The Open Rheumatology Journal




ISSN: 1874-3129 ― Volume 13, 2019

Infections Are Not Increased in Scleroderma Compared to Non-Inflammatory Musculoskeletal Disorders Prior to Disease Onset



Janet E Pope*, Jodi L Goodwin, Janine M Ouimet, Adriana Krizova, Matthew Laskin
Division of Rheumatology, Department of Medicine, The University of Western Ontario, London, Canada

Abstract

The etiology of scleroderma (SSc) is unknown; immunogenic stimuli such as infections and vaccinations could theoretically be risk factors for scleroderma. Our objective was to assess the relationship between viral and bacterial infec-tions, and vaccinations, prior to diagnosis of SSc compared to non-inflammatory controls. Methods: A questionnaire was sent to individuals with SSc (n =83) and controls (n=351) with non-inflammatory musculoskeletal (MSK) disorders (os-teoarthritis, n = 204; tendonitis, n = 58; fibromyalgia, n= 89) from a rheumatology practice. Questions ascertained past in-fections, exposure to infectious agents and vaccination history. Results: The response rate was 78% (SSc) and 56% (MSK controls). The mean age was 56 ± 1.6 (SSc) and 58 ± 0.9 (MSK); 88% (SSc) and 82% (MSK) were female. No association between prior infections and SSc was observed. In fact, controls were more likely than SSc subjects to report any infec-tion within 1-year prior to disease diagnosis (35% vs. 16%, p<0.006), or to have suffered a trauma to affected joints prior to diagnosis (44% vs. 19%, p<0.0002). Within the 1-year prior to disease diagnosis, controls reported slightly more strep-tococcal infections (p<0.2), infections with diarrhea and vomiting (p<0.3), and antibiotic use (p<0.09), although none of these results were statistically significant. Histories of any hepatitis, rubella, any bacterial infection, and having had a pre-vious positive tuberculosis skin test were not significantly different between groups and were actually more often reported by the control subjects. SSc reported slightly more hepatitis B (p<0.08), more rheumatic fever (p<0.8) in past, and herpes zoster (p<0.4), although no differences reached significance. Conclusion: This study does not support that self-report of symptomatic infections are more likely to occur ever (prior to diagnosis) or within 1-year prior to symptom onset of SSc, or that vaccinations in adulthood trigger SSc.

Keywords: Scleroderma, etiology, infectious triggers, bacterial infections, viral infections, vaccinations..


Article Information


Identifiers and Pagination:

Year: 2007
Volume: 1
First Page: 12
Last Page: 17
Publisher Id: TORJ-1-12
DOI: 10.2174/1874312900701010012

Article History:

Received Date: 28/9/2007
Revision Received Date: 26/10/2007
Acceptance Date: 28/10/2007
Electronic publication date: 8/11/2007
Collection year: 2007

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2007 Bentham Science Publishers Ltd.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.5/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.


* Address correspondence to this author at the Division of Rheumatology, Department of Medicine, The University of Western Ontario, London, Canada; E-mail: janet.pope@sjhc.london.on.ca




INTRODUCTION

Systemic sclerosis (SSc) is a connective tissue disorder characterized by excessive deposition of collagen in the skin and multiple internal organs [1Seibold JR. Connective tissue diseases characterized by fibrosis In: Kelley W, Ruddy S, Harris ED, Jr., Sledge C, Eds. Textbook of Rheumatology . 5th Edn. Toronto WB: Saunders Company 1997; pp. 1133-60.]. There is some debate as to whether SSc is primarily an autoimmune disease or whether a positive ANA test is an epiphenomenon of the condition. Thus far, immunosuppressive agents have not been very successful in treating SSc [2Pope JE. What causes scleroderma? CRAJ 2001; 11(3): 3-4.]. The etiology of scleroderma remains unknown, though both genetic and environmental factors have been implicated [3Thompson AE, Pope JE. Increased prevalence of scleroderma in southwestern Ontario: a cluster analysis J Rheumatol 2002; 29(9): 1867-73.]. Reports of familial occurrences of SSc are infrequent, but can occur, and studies investigating an underlying genetic predisposition have used serological techniques to suggest linkages between SSc and HLA-A1;B8;DR3;DR52 haplotypes in certain ethnic populations such as the Choctaw Indians in Oklahoma and Japanese subjects [4Arnett FC, Howard RF, Tan F, et al. Increased prevalence of systemic sclerosis in a Native American tribe in Oklahoma Arthritis Rheum 1996; 39: 1362-70.]. Furthermore, major histocompatibility complex (MHC) analyses have revealed strong associations of HLA class II alleles with serologically and clinically defined subsets of SSc [1Seibold JR. Connective tissue diseases characterized by fibrosis In: Kelley W, Ruddy S, Harris ED, Jr., Sledge C, Eds. Textbook of Rheumatology . 5th Edn. Toronto WB: Saunders Company 1997; pp. 1133-60.,5Arnett FC. HLA and autoimmunity in scleroderma (systemic sclerosis) Int Rev Immunol 1995; 12(2-4): 107-28.].

Early case studies described SSc and acid-fast bacterial infections [6Cantwell AR Jr., Kelso DW. Acid-fast bacteria in scleroderma and morphea Arch Dermatol 1971; 104(1): 21-5.-8Cantwell AR Jr. Autopsy findings of nonacid-fast bacteria in scleroderma Dermatologica 1980; 160(2): 90-.]. We could also postulate an altered immune system or unknown co-factor increasing the risk of both tuberculosis (TB) and SSc. Circumstantial evidence for a probable infectious cause (via an immune cross-reactivity mechanism where increased activation of a gene regulating the synthesis of a heat shock protein (HSP) in SSc fibroblasts) has been described [9Smiley JD, Hoffman WL. The role of infections in the rheumatic diseases: molecular mimicry between bacterial and human stress proteins? Am J Med Sci 1991; 301(2): 138-49.]. Others reported that bacterial HSPs and serum antibodies to Mycobacterium tuberculosis(MTB) HSP65 were present in 47% of SSc patients examined [10Danieli MG, Candela M, Ricciatti AM. Antibodies to mycobacterial 65 kDa heat shock protein in systemic sclerosis J Autoimmunity 1992; 5(4): 443-52.]. A SSc-RA overlap syndrome patient with Mycobacterium kansassi pulmonary infection showed improvement in both clinical symptoms and serum levels of IgM-RF and anti-mycobacterial HSP65 with anti-tuberculosis treatment [11Iwata H, Kinoshita M, Sumiya M. Emergence of erosive polyarthritis coincident with mycobacterium kansassi pulmonary infection in a patient with systermic sclerosis-rheumatoid arthritis overlap syndrome Clin Exp Rheumatol 1999; 17(6): 757-8.]. Similarly, regression of skin changes in a patient with SSc following treatment for bacterial overgrowth with chronic ciprofloxacin has been reported [12Over KE, Bucknall RC. Regression of skin changes in a patient with systemic sclerosis following treatment for bacterial overgrowth with ciprofloxacin Br J Rheumatol 1998; 37: 696-706.]. The high homology between the microbial and human HSP65 proteins support a connection exists between tuberculosis and the development of SSc [10Danieli MG, Candela M, Ricciatti AM. Antibodies to mycobacterial 65 kDa heat shock protein in systemic sclerosis J Autoimmunity 1992; 5(4): 443-52., 13Roddy J, Holtby S, Seigel S. Scleroderma concurrent with culture proven tuberculosis in a Japanese Canadian patient J Rheumatol 1996; 23(12): 2168-70.]. There are Canadian, Russian and Norwegian cases describing temporal presentations of TB and SSc [13Roddy J, Holtby S, Seigel S. Scleroderma concurrent with culture proven tuberculosis in a Japanese Canadian patient J Rheumatol 1996; 23(12): 2168-70.-15Frostad S, Vandbakk O. Case of scleroderma and pulmonary tuberculosis Tidsskr Nor Laegeforen 1966; 86(17): 1196-8.]. However, the majority of SSc patients do not have TB.

Various viruses, most prominently herpes and retroviruses, have been described with SSc [16Douvas A, Sobelman S. Multiple overlapping homologies between two rheumatoid antigens and immunosuppressive viruses Proc Natl Acad Sci USA 1991; 88(14): 6328-32.-21Neidhart M, Kuchen S, Distler O, et al. Increased serum levels of antibodies against human cytomegalovirus and prevalence of autoantibodies in systemic sclerosis Arthritis Rheum 1999; 42(2): 389-92.]. One study found amino acid sequence homologies between both HIV-1 and HSV-1 proteins and autoimmune nuclear antigens, suggesting that co-expression of heterologous viruses having common immunosuppressive functions may generate auto-antibodies cross-reacting with certain nuclear proteins [16Douvas A, Sobelman S. Multiple overlapping homologies between two rheumatoid antigens and immunosuppressive viruses Proc Natl Acad Sci USA 1991; 88(14): 6328-32.]. In 1979, there was a report of varicella occurring prior to diagnosis in a patient with SSc [18Spirer Z, Hie B, Pick IA, Yaron M. Localized scleroderma following varicella in a three-year-old girl with IgA deficiency Acta Paediatr Scand 1979; 68(5): 83-5.], although a later study found the frequency of varicella in SSc patients to be lower than that found in SLE patients (9.5% vs. 46.6%) [22Ishikawa O, Abe M, Miyachi Y. Herpes zoster in Japanese patients with systemic lupus erythematosus Clin Exp Dermatol 1999; 24(4): 327-8.]. Evidence of previous mononucleosis infection over a period of three years in 4 of 5 children suffering from localized SSc has been reported [17Longo F, Saletta S, Lepore L, Pennesi M. Localized scleroderma after infection with Epstein-Barr virus Clin Exp Rheumatol 1993; 11(6): 681-3.], and another study reported anti-fibrillarin antibodies in 58% of SSc patients and found that sequence homologies between fibrillarin, herpes virus type 1 and EBV proteins were suggestive of the notion that molecular mimicry may have played an important role in the induction of the antibodies [23Kasturi KN, Hatakeyama A, Spiera H, Bona CA. Antifibrillarin autoantibodies present in systemic sclerosis and other connective tissue diseases interact with similar epitopes J Exp Med 1995; 181(3): 1027-36.]. Elevated levels of IgG antibodies to CMV and EBV titers have been found in patients with SSc [21Neidhart M, Kuchen S, Distler O, et al. Increased serum levels of antibodies against human cytomegalovirus and prevalence of autoantibodies in systemic sclerosis Arthritis Rheum 1999; 42(2): 389-92.]. Vaughan et al assayed SSc EBV and CMV in subjects with limited and diffuse SSc after observing that autoantibodies to the autoantigen p542 (presumed to be derived from the EBV antigen) occur in both mononucleosis and in SSc. Anti-CMV titers were significantly higher in the anti-p542 positive SSc patients than they were in anti-p542 negative patients. Anti-EBV titers were not different between those positive vs. negative for anti-p542, but were higher in all SSc groups than in a healthy control group, p<0.02. However, although CMV and EBV findings were not significantly different in skin biopsies from 13 SSc and 17 controls, investigators concluded that the incidence of the viruses was high, and they may be related to the process involved in the initiation of autoimmunity in SSc [24Vaughn JH, Shaw PX, Nguyen M-D. Evidence of activation of 2 herpes viruses, Epstein-Barr virus and cytomegalovirus in systemic sclerosis and normal skins J Rheumatol 2000; 27(3): 821-3.].

Borrelia burgdorferi (Bb) has been implicated in generalized morphea [25Nakashima T, Maeda M, Havashi T, Kitamura K. A case of generalized morphea with a high titer of anti-Borrelia burgdorferi antibodies J Dermatol 1999; 26(12): 821-4.]. Additionally, an earlier study found 38% of seropositive (n=5) and 23% of seronegative (n=26) patients with morphea exhibited elevated B.burgdorferi induced lymphocyte proliferation, supporting a causal role, at least for some patients with morphea [26Breier P, Klade H, Stanek G. Lymphoproliferative responses to Borrelia burgdorferi in circumscribed scleroderma Br J Dermatol 1996; 134(2): 285-91.]. One study in Western Turkey (n=10 subjects with morphea and n=12 subjects with lichen sclerosus) found the presence of Bb DNA in 30% of morphea and 50% of lichen sclerosus patients suggesting a potential role in both conditions [27Ozkan S, Atabey N, Fetil E, Erkizan V, Gunes AT. Evidence for Borrelia burgdorferi in morphea and lichen sclerosus Int J Dermatol 2000; 39(4): 278-83.]; whereas, another study conducted in the U.S.A. (n = 35) did not find Bb spirochete in the pathogenesis of morphea and lichen sclerosus [28De Vito JR, Merogi AJ, Vo T. Role of Borrelia burgdorferi in the pathogenesis of morphea/scleroderma and lichen sclerosus et atrophicus: a PCR study of thirty-five cases J Cutan Pathol 1996; 23(4): 350-8.]. A more recent study reviewing the causal role of Bb in morphea concluded that previous conflicting results of European and American scientists could either be due to the fact that Bb is not a causative agent for morphea or that a subset of morphea is caused by a special subspecies of Bb present in Europe and Asia but not the U.S.A [29Weide B, Walz T, Garbe C. Is morphea caused by Borrelia burgdorderi?A review Br J Dermatol 2000; 142(4): 636-44.].

The evidence surrounding the potential importance of retroviruses in SSc is contradictory. One study of antibodies to retroviral proteins in SSc found that 8 of 29 SSc patients had antibodies to HIV proteins [20Haustein UF, Pustowoit B, Krusche U, Herrmann K. Antibodies to retrovirus proteins in scleroderma Acta Derm Venereol 1993; 73(2): 116-8.]. It was unclear whether a retrovirus was involved in the pathogenesis of SSc or whether the antibodies cross-reacted (molecular mimicry). Studies by Jimenez et al have demonstrated the ability of endogenous retroviruses to be expressed into proteins which can regulate cellular functions and lead to the occurrence of pathological conditions, but no conclusive evidence supporting pathogenesis for retroviruses in SSc was found [30Jimenez BA, Batuman O. Immunopathogenesis of systemic sclerosis: possible role of retroviruses Automimmunity 1993; 16(3): 225-33., 31Jimenez BA, Diaz A, Khalili K. Retroviruses and the pathogenesis of systemic sclerosis Int Rev Immunol 1995; 12: 159-75.]. Other studies have found links with paramyxoviruses [32Hashimoto K, Thompson DF. Discoid lupus erythmatosus.Electron microscopic studies of paramyxovirus structures Arch Dermatol 1970; 101(5): 565-7.], congenital rubella [33Espanol T, Pascual C, Huguet P, Caragol I, Hernandez M, Bertran JM. Circumscribed scleroderma in congenital rubella syndrome with hypogammaglobulinemia Allergy 1998; 53(10): 005-6.], and parvovirus B19 [34Ferri C, Zakrzewska K, Longombardo G. Parvovirus B19 infection of bone marrow in systemic sclerosis patients Clin Exp Rheumatol 1999; 17(6): 18-20.].

In light of the existing body of research, it was expected that SSc patients would report more infections than a comparison group with non-inflammatory musculoskeletal (MSK) complaints prior to diagnosis, particularly in the 12 months prior to symptom onset. This study was designed to test if the self-reported frequency of certain infections and vaccinations was different between SSc and control groups, but also as an exploratory study to determine any potential infectious triggers (such as viruses or bacteria) that could be studied in greater depth in future research.

MATERIALS AND METHODOLOGY

A five-page questionnaire consisting of 23 questions was developed to assess: whether subjects had ever had specific infections; whether they had had any infection or antibiotic exposure 12 months prior to their SSc diagnosis; travel history (and any associated illnesses) outside of North America in the 12 months preceding; vaccine history since 18 years of age; and whether or not they had ever been positive for a TB skin test. Specific questions addressed rubella, parvovirus, and herpes infections as well as rheumatic fever, illnesses that induced rash or fever, and previous hepatitis A, B and C exposure. The questionnaire was approved by the University of Western Ontario Health Sciences Research Ethics Board and it was pre-tested on clinic patients (controls) to ensure that it was understandable and that no consistent misinterpretations were being made. The questionnaire had been validated previously in a study of systemic lupus erythematosus (SLE) patients in the same rheumatology practice, which reported an increased frequency of herpes zoster clustered around the time of diagnosis with SLE [35Pope JE, Krizova A, Ouimet JM, Goodwin JL, Laskin MD. Close association of herpes zoster reactivation and systemic lupus erythematosus (SLE) diagnosis: case control study of patients with SLE or non-inflammatory musculoskeletal disorders J Rheumatol 2004; 31(2): 274-9.].

The rheumatologist who conducted this research, based in London, Ontario, is a clinical expert in scleroderma servicing Southwestern Ontario. Referrals are from a large population base of approximately one million, but also from more geographically remote northern areas. Although many of the SSc cases from the referral catchment area are seen in the London clinic, not all cases will be recognized and referred to tertiary care, and other cases may be followed elsewhere. The challenge of obtaining a representative study sample of SSc from clinical cohorts has been described in the literature and although estimates vary, it is generally accepted that less severe cases will generally be under-represented [36Mayes M, Lacey JV Jr., Beebe-Dimmer J. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population Arthritis Rheum 2003; 48(8): 2246-55.-38MichetCJ Jr, McKenna CH, Elveback LR. Epidemiology of systemic lupus erythematosus and other connective tissue disease in Rochester, Minnesota, 1950 through 1979 Mayo Clin Proc 1985; 60: 105-3.].

Patient selection was completed using the computerized billing system to identify all patients who had been seen in the clinic for SSc over the past 2 years and who were current patients with accurate addresses. Controls with non-inflammatory musculoskeletal disorders were subsequently chosen at a ratio of 4 controls:1 SSc patient using the same method (a billing list based on date of last clinic visit who had been seen for non-inflammatory MSK conditions). Controls were over-sampled as it was expected that the response rate would be less. The questionnaire was sent to scleroderma subjects (n=83, cases) and control subjects (n=351), who had non-inflammatory MSK disorders such as osteoarthritis (n=204), tendonitis (n=58) and fibromyalgia (n=89), from the same practice.

All subjects were blinded as to the hypothesis and were sent questionnaire packages that included a stamped return addressed envelope, a letter of information and the questionnaire. Written informed consent was obtained from the study participants. Data were entered and statistical analyses were performed using SAS-based JMP statistical software (Version 4.0) [39SAS Institute Inc Cary NC USA. JMP Statistical Software - Version 4, 2000.]. Trends in survey responses were studied. For each survey question, responses of uncertainty were excluded from the analyses. Group means, odds ratios and 95% confidence intervals were calculated for exposures of interest.

In order to further characterize the SSc cohort of subjects a post hoc chart review was conducted to obtain information on type of SSc (limited vs. diffuse), disease duration, age at diagnosis with SSc, and the Modified Rodnan skin score (MRSS) (MRSS ranges from 0 to 78 with lower scores representing less skin involvement) [40Giordano M, Ara M, Capelli L. Griseofulvin in scleroderma In: Black CM, Myers AR, Eds. Systemic Sclerosis (Scleroderma)Gower Medical. New York: Gower Medical 1985; pp. 46-8.] and Health Assessment Questionnaire Disability Index (HAQ-DI) (HAQ-DI ranges from 0-3 with higher scores indicating more functional disability) [41Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis Arthritis Rheum 1980; 23: 137-45.].

RESULTS

The response rate in the SSc group was 78% (n=65) and in the controls it was 56% (n=196).As can be seen in Table 1, the mean age was 56 ± 1.6 in the SSc group and 58 ± 0.9 in the controls (MSK); 88% and 82% were female in the SSc and MSK groups. The SSc group was comprised of 37% diffuse SSc, had a mean overall MRSS score of 9.5 ± 1.63, and a mean HAQ-DI score of 1.12 ±0.106 (Table 2). The mean disease duration for the SSc group was 9.75 ± 0.53 years, and the mean age of diagnosis was 50.05 ± 1.64 years old (Table 2). Patients were primarily Caucasian; a very few were Native Canadian, Asian or African Canadians.

Table 1

Demographic Factors for Subjects with SSc or Non-Inflammatory MSK Disorders. Given as Percentage (N = Total Num-ber of Subjects who Responded, with Missing Data Excluded)




Table 2

Characteristics of the Subjects in the London, Ontario SSc Cohort who Responded to the Study Questionnaire. Given as Mean ± SEM or as Percentage (Where Applicable). The Total Number of Subjects for whom a Measurement of the Characteristic was Available has been Indicated in Parentheses.




Table 3

Infections, Vaccinations and/or Trauma Experienced (Ever) Prior to Diagnosis, or One-Year Prior to Diagnosis of SSc/Non-Inflammatory MSK Disorder. Given as Percentage (N).




MRSS and HAQ-DI values were determined by subsequent chart review to further characterize the cohort of SSc subjects who responded to this research questionnaire. Scores were available for only 28 and 45, respectively, of the 65 subjects who participated in the research study.

The data in Table 3 show that no association between recalled symptomatic prior infections and scleroderma was observed. For several types of infections numbers were small and results were not statistically significant, and thus, there were no meaningful differences in reported infections between the cases and controls. Frequencies in controls compared to SSc cases included: hepatitis A (3% vs. 1.6%, p=0.6), hepatitis B (0% vs. 1.6%, p=0.08), hepatitis C (2% vs. 1.6%, p=0.8), hepatitis of any kind (including any of A, B, C or if unable to recall which type; 7% vs. 5%, p=0.4), rubella (58% vs. 51%, p=0.4), any bacterial infection (78% vs. 68%, p=0.1), positive tuberculosis skin test (13% vs. 8%, p=0.2), past rheumatic fever (7% vs. 8%, p=0.8), and herpes zoster prior to disease diagnosis (8% vs. 12%, p=0.4). Subjects with non-inflammatory MSK disorders were significantly more likely to report a previous joint trauma (44% vs. 19%, p=0.0002), and this finding was used as internal validation where those with non-inflammatory MSK conditions should have more preceding trauma.

Data focusing on the 12-month period prior to diagnosis of SSc or non-inflammatory MSK disorders demonstrated that controls were significantly more likely than SSc subjects to report having experienced any infection within the 12 months prior to disease diagnosis (35% vs. 16%, p<0.006). Controls reported that within the year prior to disease diagnosis, they had an increased occurrence of: streptococcal infections (13% vs. 8%, p<0.3), infections with diarrhea and vomiting (15% vs. 10%, p<0.3), and antibiotic use (50% vs. 34%, p<0.09), although none of these questions were statistically significant (Table 3).

DISCUSSION

We found no trends of increased self-reported infection in SSc prior to symptom onset compared to controls. In contrast to the literature, our findings did not support that more subjects with SSc had been exposed to TB, but the prevalence of TB exposure was very low in our series. We did not have Lyme disease in either the cases or the controls, as it is rare in Southwestern Ontario. Since there were no signals of increased infections we did not subset our patients into diffuse and limited, as exploratory analyses were not warranted. However, patients with limited SSc may have a long time between first symptoms and diagnosis.

Consistent with the concept that herpes family viruses may be involved in the development of autoimmunity without being the specific triggering event, we have also reported a temporal clustering of varicella zoster virus (VZV) reactivation around the time of disease diagnosis in patients with systemic lupus erythematosus, whereby VZV infections were clustered just prior to or after diagnosis in SLE but were more widely temporally spaced in the controls (the mean time until VZV reactivation in SLE subjects was 1 ± 4.5 years after the diagnosis of SLE, compared to controls which was 14.7 ± 4 years before the diagnosis of non-inflammatory MSK disorder; p<0.003) [35Pope JE, Krizova A, Ouimet JM, Goodwin JL, Laskin MD. Close association of herpes zoster reactivation and systemic lupus erythematosus (SLE) diagnosis: case control study of patients with SLE or non-inflammatory musculoskeletal disorders J Rheumatol 2004; 31(2): 274-9.]. However, no longitudinal study has demonstrated that a viral illness can increase the risk of scleroderma (2). Fifty SSc patients were negative for anti-HEV antibodies (all patients tested), suggesting that hepatitis E is not involved in the pathogenesis of SSc [42Ferri C, Longombardo G. Hepatitis E virus and systemic sclerosis Q J Med 1998; 91: 375-6.].

This case control survey study provided no evidence that the occurrence of infectious events (either bacterial or viral) was more common in the one-year period prior to the development of SSc compared to controls with non-inflammatory MSK conditions. In fact, the study controls were more likely to report having had a bacterial infection ever prior to diagnosis, or any infection in the one-year prior to disease diagnosis. Although it appears that there is no relationship between self-reported infectious exposures and the subsequent development of SSc, this relationship may be modified by genetics or other unknown factors. If this paradigm holds, then only certain susceptible people would develop SSc following exposure to an infectious agent. Thus, the rates of infections could be similar between the cases and controls, but the underlying genetics (or other unknown modifying factors) could alter the response to the infectious agent in a way that would result in the development of SSc only in those with a certain genetic complement. It is also possible that genetic factors, as well as several types of exogenous factors, could be required for scleroderma to develop, and hence infectious triggers may be involved in the etiology of SSc but exert an effect as part of a complicated process of disease development.

Our data do not support previous studies that found a causal link between infectious triggers and the subsequent development of SSc; but SSc patients were slightly (but not significantly) more likely than controls to report previous herpes zoster infections, and others have also observed this [2Pope JE. What causes scleroderma? CRAJ 2001; 11(3): 3-4.]. A case control study using objective evidence of past infection with herpes zoster will be needed to clarify the link between the two. Given that IgG antibodies have been found at increased levels in certain herpes viruses in scleroderma [2Pope JE. What causes scleroderma? CRAJ 2001; 11(3): 3-4.], and herpes viruses have been detected in SSc patients in several case studies [18Spirer Z, Hie B, Pick IA, Yaron M. Localized scleroderma following varicella in a three-year-old girl with IgA deficiency Acta Paediatr Scand 1979; 68(5): 83-5., 22Ishikawa O, Abe M, Miyachi Y. Herpes zoster in Japanese patients with systemic lupus erythematosus Clin Exp Dermatol 1999; 24(4): 327-8.], and that studies have found sequence homologies between herpes virus and endogenous proteins [21Neidhart M, Kuchen S, Distler O, et al. Increased serum levels of antibodies against human cytomegalovirus and prevalence of autoantibodies in systemic sclerosis Arthritis Rheum 1999; 42(2): 389-92.], the possible association between herpes viruses and SSc merits further research.

This study has limitations. These include the lower response rate in the control group, and that recall bias may have occurred. The differential response rate in the controls is likely due to the fact that the SSc patients in this cohort were followed regularly (usually twice a year), whereas many OA or other non-inflammatory patients are seen less often (if followed at all) and may be less apt to complete a questionnaire. Additionally, those with SSc (especially diffuse SSc) may attach more importance to research to identify the etiology of their potentially life-threatening disease compared to patients with OA or other MSK conditions who may have been told that their disease has at least partially been caused by trauma or “wear and tear” of joints.

Further limitations included that this retrospective study had patients remember infections 1-year prior to diagnosis, which may have occurred (on average) more than nine years ago. However, patients often search for answers and may over interpret events that occurred prior to disease onset, so the bias should have been that more infections were found in the SSc group due to a diagnosis of a serious disease. Patients may have misinterpreted survey questions, but this should not have been different between the two groups. If there was recall bias, we would have expected it to occur in favour of our hypothesis of increased infection in SSc; however, this was not the case. Additionally, asymptomatic infections would not be reported in either group. Diagnostic and viral serologic tests were not done. However, past research has been conducted for which self-report of medical conditions by subjects with SSc has been validated [43Hans GK, Pope J. Validity of a self-report questionnaire about osteoporosis used in a case control study of subjects with scleroderma, rheumatoid arthritis, and non-inflammatory musculoskeletal disease J Rheumatol 2004; 31(7): 1446.].

CONCLUSION

Self-report of infections prior to diagnosis in SSc is not increased compared to non-inflammatory controls. This study does not support that self-report of symptomatic infections are more likely to occur prior to diagnosis ever or within 1-year prior to symptom onset of SSc, or that vaccinations in adulthood trigger SSc.

REFERENCES

[1] Seibold JR. Connective tissue diseases characterized by fibrosis In: Kelley W, Ruddy S, Harris ED, Jr., Sledge C, Eds. Textbook of Rheumatology . 5th Edn. Toronto WB: Saunders Company 1997; pp. 1133-60.
[2] Pope JE. What causes scleroderma? CRAJ 2001; 11(3): 3-4.
[3] Thompson AE, Pope JE. Increased prevalence of scleroderma in southwestern Ontario: a cluster analysis J Rheumatol 2002; 29(9): 1867-73.
[4] Arnett FC, Howard RF, Tan F, et al. Increased prevalence of systemic sclerosis in a Native American tribe in Oklahoma Arthritis Rheum 1996; 39: 1362-70.
[5] Arnett FC. HLA and autoimmunity in scleroderma (systemic sclerosis) Int Rev Immunol 1995; 12(2-4): 107-28.
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[11] Iwata H, Kinoshita M, Sumiya M. Emergence of erosive polyarthritis coincident with mycobacterium kansassi pulmonary infection in a patient with systermic sclerosis-rheumatoid arthritis overlap syndrome Clin Exp Rheumatol 1999; 17(6): 757-8.
[12] Over KE, Bucknall RC. Regression of skin changes in a patient with systemic sclerosis following treatment for bacterial overgrowth with ciprofloxacin Br J Rheumatol 1998; 37: 696-706.
[13] Roddy J, Holtby S, Seigel S. Scleroderma concurrent with culture proven tuberculosis in a Japanese Canadian patient J Rheumatol 1996; 23(12): 2168-70.
[14] Ozerova LV, Zhuravleva OA. A case of systemic scleroderma in a patient with pulmonary tuberculosis Klin Med (Mosk) 1966; 44(7): 135-6.
[15] Frostad S, Vandbakk O. Case of scleroderma and pulmonary tuberculosis Tidsskr Nor Laegeforen 1966; 86(17): 1196-8.
[16] Douvas A, Sobelman S. Multiple overlapping homologies between two rheumatoid antigens and immunosuppressive viruses Proc Natl Acad Sci USA 1991; 88(14): 6328-32.
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