Circulating CD19+CD24hiCD38hi regulatory B cells as biomarkers of response to methotrexate in early rheumatoid arthritis.

OBJECTIVE: The protagonism of regulatory B cells seems to vary along the course of the disease in murine models of inflammatory conditions. Decreased numbers of circulating regulatory CD19+CD24hiCD38hi transitional (cTr) B cells have been described in patients with long-standing RA, thus our objective was to examine the frequency and evolution of cTr B cells in the peripheral blood of early RA (ERA) patients. METHODS: Freshly isolated peripheral blood mononuclear cells from 48 steroid- and DMARD-naïve ERA patients with a disease duration of <24 weeks and 48 healthy controls (HCs) were examined by flow cytometry. Co-cultures of isolated memory B cells were established with autologous T cells in the absence or presence of Tr B cells. RESULTS: As compared with HCs, ERA patients demonstrated an increased frequency of cTr B cells. cTr B cells of ERA patients and HCs displayed an anti-inflammatory cytokine profile and were able to downregulate T cell IFN-γ and IL-21 production, together with ACPA secretion in autologous B/T cell co-cultures. Basal frequencies of cTr B cells above the median value observed in HCs were associated with a good EULAR response to MTX at 12 months [relative risk 2.91 (95% CI 1.37, 6.47)]. A significant reduction of cTr B cells was observed 12 months after initiating MTX, when the cTr B cell frequency was no longer elevated but decreased, and this was independent of the degree of clinical response or the intake of prednisone. CONCLUSION: An increased frequency of regulatory cTr B cells is apparent in untreated ERA and the baseline cTr B cell frequency is associated with the clinical response to MTX at 12 months.

Reducing or Maintaining the Dose of Subcutaneous Tocilizumab in Patients With Rheumatoid Arthritis in Clinical Remission: A Randomized, Open-Label Trial.

OBJECTIVE: To evaluate the efficacy and safety of increasing the dose interval of subcutaneous tocilizumab (TCZ-SC) in patients with rheumatoid arthritis (RA) who are in clinical remission. METHODS: RA patients with active disease and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or to a biologic agent were entered into a single-arm treatment phase with 162 mg of TCZ-SC administered once weekly (TCZ-SC 162 mg qw) as monotherapy or in combination with a csDMARD for 24 weeks. Patients who achieved clinical remission at weeks 20 and 24 were randomized to continue with the same regimen or to switch to 162 mg TCZ-SC administered every 2 weeks (TCZ-SC 162 mg q2w) for 24 weeks (open-label). Patients with a Disease Activity Score in 28 joints (DAS28) of <2.6 were considered to be in clinical remission. RESULTS: In total, 179 (45%) of 401 patients in the single-arm phase achieved clinical remission and were randomized to continue to receive TCZ-SC 162 mg qw (n = 89) or to switch to TCZ-SC 162 mg q2w (n = 90) for 24 weeks. At week 48, significantly more patients treated with TCZ-SC 162 mg qw remained in clinical remission compared to patients who received TCZ-SC 162 mg q2w (90% versus 73%; P = 0.004). The results of other efficacy measures revealed greater efficacy with TCZ-SC 162 mg qw, but none of the efficacy outcomes in this group were significantly different from those in patients treated with TCZ-SC 162 mg q2w, except for the mean change from baseline in the DAS28 score at week 48 (mean change -4.07 points [SD 1.29] versus -3.65 points [SD 1.35]; P = 0.034). Tolerability and safety parameters were similar between the treatment groups. CONCLUSION: Increasing the dose interval of TCZ-SC in patients with RA was associated with a lower likelihood of maintaining remission after 24 weeks and was not associated with better tolerability. However, most patients were able to sustain remission with a half-dose of TCZ-SC, and therefore this strategy deserves further investigation.

Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring in clinical practice: the spanish cohort of the COMORA study / Prevalencia de comorbilidades en artritis reumatoide y evaluación de su manejo en la clínica diaria: cohorte española del estudio COMORA

Objectives: To describe the prevalence of comorbidities in patients with RA in Spain and discuss their management and implications using data from the Spanish cohort of the multinational study on COMOrbidities in Rheumatoid Arthritis (COMORA). Methods: This is a national sub-analysis of the COMORA study. We studied the demographics and disease characteristics of 200 adults patients diagnosed with RA (1987 ACR), and routine practices for screening and preventing the following selected comorbidities: cardiovascular, infections, cancer, gastrointestinal, pulmonary, osteoporosis and depression. Results: Patients had a mean age of 58 years and a mean RA duration of 10 years. Mean DAS28 score was 3.3 and approximately 25% of patients were in remission (DAS28 <2.6). Forty-four (22%) patients had ≥1 comorbidity, the most frequent being depression (27%) and obesity (26%). A history of myocardial infarction or stroke was observed in 5% and 1% of patients, respectively, and any solid tumor in 6%. Having a Framingham Risk Score >20% (51%), hypercholesterolemia (46%) or hypertension (41%) and smoking (25%) were the most common CV risk factors. For prostate, colon and skin cancers, only 9%, 10% and 18% of patients, respectively, were optimally monitored. Infections were also inadequately managed, with 7% and 17% of patients vaccinated against influenza and pneumococcal, respectively, as was osteoporosis, with 47% of patients supplemented with vitamin D and 56% with a bone densitometry performed. Conclusions: In Spain, the prevalence of comorbidities and CV risk factors in RA patients with established and advanced disease is relatively high, and their management in clinical daily practice remains suboptimal

Objetivos: Describir la prevalencia de comorbilidades en pacientes con AR en España y discutir sobre su manejo en la clínica diaria utilizando los datos de la cohorte española del estudio internacional COMORA. Métodos: Subanálisis nacional del estudio COMORA en el que se analizaron las características demográficas y clínicas de 200 pacientes con AR (1987 ACR) y las prácticas rutinarias para el cribado y la prevención de eventos cardiovasculares (CV), gastrointestinales y pulmonares, infecciones, cáncer, osteoporosis y depresión. Resultados: Los pacientes tenían una edad media de 58 años, una duración media de la enfermedad de 10 años, un DAS28 de 3,3 y el 25% estaba en remisión (DAS28 <2,6). El 22% de los pacientes presentaba al menos una comorbilidad, principalmente depresión (27%) y obesidad (26%). El 5% tenía historia de infarto de miocardio, el 1% de ictus y el 6% de tumor sólido. Una puntuación de Framingham >20% (51%), tener hipercolesterolemia (46%), hipertensión (41%) y fumar (25%) fueron los factores de riesgo CV más comunes. En relación con el cáncer de próstata, colon y piel, solo el 9, 10 y el 18% de los pacientes, respectivamente, estaban óptimamente controlados. Las infecciones tampoco se manejaban de forma óptima, con solo el 7 y el 17% de los pacientes vacunados contra la influenza y neumococo, respectivamente, al igual que la osteoporosis, con el 47% suplementados con la vitamina D y el 56% con una densitometría realizada. Conclusiones: En España, la prevalencia de comorbilidades y factores de riesgo CV en pacientes con AR establecida y avanzada es relativamente alta, y su manejo en la clínica diaria continúa siendo subóptimo

Efficacy of tocilizumab monotherapy after response to combined tocilizumab and methotrexate in patients with rheumatoid arthritis: the randomised JUST-ACT study.

OBJECTIVES: The aim of the JUST-ACT study was to assess whether the add-on effect of tocilizumab (TCZ) to background methotrexate (MTX) observed in MTX-inadequate responders with active rheumatoid arthritis (RA), would be sustained when MTX is withdrawn. METHODS: A double-blind, parallel-group, phase 3 study in biologic-naïve RA patients with a disease activity score 28 (DAS28)>3.2 despite MTX which were treated with TCZ+MTX for an initial 16-week period. Patients who at week 16 achieved low disease activity (LDA) (DAS28≤3.2) were randomised to continue with TCZ+MTX or switch to TCZ + placebo (PBO) for an additional 12 weeks. The primary endpoint was the change in DAS28-ESR from the randomisation at week 16 to week 28. Non-inferiority was confirmed if the upper limit of the two-sided 95%CI for the treatment difference between TCZ+MTX and TCZ monotherapy groups was lower than the selected non-inferiority margin of 0.6. RESULTS: 261 patients completed the first 16 weeks of TCZ+MTX treatment and 165 were randomised (83 to TCZ+MTX and 82 to TCZ+PBO). For the primary endpoint, the adjusted treatment difference (95% CI) in mean change of DAS28-ESR was -0.06 (-0.40 to 0.27), and therefore the non-inferiority of switching to TCZ monotherapy versus continuing with TCZ+MTX was demonstrated. In both treatment groups, the percentage of patients in clinical remission from 16 to 28 weeks was similar as were the improvements in disease activity, functional disability and quality of life. CONCLUSIONS: In MTX non-responder patients achieving LDA with TCZ+MTX, switching to TCZ monotherapy is non-inferior to continuing the combination.

Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring in clinical practice: the spanish cohort of the COMORA study.

OBJECTIVES: To describe the prevalence of comorbidities in patients with RA in Spain and discuss their management and implications using data from the Spanish cohort of the multinational study on COMOrbidities in Rheumatoid Arthritis (COMORA). METHODS: This is a national sub-analysis of the COMORA study. We studied the demographics and disease characteristics of 200 adults patients diagnosed with RA (1987 ACR), and routine practices for screening and preventing the following selected comorbidities: cardiovascular, infections, cancer, gastrointestinal, pulmonary, osteoporosis and depression. RESULTS: Patients had a mean age of 58 years and a mean RA duration of 10 years. Mean DAS28 score was 3.3 and approximately 25% of patients were in remission (DAS28 <2.6). Forty-four (22%) patients had ≥1 comorbidity, the most frequent being depression (27%) and obesity (26%). A history of myocardial infarction or stroke was observed in 5% and 1% of patients, respectively, and any solid tumor in 6%. Having a Framingham Risk Score >20% (51%), hypercholesterolemia (46%) or hypertension (41%) and smoking (25%) were the most common CV risk factors. For prostate, colon and skin cancers, only 9%, 10% and 18% of patients, respectively, were optimally monitored. Infections were also inadequately managed, with 7% and 17% of patients vaccinated against influenza and pneumococcal, respectively, as was osteoporosis, with 47% of patients supplemented with vitamin D and 56% with a bone densitometry performed. CONCLUSIONS: In Spain, the prevalence of comorbidities and CV risk factors in RA patients with established and advanced disease is relatively high, and their management in clinical daily practice remains suboptimal.

Induction of sustained remission in early inflammatory arthritis with the combination of infliximab plus methotrexate: the DINORA trial.

BACKGROUND: In the present study, we explored the effects of immediate induction therapy with the anti-tumour necrosis factor (TNF)α antibody infliximab (IFX) plus methotrexate (MTX) compared with MTX alone and with placebo (PL) in patients with very early inflammatory arthritis. METHODS: In an investigator-initiated, double-blind, randomised, placebo-controlled, multi-centre trial (ISRCTN21272423, http://www.isrctn.com/ISRCTN21272423 ), patients with synovitis of 12 weeks duration in at least two joints underwent 1 year of treatment with IFX in combination with MTX, MTX monotherapy, or PL randomised in a 2:2:1 ratio. The primary endpoint was clinical remission after 1 year (sustained for at least two consecutive visits 8 weeks apart) with remission defined as no swollen joints, 0-2 tender joints, and an acute-phase reactant within the normal range. RESULTS: Ninety patients participated in the present study. At week 54 (primary endpoint), 32% of the patients in the IFX + MTX group achieved sustained remission compared with 14% on MTX alone and 0% on PL. This difference (p < 0.05 over all three groups) was statistically significant for IFX + MTX vs PL (p < 0.05), but not for IFX + MTX vs MTX (p = 0.10), nor for MTX vs PL (p = 0.31). Remission was maintained during the second year on no therapy in 75% of the IFX + MTX patients compared with 20% of the MTX-only patients. CONCLUSIONS: These results indicate that patients with early arthritis can benefit from induction therapy with anti-TNF plus MTX compared with MTX alone, suggesting that intensive treatment can alter the disease evolution. TRIAL REGISTRATION: The trial was registered at http://www.isrctn.com/ISRCTN21272423 on 4 October 2007 (date applied)/12 December 2007 (date assigned). The first patient was included on 24 October 2007.

Color Doppler and spectral Doppler ultrasound detection of active sacroiliitis in spondyloarthritis compared to physical examination as gold standard.

Sacroiliac joint (SIJ) involvement is a distinctive feature of spondyloarthritis (SpA). The main objective of this study was to assess the validity of color Doppler ultrasound (CDUS) in SIJ. This was a cross-sectional, blinded, case-control study of 108 cases divided into three groups: (a) 53 SpA patients with inflammatory back pain (IBP); (b) 28 SpA patients with no IBP; and (c) 27 healthy mechanical lumbar pain subjects. Physical examinations of the SIJs were assessed as positive or negative in each SIJ and were used as the gold standard. SIJs were examined with CDUS and spectral Doppler, and the SIJs were assessed as positive when both color Doppler and the resistance index (RI) were less than the cut-off point within the SIJs area. A total of 108 cases (53 female; mean age 36 ± 10 years old) were studied. The physical examination of the SIJs was positive in 38 patients (59 SIJs). Ultrasound detected Doppler signal within the SIJs in 37 cases (58 SIJs): 33 of them had symptomatic SpA (52 SIJs), 3 of them had asymptomatic SpA (5 SIJs), and 1 was a healthy control (1 SIJ). The accuracy of CDUS, when compared to physical SIJ examination, at the patient level in the overall group had a sensitivity of 70.3%, a specificity of 85.7%, a positive likelihood ratio of 4.9, and a negative likelihood ratio of 0.36. For the spectral Doppler RI, with an optimal cut-off point ≤0.75, the sensitivity was 76.2%, and the specificity was 77.8%. CDUS of SIJs seems to be a feasible and valid method for detecting active inflammation in patients with SpA.

Increased frequency of circulating CD19+CD24hiCD38hi B cells with regulatory capacity in patients with Ankylosing spondylitis (AS) naïve for biological agents.

Our objective was to study the frequency of circulating CD19+CD24hiCD38hi B cells (Breg) in AS patients. To this end, peripheral blood was drawn from AS patients naïve for TNF blockers (AS/nb) (n = 42) and healthy controls (HC) (n = 42). Six patients donated blood for a second time, 6 months after initiating treatment with anti-TNFα drugs. After isolation by Ficoll-Hypaque, PBMCs were stained with antibodies to CD3, CD4, CD19, CD24, and CD38, and examined by cytometry. For functional studies, total CD19+ B cells were isolated from PBMCs of 3 HC by magnetical sorting. Breg-depleted CD19+ B cells were obtained after CD19+CD24hiCD38hi B cells were removed from total CD19+ cells by cytometry. Total CD19+ B cells or Breg-depleted CD19+ B cells were established in culture and stimulated through their BCR. Secretion of IFNγ was determined by ELISA in culture supernatants. When compared with HC, AS/nb patients demonstrated a significantly increased frequency of Breg cells, which was independent of disease activity. Anti-TNFα drugs induced a significant reduction of circulating Breg numbers, which were no longer elevated after six months of treatment. Functional in vitro studies showed that the secretion of IFNγ was significantly higher in Breg-depleted as compared with total CD19+ B cells, indicating that Breg can downmodulate B cell pro-inflammatory cytokine secretion. In summary, an increased frequency of circulating CD19+CD24hiCD38hi B cells is observed in AS/nb patients, that is not related with disease activity; anti-TNFα drugs are able to downmodulate circulating Breg numbers in AS.

Ultrasound sensitivity to changes in gout: a longitudinal study after two years of treatment.

OBJECTIVES: The goals of our study are to evaluate the urate-lowering therapy (ULT) effect on gout ultrasound (US) lesions and to explore US sensitivity to change in gout patients. METHODS: Patients with chronic and symptomatic gout, confirmed by crystal identification, were prospectively included. Clinical and US assessments were performed at baseline and after 6, 12 and 24 months of ULT. The presence of double contour sign (DCS) and US- detectable tophi were assessed in the first metatarsophalangeals, the knees and patellar tendons. The mean and standard deviation were calculated for each parameter. The correlation between the clinical and US parameters was assessed by calculating Pearson's correlation coefficient. Sensitivity to change in the US examinations was assessed by estimating the smallest detectable difference (SDD). RESULTS: Twenty-three consecutive patients were included (96% men; mean age 59 ± 11 years). DCS and US tophi were detected in 73.9% and 91.3% of patients at baseline. A significant parallel improvement in the serum urate, clinical parameters and US lesions was found at the follow-up assessment. The SDD values for the global DCS and tophi were 0.52 and 0.69, respectively, which were smaller than the differences achieved over the course of the two years. A significant correlation between DCS and clinical parameters was observed (r =0.49, p=0.038). CONCLUSIONS: Ultrasound findings in gout patients show sensitivity to change and concurrent validity with uric acid reduction after ULT in gout patients. US can be a useful tool for gout tophus burden monitoring.

Adaptation of the osteoarthritis-specific quality of life scale (the OAQoL) for use in Germany, Hungary, Italy, Spain and Turkey.

The Osteoarthritis Quality of Life scale (OAQoL) is specific to individuals with osteoarthritis. The present study describes the adaptation of the OAQoL for use in the following five European languages: German, Hungarian, Italian, Spanish and Turkish. The study involved three stages in each language; translation, cognitive debriefing (face and content validity) and validation. The validation stage assessed internal consistency (Cronbach's alpha), reproducibility (test-retest reliability using Spearman's rank correlations), convergent and divergent validity (correlations with the Health Assessment Questionnaire, The Western Ontario and McMaster Universities Index of osteoarthritis and Nottingham Health Profile) and known group validity. The OAQoL was successfully translated into the target languages with minimal problems. Cognitive debriefing interviewees found the measures easy to complete and identified few problems with content. Internal consistency ranged from 0.94 to 0.97 and test-retest reliability (reproducibility) from 0.87 to 0.98. These values indicate that the new language versions produce very low levels of measurement error. Median OAQoL scores were higher for patients reporting a current flare of osteoarthritis in all countries. Scores were also related, as expected, to perceived severity of osteoarthritis. The OAQoL was successfully adapted for use in Germany, Hungary, Italy, Spain and Turkey. The addition of these new language versions will prove valuable to multinational clinical trials and to clinical practice in the respective countries.

Patients' and rheumatologists' preferences for the attributes of biological agents used in the treatment of rheumatic diseases in Spain.

PURPOSE: To define importance values assigned to attributes of biological agents (BAs) by Spanish patients with rheumatic diseases (rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis) and rheumatologists. PATIENTS AND METHODS: This was an observational, cross-sectional design based upon a rank-based full-profile conjoint analysis. A literature review and four focus groups were undertaken to identify attributes and levels. An orthogonal matrix, combining the selected levels of attributes, was used to define scenarios. Participants ranked eight scenarios from 1 (most preferred) to 8 (least preferred). The relative importance (RI) of attributes was calculated. Multivariate regression analysis was performed to identify the characteristics that influenced the values of RI. A total of 488 patients (male 50.9%, mean age 50.6 [standard deviation {SD} 12.06] years, rheumatoid arthritis 33.8%, ankylosing spondylitis 32.4%, psoriatic arthritis 33.8%; mean time since diagnosis 12.6 [SD 8.2] years) and 136 rheumatologists (male 50.4%, mean age 46.4 [SD 9.1] years, mean time of practice 16.7 [SD 8.8] years) participated. RESULTS: The ideal BAs for patients and physicians, respectively, should allow pain relief and improvement of functional capacity (RI 39% and 44.7%), with low risk of adverse events (RI 24.9% and 30.5%), a long time prior to perceiving the need for a new dose (RI 16.4% and 12.4%), and self-administration at home (RI 19.7% and 12.5%), as identified through their preferences. CONCLUSION: Although efficacy and safety are paramount for patients and rheumatologists to make a choice regarding BAs, the need for a low frequency of administration and the administration method also play a role as preference attributes for BAs.

The Minimum Clinically Important Improvement and Patient-acceptable Symptom State in the BASDAI and BASFI for Patients with Ankylosing Spondylitis.

OBJECTIVE: To establish cutoffs for the minimum clinically important improvement (MCII) and the patient-acceptable symptom state (PASS) for the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis Functional Index (BASFI) in patients with ankylosing spondylitis (AS). METHODS: Patients with AS who started nonsteroidal antiinflammatory drugs were included. After 4 weeks, the PASS and the MCII were defined using external anchor questions (for the PASS, patients considering their condition of AS over the prior 48 h as "acceptable" forever; and for the MCII, those reporting moderate or slightly important improvement). Consistency of the MCII and PASS were tested according to HLA-B27 status, presence/absence of SpA extraarticular manifestations, age, sex, disease duration, and baseline BASDAI/BASFI score. The 75th percentile of the cumulative distribution was used to determine the MCII and PASS. RESULTS: In total, 283 patients from a multinational cohort were included. Overall cutoffs for the PASS were 4.1 in the BASDAI and 3.8 in the BASFI. Cutoffs for the MCII were 0.7 and 0.4 for the BASDAI and BASFI, respectively. Subgroup analyses revealed that disease duration and baseline BASDAI/BASFI were significantly associated with the PASS and MCII. In a subanalysis limited to patients with active disease (baseline BASDAI ≥ 4), the MCII was 1.1 for the BASDAI and 0.6 for the BASFI. CONCLUSION: The conceptual viability of the PASS for the BASDAI is questionable because levels approach those required for the start of biological therapy. Because the MCII is less variable than the PASS, we propose its exclusive use, with cutoffs of 1.1/0.6 for the BASDAI/BASFI in patients with active disease. Because these values are based on a subset of the study population, we recommend confirmation in larger studies focused on patients with baseline BASDAI ≥ 4.

Anti-citrullinated peptide antibodies and their value for predicting responses to biologic agents: a review.

Anti-citrullinated peptide antibodies (ACPAs) play an important pathogenic role both at the onset and during the disease course. These antibodies precede the clinical appearance of rheumatoid arthritis (RA) and are associated with a less favorable prognosis, both clinically and radiologically. The objective of this work was to conduct a comprehensive review of studies published through September 2015 of ACPAs' role as a predictor of the therapeutic response to the biological agents in RA patients. The review also includes summary of the biology and detection of ACPAs as well as ACPAs in relation to joint disease and CV disease and the possible role of seroconversion. The reviews of studies examining TNF inhibitors and tocilizumab yielded negative results. In the case of rituximab, the data indicated a greater probability of clinical benefit in ACPA(+) patients versus ACPA(-) patients, as has been previously described for rheumatoid factor. Nonetheless, the effect is discreet and heterogeneous. Another drug that may have greater effectiveness in ACPA(+) patients is abatacept. Some studies have suggested that the drug is more efficient in ACPA(+) patients and that those patients show greater drug retention. In a subanalysis of the AMPLE trial, patients with very high ACPA titers who were treated with abatacept had a statistically significant response compared to patients with lower titers. In summary, the available studies suggest that the presence of or high titers of ACPA may predict a better response to rituximab and/or abatacept. Evidence regarding TNFi and tocilizumab is lacking. However, there is a lack of studies with appropriate designs to demonstrate that some drugs are superior to others for ACPA(+) patients.

Comparing a tapering strategy to the standard dosing regimen of TNF inhibitors in rheumatoid arthritis patients with low disease activity.

OBJECTIVES: The aim of this study is to compare clinical outcomes, incidence of flares and administered drug reduction between rheumatoid arthritis (RA) patients under TNF inhibitors (TNFi) tapering strategy and RA patients on standard regimen. METHODS: Two groups of RA patients on TNFi with DAS28<3.2 were compared: the tapering group (TG: 67 pts from Spain) and the control group with standard therapy regimen (CG: 77 pts from the Netherlands). DAS28 was measured at different time points: visit 0 (prior starting TNFi), visit 1 (prior to start tapering in TG and with DAS28<3.2 in TG and CG), visit 2 (6 months after visit 1), visit 3 (1 year after visit 1), visit 4 (the last visit available after visit 1) and visit-flare (visit with the worst flare between visit 1 and visit 4). RESULTS: Despite the reduction of administered drug at visit 4 in the TG (interval elongation of 32.8% in infliximab, 52.9% in adalimumab and 52.6% in etanercept), the DAS28 remained similar between groups at the end of the study (DAS28: 2.7±0.9 in TG vs. 2.5±1 in CG, p=0.1). No differences were seen in the number of patients with flares [26/67 (38.9%) in the TG vs. 30/77 (39%) in the CG, p=0.324] and only nineteen out of 136 patients (14%) had anti-drug antibodies at the end of the study. CONCLUSIONS: The tapering strategy of TNFi in RA patients result in a reduction of the drug administered, while the disease control is not worse than patients on the standard regimen.

Anti-TNF discontinuation and tapering strategies in patients with axial spondyloarthritis: a systematic literature review.

OBJECTIVE: The aim was to evaluate whether anti-TNF discontinuation and tapering strategies are efficacious for maintaining remission or low disease activity (LDA) in patients with axial spondyloarthritis. METHODS: A systematic literature review up to September 2014 was performed using Medline, EMBASE and Cochrane databases. Longitudinal studies evaluating the efficacy of discontinuation/tapering of anti-TNF therapy to maintain clinical response achieved after receiving a standard dose of the same drug were included. The results were grouped according to the type of strategy (discontinuation or tapering) evaluated. RESULTS: Thirteen studies out of 763 retrieved citations were included. Overall, published data are scarce and the level of evidence of the studies is weak. Five studies provided evidence for assessing discontinuation strategy. The frequency of patients developing flare during the follow-up period ranged between 76 and 100%. The median (range) follow-up period was 52 (36-52) weeks and time to flare 16 (6-24) weeks. Additionally, eight studies evaluating tapering strategy were selected. The percentage of patients maintaining LDA or remission was reported in five studies and ranged between 53 and 100%. The remaining three studies reported the mean change in BASDAI and CRP after reducing the anti-TNF dose and did not observe any relevant increase in these parameters. CONCLUSION: Published data indicate that a tapering strategy for anti-TNF therapy is successful in maintaining remission or LDA in most patients with axial spondyloarthritis. However, a discontinuation strategy is not recommended because it leads to flare in most cases. Further studies with an appropriate design covering the whole spectrum of the disease are required to confirm these results.

Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force.

BACKGROUND: Reaching the therapeutic target of remission or low-disease activity has improved outcomes in patients with rheumatoid arthritis (RA) significantly. The treat-to-target recommendations, formulated in 2010, have provided a basis for implementation of a strategic approach towards this therapeutic goal in routine clinical practice, but these recommendations need to be re-evaluated for appropriateness and practicability in the light of new insights. OBJECTIVE: To update the 2010 treat-to-target recommendations based on systematic literature reviews (SLR) and expert opinion. METHODS: A task force of rheumatologists, patients and a nurse specialist assessed the SLR results and evaluated the individual items of the 2010 recommendations accordingly, reformulating many of the items. These were subsequently discussed, amended and voted upon by >40 experts, including 5 patients, from various regions of the world. Levels of evidence, strengths of recommendations and levels of agreement were derived. RESULTS: The update resulted in 4 overarching principles and 10 recommendations. The previous recommendations were partly adapted and their order changed as deemed appropriate in terms of importance in the view of the experts. The SLR had now provided also data for the effectiveness of targeting low-disease activity or remission in established rather than only early disease. The role of comorbidities, including their potential to preclude treatment intensification, was highlighted more strongly than before. The treatment aim was again defined as remission with low-disease activity being an alternative goal especially in patients with long-standing disease. Regular follow-up (every 1-3 months during active disease) with according therapeutic adaptations to reach the desired state was recommended. Follow-up examinations ought to employ composite measures of disease activity that include joint counts. Additional items provide further details for particular aspects of the disease, especially comorbidity and shared decision-making with the patient. Levels of evidence had increased for many items compared with the 2010 recommendations, and levels of agreement were very high for most of the individual recommendations (≥9/10). CONCLUSIONS: The 4 overarching principles and 10 recommendations are based on stronger evidence than before and are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA.

Effectiveness of Tapentadol Prolonged Release (PR) Compared with Oxycodone/Naloxone PR for the Management of Severe Chronic Low Back Pain with a Neuropathic Component: A Randomized, Controlled, Open-Label, Phase 3b/4 Study.

OBJECTIVE: To evaluate the effectiveness of tapentadol prolonged release (PR) vs. oxycodone/naloxone PR in non-opioid-pretreated patients with severe chronic low back pain with a neuropathic pain component. METHODS: Eligible patients (average pain intensity [numerical rating scale-3 (NRS-3)] ≥6; painDETECT positive/unclear) were randomized to twice-daily tapentadol PR 50 mg or oxycodone/naloxone PR 10 mg/5 mg. After a 21-day titration (maximum twice-daily doses: tapentadol PR 250 mg, or oxycodone/naloxone PR 40 mg/20 mg plus oxycodone PR 10 mg), target doses were continued for 9 weeks. The primary effectiveness endpoint was the change in NRS-3 from baseline to final evaluation; the exact repeated confidence interval (RCI) for tapentadol PR minus oxycodone/naloxone PR was used to establish noninferiority (upper limit <1.3) and superiority (confirmatory analyses). RESULTS: For the primary effectiveness endpoint, tapentadol PR was noninferior to oxycodone/naloxone PR (97.5% RCI: [-1.820, -0.184]; P < 0.001). This exact RCI also yielded evidence of superiority for tapentadol PR vs. oxycodone/naloxone PR (significantly greater reduction in pain intensity; P = 0.003). Improvements (baseline to final evaluation) in painDETECT and Neuropathic Pain Symptom Inventory scores were significantly greater with tapentadol PR vs. oxycodone/naloxone PR (all P ≤ 0.005). CONCLUSIONS: The study was formally shown to be positive and demonstrated, in the primary effectiveness endpoint, the noninferiority for tapentadol PR vs. oxycodone/naloxone PR. The effectiveness of tapentadol PR was superior to that of oxycodone/naloxone PR by means of clinical relevance and statistical significance (confirmatory evidence of superiority). Tapentadol PR was associated with significantly greater improvements in neuropathic pain-related symptoms and global health status than oxycodone/naloxone PR and with a significantly better gastrointestinal tolerability profile. Tapentadol PR may be considered a first-line option for managing severe chronic low back pain with a neuropathic pain component.

Effect of Infliximab Dose Increase in Rheumatoid Arthritis at Different Trough Concentrations: A Cohort Study in Clinical Practice Conditions.

BACKGROUND: Evidence supporting treatment intensification in rheumatoid arthritis (RA) is limited and controversial. We explored outcomes of infliximab dose increases and accounted for pre-existing trough levels in patients with active RA. METHODS: This study was a retrospective study of 42 RA patients who received increased infliximab following an insufficient response (DAS28 >3.2). Serum concentrations of infliximab and antibodies to infliximab (ATI) and DAS28 and EULAR clinical response parameters were recorded for 1 year. Analyses were performed in three patient groups that were defined by infliximab serum concentration prior to treatment enhancement: no detectable, low (<1.1 µg/mL) or high (≥1.1 µg/mL) drug levels. RESULTS: No circulating infliximab was detected in 20 patients (47.6%), but 13 (31%) and 9 (21.4%) patients exhibited low and high levels, respectively. ATI was only detected in patients with no detectable drug levels because the drug interferes with ELISA. DAS28 disease activity globally showed a modest improvement after dose escalation, but this improvement did not persist after 6 and 12 months. Infliximab serum levels increased significantly in the high group (p = 0.016), but no increase was achieved in the low and no detectable groups. The three study groups exhibited similar disease activity over time, and no improvement was observed in the non-responder EULAR rates. CONCLUSION: These results suggest that the efficacy of an infliximab dose increase is limited, and the response is independent of the infliximab trough serum concentration that is achieved prior to escalation.

Actualización 2014 del Documento de Consenso de la Sociedad Española de Reumatología sobre el uso de terapias biológicas en la artritis reumatoide / 2014 update of the Consensus Statement of the Spanish Society of Rheumatology on the use of biological therapies in rheumatoid arthritis

Objetivo. Establecer recomendaciones para el manejo de pacientes con artritis reumatoide (AR) centrado en el papel de los fármacos antirreumáticos modificadores de enfermedad (FAME) sintéticos y biológicos disponibles, que sirvan de referencia para todos los profesionales implicados en la atención de estos pacientes. Métodos. Las recomendaciones se consensuaron a través de un panel de 14 expertos previamente seleccionados por la Sociedad Española de Reumatología (SER). Se recogió la evidencia disponible mediante la actualización de las 3 revisiones sistemáticas (RS) que se utilizaron para las recomendaciones EULAR 2013, a las que se añadió una nueva RS para dar respuesta a una pregunta adicional. Todas fueron realizadas por miembros del grupo de revisores de la SER. La clasificación del nivel de la evidencia y del grado de la recomendación se realizó utilizando el sistema del Centre for Evidence-Based Medicine de Oxford. Se utilizó la metodología Delphi para evaluar el grado de acuerdo entre los panelistas para cada recomendación. Resultados. Se emiten un total de 13 recomendaciones sobre el manejo terapéutico de pacientes con AR del adulto. El objetivo terapéutico debe ser tratar al paciente en fases precoces de la enfermedad, con el objetivo de la remisión clínica, teniendo un papel central el metotrexato como FAME sintético de referencia. Se actualizan las indicaciones de los FAME biológicos disponibles, se enfatiza la importancia de los factores pronósticos y se incide en el concepto de optimización de biológicos. Conclusiones. Se presenta la quinta actualización de las recomendaciones SER para el manejo de la AR con FAME sintéticos y biológicos (AU)

Objective. To establish recommendations for the management of patients with rheumatoid arthritis (RA) to serve as a reference for all health professionals involved in the care of these patients, and focusing on the role of available synthetic and biologic disease-modifying antirheumatic drugs (DMARDs). Methods. Consensual recommendations were agreed on by a panel of 14 experts selected by the Spanish Society of Rheumatology (SER). The available scientific evidence was collected by updating three systematic reviews (SR) used for the EULAR 2013 recommendations. A new SR was added to answer an additional question. The literature review of the scientific evidence was made by the SER reviewer's group. The level of evidence and the degree of recommendation was classified according to the Oxford Centre for Evidence-Based Medicine system. A Delphi panel was used to evaluate the level of agreement between panellists (strength of recommendation). Results. Thirteen recommendations for the management of adult RA were emitted. The therapeutic objective should be to treat patients in the early phases of the disease with the aim of achieving clinical remission, with methotrexate playing a central role in the therapeutic strategy of RA as the reference synthetic DMARD. Indications for biologic DMARDs were updated and the concept of the optimization of biologicals was introduced. Conclusions. We present the fifth update of the SER recommendations for the management of RA with synthetic and biologic DMARDs (AU)