IgG4-related disease associated with renal microaneurysms and polycythaemia

Rheumatology key message IgG4-related disease associated with renal vasculitis mimicking polyarteritis nodosa revealed polycythaemia. Sir, In this report, we describe the first case of IgG4-related disease (IgG4-RD) revealed by renal involvement mimicking polyarteritis nodosa with secondary polycythaemia. A 60-year-old Tunisian man was admitted for suspicion of primary SS (pSS) based on sicca symptoms and bilateral parotid gland swelling. His medical history was characterized by high blood pressure and type 2 diabetes. He presented with xerostomia and, for several weeks, unusual headache. Clinical examination revealed Schirmer’s test <5 mm in both eyes, keratoconjunctivitis sicca, painless swollen parotid glands, cervical lymphadenopathy and palmar erythrosis. Biological tests showed polycythaemia, with a haemoglobin level of 20.6 g/dl, haematocrit 60%, 225 000 platelets/mm3, 6180 leucocytes/mm3, including 1220 lymphocytes/mm3. Mutations in the JAK2 V617F gene and exon 12 were not found. The erythropoietin (EPO) level, expected to be very low due to polycythaemia, was within the normal range: 6.3 IU/l (normal 5–25). Creatininemia was normal (87 μmol/l) with a glomerular filtration rate (Modification of Diet in Renal Disease method) estimated at 78 ml/min/1.73 m2, with no proteinuria and no haematuria. Other biological examinations showed hypergammaglobulinemia (21 g/l), normal serum free light chain κ/λ ratio, low C4 level (0.12 g/l; normal 0.18–0.42), but normal C3 level. RF was positive at 189 IU/ml, as well as ANA at 1/320, without specificity. The cryoglobulin tests were negative. HIV, HBV and HCV serologies were negative. Labial minor salivary gland biopsy (MSGB) showed lymphocytic sialadenitis with a focus score of 1.32 without any germinal centre. A computed tomography (CT) scan showed bilateral defects in renal perfusion, associated with micro-aneurysms, without other aortic and periaortic disease (Fig. 1A). Positron emission tomography–CT showed a diffuse abnormal accumulation of 18F-fludeoxyglucose in the kidneys. Renal arteriography confirmed the presence of micro-aneurysms and multiple renal infarctions suggestive of polyarteritis nodosa (PAN)–like renal involvement (Fig. 1B). Renal biopsy was not performed because of the haemorrhagic risk linked to micro-aneurysms. Renal (A) CT, (B) angiography and (C–E) labial minor salivary gland biopsy (A) Abdominal CT showing infiltration of the renal parenchyma and multiple renal infractions. (B) Renal arteriography showing the presence of micro-aneurysms (arrows) and kidney ischaemic lesions with multiple renal infarctions (stars). (C) Minor salivary gland biopsy showing dense periductal lymphoplasmacytic infiltrate on haematoxylin and eosin saffron staining (HES, 400×). Immunostaining for (D) IgG and (E) IgG4 (400×). The majority of IgG+ plasma cells express IgG4. IgG4-related disease was suspected because of the parotid gland swelling in a 60-year-old man with multisystemic manifestations. Diagnosis was confirmed by an increase in the IgG4 serum level to 3.70 g/l (normal 0.04–0.86) and a high IgG4+/IgG+ plasma cell ratio (80%) on histological and immunohistochemical examinations of the MSGB (Fig. 1C–E) and parotid gland. Cervical lymph node biopsy showed an aspect of lymphadenitis with an IgG4+/IgG+ plasma cell ratio of 50%. Glucocorticoids were initiated with prednisolone at a dose of 1 mg/kg body weight/day. Two phlebotomies were necessary to decrease the haematocrit level to <50%. At 6 weeks, his general health and haemoglobin level were normalized (14 g/dl) without any additional phlebotomy. Parotid gland swelling had decreased by 50%. At 6 months, rituximab was initiated at a dose of 1 g 2 weeks apart as a corticoid-sparing agent, because of relapsing parotid gland swelling with a dosage <10 mg/day. IgG4-RD is defined by histopathological analysis of biopsy specimens showing lymphoplasmacytic infiltrate rich in IgG4+ plasma cells that is organized in a storiform pattern [1]. An IgG4+/IgG+ plasma cell ratio >40% is mandatory for histological diagnosis of IgG4-RD. In our observation, swelling parotids in a 60-year-old man suffering from xerostomia and the absence of anti-SSA and anti-SSB antibodies was suggestive of IgG4-RD [2]. In this case, renal PAN-like disease with micro-aneurysms and renal infarction was confirmed by arteriography. In the literature, IgG4-RD arterial lesions may occur, but are located in the thoracic aorta, abdominal aorta to iliac arteries, superior mesenteric artery, inferior mesenteric artery and splenic artery [3]. IgG4-RD may also manifest as idiopathic retroperitoneal fibrosis, inflammatory aortic aneurysm and inflammatory pericarditis [4]. Otherwise, tubulo-interstitial nephritis is the most dominant feature of IgG4-RD kidney involvement and may cause acute or chronic renal dysfunction, although some glomerular lesions such as membranous nephropathy are sometimes found [5, 6]. To our knowledge, PAN-like renal involvement has never been described in IgG4-RD. Interestingly, in a recent review, Saeki et al. [5] stated that most common findings of renal involvement are multiple low-density lesions seen on enhanced CT scans, but our observation is the first to describe micro-aneurysms confirmed by renal arteriography. Moreover, our patient presented with polycythaemia probably due to non-adapted secretion of EPO, in the absence of JAK2 mutations. It is probable that this EPO abnormal secretion was due to IgG4-RD renal involvement, but this hypothesis could not be demonstrated since a renal biopsy was not performed because of the haemorrhagic risk. Normalization of the haemoglobin level with steroid therapy favours this hypothesis [7]. However, renal imaging favoured renal infiltration. We hypothesized that renal interstitial macrophages stimulated local renal EPO-producing cells. Interestingly, it was recently demonstrated that renal EPO-producing cells could also be responsible for fibrosis synthesis [8]. Therefore these cells could be responsible for both renal fibrosis, a key feature in renal IgG4-RD, and the increased EPO production found in our patient. IgG4-RD is a systemic disease with pleotropic manifestations, including renal PAN-like disease complicated by symptomatic secondary polycythaemia. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article. Disclosure statement: The authors declare no conflict of interest.

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