Rheumatology

Oligoarthritis (Persistent or Extended)

Oligoarticular JIA is defined as arthritis in one to four joints and accounts for 40% to 50% of cases of JIA. The large joints (knees, ankles, and elbows) are often asymmetrically involved. Systemic symptoms do not dominate the clinical picture. Persistent disease affects no more than four joints throughout the disease. Extended disease affects more than four joints after the first 6 months.

Polyarthritis (Rheumatoid Factor Negative)

Polyarticular JIA (RF-negative or seronegative) accounts for approximately 20% to 25% of all children with JIA. To make the diagnosis, five or more joints must be involved in the absence of prominent systemic signs and symptoms. RF negative polyarthritis can occur as young as 1 year old, with a peak incidence at 2 years old.

The onset of polyarthritis may be insidious or acute. Children with seronegative disease generally have a better prognosis, but a subset can progress to joint destruction and flexion contractures. Any synovial joint may be involved in the inflammatory process, including the knees, wrists, elbows, and ankles, small joints of the feet, and proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints. The lumbosacral spine is usually spared.

Polyarthritis (Rheumatoid Factor Positive)

The seropositive group is believed to be nearly identical to the adult entity of rheumatoid arthritis. Although onset of RF positive polyarthritis can occur as early as 8 years old, it usually occurs in the early teens and girls predominate. Whereas 80% of all adult patients are seropositive, only 5% of children with JIA are positive for RF. This seropositive subgroup tends to progress to destructive synovitis with prolonged chronic course.

Physical findings provide some additional clues to a diagnosis of seropositive disease. The subcutaneous nodules that occur in seropositive disease are firm, nontender nodules on the skin surface with a predilection for pressure points or extensor areas. The most common location is the elbow, but the nodules also can occur on the heels, hands, knees, ears, scapula, sacrum, and buttocks. Other features of seropositive disease may include cutaneous vasculitis, Felty syndrome (leukopenia and splenomegaly), and Sjögren syndrome (keratoconjunctivitis sicca and xerostomia with or without parotid swelling).

Psoriatic Arthritis

Psoriatic arthritis is diagnosed in a child with arthritis and psoriasis. Criteria are also met when a child with arthritis has two of the three findings: dactylitis (“sausage digit”), nail pitting (or onycholysis), or psoriasis in a first-degree relative. Whereas the forms of arthritis previously discussed have weak genetic penetrance, psoriasis and its related disorders are often found through a given family’s pedigree. A patient may often present to their physician with just dactylitis of one or multiple toes. In such a situation, in addition to a detailed joint examination, a detailed skin and nail examination should be performed ( Fig. 7.6 ). Special attention should be paid to the scalp, the umbilicus, posterior surface of the external ears, gluteal cleft, and shins for the detection of psoriasiform lesions.

Enthesitis-Related Arthritis

Arthritis with enthesitis features inflammation of the tendon and tendon insertion site (i.e., Achilles). The other features that distinguish this disease group include sacroiliitis, HLA-B27 positivity, male predominance, and acute uveitis (presenting with eye pain and redness). This group also has a strong family predominance with first-degree relatives with ankylosing spondylitis, inflammatory bowel disease, and reactive arthritis. A male patient older than 6 years old presenting with arthritis should raise suspicion for ERA. Younger patients present with peripheral arthritis. Axial arthritis affecting the spine often does not present until the late teen years or second decade.

Systemic Arthritis

Systemic juvenile idiopathic arthritis (sJIA), also known as Still’s disease, accounts for approximately 10% of all children with JIA. Fever, rash, irritability, arthritis, and visceral involvement dominate the clinical presentation. The patient’s temperature usually rises to greater than 102.2°F (39°C), and this often occurs twice daily in a double quotidian pattern. Although the late afternoon is a typical time for a temperature rise, many other patterns may occur. Chills are associated with fever, but rigors rarely occur. Other manifestations of sJIA, such as rash and joint symptoms, may wax and wane during febrile periods. A helpful clinical feature during the febrile phase is one subnormal temperature during every 24-hour period, which suggests sJIA.

The rash of sJIA is macular, 2 to 6 mm in diameter, evanescent with fever, and salmon or red in color, with slightly irregular margins ( Fig. 7.7 ). An area of central clearing often exists. The rash usually occurs on the trunk and proximal extremities, but it may also be distal in distribution, with palms and soles affected. Although the rash generally does not produce discomfort, some older patients report pruritus. Superficial mild trauma to the skin, exposure to warmth, and emotional upset may precipitate the rash (Koebner phenomenon). Arthritis does not occur invariably at the onset of sJIA, though approximately 50% of patients with sJIA progress to a chronic, destructive inflammatory arthritis.

When fever of unknown origin is the sole initial presentation of systemic arthritis, it must remain a diagnosis of exclusion until the clinician observes other features during the physical and laboratory examination. Nonspecific arthralgia and myalgia can be prominent early, as can hepatosplenomegaly and lymphadenopathy. Serositis, pleuritis, pericarditis, hyperbilirubinemia, liver enzyme elevation, leukocytosis, and anemia are supporting clinical features.

Patients with sJIA are at risk for developing a potentially fatal disorder called macrophage activation syndrome (MAS). Patients present with a toxic appearance, fever, hepatosplenomegaly, and lymphadenopathy. If not recognized early, MAS can progress to hepatic failure, encephalopathy, and disseminated intravascular coagulation. Development of MAS is not unique to sJIA, and a diligent search for other etiologies should be undertaken ( Box 7.3 ). Laboratory testing that supports a diagnosis of MAS includes evidence of hepatitis, coagulopathy, and hyperferritinemia. In addition, the white blood cell (WBC) count, hemoglobin, and platelet counts are depressed, with a normal or low sedimentation rate associated with hypofibrinogenemia ( Table 7.3 ). Diagnosis can be aided by bone marrow aspiration, demonstrating activated macrophages engulfing surrounding cells, but this is not required for diagnosis.

Extraarticular Manifestations of Juvenile Idiopathic Arthritis

Patients with JIA are at risk of developing iridocyclitis (or uveitis). Although photophobia, eye pain, and erythema can occur, uveitis is often asymptomatic. For that reason, children with oligoarticular, psoriatic, and polyarticular JIA must receive slit-lamp examinations frequently.

The first clinical sign of uveitis is cellular exudate in the anterior chamber. If the uveitis is left untreated, synechiae (adhesions) between the iris and lens may develop, leading to an irregular and poorly functioning pupil ( Fig. 7.8 ). Further along in the clinical course, band keratopathy (calcium deposits in the cornea; Fig. 7.9 ) may occur, as well as cataracts or glaucoma. Ophthalmologic complications do not parallel the activity of the arthritis, so strict adherence to the recommendations for eye examination outlined in Table 7.4 is necessary to help prevent visual loss.

Linear growth retardation may occur in the child with active JIA, especially with systemic or polyarticular disease. Oligoarticular arthritis can present with growth abnormalities as well, usually confined to leg length discrepancy or an enlarged hand or foot related to refractory ankle or wrist involvement. During early illness, bony development may be advanced with premature epiphyseal fusion; later in the course of the illness the opposite may be true. The overall degree of growth retardation and the ultimate prognosis for reaching adult height are related to the severity and duration of inflammation as well as the use of systemic corticosteroids. Treatment with steroid-sparing agents such as NSAIDs, disease-modifying antirheumatic drugs (DMARDs) (i.e., methotrexate), biologic agents (i.e., rituximab, tociluzumab, infliximab), or small molecules (i.e., tofacitinib) is currently preferred.

Cardiac involvement occurs in more than one-third of patients with sJIA. Pericarditis, myocarditis, and endocarditis occur, with pericarditis being the most common. Chest pain, a friction rub, tachycardia, and dyspnea, may occur, with supportive chest radiograph, electrocardiogram, and echocardiographic findings. These episodes may last for weeks to months and are usually associated with a generalized flare of disease. Various other extraarticular manifestations, including hepatosplenomegaly and lymphadenopathy, are particularly common in sJIA. A more recently described complication of sJIA is high-fatality parenchymal lung disease and pulmonary hypertension that occurs in a small subset of patients. Children may exhibit cough, tachypnea, erythematous clubbing of the fingers or hypoxia at diagnosis of lung disease, but many patients have no respiratory symptoms until late in the disease course. Diagnosis is made by findings of septal thickening, crazy paving, peripheral/peribronchovascular consolidation, or ground-glass opacities on computed tomography (CT) of the chest. Associations with the development of parenchymal lung disease include younger age of sJIA onset, trisomy 21, atypical pruritic rash, diagnosis of MAS, and history of anaphylaxis to tocilizumab.

Differential Diagnosis

Because JIA is a clinical diagnosis, strict clinical criteria have been established to make the diagnosis. Children should have objective joint findings (arthritis) for a minimum of 6 consecutive weeks coupled with the exclusion of other causes of arthritis in children ( Box 7.4 ).

Because of its destructive nature, pyogenic arthritis (e.g., Staphylococci , Streptococci , Haemophilus influenzae ) must be ruled out in any child with active joint disease, especially monoarthritis. Any intensely red and tender joint should raise suspicion of a bacterial pathogen. This combined with systemic symptoms of infection (fever, chills, malaise, rigors) should prompt the clinician to perform diagnostic arthrocentesis early in the course of the illness.

Lyme arthritis can mimic oligoarticular JIA. This tick-borne illness is caused by the spirochete Borrelia burgdorferi with acute manifestations, including a distinctive rash, known as erythema migrans (see Chapter 13 , Fig. 13.50 ). A child may develop arthritis as a late manifestation months or years after exposure, often without having recalled a tick bite or the acute manifestations. The arthritis seen in Lyme usually affects the knee but may affect other large joints in a monoarticular pattern with spontaneous exacerbations and remissions ( Fig. 7.10 ).

Other infections cause a reactive arthritis that dissipates in less than 6 weeks. Recent infection with Salmonella, Shigella, Yersinia, and Campylobacter organisms should also be considered. Many viruses also cause arthritis. These include rubella, hepatitis B, adenovirus, and herpesviruses, including Epstein-Barr virus, cytomegalovirus, varicella zoster, and herpes simplex. Parvoviruses, mumps, and enteroviruses, including echovirus and coxsackievirus, are associated with acute polyarthritis and occasionally have been recovered from joints. Other viruses result in reactive arthritis and may not infect the joint directly.

Poststreptococcal phenomena include ARF and poststreptococcal reactive arthritis. In ARF, Jones criteria are used for diagnosis. Arthritis presents in migratory fashion and pain may be out of proportion to examination. Use of NSAIDs alters the course of the arthritis. The child must be monitored for cardiac sequelae, such as valvulitis and congestive heart failure. In poststreptococcal reactive arthritis, Jones criteria are not met, but evidence of preceding streptococcal infection is present. Arthritis will resolve but arthralgia can last for 6 months. The joint pain may be axial and affect the spine. In both cases, children are given prophylactic antibiotics to prevent future streptococcal infections.

Malignancies, such as neuroblastoma and leukemia, may present with musculoskeletal pain. More careful evaluation generally reveals bone pain. Sickle cell disease can have prominent digital involvement or deep bone pain related to infarction. Hemophilia, tuberculosis, and gonorrhea infection must be considered in the patient with oligoarthritis. Differential diagnoses of joint pain are proposed in Box 7.4 .

Clinical Manifestations of Systemic Lupus Erythematosus

The early symptoms are often nonspecific and sometimes go unrecognized as harbingers of serious disease. Fever, fatigue, malaise, anorexia, and weight loss may be the only symptoms. In the adolescent population, these symptoms may be all the more difficult to interpret. Conversely, this multisystem disease may present with a plethora of physical findings, and the presentation may be so dramatic that the diagnosis is readily apparent. The most common organ manifestations at disease presentation in pSLE are musculoskeletal, cutaneous, renal, and hematologic.

Mucocutaneous Manifestations

Cutaneous manifestations of SLE occur at some time during the course of the disease in 80% of affected individuals. There are a variety of cutaneous findings, including a malar rash ( Fig. 7.11 ), photosensitive rash, palmar erythema ( Fig. 7.12 ), annular erythema, vasculitic skin lesions with nodules or ulcerations, Raynaud phenomenon ( Table 7.6 ), and associated ulcerations, alopecia, and discoid lupus. The most frequent skin manifestations of SLE are malar rash and photosensitive rash. The classic malar “butterfly” rash is a maculopapular rash distributed over the cheeks (malar eminences) and extending over the bridge of the nose, while sparing the nasolabial folds. The malar rash is photosensitive in 30% of patients. In general, sun exposure may not only exacerbate the skin disease but also cause a systemic flare of disease. Appropriate sun protection and avoidance is strongly encouraged. An annular photosensitive rash is frequently associated with the “Sjögren syndrome antibodies” anti-Ro (SS-A) and anti-La (SS-B). The typical morphology of the rash of lupus is defined as reddish purple and raised with a whitish scale ( Fig. 7.13 ). Vasculitic rashes are more violaceous and may be associated with nodules, ulceration, and palpable purpura ( Fig. 7.14 ). These lesions are commonly found in an acral distribution, and typically result in postinflammatory hyperpigmentation. Discoid lupus, although uncommon (5% to 10% of patients with pSLE), leaves the most damage, with follicular plugging and scarring. Isolated discoid lupus is rarely seen in children; but when it occurs, it is usually without systemic manifestations. The same holds true for subacute cutaneous lupus, which is uncommon, and presents as a serpiginous-like photosensitive erythematous rash associated with positive anti-Ro (SS-A) antibody. Mucosal erosions and ulcers of the oral cavity and nasal mucosa are part of lupus as well; the most well-recognized manifestation is the “silent” large violaceous ulceration of the hard palate ( Fig. 7.15 ). Alopecia occurs in 20% of patients and may present as broken hair shafts or patchy, red, scaling areas on the scalp, which may eventually scar and cause permanent hair loss ( Fig. 7.16 ). Other reported mucocutaneous findings are livedo reticularis (lacy, fishnet appearance of the skin), urticaria, and telangiectasia. The presence of a livedoid rash may be the clinician’s only clue to an associated hypercoagulable state manifested by anti-phospholipid antibodies.

Table 7.6

Common Benign and Pathologic Color Change Syndromes of the Extremities

• Fleck DE, Hoeltzel MF. Hand and foot color change: diagnosis and management. Pediatr Rev . 2017;38;511.

• Cappel JA, Wetter DA. Clinical characteristics, etiologic associations, laboratory findings, treatment, and proposal of diagnostic criteria of pernio (chilblains) in a series of 104 patients at Mayo Clinic, 2000 to 2011. Mayo Clin Proc . 2014;89(2):207.

Disease	Epidemiology	Triggers	Duration	Clinical Exam	Associated Disorders	Comments
Raynaud phenomenon, primary	Common, 10%–15% prevalence, F>M,	Cold exposure, emotion, stimulants, smoking	Minutes to hours	Triphasic (white/blue/red) color change of fingers/toes with clear demarcation; Numb when ischemic, aching/painful with reperfusion	None	May be limited to single digit
Raynaud phenomenon, secondary	Uncommon, variable prevalence in underlying conditions	Cold exposure, disease activity	Hours to Continuous	Triphasic changes; chronic digital ulcers or skin pits; poor nail health; abnormal nailfold capillaries	SLE SSc MCTD aPLS Vasculitis	Often requires vasodilators
Acrocyanosis	Common, 10%–15% prevalence, F>M, onset in adolescence, low BMI is a risk factor	Cold exposure, limb in dependent position, medications (stimulants, TCAs)	Minutes	Symmetric, painless blue/purple discoloration of hands/feet without clear demarcation; blanching with pressure; affected skin/nails appear healthy	Anorexia nervosa POTS Genetic CTDs	May be accompanied by cutis marmorata on affected limbs
Perniosis	Uncommon, F>M, peak 2nd–5th decades of life, low BMI is a risk factor	Cold and damp conditions	Continuous for 1–3 weeks	Edematous, erythematous or violaceous papules/plaques/nodules on the dorsum of fingers or toes; blisters or ulcers may develop; onset 12–24 h after cold exposure	None	Symptoms usually limited to winter months
Erythromelalgia	Rare, F>M, onset in early adolescence	Exercise, heat exposure	Minutes to continuous	Symmetrical, diffuse, painful erythema of hands, feet, or face; affected areas feel hot	Myeloproliferative disorder (adults-only); rarely inherited	Pain is often severe and disabling

aPLS, Antiphospholipid antibody syndrome; BMI, body mass index; CTD, connective tissue disease; MCTD, mixed connective tissue disease; POTS, postural orthostatic tachycardia syndrome; SLE, systemic lupus erythematosus; SSc, systemic sclerosis; TCA, tricyclic antidepressants.

Cardiac Manifestations

The heart is often significantly involved in patients with lupus. Although the pericardium is involved most commonly, the myocardium and the endocardium may also be of clinical importance. Pericarditis with associated pericardial effusion can be painless and may present only as cardiomegaly on a chest radiograph ( Fig. 7.17 ) or as pericardial effusion on an echocardiogram. Although pericarditis is usually mild, it can progress to life-threatening cardiac tamponade. If the myocardium is affected, serious complications including dysrhythmias, heart failure, and infarction can result. Libman-Sacks endocarditis is the term given to the verrucous projections of fibrinoid necrosis in the endocardium. These lesions rarely cause clinical symptoms, although the presence of a murmur raises suspicion of endocardial disease. The mitral valve is most commonly involved, although aortic and tricuspid valves may be similarly affected. The presence of Libman-Sacks endocarditis should also alert the clinician to the possibility of an underlying anti-phospholipid antibody syndrome. The major cardiac morbidity associated with SLE, which is gaining more recognition in the adolescent pSLE population, is premature atherosclerosis. Several factors contribute to the risk of atherosclerosis, including chronic inflammatory processes, altered endothelial function, lipid abnormalities, nephritis, and proteinuria. Monitoring and controlling classic Framingham risk factors in addition to factors attributable to lupus are critical to address long-term morbidity.