Early in the course of a vasculitis, nonspecific findings reflecting systemic inflammation

• fever

• malaise

• fatigue

• failure to thrive

• elevated acute-phase reactants

As vessel damage progresses…

• evidence of vascular compromise

• elevation of markers of vascular injury

– von Willebrand’s factor antigen,

– pentraxin 3

• distinctive autoantibodies

– especially antineutrophil cytoplasmic antibodies [ANCA]

– or anti-endothelial antibodies

‘‘Catch-22’’

• becomes more evident only after severe and irreversible morbidity is present.

• little information suggestive of vasculitis when the diagnosis needs to be made.

Size of vessel

• Large vessels to the extremities – claudication.

• visceral vessels.

– hypertension (renal arteries),

– abdominal pain (mesenteric and celiac axes),

– chest pain (aortic or coronary artery involvement),

– neurologic symptoms (focal neurologic deficits or neuropathic pain).

Inflammation of smaller arteries and arterioles

Symptoms in richly vascularized organs.

Skin involvement.

livedo reticularis,

purpuric (generally palpable) or nonblanching lesions,

palmar or plantar rashes.

Pulmonary, renal, and gastrointestinal arterial.

hemoptysis,

hematuria,

hypertension.

abdominal pain, or melena.

Capillary and venous.

less of an acute emergency than arteritis.

Clues to Dg

• history and general physical examination

• recent illnesses, in particular infections,

• over-the-counter drugs

• travel

• family history

• All pulses must be palpated carefully

• Allen’s tests

• auscultation for bruits,

• blood pressures in all four extremities

• skin nodules

• ocular fundi and nailbed capillaries

Laboratory studies specific for the diagnosis of vasculitis are not yet available.

• CBC

• ESR

• C-reactive protein [CRP])

• Immunoglobulines

• ANCA

• Von Willebrand factor antigen

•

• PTX3, a pentraxin expressed by endothelial cells and monocytes

Imaging procedures

large- or medium-sized vessels

• Vascular imaging

• Doppler US studies

• CT or MRI angiograms

Histopathologic demonstration of vascular inflammation

• The reference standard for diagnosing a vasculitis.

• Inaccessibility of lesions or patchiness of the vascular involvement.

Classification

• Clinical manifestations.

• Size of blood vessels involved.

• Histology of vascular damage.

• Presumed disease pathogenesis.

An etiologic classification

• TNF seems to be effective in TA

• But apparently is less so in Wegener’s

• Rituximab effective in ANCA-associated vasculitides

Classification of pediatric vasculitides

• Primary vasculitides

• Large vessel diseases

• Takayasu arteritis

• Giant cell (temporal) arteritis

Medium vessel disease

• Polyarteritis nodosa

– Cutaneous

– Systemic

• Cogan’s syndrome

• Kawasaki disease

Small-vessel disease

• Henoch-Schonlein purpura

• Hypersensitivity vasculitis

• Primary angiitis of the central nervous system

• ANCA-positive vasculitis

• Wegener’s granulomatosis

• Microscopic periarteritis

• Churg–Strauss syndrome

Secondary vasculitides

• Infection-related vasculitis

• Hepatitis viruses

• Herpes viruses (EBV, CMV, varicella)

Vasculitis secondary to connective tissue disease

• Dermatomyositis,

• Systemic lupus erythematosus,

• Rheumatoid arthritis

• Hypocomplementemic uticarial vasculitis

• Drug hypersensitivity –related vasculitis

•

• Malignancy-related vasculitis

•

• Post–organ transplant vasculitis

•

• Pseudovasculitic syndromes

– Myxoma

– Endocarditis

– Sneddon syndrome

Vasculitides with strong genetic component

• Periodic fever syndromes.

• Behet’s disease.

Modified from Hunder GG, Wilking AP.

Classification of the vasculitides.

in children. UpToDate, 2005. Available at: http://www.utdol.com/application/search.asp.

Epidemiology

• Primary vasculitis among children < 17 years of age was 20.4/100 000,

• Henoch-Schfnlein purpura (HSP) the most prevalent.

Pathogenesis

Generally not understood

1. Humoral factors:

• Vascular damage secondary to specific antibodies is best demonstrated in the ANCA-associated vasculitides

• Activate neutrophils, causing vascular inflammation,

• Antiendothelial antibodies are also present in a variety of vasculitides

2. Immune complexes:

• The size, charge, and immunoreactivity of immune complexes help explain aspects of the pathogenesis of HSP and cryoglobulinemic vasculitis

• Similarly, PAN associated with hepatitis B or C seems to be triggered by inflammation incited by immune complexes deposited upon vessel walls

3. T lymphocytes attracted to damaged or infected endothelium

• Suppression of autoreactive lymphocytes.

• T-regulatory cells - breaking of tolerance and development of autoimmunity.

• Biopsy samples from different types of vasculitis demonstrate different populations of cells invading vessel walls (eg, macrophages in KD and eosinophils in Churg–Strauss syndrome [CSS])

4. The characteristic predilection of different vasculitides for different anatomic sites

• Remains unexplained,

• Depend on a variety of factors, including.

– specificity of the triggering antigen,

– regional variations in cell surface receptors,

– and unidentified contributions of surrounding tissues.

Recluse Spiders

• Genus Loxosceles

• Family Sicariidae

• Six-eyed sicariid spiders

• Necrotic arachnidism

• Loxoscelism “gangrenous spot of Chile"

• At least 56 species

• One from the Mediterranean region

• Inside houses

• Hiding in the folds of clothing, shoes, or underneath boxes in storage rooms

Henoch-Schonlein purpura

• IgA immune complex–mediated small-vessel.

• leukocytoclastic vasculitis.

• Triad of:

– nonthrombocytopenic palpable purpura,

– colicky abdominal pain.

– arthritis.

• May progress to chronic renal failure in 1%.

A wide variety of infections may trigger HSP.

• Group A streptococcus is the most common precipitant, (one third).

• Bartonella,

• Haemophilus parainfluenza, and numerous vaccines and drugs.

In rare cases, CNS or respiratory lesions may.

lead to hemorrhage with serious sequelae.

HSP

• Slightly more common in boys

• More commonly during winter and spring

• May begin as urticaria, progresses to dramatic purple, nonblanching lesions

Predilection to lower body

• Activation of the alternate pathway of complement by large IgA containing immune complexes.

• Gravity causes immune complexes to deposit and incite inflammation in dependent areas.

Gastrointestinal involvement

• Ranges from colicky abdominal pain to profuse bleeding, intussusception (typically ilio-ilial) and perforation

• Pancreatitis, cholecystitis, and protein-losing enteropathy

Renal disease

• In most cases, the first days or weeks.

• First 3 months of the illness in 97% of patients.

Risk factors:

• age over 47 years,

• gastrointestinal bleeding,

• purpura of more than 1 month’s duration,

• factor XIII activity < 80% of normal,

• factor XIII concentrate treatment.

Recurrence

• HSP recurs in about one third of patients,

• especially those with nephritis.

• first 4 to 6 months.

Outcome

• Patients demonstrating both nephritic and nephrotic changes at greatest risk.

• Renal biopsy is useful for confirming the extent and severity of nephritis and planning treatment:

• The higher the percentage of glomeruli with crescents, the more likely is development of end-stage renal disease.

• High serum levels of nitric oxide and urinary nitrate excretion.

• Increased urinary excretion of the tubular proteins N-acetyl b-d-glucoseaminidase and a-1-microglobulin also proved useful in identifying.

• Patients at higher risk of long-term renal disease.

• 1% to 5% of HSP patients develop some degree of chronic renal disease.

Acute hemorrhagic edema of infancy

• Fever,

• Large purpuric lesions, and edema.

• A self-limited condition,

• Likely to resolve within weeks.

Hypersensitivity vasculitis

Clinical features.

• Fever,

• Urticaria,

• Lymphadenopathy,

• Arthralgias,

• low serum complement levels, and elevated ESR.

• Low serum concentrations of C3 and C4 and the absence of IgA.

• deposition in vessel walls help to distinguish this entity from HSP.

Therapy of HSP is primarily supportive

• NSAIDs, no evidence of increased likelihood of GI hemorrhage in HSP.

• Use of steroids continues to be controversial.

Prednisone

• Prednisone, 2 mg/kg/day,

• Relieve symptoms rapidly in most cases,

• Must avoid excessively rapid tapering of the steroids,

• precipitate a flare of symptoms

Immunosuppressive agents

• Such as cyclophosphamide or azathioprine,

• Reserved for children with biopsy-proven crescentic glomerulonephritis

• other life-threatening complications such as cerebral or pulmonary hemorrhage

Kawasaki disease

• Although KD or mucocutaneous lymph node syndrome it is a self-limited condition, with fever and manifestations of.

• Acute inflammation lasting for an average of 12 days without therapy.

• Diagnosed by clinical criteria not histology or angiography.

Kawasaki disease

• 80% to 90% of >fifth birthday.

• 1.5% of untreated children died from KD.

• More than 140,837 cases of KD have been registered in Japan since its initial description in 1967.

Kawasaki disease

• susceptibility of different ethnic groups to KD

• Genetic factors,

• polymorphisms of chemokines

• and TNF receptors

• variations in HLA haplotypes

•

• Overall, Asians are affected 5 to 10 times as frequently as whites;

• blacks and Hispanics have an intermediate risk

The cause of KD remains unknown.

Criteria for diagnosis of Kawasaki disease

• Fever lasting 5 days or more (4 days if treatment with IVIG

• eradicates fever) plus at least four of the following clinical signs

• not explained by another disease process

Modified from Centers for Disease Control. Revised diagnostic criteria
for Kawasaki disease. MMWR Morb Mortal Wkly Rpt 1990;
39(No. 44-13):27–8.

1. Bilateral conjunctival injection (80%–90%)

2. Changes in the oropharyngeal mucous membranes (including

one or more of the following symptoms: injected or fissured

lips, strawberry tongue, injected pharynx) (80%–90%)

3. Changes in the peripheral extremities, including erythema

or edema of the hands and feet (acute phase) or periungual

desquamation (convalescent phase) (80%)

4. Polymorphous rash, primarily truncal; nonvesicular (N 90%)

5. Cervical lymphadenopathy: anterior cervical lymph note at

least 1.5 cm in diameter (50%)

Pathologically, however, KD seems to be unique:

• Macrophages and IgA-producing plasma cells in the vessel walls, features recognized in no other conditions.

• Many aspects of KD suggest that it is caused by a transmissible agent.

• A synthetic monoclonal IgA antibody was found to bind to an unidentified cytoplasmic.

• Component of macrophages within the coronary arteries of 9 of.

• 12 fatal cases of KD but in none of 10 controls.

Kawasaki disease

• Similar binding to the respiratory epithelium of proximal bronchi was noted in 77% of fatal cases, never in controls.

• One interpretation is that a particular respiratory pathogen may be associated with KD.

Kawasaki disease

Many epidemiologic data also support the.

theory that KD is triggered by a transmissible.

agent or agents;

• Boys > 50% more commonly than girls, a feature typical of infectious diseases.

• The average age of children with KD is.

• about 2 years, and occurrence beyond late childhood is extremely rare.

nonetheless

• viruses (eg, Epstein–Barr virus, parvovirus, HIV-2) or bacterial toxins (eg, streptococcal erythrogenic toxin, staphylococcal toxic shock toxin) account for the majority of cases have not been substantiated

• Thus, many researchers now believe that KD represents a final common pathway of immune-mediated vascular inflammation following a variety of inciting infections.

•

Clinical manifestations

• Guidelines for the diagnosis of KD were established by Tomisaku Kawasaki 1967.

• Diagnosis requires the presence of fever lasting 5 days or more without any other explanation, combined with at least four of five manifestations of mucocutaneous inflammation.

• Children who do not meet the criteria may have an incomplete or atypical form of KD.

• at least 10% of children who develop coronary artery aneurysms never meet criteria for KD

• Fever is probably the most consistent manifestation of KD.

• It reflects elevated levels of proinflammatory cytokines such as TNF and interleukin (IL)-1 that are also thought to mediate the underlying vascular inflammation.

• The fever is typically hectic, minimally responsive to antipyretic agents, and remains > 38.58C during most of the illness.

• Bilateral nonexudative conjunctivitis is present in as many as 90% of cases.

Bulbar injection

• Begins within days of the onset of fever, and the eyes have a brilliant erythema that spares the limbus.

• Children are also frequently photophobic, and anterior uveitis may develop.

• Slit-lamp examination may be helpful in ambiguous cases; the presence of uveitis.

Cracked, red lips

• Cracked, red lips and a strawberry tongue are characteristic.

• caused by sloughing of filiform papillae and denuding of the inflamed glossal tissue.

• Discrete oral lesions, such as vesicles or ulcers, as well as tonsillar exudate, suggest a viral or bacterial.

cutaneous manifestations

• Polymorphous rash typically begins as perineal erythema and desquamation,

• followed by macular, morbilliform,

• or targetoid lesions of the trunk and extremities.

• Vesicular or bullous lesions are rare.

Changes in the extremities

• generally the last manifestation of KD to develop.

• an indurated edema of the dorsum of the hands and feet and.

• a diffuse erythema of the palms and soles.

The convalescent phase of KD

• sheetlike desquamation that begins in the periungual region of the hands and feet and by linear nail creases (Beau’s lines).

The convalescent phase of KD

• one third of children have arthritis.

• The arthritis is typically a small joint polyarthritis during the first week of illness, followed by a large joint pauciarthritis.

• It never persists beyond 1 to 2 months, nor is it erosive.

Cervical lymphadenopathy

• is the least consistent.

• absent in as many as 50% of children with the disease.

• involve primarily the anterior cervical nodes overlying the sternocleidomastoid muscle.

• Children suspected of having KD who have fewer than four signs of mucocutaneous inflammation may have incomplete or atypical KD.

•  .

• most incomplete and atypical in the youngest patients.

• In a retrospective review of 45 cases of KD,

• 5 of 11 infants (45%) had atypical disease,

• compared with 4 of 33 older children (12%)

• Coronary artery complications occurred in 64% infants compared with 9% older children (and occurred in all five infants with incomplete disease).

Japanese nationwide survey of KD in 1995 and 1996

• Infants < 1 year of age had an odds ratio of 1.54 for developing cardiac sequelae.

• Similarly, in a recent retrospective survey, the rate of treatment failure was 8.5% in patients under 12 months of age.

• compared with a 1.8% incidence of coronary artery abnormalities in those at > 12 months of age.

Japanese nationwide survey of KD in 1995 and 1996: 140,837

• The incidence rates per 100,000 children of <5 years old were 102.6.

• Recurrent cases 3–5%.

• Peak age of incidence 1 year of age.

• 80–85% of cases < 5 years.

• Male to female ratio is 1.5:1.

Epidemiology of Kawasaki Disease in Ontario, Canada, 1995-1997

• 408 cases - 81% typical KD

• annual incidence (per 100,000) by age was 13.6 in <5 yrs

• males vs. females of 1.73

Epidemiology of Kawasaki Disease in Ontario, Canada, 1995-1997

• Coronary artery involvement included ectasia in 35%.

• non-giant aneurysms in 9%.

• giant aneurysms (>8 mm) in 1.4%.

• with ventricular dysfunction noted in 2.7%.

Laboratory

• Elevation of acute phase reactants (eg, CRP, ESR, and alpha-1 antitrypsin),

• Leukocytosis, and a left shift.

• By the second week of illness, platelet counts > 1,000,000/mm3 in the most severe cases.

• Normocytic, normochromic anemia;

• urinalysis - white blood cells on microscopic.

• The pyuria is of urethral origin and therefore will be missed on urinalyses obtained by bladder tap or catheterization.

•  .

• Renal involvement may occur in KD but is uncommon.

• elevated transaminase levels or mild hyperbilirubinemia caused by intrahepatic congestion.

• Cerebrospinal fluid (CSF) typically displays a mononuclear pleocytosis without hypoglycorrhachia or elevation of CSF protein.

• Review of 46 children with KD found that 39% had elevated CSF white cell counts.

• Obstructive jaundice from hydrops of the gallbladder.

Differential diagnosis

• KD is most commonly confused with infectious exanthems of childhood

• Measles, echovirus, and adenovirus may share many of the signs of mucocutaneous

Differential diagnosis

• Toxin-mediated illnesses, especially b hemolytic streptococcal infection and toxic shock syndrome,

• Rocky Mountain spotted fever and leptospirosis

• Drug reactions such as Stevens–Johnson syndrome or serum sickness

• Systemic-onset juvenile idiopathic arthritis

• Mercury hypersensitivity reaction (acrodynia)

Therapy

IVIG and aspirin.

Markers of increased risk of developing coronary artery aneurysms,

• age under 1 year,

• signs of severe systemic inflammation

• consumptive coagulopathy,

• Aspirin was the first medication used for treatment of KD because of its antiinflammatory and antithrombotic effects

• Therapy within the first 10 days of illness reduces the incidence of coronary artery aneurysms by more than 70%

• IVIG therapy also largely eliminates the

– development of giant coronary artery aneurysms (more than 8 mm in diameter), which are associated with the highest risk of morbidity and mortality,

– and rapidly restores disordered lipid metabolism and depressed myocardial contractility to normal

• Aspirin traditionally is given initially in relatively high doses to achieve an anti-inflammatory effect; doses of 30 mg/kg/day to more than 80 mg/kg/day in four divided doses have been used during the acute phase of illness.

• Subsequently, aspirin is administered in low doses (3 to 5 mg/kg/day) for its antiplatelet action.

• No study has demonstrated long-term benefit from the use of aspirin, and a recent trial found no differences in outcomes between children treated with IVIG alone and those who also received aspirin

aspirin

• 100 mg/kg/day.

• Once fever resolves, patients receive a dose of 3 to 5 mg/kg/day.

• Treatment with aspirin is continued until laboratory studies (eg, platelet count and sedimentation rate) return to normal, unless coronary artery abnormalities are detected by echocardiography.

corticosteroids

• A retrospective survey of the records of almost 300 children treated with or without steroids between 1982 and 1998.

• and two open, randomized, prospective trials found that patients who received corticosteroids in addition to IVIG had shorter durations of fever and more rapid decrease in inflammatory markers than those in the standard-therapy group.

Corticosteroids

• In all reports, corticosteroid therapy has been well tolerated, with no significant adverse effects.

• At present, most clinicians who specialize in the care of KD use pulsed doses of intravenous methylprednisolone (IVMP) in children whose inflammation persists despite at least two doses of IVIG.

IVMP

• A trial supported by the National Institutes of Health comparing outcomes in children who received initial therapy with IVMP plus IVIG versus IVIG alone has completed enrollment.

• Results of this trial soon should supply definitive information concerning the potential role of steroids in the primary treatment of KD.

Re-treatment

• Fever persists or returns 48 hours after the start of initial treatment with IVIG in 10% to 15% of patients

• Persistent or recrudescent fever is particularly concerning, indicating ongoing vasculitis with increased risk of developing coronary artery aneurysms (12.2% versus 1.4% in one analysis)

• In another study, persistent fever was the only factor that predicted subsequent development of aneurysms

• It is extremely important not to dismiss mild temperature elevations in children with KD;

• Patients who remain febrile after the first dose of IVIG are usually treated with a second and perhaps even a third dose of IVIG, 2 g/kg

• This practice is based on the apparent dose–response effect of IVIG

• most specialists treat children who have not responded to IVIG and still have active KD with one to three daily doses of pulsed methylprednisolone (30 mg/kg)

• If this treatment is ineffective, a single dose of infliximab, 5 mg/kg, may be beneficial

Additional considerations

• An echocardiogram should be obtained early in the acute phase of illness and 6 to 8 weeks after onset to confirm the efficacy of treatment

• Children with coronary artery abnormalities receive long-term antithrombotic therapy with aspirin, dipyridamole, or other agents, as well as regular cardiac evaluations.

• Coronary artery dilatation of less than 8 mm regresses over time, and most smaller aneurysms fully resolve by echocardiogram.

• Healing is by fibrointimal proliferation, often accompanied by calcification, and vascular reactivity does not return to normal despite grossly normal appearance

• Children should thus be followed indefinitely after KD, a point highlighted by a report of the sudden death of a 3.5-year-old child 3 months after dilated coronary arteries had regained a normal echocardiographic appearance

• Autopsy revealed obliteration of the lumen of the left anterior descending coronary artery by fibrosis, with evidence of ongoing active inflammation in the epicardial arteries.

• Children with severe KD who develop coronary occlusion may experience myocardial infarction, arrhythmias, or sudden death, and those who develop peripheral artery occlusion may experience ischemia or gangrene.

• At least one report suggests a potential role for abciximab, a monoclonal antibody that inhibits platelet glycoprotein IIb/IIIa receptor.

• increased resolution of aneurysms in patients with KD who received abciximab compared with those who received conventional treatment.

• Overall, with modern treatment and cardiologic follow-up, the prognosis of children with KD is excellent.

• Long-term follow-up of children without persistent coronary artery abnormalities in Japan has demonstrated no increase in morbidity or mortality after 25 years.

• In fact, studies suggest that fear of a cardiac event is more disabling than actual medical problems in most children who have had KD.

• Thus, caregivers should be particularly careful to reassure families when appropriate.

Polyarteritis nodosa

• A systemic necrotizing vasculitis.

• With aneurysm formation.

• Medium or small arteries.

• Historically as the first noninfectious cause of vascular damage.

1866, Kussmaul and Maier’s

• At least one third of children with PAN, have a more limited form, restricted largely to the skin and joints.

• is most commonly associated with hepatitis B or C infections.

• pediatric PAN is quite rare,

• peaks at 9 to 10 years of age,

• No clear genetic association.

• association with familial Mediterranean fever (FMF).

• Up to 1% of FMF patients develop PAN, milder than idiopathic disease.

Cutaneous PAN

• limited to skin and the musculoskeletal system.

• Post streptococcal pharyngitis.

• Livedo reticularis,

• maculopapular rash,

• painful skin nodules, panniculitis,

• brawny edema,

• Arthritis mostly affect the knees and ankles.

• Acute-phase reactants may be normal or elevated,

• Constitutional symptoms are generally mild.

• Tends to persist or relapse,

• Many patients require steroid-sparing agents for long-term management.

• Methotrexate or other immunosuppressive agents;

• TNF inhibitors have been reported to be effective, as well

• Penicillin prophylaxis

Systemic PAN

• Any muscular artery.

• Constitutional symptoms.

• A vast array of organ dysfunction.

• Palpable purpura, livedo, necrotic dermal lesions.

• Abdominal pain, arthritis/arthralgia, myositis/myalgia,

• Renovascular hypertension,

• Neurologic deficits,

• Pulmonary disease, coronary arteritis.

PAN DD

• Systemic-onset juvenile rheumatoid arthritis,

• KD,

• Dermatomyositis.

• Glomerulonephritis typically is not a feature of this condition.

Laboratory evaluation

• Anemia, leukocytosis, thrombocytosis, and elevated ESR, CRP, and immunoglobulins.

• A positive ANCA generally indicates pauci-immune glomerulonephritidies rather than PAN.

• Proteinuria, hematuria, and increases in serum urea nitrogen and creatinine levels are also common findings.

• Complement levels are normal.

The diagnosis usually requires tissue biopsy or radiologic documentation of vasculitis.

• Typical beading of vessels.

• Alternating areas of vascular narrowing and dilatation that give PAN its name.

• Pathologically this manifestation corresponds to segmental vascular involvement with nodule and aneurysm formation resulting from panmural fibrinoid necrosis.

• No overt complement or immunoglobulin deposition is seen.

Treatment

• High-dose steroids.

• Other immunosuppressive agents,

• daily oral or monthly intravenous doses of cyclophosphamide,

• Azathioprine, methotrexate, IVIG, and,

• TNF-inhibitors,

• A 4-year mortality rate under 5%.

Takayasu arteritis

• TA is the third most common form of childhood vasculitis

• The cause of TA remains unknown,

• a primarily T-cell–mediated mechanism

• granulomatous changes progressing from the vascular adventitia to the media,

• indistinguishable from those seen in giant cell arteritis and temporal arteritis

The diagnosis of TA is based on the distribution of involvement

• primarily the aorta and its branches—

• and the young age of patients,

• typically under 40 years

Takayasu arteritis

• childhood disease has been reported as early as the first year of life

• significant preponderance of female patients in children with TA,

• mean age of onset was 11.4 years,

• two thirds of the patients were female

Takayasu arteritis

• Signs and symptoms.

– hypertension,

– cardiomegaly,

– elevated ESR,

– fever, fatigue, palpitations,

– vomiting, nodules, abdominal pain,

– arthralgia,

– claudication,

– weight loss, and chest pain.

• The delay in diagnosis in children was 19 months.

Angiography the standard method used for diagnosis.

• CT and MR angiograms have proven to be as useful as traditional angiograms.

• MRI has the added advantage of revealing evidence of ongoing vessel wall inflammation.

•  .

• Laboratory markers may be entirely normal despite ongoing inflammation.

• Steroids

• cyclophosphamide,

• methotrexate,

• Azathioprine

• TNF-inhibitors

Primary angiitis of the central nervous system

• one of the most challenging diseases a physician might face,

• systemic manifestations of the disease are usually absent,

• acute-phase reactants are typically normal,

• and examination of CSF might be unrevealing as well

• high level of suspicion when children have even scanty suggestion of a vasculitis.

• A recent review 62 patients with childhood PACNS (cPACNS)

• Headache (80%) and

• focal neurologic deficits (78%)

• hemiparesis in 62%.

• Normal MRI together with normal CSF have high negative predictive value for cPACNS.

•

• 5% to 10% of cases of cPACNS, only a meningeal and brain biopsy proved the vasculitis.

•

• PACNS may be rapidly progressive and neurologically devastating,

Treatment invariably includes

• corticosteroids and a potent immunosuppressive agent, usually cyclophosphamide.

• methotrexate or azathioprine for maintenance therapy, excellent results

Anti-neutrophil cytoplasmic antibody-associated vasculitides Wegener’s granulomatosis Wegener’s granulomatosis (WG)

• is uncommon in children.

• a necrotizing granulomatous inflammation of small- to medium-sized vessels

• kidneys and upper and lower respiratory tracts.

• biopsies - a microscopic pauci-immune polyangiitis.

• cANCA directed against PR-3.

• nasal and sinus involvement were seen in 100%,

• respiratory disease in 87%,

• arthralgias, ocular findings, or skin or renal involvement each in just over 50%,

• gastrointestinal disease in 41%,

• and CNS involvement in 12%

• subglottic stenosis in almost 50%

cause of WG

• ANCA most likely stabilize adherence of rolling neutrophils to endothelium and activate neutrophils and monocytes to undergo an oxidative burst.

• Activation of phagocytic cells causes increased expression of proinflammatory cytokines (eg, TNF-a and IL-8), with resultant localized endothelial cell cytotoxicity

Upper respiratory symptoms

• Epistaxis, sinusitis, otitis media, or hearing loss.

• Cough, wheezing, dyspnea, and hemoptysis.

• Kidney involvement may initially be asymptomatic.

• Chest radiographs - one third have radiographic abnormalities in asymptomatic children

• diagnosis of WG relies heavily on biopsy

• Necrotizing granulomatous vascular inflammation is strongly suggestive

• cANCA targeted against PR-3 is positive in most patients

• Although this autoantibody is highly specific, it may be found in other diseases, such as cystic fibrosis,

• ANCA titer should not replace a tissue biopsy.

• role of monitoring of ANCA titers as a marker of disease activity is controversial.

• Without immunosuppressive therapy, WG is rapidly progressive and even fatal.

– cyclophosphamide,

– azathioprine, methotrexate, and, more recently, mycophenolate mofetil and.

– TNF-a blockers.

– Preliminary data showed that the anti-TNF agent etanercept did vasculitis in children.

•  .

• but infliximab apparently was effective.

• trimethoprim/sulfamethoxazole has been shown to be beneficial.

• perhaps by suppressing upper respiratory infections that might activate vascular inflammation.

Microscopic polyangiitis

A necrotizing vasculitis of the small vessels without.

granuloma formation.

Clinical manifestations;

• kidney and pulmonary involvement,

• focal segmental glomerulonephritis and pulmonary hemorrhage.

• positive pANCA with reactivity to myeloperoxidase (MPO).

Microscopic polyangiitis

• Most patients seem to require cyclophosphamide.

• Milder agents may be adequate for maintaining remissions.

• Most recently, a single 4-week course of rituximab might replace both cyclophosphamide and long-term steroids.

Churg–Strauss syndrome

• CSS is extremely rare in children.

• A prodromal phase of an allergic rhinitis and asthma,

• may persist for many years.

• The second phase - worsening asthma,

• peripheral eosinophilia, and pulmonary infiltrates.

the third or vasculitic phase - systemic vasculitis

• weight loss,

• fever,

• arthralgia,

• myalgia,

• nodular rash,

• neuropathy.

• Asthma symptoms usually subside during the vasculitic phase.

Churg–Strauss syndrome

• Tissue biopsy is generally diagnostic,

• Significant perivascular eosinophilic infiltrates and occasional extravascular granulomas.

• ANCA directed against both PR-3 and MPO may be seen in CSS.

Churg–Strauss syndrome

• An initial aggressive remittive therapy,

• Followed by milder maintenance treatment,

• Most deaths are caused by cardiac involvement,

– followed by severe gastrointestinal and CNS disease.

• exquisitely sensitive to corticosteroids,

Secondary vasculitides

• Infections,

• Medications,

• Systemic diseases.

Secondary vasculitides

• viruses (parvovirus B19, HIV, varicella),

• Rickettsia,

• bacteria,

• fungi,

• mycobacteria,

systemic inflammatory conditions

• SLE, juvenile dermatomyositis [JDMS], juvenile rheumatoid arthritis, sarcoidosis, inflammatory bowel syndrome, tumors), CF.

• Drugs.

• Both leukocytoclastic and necrotizing vasculitis have been reported.

• Removal of the trigger or control of the inciting condition leads to remission of the vasculitis.

Behcet’s disease

• A multisystem inflammatory disorder

• BD is characterized by the triad of

– recurrent oral ulcers,

– genital ulcers,

– and uveitis,

• Any organ system may be involved including

– skin,

– joints

– CNS,

– or gastrointestinal tract,

Behcet’s disease

• Vascular inflammation is often a prominent feature.

• Both arteries and veins may be affected.

• A particular predilection for the venules.

• A propensity for development of thromboses,

• Including deep vein thrombosis and thrombophlebitis.

• Arterial aneurysms may also occur - pulmonary aneurysms.

Behcet’s disease

• BD is thought to occur when an infectious agent triggers an amplified inflammatory response in a genetically susceptible host.

• In the Japanese and Turkish vasculitis populations, in whom the disease is most prevalent, HLA-B51 is a marker for BD.

• and the aberrant cellular immune response seems to involve gd-T cells.

• Antibody-mediated immune mechanisms may also play a role.

Various immunomodulatory agents

• IFN-a,

• thalidomide,

• dapsone,

• steroids,

• cyclophosphamide,

• azathioprine

Periodic fever syndromes

• During the past 5 years,

• novel autoinflammatory conditions caused by mutations in regulators of inflammation have been described.

Summary

• Vasculitis is rare in children,

• Apart from HSP and perhaps KD,

• Most practicing pediatricians will never encounter a case.

Summary

It is important to consider vasculitis as a.

potential cause of;

• unexplained inflammation,

• perplexing rashes,

• or strange combinations of symptoms.