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Increased Risk for Non-Hodgkin Lymphoma in Individuals With Celiac Disease and a Potential Familial Association

  • Ying Gao
    Correspondence
    Address requests for reprints to: Dr Ying Gao, Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Bldg. EPS/Room 7016, NIH/NCI, Bethesda, MD 20892-7236. fax: (301) 402-4489
    Affiliations
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Sigurdur Y. Kristinsson
    Affiliations
    Department of Medicine, Division of Hematology, Karolinska University Hospital Solna and Institutet, Stockholm, Sweden
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  • Lynn R. Goldin
    Affiliations
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Magnus Björkholm
    Affiliations
    Department of Medicine, Division of Hematology, Karolinska University Hospital Solna and Institutet, Stockholm, Sweden
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  • Neil E. Caporaso
    Affiliations
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Ola Landgren
    Affiliations
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

    Department of Medicine, Division of Hematology, Karolinska University Hospital Solna and Institutet, Stockholm, Sweden
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Published:September 26, 2008DOI:https://doi.org/10.1053/j.gastro.2008.09.031

      Background & Aims

      Celiac disease (CD), a common digestive disease, is well known to be associated with excess non-Hodgkin lymphoma (NHL) risk. However, there are only limited data on risk in the current era of serologic testing and human leukocytes antigen typing to screen for CD. There is also no information on the role of family history of CD in relation to lymphoma risk.

      Methods

      We identified 37,869 NHL, 8323 Hodgkin lymphoma (HL), and 13,842 chronic lymphocytic leukemia patients diagnosed in Sweden between 1965 and 2004, as well as 236,408 matched controls and 613,961 first-degree relatives. Using logistic regression, we calculated odds ratios and 95% confidence intervals as measures of risks adjusted for matching factors.

      Results

      Overall we found persons with a hospital discharge diagnosis of CD to have a 5.35-fold (95% CI, 3.56–8.06) increased NHL risk. Risk of HL was borderline increased (OR = 2.54, 95% CI, 0.99–6.56); however, there was no excess chronic lymphocytic leukemia risk. Persons diagnosed with CD in 1975–1984, 1985–1994, and 1995–2004 had a 13.2-fold (95% CI, 3.63–48.0), 7.90-fold (95% CI, 3.38–18.5), and 3.84-fold (95% CI, 2.28–6.45) increased risk of NHL, respectively (Ptrend < .0001). Individuals with a sibling affected with CD had a 2.03-fold (95% CI, 1.29–3.19) increased NHL risk.

      Conclusions

      Persons with CD have an increased NHL risk; however, the excess risk has tapered off substantially in the last 4 decades. The observed excess NHL risk among individuals with a sibling affected with CD suggests shared susceptibility. Future studies are needed to explore the roles of gluten intake, secondary intestinal inflammation, and susceptibility genes in relation to subsequent risk of developing lymphoma.

      Abbreviations used in this paper:

      CD (celiac disease), HL (Hodgkin lymphoma), HLA (human leukocytes antigen), NHL (non-Hodgkin lymphoma), OR (odds ratio), CLL (chronic lymphocytic leukemia)
      See editorial on page 32.
      Celiac disease (CD) is characterized by a T-cell–mediated response to ingested wheat gluten and related proteins of rye and barley. This response leads to a chronic inflammation with autoimmune features typified by diffuse damage to the proximal small intestinal mucosa that results in malabsorption of most nutrients.
      • Ciclitira P.J.
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      • et al.
      The pathogenesis of coeliac disease.
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      • Cellier C.
      Celiac disease.
      The disease has a wide spectrum of clinical manifestations including diarrhea, abdominal distention, abdominal pain, weight loss, fatigue, malnutrition, and osteoporosis.
      • Green P.H.
      • Rostami K.
      • Marsh M.N.
      Diagnosis of coeliac disease.
      • Fasano A.
      Clinical presentation of celiac disease in the pediatric population.
      Celiac disease may also present with extraintestinal manifestations such as dermatitis herpetiformis, iron deficiency, and short stature.
      The gold standard for CD diagnosis is duodenal biopsy, showing characteristic, though not specific, intraepithelial lymphocytosis, crypt hyperplasia, and various degrees of villous height reduction, together with symptomatic and histological improvement on dietary gluten withdrawal. Today, in clinical practice, serologic testing (IgA anti human tissue transglutaminase and IgA endomysial antibody immunofluorescence) and human leukocytes antigen (HLA) typing (HLA-DQ1 and HLA-DQ8) are commonly used techniques with reported 90% sensitivity and specificity, to screen persons with a clinical suspicion for CD and to better identify candidates for intestinal biopsy.
      • Green P.H.
      • Rostami K.
      • Marsh M.N.
      Diagnosis of coeliac disease.
      As a consequence of these commonly available screening tools, today CD is considered one of the most common digestive diseases in humans, with an estimated prevalence of 1:100 to 1:300 in North America and Europe.
      • Ciclitira P.J.
      • Johnson M.W.
      • Dewar D.H.
      • et al.
      The pathogenesis of coeliac disease.
      • Fasano A.
      • Berti I.
      • Gerarduzzi T.
      • et al.
      Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study.
      Celiac disease is possibly affecting as many as 3 million Americans, or roughly 1% of the U.S. population. The only effective treatment to date is a gluten-free diet.
      For more than 70 years, it has been recognized that CD is associated with an increased risk of developing non-Hodgkin lymphoma (NHL).
      • Fairly N.
      • Mackie F.
      The clinical and biochemical syndrome in lymphoma and allied diseases involving the mesenteric lymph glands.
      Risks have been consistently reported to be highest for enteropathy-type T-cell lymphoma and B-cell NHL of the gut (odds ratios [ORs] over 10); however, extraintestinal lymphomas including Hodgkin lymphoma (HL) have also been observed.
      • Askling J.
      • Linet M.
      • Gridley G.
      • et al.
      Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis.
      • Goldacre M.J.
      • Wotton C.J.
      • Yeates D.
      • et al.
      Cancer in patients with ulcerative colitis, Crohn's disease and coeliac disease: record linkage study.
      Earlier studies reported CD to be associated with up to a 100-fold elevated risk of lymphoma.
      • Fasano A.
      • Catassi C.
      Current approaches to diagnosis and treatment of celiac disease: an evolving spectrum.
      • Leonard J.N.
      • Tucker W.F.
      • Fry J.S.
      • et al.
      Increased incidence of malignancy in dermatitis herpetiformis.
      However, more recent investigations, primarily focusing on the mid-1970s to the mid-1990s, have estimated the excess risk of lymphoma among persons with CD to be more modest, reflected in ORs ranging from 2 to 11 (Table 1).
      • Askling J.
      • Linet M.
      • Gridley G.
      • et al.
      Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis.
      • Goldacre M.J.
      • Wotton C.J.
      • Yeates D.
      • et al.
      Cancer in patients with ulcerative colitis, Crohn's disease and coeliac disease: record linkage study.
      • Anderson L.A.
      • McMillan S.A.
      • Watson R.G.
      • et al.
      Malignancy and mortality in a population-based cohort of patients with coeliac disease or “gluten sensitivity”.
      • Silano M.
      • Volta U.
      • Mecchia A.M.
      • et al.
      Delayed diagnosis of coeliac disease increases cancer risk.
      • Smedby K.E.
      • Hjalgrim H.
      • Askling J.
      • et al.
      Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype.
      • Mearin M.L.
      • Catassi C.
      • Brousse N.
      • et al.
      European multi-centre study on coeliac disease and non-Hodgkin lymphoma.
      • Viljamaa M.
      • Kaukinen K.
      • Pukkala E.
      • et al.
      Malignancies and mortality in patients with coeliac disease and dermatitis herpetiformis: 30-year population-based study.
      • Smedby K.E.
      • Akerman M.
      • Hildebrand H.
      • et al.
      Malignant lymphomas in coeliac disease: evidence of increased risks for lymphoma types other than enteropathy-type T cell lymphoma.
      • Card T.R.
      • West J.
      • Holmes G.K.
      Risk of malignancy in diagnosed coeliac disease: a 24-year prospective, population-based, cohort study.
      • West J.
      • Logan R.F.
      • Smith C.J.
      Malignancy and mortality in people with coeliac disease: population based cohort study.
      • Farre C.
      • Domingo-Domenech E.
      • Font R.
      • et al.
      Celiac disease and lymphoma risk: a multicentric case--control study in Spain.
      • Green P.H.
      • Fleischauer A.T.
      • Bhagat G.
      • et al.
      Risk of malignancy in patients with celiac disease.
      • Peters U.
      • Askling J.
      • Gridley G.
      • et al.
      Causes of death in patients with celiac disease in a population-based Swedish cohort.
      • Howdle P.D.
      • Jalal P.K.
      • Holmes G.K.
      • et al.
      Primary small-bowel malignancy in the UK and its association with coeliac disease.
      • Catassi C.
      • Fabiani E.
      • Corrao G.
      • et al.
      Risk of non-Hodgkin lymphoma in celiac disease.
      • Green P.H.R.
      • Stavropoulos S.N.
      • Panagi S.G.
      • et al.
      Characteristics of adult celiac disease in the USA: results of a national survey.
      • Cottone M.
      • Termini A.
      • Oliva L.
      • et al.
      Mortality and causes of death in celiac disease in a Mediterranean area.
      At this time, there are only sparse data available on the risk of lymphoma among patients diagnosed with CD using modern and widely available serologic testing and HLA typing. Indeed, to our knowledge, no large epidemiologic study has been carried out to define the association between CD and following lymphoma risk in the early 21st century, compared with a group of patients from the same population in earlier years. This is of clinical importance in that it allows us to establish the impact of early detection and treatment of CD in the context of lymphomagenesis.
      Table 1CD and Risk of Lymphomas in Selected Reported Studies
      LocationLymphoma cases, nCD cases, nPersonal history of CD and lymphoma riskStudy designStudy periodReference
      United Kingdom111997RR = 3.28
      P < .05.
      NHL
      Hospital-based cohort1963–1999Goldacre et al 2008
      • Goldacre M.J.
      • Wotton C.J.
      • Yeates D.
      • et al.
      Cancer in patients with ulcerative colitis, Crohn's disease and coeliac disease: record linkage study.
      RR = 5.07 HL
      United Kingdom2490SIR = 7.47
      P < .05.
      NHL
      Population-based cohort1993–1996Anderson et al 2007
      • Anderson L.A.
      • McMillan S.A.
      • Watson R.G.
      • et al.
      Malignancy and mortality in a population-based cohort of patients with coeliac disease or “gluten sensitivity”.
      Italy201968SIR = 4.7
      P < .05.
      NHL
      Population-based cohort1982–2005Silano et al 2007
      • Silano M.
      • Volta U.
      • Mecchia A.M.
      • et al.
      Delayed diagnosis of coeliac disease increases cancer risk.
      Denmark and Sweden305528OR = 2.1
      P < .05.
      NHL
      Population-based case-control
      • Denmark 2000–2002
      • Sweden 1999–2002
      Smedby et al 2006
      • Smedby K.E.
      • Hjalgrim H.
      • Askling J.
      • et al.
      Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype.
      10 European countries144666OR = 2.6
      P < .05.
      NHL
      Prospective, multicenter case-control1998–2001Mearin et al 2006
      • Mearin M.L.
      • Catassi C.
      • Brousse N.
      • et al.
      European multi-centre study on coeliac disease and non-Hodgkin lymphoma.
      Finland5781SIR = 3.2
      P < .05.
      NHL
      Population-based cohort1960–2000Viljamaa et al 2006
      • Viljamaa M.
      • Kaukinen K.
      • Pukkala E.
      • et al.
      Malignancies and mortality in patients with coeliac disease and dermatitis herpetiformis: 30-year population-based study.
      Sweden5611,650SIR = 6.6
      P < .05.
      NHL
      Population-based cohort1970–1995Smedy et al 2005
      • Smedby K.E.
      • Akerman M.
      • Hildebrand H.
      • et al.
      Malignant lymphomas in coeliac disease: evidence of increased risks for lymphoma types other than enteropathy-type T cell lymphoma.
      SIR = 1.0 HL
      United Kingdom12869SIR = 5.8
      P < .05.
      NHL
      Population-based cohort1978–2001Card et al 2004
      • Card T.R.
      • West J.
      • Holmes G.K.
      Risk of malignancy in diagnosed coeliac disease: a 24-year prospective, population-based, cohort study.
      United Kingdom234732HR = 4.8
      P < .05.
      lymphoma
      Population-based cohort1987–2002West et al 2004
      • West J.
      • Logan R.F.
      • Smith C.J.
      Malignancy and mortality in people with coeliac disease: population based cohort study.
      Spain2985OR = 0.62 lymphomaMulticenter case-control1998–2000Farre et al 2004
      • Farre C.
      • Domingo-Domenech E.
      • Font R.
      • et al.
      Celiac disease and lymphoma risk: a multicentric case--control study in Spain.
      USA9381SMR = 5.3-9.1
      P < .05.
      NHL
      Hospital-based cohort1981–2000Green et al 2003
      • Green P.H.
      • Fleischauer A.T.
      • Bhagat G.
      • et al.
      Risk of malignancy in patients with celiac disease.
      Sweden2210,032SMR = 11.4
      P < .05.
      NHL
      Population-based cohort1964–1993Peters et al 2003
      • Peters U.
      • Askling J.
      • Gridley G.
      • et al.
      Causes of death in patients with celiac disease in a population-based Swedish cohort.
      United Kingdom863737/86 lymphomaClinical registry-based cohort1998–2000Howdle et al 2003
      • Howdle P.D.
      • Jalal P.K.
      • Holmes G.K.
      • et al.
      Primary small-bowel malignancy in the UK and its association with coeliac disease.
      Italy6536OR = 3.1
      P < .05.
      NHL
      Multicenter case-control1996–1999Catassi et al 2002
      • Catassi C.
      • Fabiani E.
      • Corrao G.
      • et al.
      Risk of non-Hodgkin lymphoma in celiac disease.
      Sweden4411,019SIR = 6.3
      P < .05.
      NHL
      Population-based cohort1964–1994Askling et al 2002
      • Askling J.
      • Linet M.
      • Gridley G.
      • et al.
      Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis.
      SIR = 4.6* HL
      USA31612RR = 300 lymphomaNationwide cross-sectional survey1996–1997Green et al 2001
      • Green P.H.R.
      • Stavropoulos S.N.
      • Panagi S.G.
      • et al.
      Characteristics of adult celiac disease in the USA: results of a national survey.
      Italy62286/228 lymphomaHospital-based cohort1980–1997Cottone et al 1999
      • Cottone M.
      • Termini A.
      • Oliva L.
      • et al.
      Mortality and causes of death in celiac disease in a Mediterranean area.
      RR, relative risk; SIR, standardized incidence ratio; SMR, standardized mortality ratio.
      a P < .05.
      We have conducted a comprehensive population-based case-control study including over 60,000 lymphoma patients diagnosed in Sweden between 1965 and 2004, almost 240,000 frequency matched controls; and more than 750,000 linkable relatives of patients and controls. Because CD has been found to be associated with excess risk of extraintestinal lymphomas, we expanded our study to include all types of lymphomas (NHL, HL, and chronic lymphocytic leukemia [CLL]). The aim of our study was to quantify the secular trend of lymphoma risks among individuals with a prior diagnosis of CD. In particular, we were interested in assessing the relationship between CD and lymphoma during the past decade (1995–2004), in the era of commonly available serologic markers and HLA typing screening tools.
      • Fasano A.
      • Berti I.
      • Gerarduzzi T.
      • et al.
      Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study.
      • Catassi C.
      • Fabiani E.
      • Ratsch I.M.
      • et al.
      The coeliac iceberg in Italy A multicentre antigliadin antibodies screening for coeliac disease in school-age subjects.
      • Bonamico M.
      • Ferri M.
      • Mariani P.
      • et al.
      Serologic and genetic markers of celiac disease: a sequential study in the screening of first degree relatives.
      Furthermore, CD shows inherited predisposition where first-degree relatives have a 5%–10% risk of CD (depending on the screening method), the highest risk being found in siblings at risk with the HLA genotypes.
      • Rubio-Tapia A.
      • Van Dyke C.T.
      • Lahr B.D.
      • et al.
      Predictors of family risk for celiac disease: a population-based study.
      One could hypothesize that the association of lymphoma and CD is due to common genes predisposing to both conditions. This would predict aggregation of CD and lymphoma in the same families. To test this hypothesis, we tested for increased risk of lymphoma among individuals with a family history of CD.

      Methods

       Central Registries, Patients, Controls and First-Degree Relatives

      All residents of Sweden are, upon birth or immigration, assigned a unique national registration number that is used in government-maintained nationwide health care and population registers, whereby record linkage is possible with a high degree of accuracy. For each individual the date of death is centrally registered in the Swedish Cause of Death Registry.
      Since 1958, all physicians and pathologists/cytologists in Sweden are obligated by law to report each incident case of cancer that they diagnose and/or treat, to the centralized nationwide Swedish Cancer Registry. The Registry contains information on diagnosis, sex, date of birth, date of diagnosis, and region/hospital where the diagnosis was made.
      The National Board of Health and Welfare
      Cancer Incidence in Sweden 2001.
      In a recent validation study focusing on lymphoproliferative hematologic tumors diagnosed between 1964 and 2003, we found the completeness and the diagnostic accuracy of the Registry to be >90%–95%.
      • Turesson I.
      • Linet M.S.
      • Bjorkholm M.
      • et al.
      Ascertainment and diagnostic accuracy for hematopoietic lymphoproliferative malignancies in Sweden 1964-2003.
      In this study, we identified all living incident patients diagnosed from January 1, 1965, to December 30, 2004, with NHL, HL, and CLL from the nationwide Swedish Cancer Registry. For each lymphoma patient, 4 population-based controls matched by sex, year of birth, and county of residence were chosen randomly from the Swedish Population database. All controls had to be alive at the time of lymphoma diagnosis (index date) for the corresponding case and free of cancer at the index date.
      From the Swedish Multigenerational Registry,
      • Skarle A.
      Population Statistics.
      which includes information on parent-offspring relations for all Swedish citizens who were born 1932 and later, we obtained information on all linkable first-degree relatives (parents, siblings, and offspring) for cases and controls, and linked them to the Swedish Cancer Registry in order to obtain information on living incident cancer cases.
      All patients, controls, and relatives were further linked with the Swedish Inpatient Registry 1964–2005,
      • Skarle A.
      Population Statistics.
      which contains information on discharge diagnoses and discharge listing from inpatient care (coded according to ICD-7 to ICD-10), which had a gradually increasing geographical coverage (50% of the population in the mid-1970s and by 1987 all counties were included).
      • Skarle A.
      Population Statistics.
      The National Board of Health and Welfare
      Cancer Incidence in Sweden 2003.
      Through this linkage, we collected information on patients who were diagnosed as having CD.
      Approval was obtained from the Karolinska institutional review board for this study. Informed consent was waived because we had no contact with study subjects. An exemption from institutional review board review was obtained from the NIH Office of Human Subjects Research because we used existing data without personal identifiers.

       Statistical Analysis

      To avoid inclusion of lymphoma patients with CD as a presenting feature, to reduce potential surveillance bias, and to prevent counting CD that was recorded only among patients as secondary diagnoses at admissions for symptoms of lymphoma, we did not capture information on CD up to 1 year prior to lymphoma diagnosis (for controls, 1 year prior to the index date).
      First, we calculated overall ORs with 95% confidence intervals as measures of association between lymphoma risk and personal history of CD using unconditional logistic regression, adjusting for the matching factors: gender, year of birth, calendar period of lymphoma diagnosis for cases and index date for controls, and county. To validate this model, we also conducted analyses using conditional logistic regression according to the matched design. Given that the models resulted in similar results, we only present results from unconditional logistic regression. Second, to explore if there were interactions with age and gender we conducted stratifying analyses by gender and age. In accord with prior studies, we used the following cutoff for age: NHL and CLL
      • Landgren O.
      • Engels E.A.
      • Caporaso N.E.
      • et al.
      Patterns of autoimmunity and subsequent chronic lymphocytic leukemia in Nordic countries.
      • Mellemkjaer L.
      • Pfeiffer R.M.
      • Engels E.A.
      • et al.
      Autoimmune disease in individuals and close family members and susceptibility to non-Hodgkin's lymphoma.
      (above/below 65 years) and HL
      • Landgren O.
      • Engels E.A.
      • Pfeiffer R.M.
      • et al.
      Autoimmunity and susceptibility to Hodgkin lymphoma: a population-based case-control study in Scandinavia.
      (above/below 45 years). Third, we analyzed the association between CD and lymphoma by latency (ie, the time between the first discharge record diagnosis of CD and the date of lymphoma diagnosis for cases or index date for controls: 1–4.99 years, 5–9.99 years, and 10 or more years). Fourth, we evaluated the association by calendar period of lymphoma diagnosis for cases and index date for controls (1965–1974, 1975–1984, 1985–1994, and 1995–2004). Lastly, we quantified the risk of developing lymphoma among persons with a parent, sibling, or offspring affected with CD (ie, family history of CD). Using logistic regression models (adjusted for gender, year of birth, calendar period of lymphoma diagnosis or index date, county, and personal history of CD), we calculated ORs as measures of relative risks. In sub-analyses, we defined relative risks stratifying by gender and age.

      Results

      As shown in Table 2, we included 37,869 NHL, 8323 HL, and 13,842 CLL patients; 236,408 frequency matched controls; and 753,983 linkable first-degree relatives of patients and controls. About 60% of the lymphoma patients were male. Median age at diagnosis was 69 years, 52 years, and 72 years, for NHL, HL, and CLL patients, respectively.
      Table 2Characteristics of Lymphoma Patients and Controls
      VariableNHLHLCLL
      PatientsControlsPatientsControlsPatientsControls
      Total number37,869149,740832333,16013,82454,508
      Age
      Age at lymphoma diagnosis (index date for controls), median (interquartile range).
      69 (58–77)52 (29–70)52 (29–69.5)72 (64–79)72 (64–78)
      Age group
      Age at lymphoma diagnosis (index date for controls), median (interquartile range).
      (%)
       <15 y647 (2)2591 (2)272 (3)1088 (3)6 (<1)24 (<1)
       15-24 y457 (1)1836 (1)1230 (15)4919 (15)9 (<1)36 (<1)
       25–34 y806 (2)3308 (2)1183 (14)4753 (14)44 (<1)175 (<1)
       35–44 y1730 (5)7102 (5)880 (11)3540 (11)195 (1)779 (1)
       45–54 y3920 (10)15,782 (10)821 (10)3287 (10)949 (7)3792 (7)
       55–64 y6939 (18)27,660 (18)1117 (13)4449 (13)2507 (18)9981 (18)
       65–74 y10,685 (28)42,081 (28)1482 (18)5859 (18)4555 (33)17,941 (33)
       >75 y12,684 (33)49,380 (33)1338 (16)5265 (16)5559 (40)21,780 (40)
      Gender (%)
       Male20,902 (55)83,107 (55)4801 (58)19,181 (58)8536 (62)33,760 (62)
       Female16,967 (45)66,633 (45)3522 (42)13,979 (42)5288 (38)20,748 (38)
      Calendar year
      Calendar year at lymphoma diagnosis (index date for controls), median (interquartile range).
      1991 (1984–1998)1982 (1973–1993)1987 (1978–1997)
      Linkable first-degree relatives, n/N
      n/N = number of first-degree relatives per proband.
      96,186391,10924,362107,55627,074107,696
      Parents17,041 (0.4)71,345 (0.5)6710 (0.8)28,689 (0.9)3215 (0.2)13,022 (0.2)
       Sibling17,877 (0.5)73,374 (0.5)6942 (0.8)30,448 (0.9)3177 (0.2)12,946 (0.2)
       Offspring61,268 (1.6)246,390 (1.6)10,710 (1.3)48,419 (1.5)20,682 (1.5)81,728 (1.5)
      a Age at lymphoma diagnosis (index date for controls), median (interquartile range).
      b n/N = number of first-degree relatives per proband.
      c Calendar year at lymphoma diagnosis (index date for controls), median (interquartile range).

       Personal History of CD and Risk of NHL

      After excluding individuals with a diagnosis of lymphoma within 1 year after CD diagnosis, there were a total of 54 NHL patients and 40 frequency-matched controls with a personal history of CD. As shown in Table 3, an overall 5-fold increased risk for developing NHL (OR = 5.35, 95% CI, 3.56–8.06) was estimated. In stratified analyses, we found the risk of NHL to be higher for female subjects (OR = 7.12, 95% CI, 3.87–13.1) than male subjects (OR = 4.16, 95% CI, 2.38–7.29); however, the difference was not significant (Pinteraction = .20). Although the association between CD and NHL was more prominent among persons diagnosed with NHL before the age of 65 years (OR = 6.71, 95% CI, 3.54–12.7) compared to those diagnosed at the age of 65 years or older (OR = 4.55, 95% CI, 2.66–7.77), the difference was not significant (Pinteraction = .50).
      Table 3Personal and Family History of CD and Risk of NHL
      VariablePatients (n = 37,869)Controls (n = 149,740)OR (95% CI)
      Personal history of CD
      Individuals diagnosed with lymphoma (index date for controls) within 1 year after CD diagnosis were excluded.
      54405.35 (3.56–8.06)
       Gender
        Male25244.16 (2.38–7.29)
        Female29167.12 (3.87–13.1)
       Age of proband
      Age at lymphoma diagnosis (index date for controls).
      , y
        Younger than 6525156.70 (3.53–12.7)
        65 or older29254.55 (2.66–7.77)
       Latency
      Time between a discharge record diagnosis of CD and a subsequent diagnosis of NHL (index date for controls).
      , y
        1–4.9931167.64 (4.18–14.0)
        5–9.9912133.66 (1.67–8.02)
        10 or more11113.98 (1.72–9.17)
        Ptrend<.0001
       Calendar year
      Calendar year at lymphoma diagnosis (index date for controls).
        1965–197400N.A.
        1975–198410313.2 (3.63–48.0)
        1985–19941687.90 (3.38–18.5)
        1995–200428293.84 (2.28–6.45)
        Ptrend<.0001
      Family history of CD
      Defined as having either a parent, sibling, or an offspring affected with CD. All logistic regression models were adjusted for birth year, sex, calendar period of lymphoma diagnosis, and region; models estimating risk associated with a family history of CD were also adjusted for personal history of CD.
      762711.12 (0.87–1.45)
       Gender of proband
        Male421611.04 (0.75–1.47)
        Female341101.23 (0.84–1.81)
       Age of proband
      Age at lymphoma diagnosis (index date for controls).
      , y
        Young age (<65)501881.08 (0.79–1.47)
        Late age (≥65)26831.23 (0.79–1.91)
       Type of first-degree relative
        Parent9460.79 (0.39–1.62)
         Mother4240.67 (0.23–1.94)
         Father5220.92 (0.35–2.42)
        Sibling28562.03 (1.29–3.19)
        Offspring401700.94 (0.66–1.32)
      N.A., not applicable.
      a Individuals diagnosed with lymphoma (index date for controls) within 1 year after CD diagnosis were excluded.
      b Time between a discharge record diagnosis of CD and a subsequent diagnosis of NHL (index date for controls).
      c Age at lymphoma diagnosis (index date for controls).
      d Calendar year at lymphoma diagnosis (index date for controls).
      e Defined as having either a parent, sibling, or an offspring affected with CD. All logistic regression models were adjusted for birth year, sex, calendar period of lymphoma diagnosis, and region; models estimating risk associated with a family history of CD were also adjusted for personal history of CD.
      When we assessed NHL risk in relation to the time between a first hospitalization for CD and a subsequent NHL diagnosis (ie, latency) (Table 3), we found risk of NHL to be most prominent in the first latency period (1–5 y) (OR = 7.64, 95% CI, 4.18–14.0). Although NHL risk declined with latency elongation (Ptrend < .0001), the risk was still highly elevated after 10 years latency (OR = 3.98, 95% CI, 1.72–9.17).
      When the association was evaluated by calendar year period, we found persons diagnosed with CD in 1975–1984, 1985–1994, and 1995–2004 to have 13.2-fold (95% CI, 3.63–48.0), 7.90-fold (95% CI, 3.38–18.5), and 3.84-fold (95% CI, 2.28–6.45) risk of developing NHL, respectively (Ptrend < .0001) (Table 3) (Figure 1). In our database, there were no individuals diagnosed with CD between 1965 and 1974.
      Figure thumbnail gr1
      Figure 1CD and risk of NHL by calendar period.

       Family History of CD and Risk of NHL

      We observed a total of 76 NHL patients and 271 controls with a family member (parents, sibling, or offspring) affected with CD. When adjusting for personal history of CD, we found no overall increased risk of NHL (OR = 1.12, 95% CI, 0.87–1.45) among persons with a first-degree relative affected with CD (Table 3). However, when we assessed NHL risk by type of first-degree relative, we found a 2-fold (OR = 2.03, 95% CI, 1.29–3.19) excess risk among persons with a sibling affected with CD. In contrast, we found no statistical association between NHL risk and having a parent or an offspring diagnosed with CD.

       Personal and Family History of CD and Risk of HL and CLL

      Based on 7 HL and 4 CLL patients with a personal history of CD, we found a borderline significant association between a personal history of CD and the subsequent risk of developing HL (OR = 2.54, 95% CI, 0.99–6.56). However, for CLL there was no significant excess risk (OR = 1.12, 95% CI, 0.37–3.41). When we assessed the risk by gender, male subjects affected with CD had a borderline elevated risk of HL (OR = 3.32, 95% CI, 1.01–10.9), but the risk was not different between male and female subjects (Pinteraction = .48). Among individuals diagnosed with HL at age 45 years or older, we found CD to be associated with 4-fold risk increase (OR = 3.97, 95% CI, 1.28–12.3). Again, the difference in risk between different age groups was not significant (Pinteraction = .83). Among HL and CLL patients, we observed a total of 14 and 11 patients, respectively, to have a relative affected with CD. Overall we found no statistical association between a family history of CD and risk of developing HL or CLL.

      Discussion

      In this large population-based study based on Swedish high-quality data obtained over 4 decades, we found individuals with a hospital discharge diagnosis of CD to have an overall 5.4-fold increased risk of developing NHL. However, there was no significantly increased risk of HL or CLL. When we defined risk of NHL by calendar period, it exhibited a steady decline: a highly elevated 13.2-fold risk in the earlier years (1975–1984), a 7.9-fold increased risk in the following decade (1985–1994), and a more moderately 3.8-fold increased risk in the most recent decade (1995–2004). These findings have clinical implications for patients and health care professionals in that they shed light on the impact of modern serologic markers and HLA typing for CD diagnosis in clinical practice, as well as early treatment (ie, gluten-free diet), to reduce the risk of developing NHL. While diagnosis is more accurate and specific, it is more likely that milder cases are increasingly detected. Clinic presentation of diarrhea and malabsorption are less common and atypical and silent presentations are increasing. Furthermore, for the first time, in this investigation we found a significantly increased risk of NHL among individuals with a sibling affected by CD. This finding supports the operation of shared (genetic or environmental, or both) susceptibility for NHL and CD and it needs to be followed up in future investigations.
      Our findings confirm and expand on the results from a prior survey by Askling et al, who assessed lymphoma risk among a cohort of patients with a hospital discharge diagnosis of CD between 1964 and 1995.
      • Askling J.
      • Linet M.
      • Gridley G.
      • et al.
      Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis.
      In their study, a decreased trend of standardized incidence ratios for overall lymphomas (including NHL and HL patients combined) was observed. In our investigation (including 37,869 NHL, 8323 HL, and 13,842 CLL patients diagnosed in Sweden in 1965–2004 and 236,408 matched controls), we were able to quantify risks over time for NHL, HL, and CLL separately. A novel and important clinical message from our study is the finding that persons diagnosed with CD at present have a substantially lower risk of developing NHL than previously published studies based on CD diagnosed in earlier years.
      • Askling J.
      • Linet M.
      • Gridley G.
      • et al.
      Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis.
      • Leonard J.N.
      • Tucker W.F.
      • Fry J.S.
      • et al.
      Increased incidence of malignancy in dermatitis herpetiformis.
      • Smedby K.E.
      • Akerman M.
      • Hildebrand H.
      • et al.
      Malignant lymphomas in coeliac disease: evidence of increased risks for lymphoma types other than enteropathy-type T cell lymphoma.
      • Peters U.
      • Askling J.
      • Gridley G.
      • et al.
      Causes of death in patients with celiac disease in a population-based Swedish cohort.
      We also observed 7 HL cases with a prior diagnosis of CD (OR = 2.54, 95% CI, 0.99–6.56). Based on only 4 cases, we found no excess risk of CLL following CD.
      Our study is unique in that it provides population-based information on lymphoma risk based on a large number of patients diagnosed with CD in the era of modern serologic markers and HLA typing. Simultaneously, for comparison over time, our study also gives the risk of lymphoma among a large group of patients diagnosed with CD in earlier years in the same population. There are several explanations for the decreased risk of NHL over time.
      Primarily, serologic markers and HLA typing for CD have been developed to noninvasively screen persons with symptoms suspicious for CD, and to allow identification of persons who might be candidates for duodenal biopsy, the gold standard method to diagnose CD.
      • Green P.H.
      • Rostami K.
      • Marsh M.N.
      Diagnosis of coeliac disease.
      The increased use of serologic markers and HLA typing has contributed to increased detection rate of early stage (atypical or silent) CD.
      • Catassi C.
      • Fabiani E.
      • Ratsch I.M.
      • et al.
      The coeliac iceberg in Italy A multicentre antigliadin antibodies screening for coeliac disease in school-age subjects.
      • Bonamico M.
      • Ferri M.
      • Mariani P.
      • et al.
      Serologic and genetic markers of celiac disease: a sequential study in the screening of first degree relatives.
      Based on our clinical experience, in Sweden, serologic markers and HLA typing have been widely used in clinical practice since the mid 1990s. Current estimations indicate that the prevalence of CD in North America and Europe, as well as Asia, is about 1:100 to 1:300
      • Ciclitira P.J.
      • Johnson M.W.
      • Dewar D.H.
      • et al.
      The pathogenesis of coeliac disease.
      • Fasano A.
      • Berti I.
      • Gerarduzzi T.
      • et al.
      Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study.
      National Institutes of Health Consensus Development Conference Statement on Celiac Disease, June 28-30, 2004.
      , but it is thought to be under-diagnosed. Although the literature is not consistent,
      • Hall R.P.
      Dietary management of dermatitis herpetiformis.
      • Janatuinen E.K.
      • Kemppainen T.A.
      • Julkunen R.J.
      • et al.
      No harm from five year ingestion of oats in coeliac disease.
      • Kumar P.J.
      • Farthing M.G.
      Oats and celiac disease.
      • Hogberg L.
      • Grodzinsky E.
      • Stenhammar L.
      Better dietary compliance in patients with coeliac disease diagnosed in early childhood.
      a gluten-free diet is highly effective in eliminating CD-characteristic intestinal lesions. Prior studies have shown that a gluten-free diet induces clinical improvement and histological recovery.
      • Lee S.K.
      • Lo W.
      • Memeo L.
      • Rotterdam H.
      • Green P.H.
      Duodenal histology in patients with celiac disease after treatment with a gluten-free diet.
      • Matysiak-Budnik T.
      • Malamut G.
      • de Serre N.P.
      • et al.
      Long-term follow-up of 61 coeliac patients diagnosed in childhood: evolution toward latency is possible on a normal diet.
      In Sweden, since the late 1970s, federal laws [SFS 1979:1132] state that public preschools are required to provide a gluten-free diet to children with CD.
      • Mikkelsen A.
      • Borres M.
      • Kristiansson B.
      • et al.
      Different policy on gluten-free food in child day care centers Unified national guidelines are needed.
      On a national level, the awareness of a gluten-free diet for persons affected with CD has been increasing since then. Consequently, it is reasonable to hypothesize that lymphomagenesis among CD patients is due to secondary intestinal inflammation. Based on these facts, one explanation might be that early detection of CD in recent years has allowed the responsible clinician to provide dietary guidance to the patients and thereby prevent complications, including lymphoma development. Another explanation might be that the detection of CD in individuals who are asymptomatic or in an earlier stage (ie, less severe intestinal inflammation and immune disruption at diagnosis) results in a lower risk of developing lymphoma per se. Alternatively there might be a combination of these mechanisms, or other factors might be involved as well. Also, many cases may have manifested various symptoms including intestinal atrophy that in some cases were due to other disorders (such as other autoimmune diseases) that were strongly associated with NHL. More specific diagnostic tools have enabled better diagnostic accuracy, eliminating these cases. Independent of the exact underlying mechanisms, our findings are important in that they provide novel clinical insights of value for both patients and health care professionals. Future prospective studies monitoring gluten intake, intestinal inflammation, and risks of developing lymphomas are needed to better understand the operation of these capacities.
      Our finding of an increased lymphoma risk among persons with a sibling affected with CD suggests that there might be some common genes causing risk for both CD and lymphoma. Celiac disease has been shown to have a significant heritable component, partly due to HLA DQ2 or DQ8 genotypes.
      • Louka A.S.
      • Sollid L.M.
      HLA in coeliac disease: unravelling the complex genetics of a complex disorder.
      However, HLA does not account for all of the familial aggregation and there is some evidence for the involvement of other non-HLA genes.
      • Louka A.S.
      • Sollid L.M.
      HLA in coeliac disease: unravelling the complex genetics of a complex disorder.
      • Monsuur A.J.
      • Wijmenga C.
      Understanding the molecular basis of celiac disease: what genetic studies reveal.
      The fact that CD aggregates most strongly in siblings
      • Rubio-Tapia A.
      • Van Dyke C.T.
      • Lahr B.D.
      • et al.
      Predictors of family risk for celiac disease: a population-based study.
      suggests recessive inheritance or gene dosage effects. Our observation that there was a familial association between lymphoma and CD only in siblings suggests a similar mechanism that could involve the HLA region, or other immune/inflammatory genes.
      Our study is the largest and most comprehensive to date to assess the association of personal history and family history of CD with risk of lymphomas. The population-based approach involving lymphoma patients, controls, and relatives reduces the possibility for selection bias and eliminates recall bias. Furthermore, to limit the influence of detection bias, in our risk estimations we excluded lymphomas diagnosed within 1 year of latency following CD diagnosis. Limitations of our study include incomplete numbers of first-degree relatives of lymphoma patients and controls, lack of information on potential confounders, and information on lymphoma subtypes, as well as diagnostic validation and clinical details for single individuals in the study. However, in a previous Swedish study (1964–1994), the validation of hospital registry-based discharge diagnoses for CD was found to be very high.
      • Askling J.
      • Linet M.
      • Gridley G.
      • et al.
      Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis.
      Another limitation is the lack of outpatient data that would likely lead to under-ascertainment of CD. However, since personal and family history of CD were assessed among matched controls using the same hospital discharge registries, under-diagnosis of CD in subjects or their first-degree relatives should be nondifferential between lymphoma patients and their matched controls, and thus any bias should have been conservative. Finally, as pointed out previously,
      • Olen O.
      • Montgomery S.M.
      • Elinder G.
      • et al.
      Increased risk of immune thrombocytopenic purpura among inpatients with coeliac disease.
      a potential consideration with the use of a hospital-based register is the fact that persons affected with CD may have a more severe type of disease. However, in Sweden, particularly in earlier years, hospital admissions were common for gastrointestinal work-up and even today some individuals are admitted to hospital when undergoing endoscopy with general anesthesia. Overall, our CD cohort contains both patients hospitalized for either diagnostic or therapeutic reasons, as well as those hospitalized for other medical conditions. Therefore, our results may not be applicable to individuals with asymptomatic CD diagnosed through screening.
      In summary, during the entire study period, we found individuals with CD to have an overall 5.4-fold increased risk of developing NHL, but no statistically increased risk of developing HL or CLL. When we estimated risks of developing NHL among patients diagnosed with CD in the recent decade, compared to those diagnosed with CD in 1975–1984 in the same population, we observed the risk to drop from over 30-fold to 3.8-fold. Our observation that NHL risk was increased among persons with a sibling affected with CD suggests shared susceptibility for CD and NHL. There is a great need to improve our understanding regarding underlying mechanisms of our findings and to develop better biomarkers for prediction of lymphomagenesis among patients with immune-related and inflammatory conditions.
      • Mellemkjaer L.
      • Pfeiffer R.M.
      • Engels E.A.
      • et al.
      Autoimmune disease in individuals and close family members and susceptibility to non-Hodgkin's lymphoma.
      • Landgren O.
      • Engels E.A.
      • Pfeiffer R.M.
      • et al.
      Autoimmunity and susceptibility to Hodgkin lymphoma: a population-based case-control study in Scandinavia.

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      Linked Article

      • Celiac Disease and Its Complications: A Time Traveller's Perspective
        GastroenterologyVol. 136Issue 1
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          In 1888, a short story “The Chronic Argonauts” by H.G. Wells1 was published by the Royal College of Science in which his concept of a time machine was first introduced. Writing in the preface to the 1931 edition of his now famous novel “The Time Machine” Wells says that “it is obviously a work of an inexperienced writer, but certain originalities in it saved it from extinction.” Samuel Gee, although far from inexperienced, in the same year wrote about another original concept that has stood the test of time.
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