Neurological (see also p. 90) A wide variety of neurological or psychiatric conditions occu r in SLE (Table 8.2). Neurological manifestations occur in the majority of patients, with c ognitive dysfunction, CHAPTER 8 Autoimmune connective tissue diseases 245 Cardiovascular All layers of the heart may be affected in SLE and acceler- ated atheroscler osis is the major cause of premature mortality. Pericardial involvement is common, occurrin g in 66%; symptomatic in 33%. Subclinical myocarditis is probably also common, but signi \201 cant clinical features occur in 10%. Endocardial lesions are associated with anti-ph ospholipid antibodies (Libman \200\223Sacks endocarditis). The incidence of subacute bacter ial endocarditis may also be increased both by generalized immunosuppression in SLE and by pre-exisitng endocardial lesions. Incidence of MI and stroke is increased between 3- and 10 -fold. Table 8.2 Manifestations of neuropsychiatric lupus Central nervous system Peripheral nervous system Aseptic meningitis Guillain \200\223Barre syndrome Cerebrovascular disease Autonomic neuropathy Demyelinating syndrome Mononeuropathy Headache Myasthenia gravis Movement disorder Cranial neuropathy Myelopathy Plexopathy Seizures Polyneuropathy Other general issues \200 Acute confusional state Sj gren \200\231s syndrome occurs in up to 20% of SLE patients. Thyroid disease: hypothyro idism occurs in 6% SLE patients, compared with 1% of the general population. Hyperthyroid ism is not signi \201 cantly increased. Osteoporosis: approximately 25% of patients with S LE have densitometry-defined osteoporosis and 10% suffer fractures. Vitamin D deficiency: approximately 75% of SLE patients have vitamin D insuf \201 ciency (<30 ng/ml) and 15% ha ve vitamin D de \201 ciency (<10 ng/ml). Osteonecrosis has been estimated to occur in 10% of SLE patients and is associated with GC therapy. Infections are increased in SLE (relati ve risk of 1.6 compared with controls overall). UTI, pneumonia, and bacteraemia with unkno wn source are the commonest types of infection. E. coli is the most frequently isolated org anism. CNS infections are uncommon in SLE; organ- isms include M. tuberculosis, Cryptococcu s, Listeria, Klebsiella and Aspergillus. Septic arthritis is also rare in SLE, but most fre quently involves the hip and presents with avascular necrosis; Salmonella enteritidis is th e most common pathogen in septic joints. Malignancy: the standardized incidence ratio (SIR) for all malignancies in SLE 1.15. Notable associations include NHL SIR 3.6 and hepatobilia ry cancers SIR 2.6. Infertility is rarely a problem in SLE, but may be associ- ated with ac tive disease, renal failure, or use of NSAIDs, high dose GCs or cyclophosphamide. Miscarria ges are associated with antiphospholipid antibodies. Anxiety disorder Cognitive dysfunction Mood disorder Psychosis mood disorder, headache, cerebrovascular disease and seizures being the most common problem s. Attribution of neurological phenomena to SLE is problematic, since this relies on the ex clusion of another cause and some condi- tions, e.g. headache and depression are common in the general population. Hematological \200 Anemia is present in >70%.and may be normochromic normocytic, hypochromic microcytic (iron de \201 cient?), macrocytic (hypothyroid? vitamin B12 or folate de \201 - cient?), autoim mune or microangiopathic haemolytic. Lymphopenia is common and correlates with disease acti vity. Neutropaenia is uncommon, but may occur as a result of drug toxicity. Thrombocytopaen ia occurs in 20%, but serious bleeding is uncommon. APLS. Lymphadenopathy is common in SLE , but the incidence of non-Hodgkin \200\231s lymphoma is increased 7-fold. Functional hypo splenism occurs in 5% patients with SLE, probably due to blocking of Fc receptors by circu - lating immune complexes. This results in a susceptibility to infection with Pneumococcus, Meningococcus, Haemophilus in \202 uenzae., and occasionally protozoa. Key features in history Mucocutaneous involvement Enquire about malar rash, photosensitivit y (adult-onset?), alopecia, other rashes, and unusual mouth or nose ulcers. When urticarial lesions occur, ask if painful/lesions lasting >24 h (probably vasculitic) or itchy, and re solving within 24 h (probably allergic). Gastrointestinal (see also p. 82) Mouth ulcers are common. Mucosal ulceration may occur in the small intestine, occasionally leading to strictures. Oesophageal dysmotility may occur, but is rarely a serious problem. Similarly, hepato- and/or splenomegaly are found in 10 \200\22330%, but are rarely serious problems. \200 Patients with SLE frequently report episodic abdominal pain, bloating, constipation, and di arrhea. Rare, but serious complications include autoimmune hepatitis, malabsorption, coliti s, mesenteric vasculitis, and mesenteric or hepatic artery or vein thrombosis. Musculoskeletal Joint pains, swelling, duration of early morning stiffness; muscle pain/wea kness; note that a single disproportionately painful, swollen, warm joint may be septic. Hematological Enquire about history of thromboembolic disease (DVT, PE and fetal loss), whi ch may indicate APLS. Anemia may contribute to fatigue and dyspnoea. Enquire about sore thr oats and infections in patients with neutropaenia (uncommon \200\223 note risk of fungal i nfections) or severe lym- phopaenia (consider infection with atypical organisms). Easy brui sing/bleeding may be symptoms of thrombocyto- paenia. Ask about swollen lymph glands, and f evers and Pulmonary (see also p. 54) Pleurisy occurs in 50% and pleural effusion in 25%. Subtle abn ormalities of pulmonary function tests are com- mon but signi \201 cant interstitial lung disease (ILD) occurs in 20%. Recurrent pneumonia may occur, particularly in patients with splenic hypofunction. Pulmonary embolus is associated with antiphospholipid antibodies. Shr inking lung (related to diaphragmatic dysfunction) and pulmonary hypertension are rare. SYSTEMIC LUPUS ERYTHEMATOSUS 246 night sweats; while these all occur in active SLE, their presence should raise suspicion of lymphoma. Table 8.3 Mini-mental state examination Domain Maximum points Gastrointestinal Enquire about dyspepsia, nausea, vomiting, abdominal pain or distention, a nd diarrhea or constipation. Orientation Pulmonary Enquire about chest pain (pleuritic or chest wall tender- ness), dyspnoea, cough, sputum, haemoptysis, and history of pneumonia. What is the time, date, day, month, year? 5 What is the name of this ward, hospital, district, town, country? 5 Registration Cardiovascular Enquire about chest pains (pericarditic \200\223 relieved by sitting forwar d; angina \200\223 central, tight, radiating to L arm or jaw, exertional, associated with dyspnoea), palpitations, ankle swelling, and dyspnoea. 3 Name three objects once only. Score 1 point for each correct repetition. Repeat the objects until patient can repeat them accurately (for later recall) Attention and calculation Subtract 7 from 100 and then 7 from the result four more times 5 Neurological Enquire about and clarify the natures of \201 ts, \200\230funny turns \200 \231, headache, tingling/numbness, altered mood and dif \201 culty with concentration or m emory. An account from a close friend or relative is often revealing. A mini-mental state e xamination is useful if the presence of signi \201 cant cognitive dysfunction. Erectile dy sfunction may occur with autonomic neuropathy. Recall Repeat the names of the three objects registered earlier 3 Language Name 2 objects (e.g. pen and watch) 2 Repeat phrase \200\230No ifs, ands or buts \200\231 1 Other \200 \200 3 Perform a 3-stage command, e.g. \200\230With the index \201 nger of your right hand touc h your nose and then your left ear \200\231 Enquire about dry eyes, mouth, vagina. Raynaud \200\231s phenomenon (RP): classic triphasic (red/ white/blue) color change, but all colors not required for diagnosis of RP; age > 30 years at onset and severe ischaemic pain suggest secondary RP. Lifestyle: smoking, occupati onal/recreational history. Drugs: include history of possible triggering agents for SLE and use of drugs associated with common co- morbidity, e.g. GCs, NSAIDs. Past medical history: ask about diseases that may have been a previous manifestation of SLE or which may in \202 u- ence management, e.g. cardiovascular disease, diabetes mellitus, miscarriages, thro mboembolic disease, oste- oporosis, pleurisy. 1 Show the patient the written message \200\230Close your eyes \200\231 (score 1 point if th e patient follows the instructions) \200 Ask the patient to write a sentence (score 1 point if it makes sense and includes a noun an d a verb) 1 Draw a pair of intersecting pentagons (Score 1 point if accurately copied) 1 Total maximum score 30 Neurological A basic neurological examination should be performed at diagnosis and at annua l review. Otherwise, examination should be performed in response to the development of new symptoms. Include fundoscopy in patients with (early morning?) headache and assess pupillar y responses and postural BP drop where the history suggests autonomic neuropathy. A mini-me ntal state examination (Table 8.3) is useful in patients with cognitive dif \201 culties. Key features on examination Skin involvement Look for subtle malar rash, which patients oft en overlook, discoid lesions, evidence of alopecia, pigmentation, vitiligo, livedo reticula ris, and signs of small vessel vasculitis (palpable purpura, urticaria). Circling urticaria l lesions facilitates the patient monitoring whether they persist longer than 24 h. Be aler t to the presence of evolving lesions, which could indicate skin cancer. Hematological \200 Pallor indicates anemia. Urobilinogen on urinalysis and, less commonly, jaundice are manife stations of haemo- lytic anemia. Bruising and bleeding (e.g. from gums) may occur with seve re thrombocytopaenia, with a de \201 ciency of clotting factors (?liver failure) or, in th e acutely ill patient, as part of disseminated intravascular coagulation. However, note tha t GC therapy is the usual reason for excessive bruising in SLE patients. Livedo reticularis frequently occurs in patients with APLS. Lymphadenopathy may merely be a correlate of acti ve disease, but large, unresolving nodes should prompt investigation for lymphoma. Musculoskeletal Look for synovitis (consider septic arthritis if one joint disproportionate ly in \202 amed or in presence of hip irritability; note that immunosuppression may mask u sual signs of septic arthritis), tenosynovitis, Jaccoud \200\231s arthropathy (reducible de formities), proximal muscle weakness, muscle tenderness, and \201 bromyalgia trigger poin ts (see Plate 6). Renal BP and urinalysis; haematuria, proteinuria or pyuria (persis- tent leucouria in the a bsence of infection) may occur. Enquire about menstruation in women with isolated hae- matu ria. Note that hypertension and azotemia (increased nitrogen-containing compounds in blood \200\223 manifest as skin pallor and \200\230frost \200\231 from nitrogen-containing comp ounds excreted in sweat) are more severe in APLS when throm- botic microangiopathy affects the kidney. Gastrointestinal Look for pallor, jaundice, lymphadenopathy, clubbing, spider naevi, signs of nutritional de \201 ciency (low BMI, angular cheilosis, leuconychia, koilonychia) abdom inal distention. CHAPTER 8 Autoimmune connective tissue diseases 247 Note that this formula is inaccurate in patients with oedema due to nephrotic syndrome. \200 A rash suggestive of dermatitis herpetiformis may indicate the co-existence of coeliac dise ase. Consider partial lipod- ystrophy and, if present, the distribution (C3 nephritic facto r is usually associated with fat loss over face and upper limbs). Check for mouth ulcers an d xerostomia (excessive dental caries?). Palpate abdomen for tenderness (surgical abdomen?) and organomegaly. Early morning urinary protein to creatinine ratio is prob- ably as accurate as 24 h urine c ollection for quantifying severity of proteinuria. If RTA is suspected, check blood and uri ne pH (early morning urine sample preferable); pH>5.3 despite metabolic acidosis indicates RTA. Also plasma bicarbonate <21 mmol/l in RTA. 24 h urinary calcium measurement may be mad e if RTA is suspected and to monitor response to treatment. Acid load test (used if plasma bicarbonate >21 mmol/l, but RTA still suspected). For this 100 mg/kg ammonium chloride is a dministered orally. Urine pH is monitored hourly and plasma bicarbonate at 3 h. In RTA, bic arbonate drops below 21 mmol/l, but urine pH remains <5.3. Liver function tests: screen for autoimmune hepatitis, PBC, or drug toxicity. CK elevation can suggest myositis. Thyroid fu nction tests: hypothyroidism common. Bone biochemistry including 25-hydroxyvitamin D and PT H as vitamin D de \201 ciency is common. Vitamin B12, folate, and ferritin. Fasting lipid pro \201 le in patients with any CV risk factor other than the diagnosis (within 10 years) of SLE itself. Troponin I \200\223 if myocarditis or MI suspected. CSF: see under lumbar puncture. Pulmonary Examine for respiratory rate, clubbing, pallor, central cyanosis, chest expansion , costochondral and costoverte- bral tenderness, stony dull percussion note (pleural effusi on), pleural rub, basal inspiratory crepitations (ILD or left ventricular failure), and sig ns of consolidation in suspected pneumonia. Cardiovascular Assess pulse rate and rhythm and blood pressure at each visit. Examine JVP f or right heart failure, praecordium for signs of left ventricular pressure or volume overlo ad, and right heart strain; auscultate for murmurs and gallop rhythm. Palpate peripheral pu lses and listen for carotid bruit at annual review. \200 \200 Ophthalmological SLE is associated with a number of retinal lesions (see p. 48). \200 \200 Investigations Recommended lab investigations for annual review Hematology \200 Immunology \200 FBC with differential white cell count may show evidence of anemia of chronic disease (norm ocytic hypochro- mic). However, a hypochromic microcytic picture should prompt investigatio ns for iron de \201 ciency and blood loss (peptic ulcers \200\223 NSAID use?). A macrocyt ic picture raises the possibility of hypothyroidism, haemolysis (reticulocytes raise the MC V), excessive alcohol intake, liver disease, and is a normal finding in pregnancy. Thromboc ytopaenia and lymphopaenia are common in SLE. Neutrophilia may indicate infection but also occurs with GC treatment. Blood \201 lm \200\223 request to clarify numbers of white blo od cell types or of platelets (clumping?), to clarify whether an apparent normocytic normoc hromic anemia actually re \202 ects a mixed micro- and macrocytic picture, to seek the How ell \200\223Jolly bodies indicative of hyposplenism, or the helmet cells of microangiopathi c haemolytic anemia, and to quantify reticulocytes in suspected haemolysis (normal <1%). ES R classically is elevated in the absence of a raised CRP in patients with SLE. Note that th e ESR may be raised due to anemia and that some SLE patients do exhibit a raised CRP with a ctive disease, most commonly with serositis. ANA is positive in >95% of patients with SLE (usually by ELISA). Request the more sensitive immuno \202 uorescence ANA assay, if borderline ANA by ELISA. Anti-extractable nuclear an tigens (ENAs) will usually be checked for when ANA is positive. Table 8.4 Signi \201 cance of antibodies to extractable nuclear antigens (ENA) in SLE ENA Prevalence in SLE Clinical Associations Sm 5% (Caucasian) 40% (Afro-Caribbean) Vasculitis, CNS lupus Ro 40% Sj gren \200\231s Photosensitivity, rashes, neonatal LE, congenital heart block La 15% Sj gren \200\231s U1RNP 30% Raynaud \200\231s ENAs for which antibodies are routinely measured in SLE patients are listed, indicating the prevalence of antibodies and the associated clinical features. \200 Anti-histone antibodies in suspected drug-related lupus. Anticardiolipin antibodies (measur ed by ELISA) and lupus anticoagulant (functional test; higher speci \201 city for clinical events in APLS) should both be measured at baseline and annually. Other autoantibodies may be positive in overlap AICTD syndromes, e.g. rheumatoid factor (RA), anti-dsDNA (SLE), lup us anticoagulant and APLS, anti-smooth muscle antibodies and anti-liver-kidney microsomal a ntibodies (autoimmune hepatitis) and anti-mitochondrial antibodies (PBC). Refer to \200 \230The Nervous System and Rheumatological Disease \200\231 (p. 90) for autoantibodies asso ciated with autoimmune neurological syndromes. Coeliac disease associated antibodies (anti- tissue trans- glutaminase or anti-endomysial antibodies) should be Biochemistry \200 Renal function tests. Note that \200\230normal range \200\231 creatinine is not likely to be normal in a patient with low BMI (or low muscle bulk). Electrolyte disturbances may aris e from renal, endocrine, or neurological involvement or drug toxicity, and may cause neurom uscular or cardiac symptoms. Estimated creatinine clearance from Cockcroft \200\223Gault fo rmula: Estimated CrCl = [(140 \200\223 age) \227 weight (kg)]/ serum Cr ( mol/L) (multiply by 0 .85 in women) SYSTEMIC LUPUS ERYTHEMATOSUS 248 Other investigations \200 considered in patients with malabsorption and/or a rash suggestive of dermatitis herpetifor mis. Complement C3 and C4 can vary inversely with disease activity in some patients. C3 nep hritic factor. Request in patients with lipodystrophy (unexplained fat loss) or if C3 is lo w in the presence of a normal C4. Anti-C1 esterase inhibitor. Request if ?angio-oedema. Imm unoglobulins and both serum and urine protein electrophoresis. Request at diagnosis as part of a screen for neoplasia; repeat annually for patients with SLE- associated Sj gren \200 \231s. Pulmonary function tests: spirometry and transfer factor, useful to screen for and monitor interstitial lung disease (ILD), and to screen for pulmonary arterial hypertension (occurs occasionally in SLE). Echocardiogram: performed to detect pericardial effu- sion, LVH, redu ced LV ejection fraction, valvular lesions (especially in APLS), and as a screening test fo r PAH. ECG: useful screen for arrhythmia, ischaemia, LVH. Thiopurine methyltransferase (TPM T) genotype: checked in some centers prior to prescribing azathio- prine, since patients wh o have reduced/absent TPMT activity may have increased risk of myelotoxicity at the standar d doses of azathioprine. Upper GI endoscopy is required as investigation of possible peptic ulcer disease. Ankle/Brachial Pressure Index, Doppler ultrasound, MRA, or conventional ang iography to investigate suspected peripheral vascular disease. Carotid ultrasound: for inve stigation of carotid bruit or of TIA/stroke. DXA scan in all postmenopausal women is advisa ble. Lumbar puncture is indicated for some central neuro- logical features. Check for raise d intracranial pressure prior to LP, with CT brain, if urgent. Measure opening pressure (no rmal 60 \200\223150 mmHg). Send sample to bio- chemistry for protein (normal 0.2 \200\2230. 4 g/l), glucose (with paired blood glucose; CSF glucose should be 50 \200\22366% of blood g lucose) and LDH. Liaise with microbiologist to request gram stain, Ziehl \200\223Nielson st ain (for MTB), India ink stain for Cryptococcus, culture (request prolonged culture for Noc ardia), sensitivity, PCR and measurement of antibodies for a microbial agents, which may in fect immunosuppressed individuals. Refer to \200\230The Nervous System and Rheumatological Disease \200\231 (p. 90) for further details. EEG/EMG/NCS: Ocular investigations. Refer to \200\230The Eye in Rheumatological Disease \200\231 (p. 48). \200 \200 Other laboratory investigations \200 Midstream urine. Request microscopy to look for \200\230active \200\231 renal sediment (e. g. red cell casts), as well as culture/ sensitivity. Synovial \202 uid urgent microscopy and culture, if septic arthritis suspected. Blood cultures (multiple sets) should be perfor med whenever bacterial infection is suspected (e.g. possible septic arthritis, endocarditis , meningitis). \200 Imaging \200 CXR is useful at diagnosis as part of a screen for neoplasia, if the diagnosis is unclear. Useful post-diagnosis if new cough or dyspnoea, although may be unnecessary if a high resol ution CT chest is planned. High resolution (HR) CT chest may reveal honeycombing and ground glass opacities typical of non-speci \201 c inter- stitial (NSIP) associated with AICTDs. CT is imaging modality of choice for detecting the thickened bowel of SLE-associated bowel disease. Radiographs and Doppler US of joints to exclude erosive joint disease patients wi th RA pattern synovitis or if septic arthritis is suspected. MR head/spinal cord should be performed in patients with clinical focal neurological de \201 cit or with unusual headach es or cognitive defects. See also: The Nervous System and Rheumatological Disease (p. 90) . \200 Histology \200 Differential diagnosis Mainly the other AICTDs and the primary vasculitides, Beh et \200 \231s disease, cryoglobulinaemia, and hypocomplemen- taemic urticarial vasculitis. Also: \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Renal biopsy should be considered in patients with an \200\230active \200\231 renal sedime nt on urinalysis or isolated proteinu- ria (+++ or >1 g/l). Liaise with renal team. See: T he Kidney and Rheumatological Disease (p. 74) for the classi \201 cation of histological \201 ndings in lupus nephritis (classes I \200\223VI) Skin biopsy classically reveals IgG or IgM ( comple- ment) deposition at the dermal/epidermal junction, giving rise to the lupus band . Clinically uninvolved skin usually also shows this deposition \200\230band \200\231. Macules or papules, which are growing and/or ulcerating, or which show changing a nd/or irregular pigmentation should be biopsied to exclude skin cancer. Sural nerve biopsy should be considered in suspected mononeuritis. Muscle biopsy in patients with signi \201 cantly elevated CK. Liver biopsy (usually under US control) if autoimmune hepatitis is susp ected. Small bowel biopsy if malabsorption suspected (consider infection, coeliac disease, lymphoma, and Whipple \200\231s disease). Meningeal biopsy or biopsy of non-dominant fronta l lobe may occasionally be required. Drug-related lupus. Hepatitis B, Hepatitis C. EBV, CMV, Parvovirus B19. Sarcoidosis. Whippl e \200\231s disease. MTB. Lyme disease. Paraneoplastic manifestation of malignancy. Periodi c fever syndromes. Primary immunode \201 ciency with autoimmune features. Drug-related lupus Typical features of DRL are constitutional symptoms, arthralgias/arthrit is, myalgia, rashes, serositis, raised ESR, and a positive ANA with elevated anti-histone a ntibodies, all of which rise weeks to months after introduction of triggering medication. N ote that anti-dsDNA antibodies suggest SLE rather than DLE. \200 To resolve, withdraw the suspected triggering medica- tion and symptoms usually improve wit hin days to weeks. CHAPTER 8 Autoimmune connective tissue diseases 249 therapy is often effective (e.g. Rituximab 1 g \2272 over 2 weeks, repeated at 6-month int ervals). Note that sev- eral weeks elapse before clinical bene \201 t occurs. ANA and anti-histone antibodies may persist for months to years. Treatment The objectives of management are to control of disease activity, minimize damage and manage co-morbidity. Lupus nephritis (see also pp. 75 \200\22377) \200 \200 Class I lesions do not require speci \201 c treatment. Class II disease is usually treated with a tapering course of GCs; establish patient on hydroxychloroquine, if tolerated. Clas s III and IV disease: standard treatment consists of induction of remission with a combinat ion of a tapering course of prednisolone (starting at 1 mg/kg/day) and pulses of intravenou s cyclophosphamide 0.5 \200\2231 g/m2, given at monthly intervals for 6 months (with oral o ndansetron to minimize nausea and mesna to reduce risk of haemorrhagic cystitis, and subseq uent bladder malignancy). Patients in remission may be maintained with 3-monthly pulses of cyclophosphamide or, more commonly, azathioprine or mycophenolate mofetil. Recent trial dat a suggests that mycophenolate mofetil (in combination with prednisolone) may be a more effe ctive and less toxic agent with which to induce remis- sion than cyclophosphamide. Case rep orts also indicate that rituximab may be an effective induction and maintenance agent. Succ ess with anti-TNFA agents in class IV lupus nephritis has been reported. However, these age nts should be used with caution in SLE owing to their association with the induc- tion of A NA and other lupus-related features. In Class V disease mycophenolate mofetil appears to be effective although RCTs are awaited. Control of SLE disease activity General principles \200 Educate and advise patients regarding nature of SLE and lifestyle issues (see below). Manag ement of disease activity in SLE depends on the severity and location of the activity. Syst emic immunosuppression tailored to control activity in the most sensitive tissue and/or the tissue displaying the greatest activity will usually provide adequate control of less seve re manifestations of lupus. Clinical scores (SLEDAI, SLAM, BILAG) can be used to assess dis ease activity. Attribution of a BILAG score of A to an organ system implies that immunosu ppression with prednisolone >20 mg daily and/or another agent is required. Attribution of a BILAG score of B to an organ system implies that treatment with prednisolone <20 mg dail y, hydroxychloroquine or NSAIDs will be adequate. GCs >20 mg daily are particularly useful for gaining rapid control of activity, but their long-term use should be minimized. Use top ical/local GCs in preference to systemic GCs whenever possible. Hydroxychloroquine is assoc iated with reduced \202 ares and reduced accumulation of damage and should be used in the majority of patients \200\223 alone for mild cases and in combination for more severe dis ease. Management of serious or common scenarios \200\230Mild spectrum \200\231 SLE Rashes and mild polyarthritis can often be managed with high factor sunblock and antimalarials (e. g. hydroxychloro- quine 200 mg bd). Intermittent use of topical GC cream and NSAIDs or simp le analgesics may also be used. \200\230Moderate \200\231 SLE activity \200 Cerebral SLE Open label trial data suggest that IV cyclophosphamide plus prednisolone is mo re effective than prednisolone alone or with antimalarials. Successful use of intravenous i mmunoglobulin and plasma exchange has been reported and Rituximab appears also to be effect ive in small series. Anti-TNFA agents should generally be avoided due to the risk of SLE ex acerbation and their association with exacer- bation of demyelination. Cutaneous SLE/lupus In cases where cutaneous lupus is the only or dominant feature, topical or intra-lesional treatment with GCs may be used. In resistant cases, the following may be effective: topical tacrolimus, systemic dapsone (check G6PD status; monitor FBC and LFT) o r thalidomide (BEWARE teratoge- nicity and cumulative peripheral neuropathy, thus monitor n erve conduction studies). Methotrexate, efalizumab (anti-CD11a \200\223 effective in psori asis and used in refractory discoid LE) can also be used. Patients who cannot tolerate antimalarials or, in whom significant disease activity persist s, can be treated with azathioprine or mycophenolate mofetil (Table 8.5 provides examples o f initiation and monitoring regimes below). Methotrexate, ciclosporin, and sirolimus may al so be used. If the conventional immunosuppressives are either not tolerated or inadequate ly effective, B cell depletion Table 8.5 Initiation and monitoring of azathioprine and mycophenolate Initiation of azathioprine Initiation of mycophenolate Give 500 mg od for 1 week then 500 mg bd for 1 week - Check FBC, Creat U&Es and LFTs. If re sults are satisfactory Give 50 mg od for 2 weeks - Check FBC and LFT. If results are satisfactory: 100 mg od for 2 weeks - Check FBC and LFT. If results are satisfactory increase in 25 mg then give 750 mg bd for 1 week then 1 g bd for 1 week increments to 2 \200\2232.5 mg/kg/day. Check bloods every 2 weeks until stable dose then monthly. Check bloods every 2 weeks until stable dose then monthly. Halve doses in TPMT de \201 ciency Initiation and monitoring of immunosuppressants such as azathioprine and mycophenolate can often be managed by shared care with local GPs. In these cases, a \200\230shared care \200 \231 or monitoring booklet should be provided, in which the patient can collate their blood results. Education and empowerment of patients in this monitoring process greatly improves safety. SYSTEMIC LUPUS ERYTHEMATOSUS 250 Synovitis Dominant involvement of a single joint should prompt exclusion of septic arthriti s. SLE activity restricted to one or two joints may be managed by intra-articular injection . Polyarthritis should be treated systemically as for \200\230moderate \200\231 SLE. controversial. Generally, the bene \201 ts of aspirin outweigh the risks in individuals wi th a 10 years CVD risk >6%. Lipid-lowering is important, but there is no consensus for targ ets. A pragmatic approach would be to aim for a fasting LDLc <2.6 mmol/L in all SLE patient s. Given the logistic problem of obtaining fasting lipid pro- \201 les, an alternative pr oposal suggests stratifying patients into the following risk groups: \200 Pregnancy in SLE Available data suggest that patients with current or historical moderate/s evere SLE can be maintained on aza- thioprine and hydroxychloroquine during pregnancy. Flar es may be treated with GCs. Note that a woman on a regular GC dose may need additional GC r eplacement during labor. \200 low risk \200\223 SLE is the only risk factor for CVD; target total cholesterol <5.2 mmol/ l; medium risk \200\223 additional risk factors but not in the high-risk group; target LDL c <2.6 mmol/l; high risk \200\223 patient has CHD or equivalent condition; target LDLc <2. 0 mmol/l. Note that other medications taken by the patient should be carefully reviewed since many an ti-hypertensives are contraindicated (calcium channel blockers appear to be safe). The chal lenges in preparing for pregnancy in SLE are: \200 Osteoporosis (see also p. 395) SLE is associated with osteoporosis, but also hypovitaminosi s- D and secondary hyperparathyroidism. Use DXA data, biochemistry results (including PTH) and absolute fracture risk algorithms (e.g. FRAX) to guide management. \200 to maintain control of disease but avoid teratogenic or other harmful effects on the fetus; identi \201 cation of risk factors for complications; to optimize chances of conception i n individuals who may be sub-fertile due to disease or drugs. Keep replete in vitamin D (25-OHD >75 nmol/l) and avoid secondary hyperparathyroidism. Calc ium and vitamin D supplements may be needed (use D3 not D2). In gross calcium de \201 cien cy (indicated by marked second- ary hyperparathyroidism plus high ALP, low calcium excretio n and serum 25-OHD) rule out coeliac disease. In GC-induced osteoporosis (GIO), there is hi gh frac- ture risk post-menopause, those >65 years, in those with a fragility fracture and where hip of spine T score on DXA is \211 \200\2231.5) thus prescribe a bisphosphonate. \200 Control of SLE activity at conception is a marker for good control throughout the pregnancy . Tetratogenic drugs (e.g. methotrexate, mycophenolate mofetil) must be withdrawn at least 3 months prior to attempts to conceive. Azathioprine, hydroxychloroquine, and GCs are relat ively safe to use through pregnancy. Emerging data suggest that rituximab, in the \201 rs t trimester, has no major effect on the fetus or neonate; rituximab administered in the thi rd trimester has been reported to cause transient neonatal B cell depletion. Risk factors f or pregnancy should be clari \201 ed, including presence of anti-Ro antibodies, anti-cardi olipin antibodies and/or lupus anticoagulant, history of thromboembolic disease and of prev ious fetal loss. Screening for pulmonary hypertension should include ECHO and pulmonary fun ction tests, with referral for further investigation if these indicate PAH. Folic acid and calcium/vitamin D supplementation should be prescribed. The chance of conception may be opt imized by control- ling disease activity and avoiding NSAIDs (may prevent ovulation). Some patients may require referral for assisted conception. Other co-morbidities \200 \200 Dyspepsia: proton pump inhibitors and anti-acids. Constipation: stool softeners and bulking agents, e.g. lactulose and fybogel. Diarrhea \200\223 loperamide. Malabsorption: refer to dietician and check tTG anti- bodies to rule out coeliac disease. Consider using cal- cium , folate and iron supplements and parenteral administration of vitamin B12. Chronic renal f ailure: liaise with renal team - phosphate binders, alfacalcidol, erythropoietin, BP contro l and, ultimately, dialysis may be required. Hypothyroidism: replacement therapy. Depressio n: SSRIs (e.g. citalopram; \202 uoxetine may have some ef \201 cacy for RP also), amitri ptyline, or duloxetine may be useful in patients with coexisting \201 bromyalgia. Sicca s ymptoms: see Sj gren \200\231s syndrome, p. 254 Interstitial lung disease: vaccinate again st in \202 uenza, Pneumococcus and Haemophilus influenzae; prompt treatment of intercurren t infection. Menopausal symptoms: generally avoid HRT, since it increases risk of breast ca rcinoma, thrombosis and accel- erates atherosclerosis. However, HRT may be considered in pa tients with premature ovarian failure (particularly <45 years) or for very troublesome meno pausal symp- toms. A history of breast cancer or thromboembolic disease is a contraindicati on to using HRT. The presence of anti-cardiolipin antibodies or a lupus anticoagulant shoul d be considered a relative contra-indication. Hyposplenism: vaccinate against Pneumococcus, Meningococcus and Haemophilus in \202 uenzae, and check antibody titres to con \201 rm s uccessful vaccination. Advise against visiting any endemic malarial zone. Provide prophylac tic antibiotics or stand-by antibiotics. \200 \200 Management of associated morbidity Cardiovascular disease. There is currently no standard p ractice for cardiovascular risk reduction and a dearth of appropriate clinical trials to in form management. However, it is clear that SLE patients are at substantially increased risk . General principles \200 Stop smoking. \200 Optimize BP (<140/85). \200 Aim for BMI of 22 \200\22325. \200 Control disease activity, using a minimal dose of GCs. \200 Includ e hydroxychloroquine in treatment regime. \200 Use antiplatelet agents in patients with S LE/APLS. The threshold for use of aspirin in other SLE patients is CHAPTER 8 Autoimmune connective tissue diseases 251 Laboratory investigations: FBC and differential, ESR, CRP, Creatinine and electrolytes (wit h estimation of creati- nine clearance by Cockcroft \200\223Gault formula), liver func- tio n tests, bone function tests including vitamin D and PTH, creatine kinase, thyroid function tests, vitamin B12, folate, ferritin, total cholesterol (low risk group), fasting lipid pr o \201 le (medium and high risk groups), ANA (and ENA), anticardiolipin antibodies, lupus anticoagulant, complement C3 and C4, immunoglobulin, and protein electrophoresis. Consider also DXA scan, ECG, ECHO, lung function tests (including spirometry and transfer factor). Infections: liaise with infectious diseases team to select appropriate antimicrobial therap y according to current local policies. Bronchiectasis: physiotherapy to teach lung clearanc e techniques; vaccination against in \202 uenza, Pneumococcus and Haemophilus in \202 uen zae; rotating courses of antibiotics (continuous or covering winter months only). Multidisciplinary therapy \200 \200 \200 \200 \200 \200 \200 \200 Renal physician. Dermatologist. Dentist and oral medicine specialist. Chest physician. Gast roenterologist. Ophthalmologist. Orthopedic surgeon and vascular surgeon. Physiotherapist \200\223 exercises to retain mobility and to optimize chest function. Occupational therapis t. Hand exercises and aids/strategies for overcoming disabilities. Dietician \200\223 weig ht reduction, management of hyperten- sion, hyperlipidaemia, renal failure, malabsorption, or functional gastrointestinal symptoms. Monitoring lupus nephritis 10-year survival rate is 70%, but a signi \201 cant proportion (ranges from 5 to 50% in different series) progress to end-stage renal failure (ESRF) with in 5 years. Risk factors for ESRF include: \200 \200 Abnormal renal function at presentation. Delay between detection of renal disease and \201 rst renal biopsy (probably because appropriate treatment is delayed). Male. Haemotolog ical features of SLE. Younger age of diagnosis of lupus nephritis. Antiphospholipid antibod ies. Low socio-economic group. African-American or Hispanic ancestry. Failure to achieve cl inical remission with treatment. Flares of lupus nephritis. \200 \200 \200 \200 \200 \200 \200 Patient advice \200 \200 Avoid smoking. Avoid exposure to ultraviolet light \200\223 use high spf sunblock and skin -shielding clothing. For patients with Raynaud \200\231s keep core and extremities warm, e. g. put coat on several minutes before leaving house, use thermal gloves and socks in cold t emperatures. For patients with sicca symptoms maintain careful oral hygiene and arrange reg ular dental checks. Gentle regular aerobic exercise to maintain cardiovascular/ respiratory \201 tness. Education regarding cardiovascular risk and importance of regular aerobic ex ercise and healthy diet. Education regarding drug monitoring and important adverse effects (e.g. hydroxychloroquine \200\223 regular eye checks; cytotoxic/antiproliferative drugs \200\223 monthly FBC, LFTs; report cough or dyspnoea with methotrexate). Recognizing cardiovascular disease (CVD) risk CVD accounts for most of the premature mortal ity in SLE. Incidence of cardiovascular events in SLE is increased between 3 \200\22310-fol d. Traditional risk factors Assess for regularly and address accordingly: \200 \200 \200 \200 \200 \200 \200 Hypertension. Hyperlipidaemia. Diabetes mellitus. Smoking. Increased BMI. Sedentary lifesty le. Elevated CRP. Follow up \200 Patients with very active disease and/or commencing new therapies may need 1 \200\2233-mont hly review. Six-monthly follow up is recommended for patient with signi \201 cant disease activity. Annual follow-up may be appropriate for patients with mild or quiescent disease. BMI, urinalysis, and blood pressure monitoring should be routinely performed in the follow up visits. Non-traditional risk factors \200 Treatment with GCs. Optimize dose, don \200\231t over-treat and use immunosuppressant \200 \230steroid sparing \200\231 therapy. Pro-in \202 ammatory HDL. Anti-HSP antibodies. Incre ased oxidized LDLc. Circulating immune complexes. High in \202 ammatory mediators (e.g. IL -6, TNFA). Antiphospholipid antibodies. Antibodies to lipoprotein lipase. Increased asymmet ric dimethylarginine levels. Duration of SLE. Activity of SLE. \200 \200 \200 \200 \200 \200 \200 \200 \200 At annual review \200 