Epidemiology of hypocomplementaemic urticarial vasculitis (anti-C1q vasculitis)

Epidemiology of hypocomplementaemic urticarial vasculitis (anti-C1q vasculitis) Abstract Objectives The aim was to describe the clinical characteristics and epidemiology of hypocomplementaemic urticarial vasculitis (HUV; anti-C1q vasculitis) in two geographically defined areas of Sweden. Methods In the health-care districts surrounding Skåne University Hospital (mean population 950 560) and Linköping University Hospital (mean population 428 503), all incident cases of HUV residing within the study areas at the onset of disease were identified during the years 2000–15. The diagnosis of HUV was confirmed by review of medical records. Only patients meeting the proposed diagnostic HUV criteria and/or the 2012 Chapel Hill consensus definitions in combination with an ever-positive anti-C1q antibody test were included. Results Sixteen patients (14 females) were identified during the study period. The median (interquartile range) age at diagnosis was 51 (40.7–56.7) years. Median (interquartile range) time of follow-up from diagnosis to 31 December 2015, or death, was 94 (46.5–136.2) months. The most frequent manifestations at diagnosis were urticaria (100%), arthritis (88%), followed by biopsy-proven glomerulonephritis (19%), episcleritis/scleritis (19%) and recurrent abdominal pain (13%). The annual incidence rate per million inhabitants was estimated as 0.7 (95% CI: 0.4, 1.1). Sixty-three per cent suffered from pulmonary disease at the last follow-up. Two patients died during the follow-up period. One patient underwent lung transplantation, and two patients proceeded to end-stage renal disease. The point prevalence on 31 December 2015 was 9.5/million (95% CI: 4.5, 14.5). Conclusion Hypocomplementaemic urticarial vasculitis constitutes a rare, but not always benign condition. Renal and lung manifestations were severe in some cases, highlighting the need for careful screening and monitoring of this potentially serious condition. epidemiology, anti-C1q antibody, urticarial vasculitis, population based, outcome Rheumatology key messages The incidence of hypocomplementaemic urticarial vasculitis is 0.7/million and is significantly higher in females. Hypocomplementaemic urticarial vasculitis is a rare and potentially serious condition. Some cases of hypocomplementaemic urticarial vasculitis demonstrated severe renal and lung manifestations, highlighting the need for careful screening and monitoring. Introduction Hypocomplementaemic urticarial vasculitis (HUV)—also named anti-C1q vasculitis in the 2012 revised international Chapel Hill Consensus Conference (CHCC) nomenclature of vasculitides [1]—has been recognized as a specific autoimmune disorder involving ⩾6 months of urticaria with hypocomplementaemia in the presence of systemic manifestations, such as arthritis/arthralgia, glomerulonephritis, uveitis or recurrent abdominal pain [2]. In addition, pulmonary involvement with chronic obstructive pulmonary disease (COPD) is frequently found and constitutes a leading cause of morbidity and mortality [3]. Skin biopsy is essential in the diagnosis of HUV, and the presence of antibodies against complement (C) protein 1q (anti-C1q) has a high sensitivity for this condition [4, 5]. Other typical laboratory findings include low levels of classical complement pathway components (at least one of C1q, C3 and C4) and/or reduced classical complement function in plasma. The histopathology of characteristic urticarial lesions reveals a vasculitis affecting small blood vessels (i.e. capillaries, venules and arterioles), often with leucocytoclasia and perivascular infiltrates composed of neutrophils. The detection of classical complement components with IF microscopy in tissues further strengthens the diagnosis of HUV [6]. The present knowledge of epidemiology, disease outcome, prognosis and clinical features of HUV is limited. In 2015, Jachiet et al. [7] presented the hitherto largest study from a French nationwide retrospective cohort including 57 cases with data on clinical and laboratory findings and on therapeutic management. However, there are currently no available figures on the prevalence and incidence of this condition. Thus, the objectives of this study were to describe the epidemiology and clinical characteristics of HUV (anti-C1q vasculitis) in two geographically defined populations of Sweden during a 16-year period. Methods Study areas and population Swedish health care is public, tax funded and offers universal access. This study was carried out in two separate geographical areas of Sweden (Fig. 1): Skåne, the southernmost county of Sweden (study area A), and the county of Östergötland located ∼400 km northeast of Skåne (study area B). The total population of the two study areas was 1 284 022 inhabitants in the year 2000 and 1 474 105 inhabitants in December 2015. Fig. 1 View largeDownload slide Study areas To the right is the map of Sweden. The left map shows study area A (within the county of Skåne) and study area B (Östergötland county). The distance between areas A and B is ∼400 km. Fig. 1 View largeDownload slide Study areas To the right is the map of Sweden. The left map shows study area A (within the county of Skåne) and study area B (Östergötland county). The distance between areas A and B is ∼400 km. Study area A consists of three health-care districts, with a mean population of 950 560 inhabitants during the study period. There are 22 municipalities in the area with Malmö as the largest city. The area is served by four hospitals, all public, with Skåne University Hospital in Lund and Malmö as a tertiary referral centre offering high-specialized health-care services. Study area B had a mean population of 428 503 inhabitants during the study period and consists of the entire county of Östergötland, including 13 municipalities. The University Hospital in Linköping is a tertiary referral centre serving the two other regional public hospitals. The age and sex distributions were similar in both study areas: 0–14 years 18%; 15–54 years 54%; and ⩾55 years 28%, and the female proportion was ∼50% [8]. Case identification, ascertainment of diagnosis and inclusion criteria Patients were retrieved from two main registries including both clinical and laboratory databases. All new cases with a diagnosis of HUV during the years 2000–15 were identified from the registries at the Departments of Rheumatology, Skåne University Hospital and Linköping University Hospital. The second source was the registry at the Department of Clinical Immunology, Skåne University Hospital in Lund. Since the early 1980s, all C1q and anti-C1q antibody analyses for both study areas have been carried out at the Department of Clinical Immunology in Lund. Thus, all samples that tested anti-C1q antibody positive for analyses during the years 2000–15 were reviewed. All case records of patients identified by any of the two retrieval sources were reviewed to ascertain a diagnosis of HUV according to the study criteria. Patients who had a clinical diagnosis of SLE were excluded from the study. Only cases meeting the following criteria were included in this study: a positive anti-C1q antibody test by ELISA; residing within the study areas at the time of HUV diagnosis; and a diagnosis of HUV based on either the CHCC definition [1] and/or typical urticarial skin lesions combined with low levels of classical complement proteins in plasma, plus at least two of the following manifestations: dermal venulitis, arthritis, glomerulonephritis, episcleritis or uveitis, recurrent abdominal pain and anti-C1q antibodies [3]. Data collection Demographics, clinical and laboratory data and pathology reports were obtained retrospectively by review of case records. The following data were collected: sex, age at diagnosis, age at disease onset (i.e. first symptoms attributed to HUV), organ involvement at diagnosis and at follow-up, and relevant laboratory data, including autoantibodies and complement consumption. In addition, data on smoking habits were obtained. The patients were stratified into two main groups according to their smoking habits: ever-smokers (active and former smokers) and never-smokers (patients who had never smoked continuously). Data on the outcome in terms of the patient’s survival and renal outcome were registered, as either estimated glomerular filtration rate (eGFR) at the last follow-up or the occurrence of end-stage renal disease (ESRD). The eGFR was calculated using the modification of diet in renal disease equation [9]. Analysis of anti-C1q antibodies Anti-C1q antibodies were analysed by ELISA and by western blot. For samples obtained between 2000 and August 2011, only the collagenous part of the C1q molecule was used as the antigen in the ELISA, essentially as described by Mårtensson et al. [10]. For samples taken from September 2011 onwards, whole C1q (Calbiochem, San Diego, CA, USA) was used as antigen [11]. Western blot of separated C1q protein A, B and C chains was performed essentially as described by Mårtensson et al. [10]. Statistical analyses Statistical analyses were performed using the Statistical Package for the Social Sciences, SPSS version 22.0 for Windows (IBM SPSS Statistics). Differences between groups were analysed by Student’s t test, Mann–Whitney U test and χ2 test, and data were presented as the mean and s.d. or the median and interquartile range (IQR) when appropriate. The numerator for the incidence estimates was the number of patients diagnosed with HUV between 2000 and 2015. The denominator population for the incidence rates is the mean adult population during the study period. For the prevalence estimates, the numerator was all patients with HUV who were alive and living in the study area at the date of point prevalence estimates, that is, 31 December 2015. The denominator was the total adult population on the date of point prevalence estimate. A value of P < 0.05 was considered significant. The Kaplan–Meier method was used to estimate survival rates. The 95% CI was calculated assuming a Poisson distribution of the observed cases. The study protocol was approved by the Regional Ethics Review Board, Lund, Sweden (2010/668 and 2012/252). Patient consent was not required by the ethical board. Results Sixteen patients with HUV (anti-C1q vasculitis), 14 of whom were female (88%), were identified during the study period. Demographics, clinical and laboratory characteristics of patients are detailed in Table 1. All patients were of Swedish ancestry. The median (IQR) age at diagnosis was 51 (40.7–56.7) years. Median (IQR) diagnosis delay, that is, time from first symptom attributable to HUV until diagnosis, was 12 (5.0–19.7) months. The diagnosis was based on pathology reports (any biopsy) in 13 of 16 cases (81%). Fifteen of 16 patients (94%) had reduced levels of classical complement components in plasma, and all patients tested positive for anti-C1q antibodies by ELISA at least once during the study period. Western blot was performed in 15 of 16 patients, and confirmed positive in 9 of these (60%). Table 1 Clinical and laboratory characteristics of 16 patients with hypocomplementaemic urticarial vasculitis (anti-C1q vasculitis) in Sweden Variable  Value  Number of patients  16  Female, n (%)  14 (88)  Age at diagnosis, median (IQR), years  51 (40.7–56.7)  Age at last follow-up, median (IQR), years  58 (47.0–67.2)  Duration of follow-up, months (IQR)  94 (46.5–136.2)  Diagnosis delay, months (IQR)  12 (5.0–19.7)  Laboratory results at diagnosis, median (IQR)      Haemoglobin, g/l  124.5 (116.5–131.5)      White blood cell count  7.2 (5.7–11.5)      Thrombocyte count  311 (250–451)      ESR, mm/h  18.5 (8.5–30.2)      CRP, mg/l  14 (10–29)      Plasma creatinine, median (IQR), µmol/l  79.5 (57.5–85.0)      eGFR, ml/min/1.73 m2  75.5 (65.2–108.2)  Criteria at diagnosis      Low complement  15 (94)      Dermal venulitis  1 (6)      Arthritis  14 (88)      Glomerulonephritis (on biopsy)  3 (19)      Episcleritis/scleritis  3 (19)      Recurrent abdominal pain  2 (13)      Histopathology diagnosis  13 (81)      ESRD  2 (13)      Death  2 (13)  Serology data at diagnosis      Anti-C1q antibody  16 (100)      Low C1q complement level  15 (94)      ANA positive by IF  7 (44)      ENA positive  5 (31)a      Anti-dsDNA antibody  0 (0)      aCL  2 (13)  Variable  Value  Number of patients  16  Female, n (%)  14 (88)  Age at diagnosis, median (IQR), years  51 (40.7–56.7)  Age at last follow-up, median (IQR), years  58 (47.0–67.2)  Duration of follow-up, months (IQR)  94 (46.5–136.2)  Diagnosis delay, months (IQR)  12 (5.0–19.7)  Laboratory results at diagnosis, median (IQR)      Haemoglobin, g/l  124.5 (116.5–131.5)      White blood cell count  7.2 (5.7–11.5)      Thrombocyte count  311 (250–451)      ESR, mm/h  18.5 (8.5–30.2)      CRP, mg/l  14 (10–29)      Plasma creatinine, median (IQR), µmol/l  79.5 (57.5–85.0)      eGFR, ml/min/1.73 m2  75.5 (65.2–108.2)  Criteria at diagnosis      Low complement  15 (94)      Dermal venulitis  1 (6)      Arthritis  14 (88)      Glomerulonephritis (on biopsy)  3 (19)      Episcleritis/scleritis  3 (19)      Recurrent abdominal pain  2 (13)      Histopathology diagnosis  13 (81)      ESRD  2 (13)      Death  2 (13)  Serology data at diagnosis      Anti-C1q antibody  16 (100)      Low C1q complement level  15 (94)      ANA positive by IF  7 (44)      ENA positive  5 (31)a      Anti-dsDNA antibody  0 (0)      aCL  2 (13)  Values are n (%) unless otherwise indicated. aIsolated Ro/SSA in three cases; Ro/SSA in combination with La/SSB in two cases. eGFR: estimated glomerular filtration rate; ESRD: end-stage renal disease; IQR: interquartile range. Table 1 Clinical and laboratory characteristics of 16 patients with hypocomplementaemic urticarial vasculitis (anti-C1q vasculitis) in Sweden Variable  Value  Number of patients  16  Female, n (%)  14 (88)  Age at diagnosis, median (IQR), years  51 (40.7–56.7)  Age at last follow-up, median (IQR), years  58 (47.0–67.2)  Duration of follow-up, months (IQR)  94 (46.5–136.2)  Diagnosis delay, months (IQR)  12 (5.0–19.7)  Laboratory results at diagnosis, median (IQR)      Haemoglobin, g/l  124.5 (116.5–131.5)      White blood cell count  7.2 (5.7–11.5)      Thrombocyte count  311 (250–451)      ESR, mm/h  18.5 (8.5–30.2)      CRP, mg/l  14 (10–29)      Plasma creatinine, median (IQR), µmol/l  79.5 (57.5–85.0)      eGFR, ml/min/1.73 m2  75.5 (65.2–108.2)  Criteria at diagnosis      Low complement  15 (94)      Dermal venulitis  1 (6)      Arthritis  14 (88)      Glomerulonephritis (on biopsy)  3 (19)      Episcleritis/scleritis  3 (19)      Recurrent abdominal pain  2 (13)      Histopathology diagnosis  13 (81)      ESRD  2 (13)      Death  2 (13)  Serology data at diagnosis      Anti-C1q antibody  16 (100)      Low C1q complement level  15 (94)      ANA positive by IF  7 (44)      ENA positive  5 (31)a      Anti-dsDNA antibody  0 (0)      aCL  2 (13)  Variable  Value  Number of patients  16  Female, n (%)  14 (88)  Age at diagnosis, median (IQR), years  51 (40.7–56.7)  Age at last follow-up, median (IQR), years  58 (47.0–67.2)  Duration of follow-up, months (IQR)  94 (46.5–136.2)  Diagnosis delay, months (IQR)  12 (5.0–19.7)  Laboratory results at diagnosis, median (IQR)      Haemoglobin, g/l  124.5 (116.5–131.5)      White blood cell count  7.2 (5.7–11.5)      Thrombocyte count  311 (250–451)      ESR, mm/h  18.5 (8.5–30.2)      CRP, mg/l  14 (10–29)      Plasma creatinine, median (IQR), µmol/l  79.5 (57.5–85.0)      eGFR, ml/min/1.73 m2  75.5 (65.2–108.2)  Criteria at diagnosis      Low complement  15 (94)      Dermal venulitis  1 (6)      Arthritis  14 (88)      Glomerulonephritis (on biopsy)  3 (19)      Episcleritis/scleritis  3 (19)      Recurrent abdominal pain  2 (13)      Histopathology diagnosis  13 (81)      ESRD  2 (13)      Death  2 (13)  Serology data at diagnosis      Anti-C1q antibody  16 (100)      Low C1q complement level  15 (94)      ANA positive by IF  7 (44)      ENA positive  5 (31)a      Anti-dsDNA antibody  0 (0)      aCL  2 (13)  Values are n (%) unless otherwise indicated. aIsolated Ro/SSA in three cases; Ro/SSA in combination with La/SSB in two cases. eGFR: estimated glomerular filtration rate; ESRD: end-stage renal disease; IQR: interquartile range. Organ involvement, initial therapies, co-morbidities and outcome are summarized in Table 2. At the time point of diagnosis, the most frequent clinical manifestations were urticaria (n = 16, 100%), followed by arthritis/arthralgia (n = 14, 88%), biopsy-proven glomerulonephritis, episcleritis/scleritis and dyspnoea (n = 3, 19%, each), and recurrent abdominal pain (n = 2, 13%). The cumulative frequency of organ manifestations during follow-up was as follows: urticaria (n = 16, 100%), arthritis/arthralgia (n = 14, 88%) and pulmonary involvement (n = 10, 63%). There were no differences in demographic, clinical or laboratory characteristics at the time of diagnosis between patients with and without positive anti-C1q analyses carried out by western blot (data not shown). The most common initial therapy used was prednisolone (n = 14, 88%), followed by HCQ (n = 9, 56%), MMF (n = 5, 31%) and AZA (n = 3, 19%). The median (IQR) prednisolone dose at diagnosis was 30 (15–40) mg/day. Data on smoking habits were available for 15 patients; 13 were ever-smokers (4 current smokers and 9 former smokers at diagnosis), and 2 were never-smokers. Table 2 Demographics, clinical characteristics of 16 patients with hypocomplementaemic urticarial (anti-C1q) vasculitis No.  Sex  Age,a years  Year of diagnosis  Organ involvement  Initial therapies  Prednisolone dose,a mg  Biopsy  Co-morbidities/past medical history  Age at last follow-up, years  Outcome  1  F  48  2005  S, E, L  Pred, CSA  30  Skin  Hypertension, B12 deficiency, COPD  59    2  M  60  2002  S, J, L  Pred, MMF  15  Skin  Psoriasis, coeliac disease, COPD  73  Lung transplantation  3  F  48  2007  S, E, J, LN  Pred, HCQ  50  Skin    57    4  F  56  2013  S, J, L  Pred, MMF, HCQ  25  Skin  Hypertension, COPD  59    5  F  63  2014  S, H, J, L  Pred, HCQ  30  Skin  DM, thyroiditis, pernicious anaemia, COPD  65    6  F  53  2006  S, H, K, L  Pred, MMF, HCQ  40  Skin, kidney  Sarcoidosis, COPD  57  ESRD, death  7  F  64  2001  S, J, K  Pred, CYC, antihistamines, PE  40  Skin, kidney  Addison’s, thyroiditis, hypertension, IHD, pernicious anaemia  70  ESRD, death  8  F  29  2003  S, J  HCQ  –  Skin    42    9  F  49  2015  S, J, K  Pred, MMF, HCQ  15  Skin, kidney  DM, vitiligo, hypertension, Tietze’s syndrome  50    10  F  53  2000  S, J, L  Pred, AZA  15  Skin  Varicose veins, COPD  69    11  F  55  2006  S, J, CNS, PNS, L  Pred, AZA  40  Skin  None  65    12  F  31  2006  S, J  Pred, AZA  40  Skinb  Biliary stones  40    13  F  57  2004  S, J, K, L  Pred, HCQ  40  Skin    68    14  F  46  2010  S, J, L  HCQ  1.25  –  Sarcoidosis, coeliac disease, COPD  51    15  M  38  2012  S, J  Pred, HCQ  20  –    42    16  F  39  2009  S, J, K, L  Pred, MMF  60  Skin  COPD  46    No.  Sex  Age,a years  Year of diagnosis  Organ involvement  Initial therapies  Prednisolone dose,a mg  Biopsy  Co-morbidities/past medical history  Age at last follow-up, years  Outcome  1  F  48  2005  S, E, L  Pred, CSA  30  Skin  Hypertension, B12 deficiency, COPD  59    2  M  60  2002  S, J, L  Pred, MMF  15  Skin  Psoriasis, coeliac disease, COPD  73  Lung transplantation  3  F  48  2007  S, E, J, LN  Pred, HCQ  50  Skin    57    4  F  56  2013  S, J, L  Pred, MMF, HCQ  25  Skin  Hypertension, COPD  59    5  F  63  2014  S, H, J, L  Pred, HCQ  30  Skin  DM, thyroiditis, pernicious anaemia, COPD  65    6  F  53  2006  S, H, K, L  Pred, MMF, HCQ  40  Skin, kidney  Sarcoidosis, COPD  57  ESRD, death  7  F  64  2001  S, J, K  Pred, CYC, antihistamines, PE  40  Skin, kidney  Addison’s, thyroiditis, hypertension, IHD, pernicious anaemia  70  ESRD, death  8  F  29  2003  S, J  HCQ  –  Skin    42    9  F  49  2015  S, J, K  Pred, MMF, HCQ  15  Skin, kidney  DM, vitiligo, hypertension, Tietze’s syndrome  50    10  F  53  2000  S, J, L  Pred, AZA  15  Skin  Varicose veins, COPD  69    11  F  55  2006  S, J, CNS, PNS, L  Pred, AZA  40  Skin  None  65    12  F  31  2006  S, J  Pred, AZA  40  Skinb  Biliary stones  40    13  F  57  2004  S, J, K, L  Pred, HCQ  40  Skin    68    14  F  46  2010  S, J, L  HCQ  1.25  –  Sarcoidosis, coeliac disease, COPD  51    15  M  38  2012  S, J  Pred, HCQ  20  –    42    16  F  39  2009  S, J, K, L  Pred, MMF  60  Skin  COPD  46    a At diagnosis. b Biopsy showed perivascular inflammation. COPD: chronic obstructive pulmonary disease; DM: diabetes mellitus; E: eyes; ESRD: end-stage renal disease; F: female; H: heart (including pericarditis); IHD: ischemic heart disease; J: joints; K: kidney; L: lungs; M: male; NA: not available, last follow-up for all patients 31 December 2015 or death; PE: plasma exchange; PNS: peripheral nervous system; Pred: prednisolone; S: skin. Table 2 Demographics, clinical characteristics of 16 patients with hypocomplementaemic urticarial (anti-C1q) vasculitis No.  Sex  Age,a years  Year of diagnosis  Organ involvement  Initial therapies  Prednisolone dose,a mg  Biopsy  Co-morbidities/past medical history  Age at last follow-up, years  Outcome  1  F  48  2005  S, E, L  Pred, CSA  30  Skin  Hypertension, B12 deficiency, COPD  59    2  M  60  2002  S, J, L  Pred, MMF  15  Skin  Psoriasis, coeliac disease, COPD  73  Lung transplantation  3  F  48  2007  S, E, J, LN  Pred, HCQ  50  Skin    57    4  F  56  2013  S, J, L  Pred, MMF, HCQ  25  Skin  Hypertension, COPD  59    5  F  63  2014  S, H, J, L  Pred, HCQ  30  Skin  DM, thyroiditis, pernicious anaemia, COPD  65    6  F  53  2006  S, H, K, L  Pred, MMF, HCQ  40  Skin, kidney  Sarcoidosis, COPD  57  ESRD, death  7  F  64  2001  S, J, K  Pred, CYC, antihistamines, PE  40  Skin, kidney  Addison’s, thyroiditis, hypertension, IHD, pernicious anaemia  70  ESRD, death  8  F  29  2003  S, J  HCQ  –  Skin    42    9  F  49  2015  S, J, K  Pred, MMF, HCQ  15  Skin, kidney  DM, vitiligo, hypertension, Tietze’s syndrome  50    10  F  53  2000  S, J, L  Pred, AZA  15  Skin  Varicose veins, COPD  69    11  F  55  2006  S, J, CNS, PNS, L  Pred, AZA  40  Skin  None  65    12  F  31  2006  S, J  Pred, AZA  40  Skinb  Biliary stones  40    13  F  57  2004  S, J, K, L  Pred, HCQ  40  Skin    68    14  F  46  2010  S, J, L  HCQ  1.25  –  Sarcoidosis, coeliac disease, COPD  51    15  M  38  2012  S, J  Pred, HCQ  20  –    42    16  F  39  2009  S, J, K, L  Pred, MMF  60  Skin  COPD  46    No.  Sex  Age,a years  Year of diagnosis  Organ involvement  Initial therapies  Prednisolone dose,a mg  Biopsy  Co-morbidities/past medical history  Age at last follow-up, years  Outcome  1  F  48  2005  S, E, L  Pred, CSA  30  Skin  Hypertension, B12 deficiency, COPD  59    2  M  60  2002  S, J, L  Pred, MMF  15  Skin  Psoriasis, coeliac disease, COPD  73  Lung transplantation  3  F  48  2007  S, E, J, LN  Pred, HCQ  50  Skin    57    4  F  56  2013  S, J, L  Pred, MMF, HCQ  25  Skin  Hypertension, COPD  59    5  F  63  2014  S, H, J, L  Pred, HCQ  30  Skin  DM, thyroiditis, pernicious anaemia, COPD  65    6  F  53  2006  S, H, K, L  Pred, MMF, HCQ  40  Skin, kidney  Sarcoidosis, COPD  57  ESRD, death  7  F  64  2001  S, J, K  Pred, CYC, antihistamines, PE  40  Skin, kidney  Addison’s, thyroiditis, hypertension, IHD, pernicious anaemia  70  ESRD, death  8  F  29  2003  S, J  HCQ  –  Skin    42    9  F  49  2015  S, J, K  Pred, MMF, HCQ  15  Skin, kidney  DM, vitiligo, hypertension, Tietze’s syndrome  50    10  F  53  2000  S, J, L  Pred, AZA  15  Skin  Varicose veins, COPD  69    11  F  55  2006  S, J, CNS, PNS, L  Pred, AZA  40  Skin  None  65    12  F  31  2006  S, J  Pred, AZA  40  Skinb  Biliary stones  40    13  F  57  2004  S, J, K, L  Pred, HCQ  40  Skin    68    14  F  46  2010  S, J, L  HCQ  1.25  –  Sarcoidosis, coeliac disease, COPD  51    15  M  38  2012  S, J  Pred, HCQ  20  –    42    16  F  39  2009  S, J, K, L  Pred, MMF  60  Skin  COPD  46    a At diagnosis. b Biopsy showed perivascular inflammation. COPD: chronic obstructive pulmonary disease; DM: diabetes mellitus; E: eyes; ESRD: end-stage renal disease; F: female; H: heart (including pericarditis); IHD: ischemic heart disease; J: joints; K: kidney; L: lungs; M: male; NA: not available, last follow-up for all patients 31 December 2015 or death; PE: plasma exchange; PNS: peripheral nervous system; Pred: prednisolone; S: skin. Annual incidence rate The mean annual incidence rate per million inhabitants was estimated to be 0.7 (95% CI: 0.4, 1.1) and was significantly higher among females than males [1.3 (95% CI: 0.6, 1.9) vs 0.2 (95% CI: 0, 0.4), P = 0.003; Table 3]. The incidence rate was slightly higher in Östergötland (study area B) than in Skåne (study area A), 1.3 per million inhabitants (95% CI: 0.5, 2.2) vs 0.5 (95% CI: 0.1, 0.8), P = 0.03. Ten cases were diagnosed in the age group 15–54 years and six in the age group ⩾55 years. The age-specific incidence rates were comparable among age groups 15–54 and ⩾55 years (P = 0.88; Table 4). No cases were diagnosed in the age group 0–14 years. The incidence rate per year was stable throughout the study period. During the years 2000–05, 2007, 2009, 2010 and 2012–15, one patient was diagnosed each year, and three patients were diagnosed in 2006. Table 3 Annual incidence rate of hypocomplementaemic urticarial (anti-C1q) vasculitis in Sweden Patients  No. of patients  Incidence (95% CI)  All  16  0.7 (0.4, 1.1)      Women  14  1.3 (0.6, 1.9)      Men  2  0.2 (0, 0.4)  Study area A (Skåne)  7  0.5 (0.1, 0.8)      Women  6  0.8 (0.2, 1.4)      Men  1  0.1 (0, 0.4)  Study area B (Östergötland)  9  1.3 (0.5, 2.2)      Women  8  2.3 (0.7, 4.0)      Men  1  0.3 (0, 0.9)  Patients  No. of patients  Incidence (95% CI)  All  16  0.7 (0.4, 1.1)      Women  14  1.3 (0.6, 1.9)      Men  2  0.2 (0, 0.4)  Study area A (Skåne)  7  0.5 (0.1, 0.8)      Women  6  0.8 (0.2, 1.4)      Men  1  0.1 (0, 0.4)  Study area B (Östergötland)  9  1.3 (0.5, 2.2)      Women  8  2.3 (0.7, 4.0)      Men  1  0.3 (0, 0.9)  Mean annual incidence rate (2000–15) estimated per million inhabitants. Table 3 Annual incidence rate of hypocomplementaemic urticarial (anti-C1q) vasculitis in Sweden Patients  No. of patients  Incidence (95% CI)  All  16  0.7 (0.4, 1.1)      Women  14  1.3 (0.6, 1.9)      Men  2  0.2 (0, 0.4)  Study area A (Skåne)  7  0.5 (0.1, 0.8)      Women  6  0.8 (0.2, 1.4)      Men  1  0.1 (0, 0.4)  Study area B (Östergötland)  9  1.3 (0.5, 2.2)      Women  8  2.3 (0.7, 4.0)      Men  1  0.3 (0, 0.9)  Patients  No. of patients  Incidence (95% CI)  All  16  0.7 (0.4, 1.1)      Women  14  1.3 (0.6, 1.9)      Men  2  0.2 (0, 0.4)  Study area A (Skåne)  7  0.5 (0.1, 0.8)      Women  6  0.8 (0.2, 1.4)      Men  1  0.1 (0, 0.4)  Study area B (Östergötland)  9  1.3 (0.5, 2.2)      Women  8  2.3 (0.7, 4.0)      Men  1  0.3 (0, 0.9)  Mean annual incidence rate (2000–15) estimated per million inhabitants. Table 4 Age-specific annual incidence rate of hypocomplementaemic urticarial (anti-C1q) vasculitis in Sweden Age group at diagnosis  No. of patients  Incidence (95% CI)  0–14 years  0  0.0 (0.0)  15–54 years  10  0.9 (0.3, 1.4)      Study area A  5  0.6 (0.1, 1.2)      Study area B  5  1.4 (0.2, 2.6)  ≥55 years  6  0.9 (0.2, 1.7)      Study area A  2  0.5 (0.0, 1.1)      Study area B  4  1.9 (0.0, 3.8)  Age group at diagnosis  No. of patients  Incidence (95% CI)  0–14 years  0  0.0 (0.0)  15–54 years  10  0.9 (0.3, 1.4)      Study area A  5  0.6 (0.1, 1.2)      Study area B  5  1.4 (0.2, 2.6)  ≥55 years  6  0.9 (0.2, 1.7)      Study area A  2  0.5 (0.0, 1.1)      Study area B  4  1.9 (0.0, 3.8)  Mean annual incidence rate (2000–15) estimated per million inhabitants. Table 4 Age-specific annual incidence rate of hypocomplementaemic urticarial (anti-C1q) vasculitis in Sweden Age group at diagnosis  No. of patients  Incidence (95% CI)  0–14 years  0  0.0 (0.0)  15–54 years  10  0.9 (0.3, 1.4)      Study area A  5  0.6 (0.1, 1.2)      Study area B  5  1.4 (0.2, 2.6)  ≥55 years  6  0.9 (0.2, 1.7)      Study area A  2  0.5 (0.0, 1.1)      Study area B  4  1.9 (0.0, 3.8)  Age group at diagnosis  No. of patients  Incidence (95% CI)  0–14 years  0  0.0 (0.0)  15–54 years  10  0.9 (0.3, 1.4)      Study area A  5  0.6 (0.1, 1.2)      Study area B  5  1.4 (0.2, 2.6)  ≥55 years  6  0.9 (0.2, 1.7)      Study area A  2  0.5 (0.0, 1.1)      Study area B  4  1.9 (0.0, 3.8)  Mean annual incidence rate (2000–15) estimated per million inhabitants. Point prevalence On the date of point prevalence estimate, 14 cases were alive and living within the study area, resulting in a point prevalence per million inhabitants of 9.5 (95% CI: 4.5, 14.5) for all patients, 16.2 (95% CI: 7, 25.4) for females and 2.7 (95% CI: 0, 6.5) for males (P = 0.007). The prevalence did not differ significantly between the two study areas [study area A: 6.8 (95% CI: 1.8, 11.8) vs 15.7 (95% CI: 4.1, 27.3), P = 0.10; Table 5]. The point prevalence in the age group ⩾55 years (57% of cases) was 18.1 per million inhabitants (95% CI: 5.5, 30.6) for all patients, 10.0 per million inhabitants (95% CI: 0.0, 21.2) in study area A and 35.2 per million inhabitants (95% CI: 4.4, 66.1) in study area B (P = 0.06). Table 5 Point prevalence of hypocomplementaemic urticarial (anti-C1q) vasculitis in Sweden Patients  No. of patients  Point prevalence (95% CI)  All  14  9.5 (4.5, 14.5)      Women  12  16.2 (7.0, 25.4)      Men  2  2.7 (0, 6.5)  Study area A (Skåne)  7  6.8 (1.8, 11.8)      Women  6  11.6 (2.3, 20.9)      Men  1  2.0 (0, 5.8)  Study area B (Östergötland)  7  15.7 (4.1, 27.3)      Women  6  27.1 (5.4, 48.8)      Men  1  4.5 (0, 13.2)  Patients  No. of patients  Point prevalence (95% CI)  All  14  9.5 (4.5, 14.5)      Women  12  16.2 (7.0, 25.4)      Men  2  2.7 (0, 6.5)  Study area A (Skåne)  7  6.8 (1.8, 11.8)      Women  6  11.6 (2.3, 20.9)      Men  1  2.0 (0, 5.8)  Study area B (Östergötland)  7  15.7 (4.1, 27.3)      Women  6  27.1 (5.4, 48.8)      Men  1  4.5 (0, 13.2)  Point prevalence estimated per million inhabitants on 1 January 2016. Table 5 Point prevalence of hypocomplementaemic urticarial (anti-C1q) vasculitis in Sweden Patients  No. of patients  Point prevalence (95% CI)  All  14  9.5 (4.5, 14.5)      Women  12  16.2 (7.0, 25.4)      Men  2  2.7 (0, 6.5)  Study area A (Skåne)  7  6.8 (1.8, 11.8)      Women  6  11.6 (2.3, 20.9)      Men  1  2.0 (0, 5.8)  Study area B (Östergötland)  7  15.7 (4.1, 27.3)      Women  6  27.1 (5.4, 48.8)      Men  1  4.5 (0, 13.2)  Patients  No. of patients  Point prevalence (95% CI)  All  14  9.5 (4.5, 14.5)      Women  12  16.2 (7.0, 25.4)      Men  2  2.7 (0, 6.5)  Study area A (Skåne)  7  6.8 (1.8, 11.8)      Women  6  11.6 (2.3, 20.9)      Men  1  2.0 (0, 5.8)  Study area B (Östergötland)  7  15.7 (4.1, 27.3)      Women  6  27.1 (5.4, 48.8)      Men  1  4.5 (0, 13.2)  Point prevalence estimated per million inhabitants on 1 January 2016. Outcomes Patients were followed from the time of diagnosis to 31 December 2015 or death. The median (IQR) time of follow-up was 94 (46.5–136.2) months. The median (IQR) age at last follow-up (14 patients) was 58 (45.0–65.7) years. One patient diagnosed with both COPD and pulmonary emphysema underwent lung transplantation 22 months after HUV diagnosis, and two patients proceeded to ESRD 36 and 49 months after HUV diagnosis, respectively. The remaining 14 patients with native kidney function at last follow-up had a median (IQR) eGFR of 89.5 (66.2–101.5) ml/min/1.73 m2. During follow-up, 8 out of 16 patients were diagnosed with COPD; 6 of whom suffered from both COPD and emphysema. Of the patients with COPD, five were current smokers at time of HUV diagnosis, two were former smokers, and one patient had never smoked. The mean (s.d.) age at diagnosis for patients who developed COPD was 52.2 (7.7) years compared with 46.3 (12.6) years for those without concomitant COPD (P = 0.30). Patients with COPD had longer diagnosis delay than those without COPD (13.5 vs 5.5 months), although these differences were not statistically significant (P = 0.61). Two patients were deceased during the follow-up period; one 57-year-old female patient died from COPD, septicaemia and ESRD 52 months after diagnosis of HUV, and one 72-year-old female patient died from ESRD 65 months after the HUV diagnosis. The 1-, 5- and 10-year survivals were 100, 92 and 83%, respectively. Discussion Although >45 years have passed since HUV (anti-C1q vasculitis) was first described by McDuffie et al. [2] at the Mayo Clinic, the data on epidemiology, disease outcomes, prognosis and clinical features are still limited. To our knowledge, we are presenting the first comprehensive epidemiological data on HUV. Earlier observations, and a more recent study, suggest a rare prevalence of urticarial vasculitis among patients with cutaneous vasculitis, with very few patients in the study progressing to HUV [12, 13]. Thus, it is hard to compare our results on the epidemiology of HUV directly with mentioned studies because we adhered strictly to the CHCC 2012 definitions of HUV [1]. However, the overall annual incidence rate of 0.7 per million inhabitants is comparable to that of other vasculitides of small and medium-sized vessels, such as polyarteritis nodosa and eosinophilic granulomatosis with polyangiitis [14]. Studying the epidemiology of rare diseases is challenging because it requires a long period of observation and a large population. Furthermore, the availability of consensus criteria or definitions is crucial for performing such studies. The CHCC 2012 defined the HUV syndrome as ‘vasculitis accompanied by urticaria and hypocomplementaemia affecting small vessels and accompanied with anti-C1q antibodies’ [1]. All the patients in the present study fulfilled the CHCC definitions. Our study also showed a significantly higher incidence of HUV among women, with a female to male ratio of 7:1, comparable to the 8:1 ratio previously reported in a study by Wisnieski et al. [15]. Such a difference in sex specific incidence is not evident in ANCA associated vasculitis [16], but rather similar to what has been described in epidemiological studies of SLE [17, 18]. The hitherto largest series of HUV patients was compiled by Jachiet et al. [7], but did not include estimates of prevalence. They reported two peaks in the age-specific incidence rates (i.e. 40–50 and 60–70 years), which is in line with our findings. However, the French study also included many cases without detectable anti-C1q antibodies, albeit the vast majority of these patients showed decreased levels of C1q. Which anti-C1q assay was used in their study, and whether or not the same assay was used for all 57 patients, is uncertain. Given that the presence of positive anti-C1q antibodies was a mandatory criterion in the present study, it is unclear how our epidemiological data would have changed if applying the criteria used by Jachiet et al. [7]. Even though their cohort was almost four times as large as the Swedish one, and despite the mentioned differences in serology, the clinical phenotypes of included patients were similar. The exception was COPD, which had a higher prevalence in the present study compared with that reported by Jachiet et al. [7]. Although rare, HUV is a potentially life-threatening condition. In this cohort, 50% of our patients were diagnosed with COPD during the disease course. Sixty-one per cent of the patients in a study by Wisnieski et al. [15] suffered from progressive dyspnoea and moderate to severe airway obstruction in pulmonary function testing. Compared with SLE, this is a high figure, as shown in a study from southern Sweden, where 17% of the patients with SLE suffered from COPD [19]. The association between tobacco smoking and COPD is well known, and considering the high prevalence of ever-smokers in the present study, an association between COPD and smoking among the patients in the present study cannot be excluded. However, the prevalence of smoking in our cohort does not fully explain this high figure, because not all smokers developed COPD. Although the number of patients is small, this suggests that there might be other factors related to HUV that predispose to the development of COPD. Two retrieval sources were used to identify potential HUV cases in the present study: medical records and the clinical immunology database in Lund. Given that the clinical characteristics were carefully collected by the authors, including a critical review to ascertain diagnosis, we feel confident that the specificity of HUV diagnosis among the 16 patients is the highest possible. Whether the sensitivity of HUV case retrieval is equally high remains somewhat more uncertain owing to the lack of a specific and widely accepted ICD-code for HUV. Thus, all patients in whom anti-C1q antibodies were analysed and detected during the study period are captured herein. In addition, the access to health care in Sweden is universal, which offers extraordinarily good opportunities to perform epidemiological studies and prevents potential bias with regard to the sensitivity of case retrieval. We have recently used similar methods to identify cases with renal involvement in SLE and ANCA-associated vasculitis [20]. Worldwide, anti-C1q antibodies are mainly analysed by ELISA-based techniques [21, 22]. The target epitopes of anti-C1q found in HUV are usually different from that of anti-C1q in SLE, and this can be used to differentiate between the two conditions [10]. Anti-C1q antibodies from SLE patients typically are positive only by ELISA and do not bind separated C1q protein chains, whereas the antibodies from HUV patients in the majority of cases bind the C1q B and C protein chains on western blot analysis, in addition to binding the collagenous part of the intact C1q molecule in ELISA [10]. In the present cohort, we found no differences in clinical characteristics between patients with and without positive anti-C1q analyses carried out by western blot. Our study has limitations. The retrospective design of the study constitutes a potential cause of some missing data. As there is no generally accepted diagnosis code for the HUV, physicians might use different ICD-codes for this disease, which might have affected the complete case findings in our study. By definition, we chose to present data on anti-C1q vasculitis, which with no doubt will affect the comparability of our study with other case series in which anti-C1q seropositivity was not a mandatory criterion. To conclude, we are presenting here the first epidemiological study of HUV (anti-C1q vasculitis) including data on prevalence, incidence, disease outcomes, prognosis and clinical features from two separate areas of Sweden during a 16-year period. The high coverage of patients, which was enabled by the public and tax-funded Swedish health-care system, constitutes a major strength of the study. The estimation of incidence and prevalence indicates that this condition is rare but not always benign. Renal and lung manifestations were severe in some cases, highlighting the need for careful screening and monitoring of this potentially serious disease. Acknowledgements We would like to thank Dr Per Eriksson, Rheumatology unit at Linköping University Hospital, for his contribution in diagnosing and treating patients with HUV. We are also sincerely grateful for the late Professor Gunnar Sturfelt’s valuable contributions in planning studies on HUV in southern Sweden. Funding: The study was supported by the Region Östergötland, the Swedish Rheumatism Association (Reumatikerförbundet), the Swedish Society of Medicine (Läkarsällskapet) and the King Gustaf V’s 80-year foundation. Disclosure statement: The authors have declared no conflicts of interest. References 1 Jennette JC, Falk RJ, Bacon PA et al.   2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum  2013; 65: 1– 11. Google Scholar CrossRef Search ADS PubMed  2 McDuffie FC, Sams WMJr, Maldonado JE et al.   Hypocomplementemia with cutaneous vasculitis and arthritis. Possible immune complex syndrome. Mayo Clinic Proc  1973; 48: 340– 8. 3 Schwartz HR, McDuffie FC, Black LF, Schroeter AL, Conn DL. Hypocomplementemic urticarial vasculitis: association with chronic obstructive pulmonary disease. Mayo Clinic Proc  1982; 57: 231– 8. 4 Kallenberg CG. Anti-C1q autoantibodies. Autoimmun Rev  2008; 7: 612– 5. Google Scholar CrossRef Search ADS PubMed  5 Wisnieski JJ, Jones SM. IgG autoantibody to the collagen-like region of Clq in hypocomplementemic urticarial vasculitis syndrome, systemic lupus erythematosus, and 6 other musculoskeletal or rheumatic diseases. J Rheumatol  1992; 19: 884– 8. Google Scholar PubMed  6 Davis MD, Brewer JD. Urticarial vasculitis and hypocomplementemic urticarial vasculitis syndrome. Immunol Allergy Clin North Am  2004; 24: 183– 213. Google Scholar CrossRef Search ADS PubMed  7 Jachiet M, Flageul B, Deroux A et al.   The clinical spectrum and therapeutic management of hypocomplementemic urticarial vasculitis: data from a French nationwide study of fifty-seven patients. Arthritis Rheumatol  2015; 67: 527– 34. Google Scholar CrossRef Search ADS PubMed  8 Statistics Sweden. Statistics Sweden (Internet). September 8, 2017. Website in Swedish. www.scb.se. 9 Levey AS, Bosch JP, Lewis JB et al.   A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med  1999; 130: 461– 70. Google Scholar CrossRef Search ADS PubMed  10 Mårtensson U, Sjöholm AG, Sturfelt G, Truedsson L, Laurell AB. Western blot analysis of human IgG reactive with the collagenous portion of C1q: evidence of distinct binding specificities. Scand J Immunol  1992; 35: 735– 44. Google Scholar CrossRef Search ADS PubMed  11 Skattum L, Tydén H, Orsander K et al.   Anti-C1q antibodies and C1q in SLE: comparison between methods and relation to nephritis and disease activity. Mol Immunol  2011; 48: 1724. Google Scholar CrossRef Search ADS   12 Black AK. Urticarial vasculitis. Clin Dermatol  1999; 17: 565– 9. Google Scholar CrossRef Search ADS PubMed  13 Loricera J, Calvo-Rio V, Mata C et al.   Urticarial vasculitis in northern Spain: clinical study of 21 cases. Medicine  2014; 93: 53– 60. Google Scholar CrossRef Search ADS PubMed  14 Mohammad AJ, Jacobsson LT, Westman KWA, Sturfelt G, Segelmark M. Incidence and survival rates in Wegener's granulomatosis, microscopic polyangiitis, Churg–Strauss syndrome and polyarteritis nodosa. Rheumatology  2009; 48: 1560– 5. Google Scholar CrossRef Search ADS PubMed  15 Wisnieski JJ, Baer AN, Christensen J et al.   Hypocomplementemic urticarial vasculitis syndrome. Clinical and serologic findings in 18 patients. Medicine  1995; 74: 24– 41. Google Scholar CrossRef Search ADS PubMed  16 Watts RA, Mahr A, Mohammad AJ et al.   Classification, epidemiology and clinical subgrouping of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Nephrol Dial Transplant  2015; 30 (Suppl 1): i14– 22. Google Scholar CrossRef Search ADS PubMed  17 Ståhl-Hallengren C, Jönsen A, Nived O, Sturfelt G. Incidence studies of systemic lupus erythematosus in Southern Sweden: increasing age, decreasing frequency of renal manifestations and good prognosis. J Rheumatol  2000; 27: 685– 91. Google Scholar PubMed  18 Johnson AE, Gordon C, Palmer RG, Bacon PA. The prevalence and incidence of systemic lupus erythematosus in Birmingham, England. Relationship to ethnicity and country of birth. Arthritis Rheum  1995; 38: 551– 8. Google Scholar CrossRef Search ADS PubMed  19 Jönsen A, Bengtsson AA, Hjalte F et al.   Total cost and cost predictors in systemic lupus erythematosus – 8-years follow-up of a Swedish inception cohort. Lupus  2015; 24: 1248– 56. Google Scholar CrossRef Search ADS PubMed  20 Mohammad AJ, Weiner M, Sjöwall C et al.   Incidence and disease severity of anti-neutrophil cytoplasmic antibody-associated nephritis are higher than in lupus nephritis in Sweden. Nephrol Dialysis, Transplant  2015; 30 (Suppl 1): i23– 30. 21 Mahler M, van Schaarenburg RA, Trouw LA. Anti-C1q autoantibodies, novel tests, and clinical consequences. Front Immunol  2013; 4: 117. Google Scholar CrossRef Search ADS PubMed  22 Stojan G, Petri M. Anti-C1q in systemic lupus erythematosus. Lupus  2016; 25: 873– 7. 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: journals.permissions@oup.com 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) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Epidemiology of hypocomplementaemic urticarial vasculitis (anti-C1q vasculitis)

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com
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1462-0324
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10.1093/rheumatology/key110
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Abstract

Abstract Objectives The aim was to describe the clinical characteristics and epidemiology of hypocomplementaemic urticarial vasculitis (HUV; anti-C1q vasculitis) in two geographically defined areas of Sweden. Methods In the health-care districts surrounding Skåne University Hospital (mean population 950 560) and Linköping University Hospital (mean population 428 503), all incident cases of HUV residing within the study areas at the onset of disease were identified during the years 2000–15. The diagnosis of HUV was confirmed by review of medical records. Only patients meeting the proposed diagnostic HUV criteria and/or the 2012 Chapel Hill consensus definitions in combination with an ever-positive anti-C1q antibody test were included. Results Sixteen patients (14 females) were identified during the study period. The median (interquartile range) age at diagnosis was 51 (40.7–56.7) years. Median (interquartile range) time of follow-up from diagnosis to 31 December 2015, or death, was 94 (46.5–136.2) months. The most frequent manifestations at diagnosis were urticaria (100%), arthritis (88%), followed by biopsy-proven glomerulonephritis (19%), episcleritis/scleritis (19%) and recurrent abdominal pain (13%). The annual incidence rate per million inhabitants was estimated as 0.7 (95% CI: 0.4, 1.1). Sixty-three per cent suffered from pulmonary disease at the last follow-up. Two patients died during the follow-up period. One patient underwent lung transplantation, and two patients proceeded to end-stage renal disease. The point prevalence on 31 December 2015 was 9.5/million (95% CI: 4.5, 14.5). Conclusion Hypocomplementaemic urticarial vasculitis constitutes a rare, but not always benign condition. Renal and lung manifestations were severe in some cases, highlighting the need for careful screening and monitoring of this potentially serious condition. epidemiology, anti-C1q antibody, urticarial vasculitis, population based, outcome Rheumatology key messages The incidence of hypocomplementaemic urticarial vasculitis is 0.7/million and is significantly higher in females. Hypocomplementaemic urticarial vasculitis is a rare and potentially serious condition. Some cases of hypocomplementaemic urticarial vasculitis demonstrated severe renal and lung manifestations, highlighting the need for careful screening and monitoring. Introduction Hypocomplementaemic urticarial vasculitis (HUV)—also named anti-C1q vasculitis in the 2012 revised international Chapel Hill Consensus Conference (CHCC) nomenclature of vasculitides [1]—has been recognized as a specific autoimmune disorder involving ⩾6 months of urticaria with hypocomplementaemia in the presence of systemic manifestations, such as arthritis/arthralgia, glomerulonephritis, uveitis or recurrent abdominal pain [2]. In addition, pulmonary involvement with chronic obstructive pulmonary disease (COPD) is frequently found and constitutes a leading cause of morbidity and mortality [3]. Skin biopsy is essential in the diagnosis of HUV, and the presence of antibodies against complement (C) protein 1q (anti-C1q) has a high sensitivity for this condition [4, 5]. Other typical laboratory findings include low levels of classical complement pathway components (at least one of C1q, C3 and C4) and/or reduced classical complement function in plasma. The histopathology of characteristic urticarial lesions reveals a vasculitis affecting small blood vessels (i.e. capillaries, venules and arterioles), often with leucocytoclasia and perivascular infiltrates composed of neutrophils. The detection of classical complement components with IF microscopy in tissues further strengthens the diagnosis of HUV [6]. The present knowledge of epidemiology, disease outcome, prognosis and clinical features of HUV is limited. In 2015, Jachiet et al. [7] presented the hitherto largest study from a French nationwide retrospective cohort including 57 cases with data on clinical and laboratory findings and on therapeutic management. However, there are currently no available figures on the prevalence and incidence of this condition. Thus, the objectives of this study were to describe the epidemiology and clinical characteristics of HUV (anti-C1q vasculitis) in two geographically defined populations of Sweden during a 16-year period. Methods Study areas and population Swedish health care is public, tax funded and offers universal access. This study was carried out in two separate geographical areas of Sweden (Fig. 1): Skåne, the southernmost county of Sweden (study area A), and the county of Östergötland located ∼400 km northeast of Skåne (study area B). The total population of the two study areas was 1 284 022 inhabitants in the year 2000 and 1 474 105 inhabitants in December 2015. Fig. 1 View largeDownload slide Study areas To the right is the map of Sweden. The left map shows study area A (within the county of Skåne) and study area B (Östergötland county). The distance between areas A and B is ∼400 km. Fig. 1 View largeDownload slide Study areas To the right is the map of Sweden. The left map shows study area A (within the county of Skåne) and study area B (Östergötland county). The distance between areas A and B is ∼400 km. Study area A consists of three health-care districts, with a mean population of 950 560 inhabitants during the study period. There are 22 municipalities in the area with Malmö as the largest city. The area is served by four hospitals, all public, with Skåne University Hospital in Lund and Malmö as a tertiary referral centre offering high-specialized health-care services. Study area B had a mean population of 428 503 inhabitants during the study period and consists of the entire county of Östergötland, including 13 municipalities. The University Hospital in Linköping is a tertiary referral centre serving the two other regional public hospitals. The age and sex distributions were similar in both study areas: 0–14 years 18%; 15–54 years 54%; and ⩾55 years 28%, and the female proportion was ∼50% [8]. Case identification, ascertainment of diagnosis and inclusion criteria Patients were retrieved from two main registries including both clinical and laboratory databases. All new cases with a diagnosis of HUV during the years 2000–15 were identified from the registries at the Departments of Rheumatology, Skåne University Hospital and Linköping University Hospital. The second source was the registry at the Department of Clinical Immunology, Skåne University Hospital in Lund. Since the early 1980s, all C1q and anti-C1q antibody analyses for both study areas have been carried out at the Department of Clinical Immunology in Lund. Thus, all samples that tested anti-C1q antibody positive for analyses during the years 2000–15 were reviewed. All case records of patients identified by any of the two retrieval sources were reviewed to ascertain a diagnosis of HUV according to the study criteria. Patients who had a clinical diagnosis of SLE were excluded from the study. Only cases meeting the following criteria were included in this study: a positive anti-C1q antibody test by ELISA; residing within the study areas at the time of HUV diagnosis; and a diagnosis of HUV based on either the CHCC definition [1] and/or typical urticarial skin lesions combined with low levels of classical complement proteins in plasma, plus at least two of the following manifestations: dermal venulitis, arthritis, glomerulonephritis, episcleritis or uveitis, recurrent abdominal pain and anti-C1q antibodies [3]. Data collection Demographics, clinical and laboratory data and pathology reports were obtained retrospectively by review of case records. The following data were collected: sex, age at diagnosis, age at disease onset (i.e. first symptoms attributed to HUV), organ involvement at diagnosis and at follow-up, and relevant laboratory data, including autoantibodies and complement consumption. In addition, data on smoking habits were obtained. The patients were stratified into two main groups according to their smoking habits: ever-smokers (active and former smokers) and never-smokers (patients who had never smoked continuously). Data on the outcome in terms of the patient’s survival and renal outcome were registered, as either estimated glomerular filtration rate (eGFR) at the last follow-up or the occurrence of end-stage renal disease (ESRD). The eGFR was calculated using the modification of diet in renal disease equation [9]. Analysis of anti-C1q antibodies Anti-C1q antibodies were analysed by ELISA and by western blot. For samples obtained between 2000 and August 2011, only the collagenous part of the C1q molecule was used as the antigen in the ELISA, essentially as described by Mårtensson et al. [10]. For samples taken from September 2011 onwards, whole C1q (Calbiochem, San Diego, CA, USA) was used as antigen [11]. Western blot of separated C1q protein A, B and C chains was performed essentially as described by Mårtensson et al. [10]. Statistical analyses Statistical analyses were performed using the Statistical Package for the Social Sciences, SPSS version 22.0 for Windows (IBM SPSS Statistics). Differences between groups were analysed by Student’s t test, Mann–Whitney U test and χ2 test, and data were presented as the mean and s.d. or the median and interquartile range (IQR) when appropriate. The numerator for the incidence estimates was the number of patients diagnosed with HUV between 2000 and 2015. The denominator population for the incidence rates is the mean adult population during the study period. For the prevalence estimates, the numerator was all patients with HUV who were alive and living in the study area at the date of point prevalence estimates, that is, 31 December 2015. The denominator was the total adult population on the date of point prevalence estimate. A value of P < 0.05 was considered significant. The Kaplan–Meier method was used to estimate survival rates. The 95% CI was calculated assuming a Poisson distribution of the observed cases. The study protocol was approved by the Regional Ethics Review Board, Lund, Sweden (2010/668 and 2012/252). Patient consent was not required by the ethical board. Results Sixteen patients with HUV (anti-C1q vasculitis), 14 of whom were female (88%), were identified during the study period. Demographics, clinical and laboratory characteristics of patients are detailed in Table 1. All patients were of Swedish ancestry. The median (IQR) age at diagnosis was 51 (40.7–56.7) years. Median (IQR) diagnosis delay, that is, time from first symptom attributable to HUV until diagnosis, was 12 (5.0–19.7) months. The diagnosis was based on pathology reports (any biopsy) in 13 of 16 cases (81%). Fifteen of 16 patients (94%) had reduced levels of classical complement components in plasma, and all patients tested positive for anti-C1q antibodies by ELISA at least once during the study period. Western blot was performed in 15 of 16 patients, and confirmed positive in 9 of these (60%). Table 1 Clinical and laboratory characteristics of 16 patients with hypocomplementaemic urticarial vasculitis (anti-C1q vasculitis) in Sweden Variable  Value  Number of patients  16  Female, n (%)  14 (88)  Age at diagnosis, median (IQR), years  51 (40.7–56.7)  Age at last follow-up, median (IQR), years  58 (47.0–67.2)  Duration of follow-up, months (IQR)  94 (46.5–136.2)  Diagnosis delay, months (IQR)  12 (5.0–19.7)  Laboratory results at diagnosis, median (IQR)      Haemoglobin, g/l  124.5 (116.5–131.5)      White blood cell count  7.2 (5.7–11.5)      Thrombocyte count  311 (250–451)      ESR, mm/h  18.5 (8.5–30.2)      CRP, mg/l  14 (10–29)      Plasma creatinine, median (IQR), µmol/l  79.5 (57.5–85.0)      eGFR, ml/min/1.73 m2  75.5 (65.2–108.2)  Criteria at diagnosis      Low complement  15 (94)      Dermal venulitis  1 (6)      Arthritis  14 (88)      Glomerulonephritis (on biopsy)  3 (19)      Episcleritis/scleritis  3 (19)      Recurrent abdominal pain  2 (13)      Histopathology diagnosis  13 (81)      ESRD  2 (13)      Death  2 (13)  Serology data at diagnosis      Anti-C1q antibody  16 (100)      Low C1q complement level  15 (94)      ANA positive by IF  7 (44)      ENA positive  5 (31)a      Anti-dsDNA antibody  0 (0)      aCL  2 (13)  Variable  Value  Number of patients  16  Female, n (%)  14 (88)  Age at diagnosis, median (IQR), years  51 (40.7–56.7)  Age at last follow-up, median (IQR), years  58 (47.0–67.2)  Duration of follow-up, months (IQR)  94 (46.5–136.2)  Diagnosis delay, months (IQR)  12 (5.0–19.7)  Laboratory results at diagnosis, median (IQR)      Haemoglobin, g/l  124.5 (116.5–131.5)      White blood cell count  7.2 (5.7–11.5)      Thrombocyte count  311 (250–451)      ESR, mm/h  18.5 (8.5–30.2)      CRP, mg/l  14 (10–29)      Plasma creatinine, median (IQR), µmol/l  79.5 (57.5–85.0)      eGFR, ml/min/1.73 m2  75.5 (65.2–108.2)  Criteria at diagnosis      Low complement  15 (94)      Dermal venulitis  1 (6)      Arthritis  14 (88)      Glomerulonephritis (on biopsy)  3 (19)      Episcleritis/scleritis  3 (19)      Recurrent abdominal pain  2 (13)      Histopathology diagnosis  13 (81)      ESRD  2 (13)      Death  2 (13)  Serology data at diagnosis      Anti-C1q antibody  16 (100)      Low C1q complement level  15 (94)      ANA positive by IF  7 (44)      ENA positive  5 (31)a      Anti-dsDNA antibody  0 (0)      aCL  2 (13)  Values are n (%) unless otherwise indicated. aIsolated Ro/SSA in three cases; Ro/SSA in combination with La/SSB in two cases. eGFR: estimated glomerular filtration rate; ESRD: end-stage renal disease; IQR: interquartile range. Table 1 Clinical and laboratory characteristics of 16 patients with hypocomplementaemic urticarial vasculitis (anti-C1q vasculitis) in Sweden Variable  Value  Number of patients  16  Female, n (%)  14 (88)  Age at diagnosis, median (IQR), years  51 (40.7–56.7)  Age at last follow-up, median (IQR), years  58 (47.0–67.2)  Duration of follow-up, months (IQR)  94 (46.5–136.2)  Diagnosis delay, months (IQR)  12 (5.0–19.7)  Laboratory results at diagnosis, median (IQR)      Haemoglobin, g/l  124.5 (116.5–131.5)      White blood cell count  7.2 (5.7–11.5)      Thrombocyte count  311 (250–451)      ESR, mm/h  18.5 (8.5–30.2)      CRP, mg/l  14 (10–29)      Plasma creatinine, median (IQR), µmol/l  79.5 (57.5–85.0)      eGFR, ml/min/1.73 m2  75.5 (65.2–108.2)  Criteria at diagnosis      Low complement  15 (94)      Dermal venulitis  1 (6)      Arthritis  14 (88)      Glomerulonephritis (on biopsy)  3 (19)      Episcleritis/scleritis  3 (19)      Recurrent abdominal pain  2 (13)      Histopathology diagnosis  13 (81)      ESRD  2 (13)      Death  2 (13)  Serology data at diagnosis      Anti-C1q antibody  16 (100)      Low C1q complement level  15 (94)      ANA positive by IF  7 (44)      ENA positive  5 (31)a      Anti-dsDNA antibody  0 (0)      aCL  2 (13)  Variable  Value  Number of patients  16  Female, n (%)  14 (88)  Age at diagnosis, median (IQR), years  51 (40.7–56.7)  Age at last follow-up, median (IQR), years  58 (47.0–67.2)  Duration of follow-up, months (IQR)  94 (46.5–136.2)  Diagnosis delay, months (IQR)  12 (5.0–19.7)  Laboratory results at diagnosis, median (IQR)      Haemoglobin, g/l  124.5 (116.5–131.5)      White blood cell count  7.2 (5.7–11.5)      Thrombocyte count  311 (250–451)      ESR, mm/h  18.5 (8.5–30.2)      CRP, mg/l  14 (10–29)      Plasma creatinine, median (IQR), µmol/l  79.5 (57.5–85.0)      eGFR, ml/min/1.73 m2  75.5 (65.2–108.2)  Criteria at diagnosis      Low complement  15 (94)      Dermal venulitis  1 (6)      Arthritis  14 (88)      Glomerulonephritis (on biopsy)  3 (19)      Episcleritis/scleritis  3 (19)      Recurrent abdominal pain  2 (13)      Histopathology diagnosis  13 (81)      ESRD  2 (13)      Death  2 (13)  Serology data at diagnosis      Anti-C1q antibody  16 (100)      Low C1q complement level  15 (94)      ANA positive by IF  7 (44)      ENA positive  5 (31)a      Anti-dsDNA antibody  0 (0)      aCL  2 (13)  Values are n (%) unless otherwise indicated. aIsolated Ro/SSA in three cases; Ro/SSA in combination with La/SSB in two cases. eGFR: estimated glomerular filtration rate; ESRD: end-stage renal disease; IQR: interquartile range. Organ involvement, initial therapies, co-morbidities and outcome are summarized in Table 2. At the time point of diagnosis, the most frequent clinical manifestations were urticaria (n = 16, 100%), followed by arthritis/arthralgia (n = 14, 88%), biopsy-proven glomerulonephritis, episcleritis/scleritis and dyspnoea (n = 3, 19%, each), and recurrent abdominal pain (n = 2, 13%). The cumulative frequency of organ manifestations during follow-up was as follows: urticaria (n = 16, 100%), arthritis/arthralgia (n = 14, 88%) and pulmonary involvement (n = 10, 63%). There were no differences in demographic, clinical or laboratory characteristics at the time of diagnosis between patients with and without positive anti-C1q analyses carried out by western blot (data not shown). The most common initial therapy used was prednisolone (n = 14, 88%), followed by HCQ (n = 9, 56%), MMF (n = 5, 31%) and AZA (n = 3, 19%). The median (IQR) prednisolone dose at diagnosis was 30 (15–40) mg/day. Data on smoking habits were available for 15 patients; 13 were ever-smokers (4 current smokers and 9 former smokers at diagnosis), and 2 were never-smokers. Table 2 Demographics, clinical characteristics of 16 patients with hypocomplementaemic urticarial (anti-C1q) vasculitis No.  Sex  Age,a years  Year of diagnosis  Organ involvement  Initial therapies  Prednisolone dose,a mg  Biopsy  Co-morbidities/past medical history  Age at last follow-up, years  Outcome  1  F  48  2005  S, E, L  Pred, CSA  30  Skin  Hypertension, B12 deficiency, COPD  59    2  M  60  2002  S, J, L  Pred, MMF  15  Skin  Psoriasis, coeliac disease, COPD  73  Lung transplantation  3  F  48  2007  S, E, J, LN  Pred, HCQ  50  Skin    57    4  F  56  2013  S, J, L  Pred, MMF, HCQ  25  Skin  Hypertension, COPD  59    5  F  63  2014  S, H, J, L  Pred, HCQ  30  Skin  DM, thyroiditis, pernicious anaemia, COPD  65    6  F  53  2006  S, H, K, L  Pred, MMF, HCQ  40  Skin, kidney  Sarcoidosis, COPD  57  ESRD, death  7  F  64  2001  S, J, K  Pred, CYC, antihistamines, PE  40  Skin, kidney  Addison’s, thyroiditis, hypertension, IHD, pernicious anaemia  70  ESRD, death  8  F  29  2003  S, J  HCQ  –  Skin    42    9  F  49  2015  S, J, K  Pred, MMF, HCQ  15  Skin, kidney  DM, vitiligo, hypertension, Tietze’s syndrome  50    10  F  53  2000  S, J, L  Pred, AZA  15  Skin  Varicose veins, COPD  69    11  F  55  2006  S, J, CNS, PNS, L  Pred, AZA  40  Skin  None  65    12  F  31  2006  S, J  Pred, AZA  40  Skinb  Biliary stones  40    13  F  57  2004  S, J, K, L  Pred, HCQ  40  Skin    68    14  F  46  2010  S, J, L  HCQ  1.25  –  Sarcoidosis, coeliac disease, COPD  51    15  M  38  2012  S, J  Pred, HCQ  20  –    42    16  F  39  2009  S, J, K, L  Pred, MMF  60  Skin  COPD  46    No.  Sex  Age,a years  Year of diagnosis  Organ involvement  Initial therapies  Prednisolone dose,a mg  Biopsy  Co-morbidities/past medical history  Age at last follow-up, years  Outcome  1  F  48  2005  S, E, L  Pred, CSA  30  Skin  Hypertension, B12 deficiency, COPD  59    2  M  60  2002  S, J, L  Pred, MMF  15  Skin  Psoriasis, coeliac disease, COPD  73  Lung transplantation  3  F  48  2007  S, E, J, LN  Pred, HCQ  50  Skin    57    4  F  56  2013  S, J, L  Pred, MMF, HCQ  25  Skin  Hypertension, COPD  59    5  F  63  2014  S, H, J, L  Pred, HCQ  30  Skin  DM, thyroiditis, pernicious anaemia, COPD  65    6  F  53  2006  S, H, K, L  Pred, MMF, HCQ  40  Skin, kidney  Sarcoidosis, COPD  57  ESRD, death  7  F  64  2001  S, J, K  Pred, CYC, antihistamines, PE  40  Skin, kidney  Addison’s, thyroiditis, hypertension, IHD, pernicious anaemia  70  ESRD, death  8  F  29  2003  S, J  HCQ  –  Skin    42    9  F  49  2015  S, J, K  Pred, MMF, HCQ  15  Skin, kidney  DM, vitiligo, hypertension, Tietze’s syndrome  50    10  F  53  2000  S, J, L  Pred, AZA  15  Skin  Varicose veins, COPD  69    11  F  55  2006  S, J, CNS, PNS, L  Pred, AZA  40  Skin  None  65    12  F  31  2006  S, J  Pred, AZA  40  Skinb  Biliary stones  40    13  F  57  2004  S, J, K, L  Pred, HCQ  40  Skin    68    14  F  46  2010  S, J, L  HCQ  1.25  –  Sarcoidosis, coeliac disease, COPD  51    15  M  38  2012  S, J  Pred, HCQ  20  –    42    16  F  39  2009  S, J, K, L  Pred, MMF  60  Skin  COPD  46    a At diagnosis. b Biopsy showed perivascular inflammation. COPD: chronic obstructive pulmonary disease; DM: diabetes mellitus; E: eyes; ESRD: end-stage renal disease; F: female; H: heart (including pericarditis); IHD: ischemic heart disease; J: joints; K: kidney; L: lungs; M: male; NA: not available, last follow-up for all patients 31 December 2015 or death; PE: plasma exchange; PNS: peripheral nervous system; Pred: prednisolone; S: skin. Table 2 Demographics, clinical characteristics of 16 patients with hypocomplementaemic urticarial (anti-C1q) vasculitis No.  Sex  Age,a years  Year of diagnosis  Organ involvement  Initial therapies  Prednisolone dose,a mg  Biopsy  Co-morbidities/past medical history  Age at last follow-up, years  Outcome  1  F  48  2005  S, E, L  Pred, CSA  30  Skin  Hypertension, B12 deficiency, COPD  59    2  M  60  2002  S, J, L  Pred, MMF  15  Skin  Psoriasis, coeliac disease, COPD  73  Lung transplantation  3  F  48  2007  S, E, J, LN  Pred, HCQ  50  Skin    57    4  F  56  2013  S, J, L  Pred, MMF, HCQ  25  Skin  Hypertension, COPD  59    5  F  63  2014  S, H, J, L  Pred, HCQ  30  Skin  DM, thyroiditis, pernicious anaemia, COPD  65    6  F  53  2006  S, H, K, L  Pred, MMF, HCQ  40  Skin, kidney  Sarcoidosis, COPD  57  ESRD, death  7  F  64  2001  S, J, K  Pred, CYC, antihistamines, PE  40  Skin, kidney  Addison’s, thyroiditis, hypertension, IHD, pernicious anaemia  70  ESRD, death  8  F  29  2003  S, J  HCQ  –  Skin    42    9  F  49  2015  S, J, K  Pred, MMF, HCQ  15  Skin, kidney  DM, vitiligo, hypertension, Tietze’s syndrome  50    10  F  53  2000  S, J, L  Pred, AZA  15  Skin  Varicose veins, COPD  69    11  F  55  2006  S, J, CNS, PNS, L  Pred, AZA  40  Skin  None  65    12  F  31  2006  S, J  Pred, AZA  40  Skinb  Biliary stones  40    13  F  57  2004  S, J, K, L  Pred, HCQ  40  Skin    68    14  F  46  2010  S, J, L  HCQ  1.25  –  Sarcoidosis, coeliac disease, COPD  51    15  M  38  2012  S, J  Pred, HCQ  20  –    42    16  F  39  2009  S, J, K, L  Pred, MMF  60  Skin  COPD  46    No.  Sex  Age,a years  Year of diagnosis  Organ involvement  Initial therapies  Prednisolone dose,a mg  Biopsy  Co-morbidities/past medical history  Age at last follow-up, years  Outcome  1  F  48  2005  S, E, L  Pred, CSA  30  Skin  Hypertension, B12 deficiency, COPD  59    2  M  60  2002  S, J, L  Pred, MMF  15  Skin  Psoriasis, coeliac disease, COPD  73  Lung transplantation  3  F  48  2007  S, E, J, LN  Pred, HCQ  50  Skin    57    4  F  56  2013  S, J, L  Pred, MMF, HCQ  25  Skin  Hypertension, COPD  59    5  F  63  2014  S, H, J, L  Pred, HCQ  30  Skin  DM, thyroiditis, pernicious anaemia, COPD  65    6  F  53  2006  S, H, K, L  Pred, MMF, HCQ  40  Skin, kidney  Sarcoidosis, COPD  57  ESRD, death  7  F  64  2001  S, J, K  Pred, CYC, antihistamines, PE  40  Skin, kidney  Addison’s, thyroiditis, hypertension, IHD, pernicious anaemia  70  ESRD, death  8  F  29  2003  S, J  HCQ  –  Skin    42    9  F  49  2015  S, J, K  Pred, MMF, HCQ  15  Skin, kidney  DM, vitiligo, hypertension, Tietze’s syndrome  50    10  F  53  2000  S, J, L  Pred, AZA  15  Skin  Varicose veins, COPD  69    11  F  55  2006  S, J, CNS, PNS, L  Pred, AZA  40  Skin  None  65    12  F  31  2006  S, J  Pred, AZA  40  Skinb  Biliary stones  40    13  F  57  2004  S, J, K, L  Pred, HCQ  40  Skin    68    14  F  46  2010  S, J, L  HCQ  1.25  –  Sarcoidosis, coeliac disease, COPD  51    15  M  38  2012  S, J  Pred, HCQ  20  –    42    16  F  39  2009  S, J, K, L  Pred, MMF  60  Skin  COPD  46    a At diagnosis. b Biopsy showed perivascular inflammation. COPD: chronic obstructive pulmonary disease; DM: diabetes mellitus; E: eyes; ESRD: end-stage renal disease; F: female; H: heart (including pericarditis); IHD: ischemic heart disease; J: joints; K: kidney; L: lungs; M: male; NA: not available, last follow-up for all patients 31 December 2015 or death; PE: plasma exchange; PNS: peripheral nervous system; Pred: prednisolone; S: skin. Annual incidence rate The mean annual incidence rate per million inhabitants was estimated to be 0.7 (95% CI: 0.4, 1.1) and was significantly higher among females than males [1.3 (95% CI: 0.6, 1.9) vs 0.2 (95% CI: 0, 0.4), P = 0.003; Table 3]. The incidence rate was slightly higher in Östergötland (study area B) than in Skåne (study area A), 1.3 per million inhabitants (95% CI: 0.5, 2.2) vs 0.5 (95% CI: 0.1, 0.8), P = 0.03. Ten cases were diagnosed in the age group 15–54 years and six in the age group ⩾55 years. The age-specific incidence rates were comparable among age groups 15–54 and ⩾55 years (P = 0.88; Table 4). No cases were diagnosed in the age group 0–14 years. The incidence rate per year was stable throughout the study period. During the years 2000–05, 2007, 2009, 2010 and 2012–15, one patient was diagnosed each year, and three patients were diagnosed in 2006. Table 3 Annual incidence rate of hypocomplementaemic urticarial (anti-C1q) vasculitis in Sweden Patients  No. of patients  Incidence (95% CI)  All  16  0.7 (0.4, 1.1)      Women  14  1.3 (0.6, 1.9)      Men  2  0.2 (0, 0.4)  Study area A (Skåne)  7  0.5 (0.1, 0.8)      Women  6  0.8 (0.2, 1.4)      Men  1  0.1 (0, 0.4)  Study area B (Östergötland)  9  1.3 (0.5, 2.2)      Women  8  2.3 (0.7, 4.0)      Men  1  0.3 (0, 0.9)  Patients  No. of patients  Incidence (95% CI)  All  16  0.7 (0.4, 1.1)      Women  14  1.3 (0.6, 1.9)      Men  2  0.2 (0, 0.4)  Study area A (Skåne)  7  0.5 (0.1, 0.8)      Women  6  0.8 (0.2, 1.4)      Men  1  0.1 (0, 0.4)  Study area B (Östergötland)  9  1.3 (0.5, 2.2)      Women  8  2.3 (0.7, 4.0)      Men  1  0.3 (0, 0.9)  Mean annual incidence rate (2000–15) estimated per million inhabitants. Table 3 Annual incidence rate of hypocomplementaemic urticarial (anti-C1q) vasculitis in Sweden Patients  No. of patients  Incidence (95% CI)  All  16  0.7 (0.4, 1.1)      Women  14  1.3 (0.6, 1.9)      Men  2  0.2 (0, 0.4)  Study area A (Skåne)  7  0.5 (0.1, 0.8)      Women  6  0.8 (0.2, 1.4)      Men  1  0.1 (0, 0.4)  Study area B (Östergötland)  9  1.3 (0.5, 2.2)      Women  8  2.3 (0.7, 4.0)      Men  1  0.3 (0, 0.9)  Patients  No. of patients  Incidence (95% CI)  All  16  0.7 (0.4, 1.1)      Women  14  1.3 (0.6, 1.9)      Men  2  0.2 (0, 0.4)  Study area A (Skåne)  7  0.5 (0.1, 0.8)      Women  6  0.8 (0.2, 1.4)      Men  1  0.1 (0, 0.4)  Study area B (Östergötland)  9  1.3 (0.5, 2.2)      Women  8  2.3 (0.7, 4.0)      Men  1  0.3 (0, 0.9)  Mean annual incidence rate (2000–15) estimated per million inhabitants. Table 4 Age-specific annual incidence rate of hypocomplementaemic urticarial (anti-C1q) vasculitis in Sweden Age group at diagnosis  No. of patients  Incidence (95% CI)  0–14 years  0  0.0 (0.0)  15–54 years  10  0.9 (0.3, 1.4)      Study area A  5  0.6 (0.1, 1.2)      Study area B  5  1.4 (0.2, 2.6)  ≥55 years  6  0.9 (0.2, 1.7)      Study area A  2  0.5 (0.0, 1.1)      Study area B  4  1.9 (0.0, 3.8)  Age group at diagnosis  No. of patients  Incidence (95% CI)  0–14 years  0  0.0 (0.0)  15–54 years  10  0.9 (0.3, 1.4)      Study area A  5  0.6 (0.1, 1.2)      Study area B  5  1.4 (0.2, 2.6)  ≥55 years  6  0.9 (0.2, 1.7)      Study area A  2  0.5 (0.0, 1.1)      Study area B  4  1.9 (0.0, 3.8)  Mean annual incidence rate (2000–15) estimated per million inhabitants. Table 4 Age-specific annual incidence rate of hypocomplementaemic urticarial (anti-C1q) vasculitis in Sweden Age group at diagnosis  No. of patients  Incidence (95% CI)  0–14 years  0  0.0 (0.0)  15–54 years  10  0.9 (0.3, 1.4)      Study area A  5  0.6 (0.1, 1.2)      Study area B  5  1.4 (0.2, 2.6)  ≥55 years  6  0.9 (0.2, 1.7)      Study area A  2  0.5 (0.0, 1.1)      Study area B  4  1.9 (0.0, 3.8)  Age group at diagnosis  No. of patients  Incidence (95% CI)  0–14 years  0  0.0 (0.0)  15–54 years  10  0.9 (0.3, 1.4)      Study area A  5  0.6 (0.1, 1.2)      Study area B  5  1.4 (0.2, 2.6)  ≥55 years  6  0.9 (0.2, 1.7)      Study area A  2  0.5 (0.0, 1.1)      Study area B  4  1.9 (0.0, 3.8)  Mean annual incidence rate (2000–15) estimated per million inhabitants. Point prevalence On the date of point prevalence estimate, 14 cases were alive and living within the study area, resulting in a point prevalence per million inhabitants of 9.5 (95% CI: 4.5, 14.5) for all patients, 16.2 (95% CI: 7, 25.4) for females and 2.7 (95% CI: 0, 6.5) for males (P = 0.007). The prevalence did not differ significantly between the two study areas [study area A: 6.8 (95% CI: 1.8, 11.8) vs 15.7 (95% CI: 4.1, 27.3), P = 0.10; Table 5]. The point prevalence in the age group ⩾55 years (57% of cases) was 18.1 per million inhabitants (95% CI: 5.5, 30.6) for all patients, 10.0 per million inhabitants (95% CI: 0.0, 21.2) in study area A and 35.2 per million inhabitants (95% CI: 4.4, 66.1) in study area B (P = 0.06). Table 5 Point prevalence of hypocomplementaemic urticarial (anti-C1q) vasculitis in Sweden Patients  No. of patients  Point prevalence (95% CI)  All  14  9.5 (4.5, 14.5)      Women  12  16.2 (7.0, 25.4)      Men  2  2.7 (0, 6.5)  Study area A (Skåne)  7  6.8 (1.8, 11.8)      Women  6  11.6 (2.3, 20.9)      Men  1  2.0 (0, 5.8)  Study area B (Östergötland)  7  15.7 (4.1, 27.3)      Women  6  27.1 (5.4, 48.8)      Men  1  4.5 (0, 13.2)  Patients  No. of patients  Point prevalence (95% CI)  All  14  9.5 (4.5, 14.5)      Women  12  16.2 (7.0, 25.4)      Men  2  2.7 (0, 6.5)  Study area A (Skåne)  7  6.8 (1.8, 11.8)      Women  6  11.6 (2.3, 20.9)      Men  1  2.0 (0, 5.8)  Study area B (Östergötland)  7  15.7 (4.1, 27.3)      Women  6  27.1 (5.4, 48.8)      Men  1  4.5 (0, 13.2)  Point prevalence estimated per million inhabitants on 1 January 2016. Table 5 Point prevalence of hypocomplementaemic urticarial (anti-C1q) vasculitis in Sweden Patients  No. of patients  Point prevalence (95% CI)  All  14  9.5 (4.5, 14.5)      Women  12  16.2 (7.0, 25.4)      Men  2  2.7 (0, 6.5)  Study area A (Skåne)  7  6.8 (1.8, 11.8)      Women  6  11.6 (2.3, 20.9)      Men  1  2.0 (0, 5.8)  Study area B (Östergötland)  7  15.7 (4.1, 27.3)      Women  6  27.1 (5.4, 48.8)      Men  1  4.5 (0, 13.2)  Patients  No. of patients  Point prevalence (95% CI)  All  14  9.5 (4.5, 14.5)      Women  12  16.2 (7.0, 25.4)      Men  2  2.7 (0, 6.5)  Study area A (Skåne)  7  6.8 (1.8, 11.8)      Women  6  11.6 (2.3, 20.9)      Men  1  2.0 (0, 5.8)  Study area B (Östergötland)  7  15.7 (4.1, 27.3)      Women  6  27.1 (5.4, 48.8)      Men  1  4.5 (0, 13.2)  Point prevalence estimated per million inhabitants on 1 January 2016. Outcomes Patients were followed from the time of diagnosis to 31 December 2015 or death. The median (IQR) time of follow-up was 94 (46.5–136.2) months. The median (IQR) age at last follow-up (14 patients) was 58 (45.0–65.7) years. One patient diagnosed with both COPD and pulmonary emphysema underwent lung transplantation 22 months after HUV diagnosis, and two patients proceeded to ESRD 36 and 49 months after HUV diagnosis, respectively. The remaining 14 patients with native kidney function at last follow-up had a median (IQR) eGFR of 89.5 (66.2–101.5) ml/min/1.73 m2. During follow-up, 8 out of 16 patients were diagnosed with COPD; 6 of whom suffered from both COPD and emphysema. Of the patients with COPD, five were current smokers at time of HUV diagnosis, two were former smokers, and one patient had never smoked. The mean (s.d.) age at diagnosis for patients who developed COPD was 52.2 (7.7) years compared with 46.3 (12.6) years for those without concomitant COPD (P = 0.30). Patients with COPD had longer diagnosis delay than those without COPD (13.5 vs 5.5 months), although these differences were not statistically significant (P = 0.61). Two patients were deceased during the follow-up period; one 57-year-old female patient died from COPD, septicaemia and ESRD 52 months after diagnosis of HUV, and one 72-year-old female patient died from ESRD 65 months after the HUV diagnosis. The 1-, 5- and 10-year survivals were 100, 92 and 83%, respectively. Discussion Although >45 years have passed since HUV (anti-C1q vasculitis) was first described by McDuffie et al. [2] at the Mayo Clinic, the data on epidemiology, disease outcomes, prognosis and clinical features are still limited. To our knowledge, we are presenting the first comprehensive epidemiological data on HUV. Earlier observations, and a more recent study, suggest a rare prevalence of urticarial vasculitis among patients with cutaneous vasculitis, with very few patients in the study progressing to HUV [12, 13]. Thus, it is hard to compare our results on the epidemiology of HUV directly with mentioned studies because we adhered strictly to the CHCC 2012 definitions of HUV [1]. However, the overall annual incidence rate of 0.7 per million inhabitants is comparable to that of other vasculitides of small and medium-sized vessels, such as polyarteritis nodosa and eosinophilic granulomatosis with polyangiitis [14]. Studying the epidemiology of rare diseases is challenging because it requires a long period of observation and a large population. Furthermore, the availability of consensus criteria or definitions is crucial for performing such studies. The CHCC 2012 defined the HUV syndrome as ‘vasculitis accompanied by urticaria and hypocomplementaemia affecting small vessels and accompanied with anti-C1q antibodies’ [1]. All the patients in the present study fulfilled the CHCC definitions. Our study also showed a significantly higher incidence of HUV among women, with a female to male ratio of 7:1, comparable to the 8:1 ratio previously reported in a study by Wisnieski et al. [15]. Such a difference in sex specific incidence is not evident in ANCA associated vasculitis [16], but rather similar to what has been described in epidemiological studies of SLE [17, 18]. The hitherto largest series of HUV patients was compiled by Jachiet et al. [7], but did not include estimates of prevalence. They reported two peaks in the age-specific incidence rates (i.e. 40–50 and 60–70 years), which is in line with our findings. However, the French study also included many cases without detectable anti-C1q antibodies, albeit the vast majority of these patients showed decreased levels of C1q. Which anti-C1q assay was used in their study, and whether or not the same assay was used for all 57 patients, is uncertain. Given that the presence of positive anti-C1q antibodies was a mandatory criterion in the present study, it is unclear how our epidemiological data would have changed if applying the criteria used by Jachiet et al. [7]. Even though their cohort was almost four times as large as the Swedish one, and despite the mentioned differences in serology, the clinical phenotypes of included patients were similar. The exception was COPD, which had a higher prevalence in the present study compared with that reported by Jachiet et al. [7]. Although rare, HUV is a potentially life-threatening condition. In this cohort, 50% of our patients were diagnosed with COPD during the disease course. Sixty-one per cent of the patients in a study by Wisnieski et al. [15] suffered from progressive dyspnoea and moderate to severe airway obstruction in pulmonary function testing. Compared with SLE, this is a high figure, as shown in a study from southern Sweden, where 17% of the patients with SLE suffered from COPD [19]. The association between tobacco smoking and COPD is well known, and considering the high prevalence of ever-smokers in the present study, an association between COPD and smoking among the patients in the present study cannot be excluded. However, the prevalence of smoking in our cohort does not fully explain this high figure, because not all smokers developed COPD. Although the number of patients is small, this suggests that there might be other factors related to HUV that predispose to the development of COPD. Two retrieval sources were used to identify potential HUV cases in the present study: medical records and the clinical immunology database in Lund. Given that the clinical characteristics were carefully collected by the authors, including a critical review to ascertain diagnosis, we feel confident that the specificity of HUV diagnosis among the 16 patients is the highest possible. Whether the sensitivity of HUV case retrieval is equally high remains somewhat more uncertain owing to the lack of a specific and widely accepted ICD-code for HUV. Thus, all patients in whom anti-C1q antibodies were analysed and detected during the study period are captured herein. In addition, the access to health care in Sweden is universal, which offers extraordinarily good opportunities to perform epidemiological studies and prevents potential bias with regard to the sensitivity of case retrieval. We have recently used similar methods to identify cases with renal involvement in SLE and ANCA-associated vasculitis [20]. Worldwide, anti-C1q antibodies are mainly analysed by ELISA-based techniques [21, 22]. The target epitopes of anti-C1q found in HUV are usually different from that of anti-C1q in SLE, and this can be used to differentiate between the two conditions [10]. Anti-C1q antibodies from SLE patients typically are positive only by ELISA and do not bind separated C1q protein chains, whereas the antibodies from HUV patients in the majority of cases bind the C1q B and C protein chains on western blot analysis, in addition to binding the collagenous part of the intact C1q molecule in ELISA [10]. In the present cohort, we found no differences in clinical characteristics between patients with and without positive anti-C1q analyses carried out by western blot. Our study has limitations. The retrospective design of the study constitutes a potential cause of some missing data. As there is no generally accepted diagnosis code for the HUV, physicians might use different ICD-codes for this disease, which might have affected the complete case findings in our study. By definition, we chose to present data on anti-C1q vasculitis, which with no doubt will affect the comparability of our study with other case series in which anti-C1q seropositivity was not a mandatory criterion. To conclude, we are presenting here the first epidemiological study of HUV (anti-C1q vasculitis) including data on prevalence, incidence, disease outcomes, prognosis and clinical features from two separate areas of Sweden during a 16-year period. The high coverage of patients, which was enabled by the public and tax-funded Swedish health-care system, constitutes a major strength of the study. The estimation of incidence and prevalence indicates that this condition is rare but not always benign. Renal and lung manifestations were severe in some cases, highlighting the need for careful screening and monitoring of this potentially serious disease. Acknowledgements We would like to thank Dr Per Eriksson, Rheumatology unit at Linköping University Hospital, for his contribution in diagnosing and treating patients with HUV. We are also sincerely grateful for the late Professor Gunnar Sturfelt’s valuable contributions in planning studies on HUV in southern Sweden. Funding: The study was supported by the Region Östergötland, the Swedish Rheumatism Association (Reumatikerförbundet), the Swedish Society of Medicine (Läkarsällskapet) and the King Gustaf V’s 80-year foundation. Disclosure statement: The authors have declared no conflicts of interest. References 1 Jennette JC, Falk RJ, Bacon PA et al.   2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum  2013; 65: 1– 11. Google Scholar CrossRef Search ADS PubMed  2 McDuffie FC, Sams WMJr, Maldonado JE et al.   Hypocomplementemia with cutaneous vasculitis and arthritis. Possible immune complex syndrome. Mayo Clinic Proc  1973; 48: 340– 8. 3 Schwartz HR, McDuffie FC, Black LF, Schroeter AL, Conn DL. Hypocomplementemic urticarial vasculitis: association with chronic obstructive pulmonary disease. Mayo Clinic Proc  1982; 57: 231– 8. 4 Kallenberg CG. Anti-C1q autoantibodies. Autoimmun Rev  2008; 7: 612– 5. Google Scholar CrossRef Search ADS PubMed  5 Wisnieski JJ, Jones SM. IgG autoantibody to the collagen-like region of Clq in hypocomplementemic urticarial vasculitis syndrome, systemic lupus erythematosus, and 6 other musculoskeletal or rheumatic diseases. J Rheumatol  1992; 19: 884– 8. Google Scholar PubMed  6 Davis MD, Brewer JD. Urticarial vasculitis and hypocomplementemic urticarial vasculitis syndrome. Immunol Allergy Clin North Am  2004; 24: 183– 213. Google Scholar CrossRef Search ADS PubMed  7 Jachiet M, Flageul B, Deroux A et al.   The clinical spectrum and therapeutic management of hypocomplementemic urticarial vasculitis: data from a French nationwide study of fifty-seven patients. Arthritis Rheumatol  2015; 67: 527– 34. Google Scholar CrossRef Search ADS PubMed  8 Statistics Sweden. Statistics Sweden (Internet). September 8, 2017. Website in Swedish. www.scb.se. 9 Levey AS, Bosch JP, Lewis JB et al.   A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med  1999; 130: 461– 70. Google Scholar CrossRef Search ADS PubMed  10 Mårtensson U, Sjöholm AG, Sturfelt G, Truedsson L, Laurell AB. Western blot analysis of human IgG reactive with the collagenous portion of C1q: evidence of distinct binding specificities. Scand J Immunol  1992; 35: 735– 44. 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Medicine  1995; 74: 24– 41. Google Scholar CrossRef Search ADS PubMed  16 Watts RA, Mahr A, Mohammad AJ et al.   Classification, epidemiology and clinical subgrouping of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Nephrol Dial Transplant  2015; 30 (Suppl 1): i14– 22. Google Scholar CrossRef Search ADS PubMed  17 Ståhl-Hallengren C, Jönsen A, Nived O, Sturfelt G. Incidence studies of systemic lupus erythematosus in Southern Sweden: increasing age, decreasing frequency of renal manifestations and good prognosis. J Rheumatol  2000; 27: 685– 91. Google Scholar PubMed  18 Johnson AE, Gordon C, Palmer RG, Bacon PA. The prevalence and incidence of systemic lupus erythematosus in Birmingham, England. Relationship to ethnicity and country of birth. Arthritis Rheum  1995; 38: 551– 8. Google Scholar CrossRef Search ADS PubMed  19 Jönsen A, Bengtsson AA, Hjalte F et al.   Total cost and cost predictors in systemic lupus erythematosus – 8-years follow-up of a Swedish inception cohort. Lupus  2015; 24: 1248– 56. Google Scholar CrossRef Search ADS PubMed  20 Mohammad AJ, Weiner M, Sjöwall C et al.   Incidence and disease severity of anti-neutrophil cytoplasmic antibody-associated nephritis are higher than in lupus nephritis in Sweden. Nephrol Dialysis, Transplant  2015; 30 (Suppl 1): i23– 30. 21 Mahler M, van Schaarenburg RA, Trouw LA. Anti-C1q autoantibodies, novel tests, and clinical consequences. Front Immunol  2013; 4: 117. Google Scholar CrossRef Search ADS PubMed  22 Stojan G, Petri M. Anti-C1q in systemic lupus erythematosus. Lupus  2016; 25: 873– 7. 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: journals.permissions@oup.com 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)

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RheumatologyOxford University Press

Published: Apr 30, 2018

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