CHAPTER 157

Autoimmune Connective Tissue Diseases

Deborah McCurdy, MD, FAAP; Amy C. Gaultney, MD, MTS; and Miriam F. Parsa, MD, MPH, FAAP

Although the diseases discussed in this chapter have been called “collagen vascular diseases” and “connective tissue diseases,” their etiology is the result not of a gene mutation (as is the case with collagen gene mutations in osteogenesis imperfecta) but of inflammation and damage to connective tissues, blood vessels, and other organs resulting from aberrant immune responses in individuals genetically predisposed to autoimmunity. Significant progress has been made in classifying each disease with criteria for diagnosis, including clinical and laboratory findings. Most of the diseases discussed herein have associated autoantibodies that aid in diagnosis; however, these autoantibodies have not been definitively implicated in the disease pathogenesis.

Treatment algorithms for autoimmune connective tissue disorders have been proposed by the Childhood Arthritis and Rheumatology Research Alliance (comprising pediatric rheumatologists from Canada and the United States) and the Paediatric Rheumatology INternational Trials Organisation (a European organization). Generally, treatment for these diseases, which usually includes steroids and immunosuppressive therapies, must be started early and often aggressively to prevent organ damage. Although great progress has been made in the management of juvenile idiopathic arthritis (see Chapter 156) with the new biologic therapies, many other autoimmune diseases are still managed with medications used for the past several decades. One exception is belimumab (ie, Benlysta), a B lymphocyte stimulator-specific inhibitor approved in 2011 and used to treat systemic lupus erythematosus (SLE). Although belimumab appears to help with autoimmune rashes and arthritis, it does not appear to adequately treat lupus nephritis. Still, with the advent of the biologic therapies and enzyme inhibitors, steroid sparing, targeted therapies for these autoimmune diseases are under investigation.

Evaluation for Autoimmune Disease: General Considerations

History

Generally, the rheumatologic diseases are diagnoses of exclusion and warrant consideration in the context of a comprehensive differential diagnosis. The history is important to determine if an autoimmune disease is likely and should clearly delineate the onset (eg, whether a patient had a prior illness or injury), duration (eg, continuous or intermittent symptoms), and extent of the symptoms (eg, systems involved, severity of pain, swelling) (Box 157.1).

Physical Examination

A complete physical examination should be performed. The vital signs should be measured and noted if abnormal. The full physical examination must include complete examination of the skin; a thorough musculoskeletal examination, including assessment of spinal flexibility and muscle strength; and a neurologic and neuropsychiatric assessment. Lymphadenopathy should be noted as well as the presence of organomegaly. The presence of edema is noted by puffiness around the eyes in the morning and pitting edema of the feet, ankles, and even up to the knee at the end of the day. Pitting edema may be indicative of renal disease.

Laboratory Tests

Generally, laboratory tests should include a complete blood cell count, erythrocyte sedimentation rate, C-reactive protein, urinalysis, and other studies as determined by the differential diagnosis. The patient with suspected SLE should undergo an evaluation of autoantibodies, including antinuclear antibody (ANA), anti-dsDNA, anti-ribonucleoprotein (RNP)/anti-Smith (Sm), and anti-SS-A (Ro)/ anti-SS-B (La). Low complement levels (resulting from consumption) are important indicators of active SLE. It is appropriate to obtain electrocardiograms (ECGs) and echocardiograms in the patient with SLE and with suspected cardiac involvement. Concern about vasculitis warrants antineutrophil cytoplasmic antibody (ANCA) testing. The renal system may be involved in many of the autoimmune diseases, and a urine protein/creatinine ratio can help quantify any existing proteinuria. Suspicion for inflammatory myopathies warrants measurement of creatinine phosphokinase, aldolase, and lactate dehydrogenase levels, and, if autoimmune myositis is suspected, myositis-specific antibodies. Magnetic resonance (MR) imaging of the muscle, electromyography, and muscle biopsy may be indicated if the diagnosis is not clear.

Imaging Studies

Radiography is helpful in the initial evaluation. Chest radiography might reveal an enlarged heart, pulmonary edema or other pulmonary lesions, or bony abnormalities. Additionally, radiographs reveal changes in the joints and help assess the acuity and chronicity of joint swelling. High-resolution chest computed tomography (CT) may show subtle changes in the lung parenchyma. Magnetic resonance imaging and MR angiography are helpful in the evaluation of central nervous system (CNS) lupus, and an MR image of the muscle may show inflamed joints in juvenile dermatomyositis (JDM).

Management

The management of autoimmune diseases is based on the diagnosis and disease severity.

Systemic Lupus Erythematosus

Systemic lupus erythematosus is a classic autoimmune disease, with most patients having 6 or more different autoantibodies. The disorder is characterized by multiorgan system involvement and a waxing and waning course. The clinical presentation is variable and may be mild, presenting primarily with rash and arthritis. In the pediatric population, however, the presentation often is more severe, with frequent renal and other organ system involvement. Systemic lupus erythematosus can present in any organ and should be considered in any child with multiorgan system symptoms. Antinuclear antibodies are present in greater than 90% of patients with SLE but can also be seen in many other diseases. Up to 20% of the healthy population has a positive ANA but have no SLE. Other, more specific autoantibodies usually are present and may be associated with disease manifestations. Studies have shown that symptoms of SLE may be present well before the diagnosis is made, and it may take time to see the full picture. The goal of treatment is to decrease the inflammation and bring the immune system into balance.

Epidemiology

Systemic lupus erythematosus is not a common disease, but those with Hispanic, African, Native American, or Asian ancestry have an increased incidence and prevalence. Approximately 20% of cases of SLE are diagnosed in the pediatric population (ie, <19 years of age). The prevalence is approximately 6 to 18.9 per 100,000 among white females, 20 to 30 per 100,000 among black females, 16 to 36.7 per 100,000 among Puerto Rican females (13 per 100,000 for Hispanics in general), and up to 31 per 100,000 for those of Asian descent. The female to male ratio varies from 4:1 to 13:1 depending on the ethnicity of the cohort. In the 1960s, before therapy was initiated early and aggressively, children with SLE lived for approximately 2 years after diagnosis. Currently, with early recognition and therapy, the 5- and 10-year survival rates for pediatric SLE have improved to greater than 95% and 92%, respectively. Survival is affected by socioeconomic status, access to health care, educational background, racial and ethnic background, endemic infection rates, disease activity, and renal or CNS involvement. In the first 2 years following diagnosis, mortality is often associated with severe disease, and death results from pancreatitis, pulmonary hemorrhage, infection, throm-boembolic disease, and active neuropsychiatric disease. More than 5 years after diagnosis, causes of mortality include complications of end-stage renal disease, atherosclerosis, suicide, and, less commonly, active SLE or infection.

Etiology and Pathogenesis

Systemic lupus erythematosus is the prototype of autoimmune disease with multiple autoantibodies. The current hypothesis is that a genetic predisposition to SLE exists that is activated by environmental factors. The genome-wide association studies done in 2008 and expanded on in subsequent studies have identified more than 50 robust susceptibility loci of genes associated with SLE. These candidate genes are mostly involved in a variety of pathways, including immune complex processing, toll-like receptor signaling, activation of adaptive immunity, and type I interferon production. In addition, there is a clear association with deficiencies in early components of complement and SLE. This association is noted in certain consanguineous populations in which there is a high prevalence of SLE that affects young children from families with these complement defects. Environmental factors include ultraviolet radiation, viral infections (a strong association exists between SLE and Epstein-Barr virus), and drugs and chemicals.

Additionally, a well-studied immune dysregulation exists that involves the innate and adaptive immune systems. The loss of tolerance in SLE results in recognition of a self-antigen as foreign, with subsequent autoantibody production (antibodies to DNA, histones, and small RNA proteins), increase in both proinflammatory cytokines and immune complexes. Theories include the generation of self- antigens on cell surfaces following apoptosis; abnormalities of innate immunity, including toll-like receptors; abnormalities of all arms of the adaptive immune system, including antigen-presenting cells, T cells, and B cells; and abnormal regulation of interferon-α.

The increased incidence of SLE in females has been attributed in part to an estrogen hormonal effect. Most children with SLE present around the time of puberty, which suggests that the increased estrogen may exacerbate the disease process. Additionally, there may be factors on the X chromosome that predispose to the lupus pathogenesis. For example, men with Klinefelter syndrome (XXY) have a 14-fold increased risk of developing lupus compared with XY men, whereas women with Turner syndrome (XO) have a decreased risk of lupus.

Clinical Presentation

In 1982, criteria for the diagnosis of SLE were established by the American College of Rheumatology and modified in 1997 to include antiphospholipid (aPL) antibodies. To fulfill the criteria for a diagnosis of SLE, 4 of the 11 clinical and laboratory findings must be present at some point during the disease. The criteria are approximately 95% specific and sensitive for diagnosis (Box 157.2). At the 2017 annual European Congress on Rheumatology, weighted criteria were proposed and are being evaluated to more specifically diagnose SLE.

Usually, patients present with constitutional symptoms such as fever, fatigue, and weight loss. Often, a history is present of a photosensitive rash and swelling of the joints. Additionally, the patient may exhibit systemic inflammation with lymphadenopathy and hepatosplenomegaly. In the pediatric population, more than 80% of patients have renal involvement at onset or at some point in the disease.

Adapted with permission from Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725.

Mucocutaneous Involvement

Although the butterfly rash is strongly associated with SLE, only 60% of patients have this type of rash at onset, although up to 85% will have the butterfly rash at some point in their disease. This rash is usually photosensitive, crosses the nose, and is present on both cheeks but spares the nasolabial folds. Other photosensitive rashes exist, including palpable purpura. Less common in the pediatric population is the discoid rash, which involves the dermis and can result in scarring. The discoid rash most often occurs in blacks. Approximately 10% to 30% of patients will have painless oral and nasal ulcers. Raynaud phenomenon is noted in 15% to 20% of children, but it is not specific for SLE.

Musculoskeletal Involvement

Often from onset and throughout the course of the disease, most patients with SLE will experience arthritis, arthralgia, or tenosynovitis. Typically, the arthritis is a symmetric polyarthritis affecting large and small joints, especially the metacarpophalangeal and proximal interphalangeal joints of the fingers. The arthritis is nonerosive and usually responds to treatments administered to control other aspects of the disease. Myalgia, and more rarely myositis, occur in SLE and are usually responsive to treatment. Some patients, however, develop a myopathy related to steroid treatment itself. Up to 20% of patients with SLE may develop a secondary pain amplification syndrome (ie, fibromyalgia).

Renal Involvement

After skin and joints, the organ system most frequently involved in SLE in the pediatric population is the kidney. Approximately 50% of patients present with lupus nephritis, but by the end of the first year following diagnosis, 80% to 90% of patients with SLE manifest renal involvement. Treatment and prognosis is based on the histologic classification of nephritis as established by the World Health Organization (WHO) using renal biopsy (class I–VI) (Box 157.3). The clinical markers (ie, proteinuria, hematuria, creatinine level) may not correspond to histologic classifications, but often WHO classes III and IV are associated with hypertension and impaired renal function and are managed with high-dose steroids and immunosuppression. The patients with WHO class III, IV, or V may also present with peripheral edema requiring steroid therapy. With more aggressive and consistent treatment, overall survival for patients with renal involvement has improved, with markedly increased 5- and 10-year survival rates.

Neuropsychiatric Involvement

Often, neuropsychiatric manifestations are underappreciated because patients often present with headaches, poor school performance, and features of depression. Involvement of the CNS or peripheral nervous system may be present in 20% to 95% of patients with SLE (thus, the term “neuropsychiatric SLE”). Headaches are the most frequent presentation, with a lupus headache defined as a migraine-like, unremitting headache requiring narcotic analgesics. Headaches refractory to treatment can be indicative of active CNS vasculitis, increased intracranial pressure, or cerebral vein thrombosis. Thrombotic events in the CNS or elsewhere often are associated with aPLs in patients with lupus, and a full workup with urgent imaging is indicated. In these cases, MR angiography often shows vasculitis or evidence of bleeding or ischemia. Psychosis manifested by visual and tactile hallucinations may be present in 30% to 50% of patients. Hallucinations are usually visual but may also be auditory. Imaging studies in patients with hallucinations may be normal, but often autoantibodies are found in the blood or spinal fluid. Psychosis in isolation warrants consideration of the secondary effects of glucocorticoids. More difficult to delineate is cognitive impairment, which may present as a broad range of symptoms from difficulty concentrating to confusion and coma. Other, less common neurologic symptoms include seizures, movement disorders (eg, chorea), and cranial nerve abnormalities. Imaging studies are an important part of the workup and may show vasculitis, hemorrhage or clot, or demyelination; alternatively, such studies may be normal in antibody-mediated CNS disease.

Hematologic Involvement

Anemia, thrombocytopenia, and lymphopenia may be present in 50% to 75% of patients. During active disease, a patient often has a normochromic, normocytic anemia typical of anemia of chronic disease. The Coombs test is positive in 30% to 40% of patients, but only 10% to 15% of patients with SLE have significant hemolysis. Thrombocytopenia is present in 15% to 45% of patients. Patients with chronic autoimmune idiopathic thrombocytopenic purpura (AITP) and Evans syndrome (ie, AITP and Coombs-positive anemia) with a positive ANA test are more frequently diagnosed with SLE. Lymphopenia is thought to represent a general marker of disease activity.

Antiphospholipid Antibody Syndrome

The antiphospholipid antibody syndrome (APS) is a prothrombotic state that is secondary to acquired autoantibodies, including anticardiolipin (aCL) antibodies, the lupus anticoagulant (LAC; usually measured by partial thromboplastin time mixing studies or the dilute Russell viper venom time), and β2-glycoprotein I (β2GPI, apolipoprotein H). These aPL antibodies are directed against phospholipids that are found in cell membranes throughout the body and, as such, are composed of many different antibodies with different epitopes. The most common aPL antibodies are the aCLs and the LAC. The term “lupus anticoagulant” is a misnomer, however, and the condition is so called because the phospholipid-dependent partial thromboplastin time cascade is prolonged in the presence of aPL antibodies. In contrast, the affected patient is at risk for a thrombotic event because the aPL antibodies bind to the epithelial membranes of blood vessels and activate clotting mechanisms. Antiphospholipid antibodies alone may be associated with infection, malignancies, or autoimmune states; however, they are usually benign and transient. A risk of thrombosis is present with high titer aCL immunoglobulin (Ig) G or IgM, LAC positive status, or high titers of IgG or IgM β2GPI antibodies.

Antiphospholipid antibody syndrome can occur as a primary disease without an associated autoimmune disease but most often occurs patients with SLE. In children with SLE, aCL, β2GPI, occur in 44%, 40%, and 22%, respectively. The child may present with arterial, venous, or small vessel thrombosis. Although only 16% to 36% of children with aPL antibodies are at risk for a thrombotic event, those with LAC positivity have a 28-fold increased risk. The most frequent thrombotic event is deep vein thrombosis, followed by cerebral sinus vein thrombosis, portal vein thrombosis, thromboses in the deep veins of the upper extremities, and superficial vein thromboses. Thrombocytopenia and hemolytic anemia may also be secondary to aCL binding to the red cell and platelet membranes. Because children are at low risk for thrombosis, most are monitored without specific therapy. Some physicians start hydroxychloroquine sulfate (eg, Plaquenil, Quineprox), which has been shown to decrease erythrocyte aggregation on the endothelium. Low-dose aspirin is often used as an anticoagulant, but its efficacy is in question. In the patient with a documented thrombotic event, anticoagulation (eg, warfarin [Coumadin, Jantoven]) is used, but low-molecular-weight heparin (eg, Enoxaparin) or another anticoagulant can also be used, often for 6 months or longer.

Catastrophic APS is of concern because this is a life-threatening disease process in which 3 or more organ systems develop small vessel occlusions within 1 week in association with aPL. These children present with adult respiratory distress syndrome, hypertension, renal failure, and multiple other organ system involvement requiring intensive care therapies. Immediate and aggressive therapy, including anticoagulation, plasmapheresis, and corticosteroids, is necessary to reverse the thrombotic storm, but the mortality rate is still high (up to 50% in some reports). After recovery from catastrophic APS, lifelong anticoagulant therapy is indicated.

Cardiac Involvement

Pericarditis is not uncommon in SLE (15%–25% symptomatic; however, ECG changes are noted in up to 68%), and the affected patient may be asymptomatic. The myocardium and pericardium may also be involved, as well as the valves (ie, aortic, tricuspid, mitral) with sterile verrucous vegetations or Libman-Sacks endocarditis. Libman-Sacks endocarditis may be associated with aPLs and increase the risk for subacute bacterial endocarditis. A patient may present with chest pain that is worse when lying down or taking a deep breath. Chronic inflammation is associated with an increased risk of premature arthrosclerosis, and myocardial infarction is a leading cause of death in young adults with SLE.

Pleuropulmonary Involvement

The lungs may be involved in 25% to 75% of patients with SLE, with higher numbers noted by abnormal findings on pulmonary function tests (PFTs) in an otherwise asymptomatic patient. Pleurisy is the most common manifestation and may be associated with pericarditis. Symptoms include chest pain, orthopnea, and dyspnea, and a chest radiograph may show a pleural effusion (frequently unilateral). The patient may present with pleuritic chest pain and respiratory distress associated with acute lupus pneumonitis or pulmonary hemorrhage or may have a more indolent course with interstitial lung disease and shrinking lung syndrome (ie, loss of lung volume resulting from diaphragmatic dysfunction or phrenic nerve dysfunction). Pulmonary hypertension may be insidious and is a life-threatening complication of pulmonary involvement. Because of the disease and medications, opportunistic infections are also problematic. Imaging studies, especially a high-resolution chest CT, as well as PFTs are indicated if pulmonary disease is suspected.

Gastrointestinal Involvement

Gastrointestinal (GI) involvement may be difficult to diagnose and differentiate from adverse effects from medication. The GI system is involved in approximately 20% of patients with SLE. During active inflammation, a patient often has hepatosplenomegaly. High transaminase levels are suspicious for lupoid hepatitis. Symptoms may include abdominal pain and diarrhea. Underlying pathology may be lupus peritonitis, enteropathy, or, in the setting of copious diarrhea, protein-losing enteropathy. Severe abdominal pain is seen with mesenteric vasculitis. Celiac disease has been associated with SLE and should be considered in the setting of severe weight loss. Pancreatitis may occur in association with active lupus or with steroid use and often presents with abdominal pain, nausea, and vomiting.

Endocrine Involvement

Antithyroid antibodies are common in SLE (up to 35%), and 10% to 15% of patients develop hypothyroidism. Thyroid-stimulating hormone should be checked annually in the patient with SLE. Diabetes can be associated with SLE, but more frequently, diabetes is induced by corticosteroid treatment. Growth failure is a consequence of active disease and corticosteroid therapy. The potential exists for a delay in puberty and menstrual abnormalities and, rarely, autoimmune ovarian failure. Ovarian failure may also occur as a result of immunosuppressive treatment with cyclophosphamide.

Ocular Involvement

Active disease with retinal vasculitis may cause cytoid bodies (cotton-wool spots) noted on retinal examination. Antiphospholipid antibodies may cause retinal vein occlusion and vision loss. Episcleritis and scleritis may occur. Keratoconjunctivitis sicca may occur in the patient with secondary Sjögren syndrome.

Autoantibodies in Systemic Lupus Erythematosus

Autoantibodies are the hallmark of SLE, and most patients have more than 6 autoantibodies (Box 157.4). A positive ANA is found in nearly all patients, but this is not specific for or associated with a certain disease manifestation. The antibodies of SLE are directed against histone, nonhistone, RNA-binding, cytoplasmic, and nuclear proteins. These include anti-DNA (65%–95%), anti–RNA-binding proteins, and anti-U1RNP (27%–34%) and anti-Sm antibodies (32%–34%). Anti–SS-A and anti–SS-B antibodies (27%–33%) are seen less frequently but are associated with skin disease and neonatal lupus. Anticardiolipin (19%–87%) and the LAC (10%–62%) are the most common aPLs.

Management

Treatment of children and adolescents with SLE must be started early to prevent organ damage. Treatments must be tailored to the symptoms, but young patients are reported to have more severe disease and often require aggressive therapy. A summary of treatments used in pediatric lupus and their most common adverse effects are enumerated in Table 157.1.

Vasculitis

Vasculitis is an inflammatory process involving the blood vessel wall; thus, any organ system may be involved. Vasculitis may be the primary disease process or complicate an autoimmune disease, infection, or malignancy. Patients with SLE often have vasculitis.

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