339 Pregnancy and SLE \200 There is a disparity in the literature about whether pregnancy is associated with an increased risk of lupus \202 are. However, pregnancy does not appear t o worsen the long-term outcome of SLE Active disease greatly increases the risk of miscarriage and preterm birth. A major complication is preeclampsia. Preexisting renal disease may be an important risk factor. SLE is associated with an increased rate of fetal death late in pregnancy and overall appro ximately 10% of lupus pregnancies result in fetal loss. \200 Anti-Ro antibodies are assoc iated with fetal heart block and neonatal lupus. Obstetric ultrasound should be performed every trimester. If the mother has anti-Ro antibod ies, fetal echocardiogram should be performed weekly, from the 16 th week to the 32 nd week of gestation. If the mother lacks anti-Ro antibodies, biweekly fetal echocardiograms shoul d be performed, starting with the 26 th week of gestation. The antiphospholipid antibody syndrome and its associated complications during pregnancy is discussed in Chapter 10. Drug safety in pregnancy is discussed in Chapter 5. CHAPTER 10 Systemic lupus erythematosus (SLE) 340 Diagnosis and investigation of SLE \200 The majority of investigations are aimed speci \201 cally at end-organ disease. Investigation in the form of radiographs, CBC, coagulation screen, ESR, CRP, and renal and liver biochemistry, urinalysis, and blood pressure may lea d to other tests, e.g., of hemolysis or pleuritic pain. The physician is directed to autoan tibody and complement tests (see Table 10.4). There are a variety of circulating autoantibodies to a range of nuclear, cytoplasmic, and plasma membrane antigens. Most patients (98% or more) will have a ntinuclear antibodies. Approximately 60% have elevated titers of dsDNA antibodies (detected by the immuno \202 uorescent Crithidia test or by speci \201 c ELISA or radioimmunoassay ). Some patients have varying combinations of antibody pro \201 le that may change over th e course of the disease. The antibodies, their prevalence and clinical association are show n in Table 9.4. Lupus is associated with de \201 ciencies of the early classical pathway of complement (e. g., C1q, C1r, C1s, C2). The overall consequence is decreased clearance and increased deposi tion of complexes. Reduced levels of complement C3 and C4 are common in SLE. A subset of patients will be \200\234serologically active but clinically quiescent, \200\235 meaning they will have low complement levels and raised dsDNA titers bu t no signs of active disease. Patients should always be treated on the basis of symptoms ra ther than blood tests alone. Some individuals may have high levels of RF and features of an erosive RA type disease. Thi s \200\234overlap \200\235 syndrome is sometimes called rhupus. The mix of clinical featur es and autoantibodies is not peculiar to SLE, and all the autoimmune rheumatic diseases are subject to the phenomenon of \200\234overlap \200\235 or \200\234undifferentiated \200 \235 disease. In this situation, a number of clinical features and antibodies common to sev eral diseases are present. Treatment is determined by the end-organ disease that is present . The concept of \200\234mixed connective tissue disease \200\235 as a speci \201 c diagn osis, rather than \200\234undifferentiated \200\235 disease remains controversial, since m ost patients eventually declare themselves as either SLE or scleroderma. When this term is used, mixed connective tissue disease refers speci \201 cally to patients who have high-titer antibodies to RNP. These patients can hav e features of both SLE and scleroderma, with a tendency to develop Raynad \200\231s phenome non and pulmonary \201 brosis. \200 The assessment of disease activity is central to pa tient management. Several global activity indices have been produced that correlate well an d are reliable. Awareness of changes in lupus activity, whether improvement of disease or n ot, is an essential part of decision making and drug treatment. Global scoring systems such as the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the British Isles Lupus Assessment Group (BILAG) activity index are of some value, both in the context of cli nical trials and long-term follow-up of patients. DIAGNOSIS AND INVESTIGATION OF SLE 341 Table 10.4 Autoantibodies of systemic lupus erythematosus used in clinical practice Autoantibody Prevalence (%) Associations Intracellular: DNA 40 \200\22390 Renal disease Histone 30 \200\22380 Drug-induced lupus Sm 30 (Africans, Caribbeans), 10 (Caucasians) Ul RNP 20 \200\22330 rRNP 5 \200\22315 Ro/SS-A 25 \200\22340 Sj gren \200\231s syndrome, cutaneous lupus, congenital heart block La/SS-B 10 \200\22315 Ro/SS-A Cell membrane: Cardiolipin 20 \200\22340 Pregnancy loss, thrombosis Red cell < 10 Hemolytic anemia Platelets < 10 Immune thrombocytopenia Extracellular: RF 25 Complement Clq 50 Renal disease Equally constructive is the concept of an index of damage as distinct from disease activity . For example, a patient with shortness of breath may have an active but reversible pneumon itis or an irreversible \201 brosis; the distinction between disease activity and damage is important since the treatments are different. The SLICC (Systemic Lupus International Co llaborating Clinics) damage index has been developed as a method of recording damage in pat ients with SLE. The reader is referred to two articles by Gladman et al. 1 , 2 as the backg round for the current scoring system. 1 Gladman DD et al. Senitivity to change of 3 systemic lupus erythematosus disease activity indices: international validation. Journal of Rheumatology, 1994; 21: 1468 \200\22371 2 Gl adman DD et al. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus ery- thematosus. Arthritis and Rheumatism, 1996; 39: 363 \200\2239 CHAPTER 10 Systemic lupus erythematosus (SLE) 342 Drug-induced lupus erythematosus (DILE) \200 Many drugs have been implicated in causing D ILE. Those de \201 nitely and most commonly associated with DILE are: \200 minocycline \200 hydralazine \200 procai namide \200 isoniazid \200 quinidine \200 methyldopa \200 chlorpromazine \200 sul fasalazine \200 anti-TNF inhibitors Hydralazine-associated DILE is considered to be dose dependent, while procainamide-associat ed DILE may be time-dependent. Up to 90% of cases taking procainamide develop a positive antinuclear antibody (ANA) and 30% of these develop DILE. Renal, central nervous system, and skin features of SLE are rare in DILE. Other features of SLE such as articular and serosal disease are common. In the majority of cases, the condition subsides after drug withdrawal. There is no contrai ndication to using these drugs in idiopathic SLE. This page intentionally left blank CHAPTER 10 Systemic lupus erythematosus (SLE) 344 The treatment of SLE \200 Several general measures are important: rest as appropriate \200 avoid overexposure to sunlight \200 sunblock should be SPF 30 or greater, and should protect against both UVA and UVB control cardiovascular risk factors. Initial evaluation should include an assessment of risk for glucocorticoid induced osteoporosis. Most patients should take calcium and vitamin D. Patie nts on prednisone >5 mg daily should be offered a bisphosphonate (assuming not contraindica ted e.g., premenopausal women, renal insuf \201 ciency) as prophylaxis against steroid-ind uced osteoporosis. Vaccinations, apart from \200\234live \200\235 vaccine (e.g., varicella, MMR, yellow fever , live polio) in patients on immunosuppressive drugs, are not contraindicated, but the degr ee of response differs from the healthy individual. Estrogen contraceptive pills should be avoided in those with antiphopholipid antibodies, very active disease, or nephrotic syndrome. Progesterone-only o r other methods of contraception can be used. Many patients tolerate hormone replacement th erapy (HRT) but use in the menopause is controversial: there is a 20% increase in SLE \202 ares among women taking HRT. Reduction of cardiovascular disease risk factors \200 Management of traditional risk fact ors (smoking, hypertension, diabetes, obesity) Statins for hypercholesterolemia \200 Aspirin if antiphospholipid antibodies are present \200 Tighter control of SLE disease activity. Table 10.5 outlines the common therapies us ed to treat the various clinical manifestations of SLE. The management of SLE as an acute r heumatologi- cal emergency is discussed in Chapter 21. Standard therapies for SLE SLE is generally treated with glucocorticoids in combination wit h a steroid-sparing agent, such as the drugs listed below. The initial dose of glucocortico ids should re \202 ect the severity of the disease manifestations; in severe cases of lupu s nephritis or neuropsychiatric lupus, for example, it is not uncommon to treat with high d ose intravenous methylprednisolone (e.g., 1000 mg daily for three days) prior to starting t reatment with oral prednisone at 1 mg/kg/day. Low dose glucocorticoids are also sometimes u sed as part of a chronic remission-maintenance regimen, although this strategy may increase the long-term risk of cardiovascular events and osteoporosis. The steroid sparing agent is often selected based on the predominant disease manifestations (e.g., hydroxychloroquine for serositis, methotrex- ate for arthritis, mycophenolate mofet il for glomerulonephritis), with THE TREATMENT OF SLE 345 cyclophosphamide and belimumab reserved for patients with the greatest disease activity. Hydroxychloroquine All patients with SLE should receive treatment with hydroxychloroquine ( 400 mg daily). It is especially effective for the treatment of serositis, arthralgias, and cutaneous manifestations of SLE; in addition, chronic use leads to a reduction in \202 ar es, delays onset of renal and neurologic involvement, and potentiates response to mycopheno late mofetil. Patients taking hydroxychloroquine should have a yearly examination to look f or evidence of retinopathy. Cyclophosphamide Intravenous cyclophosphamide (750 mg/m 2 BSA monthly for six months) is of ten used for the treatment of severe SLE \202 ares. Intravenous hydration and mesna (300 mg/m 2 administered both prior to the infusion and four hours after the start of the infusi on) may be helpful to prevent bladder toxicity; leuprolide injections (3.75 mg IM 2 weeks p rior to each cyclophosphamide treatment) may help preserve fertility in women. Lower dose c yclophospha- mide regimens (EuroLupus) have chie \202 y been validated in Caucasian popula - tions, and their ef \201 cacy for African American patients is less clear. Azathioprine Milder forms of SLE may respond to treatment with azathioprine (1.5 \200\2232. 5 mg/kg/day). Unlike other drugs commonly used for SLE, azathioprine and hydroxychloroquine are not contraindicated during pregnancy. Mycophenolate mofetil (MMF) MMF (1.0 \200\2231.5 g twice daily) has become the treatment of choice for lupus nephritis, with the possible exception of rapidly-progressive glomerulone - phritis, for which cyclophosphamide should still be considered. When used for remission i nduction of lupus nephritis, rates of remission, relapse, and infection are superior to tho se achieved by treatment with cyclophos- phamide followed by azathioprine maintenance thera py. MMF was not associated with amenorrhea; bone marrow suppression is uncommon Belimumab (Benlysta ) B lymphocyte stimulator (BLyS, also known as BAFF) is required for t he development of mature plasma B-cells. Belimumab (Benlysta ), a mono clonal antibody tha t targets BLyS, has been approved by the United States Food and Drug Administration for the treatment of SLE among patients with moderate to severe disease. Belimumab 10 mg/kg admini stered intra- venously on days 0, 14, 28 and every 28 days afterwards has been dem- onstrat ed in two randomized clinical trials to decrease disease activity and increase time to \201 rst \202 are when added to standard-of-care therapies. Patients should receive preme dication with acetaminophen and diphenhy- dramine, and the drug should be administered over 1 hour. Patients with anti-dsDNA antibodies and low serum complements are the most likely to respon d to therapy. Belimumab should not be used for the treatment of lupus nephritis, since it h as not been well studied for this indication. CHAPTER 10 Systemic lupus erythematosus (SLE) 346 Other therapies for SLE Rituximab Encouraging results were seen initially in open label ser ies using this anti-CD20 monoclonal antibody in patients with active systemic disease who h ad failed, or only had partial response to, conventional treatments. However, randomized pl acebo-controlled trials have failed to demon- strate that rituximab was bene \201 cial to patients with moderate-to-severe SLE. Additionally, progressive multifocal leukoencephalopa thy has been reported in association with rituximab therapy, leading to a black box warning . Rituximab may be appropriate for the treatment of immune-mediated thrombocytopenia associat ed with SLE, or for patients with truly refrac- tory disease, who have failed all other the rapies, but likely does not have a role in the routine treatment of SLE. Autologous hemopoietic stem cell transplantation (HSCT) HSCT is used to treat hematological diseases, but has been used in patients with severe refractory SLE. The procedure is effec tive in induc- ing remission, and is curative in <50% in non-blinded studies. Mortality is high and long-term effects are unknown. New autoimmune conditions have been reported after HSCT. It is currently used only in those with life-threatening SLE. High dose intravenous cyclophosphamide (50 mg/kg daily for 4 days) without stem cell transp lant has been explored for the treatment of sev- eral autoimmune diseases. Although this op tion allows patients to avoid the toxicity associated with HSCT, it appears to be no more e ffective than standard-dose intravenous cyclophosphamide regimens. Other agents \200 Pooled immunoglobulin (IVIG 0.4 g/kg IV daily for \201 ve days) may be of use in severely ill patients not responding to other therapies, and perhaps moreso in situations where sepsis is the trigger and is life-threatening. It may have a role in drug -resistant membranous and membranoproliferative nephritis, and has been used in severe auto immune thrombocytopenia and hemolytic anemia with good effect. The ef \201 cacy of anti-TNF- A therapy in SLE is at present not clear. 16% of RA patients on these therapies develop double-stranded DNA antibodies, and 0.2% develop a transient lu pus-like syndrome. A small, open label study has shown bene \201 t in lupus nephritis and lupus arthritis, but with a high proportion of complications. Table 10.5 Recommendations for drug use in SLE Symptom Drug Regimen Arthralgias/fever NSAIDs (caution with renal disease) Hydroxychloroquine No special recommendation Hydroxychloroquine 400 mg daily; ophthalmic examination yearly, a lthough the risk of untoward events is low. Malar/discoid rash Prednisone, hydroxychloroquine, sunscreen Arthritis/serositis/myositis Prednisone, methotrexate, azathioprine, le \202 unomide 20 \200\22340 mg daily for 2 \200\2234 weeks, then reducing dose 5 mg steps each week. Requ ire bone prophylaxis against osteoporosis if dose remains at 7.5 mg or above for more than 3 months. Autoimmune anemia or thrombocytopenia (ITP) Prednisone, azathioprine, IVIG 60 \200\22380 mg prednisolone daily for 2 weeks, reducing in 10 mg steps per week after dep ending on response. 2.5 mg/kg azathioprine.ITP might also require immunoglobulin or splenec tomy T H E Renal Prednisone, mycophenolate, azathioprine, cyclophosphamide Severe disease may require monthly IV steroid and cyclophosphamide for 6 months then 2 \200 \2233 monthly for 2 years T R E A T M E N T O F Central nervous system Prednisone, azathioprine Up to 80 mg daily of prednisone (1 mg/kg/day) Raynaud \200\231s disease See Chapter 13 S L E 3 4 7 CHAPTER 10 Systemic lupus erythematosus (SLE) 348 Prognosis and survival in SLE \200 Many studies of the duration of disease and survival r ates are confounded by inadequate attention paid to the ethnic group, age of onset, and socioeconomi c status of individual patients. The number of patients lost to follow-up is also high. Wit h the division of patients into those with or without overt nephritis, it is reasonable to state a 5-year survival in lupus of 90%. At 15 years, only 60% of those with nephritis will be alive compared with 85% of those patients without renal disease. Overall, men have a worse prognosis than women; men with SLE have increased mortality, and are more likely to develop nephrotic syndrome, renal failure, and myocardial infarction tha n women with SLE. A bimodal mortality curve is considered to exist. Patients who die within 5 years usually have very active disease, requiring high doses of immunosuppressives . Those patients dying later tend to do so from cardiovascular disease, renal disease, and possibly infection. The combined effect of the disease and its treatment is to render the immune system prone t o infection. It is often dif \201 cult to apportion responsibility to one or other. The po ssibility of infection must always be kept in mind and treated aggressively as outcome from sepsis can be very poor. Controlling risk factors for cardiovascular disease is important. \200 Lupus itself incre ases the risk of malignancy. However, immunosuppression is also associated with an increased risk of malignancy. CHILDHOOD SLE 349 Childhood SLE \200 This is a rare disease with an estimated incidence of 0.4 per 100,000. There are several features of childhood SLE that differ from the adult disease, although t he main features and treatment are similar. General management strategies (i.e., not includ ing pharmacological agents) for child welfare are the same as those employed in the managem ent of all pediatric arthritides \200\224see Chapter 9. The overall prepubertal male to female ratio is 3:1, suggesting a higher male frequency in childhood SLE as compared to that seen in adults; the ratio reverts to the more classic adu lt ratio of 9:1 post-puberty. \200 The disease is more common and severe in those of Afri can-American and Asian origin. The main features at presentation are arthritis, myalgias, fever, and rash (all features with a frequency of approximately 60 \200\22380% of cases at diagnosis). Malar rash is present in 30% of cases at diagnosis, and renal disease at onset of disease is high (up to 60%). True myositis with proximal weakness occurs in < 10% of cases. Neurops ychiatric disease is present in up to 40% cases. Avascular necrosis is more common in children than adults with SLE (10 \200\22315% of cases ), and is more common in SLE than other pediatric autoimmune rheumatic diseases where prolo nged high-dose steroids are used. Raynaud \200\231s phenomenon is less common in childhood lupus and occurs in 10 \200\22320% of patients. As in adult disease, hydroxychloroquine and NSAIDs can be used for mild skin and joint disease. Oral or IV corticosteroids are given for disease not responding to the above measures, or in moderate-to-severe multisystem disease. \200 Growth retardation sec ondary to corticosteroids is a major concern, and the lowest possible dose of steroid should be used. Bone protection with calcium and vi tamin D should also be given. Cyclophosphamide, azathioprine, methotrexate and mycophenolate mofetil are used as in adult disease. Case reports of successful autologous stem cell trans plantation have been described. The 10-year survival for SLE in childhood is currently estimated at 85%. CHAPTER 10 Systemic lupus erythematosus (SLE) 350 Neonatal SLE \200 This is a rare condition found in the newborn and characterized by suba cute cutaneous lupus skin lesions, hemolytic anemia, hepatitis, thrombocytopenia, and conge nital heart block (CHB). It is associated with placental transmission of maternal Ro and La antibodies. The noncardiac manifestations resolve within 1 year. Cardiac involvement often requires early pacemaker insertion, and mortality in the \201 rst 3 yea rs of life is up to 30%. In women with anti-Ro/La antibodies, there is a 5% chance of their \201 rst child being b orn with CHB; this rises to 15% with subsequent pregnancies. Fetal monitoring with echocardiography in the antenatal period is essential. Maternal use of hydroxychloroquine prior to and during pregnancy appears to decrease the ri sk of either cardiac or cutaneous neonatal lupus. 351 Chapter 11 The antiphospholipid (antibody) syndrome (APS) Introduction 352 Epidemiology and pathology 353 Clinical features of APS 354 Treatment of A PS 356 Catastrophic APS (CAPS) 358 CHAPTER 11 The antiphospholipid syndrome 352 Introduction The antiphospholipid syndrome (APS) was \201 rst described in the 1980s, and is characterized by arterial and venous thrombosis (with or without pregnancy morbidity) i n the presence of anticardiolipin (aCL) antibodies or the lupus anticoagulant (LAC). It can be primary, or secondary to other autoimmune diseases, most commonly systemic lupus erythe matosus (see Chapter 10). APS can affect almost any organ system, and presents to many medical specialties, including rheumatology, dermatology, neurology, and cardiol- ogy. Classi \201 cation criteria were produced in 1999, and updated in 2006 to re \202 ect the use of anti- B 2 glycoprotein-1 f or diagnosis (see Table 11.1). Table 11.1 Classi \201 cation criteria for the antiphospholipid syndrome Clinical Criteria Vascular thrombosis 1 or more clinical episodes of arterial, venous or small vessel thrombosis in any tissue or organ, con \201 rmed by objective criteria. Histopathology should show thrombosis without signi \201 cant in \202 ammation in the vessel wall. Pregnancy morbidity 1 or more unexplained deaths of a morphologically normal fetus at or beyond 10 weeks gestat ion OR 1 or more premature births of a morphologically normal neonate at or before 34 weeks gestat ion due to pre-eclampsia, eclampsia or placental insuf \201 ciency OR 3 or more unexplained, consecutive, spontaneous abortions before 10 weeks gestation, exclud ing maternal anatomical or hormonal abnormalities, and excluding maternal and paternal chro mosomal causes. Laboratory criteria Medium/high titer of IgG and/or IgM isotype anticardiolipin antibody in blood on 2 or more occasions at least 12 weeks apart using standard assays. Lupus anticoagulant present in plasma on 2 or more occasions at least 12 weeks apart. Anti- B 2 glycoprotein-I IgG or IgM in blood on 2 or more occasions at least 12 weeks apart usin g standard assays. Adapted from Miyakis S. et al. International consensus statement on an update of the classi \201 cation criteria for de \201 nite antiphospholipid syndrome (APS). J Thrombosis Haem ostasis 2006; 4: 295 \200\223306. EPIDEMIOLOGY AND PATHOLOGY 353 Epidemiology and pathology \200 Antiphospholipid (APL) is the overall term used. Patients may be classi \201 ed in terms of the antibody present: anticardiolipin (aCL), lupus anticoagulan t (LAC), or anti- B 2 glycoprotein-I. Antibodies are directed at protein \200\223phospholipid complexes. Recently antibodies to B 2 -glycoprotein I ( B 2 GPI) have been found to be the main target antigen involved in the binding of anticardiolipin antibodies to anionic phospholipids. Case control studies estimate the prevalence of aCL in the normal population to be 1 \200 \2234%. Prevalence in those >65 years increases to 12 \200\22350% depending on the study. P revalence of aCL and LAC in SLE patients is estimated at 20 \200\22340% and 10 \200\22320% respectively. These differences arise due to treatment history and the lack of uniformity o f assay methods. Ethnicity also plays a role in the frequency and clinical importance of th ese antibodies. The LAC and aCL antibody tests are the most useful antibodies for identifying patients with the syndrome. The LAC test cannot be performed reliably if a patient is receiving heparin or oral anticoagulant. LAC is most strongly associated with both thrombosis and adverse pre gnancy outcomes. The two tests can be discordant in up to 40% of cases and their unrelated behavior in the course of disease and in the individual patient means that both assays may be required to identify cases of APS. Apart from a clinical suspicion leading to a request for antiphospholipid antibody assays, a clue to their presence lies in \201 nding a prolonged clotting time in assays for the \200\230internal pathway \200\231-clotting cascade. \200 The speci \201 city of antiphos pholipid antibodies probably differs in various disorders. Studies suggest that LAC and hig h titers of IgG aCL antibodies are associated with greater risk of thrombosis; the risk is much lower in patients with infection-related or drug-induced antibodies, which tend to be of the IgM isotype. 10% of patients with APS only have antibodies to B 2 GPI. There is evid ence that B 2 GPI titer and simultanous presence of aCL or LAC are associated with disease severity. The differential diagnosis of unexplained thrombosis includes genetic causes (e.g., protein C and S, and antithrombin III de \201 ciencies, factor V Leyden and prothombin mutations) and drugs (including estrogen, thalidomide, IVIG). However, these are usually associated w ith recurrent venous thrombosis. Most striking about APS is the feature of thrombosis in th e setting of thrombocytopenia. The main differential diagnosis is thrombotic thrombocytopen ic purpura (TTP) and heparin induced thrombocytopenia (HIT). TTP is a microvascular disorde r most often associated with neurological features of confusion, seizures, and changes in c onsciousness level that can mimic the catastrophic form of APS. Only a third of all patients with aPL ever experience thrombosis. After the \201 rst thro mbotic event (either arterial or venous), recurrence is common, but can be prevented by tre atment with warfarin. CHAPTER 11 The antiphospholipid syndrome 354 Clinical features of APS Table 11.2 summarizes the main clinical features of APS and some o f the less common \201 ndings. Thrombosis \200 Antiphospholipid antibodies are paradoxically associated with thrombosis rather than hemorrhage. Vessels of all sizes, venous or arterial, may be affected without evidence of an in \202 ammatory in \201 ltrate (i.e., vasculitis). This distinction is im portant not only in trying to understand the pathogenesis of the disorder but also in the c hoice of treatment. Unlike most clotting disorders, arterial thrombosis is a major feature of APS. The antibodies should be sought particularly in the younger stroke patient where th ey may account for up to 20% of cases. Widespread thrombosis is the feature of life-threatening \200\230catastrophic antiphosphol ipid syndrome \200\231. In this situation the patient may present with acute medical collap se, severe thrombocytopenia, multi-organ failure (notably cerebral and renal), and adult re spiratory distress syndrome. Thrombocytopenia This is common but usually not severe enough to cause bleeding. ACL antibo dies have been found in up to 30% of cases of presumed immune thrombocytopenic purpura (ITP ). Some patients also develop a concomi- tant Coombs \200\231 positive hemolytic anemia (Ev an \200\231s syndrome). Fetal loss Recurrent spontaneous pregnancy loss is a common complication of APS. This can o ccur either as recurrent early loss or intrauterine fetal demise. Screening for the antibod ies in the general population is not of value. Previous pregnancy history is of importance in determining the signi \201 cance of a positive antibody titer. Other features of APS \200 Transverse myelopathy, though rare, has a strong association w ith the presence of antiphospholipid antibodies. Chorea has also been observed APS may be associated with multiple cardiovascular complications including accelerated athe rosclerosis, valvular heart disease, and intracardiac thrombi. However, cardiac manifestati ons of APS result in signi \201 cant morbidity for only 5% of patients. In a European coho rt, myocardial infarction was the presenting feature of APS in 3% of patients, and was seen during follow-up in 5.5%. The prevalence of aCL in patients with myocardial infarction is estimated at 5 \200\22315%; however screening is not indicated, except in younger patients, those with other symptoms and signs of APS, and those with a family history of autoimmune disease. Mitral and aortic valve thickening and dysfunction are sometimes seen on echocardi ography, but signi \201 cant morbidity is uncommon. CLINICAL FEATURES OF APS 355 Table 11.2 Clinical features of the antiphospholipid syndrome Feature Subgroup Frequency Major features: Thrombosis Deep vein thrombosis 38.9% Pulmonary embolism 14.1% Arterial thrombosis, legs 4.3% Arterial thrombosis, arms 2.7% Stroke 19.8% Transient ischemic attack 11.1% Valve thickening/dysfunction 11.6% Livedo reticularis 24.1% Fetal manifestations Early loss (<10 wks) Late loss ( (cid:4)(cid:3)10 wks) Live birth 35.4% 16.9% 47.7% Premature birth 10.6% Thrombocytopenia 29.6% Associated features: Leg ulcers, livedo reticularis, thrombophlebitis Heart valve lesions and myocardial infarction Transverse myelitis, chorea, Pulmonary hypertension Less common \201 ndings: Splinter hemorrhages, digital gangrene, leg ulcers Amaurosis fugax, retinal artery and vein occlusion Renal artery stenosis/thrombosis Ischemic bone necrosis Addison \200\231s disease Cervera R. et al. Antiphospholipid syndrome: Clinical and immunologic manifestations and pa tterns of disease expression in a cohort of 1000 patients. Arthritis Rheum 2002; 46: 1019 \200\2231027. CHAPTER 11 The antiphospholipid syndrome 356 Treatment of APS Treatment of APS is summarized in Table 11.4. \200 Studies suggest that lifelong and oral anticoagulation is an effective therapeutic option in the secondary prevention of thrombosis. Care should be taken to maint ain the INR between 2 and 3. Mild thrombocytopenia need not be treated. Severe cases (<50 x 10 9 / liter) should be trea ted with oral corticosteroids. In those failing to respond, gamma-globulin, danazol, and sp lenectomy have been used with varying success. The presence of antiphospholipid antibodies in pregnancy, in the absence of a history of thrombosis or fetal loss, is not an indication for anticoagulation. We would, however, recommend the use of aspirin (81 mg) in these settings. Prophylactic heparin after surgery for DVT prophylaxis is recommended. Women with APS on warfarin should be converted to standard heparin or low-molecular-weight heparins prior to conception, although the reader should be aware that the latter may not b e licensed for this purpose. Aspirin should also be introduced. Other advances have been the realization that high-dose immunosuppression is unwarranted and that combined care between rheumatology, obstetrics, a nd hematology, with judicious monitoring and timely intervention, has a signi \201 cant im pact on outcome in pregnancy. TREATMENT OF APS 357 Table 11.3 The treatment of APS Clinical situation Treatment Asymptomatic Observation and/or low-dose aspirin Thrombosis Deep venous \200\2241st event Lifelong warfarin (INR 2 \200\2233) 1st stroke Lifelong warfarin (INR 2 \200\2233) and/or low-dose aspirin Transient ischemia Low-dose aspirin 1st non-cerebral arterial event Warfarin (INR 2 \200\2233) and aspirin Recurrent arterial/ venous event ? warfarin (INR 3 \200\2234) or LMWH, or add aspirin Catastrophic APS IV heparin IV methylprednisolone pulse Plasmapheresis OR IVIG Pregnancy No previous history Observation and/or low-dose aspirin Recurrent \201 rst trimester or second/ third trimester fetal loss Low-dose aspirin and heparin prophylaxis Previous thrombosis Low-dose aspirin and therapeutic LMWH Repeat fetal loss despite heparin and aspirin Consider hydroxychloroquine and prednisone 10 mg, in addition to the above Thrombocytopenia Mild (100 \200\223150 count) Observe Moderate (50 \200\223100) Observe Severe (<50) Corticosteroids (as ITP), IVIG, immunosuppression (e.g., rituximab) LMWH = low molecular weight heparin CHAPTER 11 The antiphospholipid syndrome 358 Catastrophic APS (CAPS) Introduction \200 This rare variant of APS affects small vessels and visceral organs and was \201 rst described in 1992. It is an important and serious co ndition that can present to many medical specialties. It can present in previously asymptomatic patients. \200 CAPS is associated with other au toimmune conditions such as SLE (see Chapter 9), RA (see Chapter 5) and SScl (see Chapter 1 2). \200 The trigger is an infection in 20% cases. Other precipitating factors include tr auma/surgery, malignancy, warfarin withdrawal in a patient with APS, pregnancy, and oral co ntraceptives. Despite these risk factors it is estimated that 45% cases have no known trigger. Mortality is greater than at 50% and many patients will require critical care. Clinical features \200 Rapid onset, diffuse peripheral and central thrombosis occurs lead ing to: \200 arterial and venous occlusion in the extremities \200 intra-abdominal organ in farction including renal failure (i.e., antiphospholipid-associated nephropathy) pulmonary emboli and adult respiratory distress syndrome \200 small vessel cerebrovascula r disease \200 aortic and mitral valve defects and myocardial infarction \200 other thr ombotic complications such as ovarian, testicular, adrenal and retinal vessel occlusion. Livedo reticularis, gangrene, and purpura are visible markers of the disorder on the skin. Bone marrow infarction and ARDS have also been reported. \200 Classi \201 cation criteri a have recently been produced. 1 Laboratory features These include: \200 Moderate to severe thrombocytopenia \200 Hemoly sis with schistocytes \200 Disseminated intravascular coagulation \200 High levels of I gG aCL antibodies or presence of lupus anticoagulant The differential diagnosis The clinician should consider the following conditions \200 Th rombotic thrombocytopenic purpura (red cell fragments more numerous than in CAPS) Heparin induced thrombocytopenia \200 HELLP syndrome (hemolysis, elevated liver enzymes a nd low platelets) 1 Cervera R, Font J, Gomez-Puerta JA et al . Validation of the preliminary criteria for the classi \201 ca- tion of the catastrophic antiphospholipid syndrome. Ann Rheum Dis, 2005; 64: 1205 \200\2231209. CATASTROPHIC APS (CAPS) 359 Hemolytic \200\223uremic syndrome \200 Cryoglobulinemia \200 Vasculitis \200 Dissemin ated intravascular coagulation \200 Sepsis \200 Paroxysmal nocturnal hemoglobinuria Treatment and prognosis \200 Treatment should always include an attempt to identify and t o address the precipitating event, as well as supportive care. In addition, IV heparin and high-dose corticosteroids should be considered. Life threatening CAPS should also be treated with plasmaphersis versus intravenous immunoglobulin (for 5 days at a dose of 0.4 g/kg/day). Case reports exist in single patients describing the use of prostacyclin, cyclosporin A, de \201 brotide, \201 brinolytics, and rituximab. \200 25% of survivors will develop further APS-related events. \200 Recurrence of CAPS is very rare. This page intentionally left blank 361 Chapter 12 Sj gren \200\231s syndrome (SS) Epidemiology and pathology 362 Clinical manifestations of SS 364 Investigation of SS 368 Tr eatment of SS 370 CHAPTER 12 Sj gren \200\231s syndrome (SS) 362 Epidemiology and pathology \200 Sj gren \200\231s syndrome (SS) is a chronic autoimmun e disease of unknown etiology, characterized by lymphocyte in \201 ltration of exocrine gl ands resulting in xerostomia and keratoconjunctivitis sicca. The condition may be primary, associated with speci \201 c extraglandular (systemic) disea se, or secondary, in association with a number of other autoimmune rheumatic diseases, incl uding RA (see Chapter 5) and SLE (see Chapter 10). Sj gren \200\231s syndrome is also strongly associated with the development of lymphoma. The syndrome affects women more than men in a ratio of 9:1, and tends to occur at 40 \200\22350 years of age. It can, however, occur at any age. Population prevalence is estimated at 0.1 \200\2230.5%. \200 The triggering of autoimmuni ty and the development and continuation of an autoimmune response remain a great source of interest in SS. The links between environmental stimulus and immunogenetics, and the studie s of humoral and lymphocyte activity may help to untangle the mechanisms whereby immunologi cal dysregulation can lead to malignant transformation of B cells involved in the immune pr ocess. \200 Epstein \200\223Barr and retroviruses have been implicated in pathogenesis. \200 HLA DR3 is strongly associated with SS. \200 Antibodies to the ribonucleoprotein co mplexes Ro and La are found and are thought to be formed when these antigens are exposed on the surface of apoptotic ce lls. RF and antinuclear antibodies are also common and patients may be erroneously diagnosed with RA. Recently discovered autoantigens in SS include fodrin and muscarinic acetylcholine receptor M3. Two sets of classi \201 cation criteria for primary SS are listed in Tables 12.1 and 12.2. \200 To satisfy classi \201 cation criteria for primary SS using the American- European Consensus Group (AECG) criteria, focal lymphocytic sialoadenitis (with a focus score of 1 or greater), or antibodies to Ro and/or La must be present. The 2012 American College of Rheumatology criteria emphasize the use of objective, rather than subjective, \201 ndings. Patients with a history of head and neck radiation, hepatitis C infection, HIV/AIDS, sarcoidosis, amyloidosis, graft-versus-host disease, and IgG4-related diseases ar e excluded by ACR criteria from participating in studies of Sj gren \200\231s syndrome, due to the presence of overlapping clinical features that may interfere with objective meas ures. EPIDEMIOLOGY AND PATHOLOGY 363 Table 12.1 Classi \201 cation criteria for primary Sj gren \200\231s syndrome. For clas si \201 cation purposes, 4 of 6 criteria must be present. Criteria Comment Ocular symptoms Dry eyes > 3 months, sense of sand/gravel in eyes, or use of tear substitutes >3 times/day Oral symptoms Dry mouth > 3 months, recurrent swollen salivary glands, frequent use of liquid to swallow Ocular signs Schirmer \200\231s test Corneal and conjunctival staining Oral signs Parotid scintigraphy Sialography Salivary \202 ow Focus score (# lymphocyte aggregates per 4 mm 2 ) must be \211 1 Focal lymphocytic sialadenitis Antibodies to Ro/La One of these two criteria must be positive for this diagnosis. Vitali C, et al. Classi \201 cation criteria for Sj gren \200\231s syndrome; a revised version of the European c riteria proposed by the American-European consensus group. Ann Rheum Dis, 2002; 61: 554 \200\2238. Table 12.2 American College of Rheumatology 2012 Classi \201 cation Criteria for Sj gre n \200\231s Syndrome. For classi \201 cation purposes, two of the three must be present Criteria Comment Serology