Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a group of rare autoimmune diseases. Although the aetiology of AAV is uncertain, it is likely that genetic and environmental factors contribute. We report the unusual case of two brothers presenting with AAV with differing clinical pictures and differing ANCA specificity. There is a recently identified difference in genetic risk factors associated with ANCA specificity, making it surprising that first-degree relatives develop AAV with differing clinical and serological features. Our report illustrates the complex aetiology of AAV and suggests that further research on the interaction of genetic and environmental factors is needed

Cairns, T

Prendecki, M

Pusey, CD

Clinical Kidney Journal

English

PubMed

Spiral - Imperial College Digital Repository

EXC E PT I ONA L CAS EFamilial vasculitides: granulomatosis with polyangitisand microscopic polyangitis in two brothers withdiffering anti-neutrophil cytoplasm antibody specificityMaria Prendecki, Tom Cairns and Charles D. PuseyImperial College Renal and Transplant Centre, Hammersmith Hospital, London, UKCorrespondence and offprint requests to: Maria Prendecki; E-mail: m.prendecki@imperial.ac.ukAbstractAnti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a group of rare autoimmune diseases. Although theaetiology of AAV is uncertain, it is likely that genetic and environmental factors contribute. We report the unusual case of twobrothers presenting with AAV with differing clinical pictures and differing ANCA specificity. There is a recently identifieddifference in genetic risk factors associated with ANCA specificity, making it surprising that first-degree relatives develop AAVwith differing clinical and serological features. Our report illustrates the complex aetiology of AAV and suggests that furtherresearch on the interaction of genetic and environmental factors is needed.Key words: ANCA, familial, vasculitisBackgroundAnti-neutrophil cytoplasm antibody (ANCA)-associated vascu-litis (AAV) is the term used to describe a group of systemicdiseases characterized by small vessel vasculitis [1]. There arethree clinical syndromes: granulomatosis with polyangitis(GPA); microscopic polyangitis (MPA); and eosinophilic granulo-matosis with polyangitis (EGPA). Within a Caucasian population,GPA is usually associated with antibodies against proteinase-3(PR3), MPA is usually associated with antibodies against myelo-peroxidase (MPO) and EGPA is often associated with anti-MPOantibodies but is sometimesANCAnegative. Renal limited vascu-litis is also recognized with either antibody specificity. These arerare conditions with an annual incidence of around 20 cases permillion within the UK [2]. They are often associated with signifi-cant morbidity and mortality despite progress in immunosup-pressive regimens designed to maximize efficiency and limittoxicity [3]. The aetiology of AAV remains uncertain; however, itis likely that both genetic predisposition and environmental trig-gers are important. There is also mounting evidence for thepathogenicity of ANCA [4]. We report the very unusual occur-rence of two brothers with AAV, but with differing clinical syn-dromes and ANCA types.Case reportsPatient 1A 49-year-old Caucasian man presented as an emergency with a1 day history of severe epistaxis. He had a 3-month history ofnasal congestion, left ear and supraorbital pain, and lethargy.On examination he had bilateral uveitis and episcleritis and afaint purpuric rash over his groin. Flexible nasendoscopy demon-strated copious dried blood and secretions. Urine dipstickshowed 4+ blood and 4+ protein.Received: December 2, 2015. Accepted: February 26, 2016© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA.This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.For commercial re-use, please contact journals.permissions@oup.comClinical Kidney Journal, 2016, vol. 9, no. 3, 429–431doi: 10.1093/ckj/sfw016Advance Access Publication Date: 14 April 2016Exceptional Case429CLINICALKIDNEYJOURNAL at Imperial College London on July 11, 2016http://ckj.oxfordjournals.org/Downloaded from Investigations showed preserved renal function, creatinine91 µmol/L and mild anaemia, haemoglobin 12 g/dL. Inflamma-tory markers were raised, C-reactive protein 368 mg/L anderythrocyte sedimentation rate 119 mm/h. Computed tomog-raphy (CT) chest demonstrated diffuse ground glass infiltratesthroughout both lung fields (Figure 1). CT sinuses showed diffusemucosal thickening of the maxillary sinuses. A diagnosis ofprobable vasculitis was made and the patient was started on30 mg/day of oral prednisolone. Hewas found to be C-ANCA posi-tivewith anti-PR3 titre of 431 IU (normal range <25). He developedhaemoptysis with a fall in his haemoglobin to 10.5 g/dL, andacute kidney injury with peak creatinine 185 µmol/L. Nasalswabs were negative for methicillin-resistant staphylococcalaureus but were not tested for methicillin-sensitive staphylococ-cal aureus.The diagnosis of GPAwasmade and hewas transferred to ourcentre and treated by our current protocol for vasculitis with pul-monary haemorrhage. He received 60 mg/day oral prednisolone,1 g IV cyclophosphamide and ten 4 L plasma exchanges. Renalbiopsy was not performed because of the urgency of startingtreatment. Following discharge he received five further doses ofIV cyclophosphamide (total 4 g) and 2× 1 g IV rituximab (againin keeping with our current protocol). Prednisolone was weanedgradually and stopped by 9 months as he became Cushingoid.He was maintained on azathioprine alone at a dose of 150 mgonce daily. He had some minor infective complications withrecurrent dental infections due to underlying dental carieswhich resolved following tooth extraction. Two and a half yearslater he is in complete remission with a creatinine of 82 µmol/L,although he remains C-ANCApositivewith anti-PR3 titre of 70 IU.Patient 2Six months later the patient’s brother presented at the age of53 yearswith 6weeks ofworsening lethargy,myalgia and arthral-gia. He had a dry cough but no haemoptysis, and weight loss of10 kg. Urine dipstick showed 3+ blood and 1+ protein. Investiga-tions showed acute kidney injury, creatinine 338 µmol/L (nobaseline available but 213 µmol/L when checked by his generalpractitioner 2 days previously). He was P-ANCA positive withanti-MPO titre of 357 IU (normal range <25). CT chest was unre-markable except for a single pulmonary nodule which did notmeet criteria for further investigation. Renal biopsy showedpauci-immune crescentic glomerulonephritis and necrotizingvasculitis (Figure 2).The diagnosis of MPA was made, and he was treated with60 mg/day oral prednisolone, 1 g IV rituximab and 750 mg IVcyclophosphamide. Following discharge he received a further1 g IV rituximab and five further doses of IV cyclophosphamide(total 3.5 g) and was maintained on low-dose oral prednisolone(5 mg/day) and azathioprine 75 mg/day. His treatment was byour current protocol for treatment of patients with vasculitisbut not requiring dialysis and without pulmonary haemorrhage.His treatment course was uneventful with no infectious compli-cations. He remains in remission 2 years later with stable renalfunction (creatinine 140 µmol/L) although still P-ANCA positivewith anti-MPO titre of 40 IU.DiscussionWe describe the occurrence of two different ANCA-associatedvasculitides, GPA and MPA, in two brothers who were broughtup together in West London. They presented within 6 monthsof each other with distinct clinical pictures and differing ANCAspecificity. One brother had renal, pulmonary, and ear, noseand throat (ENT) involvement with positive PR3-ANCA typicalof GPA, and the other brother had positiveMPO-ANCA and clinic-al features in keeping with MPA. They had no significant familyhistory, in particular no history of vasculitis or autoimmune dis-ease. The brothers have a sharedHLAhaplotype ofA*3, B*44, Cw7,DR*11, DQ*7, DQB1*03/05, which to our knowledge has not beenreported to be associated with AAV.There are few previous reports of familial AAV. The majoritydescribe familial clusters of patients presenting separated intime, but with similar clinical phenotypes and the same ANCAtype. We previously reported three members of an Indo-Asianfamily with GPA who all presented with ENT and renal involve-ment [5]. Hay et al. [6] reported on two siblings with GPA, bothwith renal and pulmonary involvement, and Sewell and Hamil-ton [7] reported a mother and daughter with GPA, both withENT and renal involvement. There are even fewer reportedcases of first-degree relatives presentingwith small vessel vascu-litis with different ANCA types. A family reported by Gomes et al.[8] includes a father and daughter who both presented with renaldisease; one was anti-PR3 positive and the other anti-MPO posi-tive. Manganelli et al. [9] reported two brothers with EGPA (ANCAnegative) and GPA (anti-PR3 positive).AAV is known to have important genetic associations. A gen-ome-wide association study [10] identified four single nucleotidepolymorphisms (SNPs) that associated with AAV. GPA/PR3-ANCAFig. 1. CT chest image from Patient 1 showing bilateral diffuse ground glassinfiltrates.Fig. 2. Renal biopsy from Patient 2. Silver stain showing glomerulus with cellularcrescent formation (courtesy of Professor Terry Cook).430 | M. Prendecki et al.CLINICALKIDNEYJOURNAL at Imperial College London on July 11, 2016http://ckj.oxfordjournals.org/Downloaded from associated with SNPs within HLA-DP, SERPINA1 (which encodesα1-antitrypsin) and PRTN3 (which encodes proteinase 3), where-as a SNP within HLA-DQ associated with MPA/MPO-ANCA. Fur-ther analysis showed that these SNPs were more stronglyassociated with ANCA type than with clinical phenotype, sug-gesting that these diseases should perhaps be re-classified asPR3-ANCA or MPO-ANCA vasculitis, rather than GPA or MPA.Environmental factors are also likely to be important in thepathogenesis of AAV and a variety of toxins, infections anddrugs have been implicated [3]. Silica is the environmentaltoxin for which there is the greatest evidence, with a populationcase–control study showing high lifetime silica exposure asso-ciated with AAV [11]. Brener et al. [12] reported the case of twobrothers with pulmonary and renal vasculitis (anti-MPO posi-tive); both brothers had been exposed to silica but four other un-exposed siblings did not have vasculitis. Neither of our patientsreported exposure to any environmental factor which couldhave predisposed them to developing AAV.Given the identification of a difference in genetic risk factorsassociated with different AAV phenotypes and ANCA specificityit is perhaps surprising that first-degree relatives develop AAVwith differing clinical and serological features. It may be thatthere was some unrecognized environmental exposure, such asa toxin or infection, within their shared upbringing. Our report il-lustrates the complex aetiology of AAV and suggests that furtherresearch on the interaction of genetic and environmental factorsis needed.AcknowledgementsWe acknowledge support from the NIHR Imperial Biomedical Re-search Centre, and thank our colleagues who have looked afterthese patients.Weare grateful toDr Paul Brookes, whoperformedthe tissue typing.Conflict of interest statementThe authors have no conflicts of interests to declare.References1. Jennette JC, Falk RJ, Bacon PA. 2012 revised International Cha-pel Hill consensus conference nomenclature of vasculitides.Arthritis Rheum 2013; 65: 1–112. Watts RA, Mooney J, Skinner J et al. The contrasting epidemi-ology of granulomatosis with polyangitis (Wegener’s) andmicroscopic polyangitis. Rheumatology 2012; 15: 926–9313. Hamour S, Salama AD, Pusey CD. Management of ANCA-associated vasculitis: current trends and future prospects.Ther Clin Risk Manag 2010; 6: 253–2644. Jennette JC, Falk RJ, Hu P et al. Pathogenesis of antineutrophilcytoplasmic autoantibody-associated small-vessel vascu-litis. Annu Rev Pathol 2013; 8: 139–1605. Tanna A, Salama AD, Brookes P et al. Familial granulomatosiswith polyangitis: three cases of this rare disorder in one In-doasian family carrying an identical HLA DPB1 allele. BMJCase Rep 2012; doi:10.1136/bcr.01.2012.55026. Hay EM, BeamanM, Ralston AJ et al. Wegener’s granulomato-sis occurring in siblings. Br J Rheumatol 1991; 30: 144–1457. Sewell RF, Hamilton DV. Time associatedWegener’s granulo-matosis in two members of a family. Nephrol Dial Transplant1992; 7: 828. Gomes AM, Nery F, Almeida C et al. Familial clusters of ANCAsmall-vessel vasculitis. NDT Plus 2009; 2: 34–359. Manganelli P, Giacosa R, Fietta P et al. Familial vasculitides:Churg-Strauss syndrome and Wegener’s granulomatosis in2 first-degree relatives. J Rheumatol 2003; 30: 618–62110. Lyons PA, Rayner TF, Trivedi S et al. Genetically distinct sub-sets within ANCA-associated vasculitis. N Engl J Med 2012;367: 214–22311. Hogan SL, Cooper GS, Savitz DA et al. Association of silicaexposure with anti-neutrophil cytoplasmic autoantibodysmall-vessel vasculitis: a population-based, case-controlstudy. Clin J Am Soc Nephrol 2007; 2: 290–29912. Brener Z, Cohen L, Goldberg SJ et al. ANCA-associated vascu-litis in Greek siblings with chronic exposure to silica. Am JKidney Dis 2001; 38: E28Brothers with vasculitis and differing ANCA types | 431CLINICALKIDNEYJOURNAL at Imperial College London on July 11, 2016http://ckj.oxfordjournals.org/Downloaded from 

Familial vasculitides: granulomatosis with polyangitis and microscopic polyangitis in two brothers with differing anti-neutrophil cytoplasm antibody specificity

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Familial vasculitides: granulomatosis with polyangitis and microscopic polyangitis in two brothers with differing anti-neutrophil cytoplasm antibody specificity

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