Prednisone use, disease activity and the occurrence of hyperglycaemia and diabetes in patients with early rheumatoid arthritis: a 10-year subanalysis of the BeSt study.

OBJECTIVES: To assess whether prednisone use and/or disease activity score (DAS) are associated with the development of hyperglycaemia and diabetes in rheumatoid arthritis (RA). METHODS: We included 504 non-diabetic early RA patients from the BeSt study (Dutch acronym for treatment strategies). Patients were randomised to four DAS-steered treatment arms and followed for 10 years. The associations between DAS and prednisone use with glucose levels and the occurrence of hyperglycaemia over time were assessed with linear and logistic mixed effects regression models. Development of diabetes was analysed with Cox regression. Sensitivity analyses were performed in patients who had a first episode of hyperglycaemia. RESULTS: 31 of 504 patients (6.2%) with a mean age of 54 years developed diabetes during follow-up; 11 of these (35%) had received prior treatment with prednisone. Prednisone use was not associated with development of hyperglycaemia or diabetes after correction for multiple testing in main or sensitivity analyses. In the main analyses, DAS was significantly associated with development of diabetes (HR 1.802 per 1 point DAS increase, 95% CI 1.284 to 2.529) but not with glucose levels nor hyperglycaemia. In patients with previous hyperglycaemia, DAS was associated with glucose levels, recurrence of hyperglycaemia and diabetes. CONCLUSIONS: In non-diabetic early RA patients, the use of prednisone was not associated with developing hyperglycaemia or diabetes. However, high DAS increased the risk of diabetes. Potential risks associated with prednisone use may have been mitigated by its effect on DAS.

Bone loss and new vertebral fractures during treatment with romosozumab: a case-report.

PURPOSE: This study aimed to illustrate the possibility of an unfavorable response to treatment with the anabolic agent romosozumab for patients with severe osteoporosis and to discuss explanations for treatment failure. METHODS: Dual-energy x-ray absorptiometry (DXA) including vertebral fracture assessment (VFA) and X-rays of the thoracolumbar spine was used to assess bone mineral density (BMD) and the presence of vertebral fractures before and after treatment with romosozumab. RESULTS: Our patient developed a decrease in the BMD of the hip, two incident new vertebral fractures, and worsening of one prevalent vertebral fracture during 1 year treatment with romosozumab. We have not detected non-adherence, there was no pretreatment with anti-resorptives, and we observed no signs of secondary osteoporosis and/or comorbidities. CONCLUSION: As the number of patients treated with romosozumab is rising, it becomes more likely that more patients will be found with new fractures and/or an unfavorable BMD response. Probably, the unfavorable response is a (bad) chance finding, but we think it is crucial for clinicians and patients to exclude nonadherence, new comorbidities and pretreatment with anti-resorptives as explanation in these patients.

Initial glucocorticoid bridging in rheumatoid arthritis: does it affect glucocorticoid use over time?

OBJECTIVES: To compare the use of glucocorticoids (GC) over time in patients with rheumatoid arthritis (RA) who were or were not treated initially with GC bridging therapy. METHODS: Data from the BeSt, CareRA and COBRA trials were combined in an individual patient data (IPD) meta-analysis. We compared GC use between bridgers and non-bridgers at 12, 18 and 24 months from baseline with mixed-effects regression analysis. Secondary outcomes were mean cumulative GC dose until 24 months after baseline with and without the bridging period, Disease Activity Score based on 28 joints (DAS28) over time and number of disease-modifying antirheumatic drug (DMARD) changes. RESULTS: 252/625 patients (40%) were randomised to GC bridging (bridgers). Excluding the period of bridging, later GC use was low in both groups and cumulative doses were similar. Mean DAS28 was similar between the groups, but bridgers improved more rapidly (p<0.001) in the first 6 months and the bridgers required significantly fewer changes in DMARDs (incidence rate ratio 0.59 (95% CI 0.38 to 0.94)). GC use was higher in the bridgers at t=12 months (OR 3.27 (95% CI 1.06 to 10.08)) and the bridging schedules resulted in a difference in cumulative GC dose of 2406 mg (95% CI 1403 to 3408) over 24 months. CONCLUSION: In randomised trials comparing GC bridging and no GC bridging, bridgers had a more rapid clinical improvement, fewer DMARD changes and similar late use of GC compared with non-bridgers. GC bridging per protocol resulted, as could be expected, in a higher cumulative GC dose over 2 years.

Long-term mortality in treated-to-target RA and UA: results of the BeSt and IMPROVED cohort.

OBJECTIVES: To study long-term (up to 20-year) mortality of two treat-to-target trial cohorts in undifferentiated arthritis (UA) and early rheumatoid arthritis (RA). METHODS: The BeSt (BehandelStrategieën) study (n=508, early RA) was performed between 2000 and 2012. For 10 years, patients were treated-to-target disease activity score (DAS)≤2.4.The Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED) study (n=610, early RA/UA) was performed between 2007 and 2015. For 5 years, patients were treated-to-target DAS<1.6.Vital status of BeSt/IMPROVED participants was assessed up to and including 31 December 2021. Standardised mortality ratios (SMRs) were calculated. Stratified analyses for anticitrullinated protein antibody (ACPA) and smoking status were performed. Death causes and the potential effect of disease activity during the trial period on late mortality were assessed. RESULTS: Excess mortality was found in both BeSt (SMR 1.32, 95% CI 1.14 to 1.53) and IMPROVED (SMR 1.33, 95% CI 1.10 to 1.63) and became manifest after 10 years. Excess mortality was statistically significant in ACPA+ patients who smoked (BeSt: SMR 2.80, 95% CI 2.16 to 3.64; IMPROVED: 2.14, 95% CI 1.33 to 3.45). Mean survival time was 10 (95% CI 5 to 16) months shorter than expected in BeSt and 13 (95% CI 11 to 16) months in IMPROVED. The HR for mortality was 1.34 (95% CI 0.96 to 1.86; BeSt)/1.13 (95% CI 0.67 to 1.91; IMPROVED) per 1 point increase in mean DAS during the trial. The main cause of death was malignancy. CONCLUSIONS: After long-term treatment-to-target, excess mortality occurred in patients with RA after>10 years since treatment start, with smoking as an important risk factor.

[Rheumatic adverse events due to immune checkpoint inhibitors]. / Reumatische klachten door immunotherapie bij kanker.

BACKGROUND: Oncological survival and quality-of-life improved significantly after introduction of immune checkpoint inhibitors (ICIs). Immunotherapy, however, also decreases immunotolerance, potentially inducing autoimmune reactions. This can result in symptoms mimicking rheumatic diseases. CASE DESCRIPTION: Patient A, 51-years-old, female, was treated with adjuvant nivolumab for metastatic melanoma. After 9 months, she developed arthritis. Prednisone 30 mg/ day and methotrexate significantly improved arthritis, followed by prednisone tapering. Patient B, 75-year-old, male with metastatic melanoma treated with Ipilimumab/Nivolumab developed malaise and reduced muscle strength shortly after treatment start. Patient was suspected of myositis/myocarditis, treated with methylprednisolone, which resulted in a rapid improvement. CONCLUSION: ICIs can cause rheumatic adverse events, resulting in decreased quality of life that may require immunesuppressive treatment. Disruption or cessation of ICIs may occur. These adverse events demand low-threshold rheumatological referral and collaboration between oncologist and rheumatologist. Further research must indicate the most effective immunosuppressive therapies with minimized negative oncological impact.

Three-month tapering and discontinuation of long- term, low-dose glucocorticoids in senior patients with rheumatoid arthritis is feasible and safe: placebo-controlled double blind tapering after the GLORIA trial.

OBJECTIVE: The randomised placebo-controlled GLORIA (Glucocorticoid LOw-dose in RheumatoId Arthritis) trial evaluated the benefits and harms of prednisolone 5 mg/day added to standard care for 2 years in patients aged 65+ years with rheumatoid arthritis (RA). Here, we studied disease activity, flares and possible adrenal insufficiency after blinded withdrawal of study medication. METHODS: Per protocol, patients successfully completing the 2-year trial period linearly tapered and stopped blinded study medication in 3 months. We compared changes in disease activity after taper between treatment groups (one-sided testing). Secondary outcomes (two-sided tests) comprised disease flares (DAS28 (Disease Activity Score 28 joints) increase >0.6, open-label glucocorticoids or disease-modifying antirheumatic drug (DMARD) increase/switch after week 4 of tapering) and symptoms/signs of adrenal insufficiency. In a subset of patients from 3 Dutch centres, cortisol and ACTH were measured in spot serum samples after tapering. RESULTS: 191 patients were eligible; 36 met treatment-related flare criteria and were only included in the flare analysis. Mean (SD) DAS28 change at follow-up: 0.2 (1.0) in the prednisolone group (n=76) vs 0.0 (1.2) in placebo (n=79). Adjusted for baseline, the between-group difference in DAS28 increase was 0.16 (95% confidence limit -0.06, p=0.12). Flares occurred in 45% of prednisolone patients compared with 33% in placebo, relative risk (RR) 1.37 (95% CI 0.95 to 1.98; p=0.12). We found no evidence for adrenal insufficiency. CONCLUSIONS: Tapering prednisolone moderately increases disease activity to the levels of the placebo group (mean still at low disease activity levels) and numerically increases the risk of flare without evidence for adrenal insufficiency. This suggests that withdrawal of low-dose prednisolone is feasible and safe after 2 years of administration.

Post-COVID condition in patients with inflammatory rheumatic diseases: a prospective cohort study in the Netherlands.

Background: Studies on long-term consequences of COVID-19, commonly referred to as post-COVID condition, in patients with inflammatory rheumatic diseases are scarce and inconclusive. Furthermore, classifying patients with inflammatory rheumatic diseases as having post-COVID condition is complicated because of overlapping symptoms. Therefore, we investigated the risk of post-COVID condition and time until recovery, and compared the prevalence of symptoms seen in post-COVID condition, between patients with inflammatory rheumatic diseases and healthy controls, with and without a history of COVID-19. Methods: In this substudy we used data from an ongoing prospective cohort study in the Netherlands. All adult patients with inflammatory rheumatic diseases from the Amsterdam Rheumatology and Immunology Center in Amsterdam, the Netherlands, were invited to participate in the study between April 26, 2020, and March 1, 2021. All patients were asked, but not obliged, to recruit their own control participant of the same sex, of comparable age (< 5 years), and without an inflammatory rheumatic disease. Demographic and clinical data, including data on the occurrence of SARS-CoV-2 infections, were collected via online questionnaires. On March 10, 2022, all study participants received a questionnaire on the occurrence, onset, severity, and duration of persistent symptoms during the first 2 years of the COVID-19 pandemic, independent of their history of SARS-CoV-2 infection. Additionally, we prospectively monitored a subset of participants who had a PCR or antigen confirmed SARS-CoV-2 infection in the 2-month period surrounding the questionnaire in order to assess COVID-19 sequelae. In line with WHO guidelines, post-COVID condition was defined as persistent symptoms that lasted at least 8 weeks, started after the onset and within 3 months of a PCR or antigen-confirmed SARS-CoV-2 infection, and could not be explained by an alternative diagnosis. Statistical analyses included descriptive statistics, logistic regression analyses, logistic-based causal mediation analyses, and Kaplan-Meier survival analyses for time until recovery from post-COVID condition. In exploratory analyses, E-values were calculated to investigate unmeasured confounding. Findings: A total of 1974 patients with inflammatory rheumatic disease (1268 [64%] women and 706 [36%] men; mean age 59 years [SD 13]) and 733 healthy controls (495 [68%] women and 238 [32%] men; mean age 59 years [12]) participated. 468 (24%) of 1974 patients with inflammatory rheumatic disease and 218 (30%) of 733 healthy controls had a recent SARS-CoV-2 omicron infection. Of those, 365 (78%) of 468 patients with inflammatory rheumatic disease and 172 (79%) of 218 healthy controls completed the prospective follow-up COVID-19 sequelae questionnaires. More patients than controls fulfilled post-COVID condition criteria: 77 (21%) of 365 versus 23 (13%) of 172 (odds ratio [OR] 1·73 [95% CI 1·04-2·87]; p=0·033). The OR was attenuated after adjusting for potential confounders (adjusted OR 1·53 [95% CI 0·90-2·59]; p=0·12). Among those without a history of COVID-19, patients with inflammatory diseases were more likely to report persistent symptoms consistent with post-COVID condition than were healthy controls (OR 2·52 [95% CI 1·92-3·32]; p<0·0001). This OR exceeded the calculated E-values of 1·74 and 1·96. Recovery time from post-COVID condition was similar for patients and controls (p=0·17). Fatigue and loss of fitness were the most frequently reported symptoms in both patients with inflammatory rheumatic disease and healthy controls with post-COVID condition. Interpretation: Post-COVID condition after SARS-CoV-2 omicron infections was higher in patients with inflammatory rheumatic disease than in healthy controls based on WHO classification guidelines. However, because more patients with inflammatory rheumatic disease than healthy controls without a history of COVID-19 reported symptoms that are commonly used to define a post-COVID condition during the first 2 years of the pandemic, it is likely that the observed difference in post-COVID condition between patients and controls might in part be explained by clinical manifestations in the context of underlying rheumatic diseases. This highlights the limitations of applying current criteria for post-COVID condition in patients with inflammatory rheumatic disease, and suggests it might be appropriate for physicians to keep a nuanced attitude when communicating the long-term consequences of COVID-19. Funding: ZonMw (the Netherlands organization for Health Research and Development) and Reade foundation.

Repair of joint damage in patients with rheumatoid arthritis does not relate to previous suppression of inflammation: a subanalysis after 8 years treat-to-target in the BeSt-trial.

OBJECTIVES: To investigate whether repair of erosions and joint space narrowing (JSN) in rheumatoid arthritis (RA) occurs and whether clinical variables predict this. METHODS: Eight-year follow-up data of the BeSt-study were used. Patients with recent onset RA (1987 criteria) were randomised to four treatment strategies and treated-to-target (Disease Activity Score (DAS)≤2.4). Yearly radiographs of hands and feet were scored in non-chronological order by four independent readers, using the Sharp/van der Heijde score (SHS). Damage repair was defined as a negative ΔSHS in an individual joint, seen by ≥3 out of 4 readers and persisting ≥2 consecutive years. Associations between repair and DAS, prednisone use, infliximab use, anticitrullinated protein antibody, gender, age, body mass index, symptom duration and randomisation arm were investigated with logistic regression analyses, corrected for mean SHS. RESULTS: Repair was seen in 17 patients (5.3%); 10 had regression of JSN, 7 of erosions, none had both. There were no significant associations in any of the regression analyses. CONCLUSION: After 8 years of treatment to target DAS≤2.4 in 508 patients with recent onset RA, repair of JSN and erosions was seen in 17/320 patients (5.3%). Probably due to the rarity of repair, we found no associations with suppression of disease activity or other predictors and repair.

Fracture risk reduction and safety by osteoporosis treatment compared with placebo or active comparator in postmenopausal women: systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials.

OBJECTIVE: To review the comparative effectiveness of osteoporosis treatments, including the bone anabolic agents, abaloparatide and romosozumab, on reducing the risk of fractures in postmenopausal women, and to characterise the effect of antiosteoporosis drug treatments on the risk of fractures according to baseline risk factors. DESIGN: Systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials. DATA SOURCES: Medline, Embase, and Cochrane Library to identify randomised controlled trials published between 1 January 1996 and 24 November 2021 that examined the effect of bisphosphonates, denosumab, selective oestrogen receptor modulators, parathyroid hormone receptor agonists, and romosozumab compared with placebo or active comparator. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials that included non-Asian postmenopausal women with no restriction on age, when interventions looked at bone quality in a broad perspective. The primary outcome was clinical fractures. Secondary outcomes were vertebral, non-vertebral, hip, and major osteoporotic fractures, all cause mortality, adverse events, and serious cardiovascular adverse events. RESULTS: The results were based on 69 trials (>80 000 patients). For clinical fractures, synthesis of the results showed a protective effect of bisphosphonates, parathyroid hormone receptor agonists, and romosozumab compared with placebo. Compared with parathyroid hormone receptor agonists, bisphosphonates were less effective in reducing clinical fractures (odds ratio 1.49, 95% confidence interval 1.12 to 2.00). Compared with parathyroid hormone receptor agonists and romosozumab, denosumab was less effective in reducing clinical fractures (odds ratio 1.85, 1.18 to 2.92 for denosumab v parathyroid hormone receptor agonists and 1.56, 1.02 to 2.39 for denosumab v romosozumab). An effect of all treatments on vertebral fractures compared with placebo was found. In the active treatment comparisons, denosumab, parathyroid hormone receptor agonists, and romosozumab were more effective than oral bisphosphonates in preventing vertebral fractures. The effect of all treatments was unaffected by baseline risk indicators, except for antiresorptive treatments that showed a greater reduction of clinical fractures compared with placebo with increasing mean age (number of studies=17; ß=0.98, 95% confidence interval 0.96 to 0.99). No harm outcomes were seen. The certainty in the effect estimates was moderate to low for all individual outcomes, mainly because of limitations in reporting, nominally indicating a serious risk of bias and imprecision. CONCLUSIONS: The evidence indicated a benefit of a range of treatments for osteoporosis in postmenopausal women for clinical and vertebral fractures. Bone anabolic treatments were more effective than bisphosphonates in the prevention of clinical and vertebral fractures, irrespective of baseline risk indicators. Hence this analysis provided no clinical evidence for restricting the use of anabolic treatment to patients with a very high risk of fractures. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019128391.

[Increased fracture risk and fracture prevention]. / Verhoogd fractuurrisico en fractuurpreventie.

An increased fracture risk is a common chronic condition leading to a rising number of fractures, which are injurious to patients and costly to the health care system. Effective diagnostic and treatment options are available for primary and secondary prevention. In this article, we will answer specific practical questions with respect to increased fracture risk and fracture prevention. Topics discussed include definitions, risk factors, the diagnostic modalities and treatment options.

[Vitamin D supplementation not useful for all older people]. / Vitamine D niet zinvol voor alle 50-plussers.

An estimated 1.5 million Dutch people take vitamin D supplements on prescription, not including those who take multivitamins or vitamin D over the counter. Yet, controversial health benefits of vitamin D supplementation in the general population continues, often explained with not adequately powered studies, combination therapy with calcium, high bolus doses of vitamin D and poor study designs. Recently, the VITAL study does not show an effect in fracture incidence after treatment with daily vitamin D (2000IU) compared to placebo. However, zooming into the results a positive trend is observed in patients with a fragility fracture and/or using anti-osteoporosis medication. Additionally this study does not rule out a positive effect of vitamin D supplementation in severe vitamin D deficiency and high fracture risk patients.

Cartilage tissue turnover increases with high- compared to low-intensity resistance training in patients with knee OA.

OBJECTIVES: To investigate cartilage tissue turnover in response to a supervised 12-week exercise-related joint loading training program followed by a 6-month period of unsupervised training in patients with knee osteoarthritis (OA). To study the difference in cartilage tissue turnover between high- and low-resistance training. METHOD: Patients with knee OA were randomized into either high-intensity or low-intensity resistance supervised training (two sessions per week) for 3 months and unsupervised training for 6 months. Blood samples were collected before and after the supervised training period and after the follow-up period. Biomarkers huARGS, C2M, and PRO-C2, quantifying cartilage tissue turnover, were measured by ELISA. Changes in biomarker levels over time within and between groups were analyzed using linear mixed models with baseline values as covariates. RESULTS: huARGS and C2M levels increased after training and at follow-up in both low- and high-intensity exercise groups. No changes were found in PRO-C2. The huARGS level in the high-intensity resistance training group increased significantly compared to the low-intensity resistance training group after resistance training (p = 0.029) and at follow-up (p = 0.003). CONCLUSION: Cartilage tissue turnover and cartilage degradation appear to increase in response to a 3-month exercise-related joint loading training program and at 6-month follow-up, with no evident difference in type II collagen formation. Aggrecan remodeling increased more with high-intensity resistance training than with low-intensity exercise. These exploratory biomarker results, indicating more cartilage degeneration in the high-intensity group, in combination with no clinical outcome differences of the VIDEX study, may argue against high-intensity training.

Frequency of joint inflammation is associated with local joint damage progression in rheumatoid arthritis despite long-term targeted treatment.

OBJECTIVES: To investigate whether in rheumatoid arthritis (RA) frequency of local joint inflammation is associated with radiographic joint damage progression in that joint. METHODS: Data from 473 patients with RA and available radiographs from the BeSt study were used. Patients were treated to target (Disease Activity Score of ≤2.4) for a median of 10 years. At each study visit every 3 months, joints were assessed for swelling and tenderness. Radiographs of hands and feet were made yearly. A generalised linear mixed model was used to assess the association between the percentage of study visits at which clinical inflammation was observed in a joint (cumulative inflammation) and radiographic joint damage in that same joint. Clinical inflammation was primarily defined as joint swelling (with or without joint tenderness). For secondary analyses, we also investigated joint tenderness without joint swelling. Damage was measured as the percentage of the maximum possible Sharp-Van der Heijde score in a particular joint. RESULTS: Cumulative local joint swelling was associated with local progression of radiographic damage in the same joint (ß=0.14, 95% CI 0.13 to 0.15). This association was also found in a subset of joints that were swollen at least once. Cumulative local joint tenderness without concurrent local joint swelling was less strongly associated with local radiographic joint damage progression (ß=0.04, 95% CI 0.03 to 0.05). CONCLUSIONS: In RA, long-term cumulative local joint inflammation is associated with joint damage progression in the same joint.

[18F]Fluoride PET provides distinct information on disease activity in ankylosing spondylitis as compared to MRI and conventional radiography.

PURPOSE: To relate [18F]fluoride uptake on PET with abnormalities on magnetic resonance imaging (MRI) and conventional radiography (CR) in ankylosing spondylitis (AS) patients. METHODS: Ten clinically active AS patients (female 6/10, age 38 ± 11 years) were included, and both spine and SI-joints were examined. PET scans were dichotomously scored for enhanced [18F]fluoride uptake, MRI scans were scored for fatty lesions, erosions, ankylosis, and bone marrow edema (BME), and CR was scored for erosions, syndesmophytes, and ankylosis. The overlap of lesions across all modalities was evaluated through univariate and multivariate analyses using a generalized mixed model. RESULTS: In the spine, 69 lesions with enhanced [18F]fluoride uptake, 257 MRI lesions, and 88 CR lesions were observed. PET lesions were mostly located in costovertebral and facet joints, outside the field of view (FOV) of the MRI and CR. However, PET lesions inside the FOV of MRI and CR partially showed no abnormality on MRI and CR. In lesions with abnormalities on multiple modalities, both univariate and multivariate analysis showed that PET activity had the strongest association with BME on MRI and ankylosis on CR. In the SI joints, 15 lesions (75%) with PET uptake were found, with 87% showing abnormalities on MRI and CR. CONCLUSION: [18F]fluoride PET lesions are often found outside the scope of MRI and CR, and even in the same location show only partial overlap with abnormalities on MRI (especially BME) and CR (especially ankylosis). This suggests that [18F]fluoride PET partially visualizes aspects of AS separate from MRI and CR, providing novel information. CLINICAL TRIAL REGISTRATION: NL43223.029.13 registered at 02-05-2013.  https://www.toetsingonline.nl/to/ccmo_search.nsf/fABRpop?readform&unids=C1257BA2002CC066C1257B4E0049A65A.

Individual patient data meta-analysis on continued use of glucocorticoids after their initiation as bridging therapy in patients with rheumatoid arthritis.

OBJECTIVES: To investigate whether patients with rheumatoid arthritis (RA) can discontinue glucocorticoids (GC) after GC 'bridging' in the initial treatment step and to identify factors that may affect this. METHODS: Data from 7 clinical trial arms (with 1653 patients) that included a GC bridging schedule, previously identified in a systematic literature search, were combined in an individual patient data meta-analysis. Outcomes were GC use (yes/no) at predefined time points (1/3/6/12/18 months after bridging had ended), cumulative GC dose and continuous (≥3 months) GC use after bridging had ended. Age, sex, ACPA status, initial GC dose, duration of bridging schedule, oral versus parenteral GC administration and initial co-treatment were univariably tested with each outcome. RESULTS: The probability of using GC 1 month after bridging therapy had ended was 0.18, decreasing to 0.07 from 6 until 18 months after bridging had ended. The probability of continuous GC use after bridging had ended was 0.18 at 1 year and 0.30 at 2 years of follow-up. In oral GC bridging studies only, the probabilities of later and continuous GC use and the cumulative GC doses were higher compared to the combined analyses with also parenteral GC bridging studies included. A higher initial dose and a longer GC bridging schedule were associated with higher cumulative GC doses and more patients on GC at 18 months after bridging had ended. CONCLUSIONS: Based on these RA clinical trial arms with an initial GC bridging schedule, the probability of subsequent ongoing GC use following bridging is low.

Pharmacokinetics of oral and subcutaneous methotrexate in red and white blood cells in patients with early rheumatoid arthritis: the methotrexate monitoring trial.

OBJECTIVE: To investigate the pharmacokinetics of methotrexate polyglutamate (MTX-PG) accumulation in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) in patients with early rheumatoid arthritis (RA) after oral and subcutaneous MTX treatment. METHODS: In a clinical prospective cohort study (Methotrexate Monitoring study), newly diagnosed patients with RA were randomised for oral or subcutaneous MTX. At 1, 2, 3 and 6 months after therapy initiation, blood was collected and RBCs and PBMCs were isolated. MTX-PG1-6 concentrations were determined by mass spectrometry methods using stable isotopes of MTX-PG1-6 as internal standards. RESULTS: 43 patients (mean age: 58.5 years, 77% female) were included. PBMCs and RBCs revealed disparate pharmacokinetic profiles in both absolute MTX-PG accumulation levels and distribution profiles. Intracellular MTX-PG accumulation in PBMCs was significantly (p<0.001) 10-fold to 20-fold higher than RBCs at all time points, regardless of the administration route. MTX-PG distribution in PBMCs was composed of mostly MTX-PG1 (PG1>PG2>PG3). Remarkably, the distribution profile in PBMCs remained constant over 6 months. RBCs accumulated mainly MTX-PG1 and lower levels of MTX-PG2-5 at t=1 month. After 3 months, MTX-PG3 was the main PG-moiety in RBCs, a profile retained after 6 months of MTX therapy. Subcutaneous MTX administration results in higher RBC drug levels than after oral administration, especially shortly after treatment initiation. CONCLUSIONS: This is the first study reporting disparate MTX-PG accumulation profiles in RBCs versus PBMCs in newly diagnosed patients with RA during 6 months oral or subcutaneous MTX administration. This analysis can contribute to improved MTX therapeutic drug monitoring for patients with RA. TRIAL REGISTRATION NUMBER: NTR 7149.