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Infections as risk factor for autoimmune diseases – A nationwide study
Journal of Autoimmunity xxx (2016) 1e6
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Infections as risk factor for autoimmune diseases e A nationwide study Philip Rising Nielsen a, *, Tue Wenzel Kragstrup b, c, Bent Winding Deleuran b, c, Michael Eriksen Benros d National Center for Register-based Research, Fuglesangs All e 4, Aarhus University, Aarhus, Denmark Department of Biomedicine, Aarhus University, Wilhelm Meyers All e 4, Aarhus, Denmark c Department of Rheumatology, Aarhus University Hospital, Nørrebrogade 44, Aarhus, Denmark d Mental Health Center Copenhagen, Copehagen University Hospital, Copenhagen, Denmark a
b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 25 April 2016 Received in revised form 25 May 2016 Accepted 31 May 2016 Available online xxx
Viruses, bacteria and other infectious pathogens are the major postulated environmental triggers of autoimmunity. In the present nation-wide study we describe the association between infections and 29 autoimmune diseases. We used the Danish Civil Registration System to identify 4.5 million persons born between 1945 and 2000. Information on infections and autoimmune diseases was obtained from the Danish Hospital Register. The cohort was followed from 1977 to 2012. Incidence rate ratios for developing an autoimmune disease were estimated using poisson regression. We found an association between hospital admission for an infection and 29 autoimmune diseases. This study shows that infections are risk factors for a broad spectrum of autoimmune diseases in a dose-response and temporal manner, in agreement with the hypothesis that infections are an environmental risk factor contributing to the etiology of autoimmune diseases together with genetic factors. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Epidemiology Autoimmune disease Infections
1. Introduction Autoimmune disease is a group of disorders in which the primary cause is the inflammatory reaction caused by the immune system attacking the body’s own tissues. Both inherent genetic susceptibility and environmental factors play a major role in determining risk of development of autoimmune diseases. An environmental factor thought to play an important role in the development of autoimmunity is infection. The impact of infections on autoimmunity is substantial, and various mechanisms have been suggested to explain the relationship. Possible mechanisms linking infections and autoimmune disease include alterations in target cells, alterations in immune cells, immune responses against the determinant shared by host and virus, and cross-reaction between idiotype and the antiviral antibody and respective autoantigens. Much of what we know about these mechanisms has come from studies in animal models, showing evidence that viruses
* Corresponding author. National Centre for Register-Based Research, Aarhus 4, Aarhus, DK 8210 V, Denmark. Tel.: þ45 87165753; University, Fuglesangs Alle fax: þ45 87164601. E-mail address: [email protected] (P.R. Nielsen).
can play a causative role in chronic autoimmune disease [1,2]. However, there is also compelling epidemiologic evidence that infection in humans predisposes to autoimmune disease [1,3e5]. Studies have focused on specific infections and specific autoimmune diseases [4e7]. However, no known virus has been proven to regularly induce or promote autoimmune disorders. The high prevalence and frequent severity of autoimmune diseases make the exploration and understanding of the precipitating factors a clinical imperative. The purpose of this study therefore was to investigate whether hospitalization for an infection is a risk factor for developing a range of autoimmune diseases. Furthermore, we wanted to investigate the temporal relationship between time of diagnosis for infection and autoimmune diseases. Finally, we wanted to investigate the difference between the types of infection. 2. Method 2.1. Registers Since 1968, the Danish Civil Registration System has recorded information, such as gender, first-degree relatives, and date of birth,
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on all people living in Denmark [8]. A unique Civil Registration System number is assigned to each individual at birth that ensures accurate linkage between the different registers. The National Hospital Register holds information on all admissions to and discharges from hospitals since 1977 (type 1 diabetes since 1987) and registration of outpatients and emergency department contacts since 1995 [9]. The Danish version of ICD-8 [10] was the diagnostic system used from 1969 to 1993, and ICD-10 was used from 1994 onward [11]. All personal information from the registers is anonymized when used for research purposes, and the present study was approved by the Danish Data Protection Agency.
2.6. Statistical analysis Incidence rate ratios, also referred to as relative risks, of each autoimmune disease were estimated by log-linear Poisson regression using the GENMOD procedure in SAS, version 9.3 (SAS Institute, Cary, N.C.). All estimates were adjusted for calendar year, age, and sex. Age, calendar year, Charlson Comorbidity Index, and time since infection were treated as time-dependent variables, whereas sex was considered time independent. The p values and 95% confidence intervals were based on likelihood ratio tests. 3. Results
2.2. Study population The total study population included 4.5 million persons born in Denmark between January 1, 1945, and December 31, 2010, and who were alive and a resident of Denmark during our study period. They were followed from date of birth or January 1, 1977, until onset of the autoimmune disease in question, death, emigration from Denmark, or December 31, 2010, whichever came first. Follow-up for diabetes was initiated from 1987, since type 1 diabetes could not be distinguished from type 2 diabetes in the register system until then, and all previous diagnoses of diabetes were excluded. 2.3. Assessment of autoimmune diseases The date at onset was defined as the first day of the first hospital contact for the relevant disease, irrespective of other previous diagnosis. Each person could have a history of more than one autoimmune disease. We omitted all ICD-8 diagnoses that bore the modification code “suspected” or “not found,” and ICD-10 diagnoses with similar codes were also omitted. Persons were classified as having an autoimmune disease if they were registered with one of the 29 autoimmune diseases listed in Table S1 of the online data supplement that accompanies this article. 2.4. Assessment of infections A history of infection was defined as the person having been listed with a diagnosis of infection in the Danish National Hospital Register. We omitted all ICD-8 diagnoses that bore the modification code “suspected” and “not found”. Similar codes were omitted for the ICD-10. All infection codes were grouped according to type of infection: bacterial, viral, and other type of infection. For the diagnostic codes, see Table S2 of the online data supplement. 2.5. Charlson Comorbidity Index To account for the effect of other comorbidities, the Charlson comorbidity index was included in the analysis as a possible confounder. The Charlson Comorbidity Index, a score that categorizes and assigns weights and severities to 19 different patient comorbidities, was first reported in 1987 to estimate the probability of death within 1 year [12] and it has later been adapted to fit with ICD-10 diagnoses [13]. The Charlson comorbidity index is a widely accepted and validated method used to quantify comorbidity and summarizes 19 mortality-weighted conditions ranging from myocardial infarction to malignant disease. We used the Charlson Comorbidity Index to adjust for severe chronic somatic diseases. We modified the index by excluding the groups, Diabetes 1 þ 2, connective tissue, mild liver diseases and AIDS. The Charlson Comorbidity Index was created in five categories: 0, 1, 2, 3, and 4þ.
In our study population consisting of 4.5 million people born in Denmark after 1945, a total of 166,090 individuals were diagnosed with an autoimmune disease (94,857 females and 71,233 males) during the follow-up period from 1977 to 2010 (107.1 million person-years of risk). Prior to the diagnosis of the autoimmune diseases, a total of 58,265 patients (35.08%) were diagnosed as having one or more infections (33,285 females and 21,980 males). Table 1 displays the overall effect of exposure to infection and the number of exposed cases according to type of autoimmune disease. A previous hospital contact for infection was associated with an increased IRR of 1.64 (95% CI: 1.62e1.65) for developing an autoimmune disease compared with persons with no hospital contact for infection. After adjustment for Charlson Comorbidity Index the IRR was reduced to 1.46 (95% CI: 1.44e1.47). Table 2 displays the temporal proximity of the infection to the autoimmune diagnosis. Persons hospitalized for an infection had a significantly increased risk for subsequent diagnosis of a range of autoimmune diseases. When investigating the risk of autoimmune disease in relation to time since first hospital contact for infection, divided into five time periods less than 1 month, 2e12 months, 1e4 years, 5e9 years and 10 years or more, we found the risk to be highest for those hospitalized with an infection in close proximity to their autoimmune disease (less than a month). The disease for which the greatest difference between the concurrent and the delayed period was observed was for Granulomatosis with polyangiitis with an increased IRR of 73.80 (95% CI: 50.36e104.27) in the first month to an IRR of 1.72 (95% CI: 1.32e2.13) 10 years or more before onset of Granulomatosis with polyangiitis. Table 3 shows the number of infections and incidence rate ratio for autoimmune disease. We observed that an increase in number of infections increased the risk of autoimmune disease in a dose response manner. The largest increase was observed for primary adrenocortical insufficiency, having been hospitalized for one infection was associated with an increased risk of 2.03 (1.68e2.43), whereas having five or more infections increased the risk to 13.46 (10.76e16.70). Table 4 displays the type of infection, bacterial, viral and other type of infections. Bacterial infection was associated with an increased risk of autoimmune disease with an IRR of 1.71 (95% CI: 1.69e1.74). In general, we found similar effect sizes for all three types of infections. 4. Discussion In this national cohort study, we observed that individuals hospitalized for a serious infection were at increased risk of subsequent diagnosis of autoimmune diseases. Individuals with multiple hospitalizations with infections and persons hospitalized for a serious infection in close proximity to the autoimmune diagnosis were at greatest risk. We found no difference between being hospitalized for a viral infection and other types of infection. This is the first study to provide a general overview of the possible association
Please cite this article in press as: P.R. Nielsen, et al., Infections as risk factor for autoimmune diseases e A nationwide study, Journal of Autoimmunity (2016), http://dx.doi.org/10.1016/j.jaut.2016.05.013
P.R. Nielsen et al. / Journal of Autoimmunity xxx (2016) 1e6
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Table 1 Incidence rate ratios of autoimmune diseases associated with hospital contact for an infection. Autoimmune disease
Number of cases
Any autoimmune disease Thyrotoxicosis Autoimmune thyroiditis Type 1 diabetes Primary andrenocortical insufficiency Celiac disease Pernicious anemia Autoimmune hemolytic anemia Idiopathic thrombocytopenic purpura Multiple sclerosis Idiopathic polyneuritis Iridocyclitis Granulomatosis with polyangiitis Crohn’s disease Ulcerative colitis Primary biliary cirrhosis Pemphigoid Pemphigus Psoriasis vulgaris Alopecia areata Vitiligo Seropositive rheumatoid arthritis Dermatopolymyositis Polymyalgia rheumatica Myasthenia gravis Scleroderma Systemic lupus erythematosus Sjogren’s syndrome Juvenile arthritis Ankylosing spondylitis a b
166,090 17,712 3436 37,811 949 3512 1157 500 2497 11,120 2247 9598 613 13,115 24,382 496 210 276 15,340 1716 1215 17,131 756 2241 728 1128 2443 1977 4948 4096
Number of exposed cases
58,265 5927 1260 13,505 437 1351 419 182 897 3192 651 3432 257 5527 7737 215 89 106 5137 639 442 5787 260 819 211 448 961 903 1653 1342
Basic adjustmenta
Fully adjustedb
Incidence rate ratio (95% CI)
Incidence rate ratio (95% CI)
1.64 1.31 1.34 2.02 3.26 1.78 1.77 2.00 1.59 1.29 1.93 1.68 2.31 2.23 1.44 2.34 2.15 2.17 1.70 1.74 1.57 1.59 1.89 1.68 1.51 2.15 2.30 2.44 1.71 1.60
1.46 1.24 1.29 1.40 2.58 1.62 1.56 1.59 1.47 1.21 1.74 1.63 1.76 2.10 1.39 1.90 1.86 1.93 1.60 1.61 1.50 1.50 1.70 1.50 1.39 1.63 1.94 2.17 1.64 1.56
(1.62,1.65) (1.27,1.35) (1.25,1.44) (1.98,2.07) (2.84,3.73) (1.66,1.91) (1.56, 2.00) (1.66,2.41) (1.46,1.72) (1.23,1.34) (1.75,2.12) (1.61,1.76) (1.96,2.72) (2.15,2.31) (1.40,1.49) (1.95,2.81) (1.63e2.84) (1.69e2.79) (1.64e1.76) (1.58e1.93) (1.39e1.77) (1.54e1.64) (1.62e2.21) (1.54e1.83) (1.27e1.78) (1.90e2.43) (2.12e2.51) (2.23e2.67) (1.61e1.82) (1.49e1.71)
(1.44,1.47) (1.20,1.28) (1.20,1.39) (1.37,1.43) (2.24,2.97) (1.51,1.74) (1.37,1.77) (1.31,1.93) (1.35,1.60) (1.15,1.26) (1.57,1.91) (1.56,1.70) (1.48,2.08) (2.03,2.18) (1.35,1.43) (1.57,2.29) (1.39,2.46) (1.49,2.49) (1.54,1.65) (1.45,1.78) (1.33,1.70) (1.46,1.56) (1.45,1.99) (1.37,1.63) (1.17,1.64) (1.43,1.85) (1.78,2.11) (1.98,2.38) (1.54,1.74) (1.46,1.68)
Adjusted for calendar year, sex and its interaction with age. Adjusted for calendar year, sex and its interaction with age, and Charlson comorbidity index.
Table 2 Time since first hospitalization with an infection and risk of autoimmune diseases.a Less than 1 month
2-12 months
1-4 years
5-9 years
10 years or more
Incidence rate ratio (95% Incidence rate ratio (95% Incidence rate ratio (95% Incidence rate ratio (95% Incidence rate ratio (95% CI) CI) CI) CI) CI) Any autoimmune disease Thyrotoxicosis Autoimmune thyroiditis Type 1 diabetes Primary andrenocortical insufficiency Celiac disease Pernicious anemia Autoimmune hemolytic anemia Idiopathic thrombocytopenic purpura Multiple sclerosis Idiopathic polyneuritis Iridocyclitis Granulomatosis with polyangiitis Crohn’s disease Ulcerative colitis Primary biliary cirrhosis Pemphigoid Pemphigus Psoriasis vulgaris Alopecia areata Vitiligo Seropositive rheumatoid arthritis Dermatopolymyositis Polymyalgia rheumatica Myasthenia Gravis Scleroderma Systemic lupus erythematosus Sjogren’s syndrome Juvenile arthritis Ankylosing spondylitis a b
10.94 (10.38,11.52) 5.09 (3.99,6.37) 4.00 (2.07,6.86) 10.33 (9.17,11.58) 22.78 (12.74,37.23)
2.62 1.70 1.47 2.56 5.86
(2.54e2.70) (1.51,1.92) (1.08,1.94) (2.38,2.74) (4.18,7.99)
1.80 1.35 1.51 2.17 4.09
(1.76e1.83) (1.26,1.44) (1.30,1.74) (2.09,2.26) (3.31,5.02)
1.60 1.33 1.38 2.12 2.96
(1.57e1.63) (1.25,1.41) (1.20,1.57) (2.05,2.20) (2.34,3.70)
1.44 1.25 1.27 1.79 2.49
(1.42e1.46) (1.20e1.30) (1.17,1.38) (1.74e1.84) (2.08,2.98)
10.69 10.12 31.28 11.51
3.51 4.17 4.80 2.25
(2.96,4.13) (3.00,5.62) (3.08,7.13) (1.79,2.79)
1.99 1.54 2.20 1.80
(1.77,2.23) (1.19,1.97) (1.57,3.00) (1.57,2.04)
1.48 1.62 1.94 1.16
(1.30,1.67) (1.28,2.03) (1.37,2.67) (0.98,1.36)
1.49 1.64 1.30 1.45
(1.34,1.64) (1.40,1.92) (0.97e1.71) (1.28,1.64)
1.84 4.01 2.52 6.77 6.39 2.70 5.83 3.75 2.61 2.49 1.76 1.74 2.08 3.84 2.40 2.62 4.57 5.05 3.44 2.91 2.22
(1.58,2.12) (3.17,5.00) (2.19,2.88) (4.65,9.52) (5.89,6.92) (2.48,2.93) (3.58,8.93) (1.58e7.46) (1.17e4.98) (2.23e2.77) (1.21e2.46) (1.11e2.60) (1.85e2.33) (2.55e5.55) (1.77e3.18) (1.58e4.07) (3.27e6.21) (4.11e6.13) (2.53e4.55) (2.52e3.34) (1.75e2.77)
1.20 2.15 1.88 2.62 2.60 1.68 2.35 3.68 2.51 1.88 1.84 1.60 1.69 2.03 1.83 1.54 2.43 2.45 3.23 1.66 1.55
(1.09,1.31) (1.83,2.52) (1.73,2.03) (1.94,3.47) (2.44,2.77) (1.59,1.77) (1.62,3.31) (2.39e5.47) (1.66e3.67) (1.77e2.01) (1.52e2.19) (1.26e2.00) (1.59e1.80) (1.52e2.64) (1.54e2.17) (1.11e2.07) (1.93e3.03) (2.11e2.84) (2.75e3.77) (1.50e1.82) (1.35e1.78)
1.25 1.67 1.60 1.21 1.99 1.30 2.88 1.53 1.73 1.74 1.94 1.47 1.47 1.42 1.69 1.24 1.99 1.99 2.34 1.49 1.68
(1.15,1.36) (1.40,1.98) (1.48,1.74) (0.80,1.75) (1.86,2.12) (1.23,1.37) (2.10,3.86) (0.82e2.61) (1.05e2.70) (1.63e1.85) (1.63e2.29) (1.17e1.83) (1.38e1.57) (1.02e1.92) (1.43e2.00) (0.88e1.70) (1.57e2.49) (1.70e2.32) (1.97e2.75) (1.35e1.66) (1.48e1.90)
1.26 1.40 1.46 1.72 1.70 1.25 1.87 1.57 1.88 1.52 1.60 1.55 1.53 1.66 1.51 1.47 1.88 1.90 2.16 1.42 1.49
(1.20,1.33) (1.21,1.62) (1.38,1.54) (1.38e2.13) (1.62,1.78) (1.20e1.29) (1.48,2.35) (1.06e2.26) (1.30e2.65) (1.45e1.59) (1.40e1.82) (1.33e1.80) (1.47e1.60) (1.35e2.04) (1.36e1.68) (1.17e1.82) (1.61e2.20) (1.70e2.13) (1.94e2.41) (1.27e1.58) (1.37e1.63)
(7.72,14.36) (4.84,18.34) (17.42,51.48) (8.19,15.64)
4.29 (3.06,5.81) 20.55 (14.49,28.15) 21.10 (17.94,24.63) 73.80 (50.36,104.27) 25.33 (22.13,28.83) 13.69 (12.09,15.43) b b
21.92 (8.60,45.41) 6.23 (4.92,7.76) 3.72 (1.47,7.56) 6.27 (2.69,12.20) 6.45 (5.16,7.95) 19.19 (10.21e32.47) 13.30 (8.56,19.58) b
7.68 (3.04,15.64) 22.13 (15.90,29.86) 9.89 (5.28,16.64) 11.22 (8.68,14.24) 8.17 (5.31e11.91)
The reference group for each autoimmune disease is people with no hospital contact for infection. Too few cases.
Please cite this article in press as: P.R. Nielsen, et al., Infections as risk factor for autoimmune diseases e A nationwide study, Journal of Autoimmunity (2016), http://dx.doi.org/10.1016/j.jaut.2016.05.013
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P.R. Nielsen et al. / Journal of Autoimmunity xxx (2016) 1e6
Table 3 Incidence rate ratios of autoimmune diseases according to number of infections.a
Any autoimmune disease Thyrotoxicosis Autoimmune thyroiditis Type 1 diabetes Primary andrenocortical insufficiency Celiac disease Pernicious anemia Autoimmune hemolytic anemia Idiopathic thrombocytopenic purpura Multiple Sclerosis Idiopathic polyneuritis Iridocyclitis Granulomatosis with polyangiitis Crohn’s disease Ulcerative colitis Primary biliary cirrhosis Pemphigoid Pemphigus Psoriasis vulgaris Alopecia areata Vitiligo Seropositive rheumatoid arthritis Dermatopolymyositis Polymyalgia rheumatica Myasthenia gravis Scleroderma Systemic lupus erythematosus Sjogren’s syndrome Juvenile arthritis Ankylosing spondylitis a
1 infection
2e4 infections
5 infections or more
Incidence rate ratio (95% CI)
Incidence rate ratio (95% CI)
Incidence rate ratio (95% CI)
1.35 1.22 1.29 1.50 2.03 1.42 1.42 1.59 1.26 1.20 1.49 1.39 1.60 1.62 1.22 1.93 1.47 1.59 1.33 1.48 1.45 1.36 1.54 1.43 1.30 1.67 1.56 1.89 1.46 1.41
1.95 1.38 1.38 2.59 3.87 2.10 2.03 2.48 1.93 1.39 2.54 2.02 3.00 2.83 1.68 2.33 2.51 2.58 2.19 1.88 1.72 1.83 2.26 1.93 1.49 2.47 3.03 2.75 1.90 1.83
3.09 1.76 1.64 5.22 13.46 3.28 3.83 5.19 2.81 1.55 4.40 3.05 6.04 4.94 2.40 6.43 6.84 9.39 3.26 3.53 2.07 2.58 3.80 2.40 3.79 5.38 6.74 5.95 3.33 2.37
(1.34,1.37) (1.17,1.27) (1.18,1.41) (1.46,1.55) (1.68,2.43) (1.30,1.56) (1.20,1.66) (1.24,2.03) (1.13,1.41) (1.14,1.27) (1.31,1.68) (1.31,1.46) (1.28,2.00) (1.55,1.70) (1.17,1.26) (1.52,2.42) (0.98,2.12) (1.12,2.21) (1.27,1.39) (1.30,1.68) (1.25,1.68) (1.30,1.41) (1.25,1.87) (1.28,1.60) (1.05,1.60) (1.42,1.96) (1.39,1.75) (1.69,2.12) (1.35,1.58) (1.30e1.54)
(1.92,1.98) (1.32,1.44) (1.25,1.52) (2.52,2.67) (3.22,4.62) (1.91,2.30) (1.70,2.40) (1.90,3.18) (1.73,2.16) (1.31,1.48) (2.22,2.90) (1.90,2.14) (2.41,3.71) (2.70,2.97) (1.62,1.75) (1.78,3.00) (1.71e3.61) (1.80e3.62) (2.09e2.29) (1.63e2.16) (1.46e2.03) (1.75e1.92) (1.82e2.79) (1.71e2.17) (1.15e1.90) (2.08e2.92) (2.70e3.38) (2.43e3.11) (1.75e2.07) (1.68e2.01)
(3.01,3.17) (1.61,1.92) (1.35,1.97) (4.98,5.47) (10.76,16.70) (2.79,3.83) (2.88,4.99) (3.45,7.50) (2.29,3.40) (1.36,1.76) (3.45,5.52) (2.75,3.38) (4.33,8.21) (4.57,5.33) (2.23,2.58) (4.48,8.96) (4.06e10.89) (6.06e14.02) (3.00e3.54) (2.79e4.39) (1.47e2.81) (2.37e2.80) (2.59e5.38) (1.92e2.97) (2.58e5.37) (4.13e6.88) (5.66e7.96) (4.96e7.08) (2.87e3.83) (1.96e2.83)
Reference group people with no hospital contact for an infection.
Table 4 Incidence rate ratios of autoimmune diseases according to type of infection.a
Any autoimmune disease Thyrotoxicosis Autoimmune thyroiditis Type 1 diabetes Primary andrenocortical insufficiency Celiac disease Pernicious anemia Autoimmune hemolytic anemia Idiopathic thrombocytopenic purpura Multiple Sclerosis Idiopathic polyneuritis Iridocyclitis Granulomatosis with polyangiitis Crohn’s disease Ulcerative colitis Primary biliary cirrhosis Pemphigoid Pemphigus Psoriasis vulgaris Alopecia areata Vitiligo Seropositive rheumatoid arthritis Dermatopolymyositis Polymyalgia rheumatica Myasthenia gravis Scleroderma Systemic lupus erythematosus Sjogren’s syndrome Juvenile arthritis Ankylosing spondylitis a
Bacterial
Viral
Other
Incidence rate ratio (95% CI)
Incidence rate ratio (95% CI)
Incidence rate ratio (95% CI)
1.71 1.32 1.28 2.36 3.00 1.52 1.72 1.82 1.63 1.27 2.18 1.55 2.00 2.60 1.50 2.46 2.37 2.45 1.82 1.81 1.55 1.63 1.99 1.64 1.35 2.17 2.22 2.24 2.21 1.66
1.59 1.25 1.29 1.79 3.33 1.92 1.41 2.25 1.61 1.55 1.70 1.63 2.10 1.87 1.39 2.94 1.90 2.48 1.72 2.00 1.59 1.52 2.01 1.43 2.05 2.46 2.40 2.70 1.60 1.54
1.57 1.31 1.44 1.80 3.51 1.93 1.96 2.10 1.54 1.21 1.77 1.84 2.74 2.04 1.41 1.95 1.99 1.78 1.57 1.57 1.59 1.57 1.74 1.81 1.49 2.01 2.38 2.70 1.56 1.56
(1.69,1.74) (1.27,1.37) (1.17,1.40) (2.29,2.43) (2.51,3.58) (1.37,1.69) (1.46,2.01) (1.39,2.35) (1.44,1.85) (1.20,1.34) (1.92,2.48) (1.46,1.64) (1.60,2.49) (2.48,2.73) (1.44,1.56) (1.98,3.05) (1.65,3.33) (1.73,3.39) (1.74,1.91) (1.56,2.08) (1.30,1.84) (1.56,1.69) (1.61,2.44) (1.47,1.82) (1.06,1.70) (1.86,2.53) (1.99,2.47) (2.01,2.50) (2.00,2.43) (1.51e1.82)
(1.55e1.62) (1.15,1.34) (1.10,1.49) (1.71,1.87) (2.56,4.28) (1.70,2.16) (1.03,1.88) (1.54,3.19) (1.39,1.85) (1.42,1.70) (1.37,2.08) (1.49,1.79) (1.43,2.98) (1.74,2.01) (1.31,1.47) (1.97,4.24) (0.99e3.34) (1.55e3.80) (1.60e1.85) (1.67e2.38) (1.26e1.98) (1.41e1.64) (1.45e2.73) (1.11e1.82) (1.47e2.79) (1.89e3.15) (2.01e2.86) (2.20e3.28) (1.45e1.77) (1.33e1.78)
(1.55e1.60) (1.25,1.38) (1.30,1.58) (1.74,1.85) (2.94,4.16) (1.76,2.11) (1.66,2.32) (1.61,2.69) (1.37,1.72) (1.14,1.29) (1.55,2.03) (1.74,1.95) (2.22,3.38) (1.95,2.14) (1.36,1.47) (1.46,2.57) (1.32e2.91) (1.22e2.53) (1.49e1.65) (1.36e1.80) (1.35e1.86) (1.49e1.64) (1.39e2.17) (1.59e2.04) (1.17e1.88) (1.68e2.40) (2.11e2.68) (2.38e3.05) (1.43e1.69) (1.42e1.71)
Reference group people with no hospital contacts for an infection.
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between a range of serious infections and autoimmune diseases. The precise timing, location, magnitude and pathogen of the serious infection might all play an important role for the risk of developing an autoimmune disease. In our study we were able to control for the timing of the serious infection and although in a somewhat crude way the type of pathogen, bacterial or viral. As to the magnitude of the inflammation, all of the infections were severe enough to require hospitalization. Our study suggests that all infections requiring hospitalization increase the risk of developing autoimmune disease regardless of type of infection but in a time dependent manner. It is challenging to firmly prove that one or more pathogens are indeed involved in the initiation and/or propagation of the autoimmune destructive process. We observed a higher risk if the diagnosis of infection and autoimmune disease occurred around the same time. This suggests that the serious infection could be the final trigger of the immune response leading to the emergence of clinical autoimmune disease. However, this association between hospitalization for a serious infection in close proximity to the autoimmune diagnosis could be biased in at least two ways. First, symptoms of infection can mimic symptoms of autoimmune disease and thus give rise to first an infection diagnosis and later an autoimmune diagnosis. Second, many autoimmune diseases increase the risk of infection and an undiagnosed autoimmune disease could thus actually be the cause of the infections in close relation to the autoimmune diagnosis [14]. Thus, serious infections might accelerate a preexisting autoimmune condition to progress to clinical disease rather than directly initiate autoimmunity. We observed an increased risk of developing autoimmune diseases with increasing number of serious infections over a time span of more than 10 years. Autoantibodies also appear years before clinical symptoms increasing in concentration before diagnosis [15,16]. Thus multiple sequential infectious events might be required to propagate the aberrant immune activation and to target the autoimmune destruction to the affected organ. Patients with autoimmune disease and healthy individuals experience numerous pathogen infections during their lifetime. At the time of diagnosis most of these pathogens have been cleared from the system. We only had access to records of serious infections that involved hospital contact. However, most infections do not require hospital contact, and it is therefore entirely possible that rather than reflecting the presence or absence of infection, our data capture instances of clinically severe infection only. In other words, our results might not be generalizable to the type of infection that go untreated or are treated by a general practitioner, which would be milder forms of infections in most cases. Our results are in line with a study from Sweden that found exposure to infections during the first year of life to be risk factors for rheumatoid arthritis and juvenile idiopathic arthritis [4]. The study was based on infections obtained from registers. However, Sandberg et al. found that infections in general do not affect the risk for rheumatoid arthritis [6]. One explanation for the divergent findings could be that the infections studied by Sandberg et al. were based on self-reports and not leading to hospitalization while we studied severe infections leading to hospitalization. It has been suggested that certain pathogen infections might protect from adverse immune reactions [17e21], such as allergy and autoimmunity, rather than enhance it. We did not find any evidence of this for any of the autoimmune diseases. This could be due to the types of infections studied, we only included severe infections requiring hospitalization. Many drugs have been associated with drug-induced autoimmunity. The appearance of autoimmune diseases following exposure to many common pharmaceutical agents is a wellcharacterized phenomenon, for example drugs that induce lupus.
5
It should be emphasized that such lupus-like syndromes become reversible when drugs are discontinued. However, there remains the possibility that the autoimmune disease may persist in some patients and it is very difficult if not impossible to identify a specific trigger in such individuals by epidemiological analysis. Thus, it is possible that some of the cases diagnosed with autoimmune disease could be influenced by drug-induced autoimmunity. The potential impact of this bias is limited as drug-induced autoimmunity is a relatively rare occurrence. In addition, by modulating innate and adaptive immunity, the microbiota and nutrition (e.g.vitamin D, iodine and gluten) may also contribute to loss of tolerance. These limitations to our study, that we did not have access to use of pharmaceutical agents and information on nutrition, made it impossible for us to distinguish between conditions mimicking autoimmune disease and autoimmune disease. A strength of this study was the ability to adjust for family history of autoimmune diseases and Charlson Comorbidity Index. Family history of autoimmune disease or prior history with autoimmune disease, were major risk factors for developing an autoimmune disease, but when adjusting for this type of comorbidity the infection risk was not affected (results not shown). Likewise having been hospitalized for one of the diseases in the Charlson Comorbidiy Index was a major risk factor for developing autoimmune disease, but again did not affect the risk for infection. It remains a limitation to our study that we were not able to adjust for an important confounding factor smoking, as this factor is known to influence the risk of infections and of certain autoimmune diseases. 5. Conclusions Our study reveals that infections are associated with the development of autoimmune diseases in a large general population. Acknowledgements This study was supported by the Lundbeck Foundation. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.jaut.2016.05.013. References [1] J.K. Olson, J.L. Croxford, S.D. Miller, Virus-induced autoimmunity: potential role of viruses in initiation, perpetuation, and progression of T-cell-mediated autoimmune disease, Viral Immunol. 14 (2001) 227e250. [2] P. Sfriso, A. Ghirardello, C. Botsios, M. Tonon, M. Zen, N. Bassi, et al., Infections and autoimmunity: the multifaceted relationship, J. Leukoc. Biol. 87 (2010) 385e395. [3] D.R. Getts, E.M. Chastain, R.L. Terry, S.D. Miller, Virus infection, antiviral immunity, and autoimmunity, Immunol. Rev. 255 (2013) 197e209. [4] C. Carlens, L. Jacobsson, L. Brandt, S. Cnattingius, O. Stephansson, J. Askling, Perinatal characteristics, early life infections and later risk of rheumatoid arthritis and juvenile idiopathic arthritis, Ann. Rheum. Dis. 68 (2009) 1159e1164. [5] J.R. Kerr, The role of parvovirus B19 in the pathogenesis of autoimmunity and autoimmune disease, J. Clin. Pathol. 69 (2015) 279e291. [6] M.E. Sandberg, C. Bengtsson, L. Klareskog, L. Alfredsson, S. Saevarsdottir, Recent infections are associated with decreased risk of rheumatoid arthritis: a population-based case-control study, Ann. Rheum. Dis. 74 (2015) 904e907. [7] R.J. Ball, A. Avenell, L. Aucott, P. Hanlon, M.A. Vickers, Systematic review and meta-analysis of the sero-epidemiological association between Epstein-Barr virus and rheumatoid arthritis, Arthritis Res. Ther. 17 (2015) 274. [8] C.B. Pedersen, H. Gotzsche, J.O. Moller, P.B. Mortensen, The Danish Civil Registration System. A cohort of eight million persons, Dan. Med. Bull. 53 (2006) 441e449. [9] T.F. Andersen, M. Madsen, J. Jorgensen, L. Mellemkjoer, J.H. Olsen, The Danish National Hospital Register. A valuable source of data for modern health sciences, Dan. Med. Bull. 46 (1999) 263e268.
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[10] World Health Organization, Klassifikation Af Sygdomme; Udvidet Dansklatinsk Udgave Af Verdenssundhedsorganisationens Internationale Klassifikation Af Sygdomme. 8 Revision, 1965 (Classification of diseases: Extended Danish-Latin version of the World Health Organization International Classification of Diseases, 8th revision, 1965), Danish National Board of Health, Copenhagen, 1971. [11] World Health Organization, WHO ICD-10: Klassifikation Af Sygdomme [WHO ICD-10: International Statistical Classification of Diseases and Health Related Problems], Munksgaard Danmark, Copenhagen, 1993. [12] M.E. Charlson, P. Pompei, K.L. Ales, C.R. MacKenzie, A new method of classifying prognostic comorbidity in longitudinal studies: development and validation, J. Chronic. Dis. 40 (1987) 373e383. [13] V. Sundararajan, T. Henderson, C. Perry, A. Muggivan, H. Quan, W.A. Ghali, New ICD-10 version of the Charlson comorbidity index predicted in-hospital mortality, J. Clin. Epidemiol. 57 (2004) 1288e1294. [14] R. Mahadeva, A.C. Dunn, R.C. Westerbeek, L. Sharples, D.B. Whitehouse, N.R. Carroll, et al., Anti-neutrophil cytoplasmic antibodies (ANCA) against bactericidal/permeability-increasing protein (BPI) and cystic fibrosis lung disease, Clin. Exp. Immunol. 117 (1999) 561e567. [15] M.R. Arbuckle, M.T. McClain, M.V. Rubertone, R.H. Scofield, G.J. Dennis,
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Contents lists available at ScienceDirect
Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm
Infections as risk factor for autoimmune diseases e A nationwide study Philip Rising Nielsen a, *, Tue Wenzel Kragstrup b, c, Bent Winding Deleuran b, c, Michael Eriksen Benros d National Center for Register-based Research, Fuglesangs All e 4, Aarhus University, Aarhus, Denmark Department of Biomedicine, Aarhus University, Wilhelm Meyers All e 4, Aarhus, Denmark c Department of Rheumatology, Aarhus University Hospital, Nørrebrogade 44, Aarhus, Denmark d Mental Health Center Copenhagen, Copehagen University Hospital, Copenhagen, Denmark a
b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 25 April 2016 Received in revised form 25 May 2016 Accepted 31 May 2016 Available online xxx
Viruses, bacteria and other infectious pathogens are the major postulated environmental triggers of autoimmunity. In the present nation-wide study we describe the association between infections and 29 autoimmune diseases. We used the Danish Civil Registration System to identify 4.5 million persons born between 1945 and 2000. Information on infections and autoimmune diseases was obtained from the Danish Hospital Register. The cohort was followed from 1977 to 2012. Incidence rate ratios for developing an autoimmune disease were estimated using poisson regression. We found an association between hospital admission for an infection and 29 autoimmune diseases. This study shows that infections are risk factors for a broad spectrum of autoimmune diseases in a dose-response and temporal manner, in agreement with the hypothesis that infections are an environmental risk factor contributing to the etiology of autoimmune diseases together with genetic factors. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Epidemiology Autoimmune disease Infections
1. Introduction Autoimmune disease is a group of disorders in which the primary cause is the inflammatory reaction caused by the immune system attacking the body’s own tissues. Both inherent genetic susceptibility and environmental factors play a major role in determining risk of development of autoimmune diseases. An environmental factor thought to play an important role in the development of autoimmunity is infection. The impact of infections on autoimmunity is substantial, and various mechanisms have been suggested to explain the relationship. Possible mechanisms linking infections and autoimmune disease include alterations in target cells, alterations in immune cells, immune responses against the determinant shared by host and virus, and cross-reaction between idiotype and the antiviral antibody and respective autoantigens. Much of what we know about these mechanisms has come from studies in animal models, showing evidence that viruses
* Corresponding author. National Centre for Register-Based Research, Aarhus 4, Aarhus, DK 8210 V, Denmark. Tel.: þ45 87165753; University, Fuglesangs Alle fax: þ45 87164601. E-mail address: [email protected] (P.R. Nielsen).
can play a causative role in chronic autoimmune disease [1,2]. However, there is also compelling epidemiologic evidence that infection in humans predisposes to autoimmune disease [1,3e5]. Studies have focused on specific infections and specific autoimmune diseases [4e7]. However, no known virus has been proven to regularly induce or promote autoimmune disorders. The high prevalence and frequent severity of autoimmune diseases make the exploration and understanding of the precipitating factors a clinical imperative. The purpose of this study therefore was to investigate whether hospitalization for an infection is a risk factor for developing a range of autoimmune diseases. Furthermore, we wanted to investigate the temporal relationship between time of diagnosis for infection and autoimmune diseases. Finally, we wanted to investigate the difference between the types of infection. 2. Method 2.1. Registers Since 1968, the Danish Civil Registration System has recorded information, such as gender, first-degree relatives, and date of birth,
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on all people living in Denmark [8]. A unique Civil Registration System number is assigned to each individual at birth that ensures accurate linkage between the different registers. The National Hospital Register holds information on all admissions to and discharges from hospitals since 1977 (type 1 diabetes since 1987) and registration of outpatients and emergency department contacts since 1995 [9]. The Danish version of ICD-8 [10] was the diagnostic system used from 1969 to 1993, and ICD-10 was used from 1994 onward [11]. All personal information from the registers is anonymized when used for research purposes, and the present study was approved by the Danish Data Protection Agency.
2.6. Statistical analysis Incidence rate ratios, also referred to as relative risks, of each autoimmune disease were estimated by log-linear Poisson regression using the GENMOD procedure in SAS, version 9.3 (SAS Institute, Cary, N.C.). All estimates were adjusted for calendar year, age, and sex. Age, calendar year, Charlson Comorbidity Index, and time since infection were treated as time-dependent variables, whereas sex was considered time independent. The p values and 95% confidence intervals were based on likelihood ratio tests. 3. Results
2.2. Study population The total study population included 4.5 million persons born in Denmark between January 1, 1945, and December 31, 2010, and who were alive and a resident of Denmark during our study period. They were followed from date of birth or January 1, 1977, until onset of the autoimmune disease in question, death, emigration from Denmark, or December 31, 2010, whichever came first. Follow-up for diabetes was initiated from 1987, since type 1 diabetes could not be distinguished from type 2 diabetes in the register system until then, and all previous diagnoses of diabetes were excluded. 2.3. Assessment of autoimmune diseases The date at onset was defined as the first day of the first hospital contact for the relevant disease, irrespective of other previous diagnosis. Each person could have a history of more than one autoimmune disease. We omitted all ICD-8 diagnoses that bore the modification code “suspected” or “not found,” and ICD-10 diagnoses with similar codes were also omitted. Persons were classified as having an autoimmune disease if they were registered with one of the 29 autoimmune diseases listed in Table S1 of the online data supplement that accompanies this article. 2.4. Assessment of infections A history of infection was defined as the person having been listed with a diagnosis of infection in the Danish National Hospital Register. We omitted all ICD-8 diagnoses that bore the modification code “suspected” and “not found”. Similar codes were omitted for the ICD-10. All infection codes were grouped according to type of infection: bacterial, viral, and other type of infection. For the diagnostic codes, see Table S2 of the online data supplement. 2.5. Charlson Comorbidity Index To account for the effect of other comorbidities, the Charlson comorbidity index was included in the analysis as a possible confounder. The Charlson Comorbidity Index, a score that categorizes and assigns weights and severities to 19 different patient comorbidities, was first reported in 1987 to estimate the probability of death within 1 year [12] and it has later been adapted to fit with ICD-10 diagnoses [13]. The Charlson comorbidity index is a widely accepted and validated method used to quantify comorbidity and summarizes 19 mortality-weighted conditions ranging from myocardial infarction to malignant disease. We used the Charlson Comorbidity Index to adjust for severe chronic somatic diseases. We modified the index by excluding the groups, Diabetes 1 þ 2, connective tissue, mild liver diseases and AIDS. The Charlson Comorbidity Index was created in five categories: 0, 1, 2, 3, and 4þ.
In our study population consisting of 4.5 million people born in Denmark after 1945, a total of 166,090 individuals were diagnosed with an autoimmune disease (94,857 females and 71,233 males) during the follow-up period from 1977 to 2010 (107.1 million person-years of risk). Prior to the diagnosis of the autoimmune diseases, a total of 58,265 patients (35.08%) were diagnosed as having one or more infections (33,285 females and 21,980 males). Table 1 displays the overall effect of exposure to infection and the number of exposed cases according to type of autoimmune disease. A previous hospital contact for infection was associated with an increased IRR of 1.64 (95% CI: 1.62e1.65) for developing an autoimmune disease compared with persons with no hospital contact for infection. After adjustment for Charlson Comorbidity Index the IRR was reduced to 1.46 (95% CI: 1.44e1.47). Table 2 displays the temporal proximity of the infection to the autoimmune diagnosis. Persons hospitalized for an infection had a significantly increased risk for subsequent diagnosis of a range of autoimmune diseases. When investigating the risk of autoimmune disease in relation to time since first hospital contact for infection, divided into five time periods less than 1 month, 2e12 months, 1e4 years, 5e9 years and 10 years or more, we found the risk to be highest for those hospitalized with an infection in close proximity to their autoimmune disease (less than a month). The disease for which the greatest difference between the concurrent and the delayed period was observed was for Granulomatosis with polyangiitis with an increased IRR of 73.80 (95% CI: 50.36e104.27) in the first month to an IRR of 1.72 (95% CI: 1.32e2.13) 10 years or more before onset of Granulomatosis with polyangiitis. Table 3 shows the number of infections and incidence rate ratio for autoimmune disease. We observed that an increase in number of infections increased the risk of autoimmune disease in a dose response manner. The largest increase was observed for primary adrenocortical insufficiency, having been hospitalized for one infection was associated with an increased risk of 2.03 (1.68e2.43), whereas having five or more infections increased the risk to 13.46 (10.76e16.70). Table 4 displays the type of infection, bacterial, viral and other type of infections. Bacterial infection was associated with an increased risk of autoimmune disease with an IRR of 1.71 (95% CI: 1.69e1.74). In general, we found similar effect sizes for all three types of infections. 4. Discussion In this national cohort study, we observed that individuals hospitalized for a serious infection were at increased risk of subsequent diagnosis of autoimmune diseases. Individuals with multiple hospitalizations with infections and persons hospitalized for a serious infection in close proximity to the autoimmune diagnosis were at greatest risk. We found no difference between being hospitalized for a viral infection and other types of infection. This is the first study to provide a general overview of the possible association
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3
Table 1 Incidence rate ratios of autoimmune diseases associated with hospital contact for an infection. Autoimmune disease
Number of cases
Any autoimmune disease Thyrotoxicosis Autoimmune thyroiditis Type 1 diabetes Primary andrenocortical insufficiency Celiac disease Pernicious anemia Autoimmune hemolytic anemia Idiopathic thrombocytopenic purpura Multiple sclerosis Idiopathic polyneuritis Iridocyclitis Granulomatosis with polyangiitis Crohn’s disease Ulcerative colitis Primary biliary cirrhosis Pemphigoid Pemphigus Psoriasis vulgaris Alopecia areata Vitiligo Seropositive rheumatoid arthritis Dermatopolymyositis Polymyalgia rheumatica Myasthenia gravis Scleroderma Systemic lupus erythematosus Sjogren’s syndrome Juvenile arthritis Ankylosing spondylitis a b
166,090 17,712 3436 37,811 949 3512 1157 500 2497 11,120 2247 9598 613 13,115 24,382 496 210 276 15,340 1716 1215 17,131 756 2241 728 1128 2443 1977 4948 4096
Number of exposed cases
58,265 5927 1260 13,505 437 1351 419 182 897 3192 651 3432 257 5527 7737 215 89 106 5137 639 442 5787 260 819 211 448 961 903 1653 1342
Basic adjustmenta
Fully adjustedb
Incidence rate ratio (95% CI)
Incidence rate ratio (95% CI)
1.64 1.31 1.34 2.02 3.26 1.78 1.77 2.00 1.59 1.29 1.93 1.68 2.31 2.23 1.44 2.34 2.15 2.17 1.70 1.74 1.57 1.59 1.89 1.68 1.51 2.15 2.30 2.44 1.71 1.60
1.46 1.24 1.29 1.40 2.58 1.62 1.56 1.59 1.47 1.21 1.74 1.63 1.76 2.10 1.39 1.90 1.86 1.93 1.60 1.61 1.50 1.50 1.70 1.50 1.39 1.63 1.94 2.17 1.64 1.56
(1.62,1.65) (1.27,1.35) (1.25,1.44) (1.98,2.07) (2.84,3.73) (1.66,1.91) (1.56, 2.00) (1.66,2.41) (1.46,1.72) (1.23,1.34) (1.75,2.12) (1.61,1.76) (1.96,2.72) (2.15,2.31) (1.40,1.49) (1.95,2.81) (1.63e2.84) (1.69e2.79) (1.64e1.76) (1.58e1.93) (1.39e1.77) (1.54e1.64) (1.62e2.21) (1.54e1.83) (1.27e1.78) (1.90e2.43) (2.12e2.51) (2.23e2.67) (1.61e1.82) (1.49e1.71)
(1.44,1.47) (1.20,1.28) (1.20,1.39) (1.37,1.43) (2.24,2.97) (1.51,1.74) (1.37,1.77) (1.31,1.93) (1.35,1.60) (1.15,1.26) (1.57,1.91) (1.56,1.70) (1.48,2.08) (2.03,2.18) (1.35,1.43) (1.57,2.29) (1.39,2.46) (1.49,2.49) (1.54,1.65) (1.45,1.78) (1.33,1.70) (1.46,1.56) (1.45,1.99) (1.37,1.63) (1.17,1.64) (1.43,1.85) (1.78,2.11) (1.98,2.38) (1.54,1.74) (1.46,1.68)
Adjusted for calendar year, sex and its interaction with age. Adjusted for calendar year, sex and its interaction with age, and Charlson comorbidity index.
Table 2 Time since first hospitalization with an infection and risk of autoimmune diseases.a Less than 1 month
2-12 months
1-4 years
5-9 years
10 years or more
Incidence rate ratio (95% Incidence rate ratio (95% Incidence rate ratio (95% Incidence rate ratio (95% Incidence rate ratio (95% CI) CI) CI) CI) CI) Any autoimmune disease Thyrotoxicosis Autoimmune thyroiditis Type 1 diabetes Primary andrenocortical insufficiency Celiac disease Pernicious anemia Autoimmune hemolytic anemia Idiopathic thrombocytopenic purpura Multiple sclerosis Idiopathic polyneuritis Iridocyclitis Granulomatosis with polyangiitis Crohn’s disease Ulcerative colitis Primary biliary cirrhosis Pemphigoid Pemphigus Psoriasis vulgaris Alopecia areata Vitiligo Seropositive rheumatoid arthritis Dermatopolymyositis Polymyalgia rheumatica Myasthenia Gravis Scleroderma Systemic lupus erythematosus Sjogren’s syndrome Juvenile arthritis Ankylosing spondylitis a b
10.94 (10.38,11.52) 5.09 (3.99,6.37) 4.00 (2.07,6.86) 10.33 (9.17,11.58) 22.78 (12.74,37.23)
2.62 1.70 1.47 2.56 5.86
(2.54e2.70) (1.51,1.92) (1.08,1.94) (2.38,2.74) (4.18,7.99)
1.80 1.35 1.51 2.17 4.09
(1.76e1.83) (1.26,1.44) (1.30,1.74) (2.09,2.26) (3.31,5.02)
1.60 1.33 1.38 2.12 2.96
(1.57e1.63) (1.25,1.41) (1.20,1.57) (2.05,2.20) (2.34,3.70)
1.44 1.25 1.27 1.79 2.49
(1.42e1.46) (1.20e1.30) (1.17,1.38) (1.74e1.84) (2.08,2.98)
10.69 10.12 31.28 11.51
3.51 4.17 4.80 2.25
(2.96,4.13) (3.00,5.62) (3.08,7.13) (1.79,2.79)
1.99 1.54 2.20 1.80
(1.77,2.23) (1.19,1.97) (1.57,3.00) (1.57,2.04)
1.48 1.62 1.94 1.16
(1.30,1.67) (1.28,2.03) (1.37,2.67) (0.98,1.36)
1.49 1.64 1.30 1.45
(1.34,1.64) (1.40,1.92) (0.97e1.71) (1.28,1.64)
1.84 4.01 2.52 6.77 6.39 2.70 5.83 3.75 2.61 2.49 1.76 1.74 2.08 3.84 2.40 2.62 4.57 5.05 3.44 2.91 2.22
(1.58,2.12) (3.17,5.00) (2.19,2.88) (4.65,9.52) (5.89,6.92) (2.48,2.93) (3.58,8.93) (1.58e7.46) (1.17e4.98) (2.23e2.77) (1.21e2.46) (1.11e2.60) (1.85e2.33) (2.55e5.55) (1.77e3.18) (1.58e4.07) (3.27e6.21) (4.11e6.13) (2.53e4.55) (2.52e3.34) (1.75e2.77)
1.20 2.15 1.88 2.62 2.60 1.68 2.35 3.68 2.51 1.88 1.84 1.60 1.69 2.03 1.83 1.54 2.43 2.45 3.23 1.66 1.55
(1.09,1.31) (1.83,2.52) (1.73,2.03) (1.94,3.47) (2.44,2.77) (1.59,1.77) (1.62,3.31) (2.39e5.47) (1.66e3.67) (1.77e2.01) (1.52e2.19) (1.26e2.00) (1.59e1.80) (1.52e2.64) (1.54e2.17) (1.11e2.07) (1.93e3.03) (2.11e2.84) (2.75e3.77) (1.50e1.82) (1.35e1.78)
1.25 1.67 1.60 1.21 1.99 1.30 2.88 1.53 1.73 1.74 1.94 1.47 1.47 1.42 1.69 1.24 1.99 1.99 2.34 1.49 1.68
(1.15,1.36) (1.40,1.98) (1.48,1.74) (0.80,1.75) (1.86,2.12) (1.23,1.37) (2.10,3.86) (0.82e2.61) (1.05e2.70) (1.63e1.85) (1.63e2.29) (1.17e1.83) (1.38e1.57) (1.02e1.92) (1.43e2.00) (0.88e1.70) (1.57e2.49) (1.70e2.32) (1.97e2.75) (1.35e1.66) (1.48e1.90)
1.26 1.40 1.46 1.72 1.70 1.25 1.87 1.57 1.88 1.52 1.60 1.55 1.53 1.66 1.51 1.47 1.88 1.90 2.16 1.42 1.49
(1.20,1.33) (1.21,1.62) (1.38,1.54) (1.38e2.13) (1.62,1.78) (1.20e1.29) (1.48,2.35) (1.06e2.26) (1.30e2.65) (1.45e1.59) (1.40e1.82) (1.33e1.80) (1.47e1.60) (1.35e2.04) (1.36e1.68) (1.17e1.82) (1.61e2.20) (1.70e2.13) (1.94e2.41) (1.27e1.58) (1.37e1.63)
(7.72,14.36) (4.84,18.34) (17.42,51.48) (8.19,15.64)
4.29 (3.06,5.81) 20.55 (14.49,28.15) 21.10 (17.94,24.63) 73.80 (50.36,104.27) 25.33 (22.13,28.83) 13.69 (12.09,15.43) b b
21.92 (8.60,45.41) 6.23 (4.92,7.76) 3.72 (1.47,7.56) 6.27 (2.69,12.20) 6.45 (5.16,7.95) 19.19 (10.21e32.47) 13.30 (8.56,19.58) b
7.68 (3.04,15.64) 22.13 (15.90,29.86) 9.89 (5.28,16.64) 11.22 (8.68,14.24) 8.17 (5.31e11.91)
The reference group for each autoimmune disease is people with no hospital contact for infection. Too few cases.
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P.R. Nielsen et al. / Journal of Autoimmunity xxx (2016) 1e6
Table 3 Incidence rate ratios of autoimmune diseases according to number of infections.a
Any autoimmune disease Thyrotoxicosis Autoimmune thyroiditis Type 1 diabetes Primary andrenocortical insufficiency Celiac disease Pernicious anemia Autoimmune hemolytic anemia Idiopathic thrombocytopenic purpura Multiple Sclerosis Idiopathic polyneuritis Iridocyclitis Granulomatosis with polyangiitis Crohn’s disease Ulcerative colitis Primary biliary cirrhosis Pemphigoid Pemphigus Psoriasis vulgaris Alopecia areata Vitiligo Seropositive rheumatoid arthritis Dermatopolymyositis Polymyalgia rheumatica Myasthenia gravis Scleroderma Systemic lupus erythematosus Sjogren’s syndrome Juvenile arthritis Ankylosing spondylitis a
1 infection
2e4 infections
5 infections or more
Incidence rate ratio (95% CI)
Incidence rate ratio (95% CI)
Incidence rate ratio (95% CI)
1.35 1.22 1.29 1.50 2.03 1.42 1.42 1.59 1.26 1.20 1.49 1.39 1.60 1.62 1.22 1.93 1.47 1.59 1.33 1.48 1.45 1.36 1.54 1.43 1.30 1.67 1.56 1.89 1.46 1.41
1.95 1.38 1.38 2.59 3.87 2.10 2.03 2.48 1.93 1.39 2.54 2.02 3.00 2.83 1.68 2.33 2.51 2.58 2.19 1.88 1.72 1.83 2.26 1.93 1.49 2.47 3.03 2.75 1.90 1.83
3.09 1.76 1.64 5.22 13.46 3.28 3.83 5.19 2.81 1.55 4.40 3.05 6.04 4.94 2.40 6.43 6.84 9.39 3.26 3.53 2.07 2.58 3.80 2.40 3.79 5.38 6.74 5.95 3.33 2.37
(1.34,1.37) (1.17,1.27) (1.18,1.41) (1.46,1.55) (1.68,2.43) (1.30,1.56) (1.20,1.66) (1.24,2.03) (1.13,1.41) (1.14,1.27) (1.31,1.68) (1.31,1.46) (1.28,2.00) (1.55,1.70) (1.17,1.26) (1.52,2.42) (0.98,2.12) (1.12,2.21) (1.27,1.39) (1.30,1.68) (1.25,1.68) (1.30,1.41) (1.25,1.87) (1.28,1.60) (1.05,1.60) (1.42,1.96) (1.39,1.75) (1.69,2.12) (1.35,1.58) (1.30e1.54)
(1.92,1.98) (1.32,1.44) (1.25,1.52) (2.52,2.67) (3.22,4.62) (1.91,2.30) (1.70,2.40) (1.90,3.18) (1.73,2.16) (1.31,1.48) (2.22,2.90) (1.90,2.14) (2.41,3.71) (2.70,2.97) (1.62,1.75) (1.78,3.00) (1.71e3.61) (1.80e3.62) (2.09e2.29) (1.63e2.16) (1.46e2.03) (1.75e1.92) (1.82e2.79) (1.71e2.17) (1.15e1.90) (2.08e2.92) (2.70e3.38) (2.43e3.11) (1.75e2.07) (1.68e2.01)
(3.01,3.17) (1.61,1.92) (1.35,1.97) (4.98,5.47) (10.76,16.70) (2.79,3.83) (2.88,4.99) (3.45,7.50) (2.29,3.40) (1.36,1.76) (3.45,5.52) (2.75,3.38) (4.33,8.21) (4.57,5.33) (2.23,2.58) (4.48,8.96) (4.06e10.89) (6.06e14.02) (3.00e3.54) (2.79e4.39) (1.47e2.81) (2.37e2.80) (2.59e5.38) (1.92e2.97) (2.58e5.37) (4.13e6.88) (5.66e7.96) (4.96e7.08) (2.87e3.83) (1.96e2.83)
Reference group people with no hospital contact for an infection.
Table 4 Incidence rate ratios of autoimmune diseases according to type of infection.a
Any autoimmune disease Thyrotoxicosis Autoimmune thyroiditis Type 1 diabetes Primary andrenocortical insufficiency Celiac disease Pernicious anemia Autoimmune hemolytic anemia Idiopathic thrombocytopenic purpura Multiple Sclerosis Idiopathic polyneuritis Iridocyclitis Granulomatosis with polyangiitis Crohn’s disease Ulcerative colitis Primary biliary cirrhosis Pemphigoid Pemphigus Psoriasis vulgaris Alopecia areata Vitiligo Seropositive rheumatoid arthritis Dermatopolymyositis Polymyalgia rheumatica Myasthenia gravis Scleroderma Systemic lupus erythematosus Sjogren’s syndrome Juvenile arthritis Ankylosing spondylitis a
Bacterial
Viral
Other
Incidence rate ratio (95% CI)
Incidence rate ratio (95% CI)
Incidence rate ratio (95% CI)
1.71 1.32 1.28 2.36 3.00 1.52 1.72 1.82 1.63 1.27 2.18 1.55 2.00 2.60 1.50 2.46 2.37 2.45 1.82 1.81 1.55 1.63 1.99 1.64 1.35 2.17 2.22 2.24 2.21 1.66
1.59 1.25 1.29 1.79 3.33 1.92 1.41 2.25 1.61 1.55 1.70 1.63 2.10 1.87 1.39 2.94 1.90 2.48 1.72 2.00 1.59 1.52 2.01 1.43 2.05 2.46 2.40 2.70 1.60 1.54
1.57 1.31 1.44 1.80 3.51 1.93 1.96 2.10 1.54 1.21 1.77 1.84 2.74 2.04 1.41 1.95 1.99 1.78 1.57 1.57 1.59 1.57 1.74 1.81 1.49 2.01 2.38 2.70 1.56 1.56
(1.69,1.74) (1.27,1.37) (1.17,1.40) (2.29,2.43) (2.51,3.58) (1.37,1.69) (1.46,2.01) (1.39,2.35) (1.44,1.85) (1.20,1.34) (1.92,2.48) (1.46,1.64) (1.60,2.49) (2.48,2.73) (1.44,1.56) (1.98,3.05) (1.65,3.33) (1.73,3.39) (1.74,1.91) (1.56,2.08) (1.30,1.84) (1.56,1.69) (1.61,2.44) (1.47,1.82) (1.06,1.70) (1.86,2.53) (1.99,2.47) (2.01,2.50) (2.00,2.43) (1.51e1.82)
(1.55e1.62) (1.15,1.34) (1.10,1.49) (1.71,1.87) (2.56,4.28) (1.70,2.16) (1.03,1.88) (1.54,3.19) (1.39,1.85) (1.42,1.70) (1.37,2.08) (1.49,1.79) (1.43,2.98) (1.74,2.01) (1.31,1.47) (1.97,4.24) (0.99e3.34) (1.55e3.80) (1.60e1.85) (1.67e2.38) (1.26e1.98) (1.41e1.64) (1.45e2.73) (1.11e1.82) (1.47e2.79) (1.89e3.15) (2.01e2.86) (2.20e3.28) (1.45e1.77) (1.33e1.78)
(1.55e1.60) (1.25,1.38) (1.30,1.58) (1.74,1.85) (2.94,4.16) (1.76,2.11) (1.66,2.32) (1.61,2.69) (1.37,1.72) (1.14,1.29) (1.55,2.03) (1.74,1.95) (2.22,3.38) (1.95,2.14) (1.36,1.47) (1.46,2.57) (1.32e2.91) (1.22e2.53) (1.49e1.65) (1.36e1.80) (1.35e1.86) (1.49e1.64) (1.39e2.17) (1.59e2.04) (1.17e1.88) (1.68e2.40) (2.11e2.68) (2.38e3.05) (1.43e1.69) (1.42e1.71)
Reference group people with no hospital contacts for an infection.
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P.R. Nielsen et al. / Journal of Autoimmunity xxx (2016) 1e6
between a range of serious infections and autoimmune diseases. The precise timing, location, magnitude and pathogen of the serious infection might all play an important role for the risk of developing an autoimmune disease. In our study we were able to control for the timing of the serious infection and although in a somewhat crude way the type of pathogen, bacterial or viral. As to the magnitude of the inflammation, all of the infections were severe enough to require hospitalization. Our study suggests that all infections requiring hospitalization increase the risk of developing autoimmune disease regardless of type of infection but in a time dependent manner. It is challenging to firmly prove that one or more pathogens are indeed involved in the initiation and/or propagation of the autoimmune destructive process. We observed a higher risk if the diagnosis of infection and autoimmune disease occurred around the same time. This suggests that the serious infection could be the final trigger of the immune response leading to the emergence of clinical autoimmune disease. However, this association between hospitalization for a serious infection in close proximity to the autoimmune diagnosis could be biased in at least two ways. First, symptoms of infection can mimic symptoms of autoimmune disease and thus give rise to first an infection diagnosis and later an autoimmune diagnosis. Second, many autoimmune diseases increase the risk of infection and an undiagnosed autoimmune disease could thus actually be the cause of the infections in close relation to the autoimmune diagnosis [14]. Thus, serious infections might accelerate a preexisting autoimmune condition to progress to clinical disease rather than directly initiate autoimmunity. We observed an increased risk of developing autoimmune diseases with increasing number of serious infections over a time span of more than 10 years. Autoantibodies also appear years before clinical symptoms increasing in concentration before diagnosis [15,16]. Thus multiple sequential infectious events might be required to propagate the aberrant immune activation and to target the autoimmune destruction to the affected organ. Patients with autoimmune disease and healthy individuals experience numerous pathogen infections during their lifetime. At the time of diagnosis most of these pathogens have been cleared from the system. We only had access to records of serious infections that involved hospital contact. However, most infections do not require hospital contact, and it is therefore entirely possible that rather than reflecting the presence or absence of infection, our data capture instances of clinically severe infection only. In other words, our results might not be generalizable to the type of infection that go untreated or are treated by a general practitioner, which would be milder forms of infections in most cases. Our results are in line with a study from Sweden that found exposure to infections during the first year of life to be risk factors for rheumatoid arthritis and juvenile idiopathic arthritis [4]. The study was based on infections obtained from registers. However, Sandberg et al. found that infections in general do not affect the risk for rheumatoid arthritis [6]. One explanation for the divergent findings could be that the infections studied by Sandberg et al. were based on self-reports and not leading to hospitalization while we studied severe infections leading to hospitalization. It has been suggested that certain pathogen infections might protect from adverse immune reactions [17e21], such as allergy and autoimmunity, rather than enhance it. We did not find any evidence of this for any of the autoimmune diseases. This could be due to the types of infections studied, we only included severe infections requiring hospitalization. Many drugs have been associated with drug-induced autoimmunity. The appearance of autoimmune diseases following exposure to many common pharmaceutical agents is a wellcharacterized phenomenon, for example drugs that induce lupus.
5
It should be emphasized that such lupus-like syndromes become reversible when drugs are discontinued. However, there remains the possibility that the autoimmune disease may persist in some patients and it is very difficult if not impossible to identify a specific trigger in such individuals by epidemiological analysis. Thus, it is possible that some of the cases diagnosed with autoimmune disease could be influenced by drug-induced autoimmunity. The potential impact of this bias is limited as drug-induced autoimmunity is a relatively rare occurrence. In addition, by modulating innate and adaptive immunity, the microbiota and nutrition (e.g.vitamin D, iodine and gluten) may also contribute to loss of tolerance. These limitations to our study, that we did not have access to use of pharmaceutical agents and information on nutrition, made it impossible for us to distinguish between conditions mimicking autoimmune disease and autoimmune disease. A strength of this study was the ability to adjust for family history of autoimmune diseases and Charlson Comorbidity Index. Family history of autoimmune disease or prior history with autoimmune disease, were major risk factors for developing an autoimmune disease, but when adjusting for this type of comorbidity the infection risk was not affected (results not shown). Likewise having been hospitalized for one of the diseases in the Charlson Comorbidiy Index was a major risk factor for developing autoimmune disease, but again did not affect the risk for infection. It remains a limitation to our study that we were not able to adjust for an important confounding factor smoking, as this factor is known to influence the risk of infections and of certain autoimmune diseases. 5. Conclusions Our study reveals that infections are associated with the development of autoimmune diseases in a large general population. Acknowledgements This study was supported by the Lundbeck Foundation. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.jaut.2016.05.013. References [1] J.K. Olson, J.L. Croxford, S.D. Miller, Virus-induced autoimmunity: potential role of viruses in initiation, perpetuation, and progression of T-cell-mediated autoimmune disease, Viral Immunol. 14 (2001) 227e250. [2] P. Sfriso, A. Ghirardello, C. Botsios, M. Tonon, M. Zen, N. Bassi, et al., Infections and autoimmunity: the multifaceted relationship, J. Leukoc. Biol. 87 (2010) 385e395. [3] D.R. Getts, E.M. Chastain, R.L. Terry, S.D. Miller, Virus infection, antiviral immunity, and autoimmunity, Immunol. Rev. 255 (2013) 197e209. [4] C. Carlens, L. Jacobsson, L. Brandt, S. Cnattingius, O. Stephansson, J. Askling, Perinatal characteristics, early life infections and later risk of rheumatoid arthritis and juvenile idiopathic arthritis, Ann. Rheum. Dis. 68 (2009) 1159e1164. [5] J.R. Kerr, The role of parvovirus B19 in the pathogenesis of autoimmunity and autoimmune disease, J. Clin. Pathol. 69 (2015) 279e291. [6] M.E. Sandberg, C. Bengtsson, L. Klareskog, L. Alfredsson, S. Saevarsdottir, Recent infections are associated with decreased risk of rheumatoid arthritis: a population-based case-control study, Ann. Rheum. Dis. 74 (2015) 904e907. [7] R.J. Ball, A. Avenell, L. Aucott, P. Hanlon, M.A. Vickers, Systematic review and meta-analysis of the sero-epidemiological association between Epstein-Barr virus and rheumatoid arthritis, Arthritis Res. Ther. 17 (2015) 274. [8] C.B. Pedersen, H. Gotzsche, J.O. Moller, P.B. Mortensen, The Danish Civil Registration System. A cohort of eight million persons, Dan. Med. Bull. 53 (2006) 441e449. [9] T.F. Andersen, M. Madsen, J. Jorgensen, L. Mellemkjoer, J.H. Olsen, The Danish National Hospital Register. A valuable source of data for modern health sciences, Dan. Med. Bull. 46 (1999) 263e268.
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Please cite this article in press as: P.R. Nielsen, et al., Infections as risk factor for autoimmune diseases e A nationwide study, Journal of Autoimmunity (2016), http://dx.doi.org/10.1016/j.jaut.2016.05.013