Safety of biological and targeted synthetic disease-modifying antirheumatic drugs for rheumatoid arthritis as used in clinical practice: results from the ARTIS programme.

OBJECTIVE: Longitudinal clinical registry-infrastructures such as Anti-Rheumatic Therapies in Sweden (ARTIS) allow simultaneous comparison of the safety of individual immunomodulatory drugs used in clinical practice, with consistent definitions of treatment cohorts, follow-up and outcomes. Our objective was to assess and compare incidence rates of key safety outcomes for individual targeted synthetic or biological disease-modifying antirheumatic drugs (b/ts DMARDs) in rheumatoid arthritis (RA), updating previous reports and including newer treatments including Janus Kinase inhibitors (JAKi). METHODS: Nationwide register-based cohort study including all patients with RA in Sweden registered as starting any b/tsDMARD 1 January 2010 through 31 December 2020, followed until 30 June 2021 (N=20 117). The incidence rates of selected outcomes, identified through national healthcare registers, were compared between individual b/tsDMARDs, adjusted for confounding by demographics, RA disease characteristics and comorbidity. RESULTS: There were marked differences in treatment discontinuations due to adverse events (rates per 1000 person-years ranged from 18 on rituximab to 57 on tofacitinib), but few significant differences were observed for the serious adverse events under study. Neither cardiovascular events nor general serious infections were more frequent on baricitinib or tofacitinib versus bDMARDs, but JAKi were associated with higher rates of hospital-treated herpes zoster (HR vs etanercept, 3.82 (95% CI 2.05 to 7.09) and 4.00 (1.59 to 10.06)). Low number of events limited some comparisons, in particular for sarilumab and tofacitinib. CONCLUSION: Data from ARTIS supports that the b/tsDMARDs currently used to treat RA have acceptable and largely similar safety profiles, but differences exist in particular concerning tolerability and specific infection risks.

Genome-wide investigation of persistence to treatment with methotrexate in early rheumatoid arthritis.

OBJECTIVES: To investigate the influence of genetic factors on persistence to treatment of early rheumatoid arthritis (RA) with methotrexate (MTX) monotherapy. METHODS: We conducted a genome-wide association study (GWAS) in a sample of 3902 Swedish early RA patients initiating MTX in DMARD-monotherapy as their first ever DMARD. The outcome, short- and long-term persistence to this treatment, was defined as remaining on MTX at one and at three years, respectively, with no additional DMARDs added. As genetic predictors, we investigated individual SNPs, and a polygenic risk score (PRS) based on SNPs associated with RA risk. The SNP-based heritability of persistence was estimated overall and by RA serostatus. RESULTS: No individual SNP reached genome-wide significance (p < 5e-8), neither for persistence at one nor at three years. The RA PRS was not significantly associated with persistence at one (RR = 0.98 (0.96-1.01)) nor three years (RR = 0.96 (0.93-1.00)). The heritability for persistence was estimated to be 0.45 (0.15-0.75) at one year and 0.14 (0-0.40) at three years. Results in seropositive RA were comparable to those in the analysis of RA overall, while heritability estimates and PRS RRs were attenuated towards the null in seronegative RA. CONCLUSIONS: Despite being the largest GWAS on an MTX treatment outcome to date, no genome-wide significant associations were detected. The modest heritability observed, coupled with the broad spread of suggestively associated loci, indicate that genetic influence is of polygenic nature. Nevertheless, persistence to MTX monotherapy was lower in patients with a greater genetic disposition, per the PRS, towards RA.

Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset.

OBJECTIVES: To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. METHODS: We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ~1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). RESULTS: We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1×10-9), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3×10-160). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6×10-11). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10-9-10-27) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. CONCLUSION: Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.

Superior outcome for splenectomised patients in a population-based study of splenic marginal zone lymphoma in Sweden.

Splenic marginal zone lymphoma (SMZL) is a rare low-grade B-cell lymphoma where associations with viral hepatitis and autoimmune and inflammatory diseases (AID) have been indicated. We aimed at assessing the prevalence of viral hepatitis and AID at SMZL diagnosis and outcome by treatment in a Swedish population-based study. A total of 277 SMZL patients registered in the Swedish Lymphoma Register in 2007-2017 were included. A history of viral hepatitis was reported in five (2%) patients and AID prior to SMZL in 72/240 (30%) patients. Treatment was given up front for 207 (75%) patients. Splenectomy with or without systemic treatment was performed in 119 (57%) and was associated with statistically significantly better overall survival [hazard ratio, HR = 0·47 (95% confidence interval, CI: 0·23-0·93), P = 0·03] and progression-free survival (HR = 0·55, 95% CI: 0·35-0·86, P = 0·008) compared to non-splenectomised patients in multivariable analyses. The up-front splenectomised group was younger and generally had a lower Ann Arbor stage, but also more frequently B symptoms and high lactate dehydrogenase than the non-splenectomised group. Viral hepatitis and AID history did not affect SMZL outcome. We report high incidence of AIDs and low incidence of viral hepatitis in this population-based study of SMZL. Splenectomy up front was associated with a favourable outcome.

Impact of the COVID-19 pandemic on morbidity and mortality in patients with inflammatory joint diseases and in the general population: a nationwide Swedish cohort study.

OBJECTIVES: To estimate absolute and relative risks for all-cause mortality and for severe COVID-19 in inflammatory joint diseases (IJDs) and with antirheumatic therapies. METHODS: Through Swedish nationwide multiregister linkages, we selected all adult patients with rheumatoid arthritis (RA, n=53 455 in March 2020), other IJDs (here: spondyloarthropathies, psoriatic arthritis and juvenile idiopathic arthritis, n=57 112), their antirheumatic drug use, and individually matched population referents. We compared annual all-cause mortality March-September 2015 through 2020 within and across cohorts, and assessed absolute and relative risks for hospitalisation, admission to intensive care and death due to COVID-19 March-September 2020, using Cox regression. RESULTS: During March-September 2020, the absolute all-cause mortality in RA and in other IJDs was higher than 2015-2019, but relative risks versus the general population (around 2 and 1.5) remained similar during 2020 compared with 2015-2019. Among patients with IJD, the risks of hospitalisation (0.5% vs 0.3% in their population referents), admission to intensive care (0.04% vs 0.03%) and death (0.10% vs 0.07%) due to COVID-19 were low. Antirheumatic drugs were not associated with increased risk of serious COVID-19 outcomes, although for certain drugs, precision was limited. CONCLUSIONS: Risks of severe COVID-19-related outcomes were increased among patients with IJDs, but risk increases were also seen for non-COVID-19 morbidity. Overall absolute and excess risks are low and the level of risk increases are largely proportionate to those in the general population, and explained by comorbidities. With possible exceptions, antirheumatic drugs do not have a major impact on these risks.

Lymphoma risks in patients with rheumatoid arthritis treated with biological drugs-a Swedish cohort study of risks by time, drug and lymphoma subtype.

OBJECTIVES: To estimate the association between biological DMARDs (bDMARDs; overall and by drug) as used in RA and the risk of malignant lymphomas including subtypes. METHODS: By linking nationwide Swedish registers we identified cohorts of patients with RA initiating treatment with a bDMARD (n = 16 392), bDMARD-naïve (n = 55 253), an age- and sex-matched general population comparator cohort (n = 229 047), and all incident lymphomas 2001-16. We used Cox regression to calculate hazard ratios (HRs) of lymphoma taking calendar period and other factors into account. RESULTS: There were 82 lymphomas among the bDMARD-treated patients with RA, crude incidence rate 76/100 000 person-years, and 310 lymphomas among the bDMARD-naïve patients with RA, crude incidence rate 90/100 000 person-years. This resulted in an adjusted HR (aHR) associated with bDMARD treatment (vs not) of 1.08 (95% CI: 0.83, 1.41). The corresponding aHR for bDMARD-treated and bDMARD-naïve vs the general population was 1.65 (95% CI: 1.31, 2.08) and 1.56 (95% CI: 1.37, 1.78) respectively. Restricting follow-up period to after 2006, the aHR of lymphoma for patients with RA starting a first bDMARD vs bDMARD-naïve was 0.69 (95% CI: 0.47, 1.00), and for bDMARD treated vs patients with RA switching from one conventional synthetic DMARDs to another, aHR was 0.46 (95% CI: 0.28, 0.73). There were no signals of different risks with any particular TNF inhibitor (TNFi) agent. We found no different lymphoma subtype pattern following bDMARD therapy. CONCLUSION: Treatment with bDMARDs, including both TNFi and non-TNFi bDMARDs, does not further increase the lymphoma risk in RA; instead, bDMARD treatment may actually reduce the excess lymphoma risk in RA.

Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome.

OBJECTIVES: Clinical presentation of primary Sjögren's syndrome (pSS) varies considerably. A shortage of evidence-based objective markers hinders efficient drug development and most clinical trials have failed to reach primary endpoints. METHODS: We performed a multicentre study to identify patient subgroups based on clinical, immunological and genetic features. Targeted DNA sequencing of 1853 autoimmune-related loci was performed. After quality control, 918 patients with pSS, 1264 controls and 107 045 single nucleotide variants remained for analysis. Replication was performed in 177 patients with pSS and 7672 controls. RESULTS: We found strong signals of association with pSS in the HLA region. Principal component analysis of clinical data distinguished two patient subgroups defined by the presence of SSA/SSB antibodies. We observed an unprecedented high risk of pSS for an association in the HLA-DQA1 locus of odds ratio 6.10 (95% CI: 4.93, 7.54, P=2.2×10-62) in the SSA/SSB-positive subgroup, while absent in the antibody negative group. Three independent signals within the MHC were observed. The two most significant variants in MHC class I and II respectively, identified patients with a higher risk of hypergammaglobulinaemia, leukopenia, anaemia, purpura, major salivary gland swelling and lymphadenopathy. Replication confirmed the association with both MHC class I and II signals confined to SSA/SSB antibody positive pSS. CONCLUSION: Two subgroups of patients with pSS with distinct clinical manifestations can be defined by the presence or absence of SSA/SSB antibodies and genetic markers in the HLA locus. These subgroups should be considered in clinical follow-up, drug development and trial outcomes, for the benefit of both subgroups.

Prior antithymocyte globulin therapy and survival in post-transplant lymphoproliferative disorders.

Background: Treatment with antithymocyte globulin (ATG) is a well-recognized risk factor for the development of post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation, but it is unknown how its use affects overall survival after PTLD.Methods: A total of 114 patients with PTLD and available data on immunosuppressive regimen were included from a nation-wide case series of solid organ transplant recipients in Sweden. Prior use of ATG was correlated to clinical features, PTLD subtype, and survival.Results: A total of 47 (41%) patients had received ATG prior to the diagnosis of PTLD. The ATG-treated patients were more likely to be recipients of hearts or lungs, and less likely of kidneys (p < 0.01). They had experienced more acute rejections (p = 0.02). The PTLDs arose earlier, median 2.0 vs. 6.6 years post-transplant (p = 0.002) and were more often situated in the allograft (32% vs. 7%, p < 0.001) in patients with prior ATG vs. no ATG treatment. The PTLDs in the ATG group were more often Epstein-Barr virus-positive (80% vs. 40%, p < 0.001). There were more polymorphic PTLDs (17% vs. 1.5%, p = 0.004) and less T-cell PTLDs (4% vs. 19%, p = 0.02) in the ATG group than in the no ATG group. Diffuse large B-cell lymphoma was equally common in patients with and without prior ATG therapy, but the non-germinal center subtype was more frequent in the ATG group (p = 0.001). In an adjusted Cox proportional hazards regression model, prior ATG treatment and better performance status were associated with superior overall survival, whereas older age, T-cell subtype of PTLD, presence of B symptoms, and elevated lactate dehydrogenase were associated with inferior overall survival. Patients receiving ATG solely as rejection therapy had superior overall survival compared with those receiving ATG as induction therapy or both (p = 0.03).Conclusions: ATG therapy, especially rejection therapy, prior to PTLD development is an independent prognostic factor for superior overall survival after PTLD diagnosis.

Autoimmune disease in patients with diffuse large B-cell lymphoma: occurrence and impact on outcome.

Background: Patients with certain autoimmune diseases (AID) have an increased risk of developing diffuse large B-cell lymphoma (DLBCL). However, the occurrence of AID in patients with DLBCL as well as the impact of AID on outcome has not been extensively studied. The main purpose of this study was to establish the occurrence of AIDs in a population-based cohort of DLBCL patients and to compare outcomes in patients with or without AID treated with rituximab(R)-CHOP/CHOP-like treatment. We also aimed to analyse gender differences and the potential role of different AIDs on outcome and the frequency of treatment-associated neutropenic fever. Patients and methods: All adult patients treated 2000-2013 with R-CHOP/CHOP-like treatment for DLBCL in four counties of Sweden were included (n = 612). Lymphoma characteristics, outcome and the presence of AID were obtained through medical records. Results: The number of patients with AID was 106 (17.3%). Thyroid disease dominated (n = 33, 31.1%) followed by rheumatoid arthritis (RA) (n = 24, 22.6%). The proportion of AID was significantly higher in females (59/254, 23.2%) vs. in males (47/358, 13.1%) (p = .001). In the whole cohort there was no difference in event free survival (EFS) or overall survival (OS) between patients with or without AID. However, patients with an AID primarily mediated by B-cell responses (thyroid disorders excluded) had a worse OS (p = .037), which seemed to affect only women. The AID group more often had neutropenic fever after first treatment (16.0% vs 8.7%, p = .034) and those with neutropenic fever had a worse OS (p = .026) in Kaplan-Meier analyses. Conclusion: There is a high prevalence of AID among patients with DLBCL. AIDs categorized as primarily B-cell mediated (in this study mainly RA, systemic lupus erythematosus and Sjögren's syndrome) may be associated with inferior OS. AID patients may be more prone to neutropenic fever compared to patients without concomitant AID.

Patient characteristics influence the choice of biological drug in RA, and will make non-TNFi biologics appear more harmful than TNFi biologics.

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.

Spectrum of lymphomas across different drug treatment groups in rheumatoid arthritis: a European registries collaborative project.

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.

Population-based experience on primary central nervous system lymphoma 2000-2012: the incidence is increasing.

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.

Sporadic occurrence of non-diagnosed IgG4-related disease in lymphoma patients with a previous Sjögren's syndrome diagnosis.

BACKGROUND: IgG4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory disorder, which may affect many organs, and often comes to clinical attention due to tumor-like organ swelling or is identified incidentally by specific biopsy findings. Typical histopathology of IgG4-RD is lymphoplasmacytic infiltration rich in IgG4 + plasma cells (PCs), storiform fibrosis, and obliterative phlebitis. Patients with sicca symptoms can be misdiagnosed as primary Sjögren's syndrome (pSS) instead of IgG4-RD because of clinical and histopathological similarities. Moreover, an association with lymphoma development is described in both diseases. This study investigated signs of IgG4-RD in a population-based cohort of patients diagnosed with pSS complicated by lymphoma. METHODS: Patients with pSS and lymphoma diagnoses and available lymphoma specimens were identified by linkage with the Swedish Patient Register 1964-2007 and the Cancer Register 1990-2007 (n = 79). Clinical data and lymphomas were reviewed and the diagnoses evaluated. All lymphoma tissues and available minor salivary gland biopsies (n = 11) were immunostained for IgG4 + PCs and evaluated for other histopathological signs of IgG4-RD. In a case with specific findings of IgG4-RD, other available tissue specimens of the same patient were investigated for IgG4-RD. RESULTS: Only one patient of 79 (1.3%) had >10 IgG4 + PCs/high power field (HPF) in the lymphoma tissue, an unspecified low-grade B-cell lymphoma localized in the submandibular gland. This patient also had other histopathological features of IgG4-RD in the lymphoma and a surgical lung biopsy taken five years before lymphoma diagnosis and, therefore, fulfilled the criteria for IgG4-RD. Occasional IgG4 + PCs (<10/HPF) without signs of IgG4-RD were observed in another six lymphomas. No IgG4 + PCs were identified in the minor salivary gland biopsies. CONCLUSION: Histopathological findings of IgG4-RD may co-exist with low malignant B-cell lymphoma in patients with initially suspected pSS and may be associated with an underlying IgG4-RD.

Lymphoma development in patients with autoimmune and inflammatory disorders--what are the driving forces?

For decades, it has been known that patients with certain autoimmune and inflammatory disorders, such as rheumatoid arthritis (RA) and primary Sjögren'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.

Are patients with rheumatoid arthritis still at an increased risk of tuberculosis and what is the role of biological treatments?

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.

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.

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.

Risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008--a Swedish population-based study.

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, SIR(cancer excl SCC) 2.4 (95% CI, 2.2-2.5); SIR(SCC) 121 (95% CI, 116-127). Cancer risks were most increased among heart and/or lung recipients SIR(cancer excl SCC) 3.3 (95% CI, 2.8-4.0); SIR(SCC) 198 (95% CI, 174-224), followed by kidney SIR(cancer excl SCC) 2.3 (95% CI, 2.1-2.4); SIR(SCC) 121 (95% CI, 116-127) and liver recipients SIR(cancer excl SCC) 2.3 (95% CI, 1.9-2.8); SIR(SCC) 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.

Lifestyle factors, autoimmune disease and family history in prognosis of non-hodgkin lymphoma overall and subtypes.

Lifestyle factors and medical history are known to influence risk of non-Hodgkin lymphoma (NHL). Whether these factors affect the prognosis of NHL, especially its subtypes, is unclear. To investigate this, the association between these factors and all-cause and lymphoma-related mortality was assessed in a population-based cohort of 1,523 Swedish NHL patients included in the Scandinavian Lymphoma Etiology study in 1999-2002. Participants contributed time from NHL diagnosis until death or October 1, 2010, with virtually complete follow-up through linkage to the Swedish Cause of Death Register. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using stratified and multivariable-adjusted Cox regression models. During a median follow-up of 8.8 years, 670 patients (44%) died, with the majority of deaths attributed to lymphoma (86%). Current versus never smoking at diagnosis was associated with increased rate of all-cause death for all NHL (HR = 1.5, 1.2-1.8) and diffuse large B-cell lymphoma (HR = 1.8, 1.2-2.7). Low educational level (HR = 1.3, 1.1-1.7, <9 vs. >12 years) and NHL risk-associated autoimmune disease (HR = 1.4, 1.0-1.8) were associated with death for all NHL combined. However, evidence of an association with lymphoma-related death was limited. Body mass index, recent sunbathing and family history of hematopoietic malignancy were not consistently associated with death after NHL or its specific subtypes. These results add to the evidence that cigarette smoking, socioeconomic status and certain autoimmune diseases affect survival after NHL. Further investigations are needed to determine how these factors should be incorporated into clinical prognostic assessment.