Lupus is both an acute and a chronic autoimmune, multisystem illness. Lupus has several forms: systemic (SLE), discoid (DLE, scarring rash only), drug-induced (DILE), and neonatal (NLE). For purposes of brevity, drug-induced lupus, which is relatively rare, and discoid lupus are not discussed in this chapter.
Discoid rash in lupus erythematosus. This rash occurs in patients with systemic lupus and with discoid lupus.
Absence of systemic symptoms, not the discoid rash itself, distinguishes discoid from systemic LE, since the discoid rash can occur in either.
Subacute cutaneous lupus is a form of systemic lupus in which a characteristic rash predominates, serology is strongly positive (see below), and visceral involvement is usually mild. NLE occurs in infants of women with a specific serological profile; it is briefly discussed in the section on pregnancy (below).
Rash of Subacute cutaneous lupus
SLE affects women nine times as often as men, and blacks four times as often as whites. The reasons for this distribution, and for lupus' predilection to affect mostly people between the ages of 15 and 45, are unknown. Differential diagnosis and management differ if the patient is newly diagnosed and untreated patient or if the patient has been treated for many years., Two recent American textbooks present extensively referenced and detailed discussion of all aspects of these illnesses.,
Lupus nephritis, in mice and men, is the prototype for explanations of the pathogenesis of SLE; however, principles that explain lupus nephritis may not apply to lupus arthritis, rash, thrombocytopenia, fever, adenopathy, alopecia, neurologic, or cardiac valvular disease. Family, twin, and genetic studies implicate a strong genetic predisposition to the disease. Most likely the important genes, when identified, will be those that modulate or control processing of immune complexes or antigens and those that terminate immune response. A particularly attractive theory suggests that failure to process the products of an immune response (the garbage managing aspect of immunity) is defective in SLE patients. Antibody to double-stranded DNA, possibly induced by exogenous infecting agents, when bound to antigen, triggers an inflammatory response that activates complement, leukocytes, the coagulation system, and pro-inflammatory cytokines, inducing local tissue damage. New work suggests that interferon is overactive in SLE; it is not clear whether the abnormality is a cause or result of SLE, but current theories suggest that it is a cause.
Some drugs, notably hydralazine and procaine amide, induce DILE, which is strikingly similar to idiopathic SLE; chronic infections, such as leprosy, and acute infections, such as rheumatic fever and several common viruses, induce transient clinical and serologic phenomena that resemble SLE. These are the only present clues suggesting that the primary cause of SLE is an exogenous agent affecting a genetically incompetent (for this agent only) host.
A. New diagnosis
The classical patient with lupus is easy to recognize: a young woman with fever, lymphadenopathy, butterfly rash, symmetrical small joint arthritis, alopecia, pleuritic pain, and proteinuria. However, most patients have symptoms in only one or two systems at onset; many accumulate organ system involvement over several years. In order of frequency, these are the common presenting symptoms of lupus.
1. Polyarthritis, usually of the metacarpophalangeal, interphalangeal, and wrist joints may be fleeting or sustained. On occasion, lupus arthritis is indistinguishable from rheumatoid arthritis;
2. Constitutional symptoms include malaise, fatigue, low grade fevers (sometimes high fever), lymphadenopathy, and weight loss.
3. Mucocutaneous symptoms include rashes, alopecia, vasculitic lesions, and mucosal ulcers. Rashes characteristically involve the malar areas, bridge of the nose, hairline, shawl area, and extensor surfaces of the upper arms, the finger pulps and periungual areas. Erythema is commoner than a raised rash, but only the raised rash is diagnostic. Small vasculitic lesions occur on the extensor surface of the elbow. Involvement of the face is characteristic; the classical butterfly (over the bridge of the nose) occurs in a minority of patients.
Butterfly rash of SLE. Occurrence over the bridge of the nose is characteristic.
Digital vasculitis in SLE.
4. Hair loss, particularly frontal, with short, broken hairs, is common.
Alopecia in SLE.
5. Ulcers on the roof of the mouth usually indicate severe disease. These ulcers are generally painless and must be specifically sought.
Hard palate ulcer in SLE (arrow).
6. Proteinuria (see below).
7. Hematologic abnormalities (anemia, leukopenia, cytopenia; see below).
8. Serositis: Pleuropericardial pain is more frequent than is rub or effusion; it is often transient. Abdominal pain is usually non-descript and undefinable by radiography or endoscopy.
9. Neuropsychiatric: Any neurologic symptom is consistent with lupus; headache, mood disorder, cognitive disorder, psychosis, seizure, stroke, meningitis, and movement disorder all occur. No single manifestation is diagnostic of neurologic lupus; attribution of any to lupus, as opposed to infectious meningitis, for instance, is by exclusion.
10. Incidental finding of a test abnormality, such as leukopenia, thrombocytopenia, or positive antinuclear antibody.
Myelopathy, myocarditis, pulmonary hypertension, acute lupus pneumonitis, pulmonary fibrosis, lupus profundus, and acute psychosis are rare initial symptoms of lupus.
B. Established diagnosis
Patients with SLE follow three types of courses: chronic active, relapsing-remitting, and long-remitting. The chronic active form is most common, accounting for about half of patient-years. A common mistake in treating a patient with known SLE is to attribute any deterioration in health in a patient to lupus activity. Attribution of a complication to active SLE should always occur by exclusion, after infection, drug reaction, atherosclerosis, and neoplasm have been ruled out. Even arthritis in a lupus patient may be due to infection or to osteonecrosis. Osteoporosis with fracture may be a cause of extremity or back pain.
Initial evaluation of a patient suspected of having lupus should include: complete blood count, sedimentation rate, chemistry profile, lipid profile, and urinalysis. If the urinalysis is abnormal, 24-hour urine protein and creatinine clearance measurements are indicated. Other available tests add to general information about the patient but are not critical for management unless indicated by specific symptoms.
B. Serological tests
Initial immunological evaluation should include: antinuclear antibody, anti-double-stranded DNA antibody, anti-Sm (which stands for anti-Smith, not anti-smooth muscle) antibody, complement (as C3, C4, and/or CH50). If vascular occlusion or pregnancy loss is suspected or has previously occurred, tests for anticardiolipin antibody and lupus anticoagulant (antiphospholipid antibody) are helpful. If a woman is contemplating pregnancy, in addition to antiphospholipid antibody, tests for antibody to Ro/SSA and La/SSB will be predictive for occurrence of neonatal lupus in the fetus. Other serological tests may be of interest in special circumstances but are not, as a rule, critical for management.
A. Confusing other diseases
Infections such as mononucleosis, HIV, endocarditis, and streptococcal sequelae (rheumatic fever, post-streptococcal glomerulonephritis) resemble SLE. Lymphomas, leukemias, and rarely myxoma and renal cell carcinoma may induce lupus-like symptoms. The rash of rosacea is easy to confuse with that of SLE; polymorphous light eruption and antibiotic-induced photosensitivities also resemble lupus rashes. The presentations of idiopathic or drug-induced thrombocytopenia and of post-streptococcal or IgA glomerulonephritis resemble these organ system presentations of lupus. Lupus' capacity for causing abnormalities of multiple organ systems distinguishes it as a specific diagnosis.
B. Overlap diseases
Some lupus patients have symptoms that overlap those of rheumatoid arthritis, scleroderma, dermatomyositis, Sjogren syndrome, or systemic vasculitis. In such patients, the diagnostic label is less important than are the symptoms and organ systems involved, since treatment is directed to specific abnormalities of specific organ systems.
C. ACR Criteria and how to use them
The American College of Rheumatology has devised Classification Criteria for SLE (See Table 1). When a patient has four of the following, she is said to have SLE: malar rash; discoid rash; photosensitivity; oral ulcers; nonerosive arthritis; pleuritis or pericarditis; renal disorder; neurologic disorder; hematologic disorder; anti-DNA, anti-Sm, or antiphospholipid antibody; and antinuclear antibody.
These criteria classify groups of patients for clinical studies and do not diagnose individual patients. In individual patients, the diagnosis of lupus is fully sustainable with fewer criteria. For instance, a patient who has high titer antinuclear antibody and lupus glomerulonephritis on biopsy, but who has no other symptoms, clearly has lupus even though she has only two criteria. Conversely, a patient with rheumatoid arthritis might have antinuclear antibody, hemolytic anemia or thrombocytopenia, proteinuria, and pleurisy-more than four criteria-and not have lupus. Hence the ACR Criteria should not be used to exclude or confirm the diagnosis of lupus in an individual patient.
|Malar rash||Fixed erythema over malar areas, sparing nasolabial folds|
|Discoid rash||Erythematous raised patches with keratotic scaling and follicular plugging|
|Photosensitivity||Skin rash after exposure to sunlight, history or physical exam|
|Oral ulcers||Oral or nasopharyngeal, painless, by physical exam|
|Nonerosive arthritis||Tenderness, swelling, effusion in 2 or more peripheral joints|
|Pleuritis or pericarditis||Convincing history or physical exam or ECG or other evidence|
|Renal disorder||>0.5g protein/d or 3+ or cellular casts|
|Seizures, psychosis||Not due to drugs, metabolic derangement, etc.|
|Hematologic disorder||Hemolytic anemia or leukopenia (<4000 twice) or lymphopenia (<1500 twice) or thromobocytopenia (<100,000) without other causes|
|Immunologic disorder||Anti-dsDNA or anti-Sm or antiphospholipid antibodies (anticardiolipin, lupus anticoagulant, or false positive test for syphilis)|
|Positive ANA||Not drug-induced|
Table 1. 1997 Update of the 1982 American College of Rheumatology Classification Criteria for SLE (Hochberg, Arthritis Rheum 1997;40:1725).
A. Indications to Treat
Asymptomatic patients need not be treated, except when laboratory tests reveal proteinuria, hematuria or severe thrombocytopenia (<50,000/mm3). Anti-DNA antibody and complement should be monitored, but do not by themselves demand treatment if there are no associated clinical findings of disease activity.
Treatment includes non-steroidal anti-inflammatory drugs (NSAIDs), antimalarials, and low dose (20 mg prednisone/day) corticosteroids. Dosing sufficient to suppress symptoms is appropriate for patients with arthritis, fever, rash, lymphadenopathy, anemia, and serositis, but more aggressive therapy is indicated for nephritis and neurologic disease. High dose corticosteroid and immunosuppressive drugs are appropriate for systemic flare, glomerulonephritis, severe thrombocytopenia, neurologic disease, and vasculitis. Life-threatening disease mandates use of all available treatment modalities, including experimental drugs and procedures.
No agent among the new biologics has yet emerged as effective therapy, though many are now under test.
A. Lupus nephritis
Between one-third and one-half of lupus patients develop kidney disease; those with high levels of anti-DNA antibody and low serum complement levels are most at risk. Lupus nephritis is likely when urinary protein, erythrocytes, or leukocytes (in the absence of infection) occur, or when creatinine clearance falls. Renal stone, obstruction, infection, and neoplasm must be excluded. Although lupus nephritis can occur in patients with normal urinalyses and normal renal function, if serum complement is normal, important disease is unlikely.
When to do a kidney biopsy
A kidney biopsy is appropriate when the results will change treatment. The commonest reason to do a biopsy is new discovery of a modest proteinuria or celluria with normal, near normal, or recently changed creatinine clearance. A patient with normal urinalysis and renal function is not a candidate for biopsy, since likelihood of a lesion that needs treatment is low, nor is a patient with rapidly progressive renal failure, severe proteinuria, or cellular casts, since aggressive therapy is mandatory. However, in a patient with rapidly progressive disease, a biopsy to assess whether any salvageable kidney remains may occasionally be appropriate, since the results may justify withdrawal or persistence with aggressive treatment if completely scarred or potentially viable glomeruli, respectively, are found.
Types of lupus glomerulonephritis
By biopsy criteria, the following types of lupus glomerulonephritis are recognized.
A revised classification of lupus nephritis provides new details to this classification, including more focus on the blood vessels and on the renal tubules.
Despite advances in therapy, lupus nephritis causes renal failure in a minority of patients. Of those entering dialysis during acute flare, one-third will be able to discontinue dialysis within the first year. The remaining two-thirds, and those suffering gradual deterioration of renal function over several years, do not recover; they tolerate dialysis and kidney transplantation well. Despite statements to the contrary, active lupus does occur in patients on dialysis. Symptoms of lupus flare in dialysis patients are modified from those of early disease; low-grade fevers and failure-to-thrive syndromes predominate. A rising level of anti-DNA antibody is the best confirmation of active lupus in a patient on dialysis. Ordinarily, low dose oral corticosteroid is sufficient to control the flare.
Although flares of lupus in individual patients tend to repeat themselves-a patient whose prior flares have been characterized by arthritis and rash is likely to have similar future flares-the disease does change over time. Patients may develop rheumatoid-like arthritis or scleroderma-like skin; nephritis, present early in the illness in most patients who have nephritis, may nonetheless develop late.
C. Organ dysfunction and failure (non-renal)
Patients after many years of disease develop hypertension, accelerated atherosclerosis, valvular heart disease, and renal failure. Systemic vasculitis tends to be a late complication. Patients with antiphospholipid antibody develop arterial and venous thromboses and valvular heart disease. Atherosclerosis is most likely in patients who have continuing, low-grade disease activity. Cytopenias, glomerulonephritis, and hypertension are the only complications of lupus that do not cause symptoms until they are advanced. All lupus patients should therefore have periodic blood counts and urinalyses. New onset hypertension often reflects worsening nephritis. Hypertension should be treated vigorously, since hypertension itself damages renal function. Other complications will cause symptoms that patients will report. Rising anti-DNA antibody and falling complement levels are rough but unspecific guides to impending flares, especially renal. Chest pain, dyspnea, or reduced exercise tolerance, even in patients in their thirties, should alert the physician to the development of coronary artery disease due to vasculitis or accelerated atherosclerosis, or to the occurrence of pulmonary hypertension. Heart-lung transplantation is possible in the rare patient with advanced pulmonary hypertension, pulmonary fibrosis, or cardiomyopathy who is otherwise well.
Pregnancy is possible in most patients with lupus. Complications are frequent; all patients must be considered high risk. In pregnancy or planned pregnancy, referral for specialty care is always appropriate. Patients with antiphospholipid antibody are at risk for pregnancy loss; patients with anti-Ro/SSA and anti-La/SSB antibodies are at risk for delivering a child with neonatal lupus.
E. Hormones: oral contraceptive pills, estrogen replacement therapy
Controlled clinical trials recently completed suggest that oral contraceptive and post-menopausal estrogen replacement therapies are reasonably safe for lupus patients who do not have high titer antiphospholipid antibody. Since there is risk of inducing thrombosis in the latter subgroup, assessing antiphospholipid antibody status before prescribing such drugs is recommended.
Severity of lupus varies from trivial to rapidly lethal. Glomerulonephritis and neurologic disease worsen an individual patient's prognosis more than do arthritis, rash, or other organ pathology. Ten-year survival of all patients is more than 80%, but disabilities are common. Long-term complications include: renal failure, accelerated atherosclerosis (with myocardial infarction and stroke), cardiac and respiratory failure (including pulmonary hypertension), and osteoporosis and other complications of (corticosteroid) therapy. Active SLE and infection cause the majority of early deaths; atherosclerosis and renal failure are prominent causes of late death.
The American College of Rheumatology has suggested the following reasons for a primary care physician to refer a suspected lupus patient to a rheumatologist:
In lupus patients, life-threatening disease manifestations may be cardiac, hematologic, neurologic, pulmonary, renal, and generalized systemic. Severe other organ system disease may occur in the joints, skin, and gastrointestinal tract. Referral is appropriate for any severe manifestation of disease, for prognostication and life-planning, for pregnancy, for milder disease that is refractory to therapy, and for any circumstance in which the patient or the physician is uncomfortable with current diagnosis or management. It is particularly important to consider, and seek advice on, new or unexpected developments in an otherwise stable patient. Often the rheumatologist is the first to suspect that the new event is not due to active lupus but is an independent, usually infectious, event.
 Rubin R. Etiology and mechanisms of drug induced lupus. Curr Opin Rheumatol 1999;11:357-363. Contemporary thinking on drug-induced lupus, now a somewhat rare problem, but important in understanding pathogenesis.
 Boumpas DT, Austin HA III, Fessler BJ, Balow JE, Klippel JH, Lockshin MD. Systemic lupus erythematosus: Emerging concepts. Part 1: Renal, neuropsychiatric, cardiovascular, pulmonary, and hematologic disease. Ann Intern Med 1995;122:940-940
 Boumpas DT, Fessler BJ, Austin HA III, Balow JE, Klippel JH, Lockshin MD. Systemic lupus erythematosus: Emerging concepts. Part 2: dermatologic and joint disease, the antiphospholipid antibody syndrome, pregnancy and hormonal therapy, morbidity and mortality, and pathogenesis. Ann Intern Med 1995;123:42-53. These two articles summarize the important new information in almost all aspects of lupus up to the moment of publication. Important advances since these articles were published are: emergence of new criteria and more formal classification systems for various complications of lupus and initial case reports (but no definitive controlled clinical trials) on use of biologics and other new therapies.
 Lahita RG (editor). Systemic Lupus Erythematosus. 4th edition. San Diego:Academic Press, 2004. One of two major American textbooks, covering all aspects of lupus.
 Wallace DJ, Hahn BH (editors). Dubois' Lupus Erythematosus. 5th edition. Baltimore:Williams & Wilkins, 1997. One of two major American textbooks, covering all aspects of lupus.
 Hahn BH. Mechanisms of disease: antibodies to DNA. N Engl J Med. 1998;338:1359-1368. This is a detailed description of lupus pathogenesis based on the idea that specific antibody characteristics determine outcome. The model is murine lupus nephritis, so the conclusions may not apply to other manifestations of lupus in humans.
 Walport MJ. Lupus, DNase and defective disposal of cellular debris. Nat Genet. 2000;25:135-136. Contemporary theory of the basic type of defect underlying susceptibility to lupus.
 Barr SG, Zonana-Nacach A, Magder LS, Petri M. Patterns of disease activity in systemic lupus erythematosus. Arthritis Rheum 1999;42:2682-2688. This paper makes an important point: lupus is less an intermittent than a chronically present disease. The implications are that treatment should not be considered transient, but when initiated may be for very long periods of time.
 American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Guidelines for referral and management of systemic lupus erythematosus in adults. Arthritis Rheum. 1999; 42:1785-1796 This article is the 'official word' of the American College of Rheumatology on referral. The article itself tries to be a mini-textbook. It covers most essential issues, somewhat superficially and to a degree in a self-promotional way; however, the article is a good quick reference for 1999 thinking on most import lupus issues.
 Tsakonas E, Joseph L, Esdaile JM, Choquette D, Senecal JL, Cividino A, Danoff D, Osterland CK, Yeadon C, Smith CD. A long-term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group. Lupus. 1998;7:80-85.
 Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, Garrido Ed Ede R, Danieli MG, Abramovicz D, Blockmans D, Mathieu A, Direskeneli H, Galeazzi M, Gul A, Levy Y, Petera P, Popovic R, Petrovic R, Sinico RA, Cattaneo R, Font J, Depresseux G, Cosyns JP, Cervera R. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum. 2002;46:2121-2131. An experience suggesting that an easier, less toxic method of administering cyclophosphamide is equally effective as the standard NIH dosing schedule. Since the "low-dose" is given biweekly, the total amount of cyclophosphamide may not be as low as appears.
 Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, Laskin C, Fortin P, Anderson D, Kearon C, Clarke A, Geerts W, Forgie M, Green D, Costantini L, Yacura W, Wilson S, Gent M, Kovacs MJ. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 2003 Sep 18;349(12):1133-8. A prospective, randomized controlled study on warfarin dose in antiphospholipid syndrome. INR 2.0-3.0 is as effective as one 3.0-4.0.
 Van Vollenhoven RF, Engleman EG, McGuire JL. Dehydroepiandrosterone in systemic lupus erythematosus: results of a double-blind, placebo-controlled randomized clinical trial. Arthritis Rheum. 1995;38:1826-1831. This paper represents the strongest evidence favoring use of this drug. The apparent benefits are marginal at best.
 Esdaile JM. Current role of renal biopsy in SLE. Baillieres Clin Rheumatol 1998;12:433-438. A detailed description of the pros and cons of biopsy, from an expert in epidemiologic methodology.
 Weening JJ, D'Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, Balow JE, Bruijn JA, Cook T, Ferrario F, Fogo AB, Ginzler EM, Hebert L, Hill G, Hill P, Jennette JC, Kong NC, Lesavre P, Lockshin M, Looi LM, Makino H, Moura LA, Nagata M; On behalf of the International Society of Nephrology and Renal Pathology Society Working Group on the Classification of Lupus Nephritis. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 2004 Feb; 65(2): 521-530.
 Petri M. Hopkins Lupus Cohort. 1999 update. Rheum Dis Clin North Am. 2000 May;26(2):199-213 A review of a large, well analyzed clinical experience, focusing on atherosclerosis.
 Roman MJ, Shanker BA, Davis A, Lockshin MD, Sammaritano L, Simantov R, Crow MK, Schwartz JE, Paget SA, Devereux RB, Salmon JE. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med. 2003 Dec 18;349(25):2399-406. A cross-sectional ascertainment of atherosclerosis prevalence in an ambulatory SLE population: the atherosclerosis risk of having SLE is greater than that of having diabetes. Atherosclerosis correlates with low grade untreated SLE and not with cholesterol, smoking, or other risk factors.