Системний червоний вовчак (СЧВ)

Joint symptoms, ranging from intermittent arthralgias to acute polyarthritis, occur in about 90% of patients and may precede other manifestations by years. Most lupus polyarthritis is nondestructive and nondeforming. However, in long-standing disease, deformities without bone erosions may develop (eg, the metacarpophalangeal and interphalangeal joints may rarely develop reducible ulnar drift or swan-neck deformities without bony or cartilaginous erosions [Jaccoud arthritis]). As in many other chronic diseases, the prevalence of fibromyalgia is increased, which may cause diagnostic confusion in patients with periarticular and generalized pain and fatigue.

Skin lesions include malar butterfly erythema (flat or raised) that generally spares the nasolabial folds. The absence of papules and pustules and presence of skin atrophy help distinguish SLE from rosacea. A variety of other erythematous, firm, maculopapular lesions can occur elsewhere, including exposed areas of the face and neck, upper chest, and elbows. Skin blistering and ulceration are rare, although recurrent ulcers on mucous membranes (particularly the central portion of the hard palate near the junction of the hard and soft palate, the buccal and gum mucosa, and the anterior nasal septum) are common (sometimes called mucosal lupus); findings can sometimes mimic toxic epidermal necrolysis.

Дискоїдний вовчак (пальці)

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Generalized or focal alopecia is common during active phases of SLE. Panniculitis can cause subcutaneous nodular lesions (sometimes called lupus panniculitis or profundus). Vasculitic skin lesions may include mottled erythema on the palms and fingers, periungual erythema, nail-fold infarcts, urticaria, and palpable purpura. Petechiae may develop secondary to thrombocytopenia. Photosensitivity occurs in some patients.

Lupus erythematosus tumidus is characterized by pink to violaceous urticarial nonscarring plaques and/or nodules, some annular, in light-exposed areas.

системний червоний вовчак (малярний висип)

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Chilblain lupus is characterized by tender, bright red to reddish blue nodules on the toes, fingers, nose, or ears that occur in cold weather. Some patients with SLE have features of lichen planus.

Raynaud syndrome due to vasospasm in the fingers and toes causes characteristic blanching and cyanosis.

(See also Variant Forms of Lupus.)

Cardiopulmonary symptoms commonly include recurrent pleurisy, with or without pleural effusion. Pneumonitis is rare, although minor impairments in pulmonary function are common. Diffuse alveolar hemorrhage occasionally occurs. Prognosis has traditionally been poor. Other complications include pulmonary emboli, pulmonary hypertension, and shrinking lung syndrome. Cardiac complications include pericarditis (most commonly) and myocarditis. Serious, rare complications are coronary artery vasculitis, valvular involvement, and Libman-Sacks endocarditis. Accelerated atherosclerosis is an increasing cause of morbidity and mortality. Congenital heart block can develop in neonates whose mother has the antibodies against Ro (SSA) or La (SSB).

Generalized adenopathy is common, particularly among children, young adults, and Black people; however, mediastinal adenopathy is not common. Splenomegaly occurs in 10% of patients.

Neurologic symptoms can result from involvement of any part of the central or peripheral nervous system or meninges. Mild cognitive impairment is common. There may also be headaches, personality changes, ischemic stroke, subarachnoid hemorrhage, seizures, psychoses, aseptic meningitis, peripheral and cranial neuropathies, transverse myelitis, choreoathetosis, or cerebellar dysfunction.

Renal involvement can develop at any time and may be the only manifestation of SLE (see Lupus Nephritis). It may be benign and asymptomatic or progressive and fatal. Renal lesions can range in severity from a focal, usually benign, glomerulitis to a diffuse, potentially fatal, membranoproliferative glomerulonephritis. Common manifestations include proteinuria (most often), an abnormal urinary sediment manifested by red blood cell casts and leukocytes, hypertension, and edema. Early lupus glomerulonephritis may be misdiagnosed as asymptomatic urinary tract infection.

Obstetric manifestations include early and late fetal loss. In patients with antiphospholipid antibodies, the risk of recurrent miscarriages is increased. Pregnancy can be successful (see SLE in Pregnancy), particularly after 6 to 12 months of remission, but SLE flares are common during pregnancy and especially during the postpartum period. Pregnancy should be timed for when disease is in remission. During pregnancy, the patient should be monitored closely for any disease flare or thrombotic events by a multidisciplinary team that includes an obstetrician who specializes in high-risk pregnancies. Women who are SSA antibody-positive should have weekly fetal ultrasonography between week 18 and week 26 to assess for congenital heart block.

Hematologic manifestations include anemia (anemia of chronic disease, autoimmune hemolytic anemia), leukopenia (usually lymphocytopenia, with < 1500 cells/mcL), and thrombocytopenia (usually mild but sometimes life-threatening autoimmune thrombocytopenia). Recurrent arterial or venous thrombosis, thrombocytopenia, and a high probability of obstetric complications occur in patients with antiphospholipid antibodies. Thromboses probably account for many of the complications of SLE, including obstetric complications. Macrophage activation syndrome can occur.

Gastrointestinal manifestations can result from bowel vasculitis or impaired bowel motility. In addition, pancreatitis can rarely result from SLE. Manifestations may include abdominal pain resulting from serositis, nausea, vomiting, manifestations of bowel perforation, and pseudo-obstruction. SLE rarely causes parenchymal liver disease.

The fluorescent test for ANA is the best initial test for SLE in patients who have compatible symptoms and signs; positive ANA tests (usually in high titer: > 1:80) occur in > 98% of people with SLE. However, positive ANA tests can also occur in rheumatoid arthritis, other connective tissue disorders, autoimmune thyroid disease, cancers, and even in the general population. The false-positive rate varies from about 3% with ANA titers of 1:320 to about 30% for ANA titers of 1:40 among healthy controls. Drugs such as hydralazine, procainamide, and tumor necrosis factor-alpha antagonists can produce positive ANA results as well as a lupus-like syndrome; the ANA eventually becomes negative if the drug is stopped. Positive ANA should prompt more specific testing such as anti-dsDNA antibodies; high titers of anti-dsDNA are highly specific for SLE but occur in < 70% of people with SLE.

The ANA test is very sensitive, but it is not specific for SLE; thus, evidence of other autoantibodies is used to aid in diagnosis. They include Ro (SSA), La (SSB), Smith (Sm), ribonucleoprotein (RNP), and dsDNA. Ro is predominantly cytoplasmic; anti-Ro antibodies are occasionally present in ANA-negative SLE patients presenting with chronic cutaneous lupus. Anti-Ro is the causal antibody for neonatal lupus and congenital heart block. Anti-Sm is highly specific for SLE but, like anti-dsDNA, is not sensitive. Anti-RNP occurs in patients with SLE, mixed connective tissue disease, and occasionally other systemic autoimmune disorders and systemic sclerosis.

Leukopenia (usually lymphopenia) is common. Hemolytic anemia may occur, but low hemoglobin and red blood cell counts are more often due to the anemia of chronic disease. Thrombocytopenia in SLE may be difficult or impossible to differentiate from idiopathic thrombocytopenic purpura except that patients have other features of SLE and/or SLE-specific antibodies (anti-dsDNA or anti-Sm). False-positive serologic tests for syphilis occur in 5 to 10% of SLE patients. These test results may be associated with the lupus anticoagulant and a prolonged partial thromboplastin time (PTT). Abnormal values in one or more of these assays suggest the presence of antiphospholipid antibodies (eg, anticardiolipin antibodies), which should then be measured directly by enzyme-linked immunosorbent assay (ELISA). Antiphospholipid antibodies are associated with arterial or venous thrombosis, thrombocytopenia, and, during pregnancy, spontaneous abortion or late fetal death but may be present in asymptomatic patients.

Other tests help monitor disease severity and determine the need for treatment. Serum complement levels (C3, C4) are often depressed in active disease and are usually lowest in patients with active nephritis. Erythrocyte sedimentation rate (ESR) is elevated frequently during active disease. C-reactive protein levels are not necessarily elevated; high levels raise the concern for infection and/or serositis.

Screening for renal involvement begins with urinalysis. Red blood cell (RBC) and/or white blood cell casts suggest active nephritis. Urinalysis should be done at regular intervals (eg, every 3 to 6 months), even for patients in apparent remission, because kidney disease is usually asymptomatic. Proteinuria can be estimated by the urine protein/creatinine ratio or measured in a 24-hour urine collection. Renal biopsy is indicated in patients whose protein excretion is > 500 mg/day and who have hematuria (thought to be glomerular) or RBC casts and is helpful in evaluating the status of renal disease (ie, active inflammation vs postinflammatory scarring) and in guiding therapy. Patients with chronic renal insufficiency and mostly sclerotic glomeruli are not likely to benefit from aggressive immunosuppressive therapy.

Arthralgias are usually controlled with NSAIDs. However, chronic NSAID use is discouraged because of gastrointestinal adverse effects (eg, peptic ulcer disease) and potential coronary and renal toxicity (eg, interstitial nephritis, papillary necrosis). Topical agents (corticosteroids, tacrolimus) can be used for skin disease, usually under the guidance of dermatology.

Antimalarials, such as hydroxychloroquine, are useful for joint and skin manifestations. Hydroxychloroquine reduces the frequency of SLE flares and decreases mortality, and is therefore used in virtually all patients with SLE. Dose is 5 mg/kg of actual body weight orally once a day. Baseline ophthalmologic examination should be done before starting therapy to exclude maculopathy because chronic hydroxychloroquine use increases the risk of toxic maculopathy. Ophthalmologic screening should be done yearly after the drug has been used for 5 years to assess for retinal toxicity. Alternatives include oral chloroquine 250 mg once a day and oral quinacrine 50 to 100 mg once a day. (See also recommendations on screening for chloroquine and hydroxychloroquine retinopathy.) Hydroxychloroquine can rarely cause skeletal or cardiac muscle toxicity.

Methotrexate (15 to 20 mg orally or subcutaneously once a week), azathioprine (2 mg/kg orally once a day), or mycophenolate mofetil (1 to 1.5 grams orally twice a day) can be added to hydroxychloroquine in patients with uncontrolled mild to moderate disease who would otherwise be candidates for a course of corticosteroids. The ultimate goal is to maintain disease remission either without the need for corticosteroids or with only the lowest dose possible.

Belimumab (10 mg/kg IV every 2 weeks for 3 doses, then 10 mg/kg IV once a month or 200 mg subcutaneously once a week) should be considered if patients have uncontrolled disease or frequent flares, particularly for joint, skin, or nonsevere hematologic manifestations (2). It can be used in addition to hydroxychloroquine and in combination with other drugs depending on the specific system involved and severity of disease.

Treatment includes induction therapy to control acute severe manifestations followed by maintenance therapy. Corticosteroids are first-line therapy. A combination of a corticosteroid and other immunosuppressants is typically used in active severe disease (ie, lupus nephritis with impaired renal function or CNS involvement).

The complication for which there is the strongest evidence for treatment efficacy is lupus nephritis. Methylprednisolone 1 g by slow (1-hour) IV infusion on 3 successive days is often the initial treatment, although trial evidence for this pulse corticosteroid therapy is lacking. Then, oral prednisone given in doses of 0.5 to 1 mg/kg once a day (usually 40 to 60 mg once a day) is initiated and the dose is adjusted according to the manifestation of SLE. Corticosteroids should be tapered as soon as allowed by the disease, usually within 6 months, to limit adverse effects. Cyclophosphamide (see table IV Cyclophosphamide Protocols for Systemic Lupus Erythematosus) or mycophenolate mofetil (3 g a day orally in 2 doses) is also used for induction therapy along with corticosteroids.

Recently, adding belimumab in a dose of 10 mg/kg IV monthly to corticosteroids and mycophenolate or corticosteroids and cyclophosphamide has been shown to lead to a better renal response and complete renal response at 6 months compared to corticosteroids and mycophenolate or corticosteroids and cyclophosphamide alone (3). Vocloscorin in a dose of 23.7 mg orally twice a day in combination with mycophenolate mofetil and a rapidly tapered course of corticosteroid has been shown to lead to better renal outcomes at one year than corticosteroids and mycophenolate mofetil alone (4). Both belimumab and voclosporin are now often being used to treat lupus nephritis (class III, IV, V), but clear guidelines for their use are not yet available (5). Classification of lupus nephritis is based on histologic findings on renal biopsy (see table Classification of Lupus Nephritis).

Cyclophosphamide use for more than 6 months is discouraged because of potential toxicities, including increased risk of cancer. Once disease control is achieved, patients are transitioned to either mycophenolate mofetil (1 to 1.5 g orally 2 times a day) or azathioprine (0.5 to 1.5 mg/kg orally twice a day) for maintenance. Women of childbearing age for whom cyclophosphamide is being considered should be informed about the risk of gonadal toxicity and offered a fertility consult for ovarian protection or egg harvesting when possible.

In CNS lupus, including transverse myelitis, treatment recommendations are based on anecdotal evidence, and options include IV cyclophosphamide or IV rituximab (eg, 1 g on day 1 and day 15 given at 6-month intervals) in addition to a corticosteroid.

First-line therapy for thrombocytopenia and hemolytic anemia includes moderate- or high-dose corticosteroids (typically prednisone, 1 mg/kg orally once a day, maximum 80 mg a day) along with an immunosuppressant (azathioprine 2 mg/kg orally once a day  or mycophenolate mofetil 1 g orally every 12 hours). IV immune globulin 400 mg/kg once a day for 5 consecutive days or 1 g/kg once a day for 2 days may be useful, particularly if high-dose corticosteroids are contraindicated (eg, in patients with active infection). Rituximab is an alternative option for refractory cases (2).

Patients with end-stage renal disease can undergo kidney transplantation, as an alternative to dialysis, with a successful outcome, especially if their disease has been in remission.

Improvement of severe SLE often takes 4 to 12 weeks. Thrombosis or embolism of cerebral, pulmonary, or placental vessels requires short-term treatment with heparin and longer treatment with warfarin. If the diagnosis of antiphospholipid syndrome is confirmed, lifelong therapy (usually warfarin) is usually indicated. The initial target international normalized ratio is usually 2 to 3.

A new drug anifrolumab (IgG1κ monoclonal antibody to type I interferon receptor), at a dose of 300 mg IV every 4 weeks, may be added to standard therapy for the management of moderate to severe systemic lupus erythematosus, particularly in those with severe skin disease. However, patients with active and severe neuropsychiatric or renal disease were not included in the pivotal trial (6).

Chronic disease should be treated with the lowest dose of corticosteroids (eg, oral prednisone ≤ 7.5 mg once a day or its equivalent) and other drugs that control inflammation (eg, antimalarials, immunosuppressants [mycophenolate mofetil or azathioprine]) to maintain remission (2). Treatment should be guided by clinical features primarily, although anti-dsDNA antibody titers or serum complement levels may be followed, particularly if they have correlated with disease activity in the past. However, anti-dsDNA antibody titers or serum complement levels may not parallel nonrenal disease flares. Other pertinent blood and urine tests may be used to assess specific organ involvement.

Calcium, vitamin D, and bisphosphonate therapy (see prevention of osteoporosis) should be considered in patients taking corticosteroids long term.

If combination immunosuppressive therapy is used, patients should be given prophylaxis for opportunistic infections, such as Pneumocystis jirovecii (see prevention of Pneumocystis jirovecii pneumonia), and vaccines against common infections (eg, streptococcal pneumonia, influenza, COVID-19).

All patients should be closely monitored for atherosclerosis, and cardiovascular risk reduction is a key part of management (see treatment of atherosclerosis). Long-term anticoagulation is vital in patients with antiphospholipid antibodies and history of thrombosis (see also Anticoagulants).

Pregnant women should remain on hydroxychloroquine throughout their pregnancy, and low-dose aspirin is recommended as well. When clinical antiphospholipid syndrome is present, as manifested by prior thrombotic events, full anticoagulation therapy with low molecular weight or unfractionated heparin is advised. If the pregnant woman has positive antiphospholipid syndrome antibodies and prior late-stage fetal loss or recurrent 1st trimester miscarriages, prophylactic low molecular weight or unfractionated heparin can be considered during pregnancy and 6 weeks postpartum. When the patient has positive serologies but no prior obstetric or thrombotic events, recommendations are less clear. Co-management by a hematologist, an obstetrician, and a rheumatologist should be considered when managing these patients.

Mycophenolate mofetil is teratogenic. Because of this teratogenicity and the known poor outcomes related to active SLE during pregnancy, women should ideally conceive after their disease has been in remission for 6 months or longer. If the patient needs to remain on immunosuppression (eg, ongoing maintenance therapy for lupus nephritis), mycophenolate mofetil is usually switched to azathioprine at least 6 months prior to conceiving.

1. 1. Alarcón GS, McGwin G, Bertoli AM, et al: Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: Data from LUMINA, a multiethnic US cohort (LUMINA L). Ann Rheum Dis 66(9):1168–1172, 2007. doi: 10.1136/ard.2006.068676

2. 2. Fanouriakis A, Kostopoulou M, Alunno A, et al: 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis 78(6):736-745, 2019. doi:10.1136/annrheumdis-2019-215089

3. 3. Furie R, Rovin BH, Houssiau F, et al: Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med 383(12):1117-1128, 2020. doi:10.1056/NEJMoa2001180

4. 4. Rovin BH, Teng YKO, Ginzler EM, et al: Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial.Lancet 397(10289):2070-2080, 2021. doi:10.1016/S0140-6736(21)00578-X. Erratum in: Lancet 397(10289):2048, 2021.

5. 5. Bajema IM, Wilhelmus S, Alpers CE, et al. Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices. Kidney Int 93(4):789-796, 2018. doi:10.1016/j.kint.2017.11.023

6. 6. Morand EF, Furie R, Tanaka Y, et al: Trial of anifrolumab in active systemic lupus erythematosus. N Engl J Med 382(3):211-221, 2020. doi:10.1056/NEJMoa1912196