Rheumatology key message Whipple’s disease with systemic involvement can mimic granulomatosis with polyangiitis. Sir, Whipple’s disease is an extremely rare condition (3 cases/1 000 000 inhabitants in Northern Italy ), often presenting with non-specific systemic symptoms such as fatigue, weight loss and arthralgia. This is also why most patients suffering from this disease are correctly diagnosed only after several months to years . Herein, we report the case of a 43-year-old man who was referred to our unit with a diagnosis of refractory ANCA-associated granulomatous vasculitis. The patient had a history of childhood-onset asthma and was a heavy smoker. In 2011 he started complaining of diffuse low-back pain and arthralgia, particularly involving the IP joints of the hands, often with an asymmetrical and migratory pattern. He received a tentative diagnosis of HLA B27-negative spondyloarthritis and was treated with MTX, steroids and NSAIDs. In March 2016 he developed palpable purpura of the lower limbs of suspected vasculitic origin (no skin biopsy was performed), generalized lymphadenopathy, abdominal pain and fever, with blood tests showing an increase in neutrophil count and inflammatory markers. Autoimmunity tests were negative. A lymph node biopsy and an oesophagogastroduodenoscopy were performed, the first demonstrating a granulomatous necrotizing lymphadenitis (Fig. 1B), the latter showing mild gastritis. He was thus diagnosed with ANCA-negative granulomatous vasculitis and treated with prednisolone (initial dose, 75 mg/day, tapered during the following months) and MTX (15 mg/week); MTX was stopped in December 2016 and AZA was prescribed, but the patient refused to take it and continued with prednisone alone. Fig. 1 View largeDownload slide Radiological and histological findings Whole-body contrast-enhanced CT (coronal view) with thoracic and abdominal axial slices: CT allows a reliable and comprehensive visualization of lymphadenopathies. Arrowheads indicate round enlarged lymph nodes in the mediastinum (i) and (ii), as well as in the peritoneal space (iii) and (iv) (A). Granulomatous necrotizing lymphadenitis—original magnification 10×, haematoxylin eosin staining (B). PAS-positive macrophages infiltrating the lymph node—original magnification 10×, PAS staining (C). Massive infiltration by foamy PAS-positive macrophages in the lamina propria of the duodenum—original magnification 10×, PAS staining (D) and 40×, PAS staining (E). PAS: periodic acid–Schiff. Fig. 1 View largeDownload slide Radiological and histological findings Whole-body contrast-enhanced CT (coronal view) with thoracic and abdominal axial slices: CT allows a reliable and comprehensive visualization of lymphadenopathies. Arrowheads indicate round enlarged lymph nodes in the mediastinum (i) and (ii), as well as in the peritoneal space (iii) and (iv) (A). Granulomatous necrotizing lymphadenitis—original magnification 10×, haematoxylin eosin staining (B). PAS-positive macrophages infiltrating the lymph node—original magnification 10×, PAS staining (C). Massive infiltration by foamy PAS-positive macrophages in the lamina propria of the duodenum—original magnification 10×, PAS staining (D) and 40×, PAS staining (E). PAS: periodic acid–Schiff. In March 2017 the patient was hospitalized for fever and severe weight loss. He underwent colonoscopy, which was reported as negative. Autoimmunity tests showed C-ANCA positivity (1:10 titre) with positive anti-PR3 antibodies (14 U/ml with EliA method; negative if <7 U/ml, positive if >10 U/ml), while all the other autoimmune tests (anti-nuclear, anti-mitochondrial, anti-smooth muscle, anti-liver/kidney-microsome, anti-dsDNA, anti-gliadin, anti-transglutaminase antibodies and cryoglobulins) were negative. Serum IgM for Rubella, CMV, HSV and EBV, and IgM for Toxoplasma were negative. Given the ANCA-positivity, the initial suspicion of granulomatous vasculitis became stronger and the patient was therefore diagnosed as having ANCA-positive granulomatosis with polyangiitis (GPA). Prednisone (initial dose, 50 mg/day) and CYC (50 mg/day) were started. Since the patient’s symptoms worsened after a month of treatment, in April 2017 he came to our centre for further evaluation. His major complaints were weight loss (20 kg over the previous 6 months), abdominal pain, diarrhoea, arthralgia and low-grade fever. Reassessing his clinical history, we considered that his clinical, serological and histological data were not consistent with GPA; we thus discontinued CYC and reduced the prednisone dose. Our lab tests demonstrated thrombocytosis (698 000/µl) and confirmed the increase in neutrophil count (white blood cell count 20 210/µl, neutrophils 78%); CRP was 55 mg/l and ESR 66 mm/h; ANCA were negative, using both immunofluorescence and ELISA for PR3 and MPO antibodies. Whole-body contrast-enhanced CT showed diffuse lymphadenopathies (Fig. 1A) and thus we repeated a lymph node biopsy (right supra-clavear lymph node), which on histological examination showed massive infiltration by foamy periodic acid–Schiff-positive macrophages (Fig. 1C), while the granulomatous and the necrotizing features that characterized the first biopsy (Fig. 1B) had disappeared. Oesophagogastroduodenoscopy was therefore repeated: marked infiltration by foamy periodic acid–Schiff-positive macrophages was found at the level of the intestinal mucosa (Fig. 1D and E). Based on these histological (intestinal and lymph node) findings, we eventually made a diagnosis of Whipple’s disease. We also considered that clinical manifestations such as arthralgia, systemic symptoms, diarrhoea and weight loss, as well as lymphadenopathies, were all compatible with Whipple’s disease. Arthralgia started a few years before the correct diagnosis, as previously reported . The patient was started on intramuscular ceftriaxone (2 g/day) for 2 weeks followed by oral co-trimoxazole (800–160 mg twice a day). Since the patient was previously treated with immunosuppressive drugs, prednisone was increased to 25 mg/day and slowly tapered down, to reduce the risk of an immune reconstitution inflammatory syndrome . His symptoms dramatically subsided. At last follow-up visit, 5 months after the beginning of therapy, he had no diarrhoea and had gained 15 kg. His blood count and ESR were normal, while his CRP level was still increased. Arthralgia persisted, requiring prednisone (10 mg/day). The diagnosis of GPA may be difficult when classical manifestations such as upper respiratory tract or renal involvement are absent. Our patient’s signs and symptoms could be interpreted as atypical manifestations of the disease: he had multi-organ manifestations compatible with vasculitis (palpable purpura, arthralgia, fever, gastrointestinal symptoms including chronic diarrhoea and marked weight loss), a granulomatous necrotizing process involving multiple lymph nodes and low titre PR3-ANCA. However, since ANCA can be positive in several conditions other than GPA , clinicians should not use them as diagnostic of vasculitis. As demonstrated by our case and by previous reports [5, 6], Whipple’s disease can mimic an atypical form of GPA, and in patients suffering from the disease C-ANCA may be present. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. References 1 Biagi F , Balduzzi D , Delvino P et al. Prevalence of Whipple’s disease in North-Western Italy . Eur J Clin Microbiol Infect Dis 2015 ; 34 : 1347 – 8 . Google Scholar CrossRef Search ADS PubMed 2 Marth T , Moos V , Müller C , Biagi F , Schneider T. Tropheryma whipplei infection and Whipple’s disease . Lancet Infect Dis 2016 ; 16 : e12 – 21 . Google Scholar CrossRef Search ADS 3 Puéchal X. Whipple’s disease . Ann Rheum Dis 2013 ; 72 : 797 – 803 . Google Scholar CrossRef Search ADS PubMed 4 Gaffo AL. Diagnostic approach to ANCA-associated vasculitides . Rheum Dis Clin North Am 2010 ; 36 : 491 – 506 . Google Scholar CrossRef Search ADS PubMed 5 Relandison S , Fabre S , Colcombet C , Cohen JD , Jorgensen C. ANCA positive polyarthritis revealing Whipple’s disease . Clin Exp Rheumatol 2008 ; 26 (Suppl 49) : 154 . 6 Agard C , Brisseau JM , Grossi O et al. Two cases of atypical Whipple’s disease associated with cytoplasmic ANCA of undefined specificity . Scand J Rheumatol 2012 ; 41 : 246 – 8 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: firstname.lastname@example.org This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
Rheumatology – Oxford University Press
Published: Mar 20, 2018
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