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Familial occurrence of systemic vasculitis and rapidly progressive glomerulonephritis
SPECIAL ARTICLE
Familial Occurrence of Systemic Vasculitis and Rapidly Progressive Glomerulonephritis Rainer Nowack, MD, Harald Lehmann, MD, Luis Felipe Flores-Sua´rez, MD, Alice Nanhou, and Fokko J. van der Woude, MD ● Two familial clusters of systemic vasculitis are described. In one family, microscopic polyangiitis and rapidly progressive glomerulonephritis occurred in HLA-identical siblings; in the second family, 3 second- and fourthdegree related members were affected by Wegener’s granulomatosis. Published clusters of systemic vasculitides and Goodpasture’s syndrome are reviewed, and, together with the observed families, the evidence for genetic susceptibility and a causative role of environmental factors for these diseases with special emphasis on the HLA system is discussed. 娀 1999 by the National Kidney Foundation, Inc. INDEX WORDS: Systemic vasculitis; Wegener’s granulomatosis; microscopic polyangiitis; panarteritis nodosa; rapidly progressive glomerulonephritis; Goodpasture’s syndrome; familial occurrence; human lymphocyte antigens (HLA).
I
N THIS OBSERVATIONAL study, we describe two families with several members affected by systemic vasculitis (SV). Reported clusters of SV are reviewed, and an effort is made to establish hypotheses on the hitherto unknown cause of these diseases from the pattern of these clusters. CASE REPORTS
Family 1 Case 1. A 21-year-old man presented in May 1971 with hemoptysis and a pulmonary infiltrate unresponsive to antibiotics. He had had arthralgias for months. Six weeks later, hemoptysis recurred, and he suffered from diarrhea and vomiting. Uremia due to Goodpasture’s syndrome was diagnosed and hemodialysis started. Anti–glomerular basement membrane (GBM) antibodies were negative when they were first measured years after disease onset. Antineutrophil cytoplasmic antibodies (ANCA) were never tested. In 1972, the patient was bilaterally nephrectomized to prevent further
From the Vth Medical Clinic (Nephrology, Endocrinology), University-Clinic Mannheim, University of Heidelberg, and Evangelisches Krankenhaus, Zweibru¨cken, Germany. Received September 22, 1998; accepted for publication January 5, 1999. Dr Flores-Sua´rez is a staff physician of, and is supported by, the Instituto Nacional de la Nutricio´n Salvador Zubira´n in Tlalpan, Mexico City Mexico, and he is a recipient of a grant from Consejo Nacional de Ciencia y Tecnologia (CONACYT), Mexico 110912/111045. Address reprint requests to Rainer Nowack, MD, Vth Medical Clinic (Nephrology, Endocrinology), UniversityClinic Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. E-mail: [email protected]
娀 1999 by the National Kidney Foundation, Inc. 0272-6386/99/3402-0026$3.00/0 364
pulmonary hemorrhage. He received a cadaveric renal allograft in 1976, which was lost because of chronic rejection 6 years later. From 1983 until 1986, he was again on hemodialysis. In 1986, he received a second renal graft from his HLA-identical sister. Graft function deteriorated in 1992, and he received repeated steroid-pulses. In 1993, the patient had to start dialysis again, and at the same time a widely metastasized seminoma was detected. The patient died shortly after that diagnosis. He had spent his entire life in a village in a rural environment, where he worked as a carpenter. He had smoked occasionally. Case 2. The sister of this patient donated her left kidney to her brother in 1986, when she was 35 years old and healthy. Her HLA-antigens that she completely shared with her brother were: A29, A32, B7, Cw7, DR2. She had always lived in the same village as her brother, where she was a housewife and worked part-time in a grocery. She was an occasional smoker. The patient had had recurrent mild arthralgias, predominantly of the small joints of both hands since early 1990 and suffered from severe loin pain, macrohematuria, and arthralgias since 1992. Her renal function deteriorated within weeks, and an open biopsy of the remaining kidney showed extracapillary, necrotizing pauci-immune glomerulonephritis. P-ANCA was positive with anti-myeloperoxidase specificity and anti-GBM antibodies were negative. She received several pulses of intravenous methylprednisolone, but renal function gradually declined. Hemodialysis was started in early 1996. In September 1997, she received a currently well-functioning cadaveric transplant. Comment to Family 1. Although the diagnosis of the first patient was not confirmed by immunohistology or serology, both siblings most probably suffered from microscopic polyangiitis (MPA) with rapidly progressive glomerulonephritis (RPGN), according to the Chapel Hill criteria.1 The patients have two further siblings, a brother and a sister, both living in the same village. HLA-typification and ANCA-testing were performed in the parents and the healthy siblings (Fig 1). They were all ANCA-negative. The HLAidentity of the affected siblings is striking, as well as their
American Journal of Kidney Diseases, Vol 34, No 2 (August), 1999: pp 364-373
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Fig 1. Pedigree of family 1 with HLA-haplotypes. The siblings with MPA are HLAidentical. Their HLA-haplotypes do occur also in the healthy siblings but in combination with other HLA-haplotypes.
homozygocity for DR2, an HLA-antigen with documented association with SV and anti-GBM disease. The healthy siblings were both heterozygous for DR2.
Family 2 Case 1. A 33-year-old man fell ill in 1993 with bilateral hearing loss, conjunctivitis and keratitis, bilateral pulmonary infiltrates unresponsive to antibiotic treatment, granulomatous prostatitis, and glomerulonephritis with renal impairment. Wegener’s granulomatosis (WG) was diagnosed based on pulmonary histology showing granulomata and a positive C-ANCA. Treatment with cyclophosphamide and oral corticosteroids induced remission, but renal function did not fully recover (s-creatinine: 2.0 mg/dL). The patient lives in a small village in the rural district of the Palatinate in southwest Germany and is working in the computer business. The patient has an uncle (4th-degree relative, case 2) and an aunt (2nd-degree relative, case 3), both with WG, living in villages next to his domicile. The grandfather of case 3 had died of a pulmonary disease of unknown origin. Case 2. A 52-year-old man presented in 1994 with chronic maxillary and ethmoidal sinusitis and intermittent arthralgias of the metatarsophalangeal joints, the shoulders, and elbows and complained about hypesthesia and paresthesias of the left leg. He later developed hemorrhagic rhinitis and bilateral otitis media, pulmonary infiltrates, and microhematuria. A biopsy from the left nasal concha showed granulomatous vasculitis. C-ANCA was positive and HLA-typing was performed: A2, A11, B14, B22, Cw1, DR1, DR2, DQ1, DQ5. The patient responded to standard immunosuppression with cyclophosphamide and steroids and is currently well. Case 3. A 43-year-old woman fell ill with otitis media unresponsive to antibiotic treatment and a pulmonary infiltrate of the lingula segment in 1984. Subsequently, she developed hemoptysis, and a transbronchial biopsy of the
lung showed granulomatous inflammation. She was CANCA positive. The disease progressed with perimyocarditis and rapidly progressive glomerulonephritis, and she became dialysis-dependent for several weeks. WG was diagnosed, and she was treated with cyclophosphamide and steroids and fully recovered. The patient is a housewife. Comment to Family 2. In this family, three relatives of 2nd and 4th degree are affected by WG (Fig 2). They all live in a rural environment, and their domiciles are only a few miles apart. The disease onset was close for patients 1 and 2, although patient 3 fell ill 10 years earlier. HLA-typing was performed in only one patient, who carries HLA-DR2, an antigen possibly associated with the disease.
REVIEW OF THE LITERATURE
A search for familial clusters of SV reported in the literature was made using the database MEDLINE. The following terms were used for the search, which was otherwise unrestricted: vasculitis, systemic vasculitis, panarteritis nodosa, polyarteritis nodosa, Wegener’s granulomatosis, morbus Wegener, Wegener’s disease, ChurgStrauss syndrome, microscopic polyangiitis, Goodpasture’s syndrome, rapidly progressive glomerulonephritis. This review addresses all articles on SV-clusters detected by this search that are observational studies. Wegener’s Granulomatosis (WG) Knudsen et al2 reported a family of 8 siblings from Denmark, 2 brothers of whom were sus-
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Fig 2. Pedigree of family 2. Three relatives with Wegener’s granulomatosis (WG) and an ancestor with fatal pulmonary disease of unknown diagnosis.
pected of having WG. The disease was diagnosed at different ages of the brothers and with a lag of 10 years in between. WG, however, is doubtful in one of them, because the renal histology rather suggests immunoglobulin A (IgA) nephropathy (mesangial proliferation and IgA and C-3 deposits). That this patient had an ANCA titer would be compatible with certain ANCAassociated forms of IgA nephropathy.3,4 Of the unaffected siblings, one sister had a positive ANCA titer without clinical disease. The affected brothers had lived apart from each other for years before disease onset. The patients and their sister with positive ANCA shared one parental haplotype: HLA-A2, B7, DRw12. Stoney et al5 observed two brothers with WG, a 42-year-old baker with severe ear-nose-throat– disease and orbital granulomata, and his 30-yearold brother, an ambulance driver, with similar symptoms. Two further siblings were unaffected. The affected brothers shared the HLA-haplotype A31, Bw60, DR4, inherited from their healthy mother. WG occurred in two sisters who lived in an urban area and worked in a supermarket.6 They had a resembling course of WG with onset at the age of 8 years and 15 years, respectively. Their parents and a third sister stayed healthy. WG with positive C-ANCA was diagnosed in a 63-year-old mother and her 38-year-old daughter within a 2-month interval.7 HLA typing
showed DR2 to be present only in the mother, who had, in contrast to her daughter, a severe renal involvement with crescentic glomerulonephritis. HLA-DR2 was shown to be associated with WG and RPGN of other causes.8,9 Hay et al10 reported a 57-year-old man with ANCA-positive generalized WG and his sister, who had fallen ill with similar symptoms 5 years earlier, when she was 49 years old. The siblings shared the HLA-B8 antigen. Clusters of WG have also been reported for unrelated persons. Nagibov et al11 described a married couple with WG. The husband died of pulmonary WG, and a year later the widow presented with upper respiratory WG and skin granulomata. Barrett et al12 observed a 22-year-old man with C-ANCA–positive WG whose 3-year-old stepson suffered from pericarditis associated with C-ANCA 2 years later. HLA typing showed that both patients had inherited the HLA-B8 antigen independently. HLA-B8 was shown to be associated with WG in 2 studies.13,14 Weiner et al15 described twins discordant for WG. The identical maternal twins had spent their life together and shared their jobs, recreational interests, and most of their medical history, including psoriasis with psoriasis-associated arthritis, when only one of them developed generalized WG at the age of 44 years. Their sister
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suffered from systemic lupus erythematosus (SLE). More twins discordant for WG have been reported.16 Rottem et al17 described a family with a cluster of WG and polyarteritis nodosa (PAN): The father died of WG with renal failure at the age of 51 years, whereas his 29-year-old son subsequently died of PAN after a hepatitis B infection. Two years later, the sister of the second patient and daughter of the first presented with pulmonary WG. Classic Polyarteritis Nodosa (PAN) Rottem et al17 also reported three daughters of a healthy couple with PAN occurring at the age of 7 years. The three daughters had inherited the same HLA-haplotype from their healthy father, with the exception of a single DQ-locus. Mason et al18 observed two siblings affected by PAN with similar symptoms and P-ANCA positivity. They had lived together when the first sibling fell ill and had inherited the same haplotype from their healthy mother. Leff et al19 reported fatal PAN at early childhood, occurring 2 years apart in 2 siblings of a family with several autoimmune diseases, that is, SLE and allergies. Schneider and Goldman20 observed the simultaneous occurrence of PAN in a 60-year-old man and his 12-years younger sister. Finally, PAN21 occurred in two identical twin sisters, with an interval of several years between disease onsets. A PAN cluster in a family with high prevalence of autoimmune disease seems to illustrate the relative contribution of genes and environment for this disease.22 The father had hepatitis B and PAN, and he had shared his razor with both of his sons, who subsequently acquired hepatitis B. However, only one of them got PAN, and it is striking that they had inherited different haplotypes from their father. Microscopic Polyangiitis (MPA) Barbiano di Belgiojoso et al23 found necrotizing pauci-immune glomerulonephritis with renal vasculitis and P-ANCA positivity in a father and a son. The disease onset within 3 months, and both had a prodromal respiratory disease. They subsequently became dialysis-dependent but recovered in response to immunosuppressive therapy. Father and son shared the HLA-A11 and B35 antigens.
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Heuze-Claudet et al24 reported two Moroccan siblings, whose parents were first cousins, with a P-ANCA–associated pulmonary syndrome, and Franssen et al25 observed another sibling pair with P-ANCA–associated vasculitis. Goodpasture’s Syndrome In early reports of clusters of RPGN, ANCAassociated RPGN and anti-GBM disease could not be discriminated, and the label Goodpasture’s syndrome (GS)26 was generally used. Clusters of GS are therefore included in this review, and also because of their close relationship with SV, as suggested by the simultaneous or subsequent appearance of ANCA and anti-GBM antibodies.27-29 Two reports describe GS in twins.30,31 GS with fatal outcome was also diagnosed in two brothers who both fell ill at the age of 25 years but lived in different environments.32 Two further families with two affected brothers and cousins, respectively,33,34 are reported. GS was also found to be associated with other diseases in families, for example, in a large family described by Mu¨ntefering et al,35 in which several members had different renal diseases and bronchial asthma. Two brothers died of uremia due to RPGN with pulmonary hemorrhage. DISCUSSION
The clusters of SV described in this report, and those already published, are the result of simultaneous or subsequent occurrence of only one entity from the spectrum of SV in a community, with the exception of one cluster of different entities of SV.17 In most clusters, no more than two persons, mostly siblings or one parent and a child, were affected by the disease (Table 1). Distantly related members of a family are either rarely concordantly affected by SV or these clusters are overlooked or underreported. Relative to the number of concordant siblings, there are few reported twins with concordance for SV. There are indeed more published twins discordant for SV.15,16 The clusters may provide useful information on the causes of SV. First of all, the pattern of clusters itself may indicate clues to the cause of (1) SV and (2) the information pertaining to these clusters may add to existing hypotheses on
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NOWACK ET AL Table 1. Published Clusters of SV: Number and Relationship of Affected Patients and HLA Associations
Reference
Entity
No. of Affected Members
Knudsen et al2
WG
2
Stoney et al5
WG
2
Muniain et al6 Hay et al10
WG WG
2 2
Sewell and Hamilton7
WG
2
Rottem et al17 Barrett et al12
WG/PAN WG
3 2
Nagibov and Cheranov11 Harris and Jones21 Rottem et al17
WG PAN PAN
2 2 3
Mason et al18
PAN
2
Leff et al19 Schneider and Goldman20 Reveille et al22
PAN PAN PAN
2 2 2
Franssen et al25 Heuze-Claudot et al24 Barbiano di Belgiojoso et al23 Simonsen et al31 D’Apice et al30 Mu¨ntefering et al35 Stanton and Tange34 Maddock et al33
MPA MPA MPA GS GS GS GS GS
2 2 2 2 2 2 2 2
Relationship of Affected Members
HLA Associations
Siblings
Both patients and the ANCA-positive sibling share one parental haplotype: HLA-A2, B7, DRw12 Siblings Same haplotype from the mother: HLA-A31, Bw60, DR4 Siblings Not studied Siblings Siblings share HLA-B8 Brother: HLA-A3, A10, B8, B17, DR3, DR7 Sister: A3, A10, B8, DR3, DR4 Mother and daughter Mother: A9, A11, B14, B18, DR1, DR2 Daughter: A2, A9, B12, B14, Bw4, Bw6, DR1 Father and 2 siblings Not studied Unrelated: father and stepson HLA-B8 inherited by both patients independently Unrelated: spouses Not studied Twins Not studied Siblings All three siblings had inherited the same haplotype from their healthy father, with the exception of a single DQ-locus: HLA-A2, B57, Cw6, DR7, DQ9(2), DR53 Siblings Same haplotype: A11, B5, DR5, DQw7 Siblings Not studied Siblings Not studied Father and son Affected son and a second healthy son had inherited different haplotypes from their father Siblings Not studied Siblings Not studied Father and son Patients shared HLA-A11 and B35 Twins Not studied Twins Not studied Siblings Not studied Siblings Not studied Cousins Not studied
Abbreviations: WG, Wegener’s granulomatosis; MPA, microscopic polyangiitis; PAN, polyarteritis nodosa; GS, Goodpasture’s syndrome.
a genetic predisposition and (3) the role of environmental factors for SV. Clusters of SV occur in first-degree relatives, whereas pedigrees with SV in several generations, or pedigrees whose affected members grew up and lived in separated environments before disease onset, have not been reported. This pattern suggests that environmental triggers have a strong impact for the outbreak of SV, because siblings or parents and their children share, besides their genetic background, much of the
environment. Shared environment until disease onset was explicitly mentioned for many clusters,6,7,17,22 and the presence of an environmental trigger was suspected because of a close disease onset and a strikingly similar course of the disease. A strong environmental influence is also suggested by the occurrence of SV in unrelated members of communities11,12 and the low concordance rate in twins. However, SV clusters in unrelated patients are exceptionally rare relative to the number of famil-
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ial clusters, and this again is an argument for a genetic susceptibility for SV. In synopsis, the pattern of SV clusters can be explained by a combined contribution of environmental triggers and a genetically determined susceptibility. Several human autoimmune diseases are associated with certain HLA class II antigens,36 for example, rheumatoid arthritis with HLA-DR4.37 Because HLA associations have been suggested also for SV, information on HLA antigens was provided for many clusters (Fig 1, Table 1). In family 1 of this report, the affected siblings had inherited the same HLA haplotype from both their parents, which makes them HLA-identical, whereas the unaffected siblings had each inherited one other HLA haplotype from their parents. In four further clusters, siblings concordant for SV had inherited the same haplotype from one of their healthy parents,2,5,17,18 and in one case of striking discordance in siblings for PAN despite obvious environmental similarity, they had inherited a different haplotype from the affected father.22 This situation is reminiscent of rheumatoid arthritis, where HLA-haplotype sharing has been found in affected sibships.38 Studies on association of HLA-antigens with SV have obtained different results: positive associations for DR2,8,39,40 DR4,41 DQ7,40,41 and B813,14; negative association for DR339-41 and DR13DR642; and no association.43-45 DR2 seems to be associated not only with SV but also with other autoimmune disorders. Approximately 20% of the general population have the DR2 antigen. Overrepresentation of DR2 was found in patients with P-ANCA–associated drug-induced SLE,48 in allergic disorders,47 and in cutaneous vasculitis.46 The strongest association is present for anti-GBM disease, where the frequency of DR2 is increased to 80%.9 SV-associated HLA-antigens also have been detected within the reported clusters. The HLAidentical siblings in our family 1 are homozygous for DR2, and in the unaffected siblings DR2 was paired with either DR7 or DR11. The one patient of family 2, who was HLA-typified, was also a carrier of DR2. In the family reported by Sewell and Hamilton,7 the mother with severe renal involvement of WG had DR2. In Stoney et al’s report,5 the affected siblings had inherited with their mother’s haplotype the HLA-DR4
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antigen. HLA-B8 was inherited to both affected siblings in Hay et al’s report.10 Finally, the father and his stepson, both with ANCA-associated diseases, had independently inherited the HLAB8–antigen.12 DR3 was indeed rarely found within the clusters, but it was present in the 2 affected siblings reported by Hay et al.10 Several of the patients completely miss SV-associated HLA-antigens.2,18 In conclusion, the degree of HLA resemblance seems to be connected with the risk for SV in these clusters, but HLA antigens clearly conferring that risk cannot be identified. The reported associations of SV with other polymorphic gene loci, such as complement,49,51 or alpha-1-antitrypsin deficiency50 or tumor necrosis factor-alpha,52 have not been studied within the familial clusters. Other autoimmune diseases and allergies were prevalent within several clusters.15,17,19,22,35 This is in agreement with many case-reports of SV patients who suffer from another autoimmune disease53-88 (Table 2), although this has never been studied systematically. Few hard data about environmental triggers for SV are available from the reported clusters. In one PAN cluster, a hepatitis B infection is quite obviously the trigger,22 and in other clusters of PAN and MPA, the presence of an infectious trigger was highly probable, although this could not be proved. For ANCA-associated SV, only one report discussed a Coxsackie virus infection as a possible cause.12 This is in contrast to the numerous sporadic cases of SV that had been related to a number of infectious organisms89 and the role of infection for relapses of SV,90 especially for WG, where a specific risk goes with the nasal carriage of Staphylococcus aureus.91 Other antigen exposure, for example, through hyposensibilisation92 or vaccination,93 which had been linked to the occurrence of SV, is also missing within the reported clusters. The occupational histories of the affected patients in the SV clusters provide no clues to possible environmental causes of SV and antiGBM disease, such as silicon exposure for ANCA-associated vasculitides94-96 and hydrocarbon exposure for anti-GBM-disease and SV.97-99 In summary, the reported two clusters of MPA and WG, together with published clusters of
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NOWACK ET AL Table 2. Other Autoimmune Diseases in Patients With SV Reference
Entity of SV
Associated Autoimmune Disease
Dolman et al53 Masor et al54 Armbruster and Vetter55 Kitahara et al56 Small et al57 Sugimoto et al58 Wedderburn et al59 Ohashi et al60 Svirskii et al61 Tanemoto et al62 Tanaka et al63 Yuasa et al64 Harper et al65 Steuer et al66 Weidensaul et al67 Hillis et al68 Bonomini et al69 Waisburg et al70 Boutin et al71 Guillevin et al72 Herreman et al73 Lahoz Rallo et al74 Asherson et al75 Tohme et al76 Sattar77 Galeazzi et al78 Ferreiro Seoane et al79 Lain Martı´nez80 Vivancos et al81 Schoonjans et al82 Dasgupta et al83 Stockmann84 Kojima et al85 Peces et al86 Yamazaki et al87
WG* WG WG WG* WG WG WG WG WG MPA† MPA (renal-limited) MPA (renal-limited)* MPA* MPA MPA MPA MPA PAN PAN‡ PAN PAN§ PAN PAN PAN PAN PAN (HBV and HCV related) PAN PAN PAN PAN PAN CSS㛳 CSS GS GS
Graves’ disease (2 cases) Hashimoto’s thyroiditis Hashimoto’s thyroiditis Autoimmune thyroiditis Relapsing polychondritis Insulin-dependent diabetes mellitus Juvenile chronic arthritis Rheumatoid arthritis Rheumatoid arthritis Graves’ disease (3 cases) Subclinical autoimmune thyroiditis Autoimmune thyroiditis (2 cases) Autoimmune thyroiditis Rheumatoid arthritis Primary antiphospholipid syndrome Scleroderma Hashimoto’s thyroiditis and atrophic gastritis Multiple sclerosis–like syndrome Graves’ disease Graves’ disease Sjogren syndrome Sjogren syndrome Juvenile rheumatoid arthritis Ankylosing spondylitis Ankylosing spondylitis Ankylosing spondylitis Ankylosing spondylitis and rheumatoid arthritis Rheumatoid arthritis Systemic lupus erythematosus Primary antiphospholipid syndrome Primary antiphospholipid syndrome Rheumatoid arthritis (2 cases) Autoimmune hemolytic anemia Rheumatoid arthritis Systemic lupus erythematosus
*Possibly associated with treatment with propylthiouracil. †Possibly associated with treatment with propylthiouracil and methimazole. ‡Possibly associated with treatment with carbimazole. §After stopping treatment for PAN, the patient developed a non-Hodgkins lymphoplasmocytic lymphoma. 㛳One case possibly related to D-penicillamine treatment.
these and related diseases, suggest a combination of genetic susceptibility and environmental triggers as cause. Which genes confer this susceptibility remains unknown, although there is some indication that HLA antigens are of importance. With the exception of hepatitis B virus for a cluster of PAN, the environmental triggers for SV in these clusters remain unidentified. Further studies of larger populations of SV patients are needed to gather new information and to substantiate hypotheses on the cause of SV, which have so far been based on small observational studies. Because of the low fre-
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39. Mu¨ller GA, Gebhardt M, Kompf J, Baldwin W, Ziegenhagen D, Bohle A: Association between rapidly progressive glomerulonephritis and the properdin factor BfF and different HLA-D region products. Kidney Int 25:115118, 1984 40. Spencer SJW, Burns A, Gaskin G, Pusey CD, Rees AJ: HLA class II specificities in vasculitis with antibodies to neutrophil cytoplasmic antigens. Kidney Int 41:1059-1063, 1992 41. Coulthart A, Fisher M, Gaskin G, Pusey CD: HLA Class II genes in ANCA-associated vasculitis. Clin Exp Immunol 112:S53A, 1998 (abstr; suppl 1) 42. Hagen EC, Stegeman CA, D’Amaro J, Schreuder GM, Lems SP, Tervaert JW, de Jong GM, Hene RJ, Kallenberg CG, Daha MR, van der Woude FJ: Decreased frequency of HLA-DR13DR6 in Wegener’s granulomatosis. Kidney Int 48:801-805, 1995 43. Strimlan CV, Taswell HF, Kueppen F, DeRemee RA, McDonald TJ: HLA antigens of patients with Wegener’s granulomatosis: Tissue antigens 11:129-131, 1978 44. Murty GE, Mains BT, Middleton D, Maxwell AP, Savage DA: HLA antigen frequencies of patients with Wegener’s granulomatosis. Clin Otolaryngol 16:448-451, 1991 45. Zhang L, Jayne DR, Zhao MH, Lockwood CM, Oliveira DB: Distribution of MHC class II alleles in primary systemic vasculitis. Kidney Int 47:294-298, 1995 46. Glass D, Soter NA, Gibson D, Carpenter CB, Schur PH: Association between HLA and cutaneous necrotizing vasculites. Arthritis Rheum 19:945-949, 1976 47. Marsh DG, Hsu SH, Roebber M, Ehrlich-Kautzky E, Freidhoff LR, Meyers DA, Pollard MK, Bias WB: HLADR2: A genetic marker for human immune response to short ragweed pollen allergen Ra5: Response resulting primarily from natural antigenic exposure. J Exp Med 155:1439-1451, 1982 48. Dunphy J, Rands A, Cox B, Dunlevy L, McHugh NJ: MHC Class II associations with ANCA positivity in idiopathic and drug-induced SLE. Clin Exp Immunol 112:S31A, 1998 (suppl 1; abstr) 49. Papiha SS, Murty GE, Ad Hia A, Mains BT, Venning M: Association of Wegener’s granulomatosis with HLA antigens and other genetic markers. Ann Rheum Dis 51:246248, 1992 50. Hagen EC, Hiemstra PS, van der Linden AC, Jong de GMTh, Daha MR, van der Woude JF: Alpha1-antitrypsin deficiency in systemic vasculitis (submitted for publication) 51. Persson U, Truedsson L, Westman K, Segelmark M: Increased frequency of the C3f allele in Pr 3-ANCA positive vasculitis. Clin Exp Immunol 112:S25A, 1998 (suppl 1; abstr) 52. Schmitt WH, Mascher B, Csernok E, Tatsis E, Reil A, Gross WL: Polymorphisms in the tumor necrosis factor genes in Wegener’s granulomatosis. Clin Exp Immunol 112:S33A, 1998 (suppl 1; abstr) 53. Dolman KM, Gans ROB, Vervaat TJ, Zevenbergen G, Maingay D, Nikkels RE, Donker AJM, von dem Borne AEGK, Goldschmeding R: Vasculitis and antineutrophil cytoplasmic autoantibodies associated with propylthiouracil therapy. Lancet 342:651-652, 1993 54. Masor JJ, Gal AA, Livolsi A: Case report: Hashi-
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moto’s thyroiditis associated with Wegener’s granulomatosis. Am J Med Sci 308:112-114, 1994 55. Armbruster C, Vetter N: Wegenersche Granulomatose mit Milzbeteiligung und Thyreoiditis lymphomatosa Hashimoto. Pneumologie 45:28-31, 1991 56. Kitahara T, Hiromura K, Maezawa A, Ono K, Narabara N, Yano S, Naruse T, Takenouchi K, Yasumoto Y: Case of propylthiouracil-induced vasculitis associated with antineutrophil cytoplasmic antibody (ANCA): Review of literature. Clin Nephrol 47:336-340, 1997 57. Small P, Black M, Davidman M, Brisson de Champlain ML, Kapusta MA, Kreisman H: Wegener’s granulomatosis and relapsing polychondritis: A case report. J Rheumatol 7:915-918, 1980 58. Sugimoto A, Sugimoto S, Tanaka M, Kuribayashi T, Takemura J, Matsukura S, Sugiyama S: Wegener’s granulomatosis (WG) and insulin dependent diabetes mellitus (IDDM). Jpn J Med 28:374-378, 1989 59. Wedderburn LR, Kwan JT, Thompson PW, Rudge SR: Juvenile chronic arthritis and Wegener’s granulomatosis. Br J Rheumatol 31:121-123, 1992 60. Ohashi H, Itoh M, Ogawa N, Sudo Y, Endo S, Okugawa T, Ito H, Mineta H, Nozue M: Wegener’s granulomatosis in a patient with rheumatoid arthritis. Intern Med 31:1128-1131, 1992 61. Svirskii AA, Potapenkov MA, Shchipulin PP, Kharitonov VM, Zelenin VS: Wegener’s granulomatosis in a patient with rheumatoid arthritis. Lik Sprava 2:92-94, 1994 62. Tanemoto M, Miyakawa H, Hanai J, Yago M, Kitaoka M, Uchida S: Myeloperoxidase-antineutrophil cytoplasmic antibody-positive crescentic glomerulonephritis complicating the course of Graves’ disease: Report of three adult cases. Am J Kidney Dis 26:774-780, 1995 63. Tanaka H, Waga S, Kakizaki Y, Sugimoto K, Ito T, Tateyama T: An adolescent case of anti-neutrophil cytoplasmic autoantibodies-associated crescentic glomerulonephritis complicated with subclinical autoimmune thyroiditis. Nippon Jinzo Gakkai Shi 38:463-468, 1996 64. Yuasa S, Hashimoto M, Yura T: Antineutrophil cytoplasmic antibodies associated crescentic glomerulonephritis and propylthiouracil therapy. Nephron 73:701-703, 1996 65. Harper L, Cockwell P, Savage COS: Case of propylthiouracil-induced ANCA associated small vessel vasculitis. Nephrol Dial Transplant 13:455-458, 1998 66. Steuer A, Palmer A, Colaco CB: A patient with rheumatoid arthritis and microscopic polyarteritis. Br J Rheumatol 34:1185-1186, 1995 67. Weidensaul D, Vassa N, Luger A, Walker SE, McMurray RW: Primary antiphospholipid syndrome and microscopic polyarteritis in the puerperium: A case report. Int Arch Allergy Immunol 103:311-316, 1994 68. Hillis GS, Khan ICH, Simpson JG, Rees AJ: Scleroderma, D-penicillamine treatment, and progressive renal failure associated with positive antimyeloperoxidase antineutrophil cytoplasmic antibodies. Am J Kidney Dis 20:279281, 1997 69. Bonomini M, Settefrati N, Uncini A, Di Muzio A, Albertazzi A: Microscopic polyarteritis with antineutrophil cytoplasmic antibodies in polyglandular autoimmunity. Nephrol Dial Transplant 13:813-814, 1998 70. Waisburg H, Meloff KL, Buncic R: Polyarteritis no-
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dosa complicated by a multiple sclerosis like syndrome. Can J Neurol Sci 1:250-252, 1974 71. Boutin J, Cornec A, Chevrant-Breton J, Almange C, Guerin D: Hyperacute periarteritis nodosa complicating Basedow’s disease. Semin Hop 54:1430-1432, 1978 72. Guillevin L, Krivitzky A, Rouby JJ, Guesde D, Bletry O, Langlois P, Godeau P: Fatal polyarteritis nodosa following Graves’ disease. Semin Hop 56:1877-1878, 1980 73. Herreman G, Ferme I, Diebold J, Baviera E, Audouin J, Bazin C, Godeau P: Gourgerot-Sjogren syndrome, periarteritis nodosa, non-Hodgkin’s lymphoplasmocytic lymphoma and acquired C4 deficiency. Ann Med Intern (Paris) 134:19-25, 1983 74. Lahoz Rallo C, Arribas Lo´pez JR, Arnalich Ferna´ndez F, Monereo Alonso A, Llanos Chavarri MC, Camacho Siles J: Necrotizing vasculitis of the panarteritis nodosa type in a long-course primary Sjogren’s syndrome. Ann Med Intern 7:538-530, 1990 75. Asherson RA, Mackworth-Young CG, Hughes GR: Juvenile rheumatoid arthritis in two siblings: Co-existence with polyarteritis nodosa in one parent. Clin Exp Rheumatol 2:177-179, 1984 76. Tohme A, Clemencon M, Durin R, Breville P, Du Lac de Fugeres Y, Waltzing P: The association of ankylosing spondylarthritis and periarteritis nodosa. Presse Med 19: 1946, 1990 77. Sattar MA: Coexisting HLA-B27 positive spondyloarthritis and polyarteritis nodosa. Ann Rheum Dis 51:13381339, 1992 78. Galeazzi M, Fioravanti A, Minari C, Selvi E, Veronesi M, Marcolongo R: HLA-B27 positive ankylosing spondylitis and polyarteritis nodosa: A case report. Clin Rheumatol 15:204-206, 1996 79. Ferreiro Seoane JL, Go´mez Rodrı´guez N, Formigo Rodrı´guez E, Martı´nez Isla A, Anton Badiola I: The coexistence of rheumatoid arthritis, ankylosing spondylitis and intestinal necrotizing vasculitis. Ann Med Interna 10:452454, 1993 80. Laı´n Martı´nez P: An unusual association: Panarteritis nodosa and rheumatoid arthritis as an overlapping collagenous syndrome. Rev Clin Esp 190:455-457, 1992 81. Vivancos J, Soler-Carrillo J, Ara-del Rey J, Font J: Development of polyarteritis nodosa in the course of inactive systemic lupus erythematosus. Lupus 4:494-495, 1995 82. Schoonjans R, van Vlem B, Weyers S, de Keyser F, Praet M, Versieck J, Elewaut A: Polyarteritis nodosa and the antiphospholipid syndrome. Clin Rheumatol 15:410-413, 1996 83. Dasgupta B, Almond MK, Tanqueray A: Polyarteritis nodosa and the antiphospholipid syndrome. Br J Rheumatol 36:1210-1212, 1997 84. Stockmann G: The status of Churg-Strauss syndrome among other hypereosinophilic, granulomatous and vasculitic diseases. Z Rheumatol 47:388-396, 1988 85. Kojima K, Omoto E, Katayama Y, Uno M, Takada I, Kimura G, Kanehiro A, Tada S, Hayashi K, Kimura I, Sanada H, Harada M: Autoimmune hemolytic anemia in allergic granulomatous angitis (Churg-Strauss syndrome). Int J Hematol 63:149-154, 1996
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86. Peces R, Riera JR, Arboleya LR, Lo´pez-Larrea C, Alvarez J: Goodpasture’s syndrome in a patient receiving penicillamine and carbimazole. Nephron 45:316-320, 1987 87. Yamazaki K, Fujita J, Doi I, Abe S, Kawakami Y, Fukuzawa Y: A case of acute pulmonary hemorrhage and positive anti-glomerular basement membrane antibody in systemic lupus erythematosus. Nippon Kyobu Shikkan Gakkai Zasshi 31:251-256, 1993 88. Westman KWA, Ericsson UB, Wielander J, Erfurth EM: Thyroid disease and thyroid antibodies in patients with Wegener’s granulomatosis or microscopic polyangiitis with renal involvement (submitted for publication) 89. Somer T, Finegold SM: Vasculitides associated with infections, immunization, and antimicrobial drugs. Clin Infect Dis 20:1010-1036, 1995 90. Pinching AJ, Rees AJ, Pussell BA, Lockwood CM, Mitchison RS, Peters DK: Relapses in Wegener’s granulomatosis: The role of infection. BMJ 281:836-838, 1980 91. Stegeman CA, Cohen Tervaert JW, Sluiter WJ, Manson WL, de Jong PE, Kallenberg CGM: Association of chronic nasal carriage of staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med 120:12-17, 1994 92. Phanuphak P, Kohler PF: Onset of polyarteritis nodosa during allergic hyposensitization treatment. Am J Med 68:479-485, 1980 93. Mader R, Narendran A, Lewtas J, Bykerk V, Goodman RC, Dickson JR, Keystone EC: Systemic vasculitis following influenza vaccination: Report of 3 cases and literature review. J Rheumatol 20:1429-1431, 1993 94. Gregorini G, Ferioli A, Donato F, Tira P, Morassi L, Tardanico R, Lancini L, Maiorca R: Association between silica exposure and necrotizing crescentic glomerulonephritis with p-ANCA and anti-MPO antibodies: A hospital-based case-control study. Adv Exp Med Biol 336:435-440, 1993 95. Nuyts GD, Van Vlem E, De Vos A, Daelemans RA, Rorive G, Elseviers MM, Schurgers M, Segaert M, D’Haese PC, De Broe ME: Wegener granulomatosis is associated to exposure to silicon compounds: A case-control study. Nephrol Dial Transplant 10:1162-1165, 1995 96. Satterly KK, Hogan SL, Nachman PH, Dooley MA, Jennette JC, Falk RJ: ANCA-associated diseases with renal involvement but not lupus nephritis are associated with silica exposure. Clin Exp Immunol 112:S25A, 1998 (suppl 1; abstr) 97. Yaqoob M, Bell GM, Percy DF, Finn R: Primary glomerulonephritis and hydrocarbon exposure: A casecontrol study and literature review. Q J Med 83:409-418, 1992 98. Bell GM, Gordon ACH, Lee P, Doig A, MacDonald MK, Thomson D, Anderton JL, Robson JS: Proliferative glomerulonephritis and exposure to organic solvents. Nephron 40:161-165, 1985 99. Pai P, Bone JM, Bell GM: Hydrocarbon exposure and glomerulonephritis due to systemic vasculitis (letter). Nephrol Dial Transplant 13:1321-1323, 1998
Familial Occurrence of Systemic Vasculitis and Rapidly Progressive Glomerulonephritis Rainer Nowack, MD, Harald Lehmann, MD, Luis Felipe Flores-Sua´rez, MD, Alice Nanhou, and Fokko J. van der Woude, MD ● Two familial clusters of systemic vasculitis are described. In one family, microscopic polyangiitis and rapidly progressive glomerulonephritis occurred in HLA-identical siblings; in the second family, 3 second- and fourthdegree related members were affected by Wegener’s granulomatosis. Published clusters of systemic vasculitides and Goodpasture’s syndrome are reviewed, and, together with the observed families, the evidence for genetic susceptibility and a causative role of environmental factors for these diseases with special emphasis on the HLA system is discussed. 娀 1999 by the National Kidney Foundation, Inc. INDEX WORDS: Systemic vasculitis; Wegener’s granulomatosis; microscopic polyangiitis; panarteritis nodosa; rapidly progressive glomerulonephritis; Goodpasture’s syndrome; familial occurrence; human lymphocyte antigens (HLA).
I
N THIS OBSERVATIONAL study, we describe two families with several members affected by systemic vasculitis (SV). Reported clusters of SV are reviewed, and an effort is made to establish hypotheses on the hitherto unknown cause of these diseases from the pattern of these clusters. CASE REPORTS
Family 1 Case 1. A 21-year-old man presented in May 1971 with hemoptysis and a pulmonary infiltrate unresponsive to antibiotics. He had had arthralgias for months. Six weeks later, hemoptysis recurred, and he suffered from diarrhea and vomiting. Uremia due to Goodpasture’s syndrome was diagnosed and hemodialysis started. Anti–glomerular basement membrane (GBM) antibodies were negative when they were first measured years after disease onset. Antineutrophil cytoplasmic antibodies (ANCA) were never tested. In 1972, the patient was bilaterally nephrectomized to prevent further
From the Vth Medical Clinic (Nephrology, Endocrinology), University-Clinic Mannheim, University of Heidelberg, and Evangelisches Krankenhaus, Zweibru¨cken, Germany. Received September 22, 1998; accepted for publication January 5, 1999. Dr Flores-Sua´rez is a staff physician of, and is supported by, the Instituto Nacional de la Nutricio´n Salvador Zubira´n in Tlalpan, Mexico City Mexico, and he is a recipient of a grant from Consejo Nacional de Ciencia y Tecnologia (CONACYT), Mexico 110912/111045. Address reprint requests to Rainer Nowack, MD, Vth Medical Clinic (Nephrology, Endocrinology), UniversityClinic Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. E-mail: [email protected]
娀 1999 by the National Kidney Foundation, Inc. 0272-6386/99/3402-0026$3.00/0 364
pulmonary hemorrhage. He received a cadaveric renal allograft in 1976, which was lost because of chronic rejection 6 years later. From 1983 until 1986, he was again on hemodialysis. In 1986, he received a second renal graft from his HLA-identical sister. Graft function deteriorated in 1992, and he received repeated steroid-pulses. In 1993, the patient had to start dialysis again, and at the same time a widely metastasized seminoma was detected. The patient died shortly after that diagnosis. He had spent his entire life in a village in a rural environment, where he worked as a carpenter. He had smoked occasionally. Case 2. The sister of this patient donated her left kidney to her brother in 1986, when she was 35 years old and healthy. Her HLA-antigens that she completely shared with her brother were: A29, A32, B7, Cw7, DR2. She had always lived in the same village as her brother, where she was a housewife and worked part-time in a grocery. She was an occasional smoker. The patient had had recurrent mild arthralgias, predominantly of the small joints of both hands since early 1990 and suffered from severe loin pain, macrohematuria, and arthralgias since 1992. Her renal function deteriorated within weeks, and an open biopsy of the remaining kidney showed extracapillary, necrotizing pauci-immune glomerulonephritis. P-ANCA was positive with anti-myeloperoxidase specificity and anti-GBM antibodies were negative. She received several pulses of intravenous methylprednisolone, but renal function gradually declined. Hemodialysis was started in early 1996. In September 1997, she received a currently well-functioning cadaveric transplant. Comment to Family 1. Although the diagnosis of the first patient was not confirmed by immunohistology or serology, both siblings most probably suffered from microscopic polyangiitis (MPA) with rapidly progressive glomerulonephritis (RPGN), according to the Chapel Hill criteria.1 The patients have two further siblings, a brother and a sister, both living in the same village. HLA-typification and ANCA-testing were performed in the parents and the healthy siblings (Fig 1). They were all ANCA-negative. The HLAidentity of the affected siblings is striking, as well as their
American Journal of Kidney Diseases, Vol 34, No 2 (August), 1999: pp 364-373
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Fig 1. Pedigree of family 1 with HLA-haplotypes. The siblings with MPA are HLAidentical. Their HLA-haplotypes do occur also in the healthy siblings but in combination with other HLA-haplotypes.
homozygocity for DR2, an HLA-antigen with documented association with SV and anti-GBM disease. The healthy siblings were both heterozygous for DR2.
Family 2 Case 1. A 33-year-old man fell ill in 1993 with bilateral hearing loss, conjunctivitis and keratitis, bilateral pulmonary infiltrates unresponsive to antibiotic treatment, granulomatous prostatitis, and glomerulonephritis with renal impairment. Wegener’s granulomatosis (WG) was diagnosed based on pulmonary histology showing granulomata and a positive C-ANCA. Treatment with cyclophosphamide and oral corticosteroids induced remission, but renal function did not fully recover (s-creatinine: 2.0 mg/dL). The patient lives in a small village in the rural district of the Palatinate in southwest Germany and is working in the computer business. The patient has an uncle (4th-degree relative, case 2) and an aunt (2nd-degree relative, case 3), both with WG, living in villages next to his domicile. The grandfather of case 3 had died of a pulmonary disease of unknown origin. Case 2. A 52-year-old man presented in 1994 with chronic maxillary and ethmoidal sinusitis and intermittent arthralgias of the metatarsophalangeal joints, the shoulders, and elbows and complained about hypesthesia and paresthesias of the left leg. He later developed hemorrhagic rhinitis and bilateral otitis media, pulmonary infiltrates, and microhematuria. A biopsy from the left nasal concha showed granulomatous vasculitis. C-ANCA was positive and HLA-typing was performed: A2, A11, B14, B22, Cw1, DR1, DR2, DQ1, DQ5. The patient responded to standard immunosuppression with cyclophosphamide and steroids and is currently well. Case 3. A 43-year-old woman fell ill with otitis media unresponsive to antibiotic treatment and a pulmonary infiltrate of the lingula segment in 1984. Subsequently, she developed hemoptysis, and a transbronchial biopsy of the
lung showed granulomatous inflammation. She was CANCA positive. The disease progressed with perimyocarditis and rapidly progressive glomerulonephritis, and she became dialysis-dependent for several weeks. WG was diagnosed, and she was treated with cyclophosphamide and steroids and fully recovered. The patient is a housewife. Comment to Family 2. In this family, three relatives of 2nd and 4th degree are affected by WG (Fig 2). They all live in a rural environment, and their domiciles are only a few miles apart. The disease onset was close for patients 1 and 2, although patient 3 fell ill 10 years earlier. HLA-typing was performed in only one patient, who carries HLA-DR2, an antigen possibly associated with the disease.
REVIEW OF THE LITERATURE
A search for familial clusters of SV reported in the literature was made using the database MEDLINE. The following terms were used for the search, which was otherwise unrestricted: vasculitis, systemic vasculitis, panarteritis nodosa, polyarteritis nodosa, Wegener’s granulomatosis, morbus Wegener, Wegener’s disease, ChurgStrauss syndrome, microscopic polyangiitis, Goodpasture’s syndrome, rapidly progressive glomerulonephritis. This review addresses all articles on SV-clusters detected by this search that are observational studies. Wegener’s Granulomatosis (WG) Knudsen et al2 reported a family of 8 siblings from Denmark, 2 brothers of whom were sus-
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Fig 2. Pedigree of family 2. Three relatives with Wegener’s granulomatosis (WG) and an ancestor with fatal pulmonary disease of unknown diagnosis.
pected of having WG. The disease was diagnosed at different ages of the brothers and with a lag of 10 years in between. WG, however, is doubtful in one of them, because the renal histology rather suggests immunoglobulin A (IgA) nephropathy (mesangial proliferation and IgA and C-3 deposits). That this patient had an ANCA titer would be compatible with certain ANCAassociated forms of IgA nephropathy.3,4 Of the unaffected siblings, one sister had a positive ANCA titer without clinical disease. The affected brothers had lived apart from each other for years before disease onset. The patients and their sister with positive ANCA shared one parental haplotype: HLA-A2, B7, DRw12. Stoney et al5 observed two brothers with WG, a 42-year-old baker with severe ear-nose-throat– disease and orbital granulomata, and his 30-yearold brother, an ambulance driver, with similar symptoms. Two further siblings were unaffected. The affected brothers shared the HLA-haplotype A31, Bw60, DR4, inherited from their healthy mother. WG occurred in two sisters who lived in an urban area and worked in a supermarket.6 They had a resembling course of WG with onset at the age of 8 years and 15 years, respectively. Their parents and a third sister stayed healthy. WG with positive C-ANCA was diagnosed in a 63-year-old mother and her 38-year-old daughter within a 2-month interval.7 HLA typing
showed DR2 to be present only in the mother, who had, in contrast to her daughter, a severe renal involvement with crescentic glomerulonephritis. HLA-DR2 was shown to be associated with WG and RPGN of other causes.8,9 Hay et al10 reported a 57-year-old man with ANCA-positive generalized WG and his sister, who had fallen ill with similar symptoms 5 years earlier, when she was 49 years old. The siblings shared the HLA-B8 antigen. Clusters of WG have also been reported for unrelated persons. Nagibov et al11 described a married couple with WG. The husband died of pulmonary WG, and a year later the widow presented with upper respiratory WG and skin granulomata. Barrett et al12 observed a 22-year-old man with C-ANCA–positive WG whose 3-year-old stepson suffered from pericarditis associated with C-ANCA 2 years later. HLA typing showed that both patients had inherited the HLA-B8 antigen independently. HLA-B8 was shown to be associated with WG in 2 studies.13,14 Weiner et al15 described twins discordant for WG. The identical maternal twins had spent their life together and shared their jobs, recreational interests, and most of their medical history, including psoriasis with psoriasis-associated arthritis, when only one of them developed generalized WG at the age of 44 years. Their sister
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suffered from systemic lupus erythematosus (SLE). More twins discordant for WG have been reported.16 Rottem et al17 described a family with a cluster of WG and polyarteritis nodosa (PAN): The father died of WG with renal failure at the age of 51 years, whereas his 29-year-old son subsequently died of PAN after a hepatitis B infection. Two years later, the sister of the second patient and daughter of the first presented with pulmonary WG. Classic Polyarteritis Nodosa (PAN) Rottem et al17 also reported three daughters of a healthy couple with PAN occurring at the age of 7 years. The three daughters had inherited the same HLA-haplotype from their healthy father, with the exception of a single DQ-locus. Mason et al18 observed two siblings affected by PAN with similar symptoms and P-ANCA positivity. They had lived together when the first sibling fell ill and had inherited the same haplotype from their healthy mother. Leff et al19 reported fatal PAN at early childhood, occurring 2 years apart in 2 siblings of a family with several autoimmune diseases, that is, SLE and allergies. Schneider and Goldman20 observed the simultaneous occurrence of PAN in a 60-year-old man and his 12-years younger sister. Finally, PAN21 occurred in two identical twin sisters, with an interval of several years between disease onsets. A PAN cluster in a family with high prevalence of autoimmune disease seems to illustrate the relative contribution of genes and environment for this disease.22 The father had hepatitis B and PAN, and he had shared his razor with both of his sons, who subsequently acquired hepatitis B. However, only one of them got PAN, and it is striking that they had inherited different haplotypes from their father. Microscopic Polyangiitis (MPA) Barbiano di Belgiojoso et al23 found necrotizing pauci-immune glomerulonephritis with renal vasculitis and P-ANCA positivity in a father and a son. The disease onset within 3 months, and both had a prodromal respiratory disease. They subsequently became dialysis-dependent but recovered in response to immunosuppressive therapy. Father and son shared the HLA-A11 and B35 antigens.
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Heuze-Claudet et al24 reported two Moroccan siblings, whose parents were first cousins, with a P-ANCA–associated pulmonary syndrome, and Franssen et al25 observed another sibling pair with P-ANCA–associated vasculitis. Goodpasture’s Syndrome In early reports of clusters of RPGN, ANCAassociated RPGN and anti-GBM disease could not be discriminated, and the label Goodpasture’s syndrome (GS)26 was generally used. Clusters of GS are therefore included in this review, and also because of their close relationship with SV, as suggested by the simultaneous or subsequent appearance of ANCA and anti-GBM antibodies.27-29 Two reports describe GS in twins.30,31 GS with fatal outcome was also diagnosed in two brothers who both fell ill at the age of 25 years but lived in different environments.32 Two further families with two affected brothers and cousins, respectively,33,34 are reported. GS was also found to be associated with other diseases in families, for example, in a large family described by Mu¨ntefering et al,35 in which several members had different renal diseases and bronchial asthma. Two brothers died of uremia due to RPGN with pulmonary hemorrhage. DISCUSSION
The clusters of SV described in this report, and those already published, are the result of simultaneous or subsequent occurrence of only one entity from the spectrum of SV in a community, with the exception of one cluster of different entities of SV.17 In most clusters, no more than two persons, mostly siblings or one parent and a child, were affected by the disease (Table 1). Distantly related members of a family are either rarely concordantly affected by SV or these clusters are overlooked or underreported. Relative to the number of concordant siblings, there are few reported twins with concordance for SV. There are indeed more published twins discordant for SV.15,16 The clusters may provide useful information on the causes of SV. First of all, the pattern of clusters itself may indicate clues to the cause of (1) SV and (2) the information pertaining to these clusters may add to existing hypotheses on
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NOWACK ET AL Table 1. Published Clusters of SV: Number and Relationship of Affected Patients and HLA Associations
Reference
Entity
No. of Affected Members
Knudsen et al2
WG
2
Stoney et al5
WG
2
Muniain et al6 Hay et al10
WG WG
2 2
Sewell and Hamilton7
WG
2
Rottem et al17 Barrett et al12
WG/PAN WG
3 2
Nagibov and Cheranov11 Harris and Jones21 Rottem et al17
WG PAN PAN
2 2 3
Mason et al18
PAN
2
Leff et al19 Schneider and Goldman20 Reveille et al22
PAN PAN PAN
2 2 2
Franssen et al25 Heuze-Claudot et al24 Barbiano di Belgiojoso et al23 Simonsen et al31 D’Apice et al30 Mu¨ntefering et al35 Stanton and Tange34 Maddock et al33
MPA MPA MPA GS GS GS GS GS
2 2 2 2 2 2 2 2
Relationship of Affected Members
HLA Associations
Siblings
Both patients and the ANCA-positive sibling share one parental haplotype: HLA-A2, B7, DRw12 Siblings Same haplotype from the mother: HLA-A31, Bw60, DR4 Siblings Not studied Siblings Siblings share HLA-B8 Brother: HLA-A3, A10, B8, B17, DR3, DR7 Sister: A3, A10, B8, DR3, DR4 Mother and daughter Mother: A9, A11, B14, B18, DR1, DR2 Daughter: A2, A9, B12, B14, Bw4, Bw6, DR1 Father and 2 siblings Not studied Unrelated: father and stepson HLA-B8 inherited by both patients independently Unrelated: spouses Not studied Twins Not studied Siblings All three siblings had inherited the same haplotype from their healthy father, with the exception of a single DQ-locus: HLA-A2, B57, Cw6, DR7, DQ9(2), DR53 Siblings Same haplotype: A11, B5, DR5, DQw7 Siblings Not studied Siblings Not studied Father and son Affected son and a second healthy son had inherited different haplotypes from their father Siblings Not studied Siblings Not studied Father and son Patients shared HLA-A11 and B35 Twins Not studied Twins Not studied Siblings Not studied Siblings Not studied Cousins Not studied
Abbreviations: WG, Wegener’s granulomatosis; MPA, microscopic polyangiitis; PAN, polyarteritis nodosa; GS, Goodpasture’s syndrome.
a genetic predisposition and (3) the role of environmental factors for SV. Clusters of SV occur in first-degree relatives, whereas pedigrees with SV in several generations, or pedigrees whose affected members grew up and lived in separated environments before disease onset, have not been reported. This pattern suggests that environmental triggers have a strong impact for the outbreak of SV, because siblings or parents and their children share, besides their genetic background, much of the
environment. Shared environment until disease onset was explicitly mentioned for many clusters,6,7,17,22 and the presence of an environmental trigger was suspected because of a close disease onset and a strikingly similar course of the disease. A strong environmental influence is also suggested by the occurrence of SV in unrelated members of communities11,12 and the low concordance rate in twins. However, SV clusters in unrelated patients are exceptionally rare relative to the number of famil-
FAMILIAL VASCULITIS
ial clusters, and this again is an argument for a genetic susceptibility for SV. In synopsis, the pattern of SV clusters can be explained by a combined contribution of environmental triggers and a genetically determined susceptibility. Several human autoimmune diseases are associated with certain HLA class II antigens,36 for example, rheumatoid arthritis with HLA-DR4.37 Because HLA associations have been suggested also for SV, information on HLA antigens was provided for many clusters (Fig 1, Table 1). In family 1 of this report, the affected siblings had inherited the same HLA haplotype from both their parents, which makes them HLA-identical, whereas the unaffected siblings had each inherited one other HLA haplotype from their parents. In four further clusters, siblings concordant for SV had inherited the same haplotype from one of their healthy parents,2,5,17,18 and in one case of striking discordance in siblings for PAN despite obvious environmental similarity, they had inherited a different haplotype from the affected father.22 This situation is reminiscent of rheumatoid arthritis, where HLA-haplotype sharing has been found in affected sibships.38 Studies on association of HLA-antigens with SV have obtained different results: positive associations for DR2,8,39,40 DR4,41 DQ7,40,41 and B813,14; negative association for DR339-41 and DR13DR642; and no association.43-45 DR2 seems to be associated not only with SV but also with other autoimmune disorders. Approximately 20% of the general population have the DR2 antigen. Overrepresentation of DR2 was found in patients with P-ANCA–associated drug-induced SLE,48 in allergic disorders,47 and in cutaneous vasculitis.46 The strongest association is present for anti-GBM disease, where the frequency of DR2 is increased to 80%.9 SV-associated HLA-antigens also have been detected within the reported clusters. The HLAidentical siblings in our family 1 are homozygous for DR2, and in the unaffected siblings DR2 was paired with either DR7 or DR11. The one patient of family 2, who was HLA-typified, was also a carrier of DR2. In the family reported by Sewell and Hamilton,7 the mother with severe renal involvement of WG had DR2. In Stoney et al’s report,5 the affected siblings had inherited with their mother’s haplotype the HLA-DR4
369
antigen. HLA-B8 was inherited to both affected siblings in Hay et al’s report.10 Finally, the father and his stepson, both with ANCA-associated diseases, had independently inherited the HLAB8–antigen.12 DR3 was indeed rarely found within the clusters, but it was present in the 2 affected siblings reported by Hay et al.10 Several of the patients completely miss SV-associated HLA-antigens.2,18 In conclusion, the degree of HLA resemblance seems to be connected with the risk for SV in these clusters, but HLA antigens clearly conferring that risk cannot be identified. The reported associations of SV with other polymorphic gene loci, such as complement,49,51 or alpha-1-antitrypsin deficiency50 or tumor necrosis factor-alpha,52 have not been studied within the familial clusters. Other autoimmune diseases and allergies were prevalent within several clusters.15,17,19,22,35 This is in agreement with many case-reports of SV patients who suffer from another autoimmune disease53-88 (Table 2), although this has never been studied systematically. Few hard data about environmental triggers for SV are available from the reported clusters. In one PAN cluster, a hepatitis B infection is quite obviously the trigger,22 and in other clusters of PAN and MPA, the presence of an infectious trigger was highly probable, although this could not be proved. For ANCA-associated SV, only one report discussed a Coxsackie virus infection as a possible cause.12 This is in contrast to the numerous sporadic cases of SV that had been related to a number of infectious organisms89 and the role of infection for relapses of SV,90 especially for WG, where a specific risk goes with the nasal carriage of Staphylococcus aureus.91 Other antigen exposure, for example, through hyposensibilisation92 or vaccination,93 which had been linked to the occurrence of SV, is also missing within the reported clusters. The occupational histories of the affected patients in the SV clusters provide no clues to possible environmental causes of SV and antiGBM disease, such as silicon exposure for ANCA-associated vasculitides94-96 and hydrocarbon exposure for anti-GBM-disease and SV.97-99 In summary, the reported two clusters of MPA and WG, together with published clusters of
370
NOWACK ET AL Table 2. Other Autoimmune Diseases in Patients With SV Reference
Entity of SV
Associated Autoimmune Disease
Dolman et al53 Masor et al54 Armbruster and Vetter55 Kitahara et al56 Small et al57 Sugimoto et al58 Wedderburn et al59 Ohashi et al60 Svirskii et al61 Tanemoto et al62 Tanaka et al63 Yuasa et al64 Harper et al65 Steuer et al66 Weidensaul et al67 Hillis et al68 Bonomini et al69 Waisburg et al70 Boutin et al71 Guillevin et al72 Herreman et al73 Lahoz Rallo et al74 Asherson et al75 Tohme et al76 Sattar77 Galeazzi et al78 Ferreiro Seoane et al79 Lain Martı´nez80 Vivancos et al81 Schoonjans et al82 Dasgupta et al83 Stockmann84 Kojima et al85 Peces et al86 Yamazaki et al87
WG* WG WG WG* WG WG WG WG WG MPA† MPA (renal-limited) MPA (renal-limited)* MPA* MPA MPA MPA MPA PAN PAN‡ PAN PAN§ PAN PAN PAN PAN PAN (HBV and HCV related) PAN PAN PAN PAN PAN CSS㛳 CSS GS GS
Graves’ disease (2 cases) Hashimoto’s thyroiditis Hashimoto’s thyroiditis Autoimmune thyroiditis Relapsing polychondritis Insulin-dependent diabetes mellitus Juvenile chronic arthritis Rheumatoid arthritis Rheumatoid arthritis Graves’ disease (3 cases) Subclinical autoimmune thyroiditis Autoimmune thyroiditis (2 cases) Autoimmune thyroiditis Rheumatoid arthritis Primary antiphospholipid syndrome Scleroderma Hashimoto’s thyroiditis and atrophic gastritis Multiple sclerosis–like syndrome Graves’ disease Graves’ disease Sjogren syndrome Sjogren syndrome Juvenile rheumatoid arthritis Ankylosing spondylitis Ankylosing spondylitis Ankylosing spondylitis Ankylosing spondylitis and rheumatoid arthritis Rheumatoid arthritis Systemic lupus erythematosus Primary antiphospholipid syndrome Primary antiphospholipid syndrome Rheumatoid arthritis (2 cases) Autoimmune hemolytic anemia Rheumatoid arthritis Systemic lupus erythematosus
*Possibly associated with treatment with propylthiouracil. †Possibly associated with treatment with propylthiouracil and methimazole. ‡Possibly associated with treatment with carbimazole. §After stopping treatment for PAN, the patient developed a non-Hodgkins lymphoplasmocytic lymphoma. 㛳One case possibly related to D-penicillamine treatment.
these and related diseases, suggest a combination of genetic susceptibility and environmental triggers as cause. Which genes confer this susceptibility remains unknown, although there is some indication that HLA antigens are of importance. With the exception of hepatitis B virus for a cluster of PAN, the environmental triggers for SV in these clusters remain unidentified. Further studies of larger populations of SV patients are needed to gather new information and to substantiate hypotheses on the cause of SV, which have so far been based on small observational studies. Because of the low fre-
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