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  • 1. Arkema, Elizabeth V
    et al.
    Jonsson, Jerker
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Bruchfeld, Judith
    Feltelius, Nils
    Askling, Johan
    Are patients with rheumatoid arthritis still at an increased risk of tuberculosis and what is the role of biological treatments?2015Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 74, nr 6, s. 1212-1217Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: To estimate the risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA) both with and without exposure to biological therapy and to directly compare the risks between therapies.

    METHODS: Data from the Swedish National Population Registers, Tuberculosis Register and the Swedish Biologics Register were used to conduct a prospective population-based national cohort study (2002-2011). We estimated the rate of incident TB in the general population and in a cohort of biological-naïve and biological-exposed patients diagnosed with RA. Cox models were used to estimate HRs with particular attention to risks by calendar and follow-up time and individual biologics.

    RESULTS: Compared to the general population, RA patients not exposed to biologicals had a fourfold increased risk of TB (HR 4.2; 95% CI 2.7 to 6.7), which did not decline over calendar time. In contrast, the risk of TB in the biological-exposed RA population decreased since 2002 compared with biological-naïve; from HR=7.9 (95% CI 3.3 to 18.9) in 2002-2006 to HR=2.4 (95% CI 0.9 to 6.1) in 2007-2011. The HRs for most recent exposure to adalimumab and infliximab compared with etanercept were 3.1 (95% CI 0.8 to 12.5) and 2.7 (95% CI 0.7 to 10.9), respectively, and the HR for etanercept compared with biological-naïve RA was 1.7 (95% CI 0.6 to 4.6).

    CONCLUSIONS: In the past decade, the risk of TB has decreased among biological-exposed RA patients but remains higher than in biological-naïve RA patients. Most cases of TB in RA occur in biological-naïve RA patients, underscoring the elevated risk also in these patients.

  • 2. Arkema, Elizabeth V.
    et al.
    Jonsson, Jerker
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Rutting, Maud
    Bruchfeld, Judith
    Feltelius, Nils
    Askling, Johan
    Are Patients With Rheumatoid Arthritis Still At An Increased Risk Of Tuberculosis and What Is The Role Of Biological Treatment?2013Inngår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, nr Suppl. 10, s. S719-S719Artikkel i tidsskrift (Annet vitenskapelig)
  • 3. Askling, J
    et al.
    Fored, C M
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Brandt, L
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Ekbom, A
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Molekylär och morfologisk patologi.
    Bertilsson, L
    Cöster, L
    Geborek, P
    Jacobsson, L T
    Lindblad, S
    Lysholm, J
    Rantapää-Dahlqvist, S
    Saxne, T
    Klareskog, L
    Feltelius, N
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Haematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists2005Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 64, nr 10, s. 1414-1420Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas, and maybe also of leukaemia and multiple myeloma. The effect of tumour necrosis factor (TNF) antagonists on lymphoma risk and characteristics is unclear.

    OBJECTIVE:

    To assess expected rates and relative risks of haematopoietic malignancies, especially those associated with TNF antagonists, in large population based cohorts of patients with RA.

    METHODS:

    A population based cohort study was performed of patients with RA (one prevalent cohort (n = 53,067), one incident cohort (n = 3703), and one TNF antagonist treated cohort 1999 through 2003 (n = 4160)), who were linked with the Swedish Cancer Register. Additionally, the lymphoma specimens for the 12 lymphomas occurring in patients with RA exposed to TNF antagonists in Sweden 1999 through 2004 were reviewed.

    RESULTS:

    Study of almost 500 observed haematopoietic malignancies showed that prevalent and incident patients with RA were at increased risk of lymphoma (SIR = 1.9 and 2.0, respectively) and leukaemia (SIR = 2.1 and 2.2, respectively) but not of myeloma. Patients with RA treated with TNF antagonists had a tripled lymphoma risk (SIR = 2.9) compared with the general population. After adjustment for sex, age, and disease duration, the lymphoma risk after exposure to TNF antagonists was no higher than in the other RA cohorts. Lymphomas associated with TNF antagonists had characteristics similar to those of other RA lymphomas.

    CONCLUSION:

    Overall, patients with RA are at equally increased risks for lymphomas and leukaemias. Patients with RA treated with TNF antagonists did not have higher lymphoma risks than other patients with RA. Prolonged observation is needed to determine the long term effects of TNF antagonists on lymphoma risk.

  • 4. Askling, J
    et al.
    Fored, C M
    Brandt, L
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Bertilsson, L
    Feltelius, N
    Medical Products Agency, Uppsala, Sweden .
    Cöster, L
    Geborek, P
    Jacobsson, L T
    Lindblad, S
    Lysholm, J
    Rantapää-Dahlqvist, S
    Saxne, T
    Klareskog, L
    Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists2005Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 64, nr 10, s. 1421-1426Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    Existing studies of solid cancers in rheumatoid arthritis (RA) reflect cancer morbidity up until the early 1990s in prevalent cohorts admitted to hospital during the 1980s.

    OBJECTIVE:

    To depict the cancer pattern of contemporary patients with RA, from updated risk data from prevalent and incident RA populations. To understand the risk of solid cancer after tumour necrosis factor (TNF) treatment by obtaining cancer data from cohorts treated in routine care rather than trials.

    METHODS:

    A population based study of three RA cohorts (one prevalent, admitted to hospital 1990-2003 (n = 53,067), one incident, diagnosed 1995-2003 (n = 3703), and one treated with TNF antagonists 1999-2003 (n = 4160)), which were linked with Swedish nationwide cancer and census registers and followed up for cancer occurrence through 2003.

    RESULTS:

    With 3379 observed cancers, the prevalent RA cohort was at marginally increased overall risk of solid cancer, with 20-50% increased risks for smoke related cancers and +70% increased risk for non-melanoma skin cancer, but decreased risk for breast (-20%) and colorectal cancer (-25%). With 138 cancers, the incident RA cohort displayed a similar cancer pattern apart from non-decreased risks for colorectal cancer. TNF antagonist treated patients displayed solid cancer (n = 67) risks largely similar to those of other patients with RA.

    CONCLUSION:

    The cancer pattern in patients treated with TNF antagonists mirrors those of other contemporary as well as historic RA cohorts. The consistent increase in smoking associated cancers in patients with RA emphasises the potential for smoking cessation as a cancer preventive measure in RA.

  • 5. Askling, J
    et al.
    Klareskog, L
    Hjalgrim, H
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Björkholm, M
    Ekbom, A
    Do steroids increase lymphoma risk? A case-control study of lymphoma risk in polymyalgia rheumatica/giant cell arteritis2005Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 64, nr 12, s. 1765-1768Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    Recent studies indicate increased risks of malignant lymphomas among individuals treated with corticosteroids, but have not taken into account the underlying reasons for steroid use, so the increased risks might be attributable to the underlying disease or concomitant treatments other than steroids. Polymyalgia rheumatica (PMR) and temporal arteritis (giant cell arteritis, GCA) are common inflammatory conditions treated with steroids as single immunosuppressive therapy, but data on lymphoma risk in GCA/PMR are limited.

    OBJECTIVE:

    To assess the risk of lymphoma associated with steroid treatment of GCA/PMR.

    METHODS:

    The association between GCA/PMR and malignant lymphomas (overall, and separately for non-Hodgkin lymphoma, Hodgkin lymphoma, and chronic lymphatic leukaemia) was examined in a nationwide, population based, case-control study of 42,676 lymphoma cases and 78,487 matched population controls, using prospectively recorded data on lymphomas from the Swedish cancer register 1964-2000 and data on pre-lymphoma hospital admissions for GCA/PMR from the Swedish inpatient register 1964-2000. Odds ratios (OR) associated with a pre-lymphoma hospital admission for GCA/PMR were calculated using conditional logistic regression.

    RESULTS:

    153 lymphoma cases and 345 population controls had a history of GCA/PMR, resulting in an overall OR for malignant lymphomas of 0.81 (95% confidence interval, 0.67 to 0.98). The OR varied little with lymphoma type, sex, age, and calendar period. The OR for GCA was 0.67 (0.48 to 0.98) and for PMR, 0.83 (0.67 to 1.04).

    CONCLUSIONS:

    Treated GCA is not associated with increased lymphoma risks, which suggests that even at considerable cumulative doses, steroids may not appreciably increase lymphoma risk.

  • 6. Askling, Johan
    et al.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Granath, F.
    Geborek, P.
    Fored, M.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Bertilsson, L.
    Cöster, L.
    Jacobsson, L. T.
    Lindblad, S.
    Lysholm, J.
    Rantapää-Dahlqvist, S.
    Saxne, T.
    van Vollenhoven, R.
    Klareskog, L.
    Feltelius, N.
    Anti-tumour necrosis factor therapy in rheumatoid arthritis and risk of malignant lymphomas: relative risks and time trends in the Swedish Biologics Register2009Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 68, nr 5, s. 648-653Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    Tumour necrosis factor (TNF) antagonists have proved effective as treatment against rheumatoid arthritis (RA), but the unresolved issue of whether the use of anti-TNF therapy increases the already elevated risk of lymphoma in RA remains a concern.

    METHODS:

    Using the Swedish Biologics Register (ARTIS), the Swedish Cancer Register, pre-existing RA cohorts and cross-linkage with other national health and census registers, a national RA cohort (n = 67,743) was assembled and patients who started anti-TNF therapy between 1998 and July 2006 (n = 6604) were identified. A general population comparator (n = 471,024) was also assembled and the incidence of lymphomas from 1999 to 31 December 2006 was assessed and compared in these individuals.

    RESULTS:

    Among the 6604 anti-TNF-treated RA patients, 26 malignant lymphomas were observed during 26,981 person-years of follow-up, which corresponded to a relative risk (RR) of 1.35 (95% CI 0.82 to 2.11) versus anti-TNF-naive RA patients (336 lymphomas during 365,026 person-years) and 2.72 (95% CI 1.82 to 4.08) versus the general population comparator (1568 lymphomas during 3,355,849 person-years). RA patients starting anti-TNF therapy in 1998-2001 accounted for the entire increase in lymphoma risk versus the two comparators. By contrast, RR did not vary significantly by time since start of first treatment or with the accumulated duration of treatment, nor with the type of anti-TNF agent.

    CONCLUSION:

    Overall and as used in routine care against RA, TNF antagonists are not associated with any major further increase in the already elevated lymphoma occurrence in RA. Changes in the selection of patients for treatment may influence the observed risk.

  • 7. Askling, Johan
    et al.
    Fored, C. Michael
    Brandt, Lena
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Bertilsson, Lennart
    Cöster, Lars
    Geborek, Pierre
    Jacobsson, Lennart T.
    Lindblad, Staffan
    Lysholm, Jörgen
    Rantapää-Dahlqvist, Solbritt
    Saxne, Tore
    Romanus, Victoria
    Klareskog, Lars
    Feltelius, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden2005Inngår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 52, nr 7, s. 1986-1992Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:

    Because treatment with tumor necrosis factor (TNF) antagonists may increase the risk of tuberculosis (TB), and because knowledge of the risk of TB in rheumatoid arthritis (RA) not treated with biologics is scarce and of uncertain generalizability to low-risk populations, this study sought to determine the risk of TB among Swedish patients with RA.

    METHODS:

    Using data from Swedish nationwide and population-based registers and data from an ongoing monitoring program of TNF antagonists, the relative risks of TB in patients with RA (versus the general population) and of TB associated with TNF antagonists (versus RA patients not treated with biologics) were determined by comparing the incidence of hospitalization for TB in 3 RA cohorts and 2 general population cohorts from 1999 to 2001. We also reviewed the characteristics of all reported cases of TB in RA patients treated with TNF antagonists in Sweden and calculated the incidence of TB per type of TNF antagonist between 1999 and 2004.

    RESULTS:

    During 1999-2001, RA patients who were not treated with TNF antagonists were at increased risk of TB versus the general population (relative risk 2.0, 95% confidence interval [95% CI] 1.2-3.4). RA patients treated with TNF antagonists had a 4-fold increased risk of TB (relative risk 4.0, 95% CI 1.3-12) versus RA patients not treated with TNF antagonists. The reported TB cases during 1999-2004 in RA patients exposed to TNF antagonists (9 infliximab, 4 etanercept, 2 both) were predominantly pulmonary. TB occurred up to 3 years following the start of treatment.

    CONCLUSION:

    Irrespective of whether TNF antagonists are administered, Swedish patients with RA are at increased risk of TB. During 1999-2001, TNF antagonists were associated with an increased risk of TB, up to 4-fold in magnitude. This increased risk may persist over time during treatment and is related to both infliximab and etanercept.

  • 8. Askling, Johan
    et al.
    Fored, C. Michael
    Brandt, Lena
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Bertilsson, Lennart
    Feltelius, Nils
    Cöster, Lars
    Geborek, Pierre
    Jacobsson, Lennart T.
    Lindblad, Staffan
    Lysholm, Jörgen
    Rantapää-Dahlqvist, Solbritt
    Saxne, Tore
    van Vollenhoven, Ronald F.
    Klareskog, Lars
    Time-dependent increase in risk of hospitalisation with infection among Swedish RA patients treated with TNF antagonists2007Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 66, nr 10, s. 1339-1344Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES:

    The degree to which treatment with tumour necrosis factor (TNF) antagonists may be associated with increased risks for serious infections is unclear. An observational cohort study was performed using prospectively collected data from the Swedish Biologics Register (ARTIS) and other national Swedish registers.

    METHODS:

    First, in the ARTIS, all 4167 rheumatoid arthritis (RA) patients starting TNF antagonist treatment between 1999 and 2003 were identified. Secondly, in the Swedish Inpatient Register, all individuals hospitalised for any reason and who also carried a diagnosis of RA, between 1964 and 2003 (n = 44 946 of whom 2692 also occurred in ARTIS), were identified. Thirdly, in the Swedish Inpatient Register, all hospitalisations listing an infection between 1999 and 2003 were identified. By cross-referencing these three data sets, RRs for hospitalisation with infection associated with TNF antagonist treatment were calculated within the cohort of 44 946 RA patients, using Cox regression taking sex, age, geography, co-morbidity and use of inpatient care into account.

    RESULTS:

    Among the 4167 patients treated with TNF antagonists, 367 hospitalisations with infections occurred during 7776 person-years. Within the cohort of 44 496 RA patients, the RR for infection associated with TNF antagonists was 1.43 (95% CI 1.18 to 1.73) during the first year of treatment, 1.15 (95% CI 0.88 to 1.51) during the second year of treatment, and 0.82 (95% CI 0.62 to 1.08) for subjects remaining on their first TNF antagonist treatment after 2 years.

    CONCLUSION:

    Treatment with TNF antagonists may be associated with a small to moderate increase in risk of hospitalisation with infection, which disappears with increasing treatment duration.

  • 9. Askling, Johan
    et al.
    van Vollenhoven, Ronald F.
    Granath, Fredrik
    Raaschou, Pauline
    Fored, C. Michael
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Dackhammar, Christina
    Feltelius, Nils
    Cöster, Lars
    Geborek, Pierre
    Jacobsson, Lennart T.
    Lindblad, Staffan
    Rantapää-Dahlqvist, Solbritt
    Saxne, Tore
    Klareskog, Lars
    Cancer risk in patients with rheumatoid arthritis treated with anti-tumor necrosis factor alpha therapies: does the risk change with the time since start of treatment?2009Inngår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, nr 11, s. 3180-3189Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:

    To determine the short-term and medium-term risks of cancer in patients receiving anti-tumor necrosis factor alpha (anti-TNFalpha) therapies that have proven effective in the treatment of chronic inflammatory conditions.

    METHODS:

    By linking together data from the Swedish Biologics Register, Swedish registers of RA, and the Swedish Cancer Register, we identified and analyzed for cancer occurrence a national cohort of 6,366 patients with RA who first started anti-TNF therapy between January 1999 and July 2006. As comparators, we used a national biologics-naive RA cohort (n = 61,160), a cohort of RA patients newly starting methotrexate (n = 5,989), a cohort of RA patients newly starting disease-modifying antirheumatic drug combination therapy (n = 1,838), and the general population of Sweden. Relative risks (RRs) were estimated using Cox regression analyses, examining overall RR as well as RR by time since the first start of anti-TNF therapy, by the duration of active anti-TNF therapy, and by the anti-TNF agent received.

    RESULTS:

    During 25,693 person-years of followup in 6,366 patients newly starting anti-TNF, 240 first cancers occurred, yielding an RR of 1.00 (95% confidence interval 0.86-1.15) versus the biologics-naive RA cohort, and similar RRs versus the other 2 RA comparators. RRs did not increase with increasing time since the start of anti-TNF therapy, nor with the cumulative duration of active anti-TNF therapy. During the first year following the first treatment start, but not thereafter, dissimilar cancer risks for adalimumab, etanercept, and infliximab were observed.

    CONCLUSION:

    During the first 6 years after the start of anti-TNF therapy in routine care, no overall elevation of cancer risk and no increase with followup time were observed.

  • 10.
    Baecklund, Eva
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Askling, Johan
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Ekbom, Anders
    Klareskog, Lars
    Rheumatoid arthritis and malignant lymphomas2004Inngår i: Current Opinion in Rheumatology, ISSN 1040-8711, E-ISSN 1531-6963, Vol. 16, nr 3, s. 254-261Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE OF REVIEW:

    The reason for the increased lymphoma risk in patients with rheumatoid arthritis (RA) has remained unclear. Reports of lymphomas in patients treated with TNF-blockers have brought renewed interest in this issue. This review summarizes data on possible associations between RA and lymphomas, including different treatments and RA disease related risk factors.

    RECENT FINDINGS:

    Some recent studies reported increased lymphoma risks linked to RA disease activity. The hypothesis that disease-modifying drugs, and in particular methotrexate, would increase the lymphoma risk receives little support. Observation times for the TNF-blocking therapies are still short, but so far no clear increased risk for lymphoma has been observed. Presence of Epstein-Barr virus, as analyzed with EBER in situ hybridization, appears to be uncommon in RA related lymphomas. Hypothetically, an increased proliferative drive caused by self or non-self antigens may play a role in lymphoma development in RA patients, but this has to be further studied.

    SUMMARY:

    Rheumatologists need to be aware of the increased lymphoma risk in their RA patients. The reason for the increased lymphoma risk in RA patients is still unclear, but available studies rather support the hypothesis of a link between RA disease severity and the risk of lymphoma than increased risks associated with specific treatment regimens. To facilitate the future evaluation of lymphoma risks in connection with treatment, we suggest that patients treated with new drugs should be subject to structured surveillance. Collected information should include data about RA disease activity and severity.

  • 11.
    Baecklund, Eva
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Iliadou, Anastasia
    Granath, Fredrik
    Ekbom, Anders
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Feltelius, Nils
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Klareskog, Lars
    Askling, Johan
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Characteristics of diffuse large B cell lymphomas in rheumatoid arthritis2006Inngår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 54, nr 12, s. 3774-3781Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:

    Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas, with a correlation between RA disease severity and lymphoma risk, most pronounced for diffuse large B cell lymphomas (DLBCLs), which also constitute the majority of RA-associated lymphomas. DLBCLs can be further subdivided into germinal center (GC)-like and non-GC-like subtypes, with different cellular origins and prognoses. This study was undertaken to investigate whether RA displays a specific association with any of the DLBCL subtypes.

    METHODS:

    We identified 139 patients with DLBCLs within a population-based case-control study of 378 RA patients with lymphoma. The DLBCLs were examined for CD10, Bcl-6, and interferon regulatory factor 4 expression patterns, subclassified into GC and non-GC subtypes, and then correlated with clinical parameters.

    RESULTS:

    We found a statistically significant predominance of the non-GC subtype (97 patients; 70% of all DLBCLs). These patients more often had an advanced stage of lymphoma at diagnosis and had a worse 5-year overall survival rate (16% versus 33%) compared with patients with the GC subtype. There was a strong association with RA disease activity in both subtypes, with >70% of the GC and non-GC cases occurring in RA patients with the highest overall disease activity scores.

    CONCLUSION: These findings suggest that severe RA is particularly associated with the non-GC subtype of DLBCL, and indicate a critical role of activated peripheral B cells as the cells of origin in these lymphomas.

  • 12.
    Baecklund, Eva
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Backlin, Carin
    Iliadou, Anastasia
    Granath, Fredrik
    Ekbom, Anders
    Amini, Rose-Marie
    Feltelius, Nils
    Enblad, Gunilla
    Sundström, Christer
    Klareskog, Lars
    Askling, Johan
    Rosenquist, Richard
    Diffuse large B-cell lymphomas in rheumatoid arthritis display a predominance of non-germinal center typeManuskript (Annet vitenskapelig)
    Abstract
  • 13.
    Baecklund, Eva
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Mansouri, Mahmoud
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Klareskog, Lars
    Askling, Johan
    Iliadou, Anastasia Nyman
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Lossos, Izidore S.
    Natkunam, Yasodha
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi.
    LMO2 protein expression predicts survival in patients with rheumatoid arthritis and diffuse large B-cell lymphoma2011Inngår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 52, nr 6, s. 1146-1149Artikkel i tidsskrift (Fagfellevurdert)
  • 14.
    Baecklund, Eva
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Rönnelid, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Toes, R
    Huizinga, Twj
    Åhlin, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Askling, J
    Hochberg, F H
    Klareskog, L
    Kay, J
    Smedby, K E
    Anti-cyclic citrullinated peptide antibodies, other common autoantibodies, and smoking as risk factors for lymphoma in patients with rheumatoid arthritis2018Inngår i: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 47, nr 4, s. 270-275Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: Patients with rheumatoid arthritis (RA) are at increased risk of lymphoma. There is no biomarker to indicate future lymphoma risk in RA and it is not known whether factors associated with an increased risk of RA also confer an increased risk of lymphoma. We investigated whether anti-cyclic citrullinated peptide (CCP) antibodies, other autoantibodies, and smoking, are associated with lymphoma development in RA.

    METHOD: subclasses of anti-CCP antibodies and for 15 antinuclear antibody (ANA)-associated specific autoantibodies. Relative risks were estimated as crude and adjusted odds ratios (adjOR) with 95% confidence intervals (CIs) using logistic regression.

    RESULTS: We found no association between anti-CCP IgG ≥ 25 units/mL (adjOR 1.4, 95% CI 0.7-2.7), anti-CCP IgG ≥ 500 units/mL (adjOR 1.4, 95% CI 0.7-3.0), anti-CCP Ig of other isotypes, other autoantibodies (adjOR any vs none 0.6, 95% CI 0.3-1.2), or cigarette smoking (adjOR ever vs never 1.1, 95% CI 0.5-2.2) and lymphoma risk among patients with RA.

    CONCLUSION: In this study, neither anti-CCP antibodies (IgG, IgG1–4, IgM, or IgA), nor other common autoantibodies, nor smoking predicted lymphoma risk in RA

  • 15.
    Baecklund, Eva
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Ekbom, Anders
    Sparén, Pär
    Feltelius, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Klareskog, Lars
    Disease activity and risk of lymphoma in patients with rheumatoid arthritis: nested case-control study1998Inngår i: British Medical Journal, Vol. 317, s. 180-181Artikkel i tidsskrift (Fagfellevurdert)
  • 16.
    Baecklund, Eva
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Hellgren, K.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Askling, J.
    Does Biological Therapy Alter the Lymphoma Risk or Distribution of Lymphoma Subtypes in Patients with ra?2013Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, nr Suppl. 3, s. 427-427Artikkel i tidsskrift (Annet vitenskapelig)
  • 17.
    Baecklund, Eva
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Iliadou, Anastasia
    Askling, Johan
    Ekbom, Anders
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Granath, Fredrik
    Catrina, Anca Irinel
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Feltelius, Nils
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Klareskog, Lars
    Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis2006Inngår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 54, nr 3, s. 692-701Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:

    Chronic inflammatory conditions such as rheumatoid arthritis (RA) have been associated with malignant lymphomas. This study was undertaken to investigate which patients are at highest risk, and whether antirheumatic treatment is hazardous or protective.

    METHODS:

    We performed a matched case-control study of 378 consecutive Swedish RA patients in whom malignant lymphoma occurred between 1964 and 1995 (from a population-based RA cohort of 74,651 RA patients), and 378 controls. Information on disease characteristics and treatment from onset of RA until lymphoma diagnosis was abstracted from medical records. Lymphoma specimens were reclassified and tested for Epstein-Barr virus (EBV). Relative risks (odds ratios [ORs]) for lymphomas (by subtype) associated with deciles of cumulative disease activity were assessed, as were ORs associated with drug treatments.

    RESULTS:

    The relative risks of lymphoma were only modestly elevated up to the seventh decile of cumulative disease activity. Thereafter, the relative risk increased dramatically (OR ninth decile 9.4 [95% confidence interval 3.1-28.0], OR tenth decile 61.6 [95% confidence interval 21.0-181.0]). Most lymphomas (48%) were of the diffuse large B cell type, but other lymphoma subtypes also displayed an association with cumulative disease activity. Standard nonbiologic treatments did not increase lymphoma risk. EBV was present in 12% of lymphomas.

    CONCLUSION:

    Risk of lymphoma is substantially increased in a subset of patients with RA, those with very severe disease. High inflammatory activity, rather than its treatment, is a major risk determinant.

  • 18.
    Baecklund, Eva
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Natkunam, Yasodha
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Iliadou, Anastasia
    Askling, Johan
    Ekbom, Anders
    Feltelius, Nils
    Klareskog, Lars
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Lossos, Izidore S.
    Levy, Ronald
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Expression of the human germinal-centre-associated lymphoma protein in diffuse large B-cell lymphomas in patients with rheumatoid arthritis2008Inngår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 141, nr 1, s. 69-72Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Diffuse large B-cell lymphomas (DLBCL) can be subdivided into germinal centre (GC)-like and non-GC-like subtypes by CD10, BCL6 and MUM1/IRF4 status. We previously reported that patients with severe rheumatoid arthritis (RA) are at increased risk of non-GC DLBCL. This study examined a new GC-marker, human germinal-centre-associated lymphoma (HGAL) protein, in RA-DLBCL. Of 111, 38 (34%) DLBCL were HGAL-positive and showed less disseminated disease and a tendency toward improved overall survival compared to HGAL-negative cases. This supports that a majority of RA-DLBCL are of non-GC origin, indicating a specific role for activated peripheral B cells in the pathogenesis of RA-DLBCL.

  • 19.
    Baecklund, Eva
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Smedby, Karin E.
    Sutton, Lesley-Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Askling, Johan
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lymphoma development in patients with autoimmune and inflammatory disorders: What are the driving forces?2014Inngår i: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 24, s. 61-70Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    For decades, it has been known that patients with certain autoimmune and inflammatory disorders, such as rheumatoid arthritis (RA) and primary Sjogren's syndrome (pSS), have an increased risk of developing malignant lymphoma. Although the clinico-biological reasons for this association remain largely unknown, our knowledge has improved and new insights have been obtained. First, the direct link between autoimmunity and lymphomagenesis has been strengthened by large epidemiological studies showing a consistent risk increase of lymphoma associated with certain autoimmune/inflammatory conditions in independent cohorts from different countries. Second, a number of local and systemic disease-related risk factors in these diseases have been repeatedly linked to lymphoma development, with the prime examples being disease severity and the degree of inflammatory activity. Considering the key role of B- and T-cell activation in the pathogenesis of both autoimmunity and lymphoma, it is perhaps not surprising that longstanding chronic inflammation and/or antigen stimulation have emerged as major predisposing factors of lymphoma in patients with active autoimmune disease. Finally, increasing evidence suggests that lymphomas associated with autoimmunity constitute a different spectrum of entities compared to lymphomas arising in patients without any known autoimmune or inflammatory conditions, pointing to a different pathobiology. In this review, we summarize the recent literature that supports a direct or indirect link between immune-mediated disease and lymphoma and describe the characteristics of lymphomas developing in the different diseases. We also discuss molecular, genetic and microenvironmental factors that may come into play in the pathobiology of these disorders.

  • 20.
    Baecklund, Eva
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Ekbom, Anders
    Catrina, Anca
    Biberfeld, Peter
    Feltelius, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Klareskog, Lars
    Lymphoma subtypes in patients with rheumatoid arthritis: Increased proportion of diffuse large B cell lymphoma2003Inngår i: Arthritis & Rheumatism, Vol. 48, nr 6, s. 1543-1550Artikkel i tidsskrift (Fagfellevurdert)
  • 21.
    Berglund, David
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Transplantationskirurgi.
    Kinch, Amelie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Edman, Elin
    Halmstad Hospital.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Larsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Molin, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Pauksens, Karlis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Expression of Intratumoral Forkhead Box Protein 3 in Posttransplant Lymphoproliferative Disorders: Clinical Features and Survival Outcomes2015Inngår i: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, nr 5, s. 1036-1042Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. The infiltration of regulatory T cells (Tregs) in lymphomas is associated with better prognosis for some types of lymphomas, but knowledge of their role in posttransplant lymphoproliferative disorders (PTLDs) is limited. We therefore investigated the association between the expression of the Treg marker forkhead box protein 3 (FoxP3) in biopsies of PTLDs and survival, PTLD subtype, and clinical characteristics.

    Methods. Seventy-four cases of PTLD after solid organ transplantation with sufficient material for further analysis were included from a population-based study of PTLDs in Sweden. The PTLD biopsies were reevaluated and stained with the 236A/E7 antibody to detect FoxP3 in lymphoma tissue. Detailed clinical data were collected retrospectively from medical records.

    Results. Based on a cutoff level of 29 FoxP3+ cells per mm2, most (80%) of the PTLDs were FoxP3-. Forty-seven of 74 PTLDs displayed no FoxP3+ cells at all. The frequency of FoxP3+ cells did not influence median overall survival. The FoxP3- PTLDs were more frequently of T-cell phenotype (P=0.04), located at the graft (P=0.03), occurred earlier after transplantation (P=0.04), were more likely to develop in lung recipients (P=0.04), and in patients that had received anti T-cell globulin as induction therapy (P=0.02). The FoxP3+ PTLDs were associated with hepatitis C seropositivity (P=0.03). In multivariate analysis, B-cell PTLD and hepatitis C infection were independent predictors of FoxP3 positivity.

    Conclusion. Our findings suggest that intratumoral FoxP3+ Tregs do not influence survival in patients with PTLD. FoxP3+ Tregs are rare in PTLD, possibly because of heavy immunosuppression.

  • 22. Björnådal, Lena
    et al.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Yin, Li
    Granath, Fredrik
    Klareskog, Lars
    Ekbom, Anders
    Decreasing mortality in patients with rheumatoid arthrithis: results from large population based cohort in Sweden 1964-952002Inngår i: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 29, nr 5, s. 906-912Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:

    To assess changes in mortality in patients with rheumatoid arthritis (RA) from 1964 to 1995.

    METHODS:

    A population based cohort of 46,917 patients with RA was identified from 1964 to 1994, using the Swedish Hospital Discharge Register, and followed until 1995 through linkage to the Cause of Death Register. Mortality was separately analyzed in each inclusion period (1964-75, 1975-84, 1985-94). The relative risk of death was estimated as standardized mortality ratio (SMR) using the Swedish population as a reference

    RESULTS:

    All-cause mortality was increased twice the expected (SMR = 2.03, 95% CI 2.00, 2.05). Coronary artery disease was the major cause of death and mortality was increased by 80% (SMR = 1.79, 95% CI 1.75, 1.83). Females with RA aged 20-39 at first discharge had a more than 5-fold increased risk of coronary death (SMR = 5.48, 95% CI 3.45-5.71). From 1975 patients with RA had decreasing all-cause mortality. This decline was most pronounced in patients aged 40-59 at first discharge, where SMR was 2.68 (95% CI 2.45, 2.92) from 1964 to 1974 compared to SMR 1.63 (95% CI 1.37, 1.92) from 1985 to 1994.

    CONCLUSION:

    The elevated mortality rates in RA patients compared to the general population have decreased during the last 20 years, possibly due to an increased access to specialized rheumatology care. An excess risk for death in coronary artery disease was, however, present in RA patients, especially patients with early onset of disease.

  • 23. Brauner, S.
    et al.
    Zhou, W.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Green, T. M.
    Folkersen, L.
    Ivanchenko, M.
    Lofstrom, B.
    Xu-Monette, Z. Y.
    Young, K. H.
    Pedersen, L. Moller
    Moller, M. Boe
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Enblad, G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Wahren-Herlenius, M.
    Reduced expression of TRIM21/Ro52 predicts poor prognosis in diffuse large B-cell lymphoma patients with and without rheumatic disease2015Inngår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 278, nr 3, s. 323-332Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ObjectiveTRIM21 (also known as Ro52) is an autoantigen in rheumatic disease and is predominantly expressed in leucocytes. Overexpression is associated with decreased proliferation, and the TRIM21 gene maps to a tumour suppressor locus. We therefore investigated the expression of TRIM21 in patients with diffuse large B-cell lymphoma (DLBCL) and its potential usefulness as a prognostic biomarker. Materials and methodsTRIM21 expression levels were assessed by immunohistochemistry in lymphoma biopsies from three cohorts of patients with DLBCL: 42 patients with rheumatic disease treated with a cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP)-like regimen, 76 CHOP-treated and 196 rituximab-CHOP-treated nonrheumatic patients. Expression was correlated with clinical and biomedical parameters. TRIM21 expression was assessed in relation to lymphocyte proliferation by quantitative PCR and correlated with H-3-thymidine incorporation and propidium iodine staining. ResultsTRIM21 expression levels differed in the lymphomas compared to normal lymphoid tissue, with reduced expression correlating with shorter overall survival in all three cohorts. In the two larger cohorts, progression-free survival was assessed and was also found to correlate with TRIM21 expression. The association was independent of commonly used clinical prognostic scores, lymphoma subtype and several previously reported prognostic biomarkers. In agreement with this clinical observation, we noted an inverse correlation between TRIM21 expression and proliferation of leucocytes invitro. ConclusionsWe show that loss of TRIM21 expression is associated with more aggressive lymphoma and increased proliferation, whereas maintenance of TRIM21 expression is associated with better prognosis in patients with DLBCL. Based on our findings, we suggest that TRIM21 should be considered as a novel biomarker for lymphoma characterization and for predicting patient survival.

  • 24. Brauner, Susanna
    et al.
    Zhou, Wei
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Green, Tina M.
    Young, Ken He
    Lofstrom, Bjorn
    Lundberg, Ingrid
    Pedersen, Lars Moller
    Moller, Michael Boe
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Baecklund, Eva
    Wahren-Herlenius, Marie
    Ro52 Expression is a Prognostic Factor for Survival in B Cell Lymphoma2013Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, nr S1, s. A40-A40Artikkel i tidsskrift (Annet vitenskapelig)
  • 25.
    Cloutier, Basile Tessier
    et al.
    McGill Univ, Clin Epidemiol, Montreal, PQ, Canada..
    Farinha, Pedro
    British Columbia Canc Agcy, Pathol, Vancouver, BC V5Z 4E6, Canada..
    Bernatsky, Sasha
    McGill MUHC RVH, Rheum Clin Epid, Montreal, PQ, Canada..
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Clarke, Ann E.
    Montreal Gen Hosp, Immunol Epidemiol, Montreal, PQ H3G 1A4, Canada..
    Ramsey-Goldman, Rosalind
    SLICC, Chicago, IL USA..
    Gascoyne, Randy
    Univ British Columbia, BC Canc Agcy, Pathol, Vancouver, BC V5Z 1M9, Canada..
    Cell of Origin of Diffuse Large B-Cell Lymphoma (DLBCL) in Patients with Systemic Lupus Erythematosus (SLE)2015Inngår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, nr Suppl. 10, artikkel-id 719Artikkel i tidsskrift (Annet vitenskapelig)
  • 26.
    Enblad, Gunilla
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Martinsson, Gustaf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Hesselager, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hagberg, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Population-based experience on primary central nervous system lymphoma 2000-2012: the incidence is increasing2017Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, nr 4, s. 599-607Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Primary central nervous system lymphomas (PCNSL) are rare lymphomas with a poor prognosis. Recently, an increased incidence has been reported. The present study is a population-based study of all patients with PCNSL in the Uppsala/Örebro region of middle Sweden.

    PATIENTS AND METHODS: All patients diagnosed with a PCNSL at Uppsala University Hospital 2000-2012 were identified. Altogether, 96 patients (50 women and 46 men) were included. The median age at diagnosis was 66 years (17-95).

    RESULTS: There was a statistically significant increase in age-standardized incidence during the study period, 30 patients were diagnosed in the first half and 66 in the second half of the period. No patient had an HIV-infection. Two patients had undergone kidney transplantation and were treated with immunosuppressive drugs. A high proportion of the patients, 29%, had a history of an autoimmune or inflammatory disease. The prognosis was poor with a median survival of only four months. In the 70 (73%) patients treated with curative intention the median survival was 12 months. Patients treated with high-dose methotrexate, radiotherapy and/or temozolomide appeared to have a better survival. There was no improvement in survival during the study period or after the introduction of rituximab. There also was no difference in any of the analyzed variables that could explain the increased incidence.

    CONCLUSION: In this population-based study we could confirm the previously described increased incidence of PCNSL. The prognosis remains poor despite the inclusion of treatment with rituximab during the study period. A high proportion of the patients had a history of an autoimmune or inflammatory disease not previously described but there was no increase during the study period.

  • 27. Fernberg, P.
    et al.
    Edgren, G.
    Adami, J.
    Ingvar, Å.
    Bellocco, R.
    Tufveson, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Transplantationskirurgi.
    Höglund, P.
    Kinch, Amelie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Simard, J. F.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Lindelöf, B.
    Pawitan, Y.
    Smedby, K. E.
    Time Trends in Risk and Risk Determinants of Non-Hodgkin Lymphoma in Solid Organ Transplant Recipients2011Inngår i: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 11, nr 11, s. 2472-2482Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Organ transplantation increases risk of non-Hodgkin lymphoma (NHL), but long-term risk and time trends have seldom been evaluated. Immunosuppressive drug load is an important risk determinant, but the details are unclear. We studied NHL risk in a nationwide Swedish cohort of 11 081 graft recipients transplanted 1970-2008. Relative risks (RRs) were estimated within the cohort and versus the general population by age, sex, follow-up time and calendar period. NHL risk was also assessed by cumulative and average doses of immunosuppressive treatments in a nested case-control design throughout 1997 using conditional logistic regression. We observed 153 NHL cases during 97 853 years of follow-up. Compared with the general population, NHL risk was eightfold increased (RR 7.9; 95% confidence interval [CI] 6.6-9.4), and increased risks persisted after >= 15 years of follow-up among kidney (6.1; 95% CI 3.5-10) and nonkidney recipients (44; 14-103). Among nonkidney recipients, NHL risk was lower in the 2000s compared with the 1990s (0.5; 95% CI 0.3-1.0; p = 0.04). A high average dose of antithymocyte immunoglobulin (ATG) conferred an eightfold increased risk of NHL (OR 8.5; 95% CI 1.9-38). To conclude, posttransplant NHL risk decreased during the last decade among nonkidney recipients, possibly because of a more careful use of ATG, the introduction of new drugs, or both.

  • 28.
    Forsman, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk virologi.
    Uzameckis, Dmitrijs
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk virologi.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Åleskog, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Bindra, Amarinder
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk virologi.
    Pipkorn, Rüdiger
    Lejniece, Sandra
    Kozireva, Svetlana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk virologi.
    Murovska, Modra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk virologi.
    Blomberg, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk virologi.
    Single-tube nested quantitative PCR: a rational and sensitive technique for detection of retroviral DNA. Application to RERV-H/HRV-5 and confirmation of its rabbit origin2003Inngår i: Journal of Virological Methods, ISSN 0166-0934, E-ISSN 1879-0984, Vol. 111, nr 1, s. 1-11Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    It was reported earlier that a few patients suffering from non-Hodgkin's lymphoma had low amounts of DNA from the so-called fifth human exogenous retrovirus, HRV-5. A sensitive and rational method for large-scale screening for HRV-5 DNA was therefore developed. It is a single-tube nested quantitative PCR (stnQPCR), which uses two functionally isolated primer pairs and one probe target distinct from related endogenous retroviral sequences, yet encompassing known HRV-5 variation, allowing optimal use of sequence conservation. DNA from lymphoma, myeloma, and follicular dendritic cell lines was tested for HRV-5 positivity, as was DNA from whole blood of blood donors, non-Hodgkin's lymphoma and systemic lupus erythematosus patients, as well as DNA from lymph node biopsies of rheumatoid arthritis patients with lymphoma. One blood donor, one systemic lupus erythematosus patient, two previously known positive non-Hodgkin's lymphoma patients, and one rheumatoid arthritis lymphoma patient, came out positive. They had 24, 2, 148, 480 and 30 proviral copies per microg of DNA from PBMC or lymphoma tissue, respectively. During the completion of this work it was reported that HRV-5 is a rabbit endogenous retrovirus (RERV-H), and that HRV-5 positivity was due to presence of rabbit DNA. DNA from six RERV-H/HRV-5 positive samples was therefore retested. Three also contained rabbit mitochondrial DNA. A search for HRV-5 antibodies using synthetic peptides was negative in sera from three RERV-H/HRV-5 positive individuals, as well as in 144 other sera, according with a noninfectious origin of the RERV-H/HRV-5 DNA in human samples. A search for possible sources of rabbit DNA contamination was negative. Methods for prevention of PCR contamination were strictly adhered to. Three samples from RERV-H/HRV-5 positive individuals positive at the Uppsala laboratory were retested at one or two other laboratories, and all three were positive. Two other samples, which were positive in the Riga laboratory, were tested also in London and also found positive. One non-Hodgkin's lymphoma patient was RERV-H/HRV-5 positive in four consecutive samples, showing that positivity was a property of that patient. It is concluded that the stnQPCR developed to detect and quantify minute amounts of RERV-H/HRV-5 DNA is a principle which can be applied widely and HRV-5 is a RERV-H. Its presence in a few human blood samples could not be explained.

  • 29.
    Frisell, T.
    et al.
    Karolinska Inst, Stockholm, Sweden..
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Bengtsson, K.
    Sahlgrens Acad, Gothenburg, Sweden..
    Di Giuseppe, D.
    Karolinska Inst, Stockholm, Sweden..
    Forsblad-d'Elia, H.
    Umea Univ, Umea, Sweden..
    Askling, J.
    Karolinska Inst, Stockholm, Sweden..
    Confounding By Indication Will Make Non-Tnfi Bdmards Appear More Harmful Than Tnfi Bdmards A Nationwide Study Of Channeling In Sweden 2010-20142017Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, s. 134-135Artikkel i tidsskrift (Annet vitenskapelig)
  • 30. Frisell, Thomas
    et al.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Bengtsson, Karin
    Di Giuseppe, Daniela
    Forsblad-d'Elia, Helena
    Askling, Johan
    Patient characteristics influence the choice of biological drug in RA, and will make non-TNFi biologics appear more harmful than TNFi biologics2018Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, nr 5, s. 650-657Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: With the wide range of biological disease-modifying anti-rheumatic drugs (bDMARDs) available for treating rheumatoid arthritis (RA), and limited evidence to guide the choice for individual patients, we wished to evaluate whether patient characteristics influence the choice of bDMARD in clinical practice, and to quantify the extent to which this would bias direct comparisons of treatment outcome.

    Methods: Register-based study of all Swedish patients with RA initiating necrosis factor inhibitor (TNFi), rituximab, abatacept or tocilizumab in 2011–2015 as their first bDMARD (n=6481), or after switch from TNFi as first bDMARD (n=2829). Group differences in demographics, clinical characteristics and medical history were assessed in multivariable regression models. Predicted differences in safety and treatment outcomes were calculated as a function of patient characteristics, through regression modelling based on observed outcomes among patients with RA starting bDMARDs 2006–2010.

    Results: Patients starting non-TNFi were older than those starting TNFi, had lower socioeconomic status, higher disease activity and higher burden of diseases including malignancy, serious infections and diabetes. Differences were most pronounced at first bDMARD initiation. These factors were linked to treatment outcome independent of therapy, yielding worse apparent safety and effectiveness for non-TNFi biologics, most extreme for rituximab. Standardising to the age/sex distribution of the TNFi group reduced differences considerably.

    Conclusions: There was significant channelling of older and less healthy patients with RA to non-TNFi bDMARDs, in particular as first bDMARD. Whether this channelling represents a maximised benefit/risk ratio is unclear. Unless differences in age, medical history and disease activity are accounted for, they will substantially confound non-randomised comparative studies of available bDMARDs’ safety and effectiveness.

  • 31.
    Gron, Kathrine Lederballe
    et al.
    Rigshosp, DANBIO, Copenhagen, Denmark;Rigshosp, Ctr Head & Orthoped, Ctr Rheumatol & Spine Dis, Copenhagen Ctr Arthrit Res COPECARE, Copenhagen, Denmark;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark.
    Arkema, Elizabeth V.
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Glintborg, Bente
    Rigshosp, DANBIO, Copenhagen, Denmark;Rigshosp, Ctr Head & Orthoped, Ctr Rheumatol & Spine Dis, Copenhagen Ctr Arthrit Res COPECARE, Copenhagen, Denmark;Copenhagen Univ Hosp, Gentofte & Herlev Hosp, Dept Rheumatol, Copenhagen, Denmark.
    Mehnert, Frank
    Aarhus Univ Hosp, Dept Clin Epidemiol, Aarhus, Denmark.
    Ostergaard, Mikkel
    Rigshosp, DANBIO, Copenhagen, Denmark;Rigshosp, Ctr Head & Orthoped, Ctr Rheumatol & Spine Dis, Copenhagen Ctr Arthrit Res COPECARE, Copenhagen, Denmark;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark.
    Dreyer, Lene
    Aalborg Univ, Dept Clin Med, Aalborg, Denmark;Aalborg Univ, Dept Rheumatol, Aalborg, Denmark;Aalborg Univ Hosp, Aalborg, Denmark.
    Norgaard, Mette
    Aarhus Univ Hosp, Dept Clin Epidemiol, Aarhus, Denmark.
    Krogh, Niels Steen
    ZiteLab ApS, Copenhagen, Denmark.
    Askling, Johan
    Karolinska Inst, Dept Med, Stockholm, Sweden;Karolinska Inst, Stockholm, Sweden.
    Hetland, Merete Lund
    Rigshosp, DANBIO, Copenhagen, Denmark;Rigshosp, Ctr Head & Orthoped, Ctr Rheumatol & Spine Dis, Copenhagen Ctr Arthrit Res COPECARE, Copenhagen, Denmark;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark.
    Risk of serious infections in patients with rheumatoid arthritis treated in routine care with abatacept, rituximab and tocilizumab in Denmark and Sweden2019Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, nr 3, s. 320-327Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective To estimate (1) crude and age-and gender-adjusted incidence rates (IRs) of serious infections (SI) and (2) relative risks (RR) of SI in patients with rheumatoid arthritis (RA) initiating treatment with abatacept, rituximab or tocilizumab in routine care. Methods This is an observational cohort study conducted in parallel in Denmark and Sweden including patients with RA in Denmark (DANBIO) and Sweden (Anti-Rheumatic Treatment in Sweden Register/Swedish Rheumatology Quality Register) who started abatacept/rituximab/tocilizumab in 2010-2015. Patients could contribute to more than one treatment course. Incident SI (hospitalisations listing infection) and potential confounders were identified through linkage to national registries. Age-and gender-adjusted IRs of SI per 100 person years and additionally adjusted RRs of SI during 0-12 and 0-24 months since start of treatment were assessed (Poisson regression). Country-specific RRs were pooled using inverse variance weighting. Results We identified 8987 treatment courses (abatacept: 2725; rituximab: 3363; tocilizumab: 2899). At treatment start, rituximab-treated patients were older, had longer disease duration and more previous malignancies; tocilizumab-treated patients had higher C reactive protein. During 0-12 and 0-24 months of follow-up, 456 and 639 SI events were identified, respectively. The following were the age-and gender-adjusted 12-month IRs for abatacept/rituximab/tocilizumab: 7.1/8.1/6.1 for Denmark and 6.0/6.4/4.7 for Sweden. The 24-month IRs were 6.1/7.5/5.2 for Denmark and 5.6/5.8/4.3 for Sweden. Adjusted 12-month RRs for tocilizumab versus rituximab were 0.82 (0.50 to 1.36) for Denmark and 0.76 (0.57 to 1.02) for Sweden, pooled 0.78 (0.61 to 1.01); for abatacept versus rituximab 0.94 (0.55 to 1.60) for Denmark and 0.86 (0.66 to 1.13) for Sweden, pooled 0.88 (0.69 to 1.12); and for abatacept versus tocilizumab 1.15 (0.69 to 1.90) for Denmark and 1.14 (0.83 to 1.55) for Sweden, pooled 1.13 (0.91 to 1.42). The adjusted RRs for 0-24 months were similar. Conclusion For patients starting abatacept, rituximab or tocilizumab, differences in baseline characteristics were seen. Numerical differences in IR of SI between drugs were observed. RRs seemed to vary with drug (tocilizumab < abatacept < rituximab) but should be interpreted with caution due to few events and risk of residual confounding.

  • 32.
    Hellbacher, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Hjorton, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Knight, Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Malignant Lymphoma In Granulomatosis With Polyangiitis2017Inngår i: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 56Artikkel i tidsskrift (Fagfellevurdert)
  • 33.
    Hellgren, K.
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Stockholm, Sweden..
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Smedby, K. E.
    Karolinska Univ Hosp, Karolinska Inst, Stockholm, Sweden..
    Askling, J.
    Karolinska Univ Hosp, Karolinska Inst, Stockholm, Sweden..
    Rheumatoid Arthritis and Risk of Malignant Lymphoma - Is the risk still increased?2017Inngår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69, nr 4, s. 700-708Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas with a strong correlation with RA disease severity. Given the changes in RA therapy over recent decades, we aimed at assessing whether lymphoma risk remains increased, and if so, to explore risk predictors and lymphoma subtypes.

    METHODS: We identified 12,656 incident RA patients from the Swedish Rheumatology Register 1997-2012 including information on therapy and inflammatory activity during the first year following diagnosis. Each patient was matched to 10 population comparator subjects. Through linkage to the Swedish Cancer Register, lymphomas including subtypes were identified. We assessed Hazard ratios (HRs) using Cox regression.

    RESULTS: Overall, the HR of lymphoma was increased, 1.6, 95% confidence interval [CI] 1.2-2.1. Taking RA duration into account, risks did not appear to have declined over successive calendar years of RA diagnosis. Neither use of methotrexate the 1(st) year following RA diagnosis nor ever use of TNF inhibitors (HR=0.9; 95% CI 0.4-1.9) increased lymphoma risk. Use of oral corticosteroids the 1(st) year following RA diagnosis was associated with a reduced risk (HR=0.6; 95% CI 0.5 -0.9). Inflammatory activity during the 1(st) year following RA diagnosis did not predict future lymphoma risk. Chronic lymphocytic lymphoma occurred less, and Hodgkin lymphoma more frequently than expected compared to the general population.

    CONCLUSION: The average lymphoma risk in recently diagnosed RA is of similar magnitude as that reported from historical cohorts. Standard anti-rheumatic treatment including TNF inhibitors did not predict future lymphoma risk. Distribution of lymphoma subtypes warrants further investigation.

  • 34. Hellgren, K.
    et al.
    Smedby, K. E.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Feltelius, N.
    Eriksson, J. K.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Askling, J.
    Ankylosing Spondylitis, Psoriatic Arthritis, and Risk of Malignant Lymphoma: A Cohort Study Based on Nationwide Prospectively Recorded Data From Sweden2014Inngår i: Arthritis & Rheumatology, ISSN 2326-5191, Vol. 66, nr 5, s. 1282-1290Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective. Data on lymphoma risk in ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are scarce. This study was undertaken to assess the risk of lymphoma in AS and PsA overall and in relation to therapies, including tumor necrosis factor inhibitor (TNFi), for which lymphoma risks are a concern. Methods. Through the Swedish National Patient Register we assembled nationwide prevalence cohorts of patients with AS (n = 8,707) and patients with PsA (n = 19,283) for whom data were obtained between 2001 and 2010. Each cohort member was matched to 5 population comparator subjects. Linkage with the nationwide Cancer Register identified all lymphomas recorded from 2001 to 2010. Through the Swedish Biologics Register (Anti-Rheumatic Therapy in Sweden [ARTIS]), we identified patients exposed to TNFi in the AS cohort (n = 1,908) and the PsA cohort (n = 2,605) before lymphoma diagnosis. Hazard ratios (HRs) for lymphoma were estimated by Cox regression. Crude incidences of lymphoma in TNFi-exposed and TNFi-naive patients were compared. Results. For AS patients, the HR of having lymphoma versus the general population was 0.9 (95% confidence interval [95% CI] 0.5-1.6) (14 lymphomas). For PsA patients, the corresponding HR was 1.2 (95% CI 0.9-1.7) (45 lymphomas). For PsA patients treated with methotrexate and/or sulfasalazine, the HR of having lymphoma was 1.7 (95% CI 1.0-3.1). The numbers and incidence of lymphoma were not materially different in TNFi-exposed versus TNFi-naive AS and PsA patients, although the numbers of lymphomas were small. Conclusion. In contrast to rheumatoid arthritis, the average risks of lymphoma in AS or PsA are not elevated, although increased risks in a subset of PsA patients cannot be excluded. Our findings indicate that TNFi does not affect the risk of lymphoma in AS or in PsA.

  • 35. Hellgren, Karin
    et al.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Smedby, Karin E.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Askling, Johan
    Rheumatoid Arthritis and Risks of Malignant Lymphoma: Are Risks Still Increased?2012Inngår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, nr S10, s. S525-S526Artikkel i tidsskrift (Annet vitenskapelig)
  • 36. Hellgren, Karin
    et al.
    Iliadou, Anastasia
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Feltelius, Nils
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Askling, Johan
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Rheumatoid arthritis, treatment with corticosteroids, and risk of malignant lymphomas: results from a case-control study2010Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 69, nr 4, s. 654-659Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:

    Benefits and risks of corticosteroid treatment in rheumatoid arthritis (RA) are debated. Patients with RA are at increased risk of malignant lymphomas. In a large case-control study of risk factors for lymphoma in RA, we recently reported that steroid treatment was associated with decreased lymphoma risk. This study sought to further assess the nature of this association.

    METHODS:

    In a cohort of 74,651 patients with RA, we identified 378 cases with lymphoma and 378 matched RA controls, and abstracted information on inflammatory activity and different aspects of steroid treatment (duration, therapeutic strategy and mode of administration) from their medical records. Lymphomas were reclassified (WHO classification) and examined for Epstein-Barr virus. Relative risks were assessed as adjusted odds ratios (OR) through conditional logistic regression.

    RESULTS:

    A total duration of oral steroid treatment less than two years was not associated with lymphoma risk (OR=0.87; 95% confidence interval [CI] 0.51-1.5), whereas total treatment longer than two years was associated with a lower lymphoma risk (OR= 0.43; 95% CI 0.26-0.72). RA duration at the initiation of oral steroids did not affect lymphoma risk. Intra-articular steroids were associated with a reduced lymphoma risk, but only when used as swift flare therapy (OR= 0.22; 95% CI 0.13-0.37). Analyses by lymphoma subtype showed a reduced risk of diffuse large B-cell lymphoma (crude OR=0.59; 95% CI 0.37-0.94).

    CONCLUSION:

    In this RA population, use of steroids was associated with reduced lymphoma risk. Whether this association is a generic effect of steroids or specific to the studied population remains unknown.

  • 37. Hellgren, Karin
    et al.
    Smedby, Karin E.
    Feltelius, Nils
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Askling, Johan
    Do rheumatoid arthritis and lymphoma share risk factors?: A comparison of lymphoma and cancer risks before and after diagnosis of rheumatoid arthritis2010Inngår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, nr 5, s. 1252-1258Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Patients with rheumatoid arthritis (RA), in particular those with the most severe disease, are at increased risk of malignant lymphoma. Whether this increase is entirely consequential to the RA disease and/or its treatment or reflective of shared susceptibility to the two diseases remains unclear. To resolve this, we assessed whether patients with RA are at increased risk of lymphoma or of other cancers, already before diagnosis of RA, and if the relative risk increases with time since RA diagnosis.

    METHODS: 6,745 patients with incident RA (ACR criteria, symptom duration < 1 year) registered in the Swedish Early RA register from 1997 through 2006 were identified. For each patient, five general population controls were randomly matched by gender, age, marital status and residence (n=33,657). All individuals were linked to the nationwide Swedish Cancer Register 1958-2006. Relative risks (RR) of lymphoma and cancer overall before and after the diagnosis of RA were estimated using conditional logistic and Cox regression, respectively.

    RESULTS: Before diagnosis of RA, no increased risk of lymphoma (RR= 0.67, 95% CI 0.37-1.23) or other cancers (RR= 0.78, 95% CI 0.70-0.88) was observed. During the first ten years following diagnosis of RA, the overall RR of lymphoma was 1.75 (95 % CI 1.04-2.96).

    CONCLUSION: Overall, a history of cancer, lymphoma included, does not increase the risk of subsequent RA development. Shared susceptibility for RA and lymphoma may thus be of limited importance. By contrast increased lymphoma risks were observed already within the first decade following RA diagnosis.

  • 38.
    Hellgren, Karin
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden.;Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Sundstrom, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Askling, Johan
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden.;Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Lymphoma in Patients with Rheumatoid Arthritis Treated with Biologic Drugs: Long-Term Follow-up of Risks and Lymphoma Subtypes2015Inngår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, nr Suppl. 10, artikkel-id 2052Artikkel i tidsskrift (Annet vitenskapelig)
  • 39.
    Hjorton, Karin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Hellbacher, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Sundstrom, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Knight, Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Lymphoma in Patients with Granulomatosis with Polyangiitis2015Inngår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, nr Suppl 10, artikkel-id 869Artikkel i tidsskrift (Annet vitenskapelig)
  • 40. Ivanchenko, Margarita
    et al.
    Brauner, Susanna
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Wahren-Herlenius, Marie
    Ro52/TRIM21 Expression is Decreased in Malignant B Cells2014Inngår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, nr 6, s. 453-454Artikkel i tidsskrift (Annet vitenskapelig)
  • 41.
    Karlsson Sundbaum, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Lulea Univ Technol, Dept Hlth Sci, Lulea, Sweden.
    Eriksson, Niclas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hallberg, Pär
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lehto, Niklas
    Lulea Univ Technol, Dept Hlth Sci, Lulea, Sweden.
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: A long-term follow-up of predictors, surveillance, and outcome in clinical practice2019Inngår i: INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, ISSN 1756-1841, Vol. 22, nr 7, s. 1226-1232Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: To assess predictors of alanine aminotransferase (ALT) elevation in methotrexate (MTX) treated rheumatoid arthritis (RA) patients, and to describe the monitoring of liver enzymes, including handling and outcome of elevated ALT.

    Methods: All RA patients starting MTX in January, 2005 to April, 2013 at a rheumatology clinic, (Uppsala University Hospital, Sweden) were identified from electronic medical records. Clinical and laboratory data were obtained from medical records, supplemented by telephone interviews. Predictors for ALT >1.5x over the upper limit of normal (ULN) were identified by multiple regression analysis.

    Results: The study comprised 213 RA patients starting MTX. During a mean follow-up of 4.3 years, 6288 ALT tests were performed; 7% of tests with ALT were >ULN. ALT >1.5x ULN was observed in 44 (21%) patients and the strongest predictor was a pre-treatment elevation of ALT (adjusted odds ratio = 6.8, 95% CI 2.2-20.5). Recurrent elevations occurred in 70% of patients who continued treatment, and the proportion was similar in those with and without interventions, for example MTX dose reduction (67% vs 73%, P = 0.43). Seven patients (3%) permanently stopped MTX due to ALT elevation, and two were eventually diagnosed with non-alcoholic fatty liver disease. No patient developed hepatic failure.

    Conclusion: Only a small number of ALT tests performed during MTX therapy in RA capture an elevation. A pre-treatment elevation of ALT was the strongest predictor for early and recurrent ALT elevations during therapy. This study supports a more individualized approach to monitoring and handling of ALT elevations during MTX therapy in RA than recommended in current guidelines.

  • 42.
    Kinch, Amelie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Ekman, Tor
    Molin, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Tufveson, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Transplantationskirurgi.
    Fernberg, Pia
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Pauksens, Karlis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    A population-based study of 135 lymphomas after solid organ transplantation: The role of Epstein-Barr virus, hepatitis C and diffuse large B-cell lymphoma subtype in clinical presentation and survival.2014Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, nr 5, s. 669-679Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. Epstein-Barr virus (EBV) plays a major role in the development of post-transplant lymphoproliferative disorder (PTLD), but there is an increasing awareness of EBV-negative PTLD. The clinical presentation of EBV-negative PTLD has not been as well characterised as EBV-positive cases. Further, there is limited knowledge on the clinical importance of diffuse large B-cell lymphoma (DLBCL) cell of origin subtype post-transplant. Materials and methods. We studied the role of EBV, hepatitis C (HCV) and DLBCL subtype in clinical presentation and survival in 135 post-transplant lymphomas diagnosed 1980-2006 in a population-based cohort of 10 010 Swedish solid organ transplant recipients. The lymphomas were re-evaluated according to WHO 2008, examined for EBV, and clinical data were collected from medical records. Results. Lymphoma incidence rate was 159/100 000 person-years and is also reported by lymphoma subtype. EBV-negative lymphomas constituted 48% and were associated with HCV infection (p = 0.02), bone marrow involvement (p < 0.001), and T-cell phenotype (p = 0.002). Among DLBCL, 78% were of non-germinal centre subtype, which was associated with EBV-positivity (69%, p = 0.001), early occurrence (p = 0.03), heart/liver/lung/pancreas recipients (p = 0.02), anti-T-cell globulin (p = 0.001), and tacrolimus treatment (p = 0.02). DLBCL subtypes had similar overall survival. Five-year overall survival was 42% in all treated patients. Independent poor prognostic factors were older age, B symptoms, ECOG 2-4, kidney/pancreas/heart recipients, T-cell lymphoma, and HCV-infection. Conclusions. With long follow-up, a large part of PTLD is EBV-negative, due to a high proportion of T-cell lymphomas and low of polymorphic PTLD. EBV-negative PTLD have a different clinical presentation. HCV may play an aetiological role in late-onset PTLD and was revealed as a new prognostic factor for inferior survival that needs to be confirmed in larger studies. The heavier immunosuppression in non-kidney transplantations seems to play a role in the development of non-germinal centre DLBCL. DLBCL cell of origin subtype lacks prognostic importance in the transplant setting.

  • 43.
    Kinch, Amelie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Cavelier, Lucia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Bengtsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Thunberg, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Pauksens, Karlis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Donor or Recipient Origin of Posttransplant Lymphoproliferative Disorders Following Solid Organ Transplantation2014Inngår i: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 14, nr 12, s. 2838-2845Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Previous studies of donor or recipient origin of posttransplant lymphoproliferative disorders (PTLDs) following solid organ transplantation (SOT) have either been small or with selected patient groups. We studied tumor origin in a population-based cohort of 93 patients with PTLD following SOT. Tumor origin of PTLD tissue was analyzed by fluorescence in situ hybridization of the sex chromosomes in cases of sex mismatch between donor and recipient (n=41), or HLA genotyping in cases of identical sex but different HLA type (n=52). Tumor origin of PTLD could be determined in 67 of the 93 cases. All 67 PTLDs were of recipient origin. They were found in recipients of kidney (n=38), liver (n=12), heart (n=10) and lung (n=7). The most common recipient-derived lymphomas were monomorphic B-cell PTLDs (n=45), monomorphic T cell PTLDs (n=9), indolent lymphomas (n=6), and polymorphic PTLD (n=4). Half of the recipient-derived PTLDs were Epstein–Barr virus-positive. Twelve of the recipient-derived PTLDs were located in the grafts: in four cases exclusively and in eight cases in combination with disseminated disease outside the graft. Tumor origin was indeterminable in 26 cases, probably due to low DNA quality. We conclude that the vast majority of PTLDs after SOT was of recipient origin.

  • 44.
    Kinch, Amelie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Molin, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Expression of PD-1, PD-L1, and PD-L2 in posttransplant lymphoproliferative disorder after solid organ transplantation2019Inngår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 60, nr 2, s. 376-384Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We studied the expression of programed death 1 (PD-1) receptor and its ligands (PD-L1/-L2) by immunohistochemistry and its association with clinicopathological features in 81 posttransplant lymphoproliferative disorders (PTLDs) following solid organ transplantation. Overall, 67% (54/81) of the PTLDs were positive in any of the three immunostainings. PD-1 was detected on tumor-infiltrating cells in 41% (33/81) of the PTLDs. PD-L1 was expressed on ≥5% of the tumor cells in 50% (40/80) and PD-L2 in 32% (23/72) of the PTLDs. All Burkitt lymphomas were PD-L1 negative. Expression of PD-L1 tended to be associated with non-germinal center-type of diffuse large B-cell lymphoma (63% vs. 33% in GC-type, p = .14) and latent membrane protein-1+ PTLD (76% vs. 44% in LPM1-, p = .09). Heart recipients had more frequent PTLDs with PD-1+ microenvironment (p = .01). The frequent expression of PD-1 or -L1/-L2 in PTLD warrants further clinical evaluation of the efficacy and safety of PD-(L)1 inhibitors for refractory PTLD.

  • 45.
    Knight, A
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Hallenberg, H
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Efficacy and safety of rituximab as maintenance therapy for relapsing granulomatosis with polyangiitis-a case series.2014Inngår i: Clinical Rheumatology, ISSN 0770-3198, E-ISSN 1434-9949, Vol. 33, nr 6, s. 841-848Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The objective of this work was to study the efficacy and safety of pre-emptive rituximab (RTX) in a series of patients with severe relapsing granulomatosis with polyangiitis (GPA). GPA is a systemic vasculitis with a high relapse rate despite successful remission induction. Drug toxicity with repeated induction treatments and long-standing immunosuppression poses a problem. Based on the findings in reports on RTX for rheumatoid arthritis, we treated patients with severe relapsing GPA with pre-emptive RTX, 1,000 mg 2 weeks apart every 6 months, aiming at achieving sustainable remission. All patients at one centre with relapsing GPA in spite of traditional maintenance treatment, who had received more than or equal to three cycles of RTX as regularly repeated pre-emptive maintenance therapy every 6 months, were included in this retrospective study. Information on disease manifestations and activity, treatments, lab parameters and adverse events was extracted from the medical files. Of the 12 included patients, all with a positive proteinase 3-anti-neutrophil cytoplasmic antibodies, generalised disease and a median disease duration of 35 months (21-270), 92 % (11/12) achieved sustainable remission during a median follow-up time of 32 months (range 21-111) from first RTX treatment. Concomitant immunosuppressants were reduced. Infections were the most common adverse events, but infections were an issue also before the start of RTX. RTX administered every 6 months seems to be an effective maintenance treatment in a population with severe, relapsing long-standing GPA. Granulomatous as well as vasculitic manifestations responded equally well. Infections are a problem in this patient group but no new safety problems were identified.

  • 46.
    Knight, Ann
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Hjorton, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Höglund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Smedby, Karin E
    Askling, Johan
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Leukemia and Myelodysplastic Syndrome in Granulomatosis with Polyangiitis: Subtypes, Clinical Characteristics, and Outcome2015Inngår i: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 42, nr 4, s. 690-694Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Previous studies have shown that patients with granulomatosis with polyangiitis (GPA) have an increased risk of hematological malignancies, especially leukemia. Our aim was to assess clinical characteristics and treatment of patients with GPA complicated by hematological malignancies with focus on leukemia and to describe these malignancies in more detail.

    METHODS: From the Swedish population-based patient register, all individuals with a diagnosis of GPA from 1964-2012 were identified (n = 3224). Through linkage with the Swedish Cancer Register, we searched for all cases of leukemia [International Classification of Diseases (ICD) 7: 204-207 and corresponding codes ICD 8-10] registered after the first discharge listing GPA. The GPA diagnosis was evaluated using the European Medical Association classification algorithm. To confirm the hematological malignancy, all diagnostic bone marrow samples were reclassified. Clinical data of both the GPA and hematological malignancy were collected from medical files.

    RESULTS: Twenty-one cases were identified, all of myeloid origin, including 9 with myelodysplastic syndrome developing to acute myeloid leukemia (MDS-AML), 7 AML, 3 MDS, and 2 chronic myeloid leukemia. The median time from GPA diagnosis to hematological malignancy was 8 years (range 5-21). All patients had severe generalized GPA and had received high doses of cyclophosphamide (CYC; median cumulative dose 96.5 g). Cytopenia occurred in 76% of the patients prior to the hematological malignancy.

    CONCLUSION: The findings emphasize the longterm risk of leukemia and MDS in CYC-treated, severely ill patients with GPA. Cytopenia during the course of GPA may be a warning sign and warrants a liberal attitude toward bone marrow examination.

  • 47. Krynitz, Britta
    et al.
    Edgren, Gustaf
    Lindelöf, Bernt
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Brattström, Christina
    Wilczek, Henryk
    Smedby, Karin E.
    Risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008: A Swedish population-based study2013Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 132, nr 6, s. 1429-1438Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Organ transplant recipients are at increased risk of a wide range of malignancies, especially cutaneous squamous cell carcinomas (SCC). Few previous population-based studies have quantified and compared cancer risks according to graft type and with long-term follow-up. Using nationwide Swedish registers, we identified 10,476 recipients transplanted from 1970 to 2008 and followed them for cancer occurrence. Relative risks of cancer in comparison with the general population were expressed as standardized incidence ratios (SIR) and within the transplanted cohort as incidence rate ratios (IRR). During a total follow-up of 93,432 person-years, patients were diagnosed with 1,175 cancers excluding SCC, and with 2,231 SCC, SIRcancer excl SCC 2.4 (95% CI, 2.2–2.5); SIRSCC 121 (95% CI, 116–127). Cancer risks were most increased among heart and/or lung recipients SIRcancer excl SCC 3.3 (95% CI, 2.8–4.0); SIRSCC 198 (95% CI, 174–224), followed by kidney SIRcancer excl SCC 2.3 (95% CI, 2.1–2.4); SIRSCC 121 (95% CI, 116–127) and liver recipients SIRcancer excl SCC 2.3 (95% CI, 1.9–2.8); SIRSCC 32 (95% CI, 24–42). During follow-up, risk of cancer excluding SCC remained stable while risk of SCC tripled over 20 years irrespective of graft type, partly due to a subgroup of patients developing new SCCs at a rapidly increasing rate. In summary, post-transplant cancer risk varied by transplanted organ and by cancer site, with the bulk of the excess risk driven by an exceptionally high and accelerating risk of SCC. These findings underscore the importance of regular skin screening in organ transplant recipients.

  • 48. Löfström, Bjorn
    et al.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Pettersson, Tom
    Lundberg, Ingrid E.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Expression of APRIL in Diffuse Large B Cell Lymphomas from Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis2011Inngår i: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 38, nr 9, s. 1891-1897Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have an increased risk of diffuse large B cell lymphoma (DLBCL). The cytokine A PRoliferating-Inducing Ligand (APRIL) is strongly expressed in DLBCL in the general population and is detected in high concentrations in sera from subgroups of patients with RA and SLE. To investigate a possible association between APRIL and DLBCL in RA and SLE, we examined APRIL expression in lymphoma biopsies from patients with RA and SLE and from DLBCL patients without inflammatory disease.

    Methods: Lymphoma tissue from 95 RA, 12 SLE, and 63 comparator DLBCL cases were stained with anti-APRIL antibodies (Aprily-2). The percentage of positively stained cells of the comparator cases were divided into quartiles (1-4, where 4 = most stained) and compared with the results for the RA and SLE lymphomas. APRIL expression was correlated to clinical variables.

    Results: The odds ratio for high expression of APRIL (quartiles 3 and 4) was elevated in the SLE DLBCL (OR 23.6, 95% CI 2.4-231.2), but not in the RA DLBCL (OR 0.8, 95% CI 0.3-2.0). RA patients in quartile 4 had higher cumulated RA disease activity than those in quartile I (p = 0.013). Epstein-Barr virus in the lymphoma tissue was associated with high APRIL expression (p = 0.009).

    Conclusion: The high expression of APRIL in DLBCL in SLE and in an RA subset might indicate an association between APRIL and lymphoma in these subsets of rheumatic diseases, but could also reflect a dysregulation of APRIL per se in these patient groups.

  • 49.
    Mercer, Louise K.
    et al.
    Univ Manchester, Arthrit Res UK Ctr Epidemiol, Manchester, Lancs, England..
    Regierer, Anne C.
    German Rheumatism Res Ctr, Epidemiol Unit, Berlin, Germany..
    Mariette, Xavier
    Univ Paris Sud, Hop Univ Paris Sud, Dept Rheumatol, Le Kremlin Bicetre, France..
    Dixon, William G.
    Univ Manchester, Arthrit Res UK Ctr Epidemiol, Manchester, Lancs, England..
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Hellgren, Karin
    Karolinska Inst, Clin Epidemiol Unit, Stockholm, Sweden..
    Dreyer, Lene
    Rigshosp, Gentofte Univ Hosp, Ctr Rheumatol & Spine Dis, Hellerup, Denmark.;Parker Inst, Frederiksberg, Denmark..
    Hetland, Merete Lund
    Rigshosp, Ctr Head & Orthopaed, Copenhagen Ctr Arthrit Res, DANBIO, Copenhagen, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark..
    Cordtz, Rene
    Rigshosp, Gentofte Univ Hosp, Ctr Rheumatol & Spine Dis, Hellerup, Denmark.;Parker Inst, Frederiksberg, Denmark..
    Hyrich, Kimme
    Univ Manchester, Arthrit Res UK Ctr Epidemiol, Manchester, Lancs, England.;Cent Manchester NHS Fdn Trust, Manchester Acad Hlth Sci, Natl Inst Hlth Res Manchester, Musculoskeletal Biomed Res Unit, Manchester, Lancs, England..
    Strangfeld, Anja
    German Rheumatism Res Ctr, Epidemiol Unit, Berlin, Germany..
    Zink, Angela
    German Rheumatism Res Ctr, Epidemiol Unit, Berlin, Germany.;Charite, Berlin, Germany..
    Canhao, Helena
    Univ Nova Lisboa, EpiDoC Unit, CEDOC, NOVA Med Sch, Lisbon, Portugal.;Natl Sch Publ Hlth, Lisbon, Portugal..
    Victoria Hernandez, M.
    Hosp Clin Barcelona, Dept Rheumatol, Barcelona, Spain..
    Tubach, Florence
    Univ Paris 06, Sorbonne Univ, Hop Pitie Salpetriere, AP HP,Dept BIOSPIM, Paris, France..
    Gottenberg, Jacques-Eric
    CHU Strasbourg, Dept Rheumatol, Strasbourg, France..
    Morel, Jacques
    Univ Montpellier, Dept Rheumatol, Montpellier, France.;Teaching Hosp Lapeyronie, Montpellier, France..
    Zavada, Jakub
    Charles Univ Prague, Fac Med 1, Inst Rheumatol, Prague, Czech Republic..
    Iannone, Florenzo
    Univ Bari, Rheumatol Unit, Bari, Italy..
    Askling, Johan
    Karolinska Inst, Clin Epidemiol Unit, Stockholm, Sweden..
    Listing, Joachim
    German Rheumatism Res Ctr, Epidemiol Unit, Berlin, Germany..
    Spectrum of lymphomas across different drug treatment groups in rheumatoid arthritis: a European registries collaborative project2017Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, nr 12, s. 2025-2030Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Lymphomas comprise a heterogeneous group of malignant diseases with highly variable prognosis. Rheumatoid arthritis (RA) is associated with a twofold increased risk of both Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL). It is unknown whether treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) affect the risk of specific lymphoma subtypes.

    Methods Patients never exposed to (bionaïve) or ever treated with bDMARDs from 12 European biologic registers were followed prospectively for the occurrence of first ever histologically confirmed lymphoma. Patients were considered exposed to a bDMARD after having received the first dose. Lymphomas were attributed to the most recently received bDMARD.

    Results Among 124 997 patients (mean age 59 years; 73.7% female), 533 lymphomas were reported. Of these, 9.5% were HL, 83.8% B-cell NHL and 6.8% T-cell NHL. No cases of hepatosplenic T-cell lymphoma were observed. Diffuse large B-cell lymphoma (DLBCL) was the most frequent B-cell NHL subtype (55.8% of all B-cell NHLs). The subtype distributions were similar between bionaïve patients and those treated with tumour necrosis factor inhibitors (TNFi). For other bDMARDs, the numbers of cases were too small to draw any conclusions. Patients with RA developed more DLBCLs and less chronic lymphocytic leukaemia compared with the general population.

    Conclusion This large collaborative analysis of European registries has successfully collated subtype information on 533 lymphomas. While the subtype distribution differs between RA and the general population, there was no evidence of any modification of the distribution of lymphoma subtypes in patients with RA treated with TNFi compared with bionaïve patients.

  • 50.
    Mercer, Louise
    et al.
    Univ Manchester, Arthrit Res UK Ctr Epidemiol, Manchester, Lancs, England..
    Mariette, Xavier
    Univ Paris 11, Dept Rheumatol, Paris, France..
    Dixon, Will
    Univ Manchester, Arthrit Res UK Ctr Epidemiol, Manchester, Lancs, England..
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Hellgren, Karin
    Karolinska Inst, Clin Epidemiol Unit, Stockholm, Sweden..
    Dreyer, Lene
    Gentofte Univ Hosp, Dept Rheumatol, Hellerup, Denmark..
    Hetland, Merete
    Univ Copenhagen, Copenhagen Ctr Arthrit Res, DANBIO, DK-1168 Copenhagen, Denmark..
    Mellemkjaer, Lene
    Danish Canc Soc, Danish Canc Soc Res Ctr, Copenhagen, Denmark..
    Hyrich, Kimme
    Univ Manchester, Arthrit Res UK Ctr Epidemiol, Manchester, Lancs, England..
    Strangfeld, Anja
    German Rheumatism Res Ctr, Epidemiol Unit, Berlin, Germany..
    Zink, Angela
    German Rheumatism Res Ctr, Epidemiol Unit, Berlin, Germany..
    Canhao, Helena
    Univ Lisbon, Rheumatol Res Unit, P-1699 Lisbon, Portugal..
    Martins, Fernando
    Univ Lisbon, Rheumatol Res Unit, P-1699 Lisbon, Portugal..
    Hernandez, Victoria
    BIOBADASER Registry, Madrid, Spain..
    Tubach, Florence
    Univ Paris Diderot, Dept Epidemiol & Rech Clin, Paris, France..
    Gottenberg, Jacques-Eric
    CHU, Dept Rheumatol, Strasbourg, France..
    Morel, Jacques
    Univ Montpellier, F-34059 Montpellier, France..
    Zavada, Jakub
    Charles Univ Prague, Inst Rheumatol, Prague, Czech Republic..
    van Riel, Piet
    Radboud Univ Nijmegen, Dept Rheumat Dis, NL-6525 ED Nijmegen, Netherlands. Univ Geneva, Geneva, Switzerland..
    Finckh, Axel
    Univ Manchester, Arthrit Res UK Ctr Epidemiol, Manchester, Lancs, England.;Univ Copenhagen, Copenhagen Ctr Arthrit Res, DANBIO, DK-1168 Copenhagen, Denmark..
    Iannone, Florenzo
    Univ Bari, Bari, Italy..
    Askling, Johan
    Karolinska Inst, Clin Epidemiol Unit, Stockholm, Sweden..
    Listing, Joachim
    German Rheumatism Res Ctr, Epidemiol Unit, Berlin, Germany..
    First Results Of A European Registries Collaborative Project To Describe The Spectrum Of Lymphomas Across Different Drug Treatment Groups In Rheumatoid Arthritis2015Inngår i: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 54, s. 25-25Artikkel i tidsskrift (Annet vitenskapelig)
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