Scientific Letter
Diffuse Alveolar Hemorrhage: A Case of Overlap Syndrome of ANCA-Associated Vasculitis in Diffuse Systemic Sclerosis
Hemorragia alveolar difusa: un caso de síndrome de superposición de vasculitis asociada a ANCA y esclerosis sistémica difusa
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Prof. Egas Moniz, n/s, 1649/035 Lisboa, Portugal" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Rheumatology Department in Centro Hospitalar Universitário Lisboa Norte, EPE, Av. Prof. Egas Moniz, n/s, 1649/035 Lisboa, Portugal" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Hemorragia alveolar difusa: un caso de síndrome de superposición de vasculitis asociada a ANCA y esclerosis sistémica difusa" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Systemic sclerosis (SSc) is an autoimmune disorder associated with chronic inflammation and vasculopathy that may progress to visceral fibrosis of multiple organs, most commonly the kidneys, lungs and heart.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">1</span></a> Pulmonary manifestations of SSc include pulmonary hypertension (PH) and interstitial lung disease.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">2,3</span></a> It is characterized by autoantibody production, such as anti-centromere or anti-Scl70 antibodies, which are of prognostic and clinical relevance.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAVs) such as granulomatous polyangiitis, microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis are autoimmune disorders characterized by small vessels’ inflammation which is directly associated with ANCA production.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">4</span></a> Diffuse alveolar hemorrhage (DAH) and rapidly progressive glomerulonephritis are clinical manifestations of those AAVs, which can be life-threatening.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The presence of ANCA in SSc is uncommon and its clinical significance is controversial, because in spite of its presence, only a minority of patients will develop AAVs.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">1,4</span></a> These overlap syndromes are rare and associated with high mortality, so a prompt and strict follow-up is extremely important. Corticosteroids induce a good response, but sometimes cyclophosphamide and plasmapheresis are needed.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The authors present the case of a sixty-two-year-old man, previous smoker of twenty packs/year, retired from automobile painter and construction. He had been diagnosed with ischemic cerebellar stroke, atrial flutter and SSc with diffuse cutaneous, polyarticular and interstitial lung involvement. Serologically characterized by antiScl70 antibody positivity. Previously medicated with methotrexate and azathioprine, both suspended because of lack of effectiveness and side effects, and cyclophosphamide in 2014 with good response. Before the present hospitalization he was on mycophenolate mofetil. Following the suspicion of PH in 2017 a right heart catheterization (RHC) was performed, revealing a mean pulmonary artery pressure (mPAP) of 22<span class="elsevierStyleHsp" style=""></span>mmHg. The patient remained on clinical and echocardiographic monitoring at the pulmonary hypertension clinic.</p><p id="par0025" class="elsevierStylePara elsevierViewall">In January 2019, the patient referred gradual worsening of dyspnea, orthopnea and leg edemas, presenting with tachypnea, diminished pulmonary sounds and crackles. Vital signs were normal apart from peripheral desaturation of 84% at room air. The patient was admitted to our intermediate care unit. Arterial blood gases presented with hypoxemia and hypocapnia, blood test showed no signs of infection, GFR was 85<span class="elsevierStyleHsp" style=""></span>mL/min and NT-proBNP 2591<span class="elsevierStyleHsp" style=""></span>pg/mL. Initial X-ray revealed diffuse alterations suggesting fibrosis and right pleural effusion. The thoracic angio-computerized tomography (CT) maintained a stable non-specific interstitial pneumonia pattern, with no thromboembolic pulmonary disease, thus documenting no deterioration when compared with previous imaging; lung function tests were normal, as previously documented, except for the <span class="elsevierStyleItalic">Diffusing Capacity for Carbon Monoxide</span> (DLCO) of 21%; echocardiogram documented a pulmonary artery systolic pressure (PSAP) of 65<span class="elsevierStyleHsp" style=""></span>mmHg, good systolic function of left ventricle, with an ejection fraction of 68%, and diminished systolic function of the right ventricle because of hypokinetics of the free wall. Re-evaluation by RHC showed pre-capillary PH with a mPAP of 31<span class="elsevierStyleHsp" style=""></span>mmHg, capillary wedge pulmonary pressure (CWPP) of 9<span class="elsevierStyleHsp" style=""></span>mmHg, cardiac index (CI) of 1.3<span class="elsevierStyleHsp" style=""></span>L/min/m<span class="elsevierStyleSup">3</span> and a pulmonary vascular resistance (PVR) of 9.1 Wood units (Wu). Right heart failure in the context of newly diagnosed PH was assumed and high dose diuretics were initiated. Etiological classification pointed toward group 1 PH<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">6</span></a> despite the pulmonary interstitial involvement, because FVC was >70%<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">7</span></a> and DLCO was disproportionately low with a FVC/DLCO ratio of 4.0 (>2.55).<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">8</span></a> Nevertheless, interstitial involvement was extensive on imaging tests and group 3<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">6</span></a> was also considered possible. Sildenafil was initiated at a dose of 75<span class="elsevierStyleHsp" style=""></span>mg/day. Despite initial improvement, on the eleventh day of admission the patient had moderate hemoptysis with worsening respiratory failure that needed high flow nasal cannula oxygen with a FiO<span class="elsevierStyleInf">2</span> of 100%. Hemoglobin level decreased 1.1<span class="elsevierStyleHsp" style=""></span>g and X-ray presented with diffuse infiltrates. Angio-CT revealed ground glass bilateral opacities predominant on the upper lobes, compatible with alveolar hemorrhage, with no signs of arterial thrombi. On blood analysis there was elevated C-reactive protein and neutrophilia, without leukocytosis. Renal function remained normal. Later on, the lupic anticoagulant, anticardiolipin antibody as well as anti-beta2glycoprotein1, anti-CPP, anti-GBM and ANA antibodies results were negative, while antibodies anti-Scl70 and anti-proteinase, PR3, (92<span class="elsevierStyleHsp" style=""></span>IU/mL) were positive. Bronchoscopy for bronchoalveolar lavage was not possible because of the severity of the respiratory failure. Large spectrum antibiotics were initiated. Methylprednisolone 1<span class="elsevierStyleHsp" style=""></span>g/day was also initiated, followed by prednisolone with slight improvement. There were many risk factors for DAH, such as the ongoing long-term hypocoagulating therapy, which was immediately stopped without any improvement; vasculitic phenomena in the context of the SSc itself<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">9,11</span></a>; the aggravated PH<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">11</span></a> and even the recent introduction of sildenafil.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">10</span></a> As many of those diagnosis would be by exclusion, the finding of PR3 positivity led to the suspicion of an overlap with AAV. The case was discussed at the multidisciplinary meeting and it was decided to initiate cyclophosphamide, leading to a gradual but clinically relevant improvement. The patient was discharged with long-term oxygen therapy with 1<span class="elsevierStyleHsp" style=""></span>L/min at rest and 6<span class="elsevierStyleHsp" style=""></span>L/min on exertion. Therapy with prednisone 20<span class="elsevierStyleHsp" style=""></span>mg/day, sildenafil 75<span class="elsevierStyleHsp" style=""></span>mg/day and monthly cyclophosphamide was maintained.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Until 2019 the reported prevalence of ANCA in SSc was between 0 and 12%. Previous studies reported predominance of anti-myeloperoxidase (MPO)<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">2</span></a> antibody, which is contradicted on the cohort from 2019 by Moxey et al., in which the prevalence of PR3 antibody is higher (15.5% against 11.2%).<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">4</span></a> Although the real number of patients manifesting AAVs as an overlap syndrome with SSc is unknown, the reported cases is diminished (0.23% of the entire cohort by Moxey et al., and only 2.6% of ANCA positive patients), and the reason why some ANCA positive patients manifest vasculitic symptoms and others do not, is not clear. Also, renal failure is frequently present,<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">1</span></a> which was not the case in our patient. It is recommended to start therapy with corticosteroids. In more severe cases, other immunosuppressants might be indicated. Cyclophosphamide is the first choice for DAH due to AAV and, in our patient, it had been previously used in the course of his disease with favorable outcome. Although the diagnosis of DAH associated to AAV was not possible to confirm, the good response to the treatment favors it. Other immunosuppressants, such as mycophenolate mofetil and rituximab, can also be used. These patients need a tight surveillance because when rapidly found and treated, rapid progression can be avoided and mortality reduced.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">5</span></a></p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of interest</span><p id="par0035" class="elsevierStylePara elsevierViewall">None.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflict of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:11 [ 0 => array:3 [ "identificador" => "bib0060" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Arad U, Balbir-Gurman A, Doenyas-Barak K, Amit-Vazina M, Caspi D, Elkayam O. <span class="elsevierStyleItalic">Anti-Neutrophil associated vasculitis in systemic sclerosis.</span> Elsevier 2011, <a target="_blank" href="doi:10.1016/j.semarthrit.2010.11.001">doi:10.1016/j.semarthrit.2010.11.001</a>." ] ] ] 1 => array:3 [ "identificador" => "bib0065" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Review article microscopic polyangiitis in systemic sclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "H. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 5 | 2 | 7 |
| 2024 October | 60 | 21 | 81 |
| 2024 September | 65 | 17 | 82 |
| 2024 August | 82 | 56 | 138 |
| 2024 July | 73 | 10 | 83 |
| 2024 June | 79 | 27 | 106 |
| 2024 May | 90 | 29 | 119 |
| 2024 April | 50 | 25 | 75 |
| 2024 March | 56 | 22 | 78 |
| 2024 February | 49 | 37 | 86 |
| 2024 January | 44 | 20 | 64 |
| 2023 December | 51 | 37 | 88 |
| 2023 November | 53 | 20 | 73 |
| 2023 October | 63 | 34 | 97 |
| 2023 September | 56 | 33 | 89 |
| 2023 August | 59 | 37 | 96 |
| 2023 July | 63 | 24 | 87 |
| 2023 June | 58 | 21 | 79 |
| 2023 May | 63 | 26 | 89 |
| 2023 April | 61 | 35 | 96 |
| 2023 March | 79 | 42 | 121 |
| 2023 February | 70 | 16 | 86 |
| 2023 January | 67 | 25 | 92 |
| 2022 December | 93 | 39 | 132 |
| 2022 November | 86 | 31 | 117 |
| 2022 October | 89 | 32 | 121 |
| 2022 September | 64 | 31 | 95 |
| 2022 August | 68 | 46 | 114 |
| 2022 July | 73 | 55 | 128 |
| 2022 June | 59 | 43 | 102 |
| 2022 May | 63 | 29 | 92 |
| 2022 April | 89 | 53 | 142 |
| 2022 March | 98 | 44 | 142 |
| 2022 February | 32 | 22 | 54 |
| 2022 January | 1 | 0 | 1 |
| 2021 October | 3 | 2 | 5 |
| 2021 September | 16 | 11 | 27 |
| 2021 May | 1 | 1 | 2 |
| 2021 March | 3 | 0 | 3 |
| 2021 February | 0 | 2 | 2 |
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