Most children are seronegative for ANA and RF. No antinuclear antibody speci \201 cities have been consistently identi \201 ed. SYSTEMIC ARTHRITIS 319 The following tests are suggested for all patients in the initial diagnostic investigation of systemic arthritis: \200 Complete blood count and differential \200 Renal and liver function tests \200 Coagulation screen \200 Serum immunoglobulins \200 Serum albumin \200 Antinuclear antibody titer \200 Blood cultures \200 Chest radiograph \200 Plai n radiographs of selected affected joints \200 Abdominal and pelvic ultrasound \200 Ele ctrocardiograph \200 Ocular slit lamp examination. The following tests should also be con sidered: \200 Muscle enzymes \200 Rheumatoid factor \200 Viral serology \200\224parvo virus, adenovirus etc. \200 Antistreptolysin antibody titers \200 Serum IgD \200 Urin e homovanillic and vanillylmandelic acid \200 Joint aspiration (for monoarthritis) \200 Tissue biopsy (including bone marrow aspirate) \200 Echocardiogram \200 Upper gastroin testinal barium series \200 Isotope bone and/or gallium scan. Table 9.4 Radiological abnormalities seen in systemic jia Feature Percentage Soft tissue swelling 80% Joint space narrowing 50% Growth abnormalities 50% Erosions 40% Subluxation 20% Ankylosis 20% Joint destruction 15% Protrusio acetabulae 10% Periosteal new bone 10% CHAPTER 9 Juvenile idiopathic arthritis (JIA) 320 The treatment of systemic arthritis \200 The general approach to the management of the ar thritis assumes the same principles as oligoarthritis. 1 However, there is increased drug- related toxicity in systemic JIA. This is seen with salicylates, NSAIDs, and DMARDs. Initial control of fever, joint pain, and serositis should be with NSAIDs; ibuprofen (60 mg /kg/day in 6 divided doses) indomethacin (1 \200\2232 mg/kg/ day in 2 divided doses) are co mmonly used. The dose should be decreased in the presence of severe hypoalbuminemia as the drugs are protein-bound. NSAIDs should be tried for at least 1 week before being deemed to have failed. Indomethacin is particularly useful for pericarditis; otherwise, this may resp ond to pulsed methylprednisolone, as does myocarditis. When NSAIDs fail to control symptoms, regular or pulsed corticosteroid treatment is indicated. Steroids will control symptoms but they do not limit the duration or alter the prognosis of the disease and should be used judiciously. The dai ly dose should be at 1 \200\2232 mg/kg/ day in divided doses. If symptoms persist past 4 \200\2238 weeks, MTX should be added, although MTX is not as effective in this situation as in oligoarticular JIA. Patients who have evide nce of severe systemic disease (including anemia, high fevers, severe serositis, malnutriti on, or macrophage activating syndrome) should be treated simultaneously with glucocorticoid s. \200 If the patient does not respond, consideration should be given to the use of IL-1 or TNF- A blockade. Anakinra may be particularly effective for the treatment of systemic arthritis, even among patients who have previously failed other therapies. Anti-TNF- A therapies may be effective in systemic JIA with persistent polyarthritis, but studies imply that in \202 iximab may be more effective than etanercept. Tocilizumab, an IL-6 receptor inhibitor, has also been approved for treatment of systemic onset JIA patients older than 2 years. Signi \201 cant cardiac compromise from effusion may require pericardiocentesis. Most patients with systemic onset JIA will experience one of three disease courses: monocyclic (11%), polycyclic (34%), or unremitting (55%). 1 Weiss JE, Ilowite NT. Juvenile idiopathic arthritis. Pediatr Clin N Am. 2005; 52: 413 \200\223442. SYSTEMIC ARTHRITIS 321 CHAPTER 9 Juvenile idiopathic arthritis (JIA) 322 Rheumatoid factor negative polyarticular JIA (previously polyarticular onset JRA) General p oints \200 There are two subtypes; rheumatoid factor (RF) negative (80%) and factor positive (20%). The arthritis usually affects 5 or more joints within the \201 rst 6 months of disease. T here must be no psoriasis in the patient or in any \201 rst- degree relative. Polyarticular onset occurs in about 25% of all patients with JIA. Clinical manifestations \200 There are three clinical subsets that have been recognized ( Table 9.5): \200 Early onset oligoarthritis, which is asymmetric, and associated with ANA -positivity and a high risk of uveitis. This form has an average age of onset <6 years old, and tends to affect girls more than boys. Symmetric synovitis with a predilection for the MCPs and tenosynovitis of the wrists and ankles. The average age of onset is 7 \200\2239 years old. Dry synovitis, which is associated with stiffness, and leads to \202 exion contractures a nd joint destruction. Carpal fusion and tendonopathies are common in the hands, leading to classical features such as boutonniere and swan-neck deformities. Flexion contracture is th e \201 rst manifestation of elbow involvement, and the shoulders are commonly affected. T his form often responds poorly to treatment. Cervical spine involvement is common with features akin to RA; apophyseal joint fusion, ins tability, and risk of cord compression. There is often fusion of the apophyseal joints of C 3 \200\223C5 leaving rigid segments that sublux above and below. Atlantoaxial subluxation, seen in RF-positive arthritis and juvenile ankylosing spondylitis, is rare in RF-negative p olyarthropathy. Temporomandibular joint involvement is common, leading to reduced growth and micrognathia. Dental malocclusion may require surgery when growth is completed. Growth disturbance is als o common, and occurs in proportion to the degree and duration of in \202 ammation. Laboratory tests The laboratory features are nonspeci \201 c in RF-negative polyarthritis. The ESR, CRP, leukocyte count, and platelet count can be elevated or normal. A low red cel l count is unusual and should prompt a search for an alterna- tive diagnosis. In patients w ith a prior diagnosis of RF-negative polyarticu- lar JIA, radiographs of the joints should be obtained yearly. Treatment \200 The management of this condition involves a common approach as discussed i n the \201 rst two sections of this chapter, with adaptations according to the different subtypes shown. RHEUMATOID FACTOR NEGATIVE POLYARTICULAR JIA 323 Table 9.5 Proposed subclassi \201 cation of RF-negative polyarthritis Subclassi \201 cation Percentage of cases Characteristics 1. Early onset oligoarthritis About 40% Female preponderance Most cases in very young (<3 years of age) Possible increased risk of eye disease Severe polyarthritis 2. Symmetric synovitis 15% Mild pain Thick pannus Equal in sexes Functional impairmen late Tenosynovitis common 3. Dry synovitis Little joint swelling 15% Progressive stiffness Chronic muscle wasting Often referred late in to onset Treatment should start with a trial of an NSAID for 4 \200\2238 weeks, moving to a second NSAID for the same period of time if the \201 rst fails. Ibuprofen, na proxyn, and diclofenac are commonly used. In nonresponders to NSAIDs, intra-articular steroid injections may be necessary. Topical st eroids should also be used from the onset with eye disease. DMARDs should also be introduced immediately, since NSAIDs alone are unlikely to induce remission. Methotrexate is the \201 rst-line drug of choice . Sulfasalazine may be used if there are features of spondyloarthropathy. Treatments should be continued for at le ast 6 months following remission. The TNF- A inhibitors are used for patients intolerant of or unresponsive to, methotrexate. In all cases, surgery and rehabilitation play an important role in management, and physical therapy and occupational therapy advice should be employed early. CHAPTER 9 Juvenile idiopathic arthritis (JIA) 324 Rheumatoid factor positive polyarticular JIA General points \200 The RF should be checked on 2 occasions, 3 months apart. RF positive disease tends to occur most often in girls; it follows a pattern similar to adult RA (see Chapter 5). Rheumatoid factor positive polyarticular JIA accounts for 5% of all cases of JIA. Clinical manifestations \200 This form of JIA is a symmetric polyarthritis that has a pre dilection for the wrists, MCPs, and PIPs. Rheumatoid nodules may be found around the elbows or other joints. \200 Associated sympto ms include tenosynovitis, low grade fever, hepatosplenomegaly, lymphadenopathy, serositis, and pericardial effusions. Uveitis is uncommon. Keratitis and dry eyes may be seen. Laboratory tests As in adult rheumatoid arthritis, children with this diagnosis may have no n- speci \201 c evidence of in \202 ammation (including anemia, neutrophilia, throm- bocy tosis, and elevated acute phase reactants). Many children will also have cyclic citrullinat ed peptide antibodies. ANA testing may be useful to distinguish this diagnosis from SLE. Treatment and prognosis \200 Treatment strategies are similar to those used for rheumatoi d-factor negative polyarticular JIA. Early immunosuppression with methotrexate or other agents is key to preventing the long-term consequences of this disease. Only 6% of patients with rheumatoid-factor positive polyarticular JIA achieve remission at 10 years. JUVENILE PSORIATIC ARTHRITIS 325 Juvenile psoriatic arthritis General points \200 Juvenile psoriatic arthritis has only re cently been recognized in children. As in adults, the arthritis may predate the rash by 15 years or longer. \200 Juvenile pso riatic arthritis accounts for 2 \200\22315% of children with JIA. Clinical manifestations \200 Juvenile psoriatic arthritis is an asymmetric arthritis asso ciated with dactylitis. It rarely involves the sacroiliac joints. This diagnosis is affects more girls than boys, and up to 20% of patients develop an asymptomatic chronic uveitis. Examination of the nails for evidence of pitting may provide evidence of psoriasis in a patient who otherwise has no evidence of skin disease. Laboratory tests There are no speci \201 c laboratory \201 ndings associated with juveni le psoriatic arthritis. Because the joint complaints can predate the onset of psoriasis, it is probably underdiagnosed. Treatment and prognosis \200 Treatment strategies are similar to those used for rheumatoi d-factor negative polyarticular JIA. Methotrexate is the treatment of choice. \200 Because this is a relatively new subset of JIA, the long-term prognosis associated with this diagnosis is largely unknown. CHAPTER 9 Juvenile idiopathic arthritis (JIA) 326 Enthesitis related arthritis General points \200 Enthesitis is tenderness at the point of insertion of a tendon, ligament, joint capsule, or fascia into bone. Enthesitis related arthritis is diagnosed if at least two of the following criteria are present: \200 Sacroiliac joint tenderness or in \202 ammatory lumbosacral p ain \200 HLA-B27 positive \200 Acute onset anterior uveitis \200 History of a spondyl oarthritis in a \201 rst degree relative. This diagnosis assumes that the patient has no evidence of another form of JIA. The patient is assumed to be rheumatoid factor-negative, with no family histor y of psoriasis (in a \201 rst-degree relative). Clinical manifestations \200 This diagnosis has a predilection for males; 70% of patients with this diagnosis are boys. The age of onset is generally between 10 \200\22312 years. This form of JIA presents with a peripheral oligoarthritis; axial involvement is a late \201 nding. Uveitis may be present in up to 25% of patients. Laboratory tests Although 70% of patients with enthesitis related arthritis are HLA-B27 pos itive, there are no truly speci \201 c laboratory \201 ndings associated with this diagn osis. Treatment and prognosis \200 Treatment strategies are similar to those used for rheumatoi d-factor negative polyarticular JIA. This form of arthritis is associated with poor outcomes, with greater levels of chronic dis ability and chronic pain than that associated with other forms of JIA. A persistently elevated ESR and/or hip arthritis are risk factors for the development of sacroiliitis. Female gender, family history of ankylosing spondylitis, and polyarthritis are all poor prognostic factors. CINCA 327 Chronic, infantile, neurological, cutaneous, & articular syndrome (CINCA) \200 Closer scr utiny of pediatric in \202 ammatory arthropathies has led to the description of syndromes that can be distinguished from systemic JIA. Among these syndromes is chronic, infantile, n eurological, cutaneous, and articular syndrome (CINCA), which is distinguished from JIA by in its involvement of the central nervous system. The pathophysiology of this condition is unknown; no immune complex, autoantibody, or immunode \201 ciency has been found. CINCA is also known as neonatal onset multisystem in \202 ammatory disease (NOMID) The \201 rst symptoms are often present at birth, generally after an uneventful pregnancy. Three-quarters of neonates (the rest usually within 6 months of birth ) have a nonpruritic urticarial rash that resembles that of Still \200\231s disease. Interm ittent \202 ares of the condition are associated with fever and enlargement of the lymph nodes and spleen. Central nervous system and sensory anomalies are important manifestations of CINCA. Chronic meningitis may result in recurrent headaches and seizures. There may also be transient episodes of hemiplegia. Sensory anomalies are progressive. These include perceptive deafness and optic atrophy. Other eye involvement includes uveitis, chorioretinitis, kerati tis, and conjunctivitis. The skull tends to have an increased cranial volume and there is delay in closure of the an terior fontanelle, and sometimes calci \201 cation of the falx and dura. Joint involvement is variable but most often involves the knee. The main \201 nding is an overgrowth of the epiphyseal plate, resulting in bony enlargement. Progressive contractures, loss of movement, and function ensue. There is progressive growth retardation and, despite normal growth hormone pro \201 les, a height below the third per centile is very frequent. Common morphological changes are also found. These include skull enlargement (often frontal bossing), a saddle-back nose, clubbing of the \201 ngers and toes, and short and thick h ands and feet. CINCA is caused by a mutation in the cold-induced autoin \202 ammatory syndrome 1 (CIAS1) gene, which encodes cryopyrin. This protein forms part of the in \202 a mmasome, which leads to the activation of interleukin-1 B . Other CIAS1 mutations lead to o ther cryopyrinopathies, including familial cold autoin \202 ammatory and Muckle-Wells synd romes. Blockade of the interleukin-1 receptor with anakinra results in dramatic improvement in the signs and symptoms associated with CINCA, but relapse occurs ra pidly after treatment is stopped. Other forms of immunosuppression, including high dose corticosteroids, may be only moderately effective. CHAPTER 9 Juvenile idiopathic arthritis (JIA) 328 Still \200\231s disease \200 This condition has similar clinical and laboratory features to systemic JIA. 75% of cases range between the ages of 16 \200\22335 years at onset. The fever pattern is identical and 90% of cases develop the typical rash. \200 One featur e not seen in juvenile disease is the complaint of sore throat during fever spikes. Pulmonary and ocular disease seem to be more common in adult on set Still \200\231s disease, and cardiac involvement less so. Patients with a chronic articular course do not do well. Several factors predict a poor out come in terms of progressive articular damage: \200 a polyarticular onset \200 axial ar thritis \200 need for steroids within 2 years of onset of disease \200 history of child hood arthritis \200 rash The treatment of Still \200\231s disease should follow the same lines as that for systemic JIA. 329 Chapter 10 Systemic lupus erythematosus (SLE) Introduction 330 The clinical features of SLE 334 Antiphospholipid (antibody) syndrome and SLE 338 Pregnancy and SLE 339 Diagnosis and investigation of SLE 340 Drug-induced lupus ery thematosus (DILE) 342 The treatment of SLE 344 Prognosis and survival in SLE 348 Childhood SLE 349 Neonatal SLE 350 CHAPTER 10 Systemic lupus erythematosus (SLE) 330 Introduction \200 Systemic lupus erythematosus (SLE) is a complex clinical syndrome chara cterized by autoimmune-mediated, systemic in \202 ammation that can affect multiple organs . This rubric encompasses a wide range of clinical manifestations of greatly varying severi ty. It is important to remember that there are variations in the incidence of clinical features between ethnic groups. With this in mind, the physician needs a keen sense of awareness of a variety of multisystem pathologies and to appreciate that SLE has taken on the mantle of syphilis as the great mimic of other conditions. The American Rheumatism Association (ARA), now the American College of Rheumatology (ACR), published its revised criteria for the classi \201 cation of SLE in 1997 (see Table 10.1). As stated in other sections of this book, criteria are for the classi \201 cation of the disease for epidemiological and research purposes mostly, and not as a diagnostic tool. In practice, however, these criteria have often been used as a guide to establish a clinical d iagnosis. In 2011, the Systemic Lupus International Collaborating Clinics (SLICC) group undertook a revision of the ACR Classi \201 cation Criteria, to re \202 ect our cur rent understanding of this disease (see Table 10.2). \200 The new criteria expand the use of immunologic criteria, which now allow the use of the direct Coombs test and hypocomplementemia to establish a classi \201 cation of SLE. The new criteria require the presence of at least one immunologic and one clinical criterio n to establish a classi \201 cation of SLE; a classi \201 cation of SLE could not be made based on immunologic criteria alone. \200 The SLICC Revision of the ACR Criteria have be tter sensitivity than the 1997 ACR Criteria (94% versus 86%), and result in fewer misclassi \201 cations. T he speci \201 city of these criteria are roughly equivalent (92% versus 93%). INTRODUCTION 331 Table 10.1 1997 ACR Classi \201 cation Criteria for SLE SLE may be diagnosed if 4 or more of the 11 criteria are present either serially or simultaneously. 1 Malar rash 2 Discoid rash 3 Photosensitivity 4 Oral ulcers 5 Arthritis 6 Serositis: Pleuritis or pericarditis 7 Renal disorder: Persistent proteinuria of >0.5 g/24 h or cellular casts 8 Neurological disorder (having excluded other causes): Seizures or psychosis 9 Hematological disorders: Hemolytic anemia or Leukopenia <4.0 x 10 9 /liter on 2 or more occasions Lymphopenia <1.5 x 10 9 /liter on 2 or more occasions Thrombocytopenia <100 x 10 9 /liter 10 Immunological disorders: Anti-ds DNA antibody Anti-Sm antibody Positive antiphospholipid antibodies 11 Antinuclear antibody in raised titer CHAPTER 10 Systemic lupus erythematosus (SLE) 332 Table 10.2 Systemic Lupus International Collaborating Clinics (SLICC) Revision of the ACR C lassi \201 cation Criteria for SLE SLE may be diagnosed if 4 criteria are present (includi ng at least one clinical and one immunologic criterion). SLE may also be diagnosed in a pat ient with biopsy-proven lupus nephritis in the presence of ANA or dsDNA. Clinical Criteria Acute or subacute cutaneous lupus Chronic cutaneous lupus Oral/nasal ulcers Non-scarring alopecia In \202 ammatory synovitis Serositis Proteinuria ( (cid:2) 500 mg/24 hr) or red blood cell casts Neurological disorder* Hemolytic anemia Leukopenia (<4000/mm 3 ) or lymphopenia (<1000/mm 3 ) Thrombocytopenia (<100,000/mm 3 ) Immunologic Criteria Antinuclear antibody (ANA) Anti-ds DNA antibody Anti-Sm antibody Antiphospholipid antibody \200 Low complement (C3, C4, or CH50) Direct Coombs test (in absence of hemolytic anemia) Neurologic disorders include seizure, psychosis, mononeuritis multiplex, myelitis, peripher al or cranial neuropathy, cerebritis (acute confusional state) \200 Evidence of antiphosp holipid antibodies include lupus anticoagulant, false-positive test for syphilis, anticardi olipin antibodies, or medium-high titer anti- B 2 glycoprotein1 This page intentionally left blank CHAPTER 10 Systemic lupus erythematosus (SLE) 334 The clinical features of SLE Lupus is 10 \200\22320 times more common in women than men, an d most likely to develop between the ages of 15 \200\22340 years. There are several nonspec i \201 c features that are also found in many other chronic diseases. Of these, leth- argy and fatigue are often the most disabling. Weight loss and persistent lymphadenopathy can a lso be seen in association with SLE. Musculoskeletal \200 Morning stiffness and polyarticular, symmetric arthralgias or arthri tis occur in 90% of cases. In most cases, symptoms outweigh objective clinical signs, and o vert joint damage from synovitis (e.g., erosions) occurs in less than 10% of patients. Reversible subluxation of joints without erosive disease (Jaccoud \200\231s arthropathy) can also occur in both the hands and feet. Avascular necrosis occurs in 5 \200\22310% of patients; most cases being associated with previous steroid use. The risk of avascular necrosis increases dramatically among patients using greater than 20 mg of prednisone daily. Myalgias are common, but true myositis in < 5%, and myopathy may be a consequence of steroid treatment. Skin Approximately half of patients diagnosed with SLE will have the classic \200\234butte r \202 y \200\235 rash of the nasal bridge and malar bones. The cutaneous mani- festations of SLE are listed in Table 10.3. Cardiovascular disease \200 Pericardial disease is the most common component of heart involvement in lupus. Most cases are clinically silent; a mild pericarditis is more common than a clinically signi \201 cant pericardial effusion. On echocardiography, pericardial t hickening is seen more frequently than pericardial effusions. Although SLE can lead to life-threatening pericardial effusions or constrictive pericarditi s, these manifestations are quite rare. Myocarditis is often asymptomatic, and may be present in 8% to 25% of patients. Clinical my ocarditis (de \201 ned by combinations of tachycardia, dysrhythmias, a prolonged PR interv al on electrocardiography, cardiomegaly, and congestive cardiac failure) is considerably le ss common. Histological studies suggest that a mild non-speci \201 c perivascular in \202 ammatory in \201 ltrate is a common feature. Corticosteroid therapy, although indicated for in \202 ammatory cardiac disease, is itself an added risk factor for atherosclerosis given its propensity to induce hypertension, hype rcholesterolemia, and obesity. Systolic murmurs are common. The classic endocarditis described by Libman and Sachs rarely causes clinically signi \201 cant lesions. Any valve vegetations identi \201 ed in a pati ent who is febrile should raise the possibility of bacterial endocarditis. Women with SLE have a 5 \200\2236% increased risk of coronary heart disease compared to the general population. This risk is increased 50% in women 35 \200\22344 . THE CLINICAL FEATURES OF SLE 335 Table 10.2 Cutaneous manifestations of SLE Frequency of occurrence Feature Common (20 \200\22350%) Malar rash Photosensitive rash Chronic discoid lesions Nonscarring alopecia Less common (5 \200\22320%) Mucosal ulcers Occasional (5%) Periorbital edema Bullous lupus Severe scarring alopecia Subacute cutaneous lupus Leg ulcers Panniculitis Cutaneous vasculitis Pulmonary disease \200 Because of the tendency for disease to be subclinical, chest radiographs and pulmonary function tests invariably indicate a greater degree of involvemen t than is evident clinically, and patients may present quite late in the disease process fo llowing a history of slow onset non-productive cough and increasing shortness of breath on exertion. Pulmonary function tests typically show both diminished total lung capacity and p eak \202 ow rates. Pleuritic pain/pleuritis is present in up to 60% of cases. \200 Pleural effusions are a f eature in one-third of patients but they are usually small and clinically insigni \201 cant. Interstitial \201 brosis, pulmonary vasculitis, and pneumonitis are found in up to one- \201 fth of lupus patients, but pulmonary hemorrhage is rare. \200 Pulmonary hypertension is found in approximately 10% of patients with SLE, and is associated with Raynaud \200\231s phenomenon, vasculitis, and antiphosphol ipid antibodies. There is great interest in antiphospholipid antibodies and thrombotic events in lupus. Patients presenting with pleuritic pain and/or pulmonary hypertension shou ld be investigated for the presence of pulmonary emboli and antiphospholipid syndrome. Renal involvement \200 Assessment of blood pressure for hypertension, urine for protein, blood, and casts, and the serum creatinine is an essential part of regular monitoring. Symp toms suggesting renal failure rarely become obvious until substantial damage has occurred. If early disease is suspected, the physician should consider a spot urine CHAPTER 10 Systemic lupus erythematosus (SLE) 336 protein/creatinine ratio, which is more accurate than urine dipstick and more convenient th an the conventional 24-h urine collection for protein and creatinine. The glomerular \201 ltration rate and renal function may also be assessed by nuclear medicine techniques. \200 Renal biopsy should be considered when > 500 mg proteinuria is detected. It must also be remembered that a renal biopsy has complications in itself. In 2003, the International Society of Nephrology (ISN) and Renal Pathology Society (RPS) released a new classi \201 cation of lupus nephritis designed to s tandardize de \201 nitions. The 2003 ISN/RPS classi \201 cation of lupus nephritis replac ed the 1982 modi \201 ed World Health Organization classi \201 cation. \200 Class I: Mi nimal mesangial lupus nephritis \200 Class II: Mesangial proliferative lupus nephritis \200 Class III: Focal lupus nephritis (< 50% of glomeruli) \200\223 Class III (A): Active lesions \200\223 Class III (A/C): Active and chronic lesio ns \200\223 Class III (C): Chronic inactive lesions Class IV: Diffuse lupus nephritis ( (cid:4) 50% glomeruli), divided into diffuse segmental (IV-S) or global (IV-G) lupus nephritis: \200\223 Class IV (A): Active l esions \200\223 Class IV (A/C): Active and chronic lesions \200\223 Class IV (C): Chronic inactive lesions Class V: Membranous lupus nephritis \200 Class VI: Advanced sclerosing lupus nephritis ( (cid:4) 90% globaly sclerosed glomeruli without evidence of activity) Chronic, inactive lesions (glomerulosclerosis) are a poor prognostic feature. Although no uniform standard exists, we would recommend that lupus patients with microscopic hematuria and/or proteinuria with a decreased glomerular \201 ltration rate should be considered for renal biopsy. However, biopsies should be read at centers experienced with the assessment of lupus nephritis. Hematopoietic involvement \200 A high ESR is a common \201 nding. \200 A normochromic , normocytic \200\230anemia of chronic in \202 ammation \200\231 is present in up to 70% of patients with lupus. Renal failure, NSAID- induced gastric bleeding, Coombs \200\231 pos itive and microangiopathic hemolysis, and red cell aplasia, are factors that may contribute to the anemia. Leukopenia and lymphopenia are common abnormalities of the white cell count in 50% and 80% of patients respectively. A leukocytosis is rare, suggesting infection or steroid therapy. There are several forms of clinical thrombocytopenia. Chronic, indolent, and uncomplicated thrombocytopenia (<100 \227 10 9 /liter) is not uncommon, part icularly among SLE patients with antiphospholipid antibodies. A rarer acute and life-threat ening severe thrombocytopenia is also recognized. This requires aggressive therapy initiall y with high-dose systemic steroids, and patients may require intravenous THE CLINICAL FEATURES OF SLE 337 immunoglobulin. Some patients may also present with what initially appears to be an idiopat hic thrombocytopenia (ITP), later followed by other manifestations of lupus. Nervous system disorders \200 Features of neurological disease range from cognitive impai rment (in up to 50% of patients) to psychoses and seizures (in 5 \200\22310% of patients over the cou rse of their disease). Thromboembolic disease associated with antiphospholipid antibodies c an cause major cerebrovascular damage (see Chapter 10). Approximately 10% of patients will develop a sensory (or less often sensorimotor) peripheral neuropathy. Cranial nerve involvement is less common. Up to 70% prevalence of psychiatric illness has been quoted in the literature. However, thi s includes anxiety and depression, rarely separated in studies from the nonspeci \201 c st resses associated with debilitating and often painful disease, as opposed to the disease pe r se. This said, it does emphasize the degree of the problem and that depression must be as sessed and managed seriously in lupus. \200 Although it is accepted that corticosteroids can induce psychiatric symptoms, in general it is felt the drugs given in lupus are not res ponsible for most of the psychiatric manifestations observed. \200 Examination of the cer ebrospinal \202 uid in neuropsychiatric disease should be performed as part of the initia l evaluation of a new neurologic \201 nding. Electroencephalography is often nonspeci \201 c. Positron emission CT (SPECT and PET) is n either speci \201 c for, nor well correlated with, central nervous system involvement. MRI with gadolinium is more sensitive than CT in detecting the small vessel vasculopathy assoc iated with SLE. Memory issues are common among patients with SLE, and may not indicate the presence of active neurologic disease. Other clinical features Other clinical features are listed in Table 10.4. Table 10.4 Other clinical features of SLE Vascular Raynaud \200\231s phenomenon Cutaneous vasculitis Digital ulcers and gangrene Gastrointestinal Hepatomegaly (25%) Abdominal serositis (10 \200\22320%) Splenomegaly (10%) Mesenteric vasculitis (rare) Pancreatitis (rare) Immunologic Hypergammaglobulinemia (60%) CHAPTER 10 Systemic lupus erythematosus (SLE) 338 Antiphospholipid (antibody) syndrome and SLE \200 Antiphospholipid antibodies include the lupus anticoagulant, anticardiolipin antibodies, and anti- B 2 glycoprotein-I antibodies. Antiphospholipid antibodies are present in up to one-third of patients with SLE. Although the presence of antiphospholipid antibodies alone is not suf \201 cient to make this diagnosis, half of patients with SLE and antiphospholipid antibodies will eventually demonstrate evidence of hypercoagulability. The manifestations of SLE-associated antiphospholipid syndrome include: \200 venous and arterial thrombosis \200 thrombocytopenia \200 cerebral dise ase \200 recurrent fetal loss \200 pulmonary hypertension \200 livedo reticularis. Some patients with antiphospholipid antibodies develop renal impairment (e.g., hypertension or proteinuria) due to multiple small thrombi. Further details, including management, may be found in Chapter 11. PREGNANCY AND SLE 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