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SARCOIDOSIS
- 1. SARCOIDOSIS Juan CarlosRivera CH Residente de Oftalmología Universidad del Valle
- 2. Sarcoidosis HISTORIA SirJonathan Hutchinson: Enfermedad de la piel? 1877 Cesar Boeck: Enfermedad multisistémica. 1910 Sarcoma= Sarcoiodosis. CLINICAL REVIEW, Owen J Dempsey,et Col Sarcoidosis,BMJ 009;339:b320 6
- 3. Sarcoidosis Enfermedad Granulomatosasistémica de etiologia desconocida Etiología desconocida. cualquier edad pero < de 50. Mujeres> Hombres. Etnia: Afroamericanos y Caucásicos. I : 10.9 x 100.000hab, Blancos, I : 35.5 x 100.000hab, Afro-Americano, CLINICAL REVIEW, Owen J Dempsey,et Col Sarcoidosis,BMJ 009;339:b320 6
- 4. Sarcoidosis: Patogenia MHCII, Cromosoma 6 Agrupaciones familiares y agrupaciones geográficas. Gatillos: mycobacterias, propinebacteriun Acnes. Disfunción entre Cels T efectoras y Cels T Restrictivas: CD1d restictivas Natural Killer. CLINICAL REVIEW, Owen J Dempsey,et Col Sarcoidosis,BMJ 009;339:b320 6
- 5. CLINICAL REVIEW, OwenJ Dempsey,et Col Sarcoidosis,BMJ 2009;339:b320 6 Enfermedad Pulmonar presente en el 90% BHL solamente. Infiltrados pulmonares+ BHL. Infiltrafos Pulmonares entre el 10 y 20%. Fibrosis Pulmonar
- 6. CLINICAL REVIEW, OwenJ Dempsey,et Col Sarcoidosis,BMJ 2009;339:b320 6 BHL solamente. Infiltrados pulmonares+ BHL. Infiltrados. Pulmonares entre el 10 y 20%. Fibrosis Pulmonar
- 7. CLINICAL REVIEW, OwenJ Dempsey,et Col Sarcoidosis,BMJ 2009;339:b320 6 BHL solamente. Infiltrados pulmonares+ BHL. Infiltrados. Pulmonares entre el 10 y 20%. Fibrosis Pulmonar
- 8. CLINICAL REVIEW, OwenJ Dempsey,et Col Sarcoidosis,BMJ 2009;339:b320 6 BHL solamente. Infiltrados pulmonares+ BHL. Infiltrados. Pulmonares entre el 10 y 20% . Fibrosis Pulmonar
- 9. CLINICAL REVIEW, OwenJ Dempsey,et Col Sarcoidosis,BMJ 2009;339:b320 6 Fatiga 66% Ocular 30- 60%. Alteraciones en Piel: 24%. Gastrointestinal o Hepatico 18% Linfadenopatía 15%. Neurológicos 5% Cardiaco 2%
- 10. Copyright ©2009 BMJPublishing Group Ltd. D empsey, O. J et al. BMJ 2009;339:b3206 Fig 3 Forearm of a patient with cutaneous sarcoidosis affecting the tail of his swallow tattoo, confirmed on biopsy (arrow). The inflammation resolved with treatment
- 11. Comité internacional detrabajo en sarcoidosis. Ásia, África, Europa y America. Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University at the Tokyo Conference Centre in Shinagawa, Tokyo, Octubre del 2006.
- 12. Carl P. Herbort,InternationalCriteria for the Diagnosis of Ocular Sarcoidosis: Results of the First International Workshop on Ocular Sarcoidosis, Ocular Immunology & Inflammation, January 2009; Accepted 12 February 2009 Test previo a la reunión donde se presentaban signos oculares y pruebas de laboratorio de 67 pacientes con Bx + para Sarcoidosis y 111 controles de pacientes con uveitis . los signos escogidos por 2/3 de los miembros, fueron escogicos . Criterios Diagnósticos en cuatro niveles de certeza, según: signos, pruebas de Laboratorio, y Biopsia
- 13. signo: PRK yNódulos
- 14. 2. Signo: Nodulos en Malla trabecular y Sinéquias Periféricas Anteriores
- 15. 3. Signo: Bolas de Nieve/ collar de perlas, opacidades vítreas
- 16. 4. Signo: Múltipleslesiones coroidorretinales periféricas.
- 17. 5. Signo: Flebitis nodular y / o peri-segmentaria en cera de la vela y/ o un macroaneurisma en un ojo inflamado
- 18. 5. Signo: Flebitis nodular y / o peri-segmentaria en cera de la vela y/ o un macroaneurisma en un ojo inflamado
- 19. 6. Signo: Granulomasdel disco óptico y / o nódulos solitarios de coroides
- 20. 6. Signo: Granulomasdel disco óptico y / o nódulos solitarios de coroides
- 21. Bilateralidad 7. signoExamen Clínico fotometria laser flare Angiografia de verde indocianina. vasculitis focos de inflamacion retinal representados por puntos hipofluorescentes
- 22. CRITERIOS DE LABORATORIOPPD negativo en paciente vacunado con BCG o previamente PPD positivo. Elevacion de ECA y/o elevada lisozima sérica. Rx Torax con Linfadenopatia hiliar bilateral. Anormalidad de enzimas hepaticas. TAC de torax en pacientes copn RX negativos.
- 23. CRITERIOS DE LABORATORIOPPD negativo en paciente vacunado con BCG o previamente PPD positivo. Elevacion de ECA y/o elevada lisozima sérica. Rx Torax con Linfadenopatia hiliar bilateral. Anormalidad de enzimas hepaticas. TAC de torax en pacientes copn RX negativos. Producto de los macrofagos. Estudio Japonez 125 la ECA 60% sensibilidad. lisozima 75% de sensibilidad. se eleva mas en niños. ECA no confiable con IECAS
- 24. CRITERIOS DE LABORATORIOPPD negativo en paciente vacunado con BCG o previamente PPD positivo. Elevacion de ECA y/o elevada lisozima sérica. Rx Torax con Linfadenopatia hiliar bilateral. Anormalidad de enzimas hepaticas. TAC de torax en pacientes copn RX negativos. El signo radiológico mas frecuente. 50-90%. Es raro en otras condiciones sistémicas excepto linfoma. La precencia de BHL determina el estadío 1 de la enfermedad.
- 25. Copyright ©2009 BMJPublishing Group Ltd.
- 26. CRITERIOS DE LABORATORIOPPD negativo en paciente vacunado con BCG o previamente PPD positivo. Elevacion de ECA y/o elevada lisozima sérica. Rx Torax con Linfadenopatia hiliar bilateral. Anormalidad de enzimas hepaticas. TAC de torax en pacientes copn RX negativos. FA: elevación 3 veces. ASAT y ALAT 2 veces.
- 27. CRITERIOS DE LABORATORIOPPD negativo en paciente vacunado con BCG o previamente PPD positivo. Elevacion de ECA y/o elevada lisozima sérica. Rx Torax con Linfadenopatia hiliar bilateral. Anormalidad de enzimas hepaticas. TAC de torax en pacientes copn RX negativos.
- 28. Criterios Diagnósticos deSarcoidosis Ocular Bx positiva + Compatible uveitis. Bx no hecha+ presencia BHL positivo+ compatible uveitis. Bx no hecha+ BHL negativa+ tres signos positivos + 2 Test positivos. Bx negativa + 4 signos positivos + 2 test positivos Dx Definitivo. Dx Presuntivo. Dx Probable. Dx Posible
- 29. CLINICAL REVIEW, OwenJ Dempsey,et Col Sarcoidosis,BMJ 2009;339:b320 6 RMN con Gadolinio: Útil en lesiones en SNC y Miocardio
- 30. CLINICAL REVIEW, OwenJ Dempsey,et Col Sarcoidosis,BMJ 2009;339:b320 6 RMN con Gadolinio: Útil en lesiones en SNC y Miocardio
- 31. caso clinico deSarcoidosis evidenciado por gamagrafía con galio 67
- 32. La Gamagrafía conGalio 67 es Util en buscar lesiones pulmonares y extrapulmonares, el galio 67 correlaciona muy bien con inflamación alveolar porque el agente localiza los macrofagos alveolares.
- 33. Copyright ©2009 BMJPublishing Group Ltd. Dempsey, O. J et al. BMJ 2009;339:b3206
- 34. caso clinico 74 años de edad, Panuveitis bilateral post Cx catarata, Rx torax normal, Lisozima +, PET : Sarcoidosis oculta
- 35. Diagnóstico Diferencial TBC.Ensayo de liberación de IFN-gamma Linfoma.
- 36. Tratamiento Prednisolona 0.5mg/KG/día por 4 semanas, reducción en los siguientes 6 meses, hasta 10mg dia. (Bifosfonato). (Hidroxicloroquina, metrotexate, Azatriopina, Ciclosporina) Inhibidores del FNT infliximab etanercept adalimumab.
- 37. Feliz Día delMédico
Notas del editor
- #5 Some investigators have highlighted the “immune paradox” of sarcoidosis—affected organs such as the lungs show an intense immune response, yet relative anergy exists elsewhere (such as the negative response to the Mantoux test).17 A disequilibrium between effector and regulatory T cells has been hypothesised. For example, patients with sarcoidosis have recently been shown to have reduced numbers of regulatory T cells called CD1d restricted natural killer T cells.w24 These cells may function as an immunological “brake” and have been shown to protect against disorders with increased CD4 positive T helper 1 responses in animals. Loss of immunoregulation by these natural killer cells could explain the amplified and persistent T cell activity that characterises sarcoidosis and other autoimmune diseases, such as diabetes mellitus and multiple sclerosis.w24 Patients with Lofgren’s syndrome have normal numbers of natural killer cells, which may explain why their prognosis is so good. The role of these and other regulatory T cells in sarcoidosis has been reviewed.w25
- #10 Fatigue (66%) —Profound fatigue is under-recognised by health professionals. It is present in two thirds of patients and has a negative effect on quality of life. 67 It may be associated with fever, weight loss, general malaise, depression, and raised C reactive protein. Skin (24%) —Erythema nodosum is one of the most recognisablemanifestations of sarcoidosis (fig 2). Lofgren’s syndrome (erythema nodosum, arthralgia, systemic malaise, and bilateral hilar lymphadenopathy on chest radiography) is associated with an excellent prognosis, and patients usually recover spontaneously.w2 w3 A wide variety of other skin abnormalities may be seen, including maculopapular lesions, lupus pernio (often associated with more chronic disease), nodules, and hyperpigmentation or hypopigmentation. Ask the patient about scars, such as appendicectomy scars or tattoos, because these are often infiltrated by granulomas and are easy to biopsy . Neurological (5%) —This is a rare yet potentially devastating complication of sarcoidosis , especially if the central nervous system is affected. It includes meningeal inflammation or infiltration, hypothalamic-pituitary effects (for example, diabetes insipidus), encephalopathy, vasculopathy, seizures, aseptic meningitis, hydrocephalus, and mass lesions. Effects on the peripheral nervous system include cranial nerve palsy, most commonly facial, andperipheral or small fibre neuropathy.w9.. Cardiac (2%) —Although rare, this can cause sudden death so all patients with cardiac symptoms, such as palpitations or abnormalities on electrocardiography, should be referred for specialist cardiology assessment, typically including a Holter monitor, echocardiography, and cardiac magnetic resonance imaging or positron emission tomography. Electrophysiologicalstudies may also be helpful.w10.
- #14 Table 1. Clinical signs suggestive of ocular sarcoidosis 1. Mutton-fat KPs (large and small) and/or iris nodules at pupillary margin (Koeppe) or in stroma (Bussacca) 2. Trabecular meshwork (TM) nodules and/or tent-shaped peripheral anterior synechiae (PAS) 3. Snowballs/string of pearls vitreous opacities. 4. Multiple chorioretinal peripheral lesions (active & atrophic) 5. Nodular and/or segmental peri-phlebitis (± candlewax drippings) and/or macroaneurism in an inflamed eye 6. Optic disc nodule(s)/granuloma(s) and/or solitary choroidal nodule 7. Bilaterality (assessed by clinical examination or investigational tests showing subclinical inflammation)... Mutton-fat/granulomatous keratic precipitates (KPs) and/or iris nodules (Koeppe/Busacca) (Figure 1). These two signs were associated in one set of clinical signs representing granulomatous reaction of the anterior segment. The type of KPs was not limited to the large mutton-fat type (Figure 1a) but also included smaller granulomatous KPs (Figure 1b). The nodules comprised pupillary margin nodules (Koeppe nodules) (Figure 1c ) and fluffy nodules at the surface of the iris margin (Figure 1d) as well as iris stromal nodules (Busacca nodules) (Figure 1e).
- #15 .Trabecular meshwork (TM) nodules and/or tent-shaped peripheral anterior synechiae (PAS) (Figure 2). This sign was estimated by some of the delegates to be associated with sarcoidosis uveitis in a high proportion. Additionally in the Japanese study, this factor had by far the highest values for all factors, including sensitivity, specificity, and positive and negative predictive values.18 The twosigns were combined as they are believed to be the consequence of the resolution and scarring of TM nodules representing the same process at different evolutionary stages..
- #16 Snowballs/string of pearls vitreous opacities (Figure 3). This type of vitreous involvement was estimated to be very suggestive of a granulomatous process, such as occurs in ocular sarcoidosis, especially in Japan. However, snowballs may also be seen in intermediate uveitis of the pars planitis type and in uveitis related to multiple sclerosis, the two diseases occurring more frequently among Caucasians. In this situation the presence of posterior irido-lenticular synechiae is another argument for ocular sarcoidosis but it was not deemed necessary to include this fact in the definition of this clinical sign...
- #17 Multiple chorioretinal peripheral lesions (active and/or atrophic) (Figure 4). This sign, preferentially seen in middle aged to elderly women, was felt to be strongly suggestive of ocular sarcoidosis.19,20..
- #18 Nodular and/or segmental periphlebitis (± candlewax drippings) and/or retinal macroaneurysm in an inflamed eye (Figure 5). Although these signs were felt to be strongly associated with ocular sarcoidosis, this group of vascular signs stimulated extensive discussion on how to qualify the type of vascular involvement and as result several descriptive terms were used..
- #19 Furthermore, the last item of this group of signs, macroaneurism, did not initially reach a twothirds majority, with the argument that noninflammatory vascular conditions could produce retinal macroaneurisms. As a result, the sign was defined as “retinal macroaneurysm in an inflamed eye.
- #20 Optic disc nodule(s)/granuloma(s) and/or solitary choroidal nodule (Figure 6). This sign was readily accepted by the group, provided all steps were taken by the ophthalmologist to exclude tuberculous uveitis...
- #21 Optic disc nodule(s)/granuloma(s) and/or solitary choroidal nodule (Figure 6). This sign was readily accepted by the group, provided all steps were taken by the ophthalmologist to exclude tuberculous uveitis...
- #22 Bilaterality. It was found to be a useful criterion to define ocular sarcoidosis. Bilaterality can be established either by clinical examination or by adjuvant methods capable of showing subclinical disease, such as laser flare photometry when flare values were elevated24 or indocyanine green angiography, which demonstrates the presence of choroidal vasculitis and/or hypofluorescent dots representing choroidal inflammatory foci.12
- #23 Table 2. Laboratory investigations in suspected ocular sarcoidosis 1. Negative tuberculin test in a BCG vaccinated patient or having had a positive PPD (or Mantoux) skin test previously 2. Elevated serum angiotensin converting enzyme (ACE) and/or elevated serum lysozymea 3. Chest x-ray; look for bilateral hilar lymphadenopathy (BHL) 4. Abnormal liver enzyme tests (any two of alcaline phosphatase, ASAT. ALAT, LDH or γ -GT) 5. Chest CT scan in patients with negative chest x-ray a Test required in patients treated with ACE inhibitors...
- #24 Elevated serum angiotensin converting enzyme (ACE) and/or elevated serum lysozyme. As both tests measure the same parameter, macrophage products roduced by granulomas, they were grouped together. The more commonly performed test is measurement of serum ACE levels. In a study on 125 sarcoidosis cases this parameter was elevated in 60% of patients.25 ACE is significantly more elevated in children than in adults, the difference, though, never reaching levels found in pathological situations such as sarcoidosis, and the test may be therefore less useful in children despite the elevated values.26 When talking about serum ACE levels this corresponds to serum ACE activity, as routinely used assays are, in fact, measuring ACE enzyme activity.26 Therefore, serum ACE levels or, more exactly, serum “ACE activity” falls below detectable levels in patients tak- ing ACE inhibitors.The test is therefore not useful in patients who are on ACE inhibitors. In such patients serum lysozyme is recommended. The same report that studied ACE levels in 125 sarcoidosis patients also showed that lysozyme was elevated even more frequently than ACEwith 76% of patients having elevated lysozyme levels.25 Serum lysozyme is more rarely used because many laboratories don’t run this test. The Japanese study on biopsy-proven ocular sarcoidosis also showed that the combination of sensitivity, specificity, and positive and negative predictive valueswas better for elevated serum lysozyme than for elevated serum ACE.
- #25 Positive chest x-ray, showing bilateral hilar lymphadenopathy (BHL). Bilateral hilar lymphadenopathy (BHL) is the most frequent radiological finding in systemic sarcoidosis, being present in 50–89% of cases.27,28 As there are rarely any other systemic conditions that cause BHL, except perhaps lymphoma, although symmetrical lymph node involvement is unusual, this is thought to be pathognomonic of sarcoidosis. In the classification of pulmonary sarcoidosis, presence of BHL determines stage 1 of the disease.29 The group also discussed the option of considering other radiological signs to call an x-ray positive for sarcoidosis, but this was not decided, leaving this as one of the topic to be addressed in future meetings.
- #26 Fig 1 Patients with sarcoidosis may present at any radiographic stage. Panel (a): stage 1--bilateral hilar lymphadenopathy only (likelihood of spontaneous remission 55-90%); panel (b): stage 2--bilateral hilar lymphadenopathy plus pulmonary infiltrates (40-70%); panel (c): stage 3--pulmonary infiltrates only (10-20%); panel (d): stage 4--pulmonary fibrosis( 0%)
- #27 Abnormal. liver enzyme tests. This laboratory test was included on the advice of the internistpulmonologists. Hepatic involvement in sarcoidosis is one of the occult sites where undetected granulomas can form. Little or no literature exists on the importance of investigating liver enzyme test abnormlties in ocular sarcoidosis. The laboratory test, however, obtained a two-thirds majority and needs to be investigated in future studies that will test the present diagnostic criteria. The test is considered to be positive when serum levels of alkaline phosphatase are more than three times the upper limit of normal values or when two of the following liver enzymes—aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), and alkaline phosphatase—are more than twice the upper limit of normal values.30
- #28 l
- #29 1. Biopsy supported diagnosis with a compatible uveitis ->Definite oculara sarcoidosis 2. Biopsy not done; presence of bilateral hilar lymphadenopathy (BHL) with a compatible uveitis -> Presumed oculara sarcoidosis 3. Biopsy not done and BHL negative; presence of three of the suggestive intraocular signs and two positive investigational tests -> Probable oculara sarcoidosis 4. Biopsy negative, four of the suggestive intraocular signsand two of the investigations are positive -> Possible oculara sarcoidosis
- #30 Fatigue (66%) —Profound fatigue is under-recognised by health professionals. It is present in two thirds of patients and has a negative effect on quality of life. 67 It may be associated with fever, weight loss, general malaise, depression, and raised C reactive protein. Skin (24%) —Erythema nodosum is one of the most recognisablemanifestations of sarcoidosis (fig 2). Lofgren’s syndrome (erythema nodosum, arthralgia, systemic malaise, and bilateral hilar lymphadenopathy on chest radiography) is associated with an excellent prognosis, and patients usually recover spontaneously.w2 w3 A wide variety of other skin abnormalities may be seen, including maculopapular lesions, lupus pernio (often associated with more chronic disease), nodules, and hyperpigmentation or hypopigmentation. Ask the patient about scars, such as appendicectomy scars or tattoos, because these are often infiltrated by granulomas and are easy to biopsy . Neurological (5%) —This is a rare yet potentially devastating complication of sarcoidosis , especially if the central nervous system is affected. It includes meningeal inflammation or infiltration, hypothalamic-pituitary effects (for example, diabetes insipidus), encephalopathy, vasculopathy, seizures, aseptic meningitis, hydrocephalus, and mass lesions. Effects on the peripheral nervous system include cranial nerve palsy, most commonly facial, andperipheral or small fibre neuropathy.w9.. Cardiac (2%) —Although rare, this can cause sudden death so all patients with cardiac symptoms, such as palpitations or abnormalities on electrocardiography, should be referred for specialist cardiology assessment, typically including a Holter monitor, echocardiography, and cardiac magnetic resonance imaging or positron emission tomography. Electrophysiologicalstudies may also be helpful.w10.
- #31 Fatigue (66%) —Profound fatigue is under-recognised by health professionals. It is present in two thirds of patients and has a negative effect on quality of life. 67 It may be associated with fever, weight loss, general malaise, depression, and raised C reactive protein. Skin (24%) —Erythema nodosum is one of the most recognisablemanifestations of sarcoidosis (fig 2). Lofgren’s syndrome (erythema nodosum, arthralgia, systemic malaise, and bilateral hilar lymphadenopathy on chest radiography) is associated with an excellent prognosis, and patients usually recover spontaneously.w2 w3 A wide variety of other skin abnormalities may be seen, including maculopapular lesions, lupus pernio (often associated with more chronic disease), nodules, and hyperpigmentation or hypopigmentation. Ask the patient about scars, such as appendicectomy scars or tattoos, because these are often infiltrated by granulomas and are easy to biopsy . Neurological (5%) —This is a rare yet potentially devastating complication of sarcoidosis , especially if the central nervous system is affected. It includes meningeal inflammation or infiltration, hypothalamic-pituitary effects (for example, diabetes insipidus), encephalopathy, vasculopathy, seizures, aseptic meningitis, hydrocephalus, and mass lesions. Effects on the peripheral nervous system include cranial nerve palsy, most commonly facial, andperipheral or small fibre neuropathy.w9.. Cardiac (2%) —Although rare, this can cause sudden death so all patients with cardiac symptoms, such as palpitations or abnormalities on electrocardiography, should be referred for specialist cardiology assessment, typically including a Holter monitor, echocardiography, and cardiac magnetic resonance imaging or positron emission tomography. Electrophysiologicalstudies may also be helpful.w10.
- #34 Fig 5 Integrated fluorodeoxyglucose positron emission tomography-computerised tomography can identify biopsy sites and extrapulmonary disease. In this patient with sarcoidosis, the technique identified active disease, the extent of which was not apparent on computed tomography imaging alone. Panel (a) is a fusion image showing increased uptake in mediastinal nodes (arrows); panel (b) is a maximum intensity projection image showing increased uptake in neck, mediastinal, coeliac, and inguinal nodes (closed arrows) and physiological uptake in kidneys (open arrows); panel (c) is an axial computed tomography and fused image at the level of the aortic arch showing increased fluorodeoxyglucose uptake in prevascular, left paratracheal, and right paratracheal nodes, none of which are enlarged by conventional size criteria.
- #36 Regardless, the most important condition that may present in a similar manner is ocular tuberculosis. In the case of a granulomatous uveitis compatible with both sarcoidosis and tuberculosis, the IFN-gamma release assay, such as Quantiferon-gold or TB spot test, is perhaps the most useful test that allows the clinician to distinguish between the 2 entities. This test is able to exclude both latent and active tuberculosis if negative. In this test blood lymphocytes are incubated with antigens from Mycobacterium tuberculosis (different from the antigens present in the BCG vaccine) and the production of gamma-interferon is assayed. If the level of gammainterferon is high, then the diagnosis of latent or active tuberculosis is made.36 This test has an extremely low rate of false-positive results (very high specificity) and tuberculosis can reasonably securely be ruled out when negative. Until such time when additional specific characteristics and investigational tests become available, allowing a more accurate appraisal of the disease, we suggest the use of these diagnostic criteria for future uveitis studies on ocular sarcoidosis. The use of the proposed four categories of sarcoid uveitis in future prospective clinical epidemiological studies and clinical trials will allow for the collation of data from which the ophthalmic community can make meaningful comparisons and draw useful conclusions based on diagnoses made on the same basis from different institutions around the world.