Multidisciplinary approach \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Chest physician. Specialist PAH unit. Gastroenterologist. Dentist. Renal physician. Dermato logist. Radiologists. Dietician. Orthopedic surgeon. Vascular surgeon. Physiotherapist \200\223 exercises to retain mobility and to optimize chest function. Occupational therapis t \200\223 hand exercises and aids/ strategies for overcoming disabilities. Speech therapi sts \200\223 for assessing and advising on severe oesophageal dysmotility. Patient advice \200 \200 Avoid smoking. Keep core and extremities warm, e.g. put coat on several minutes before leav ing house; use thermal gloves and socks in cold temperatures. Protect \201 ngers with glo ves whenever possible, e.g. dish washing and gardening. Seek medical advice with new digita l ulcers. Maintain careful oral hygiene and arrange regular dental checks. Management of associated morbidity See \200\230Patient Advice \200\231 for lifestyle measu res. \200 \200 \200 Dyspepsia: proton pump inhibitors and anti-acids. Dysmotility: metaclopramide to aid gastri c emptying. CHAPTER 8 Autoimmune connective tissue diseases 271 \200 For patients with dysphagia \200\223 avoid dry abrasive foods. For patients with gastroint estinal re \202 ux \200\223 avoid eating late in the evening, raise head of bed on blocks . For patients with delayed gastric emptying or small bowel dymotility \200\223 eat little and often. Gentle regular aerobic exercise to maintain cardiovascular/ respiratory \201 tness. Hand exercises to maintain range of movement. \201 ngers (L and R), thigh (L and R), leg (L and R), foot (L and R), score each of 20 sk in regions as follows: 0 = normal 1 = possible thickening 2 = de \201 nite thickening but mobile 3 = thickened and tethered Note: neck and back are sometimes omitted. Patient organizations Raynaud \200\231s & Scleroderma Association, 112 Crewe Road, Alsager, Cheshire, ST7 2JA, UK. Tel: 01270 872776. Freephone: 0800 9172494 (for UK enquiries only). www. raynauds.org.uk The Scleroderma Society, 3 Caple Road, London NW10 8AB, UK. Tel: 020 8961 4912. www.sclerodermasociety.co.uk Follow-up \200 Patients with rapidly-progressive disease, and/or com- mencing new therapies may need 2 \200\2233-monthly review. 6-monthly follow-up is appropriate for patients within the \201 rst 5 years of disease. Annual follow-up may be appropriate for patients with- out severe organ involvement >5 years post-diagnosis. Urinalysis, blood pressure monitoring should be routinely performed in the follow-up visits. ICD-10 codes M34 M34.1 M34.2 J99.1* G73.7* SSc CREST syndrome SSc induced by drugs and chemicals SSc with lung involvement SSc with my opathy Prognosis and natural history lcSSc \200 \200 5-year survival rate reported to be up to 86%. PAH is the most frequent cause of death. References Badesch DB, Hill, NS, et al. Sildena \201 l for pulmonary arterial hyper- tensi on associated with connective tissue disease. J Rheumatol 2007; 34: 2417 \200\22322. dcSSc \200 5-year survival of patients with severe ILD, renal crisis, or cardiac disease each around 5 0%. 5-year survival of dcSSc patients with renal crisis treated with ACE inhibitors approxi mately 70% (compared with less than 10% in the era before ACE-inhibitors were available). R isk of developing severe organ involvement is greatest during the \201 rst 5 years of dcS Sc. 10-year survival of dcSSc who do not develop severe organ involvement within the \201 rst 5 years is approxi- mately 80%. Charles C, Clements P, Furst DE. Systemic sclerosis: hypothesis- driven treatment strategies. Lancet 2006; 367: 1683 \200\22391. DeMarco PJ, Weisman MH, et al. Predictors and outcomes of scleroderma renal crisis. Arthritis Rheum 2002; 46: 2983 \200\2239. Denton CP, Humbert M, et al. Bosentan treatment for pulmonary arterial hypertension related to connective tissue disease: a sub- group analysis of the pivotal clinical trials and the ir open-label extensions. Ann Rheum Dis 2006; 65: 1336 \200\22340. Dziadzio M, Denton CP, et al. Losartan therapy for Raynaud \200\231s phenomenon and sclerod erma: clinical and biochemical \201 ndings in a \201 fteen-week, randomized, parallel-g roup, controlled trial. Arthritis Rheum 1999; 42: 2646 \200\22355. Resources Assessment Tools \200\223 general measures \200 \200 \200 \200 Girgis RE, Frost AE, et al. Selective endothelin A receptor antago- nism with sitaxsentan f or pulmonary arterial hypertension associated with connective tissue disease. Ann Rheum Dis 2007; 66: 1467 \200\22372. Scleroderma-modi \201 ed health assessment questionnaire. Creatinine and creatinine cleara nce. Blood pressure and urinalysis for proteinuria. Raynaud \200\231s Condition Score \200 \223 daily self-assessment of RP activity using a 0-10 ordinal scale. Rodnan Skin Score. Or al aperture. Pulmonary function tests: vital capacity to monitor restrictive lung disease; transfer factor to monitor pulmonary vascular disease; 6-min walk distance. Echocardiograph y \200\223 estimated mean pulmonary arterial pressure and right heart catheterization. Hyd rogen breath tests. BMI. FBC \200\223 monitoring for anemia. Gliddon AE, Dore CJ, et al. Prevention of vascular damage in sclero- derma and autoimmune R aynaud \200\231s phenomenon: a multicenter, randomized, double-blind, placebo-controlled tr ial of the angiotensin-converting enzyme inhibitor quinapril. Arthritis Rheum 2007; 56: 383 7 \200\22346. \200 \200 Henness S, Wigley FM. Current drug therapy for scleroderma and secondary Raynaud \200\231s phenomenon: evidence-based review. Curr Opin Rheumatol 19: 611 \200\22318. Herrick AL. Pathogenesis of Raynaud \200\231s phenomenon Rheumatol 2005; 44: 587 \200\22396. Herrick AL, Worthington J. Genetic epidemiology of systemic sclerosis. Arthritis Res 2002; 4: 165 \200\2238. \200 \200 Hoyles RK, Ellis RW, et al. A multicenter, prospective, randomized, double-blind, placebo-c ontrolled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathi oprine for the treatment of pulmonary \201 brosis in scleroderma. Arthritis Rheum 2006; 5 4: 3962 \200\22370. Assessing Raynaud \200\231s (condition score) Circle below the number that best indicates t he dif \201 - culty you had today with your Raynaud \200\231s condition: Extreme No 0 1 2 3 4 5 6 7 8 9 10 dif \201 culty dif \201 culty LeRoy EC, Black C, et al. Scleroderma (systemic sclerosis) classi \201 - cation, subsets a nd pathogenesis. J Rheumatol 1988 15: 202 \200\2235. Korn JH, Mayes M, et al. Digital ulcer s in systemic sclerosis: preven- tion by treatment with bosentan, an oral endothelin recept or antagonist. Arthritis Rheum 2004; 50: 3985 \200\22393. Kuwana M. Potential bene \201 t of statins for vascular disease in systemic Rodnan skin score For face, neck, anterior chest, abdomen, upper back, lower back, upper ar m (L and R), forearm (L and R), hand (L and R), sclerosis. Curr Opin Rheumatol 2006; 18: 594 \200\223600. LeRoy EC, Medsger TA, Criteria for the classi \201 cation of early systemic sclerosis. J Rheumatol 2001; 28: 1573 \200\2236. SYSTEMIC SCLEROSIS 272 Sunderk tter C and Riemekasten G. Pathophysiology and clinical consequences of Raynaud \200\231s phenomenon related to systemic sclerosis. Rheumatol 2006; 45: iii33 \200\2235. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impac t of epoprostenol therapy. Circulation 2002; 106: 1477 \200\22382. Teixeira L, Mouthon L, et al. Mortality and risk factors of sclero- derma renal crisis: a F rench retrospective study of 50 patients. Ann Rheum Dis 2008; 67: 110 \200\22316. Milio G, Corrado E, et al. Iloprost treatment in patients with Raynaud \200\231s phenomenon secondary to systemic sclerosis and the quality of life: a new therapeutic protocol. Rheum atol 2006; 45: 999 \200\2231004. Tyndall A, Furst DE. Adult stem cell treatment of scleroderma. Curr Opin Rheumatol 2007; 19: 604 \200\22310. Nietert PJ, Silver RM. Systemic sclerosis: environmental and occupational risk factors. Cur r Opin Rheumatol. 2000; 12: 520 \200\2236. S \201 kakis PP, Gorgoulis VG, et al. Imatnib f or the treatment of refrac- Zuber JP, Spertini F. Immunological basis of systemic sclerosis. Rheumatol 2006: 45: iii23 \200\2235. tory, diffuse systemic sclerosis. Rheumatol 2008; 47: 735 \200\2237. Steen VD, Medsger TA. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum 2000; 43: 2437 \200\22344. This page intentionally left blank ANTIPHOSPHOLIPID SYNDROME 274 Antiphospholipid syndrome De \201 nition Antiphospholipid antibody syndrome (APLS; also known as Hughes \200\231 Syn drome) is a systemic autoimmune disease characterized by elevated antiphospholipid (APL) an tibod- ies, and an acquired thrombophilia or clotting tendency. Primary APLS is diagnosed in patients without features of other systemic disease and second ary APLS when patients have features of SLE. For histopathologic con \201 rmation of throm bosis, a solid mass, formed in vivo and derived from blood consti- tutents, must be demonst rated in the vessel in the absence of in \202 ammation in the vessel wall. Accepted manife stations of placental insuf \201 ciency: \200 abnormal fetal surveillance test; \200 a bnormal Doppler \202 ow velocimetry waveform or analysis; \200 oligohydramnios; \200 postnatal birth weight <10th centile for gestational age. Lupus anticoagulant (LA) must be measured according to guidelines of the International Society on Thrombosis and Haemostasis (see resources). Antibodies speci \201 c for cardiolipin or B2GPI must be measured using standardized ELISAs. Classi \201 cation The Sapporo preliminary classi \201 cation criteria, published in 1999 , were amended in Sydney and published as the 2006 International Consensus Statement on the Classi \201 cation Criteria for de \201 nite APLS. Note that these criteria are de- sign ed to facilitate clinical studies/trials by including a rela- tively homogenous patient gro up. The use of the terms \200\230probable \200\231 or \200\230possible \200\231 APLS is a ppropriate in clinical prac- tice, where thromboembolic disease is associated with antiphos pholipid antibodies and no other cause is evident. Catastrophic APLS is a life-threatening form of the dis- ease, in which at least three different organ systems become involved (obj ectively) over the course of days or weeks. Table 8.7 Additional risk factors for thrombosis De \201 nite APLS Present if at least one of the Clinical criteria and one of the Laborato ry criteria are satis \201 ed. Age Males >55 years Females >65 years Established cardiovascular risk factors Hypertension Clinical criteria \200 Diabetes mellitus Vascular thrombosis: arterial, venous or small ves- sel thrombosis in any tissue or organ ( excluding superficial venous thrombosis) \200\223 confirmed by appropriate imaging or hist opathology. Pregnancy morbidity: at least one of the following: \200 one or more unexplai ned deaths of a morphologi- cally normal fetus at or beyond 10th week of ges- tation; one o r more premature births or a morphologi- cally normal neonate before 34th week of gesta- ti on due to eclampsia or severe pre-eclampsia or placental insuf \201 ciency (see below); th ree or more unexplained consecutive spontane- ous abortions before 10th week of gestation, with hormonal, chromosomal or maternal anatomic causes excluded. Elevated LDLc Reduced HDLc Smoking FH of premature CVD BMI >30 kg/m2 Microalbuminuria Estimated GFR <60 ml/min Inherited thrombophilia Oral contraceptive Nephrotic syndrome Malignancy Immobility Surgery Laboratory criteria Any must be present on 2 or more occasions at least 12 weeks apart, and must be measured according to the appropriate guidelines). \200 \200 Epidemiology High titre aCL antibodies and LA are associated with ve- nous and arterial thr omboses, pregnancy losses (mostly mid-trimester), stroke in the under 50s and accelerated a therosclerosis. Approximate \201 gures for prevalence of positive APL tests are provided below. Note that \200\230preva- lence \200\231 varies substantially due to variability bet ween stud- ies regarding the titre and persistence of aCL antibodies de \201 ned as positi ve. Lupus anticoagulant (LA) present in plasma. anticardiolipin (aCL) antibody of IgG, and/or I gM iso- type in serum or plasma anti-B2 glycoprotein-I (B2GPI) antibody of IgG and/ or IgM isotype in serum or plasma, present in medium/high titre (e.g. >99th centile). Accurate predictions of risk in categories of patients with APL antibodies are impossible w ith currently available data. \200 Comments \200 The classi \201 cation of De \201 nite APLS should not be given if the period between the positive (APL) test and clinical manifestations is <12 weeks or >5 years. Co-existing risk factors for thrombosis should not prevent classi \201 cation as De \201 nite APLS, but p atients should be classi \201 ed as such in the presence or absence of additional risk fac tors (see Table 8.7). LA appears to be more strongly associated than with arterial thromboses and thrombocytopaen ia compared with aCL antibodies. Women who are positive for both aCL antibodies and LA appe ar to be at increased risk of fetal loss compared with women who are aCL antibody positive alone. CHAPTER 8 Autoimmune connective tissue diseases 275 Effector mechanisms Autoimmune APL antibodies include antibodies speci \201 c for a variet y of phospholipid binding proteins, many of which participate in the coagulation cascade (F ig 8.8). The most important of these protein \200\230cofactors \200\231 are B2GPI and prot hrombin, but other cofactors include protein C, pro- tein S, high molecular weight (HMW) ki ninogen, annexin V, and factor XI. The prolongation of in vitro coagulation assays appears to result from the formation of complexes between the APL antibodies, and one or more of th e phos- pholipid-binding proteins that are required for the in vitro clotting assay. Table 8.8 \200\230Prevalence \200\231 of aCL antibodies or LA aCL antibodies (IgG/IgM) LA Healthy controls 1.5% 2% Pregnant women <1% 2% SLE 30% 15% RA 20% SSc 19% 4% Venous thrombosis 4 \200\22324% 1 \200\22316% Stroke <50 years 30% 4% XI HMW kinin In patients with de \201 nite APLS, the risk of fetal loss is currently 20%. There appear s to be an association between LA and pulmonary arterial hypertension (PAH) in Systemic Scl erosis (SSc). XII XIIa X Subendothelial tissues; platelets XIa IXa IX VIIa Etiology and pathophysiology Genetic Associations between HLA loci and APLS have been repor ted. Mice de \201 cient for complement C3, C5 or C5a receptors are resistant to APL-mediat ed fetal injury. VII Tissue Factor VIIIa VIII Protein S & Protein C vWF Phospholipid substrate e.g. platlelet or microparticle surface V V Va Environment Infectious triggers Many infectious agents have been associated with the de- ve lopment of antiphospholipid antibodies and with clinical manifestations of APLS. These incl ude: \200 \200 \200 \200 \200 \200 \200 Fibrinogen Xa Prothrombin Thrombin Antithrombin Fibrin hepatitis C virus (HCV). Varicella zoster virus (VZV). Cytomegalovirus (CMV). Parvovirus B1 9. HIV. Haemophilus in \202 uenzae Neisseria gonorrhoeae. Figure 8.8 Summary of coagulation cascade. Dotted lines indicate inhibitors. Gray box indic ates factors associated with a phospholipid membrane surface. Promoting thrombosis Hypotheses regarding the mechanism(s) by which APL antibodies promote thrombosis in vivo: \200 Approximately a third of the cases of catastrophic APLS have clearly been preceded by infec tions. Activation of endothelial cells to up-regulate adhesion molecules, von Willebrand factor (v WF) tissue factor and tissue plasminogen activator. Activation of platelets to release pro- coagulant throm- boxane A2. Activation of circulating monocytes to increase expression of a dhesion molecules and production of pro-in \202 ammatory cytokines. Acquired protein C res istance (B2GPI mediates binding of APL to protein C). Impaired \201 brinolysis. Non-infectious triggers/promoters \200 Drugs: chlorpromazine is associated with the develop- ment of aCL antibodies (34%) and lupu s anticoagulant (LA, 45%), but the incidence of clinical features is low. A variety of idio syncratic drug associations with APLS have been reported, including anti-epileptics, anti-h ypertensives, anti-arrhythmics, and antibiotics. Trauma is the second most frequent precipi tation factor (after infection) for catastrophic APLS. Vaccination has been suspected to in duce APLS, but there are no data currently to support this. Hypotheses regarding mechanisms by which APL antibodies impair placental development and fu nction: \200 Immunopathology Breaking tolerance Refer to SLE section (AICTD chapter, p. 240) for an over view of mechanisms believed to be involved in break- ing tolerance. The generation of antib odies speci \201 c for phospholipid/protein cofactor combinations may re \202 ect: \200 Binding to and interference with annexin V anticoagulant shield on the surface of trophob last cells. Impaired \201 brinolysis. Defective maturation and invasion of trophoblast ce lls (partially mediated by reduction in IL-3). Activation of complement and promotion of in \202 ammation. \200 Exposure of cryptic epitopes within the protein cofactor following binding to the phospholi pid target (demon- strated for B2GPI following binding to phospholipid). Molecular mimicry. Several microbial pathogens have a component that shares structural homology with the TLRV YK peptide, a peptide shown to induce clinical features of APLS in mice. Risk factors \200 LA positive: high risk of arterial and venous thrombosis (odds ratio [OR] 10). LA negative , but persistently aCL antibody positive (i.e. positive in >66% of estimations) \200\223 i ncreased risk of venous thrombosis (OR 3). ANTIPHOSPHOLIPID SYNDROME 276 Sneddon \200\231s syndrome is de \201 ned as the clinical triad of stroke, hypertension, a nd livedo reticularis. In many cases, there are APL antibodies. LA negative and transiently aCL antibody positive (i.e. positive on at least 2 occasions, b ut on <66% of estimations) \200\223 thrombosis risk is not elevated. De \201 nite APLS: r isk of fetal loss 20% (reduced from 50% pre-heparin treatment). SLE plus APL antibodies 50% develop de \201 nite APLS. LA in SLE patients: increased risk of coronary artery disea se. Mucocutaneous Livedo reticularis is a common feature and ranges from subtle to \202 orid. Splinter hemorrhages are occasion- ally noted. \200 Hematological Thrombocytopaenia is common in APLS, but bleeding is uncommon. Clinical features Main APLS clinical features \200 Gastrointestinal Rare, but serious complications include mesenteric or hepatic artery or ve in thrombosis. Arterial thrombosis including: \200 intracranial arterial thrombosis resulting in TIAs, stroke syndromes or multi-infarct demen tia; \200 myocardial infarction; \200 renal artery thrombosis; \200 mesenteric arteri al thrombosis; \200 digital artery thrombosis. Venous thrombosis including: \200 Pulmonary Pulmonary embolus is a well-recognized manifestation of APLS. LA appears to be as sociated with pulmonary arterial hypertension (PAH) in SSc and perhaps also with PAH in oth er contexts. deep venous thrombosis is frequent, sometimes complicated by pulmonary embolus; \200 Budd -Chiari Syndrome (hepatic vein thrombosis); sagittal sinus thrombosis; \200 retinal vein thrombosis; \200 axillary vein thrombosis; \200 renal vein thrombosis; \200 inferior vena caval thrombosis; \200 mesenteric venous thrombosis; \200 adrenal vein thrombosis leading to Addison \200\231s disease. \200 Maternal pregnancy complications are mainly ma nifesta- tions of thromboembolic disease, usually DVT or PE. Depression with suicidal ideat ion is also reported. These complications can start from about 15 weeks gestation. Fetal co mplications arise mainly due to placental insuf- \201 ciency and include intrauterine gro wth retardation (usually evident after 20 weeks), oligohydramnios, small placental size, an d intrauterine death. Fetal thrombosis is rare and infants born to women with APLS appear t o grow and develop normally. A mild verbal processing de \201 cit has been reported in mal e children of SLE/APLS patients. Cardiovascular Approximately 33% of APLS patients have valvular lesions (Libman \200\223Sac ks endocarditis), most commonly on the mitral valve. These pre-exisitng lesions might incre ase the incidence of subacute bacterial endocarditis. APL antibod- ies may accelerate ather osclerosis. This, together with the thrombotic tendency, probably contributes to the increa sed incidence of MI and stroke in APLS. Musculoskeletal Avascular necrosis, usually associated with high-dose glucocorticoid use, a ppears to be increased in patients with APL antibodies. Key features in history \200 \200 Previous thromboses (e.g. DVTs, PEs). Obstetric history: miscarriages, pre-eclampsia, eclam p- sia, premature delivery, low-birth-weight babies. Hematological: enquire about history o f bleeding (would suggest a different diagnosis) or thromboembolic disease (DVT, PE, and ne onatal/fetal loss or premature delivery). Pulmonary: enquire about exertional dyspnoea, che st pain (pleuritic?), and haemoptysis. Cardiovascular: calf swelling may indicate a DVT. An kle swelling may be a manifestation of nephrotic range proteinuria. Hypertension may occur with renal artery stenosis or glomerular disease. Neurological: enquire about, and clarify the nature of \201 ts, \200\230funny turns \200\231, headache, tingling/numbness, altere d mood and dif \201 culty with concentration or memory. See also \200\230The Nervous Syst em \200\231, p. 90 Gastrointestinal/Hepatic: enquire about abdominal pain, diarrhea (with b lood?). Lifestyle: certain factors increase the risk of thrombosis: Smoking, recent long ca r journeys, or \202 ights, if DVT/PE suspected. Oral contraceptive use. Summary of clinical features by body system Renal Renal artery stenosis occurs commonly in APLS patients with hypertension. Vasculo-occlusive lesions occur in smaller vessels, as wel l as result of \201 brous intimal hyperplasia in interlobular arteries and thrombotic mic roangiopathy in microvasculature. Renal vein or inferior vena caval throm- bosis are associ ated with APLS. End-stage renal failure is a rare complication in primary APLS. In patients with SLE, and secondary APLS and renal involvement, immune complex-mediated glomerulonephr itis, and glomerular thrombosis both occur. Neurological A wide range of features occur including: transient ischaemic attacks, ischaem ic stroke, cerebral venous thrombosis, headache, epilepsy, demyelination, cognitive dysfunc tion, depression, dementia, psychosis, intracranial hypertension, chorea, transverse myelit is, sensorineural hearing loss, transient global amnesia, dystonia, parkinson- ism, Guillai n \200\223Barre syndrome, amaurosis fugax, and optic neuropathy. Key features on examination \200 Cutaneous: look for livedo reticularis (may affect a small area only) and other signs of th romboembolism or vasculitis, e.g. splinter hemorrhages Musculoskeletal: synovitis is not a feature of primary APLS, but may occur as part of associated syndromes in secondary APLS. A vascular necrosis (most commonly of CHAPTER 8 Autoimmune connective tissue diseases 277 femoral head) may be associated with irritability of the hip (internal and external rotatio n). Renal: BP and urinalysis. Proteinuria (1.5 \200\22315 g/24 h) occurs in virtually all c ases of APLS nephropathy (micro- circulatory thrombosis). Sudden heavy proteinuria should r aise suspicion of renal vein thrombosis. Neurological: a basic neurological examination sho uld be performed at diagnosis and in response to the devel- opment of new symptoms. Include fundoscopy in patients with (early morning?) headache and consider a cognitive assessment. Hematological: pallor indicates anemia (not usually a feature of APLS). Bruising and exces sive bleeding may occur with severe thrombocytopaenia or with a de \201 - ciency of clotti ng factors. However, note that glucocorti- coid therapy is the usual reason for excessive b ruising in SLE/APLS patients. Gastrointestinal: palpate abdomen for tenderness and organome galy. Pulmonary: examine for respiratory rate, central cyanosis, stony dull percussion note (pleural effusion), pleural rub, signs of right heart strain. Cardiovascular: assess blood pressure at each visit. Examine for murmurs, right heart strain, peripheral pulses and car otid bruits (in cases with TIA/stroke syndromes). Renal: blood pressure and urinalysis. Sic ca signs (see Sj gren \200\231s disease, p. 254). Notify the hematology laboratory if the patient is receiving high or low-molecular weight h eparin, since this may cause prolongation of several of the screen- ing assays (dAPTT, DRVV T, dPT). Note that a strong LA can deplete factors VIII and IX, and this may erroneously ra ise suspicion of a primary factor VIII or IX de \201 ciency. Other hematology \200 FBC may show evidence of anemia and/or a profound thrombocytopaenia (may suggest an alterna tive diagnosis, e.g. thrombotic thrombocytopenic purpura [TTP] or haemolytic uremic syndrom e [HUS]). Blood \201 lm to exclude schistocytes (RBC fragments) of microangiopathic haemo lytic anemia (MAHA); this suggests TTP or HUS, rather than APLS. Direct Coombs test is usua lly negative in MAHA. ESR may indicate co-existing in \202 ammatory disease. \200 Biochemistry \200 Renal function tests \200\223 serum creatinine and estimated creatinine clearance from Coc kcroft \200\223Gault formula: Estimated CrCl = [(140 \200\223 age) \227 weight (kg)]/ serum Cr ( mol/l) (Multiply by 0.85 in women) Note that this formula is inaccurate in patients with oedema due to nephrotic syndrome. Ear ly morning urinary protein to creatinine ratio is prob- ably as accurate as 24-h urine coll ection for quantifying severity of proteinuria. Liver function tests especially in patients with abdominal pain Thyroid function tests: hypothyroidism common. \200 Investigations Laboratory Anticardiolipin antibodies Detection of aCL antibodies by ELISA i s suf \201 cient to make the diagnosis of APLS in patients with relevant clinical features , even in the absence of LA. SCREENING TEST Use at least 2 tests for lupus anticoagulant: dAPTT, DRVVT, KCT, dPT, Textar in Clotting Time The signi \201 cance of low titre IgG or IgM aCL antibodies, or of IgA aCL antibodies at any titre is controversial. Anti B2GPI and other antibodies B2G PI antibodies can also be measured by ELISA. This assay is less sensitive, but more speci \201 c than aCL assays and may be particularly helpful where an infection- associated aCL i s suspected. \200 If \211 1 positive Anti-prothrombin antibodies are measured in some centers, but the assay is not widely avail able. ELISAs for other phospholipids (phosphatidyl inositol, phosphatidylethanolamine, and phosphatidylserine) are also sometimes used in specialist centers. MIXING STUDIES Patient: Control Plasma 1:1 (Corrects prolonged clotting test if due to a fa ctor deficiency) Lupus anticoagulant A variety of different tests may be employed to demon- strate the prese nce of an LA (Fig 8.9); however, the prin- ciples common to all approaches can be summarize d as: 1 Demonstration that a phospholipid-dependent clotting Fails to correct with control plasma assay is prolonged in vitro. CONFIRMATORY TESTS Correction with a source of excess phospholipid: (Frozen platelet suspen sion or partial thromboplastin or platelet vesicles) 2 Demonstration that this is due to the presence of an inhibitor, rather than the absence o f a clotting factor. 3 Demonstration that the inhibitor is phospholipid- dependent and not a speci \201 c inhibitor of a single coagu- lation factor. \200 (Abbreviations: dAPTT dilute activated partial thromboplastin time; DRVVT dilute Russell \200\231sviper venom time: KCT kaolin cephalin time; dPT dilute prothrombin time) At least 2 screening tests are used; dAPTT is more sen- sitive for the detection of APL ant ibodies utilizing pro- thrombin as a cofactor, while DRVVT is more sensitive for the detect ion of antibodies binding to B2GPI. Figure 8.9 Functional assay use for detecting a LA. ANTIPHOSPHOLIPID SYNDROME 278 Bone function tests plus vitamin D and PTH, since vitamin D de \201 ciency is common, part icularly in patients with co-existing SLE, who use sunscreen. Fasting lipid pro \201 le \200\223 to detect and monitor co-existing hyperlipidaemia, which adds to the cardiovascula r risk of APLS itself. Troponin I if myocarditis or myocardial infarction suspected. Cerebr ospinal \202 uid (CSF) \200\223 see p. 92. in catastrophic antiphospholipid syndrome. Clotting assays (PT and APTT) are usually prolon ged and \201 brin degradation products and D-dimers are markedly raised. The context (sep sis, obstetric complication) is usually helpful in making the diagnosis. Deficiency of coag ulation regulator, e.g. protein C, protein S, or antithrombin. Paraneoplastic manifestation . TTP is characterized by fever, MAHA, thrombocytopaenia, renal impairment, and neurologica l de \201 cits. Haemolytic uraemic syndrome (HUS) de \201 ned by the triad of MAHA, throm bocytopaenia, and renal impairment. Some forms of HUS are triggered by gas- trointestinal i nfection with a Shigatoxin-producing E. coli. Genetic forms of HUS include de \201 ciencie s of comple- ment regulatory proteins, e.g. factor H or membrane cofactor protein de \201 ciency. TTP and HUS can be distinguished from APLS by pres- ence of MAHA, very low platelet counts, and absence of APL antibodies. Sneddon \200\231s syndrome, as de \201 ned as the clinical trial of stroke, hypertension and livedo reticularis, is often caused by APLS. Moy a-moya is a rare cerebrovascular occlusive disease characterized by bilateral stenoses of t he terminal inter- nal carotid artery, accompanied by abnormalities of the vascular network at the base of the brain; it usually presents with stroke syndromes in children and intrac ra- nial hemorrhages in adults. Hyperhomocysteinaemia. Evan \200\231s syndrome \200\223 ac quired haemolytic anemia and thrombocytopaenia. Pregnancy-related differential diagnoses: \200 \200 Immunology \200 ANA and, if positive, ENA to indicate the likely nature of any associated autoimmune connec tive tissue disease (AICTD). Complement C3 and C4 if co-existing immune complex- mediated d isease (e.g. rash, nephritis) is suspected. CSF \200\223 see p. 92. Check a midstream urin e if urinanalysis is positive and request microscopy to look for an \200\230active \200 \231 renal sediment, as well as culture/sensitivity. Blood cultures (multiple sets) should be performed whenever bacterial infection is suspected (e.g. possible endocarditis, meningi tis). CSF \200\223 see p. 92. \200 Imaging \200 Consider obtaining chest radiograph (CXR) if features of pleurisy. Note CXR may be normal i n PE. Ventilation-perfusion scan in cases of suspected PE with normal CXR. CT Pulmonary ang iogram \200\223 in cases of suspected PE in patients with pre-existing lung disease, if CX R abnormal or to detect pulmonary artery aneurysms. MR head/spinal cord should be obtained in patients with clinical focal neurological de \201 cit or with unusual head- aches or co gnitive defects. \200 HELLP \200\223 haemolysis elevated liver enzymes and low platelets is a pregnancy-related hypertensive disorder with underlying thrombotic microangiopathy; defec- tive control of th e alternative pathway of complement may be responsible. HELLP is sometimes considered to be a form of pre-eclampsia. Pre-eclampsia \200\223 new hypertension and proteinuria during t he second half of pregnancy are associated with placental ischaemia; may progress to the co nvul- sive state of eclampsia. Histology \200 Renal biopsy should be considered in patients with an \200\230active \200\231 renal sedime nt on urinalysis or isolated proteinuria (+++ or >1g/L). Liaise with renal team. See p. 75. Skin biopsy may reveal thrombotic microangiopathy. In \201 ltration of in \202 ammatory cells may also be evident. Other investigations \200 Treatment Objectives of management \200 \200 \200 \200 Pulmonary function tests. Spirometry and transfer factor to screen for pulmonary arterial h ypertension. See also p. 59. Echocardiogram to detect any pericardial effusion, LVH, reduce d LV ejection fraction, valvular lesions, and as a screening test for PAH. ECG \200\223 us eful screen for arrhythmia, ischaemia, left ventricular hypertrophy (LVH). Ankle/Brachial P ressure index, Doppler ultrasound, MR angiography or conventional angiography to investigat e suspected peripheral vascular disease. Carotid ultrasound for investigation of carotid br uit or of TIA/stroke. Lumbar puncture, EEG and other neurophysiology tests might be necessa ry (see also p. 90). Ocular investigations, \200\223 see The Eye, p. 48. Prevention of thromboembolic events. Management of any associated in \202 ammatory disease . Management of associated co-morbidity. Maximizing chance of successful pregnancy, whilst minimizing risks to mother. Prevention of thromboembolic events Anticoagulation The evidence base regarding ef \201 ca cy of antiplatelet and anticoagulant agents is still inadequate. Published RCTs include mai nly cases at the low-risk end of the APLS spec- trum and it is likely that high-risk APLS p atients should be anticoagulated more aggressively than these trial data would suggest (Tab le 8.9). Hydroxychloroquine (HCQ) Several studies have indicated that HCQ reduces throm- botic event s in SLE. Further study is required to assess its ef \201 cacy in primary APLS, but in vie w of its relative safety, it is widely used in all categories of APLS. Differential diagnosis \200 \200 Beh et \200\231s disease - see p. 340. Diffuse intravascular coagulation (DIC) with thromb ocy- topaenia should be considered as a differential diagnosis CHAPTER 8 Autoimmune connective tissue diseases 279 Risk factors Additional risks for thromboembolic disease should also be minimized. This inc ludes stopping smoking, treating hypertension, and managing hyperlipidaemia. Table 8.10 Recommended therapy for pregnant patient with aCL antibodies Pregnancy scenario Recommended treatment HMG-CoA reductase inhibitors (statins) The pleiotropic effect of statins has been reported to in- clude inhibition of APL-mediated up-regulation of tissue factor expression by monocy tes and endothelial cells. Low-dose aspirin? Persistent APL antibodies (LA is higher risk than aCL antibodies), but no previous thrombo- embolism (TE) or adverse obstetric history LMWH post-partum? Low-dose aspirin prophylactic LMWH. Table 8.9 Recommended therapy for categories of (non- pregnant) patients with aCL antbodies APLS with adverse obstetric history (no TE history) LMWH postpartum Category of patient Recommended therapy APLS with TE history Stop warfarin as soon as possible post-conception. Persistent aCL antibodies. No history of clinical events HCQ?* Use low-dose aspirin and therapeutic dose of LMWH then follow with warfarin postpartum Thrombosis and single positive APL antibody test Treat as for thrombosis in the general population APLS ( \201 rst venous thrombosis) Warfarin (INR 2.0 \200\2233.0) and HCQ Warfarin after organogenesis (weeks 6 \200\22312) APLS with recurrent TE disease despite full antithrombotic dose of heparin APLS (arterial or recurrent venous thrombosis) Warfarin (INR 3.0 \200\2234.0) and HCQ Breastfeeding Warfarin or heparin safe APLS (recurrent episodes on warfarin with INR 3.0 \200\2234.0) Low molecular weight or unfractionated heparin or warfarin plus antiplatelet agent Anti-in \202 ammatory treatment Increased leucocyte adhesion and complement activation hav e been demonstrated in placentae of women with APLS and obstetric complications. Heparins h ave been shown to reduce both these processes. Glucocorticoids (GCs) appear to be ineffecti ve and can cause signi \201 cant adverse effects, so should be avoided. HCQ may be bene \201 cial, but there are no outcome data to inform this at present. INR: international normalized ratio. *The APLASA study indicated that patients with persist ent aCL antibodies with or without a lupus anticoagulant did NOT bene \201 t from 81 mg as pirin daily. Management of associated morbidity Refer to SLE section (AICTDs chapter, pp. 250 \200\22325 1) for management of co-morbidity including: cardiovascular dis- ease, osteoporosis, chroni c renal failure, and depression. Pregnancy monitoring and management \200 Blood pressure and urinalysis checked at each antenatal visit at least monthly. FBC for pat ients on heparin to monitor for heparin- induced thrombocytopaenia. This is rare and the ri sk is lower with LWMH than with unfractionated heparin. INR to monitor anticoagulation with warfarin. Antifactor Xa activity can be used to monitor anticoagu- lation with LMWH. Frequ ent ultrasound scans to monitor fetal growth. Uterine and umbilical artery Doppler blood \202 ow analysis during second trimester. Manage hypertension with calcium channel antagoni sts. Calcium and vitamin D3 (e.g. adcal-D3 2 daily) may be given in pregnant and breastfeed ing patients receiving heparin. However, there is no evidence base to indicate whether this reduces the incidence or severity of heparin-induced osteoporosis. Activity of co-existing SLE may be treated with systemic GCs, HCQ, azathioprine, or rituximab. For severe thromboc ytopaenia use prednisolone 30 \200\22360 mg daily. This raises platelet count. If effective use this strategy prior to delivery. Other options include intrave- nous immunoglobulin an d early delivery. Maximizing chance of successful pregnancy whilst minimizing risks to mother Pregnancy plann ing \200 Repeat aCL antibody testing and check LA to establish whether APL antibodies are persistent . In patients with co-existing SLE, optimize disease control on non-teratogenic immunosuppr essants (see p. 368 \200\223369). Postpone pregnancy after a thromboembolic event, especial ly a stroke. Discourage pregnancy in patients with pulmonary hypertension. Determine antico agulant strategy (see Table 8.10). \200 \200 \200 Anticoagulant strategy The recommendations below are distilled from a variety of studies an d reviews. However, treatment regimes for each scenario remain controversial. HCQ appears t o be safe in pregnancy. Either unfractionated heparin or low molecular weight heparin (LMWH ) may be given in: \200 Prophylactic doses: unfractionated heparin 5000 \200\223 10 000 IU twice daily or LMWH, e.g . enoxaparin 0.5 mg/kg twice daily. Therapeutic doses: unfractionated heparin 10 000 \200 \223 36 000 IU twice daily or LMWH, e.g. enoxaparin 1 mg/kg twice daily, with monitoring. Multidisciplinary \200 Obstetrician. \200 Neonatologist. \200 Hematologist. \200 Re nal physician. \200 Dermatologist. \200 Chest physician. \200 Gastroenterologist.