Pediatric and Neonatal Lupus

Malar rash

It is a macular papular rash in the malar area and usually spares the nasolabial folds. This rash tends to be photosensitive and heals without scaring

Alopecia

It is usually mild nonscarring, but can be severe

Annular erythema

It is associated with anti-Ro and anti-La antibodies; it is circular in shape, usually on the face after exposure to the sun

Discoid rash

Erythematous round lesions common on the forehead, it is rarely present in pediatric SLE patients. This lesion heals with atrophy and scarring

Vasculitis rashes

Such as petechiae, palpable purpura, digital ulcers and periungual erythema

Raynaud phaenomenon

Seen about 15 % of pediatric SLE, patients can have the classic triphasic colour changes or even two phases only. This phaenomenon can lead to ulceration of the digits and ischaemia

Livedo reticularis

This is a lacy netlike rash. It is more common in patients who are antiphospholipid antibody positive

Fig. 25.1

An 8-year-old girl with cSLE depicting a malar rash, more prominent on the right side of the face

Fig. 25.2

Alopecia in a 10-year-old girl with cSLE

II.

Musculoskeletal involvement: It manifests as arthritis, arthralgias and myalgias. Up to 90 % of SLE patients develop arthritis and morning stiffness within the first year after diagnosis. It can involve both large and small joints and is usually symmetric. Typically, arthritis with SLE is non-erosive, but it can lead to reducible deformities which are different from deformities with juvenile idiopathic arthritis that are fixed or non-reducible [7]. The reducible joint misalignment in SLE involves ulnar deviation and is referred to as Jaccoud’s deformity.

III.

Neuropsychiatric systemic lupus erythematosus (NP–SLE): cSLE can involve the central and, albeit less frequently, the peripheral nervous system. NP-SLE is reported in as many as 50 % of children with cSLE, often manifesting initially during the first year post cSLE diagnosis [8]. In 1999 the American College of Rheumatology divided the NP-SLE into 19 defined categories (see Table 25.2). Headaches are the most common cSLE CNS manifestation.

Table 25.2

1999 ACR nomenclature and case definitions for neuropsychiatric SLE

Central nervous system

Aseptic meningitis

Cerebrovascular disease

Demyelinating syndrome

Headache (including migraine and benign intracranial hypertension)

Movement disorder (chorea)

Myelopathy

Seizure disorder

Acute confusional state

Anxiety disorder

Cognitive dysfunction

Mood disorder/depression

Psychosis

Peripheral nervous system

Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barré syndrome)

Autonomic disorder

Mononeuropathy, single/multiplex

Myasthenia gravis

Neuropathy, cranial

Plexopathy

Polyneuropathy

One of these NP case definitions with a particular importance to children is neurocognitive dysfunction (NCD). It can vary and range from a decrease in school performance, difficulty in concentration or learning disability to acute confusional state and coma. Due to subtle symptoms such as learning disabilities, NCD is sometimes difficult to diagnose clinically. Currently, there is no standard test for cognitive impairment in pediatric SLE. However Ross et al. proposed a standardized battery of neuropsychological tests that can be completed in 2.5 h. This battery appears suitable for a comprehensive assessment of cognitive domains commonly affected by cSLE [9]. General paediatricians should maintain a high level of suspicion for the presence of NCD when dealing with cSLE patients during their school years. This should lead to prompt implementation of academic adjustments to ensure school success.

IV.

Cardiac involvement: The most common manifestation is pericarditis with and without effusion. Rarely myocarditis, endocarditis (Libman-Sacks endocarditis) and premature atherosclerosis have all been described with cSLE [10].

Pulmonary involvement: This is quite common in cSLE, occurring in up to 75 % of the patients [11]. Typically, it is asymptomatic but restrictive abnormalities on pulmonary function testing (PFT) are noted often. Pulmonary manifestations of cSLE are manifold (Table 25.3).

Table 25.3

Pulmonary symptoms in cSLE

Pleuritis	It is the most common. It presents with chest pain and dyspnea
Pulmonary haemorrhage	Occurs in 5 %. Can present with haemoptysis to frank pulmonary haemorrhage. SLE should always be considered as a differential diagnosis in children presenting with it
Shrinking lung syndrome	Is due to loss of lung volume due to diaphragmatic dysfunction
Lupus pneumonitis	Rarely seen in children. Presents with chest pain and fever. It is a chronic indolent interstitial lung disease with linear opacities and occasional nodules on radiography of the chest
Infection	Patients are at high risk of infection due to the immune alterations leading to the disease and immunosuppressive medications used for treatment. Infection should always be entertained as a differential diagnosis of a SLE patient presenting with respiratory symptoms

VI.

Gastrointestinal involvement: The most common symptoms are abdominal pain and diarrhoea. Patients can develop lupus peritonitis causing ascites, protein-loosing enteropathy and GI vasculitis which places them at risk for perforation. Hepatomegaly and abnormalities of liver function testing are present in up to 50 % of patients. These changes can be related to the disease, its complication or the drugs used for treatment [11].

VII.

Haematologic features: These are present in almost all patients. Anaemia of chronic disease is the most common. Though 35 % of the patients have positive Coomb’s test, only a few of them actually develop frank haemolysis. Even in a patient with SLE, other common diagnoses of haemolysis such as sickle cell anaemia or other haemoglobinopathies also need to be excluded. Thrombocytopenia can occur secondary to antiplatelet antibodies, antiphospholipid antibody syndrome or macrophage activation syndrome (MAS). Lymphopenia is also common, especially with active cSLE. If there is bicytopenia MAS, thrombotic thrombocytopenic purpura, malignancy and infections should also be kept in mind by the treating physician [12].

VIII.

Antiphospholipid antibody syndrome (APS): It is characterized by antibodies against phospholipids and their binding proteins in addition to the presence of clinical features (venous or arterial thrombosis, pregnancy morbidity). The most common antibodies are the lupus anticoagulant (LAC), the cardiolipin and the anti-β2 glycoprotein [13]. APS may be primary, i.e. without the presence of an associated autoimmune disease or infection; or it can be secondary APS, i.e. be present in conjunction with another autoimmune disease like SLE or MCTD. It is important to remember that SLE may develop after many years after the presence of primary APS, so observation and close monitoring are important [14], especially if high-titre ANA is present. In general, venous thrombotic events are more common than arterial ones. Catastrophic APS is a term used in the setting of multiple thrombotic events that occur over a relatively short period of time. Patients usually present with thrombocytopenia, haemolytic anaemia and visceral organ thromboses involving the kidneys, liver or lungs [15].

Differential Diagnoses

None of the features observed in cSLE are unique to the disease. Thus, many diagnoses need to be considered in the differential diagnosis of cSLE (Table 25.4).

Table 25.4

Differential diagnosis of SLE

Malignancy: like leukaemia, lymphoma	As both can present with constitutional symptoms, cytopenias and fevers. However, patients with malignancies usually have negative ANA and anti-dsDNA antibodies and have normal complement levels
Infections: most likely viral infection	Again the key differences are the absence of these autoantibodies and normal or high complements in patients with infections
Juvenile idiopathic arthritis	Can be difficult to distinguish early on as both patients can have joint pain and swelling. However, important distinguishing features are that the joint deformities in SLE are often reducible and infrequently erosive on imaging
Systemic vasculitis (granulomatosis with polyangiitis, polyarteritis nodosa and others)	Patients with these types of vasculitides are usually ANA negative. Some can be ANCA positive. On exam they can have skin lesions and bruits
Juvenile dermatomyositis (JDM)	Both can have a positive ANA. The myositis in SLE patients is usually low grade; on the other hand, JDM demonstrates more overt proximal muscle weakness, and patients with JDM have characteristic skin findings (Gottron’s papules, heliotrope rash)
Systemic sclerosis (SSc)	Both can have a positive ANA. Patients with SSc usually have antibodies to an antigen called Scl-70 (topoisomerase I). SSc patients have significant Raynaud phaenomenon and telangiectasias
Serum sickness	Both can have fever, lymphadenopathy, cutaneous eruptions, arthralgias and low C3 and C4. However serum sickness usually has a negative ANA and it is self-limited

Approach to the Diagnosis

A thorough history, physical examination, high index of suspicion and appropriate laboratory tests frequently allow the physician to make the diagnosis. The diagnosis of cSLE can be straightforward in a patient who presents with several compatible clinical features and who has supportive laboratory studies. cSLE can also cause isolated cytopenias or single organ involvement (e.g. nephritis or pericarditis) or may first be detected by an incidental laboratory abnormality. High index of suspicion is important as patients may subsequently develop the characteristic multisystem features of SLE over a period of months or years.

Most patients affected with SLE have no family history of this disease. In families with multiple affected members, the disease occurrence does not follow the classic Mendelian inheritance model for a single-gene disorder. However, in a few cases, SLE is associated with rare but highly penetrant mutations resulting in deficiency of classical complement components and/or defective degradation of DNA. An extremely strong genetic risk for SLE is conferred by a complete deficiency in one of the classical complement pathway genes, such as C1Q, C1R/S, C2, C4A and C4B, even though these deficiencies are relatively rare. Patients with SLE and deficiency of C1Q or C4 usually demonstrate disease at a young age without a female predominance and have an approximate 30 % frequency of renal involvement [16].

Classification criteria have been developed for SLE as a means of categorizing patients for research purposes. These criteria may be useful to list key disease features, but their low sensitivity and specificity limit its use for diagnostic purposes. Having said that, most clinicians rely on the classification criteria developed by the American College of Rheumatology [17, 18] when diagnosing lupus. The patient is classified with SLE using the ACR criteria if four or more of the manifestations are present, either serially or simultaneously, during any interval of observations (Table 25.5) [17, 18]. In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) proposed revised classification criteria that were developed to address inherent weaknesses of the 1997 American College of Rheumatology (ACR) classification criteria (Table 25.6) [19]. Classification as having SLE by the SLICC criteria requires either that a patient satisfies at least 4 of 17 criteria, including at least 1 of the 11 clinical criteria and one of the six immunologic criteria, or that the patient has biopsy-proven nephritis compatible with SLE in the presence of antinuclear antibodies (ANAs) or anti-double-stranded DNA (dsDNA) antibodies.

Table 25.5

ACR criteria for the classification of systemic lupus erythematosus

Malar rash

Photosensitivity

Discoid rash

Oral ulcers: recurrent non-painful ulcers in the oral mucosa, palate and even nasal mucosa

Arthritis: non-erosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling or effusion

Serositis: pleuritis – convincing history of pleuritic pain or rubbing heard by a clinician or evidence of pleural effusion or pericarditis – documented by EKG, rub or evidence of pericardial effusion

Renal disorder: persistent proteinuria greater than 500 mg/24 h or greater than 3+ if quantitation not performed or cellular casts – may be red cell, haemoglobin, granular, tubular or mixed

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