Systemic Lupus Erythematosus (SLE)

Table 1.

Optimal Therapeutic Approach for this Disease

The treatment goal for systemic lupus erythematosus is to decrease inflammation to avoid organ damage. In terms of ACLE and non-specific LE cutaneous findings, controlling the underlying disease is paramount.

Sun avoidance and protection with the use of broad spectrum sunscreen that covers both the UVA and UVB ranges should be discussed with all patients with SLE. Although the exact role of UV light in the pathogenesis of non-specific LE cutaneous findings is unclear, we do know that UV light plays a role in SLE, particularly ACLE. The use of broad spectrum sunscreens to cover the UVB and UVA spectrum is necessary and ideally includes sunscreens with helioplex, mexoryl or physical blockers (titanium dioxide, zinc oxide). An SPF of at least 30 is necessary for daily use.

Cigarette smokers are found to have more severe CLE disease. Antimalarials may also be less effective in those patients who smoke. As a result, all patients with LE should begin a smoking cessation program.

Multidisciplinary interventions are paramount in the management of patients with systemic SLE and those with CLE that go on to develop major organ (renal, hematologic, pulmonary, cardiac, gastrointestinal (GI), nervous system) involvement. A rheumatologist must be part of the treatment team for all patients with organ system involvement.

Topical therapy with steroids can be initiated as first-line therapy with or without calcineurin inhibitors. Topical steroid should be tried in patients with limited and mild skin disease before starting systemic therapies. Potent topical steroids may be used on the body and weaker, class VI or VII, may be used on the face as a trial for 2 to 4 weeks.

Fluocinonide 0.05% or clobetasol 0.05% gel, ointment or cream may be used for CLE lesions on the body. For lesions on the face or skin folds desonide 0.05% or triamcinolone 0.025% cream, lotion, or ointment initially may be tried. If no improvement is seen with these low-potency topicals, you can increase the potency to mometasone 0.1% cream, lotion or ointment.

Topical calcineurin inhibitors, such as tacrolimus 0.1% ointment, have been shown to be effective in CLE and offer a decreased risk of telangiectasia development compared with topical steriods. Calcineurin inhibitors are particularly helpful for lesions on the face. Combining topical steroids and calcineurin inhibitors may provide an added benefit. These topical regimens may be used in both LE-specific, such as ACLE, and non-specific skin lesions.

Intralesional triamcinolone at doses of 3 to 5mg/mL may be used for alopecia areata in the beard and eyebrow areas in patients with SLE. For alopecia areata in the scalp, a higher dose up to 10mg/mL may be used. Depending on the number of lesions present, 1 to 3mL may be needed and can be administered every month. Side effects include hypopigmentation and skin atrophy.

Antimalarials

Antimalarials are recommended as first-line systemic therapy for CLE and SLE given its effectiveness in prevention and treatment of symptoms, such as photosensitivity, acute malar rash, DLE, oral ulcers, alopecia, arthritis, pleuritis, and pericarditis. The majority of patients with DLE respond to single-agent or combination antimalarial therapy.

Hydroxychloroquine is the treatment of choice over chloroquine given its lower ocular toxicity risk. Typically, hydroxychloroquine is started at 200mg to 400mg a day. To avoid ocular toxicity, the daily dose should not exceed 6.5mg/kg IBW per day. Ideal body weight is calculated as follows: 45.5kg (use 50kg for males) + 2.3 kg for each inch over 5 feet; or 45.5kg + 2.3kg * (height [inches]-60).

Antimalarials take 2 to 3 months for improvement to be noticed and up to 6 months for a complete response. After 8 to 12 weeks, if improvement is not satisfactory, addition of quinacrine 100mg daily may be added. Quinacrine can only be obtained at compounding pharmacies. It may cause yellow discoloration of the skin.

If the combination of hydroxychloroquine and quinacrine has not provided complete response after 6 months, changing to chloroquine plus quinacrine is an option. Chloroquine is typically started at a dose of 250mg 5 to 7 days a week and should not exceed 3.5mg/kg IBW per day. The lowest possible effective dose should be used for maintenance therapy. Antimalarials may be used safely for long periods of time.

The recommended doses listed in the Table are based on the maximal safe dose from an ocular safety perspective. The retinopathy associated with antimalarials (chloroquine) is often irreversible. The blurred vision and corneal deposition that may occur is reversible. The use of hydroxychloroquine necessitates eye examinations every 6 months and with chloroquine every 4 months. The eye examination should include visual acuity, visual fields, and fundoscopic examination. Patients with a history of retinopathy should not get hydroxychloroquine or chloroquine.

Patients who get a drug exanthem with hydroxychloroquine may be able to tolerate chloroquine, while an urticarial reaction from hydroxychloroquine would preclude use of chloroquine. Other side effects include nausea, headaches, myopathy, and bluish-gray hyperpigmentation of the skin.

In addition to a baseline eye examination, a CBC and liver function test are recommended at baseline and after 1 month of use.

If antimalarials are not effective, second-line systemic therapies including thalidomide and immunosuppressives may be required. Specifically, if refractory and widespread DLE lesions persist, or patients have concomitant SLE symptoms, they may benefit from these steroid-sparing immunosuppressants. In some instances, these immunosuppressants are initially used in combination with prednisone. Once the medication takes effect, the goal is to taper off the prednisone. However, prednisone is not often used in DLE as high doses are usually necessary to achieve a response.

Dapsone

Dapsone is the treatment of choice in bullous LE and has been shown to act quickly and effectively. The response is often dramatic with cessation of blister formation in 24 to 48 hours and clearance of the eruption in 7 to 10 days. Low doses of 25 to 50mg are usually enough for these results. It has also been shown to be effective in hypocomplementemia with urticarial vasculitis.

Severe adverse effects are related to hematotoxicity and can be seen as hemolytic anemia and/or methemoglobinemia. Both are dose dependent and occur, to some degree, in all patients who take dapsone. A glucose-6-phosphate dehydrogenase (G6PD) level should be tested in all patients being considered for dapsone, as the risk of hemolytic anemia is significantly increased if there is a deficiency.

Peripheral motor neuropathy can be observed and typically resolves completely after dose reduction or drug discontinuation. Agranulocytosis is a serious, idiosyncratic adverse effect of dapsone. Patients normally will experience a 2g/dL drop in hemoglobin, but greater drops of below 10g/dL necessitate an adjustment of dose. Patients may experience a clinically unimportant drop in their 02 saturation, which is not routinely monitored.

Baseline laboratory tests include CBC with differential, complete metabolic panel (liver function tests and renal function), urinalysis and G6PD level. During each visit, assess peripheral motor neuropathy, CBC with differential (every week while the dose is being increased, then monthly for 3 months, then every 3 months), and complete metabolic panel (every 3 months).

Prednisone

Given the chronic and recurrent nature of most CLE subsets, use of steroids should be avoided. However, there are several instances in which prednisone can and should be used. In cases of ACLE associated with systemic lupus flares, while awaiting antimalarials or immunosuppressives to take effect, or in systemic lupus disease where there is organ system involvement. Prednisone 0.5mg/kg/day to 0.75mg/kg/day can be used to control the cutaneous lesions of SLE. Prednisone should not be used alone, as lesions recur once prednisone is stopped. Tapering prednisone as soon as CLE lesions are stable is recommended.

The degree and extent of bone loss is most closely related to cumulative corticosteroid dose. The most rapid rate of bone loss is during the first 3 to 6 months of therapy. All patients starting glucocorticoids at any dose with an anticipated duration of at least 3 months or longer should start calcium 1200 to 1500mg/day and vitamin D 800 to 1000 International Units/day supplementation. These patients should also be counseled on smoking cessation and weight-bearing activities. Additionally, they should be assessed for fall risk, baseline height, and history of fragility fractures.

A baseline bone mineral density scan or radiographic imaging of the spine or vertebral fracture assessment may be done (particuarly in postmenopausal women). In childbearing-age women, the use of bisphosphonates is only considered for those with a history of fragility fractures given the unknown risk of long-term bisphosphonate use and risk to the fetus. However, postmenopausal women are recommended to begin a bisphosphonate, such as alendronate or risedronate, if the corticosteroid dose is greater than 5mg and the anticipated length of treatment is at least 3 months.

The well-known side effects of prednisone include include weight gain, fluid retention, psychiatric disturbances, hypertension, and hyperglycemia. Osteoporosis, myopathy and cushingoid changes are additional adverse reactions that can be avoided with short therapeutic courses. Of note, osteonecrosis can occur with even short courses of prednisone.

Although unlikely, if after 3 months of therapy with antimalarials and oral prednisone results are unsatisfactory, a steroid-sparing agent should be initiated. Methotrexate (MTX), mycophenolate mofetil (MMF) or azathioprine is a reasonable choice and all have been used in management of SLE symptoms.

Methotrexate

MTX use in SLE has substantial evidence. In fact, there are randomized controlled trials showing the benefit of MTX on overall SLE activity, reduction in glucocorticoid doses, and effects on lupus arthritis and lupus skin manifestations. In addition, MTX may be helpful in vasculitis, hematologic, and prehaps renal manifestations of SLE. Intrathecal MTX was successfully used in neuropsychiatric SLE. Taken together, using MTX in SLE is not only a common approach, but, at least in part, supported by evidence in clinical trials.

MTX in lupus erythematosus can be used in doses of 5 to 25mg weekly. MTX typically takes 3 to 4 weeks for clinical improvement. A typical test dose is 5mg, and then increase 5mg weekly to the dose needed to control symptoms. The lowest possible maintenance dose needed to control disease should be used. Doses as low as 5mg a week have been successfully used to maintain clinical remission.

A potential for hepatotoxicity, with long-term use, and pulmonary toxicity is an important consideration. Patients who drink alcohol should not receive MTX, and underlying viral hepatitis, obesity and diabetes are associated with an increased risk of hepatotoxicity, including liver fibrosis.

Bone marrow suppression is a severe adverse reaction. Risk factors for this side effect include drug interactions (trimethoprim/sulfamethoxazole [TMP/SMX] and NSAIDS), renal insufficiency, older age (>65) and no folate supplementation. Frequent CBCs are important to monitor for this adverse reaction and all patients should be on folate supplementation.

Baseline laboratory tests should include CBC, complete metabolic panel (liver and renal function), hepatitis B and C serologies, and HIV testing. After the first dose of MTX, a CBC and liver function laboratories should be done in 1 week. If laboratory tests are normal, repeat testing of CBC and liver function, every week as the dose is increased and then monthly thereafter for 3 months is warranted.

After a year of a stable dose with no serious toxicity, blood monitoring can decrease to every 3 months. Renal function can be evaluated once a year, or sooner if renal dysfunction is suspected. Weekly intramuscular injections may improve GI intolerance due to oral MTX.

Mycophenolate mofetil

MMF is well tolerated and has been shown to be effective in CLE and SLE. The most common adverse reaction from this therapeutic agent is GI side effects, including nausea, vomiting, diarrhea, and abdominal cramps. These symptoms are typically dose dependent and may be avoided by starting at a lower dose. In patients with GI side effects, one can start with 500mg once or twice a day and then titrate dose up per tolerability every 2 to 4 weeks to goal dose of 2 to 3g/day.

As with any immunosuppressant, MMF can increase the risk of infections. Less common side effects include myelosuppression and transaminitis. MMF typically takes approximately 4 weeks to take effect.

Baseline laboratory tests include CBC with differential and liver function tests, as well as hepatitis B and C serologies and HIV testing. Laboratory tests should be checked 2 weeks after starting therapy, and 2 weeks after increases in dose. Monthly CBC and liver function tests for the first year, then every 3 months, are recommended. Maintenance doses of 1.5 to 3g a day can be used safely.

Azathioprine

Azathioprine is an immunosuppressant that has been extensively studied in lupus erythematosus as a steroid-sparing agent. An initial dose of 50mg a day is suggested to determine acute toxicity/sensitivity. The dose can be increased by 25mg every 2 weeks with a goal of achieving a range between 2 to 3mg/kg/day. In CLE, azathioprine doses of 100 to 150mg are commonly needed to achieve desired effects. Clinical effects are typically seen in 4 to 8 weeks. The maintenance dose can range from 50 to 150mg daily and may be continued for years.

Side effects include GI symptoms of nausea, vomiting and abdominal cramping. Pancreatitis and hepatotoxicity have also been reported. Hypersensitivity reaction, aseptic meningitis and increased cancer risk are also known adverse reactions. Flu-like symptoms may occur within the first 2 weeks of use.

Prior to the use of azathioprine, a thiopurine methyltransferase (TPMT) enzyme level can be done, particularly if doses above 50mg a day are used initially. Low levels increase the risk of myelosuppression and potentially fatal neutropenia. A CBC and liver function tests should be performed every 2 weeks while the dose is being adjusted, then every month for the first year, and then every 3 months.

Intravenous immunoglobulins

Intravenous immunoglobulins (IVIG) have been shown in a few case reports to provide improvement during a systemic lupus flare and in some CLE lesions. Improvement has been seen as soon as 2 to 3 weeks. A dose of 1g/kg/day for 2 days and 0.4g/kg/day for 5 days have been reported. IVIG can be administered monthly or every 3 months depending on disease activity.

Given the high cost, close monitoring during infusions, and adverse reactions, IVIG has been used in those patients with concomitant severe SLE on high doses of corticosteroids, combined with other cytotoxic agents. Common adverse effects include headache, low-grade fever, and chills. Severe side effects include acute renal failure and thrombotic events. Individuals with IgA deficiency are at increased risk of developing an anaphylactic reaction, thus serum IgA levels should be assessed prior to administration of IVIG.

Rituximab

Rituximab has been successful in the treatment of lupus nephritis and autoimmune cytopenias seen in SLE. It has also been effective in the treatment of both the systemic and cutaneous vasculitis associated with SLE. One case of rituximab use in refractory SCLE has been reported. However, the use of this medication in patients with CLE alone is not recommended given the cost and side-effect profile. Common side effects include fever, chills, rigors, orthostatic hypotension and bronchospasms with infusions and neutropenia, thrombocytopenia, and asthenia. Rarely, progressive multifocal leukoencephalopathy can occur.

Baseline CBC, metabolic panel, urinalysis, hepatitis serologies, HIV and tuberculosis tests should be performed. No live vaccines should be administered to patients receiving rituximab.

Patient Management

The goal of any therapy for SLE, including specific and non-specific LE cutaneous features, is to minimize inflammation to avoid end-organ damage. Mainstay therapies for the majority of patients with SLE and CLE are topical therapies and antimalarials. Both of these therapies have limited severe adverse reactions. However, patients with refractory or widespread disease must begin therapies that carry higher risks for severe side effects. It is important to discuss all side effects and monitoring guidelines prior to initiating therapy.

After antimalarials, there is no one agent that is superior in the treatment of CLE lesions. Thus, when ascending the therapeutic ladder, individualizing therapy for patients based on their co-morbidities and disease severity is necessary. Furthermore, after clearance of CLE lesions, therapies should be reduced to the lowest effective dose, or discontinued.

The next step is to provide patients with therapeutic modalities that minimize disease progression and improve treatment response. All patients must be counseled on sun avoidance and protection, including avoidance of artificial tanning beds and photosensitizing medications. On a similar note, the role of smoking in disease severity must be stressed at the initial visit. All patients should be encouraged to stop smoking and begin a smoking cessation program.

Unusual Clinical Scenarios to Consider in Patient Management

SLE and other connective tissue diseases can initially present with nonspecific symptoms and clinical features that seem to overlap. Furthermore, these symptoms often change over time and an exact connective tissue disease diagnosis may not be possible early in the course of the disease. However, certain clinical and laboratory features may help predict the development of a specific established connective tissue disease.

For instance, U1-RNP antibodies predict mixed connective tissue disease; sicca symptoms plus anti-SSA/anti-SSB predict Sjõgren’s syndrome; Raynaud’s and a nucleolar ANA pattern predict scleroderma; whereas fever, serositis and homogenous ANA pattern predict progression to SLE. Mixed connective tissue disease (MCTD) is that of an overlap syndrome that embraces features of scleroderma, SLE, and an inflammatory myopathy. Thus, these patients can present with quite diverse clinical features and close follow-up is required.

The presence of CLE lesions may help clinicians differentiate SLE from other connective tissue disease, since CLE lesions are not typically seen in Sjogren’s syndrome, scleroderma or the inflammatory myopathies.

Management of SLE in the pregnant patient may be challenging. Family planning is important for these patients. Ideally, planning for pregnancy once SLE is inactive for at least 6 months is recommended. However, even if the disease is controlled, SLE patients may flare during pregnancy. Prior to conception, if not already done, checking for antiphospholipid antibodies is necessary, as anticoagulation therapy during pregnancy may be indicated. Checking for anti-SSA and anti-SSB antibodies is necessary because there is a small risk of congential heart block in women with these antibodies.

During pregnancy, monitoring for lupus nephritis with regular blood pressure and proteinuria checks is important. Differentiating between preeclampsia and lupus nephritis will require evaluation of the urinary sediment, presence of other systemic signs of lupus activity and complement levels.

As mentioned above, patients with SLE should be managed together with a rheumatologist. Depending on the severity of disease, a high-risk obstetrician may be necessary. Particularly, if the patient has active SLE with lupus nephritis, history of congenital heart block, and antiphospholipid syndrome a high-risk obstetrician and close follow-up with a rheumatologist is essential.

There is little evidence regarding therapy of SLE during pregnancy. Typically, patients with active SLE and mild disease are managed during pregnancy with oral corticosteroids. If the disease is more severe, treatment with corticosteroids, azathioprine, cyclosporine and intravenous gamma globulin may be used. At this time, there is not enough safety information on the use of MMF in pregnancy. Hydroxychloroquine has evidence for its safety and efficacy during pregnancy; however, it is still considered a class C drug by the Food and Drug Administration.

Libman-Sacks endocarditis is usually clinically silent and in rare cases can present with valvular dysfunction. Of course, embolic phenomena and bacterial endocarditis can complicate this condition and thus, osler nodes, splinter hemorrhage, and janeway lesions may be present. This is exceedingly rare.

What is the Evidence?

Danchenko, N, Satia, JA, Anthony, MS. “Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden”. Lupus. vol. 15. 2006. pp. 308-18. (A comprehensive comparison of the incidence and prevalence of SLE in the United States and throughout the world.)

Bernatsky, S, Peschken, C, Fortin, PR, Pineau, CA, Urowitz, MB, Gladman, DD. ” Medication use in systemic lupus erythematosus”. J Rheumatol. vol. 38. 2011. pp. 271-4. (Disclosed that treatment strategies are not uniform for SLE. Clinical practice patterns revealed that disease activity and damage scores were predictors of immunosuppressive use.)

Werth, V. “Current treatment of cutaneous lupus erythematosus”. Dermatol Online J. vol. 7. 2001. pp. 2(A concise discussion of the treatment options used in CLE.)

Kiani, AN, Petri, M. “Quality of life measurements versus disease activity in systemic lupus erythematosus”. Curr Rheumatol Rep. vol. 12. 2010. pp. 250-8. (Analyzes the modes of assessment in SLE and notes that disease activity or organ damage is not strongly related to quality of life.)

Bertsias, GK, Salmon, JE, Boumpas, DT. “Therapeutic opportunities in systemic lupus erythematosus: state of the art and prospects for the new decade”. Ann Rheum Dis. vol. 69. 2010. pp. 1603-11. (The article gives a concise overview of the role of autoantibodies and disease course of SLE. Etiology of disease and management is also discussed through useful schematics.)

García-Carrasco, M, Jiménez-Hernández, M, Escárcega, RO, Mendoza-Pinto, C, Galarza-Maldonado, C, Sandoval-Cruz, M. “Use of rituximab in patients with systemic lupus erythematosus: an update”. Autoimmunity Reviews. vol. 8. 2009. pp. 343-8. (The preliminary results of targeted B cell therapies is explored, including the clinical efficacy of rituximab.)