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Simultaneous presentation of IgG4-related chronic peri-aortitis and coeliac disease in a patient with Marfan's Syndrome.

SIR, It is now known that IgG4-related disease is associated with up to two-thirds of cases of idiopathic retroperitoneal fibrosis, which is now classified within a larger disease group called chronic peri-aortitis, the three major components of which are retroperitoneal fibrosis (RPF), abdominal aortitis and perianeurysmal fibrosis [1, 2]. The presence of RPF in patients with Marfan’s syndrome has been described previously, although such cases are rare [3, 4]. However, there are no previously published reports of biopsy proven IgG4-related RPF/chronic peri-aortitis in patients with Marfan’s syndrome, a condition caused by mutations in the extracellular matrix protein fibrillin 1 where aortic root disease, leading to aneurysmal dilatation, aortic regurgitation and dissection, is the main cause of morbidity and mortality [5]. Our patient, a 44-year-old male, presented with abdominal pain, low back pain, weight loss, altered bowel habits and general malaise. He had a genetically proven diagnosis of Marfan’s syndrome since the age of 8 years and required a metallic aortic valve and aortic root replacement aged 35 years. Systemic examination was normal apart from a new presentation of pain and swelling in the left scrotal area, subsequently confirmed as a varicocele. Initial blood monitoring revealed a raised CRP at 36 mg/l (normal<5 mg/l) and ESR at 36 mm/h (normal<7 mm/h). An abdominal CT scan revealed paraaortic soft tissue surrounding the abdominal aorta from below the level of renal arteries and extending to involve the proximal half of each common iliac artery (Fig. 1A). No calcification was seen. F-FDG-PET-CT scanning revealed peri-aortic FDG-avid inflammatory tissue covering the anterior aspect of the abdominal aorta extending down to and cuffing both iliac arteries (Fig. 1B). Subsequent CT angiography excluded a peri-aortic leak. There was no evidence of hydronephrosis. The immunology screen was normal/negative (including a vasculitis screen). Serum IgG was raised at 16.50 g/l (normal 6 16 g/l) and IgM was raised at 2.46 g/l (normal 0.50 2.00 g/l). Although serum IgG3 at 1.68 g/l was raised (normal 0.41 1.29 g/l), IgG4 levels were normal. A repeat CT scan after 6 months demonstrated an increase in diameter of the mass around the abdominal aorta from 14 to 19 mm. This extended to encase the right renal vein, which was not occluded. A CT-guided biopsy of the periaortic mass excluded malignancy and demonstrated thick hyalinized collagen fibres separated by spindle cells, lymphoid infiltrate of CD3-positive T cells and CD20-positive B cells, plasma cells and areas of lymphoid follicles (Fig. 1C). Subsequent immunohistochemistry demonstrated that>50% of plasma cells were IgG4-positive, consistent with a diagnosis of IgG4-related chronic periaortitis and RPF (Fig. 1D). Duodenal biopsy revealed a focal increase in intraepithelial lymphocytes with focal epithelial cell disarray suggesting non-specific chronic inflammation. However, in light of the raised tissue transglutaminase levels at 36 AU/ml, a diagnosis of coeliac disease was considered highly likely. Therapy was commenced with oral prednisolone 40 mg daily and methotrexate, which was later switched to mycophenolate 1 g twice daily due to intolerance. A gluten-free diet was initiated. Our patient’s symptoms have resolved, he has gained weight and the acute phase markers have normalized. Although serial CT angiography of the aorta shows persistent peri-aortic inflammatory tissue, this has reduced in diameter from 19 to 11 mm. Prednisolone has been gradually weaned to 7.5 mg daily. Two principle pathogenic mechanisms have been suggested for RPF [6]. An IgG-mediated allergic inflammatory response to a component of atherosclerotic plaque, which has leaked into the peri-aortic tissues from a thinned or breached aortic media, is considered an important component [4]. This is reflected in the presentation of RPF most commonly in the fifth and sixth decades. Presentation a decade earlier in our patient may reflect aortic changes in Marfan’s, which can be viewed as an accelerated and premature form of aortic ageing. Patients with aneurysms have severe medial degeneration, while those with dissections display mild degrees of cystic medial necrosis. It appears that the association between these two conditions is under-reported, one possible explanation being that mortality in patients of Marfan’s is often premature [5]. The improving long-term survival of patients with Marfan’s syndrome and an awareness of the possible association between RPF and Marfan’s may result in increased reporting of such cases. The evidence for a systemic auto-immune component to RPF pathogenesis and the close association with IgG4-related disease leads us to postulate that in our patient, the emergence of coeliac disease may also be a part of the IgG4-related disease entity. Indeed, a recent study has shown a close correlation between the grade of mucosal damage, IgG4 levels and anti-gliadin-IgA in patients with coeliac disease [7].