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1.
Ann Rheum Dis ; 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31915121

RESUMO

OBJECTIVES: Using a reversible multistate model, we prospectively examined neuropsychiatric (NP) events for attribution, outcome and association with health-related quality of life (HRQoL), in an international, inception cohort of systemic lupus erythematosus (SLE) patients. METHODS: Annual assessments for 19 NP events attributed to SLE and non-SLE causes, physician determination of outcome and patient HRQoL (short-form (SF)-36 scores) were measured. Time-to-event analysis and multistate modelling examined the onset, recurrence and transition between NP states. RESULTS: NP events occurred in 955/1827 (52.3%) patients and 592/1910 (31.0%) unique events were attributed to SLE. In the first 2 years of follow-up the relative risk (95% CI) for SLE NP events was 6.16 (4.96, 7.66) and non-SLE events was 4.66 (4.01, 5.43) compared with thereafter. Patients without SLE NP events at initial assessment had a 74% probability of being event free at 10 years. For non-SLE NP events the estimate was 48%. The majority of NP events resolved over 10 years but mortality was higher in patients with NP events attributed to SLE (16%) versus patients with no NPSLE events (6%) while the rate was comparable in patients with non-SLE NP events (7%) compared with patients with no non-SLE events (6%). Patients with NP events had lower SF-36 summary scores compared with those without NP events and resolved NP states (p<0.001). CONCLUSIONS: NP events occur most frequently around the diagnosis of SLE. Although the majority of events resolve they are associated with reduced HRQoL and excess mortality. Multistate modelling is well suited for the assessment of NP events in SLE.

2.
Arthritis Rheumatol ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31769212

RESUMO

OBJECTIVE: Evaluate the efficacy and safety of ustekinumab through 1 year in a phase II Systemic Lupus Erythematosus (SLE) trial. METHODS: Eligible patients had clinically active SLE (SLE International Collaborating Clinics criteria) despite standard background therapy. Active disease was defined as SLE Disease Activity Index 2000 (SLEDAI-2K) score ≥6 and ≥1 British Isles Lupus Assessment Group (BILAG) A and/or ≥2 BILAG B scores. Patients (n=102) were randomized (3:2) to ustekinumab (~6mg/kg single intravenous infusion at week 0, then 90 mg subcutaneous injections every 8 weeks beginning at week 8) or matching placebo added to standard of care. At week 24, the placebo group crossed over to subcutaneous ustekinumab 90 mg every 8 weeks, and the original ustekinumab group continued on therapy through week 40. Maintenance of efficacy was assessed using SLEDAI-2K, SLE Responder Index 4 (SRI-4), Physician's Global Assessment, and mucocutaneous and joint disease measures in a modified intention-to-treat population. RESULTS: SRI-4 response rate was significantly greater (p=0.006) in the ustekinumab group (62%) vs placebo (33%) in the week 24 primary endpoint analysis and maintained at week 48 (63.3%) in the ustekinumab group. In the ustekinumab group, response rates across other disease measures were maintained through week 48. Among placebo patients who crossed over to ustekinumab (n=33), increased response rates across efficacy measures were also noted. Among all ustekinumab-treated patients, 81.7% had ≥1 AE and 15.1% had ≥1 serious AE through week 56. No deaths, malignancies, opportunistic infections, or tuberculosis cases were observed. CONCLUSION: Ustekinumab provided sustained clinical benefit in patients with SLE through 1 year with a safety profile consistent with other indications.

3.
J Autoimmun ; : 102340, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31629628

RESUMO

OBJECTIVE: The soluble urokinase plasminogen activator receptor (suPAR) has potential as a prognosis and severity biomarker in several inflammatory and infectious diseases. In a previous cross-sectional study, suPAR levels were shown to reflect damage accrual in cases of systemic lupus erythematosus (SLE). Herein, we evaluated suPAR as a predictor of future organ damage in recent-onset SLE. METHODS: Included were 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who met the 1997 American College of Rheumatology classification criteria with 5-years of follow-up data available. Baseline sera from patients and age- and sex-matched controls were assayed for suPAR. Organ damage was assessed annually using the SLICC/ACR damage index (SDI). RESULTS: The levels of suPAR were higher in patients who accrued damage, particularly those with SDI≥2 at 5 years (N = 32, 46.8% increase, p = 0.004), as compared to patients without damage. Logistic regression analysis revealed a significant impact of suPAR on SDI outcome (SDI≥2; OR = 1.14; 95% CI 1.03-1.26), also after adjustment for confounding factors. In an optimized logistic regression to predict damage, suPAR persisted as a predictor, together with baseline disease activity (SLEDAI-2K), age, and non-Caucasian ethnicity (model AUC = 0.77). Dissecting SDI into organ systems revealed higher suPAR levels in patients who developed musculoskeletal damage (SDI≥1; p = 0.007). CONCLUSION: Prognostic biomarkers identify patients who are at risk of acquiring early damage and therefore need careful observation and targeted treatment strategies. Overall, suPAR constitutes an interesting biomarker for patient stratification and for identifying SLE patients who are at risk of acquiring organ damage during the first 5 years of disease.

4.
Arthritis Rheumatol ; 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31631584

RESUMO

OBJECTIVE: The Systemic Lupus International Collaborating Clinics (SLICC) frailty index (FI) has been shown to predict mortality, but its association with other important outcomes is unknown. We examined the association of baseline SLICC-FI values with damage accrual in the SLICC inception cohort. METHODS: The baseline visit was defined as the first at which both organ damage (SLICC/ACR Damage Index [SDI]) and health-related quality of life (Short-Form 36 [SF-36]) were assessed. Baseline SLICC-FI scores were calculated. Damage accrual was measured by the increase in SDI between the baseline assessment and the last study visit. Multivariable negative binomial regression estimated the association between baseline SLICC-FI values and the rate of increase in the SDI during follow-up, adjusting for relevant demographic and clinical characteristics. RESULTS: The 1549 SLE patients eligible for this analysis were mostly female (88.7%) with mean (standard deviation, SD) age 35.7 (13.3) years and median (interquartile range) disease duration 1.2 (0.9-1.5) years at baseline. Mean (SD) baseline SLICC-FI was 0.17 (0.08) with a range of 0-0.51. Over a mean (SD) follow-up of 7.2 (3.7) years, 653 patients (42.2%) had an increase in SDI. Higher baseline SLICC-FI values (per 0.05 increment) were associated with higher rates of increase in the SDI during follow-up (Incidence Rate Ratio [IRR] 1.19; 95% CI 1.13-1.25), after adjusting for age, sex, ethnicity/region, education, baseline SLEDAI-2K, baseline SDI, and baseline use of corticosteroids, antimalarials, and immunosuppressives. CONCLUSION: The SLICC-FI predicts damage accrual in incident SLE, which further supports the SLICC-FI as a valid health measure in SLE.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31609532

RESUMO

OBJECTIVES: There is a paucity of data regarding healthcare costs associated with damage accrual in systemic lupus erythematosus (SLE). We describe costs associated with damage states across the disease course using multi-state modeling. METHODS: Patients from 33 centres in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. Annual data on demographics, disease activity, damage (SLICC/American College of Rheumatology (ACR) Damage Index [SDI]), hospitalizations, medications, dialysis, and selected procedures were collected. Ten-year cumulative costs (Canadian dollars) were estimated by multiplying annual costs associated with each SDI state by the expected state duration using a multi-state model. RESULTS: 1687 patients participated, 88.7% female, 49.0% of Caucasian race/ethnicity, mean age at diagnosis 34.6 years (SD 13.3), and mean follow up 8.9 years (range 0.6-18.5). Annual costs were higher in those with higher SDIs (SDI ≥ 5: $22 006 2019 CDN, 95% CI $16 662, $27 350 versus SDI=0: $1833, 95% CI $1134, $2532). Similarly, 10-year cumulative costs were higher in those with higher SDIs at the beginning of the 10-year interval (SDI ≥ 5: $189 073, 95% CI $142 318, $235 827 versus SDI=0: $21 713, 95% CI $13 639, $29 788). CONCLUSION: Patients with the highest SDIs incur 10-year cumulative costs that are almost 9-fold higher than those with the lowest SDIs. By estimating the damage trajectory and incorporating annual costs, damage can be used to estimate future costs, critical knowledge for evaluating the cost-effectiveness of novel therapies.

6.
Arthritis Rheumatol ; 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31390162

RESUMO

OBJECTIVE: To determine the frequency, clinical characteristics, associations, and outcomes of different types of peripheral nervous system (PNS) disease in a multiethnic/multiracial, prospective inception cohort of systemic lupus erythematosus (SLE) patients. METHODS: Patients were evaluated annually for 19 neuropsychiatric (NP) events including 7 types of PNS disease. SLE disease activity, organ damage, autoantibodies, and patient and physician assessment of outcome were measured. Time to event and linear regressions were used as appropriate. RESULTS: Of 1,827 SLE patients, 88.8% were female, and 48.8% were white. The mean ± SD age was 35.1 ± 13.3 years, disease duration at enrollment was 5.6 ± 4.2 months, and follow-up was 7.6 ± 4.6 years. There were 161 PNS events in 139 (7.6%) of 1,827 patients. The predominant events were peripheral neuropathy (66 of 161 [41.0%]), mononeuropathy (44 of 161 [27.3%]), and cranial neuropathy (39 of 161 [24.2%]), and the majority were attributed to SLE. Multivariate Cox regressions suggested longer time to resolution in patients with a history of neuropathy, older age at SLE diagnosis, higher SLE Disease Activity Index 2000 scores, and for peripheral neuropathy versus other neuropathies. Neuropathy was associated with significantly lower Short Form 36 (SF-36) physical and mental component summary scores versus no NP events. According to physician assessment, the majority of neuropathies resolved or improved over time, which was associated with improvements in SF-36 summary scores for peripheral neuropathy and mononeuropathy. CONCLUSION: PNS disease is an important component of total NPSLE and has a significant negative impact on health-related quality of life. The outcome is favorable for most patients, but our findings indicate that several factors are associated with longer time to resolution.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31302695

RESUMO

OBJECTIVE: This extension study of the Phase III, randomized, placebo-controlled Belimumab International SLE Study (BLISS)-52 and BLISS-76 studies allowed non-US patients with SLE to continue belimumab treatment, in order to evaluate its long-term safety and tolerability including organ damage accrual. METHODS: In this multicentre, long-term extension study (GlaxoSmithKline Study BEL112234) patients received i.v. belimumab every 4 weeks plus standard therapy. Adverse events (AEs) were assessed monthly and safety-associated laboratory parameters were assessed at regular intervals. Organ damage (SLICC/ACR Damage Index) was assessed every 48 weeks. The study continued until belimumab was commercially available, with a subsequent 8-week follow-up period. RESULTS: A total of 738 patients entered the extension study and 735/738 (99.6%) received one or more doses of belimumab. Annual incidence of AEs, including serious and severe AEs, remained stable or declined over time. Sixty-nine (9.4%) patients experienced an AE resulting in discontinuation of belimumab or withdrawal from the study. Eleven deaths occurred (and two during post-treatment follow-up), including one (cardiogenic shock) considered possibly related to belimumab. Laboratory parameters generally remained stable. The mean (s.d.) SLICC/ACR Damage Index score was 0.6 (1.02) at baseline (prior to the first dose of belimumab) and remained stable. At study year 8, 57/65 (87.7%) patients had no change in SLICC/ACR Damage Index score from baseline, indicating low organ damage accrual. CONCLUSION: Belimumab displayed a stable safety profile with no new safety signals. There was minimal organ damage progression over 8 years. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00424476 (BLISS-52), NCT00410384 (BLISS-76), NCT00732940 (BEL112232), NCT00712933 (BEL112234).

8.
Rheumatology (Oxford) ; 58(8): 1327-1328, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31220324
10.
Front Immunol ; 10: 902, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31068954

RESUMO

Objective: The type I interferon (IFN) response in rheumatoid arthritis (RA) has been extensively studied in relation to therapy with biological DMARDs (bDMARDs). However, the effect of conventional synthetic (cs)DMARDs and glucocorticoids (GCs) on IFN response gene (IRG) expression remains largely unknown, even though csDMARDS are used throughout all disease phases, including simultaneously with biologic therapy. This study was aimed to determine the dynamics of IFN response upon immunosuppressive treatment. Methods: Whole blood was collected in PAXgene tubes from 35 RA patients who received either COBRA therapy (combination of prednisone, initially 60 mg, methotrexate and sulfasalazine) (n = 14) or COBRA-light therapy (prednisone, initially 30 mg, and methotrexate) (n = 21). Expression of 10 IRGs was determined by real-time PCR at baseline (T0), after 4 weeks (T4), and 13 weeks (T13) of treatment. IRG selection was based on the differential presence of transcription factor binding sites (TFBS), in order to study the therapy effect on different pathway components involved in IFN signaling. Results: Seven of the 10 IRGs displayed significant changes during treatment (p ≤ 0.016). These 7 IRGs all displayed a particularly pronounced decrease between T0 and T4 (≥1.6-fold, p ≤ 0.0059). The differences between IRG sensitivity to the treatment appeared related to the presence of TFBS for STAT1 and IRF proteins within the genes. The extent of the decreases between T0 and T4 was similar for the COBRA- and COBRA-light-treated group, despite the differences in drug combination and doses in those groups. Between T4 and T13, however, IRG expression in the COBRA-light-treated group displayed a significant increase, whereas it remained stable or decreased even further in most COBRA-treated patients (comparison of mean fold changes, p = 0.011). A significant association between IRG dynamics and clinical response to therapy was not detected. Conclusions: Immunosuppressive treatment with csDMARDs, in this case a combination of prednisolone, methotrexate and sulfasalazine, substantially downregulates the IFN response in RA patients. The dynamics of this downregulation were partly dependent on the presence of TFBS within the IRGs and the combination and dosages of agents, but they were irrespective of the clinical response to therapy.

12.
J Rheumatol ; 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988130

RESUMO

OBJECTIVE: To construct a Frailty Index (FI) as a measure of vulnerability to adverse outcomes among patients with systemic lupus erythematosus (SLE), using data from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort. METHODS: The SLICC inception cohort consists of recently diagnosed patients with SLE followed annually with clinical and laboratory assessments. For this analysis, the baseline visit was defined as the first study visit at which sufficient information was available for construction of an FI. Following a standard procedure, variables from the SLICC database were evaluated as potential health deficits. Selected health deficits were then used to generate a SLICC-FI. The prevalence of frailty in the baseline dataset was evaluated using established cutpoints for FI values. RESULTS: The 1683 patients with SLE (92.1% of the overall cohort) eligible for inclusion in the baseline dataset were mostly female (89%) with mean (SD) age 35.7 (13.4) years and mean (SD) disease duration 18.8 (15.7) months at baseline. Of 222 variables, 48 met criteria for inclusion in the SLICC-FI. Mean (SD) SLICC-FI was 0.17 (0.08) with a range from 0 to 0.51. At baseline, 27.1% (95% CI 25.0-29.2) of patients were classified as frail, based on SLICC-FI values > 0.21. CONCLUSION: The SLICC inception cohort permits feasible construction of an FI for use in patients with SLE. Even in a relatively young cohort of patients with SLE, frailty was common. The SLICC-FI may be a useful tool for identifying patients with SLE who are most vulnerable to adverse outcomes, but validation of this index is required prior to its use.

13.
BMJ Open ; 9(3): e025687, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30898822

RESUMO

INTRODUCTION: Belimumab, an anti-B-lymphocyte-stimulator antibody, is approved for the treatment of active, autoantibody-positive systemic lupus erythematosus (SLE). Rituximab, a B cell-depleting anti-CD20 antibody, remains in the SLE treatment armamentarium despite failed trials in lupus nephritis and extrarenal lupus. These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE. This study aims to evaluate and compare the efficacy, safety and tolerability of subcutaneous (SC) belimumab and a single cycle of rituximab in patients with SLE with belimumab alone. METHODS AND ANALYSIS: BLISS-BELIEVE is a three-arm, randomised, double-blind, placebo-controlled, 104-week superiority study. Two hundred adults with SLE will be randomised 1:2:1 to arm A, belimumab SC 200 mg/week for 52 weeks plus placebo at weeks 4 and 6; arm B, belimumab SC 200 mg/week for 52 weeks plus rituximab 1000 mg at weeks 4 and 6; arm C, belimumab SC 200 mg/week plus standard of care for 104 weeks. The 52-week treatment period (arms A and B) is followed by a 52-week observational phase. The primary efficacy endpoint is the proportion of patients with disease control (SLE Disease Activity Index (SLEDAI)-2K≤2, without immunosuppressants and with a prednisone-equivalent dose of ≤5 mg/day) at week 52. Major secondary efficacy endpoints are the proportion of patients in clinical remission (defined as SLEDAI-2K=0, without immunosuppressants and corticosteroids) at week 64, and the proportion of patients with disease control at week 104. Safety endpoints include the incidence of adverse events (AEs), serious AEs and AEs of special interest. ETHICS AND DISSEMINATION: Within 6 months of the study's primary manuscript publication, anonymised individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com. TRIAL REGISTRATION NUMBER: NCT03312907; Pre-results.

14.
Ann Rheum Dis ; 78(9): 1160-1166, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30898837

RESUMO

Giant cell arteritis (GCA) represents the most common form of primary systemic vasculitis and is frequently associated with comorbidities related to the disease itself or induced by the treatment. Systematically collected data on disease course, treatment and outcomes of GCA remain scarce. The aim of this EULAR Task Force was to identify a core set of items which can easily be collected by experienced clinicians, in order to facilitate collaborative research into the course and outcomes of GCA. A multidisciplinary EULAR task force group of 20 experts including rheumatologists, internists, epidemiologists and patient representatives was assembled. During a 1-day meeting, breakout groups discussed items from a previously compiled collection of parameters describing GCA status and disease course. Feedback from breakout groups was further discussed. Final consensus was achieved by means of several rounds of email discussions after the meeting. A three-round Delphi survey was conducted to determine a core set of parameters including the level of agreement. 117 parameters were regarded as relevant. Potential items were subdivided into the following categories: General, demographics, GCA-related signs and symptoms, other medical conditions and treatment. Possible instruments and assessment intervals were proposed for documentation of each item. To facilitate implementation of the recommendations in clinical care and clinical research, a minimum core set of 50 parameters was agreed. This proposed core set intends to ensure that relevant items from different GCA registries and databases can be compared for the dual purposes of facilitating clinical research and improving clinical care.

15.
Rheumatology (Oxford) ; 58(7): 1259-1267, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30753683

RESUMO

OBJECTIVES: To assess the prevalence of combined hormonal contraceptives (CHCs) in reproductive-age women with SLE with and without possible contraindications and to determine factors associated with their use in the presence of possible contraindications. METHODS: This observational cohort study included premenopausal women ages 18-45 years enrolled in the SLICC Registry ⩽15 months after SLE onset, with annual assessments spanning 2000-2017. World Health Organization Category 3 or 4 contraindications to CHCs (e.g. hypertension, aPL) were assessed at each study visit. High disease activity (SLEDAI score >12 or use of >0.5 mg/kg/day of prednisone) was considered a relative contraindication. RESULTS: A total of 927 SLE women contributed 6315 visits, of which 3811 (60%) occurred in the presence of one or more possible contraindication to CHCs. Women used CHCs during 512 (8%) visits, of which 281 (55%) took place in the setting of one or more possible contraindication. The most frequently observed contraindications were aPL (52%), hypertension (34%) and migraine with aura (22%). Women with one or more contraindication were slightly less likely to be taking CHCs [7% of visits (95% CI 7, 8)] than women with no contraindications [9% (95% CI 8, 10)]. CONCLUSION: CHC use was low compared with general population estimates (>35%) and more than half of CHC users had at least one possible contraindication. Many yet unmeasured factors, including patient preferences, may have contributed to these observations. Further work should also aim to clarify outcomes associated with this exposure.

16.
Arthritis Rheumatol ; 71(8): 1297-1307, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30771242

RESUMO

OBJECTIVE: To evaluate the properties of a frailty index (FI), constructed using data from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort, as a novel health measure in systemic lupus erythematosus (SLE). METHODS: For this secondary analysis, the baseline visit was defined as the first study visit at which both organ damage (SLICC/American College of Rheumatology Damage Index [SDI]) and health-related quality of life (Short-Form 36 [SF-36] scores) were assessed. The SLICC-FI was constructed using baseline data. The SLICC-FI comprises 48 health deficits, including items related to organ damage, disease activity, comorbidities, and functional status. Content, construct, and criterion validity of the SLICC-FI were assessed. Multivariable Cox regression was used to estimate the association between baseline SLICC-FI values and mortality risk, adjusting for demographic and clinical factors. RESULTS: In the baseline data set of 1,683 patients with SLE, 89% were female, the mean ± SD age was 35.7 ± 13.4 years, and the mean ± SD disease duration was 18.8 ± 15.7 months. At baseline, the mean ± SD SLICC-FI score was 0.17 ± 0.08 (range 0-0.51). Baseline SLICC-FI values exhibited the expected measurement properties and were weakly correlated with baseline SDI scores (r = 0.26, P < 0.0001). Higher baseline SLICC-FI values (per 0.05 increment) were associated with increased mortality risk (hazard ratio 1.59, 95% confidence interval 1.35-1.87), after adjusting for age, sex, steroid use, ethnicity/region, and baseline SDI scores. CONCLUSION: The SLICC-FI demonstrates internal validity as a health measure in SLE and might be used to predict future mortality risk. The SLICC-FI is potentially valuable for quantifying vulnerability among patients with SLE, and adds to existing prognostic scores.

17.
Ann Rheum Dis ; 78(7): 872-878, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30712015

RESUMO

To develop a comprehensive listing of the greatest unmet scientific and clinical needs in rheumatology. The 20th annual international Targeted Therapies meeting brought more than 100 leading basic scientists and clinical researchers in rheumatology, immunology, epidemiology, molecular biology and other specialties. During the meeting, breakout sessions were convened, consisting of five disease-specific groups with 20-30 experts assigned to each group based on expertise. Specific groups included rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, systemic lupus erythematosus, connective tissue diseases and a basic science immunology group spanning all of these clinical domains. In each group, experts were asked to consider recent accomplishments within their clinical domain in the last year and update the unmet needs in three categorical areas: basic/translational science, clinical science and therapeutic development, and clinical care. While progress was noted among some of previously identified needs, both new needs were identified and themes from prior meetings were re-iterated: the need for better understanding the heterogeneity within each disease, and for identifying preclinical states of disease allowing treatment and prevention of disease in those at risk, and the elusive ability to cure disease. Within the clinical care realm, improved comorbidity management and patient-centred care continue to be unmet needs, and the need for new and affordable therapeutics was highlighted. Unmet needs for new and accessible targeted therapies, disease prevention and ultimately cure remain a priority in rheumatology.

18.
J Rheumatol ; 46(6): 555-563, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30709958

RESUMO

OBJECTIVE: To investigate baseline levels of 12 serum biomarkers that constitute a multibiomarker disease activity test, as predictors of response to methotrexate (MTX) in patients with early rheumatoid arthritis (eRA). METHODS: In 298 patients from the Swedish Pharmacotherapy (SWEFOT) clinical trial, baseline serum levels of 12 proteins were analyzed for association with disease activity based on the 28-joint count Disease Activity Score (DAS28) after 3 months of MTX monotherapy using uni-/multivariate logistic regression. Primary outcome was low disease activity (LDA; DAS28 ≤ 3.2). RESULTS: Of 298 patients, 104 achieved LDA after 3 months on MTX. Four of the 12 biomarkers [C-reactive protein (CRP), leptin, tumor necrosis factor receptor I (TNF-RI), and vascular cell adhesion molecule 1 (VCAM-1)] significantly predicted LDA based on stepwise logistic regression analysis. Dichotomization of patients using receiver-operating characteristic curve analysis-based cutoffs for these biomarkers showed significantly higher proportions with LDA among patients with lower versus higher levels of CRP or leptin (40% vs 23%, p = 0.004, and 40% vs 25%, p = 0.011, respectively), as well as among those with higher versus lower levels of TNF-RI or VCAM-1 (43% vs 27%, p = 0.004, and 41% vs 25%, p = 0.004, respectively). Combined score based on these biomarkers, adjusted for known predictors of LDA (smoking, sex, and age), associated with decreased chance of LDA (adjusted OR 0.45, 95% CI 0.32-0.62). CONCLUSION: Low baseline levels of CRP and leptin, and high baseline levels of TNF-RI and VCAM-1 were associated with LDA after 3 months of MTX therapy in patients with eRA. Combination of these 4 biomarkers increased accuracy of prediction. [Trial registration number: NCT00764725].

19.
Sci Transl Med ; 11(477)2019 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-30700574

RESUMO

Patients with rheumatoid arthritis (RA) can be successfully treated with tumor necrosis factor (TNF) inhibitors, including the monoclonal antibody adalimumab. Once in remission, a proportion of patients can successfully discontinue treatment, indicating that blocking TNF is no longer required for disease control. To explore the dynamics of circulating TNF during adalimumab treatment, we developed a competition enzyme-linked immunosorbent assay that can quantify TNF in the presence of large amounts of TNF inhibitor, i.e., a "drug-tolerant" assay. In 193 consecutive adalimumab-treated patients with RA, we demonstrated that circulating TNF increased in average of >50-fold upon treatment and reached a stable concentration in time for most patients. A similar increase in TNF was found in 30 healthy volunteers after one dose of adalimumab. This implies that TNF in circulation during anti-TNF treatment is not primarily associated with disease activity. During treatment, TNF was in complex with adalimumab and could be recovered as inactive 3:1 adalimumab-TNF complexes. No quantitative association was found between TNF and adalimumab concentrations. Low TNF concentrations at week 4 were associated with a higher frequency of antidrug antibodies (ADAs) at subsequent time points, less frequent methotrexate use at baseline, and less frequent remission after 52 weeks. Also in healthy volunteers, early low TNF concentrations are associated with ADAs. In conclusion, longitudinal TNF concentrations are mostly stable during adalimumab treatment and may therefore not predict successful treatment discontinuation. However, early low TNF is strongly associated with ADA formation and may be used as timely predictor of nonresponse toward adalimumab treatment.

20.
Arthritis Care Res (Hoboken) ; 71(1): 71-79, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29696833

RESUMO

OBJECTIVE: Optimal targeted treatment in rheumatoid arthritis requires early identification of failure to respond. This post hoc analysis explored the relationship between early disease activity changes and the achievement of low disease activity (LDA) and remission targets with tofacitinib. METHODS: Data were from 2 randomized, double-blind, phase III studies. In the ORAL Start trial, methotrexate (MTX)-naive patients received tofacitinib 5 or 10 mg twice daily, or MTX, for 24 months. In the placebo-controlled ORAL Standard trial, MTX inadequate responder patients received tofacitinib 5 or 10 mg twice daily or adalimumab 40 mg every 2 weeks, with MTX, for 12 months. Probabilities of achieving LDA (using a Clinical Disease Activity Index [CDAI] score ≤10 or the 4-component Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [DAS28-ESR] ≤3.2) at months 6 and 12 were calculated, given failure to achieve threshold improvement from baseline (change in CDAI ≥6 or DAS28-ESR ≥1.2) at month 1 or 3. RESULTS: In ORAL Start, 7.2% and 5.4% of patients receiving tofacitinib 5 and 10 mg twice daily, respectively, failed to show improvement in the CDAI ≥6 at month 3; of those who failed, 3.8% and 28.6%, respectively, achieved month 6 CDAI-defined LDA. In ORAL Standard, 18.8% and 17.5% of patients receiving tofacitinib 5 and 10 mg twice daily, respectively, failed to improve CDAI ≥6 at month 3; of those who failed, 0% and 2.9%, respectively, achieved month 6 CDAI-defined LDA. Findings were similar when considering improvements at month 1 or DAS28-ESR thresholds. CONCLUSION: In patients with an inadequate response to MTX, lack of response to tofacitinib after 1 or 3 months predicted a low probability of achieving LDA at month 6. Lack of an early response may be considered when deciding whether to continue treatment with tofacitinib.


Assuntos
Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Progressão da Doença , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Adulto , Idoso , Artrite Reumatoide/epidemiologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Probabilidade , Fatores de Tempo , Resultado do Tratamento
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