What are the effects of treatments on joint (arthralgia and arthritis) symptoms and other nonorgan-threatening symptoms such as serositis and fatigue in persons with systemic lupus erythematosus (SLE)?

LIKELY TO BE BENEFICIAL

Hydroxychloroquine or Chloroquine

Two randomized controlled trials (RCTs) found that hydroxychloroquine or chloroquine reduced arthritis, arthralgia, and joint pain in persons with mild SLE, many of whom were also taking corticosteroids. A third RCT found that hydroxychloroquine reduced flare-ups (defined as arthritis, pleuritis, pericarditis, and cutaneous symptoms) compared with placebo in persons with mild SLE. The RCTs reported no serious adverse effects. The trials were too small and not long enough to comment on the prevention of the progression of existing manifestations, or the occurrence of major organ complications. We found no RCTs comparing hydroxychloroquine versus chloroquine.

TRADE-OFF BETWEEN BENEFITS AND HARMS

Corticosteroids (Oral)

We found no systematic review or RCTs comparing corticosteroids versus placebo, nonsteroidal anti-inflammatory drugs (NSAIDs), hydroxychloroquine or chloroquine, or immunosuppressants. There is a consensus that oral corticosteroids are effective in the management of joint symptoms, fatigue, and serositis in persons with SLE. The long-term adverse effects of corticosteroids are well documented. (Based on consensus; RCTs unlikely to be conducted.)

Methotrexate

One RCT comparing weekly oral methotrexate with placebo, in persons with mild to moderate SLE who were also taking corticosteroids, found that methotrexate reduced arthritis and arthralgia over six months. Adverse effects were common, and one person developed pulmonary tuberculosis. We found no RCTs comparing immunosuppressants versus NSAIDs, hydroxychloroquine or chloroquine, or corticosteroids.

NSAIDs

We found no systematic review or RCTs assessing the effects of NSAIDs compared with placebo, hydroxychloroquine or chloroquine, corticosteroids, or immunosuppressants on nonorgan-threatening symptoms in persons with SLE. However, NSAIDs are commonly used to relieve joint pain caused by arthralgia and arthritis. They are also beneficial in relieving pleuritis and pericarditis associated with SLE. We found no evidence that the well-documented adverse effects of NSAIDs differ in persons with SLE. (Based on consensus; RCTs unlikely to be conducted.)

What are the effects of interventions for cutaneous involvement in persons with SLE?

LIKELY TO BE BENEFICIAL

Sunblock

We found no RCTs assessing the effect of sunscreens or sunblock on cutaneous symptoms; it is unlikely that an RCT would be undertaken. However, there is consensus that sunscreens are effective, and their use is encouraged, because ultraviolet light may exacerbate SLE. (Based on consensus; RCTs unlikely to be conducted.)

Hydroxychloroquine or Chloroquine

One RCT found that chloroquine reduced cutaneous symptoms in persons with mild SLE, many of whom were also taking corticosteroids. Another RCT found that hydroxychloroquine reduced flare-ups (defined as arthritis, pleuritis, pericarditis, and cutaneous symptoms) compared with placebo in persons with mild SLE. The RCTs reported no serious adverse effects. The trials were too small and not long enough to comment on the prevention of the progression of existing manifestations or occurrence of major organ complications.

TRADE-OFF BETWEEN BENEFITS AND HARMS

Corticosteroids

There is a consensus based on clinical experience that topical, intralesional, or systemic corticosteroids are effective in the management of cutaneous manifestations of SLE. Although we found no RCT evidence of their effects on general symptoms, their benefit has been proven in lupus nephritis. The long-term adverse effects of corticosteroids are well documented. (Based on consensus; RCTs unlikely to be conducted.)

Methotrexate

One RCT found that methotrexate was superior to placebo in improving cutaneous manifestations in persons with mild to moderate SLE, all of whom also took corticosteroids. Adverse effects were more common with methotrexate, and one person developed pulmonary tuberculosis.

UNKNOWN EFFECTIVENESS

Acitretin

We found no systematic review or RCTs of acitretin for the cutaneous manifestations of SLE.

What are the effects of treatments in persons with the proliferative (World Health Organization grades 3 to 5) lupus nephritis?

TRADE-OFF BETWEEN BENEFITS AND HARMS

Combination Corticosteroids Plus Immunosuppressants (May Be More Effective Than Corticosteroids Alone but Increase Adverse Effects)

RCTs suggest that combination corticosteroids plus immunosuppressants, in particular cyclophosphamide plus corticosteroids, may be more effective in preserving renal function in proliferative lupus nephritis than corticosteroids alone. Mycophenolate mofetil may be an alternative to cyclo-phosphamide, but the results of further RCTs are awaited. Combination treatment may increase the risk of ovarian failure, infection, and bone marrow toxicity compared with corticosteroids alone.

UNKNOWN EFFECTIVENESS

Corticosteroids (Unclear How They Compare with Immunosuppressants)

One systematic review identified no RCTs of sufficient quality comparing corticosteroids versus immunosuppressants in persons with proliferative lupus nephritis.

What are the effects of treatments for neuropsychiatric involvement in persons with systemic lupus nephritis?

UNKNOWN EFFECTIVENESS

Antipsychotic Drugs

We found no RCTs assessing anti-psychotic drugs for the neuropsychiatric manifestations of SLE.

Corticosteroids (Unclear How They Compare with Immunosuppressants)

We found no RCTs comparing corticosteroids versus immunosuppressants in persons with neuropsychiatric manifestations of SLE.

Intravenous Immune Globulin

We found no RCTs assessing intravenous immune globulin for the neuropsychiatric manifestations of SLE.

Plasmapheresis

We found no RCTs assessing plasmapheresis for the neuropsychiatric manifestations of SLE.

Definition

SLE is a chronic, multisystem, inflammatory connective tissue disorder of unknown cause that can involve joints, kidneys, serous surfaces, and vessel walls. It occurs predominantly in young women, but also occurs in children. The course of SLE is highly variable and may be characterized by exacerbations. Nonorgan-threatening symptoms occur in most persons with SLE during the course of active disease. These include arthritis or arthralgia (84 percent), oral ulcers (24 percent), fever (52 percent), and serositis (pleuritis or pericarditis; 36 percent). Lupus glomerulonephritis (lupus nephritis) is the diagnosis applied to persons with renal inflammation occurring in the context of SLE¹; it occurs in 39 percent of persons.² The World Health Organization (WHO) graded the disease in 1982, based on histologic features, as follows: grade 1 = normal kidney or minor abnormalities, grade 2 = mesangial proliferation, grade 3 = focal proliferative glomerulonephritis, grade 4 = diffuse proliferative glomerulonephritis, grade 5 = membranous disease, and grade 6 = sclerosing glomerulonephritis. This review covers treatments of WHO grades 3 to 5.

Cutaneous involvement may include malar rash (which occurs in 58 percent of persons), photosensitivity (45 percent), discoid rash (10 percent), livedo reticularis (14 percent), and subacute cutaneous lesions (6 percent). Neuropsychiatric involvement occurs in 27 percent of persons and has a wide range of clinical presentations, including seizures, chronic headache, transverse myelitis, vascular brain disease, psychosis, and neural cognitive dysfunction. SLE is also characterized by hematologic features, such as hemolytic anemia (8 percent), thrombocytopenia (22 percent), and lymphadenopathy (12 percent); and cardiovascular complications such as thrombosis (14 percent) and Raynaud's phenomenon (34 percent).² Prevention and treatment of hematologic and cardiovascular complications are not covered by this review.

Diagnosis

The American College of Rheumatology has developed classification criteria for SLE. For a diagnosis to be made, four of these 11 criteria must be met: malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal disorder, neuropsychiatric disorder, hematologic disorder, immunologic disorder, and antinuclear antibody.³

Incidence and Prevalence

The prevalence of SLE worldwide varies greatly. From population-based epidemiologic studies, it has been estimated that one in 3,450 women (independent of race) in the United Kingdom, one in 250 black women in the United States, one in 1,000 Chinese women, and one in 4,200 white women in New Zealand may have SLE.^4–7 Although the prevalence of SLE is higher in black persons than in white persons in the United States and the United Kingdom, the prevalence of lupus is low in most African countries.⁸

Etiology

Although the exact cause of SLE remains unclear, genetic, environmental, and hormonal influences are all thought to play a role.^9,10

Prognosis

The manifestations of SLE that determine survival include lupus nephritis, cardiovascular complications, and neuropsychiatric involvement. In cohort studies performed since 1980, survival at five years has exceeded 90 percent, a higher survival rate than in studies performed earlier than 1980.¹¹ One multicenter study performed in Europe found a survival probability of 92 percent at 10 years after diagnosis.¹² A lower survival probability was detected in those persons who presented at the beginning of the study with nephropathy (88 percent in persons with nephropathy versus 94 percent in persons without nephropathy; P = .045). When the causes of death during the initial five years of follow-up (1990 to 1995) were compared with those during the ensuing five years (1995 to 2000), active SLE and infections (29 percent each) seemed to be the most common causes during the initial five years, although thrombosis (26 percent) became the most common cause of death during the last five years.¹² Race is an independent predictor of mortality; black persons in the United States have a worse prognosis than white persons, as do Asian persons in the United Kingdom compared with white persons in the United Kingdom.