Organ involvement other than lupus nephritis in childhood-onset systemic lupus erythematosus

Pleuritis

Pleuritis is the most common pulmonary manifestation observed in cSLE ¹⁰ with 12.5–32%^8,9 experiencing it during the course of their disease. The clinical presentation of pleuritis is characterized by inspiratory chest pain, often associated with pleural effusions visible on imaging.^3,10 Isolated pleuritis may occur, but co-occurrence of pleurisy with other forms of pulmonary involvement and/or serositis is common. ³ It remains to be determined if pleurisy is a risk factor for concurrent or future lung parenchymal disease. OPEN IN VIEWER

Acute lupus pneumonitis

Acute lupus pneumonitis (ALP) is relatively rare, occurring in 11% of cSLE patients.^8,11 ALP may be the first apparent manifestation of SLE, presenting with fever, cough, pleurisy, hypoxia/cyanosis or dyspnea.^3,11 Infiltrates are often present with ALP on imaging, and may occur in the context of pleural effusions.^3,11 cSLE patients with ALP are often severely ill, and require mechanical ventilation. ¹¹ Care must be taken to evaluate for, and empirically treat, possibly co-existing infections, as well as pulmonary hemorrhage, as both entities can initially present in the same fashion as ALP.^3,10,11

Chronic interstitial lung disease

Chronic interstitial lung disease (CILD) has been reported in as many as 14% of cSLE patients, ⁴ though a screening study using high-resolution computed tomography (HRCT) failed to find any cases in a 60-patient Norwegian cohort. ⁸ CILD often presents with chronic cough, dyspnea, exercise intolerance, fatigue, and pleurisy. ³⁴ Notably, CILD may lead to only minor non-specific abnormalities on chest radiography, ⁴ therefore HRCT is considered the imaging modality of choice for diagnosis. ⁸ Typical findings include chronic infiltrates with ground glass appearance, or evidence of fibrosis. ³ cSLE patients with CILD will show decreased DLCO (diffusion lung capacity for carbon monoxide), though the prevalence of pulmonary function testing (PFT) changes (including decreased DLCO and/or Forced Vital Capacity [FVC]) in otherwise asymptomatic patients makes isolated PFT abnormalities difficult to interpret.^8,12

Shrinking lung syndrome

Shrinking lung syndrome (SLS) is extremely rare in cSLE, with a recent report citing only six published cases in the literature. ¹³ Typical clinical features of SLS include progressive, sometimes episodic dyspnea and pleurisy, with a marked restrictive pattern on PFT, and in some cases elevated diaphragms.^13,14 The DLCO may be decreased, but usually normalizes with correction for reduced lung volumes. In the setting of isolated SLS, lung parenchymal imaging abnormalities are typically absent,^13,14 though atelectasis may be seen. The etiology of SLS remains unclear, but evidence of diaphragmatic weakness/dysfunction has been demonstrated.^13,14 Prognosis is generally good with treatment, which includes corticosteroids, with addition of azathioprine or other immunosuppressive agents, if needed. ¹³

Pulmonary hypertension

Pulmonary hypertension is described in association with both aSLE and cSLE, and can occur at any time during the course of disease.^3,15 Patients usually develop progressive dyspnea on exertion as the presenting symptom, though other features of heart failure may eventually appear. ³ An association with antiphospholipid antibodies has been reported, possibly explained by chronic production of microthrombi localized to the lung. ¹⁵ Other theorized pathogenic mechanisms include vasculitis and vasospasm. ¹⁵

Pulmonary hemorrhage

Pulmonary hemorrhage is the result of disease-mediated damage to small blood vessels in the lungs. It is heralded by the acute onset of cough, dyspnea, hypoxia, hemoptysis and diffuse radiographic infiltrates, which may have a ground glass appearance on high-resolution computered tomography (HRCT), ⁴ often accompanied by a significant drop in haemoglobin. ³ Observed diffusion lung capacity for carbon monoxide (DLCO) is often elevated due to binding of alveolar blood, and bronchoalveolar lavage may demonstrate the presence of blood or hemosiderin-laden macrophages.^3,16 Mortality of pulmonary hemorrhage is high, and in one comparative study from Brazil there was an increased incidence of both pulmonary hemorrhage, and related mortality (69% vs 13%), in cSLE vs. aSLE patients. ¹⁶ Treatment of pulmonary hemorrhage is generally aggressive, usually comprised of pulse corticosteroid plus immunosuppressive therapy using cyclophosphamide or another agent, often supplemented with Intravenous Immunoglobulin (IVIG) or plasmapheresis. ¹⁶ The authors of the comparative study also note an earlier series in adults which reported lower mortality with the addition of broad spectrum antibiotics. ¹⁷

Lupus mesenteric vasculitis

Lupus mesenteric vasculitis (LMV), also termed lupus enteritis, mesenteric arteritis, gastrointestinal vasculitis, or acute GI syndrome, is the most common cause of acute abdominal pain in cSLE. ²¹ Clinical symptoms and signs include nausea, vomiting, diarrhea, abdominal bloating, abdominal tenderness, rebound tenderness and abdominal muscle guarding. The manifestations range from non-specific abdominal pain to intestinal necrosis and perforation. Laboratory findings and autoantibody presence, including antiphospholipid antibodies, are of limited value when diagnosing LMV. Histological information is rarely obtained and is generally non-specific. Thus the diagnosis of LMV is typically based on the presence of three of the following signs on abdominal computer tomography (CT): bowel wall thickening of 3 mm or more, target sign, dilatation of intestinal segments, engorgement of mesenteric vessels, and increased attenuation of mesenteric fat. ²³ LMV has a propensity to affect the distribution of the superior mesenteric artery. Thus the jejunum and ileum are the most commonly affected sites, with rectal involvement being rare.^23–25 Multifocal segments of bowel involvement from multiple vascular territories occur over 90% of the time.^18,19 Inflammatory vasculitis is thought to be due to immune complex deposition, resulting in fibrinoid necrosis of subserosal vessels, leukocytoclasis on the vascular wall, and submucosal edema with diffuse mononuclear cell infiltrate. ²⁶ Several studies have demonstrated that LMV occurs when patients are in the active stage of their disease with elevated SLEDAI or European Consensus Lupus Activity Measure (ECLAM) scores.^21,22,25 In a multivariate logistic regression analysis the only laboratory value that was strongly associated with LMV was the serum D-dimer. ²² However, the D-dimer is elevated in active SLE involving many organ systems. Early diagnosis of LMV is important, as timely administration of high-dose corticosteroid therapy and bowel rest prevent bowel infarction. For patients lacking an adequate response to corticosteroids, or in the setting of recurrent LMV, cyclophosphamide is used.^21,24,25

Pancreatitis

Acute pancreatitis in cSLE is rare with a prevalence of 2.6–6%.^{18,20,24,27,28} Acute pancreatitis is diagnosed by the presence of at least two of the three following features: abdominal pain or vomiting; serum levels of pancreatic amylase and/or lipase at least three times greater than the upper limit of normal; and characteristic imaging findings on abdominal ultrasound or CT. ²⁹ The imaging features compatible with acute pancreatitis include: pancreatic edema, pancreatic or peripancreatic necrosis, peripancreatic inflammation, acute fluid collections, pancreatic hemorrhage, pancreatic abscess, and pancreatic pseudocyst. ²⁹ cSLE patients with acute pancreatitis commonly present with abdominal pain, nausea and vomiting, and fever. Very high erythrocyte sedimentation rate (ESR) and CRP values are frequent, as are leucopenia, lymphopenia, thrombocytopenia and anti-dsDNA antibody positivity. ²⁸ Severe pancreatitis, defined as multi-organ dysfunction and pancreatic necrosis, occurs in ∼50% of cSLE-related pancreatitis.^28,29 Pancreatitis usually occurs in the setting of a generalized SLE flare, or as a presenting manifestation, and requires emergency management in an intensive care setting. Astonishingly, reported mortality rates range from 25–54%.^27,28 When comparing cSLE with aSLE, acute pancreatitis occurs more frequently; is more severe; and is associated with higher mortality in cSLE patients. ²⁷ The pathophysiology of pancreatitis in cSLE is not well understood, but immune complex deposition, microthrombi, vasculitis, intimal thickening, and ischemia are all believed to play a role. ¹⁸ An association with antiphospholipid antibodies has not been reported.

Although corticosteroid use was once thought to be a major risk factor for acute pancreatitis development in SLE, recent studies demonstrate that initiating or intensifying corticosteroid treatment leads to resolution of pancreatitis in most patients,^18,27,28 with immunosuppression with cyclophosphamide or even plasmapheresis being successfully used as well. ³⁰

Peritonitis

The prevalence of SLE-related peritonitis is unknown. More than half of cSLE and aSLE patients with abdominal pain will have ascites, but primary lupus peritonitis is the cause of ascites in a very small percentage of these cases.^18,22,31 Acute lupus peritonitis is most common during a disease flare, and presents with abdominal pain, as well as ascites that may develop suddenly. Ascitic fluid in lupus peritonitis is exudative, culture-negative, and may contain lupus erythematosus (LE) cells. ³² Chronic lupus peritonitis is most often painless, and the ascites is present when the SLE disease activity is low. ¹⁸ Notably, simultaneous occurrence of serositis at two or more sites (pericardium, pleura, or peritoneum) is very common, ³¹ likely because these manifestations share the same pathogenesis involving immunoglobulin and complement deposition. It has been suggested that peritonitis related to SLE should be included in evaluation of disease activity, and SLE classification. Most patients with lupus peritonitis respond rapidly to moderate doses of corticosteroids, but with poly-serositis additional immunosuppression may be needed.

Intestinal pseudo-obstruction

With an estimated prevalence of 1.3%, intestinal pseudo-obstruction (IPO) is a rare, ²⁰ but well recognized feature of cSLE. IPO is characterized by the presence of clinical features of intestinal obstruction, without mechanical or obstructive factors and results from dysfunctional visceral smooth muscle. This muscle dysfunction may be due to enteric nerve and/or visceral autonomic nervous system abnormalities, and may be accompanied by vasculitis. IPO frequently coincides with ureterohydronephrosis and/or interstitial cystitis and, on rare occasions, with esophageal or biliary dilatation. ³³ Clinically, SLE-related IPO patients present with subacute onset of abdominal pain, nausea, vomiting, weight loss, abdominal distension and constipation. Physical exam reveals a diffusely tender abdomen with rebound tenderness, and sluggish or absent bowel sounds. Radiologic and CT exams of the abdomen demonstrate dilated fluid filled bowel loops, with thickened bowel wall and multiple fluid levels of small and/or large bowel. Gastric manometric studies show intestinal hypomotility. Only one third of the patients with concurrent urinary tract involvement will experience urinary symptoms and most have normal urinalysis. ²² There are no specific autoantibodies associated with IPO, but a high prevalence of anti-SSA antibodies has been reported.^34,35 IPO can be the presenting feature of SLE and frequently occurs in the setting of active disease, but can also occur with low SLE activity. ³⁵ cSLE and aSLE patients with IPO and/or ureterohydronephrosis must be regarded as having active SLE independent of the disease activity scoring and given early aggressive treatment with high-dose corticosteroids with or without other immunosuppressive agents, as well as oral broad spectrum antibiotics, promotility drugs such as octreotide, and bowel rest.^26,36 Delay in diagnosis may result in life-threatening complications such as bowel necrosis, bowel perforation and acute renal failure.

Pericarditis

Pericarditis accounts for 80–90% of the cardiac manifestations of cSLE, and is frequently associated with pleuritis.^37,39 The incidence of cSLE-associated pericarditis ranges from 10–38%.^37,39–41 The clinical presentation, electrocardiogram (EKG) and echocardiographic (ECHO) findings of pericarditis due to cSLE are indistinguishable from those from other causes. Tachycardia, fever, substernal chest discomfort, positional chest pain, diminished heart sounds and rarely friction rub are the typical presenting symptoms. EKG findings suggestive of pericarditis include PR depression and diffuse ST segment elevation. ECHO is essential to exclude cardiac tamponade, which is uncommon but life-threatening if present. In addition to pericardial effusion, a thickened pericardium may also be seen on ECHO. Analysis of pericardial fluid shows leukocytosis with increased neutrophils. The neutrophil predominance, coupled with an acidic fluid (pH < 7), strongly suggests a diagnosis of SLE, and the presence of LE cells, i.e. granulocytes that ingest hematoxylin bodies, are diagnostic if found. Microscopically, the pericardium shows thickening from fibroblastic proliferation, edema, and infiltration by lymphocytes and plasma cells. Although difficult to identify, hematoxylin bodies, i.e. dense homogeneous particles of denatured nuclei, in the pericardial fluid may be the only SLE-specific finding. ⁴² Successful treatment generally includes intravenous corticosteroids with or without concomitant immunosuppressive medications. Rarely, pericardiocentesis, a pericardial window, or even pericardial stripping is required.

Myocarditis

Acute lupus myocarditis (LM) occurs in 2–19% of cSLE patients.^37,41 Depending on the degree of cardiac dysfunction, clinical features range from mild dyspnea, chest pain, arrhythmias, and heart failure, to cardiac shock and death. Endomyocardial biopsy is considered the gold standard for diagnosis of LM, typically showing focal lymphohistiocytes and plasma cell infiltrates associated with myocyte necrosis. ⁴² Unfortunately, the sensitivity of endomyocardial biopsies is low given the focal nature of cSLE-associated myocarditis and the procedure carries a sizable risk of cardiac perforation and secondary stroke. Thus, ECHO demonstrating global hypokinesis and reduced left ventricular ejection fraction (≤45%) is frequently used to diagnose LM. In addition, cardiac magnetic resonance imaging (CMRI) revealing delayed gadolinium enhancement has a sensitivity of 44% and specificity 100% in diagnosing LM. ⁴³ Indeed, CMRI was able to identify LM in cSLE patients with cardiac symptoms and normal ECHO. ³⁸ Cardiac enzymes may be normal in LM and troponin levels are more commonly elevated than CK-MB levels. ⁴⁴ LM may be associated with skeletal myositis.^42,45 Treatment for LM is aimed at managing heart failure, arrhythmias and SLE activity including high-dose corticosteroids and cyclophosphamide. The main outcomes of LM are recovery, progression to dilated cardiomyopathy or death.

Endocarditis

Libman-Sacks endocarditis is a sterile fibrinous vegetation that primarily affects the mitral and aortic valves. A longitudinal cohort reported Libman-Sacks endocarditis to be exceedingly rare with a prevalence of 1/256 (0.39%) in cSLE patients. ⁴¹ Despite its rarity, there are case reports of Libman-Sacks endocarditis being the first manifestation of cSLE. ⁴⁶ Libman-Sacks endocarditis is asymptomatic in the majority of the cases and frequently is recognized when cSLE complications, such as superimposed bacterial endocarditis, thromboembolic events, or severe valvular dysfunction occur. Serial ECHOs may show transition from a thick and myxomatous appearance of the affected valve to a nodular appearance with worsening valve regurgitation. The development of severe valvular regurgitation is associated with the presence of antiphospholipid antibodies. ⁴⁷

Cardiovascular

Cardiovascular complications have now become a major cause of morbidity and mortality in SLE as treatments of other complications have improved. ⁴² Although myocardial infarction is exceedingly rare among children with cSLE, SLE remains a well-known independent risk factor for premature atherosclerosis.^48,49 SLE diagnosis during childhood or adolescence is associated with a more severe phenotype compared to aSLE. Thus, early assessment and treatment of cardiovascular risk is especially important in cSLE. Vigorous control of disease activity and reduction of traditional risk factors for cardiovascular disease including abstinence from tobacco use, aggressive blood pressure control, and normalization of the fasting lipid profile are required to reduce cardiovascular events later on in life.