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NDT Advance Access published online on August 8, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm493
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Association of thyroid disease and its treatment with ANCA small-vessel vasculitis: a case–control study

Sofia Lionaki1,2,{dagger}, Susan L. Hogan3,{dagger}, Ronald J. Falk3, Melanie S. Joy3, Hyunsook Chin3, Caroline E. Jennette3, J. Charles Jennette4 and Patrick H. Nachman3

1UNC Kidney Center and Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA, 2Nephrology and Transplantation Department, Laikon Hospital, Athens 11527, Greece 3UNC Kidney Center and Division of Nephrology and Hypertension and 4Department of Pathology and Laboratory Animal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

Correspondence and offprint requests to: Susan L. Hogan, UNC Kidney Center and Division of Nephrology and Hypertension, 7009 Burnett-Womack, CB #7155, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-5074, USA Email: slh{at}med.unc.edu



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Appendix. Nephropathologists who...
 Acknowledgements
 References
 
Background. Case reports have described the onset of antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis (ANCA SVV) with use of anti-thyroid agents, but an association with thyroid disease in general has not been described. This association was evaluated in a southeastern US population-based case–control study.

Methods. Cases (n = 158) had ANCA SVV with biopsy-proven glomerular involvement. Controls (n = 99) were frequency matched by age, gender and state. Use of drugs and comorbidities prior to diagnosis of ANCA SVV were assessed by telephone interview. Information on medications used for thyroid conditions was available in a subset of cases (n = 129). Logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Estimates among females were also of interest.

Results. History of thyroid disease was reported in 31 cases (20%) and 7 controls (7%) (OR = 3.7; 95% CI 1.5–9.2; P = 0.005); among females 25/65 (38%) cases and 5/53 (9%) controls (OR = 5.6; 95% CI 1.9–16.8; P = 0.002). Use of anti-thyroid agents was reported in 2 cases and 0 controls (OR not calculable). Among cases, myeloperoxidase (MPO)-ANCA was more common (86%) than proteinase 3 (PR3)-ANCA in those with a history of thyroid disease than those without (53%) (P = 0.007).

Conclusions. Thyroid disease was associated with ANCA SVV, especially among women, and was most frequently associated with MPO-ANCA. The specific diagnosis and detailed clinical history of thyroid disease were not known; a limitation of the study. Use of anti-thyroid agents was uncommon. The association of thyroid disease with ANCA SVV may reflect a propensity for autoimmune disease.



   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Appendix. Nephropathologists who...
 Acknowledgements
 References
 
Epidemiological studies and case reports have demonstrated an association between two autoimmune diseases occurring simultaneously or sequentially [1–4]. Emerging genetic data among patients with autoimmune diseases who have family members with other autoimmune disorders suggest that there may be common autoimmune genes [5]. However, to date, there is but one gene that may be associated with this family clustering of autoimmunity [6,7].

Small-vessel vasculitis (SVV) has been also reported to be associated with other autoimmune diseases. Case reports and case series have linked the onset of antineutrophil cytoplasmic antibody (ANCA)-associated SVV (ANCA SVV) with treatment for hyperactive thyroid conditions, particularly with the use of the pharmaceutical agents propylthiouracil (PTU) and methimazole [8]. A history of thyroid disease among patients with Wegener's granulomatosis has been associated with more severe vasculitic symptoms [9]. A systematic evaluation of thyroid disease and the use of thyroid function modulating drugs in ANCA SVV is necessary. The goal of our study was to determine the frequency and association of thyroid disease and its treatment to the occurrence of ANCA SVV in the southeastern United States.



   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Appendix. Nephropathologists who...
 Acknowledgements
 References
 
Data for this study were collected as part of a population-based case–control study designed to evaluate the association of environmental factors [10], drugs and coexisting diseases with ANCA SVV. Neither cases nor controls were aware of the specific exposures and disease associations of interest. The geographic region of study included North Carolina, South Carolina, Georgia or southern Virginia. All patients with ANCA SVV and renal biopsy-proven glomerular involvement diagnosed between October 1997 and October 2003 were identified and eligible for the study. Nephropathologists throughout the region (see Appendix) identified diagnoses of pauci-immune necrotizing and/or crescentic glomerulonephritis with or without granulomatous inflammation and with or without a positive ANCA test. A positive ANCA test, determined by immunofluorescence microscopy and antigen-specific ELISA [11], was verified with the patient's clinician. The nephropathologists represent all the nephropathology laboratories in the region and review virtually all renal biopsies in the represented geographic area. Patients were invited via a letter sent by their clinician to participate in a telephone interview. The study was approved by the Biomedical Institutional Review Board at the University of North Carolina at Chapel Hill (97-MED-44 and 04-MED-663) and by the home institution of each nephropathologist (see Appendix).

Patients who participated in the telephone interview were also asked, but not required, to sign consent for review of their medical record. Available medical records were reviewed to categorize patients as having cytoplasmic and/or proteinase 3-ANCA or perinuclear and/or myeloperoxidase-ANCA (PR3-ANCA or MPO-ANCA, respectively) as determined by antigen-specific ELISA or by indirect immunofluorescence microscopy [12,13]. In cases where only a perinuclear-ANCA was positive, a negative antinuclear antibody test was required. Medical records were reviewed to verify history of thyroid disease and organ involvement reported by patients, as well as to categorize patients as having Wegener's granulomatosis, microscopic polyangiitis and renal-limited disease as previously defined by the Chapel Hill Consensus Conference [14] and systematically applied to our ongoing cohort of patients [15]. The Birmingham Vasculitis Activity Score (BVAS) was used to retrospectively assess disease activity at diagnosis [16].

Controls were identified through random digit dialing and were frequency matched by age, gender and state, as described previously [10]. Age groups used for matching were 18–39, 40–59 and 60–84 years. Participants had to have resided in North Carolina, South Carolina, Georgia or southern Virginia for at least 6 months during the year either prior to their renal biopsy diagnosis for cases or prior to a uniform reference date set as 1 January 2001 for controls. This date was selected since it was the approximate median date of diagnosis among cases. Participants had to speak and understand English. No financial or other incentives were provided to study participants.

A structured telephone interview was used to collect information on lifetime occupational and medical history. Battelle Centers for Public Health Research and Evaluation managed and implemented the selection of controls and conducted the telephone interviews using a computer-assisted interview process with all study participants.

Details of the identification and response rates for the 158 cases and 99 controls in the study have been described previously [10]. In brief, of 214 cases who met the entry criteria, 158 (73.4%) participated in the study; with 129 cases completing the interview themselves and brief interviews with a proxy respondent, usually a spouse or close family member, completed for an additional 29 patients who had died or who were too sick to participate in the interview. The purpose of the proxy interviews was to evaluate potential systematic differences among cases who participated in the interview and those who did not have the opportunity to participate due to the high morbidity and mortality of the disease. Among 912 answered telephones for potential controls, 109 (12%) participated in the interview (99 completed and 10 partially completed), 5 (<1%) were determined to be eligible but declined participation, 475 (52%) declined participation without providing eligibility information and 323 (35%) did not have an eligible participant in the household. The 10 control participants who only partially completed the interview did not provide information for the section on medical history.

History of thyroid and several other diseases was assessed by asking participants if a doctor had ever told them they had specific conditions prior to their renal biopsy diagnosis (cases) or reference date (controls). If they reported a history of thyroid disease, they were asked several follow-up questions including the specific type of thyroid disease, with an open ended response allowed, and if they had ever used any prescription drugs for this condition in the 12 months before the reference date (yes/no). They were also asked specifically if they had ever taken PTU or methimazole (Thiamazole or Tapazole) [8]. If these drugs had ever been used, then participants were asked how many months they had taken each specific drug up to the diagnosis or reference date and if they had taken them in the 12 months before the reference date. Participants were also asked, as an open ended question, to provide the names of any other drugs they had taken for thyroid disease. An investigator with a Doctor of Pharmacy degree (M.S.J.) reviewed the list of all drugs and categorized them into drug classes. In the case of thyroid drugs, drug classes included anti-thyroid, thyroid replacement and others. Proxy respondents for 29 cases were only asked if the patient had any form of thyroid disease prior to their diagnosis of vasculitis, but details on specific diagnoses or drugs used for the treatment of thyroid disease were not obtained. As a disease control, history of diabetes diagnosed by a physician prior to renal biopsy diagnosis (cases) or reference date (controls) was also evaluated. History of diabetes was not evaluated for case participants interviewed by proxy.

Demographics and other measures were compared between cases and controls using continuity-adjusted chi-square and Wilcoxon rank-sum tests. These tests were also used to compare the characteristics of those who completed the full interview to those in whom a proxy interview was completed, as well as to compare cases with and without thyroid disease. Logistic regression was used to evaluate the association of thyroid disease and treatments with the disease relative to the controls. Results are expressed as odds ratios (OR) with 95% confidence intervals (CI) and P-values. All reported models are adjusted for the frequency-matched variables; age, gender and state, as well as education level and race. Models by each gender controlled for age, state, education level and race.



   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Appendix. Nephropathologists who...
 Acknowledgements
 References
 
A total of 129 cases completed the full interview and a proxy interview was done for an additional 29 patients who had either died (n = 18) or who were unable to complete the full interview due to their illness (n = 11). Ninety-nine controls participated in the interview and had complete data available for the assessment of thyroid disease.

Cases and controls completing the full interview (excluding proxy respondents) were similar with respect to state and race, but cases were significantly older, more frequently male and had less education than controls (Table 1). The differences in education status between cases and controls were less pronounced when age was controlled for (P = 0.08). Although history of having ever smoked was similar between cases and controls, cases were less likely to be current smokers at the time of diagnosis compared to controls at the reference date. A history of diabetes diagnosed by a physician was similar between cases who completed the full interview and control participants. Comparing those interviewed by proxy to those who completed the full interview there were no statistical differences, but those interviewed by proxy were several years older, had a higher representation of non-whites, and were less educated but were similar with respect to gender compared to cases who participated in the full interview (Table 1).


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  		Table 1. Sociodemographic characteristics of cases with ANCA SVV and controls

 
Fifty-nine percent of cases were MPO-ANCA positive and 41% were PR3-ANCA positive. By definition, all cases had biopsy-proven renal involvement of the disease. The most commonly involved other organs included the upper respiratory tract (59%), lungs (36%), joints (49%) and skin (24%). The frequency of disease phenotypes included 13% with Wegener's granulomatosis, 55% with microscopic polyangiitis and 32% with renal limited disease. The ANCA specificity, organ involvement and disease phenotypes in this study are representative of our larger cohort of patients [15].

A total of 38 study participants, 20% (n = 31) of cases and 7% (n = 7) of controls, reported a history of thyroid disease prior to their renal biopsy diagnosis of ANCA SVV or reference date (Table 2). Only 11 study participants specifically characterized their disease as either hypothyroidism (n = 5) or hyperthyroidism (n = 6), but all 38 participants listed the medications they were using to treat their thyroid disease. Therefore, classification by use of treatment for anti-thyroid or thyroid replacement was done for all participants who reported a history of thyroid disease. Medical chart information was available in 82 (52%) patients; 17 with thyroid and 65 without thyroid disease. A history of thyroid disease or use of thyroid replacement therapy was confirmed in all 17 patients who reported a history, and was not found in the medical record of any who did not report history of thyroid disease.


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  		Table 2. Multivariable association of thyroid disease and ANCA SVV

 
In multivariable analysis there was a 3.7 times increased odds of developing ANCA SVV with a history of thyroid disease compared to controls (95% CI 1.5–9.2; P = 0.005) (Table 2). The result was similar when including only cases who completed the detailed full interview (excluding those interviewed by a proxy respondent), with a 4.0 times increased odds (95% CI 1.6–10.2; P = 0.003).

Since the prevalence of thyroid disease is known to be higher among women than men, the associations were also evaluated within each gender separately. Among women, approximately 38% of cases (n = 25 of 65) reported a history of thyroid disease prior to their diagnosis with ANCA SVV, compared to 9% of controls (n = 5 of 53). In multivariable analysis, there was a strong association between a history of thyroid disease and ANCA glomerulonephritis among women when including all female cases (OR = 5.6; 95% CI 1.9–16.8; P = 0.002) or just female cases who completed the detailed interview (OR = 5.6; 95% CI 1.8–16.9; P = 0.002) (Table 2). Among males, odds ratios were in the direction of a positive association between thyroid disease and ANCA SVV, but the prevalence of reported thyroid disease was low, confidence intervals were wide and there was no statistical association (Table 2).

Use of specific drugs was only evaluated among cases who participated in the full interview. History of use of anti-thyroid agents was only reported by two female cases (2/129 = 1.5%) and no controls. One case reported use of PTU and one reported use of methimazole, both within the 12 months prior to their renal biopsy diagnosis.

On the other hand, the use of thyroid replacement therapy was 3.3 times more common among cases than controls (95% CI 1.2–8.9; P = 0.021) (Table 2). The association of thyroid replacement therapy with ANCA SVV was driven by the strong association among women (OR = 5.1; 95% CI 1.5–17.2; P = 0.008), with no evidence of an association or trend observed among men (OR = 0.9; 95% CI 0.1–6.0; P = 0.95).

Among cases, those with a history of thyroid disease were far more likely to have MPO-ANCA (86%) than PR3-ANCA (14%) antigen specificity compared to those without thyroid disease (53 and 47%, respectively, P = 0.007) (Table 3). There were no differences between those with and without thyroid disease with respect to age, disease phenotype, specific organ involvement, number of organs involved or disease activity as measured by BVAS at diagnosis (Table 3).


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  		Table 3. Characteristics of ANCA SVV cases with and without a history of thyroid disease

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Appendix. Nephropathologists who...
 Acknowledgements
 References
 
This population-based study confirmed the association of ANCA SVV and a history of thyroid disease or use of thyroid replacement, especially among women. In women, thyroid disease was prevalent at the time of diagnosis of ANCA SVV in as many as 40% of cases. Among men, the prevalence of thyroid disease was low, as expected, and there was no statistical association between thyroid disease or use of thyroid replacement therapy and ANCA SVV. Patients with a history of thyroid disease were far more likely to have MPO-ANCA than PR3-ANCA. The reported use of anti-thyroid agents including PTU or methimazole in the 12 months prior to the diagnosis of ANCA SVV was an uncommon finding. Thus, in this cohort of ANCA SVV patients the association with thyroid disease was not driven by use of anti-thyroid agents and these drugs are unlikely to account for many cases in the general population.

The coexistence of autoimmune thyroid disease and ANCA SVV has been described in a small case series of 10 patients with MPO-ANCA SVV [17] and in several case reports [18–20]. This, however, is the first systematic study to associate these two entities. Autoimmune thyroid disease is a common condition in the United States, with approximately 10% of the population having abnormal thyroid-stimulating hormone levels, and 5% of women having overt thyroid disease [21]. Among individuals over the age of 60 years, approximately 6% are on thyroid replacement therapy [22]. It is therefore tempting to suggest that these two conditions occur by chance alone. However, the case–control design of our study allows comparison of the prevalence of thyroid disease among patients with ANCA SVV to that of a control group from the general population. The fact that the prevalence of thyroid disease in our control group falls within the range expected for the general population [21,22] and is significantly lower than among ANCA patients refutes the contention that these two diseases occur concomitantly by chance alone.

There are case reports of patients with ANCA SVV who have been diagnosed simultaneously or serially with other autoimmune diseases including rheumatoid arthritis [23], lupus [24], temporal arteritis [25], Sjögren's syndrome [26] and scleroderma [27]. It is well known that multiple autoimmune diseases may be found in the same individual as well as in family members. The fact that several different autoimmune diseases can occur across family members supports a common genetic determinant. In particular, a polymorphism of the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene has been linked to autoimmune thyroiditis [28,29] as well as Wegener's granulomatosis [30–32], indicating a potential genetic predisposition to autoimmunity.

Indeed, numerous studies have demonstrated the coexistence of autoimmune thyroid disease with a variety of other autoimmune diseases [4,33]. In a cohort of 218 autoimmune thyroid disease patients, 14% were found to have systemic autoimmune disease [33]. In another study of 426 patients with Hashimoto or Graves disease, 30% had another form of autoimmune disease; 51% among those with Hashimoto disease and 16% among those with Graves’ disease [34]. A functional polymorphism in the protein tyrosine phosphatase gene, the PTPN22 620W allele, has been recognized as a predisposing factor for several autoimmune diseases including Graves and Hashimoto thyroid diseases [35,36], and recently for Wegener's granulomatosis and ANCA positivity [37].

Even in genetically susceptible individuals, it is likely that environmental factors, including occupational exposures and infections, play a role in the autoimmune phenotype. Exposures to a number of environmental factors such as silica [10], and infectious agents such as Staphylococcus aureus [38] have been implicated in the development of ANCA SVV, whereas exposure to Yersinia enterocolitica or retroviruses have been postulated to participate in the pathogenesis of autoimmune thyroid disease [37]. However, large studies of gene-environment interactions and pathogenetic mechanisms within specific autoimmune diseases have not been done.

The phenomenon of a greater prevalence of women with two autoimmune diseases is in concordance with the female predominance of thyroid disease and other autoimmune states, especially systemic lupus erythematosus. Graves’ disease and Hashimoto's thyroiditis affect women 5 to 10 times more frequently than males [21]. The influence of the X chromosome appears limited [39], while sex hormones themselves may significantly influence the development and function of a number of components of the immune system [40]. Estrogens likely promote the immune response by the production of cytokines and antibodies [41]. In fact, female gender has become one of the most important epidemiological risk factors for flares of autoimmune disease [41]. However, a female predominance of ANCA SVV has not been observed in our studies [15] or in European studies [42,43]. Thus, the association of ANCA SVV in females with thyroid disease must be dependent on or in conjunction with other factors.

It is intriguing that the majority of patients in our series with ANCA SVV and thyroid disease were MPO-ANCA positive. In fact, MPO-ANCA positivity was seen in 86% of patients with thyroid disease compared to 53% of patients who had no thyroid disease. These were similar to findings previously reported in drug-induced cases of thyroid disease [8]. It is reasonable to ask whether there is a cross-reactivity between thyroid peroxidase (TPO) [44], the enzyme responsible for the synthesis of thyroid hormone [45], and MPO. An extracellular portion of the TPO molecule has 42% homology to MPO [46]. Although it has been hypothesized that anti-TPO antibodies cross-react with MPO [45,47], this has been refuted in other studies [48,49]. The results of our study suggest that this possibility is unlikely to be the case since some of our patients had PR3-ANCA and thyroid disease, as has been observed by others [18,50].

It has been reported that in patients with Wegener's granulomatosis, there is a significantly higher prevalence of thyroid dysfunction among those with more severe disease (15%) compared to those with less severe manifestations of the disease (0%, P = 0.003) [9]. In our study, there was no difference among ANCA SVV patients with or without a history of thyroid disease with respect to disease phenotype, specific organs involved, the number of organs involved or level of disease activity at diagnosis. However, the impact of concurrent thyroid disease with ANCA SVV on long term outcomes such as treatment response and disease relapses has not been determined and is beyond the scope of the current study. Also of note, our cohort, 100% of whom have renal disease involvement, is likely more comparable to those with severe Wegener's granulomatosis where renal involvement was noted in 64% compared to only 29% of those with less severe disease (29%) [9]. Prevalence estimates of thyroid disease in our study (20 ± 6%) overlap with estimates in severe Wegener's granulomatosis (15 ± 6%), using standard calculations for 95% confidence intervals for proportions (14–26% and 9–21%, respectively).

There are a number of limitations to our study. The specific diagnosis of thyroid disease was not available in the majority of our study participants; however, 20 of 27 patients and six of seven controls reported use of thyroid hormone replacement therapy indicating a physician's diagnosis of hypothyroidism. Whether the hypothyroidism was a consequence of Hashimoto's thyroiditis or ‘burnt out’ Graves’ disease can only be inferred, but the association of any history of thyroid disease and ANCA SVV in the current study provides a likely example of aggregated autoimmune diseases, especially among women.

Another limitation to the study is the fact that there were fewer cases than controls and these groups were different with respect to age and gender. Although standard statistical modeling techniques controlling for these differences as well as evaluation within subgroups, in this case by gender, likely minimize the impact of these demographic differences on the results, the wide confidence intervals suggest that more precise estimates need to be confirmed in larger studies.

Also of note is that the study only included cases with renal biopsy proof of disease. Although this provided a definitive diagnosis date for use in referencing prior medical history, it is difficult to determine the time between true disease onset and the development of kidney involvement which may be variable. Also, an unknown number of ANCA SVV patients with kidney involvement may progress rapidly to kidney failure and not undergo a renal biopsy. Issues relating to access to medical care and decisions for whether or not to obtain a renal biopsy, especially among patients with biopsy proof of disease in another organ, may have also led to a selective case sample. However, the renal-biopsy population is likely to represent the majority of patients with ANCA-SVV since renal involvement is reported in up to 90% of patients [51] and renal biopsy results are used to guide treatment [52].

The role of thyroid disease in the initiation and management of ANCA SVV needs further elucidation. Monitoring women with autoimmune thyroid disease, especially those with a family history of other autoimmune diseases, for the development of ANCA and early symptoms of systemic vasculitis seems prudent. Also, at disease onset of ANCA SVV, it is sensible to evaluate for the presence and appropriate management of thyroid disease.



   Appendix. Nephropathologists who participated in the identification of patients with renal-biopsy proven ANCA glomerulonephritis (October 1997 to October 2003)
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix. Nephropathologists who...
Acknowledgements
 References
 

Nephropathologists Institutiona
J. Charles Jennette, MD, Harsharan Singh, MDb Department of Pathology, University of North Carolina at Chapel Hill, NC
Samy Iskandar, MBBCh, PhD Wake Forest University School of Medicine, Winston Salem, NC
Sally Self, MD Medical University of South Carolina, Charleston, SC
Serena Bagnasco, MD Emory University, Atlanta, GA
Ralph C. McCoy New Hanover Regional Medical Center in Wilmington, NC
David N. Howell, MD Duke University Medical Center in Durham, NC
Carol Weida, MD Carolinas Medical Center, Charlotte, NC
William F. Glass MD, PhD Eastern Virginia Medical School, Norfolk, VA

aThe nephropathology laboratories in the region not represented in the table include East Carolina University School of Medicine (see below) and the Medical College of Georgia in Augusta. IRB approval was not sought at the Medical College of Georgia because no patients were identified as diagnosed with ANCA glomerulonephritis during the study period.

bDr. Harsharan Singh is a nephropathologist at the University of North Carolina at Chapel Hill (UNC-CH), but is also responsible for reviewing renal biopsies from Eastern Carolina University. Review and recruitment of cases identified by Dr. Singh were approved the Biomedical Institutional Review Board at the University of North Carolina at Chapel Hill (97-MED-44 and 04-MED-663).



   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix. Nephropathologists who...
 Acknowledgements
References
 
The work for this manuscript was carried out at the UNC Kidney Center and Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill. This research was supported by the National Institute of Diabetes, Digestive and Kidney Disease; Program Project ‘ANCA Glomerulonephritis from Molecules to Man’ (P01-DK58335).

Conflict of interest statement. None declared.



   Notes
 
{dagger}These authors contributed equally to this work. Back



   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix. Nephropathologists who...
 Acknowledgements
 References
 

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Received for publication: 16. 3.07
Accepted in revised form: 28. 6.07


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