Effectiveness of JAK Inhibitors Compared With Biologic Disease-Modifying Antirheumatic Drugs on Pain Reduction in Rheumatoid Arthritis: Results From a Nationwide Swedish Cohort Study.

OBJECTIVE: To compare the effectiveness of JAK inhibitors (JAKis) and biologic disease-modifying antirheumatic drugs (bDMARDs) on pain in patients with rheumatoid arthritis. METHODS: In this retrospective study, we investigated patients with a diagnosis of rheumatoid arthritis, starting treatment with a JAKi (n = 1,827), a tumor necrosis factor inhibitor (TNFi; n = 6,422), an interleukin-6 inhibitor (n = 887), abatacept (n = 1,102), or rituximab (n = 1,149) in 2017 to 2019, using data from several linked Swedish national registers. Differences in change in pain, assessed with a visual analogue scale (0-100 mm), from baseline to 3 months, as well as proportions of patients remaining on initial treatment with low pain (visual analogue scale pain <20) at 12 months, were compared between treatments. Comparisons of treatment responses between JAKis and bDMARDs were evaluated using multivariable linear regression, adjusted for patient characteristics, comorbidities, current comedication, and previous treatment. RESULTS: JAKi treatment was associated with a greater decrease in pain at 3 months compared with TNFi treatment (adjusted mean additional decrease 4.0 mm; 95% confidence interval 1.6-6.3), with similar trends in comparisons with non-TNFi bDMARDs. More patients achieved low pain at 12 months on JAKis compared with TNFis, in particular among those previously treated with at least two bDMARDs (adjusted change contrast 5.3 percentage points; 95% confidence interval 1.0-9.6). CONCLUSION: JAKis had a slightly better effect on pain outcomes at 3 and 12 months compared with TNFis, with significantly greater differences in patients previously treated with at least two bDMARDs. The effect of JAKis on pain reduction was at least similar to that of non-TNFi bDMARDs.

Sex differences in patient-reported outcomes and the association with clinical factors in axial spondyloarthritis patients treated with tumour necrosis factor inhibitors.

OBJECTIVES: To investigate sex differences in patient-reported outcome measures (PROMs) among axSpA patients initiating their first TNFi and identify factors contributing to these disparities over the follow-up. METHODS: Data were included from 15 EuroSpA registries and consisted of axSpA patients initiating their first TNFi, with ≥2 measurements for each analysed PROM (BASDAI and BASFI, scale 0-100) taken at any time point. Linear mixed models were employed to analyse sex differences in PROMs over 24 months and to evaluate how baseline characteristics were related to the observed sex differences. RESULTS: We analysed 13 102 (38% women) in the BASDAI analyses and 10 623 (38% women) in the BASFI analyses. At follow-up, mean sex differences in BASDAI increased from 4.3 units at baseline (95% CI, 3.5-5.1)-8.0 (7.2-8.8) at 6 months, and in BASFI from 2.2 (1.4-3.1)-4.6 (3.6-5.5), with consistently worse scores in women. Baseline characteristics could not substantially account for the observed sex differences over time; however, the magnitude of the sex differences was reduced by HLA-B27 positivity, longer disease duration, and increased CRP levels, but increased by TNFi initiation in later years and peripheral arthritis. CONCLUSION: In axSpA patients initiating their first TNFi, baseline sex differences in BASDAI and BASFI increased two-fold after 6 months of treatment and persisted thereafter, with worse scores in women. Several baseline characteristics moderated the sex differences, though none could fully account for them. These findings improve our understanding of sex differences and underscore their importance in axSpA.

Treatment for Rheumatoid Arthritis Associated With Alterations in the Gastrointestinal Microbiota.

OBJECTIVE: Emerging research suggests that rheumatoid arthritis (RA) is associated with intestinal dysbiosis. This prospective pilot study evaluates changes in intestinal microbial composition in patients with RA initiating treatment with either methotrexate (MTX) or a tumor necrosis factor inhibitor (TNFi). METHODS: Consecutive patients, fulfilling the 2010 American College of Rheumatology/EULAR classification criteria for RA, who started treatment with either MTX or TNFi delivered a stool sample upon initiation of immunosuppression and 3 months later. A 16S ribosomal RNA gene-based validated microbiota test (GA-map Dysbiosis Index Score [DIS], Genetic Analysis, Oslo, Norway) was used to evaluate for the presence and degree of dysbiosis. Fecal levels of Prevotella copri (P. copri) were analyzed by custom-made quantitative polymerase chain reaction. Changes in microbial composition were analyzed in relation to changes in disease activity, as measured by the disease activity score based on 28-joint counts, using C-reactive protein. RESULTS: At baseline, dysbiosis was present in 33 of 50 (66%) participants and more common in participants with more than 2 years of disease duration (P = 0.019). At the 3-month follow-up, 27 of 50 (54%) were good treatment responders and the DIS had improved in 14 of 50 (28%). Participants initiating TNFi more often exhibited improvement in the DIS compared with those initiating MTX (P = 0.031). P. copri was identified in 32 of 50 (64%) at baseline. An improvement in disease activity score based on 28-joint counts, using C-reactive protein was associated with a simultaneous decrease in P. copri abundance (rs = 0.30, P = 0.036). CONCLUSION: This study affirms that dysbiosis is a feature of RA. Although patients were not randomized to MTX or TNFi, the findings suggest that specific therapies may differentially modulate the gastrointestinal microbiota in RA. The association between P. copri and treatment response requires further study.

Patient-reported outcomes in axial spondyloarthritis and psoriatic arthritis patients treated with secukinumab for 24 months in daily clinical practice.

OBJECTIVES: In patients with axial spondyloarthritis (axSpA) or psoriatic arthritis (PsA) initiating secukinumab, we aimed to assess and compare the proportion of patients achieving 6-, 12- and 24-month patient-reported outcomes (PRO) remission and the 24-month retention rates. PATIENTS AND METHODS: Patients with axSpA or PsA from 16 European registries, who initiated secukinumab in routine care were included. PRO remission rates were defined as pain, fatigue, Patient Global Assessment (PGA) ≤2 (Numeric Rating Scale (NRS) 0-10) and Health Assessment Questionnaire (HAQ) ≤0.5, for both axSpA and PsA, and were calculated as crude values and adjusted for drug adherence (LUNDEX). Comparisons of axSpA and PsA remission rates were performed using logistic regression analyses (unadjusted and adjusted for multiple confounders). Kaplan-Meier plots with log-rank test and Cox regression analyses were conducted to assess and compare secukinumab retention rates. RESULTS: We included 3087 axSpA and 3246 PsA patients initiating secukinumab. Crude pain, fatigue, PGA and HAQ remission rates were higher in axSpA than in PsA patients, whereas LUNDEX-adjusted remission rates were similar. No differences were found between the patient groups after adjustment for confounders. The 24-month retention rates were similar in axSpA vs. PsA in fully adjusted analyses (HR [95 %CI] = 0.92 [0.84-1.02]). CONCLUSION: In this large European real-world study of axSpA and PsA patients treated with secukinumab, we demonstrate for the first time a comparable effectiveness in PRO remission and treatment retention rates between these two conditions when adjusted for confounders.

Cost-effectiveness analysis of bimekizumab for the treatment of active psoriatic arthritis in Sweden.

AIMS: To evaluate the cost-effectiveness of bimekizumab, an inhibitor of IL-17F and IL-17A, against biologic and targeted synthetic disease-modifying antirheumatic drugs (DMARD) for psoriatic arthritis (PsA) from the Swedish healthcare system perspective. MATERIALS AND METHODS: A Markov model was developed to simulate the clinical pathway of biologic [b] DMARD-naïve or tumor necrosis factor inhibitor experienced [TNFi-exp] PsA patients over a lifetime horizon. Treatment response was incorporated as achievement of the American College of Rheumatology 50% (ACR50) and Psoriasis Area and Severity Index 75% (PASI75) response, and changes in the Health Assessment Questionnaire-Disability Index (HAQ-DI) score. The efficacy of bimekizumab was obtained from the BE OPTIMAL (bDMARD-naïve) and BE COMPLETE (TNFi-experienced) trials while a network meta-analysis (NMA) informed the efficacy of the comparators. Resource use and drug costs were obtained from published studies and databases of drug retail prices in Sweden. A willingness-to-pay threshold of €50,000 per quality-adjusted life year (QALY) was applied. RESULTS: In bDMARD-naïve patients, bimekizumab achieved greater QALYs (14.08) than with all comparators except infliximab (14.22), dominated guselkumab every 4 and 8 weeks, ixekizumab, secukinumab 300 mg, ustekinumab 45 mg and 90 mg, and was cost-effective against risankizumab, tofacitinib, upadacitinib and TNFis, except adalimumab biosimilar. In TNFi-experienced patients, bimekizumab led to greater QALYs (13.56) than all comparators except certolizumab pegol (13.84), and dominated ixekizumab and secukinumab 300 mg while being cost-effective against all other IL-17A-, IL-23- and JAK inhibitors. LIMITATIONS: An NMA informed the comparative effectiveness estimates. Given gaps in evidence of disease management and indirect costs specific to HAQ-DI scores, and sequential clinical trial evidence in PsA, non-PsA cost data from similar joint conditions were used, and one line of active treatment followed by best supportive care was assumed. CONCLUSIONS: Bimekizumab was cost-effective against most available treatments for PsA in Sweden, irrespective of prior TNFi exposure.

Identifying Predictors of First-Line Subcutaneous TNF-Inhibitor Persistence in Patients with Inflammatory Arthritis: A Decision Tree Analysis by Indication.

INTRODUCTION: Treatment persistence is a proxy for efficacy, safety and patient satisfaction, and a switch in treatment or treatment discontinuation has been associated with increased indirect and direct costs in inflammatory arthritis (IA). Hence, there are both clinical and economic incentives for the identification of factors associated with treatment persistence. Until now, studies have mainly leveraged traditional regression analysis, but it has been suggested that novel approaches, such as statistical learning techniques, may improve our understanding of factors related to treatment persistence. Therefore, we set up a study using nationwide Swedish high-coverage administrative register data with the objective to identify patient groups with distinct persistence of subcutaneous tumor necrosis factor inhibitor (SC-TNFi) treatment in IA, using recursive partitioning, a statistical learning algorithm. METHODS: IA was defined as a diagnosis of rheumatic arthritis (RA), ankylosing spondylitis/unspecified spondyloarthritis (AS/uSpA) or psoriatic arthritis (PsA). Adult swedish biologic-naïve patients with IA initiating biologic treatment with a SC-TNFi (adalimumab, etanercept, certolizumab or golimumab) between May 6, 2010, and December 31, 2017. Treatment persistence of SC-TNFi was derived based on prescription data and a defined standard daily dose. Patient characteristics, including age, sex, number of health care contacts, comorbidities and treatment, were collected at treatment initiation and 12 months before treatment initiation. Based on these characteristics, we used recursive partitioning in a conditional inference framework to identify patient groups with distinct SC-TNFi treatment persistence by IA diagnosis. RESULTS: A total of 13,913 patients were included. Approximately 50% had RA, while 27% and 23% had AS/uSpA and PsA, respectively. The recursive partitioning algorithm identified sex and treatment as factors associated with SC-TNFi treatment persistence in PsA and AS/uSpA. Time on treatment in the groups with the lowest treatment persistence was similar across all three indications (9.5-11.3 months), whereas there was more variation in time on treatment across the groups with the highest treatment persistence (18.4-48.9 months). CONCLUSIONS: Women have low SC-TNFi treatment persistence in PsA and AS/uSpA whereas male sex and golimumab are associated with high treatment persistence in these indications. The factors associated with treatment persistence in RA were less distinct but may comprise disease activity and concurrent conventional systemic disease-modifying anti-rheumatic drug (DMARD) treatment.

Methotrexate treatment in early psoriatic arthritis in comparison to rheumatoid arthritis: an observational nationwide study.

INTRODUCTION: We aimed to compare the proportions of patients with newly diagnosed psoriatic arthritis (PsA) and rheumatoid arthritis (RA) remaining on methotrexate (regardless of other disease-modifying antirheumatic drug (DMARD)-changes), and proportions not having started another DMARD (regardless of methotrexate discontinuation), within 2 years of starting methotrexate, as well as methotrexate effectiveness. METHODS: Patients with DMARD-naïve, newly diagnosed PsA, starting methotrexate 2011-2019, were identified from high-quality national Swedish registers and matched 1:1 to comparable patients with RA. Proportions remaining on methotrexate and not starting another DMARD were calculated. For patients with disease activity data at baseline and 6 months, response to methotrexate monotherapy was compared through logistic regression, applying non-responder imputation. RESULTS: In total, 3642/3642 patients with PsA/RA were included. Baseline patient-reported pain and global health were similar, whereas patients with RA had higher 28-joint scores and evaluator-assessed disease activity. Two years after methotrexate start, 71% of PsA vs 76% of patients with RA remained on methotrexate, 66% vs 60% had not started any other DMARD, and 77% vs 74% had not started specifically a biological or targeted synthetic DMARD. At 6 months, the proportions of patients with PsA versus RA achieving pain-scores ≤15 mm were 26% vs 36%; global health ≤20 mm: 32% vs 42%; evaluator-assessed 'remission': 20% vs 27%, with corresponding adjusted ORs (PsA vs RA) of 0.63 (95% CI 0.47 to 0.85); 0.57 (95% CI 0.42 to 0.76) and 0.54 (95% CI 0.39 to 0.75). DISCUSSION: In Swedish clinical practice, methotrexate use is similar in PsA and RA, both regarding initiation of other DMARDs and methotrexate retention. On a group level, disease activity improved during methotrexate monotherapy in both diseases, although more so in RA.

Characteristics associated with poor COVID-19 outcomes in people with psoriasis, psoriatic arthritis and axial spondyloarthritis: data from the COVID-19 PsoProtect and Global Rheumatology Alliance physician-reported registries.

OBJECTIVES: To investigate factors associated with severe COVID-19 in people with psoriasis (PsO), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). METHODS: Demographic data, clinical characteristics and COVID-19 outcome severity of adults with PsO, PsA and axSpA were obtained from two international physician-reported registries. A three-point ordinal COVID-19 severity scale was defined: no hospitalisation, hospitalisation (and no death) and death. ORs were estimated using multivariable ordinal logistic regression. RESULTS: Of 5045 cases, 18.3% had PsO, 45.5% PsA and 36.3% axSpA. Most (83.6%) were not hospitalised, 14.6% were hospitalised and 1.8% died. Older age was non-linearly associated with COVID-19 severity. Male sex (OR 1.54, 95% CI 1.30 to 1.83), cardiovascular, respiratory, renal, metabolic and cancer comorbidities (ORs 1.25-2.89), moderate/high disease activity and/or glucocorticoid use (ORs 1.39-2.23, vs remission/low disease activity and no glucocorticoids) were associated with increased odds of severe COVID-19. Later pandemic time periods (ORs 0.42-0.52, vs until 15 June 2020), PsO (OR 0.49, 95% CI 0.37 to 0.65, vs PsA) and baseline exposure to TNFi, IL17i and IL-23i/IL-12+23i (OR 0.57, 95% CI 0.44 to 0.73; OR 0.62, 95% CI 0.45 to 0.87; OR 0.67, 95% CI 0.45 to 0.98; respectively; vs no disease-modifying antirheumatic drug) were associated with reduced odds of severe COVID-19. CONCLUSION: Older age, male sex, comorbidity burden, higher disease activity and glucocorticoid intake were associated with more severe COVID-19. Later pandemic time periods, PsO and exposure to TNFi, IL17i and IL-23i/IL-12+23i were associated with less severe COVID-19. These findings will enable risk stratification and inform management decisions for patients with PsO, PsA and axSpA during COVID-19 waves or similar future respiratory pandemics.

Health-Care and Societal Costs Associated with Non-Persistence with Subcutaneous TNF-α Inhibitors in the Treatment of Inflammatory Arthritis (IA): A Retrospective Observational Study.

OBJECTIVE: A few studies have suggested that patients with inflammatory arthritis (IA) who remain persistent with subcutaneous TNF-α inhibitors (SC-TNFi) incur lower health care costs than patients who discontinue treatment, whereas data on the impact of non-persistence on indirect costs are largely lacking. Furthermore, existing estimates are based on fixed follow-ups, in relation to treatment initiation, and therefore do not measure costs in direct relation to treatment discontinuation. Therefore, by capturing costs in direct relation to treatment discontinuation, this study aimed to estimate direct and indirect costs associated with non-persistence with SC-TNFis in IA. METHODS: Adult Swedish biologic-naïve IA patients initiating biologic treatment with a SC-TNFi (adalimumab, etanercept, certolizumab or golimumab) between May 6, 2010, and December 31, 2017, were identified in population-based registers with almost complete coverage. IA was defined as a diagnosis of rheumatic arthritis, ankylosing spondylitis/unspecified spondyloarthritis or psoriatic arthritis. Non-persistent patients were matched on propensity score to patients persistent with treatment by at least an additional 12 months. This enabled comparisons of direct healthcare costs and indirect costs for sick leave and disability pension, respectively, 12 months before and 12 months after treatment discontinuation. RESULTS: A balanced cohort of 486 matched pairs was generated. The total direct and indirect costs were significantly higher among non-persistent patients already during the 12 months before index ($20,802 [18,335-23,429] vs. $16,600 [14,331-18,696]). However, while non-persistent patients increased their total direct and indirect costs, persistent patients significantly decreased the same, further widening the difference in costs during the 12-month period after index date ($22,161 [19,754-24,556] vs. $13,465 [11,415-15,729]). CONCLUSIONS: Among biologic-naïve Swedish IA patients treated with SC-TNFis, persistent patients incurred about 40% lower aggregated direct and indirect costs compared to non-persistent patients the year following SC-TNFi discontinuation. This highlights the impact of treatment persistence from an economic viewpoint, adding further aspects to the clinical perspective.

Anterior uveitis in patients with spondyloarthritis treated with secukinumab or tumour necrosis factor inhibitors in routine care: does the choice of biological therapy matter?

BACKGROUND: The effect of interleukin 17-inhibitors on anterior uveitis (AU) in spondyloarthritis (SpA) is poorly understood. This study aimed to compare the risk of AU during treatment with secukinumab versus tumour necrosis factor inhibitors (TNFi). METHODS: Patients with SpA starting secukinumab or a TNFi 2015 through 2018 were identified in the Swedish Rheumatology Quality Register. Occurrence of AU was identified based on diagnosis codes in outpatient ophthalmology care in the National Patient Register. The main outcomes were crude rates of AU-diagnoses per 100 patient-years, and adjusted HRs for AU, during treatment, in patients without AU during the year before treatment start (in order to reduce confounding by indication). HRs were adjusted for age, sex, history of AU and patient global assessment of disease activity. RESULTS: Based on 4851 treatment starts (456 secukinumab; 4395 any TNFi), the rate of AU-diagnoses per 100 patient-years was 6.8 (95% CI 5.2 to 8.7) for secukinumab. Among the TNFi, the rate varied from 2.9 (95% CI 2.1 to 3.7) for infliximab and 4.0 (95% CI 3.3 to 4.9) for adalimumab to 7.5 (95% CI 6.7 to 8.4) for etanercept. The adjusted HRs for first AU (adalimumab as reference) were: secukinumab 2.32 (95% CI 1.16 to 4.63), infliximab 0.99 (95% CI 0.49 to 1.96), etanercept 1.82 (95% CI 1.13 to 2.93), golimumab 1.59 (95% CI 0.90 to 2.80) and certolizumab 1.12 (95% CI 0.44 to 2.83). Sensitivity analyses confirmed the pattern of higher AU rates with secukinumab and etanercept versus monoclonal TNFi. CONCLUSION: As used in clinical practice in SpA, secukinumab appears to be associated with a higher risk of AU, compared with the monoclonal TNFi and a similar risk compared with etanercept.

Sustained Remission in Patients With Rheumatoid Arthritis Receiving Triple Therapy Compared to Biologic Therapy: A Swedish Nationwide Register Study.

OBJECTIVE: To compare the real-life effectiveness of biologic therapy (a biologic disease-modifying antirheumatic drug plus methotrexate [MTX]) versus triple therapy (MTX plus sulfasalazine plus hydroxychloroquine/chloroquine) for sustained remission of rheumatoid arthritis (RA). METHODS: RA patients who were registered in the nationwide Swedish Rheumatology Quality Register between 2000 and 2012 and were receiving biologic or triple therapy as a first treatment strategy after MTX monotherapy were included. Sustained remission was defined as a Disease Activity Score in 28 joints (DAS28) of <2.6 for ≥6 months (short-term sustained remission) or for ≥24 months (long-term sustained remission). Treatment groups were compared during treatment, at 1 year, and at 2 years for 1) all patients starting therapy and 2) patients continuing to receive therapy, using propensity score-adjusted regression analyses. In addition, survival analyses were used to compare treatment groups at any time during follow-up irrespective of therapy retention. RESULTS: A total of 1,502 patients were included (1,155 receiving biologic therapy and 347 receiving triple therapy). For patients starting therapy, the adjusted odds ratios (ORs) of achieving short-term and long-term remission, respectively, at 1 year after start of biologic therapy versus triple therapy were 1.79 (95% confidence interval [95% CI] 1.18-2.71) and 1.86 (95% CI 1.00-3.48). At 2 years, the ORs were 1.92 (95% CI 1.21-3.06) and 1.62 (95% CI 0.94-2.79), respectively. For patients continuing to receive therapy, corresponding results at 1 year were 1.12 (95% CI 0.72-1.75) and 1.1 (95% CI 0.59-2.16); at 2 years, 0.85 (95% CI 0.49-1.47) and 0.76 (95% CI 0.41-1.39). Hazard ratios for short-term and long-term sustained remission at any time during follow-up were 1.15 (95% CI 0.91-1.46) and 1.09 (95% CI 0.77-1.54), respectively. CONCLUSION: Among patients starting biologic or triple therapy, biologic therapy was more effective for remaining on therapy and achieving sustained remission. However, similar probabilities were found for achieving sustained remission among patients remaining on therapy and at any time during follow-up irrespective of therapy retention. Although the likelihood of reaching sustained remission is higher with biologic therapy, for certain RA patients triple therapy may still be an alternative to biologic therapy without hampering future chances of obtaining sustained remission.

Biological treatment of ankylosing spondylitis: a nationwide study of treatment trajectories on a patient level in clinical practice.

BACKGROUND: There is substantial evidence that patients with ankylosing spondylitis (AS) have high response rates to tumour necrosis factor inhibitors (TNFi), a low likelihood of successful treatment termination, but yet a limited drug retention. Whereas several reports have assessed drug retention rates for TNFi in AS, there are few, if any, studies investigating the actual treatment trajectories on a patient level, including subsequent therapy changes and dose reductions, of individual patients. The aim of this study was to describe 5-year treatment trajectories in patients with ankylosing spondylitis (AS) starting a first TNFi. METHODS: Bio-naïve patients with AS starting a TNFi in 2006-2015 were identified in the nationwide Swedish Rheumatology Quality register and followed until 31 December 2015. All changes in their anti-rheumatic treatment during follow-up were recorded. To further increase precision, these data were complimented by information on the amount of prescribed subcutaneous TNFi collected from pharmacies during each year, retrieved from the Swedish Prescribed Drug Register. RESULTS: Two thousand five hundred ninety patients started a first TNFi 2006-2015, and after 1 year, 74% remained on their first TNFi. However, after 5 years, this figure was only 46%, although at that time 63% were still on treatment with any biologic, while 30% had no anti-rheumatic treatment at all. After discontinuing the first TNFi, 46% switched directly to a second TNFi, but the drug retention for the second and third TNFi grew successively shorter compared to that for the first TNFi. In contrast, patients remaining on treatment with their first subcutaneous TNFi gradually reduced the dose, so that during the fifth year of treatment only 66% had collected ≥ 75% of the defined daily doses for that year. CONCLUSION: Less than half of patients with AS will remain on their first TNFi after 5 years, but most are still on a biologic. While patients remaining on treatment with their first TNFi appear to be able to reduce the dose over time, a large proportion cycle through several biologics, and 1/3 have no anti-rheumatic treatment after 5 years. This indicates the importance of thorough follow-up programs as well as a need for alternative therapeutic options.

Impact of extra-articular spondyloarthritis manifestations and comorbidities on drug retention of a first TNF-inhibitor in ankylosing spondylitis: a population-based nationwide study.

OBJECTIVES: To assess the impact of extra-articular spondyloarthritis (SpA) manifestations (anterior uveitis, psoriasis and inflammatory bowel disease (IBD)), and of comorbidities, on tumour necrosis factor alpha inhibitor (TNFi) drug retention in ankylosing spondylitis (AS). METHODS: We identified all bio-naïve patients with AS starting a first ever TNFi July 2006 to December 2015 from the Swedish Rheumatology Quality register and followed these from treatment start through December 2015. We determined the presence of extra-articular SpA-manifestations, comorbidities (cardiovascular disease, affective disease, diabetes, malignancies, chronic lung disease and kidney disease) and socioeconomic status before TNFi start, through linkage to five other national registers, and calculated, for each factor, crude and adjusted HRs for discontinuing the TNFi. RESULTS: 2577 patients with AS (71% men) started a first TNFi during the study period. 27% had a history of anterior uveitis, 6% psoriasis and 7% IBD. Anterior uveitis was associated with a superior TNFi drug retention (HR 0.72; 0.62 to 0.83), psoriasis with an inferior (HR 1.48; 1.18 to 1.86), whereas IBD did not affect TNFi drug retention. The effect of the SpA manifestations on TNFi drug retention was of a similar magnitude to that of the comorbidities. CONCLUSIONS: In AS, anterior uveitis and psoriasis, but not IBD, affect TNFi drug retention. Possible explanations include differential effects of TNFi on these extra-articular SpA manifestations, or inherent differences in AS, associated with the inflammatory phenotype. Further, comorbidities and socioeconomy affect TNFi drug retention to a similar magnitude as the SpA manifestations, and should, as such, receive due attention in clinical practice.

Work disability in non-radiographic axial spondyloarthritis patients before and after start of anti-TNF therapy: a population-based regional cohort study from southern Sweden.

Objective: The aim was to assess work-loss days before and after commencement of anti-TNF treatment in patients with non-radiographic axial spondylarthritis (nr-axSpA). Methods: Bionaïve nr-axSpA patients (n = 75), aged 17-62 years, fulfilling the Assessment of SpondyloArthritis international Society criteria for axial spondyloarthritis and starting anti-TNF treatment during 2004-11, were retrieved from the observational South Swedish Arthritis Treatment Group study. Patient information was linked to Swedish Social Insurance Agency data on sick leave and disability pension from 1 year before to 2 years after anti-TNF initiation. Matched population references were included for comparison and to adjust for secular trends. Results: The nr-axSpA patients had a median age of 35 years and disease duration of 6 years at the start of treatment. During the 2 years after anti-TNF initiation, mean work-loss days (including both sick leave and disability pension) in the nr-axSpA group decreased significantly from 3.4 to 1.9 times more than among the population references. The effect was seen on sick leave, whereas disability pension levels remained similar in both groups throughout. Conclusion: Anti-TNF therapy in nr-axSpA was associated with a significant and sustained improvement of work disability over 2 years. However, the proportion of work-loss days remained almost twice as high as in the general population at the end of follow-up.

Costs in Relation to Disability, Disease Activity, and Health-related Quality of Life in Rheumatoid Arthritis: Observational Data from Southern Sweden.

OBJECTIVE: To compare how costs relate to disability, disease activity, and health-related quality of life (HRQOL) in rheumatoid arthritis (RA). METHODS: Antitumor necrosis factor (anti-TNF)-treated patients with RA in southern Sweden (n = 2341) were monitored 2005-2010. Health Assessment Questionnaire (HAQ), 28-joint Disease Activity Score (DAS28), and EQ-5D scores were linked to register-derived costs of antirheumatic drugs (excluding anti-TNF agents), patient care, and work loss from 30 days before to 30 days after each visit (n = 13,289). Associations of HAQ/DAS28/EQ-5D to healthcare (patient care and drugs) and work loss costs (patients < 65 yrs) were studied in separate regression models, comparing standardized ß coefficients by nonparametric bootstrapping to assess which measure best reflects costs. Analyses were conducted based on both individual means (linear regression, comparing between-patient associations) and by generalized estimating equations (GEE), using all observations to also account for within-patient associations of HAQ/DAS28/EQ-5D to costs. RESULTS: Regardless of the methodology (linear or GEE regression), HAQ was most closely related to both cost types, while work loss costs were also more closely associated with EQ-5D than DAS28. The results of the linear models for healthcare costs were standardized ß = 0.21 (95% CI 0.15-0.27), 0.16 (0.11-0.21), and -0.15 (-0.21 to -0.10) for HAQ/DAS28/EQ-5D, respectively (p < 0.05 for HAQ vs DAS28/EQ-5D). For work loss costs, the results were standardized ß = 0.43 (95% CI 0.39-0.48), 0.27 (0.23-0.32), and -0.34 (-0.38 to -0.29) for HAQ/DAS28/EQ-5D, respectively (p < 0.05 for HAQ vs DAS28/EQ-5D and for EQ-5D vs DAS28). CONCLUSION: Overall, HAQ disability is a better marker of RA costs than DAS28 or EQ-5D HRQOL.

Does disease activity at start of biologic therapy influence work-loss in RA patients?

OBJECTIVE: To compare work-loss in RA patients starting their first biologic with high vs moderate disease activity. METHODS: We identified all RA patients aged 20-63 years in the Swedish Biologics Register who started their first biologic 2007-09 with high disease activity (DAS28 >5.1; n = 868) or moderate disease activity (DAS28 3.2-5.1; n = 854). Work days lost, defined as sick leave and disability pension days from the Swedish Social Insurance Agency, were assessed over 5 years after first bio-start. We estimated between-group mean differences adjusted for age, sex, calendar year, education level, disease duration, comorbidities and work-loss the month before bio-start. RESULTS: During 5 years after anti-TNF start, mean monthly work days lost declined from 16.0 to 9.2 (42%; P < 0.001) in patients with high disease activity at baseline and from 12.0 to 7.2 (40%; P < 0.001) in patients with moderate disease activity, with no between-group difference (adjusted mean difference 0.81; 95% CI - 0.44, 2.05). Accumulated 5-year work-loss was, however, higher in the high activity group (724 vs 548 days; adjusted mean difference 70; 95% CI 20, 120), but after stratification on baseline disability pension status, no differences in accumulated work-loss were detected. CONCLUSION: Substantial work-loss was seen in both patients with high and patients with moderate disease activity at anti-TNF start, with a 5-year decline in mean monthly work days lost by ∼40% in both groups and no between-group difference. Accumulated work-loss over 5 years was higher in the high-activity group, which may be explained by differences in baseline disability pension status.

Analysis of the DNA methylome and transcriptome in granulopoiesis reveals timed changes and dynamic enhancer methylation.

In development, epigenetic mechanisms such as DNA methylation have been suggested to provide a cellular memory to maintain multipotency but also stabilize cell fate decisions and direct lineage restriction. In this study, we set out to characterize changes in DNA methylation and gene expression during granulopoiesis using 4 distinct cell populations ranging from the oligopotent common myeloid progenitor stage to terminally differentiated neutrophils. We observed that differentially methylated sites (DMSs) generally show decreased methylation during granulopoiesis. Methylation appears to change at specific differentiation stages and overlap with changes in transcription and activity of key hematopoietic transcription factors. DMSs were preferentially located in areas distal to CpG islands and shores. Also, DMSs were overrepresented in enhancer elements and enriched in enhancers that become active during differentiation. Overall, this study depicts in detail the epigenetic and transcriptional changes that occur during granulopoiesis and supports the role of DNA methylation as a regulatory mechanism in blood cell differentiation.

Leukemia associated mutant Wilms' tumor gene 1 protein promotes expansion of human hematopoietic progenitor cells.

The transcription factor Wilms' tumor gene 1 (WT1) is highly expressed in the majority of leukemias, suggesting a role in leukemogenesis. Acquired WT1 mutations are reported as an independent predictor of poor clinical outcome, and mutations resulting in deletion of the entire DNA-binding zinc-finger domain (WT1delZ), is the most common type. The aim of this study was to study cellular effects of WT1(delZ) that may contribute to an oncogenic phenotype. We found that expression of WT1(delZ) supported proliferation of human hematopoietic CD34(+) progenitor cells. Moreover, WT1(delZ) transduced cells expressed erythroid markers, including raised levels of STAT5, independently of addition of erythropoietin. At the global gene expression level, WT1(delZ) caused upregulation of genes related to cell division and genes associated with erythroid maturation, in the absence of added erythropoietin. Our results indicate that WT1(delZ) promotes cell proliferation and expansion of progenitor cells, consistent with a possible role in leukemogenesis.