1257CHAPTER 106 Pediatric Rheumatologic Disease Laboratory Studies Laboratory studies are useful to support the diagnosis, monitor disease activity, and guide treatment Serum levels of muscle enzymes—[.]
CHAPTER 106 Pediatric Rheumatologic Disease Laboratory Studies Laboratory studies are useful to support the diagnosis, monitor disease activity, and guide treatment Serum levels of muscle enzymes—including CK, AST, ALT, aldolase, and LDH—are usually markedly elevated in active disease and normalize over time with treatment In patients with long-standing disease, however, serum enzyme levels may remain normal despite active muscle inflammation Imaging may be necessary to assess disease activity Mild anemia may be present initially, but the WBC and platelet counts are usually normal Severe anemia, leukopenia, and/or thrombocytopenia should prompt consideration of MAS or investigation of causes other than JDM ANAs are positive in approximately 70% of patients at diagnosis but are not part of diagnostic criteria for JDM Although specific myositis-associated antibodies have low sensitivity for this disease, the anti-p155/140 (TIF1) and anti-MJ (NXP2) autoantibodies are highly specific for JDM and are often useful in predicting the clinical course.63 Imaging The muscle edema and inflammation of JDM are best detected by MRI with short tau inversion recovery (STIR) sequence MRI can also help to identify an appropriate site for biopsy in cases with diagnostic uncertainty For patients with dysphonia or dysphagia, a video fluoroscopic swallowing study (VFSS) can establish aspiration risk and whether alternative feeding methods are necessary Clinical swallow examinations may be falsely reassuring in patients with JDM, as weakness of the pharyngeal muscles may impair the normal cough reflex, resulting in silent aspiration events As with other systemic immune diseases, a thorough organ survey is recommended to establish the extent of any cardiopulmonary or GI involvement Management An aggressive treatment approach is essential and typically includes high-dose IV corticosteroids, methotrexate, and IVIG Other agents—such as cyclosporine, MMF, cyclophosphamide, and rituximab—may be used in refractory or severe cases.64 In cases complicated by GI involvement, oral medications may not be absorbed reliably and parenteral administration is preferred Systemic Vasculitis Key Points Vasculitis secondary to underlying infection and/or medications (drug-induced hypersensitivity) is much more common than immune-mediated vasculitis A thorough evaluation for inciting agents is required prior to diagnosis of primary vasculitis Vascular inflammation can lead to vessel stenosis, occlusion, and/or rupture Patients are at high risk of thrombosis, insufficiency syndromes, and hemorrhage Primary vasculitides in pediatrics are often categorized as small-, medium-, or large-vessel syndromes Clinical manifestations and patterns of organ involvement can be used to help pinpoint the size of affected vessels Patients presenting with unexplained hypertension, multiorgan dysfunction, and/ or persistent signs of systemic inflammation should be evaluated for underlying vasculitis Serologic studies for evaluation of vasculitis are limited; tissue biopsy and/or vascular imaging is usually required for confirmation of diagnosis The vasculitides are a heterogeneous group of disorders that can be classified in various ways, including by size of the affected vessels and by characteristic laboratory features These disorders previously had high morbidity and mortality rates, but advances 1257 in treatment have led to markedly improved prognosis in pediatric patients.65 Primary systemic vasculitis is a diagnosis of exclusion—predisposing factors such as infection and medicationinduced syndromes must be ruled out before a diagnosis is made The most common forms of primary vasculitis in children are Henoch-Schönlein purpura (HSP) and Kawasaki disease (KD) However, children can develop other more rare disorders, such as granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), Takayasu arteritis (TA), and primary vasculitis of the CNS Small-Vessel Vasculitis Immune-Complex Small-Vessel Vasculitis Henoch-Schönlein Purpura HSP is an immunoglobulin (Ig) A–mediated small-vessel vasculitis, often triggered by a preceding infection, often b-hemolytic Streptococcus pyogenes The classic clinical features include palpable purpura predominantly on the lower extremities, arthritis or arthralgias, abdominal pain, and hematuria Most cases are mild and resolve spontaneously within about month Up to 30% of patients with HSP develop GI hemorrhage, although severe hemorrhage, irreducible intussusception, and perforation are rare.66 Rarely, pulmonary hemorrhage and CNS involvement have been reported, although these complications should prompt evaluation for other more rare forms of small-vessel vasculitis described later.67,68 Nephrotic syndrome at disease onset and increased age are associated with worse outcomes.69,70 Laboratory tests are nonspecific, usually showing only mildly elevated WBC counts and inflammatory markers Coagulation studies and platelet counts are normal The serum IgA level is often elevated but is not sensitive or specific HSP In unclear or severe cases, a skin or renal biopsy can be performed and should demonstrate leukocytoclastic vasculitis with IgA deposition Treatment of HSP In most cases, HSP is a self-limited condition that can be managed in the outpatient setting When severe manifestations are present, hospitalization may be necessary Treatment is primarily supportive, including hydration and nutritional support Pain control can often be achieved with acetaminophen or NSAIDs Oral or IV high-dose corticosteroids may be used for abdominal pain with vomiting or concern for suspected intussusception Current data suggests that while corticosteroids cannot prevent the development of renal disease, they may be an effective treatment option in certain cases for severe disease manifestations.71 Unfortunately, rebound symptoms upon taper of glucocorticoids are common and prolonged tapers are often required In children with severe disease, corticosteroids can be combined with cyclophosphamide and plasmapheresis However, data supporting this type of treatment is lacking.72 Other reported treatment options include azathioprine, MMF, cyclosporine, IVIG, and plasmapheresis Given the lack of high-quality, evidence-based trials and consensus guidelines, considerable variability in the treatment of severe HSP may exist between institutions Pauci-Immune Small-Vessel Vasculitis (Antineutrophil Cytoplasmic Antibody–Associated Vasculitis) Granulomatosis With Polyangiitis GPA (formerly known as Wegener granulomatosis) is a granulomatous vasculitis that targets the sinuses and middle ear, lungs, and kidneys Severe manifestations include subglottic stenosis 1258 S E C T I O N X I Pediatric Critical Care: Immunity and Infection with dyspnea and stridor, pulmonary hemorrhage, necrotizing cavitary lung lesions, and rapidly progressive necrotizing glomerulonephritis Additional symptoms can include fever, weight loss, hearing loss, conjunctivitis, purpura or petechiae, arthritis, headache, and dizziness For a patient presenting with pulmonary-renal syndrome, other diagnoses should be considered in addition to GPA, including MPA, Goodpasture syndrome, and SLE (eTable 106.2) Antineutrophil cytoplasmic antibodies (ANCAs) target antigens within the cytoplasm of granulocytes Cytoplasmic ANCAs (cANCAs) are seen in about 80% of children with GPA Antiproteinase-3 (PR3) antibodies are more specific and are seen in 60% of children with GPA.73 These antibodies may correlate with disease activity in certain patients WBC and inflammatory marker counts are typically elevated Urinalysis may show evidence of glomerulonephritis, including proteinuria, hematuria, and red blood cell casts Pulmonary function tests may demonstrate restrictive or obstructive findings Tests of lung diffusion capacity may be low or artificially elevated in the case of recent pulmonary hemorrhage Renal biopsy can demonstrate necrotizing glomerulonephritis, with minimal immune deposits (“pauci-immune”) on immunofluorescence staining Imaging is necessary to establish the extent of upper and lower airway involvement Sinus involvement may not be clinically apparent; CT or MRI can be helpful to identify sinus disease To assess the extent of lung involvement, HRCT can identify cavitary lung lesions and pulmonary hemorrhage as well as narrowing of the trachea, bronchi, and bronchioles Necrotizing granulomas are seen on respiratory tract biopsy.73 Microscopic Polyangiitis This small-vessel vasculitis typically affects the lungs, kidneys, GI tract, central and peripheral nervous systems, skin, and muscles Patients often present with constitutional symptoms, such as fever, fatigue, and weight loss Severe manifestations include pulmonary hemorrhage, GI bleeding or infarction, stroke, necrotizing glomerulonephritis, and renal failure The diagnosis is based primarily on clinical features, but laboratory tests may also be helpful Perinuclear ANCAs (pANCAs) are present in approximately 65% of patients with MPA, particularly for the neutrophil component myeloperoxidase (MPO) However, these antibodies can be present in other rheumatologic diseases, such as SLE or GPA, and in conditions such as inflammatory bowel disease.74 A biopsy of affected tissue (including lung, kidney, muscle, nerve, or skin) demonstrating pauci-immune, small-vessel vasculitis confirms the diagnosis Eosinophilic Granulomatosis With Polyangiitis Eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg-Strauss syndrome) is a rare small-vessel vasculitis that shares some features with the ANCA-associated vasculitides EGPA is thought to be in the spectrum of hypereosinophilic syndromes in which T helper (Th2)-mediated immune dysfunction can progress to necrotizing inflammation of blood vessels, often affecting the lungs.75 EGPA patients typically have a history of severe progressive asthma and allergic disease prior to overt vasculitis Other potential clinical manifestations include sinusitis, vasculitic rashes, peripheral neuropathy, myocarditis, GI involvement, and arthralgias In the case of pulmonary vasculitis leading to hemorrhage, pulmonary infiltrates can be seen on imaging Laboratory findings are significant for peripheral blood eosinophilia and elevated serum IgE levels These laboratory findings may be useful to monitor response to therapy but are nonspecific and not adequate for diagnosis ANCA positivity is observed in less than half of affected patients.75 Definitive diagnosis is via biopsy of affected tissue that demonstrates extravascular granulomas and eosinophilic infiltrates Treatment of ANCA-Associated Vasculitis The treatment of ANCA-associated vasculitis (AAV) in children is derived primarily from adult studies that did not differentiate GPA from MPA Thus, the approach to treatment is largely the same for both disorders EGPA is often treated similarly Immunosuppressive therapy, including cyclophosphamide and highdose IV corticosteroids, reduces mortality and induces remission in the majority of patients Traditionally, cyclophosphamide has been given as induction therapy, either enterally (2 mg/kg per day) in severe, life-threatening cases, or IV in various dosing protocols.76 Recently, there has been increasing use of rituximab (375 mg/m2 weekly for doses or two 750 mg/m2 doses given weeks apart) as induction therapy for GPA, as it targets a subset of peripheral B lymphocytes thought to be involved in pathogenesis in this disease process Rituximab has similar efficacy for remission induction when compared to cyclophosphamide, especially in patients with relapsed disease.77 Early use of rituximab may obviate or lessen the need for cyclophosphamide, which is particularly important in young patients with concerns about future fertility Early research showed that plasmapheresis may improve survival in patients with pulmonary hemorrhage and also decrease the incidence of end-stage renal disease in AAV However, subsequent studies have not confirmed this, and further research into the role of plasmapheresis is ongoing.78,79 Azathioprine, methotrexate, or MMF is used for milder cases and for long-term maintenance therapy Anti-IL5 treatment has recently shown promise in the treatment of refractory EGPA.80 Medium-Vessel Vasculitis Kawasaki Disease KD is a childhood vasculitis characterized by acute onset of fever for at least days, conjunctival injection, cervical lymphadenopathy, rash, and extremity changes (erythema, edema, or desquamation) The disease has three phases: the acute febrile phase (10–14 days), subacute phase (2–4 weeks), and convalescent phase (months to years) The most serious complication of KD is coronary artery aneurysms, which occur most commonly in the subacute phase Patients younger than 12 months are at the highest risk for developing aneurysms but may not meet the full criteria for KD, often delaying diagnosis.81 Some children present with pericarditis or myocarditis; in severe cases, this may progress to congestive heart failure.82 Patients can also present with KD shock syndrome (KDSS), which can be difficult to distinguish from septic shock or toxic shock syndrome KDSS may be refractory to IVIG; patients may then require additional therapy.83 KD can also be complicated by MAS (discussed later) There is also an increased risk for acute myocardial infarction secondary to coronary artery aneurysms Thrombosis or rupture of coronary aneurysms leads to myocardial ischemia, which can occur many years after the KD diagnosis, even in adulthood.84 Giant aneurysms (.8 mm in diameter) have the poorest prognosis In severe cases, surgical intervention for bypass grafting has been successfully performed in children.85 ESR and CRP are usually markedly elevated in KD Once IVIG has been administered, ESR will be falsely elevated and is 1258.e1 eTABLE 106.2 Pulmonary-Renal Syndromes Other Organ System Involvement Laboratory Findings Pauci-immune necrotizing glomerulonephritis Sinus, airways Usually cANCA positive (PR3) Pulmonary hemorrhage Pauci-immune necrotizing glomerulonephritis Skin, CNS Usually pANCA positive (MPO) Goodpasture syndrome Pulmonary hemorrhage Anti-GBM-positive glomerulonephritis None Anti-GBM positive SLE Pulmonary hemorrhage Proliferative or membranous changes; marked immune complex deposition Multisystem disease ANA positive, anti-dsDNA positive, anti-Sm positive, low complements Diagnosis Pulmonary Findings Renal Findings GPA Cavitating lung lesions, pulmonary hemorrhage MPA ANA, Antinuclear antibody; ANCA, antineutrophil cytoplasmic antibodies; anti-Sm, anti-Smith; cANCA, cytoplasmic ANCA; CNS, central nervous system; GBM, glomerular basement membrane; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; MPO, myeloperoxidase; pANCA, perinuclear ANCA; PR3, proteinase-3; SLE, systemic lupus erythematosus CHAPTER 106 Pediatric Rheumatologic Disease no longer a reliable marker of inflammation; thus, CRP is the best marker of ongoing disease activity Platelet counts may initially be low but can rise to more than 1,000,000/mL Anemia and elevated transaminases are also common Serial echocardiography is the best way to monitor the coronary vessels for signs of inflammation, dilation, or aneurysms Treatment of KD Like HSP, KD is a self-limited disease Thus, the primary indication for treatment is prevention of coronary artery aneurysms Prompt identification and treatment of KD with IVIG (2 g/kg, maximum dose 70 g) and high-dose aspirin (80–100 mg/kg per day divided times daily) usually helps prevent aneurysm formation Ideally, these should be given within the first 10 days of illness However, there may still be benefit to administering IVIG outside of this window for patients in whom diagnosis is delayed Long-term use of low-dose aspirin (3–5 mg/kg per day) is recommended once the acute illness is resolved for antiplatelet effect.86 Up to 20% of cases are refractory to IVIG, defined as continued fevers more than 24 to 36 hours after treatment.87 In these cases, IVIG should be repeated High-dose corticosteroids and antitumor necrosis factor-a (anti-TNF-a) agents, such as infliximab, are often used as adjunctive salvage therapy The optimal role and timing for administration of these therapeutics are currently under investigation Predictors of poor response to IVIG include young age at diagnosis, hyponatremia, thrombocytopenia, elevated neutrophil count, high AST, and high CRP.88 Patients who are identified as potential poor responders to IVIG may benefit from early administration of steroids as part of initial therapy.89 In cases complicated by myocarditis, supportive care, including inotropes and diuretic therapy, may be necessary Anticoagulation should be considered in the setting of large aneurysms to prevent further cardiovascular sequelae.90 Polyarteritis Nodosa Polyarteritis nodosa (PAN) is a systemic vasculitis affecting medium- to small-sized vessels It can be precipitated by an infection, although the classic association with hepatitis B observed in adults is rare in children Certain patients may have an underlying genetic predisposition to the condition, with several recently identified monogenic diseases that present with necrotizing vasculitis.91 PAN is rare in childhood but should be considered in any child presenting with unexplained fever, rash, hypertension, and abdominal pain Skin manifestations vary, including painful subcutaneous nodules, purpura, petechiae, or patchy edema Muscle tenderness, arthritis, and arthralgia may also occur GI vasculitis usually presents with abdominal pain, hemorrhage, necrosis, or perforation CNS features can be severe and include psychosis, seizures, strokes, or neuropathy Cardiac involvement, including coronary arteritis, is more common in children.92 There are no associated antibody tests in PAN Nonspecific markers of inflammation, such as ESR and CRP, are often elevated Urinalysis may be helpful in detecting renal involvement A biopsy of affected tissue (typically, muscle, nerve, skin, kidney, or GI tract) can be diagnostic, demonstrating necrotizing arteritis of medium- to small-sized muscular arteries Angiography is important for diagnosing and assessing the extent of vessel involvement Conventional angiography is the gold standard, but there is an increasing role for less invasive imaging, such as CT or magnetic resonance angiography Smaller vessel involvement may not be visualized on imaging; thus, biopsy of the affected area may be necessary if imaging is 1259 negative and there is a high clinical index of suspicion for PAN Characteristic pathologic findings include vessel stenosis, occlusion, and aneurysms The initial treatment approach is similar to that used in GPA or MPA, with cyclophosphamide and glucocorticoid induction Cases refractory to first-line therapies or with identified ADA-2 mutations may benefit from anti-TNF-a agents.93 In patients with vascular abnormalities, antiplatelet therapy may be necessary Large-Vessel Vasculitis Takayasu Arteritis TA causes granulomatous inflammation of the aorta and its major branches In the early inflammatory phase, patients present with fever, fatigue, weight loss, headaches, abdominal pain, and hypertension Subsequent vascular changes—such as mural thickening, aneurysm formation, and stenosis—lead to end-organ ischemia Symptoms and signs can include absent pulses, unequal blood pressures between limbs, angina, hemoptysis, abdominal pain and bloody diarrhea (due to mesenteric artery involvement), abdominal bruit, visual changes, claudication, myocardial infarction, renal artery hypertension, encephalopathy, and stroke Ultrasonography, magnetic resonance angiography, and CT angiography are all helpful for diagnosing or managing TA, establishing the severity and extent of disease, and monitoring response to therapy In some cases, a conventional angiogram may be necessary Laboratory markers are nonspecific The treatment approach is the same as for GPA, but there is an increasing role for anti-TNFa therapy, particularly infliximab.94 Methotrexate may also be used Angioplasty and stent placement have been successful and improve survival rates in pediatric TA.95 In severe cases, aortic reconstruction is necessary Close consultation with pediatric cardiology and vascular specialists is necessary Primary Vasculitis of the Central Nervous System Primary vasculitis or angiitis of the CNS is characterized by isolated inflammation of vessels in the CNS with no other organ involvement Vessels involved may range in size from small to large In pediatric patients with small-vessel disease, a common presenting feature is seizure, but patients may also present with headaches and cognitive impairment.96 In large-vessel disease, patients may present with stroke, headache, cranial neuropathy, or movement disorders The diagnosis can be considered in a child with unexplained CNS deterioration—especially if other diagnoses, such as infection or metabolic conditions, have been excluded.97 Angiography can be helpful for diagnosis but may not detect small-vessel disease, in which case a brain biopsy may be required for definitive diagnosis Aggressive treatment with high-dose corticosteroids and cyclophosphamide has been shown to improve survival.96 MMF or azathioprine is typically used for long-term maintenance therapy Autoinflammatory Syndromes Key Points Autoinflammatory syndromes are diagnosed by a characteristic constellation of symptoms and/or identified genetic mutations These syndromes are unlike many autoimmune diseases that present later in childhood or adolescence disorders of the innate immune system may present early in life, even in the neonatal period 1260 S E C T I O N X I Pediatric Critical Care: Immunity and Infection In the past decades, the term autoinflammatory syndromes has been used to describe an emerging family of related disorders.98 Autoinflammatory disorders are characterized clinically by repeated and unprovoked episodes of fevers and systemic inflammation affecting multiple organs The pathologic lesions differ between specific disorders but generally affect the innate immune system and lead to hypercytokinemia occurring in the absence of autoreactive T cells and autoantibodies The earliest described disorders included the monogenic periodic fever syndromes such as familial Mediterranean fever and TNF receptor–associated periodic syndrome However, clinicians now recognize autoinflammation as a key component of multiple conditions such as sJIA, PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis), chronic recurrent multifocal osteomyelitis, Behỗet disease, and Crohn disease.99 The clinical presentation can be variable; however, in the presence of unexplained persistent fevers and organ inflammation not responding to usual first-line measures, autoinflammatory disorders should be considered Treatment often requires the use of biological therapeutics, especially IL-1 or IL-6 inhibitors (anakinra/canakinumab and tocilizumab).100 A brief overview of several of the more well-recognized monogenic autoinflammatory disorders is presented in eTable 106.3.98,99,101,102 Systemic sclerosis and mixed connective tissue disease are discussed online at ExpertConsult.com Rheumatologic Diseases: Conditions and Complications in the Intensive Care Unit There are many serious complications of pediatric rheumatologic diseases and complications associated with the treatment of these conditions This section provides a more focused discussion of the conditions and complications that are most relevant in the intensive care setting Macrophage Activation Syndrome Key Points MAS may occur at the initial presentation or during the course of disease in sJIA, SLE, or other rheumatologic disease A ferritin level should be checked in an acutely ill ICU patient not responding to usual therapies Significant hyperferritinemia is concerning for MAS and is associated with increased risk of morbidity and mortality Common triggers of MAS include infections, disease flares, and medication changes Early aggressive treatment of MAS with high-dose steroids and IL-1 inhibition is critical to prevent mortality MAS is a severe, life-threatening complication of childhood rheumatologic disease, primarily sJIA It may also occur in the setting of infection and malignancy MAS is a form of secondary HLH—a systemic inflammatory storm characterized by overwhelming expansion and activation of T lymphocytes and macrophages, with decreased natural killer (NK) and cytotoxic T-cell function leading to multiorgan failure In rheumatologic disease, MAS may be present at the time of diagnosis, disease flare, change in medical therapy, or with intercurrent infection Diagnosis can be difficult, as findings can be confused with infection and sepsis or acute exacerbations of the underlying disease process.103 Therefore, a high index of suspicion is necessary MAS can start with no apparent clinical symptoms, but rather a mild trend of abnormal changes in the laboratory tests, and then rapidly progress to fullblown, severe disease Patients typically become ill and then become more acutely ill with unremitting high fever (different from the quotidian pattern of sJIA), lymphadenopathy, hepatosplenomegaly, cytopenias, and coagulopathy, and may even have altered mental status The skin may demonstrate characteristic sJIA rash along with petechiae, ecchymosis, and mucosal bleeding Severe manifestations include seizures, coma, and gastrointestinal bleeding, as well as heart, lung, or kidney failure Estimates of the mortality rate associated with MAS range from 4% to 15%.103 Laboratory evaluation typically reveals cytopenias (at least two of three cell lines), elevated transaminases, coagulopathy, elevated triglycerides, elevated lactate dehydrogenase, elevated d-dimers, and, most significantly, an elevated ferritin level (often 10,000 ng/mL) A falling ESR, especially with a high CRP, is concerning for MAS and is secondary to low fibrinogen in the setting of consumptive coagulopathy NK cell activity is usually low or absent The pathognomic feature of MAS is hemophagocytosis on bone marrow aspirate or biopsy, although this may not be present early in the disease course Hemophagocytosis is also not specific for MAS; it can be found in other HLH disorders and in the setting of infection Various classification criteria and scoring systems for diagnosing MAS complicating rheumatologic diseases have been developed but problems with diagnosis still remain.104 Differentiating MAS from flares of sJIA activity can be difficult If MAS is the initial presentation of sJIA, it can be difficult to distinguish from other forms of secondary HLH (i.e., EBV-related) or primary HLH Current treatment strategies for rheumatologic diseases have also complicated the diagnosis of MAS Patients on medications such as canakinumab and tocilizumab are less likely to have fevers and have lower ferritin and CRP, decreasing the sensitivity of any objective diagnostic tool.105 In clinical practice, the trend of laboratory values over time may be more important than specific cutoffs Hyperferritinemia remains one of the most readily available markers of MAS, but ferritin levels may be normal or only modestly increased initially and should be followed serially for abrupt changes Hyperferritinemia is not entirely specific for MAS; mild to moderate elevations of ferritin (500–1000 ng/mL range) have been associated with severe infections, blood transfusions and underlying liver disease However, extremely elevated ferritin (.3000 ng/mL) levels have been associated with increased risk of morbidity and mortality in a dose-dependent fashion regardless of underlying etiology.106 Alternative biomarkers for MAS—such as soluble IL-2 receptor, CD163, and IL-18—are promising candidates However, these tests are not universally available and generally have long turnaround times, limiting their clinical utility.107 Secondary cytokine storms, known as cytokine release syndrome (CRS), are increasingly reported as a complication of advanced immunotherapeutic regimens for malignancies such as chimeric antigen receptor (CAR) T-cell therapy for relapsed acute lymphoblastic leukemia.108 In these patients, peripheral blood cytokine profiles may help to identify appropriate therapeutic targets However, the use of cytokine panels in routine clinical care remains controversial and is considered investigational Familial or primary HLH is an autosomal recessive disorder linked to mutations in genes associated with perforin-mediated cytolysis, including mutations of the perforin or MUNC 13-4 gene Genetic testing can differentiate the two disorders but often takes weeks to perform Risk factors for familial HLH include young age (younger than years), significant CNS disease, more ... disease in AAV However, subsequent studies have not confirmed this, and further research into the role of plasmapheresis is ongoing.78,79 Azathioprine, methotrexate, or MMF is used for milder cases... aneurysm formation Ideally, these should be given within the first 10 days of illness However, there may still be benefit to administering IVIG outside of this window for patients in whom diagnosis is... GPA, as it targets a subset of peripheral B lymphocytes thought to be involved in pathogenesis in this disease process Rituximab has similar efficacy for remission induction when compared to cyclophosphamide,