2746 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

on the lowest possible doses of medications. LLDAS scoring uses Systemic Lupus Erythematosus Disease Activity Score-2K (SLEDAI-2K;

Touma Z et al, Lupus 19:49, 2010). SLEDAI-2K is a widely used measure of SLE disease activity; scores >3 reflect clinically active disease.

For example, active arthritis scores 4 points, rash 2 points, pleurisy

2 points, proteinuria 4 points, vasculitis 8 points, low complement 2

points, and leukopenia 1 point. LLDAS is defined currently as (1) a

SLEDAI-2K score ≤4; (2) no new lupus disease activity compared with

the previous visit; (3) physician’s global assessment ≤1 (scale 0–3); (4)

current prednisone dose ≤7.5 mg daily; and (5) well-tolerated stable

doses of antimalarials and/or immunosuppressives. LLDAS can be

achieved in 50–80% of patients and, if sustained for 2 or more years

(possible in ~30%), associates with significantly less accrual of damage

and better quality of life. Therefore, the physician should plan to induce

improvement of acute flares and then maintain improvements with

strategies that suppress symptoms to an acceptable level and prevent

organ damage. Chronic prednisone doses should be tapered to the

lowest doses possible (ideally ≤7.5 mg). Therapeutic choices depend

on (1) whether disease manifestations are life-threatening or likely

to cause organ damage, justifying aggressive therapies; (2) whether

manifestations are potentially reversible; and (3) the best approaches

to preventing complications of disease and its treatments. Therapies,

doses, and adverse effects are listed in Table 356-6.

CONSERVATIVE THERAPIES FOR

MANAGEMENT OF NON-LIFETHREATENING DISEASE

Among patients with fatigue, pain, and autoantibodies indicative of SLE

but without major organ involvement, management can be directed

to suppression of symptoms. Analgesics and antimalarials are mainstays. NSAIDs are useful analgesics/anti-inflammatories, particularly

for arthritis/arthralgias. However, two major issues indicate caution

in using NSAIDs. First, SLE patients compared with the general population are at increased risk for NSAID-induced aseptic meningitis,

elevated serum transaminases, hypertension, and renal dysfunction.

Second, all NSAIDs, particularly those that inhibit cyclooxygenase-2

specifically, may increase risk for myocardial infarction. Acetaminophen to control pain may be a good strategy, but NSAIDs are more

effective in some patients. The relative hazards of NSAIDs compared

with low-dose glucocorticoid therapy have not been established. Antimalarials (hydroxychloroquine, chloroquine, and quinacrine) often

reduce disease symptoms. Withdrawal of hydroxychloroquine results

in increased numbers of disease flares. Hydroxychloroquine prolongs

survival and reduces accrual of tissue damage, including renal damage. Some experts recommend a hydroxychloroquine blood level of

≥750 ng/mL to optimize responses in active SLE; after achieving

response, doses should be reduced. Because of potential retinal toxicity

(occurring in 6% of patients after cumulative doses of 1000 g, ~5 years

of continuing therapy), patients receiving antimalarials should undergo

ophthalmologic examinations annually. One clinical trial showed that

administration of dehydroepiandrosterone reduced activity of mild disease. If quality of life is inadequate despite these conservative measures,

treatment with low doses of systemic glucocorticoids may be necessary.

Belimumab (anti-Baff) and anifrolumab (anti-IFN type 1 receptor)

are biologics that are each effective for patients with persistent disease

activity and fatigue despite standard therapies; SLE patients most likely

to respond to belimumab have robust clinical activity (SLEDAI-2K score

of ≥10), positive anti-DNA, and low serum complement. See above

under “Management of Systemic Lupus Erythematosus” for more details

regarding SLEDAI-2K. Lupus dermatitis should be managed with topical sunscreens, anti-malarials, topical glucocorticoids, and/or tacrolimus

and, if severe or unresponsive, systemic glucocorticoids with or without

mycophenolate mofetil, azathioprine, methotrexate, or belimumab.

Anifrolumab has been highly effective in patients with lupus dermatitis.

■ LIFE-THREATENING SLE: PROLIFERATIVE FORMS

OF LUPUS NEPHRITIS

Guidelines for management of lupus nephritis have been published: see

Tables 356-3 and 356-6 and Figure 356-2. The mainstay of treatment

for any inflammatory life-threatening or organ-threatening manifestations of SLE is systemic glucocorticoids (0.5–1 mg/kg per day PO

or 500–1000 mg of methylprednisolone sodium succinate IV daily for

3 days followed by 0.5–1 mg/kg of daily prednisone or equivalent).

Evidence that glucocorticoid therapy is life-saving comes from retrospective studies from the predialysis era; survival was significantly better in people with DPGN treated with high-dose daily glucocorticoids

(40–60 mg of prednisone daily for 4–6 months) versus lower doses.

Currently, high doses are recommended for much shorter periods;

recent trials of interventions for severe SLE use 4–6 weeks of 0.5–1 mg/

kg per day of prednisone or equivalent. Thereafter, doses are tapered as

rapidly as the clinical situation permits, usually to a maintenance dose

≤7.5 mg of prednisone or equivalent per day. Many patients with an

episode of severe SLE require many years of maintenance therapy with

low-dose glucocorticoids. Frequent attempts to gradually reduce the

glucocorticoid requirement are recommended because virtually everyone develops important adverse effects (Table 356-6). High-quality

clinical studies regarding initiating therapy for severe, active SLE with

IV pulses of high-dose glucocorticoids are not available. The use of IV

pulses of glucocorticoids must be tempered by safety considerations,

such as the presence of conditions adversely affected by glucocorticoids

(e.g., infection, hyperglycemia, hypertension, osteoporosis). One open

trial showed high response rates in patients with lupus nephritis treated

with mycophenolate mofetil plus rituximab, without maintenance daily

glucocorticoids; how widely this can be used is unclear.

Cytotoxic/immunosuppressive agents added to glucocorticoids are

recommended to treat serious SLE. Almost all prospective controlled

trials in SLE involving such agents have been conducted in combination with glucocorticoids in patients with lupus nephritis. Therefore,

the following recommendations apply to treatment of nephritis. Either

cyclophosphamide (an alkylating agent) or mycophenolate mofetil

(a relatively lymphocyte-specific inhibitor of inosine monophosphatase

and therefore of purine synthesis) is an acceptable choice for induction

of improvement in severely ill patients; azathioprine (a purine analogue

and cycle-specific antimetabolite) may be effective but is associated

with more flares. In patients whose renal biopsies show ISN grade III or

IV disease, early treatment with combinations of glucocorticoids and

cyclophosphamide reduces progression to ESRD and death. Shorterterm studies with glucocorticoids plus mycophenolate mofetil (prospective randomized trials of 6 months, follow-up studies of 5 years)

show that this regimen is similar to cyclophosphamide in achieving

improvement. Comparisons are complicated by effects of race, since

higher proportions of African Americans and Latin Americansrespond

to mycophenolate than to cyclophosphamide, whereas similar proportions of whites and Asians respond to each drug. Regarding toxicity,

diarrhea is more common with mycophenolate mofetil; amenorrhea,

leukopenia, and nausea are more common with high-dose cyclophosphamide. Importantly, rates of severe infections and death are similar

in meta-analyses. Two different regimens of IV cyclophosphamide

are available for induction therapy. For white patients with northern

European backgrounds, low doses of cyclophosphamide (500 mg every

2 weeks for six total doses, followed by daily azathioprine or mycophenolate maintenance) are as effective as standard high doses, with

less toxicity. Ten-year follow-up has shown no differences between the

high-dose and low-dose groups (death or ESRD in 9–20% of patients in

each group). It is not clear whether the data apply to U.S. populations,

especially African Americans and Latinas. In general, it may be better

to induce improvement in African-American or Hispanic patients with

proliferative glomerulonephritis with mycophenolate mofetil (2–3 g

daily) rather than cyclophosphamide, with the option to switch if no

evidence of response is detectable after 2–6 months of treatment. For

whites and Asians, induction with either mycophenolate mofetil or

cyclophosphamide is acceptable. The presence of cellular or fibrotic

crescents in glomeruli with proliferative glomerulonephritis, or rapidly

progressive glomerulonephritis, indicates more severe disease and

a worse prognosis. High-dose cyclophosphamide (500–1000 mg/m2

body surface area given monthly IV for 6 months, followed by azathioprine or mycophenolate maintenance) is an acceptable approach for

patients with severe nephritis. Cyclophosphamide and mycophenolate

Systemic Lupus Erythematosus

2747CHAPTER 356

responses begin 3–16 weeks after treatment is initiated, whereas glucocorticoid responses may begin within 24 h. The incidence of ovarian

failure, a common effect of high-dose cyclophosphamide therapy

(but probably not of low-dose therapy), can be reduced by treatment with a gonadotropin-releasing hormone agonist (e.g., leuprolide

3.75 mg intramuscularly) prior to each monthly cyclophosphamide

dose. Recent studies have shown improved short-term responses with

a combination of calcineurin inhibitors (tacrolimus, voclosporin)

plus mycophenolate (MMF) plus glucocorticoids (GC) compared

with MMF or cyclophosphamide with GC. Complete renal responses

occurred in 41% on triple therapy at 52 weeks compared with 21% on

double therapy. Including partial with complete renal responses, 70%

on triple vs 50% on double therapy improved by 24 weeks. Calcineurin

inhibitors are nephrotoxic; they should probably be discontinued after

6 months if no signs of improvement occur and used for no more than

12 months in most patients.

For maintenance therapy, mycophenolate and azathioprine probably

are similar in efficacy and toxicity; both are safer than cyclophosphamide. In a multicenter international study, mycophenolate was

superior to azathioprine in maintaining renal function and survival in

patients who responded to induction therapy with either cyclophosphamide or mycophenolate. Patients with high serum creatinine levels

(e.g., ≥265 μmol/L [≥3.0 mg/dL]) many months in duration and high

chronicity scores on renal biopsy are not likely to respond to any of

these therapies. The number of SLE flares is reduced by maintenance

therapy with mycophenolate mofetil (1.5–2 g daily) or azathioprine

(1–2.5 mg/kg per day). Mycophenolate, cyclophosphamide, methotrexate, and calcineurin inhibitors can cause fetal harm; patients

should be off any of these for at least 3 months before attempting to

conceive. Azathioprine can be used if necessary to control active SLE

in patients who are pregnant. Patients treated with azathioprine may be

prescreened for homozygous deficiency of the TMPT enzyme (which is

required to metabolize the 6-mercaptopurine product of azathioprine)

because they are at higher risk for bone marrow suppression.

Most SLE patients with membranous (INS class V) nephritis also

have proliferative changes and should be treated for proliferative disease. However, some have pure membranous changes. Treatment for

this group is less well defined. Some authorities do not recommend

immunosuppression unless proteinuria is in the nephrotic range

(although treatment with angiotensin-converting enzyme inhibitors

or angiotensin II receptor blockers is recommended). Prospective

controlled trials suggest that alternate-day glucocorticoids plus cyclophosphamide or mycophenolate mofetil or cyclosporine or tacrolimus

are all effective in the majority of patients in reducing proteinuria. It

is more controversial whether any of these treatments preserve renal

function over the long term.

Good improvement occurs in approximately 60% of lupus nephritis patients receiving either cyclophosphamide or mycophenolate at

1–2 years of follow-up. Addition of a calcineurin inhibitor improves

response rates (70-80% in triple therapy vs 40-60% in double therapy)

and increases time to flare. However, at least 50% of these individuals have flares of nephritis over the next 5 years, and re-treatment

is required; such individuals are more likely to progress to ESRD.

Long-term outcome of lupus nephritis to most interventions is better

in whites than in African Americans. Small controlled trials (in Asia)

of leflunomide, a relatively lymphocyte-specific pyrimidine antagonist

licensed for use in rheumatoid arthritis, have suggested it can suppress

disease activity in some SLE patients. Methotrexate (a folinic acid

antagonist) may have a role in the treatment of arthritis and dermatitis

but probably not in nephritis or other life-threatening disease. Most

patients with SLE of any type should be treated with hydroxychloroquine since it prolongs survival and reduces overall damage. Patients

with proteinuria >500 mg daily should receive angiotensin-converting

enzyme inhibitors or angiotensin receptor blockers as they reduce the

chance for ESRD.

Use of biologics directed against B cells for active SLE is under

intense study. Anti-CD20 (rituximab), particularly in patients with

SLE who are resistant to the more standard combination therapies

discussed above, is widely used. Several open trials have shown efficacy

in a majority of such patients, both for nephritis and for extrarenal

lupus. However, prospective placebo-controlled randomized trials,

one in renal and one in nonrenal SLE, did not show a difference

between anti-CD20 and placebo when added to standard combination

therapies. A monoclonal antibody anti-CD20 that depletes tissue B

cells better than rituximab (obinutuzumab) has received fast track

approval by the U.S. Food and Drug Administration (FDA) for potential approval in SLE, but data from phase 3 clinical trials have not yet

been published. Belimumab was recently approved for treatment of

lupus nephritis in the USA: when given along with mycophenolate

plus glucocorticoids for two years it reduces renal damage significantly.

Rituximab in combination with or followed by belimumab is also

being studied in lupus nephritis. A fusion protein (telitacicept) that

inactivates both BAFF and APRIL growth factors for B cells has been

approved for fast-track review by the FDA; phase 3 clinical trials in SLE

have not yet been reported.

■ SPECIAL CONDITIONS IN SLE THAT MAY

REQUIRE ADDITIONAL OR DIFFERENT THERAPIES

Pregnancy and Lupus Fertility rates for men and women with

SLE are probably normal. However, rate of fetal loss is increased

(approximately two- to threefold) in women with SLE. Fetal demise

is higher in mothers with high disease activity, antiphospholipid

antibodies (especially the lupus anticoagulant), hypertension, and/

or active nephritis. Suppression of disease activity can be achieved

by administration of systemic glucocorticoids. A placental enzyme,

11-β-dehydrogenase 2, deactivates glucocorticoids; it is more effective

in deactivating prednisone and prednisolone than the fluorinated glucocorticoids dexamethasone and betamethasone (fluorinated steroids

should be avoided in pregnant patients). Adverse effects of prenatal

glucocorticoid exposure (primarily the fluorinated steroid betamethasone) on offspring may include low birth weight, developmental

abnormalities in the CNS, and predilection toward adult metabolic

syndrome. Glucocorticoids are listed by the FDA as“fetalrisk cannot be

ruled out.” Also in that category are hydroxychloroquine, belimumab,

cyclosporine, in the “may cause fetal harm” category are rituximab, azathioprine, cyclophosphamide, tacrolimus, and voclosporin. In the “fetal

risk has been demonstrated” or “avoid in pregnancy” are methotrexate

and mycophenolate. Therefore, active SLE in pregnant women should

be controlled with hydroxychloroquine and, if necessary, prednisone/

prednisolone at the lowest effective doses for the shortest time required.

Azathioprine may be added if these treatments do not suppress disease

activity. It is likely that each of these glucocorticoids and immunosuppressive medications gets into breast milk, at least in low levels; patients

should consider not breastfeeding if they need therapy for SLE. In

SLE patients with antiphospholipid antibodies and prior fetal losses,

treatment with heparin (usually low-molecular-weight) plus low-dose

aspirin has been shown in prospective controlled trials to increase

significantly the proportion of live births. Aspirin alone may be used,

although most consider it less effective than heparin-plus-aspirin.

Warfarin is teratogenic. Direct oral anticoagulants are usually avoided

in pregnancy because safety and efficacy have not been established in

pregnancy or APS. An additional potential problem for the fetus is the

presence of antibodies to Ro, sometimes associated with neonatal lupus

consisting of rash and/or congenital heart block with or without cardiomyopathy. The cardiac manifestations can be life-threatening; therefore, the presence of anti-Ro requires vigilant monitoring of fetal heart

rates with prompt intervention (delivery if possible) if distress occurs.

Hydroxychloroquine treatment of an anti-Ro-positive mother whose

prior infant developed congenital heart block significantly reduces the

chance that subsequent fetuses will develop heart block. Dexamethasone treatment of a mother in whom fetal first- or second-degree heart

block is detected in utero sometimes prevents progression of heart

block. Women with SLE usually tolerate pregnancy without disease

flares. However, a small proportion develops severe flares requiring

aggressive glucocorticoid therapy or early delivery.

Lupus and Antiphospholipid Syndrome Patients with SLE

who have venous or arterial clotting and/or repeated fetal losses and at

2748 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

least two positive tests for antiphospholipid antibodies have APS and

should be managed with long-term anticoagulation (Chap. 357). With

warfarin, a target international normalized ratio (INR) of 2.0–2.5 is

recommended for patients with one episode of venous clotting; an INR

of 3.0–3.5 is recommended for patients with recurring clots or arterial

clotting, particularly in the CNS. Recommendations are based on both

retrospective and prospective studies of posttreatment clotting events

and adverse effects from anticoagulation. Direct oral anticoagulants are

not effective and not recommended in APS.

Microvascular Thrombotic Crisis (Thrombotic Thrombocy- topenic Purpura, Hemolytic-Uremic Syndrome) This syndrome of hemolysis, thrombocytopenia, and microvascular thrombosis

in kidneys, brain, and other tissues carries a high mortality rate and

occurs most commonly in young individuals with lupus nephritis.

The most useful laboratory tests are identification of schistocytes on

peripheral blood smears, elevated serum levels of lactate dehydrogenase, and low levels of ADAMS13 activity”. Plasma exchange or extensive plasmapheresis is usually life-saving; most authorities recommend

concomitant glucocorticoid therapy; there is no evidence that cytotoxic

drugs are effective. Rituximab and eculizumab (an inhibitor of C5)

have been used in refractory cases.

Lupus Dermatitis Patients with any form of lupus dermatitis

should minimize exposure to ultraviolet light, using appropriate

clothing and sunscreens with a sun protection factor of at least 30.

Topical glucocorticoids and antimalarials (such as hydroxychloroquine) are effective in reducing lesion severity in most patients and

are relatively safe. Methotrexate, azathioprine, mycophenolate, belimumab and anifrolumab each may be effective in some patients who

need additional treatment. Systemic treatment with retinoic acid is a

useful strategy in patients with inadequate improvement after these

interventions on adverse effects are potentially severe (particularly

fetal abnormalities), and there are stringent reporting requirements for

its use in the United States. Extensive, pruritic, bullous, or ulcerating

dermatitides usually improve promptly after institution of systemic

glucocorticoids; tapering may be accompanied by flare of lesions, thus

necessitating use of a second medication such as hydroxychloroquine,

retinoids, or belimumab. Cytotoxic medications such as methotrexate, azathioprine, or mycophenolate mofetil may also be effective. In

therapy-resistant lupus dermatitis there are reports of success with

topical tacrolimus (caution must be exerted because of the possible

increased risk for malignancies) or with systemic dapsone or thalidomide or the related lenalidomide (the extreme danger of fetal deformities from thalidomide requires permission from and supervision by the

supplier; peripheral neuropathy is also common).

■ PREVENTIVE THERAPIES

Prevention of complications of SLE and its therapy include providing

appropriate vaccinations (the administration of influenza and pneumococcal vaccines has been studied in patients with SLE; flare rates are

similar to those receiving placebo) and suppressing recurrent urinary

tract infections. In patients receiving glucocorticoids, the higher the

daily dose, the lower is the immune response to vaccination; however,

the great majority of patients achieve protective levels. Vaccination

with attenuated live viruses is generally discouraged in patients who

are immunosuppressed; however, a recent study of vaccination of a

small number of SLE patient with Zostavax showed safety and efficacy. The availability of Shingrix (which does not contain live virus)

should replace Zostavax. Patients receiving ≥20 mg of prednisone daily

may be protected from pneumocystis infections with trimethoprimsulfamethoxazole (Bactrim) or atovaquone (we prefer the latter because

SLE patients are predisposed to allergic reactions to sulfa-containing medications) and from recurrent herpes simplex infections with

acyclovir, with preventives withdrawn when the prednisone dose is

decreased. Strategies to prevent osteoporosis should be initiated in most

patients likely to require long-term glucocorticoid therapy and/or with

other predisposing factors. Postmenopausal women can be partially

protected from steroid-induced osteoporosis with calcium supplementation, vitamin D, and either bisphosphonates or denosumab. Safety of

long-term use of these strategies in premenopausal women is not well

established. Control of hypertension and appropriate prevention strategies for atherosclerosis, including monitoring and treatment of dyslipidemias, management of hyperglycemia, and management of obesity, are

recommended. Statin therapies reduce all-cause deaths in SLE patients

and should be considered in patients with elevated LDL or total cholesterol levels. Finally, the physician must keep in mind that some cancers

are increased in SLE patients including non-Hodgkin lymphomas and

cancers of thyroid, lung, liver, and vulvar/vaginal tissues.

■ EXPERIMENTAL THERAPIES

Studies of highly targeted experimental therapies for SLE are in progress. They include (1) depletion of B cells with obinituzumab; (2)

inhibition of B cells by blocking more than one receptor for BAFF (telacicept); (3) elimination of plasma cells; (4) B-cell inhibition through

inhibition of BTK, anti-CD20 therapies more depleting than rituximab,

or a fusion protein that inhibits both BAFF and APRIL B-cell growth

factors; (5) inhibition of B-/T-cell second signal coactivation with

CTLA-Ig or anti-CD40L; (6) inhibition of innate immune activation

via TLR7 or TLR7 and TLR9; (7) induction of regulatory T cells with

peptides from immunoglobulins or autoantigens or with low doses

of IL-2; (8) inhibition of T effector cells through CD6; (9) targeting

lymphocyte migration by modulation of the S1P1 receptor; and (10)

inhibition of lymphocyte activation by blockade of Jak/Stat.

A few studies have used vigorous untargeted immunosuppression

with high-dose cyclophosphamide plus anti-T-cell strategies, with

rescue by transplantation of autologous hematopoietic stem cells for

the treatment of severe and refractory SLE. One U.S. report showed an

estimated mortality rate over 5 years of 15% and sustained remission

in 50%. Mesenchymal stem cell transplant studies are also underway in

lupus. It is hoped that in the next edition of this text, we will be able to

recommend more effective and less toxic approaches to treatment of

SLE based on some of these strategies.

PATIENT OUTCOMES, PROGNOSIS,

AND SURVIVAL

Survival in patients with SLE in the United States, Canada, Europe, and

China is ~95% at 5 years, 90% at 10 years, and 78% at 20 years. In the

United States, African Americans and Hispanic Americans with a mestizo

heritage have a worse prognosis than whites, whereas Africans in Africa

and Hispanic Americans with a Puerto Rican origin do not. The relative

importance of gene mixtures and environmental differences accounting

for ethnic differences is not known. Poor prognosis (~50% mortality in

10 years) in most series is associated with (at the time of diagnosis) high

serum creatinine levels (>124 μmol/L [>1.4 mg/dL]), hypertension, nephrotic syndrome (24-h urine protein excretion >2.6 g), anemia (hemoglobin <124 g/L [<12.4 g/dL]), hypoalbuminemia, hypocomplementemia,

antiphospholipid antibodies, male sex, ethnicity (African American,

Hispanic with mestizo heritage), and low socioeconomic status. Data

regarding outcomes in SLE patients with renal transplants show mixed

results: some series show a twofold increase in graft rejection compared to patients with other causes of ESRD, whereas others show no

differences. Overall patient survival is comparable (85% at 2 years).

Lupus nephritis occurs in ~5% of transplanted kidneys. Disability in

patients with SLE is common due primarily to chronic fatigue, arthritis,

and pain, as well as renal disease. As many as 30–50% of patients may

achieve low disease activity (defined as mild activity on hydroxychloroquine with or without low-dose glucocorticoids); <10% experience

remissions (defined as no disease activity on no medications). The

leading causes of death in the first decade of disease are systemic disease activity, renal failure, and infections; subsequently, thromboembolic events become increasingly frequent causes of mortality.

DRUG-INDUCED LUPUS

This is a syndrome of positive ANA associated with symptoms such as

fever, malaise, arthritis or intense arthralgias/myalgias, serositis, and/

or rash. The syndrome appears during therapy with certain medications and biologic agents, is predominant in whites, has less female predilection than SLE, rarely involves kidneys or brain, is rarely associated

Antiphospholipid Syndrome

2749CHAPTER 357

with anti-dsDNA, is commonly associated with antibodies to histones,

and usually resolves over several weeks after discontinuation of the

offending medication. The list of substances that can induce lupuslike disease is long. Among the most frequent are the antiarrhythmics

procainamide, disopyramide, and propafenone; the antihypertensive

hydralazine; several angiotensin-converting enzyme inhibitors and

beta blockers; the antithyroid propylthiouracil; the antipsychotics

chlorpromazine and lithium; the anticonvulsants carbamazepine and

phenytoin; the antibiotics isoniazid, minocycline, and nitrofurantoin

(Macrodantin); the antirheumatic sulfasalazine; the diuretic hydrochlorothiazide; and the antihyperlipidemics lovastatin and simvastatin.

Biologics that can cause drug-induced lupus (DIL) include inhibitors

of IFNs and TNF. In DIL, ANA usually appears before symptoms;

however, many of the medications mentioned above induce ANA in

patients who never develop symptoms of drug-induced lupus. It is

appropriate to test for ANA at the first hint of relevant symptoms and

to use test results to help decide whether to withdraw the suspect agent.

■ FURTHER READING

Chong BF, Werth VP: Management of cutaneous lupus erythematosus, in Dubois Lupus Erythematosus and Related Syndromes, 9th ed.

DJ Wallace, BH Hahn (eds). Philadelphia, Elsevier, 2019.

Deng Y, Tsao B: Genetics of human SLE, in Dubois Lupus Erythematosus and Related Syndromes, 9th ed. DJ Wallace, BH Hahn (eds).

Philadelphia, Elsevier, 2019.

Fanouriakis A et al: 2019 Update of the EULAR/ACR recommendations for the management of systemic lupus erythematosus. Ann

Rheum Dis 78:736, 2019.

Gulati G, Brunner H: Environmental triggers in systemic lupus

erythmatosus. Semin Arthritis Rheum 47:710, 2018.

Hahn BH et al: American College of Rheumatology guidelines for

screening, treatment, and management of lupus nephritis. Arthritis

Care Res (Hoboken) 64:797, 2012.

Murphy G, Isenberg DA: New therapies for systemic lupus erythematosus: Past imperfect, future tense. Nat Rev Rheumatol 15:403, 2019.

Ocampo-Piraquive V et al: Mortality in lupus erythematosus: Causes,

predictors, and interventions. Expert Rev Clin Immunol 14:12, 2018.

Rees F et al: The worldwide incidence and prevalence of systemic

lupus erythematosus: A systematic review of epidemiological studies.

Rheumatology 56:1945, 2017.

Tsokos GC: Autoimmunity and organ damage in systemic lupus erythematosus. Nat Immunol 21:605, 2020.

■ DEFINITIONS

Antiphospholipid syndrome (APS) is an autoantibody-mediated

acquired thrombophilia characterized by recurrent arterial or venous

thrombosis and/or pregnancy morbidity. It affects primarily females.

APS may occur alone (primary) or in association with other autoimmune diseases, mainly systemic lupus erythematosus (SLE) (secondary). Catastrophic APS (CAPS) is a life-threatening rapidly

progressive thromboembolic disease involving simultaneously three

or more organs.

The major autoantibodies detected in patients’ sera are directed

against negatively charged phospholipids (PLs) and/or PL-binding

plasma proteins such as β2

-glycoprotein I (β2

GPI) and prothrombin.

357 Antiphospholipid

Syndrome

Haralampos M. Moutsopoulos,

Clio P. Mavragani

PLs are components of the cytoplasmic membrane of all living cells.

The antibodies are directed against PLs, such as cardiolipin, phosphocholine, and phosphatidylserine. The plasma protein β2

GPI is a

43-kDa plasma apolipoprotein, which consists of 326 amino acids

arranged in five domains (I through V). Domain V forms a positively

charged patch, suitable to interact with negatively charged PLs. In

plasma, β2

GPI has a circular conformation with domain V binding to

and concealing the B-cell epitopes lying on domain I. The presence

of anti–domain I IgG antibodies has been recently associated with

increased thrombotic risk. Another group of antibodies termed lupus

anticoagulant (LA) prolongs clotting times in vitro, which are not

corrected by adding normal plasma (Table 357-1). Patients with APS

often possess antibodies recognizing Treponema pallidum PL/cholesterol complexes, detected by Venereal Disease Research Laboratory

(VDRL) tests and characterized as biologic false-positive serologic tests

for syphilis (BFP-STS). Since patients can present with features highly

reminiscent of APS in the absence of classical anti-PL antibodies, the

term seronegative APS has been coined. In patients with strong suspicion of seronegative APS, testing for antiphosphatidylserine/prothrombin antibodies may have a valuable diagnostic role.

■ EPIDEMIOLOGY

The incidence of APS is estimated to be ~5 cases per 100,000 persons

per year. The prevalence of APS in the general population is estimated

to be 40–50 per 100,000. Anti-PL antibodies occur in 1–5% of the

general population. Their prevalence increases with age; however, it

is questionable whether they are able to induce thrombotic events in

elderly individuals. Moreover, although one-third of patients with SLE

and other autoimmune diseases (Chap. 356) possess these antibodies,

only 5–10% of them develop APS.

■ PATHOGENESIS

The initiating events for the induction of antibodies to PL-binding proteins seem to be infections, oxidative stress, and major physical stresses

such as surgery or trauma in an appropriate genetic background, given

the previously demonstrated associations with alleles within the HLA

locus. These contributors seem to induce increased apoptosis of the

vessel endothelial cells and subsequent exposure of PLs. The latter,

bound with serum proteins such as β2

GPI or prothrombin, lead to neoantigen formation, which in turn triggersthe induction of anti-PLs. The

binding of anti-PLs to the disrupted endothelial cells leads to initiation

of intravascular coagulation and thrombus formation. Complement

TABLE 357-1 Classification and Nomenclature of Antiphospholipid

Antibodies

NAME

ASSAY FOR THEIR

DETECTION COMMENTS

Antibodies

against

cardiolipin

(aCL)

Enzyme-linked

immunosorbent assay

(ELISA) using as antigen

cardiolipin (CL), a

negatively charged

phospholipid

aCL from patients with APS

recognize β2

GPI existing in the

human serum as well as in bovine

serum, which is used to block the

nonspecific binding sites on the

ELISA plate. CL simply stabilizes

β2

GPI at high concentration on the

polystyrene surface.

Antibodies

against β2

GPI

(anti-β2

GPI)

ELISA using as antigen

affinity purified or

recombinant β2

GPI in the

absence of PL

Antibodies recognize β2

GPI bound

in the absence of CL to an oxidized

polystyrene surface, where oxygen

atoms in the moieties C–O or C=O

were introduced by γ-irradiation.

Lupus

anticoagulant

(LA)

Activated partial

thromboplastin time

(aPTT)

Kaolin clotting time (KCT)

Dilute Russel viper

venom test (DRVVT)

Antibodies recognize β2

GPI or

prothrombin (PT) and elongate

aPTT, implying that they interfere

with the generation of thrombin

by prothrombin. Prolongation of

the clotting times is an in vitro

phenomenon, and LA induces

thromboses in vivo.

Abbreviations: APL, antiphospholipid syndrome; β2

GPI, β2

-glycoprotein I; PL,

phospholipid.

2750 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

and neutrophil activation and, recently, an imbalance between type

I and III interferons have been proposed as potential mechanisms of

thrombotic events and APS-related obstetric complications.

■ CLINICAL MANIFESTATIONS AND

LABORATORY FINDINGS

Clinical manifestations represent the consequences of venous or arterial thrombosis and/or pregnancy morbidity (Table 357-2). Venous

thrombosis, superficial or deep, occurs primarily in the lower extremities, often leading to pulmonary emboli. Thrombosis of the pulmonary arteries leads to pulmonary hypertension, and thrombosis of

the inferior vena cava to Budd-Chiari syndrome. Cerebral venous

thrombosis presents with signs and symptoms of intracranial hypertension and retinal vein thrombosis. Arterial thrombosis affects more

commonly the arteries of the brain and is manifested as migraines,

cognitive dysfunction, transient ischemic attacks, stroke, and retinal

artery occlusion. Arterial thrombosis of the extremities presents with

ischemic leg ulcers, digital gangrene, and avascular bone necrosis,

TABLE 357-2 Clinical Features of Antiphospholipid Syndrome

MANIFESTATION %

Venous Thrombosis and Related Consequences

Deep-vein thrombosis

Livedo reticularis

Pulmonary embolism

Superficial thrombophlebitis

Thrombosis in various other sites

39

24

14

12

11

Arterial Thrombosis and Related Consequences

Stroke

Cardiac valve thickening/dysfunction and/or Libman-Sacks

vegetations

Transient ischemic attack

Myocardial ischemia (infarction or angina) and coronary bypass

graft thrombosis

Leg ulcers and/or digital gangrene

Arterial thrombosis in the extremities

Retinal artery thrombosis/amaurosis fugax

Ischemia of visceral organs or avascular necrosis of bone

Multi-infarct dementia

20

14

11

10

9

7

7

6

3

Neurologic Manifestations of Uncertain Etiology

Migraine

Epilepsy

Chorea

Cerebellar ataxia

Transverse myelopathy

20

7

1

1

0.5

Renal Manifestations Due to Various Reasons (Renal

Artery/Renal Vein/Glomerular Thrombosis, Fibrous Intima

Hyperplasia)

3

Musculoskeletal Manifestations

Arthralgias

Arthritis

39

27

Obstetric Manifestations (Referred to the Number of Pregnancies)

Preeclampsia

Eclampsia

10

4

Fetal Manifestations (Referred to the Number of Pregnancies)

Early fetal loss (<10 weeks)

Late fetal loss (≥10 weeks)

Premature birth among the live births

35

17

11

Hematologic Manifestations

Thrombocytopenia

Autoimmune hemolytic anemia

30

10

Source: Adapted from R Cervera et al: Arthritis Rheum 46:1019, 2002.

whereas thrombosis of other arteries leads to myocardial infarction,

renal artery stenosis, glomerular lesions, and infarcts of spleen, pancreas, and adrenals.

Livedo reticularis consists of a mottled reticular vascular pattern

that appears as a lace-like, purplish discoloration of the skin. It is probably caused by swelling of the venules due to obstruction of capillaries

by thrombi. This clinical manifestation usually occurs together with

vascular lesions in the central nervous system and with aseptic bone

necrosis. Libman-Sacks endocarditis consists of very small vegetations,

histologically characterized by organized platelet-fibrin microthrombi

surrounded by growing fibroblasts and macrophages. Glomerular

involvement is manifested with hypertension, mildly elevated serum

creatinine levels, and proteinuria/hematuria. Histologically, in an

acute phase, thrombotic microangiopathy is present in the glomerular

capillaries. In a chronic phase, fibrous intima hyperplasia, fibrous and/

or fibrocellular arteriolar occlusions, and focal cortical atrophy are

present (Table 357-2). Pregnancy morbidity manifests with increased

risk of recurrent miscarriages, intrauterine growth retardation, preeclampsia, eclampsia, and preterm birth. The major causes of these complications are due to infarctions of the placenta.

Premature atherosclerosis has been also recognized as a feature

of APS. Musculoskeletal manifestations include, in addition to bone

necrosis, arthralgia/arthritis, bone marrow necrosis, muscle infarction,

nontraumatic fractures, and osteoporosis. Coombs-positive hemolytic

anemia and thrombocytopenia are laboratory findings associated

with APS.

■ DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

The diagnosis of APS should be seriously considered in cases of

thrombosis, cerebral vascular accidents in individuals <55 years of age,

or pregnancy morbidity in the presence of livedo reticularis or thrombocytopenia. In these cases, anti-PL antibodies should be measured.

The presence of at least one clinical and one laboratory criterion is

compatible with the diagnosis, in the absence of other thrombophilia

causes. Clinical criteria include (1) vascular thrombosis, defined as one

or more clinical episodes of arterial, venous, or small vessel thrombosis

in any tissue or organ; and (2) pregnancy morbidity, defined as (a) one

or more unexplained deaths of a morphologically normal fetus at or

beyond the 10th week of gestation; (b) one or more premature births

of a morphologically normal neonate before the 34th week of gestation

because of eclampsia, severe preeclampsia, or placental insufficiency;

or (c) three or more unexplained consecutive spontaneous abortions

before the 10th week of gestation. Laboratory criteria include (1) LA,

(2) anticardiolipin (aCL), and/or (3) anti-β2

GPI antibodies, at intermediate or high titers on two occasions 12 weeks apart.

Differential diagnosis is based on the exclusion of other inherited

or acquired causes of thrombophilia (Chap. 116), Coombs-positive

hemolytic anemia (Chap. 100), and thrombocytopenia (Chap. 115).

Livedo reticularis with or without a painful ulceration on the lower

extremities may be also a manifestation of disorders affecting (1)

the vascular wall, such as atherosclerosis, polyarteritis nodosa, SLE,

cryoglobulinemia, and lymphomas; or (2) the vascular lumen, such as

myeloproliferative disorders, hypercholesterolemia, or other causes of

thrombophilia.

TREATMENT

Antiphospholipid Syndrome

It has been increasingly appreciated that the risk of thrombotic

and obstetric events is closely related to the underlying anti-PL

profile. The latter depends on the type of autoantibodies (IgG high

risk vs IgM low risk), the number of anti-PL antibodies (simultaneous presence of two or three classical autoantibodies denotes a

higher risk profile vs a single antibody), their titer (moderate-high

titer vs low), and the persistence of anti-PL positivity in repeated

measurements.

Following the first thrombotic event, APS patients should be

placed on vitamin K antagonists (VKAs) for life, aiming to achieve