Systemic lupus erythematosus (SLE) is a multisystem, inflammatory disorder. Its treatment warrants general anti-inflammatory measures as well as organ-specific, preventive, or focused measures concentrating on sets of commonalities. The author has chosen to use the eight organ/systemic components validated for use in clinical trials based on the BILAG. Otherwise known as the British Isles Lupus Assessment Group index, the third version of the BILAG compiled nearly 100 symptoms, signs, and imaging and laboratory findings and divided them into eight categories ( Table 9-1 ). The management of renal manifestations of SLE was covered in the previous chapter. This section provides an overview of a clinical approach toward managing the remaining seven systems using case presentations and discussion, differential diagnoses, and treatment overview. The reader should be cautioned that other than for the kidney, there is no established, evidence-based treatment for any of the manifestations of the seven systems reviewed in this chapter. Thus, this chapter constitutes a compilation of consensus-derived, eminence-based recommendations.
THE “GENERAL,” OR CONSTITUTIONAL SYSTEM
Patricia is a 36-year-old black woman with an established diagnosis of SLE of 5 years’ duration. The disease has been manifested by inflammatory arthritis, mild proteinuria, anemia, pleuritic pain, and rashes. Her current treatment includes hydroxychloroquine, methotrexate 15 mg weekly, 5 mg of prednisone daily, topical corticosteroids, and ibuprofen. At this visit, she relates having gone to the beach a few days before and relates that she is tired, achy, has lost her appetite, She appears toxic but denies any infection. Patricia’s temperature is 100.6 ° F, cervical adenopathy is present, and a moderate amount of synovitis is evident in the wrists, hands, ankles, and feet. An acute cutaneous lupus rash is present on her cheeks, the “V” area of the chest, and forearms. Laboratory work includes sedimentation rate 85 (nL < 20), hemoglobin 9 mg/dL (nL > 12.0), C3 complement 39 mg/dL (nL 80–120), anti DNA (Farr) 300 (normal < 5). You conclude that the patient is experiencing a generalized flare. What is the best approach for managing this problem?
Symptoms and Signs: Fatigue, Fever, Adenopathy, Weight Loss
It is common for patients with lupus to feel “unwell.” Generalized complaints of being tired and achy are present in the majority of patients who relate decreased stamina or endurance, malaise, a flu-like sensation, or “having the blahs.” The first matter a clinician needs to address is to ensure that these symptoms are not due to infection or a comorbidity. In other words, does the patient have cancer, hypothyroidism (up to 20% with SLE have thyroid antibodies), an opportunistic process, or severe anemia (e.g., heavy periods in a young woman with inflammatory activity suppressing the bone marrow)? Fatigue is highly subjective and can result from psychosocial stressors, malnutrition, substance abuse, or even an early pregnancy. Up to 30% of patients with SLE have concurrent fibromyalgia, and this syndrome can mimic lupus flares. In Patricia’s case, the aggravation of rashes by exposure to the sun, elevation of acute phase reactants, and findings of adenopathy tend to rule out these considerations, but the situation is not always clear. If fatigue and aching due to inflammation are not addressed, systemic manifestations such as rashes, fevers, or swollen glands will follow shortly. Usually, generalized nonspecific lupus activity promptly responds to anti-inflammatory regimens such as moderate doses (0.5 mg/kg/day) of prednisone for several weeks, although milder flares may respond to nonsteroidal anti-inflammatory therapy.
The presence of temperatures above 99.6 ° F is by definition a fever. Active lupus is frequently associated with fevers and tachycardia. Infection and drug-induced fevers need to be ruled out; most lupus-induced temperature elevations are nonfocal. Any persistent temperature higher than 100 ° F in a lupus patient who is on corticosteroids, salicylates, acetaminophen, or nonsteroidals should be taken seriously and may be a reason to admit the patient to the hospital.
Generalized adenopathy is present in 15% of patients with SLE during the course of disease. The lymph nodes are rubbery and movable as opposed to malignancies in which they are matted and firm. Swollen glands usually quickly disappear with anti-inflammatory regimens, such as prednisone 0.25 mg/kg daily for several weeks.
Patients with lupus may initially present with weight loss in increments of up to 10% of their body weight. Involuntary weight loss from SLE is due to inflammation, resolving nephrotic syndrome, or steroid tapering. Underlying systemic processes such as a malignancy, malnutrition or a psychiatric disorder should be ruled out ( Table 9-2 ).
|Fever||Presents early or with flares|
|Infection should be ruled out especially if on steroids/immune suppressive|
|Responds to nonsteroidals, corticosteroids|
|Fatigue||Malaise present in most lupus patients|
|Coexisting conditions should be ruled out: fibromyalgia, drug-related, metabolic|
|Antimalarials/steroids help fatigue related to inflammation|
|Ameliorated by good sleep hygiene, pacing, stress reduction|
|Adenopathy||Seen in 15% with SLE and associated with inflammation|
|Generalized, nodes are movable and rubbery|
|Responds to NSAIDs, antimalarials, steroids, immune suppressives|
|Weight loss||Often an initial presentation; responds to anti-inflammatory regimens|
|Need to rule out steroid withdrawal, resolving nephrosis|
Mr. Jenkins is a 50-year-old white man who has a long-standing history of chronic cutaneous lupus erythematosus (CCLE) with mild systemic complaints and leukopenia. He smokes two packs of cigarettes a day, and is employed in the moving and storage business. He took hydroxychloroquine for 10 years but has not been compliant with it recently. Mild flares have been treated with topical over-the-counter hydrocortisone creams. As a diabetic, he has been cautioned against using systemic steroids. Over the past 3 months, the patient reports that his skin has become gradually worse. You note that 80% of his body is covered with rash, which is more severe in sun-exposed regions. There are regions of chronic scarring, along with alopecia and acute cutaneous lesions. What therapeutic approaches would be optimal in this circumstance?
Seventy percent of patients with SLE have skin involvement, and individuals who do not fulfill criteria for systemic lupus but have pathologic evidence on skin biopsy for lupus have cutaneous lupus. Eighty percent of the latter group is termed chronic cutaneous (discoid) lupus ( Fig. 9-1 ). (The remaining 20% of patients have urticarial lupus, bullous lupus, tumid, hypertrophic, lupus pernio, subacute cutaneous lupus erythematosus, lupus pemphigoid, or lupus panniculitis. These lesions can overlap with discoid lupus [ Table 9-3 ].) CCLE is histologically characterized by hyperkeratosis, follicular plugging, and dermal atrophy.Ultraviolet light exposure, sun-sensitizing medications, and tobacco abuse are the principal aggravating factors for chronic cutaneous lupus lesions ( Table 9-4 ). New rashes associated with systemic flares are termed “acute cutaneous lupus erythematosus.”
Cutaneous lupus can coexist and be difficult to differentiate from other lesions. For example, malar rashes are prominent features of rosacea and polymorphous light eruption, but lupus uniquely tends to spare the nasolabial folds. Psoriasis and eczema can be mistaken for cutaneous lupus, and occasionally, a skin biopsy is performed. With the exception of urticarial lupus, the lesions tend not to itch.
Management of Acute Cutaneous Lupus Erythematosus
Mr. Jenkins has a mixed picture of both acute cutaneous lupus erythematosus (ACLE) and CCLE. Treating acute cutaneous lupus flares involves staging the degree of activity of systemic disease. This non-scarring rash usually responds quickly to moderate to high doses of corticosteroids (0.5 to 1 mg/kg/day of prednisone equivalent). The range of involvement of ACLE varies from a transient flare secondary to imprudent sun exposure to the onset of new, serious organ-threatening disease. A complete blood chemistry panel, complete blood count, acute phase reactants, complement levels, anti-DNA should be obtained, along with a screen for specific organ involvement. This can include a chest x-ray study, electrocardiogram, two-dimensional echocardiogram, urinalysis, or viewing a peripheral blood smear, depending on the patient’s symptoms or signs. Infections can also produce concomitant systemic flares. Steroid-sparing agents such as immune suppressants may be indicated.
Management of Chronic Cutaneous Lupus Erythematosus
As in the case of Mr. Jenkins, lifestyle can play an important role in following the activity of CCLE. His job involves some outdoor responsibilities, and ultraviolet light exposure can aggravate rashes. Two thirds of patients with SLE self-report sun sensitivity, of whom half have a “wheal and flare” reaction to the administration of ultraviolet light. Some patients observe aggravation of fatigue, fevers, or aching with ultraviolet light exposure. Sun avoidance is a key intervention for CCLE patients. They should minimize midday sun exposure and be careful at higher altitudes, where ultraviolet radiation is greater. Sunscreens consist of agents that block ultraviolet A and B light and are shown in Table 9-5 . Topical corticosteroids are best absorbed as ointments and vary widely according to potency ( Table 9-6 ). Fluorinated steroids are available by prescription only, whereas hydrocortisone preparations are sold over the counter. The former should never be used on the face for more than 2 weeks, because they can produce cutaneous atrophy and accentuate telangiectasias. Occasionally, occlusive dressings or intralesional injections may be indicated. Tacrolimus or pinecrolimus represent alternative topical interventions to corticosteroids but are not as effective.
|Level of Potency||Generic and Trade Drug Names|
|High potency||Clobetasol, betamethasone, diflorasone, halobetasol, amcinonide (e.g., Temovate, Diprolene, Psorcon, Ultravate, Elcon)|
|Midpotent||Triamcinolone, fluocinonide, fluticasone, mometasone (e.g., Diprosone, Valisone, Kenalog, Lidex, Cyclocort)|
|Mild||Hydrocortisone, dexamethasone, prednisolone, methylprednisolone (e.g., Synalar, Westcort, Locorten, Aristocort, DesOwen)|
|Rule #1: Never use fluorinated steroids on the face for more than 2 weeks, or they can lead to accelerated cutaneous atrophy.|
|Rule #2: Ointments are 80% absorbed, lotions/gels 50%, and creams 20%, but the latter is the most comfortable vehicle. Occlusive dressings, sprays, or intralesional injections may be indicated in specialized circumstances.|
|Rule #3: Apply high-potency steroids for more active or inflamed lesions, and lower potency for maintenance or mild lesions.|
Antimalarial remedies, especially hydroxychloroquine (HCQ; Plaquenil), are the cornerstone of managing CCLE. Doses of 5 mg/kg/day will heal 80% of lesions over a 3-month period. HCQ works by blocking TLR 7 and 9 (toll receptors) and raises intracellular pH, which interferes with cell signaling and decreases the area of surface receptor interactions with cytokines by invaginating them into the lysosome. Tobacco smoke also diminishes the effectiveness of antimalarial therapies and is associated with more lupus activity in general. Approximately 10% of patients cannot tolerate HCQ owing to cutaneous, musculoskeletal, or gastrointestinal reactions. Over a 10-year period, 3% of patients given HCQ develop macular changes, which is almost always reversible with the drugs discontinuation. Individuals unable to tolerate HCQ may respond to quinacrine (50–100 mg daily), an antimalarial that does not affect the eyes, or dapsone, retinoids, or thalidomide. Chloroquine is much more toxic to the retina than HCQ but may be safely used for 1 to 3 months for severe, refractory CCLE lesions. All patients with CCLE lesions should be screened for systemic activity, and because CCLE also responds to methotrexate or azathioprine, these agents may be appropriate interventions in selected circumstances ( Table 9-7 ).
Management of Other Forms of Cutaneous Lupus
Mucosal ulcerations are found in 20% of patients with SLE. They usually appear on the soft or hard palate, nasal mucosa, or vaginal wall. These lesions respond to dental gels impregnated with steroids or lidocaine, buttermilk, or peroxide gargles. Subacute cutaneous lupus erythematosus is found in 10% of patients with SLE at any given time and may coexist with CCLE. This nonscarring papulosquamous lesion can appear in an annular or polycyclic form, especially in individuals who are anti SSA (Ro) positive and is hence observed in patients with Sjögren’s syndrome. More resistant to antimalarials than CCLE, subacute cutaneous lupus rashes can also be induced by numerous prescription drugs and are ameliorated by retinoid derivatives. Lupus pemphigoid responds to mycophenolate mofetil, bullous lupus to dapsone, lupus profundus (panniculitis) is a dermal lesion that can be ameliorated with dapsone and surprisingly nonsteroidal anti-inflammatory agents.
Cutaneovascular Manifestations: Raynaud’s Phenomenon, Livedo Reticularis, and Vasculitis
Raynaud’s phenomenon is a feature noted in up to 25% of lupus patients. Usually independent of inflammatory activity, Raynaud’s phenomenon represents vasomotor instability as a manifestation of dysautonomia. Patients with Raynaud’s phenomenon respond to cold preventive measures (e.g., mittens, cold avoidance, hand warmers, not using beta blockers) and vasodilators. The latter include nitrates, calcium channel blockers, alpha-adrenergic blockade, and 5-phosphodiesterase inhibitors. Livedo reticularis is a common feature of SLE that does not warrant treatment but is associated with dysautonomia and the presence of antiphospholipid antibodies. Other uncommon cutaneovascular manifestations of SLE include erythromelalgia, leukocytoclastic vasculitis, cyroglobulinemic vasculitis, digital or peripheral vasculitis, cutaneous necrosis, vasculitis, or gangrene. They are associated with inflammation, and they can represent serious disease activity that warrants corticosteroid and immune suppressive interventions (discussed further in the vasculitis section).
You are called by the local emergency room regarding Mrs. Jones. She was diagnosed with SLE 15 years ago on the basis of acute central nervous system (CNS) disease manifested by seizures, psychosis, fever, and headache. After 2 weeks in the hospital where her disease was managed with high-dose corticosteroids and she was given the first of six monthly doses of intravenous cyclophosphamide, the disease went into remission for many years. Three weeks before admission, Mrs. Jones began complaining of numbness, burning, and tingling in her legs. Earlier tonight, she attended a concert. When the strobe lights went on, she had a grand mal seizure and paramedics transported her to your hospital. By the time you arrive, she is no longer postictal and feels well. You are asked by the hospital staff if she has had a recurrence of CNS SLE. How should her complaints be best evaluated?
NERVOUS SYSTEM MANIFESTATIONS
The American College of Rheumatology has delineated 19 specific presentations of SLE affecting the nervous system, which are listed in Table 9-8 . Twelve involve the CNS, of which five are behavioral (acute confusional state, mood disorder, anxiety disorder, psychosis, cognitive dysfunction). Just about any part of the brain can be affected by any of the lupus syndromes listed in the next section such as myelopathy, movement disorders, seizures, meningitis, and demyelination. Seven affect the peripheral nervous system ( Table 9-9 ).
Central Nervous System Vasculitis and Organic Brain Syndrome
The differential diagnosis of nervous system manifestations of SLE is among the most problematic in the disease. CNS vasculitis is one of the most difficult to evaluate and manage. It can often be the initial presentation of lupus, and most patients with CNS SLE have had the disease for less than 5 years. The typical presentation is that of low-grade fevers, cognitive dysfunction, headache, malaise, and stiff neck that progresses to seizures, stupor, and coma. Patients are often initially diagnosed as having a flu-like illness. Fortunately, prompt performance of a lumbar puncture with findings of pleocytosis, elevated spinal fluid protein, increased IgG synthesis rate, oligoclonal bands, or the presence of antineuronal antibodies can accelerate confirming the diagnosis if cultures are negative. Magnetic resonance imaging (MRI) can be normal or demonstrates diffuse, generalized changes. In the case of Mrs. Jones, the emergency room physicians suspected CNS vasculitis and administered high doses of corticosteroids for what turned out to be an organic brain syndrome. Her lupus was long standing and under good control, and the seizure represented light-induced activation of a scar focus.
Organic brain syndrome is best managed with steroid avoidance, emotional support, and cognitive behavioral therapy. CNS vasculitis responds to pulse doses of steroids, cyclophosphamide, rituximab, or in serious cases, apheresis, but there is no established evidence based management strategies. The most frequently used protocol is 1 g of methylprednisolone daily for several days followed by 1 mg/kg/day of prednisone equivalent for several weeks, followed by a slow tapering. Cyclophosphamide is usually given in doses of 750 mg/m 2 monthly for 6 months and then discontinued. A 40 to 60 mL/kg plasma exchange can be added for the first few weeks every other day if there is no initial response. Recent reports suggest that rituximab or intrathecal methotrexate can be administered in lieu of cyclophosphamide.
Vasomotor Central Nervous System Lupus: Lupus Headache and Cognitive Dysfunction
Ten percent of the United States population suffers from migraine headaches; this prevalence is doubled in SLE. Single photon emission computed tomography (SPECT), positron emission tomography (PET), and functional MRI has documented the association of this phenomena with increased cerebral blood flow. Conversely, cognitive dysfunction in SLE correlates with intermittent diminished flow and Raynaud’s phenomenon ( Fig. 9-2 ). This phenomon represents the dysautonomic aspects of SLE, which implicates sympathetic mediated vasomotor instability as the principal inciting factor of these symptoms. Headache and cognitive impairment are intermittent which distinguishes them from a brain tumor or dementia. They are worsened by anxiety and stress. High doses of corticosteroids are unnecessary but, unfortunately, temporarily often subjectively beneficial, which misleads clinicians. Neither vasodilator nor vasoconstrictive therapies are effective over the long run. Anxiolytics, psychotropic agents, antimalarials, antidepressants, cognitive behavioral therapy, and biofeedback represent the treatments of choice.
Inflammation of cranial nerves or other peripheral neuritides respond quickly to moderate-dose corticosteroid therapy for several weeks. Involvement of several single nerves (mononeuritis multiplex) can be confirmed by electrical studies or nerve biopsy and requires high-dose corticosteroids for several months and intravenous immune globulin. Acute neuropathies, such as Guillain-Barré syndrome may benefit from apheresis or intravenous immune globulin.