not uncommon, although no controlled studies have documented its efficacy.

IVIG delays the clearance of antibody-coated autologous red blood cells, competitively inhibits reticuloendothelial Fc-receptor blockade, has antiidiotypic antibody activity, modulates the release and function of proinflammatory cytokines and adhesion molecule expression, and decreases pokeweed mitogen–induced B-cell differentiation.^74,⁷⁵ Intravenous gamma globulin was first used in a patient with lupus nephritis in 1982. It may be acutely helpful for autoimmune thrombocytopenia secondary to SLE and for the neonatal thrombocytopenia that is seen in children of mothers with SLE. Gamma globulin is thought to be useful for serious disease exacerbations, such as in central nervous system lupus, pericarditis, cardiac dysfunction, acquired factor VIII deficiency, pancytopenia, refractory cutaneous lupus, myelofibrosis, nephritis, polyneuritis, hypoprothrombinemia with the lupus anticoagulant, and pulmonary hemorrhage, as well as to prevent recurrent fetal loss in patients with the antiphospholipid syndrome. In a controlled study, low–molecular-weight heparin was superior to IVIG.⁷⁶

The use of gamma globulin for the treatment of lupus nephritis is controversial. The drug is expensive and potentially dangerous. The reader should appreciate that it is often ineffective or temporarily effective. It can flare disease activity, induce acute renal failure, and promote thromboembolic disease, myocardial infarction, aseptic meningitis, and vasculitic rashes, among other symptoms. Low levels or absence of immunoglobulin A (IgA) (seen in 5% of patients with SLE) is a relative contraindication to its administration.

Evidence-based reviews confirm that IVIG is a first-line therapy for ITP, IgG subclass deficiency, and chronic inflammatory demyelinating polyneuropathy associated with SLE. It may be useful in other serious manifestations of SLE as a second-line therapeutic approach in refractory cases.