From Petty RE, Southwood TR, Manners P et al: International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, J Rheumatol 31:390–392, 2001.

JIA is a disease of childhood onset characterized primarily by arthritis persisting for at least 6 weeks with no known cause.

Oligoarthritis or Polyarticular Arthritis

Arthritis affecting one to four joints during the first 6 months of disease. Two subcategories are recognized:

• Persistent oligoarthritis: affects no more than four joints throughout the disease course

• Extended oligoarthritis: affects a cumulative total of five joints or more after the first 6 months of disease

Polyarthritis (Rheumatoid Factor Negative)

Arthritis affecting five or more joints during the first 6 months of disease; tests for rheumatoid factor are negative.

Polyarthritis (Rheumatoid Factor Positive)

Arthritis affecting five or more joints during the first 6 months of disease associated with positive rheumatoid factor tests on two occasions at least 3 months apart.

Other Arthritis

Children with arthritis of unknown cause that persists for at least 6 weeks but that either:

• Do not fulfill criteria for any of the other categories, or

• Fulfill criteria for more than one of the other categories

HLA, Human leukocyte antigen.

Systemic juvenile idiopathic arthritis (S-JIA) accounts for only approximately 10% of children with juvenile arthritis; however, it is the type most likely to present with severe extra-articular multisystem disease.

Systemic lupus erythematosus (SLE) is a multisystem disease characterized by loss of self-tolerance resulting in development of autoantibodies and formation of immune complexes.⁷ The organs targeted by the autoantibodies and sites of immune complex deposition determine the disease presentation. Females in peripubertal and postpubertal years are most likely to be affected; however, both males and younger children can develop the disease. To make a diagnosis of SLE, 4 of 11 criteria must be met (Box 98-2).⁸ However, lupus can be regarded as a medical example of Murphy’s law—what can go wrong, will—so any organ system may be affected and in ways not always listed in the criteria. Therefore a thorough evaluation of all organ systems and serologic tests for antibodies and other markers commonly found in SLE is essential if this diagnosis is being considered.

Box 98–2 Revised SLE Classification Criteria

From Hochberg MC: Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus, Arthritis Rheum 40:1725, 1997.

For the purpose of identifying patients in clinical studies, a person shall be said to have SLE if any of four or more criteria are present, serially or simultaneously, during any interval of observation.

1. Malar rash: Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds

2. Discoid rash: Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring (may occur in older lesions)

3. Photosensitivity: Skin rash as a result of unusual reaction to sunlight, by patient’s history or physician’s observation

4. Oral ulcers: Oral or nasopharyngeal ulceration, usually painless, observed by a physician

5. Arthritis: Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion

6. Serositis

a. Pleuritis, a convincing history of pleuritic pain, or rub heard by a physician or evidence of pleural effusion or

b. Pericarditis with or without documentation by electrocardiogram or rub or evidence of pericardial effusion

7. Renal disorder

a. Persistent proteinuria >0.5 g/day or greater than 3+ if quantitation not performed, or

b. Cellular casts (may be red cell, hemoglobin, granular, tubular, or mixed)

8. Neurologic disorder

a. Seizures in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance), or

b. Psychosis in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance)

9. Hematologic disorder

a. Hemolytic anemia with reticulocytosis, or

b. Leukopenia <4000/mm³ total on two or more occasions, or

c. Lymphopenia <1500/mm³ on two or more occasions, or

d. Thrombocytopenia <100,000/mm³ in the absence of offending drugs

11. An abnormal titer of ANA by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with drug-induced lupus syndrome.

Clinical Presentation

Mucocutaneous Findings

Malar rash, discoid rash, photosensitivity, and oral (especially hard palate) and nasal mucous membrane ulcerations are classically included. However, almost any kind or rash, including bullous lesions, may be seen. Skin biopsy with immunofluorescence to demonstrate immune complex deposition can be helpful.

Central Nervous System Disease

Seizures and psychosis are included in the criteria; however, strokes, severe migraines, and an encephalopathic picture are among other central nervous system (CNS) findings. CNS disease can occur with minimal serologic changes.⁹ CNS disease is related to antiphospholipid (APL) antibodies that can cause either thrombotic or embolic phenomena. These findings may be mistaken for or occur concurrently with infections, including opportunists such as nocardia. The eye can be involved in a number of ways (conjunctivitis, scleritis, episcleritis, uveitis, retinal vasculitis), and a careful eye exam is warranted in any possible rheumatic disease.

Pulmonary Involvement

Many patients have pulmonary signs and symptoms.¹⁰ Pleuritis is included in the clinical criteria and may be severe, causing respiratory compromise. Pulmonary hemorrhage is one of the most serious complications of pulmonary involvement in SLE and may be precipitated by vasculitis or infection. Dyspnea, hemoptysis, and an otherwise unexplained drop in hemoglobin make this diagnosis obvious, but are not always present. More subtle hemorrhage may be detected by pulmonary function testing, specifically elevation of the diffusion capacity if the patient is stable and able to cooperate. Radiographs or chest computed tomography (CT) of the lungs will reveal patchy ground glass infiltrates.

Pulmonary embolism maybe related to APL antibodies or other hypercoagulable states such as nephritic syndrome or inborn errors. These may be massive and immediately life-threatening, and are best diagnosed by CT imaging, often at the time of interventions to lyse the clots. Smaller and recurrent emboli are thought to be a major contributor to pulmonary hypertension. Rarely, progressive interstitial disease, and possibly chronic pleural inflammation and fibrosis, lead to a “shrinking lung” syndrome.

Gastrointestinal Involvement

Sterile peritonitis may be present as part of a polyserositis picture. Hepatitis and pancreatitis may be primarily caused by lupus, but many commonly used therapies such as corticosteroids, azathioprine, and mycophenolate (MMF) may also cause liver and pancreatic side effects.

Cardiovascular Disease

Any layer of the heart including the pericardium, myocardium, and valves (e.g., Libmann-Sacks endocarditis) may be inflamed. Vasculitis may target the coronary vessels, and the increased risk of myocardial infarction and other premature vascular diseases are related to chronic inflammation, disease and drug-related hyperlipidemia, hypertension, and sometimes steroid-related diabetes. The role of generalized chronic inflammation in premature cardiovascular disease is under study. Vasculitis may affect other organs such as the gastrointestinal (GI) tract and brain with risk of thrombotic and hemorrhagic complications.

Raynaud phenomenon is unusual in children and is often a clue to an underlying rheumatic disease. If the vascular spasm persists, it may cause compromise of digits and require ICU intervention with vasodilating agents such as iloprost.

Renal Involvement

Renal disease is more common and more severe in children with SLE, occurring in about 80% of all cases. The spectrum varies from a silent disease identified only by abnormal urinalysis or by kidney biopsy to renal failure, severe nephrotic syndrome and malignant hypertension. Both nephritic and nephrotic patterns occur, loosely correlating with diffuse proliferative disease and membranous disease, respectively.¹¹

Hematologic Involvement

Antibodies against specific cells usually reflect hematologic involvement. Anemia maybe related to Coomb positivity, but blood loss and marrow suppression should also be considered. Leukopenia is one of the criteria for SLE. If the white blood cell count is high in the context of what appears to be active SLE, then infection must be seriously considered. High-dose steroids demarginate neutrophils and therefore may also cause an elevated white cell count. Thrombocytopenia may be profound and life-threatening and may be mediated by antiplatelet antibodies or APL antibodies

Musculoskeletal Manifestations

Arthritis occurs in about 80% of patients with SLE and is a helpful clue to the diagnosis. Although a joint exam is not a regular part of the intensivist’s repertoire, it can be very useful in deciding who needs further rheumatologic evaluation. Myositis is less common. Avascular necrosis can result from the disease itself, especially if the patients have APL antibodies, or as a complication of steroids.

Endocrine Issues

Thyroid disease may present as hyperthyroidism or hypothyroidism. Diabetes is usually a complication of steroid treatment, although rarely insulin resistant diabetes related to insulin receptor antibodies causes hyperglycemia refractory to therapy. Adrenal insufficiency is usually iatrogenic secondary to adrenal suppression from exogenous steroids.

Immune Dysfunction

Many factors reduce the immune response in patients with SLE. They are intrinsically immunosuppressed related to: altered B- and T-cell function; low complement levels that impair opsonization encapsulated organisms; and both hypergammaglobulinemia and hypogammaglobulinemia. In addition, immunosuppressive agents used to control their disease increase their risk of handling infections poorly. Furthermore, many patients with immunodeficiency can present with autoimmune phenomena, particularly those with chronic granulomatous disease, common variable immunodeficiency and T-cell abnormalities such as di George syndrome and ataxia telangiectasis.

Laboratory Studies

A hallmark of lupus is a positive test for ANAs in over 95% of cases; however, a positive ANA is found in many other conditions, including other rheumatic diseases and infections. It is therefore essential to support the diagnosis with clinical features and evidence of other autoantibodies and immune complex formation.¹² Antibodies to double-stranded DNA (ds-DNA) are found in about 40% of patients at onset of their lupus and about 80% during the course of disease. These are quite specific to lupus and correlate with renal disease as the size and charge of the immune complex they form is filtered and deposited in the kidney, triggering an inflammatory response.

Smith antibodies (antiribonucleoprotein antibodies) are not quite as specific but are still part of the diagnostic criteria. Complement levels are low in active disease, reflecting consumption during immune complex formation. A total hemolytic complement should be screened to check the total complement pathway, and if zero, a search for complement component deficiency should be initiated. However, C3 and C4 are relatively quick and convenient screens of both the classic and alternate pathways and are used to monitor disease activity.

Full laboratory and imaging evaluation of all organ systems is essential to establish which organ systems are affected and the severity of the disease. A thorough clinical, laboratory, and radiographic evaluation is necessary to help guide treatment decisions.

Management

In patients ill enough to require intensive care, pulses of corticosteroids (methylprednisolone 30 mg/kg/day administered over 1 hour with careful monitoring of blood pressure, fluid and electrolyte status, and hyperglycemia for 3 days), are often indicated, with subsequent maintenance at 2 to 3 mg/day methylprednisolone divided every 8 hours. Simultaneous coverage for infection is usually advisable. Steroid-sparing agents such as cyclophophosphamide are often initiated, especially in the case of significant renal and CNS disease. Renal failure and dialysis can affect metabolism and clearance of many medications used to treat SLE, and consultation with nephrology and pharmacology services can assist in proper dosing. Careful attention to management of individual organ involvement such as hypertension, seizures, cardiac or pulmonary compromise, and hematologic abnormalities is just as important as overall disease treatment.

Neonatal Lupus Syndromes

Mothers who have autoantibodies, whether or not they are symptomatic, may transmit antibodies to the fetus causing antibody-related disease even before infants have the capacity to make antibodies of their own.¹³ usually causes neonatal heart block that is irreversible and requires a pacemaker. Anti-La, which mediates neonatal cutaneous lupus syndrome, usually causes a rash that erupts after light exposure, but is sometimes associated with hepatitis and other organ system involvement. Other maternal antibodies, such as antiplatelet or Coomb antibodies, may cause neonatal thrombocytopenia and hemolytic anemia. As the maternal antibody levels in the infant’s circulation decline, the signs usually resolve; however, exchange transfusion can remove antibodies causing serious adverse events.

Juvenile Dermatomyositis

Clinical Presentation

Juvenile dermatomyositis is an inflammatory disease characterized by rashes over the eyelids, face, “shawl” area, and extensor surfaces of the small joints of the hand, knees, and elbows (Gottron papules).^5,¹⁴ The inflammation affects striated muscle, proximal more than distal muscle groups, and can cause profound weakness of hip and shoulder girdle groups as well the palate, pharynx and upper third of the esophagus, resulting in dysphagia, dysphonia, and aspiration risk. Respiratory failure may not be obvious as muscle weakness may mask typical signs. Nailfold capillary dilatation and dropout are markers for systemic vasculitis. Vasculitis targets the GI tract and may cause bleeding, necrosis and perforation. Pulmonary hemorrhage is another complication of systemic vasculitis, and the fundi and skin may also be affected. Cardiac muscle may be inflamed, and rarely myocarditis and conduction defects have been reported. The kidneys are not usually a primary target of vasculitis, but rhabdomyolysis with secondary renal impairment rarely occurs. Severely ill patients may also demonstrate findings of MAS. An underlying malignancy is extremely rare, unlike adult-onset dermatomyositis.