Sndrome de Churg Strauss y Poliarteritis Nodosa

Por Cristhian AguilarSndrome de Churg Strauss y Poliarteritis NodosaSndrome de churg strauss Granulomatosis Eosinoflica con PoliangetisGranulomatosis Alrgica con PoliangetisAsma, eosinofilia y vasculitis sistmica.Presentaciones clnicas clsicas:Rinitis alrgica y poliposis nasalEnfermedad reactiva de la va areaEosinofilia perifrica (10 60 % de WBC)Infiltrados pulmonares evanescentes y hemorragia alveolar ocasionalNeuropata vasculticaFalla cardiacaCerca del 50% de Px con EGPA tienen ANCA + usualmente con especificidad por MPO

Aspectos esenciales

Figure 89-11 Churg-Strauss syndrome. Transmural eosinophilic infiltrate with scattered plasma cells and lymphocytes involving a small artery in the lung of a patient with Churg-Strauss syndrome (hematoxylinand eosin, 40). (Courtesy Dr. C. Farver.)3Definicin

West, S. (2015). Antineutrophil cytoplasmic antibodyassociated vasculitis. In Rheumatology Secrets (3rd ed., p. 232). Philadelphia, Pensilvania: Elsevier. 2013 American Academy of Allergy, Asthma & ImmunologyDefinicin Triada En 1951, Churg y Strauss reportaron una serie de 13 pacientes con periarteritis nodosa quienes mostraron asma severa y una inusual constelacin de sntomasLos investigadores nombraron la nueva enfermedad angetis alrgica y granulomatosis alrgica y especificaron tres criterios histolgicos:Presencia de vasculitis necrotizanteInfiltracin tisular por eosinfilosGranuloma extravascular

Historia

Am J Pathol, 27: 227-301, 1951epidemiologaMenos comn de las AAVIncidencia de 1.0 a 3.0 por millnAumenta en pacientes con asma a 34.6 por milln personas-aoAfecta edades similares que GPA y MPA (edad media: 48 aos)Ms comn en mujeres (1.2 1)Asociacin con el uso de inhibidores de leucotrienos o terapia monoclonal anti IgEFirestein, G., Budd, R., Gabriel, S., McInnes, I., & O'Dell, J. (2013). Antineutrophil cytoplasmic antibody-associated vasculitis. In KELLEYS TEXTBOOK OF RHEUMATOLOGY (9th ed., Vol. 1, p. 1670). Philadelphia, Pensilvania: Elsevier.

PatogeniaHochberg, M., Silman, A., Smolen, J., Weinblatt, M., & Weisman, M. (2015). Antineutrophil cytoplasmic antibody-associated vasculitis. In RHEUMATOLOGY (6th ed., Vol. 1, p. 1318). Philadelphia, Pensilvania: Elsevier. Fig. 157.12 Pathogenic mechanisms in antineutrophil cytoplasmic antibody (ANCA)associated vasculitis (AAV). (1) Antigen-presenting cells (APCs) interact with helper CD4 T cells and B cells for the production of ANCAs. (2) The process of tolerance break may be permitted by numerical or functional defects in the regulatory T cells (Treg), which also may limit subsequent effector pathways insufficiently. (3) ANCAs cross-link Fc receptor (FcR) and myeloperoxidase (MPO) or proteinase 3 (PR3) on the surface of primed neutrophils, which leads to cellular degranulation, production of reactive oxygen species (ROS), vascular endothelial damage, and tissue injury. (4) Type 17 helper T (Th17) cells promote neutrophil recruitment to the foci of inflammation and may provide additional effector mechanisms. (5) In granulomatosis with polyangiitis, Th1 cells and effector memory T cells (TEM), which are an important source of tumor necrosis factor- (TNF-) and interferon- (IFN-), further prime neutrophils and drive the formation of granulomatous inflammation. Granulomas are composed of activated CD4 T cells, macrophages, giant cells, neutrophils, and B cells. (6) In eosinophilic granulomatosis with polyangiitis, eosinophils are recruited to the sites of inflammation, and cytokines produced by Th2 cells (e.g., interleukin-5 [IL-5]) promote their activation with degranulation of cationic proteins (e.g., major basic protein) that cause tissue damage. (7) Positive feedback and amplification loops operate in AAV at different levels, perpetuating and augmenting the self-reacting process (e.g., neutrophil extracellular nets [NETs], cytokines [IL-6, IL-23, IL-17, TNF-, IL-25], complement factors [C5a]). TGF-, transforming growth factor-.8Criterios de Clasificacin

ClasificacinChapel Hill 1994Jennette JC, Falk RJ, Andrassy K, et al: Arthritis Rheum 1994; 37:187-192

Hallazgos ClnicosFases clnicas:Prodrmica: 28 meses en promedio pero puede persistir por aos (2 a 7 aos).Eosinofilia/infiltracin tisular: puede remitir o recurrir por aos antes de la tercera fase.Vasculitis sistmica: ocurre en promedio, 3 aos despus de la aparicin de la fase prodrmica

Principales Manifestaciones Clnicas

West, S. (2015). Antineutrophil cytoplasmic antibodyassociated vasculitis. In Rheumatology Secrets (3rd ed., p. 232). Philadelphia, Pensilvania: Elsevier. HeartCardiac involvement also occurs with a disproportionate frequency in CSS, and is a common cause of death. Some form of cardiac involvement occurred in 12.5% of patients in one large series. Congestive heart failure is the most common cardiac manifestation, although coronary arteritis and valvular abnormalities have also been reported.KidneysCSS is less likely to cause end-stage renal disease than other forms of ANCA-associated vasculitis. When glomerulonephritis does occur, however, the histopathologic findings are often indistinguishable from those of other forms of pauci-immune vasculitis (eg, Wegener granulomatosis, microscopic polyangiitis, and renal-limited vasculitis).JointsNonspecific arthralgias and frank arthritis often occur early in the course of CSS. The arthritis of CSS is migratory in nature and may assume a variety of joint patterns, from a pauciarticular syndrome of lower extremity joints to a polyarthritis of the small joints of the hands.

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Manifestaciones Clnicas ORL

Nose and SinusesUpper airway disease in CSS usually takes the form of nasal polyps or allergic rhinitis. A surprisingly high percentage of patients with CSS have histories of nasal polypectomies, usually long before suspicion of an underlying disease is raised. Although pansinusitis occurs frequently, destructive upper airway disease is not characteristic of CSS.EarsMiddle ear granulation tissue with eosinophilic infiltrates occurs in some patients, leading to conductive hearing loss. Cases of sensorineural hearing loss have also been reported.

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Manifestaciones ClnicasPulmones

LungsMore than 90% of patients with CSS have histories of asthma. Typically, the asthma represents either adult-onset reactive airway disease, or less commonly, a significant worsening of long-standing disease. Upon encroachment of the vasculitic phase of CSS, patients' asthma may improve substantially, even before therapy for vasculitis has begun. Following successful treatment of the vasculitic phase, however, glucocorticoid-dependent asthma persists in many patients.The pathologic features of lung disease in CSS vary according to the disease phase. In the early phases, there may be extensive eosinophilic infiltration of the alveoli and interstitium. During the vasculitic phase, necrotizing vasculitis and granuloma may be evident. In the current era, when many patients with asthma are treated with varying doses of systemic glucocorticoids, lung biopsy specimens showing all three histologic hallmarks of this disease are unusual.

16Manifestaciones ClnicasNeuropata vascultica

Peripheral NervesMononeuritis multiplex occurs with remarkable frequency in CSS, often with devastating effects. Vasculitic neuropathy was evident in 74 (77%) of the 96 patients in one series. Nerve infarctions may appear several weeks after the start of appropriate treatment, but do not always indicate the need to intensify therapy, particularly if patients are already on both high-dose prednisone and cyclophosphamide. This may be due to continued disease activity, but is more likely secondary to thrombosis of vessels that have become severely compromised by previously active inflammation. Nerve infarctions clinically are heralded by the abrupt occurrence of a foot drop, wrist drop, or some other focal nerve lesion. Muscle wasting secondary to nerve infarctions may continue to appear for weeks after the disease has been brought under control (Figure 352).17Manifestaciones ClnicasPiel

SkinSkin disease in CSS takes many forms, none of which is specific. Palpable purpura, papules, ulcers, and vesiculobullous lesions are common. Nodular skin lesions are usually "Churg-Strauss granuloma" (cutaneous extravascular necrotizing granuloma). These tend to occur on the extensor surfaces of the elbows and other pressure points. Skin biopsy specimens in CSS reveal eosinophilic infiltration of blood vessel walls. Splinter hemorrhages, digital ischemia, and gangrene associated with inflammation in medium-sized digital arteries are often present at the time of diagnosis.

18Hallazgos de laboratorioEosinofilia: sine qua nonConteo de eosinfilos: 60% WBCNivel de IgENiveles de complementoESRCRPANCA 50% (MPO o proteinasa-3)

Infiltrados pulmonares (1/3 al dx)MigratoriosBilaterales Hemorragia alveolarLesiones nodulares o cavitadasEcocardiografa: cardiomiopata o fibrosis miocrdica regionalEstudios de imagen

Pulmonary infiltrates are evident in approximately one-third of patients with CSS. These lesions are usually migratory infiltrates that occur bilaterally. Pulmonary hemorrhage is unusual, but has been reported. Nodular or cavitary lesions suggest the alternative diagnoses of Wegener granulomatosis or an infection. Among patients with cardiac involvement, echocardiography may confirm poor cardiac function consistent with cardiomyopathy or demonstrate findings compatible with regional myocardial fibrosis.

Figure 2 (a) Chest radiograph showing bilateral pulmonary infiltrates. (b) Radiograph paranasal sinuses showing hazy frontal sinuses. (c) Computed tomographic chest showing areas of scattered ground glass opacities in both lung fields. (d) Chest radiograph showing radiological resolution during follow-up.

20Diagnstico diferencial

The major disease entities in the differential diagnosis of CSS are shown in Table 352. There are many diseases in which patients occasionally demonstrate mild eosinophilia (eg, a peripheral blood eosinophilia on the order of 10% or so in asthma or parasitic infections). In contrast to CSS, however, only a handful of diseases can cause eosinophilia as high as 2060%, as occasionally observed with CSS and its related conditions. Strongyloides infection, which can cause both high levels of eosinophilia and asthma, should be considered in endemic areas. CSS must also be distinguished from other hypereosinophilic disorders: Lffler syndrome, chronic eosinophilic pneumonia, eosinophilic gastroenteritis, hypereosinophilic syndrome, eosinophilic fasciitis, and eosinophilic leukemia.The fleeting pulmonary infiltrates of the Lffler syndrome and the peripheral infiltrates of chronic eosinophilic pneumonia may both mimic CSS closely.However, differentiating CSS from hypereosinophilic syndrome may be the biggest challenge. Clinically, hypereosinophilic syndrome is rarely associated with reactive airway disease. Laboratory tests for the F1P1L1-PDGFR gene translocation or elevated serum tryptase levels (both of which are associated with hypereosinophilic syndrome) may also be helpful in the evaluation of such patients.Many other forms of systemic vasculitis are high on the differential diagnosis for CSS. Wegener granulomatosis, polyarteritis nodosa, microscopic polyangiitis, Goodpasture syndrome (antiglomerular basement membrane disease), cryoglobulinemia, and other vasculitic disorders have clinical features that overlap with those of CSS. However, the finding of eosinophilia superimposed upon a history of allergy or asthma usually permits the clear distinction of CSS from these other disorders.

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tratamientoGlucocorticoides solosCyclophosfamide: 2 mg/kg/d limitada a seis mesesAzathioprine: 2 mg/kg/dMethotrexate: 15 25 mg/wkMycophenolate: 2 3 g/d en dosis divididasGlucocorticoides + citotxicosInterfern alfaBroncodilatadores

FACTORES DE RIESGOMORTALIDAD A LOS 5 AOS 011.9%225,9%>246%Cundo aadir un inmunosupresor al tratamiento con corticoides:Five Factor Score(FFS)Edad > 65 aosCreatinina plasmtica > 1,58 mg/dL, Proteinuria > 1g/dCompromiso cardiacoCompromiso GI (sangrado, perforacin, infarto o pancreatitis)Sntomas ORL

Medicine (Baltimore).2011 Jan;90(1):19-27. doi: 10.1097/MD.0b013e318205a4c6

Complicaciones Neuropata vascultica: disfuncin paralizanteEfectos adversos de la terapia: asma dependiente de glucocorticoidesInmunosupresin intensaInfecciones oportunistasMielosupresinInfertilidadToxicidad vesicalMalignidades Remisin de 90%, recurrencia del 25%

Poliarteritis nodosaPoliarteritis Nodosa clsicaPeriarteritis NodosaEnfermedad de Kussmaul-MaierAspectos esencialesAparicin subaguda de molestias constitucionales, ndulos y ulceraciones en extremidades inferiores, mononeuritis multiplex, y angina intestinal.Poliarteritis nodosa cutnea es una variante de enfermedad sistmica en la cual, la vasculitis se limita a la piel, usualmente presentando como ndulos que se ulceran.Se requiere de angiograma o biopsia del rgano afectado para el diagnstico.Angiografa puede revelar microaneurismas en riones o TGI.Biopsias de piel y nervios perifricos son los medios menos invasivos para confirmar el diagnstico histopatolgicamentedefinicinHochberg, M., Silman, A., Smolen, J., Weinblatt, M., & Weisman, M. (2015). Polyarteritis nodosa and Cogan Syndrome. In RHEUMATOLOGY (6th ed., Vol. 1, p. 1290). Philadelphia, Pensilvania: Elsevier.

Primera vasculitis descrita y estudiada con detalle.John Hunter, s.XVIII (Londres) Inflamacin de venas y musculatura arterial.Franois Broussais y Jean Baptiste Bouillaud, 1840 (Francia) Arteritis ReumticaKarl Rokitansky, 1852 (Austria) primer caso de PANKssmaul y Maier, 1855 Periarteritis NodosaRudolph Virchow, 1858 endoarteritis deformans en Cellular pathologyHans Eppinger, 1887 anlisis microscpico

historiaHenry Thompson, 1877 (Inglaterra) primer reporte en Inglaterra.Veszpremi y Miklos, 1900 1 Px con PAN microscpica sin evidencia macroscpica.Enrico Ferrari, 1903 acu el trmino poliarteritis nodosaCarniegie Dickson, 1908 PAN (literatura inglesa). Beitzke(Alemania)Friedrich Wohlwill, 1922 Periarteritis nodosa microscpicaDavson y col. 1948 presencia (PAN clsica) o ausencia de glomerulonefritis (PAN microscpica)American College of Rheumatology, 1990 clasificacin de vasculitis (7 tipos)Consenso de Chapel Hill, 1992 clasificacin por calibre

Vera, O., & Halabe, J. (2006). Poliarteritis nodosa. In Vasculitis (1st ed., Vol. 1, p. 160, 161). Mxico, D. F.: Editorial Alfil. Su epidemiologa ha cambiado con el tiempo.Estudio de comparacin de incidencia en tres regiones europeas(1)Por criterios ACR : 4.4 a 9.7 por millnSegn definicin CHCC: 0 a 0.9 por millnIncidencia en Europa y EE. UU. : 2 a 9 por milln (ACR)Incidencia en Kuwait: 16 por milln (CHCC)Incidencia en Alaska: 77 por milln (Antes de ACR o CHCC) (2)

Prevalencia en Europa Occidental: 31 a 33 por milln (ACR)Prevalencia en Alemania 2 a 9 por milln (CHCC)Estudio evalu la incidencia y sobrevida de pacientes con vasculitis(3):Incidencia de PAN: 0.9 (de 0 a 1.7) por milln por aoRango etario: entre 40 y 60 aosEtnia: descendientes europeos

epidemiologaWatts RA, Lane SE, Scott DG, et al: Epidemiology of vasculitis in Europe, Ann Rheum Dis 60:11561157, 2001.McMahon BJ, Heyward WL, Templin DW, et al: Hepatitis B-associated polyarteritis nodosa in Alaskan Eskimos: clinical and epidemiologic features and long-term follow-up, Hepatology 9:97101, 1989.Mohammad AJ, Jacobsson LT, Westman KW, et al: Incidence and survival rates in Wegeners granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and polyarteritis nodosa, Rheumatology (Oxford) 48(12):15601565, 2009.patognesisMecanismos no comprendidos en su totalidadTeoras sobre relacin con complejos inmunesPAN secundaria a VHB: Antgeno de superficie complejos inmunesModelos animales:Complejos inmunes cascada del complementoANCA no tienen papel importanteSe especula sobre autoanticuerpos contra clulas endotelialesCriterios de clasificacin ACR

Vera, O., & Halabe, J. (2006). Poliarteritis nodosa. In Vasculitis (1st ed., Vol. 1, p. 163). Mxico, D. F.: Editorial Alfil. The term periarteritis nodosa was originally introduced in 1866 and subsequently used to describe any form of systemic vasculitis.1 The term has been modified to polyarteritis nodosa (PAN), and the definition has been improved to consist of necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules.2The American College of Rheumatology (ACR) criteria, which can be used to classify patients as having PAN, inorder to distinguish them from patients with other forms of primary systemic vasculitis, do not differentiate between PAN and microscopic polyangiitis (MPA); both conditions are included under the umbrella of PAN. Three of 10 criteria (listed in Table 90-1) are required.335variables predictivas

Firestein, G., Budd, R., Gabriel, S., McInnes, I., & O'Dell, J. (2013). Polyarteris Nodosa and Related Disorders. In KELLEYS TEXTBOOK OF RHEUMATOLOGY (9th ed., Vol. 1, p. 1499). Philadelphia, Pensilvania: Elsevier. The French Vasculitis Study Group proposed a set of predictive items (Table 90-2) to be used as diagnostic criteria.10 The items were derived from 949 patients with known vasculitis (including 262 described as having PAN) and not from undifferentiated patients, and therefore they are actually another form of classification criteria.The combination of nonspecific constitutional symptoms and ischemic symptoms in one or more organ systems should alert the physician to the possibility of a systemic vasculitis. PAN typically presents with nonspecific symptoms such as fever, weight loss, and myalgia in combination with single or multiorgan manifestations resulting from ischemia or infarction. The commonest organ manifestation is neurologic with mononeuritis multiplex, followed by skin lesions, abdominal pain from mesenteric ischemia, andrenal infarction. Testicular pain due to ischemic orchitis is a classic feature of PAN but is rare at presentation. Some patients may present with an acute surgical abdomen due to bowel, liver, spleen, or pancreatic infarction. Myocardial infarction, ischemic cardiomyopathy, optic ischemia, and ischemic complications of the female genital tract are possible but unusual.36Signos y sntomasPuede afectar cualquier rgano o sistema, virtualmente (Excepto pulmones)Predileccin por ciertos rganosPielNervios perifricosTGIRiones

Quejas universalesMialgiaArtritisInfarto nervioso perifricoIsquemia testicularVasculitis mesentricaSntomas constitucionalesFiebre Hallazgos clnicosPiel y articulacionesLivedo reticularisNdulos, ppulas y lcerasPrpuraIsquemia digitalArtralgia Hallazgos clnicos

TGIAngina intestinalAfeccin mesentricaInflamacin renal intraparenquimatosaPrincipal presentacin (40 %)Arterias interlobaresHipertensin mediada por reninaPuede presentar hematuria y proteinuria

Hallazgos clnicos

Necrosis fibrinoideInfiltrado pleomrfico (PMN y linfocitos)LeucocitoclasiaNecrosis segmentaria lleva a formacin de aneurismasEstadios avanzados: oclusin arterial

Piel (dermis profunda y tejido subcutneo)Ndulos, ppulas y bordes de lceras mejor que en Livedo reticularis.Msculo: altamente vascular (gastrocnemius si se biopsia nervio sural).Biopsias ciegas

Pruebas especialesBiopsiaAngiografa

Angiography is useful in patients with suspected polyarteritis, particularly if the symptoms and laboratory abnormalities do not direct the choice of biopsy. Angiography may be the diagnostic procedure of choice in patients with HBV-associated polyarteritis. The typical angiographic appearance includes long segments of smooth arterial stenosis alternating with areas of normal or dilated artery, smooth tapered occlusions, thrombosis, and a lack of significant atherosclerosis (Fig. 155.3). The dilated segments include saccular and fusiform aneurysms, which strongly suggests PAN. The most frequently involved vessels are the renal, hepatic, and mesenteric vessels.When angiography is performed, it is important that all intraabdominal vessels be studied, including the celiac axis and the mesenteric, renal, and hepatic arteries. The angiographic appearance may regress after treatment.A number of uncommon conditions can mimic the visceral angiographic appearance of vasculitis, including bacterial endocarditis, atrial myxoma, drug abuse, pancreatitis, abdominal malignancy, and disorders of connective tissue.Although most reported data are derived from conventional contrast enhanced angiography, magnetic resonance angiography (MRA) can be used as an alternative to classic angiography. A small study looking at imaging of renal involvement in PAN suggested that in the absence of microaneurysms, differentiation between PAN and pyelonephritis with computed tomography (CT) and MRI is difficult. The authors concluded that plain dynamic abdominal imaging, though diagnostically helpful, is often inconclusive and that angiography is therefore required for a definite diagnosis.19MRA and contrast-enhanced MRI can also be used to assess for coronary arteritis and myocardial dysfunction and may reveal coronary ectatic disease in patients with MPA and PAN.16Muscle biopsy specimens are positive in around 50% of patients with PAN who have muscle pain or claudication. The yield of muscle biopsy is lower in asymptomatic cases.47

Diagnstico diferencial de poliarteritis nodosaDesordenes sistmicos asociados a autoinmunidadVasculitis sistmicasLESGranulomatosis de WegenerMCTDPoliangetis microscpicaSndrome de anticuerpos antifosfolpidos catastrficoSndrome de Churg-StraussArtritis reumatoideCrioglobulinemiaEnfermedad de StillVasculitis aislada de nervios perifricosInfecciones MiscelneasEndocartis Enfermedad intestinal inflamatoriaInfecciones micticas profundasSarcoidosisEritema nodosoAtrophie blanchembolos de colesterolDisplasia fibromuscularLinfomaEfecto deletreo del uso de terapia inmunosupresora.Prednisona 1 mg/kg/dCursos de plasmafresis 3/sem x 6 semanasDosis de glucocorticoides atenuadas rpidamente (aproximadamente 2 semanas) seguido de terapia antiviral (lamivudina 100 mg/d)Glucocorticoides y citotxicosGlucocorticoides solosCiclofosfamida 2 mg/kg/d PO o 0.6 g/m2/mo IVProfilaxis contra Pneumocystis jiroveci

tratamientoPacientes con PAN idiopticaPacientes con PAN asociada a HBVRgimen de tratamiento en PAN no HBV

NonHepatitis B Virus Polyarteritis NodosaThe French Vasculitis Study Group has combined data on PAN and microscopic polyangiitis focusing more on the severity of disease manifestations rather than the type of disease in their studies of treatment or outcome. For example, Ribi and colleagues50 described the outcome of 124 patients with a new diagnosis of either PAN or MPA in whom the outcome was likely to be good (based on a lackof poor prognostic factors as measured by the Five Factor Score). All patients were treated with corticosteroids only followed by either azathioprine or cyclophosphamide if they relapsed. Ninety-eight of these patients achieved remission with steroids alone, but 46 of these patients relapsed.Primary treatment with steroids failed to control the disease in 26 patients, and 49 of the original 124 patients required additional immunosuppression. Similar rates of improvement were documented by using either azathioprine or cyclophosphamide. Therefore despite the absence of poor prognostic factors, only around 50% of patients could be managed with corticosteroids alone. A study of plasma exchange in 62 patients with a mixture of Churg-Strauss syndrome and what was described as PAN suggested that there was no clinical benefit from adding plasma exchange to standard treatment with pulse intermittent high-dose cyclophosphamide and steroid. This study from the mid-1990s describes patients with PAN, but most of these patients probably had MPA.51 Table 90-5 lists treatmentregimens for non-HBV PAN that are based on the European League Against Rheumatism guidelines on management of small and medium vessel vasculitis.5251complicacionesMononeuritis avanzadaDisfuncin nerviosa residual debilidad muscular o neuropataPerforacin intestinal y ruptura de microaneurisma mesentricoTratamiento con altas dosis de inmunosupresoresRiesgo sustancial de infecciones oportunistasOtras complicaciones del tratamientopronsticoContrario a las AAV, la PAN es ONE SHOTPacientes con PAN asociada a HBV, conversin a antgeno HBe , se relaciona con el fin de la fase activa de la vasculitis.Recurrencias en PAN idioptica se observa en un 10%