A case of myeloperoxidase-antineutrophil cytoplasmic antibody and anticardiolipin antibody-positive pyogenic arthritis, pyoderma gangrenosum, acne and hidradenitis suppurativa (PAPASH) syndrome with colitis.

A previous case report of colitis and serine proteinase 3-antineutrophil cytoplasmic antibody positivity in pyogenic arthritis, pyoderma gangrenosum (PG), acne and hidradenitis suppurativa (PAPASH) syndrome with colitis has been published. Herein, we report a similar case of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) positivity. A 26-year-old man presented with recurrent aseptic pyogenic arthritis, acne, hidradenitis suppurativa and PG. Lower gastrointestinal endoscopy was performed, and colitis was observed. No PSTPIP1 gene mutation was found in the gene-sequencing test. Based on these findings and prior case reports, we diagnosed the patient with PAPASH syndrome, a PAPA spectrum disorder complicated by colitis. This patient had PAPASH syndrome with colitis and was MPO-ANCA and anticardiolipin antibodies-positive; it is unclear whether these antibodies play a role in this disease, but it may provide clues to further elucidate its pathogenesis.

Frecuencia de ANCA positivos en una población con síntomas clínicos sugestivos de enfermedad autoinmune y la interferencia de ANA en su interpretación / Frequency of positive ANCA test in a population with clinical symptoms suggestive of autoimmune disease and the interference of ANA in its interpretation

ANTECEDENTES: Los anticuerpos anticitoplasma del neutrófilo (ANCA) se asocian con vasculitis. Existen diferentes métodos para determinar su presencia. Se ha descrito la interferencia de anticuerpos antinucleares (ANA) en la diferenciación de los patrones P-ANCA y C-ANCA. OBJETIVO: Determinar la frecuencia de ANCA en una población con manifestaciones de enfermedad autoinmune; y evaluar la interferencia de los ANA en su interpretación. MATERIALES Y MÉTODOS: Estudio de corte transversal retrospectivo, descriptivo no experimental incluyendo 3.330 datos con diagnóstico presuntivo de enfermedad autoinmune y solicitud de ANCA. Las determinaciones de ANCA y de ANA se realizaron mediante inmunofluorescencia indirecta, L-ANCA® y CytoBead® ANCA. Antiproteinasa 3 y antimieloperoxidasa fueron determinados mediante ELISA y CytoBead® ANCA. RESULTADOS: Se encontraron ANCA positivos en el 10,21% y el 12,64% con ANCA positivos presentaban ANA positivos. La concordancia kappa para antiproteinasa 3 entre CytoBead® ANCA y ELISA fue del 100% (K=1; p < 0,05), La concordancia entre antimieloperoxidasa por ELISA y CytoBead®ANCA fue alta (K=0,94; p < 0,05). El 30% de aquellos con ANCA positivos tenía diagnóstico de algún tipo de vasculitis, el 20% cursaba con alguna enfermedad autoinmune. CONCLUSIONES: Los resultados indican una solicitud sobreestimada de este marcador como ayuda diagnóstica en consulta de atención primaria no direccionada. Para una adecuada evaluación de ANCA se debe implementar la técnica de inmunofluorescencia indirecta para tamizaje y confirmar con la determinación de antígenos específicos para antiproteinasa 3 y antimieloperoxidasa por cualquiera de los ensayos confirmatorios. La alta concordancia mostrada por CytoBeads® ANCA hace que planteemos el empleo de dicha alternativa para la determinación de ANCA y su confirmación. Dada la interferencia de los ANA, se recomienda solicitar la prueba ANA por inmunofluorescencia indirecta ante la presencia de resultados P-ANCA positivos, con el fin de minimizar «falsos positivos»

BACKGROUND: Antibodies against neutrophil cytoplasm (ANCA) are associated with vasculitis. There are different methods to determine their presence. The interference of antinuclear antibodies (ANA) in the differentiation between P-ANCA and C-ANCA patterns has been described. OBJECTIVE: To determine the frequency of ANCA in a population with manifestations of autoimmune disease, and evaluate the interference of ANA in its interpretation. MATERIALS AND METHODS: Retrospective, descriptive nonexperimental cross-sectional study, including 3,330 data. The presumptive diagnosis was autoimmune disease and a test for ANCA was requested. The ANCA and ANA determinations were made by indirect immunofluorescence, L-ANCA® and CytoBead® ANCA. Anti-proteinase 3 and anti-myeloperoxidase were detected by ELISA and CytoBead® ANCA. RESULTS: ANCAs were positive in 10.21% and 12.64% of those positive for ANCA were positive for ANA. The inter-rater agreement statistic (Kappa) for anti-PR3 between CytoBead ANCA and ELISA was 100% (K=1.00; P<.05) and the agreement between anti- myeloperoxidase by ELISA and CytoBead® ANCA was high (K=0.94; P<.05). 30% of those with ANCAs had a diagnosis of a type of vasculitis; 20% of them had an autoimmune disease. CONCLUSIONS: The results suggest an overestimated request for ANCAs as a diagnostic aid in primary care which was not addressed. For an adequate evaluation of ANCAs, the indirect immunofluorescence technique should be implemented for the control and confirmation with the determination of specific antigens for anti- proteinase 3 and anti- myeloperoxidase in any of the confirmatory assays. The high concordance shown by ANCA CytoBeads makes us consider the use of this alternative for the determination of ANCAs and the confirmation. Given the interference of ANAs, the ANA test by IFI in the presence of positive P-ANCA results is recommended in order to minimize "false positives"

Determination of Subset-Restricted Anti-neutrophil Cytoplasmic Antibodies (ANCA) by Immunofluorescence Cytochemistry.

Neutrophils have long been considered a homogeneous cell type where all circulating cells of a particular individual express the same proteins. Lately, however, this view is changing and distinct neutrophil subsets, defined by the presence or absence of different proteins, are being increasingly recognized. At least two separate protein markers, CD177 and Olfactomedin-4 (OLFM4) are known to be expressed by some, but not all, circulating neutrophils of a given individual. We recently described the existence of subset-restricted serum autoantibodies targeting OLFM4; these were discovered during clinical testing for anti-neutrophil cytoplasmic antibodies (ANCAs). ANCA testing is part of the clinical examinations routinely carried out to support diagnosis of suspected autoimmune conditions, especially vasculitis. Positive sera typically react with all neutrophils from a single donor, whereas subset-restricted ANCA sera (such as those containing anti-OLFM4 antibodies) only react with a fraction of neutrophils. Described in this chapter is an indirect immunofluorescence (IIF) approach to test human sera for the presence of subset-restricted ANCA as well as instructions for costaining experiments using sera and purified antibodies directed against established subset markers.

Nefritis lúpica asociada con c-ANCA / Lupus Nephritis Associated With Cytoplasmic Anti-neutrophil Cytoplasmic Antibodies

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Hepatitis B virus induced cytoplasmic antineutrophil cytoplasmic antibody-mediated vasculitis causing subarachnoid hemorrhage, acute transverse myelitis, and nephropathy: a case report.

BACKGROUND: Transverse myelitis, subarachnoid hemorrhage, and nephropathy are established but rare complications of hepatitis B virus infection that can potentially be triggered by an antibody-mediated vasculitis as a result of a viral infection. The following is a case report detailing a patient presenting with all three of the above presentations who is cytoplasmic antineutrophil cytoplasmic antibody-positive and a chronic carrier of hepatitis B. CASE PRESENTATION: A 33-year-old Nepalese man presented to our hospital with headache, swelling of his body, paraplegia, and back pain that developed over a period of 10 days. Laboratory studies showed proteinuria and elevated levels of serum urea and creatinine. Viral serology was suggestive of chronic inactive hepatitis B carrier state. A computed tomography scan of his head revealed features suggestive of subarachnoid hemorrhage. Magnetic resonance imaging of his dorsal spine showed diffuse T2 high signal intensity within his spinal cord extending from second to 12th thoracic vertebral level which was suggestive of transverse myelitis. The origin of these symptoms was attributed to immune complex-mediated vasculitis after serum analysis for cytoplasmic antineutrophil cytoplasmic antibody came out positive. He was managed with steroids administered orally and intravenously and entecavir administered orally. CONCLUSION: This case highlights the possibility of a hepatitis B virus-induced vasculitis as the cause of subarachnoid hemorrhage, transverse myelitis, and nephropathy.

Plasma exchange in the treatment of Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and renal limited vasculitis.

PURPOSE OF REVIEW: The article reviews the use of plasma exchange (PLEX) in the management of the antineutrophil cytoplasm antibody-associated vasculitides (AAV). RECENT FINDINGS: Early mortality and end-stage renal disease (ESRD) remain frequent outcomes for AAV patients. Demonstration of the pathogenic potential of anti-neutrophil cytoplasm antibody (ANCA) has provided a rationale for antibody removal by PLEX in vasculitis therapy; however, other mechanisms may contribute to the therapeutic effect. Clinical studies have focused on the use of PLEX to rescue organ function in rapidly progressive glomerulonephritis and lung haemorrhage; other indications, including immunomodulatory actions, have received little attention. Randomized controlled trials of PLEX in renal vasculitis suggest a reduction in the risk of development of ESRD with adjunctive PLEX, although the data are not sufficiently strong to make firm recommendations and there are no controlled trials in alveolar haemorrhage. SUMMARY: It is unclear at what severity of renal failure PLEX is beneficial, the optimal PLEX dosing and type and dosing of concomitant medications. These subjects are the focus of an ongoing study (PEXIVAS). PLEX remains a nonselective, expensive therapy with common adverse events. Selective apheresis techniques (cytapheresis, immunoadsorption) offer theoretical advantages but their use is limited by incomplete understanding of the mechanism of PLEX in AAV and expense.

Vasculitis de Jacob Churg y Lotte Strauss. Descripción de 9 casos / Churg-Strauss Vasculitis. Description of 9 cases

Introducción El síndrome de Churg-Strauss (SCS) es una vasculitis que afecta a vasos de pequeño y mediano calibre, caracterizándose clínicamente por afectación predominante del aparato respiratorio, asma y eosinofilia periférica y anatomopatológicamente por la presencia de granulomas y la infiltración tisular por eosinófilos. Objetivos En el presente trabajo se detallan las características de una serie de 9 pacientes con SCS diagnosticados en un centro universitario de referencia. Pacientes y métodos Estudio retrospectivo: entre 1984 y 2007 se diagnosticaron 9 pacientes con SCS en nuestro centro. De todos ellos se obtuvieron de forma retrospectiva datos epidemiológicos, clínicos, analíticos, estudios anatomopatológicos y tratamiento recibido. Resultados De estos 9 pacientes, 7 eran hombres. La edad media en el momento del diagnóstico fue de 51 años (rango 23–76 años). Ocho de los pacientes tenían antecedente de asma bronquial. Las manifestaciones clínicas más frecuentes fueron las cutáneas (66%), musculoesqueléticas (66%), del sistema nervioso periférico (55%) y las pulmonares (55%). Todos presentaban eosinofilia periférica. Los anticuerpos anticitoplasma de neutrófilo (ANCA) fueron positivos en 6 pacientes (66%), la mayor parte de ellos con patrón perinuclear en inmunofluorescencia (p-ANCA). Todos los pacientes recibieron tratamiento con glucocorticoides y 8 de ellos requirieron, además, tratamiento inmunosupresor, principalmente ciclofosfamida. Conclusiones En este trabajo se presentan 9 pacientes diagnosticados de SCS. Las manifestaciones clínicas no difieren de las observadas en el resto de series publicadas. Sin embargo, en esta serie se observa una mayor positividad de ANCA. La mayoría de los pacientes fueron tratados con glucocorticoides e inmunosupresores, debiéndose individualizar el tratamiento de cada paciente según el grado de afectación (AU)

Introduction Churg-Strauss Síndrome (SCS) is a necrotizing vasculitis affecting small to medium-sized vessels, characterized by lung involvement, asthma and peripheral blood eosinophilia, and pathologically by the presence of granulomas and eosinophilic infiltrates. Objectives This report analizes the characteristics of 9 patients with SCS diagnosed in an university referral center. Patients and methods Retrospective study. Between 1984 and 2007 nine patients with SCS were diagnosed in our center. Epidemiological, clinical, laboratory test as well as pathologic studies and treatment required were retrospectively analyzed. Results Nine patients (7 males). The mean age at the time of diagnosis was 51 years (range 23–76 years). Eight of these patients had history of asthma. The more frequent organs involved were the skin (66%), musculoesqueletical system (66%), peripheral nervous system (55%) and the lung (55%). All patients presented peripheral eosinophilia. ANCA positivity was demonstrated in 6 patients (66%), most of the patients with the p-ANCA pattern. All patients were treated with corticosteroids, and in 8 immunosupressant treatment was required, mainly cyclophosphamide. Conclusions In this report, 9 patients with SCS are presented. Clinical characteristics are similar with the observed in other reports. We observed a major positivity of ANCA. Most of the patients were treated with corticosteroids and inmunosupresants, but the treatment should be tailored depending on the involvement of the patient (AU)

Laryngopharyngeal reflux mimicking limited wegener granulomatosis

We present a case of subglottic stenosis (SGS) in a young patient with positive ANCA but a wrong diagnosis of Wegener granulomatosis (WG). Instead, she was diagnosed as having laryngopharyngeal reflux (LPR). Pitfalls of ANCA testing in this scenario, the route to diagnosis of LPR and the contribution of this entity to subglottic stenosis (SGS) in WG are discussed. Caution when interpreting ANCA results is mandatory to avoid improper management (AU)

Presentamos un caso de estenosis subglótica (ESG) en una paciente joven con ANCA positivos, pero un diagnóstico erróneo de granulomatosis de Wegener (GW). El caso correspondió a reflujo laringofaríngeo (RLF). Se discuten los falsos positivos de la prueba de ANCA, la ruta diagnóstica del RLF y la contribución de esta entidad a la ESG en GW. Debe tenerse precaución en la interpretación de ANCA para evitar el tratamiento inapropiado (AU)

Antineutrophil cytoplasmic antibodies.

Much like other autoantibodies (eg, anti-double stranded DNA in systemic lupus erythematosus or antiglomerular basement membrane antibodies in Goodpasture's syndrome), antineutrophil cytoplasmic antibodies (ANCA) have provided doctors with a useful serological test to assist in diagnosis of small-vessel vasculitides, including Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and their localised forms (eg, pauci-immune necrotising and crescentic glomerulonephritis). 85-95% of patients with Wegener's granulomatosis, microscopic polyangiitis, and pauci-immune necrotising and crescentic glomerulonephritis have serum ANCA. ANCA directed to either proteinase 3 or myeloperoxidase are clinically relevant, yet the relevance of other ANCA remains unknown. Besides their diagnostic potential, ANCA might be valuable in disease monitoring. In addition, data seem to confirm the long-disputed pathogenic role of these antibodies. Present treatments for ANCA-associated vasculitis are not free from side-effects and as many as 50% of patients relapse within 5 years. Accurate understanding of the key pathogenic points of ANCA-associated vasculitis can undoubtedly provide a more rational therapeutic approach.

Alloimmune neonatal neutropenia: can we afford the consequences of a missed diagnosis?

The incidence of alloimmune neonatal neutropenia (ANN) is poorly defined. The reported incidence is less than or equal to 0.1%. This prospective study of unselected pregnancies found an incidence of 0.81% based on results of screening 247 'full term' cord blood samples. Alloimmune neonatal neutropenia occurred more frequently in this population than expected from published historical data. Advances in techniques for antineutrophil antibody screening may have contributed to the higher incidence found in this study. The frequency of ANN supports increased surveillance and confirmatory serological testing in infants with unexplained neutropenia.

The clinical spectrum of antinuclear antibodies associated with the nuclear dense fine speckled immunofluorescence pattern.

OBJECTIVE: Autoantibodies to lens epithelium-derived growth factor (LEDGF) depict a distinctive nuclear dense fine speckled (DFS) pattern in the indirect immunofluorescence antinuclear antibody assay (IIF-ANA). Definition of the clinical spectrum associated with anti-LEDGF antibodies has been evolving over the last decade. We investigated the frequency, clinical spectrum, and immunologic specificity of the DFS pattern in a general clinical laboratory routine. METHODS. All serum samples entered for IIF-ANA determination within a 2 year period were examined for the DFS pattern. Positive samples with consistent clinical information were studied further by IIF with isotype-specific conjugate and immunoblot analysis. RESULTS: Among 13,641 ANA-positive samples, 5081 (37%) presented the DFS pattern. Within a 6 month nested period, there were 650 samples with DFS pattern, and consistent clinical data were available for 81 of these. DFS reactivity was mainly due to IgG. Most samples (86%) presented titer > or = 1/640. Eighty of the 81 DFS samples reacted with a 75 kDa band that comigrated with the band elicited by the standard anti-LEDGF serum. Antibodies that were affinity-purified from the 75 kDa band reproduced the DFS pattern on IIF-ANA. The clinical spectrum associated with DFS reactivity included autoimmune diseases (39%) and an array of nonautoimmune conditions (61%). Among the autoimmune patients, over half presented evidence of autoimmune thyroiditis. CONCLUSION: Anti-LEDGF/p75 antibodies are a common finding among ANA-positive individuals with no evidence of rheumatic autoimmune disease, and should be regarded as a low specificity finding even when in moderate or high titer.

Vasculitis asociadas a ANCA en artritis reumatoide. Descripción de un caso de poliangeitis microscópica y otro de enfermedad de Wegener / Vasculitis associated with anti-neutrophil cytoplasmic autoantibodies in rheumatoid arthritis. Report of a case of microscopic polyangiitis and another case of Wegener’s granulomatosis

La vasculitis es una complicación infrecuente de la artritis reumatoide que se asocia con un aumento claro de la morbimortalidad, aunque son muy raras las manifestaciones sistémicas como glomerulonefritis, vasculitis cerebral o vasculitis pulmonar. A su vez, las vasculitis sistémicas con afectación renal se asocian en menos del 5% a poliartritis franca y la asociación con artritis reumatoide es excepcional. La determinación de los anticuerpos anticitoplasma de neutrófilo (ANCA), utilizados en el contexto clínico apropiado, se ha convertido en una importante herramienta diagnóstica de las vasculitis sistémicas de pequeño vaso. Presentamos 2 pacientes diagnosticados de artritis reumatoide que posteriormente desarrollaron vasculitis sistémica, en los que la determinación de ANCA fue decisiva en el diagnóstico precoz(AU)

Vasculitis is an uncommon complication of rheumatoid arthritis that is associated with a clear increase in morbidity and mortality, although systemic manifestations such as glomerulonephritis, cerebral vasculitis or pulmonary vasculitis are very rare. Systemic vasculitis with renal involvement is associated with overt polyarthritis in less than 5% and association with rheumatoid arthritis is exceptional. Determination of anti-neutrophil cytoplasmic autoantibodies (ANCA), used in the appropriate clinical context, has become an important diagnostic tool in small-vessel systemic vasculitides. We present two patients with rheumatoid arthritis who subsequently developed systemic vasculitis. ANCA determination was decisive in the early diagnosis of these patients(AU)

Use of extracorporeal membrane oxygenation in a patient with diffuse alveolar hemorrhage.

Extracorporeal membrane oxygenation (ECMO) was developed as a supportive therapy for severe respiratory failure. It has been shown to be life-saving in neonates and children with isolated respiratory failure, however, its usefulness in adults remains controversial. We report the successful use of ECMO in an adult patient with severe hypoxemic respiratory failure secondary to diffuse alveolar hemorrhage from Wegener granulomatosis.

Anti-neutrophil cytoplasmic antibodies (ANCA) in malaria.

Various autoantibodies like anti-nuclear antibodies (ANA), anti-double stranded DNA (anti-dsDNA), anti-histone antibodies (AHA), anti-neutrophil cytoplasmic antibodies (ANCA), anti-myeloperoxidase (anti-MPO), anti-proteinase3 (anti-PR3) and anti-lactoferrin (anti-LF) antibodies were studied in 173 acute hospitalised patients suffering from malaria of which 160 patients had P. falciparum and remaining 13 had P. vivax infection. Standard methods like indirect immunofluorescence (IIF) microscopy along with Confocal microscopy and ELISA were used for identifying and quantifying the autoantibodies and IIF patterns on PMN and HL-60 cells were studied for ANCA classification. Also HEp-2 cells were used for ANA detection, while estimation of anti-dsDNA, AHA, anti-MPO, anti-PR3 and anti-LF were tested using ELISA. Sera from malaria patients showed prominent immunofluorescence staining patterns where 23.8% cases had ANA in P. falciparum group as compared to 15.4% in P. vivax group and ANCA was found to be present in 20% in P. falciparum and 15.4% in P. vivax group. An interesting observation was that, of the total ANCA positives, 59% had p-ANCA, 5.9% had c-ANCA and 44.1% of the cases showed the 'atypical' or X-ANCA pattern. When p-ANCA positivity was compared with c-ANCA positivity among these patients, a good statistical correlation was noted with OR = 16, chi 2 = 16.43, EF = 0.46 and p-value = 5.037E 0.5. ELISA showed 31.2% anti-MPO and 6.2% anti-PR3 in P. falciparum cases while the two ANCA positive cases in P. vivax had anti-MPO. Anti-LF was found to be present in 40.6% cases. Neither the P. falciparum nor P. vivax contained autoantibodies with specificities similar to the characteristic lupus autoantibodies such as double stranded DNA (dsDNA). ANCA positivity develops in some types of malarial infection also with the presence of various autoantibodies which is important from a clinical point of view and should be carefully evaluated in those geographic areas where malaria is endemic. It also alerts us to the fact, whether in cases of repeated malarial infections in susceptible individuals, vasculitic disorders, which through ANCA pathways develop, could lead to renal and other complications.

Caso clínico de vasculitis C-ANCA / Clinic case of vasculitis C-ANCA

Paciente de sexo femenino, de 26 años de edad, con antecedentes de rinitis y cuadros de obstrucción bronquial estacionales que presentó cuadro de úlceras en extremidades inferiores, asociadas a compromiso pulmonar en base a hemoptisis e imágenes radiológicas anormales transitorias, eosinofilia al frotis de sangre periférico y c-ANCA positivo y que responde favorablemente a la terapia con corticoides e inmunosupresores

How and why should we detect ANCA?

Antineutrophil cytoplasmic antibodies (ANCA) have become an established tool for the diagnosis of systemic vasculitis. The major role for ANCA testing is in diagnosing renal insufficiency of unknown origin, where a positive test indicates whether the patient will benefit from immunosuppressive treatment or not. A negative test result almost completely rules out the presence of systemic vasculitis. In this clinical setting the major antigens for ANCA are proteinase 3 and myeloperoxidase, and antibodies to these antigens can best be tested by ELISA. In other clinical settings like inflammatory bowel disease, arthritis and so on, several other ANCA specificities have been described and the IIF test is preferred. However, the clinical value of these somewhat more esoteric specificities is doubtful. New developments in assay techniques and better knowledge of specific epitopes will lead to tools for the improved diagnosis as well as follow up of patients during treatment, as has already been seen with the capture assay for PR3-ANCA.

Induction of neutrophil responsiveness to myeloperoxidase antibodies by their exposure to supernatant of degranulated autologous neutrophils.

Antibodies against myeloperoxidase (MPO) and proteinase 3 (PR3) are the predominant autoantibodies present in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Their binding to the corresponding antigen on the surface of polymorphonuclear neutrophils (PMNs) is believed to trigger the disease process. Cytokines released during an inflammatory reaction are thought to prime resting PMNs, making them responsive to autoantibodies. In the present study we found that MPO but not PR3 could be detected on the cell surface of unstimulated PMNs after incubation with the supernatants of activated autologous PMNs. MPO was shown to be acquired from these supernatants, because PMNs did not express MPO when the supernatants were specifically MPO-depleted. In addition, purified soluble MPO bound to unstimulated PMNs. Unstimulated PMNs that had passively acquired MPO released oxygen radicals when incubated with monoclonal antibody anti-MPO or the immunoglobulin G fraction of a patient with MPO-ANCA. The data presented here suggest that, in ANCA-associated vasculitis, soluble MPO released by activated PMNs may bind to unstimulated PMNs, thereby making them reactive to anti-MPO antibodies. This mechanism of dispersing PMN activation would be specific for MPO-ANCA and may explain differences in the pathologic and clinical expression of MPO-ANCA versus PR3-ANCA vasculitis. (Blood. 2000;96:2822-2827)