Autoimmune disorders are not usually encountered in a general pediatric practice. However, there are many clinical situations in which physicians should broaden their differential diagnosis to include autoimmune disorders. There is not a single symptom or sign that is diagnostic of an autoimmune disorder, but there are many signs and symptoms that might be indicators of an underlying autoimmune disorder. Most symptoms and signs associated with autoimmune diseases mimic symptoms and signs associated with infectious diseases, malignancies, orthopedic disorders, metabolic diseases, and chronic pain syndromes. It is important to recognize a pattern of signs and symptoms that may be suggestive of a specific autoimmune disease. It is also important to exclude infectious and malignant disorders because the treatment of autoimmune disorders may require the use of immunosuppressants and immunemodulators, which may mask and/or modify the disease course and further management of these disorders.
The most common reason for referral to a pediatric rheumatologist is joint pain, followed by abnormal laboratory test results such as rheumatoid arthritis factor and antinuclear antibody.1 Children with juvenile idiopathic arthritis (JIA) are usually referred to other specialists before seeing a rheumatologist.2 It is commonly believed that joint pain in children would be indicative of an autoimmune disorder involving joints; however in a study by McGhee et al.1 it was shown that this is not the case. In that study, only 1 of 111 children with isolated musculoskeletal pain in the absence of any other signs or symptoms referred to a pediatric rheumatology clinic had an autoimmune disorder (ankylosing spondylitis).1 Of the 76 children diagnosed with JIA, only 12 complained of joint pain.1 This is because clinical manifestations of common autoimmune disorders are different in children than in adults.3
Clinical Manifestations that May be Indicative of An Underlying Autoimmune Disorder
Duration of fever for longer than 5 to 7 days in the presence or absence of other signs and symptoms may raise suspicion for an autoimmune disorder. Fever of unknown origin (FUO) is defined as a fever >101°F of at least 8 days in duration, where no diagnosis is made after initial outpatient or hospital evaluation that includes a careful history and physical examination and initial laboratory assessment. It is also important to understand that two benign febrile illnesses due to viral infections may occur in quick succession and give an appearance of a single episode of prolonged fever. In a large systematic review of 1,638 children with FUO, only 150 (9%) of the patients had an autoimmune disorder.4 Ninety of these patients had JIA, 22 had systemic lupus erythematosus (SLE), 27 had other forms of collagen vascular diseases (CVD), and 11 had an unspecified CVD. Eleven percent of the children had miscellaneous diseases (children with Kawasaki disease were classified under this category as well). Table 1 lists the breakdown of all disease classes that were determined to be the causes for FUO. In certain autoimmune disorders, such as PFAPA (periodic fever, aphthous ulcers, pharyngitis, and adenopathy), familial Mediterranean fever (FMF), and hyper-immunoglobulin D syndrome, fevers recur with regular frequency.
Classification of Fever of Unknown Origin by Etiology for Children Age 0 to 18 Years
Fatigue is a nonspecific symptom that may occur in many acute disorders, including autoimmune disorders such as SLE, juvenile dermatomyositis (JDM), JIA, and vasculitis. However, overwhelming fatigue with an inability to attend school indicates a chronic fatigue syndrome and/or fibromyalgia.
Autoimmune disorders may present with arthralgias; however, arthritis is a strong predictor of autoimmune disorders. Arthritis is defined as an intra-articular inflammation manifesting as a swollen joint along with two or more of the following findings on joint examination: pain on motion, loss of motion, erythema, and warmth. It is important to take a detailed history and perform a careful physical examination in these patients because in most of the cases diagnosis is established by recognizing the peculiar clinical manifestations of a particular autoimmune disorder. Laboratory tests contribute to a small degree in making a diagnosis of autoimmune disorders in patients who present with arthritis.
Table 2 indicates the components of history and physical examination that need to be the focus of an evaluation of a child with joint pain. The musculoskeletal examination should focus not only on the joints affected, but all other joints as well. A validated screening tool for quick musculoskeletal examination is the pediatric Gait, Arms, Legs, Spine (pGALS) screen (Table 3 and Figure 1).5 This is a pediatric adaptation of the GALS screen that is used for examining gait, arms, legs, and spine in adults.
Characteristic Clinical Manifestations Specific for Arthritis Disorders
The Components of the Pediatric Gait, Arms, Legs, Spine Screen
Illustration of movements in the pediatric Gait, Arms, Legs, Spine screen (see Table 3 for detailed descriptions of A–M movements). Reprinted with permission from Foster et al.5
Illustration of movements in the pediatric Gait, Arms, Legs, Spine screen (see Table 3 for detailed descriptions of N–Q movements). Reprinted with permission from Foster et al.5
Acute swelling and pain in a single joint (monoarthritis) associated with fever is always considered an emergency because it may be septic arthritis. Table 4 lists the causes of monoarthritis.
Causes of Monoarthritis
Most incidences of polyarthritis secondary to an acute viral infection are self-resolving. Arthritis lasting longer than 6 weeks makes an acute infectious etiology unlikely.6 Reactive arthritis is an immune-mediated sterile arthritis that occurs after many viral germs as well as gastrointestinal (Salmonella, Shigella, Yersinia, Campylobacter) and genitourinary (Chlamydia) infections. Acute rheumatic fever is characterized by a migratory painful polyarthritis. Pain on palpation of long bones suggests malignancy. Anemia may coexist both with malignancy and JIA. Joint pain in isolation in the absence of any joint swelling or gait disturbance has a strong negative predictive value for JIA or any chronic inflammatory conditions characterized by arthritis.1 Arthritis is present in JIA, SLE, JDM, vasculitis, Behcet disease, sarcoidosis, Kawasaki disease, and Henoch-Schonlein purpura (HSP).
JIA is the most common rheumatic disease of childhood. The International League of Associations for Rheumatology classifies JIA into seven subtypes: oligoarticular JIA, seropositive polyarticular JIA, seronegative polyarticular JIA, systemic-onset JIA (sJIA), enthesitis-related arthritis, psoriatic JIA, and undifferentiated JIA.7
The age of presentation may help narrow the differential diagnosis for polyarthritis. Kawasaki disease, HSP, and JIA present during early childhood. Juvenile psoriatic arthritis, JDM, and polyarteritis nodosa peak during mid-childhood, whereas ankylosing spondylitis and SLE present in late childhood and adolescence. HSP and Kawasaki disease may have an acute onset, but other conditions such as JIA may have a subacute or chronic onset. Uncommon findings, such as cartilage loss in the nose leading to a saddle nose deformity, occur in granulomatosis with polyangiitis. It can also occur in relapsing polychondritis and syphilis.
Proximal muscle weakness and tenderness may be indicative of muscular involvement in JDM.
Transient macular rash with fever occurs in systemic-onset JIA. Palpable purpuric rash on extensor surfaces and pressure points is suggestive of HSP. Purpuric rashes and petechiae are seen in vasculitis, whereas nonblanching erythematous papules are seen in SLE. A malar rash that spares the nasolabial folds is suggestive of SLE, whereas hyperkeratotic rash on the face and around the ears is suggestive of discoid lupus. Gottron papules and heliotrope rash along with erythematous rash on elbows and knees are pathgnomonic of JDM. Periungual telangiectasia is common in JDM, scleroderma, and secondary Raynaud phenomenon. Photosensitive rashes are seen with SLE but may also occur with antibiotics. Mucosal redness of the oral cavity, lips, and tongue is evident in Kawasaki disease. Nail pitting is seen in psoriasis. Table 5 lists the various dermatologic features of autoimmune disorders.
Skin Manifestations of Rheumatic Disorders
Mouth ulcers are seen in SLE and Behcet disease. Painless nasal ulcers and erythematous macules on the palate occur in SLE. Recurrent genital ulcers occur in Behcet disease.
Alopecia is seen in SLE and localized scleroderma, and in JDM as well.
Raynaud phenomenon refers to the triphasic sequence of blanching, cyanosis, and erythema of digits in response to cold exposure or emotional stress.8 All three phases may not be present in all patients. It can be an idiopathic primary disorder but it may also occur secondary to SLE, mixed connective tissue diseases (MCTD), scleroderma, and overlap syndromes.
Uveitis is usually asymptomatic in children in the setting of autoimmune diseases. However, complaints of red painful eyes and blurred vision may arise from uveitis. Irregularity of the pupillary margin may be caused by chronic uveitis that may be associated with juvenile chronic arthritis. Erythematous conjunctiva may result from uveitis and episcleritis associated with JIA, SLE, sarcoidosis, spondyloarthropathy, and vasculitis. Keratoconjunctivitis occurs in Sjogren syndrome. Nonexudative conjunctivitis is also seen in Kawasaki disease.
Renal involvement may occur in SLE, JIA, Kawasaki disease, HSP, and other vasculitides. Up to 65% of pediatric patients with SLE may have renal involvement presenting as anasarca, hypertension, microscopic hematuria, and azotemia.9 Renal involvement manifests after the rash in HSP and may occur in up to 35% of patients as microscopic hematuria and proteinuria, but rarely in renal failure.10 Most (97%) renal manifestations occur within 6 months of onset of rash in HSP.10
Dyspnea on exertion and crackles on auscultation may occur with interstitial lung disease due to SLE, MCTD, and systemic sclerosis. Chest pain may represent pleuritis and pleural effusion secondary to SLE. Pulmonary hemorrhage presenting as hemoptysis and respiratory failure may be indicative of granulomatosis with polyangiitis, microscopic angiitis, and SLE. Pulmonary vascular aneurysms occur in Behcet disease. Acute or chronic sinusitis may be a clinical presentation of granulomatosis with polyangiitis. Patients with sarcoidosis may have hilar adenopathy that could be visible on a chest radiograph.
Pericardial rub may occur with sJIA, SLE, and sarcoidosis. Myocardial dysfunction, and mitral and aortic regurgitation due to endocarditis may develop in these disorders as well. Hypertension may be indicative of nephritic involvement in SLE, Kawasaki disease, HSP, JIA, and polyarteritis nodosa (PAN).
Rheumatic fever may present as pancarditis and lead to sequelae and morbidity of cardiac valvular insufficiency. It is important to look for cardiac involvement with Kawasaki disease, which may be myocarditis or coronary arterial inflammation that can lead to subsequent coronary aneurysms.
Recurrent abdominal pain associated with fevers is seen in FMF, hyper-immunoglobulin D syndrome, and Behcet disease. Symptoms suggestive of inflammatory bowel disease (IBD), such as abdominal pain, poor growth, diarrhea, and hematochezia, should also be noted. In monitoring and follow up of a patient with IBD, it is important to recognize that arthritis is more common in Crohn's disease compared to ulcerative colitis.11
Generalized lymphadenopathy may be present in SLE and sJIA, whereas localized, usually unilateral, cervical lymphadenopathy is seen in patients with Kawasaki disease. Fatigue and pallor may be noted due to hemolytic anemia associated with SLE and anemia of chronic disease in JIA.
Vasculitis should be considered in patients with strokes associated with arterial abnormality or thromboembolic phenomenon. Sarcoidosis may present with headaches and neck stiffness that may be indicative of acute or chronic aseptic meningitis. Other neurologic manifestations of autoimmune diseases are seizures, psychosis, chorea, and pseudotumor cerebri. Peripheral neural involvement may occur in SLE, Churg-Strauss syndrome, and PAN.
Children with SLE may have an autoimmune-mediated hypothyroidism. JIA and IBD are known to adversely affect growth. Diabetes insipidus may be a rare manifestation of sarcoidosis.
A history of recurrent miscarriages may indicate a prothrombotic state and antiphospholipid syndrome.
Children with undiagnosed rheumatic disorders may present to the emergency department with urgency, and in this situation the diagnosis and treatment has to be expedited.
Febrile Child with Pancytopenia
A febrile child with splenomegaly, lymphadenopathy, pancytopenia, and an extremely elevated serum ferritin level may have macrophage activating syndrome (MAS), which can be a rapidly fatal condition. The autoimmune disorders associated with MAS are JIA, SLE, and Kawasaki disease.
Respiratory Distress with Renal Failure
A child who presents with respiratory distress in the presence of renal failure may have pulmonary renal syndrome, in which diffuse alveolar hemorrhage is associated with rapidly progressive glomerulonephritis. It can be rapidly fatal due to massive pulmonary hemorrhage. The three main associations are antineutrophil cytoplasmic antibody-associated vasculitis, SLE, and rarely Goodpasture syndrome.12
Pericardial tamponade is an uncommon life-threatening complication of pericarditis. Autoimmune disorders most commonly associated with pericardial effusion are SLE and JIA,13,14 and contribute to up to 30% of pericardial effusions.15 Patients present with chest pain, tachypnea, dyspnea, distended neck veins, muffled heart sounds, tachycardia, pulsus paradoxus, and hypotension. An echocardiogram and pericardial fluid analysis need to be performed urgently.
Fetal or Neonatal Heart Block
This condition occurs due to damage to the atrioventricular node from transplacentally acquired antibodies to Ro/SSA and Ro/SSB (Sjogren's-syndrome-related antigen A and B). The fetus or neonate has bradycardia due to various degrees of atrioventricular block. It may lead to congestive cardiac failure, fetal hydrops, and pericardial effusion. The neonate may have facial rash, thrombocytopenia, and liver dysfunction. The diagnosis is established by checking the antibodies in the neonate or mother.