Pauline Raaschou

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?

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.

Rheumatoid arthritis, anti-tumour necrosis factor therapy, and risk of malignant melanoma: nationwide population based prospective cohort study from Sweden

Objectives To investigate the potential association between tumour necrosis factor (TNF) inhibitor treatment and malignant melanomas in rheumatoid arthritis, melanoma risks in rheumatoid arthritis patients not treated with biological drugs, and risk of all site cancer with TNF inhibitors as used in rheumatoid arthritis. Design Population based cohort study. Setting Prospectively recorded data from national clinical, health, and demographic registers in Sweden 2001-10. Patients with rheumatoid arthritis treated (n=10 878) or not (n=42 198) with TNF inhibitors and matched general population comparators (n=162 743). Main outcome measures The primary outcome was first invasive melanoma in people without any history of invasive cancer of any type. Hazard ratios were estimated using Cox regression, comparing non-biological drug treated rheumatoid arthritis patients with the general population comparator and TNF inhibitor treated rheumatoid arthritis patients with those not treated with biological drugs. Secondary outcomes included in situ melanomas, second primary melanomas, and all site cancer. Results 113 first invasive melanomas occurred in rheumatoid arthritis patients not treated with biological drugs, and 393 occurred in the general population comparator cohort. Rheumatoid arthritis patients not treated with biological drugs were not at significantly increased risk of melanoma compared with the general population (hazard ratio 1.2, 95% confidence interval 0.9 to 1.5). 38 first invasive melanomas occurred in rheumatoid arthritis patients treated with TNF inhibitors; these patients had an increased risk of melanoma compared with rheumatoid arthritis patients not treated with biological drugs (hazard ratio 1.5, 1.0 to 2.2; 20 additional cases per 100 000 person years). The risk of a second primary melanoma was non-significantly increased (hazard ratio 3.2, 0.8 to 13.1; n=3 v 10) in rheumatoid arthritis patients treated with TNF inhibitors compared with those not treated with biological drugs. Conclusion Overall, patients with rheumatoid arthritis who have not been treated with biological drugs are not at increased risk of invasive melanoma compared with the general population. Rheumatoid arthritis patients selected for TNF inhibitor treatment are not at increased overall risk for cancer but have a 50% increased relative risk of invasive melanoma. Given the small increase in absolute risk, these finding may not markedly shift the overall risk-benefit balance of TNF inhibitors as used in clinical practice but might do so in patients at high risk of melanoma for other reasons.

Does cancer that occurs during or after anti-tumor necrosis factor therapy have a worse prognosis? A national assessment of overall and site-specific cancer survival in rheumatoid arthritis patients treated with biologic agents.

OBJECTIVE Tumor necrosis factor (TNF) may affect tumor development and spreading. While data on the incidence of cancer following anti-TNF therapy have been published, the purpose of this study was to examine the clinical presentation and outcome of cancers that develop during or after anti-TNF therapy. METHODS By linking data from Swedish clinical registries of rheumatoid arthritis (RA) patients, including Anti-Rheumatic Therapy in Sweden (ARTIS), the Swedish Biologics Register, with nationwide data on hospitalizations and outpatient visits for RA, we assembled a cohort of 78,483 RA patients who were alive in 1999 or who entered the cohort thereafter. Of these, 8,562 patients started therapy with a biologic agent (98% started an anti-TNF) during the period from January 1, 1999 to December 31, 2007. Linkage to the Swedish Cancer Register and other registers identified first primary cancers occurring during 1999-2007 as well as post-cancer survival through March 31, 2009. Through this linkage, we identified 314 cancers in patients who were undergoing, or had a history of, treatment with biologic agents and 4,650 cancers in patients who were biologics-naive at the time of cancer diagnosis. The distributions of tumor stage among the biologics-exposed and the biologics-naive patients were compared. The relative risk of death among the biologics-exposed versus the 586 matched biologics-naive cancer cases were assessed by Cox regression analyses. Through chart review in a defined subset, we gathered additional clinical information and validated the diagnoses. RESULTS For all cancers combined, the distribution of cancer stages at the time of cancer diagnosis was largely similar between those in the biologics-exposed and the matched biologics-naive groups. Based on the total of 113 deaths among those with cancer in the biologics-exposed group versus the 256 deaths among those with cancer in the biologics-naive group, the relative risk of death following cancer associated with exposure to anti-TNF was 1.1 (95% confidence interval 0.8-1.6). CONCLUSION During routine care, cancers that occur following anti-TNF therapy are not characterized by any markedly altered stage at presentation or by altered post-cancer survival rates.

TNF inhibitor therapy and risk of breast cancer recurrence in patients with rheumatoid arthritis: a nationwide cohort study

Objective To investigate the risk of breast cancer recurrence in rheumatoid arthritis (RA)—patients with tumour necrosis factor inhibitor (TNFi) treatment and a history of breast cancer, taking several breast cancer, comorbidity and RA-related prognostic factors into account. Methods 143 female TNFi-treated patients (1999–2010) with RA and a history of breast cancer before start of TNFi were identified through register linkages, and matched 1:1 from a cohort of 1598 comparable biologics-naive individuals. 120 TNFi-treated and 120 matched biologics-naive individuals with a history of equally recent/distant breast cancer met the eligibility criteria and comprised the final study population. The primary outcome was first recurrence of breast cancer. Through register-linkages and chart review, individuals were followed until 2011. HRs for recurrence were calculated using Cox regression. Results The median time from breast cancer diagnosis until TNFi-treatment/start of follow-up was 9.4 years. Modest differences in breast cancer characteristics and/or treatment among TNFi-treated and biologics-naive individuals were noted at time of breast cancer diagnosis. Median follow-up from TNFi start was 4.9 years (4.6 years among biologics-naive). Among the TNFi-treated, 9 developed a breast cancer recurrence (crude incidence rate 15/1000 person-years) during follow-up, compared with 9 among the matched biologics-naive (16/1000 person-years). The adjusted corresponding HR was 1.1 (95% CI 0.4 to 2.8). Conclusions Among patients with RA and a history of breast cancer, those who started TNFi-treatment did not experience more breast cancer recurrences than patients with RA treated otherwise. The generalisability of our findings to women with a very recent or a poor prognosis of breast cancer remains unknown.

Risk of invasive melanoma in patients with rheumatoid arthritis treated with biologics: results from a collaborative project of 11 European biologic registers

Objectives Some studies have reported a possible association between exposure to tumour necrosis factor (TNF) inhibitors and an increased risk of melanoma. The aim of this study was to investigate the incidence of invasive cutaneous melanomas in patients with rheumatoid arthritis (RA) treated with TNF inhibitors (TNFi), other biologic disease modifying drugs and non-biologic therapy. Methods Eleven biologic registers from nine European countries participated in this collaborative project. According to predefined exposure definitions, cohorts of patients with RA were selected. Using the country-specific general population of each register as reference, age, sex and calendar year standardised incidence ratios (SIRs) of invasive histology-confirmed cutaneous melanoma were calculated within each register. Pooled SIR and incidence rate ratios (IRRs) comparing biologic cohorts to biologic-naïve were calculated across countries by taking the size of the register into account. Results Overall 130 315 RA patients with a mean age of 58 years contributing 579 983 person-years were available for the analysis and 287 developed a first melanoma. Pooled SIRs for biologic-naïve, TNFi and rituximab-exposed patients were 1.1 (95% CI 0.9 to 1.4), 1.2 (0.99 to 1.6) and 1.3 (0.6 to 2.6), respectively. Incidence rates in tocilizumab and abatacept-exposed patients were also not significantly increased. IRR versus biologic-naïve patients were: TNFi 1.1 (95% CI 0.8 to 1.6); rituximab 1.2 (0.5 to 2.9). Conclusions This large European collaborative project did not confirm an overall increased risk of melanoma following exposure to TNFi.

Rheumatoid arthritis, anti-tumour necrosis factor treatment, and risk of squamous cell and basal cell skin cancer: cohort study based on nationwide prospectively recorded data from Sweden

Objective To investigate the risk of squamous cell and basal cell skin cancer in patients with rheumatoid arthritis naive to biologic drugs, in patients starting tumour necrosis factor (TNF) inhibitor treatment, and in the general population. Design Population based cohort study. Setting Nationwide data from Sweden. Participants Cohort of patients with rheumatoid arthritis naive to biologics (n=46 409), cohort of patients with rheumatoid arthritis starting TNF inhibitor treatment as first biologic in 1998-2012 (n=12 558), and matched general population comparator cohort, identified through national quality of care and health registers. Main outcome measure Hazard ratio of first in situ or invasive squamous cell skin cancer (1998-2012) and first basal cell cancer (2004-12). Results For basal cell cancer, the hazard ratio was 1.22 (95% confidence interval 1.07 to 1.41) comparing biologics-naive rheumatoid arthritis patients with the general population and 1.14 (0.98 to 1.33; 236 v 1587 events) comparing TNF inhibitor treated patients with biologics-naive patients. For squamous cell cancer, the hazard ratio was 1.88 (1.74 to 2.03) comparing biologics-naive rheumatoid arthritis patients with the general population and 1.30 (1.10 to 1.55; 191 v 847 events) comparing TNF inhibitors with biologics-naive patients; the latter translated to an annual number needed to harm in the order of 1600. Among people with a history of squamous cell or basal cell cancer, TNF inhibitors did not further increase risks. Conclusion A small to moderately increased risk of basal cell cancer was seen in biologics-naive rheumatoid arthritis patients, with no further effect of TNF inhibitors. For squamous cell cancer, the risk was nearly doubled in biologics-naive patients, with a further 30% increase in risk among patients treated with TNF inhibitors; this translates to one additional case for every 1600 years of treatment experience, assuming that this association reflected causality. Vigilance regarding skin malignancies may be advisable in rheumatoid arthritis, irrespective of TNF inhibitor treatment. Most of the increase in risk for non-melanoma skin cancer in patients with rheumatoid arthritis treated with TNF inhibitors originates from factors other than that treatment.

Tumor Necrosis Factor Inhibitors and Cancer Recurrence in Swedish Patients With Rheumatoid Arthritis: A Nationwide Population-Based Cohort Study

Tumor necrosis factor inhibitors (TNFi) (such as adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab) are widely used to treat rheumatoid arthritis (RA) and other chronic inflammatory conditions. Tumor necrosis factor is a mediator of tumor cell destruction but has also been shown to exert tumor-promoting effects (13). Inhibition of TNF may therefore either advance or protect against cancer, depending on factors related to the tumor (such as genetic or pathologic subtype) and patient (such as overall burden of inflammation). Despite concerns that TNFi treatment might affect risk for cancer incidence, most studies have provided reassuring results (49). However, because of its pleiotropic effects on cancer development, TNFi could affect risk for cancer recurrence. For instance, clinical data have linked high levels of TNF to better survival in patients with metastatic breast cancer (10). Recommendations have cautioned against use of TNFi in patients with a history of cancer (11, 12), which is problematic from a clinical point of view. The cumulative probability of any cancer diagnosis is 15% at age 65 years and 30% at age 75 years (13). For many patients with RA or other chronic inflammatory diseases, our lack of evidence may negatively affect chances of optimal disease control or risk for cancer recurrence. Only a few studies have reported risk for cancer relapse or second primary tumors of other types in patients with RA who received TNFi treatment (1419) (Appendix Table 1), and some did not differentiate between these 2 outcomes (14, 15). With relative risks below 1 (14, 18) or approximately 1 (1517), these studies are reassuring. However, they also raise the question of whether patients with previous cancer who are selected to receive TNFi tend to be those with low risk for recurrence, such as patients with a less advanced cancer stage or distant history of cancer. If that is the case, the estimated risks may apply to those types of patients without reflecting the true effect of TNFi on cancer recurrence. Appendix Table 1. Seminal Studies of Cancer Recurrence or Second Primary Cancer in Patients With Chronic Inflammatory Diseases Treated With TNFi We aimed to investigate whether TNFi is associated with increased risk for cancer recurrence in patients with RA, taking into account cancer stage and time between cancer diagnosis and start of TNFi treatment. Methods Study Design We did a population-based cohort study of patients with RA and a history of cancer using prospectively recorded data in Sweden. We compared cancer recurrence (outcome) in patients who had started TNFi treatment after their cancer diagnosis (exposed group) versus those who remained biologics-naive (unexposed group). We used both matched and unmatched approaches. We gathered information from national administrative and clinical registers with almost complete coverage of demographics, morbidity, and mortality. The study was approved by the Regional Ethical Review Board in Stockholm, Sweden. Data Sources We used linkages to the following national and population-based registers: the Swedish National Patient Register, the Swedish Prescribed Drug Register, the Swedish Cancer Registry, the Swedish Population Register, the National Register of Education, and the Swedish Cause of Death Register. The Swedish Cancer Registry contains information on date of cancer, cancer type (per the International Classification of Diseases [ICD]), and whether the tumor was in situ or invasive at diagnosis, but not on relapse. Details are described elsewhere (20) and in Appendix 2. We used data from the Swedish Rheumatology Quality Register (SRQ), which includes 85% of patients diagnosed with RA in Sweden and covers such clinical information as disease activity and treatment of chronic inflammatory rheumatic diseases, including RA. Coverage of TNFi is close to 90% (21). Study Sample In Sweden, patients with RA are typically treated and monitored by rheumatologists. Using previously devised algorithms, we identified a cohort of all persons in the Swedish National Patient Register who were living with RA in 2001 or were diagnosed with it thereafter (n= 72377) (Figure 1). Through linkage of this cohort to the Swedish Cancer Registry, we identified persons with a history of cancer (index cancer), defined as any solid, noncutaneous tumor. We included patients with in situ or invasive cancer of the following types: colon, anorectal, lung, breast, uterine, ovarian, prostate, renal, urinary tract, or central nervous system (each comprising 2% of the overall cancer incidence). Cancer could be diagnosed before or after RA. Patients with a history of another cancer type were included if that diagnosis was before the index cancer or more than 5 years before TNFi treatment was initiated. This cohort served as the source population for a series of matched and unmatched samples. Figure 1. Study flow diagram. Swedish patients with RA and a history of cancer who started TNFi treatment versus those who did not receive such treatment. RA = rheumatoid arthritis; TNFi = tumor necrosis factor inhibitor. * Matched 1:5 on sex, age, age at cancer diagnosis (5 y), cancer type, stage (invasive vs. in situ for samples A and B and tumor, node, metastasis classification system for sample C [stage IV excluded]), and year of cancer diagnosis (10 y). Through linkage to the SRQ and the Swedish Prescribed Drug Register, we identified patients in the cohort who, after their cancer diagnosis, started treatment with adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab as their first-ever biologic between 1 January 2001 and 31 December 2015 (end of follow-up). Matched Samples We defined 3 nested matched samples (A, B, and C). The most inclusive (A) comprised all patients with RA who started TNFi treatment between 2001 and 2015 and had a history of cancer recorded in the Swedish Cancer Registry in 1960 or later (n= 467). These patients were matched (1:5) to biologics-naive referents with RA for sex, age at cancer diagnosis (5 years), year of cancer diagnosis (10 years), cancer type, and invasive versus in situ cancer at diagnosis. To focus on the population with a shorter time between index cancer and TNFi treatment, we restricted matched sample B to patients whose index cancer was diagnosed in 2001 or later (n= 223). These were matched (1:5) to biologics-naive referents with RA using the same criteria as for sample A. Matched sample C allowed matching for tumor, node, metastasis classification system (TNM) stage, excluded patients with metastatic cancer at diagnosis (stage IV), and permitted adjustment for RA-related factors and prescribed medications. Thus, sample C was restricted to patients whose cancer was diagnosed in 2003 or later (when information on stage was available) and who started TNFi treatment in 2006 or later (when information on prescribed medications was available in the Swedish Prescribed Drug Register) (n= 138). Comparators were eligible for matching if they were biologics-naive at the time of matching, regardless of whether they started TNFi treatment during follow-up. If they did, they were censored as a control patient but could contribute to the TNFi group. Follow-up for the TNFi group started at initiation of TNFi treatment. To balance the main risk factor for cancer recurrence (time since cancer diagnosis), start of follow-up for each biologics-naive person was set such that time since cancer diagnosis was equal to that of the matched index patient treated with TNFi (Appendix Figure 1). Appendix Figure 1. Schematic of the matched approach. Each patient with rheumatoid arthritis (RA) and a history of cancer who later started TNFi treatment (exposed) was matched (1:5) to biologics-naive referents with RA for sex, age at cancer diagnosis (5 y), year of cancer diagnosis (10 y), cancer type, and stage (invasive vs. in situ at diagnosis for samples A and B or tumor, node, metastasis classification system stage for sample C). To balance the main risk factor for cancer recurrence (time since cancer diagnosis), follow-up for each biologics-naive person was set to a time point that made time since cancer diagnosis equal to that of the TNFi-treated index patient. TNFi = tumor necrosis factor inhibitor. Unmatched Sample The unmatched sample included all biologics-naive patients with RA who were diagnosed with cancer between 1 January 2001 and 31 December 2015 (n= 3826), some of whom initiated TNFi treatment (Figure 1). Follow-up started 450 days after the index cancer diagnosis to allow at least 9 months of cancer treatment followed by 6 months in remission. Outcomes and Follow-up All participants were required to be in cancer remission for 6 months before the start of follow-up. Remission was defined as either absence of any visit or hospitalization with the index cancer ICD code or presence of that code but no registrations in the Swedish National Patient Register with ICD codes indicating metastases, palliative care, radiation, chemotherapy, removal and exploration of lymph nodes or implantation of vascular access, or cancer-related surgery. For each cancer type, we created an algorithm for relapse based on its ICD code in combination with 1 or several visits with codes indicating the aforementioned events. The primary outcome was recurrent cancer, defined as the first registered relapse based on this algorithm or a registration in the Swedish Cancer Registry with a second primary cancer of the same type as the index cancer (Appendix Table 2). Appendix Table 2. Swedish National Patient Register Codes to Identify Outcome and Remission During Follow-up* Follow-up ended at first cancer recurrence, second primary cancer of a different type from the index cancer, death, emigration, 31 December 2015, or start of TNFi treatment (for biologics-naive participants only). Approximately 20% of patients contributed person-time first to the biologics-naive group and

Snus users had high levels of nicotine, cotinine and 3-hydroxycotinine in their breast milk and the clearance was slower than in smoking mothers.

Using snus, an oral moist tobacco, has increased among pregnant women in Sweden, the only European Union country where sales are legal. This study evaluated whether snus generated similar concentrations of nicotine and its metabolites in breastmilk to cigarette smoking.

Maternal snuff use and cotinine in late pregnancy—A validation study

Oral moist snuff is widely used in Sweden including during pregnancy. Maternal snuff use has been associated with increased risks of adverse pregnancy outcomes in epidemiological studies. Self‐reported maternal snuff use has not been validated previously. The main objective of this study was to validate self‐reported snuff use in pregnancy in a prospective cohort study and in the Medical Birth Register.

OP0308 Tnf inhibitor treatment and risk of cancer recurrence in patients with rheumatoid arthritis: a nationwide cohort study from sweden

Background Clinical guidelines caution against the use of TNFi in individuals with a recent (5–10 years) history of cancer, but evidence of an increased risk of cancer recurrence is limited (1–2). Objectives We investigated the risk of recurrent solid non-skin cancer in patients with rheumatoid arthritis and TNFi-treatment, and if time between index-cancer and TNFi-start influence this risk. Methods 61.950 individuals with RA were identified in the Swedish national outpatient-care register Jan 2001-Dec 2014. Among these, 446 Individuals with at least one diagnosis of cancer (index cancer) prior to the start of TNFi-treatment were identified through linkage to the national cancer register and the ARTIS register of biologic treatment. Individuals (n=1.278) with a history of equally recent cancer of the same type and stage (invasive/in situ) were matched 3:1 to each patient starting TNFi against a background of solid cancer. Study participants were required to be in cancer remission during a period of 6 months prior to start of follow-up. The primary outcome was first recurrence or second primary of the same cancer type, identified through register-linkages until Dec 2014. Hazard ratios (HR) for recurrence or second primary were calculated using a Cox regression model with TNFi-treatment start (and a corresponding date among the matched biologics-naïve individuals) as start of follow-up. The final models were stratified for the matching variables sex, birth year, year of diagnosis of the index cancer and index cancer type and stage (invasive vs in situ), and adjusted for education level and comorbidities. Results The mean time from index cancer diagnosis until TNFi-treatment/start of follow-up was 9.9 and 9.5 years among the TNFi treated and their matched biologics-naïve controls, respectively. The mean follow-up (SD) from TNFi start was 4.9 (3.5) and 4.1 (3.1) years, respectively. The cancer stage distribution was similar between the two groups, apart from stage IV (0.6% among the TNFi-treated and 1.6% among the biologics-naïve). Thirty individuals (7%) among the 446 TNFi-treated developed a cancer recurrence (crude incidence rate 14/1000 person-years), compared with 89 (7%) among the 1.278 matched biologics-naive (crude incidence rate 17/1000 person-years). This corresponded to an adjusted HR for recurrent cancer of 0.69 (95% CI 0.42–1.12) in the matched analysis (table 1) comparing the TNFi treated to the biologics-naïve individuals. Stratified analyses indicated no increased risk associated with any specific cancer type with the possible exception of uterine cancer where HR for recurrence was 14.8 (95% CI 1.17–187.5), based on only 1 event among the TNFi-treated. HR for recurrence among individuals starting TNFi treatment within 5 year from index cancer was 0.67 (0.31–1.44). Conclusions Among patients with RA and a history of cancer, those selected to receive TNFi-treatment in clinical practice did not experience more cancer recurrences than patients with RA treated otherwise. We detected no differential risk depending on the timing of TNFi-start in relation to the index cancer. The generalizability of our findings to individuals with a very recent cancer, or a poor prognosis, remains unknown. References Raaschou P, et al. Ann Rheum Dis 2015;74:2137–2143. Mamtani R, et al. Arthritis Rheumatol 2016; 68: 2403–2411. Disclosure of Interest P. Raaschou: None declared, J. Söderling Grant/research support from: previous research projects fully or partly funded by Novo Nordisk and Combine Sweden, and has served as an external consultant to AbbVie, Merck and Novartis., J. Askling Grant/research support from: Abbvie, Pfizer, UCB, MSD, Roche, Lilly.