1260 e1 Scleroderma (Systemic Sclerosis) Key Points Raynaud syndrome presenting in a prepubertal girl or young male should raise suspicion for underlying rheumatologic disease Careful management of hy[.]
1260.e1 eTABLE 106.3 Summary of Identified Monogenic Autoinflammatory Disorders Condition Age at Presentation Gene Symptoms Familial Mediterranean fever Childhood to adolescence MEFV Episodic erysipeloid rash, peritonitis, arthritis, fevers lasting 24–72 h Tumor necrosis factor receptorassociated periodic syndrome Childhood TNFRSF1A Episodes of fevers with erythematous rash on extremities, periorbital edema and conjunctivitis, peritonitis, pleuritis, orchitis lasting 1–4 wk Hyper IgD syndrome Infancy to childhood MVK Episodic fevers, abdominal pain, arthralgias, polyarthritis, erythematous macules (occasionally painful), aphthae, headaches, lymphadenopathy Neonatal-onset multisystem inflammatory disease Birth or early infancy NLRP3 Fever, urticaria-like rash, epiphyseal overgrowth, aseptic meningitis, high-frequency hearing loss, uveitis STING-associated vasculopathy with onset in infancy Infancy TMEM173 Acral necrosis, vasculopathy, interstitial lung disease, fevers Deficiency of adenosine deaminase Childhood CECR1 Recurrent fevers, livedo-like rash, necrotizing vasculitis, early strokes (especially lacunar strokes), hypogammaglobulinemia Deficiency of the interleukin-1 receptor antagonist Perinatal IL1RN Pustular skin rash, bone pain, sterile osteolytic bone lesions, widening of anterior ribs Blau syndrome Early childhood NOD2 Tan/brown granulomatous rash nodules, polyarticular arthritis, granulomatous uveitis, fevers, vasculopathy Familial hemophagocytic lymphohistiocytosis Infancy to childhood PRF1, UNC13D, STX11, STXBP2, others Fever, rash, hepatosplenomegaly, cytopenias, neurologic changes Scleroderma (Systemic Sclerosis) Key Points Raynaud syndrome presenting in a prepubertal girl or young male should raise suspicion for underlying rheumatologic disease Careful management of hypertension in systemic sclerosis is important to prevent acute renal failure (renal crisis) GI involvement in systemic sclerosis is often silent until clinically advanced; a high suspicion for GI involvement and careful evaluation is important early in disease course Clinical Presentation Scleroderma refers to a group of rare connective tissue diseases in which vascular changes and abnormal fibrotic response lead to inflammation and subsequent hardening of the skin and abnormalities of the internal organs, especially the lungs and GI tract Diffuse systemic sclerosis is the most severe form of the disease Features may include skin induration, Raynaud phenomenon (discussed later), digital tip ulceration, dysphagia, gastroesophageal reflux, hypertension, arthritis, neuropathy, pulmonary hypertension, and pulmonary fibrosis Progressive pulmonary fibrosis may lead to respiratory failure, and abnormal GI motility may make nutrition difficult Cardiopulmonary complications are the most common cause of death in children with systemic sclerosis—typically, heart failure secondary to lung disease Renal crisis is another serious complication (not commonly seen in children); early initiation of antihypertensive therapy with angiotensin-converting enzyme inhibitors is essential Imaging Significant pulmonary disease often occurs with little to no symptoms and an unremarkable chest radiograph Thus, PFTs and HRCT are essential for early identification of lung disease when it is still treatable Cardiac catheterization is often necessary to diagnose and assess the severity of pulmonary hypertension Barium swallow and an upper GI series with small-bowel followthrough are important to assess the extent of esophageal and small-bowel dysfunction Consultation with a pediatric GI specialist in motility disorders is recommended for full evaluation Management Systemic sclerosis is challenging to treat, as the disease is often far advanced before patients come to medical attention Thus, a thorough evaluation of all organ systems (even when there appears to be no symptoms) is necessary Therapy is directed at both halting or reversing the underlying inflammatory disease process and reducing morbidity from disease complications Acid blockade to control gastroesophageal reflux and prevention of microaspiration are important in patients with upper GI tract involvement Attention to adequate nutrition and management of malabsorption is critical in patients with intestinal involvement Patients with severe Raynaud phenomenon may require vasodilation with calcium channel blockers, sildenafil, or iloprost In patients with pulmonary hypertension, prostanoids and bosentan (a dual endothelin receptor antagonist) may reduce right ventricular and pulmonary artery pressures Rapid initiation of angiotensin-converting enzyme inhibitors significantly improves the prognosis for patients in renal crisis For treating the underlying disease, the approach is similar to the treatment of other pediatric rheumatologic diseases; responses may be variable, however High-dose corticosteroid therapy, methotrexate, mycophenolate mofetil, cyclophosphamide, and rituximab have been used Corticosteroid therapy must be used with caution in patients with renal involvement, as it has been 1260.e2 associated with renal crisis in adults In severe refractory cases, hematopoietic stem cell transplantation has been successful for treatment of the skin disease Unfortunately, GI and pulmonary damage are rarely reversible and may be the cause of significant morbidity and mortality Mixed Connective Tissue Disease Children may present with syndromes that have overlapping features of different rheumatologic diseases The most well-characterized “overlap syndrome” is termed mixed connective tissue disease Patients with mixed connective tissue disease often present with severe Raynaud phenomenon and polyarticular arthritis or tenosynovitis Over time, these patients may develop features of other rheumatologic disorders, including SLE, JDM, and/or systemic sclerosis Characteristic laboratory findings are a hightiter ANA (.1 : 320) and anti-RNP antibodies Management is governed by which organs are affected and the severity of involvement CHAPTER 106 Pediatric Rheumatologic Disease profound cytopenias, consanguinity, or family history of death due to unidentified febrile illness.109 Heterozygous mutations in the same cytolytic pathway genes have been associated with MAS in patients with sJIA, further demonstrating the overlapping role of hyperactivation of innate immunity in these conditions.110 Aggressive treatment of MAS is essential Until recently, the standard therapy consisted of rapid initiation of high-dose pulse IV methylprednisolone therapy (30 mg/kg per day for days, maximum dose 1000 mg, then 1–2 mg/kg per day divided twice daily) with a slow corticosteroid taper plus IV cyclosporine to mg/kg per day More recently, anakinra (2–4 mg/kg IV or subcutaneously every 6–24 hours) is being used in place of cyclosporine and is rapidly effective.109 Clinical trials regarding the safety and efficacy of higher doses of anakinra are ongoing Airway Compromise Patients with underlying rheumatologic diseases may have challenges in airway management due to limitations in cervical mobility, obstruction from inflammation, or inability to protect the airway because of muscle weakness These processes may be indolent or rapid in onset Intubation can be challenging, and tracheostomy may be necessary Arthritis of the cervical spine can be seen in several of the JIA categories Without appropriate treatment, persistent synovial inflammation and bony erosions in the occipitoatlantoaxial joints can lead to C1–C2 instability.111 This has important implications if hyperextension is attempted for intubation due to potential for neurologic complications In any patient with JIA with a history or findings of cervical spine disease, radiographic imaging with neck flexion/extension views should be obtained before attempted intubation If abnormalities are identified, alternative airway management, such as fiberoptic visualization or tracheostomy, should be considered The temporomandibular joints (TMJs) may also be affected in any form of JIA Active or past TMJ arthritis can lead to diminished mouth opening, which can also complicate airway management Last, the cricoarytenoid joint is an often-overlooked synovial surface that may be affected in JIA patients Cricoarytenoid inflammation may present as sore throat and hoarse voice, with localized tenderness over the larynx or with stridor and airway obstruction due to limited vocal cord mobility.112 Other rheumatologic diseases, such as SLE and GPA, and rare diseases, such as relapsing polychondritis, can be complicated by airway involvement, leading to obstruction in severe cases.113 Although rare, oropharyngeal obstruction can occur in SLE due to angioedema with acute mucosal swelling of the pharyngeal and laryngeal tissues.114 Subglottic stenosis affects 10% to 20% of patients with GPA and is five times more common in pediatric than adult-onset disease A conservative approach with medical therapy and local interventions such as intralesional steroid injections and dilation have been used successfully and may obviate the need for surgical reconstruction.115 Relapsing polychondritis, a rare disorder of recurrent cartilaginous inflammation, affects both the small and large airways and can cause upper or lower airway obstruction.113 Muscle weakness can also lead to airway compromise In JDM, muscle weakness of the palate, pharynx, larynx, and upper third of the esophagus can lead to dysphagia, dysphonia, inability to manage secretions, and airway compromise severe enough to warrant intubation 1261 Organ-Specific Complications Rheumatologic diseases can affect almost any organ system eTable 106.4 provides an overview of some of the most common patterns of organ involvement seen in the disorders discussed in this chapter Suggestive findings or key diagnostic approaches are also indicated However, a multidisciplinary approach is often necessary, as full evaluation often requires coordination between rheumatology, organ-specific subspecialists, and interventionalists Treatment-Related Complications of Rheumatologic Diseases Although treatment of rheumatologic disease can be effective and often life-saving, there are multiple risks and complications related to treatment itself Corticosteroids High-dose steroid therapy may exacerbate hypertension and cause electrolyte imbalances (particularly sodium and fluid retention) and hyperglycemia Corticosteroids can also impair neutrophil function, leading to increased susceptibility to infection Longterm effects of corticosteroids include avascular necrosis; loss of bone density, with increased risk of compression fractures; and skin atrophy, with increased risk of skin breakdown Particularly important for the ICU, one of the most serious complications of chronic corticosteroids is the potential for adrenal insufficiency due to abrupt discontinuation of the patient’s usual medications and/or inadequate adrenal response to stress.116,117 Rapid initiation of stress dose corticosteroids in the setting of acute illness or surgery is essential to avoid adrenal crisis Hyperglycemia and overt diabetes may also occur in the setting of steroid treatment, requiring insulin therapy Gastrointestinal Side Effects Corticosteroids and nonsteroidal antiinflammatory drugs (NSAIDs) can cause gastric irritation and pancreatitis GI prophylaxis with proton pump inhibitors along with monitoring pancreatic and liver enzymes is recommended Despite adequate prophylaxis, patients taking steroids or NSAIDs are still at increased risk of GI bleeding Early GI and surgical consultation are advised Imaging-guided embolization of bleeding vessels may be necessary in severe cases Infectious Side Effects Patients treated with immunosuppressive medications are susceptible to typical community-acquired bacteria, such as Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae, as well as gram-negative enteric bacteria However, patients receiving chronic immunosuppression—in particular, high-dose corticosteroids—are also at high risk for opportunistic infections with Pneumocystis jirovecii, Mycobacterium tuberculosis, Aspergillus or Mucor species, and CMV Common organisms can be found in unusual sites, such as staphylococcal endocarditis, or unusual organisms can be identified in typical sites of infection, such as mucormycosis of the sinuses Before starting antimicrobial therapy, body fluids and specimens should be obtained for culture With suspected pulmonary infection, HRCT and bronchoscopy 1261.e1 eTABLE 106.4 Patterns of Typical Organ System Involvement in Common Rheumatologic Diseases Organ System Typical Rheumatologic Diseases With Involvement Neurologic Ocular Pulmonary Cardiac Gastrointestinal Renal Hematologic MSK/Skin Signs and Symptoms Key Tests or Findings for Complication SLE Headache, seizures, psychosis, encephalitis, stroke, movement disorders (APS), neuropathy, mood disorder None diagnostic; MRI, LP, EEG may be helpful; infectious studies MAS Confusion, seizures, coma LP for cell counts, infectious studies Vasculitis (especially primary CNS vasculitis) Headache, seizures, psychosis, encephalitis, stroke MRI/angiography, brain biopsy (small vessel); infectious studies SLE Retinal vasculitis, optic neuritis, uveitis Dilated retinal examination ANCA (GPA and MPA) vasculitis Scleritis, episcleritis Nodular conjunctivitis Kawasaki disease Conjunctivitis Limbic sparing SJIA SJIA Pleuritis/pleural effusion (acute), ILD/pHTN (chronic) Chest CT, PFTs for monitoring SLE Pleuritis/pleural effusion, PE, pulmonary hemorrhage (acute), ILD, pHTN (chronic) PFTs, HRCT, bronchoscopy ANCA (GPA and MPA) vasculitis Pulmonary hemorrhage, subglottic stenosis PFTs, HRCT, bronchoscopy JDM Pharyngeal muscle weakness, aspiration, ILD VFSS, HRCT, bronchoscopy Systemic sclerosis ILD, pHTN HRCT, bronchoscopy, echocardiography, cardiac catheterization may be needed to detect early pHTN SJIA—pericarditis Pericarditis Echocardiography SLE Pericarditis, myocarditis, arrhythmias, MI, Libman-Sacks endocarditis, Echocardiography, cardiac catheterization Kawasaki disease Myocarditis Echocardiography Takayasu arteritis Coarctation, aortic regurgitation Echocardiography, angiography sJIA Serositis, hepatomegaly Abdominal ultrasound SLE Serositis, pancreatitis, hepatitis, colitis, perforation, hemorrhage Abdominal ultrasound or CT, colonoscopy, paracentesis MAS Hepatitis, colitis Abdominal CT Vasculitis (especially HSP, PAN) Mesenteric vasculitis, intussusception, abdominal angina, GI hemorrhage SLE Nephritis, nephrotic syndrome, hypertension, TMA, renal failure Albumin, creatinine, C3, C4 anti-dsDNA levels, microscopic urinalysis, urine protein/creatinine ratio, renal biopsy Vasculitis (GPA/MPA, HSP, and PAN) RPGN, nephritis, hypertension, renal failure Albumin, creatinine, microscopic urinalysis, urine protein/creatinine ratio, angiography (PAN), renal biopsy JDM Myoglobinuria, ATN Microscopic urinalysis, creatine kinase Systemic sclerosis Hypertension, acute renal crisis Abdominal ultrasound with Doppler for resistive indices SLE Leukopenia/lymphopenia, thrombocytopenia, APS, TTP/MAHA, lymphadenopathy, splenomegaly CBC with smear, LDH, retic count, haptoglobin, ADAMTS13 activity (TTP) MAS Neutropenia, anemia, thrombocytopenia (may be relative) lymphadenopathy, splenomegaly Ferritin, d-dimers, fibrinogen, triglycerides, soluble IL2 R, NK-cell function, bone marrow for hemophagocytes, CMV/EBV evaluation JIA Arthritis, rheumatoid nodules (rare) SJIA Arthritis, migratory rash SLE Arthritis, malar rash, discoid rash, petechia, myositis ANA, ENA panel, Coombs, aPLs, organ survey Continued 1261.e2 eTABLE 106.4 Patterns of Typical Organ System Involvement in Common Rheumatologic Diseases—cont’d Organ System Typical Rheumatologic Diseases With Involvement Signs and Symptoms Key Tests or Findings for Complication JDM Proximal myositis, arthritis heliotrope rash, Gottron papules MRI of proximal muscle girdle with STIR sequences; AST, ALT, CK, LDH, aldolase levels, myositis-associated antibodies (may be negative) Vasculitis Arthritis, palpable purpura, nodules, livedo reticularis (depending on vessel size) ANCA (anti-PR3 and anti-MPO) for small-vessel diseases; biopsy usually needed for confirmation ALT, Alanine transaminase; ANA, antinuclar antibody; ANCA, antineutrophil cytoplasmic antibodies; APC, activated protein C; aPLs antiphospholipid antibodies; APS, antiphospholipid syndrome; AST, aspartate transaminase; ATN, acute tubular necrosis; CBC, complete blood count; CK, creatine kinase; CMV, cytomegalovirus; CT, computed tomography; EBV, Epstein-Barr virus; EEG, electroencephalography; ENA, extractable nuclear antigen; GPA, granulomatosis with polyangiitis; HTN, hypertension; HRCT, high-resolution computed tomography; HSP, Henoch-Schönlein purpura; ILD, interstitial lung disease; JIA, juvenile idiopathic arthritis; JDM, juvenile dermatomyositis; LDH, lactate dehydrogenase; LP, lumbar puncture; MAHA, microangiopathic hemolytic anemia; MAS, macrophage activation syndrome; MI, myocardial infarction; MPA, microscopic polyangiitis; MPO, myeloperoxidase; MRI, magnetic resonance imaging; NK, natural killer; PAN, polyarteritis nodosa; PE, pulmonary embolism; PFTs, pulmonary function tests; pHTN, pulmonary hypertension; PR3, proteinase 3; RPGN, rapidly progressive glomerulonephritis; SLE, systemic lupus erythematosus; sJIA, systemic juvenile idiopathic arthritis; STIR, short tau inversion recovery; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura; VFSS, video fluoroscopic swallowing study ... interstitial lung disease; JIA, juvenile idiopathic arthritis; JDM, juvenile dermatomyositis; LDH, lactate dehydrogenase; LP, lumbar puncture; MAHA, microangiopathic hemolytic anemia; MAS, macrophage... also lead to airway compromise In JDM, muscle weakness of the palate, pharynx, larynx, and upper third of the esophagus can lead to dysphagia, dysphonia, inability to manage secretions, and airway... overview of some of the most common patterns of organ involvement seen in the disorders discussed in this chapter Suggestive findings or key diagnostic approaches are also indicated However, a multidisciplinary