Development and clinical implementation of an LC-HRMS method for ivacaftor, lumacaftor, tezacaftor and elexacaftor in human plasma and breast milk.

The four cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators, ivacaftor, lumacaftor, tezacaftor, and elexacaftor, have revolutionised the treatment of CF by direct action on the protein target behind the disease's development. The aim was to develop and validate a quantification method for these CFTR modulators in plasma and breast milk to better understand inter-patient variability in pharmacokinetics and treatment outcome, including the risk of adverse drug reactions. The ability to monitor CFTR modulators in breast milk enables the estimation of the exposure of breastfed infant, with a potential concern for CFTR modulator-induced liver injury. The analysis was performed on a Thermo Vanquish Flex Binary UHPLC system coupled to a high-resolution mass spectrometer (HRMS), Thermo Q Exactive. The analytes were detected using positive electrospray ionisation in full scan mode. After sample preparation by protein precipitation, the supernatant was injected onto the LC system and the analytes were separated using a Zorbax SB-C18 Rapid Res HPLC column (3.5 µm, 4.6 × 75 mm). This is the first published method for CFTR modulators in breast milk. The validated quantification range for ivacaftor is 0.0050-10 µg/mL with a coefficient of variation < 6% and a mean accuracy of 97-106%; for lumacaftor, tezacaftor, and elexacaftor, the validated quantification range is 0.050-100 µg/mL with a coefficient of variation < 8% and a mean accuracy 93-106%. A simple and sensitive quantification method for CFTR modulators has been developed and used for routine analysis of human plasma and breast milk samples since 2022.

Short- and longer-term cancer risks with biologic and targeted synthetic disease-modifying antirheumatic drugs as used against rheumatoid arthritis in clinical practice.

OBJECTIVE: To estimate the occurrence and relative risks of first-ever-incident non-cutaneous cancer overall and for 16 sites in patients with RA treated with biologic and targeted synthetic DMARDs (b/tsDMARDs), by time since treatment start, attained age, and duration of active treatment. METHODS: This is an observational nationwide and population-based cohort study of patients with RA (n = 69 308), treated with TNF inhibitors (TNFi; adalimumab, certolizumab, etanercept, golimumab, infliximab) or other b/tsDMARDs (abatacept, rituximab, baricitinib, tofacitinib and tocilizumab) compared with RA patients not treated with b/tsDMARDs, and matched general population referents (n = 109 532), 2001-2018. The study was based on prospectively collected data from the Swedish Rheumatology Quality Register and from other registers, linked to the national Swedish Cancer Register. Incidence rates and hazard ratios were estimated via Cox regression adjusted for co-morbidities and other health characteristics. RESULTS: Based on 8633 incident cancers among RA patients, the overall relative risk of cancer with TNFi [hazard ratio (HR) = 1.0] was neither increased nor did it change with time since treatment start, duration of active treatment, or attained age, when compared with b/tsDMARD-naïve RA. For other b/tsDMARDs, we noted no consistent signal of increased overall risks (HRs ranged from 1.0 to 1.2), but there were statistically significant estimates above 1 for abatacept with 2-5 years of active treatment, for older age groups, and between several of the bDMARDs and urinary tract cancer. CONCLUSION: TNFis, as used long term in clinical practice against RA, are not linked to increased risks for cancer overall. For other b/tsDMARDs, and for site-specific risks, our results are generally reassuring but contain signals that call for replication.

Risk of breast cancer before and after rheumatoid arthritis, and the impact of hormonal factors.

OBJECTIVES: To examine the risk of incident breast cancer in women with rheumatoid arthritis (RA), and the risk of RA in women with a history of breast cancer, taking antihormonal treatment for breast cancer into account. METHODS: Using nationwide Swedish registers, women with new-onset RA diagnosed in 2006-2016 were identified and analysed using a cohort and a case-control design. Each patient with RA was matched on age, sex and place of residence to five randomly selected subjects from the general population. Through register linkages, we collected information on breast cancer, breast cancer risk factors (reproductive history and hormone replacement therapy) and socio-economy. The relative risk of breast cancer after RA was assessed using Cox regression, and the relative risk of RA in women with a history of breast cancer was assessed using conditional logistic regression. RESULTS: The risk of incident breast cancer in women with RA was reduced and the association was not attenuated by adjustment for breast cancer risk factors (HR=0.80, 95% CI 0.68 to 0.93). The risk of RA in women with a history of breast cancer was similarly reduced (OR=0.87, 95% CI 0.79 to 0.95). Women with breast cancer treated with tamoxifen (OR=0.86, 95% CI 0.62 to 1.20) or aromatase inhibitors (OR=0.97, 95% CI 0.69 to 1.37) did not have an increased risk of RA compared with women with breast cancer treated differently. CONCLUSIONS: The decreased occurrence of breast cancer in patients with RA is present already before RA diagnosis; these reduced risks are not readily explained by hormonal risk factors. Adjuvant antihormonal therapy for breast cancer does not seem to increase RA risk.

Cervical neoplasia in systemic lupus erythematosus: a nationwide study.

Objective: The aim was to examine the risk of cervical neoplasia in women with SLE, overall and with respect to treatment, compared with women from the general population. Methods: By linking national Swedish registers, we assembled a cohort including women with SLE (n = 4976) and matched general population comparators (n = 29 703). Two subcohorts of treated SLE patients were defined on the basis of treatment with antimalarials (n = 1942) and other immunosuppressants (AZA, CYC, ciclosporin, MTX, MMF or rituximab; n = 2175). The main outcome was defined as a first cervical neoplasia (dysplasia or cancer) during follow-up. Secondary outcomes were first cervical intraepithelial neoplasia (CIN) 1; first CIN grades 2-3; and first invasive cervical cancer during follow-up (2006-12). Cox regression models estimated relative risks adjusted for age, level of education, health-care utilization, number of children, marital status, family history of cervical cancer and prior cervical screening. Results: Based on 121 events of cervical neoplasia during 23 136 person-years among SLE patients, there was an increased risk of any cervical neoplasia compared with the general population [hazard ratio (HR) = 2.12 (95% CI: 1.65, 2.71)]. The risk of CIN 1 [HR = 2.33 (95% CI: 1.58, 3.44)], CIN 2-3 [HR = 1.95 (95% CI: 1.43, 2.65)], but not invasive cervical cancer [HR = 1.64 (95% CI: 0.54, 5.02)], was increased in women with SLE. The subcohort treated with other immunosuppressants was at highest risk of cervical neoplasia. Conclusion: SLE is a risk factor for cervical neoplasia, in particular for pre-malignant cervical lesions. Among patients with SLE, the risk is higher among those treated with immunosuppresants compared with those treated with antimalarials.

Do RA or TNF inhibitors increase the risk of cervical neoplasia or of recurrence of previous neoplasia? A nationwide study from Sweden.

OBJECTIVES: To examine screening patterns and the risk of cervical neoplasia in women with rheumatoid arthritis (RA) treated or not with tumour necrosis factor inhibitors (TNFi). METHODS: We performed a nationwide register-based cohort study in Sweden of women with RA who started a first TNFi (n=9629), biologics-naive women with RA (n=34 984) and general population comparators (matched 1:10, n=300 331), followed up from 1999 to 2012. Outcomes were first cytology screening with normal outcome, first ever cervical intraepithelial neoplasia (CIN) grade 1, first ever CIN 2-3 or adenocarcinoma in situ and first ever invasive cervical cancer during follow-up. HRs were assessed through Cox regressions adjusted for age, educational level, prior cervical screens, comorbidities, marital status and prior hospitalisations. RESULTS: Biologic-naive women with RA had more screenings (HR 1.08, 95% CI 1.06 to 1.10), were at greater risk of CIN 1 (HR 1.53, 1.23 to 1.89) and CIN 2-3 (HR 1.39, 1.16 to 1.66), but not of invasive cervical cancer (HR 1.09, 0.71 to 1.65) compared with the general population. Patients who initiated TNFi therapy had similar screening patterns (HR 1.01, 0.98 to 1.05), were not at increased risk of CIN 1 (HR 1.23, 0.87 to 1.74), but were at increased risk of CIN 2-3 (HR 1.36, 1.01 to 1.82) and invasive cervical cancer (HR 2.10, 1.04 to 4.23) compared with biologics-naive women with RA. Estimates varied little with successive adjustments, but were attenuated/absent in sensitivity analyses restricted to 2006-2012 and a disease-modifying antirheumatic drugs-treated comparator. CONCLUSIONS: Women with RA in general are at elevated risk of cervical dysplasia. Compared with biologics-naive patients, women treated with TNFi are at increased risk of cervical cancer. Whether this increase is causally linked with TNFi could not be fully disentangled.

Malignant Neoplasms in Patients With Rheumatoid Arthritis Treated With Tumor Necrosis Factor Inhibitors, Tocilizumab, Abatacept, or Rituximab in Clinical Practice: A Nationwide Cohort Study From Sweden.

Importance: Considering the widespread and increasing use of biological immunomodulators (biological disease-modifying antirheumatic drugs [bDMARDs]) to treat chronic inflammatory conditions, and the concern that immunomodulation may alter cancer risk and progression, the limited available data on use of these therapies as used in clinical practice and cancer risks are a concern. Objective: To assess the risk of incident malignant neoplasms in patients with rheumatoid arthritis (RA) treated with bDMARDs. Design, Setting, and Participants: This was a national register-based prospective cohort study of the public health care system in Sweden from 2006 to 2015. Cohorts of patients with RA initiating treatment with tocilizumab (n = 1798), abatacept (n = 2021), and rituximab (n = 3586), a tumor necrosis factor inhibitor (TNFi) as first-ever (n = 10 782) or second-ever (n = 4347) bDMARD, a biologics-naive cohort treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) (n = 46 610), and a general population comparator cohort (n = 107 491). Exposures: Treatment with tocilizumab, abatacept, rituximab, or TNFi. Main Outcomes and Measures: Outcomes included a first invasive solid or hematologic malignant neoplasm, or skin cancer. Hazard ratios were calculated using Cox-regression, adjusted for age, sex, disease and treatment characteristics, and educational level. Results: We identified a total of 15 129 initiations of TNFi as the first or second bDMARD, 7405 initiations of other bDMARDs, and 46 610 csDMARD users. The mean age varied from 58 to 64 years, and the proportion of female patients varied from 71% to 80%, across the 7 cohorts under study. The observed numbers of events (crude incidence per 100 000 person-years) for a first invasive solid or hematologic malignant neoplasm were 50 (959) for tocilizumab, 61 (1026) for abatacept, 141 (1074) for rituximab, 478 (978) for initiators of TNFi as first bDMARD, and 169 (917) for TNFi as second bDMARD. There were no statistically significant differences between initiators of a first or second TNFi, or other bDMARDs, and bDMARD-naive RA for any of a total of 25 drug- and outcome-specific comparisons, with 1 exception (abatacept and increased risk of squamous cell skin cancer). Conclusions and Relevance: The overall risk of cancer among patients with RA initiating TNFi as first or second bDMARD, tocilizumab, abatacept, or rituximab does not differ substantially from that of biologic drug-naive, csDMARD-treated patients with RA, although altered risks for specific cancer types, or those with longer latency, cannot be excluded.