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Hb &#8211; of 9&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#41; and blood tests showed serum creatinine&#40;sCr&#41; of 1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL &#40;previous sCr 0&#46;89<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41;&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">At the hospital admission&#44; initial examination was unremarkable&#44; except for signs of dehydration&#46; Blood tests revealed sCr of 4&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#44; metabolic acidosis with acidemia&#44; hyperkalemia and anemia &#40;Hb 7&#46;8<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#41;&#46; C-reactive protein and sedimentation rate were elevated and serum albumin was decreased &#40;2&#46;9<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#41;&#46; Urine exam had a protein-creatinine ratio of 2&#46;1<span class="elsevierStyleHsp" style=""></span>g&#47;g crea&#44; erythrocyturia and leukocyturia&#46; Renal ultrasound was normal&#46; After intravenous fluids and hypokalemic measures&#44; the kidney function stabilized on sCr of 3&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46; Further investigation revealed elevated serum IgG &#40;1714<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41; and serum myeloperoxidase-ANCA &#91;66 &#40;&#60;20<span class="elsevierStyleHsp" style=""></span>U&#47;Q&#41;&#93;&#46; Proteinase 3-ANCA and anti-glomerular basement membrane antibodies were negative&#46; On light microscopy kidney biopsy showed a severe interstitial lymphoplasmacytic infiltrate and cellular crescentic lesions &#40;4&#47;8&#41; &#8211; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46; There were no signs of storiform pattern of fibrosis or obliterative phlebitis&#46; The immunofluorescence revealed granular deposits for C3 &#40;&#43;&#43;&#41; on tubules&#44; Bowman capsule and glomerular mesangium&#46; The immunohistochemical study revealed &#62;30 IgG4 positive plasmocytes per large magnification field&#46; Assuming AAV&#44; the patient started methylprednisolone for three days &#40;500<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; and then 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day of oral prednisolone&#46; The diagnosis of microscopic polyangiitis was made according to the EUVAS classification criteria&#46; Further results of subclasses of IgG revealed IgG1 elevated and normal IgG2&#44; IgG3 and IgG4&#46; Given the severity of the disease&#44; the patient was proposed to Rituximab &#40;375<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#41;&#46; After 2-weeks of treatment&#44; the patient showed improvement of kidney function &#40;sCr 2&#46;8<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41; and reduction of proteinuria &#40;&#60;1<span class="elsevierStyleHsp" style=""></span>g&#47;day&#41;&#46; In the three-months following rituximab&#44; the patient had several infectious complications &#40;urinary&#44; pulmonary&#44; CMV with hepatic involvement&#41;&#44; with increasing severity and requiring prolonged hospitalization&#46; Unfortunately&#44; in the last hospitalization&#44; she had a cardiorespiratory arrest and died&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">The AAV is characterized by inflammation and destruction of small- and medium-sized blood vessels and the presence of circulating ANCA&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">1</span></a> Although the glomerulus is the most affected&#44; it is common to see tubulointerstitial injury&#44; especially if there is a rupture of Bowman&#39;s capsule&#46; In rare cases&#44; the tubulointerstitial involvement is extensive and not associated with glomerular damage&#46; A recent study described the degree of plasma cell infiltrate in AAV and 2&#47;3 of the cases had at least 15&#37; of plasma cell infiltrate and some had over 45&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">2</span></a> Neutrophils and ANCA are the main mediators of vessel injury&#44; but plasma cells seem to have a role in AAV-GN&#44; although not clearly understood&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">1</span></a> It was proposed that B-cells producing ANCA autoantibodies are selected in an inflamed microenvironment and mature to pathogenic plasma cells producing proinflammatory ANCA&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">3</span></a> This role in local inflammation might be the early acute lesion in AAV-GN&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">2&#44;4</span></a> Moreover&#44; serum IgG4 elevation has also been associated to active AAV and was proposed as a biomarker of AAV activity&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">5</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">IgG4-RD&#44; on the other hand&#44; is a lymphoproliferative disease characterized by the infiltration of IgG4-positive plasma cells and elevation of serum IgG4&#47;IgG levels&#46; A dense lymphoplasmacytic infiltrate is the hallmark&#44; but the specificity of this lesion remains controversial&#46; The storiform pattern of fibrosis and obliterative phlebitis are more specific lesions and the presence of two of these three major features are required for a more confident diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">6</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Although our patient had histologic features and serologic criteria of IgG4-RD&#44; we do not believe that there is an overlap of AAV and IgG4-RD&#46; Plasma cells and IgG4 seem to have a more important role in AAV pathogenesis that we though previously&#46; We would like to highlight the importance of a careful examination to distinguish between IgG4-RD and tubulointerstitial nephritis caused by AAV&#44; and not overdiagnose IgG4-RD&#46; The differential diagnosis of these entities it is crucial in terms of treatment and prognosis&#44; since AAV require a more aggressive immunosuppression&#44; given its severity&#44; and presents a worse outcome&#44; particularly with renal involvement&#46;</p></span>"
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Letter to the Editor
ANCA-associated vasculitis and Igg4-related disease: An overlap syndrome or two distinct diseases?
Vasculitis ANCA positivas y Enfermedad relacionada con IgG4: ¿un síndrome de superposición o dos enfermedades distintas?
Inês Sala
Autor para correspondencia
inessala@gmail.com

Corresponding author.
, Joana Freitas, João Oliveira, Josefina Santos, Ana Castro, António Cabrita
Nephrology, Centro Hospitalar Universitário do Porto, Portugal
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Hb &#8211; of 9&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#41; and blood tests showed serum creatinine&#40;sCr&#41; of 1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL &#40;previous sCr 0&#46;89<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41;&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">At the hospital admission&#44; initial examination was unremarkable&#44; except for signs of dehydration&#46; Blood tests revealed sCr of 4&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#44; metabolic acidosis with acidemia&#44; hyperkalemia and anemia &#40;Hb 7&#46;8<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#41;&#46; C-reactive protein and sedimentation rate were elevated and serum albumin was decreased &#40;2&#46;9<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#41;&#46; Urine exam had a protein-creatinine ratio of 2&#46;1<span class="elsevierStyleHsp" style=""></span>g&#47;g crea&#44; erythrocyturia and leukocyturia&#46; Renal ultrasound was normal&#46; After intravenous fluids and hypokalemic measures&#44; the kidney function stabilized on sCr of 3&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46; Further investigation revealed elevated serum IgG &#40;1714<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41; and serum myeloperoxidase-ANCA &#91;66 &#40;&#60;20<span class="elsevierStyleHsp" style=""></span>U&#47;Q&#41;&#93;&#46; Proteinase 3-ANCA and anti-glomerular basement membrane antibodies were negative&#46; On light microscopy kidney biopsy showed a severe interstitial lymphoplasmacytic infiltrate and cellular crescentic lesions &#40;4&#47;8&#41; &#8211; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46; There were no signs of storiform pattern of fibrosis or obliterative phlebitis&#46; The immunofluorescence revealed granular deposits for C3 &#40;&#43;&#43;&#41; on tubules&#44; Bowman capsule and glomerular mesangium&#46; The immunohistochemical study revealed &#62;30 IgG4 positive plasmocytes per large magnification field&#46; Assuming AAV&#44; the patient started methylprednisolone for three days &#40;500<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; and then 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day of oral prednisolone&#46; The diagnosis of microscopic polyangiitis was made according to the EUVAS classification criteria&#46; Further results of subclasses of IgG revealed IgG1 elevated and normal IgG2&#44; IgG3 and IgG4&#46; Given the severity of the disease&#44; the patient was proposed to Rituximab &#40;375<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#41;&#46; After 2-weeks of treatment&#44; the patient showed improvement of kidney function &#40;sCr 2&#46;8<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41; and reduction of proteinuria &#40;&#60;1<span class="elsevierStyleHsp" style=""></span>g&#47;day&#41;&#46; In the three-months following rituximab&#44; the patient had several infectious complications &#40;urinary&#44; pulmonary&#44; CMV with hepatic involvement&#41;&#44; with increasing severity and requiring prolonged hospitalization&#46; Unfortunately&#44; in the last hospitalization&#44; she had a cardiorespiratory arrest and died&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">The AAV is characterized by inflammation and destruction of small- and medium-sized blood vessels and the presence of circulating ANCA&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">1</span></a> Although the glomerulus is the most affected&#44; it is common to see tubulointerstitial injury&#44; especially if there is a rupture of Bowman&#39;s capsule&#46; In rare cases&#44; the tubulointerstitial involvement is extensive and not associated with glomerular damage&#46; A recent study described the degree of plasma cell infiltrate in AAV and 2&#47;3 of the cases had at least 15&#37; of plasma cell infiltrate and some had over 45&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">2</span></a> Neutrophils and ANCA are the main mediators of vessel injury&#44; but plasma cells seem to have a role in AAV-GN&#44; although not clearly understood&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">1</span></a> It was proposed that B-cells producing ANCA autoantibodies are selected in an inflamed microenvironment and mature to pathogenic plasma cells producing proinflammatory ANCA&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">3</span></a> This role in local inflammation might be the early acute lesion in AAV-GN&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">2&#44;4</span></a> Moreover&#44; serum IgG4 elevation has also been associated to active AAV and was proposed as a biomarker of AAV activity&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">5</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">IgG4-RD&#44; on the other hand&#44; is a lymphoproliferative disease characterized by the infiltration of IgG4-positive plasma cells and elevation of serum IgG4&#47;IgG levels&#46; A dense lymphoplasmacytic infiltrate is the hallmark&#44; but the specificity of this lesion remains controversial&#46; The storiform pattern of fibrosis and obliterative phlebitis are more specific lesions and the presence of two of these three major features are required for a more confident diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">6</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Although our patient had histologic features and serologic criteria of IgG4-RD&#44; we do not believe that there is an overlap of AAV and IgG4-RD&#46; Plasma cells and IgG4 seem to have a more important role in AAV pathogenesis that we though previously&#46; We would like to highlight the importance of a careful examination to distinguish between IgG4-RD and tubulointerstitial nephritis caused by AAV&#44; and not overdiagnose IgG4-RD&#46; The differential diagnosis of these entities it is crucial in terms of treatment and prognosis&#44; since AAV require a more aggressive immunosuppression&#44; given its severity&#44; and presents a worse outcome&#44; particularly with renal involvement&#46;</p></span>"
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