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ID PMID Title PublicationDate abstract
28288508 Isoniazid treatment for latent tuberculosis infection is tolerable for rheumatoid arthriti 2018 Sep BACKGROUND/AIMS: To evaluate the impact of isoniazid (INH) treatment for latent tuberculosis infection (LTBI) on the development of liver function test (LFT) abnormality and the persistence of tumor necrosis factor (TNF) inhibitors in rheumatoid arthritis (RA) patients. METHODS: We retrospectively enrolled patients with RA who were treated with TNF inhibitors at a university hospital between December 2000 and November 2011. After dividing the patients into two groups based on the occurrence of LFT abnormality during follow-up, we compared demographic and clinical features between the two groups. A multivariable logistic regression analysis was performed to identify the impact of INH treatment on LFT abnormality. The impact of INH treatment on the persistence of TNF inhibitors was also evaluated with the log-rank test and the Cox-proportional hazards model. RESULTS: A total of 312 RA patients including 96 patients (30.9%) who took INH for LTBI were included in this analysis. Thirty-nine patients (12.5%) experienced LFT abnormalities while using TNF inhibitors. The use of INH was associated with LFT abnormalities (odds ratio, 3.01; 95% confidence interval [CI], 1.39 to 6.48) after adjusting for covariates, including methotrexate use. However, the persistence of TNF inhibitors over 5 years did not differ between patients receiving or not receiving INH treatment (49.4 vs. 54.6%, p = 0.79). INH treatment was not a risk factor for discontinuation of TNF inhibitors (hazard ratio, 1.01; 95% CI, 0.66 to 1.57). CONCLUSION: INH treatment for LTBI in RA patients who started TNF inhibitors is associated with the occurrence of LFT abnormality; however, it does not lead to discontinuation of TNF inhibitors.
29255211 Autoimmunity and primary immunodeficiency: two sides of the same coin? 2017 Dec 19 Autoimmunity and immunodeficiency were previously considered to be mutually exclusive conditions; however, increased understanding of the complex immune regulatory and signalling mechanisms involved, coupled with the application of genetic analysis, is revealing the complex relationships between primary immunodeficiency syndromes and autoimmune diseases. Single-gene defects can cause rare diseases that predominantly present with autoimmune symptoms. Such genetic defects also predispose individuals to recurrent infections (a hallmark of immunodeficiency) and can cause primary immunodeficiencies, which can also lead to immune dysregulation and autoimmunity. Moreover, risk factors for polygenic rheumatic diseases often exist in the same genes as the mutations that give rise to primary immunodeficiency syndromes. In this Review, various primary immunodeficiency syndromes are presented, along with their pathogenetic mechanisms and relationship to autoimmune diseases, in an effort to increase awareness of immunodeficiencies that occur concurrently with autoimmune diseases and to highlight the need to initiate appropriate genetic tests. The growing knowledge of various genetically determined pathologic mechanisms in patients with immunodeficiencies who have autoimmune symptoms opens up new avenues for personalized molecular therapies that could potentially treat immunodeficiency and autoimmunity at the same time, and that could be further explored in the context of autoimmune rheumatic diseases.
28408798 An open randomized active-controlled clinical trial with low-dose SKA cytokines versus DMA 2017 BACKGROUND: Biologic agents are currently the strongest immunosuppressive drugs able to induce remission in rheumatoid arthritis (RA). One of the objectives of the medical scientific community now is how to maintain remission or low disease activity (LDA). The aim of this trial is to evaluate the contribution of low-dose sequential kinetic activation (SKA) IL-4, IL-10, and anti-IL-1 antibodies (10 fg/mL) in patients affected by RA in maintaining LDA or remission obtained after biological therapy. METHOD: This is a randomized, open, active-controlled, prospective, Phase IV trial. Disease activity score (DAS28), clinical disease activity index, simplified disease activity index, erythrocyte sedimentation rate and C-reactive protein levels, global health assessment, and pain visual analog scale were evaluated at baseline visit and then every 3 months together with an assessment of side effects till 12 months. Thirty-nine RA patients were enrolled and randomized to continue disease-modifying antirheumatic drugs (DMARDs) therapy or to receive a combination of SKA low-dose cytokines formulated in concentration of 10 fg/mL orally administered at a dose of 20 drops/d for 12 consecutive months. RESULTS: The rate of maintenance of LDA at 12 months was superior in the group treated with low-dose cytokines compared with patients treated with DMARDs, 66.7% and 42.1%, respectively; however, the difference between the groups was not statistically significant. No side effects were reported in both groups. CONCLUSION: This is the first study using a combination of three low-dose cytokines in RA, after data published on psoriasis. These data suggest that the use of a combination of low-dose SKA cytokines may be an opportunity to explore in the management of RA.
28431182 Joint positions matter for ultrasound examination of RA patients-increased power Doppler s 2017 Aug 1 OBJECTIVE: Position of joints might influence the result of US examination in patients with RA. The purpose of this work was to compare grey-scale (GS) and power Doppler (PWD) findings obtained in neutral vs flat position of hands. METHODS: A cross-sectional study of 42 RA patients with active disease. Two dimensional and 3D sonography of wrists and MCP joints were conducted in two different joint positions: neutral position, which is a slight flexion of the fingers with relaxed extensor muscles; and flat position, where all palm and volar sides of fingers touch the Table. Two dimensional GS synovitis (GSS) and PWD signals were scored semi-quantitatively (0-3). For 3D sonography, the percentage of PWD voxels within a region of interest was calculated. GSS was not quantified using 3D sonography. RESULTS: Compared with neutral position, 2D PWD signals disappeared in 28.3% of joints upon flattening. The median global 2D PWD score (sum of all PWD scores of an individual patient) decreased from 8 to 3 ( P < 0.001), and the global 3D PWD voxel score from 3.8 to 0.9 ( P < 0.001). The reduction of PWD scores was similar in all joints (2D: minus 50%, 3D: minus 66.4-80.1%). Inter- and intrareader agreement of PWD results was good (intraclass correlation coefficient: 0.75-0.82). CONCLUSION: In RA, a neutral position of the hands is linked to a higher sensitivity of 2D and 3D sonography in detecting PWD signals at wrists and MCP joints, compared with a flat position. Standardization of the scanning procedure is essential for obtaining comparable US results in RA patients in trials and clinical routines.
28963724 The anti-CD6 antibody itolizumab provides clinical benefit without lymphopenia in rheumato 2018 Feb Itolizumab is a humanized anti-CD6 monoclonal antibody (mAb) that has previously shown encouraging results, in terms of safety and positive clinical effects, in a 6-week monotherapy clinical trial conducted in rheumatoid arthritis (RA) patients. The current Phase I study evaluated the safety and clinical response for a longer treatment of 12 itolizumab intravenous doses in subjects with active RA despite previous disease-modifying anti-rheumatic drug (DMARD) therapy. Twenty-one subjects were enrolled into four dosage groups (0·1, 0·2, 0·4 and 0·8 mg/kg). Efficacy end-points including American College of Rheumatology (ACR)20, ACR50 and ACR70 response rates and disease activity score in 28 joints (DAS28) were monitored at baseline and at specific time-points during a 10-week follow-up period. Itolizumab was well tolerated up to the highest tested dose. No related serious adverse events were reported and most adverse events were mild. Remarkably, itolizumab treatment did not produce lymphopenia and, therefore, was not associated with infections. All patients achieved a clinical response (ACR20) at least once during the study. Eleven subjects (55%) achieved at least a 20% improvement in ACR just 1 week after the first itolizumab administration. The clinical response was observed from the beginning of the treatment and was sustained during 24 weeks. The efficacy profile of this 12-week treatment was similar to that of the previous study (6-week treatment). These results reinforce the safety profile of itolizumab and provide further evidence on the clinical benefit from the use of this anti-CD6 mAb in RA patients.
27965071 A betulinic acid derivative SH479 inhibits collagen-induced arthritis by modulating T cell 2017 Feb 15 The ideal therapeutic drug for rheumatoid arthritis (RA) should not only inhibit inflammation, but also prevent articular joint damage and particularly inhibit osteoclastogenesis. Betulinic acid (BA) is a natural pentacyclic triterpene that has displayed moderate anti-inflammatory and anti-osteoclastogenesis activities in various experimental systems, suggesting that BA or its derivatives could have an inhibitory effect on RA. In this study, we screened BA derivatives and found a heterocyclic ring-fused BA derivative, SH479, which had greater inhibitory effect than BA on Th17 differentiation. Moreover, we investigated the immune regulatory activity and potential therapeutic effects of SH479 in an experimental model of rheumatoid arthritis, the collagen-induced arthritis (CIA) mouse model. SH479 significantly inhibited Th1 and Th17 polarization, antigen-specific T cell proliferation and splenic lymphocyte-induced osteoclastogenesis. Furthermore, it diminished arthritis scores as well as bone destruction and cartilage depletion in the CIA mouse model. The protective effect of SH479 was accompanied by decreased levels of pro-inflammatory cytokines IL-17 and IFN-γ, together with enhanced anti-inflammatory cytokine expression including IL-10 and IL-4, as well as elevated CD4(+) Foxp3(+) cell number. At the molecular level, our results indicated that SH479 alleviated CIA through regulation of CD4(+) T cell subtypes by JAK-STAT pathways. In conclusion, this study demonstrates that SH479 has therapeutic potential for rheumatoid arthritis through an anti-inflammatory effect by shifting a pathogenic Th17/Th1 response to a Th2/Treg phenotype, and also through an additional articular bone protection effect.
27344079 Pregnancy and foetal outcomes following anti-tumor necrosis factor alpha therapy: A prospe 2017 Mar OBJECTIVE: As many inflammatory rheumatic diseases affect patients in childbearing age, some concern has been expressed about the safety of biologic drugs during pregnancy. This study evaluated the effects of anti-tumor necrosis factor alpha (TNFα) agents on pregnancy/foetal outcomes. METHODS: Thirty-eight pregnancies were followed prospectively from November 2008 to February 2015. Information about the patients' exposure to anti-TNFα, disease activity, DMARD therapy, pregnancy/foetal outcomes were registered. RESULTS: Twenty-four/38 (71.1%) pregnancies were exposed to anti-TNFα at conception/I trimester, 11/38 (28.9%) prior to conception and 3 (11.1%) following paternal exposure. There were two congenital malformations: one infant (4.2%) was diagnosed with congenital diaphragmatic hernia and obstructive megaureter; the mother was exposed to adalimumab at conception/I trimester. While one foetus (9.1%) showed a trisomy 16, the mother 38 year-old had suspended etanercept 4 weeks before conception. There was no significant difference in pregnancy/foetal outcome between the two groups. Nor were there any significant differences in pregnancy/foetal outcomes in the various groups being treated with different anti-TNFα antagonists. No congenital malformations were found in connection to paternal exposure. CONCLUSION: Study results suggest that anti-TNFα drugs could be safe when administered during conception/I trimester and following paternal exposure.
28967035 Comparative efficacy and tolerability of monotherapy with leflunomide or tacrolimus for th 2018 Feb We aimed to assess the relative efficacy and tolerability of monotherapy with leflunomide or tacrolimus at recommended dosages in rheumatoid arthritis (RA) patients. Randomized controlled trials (RCTs) examining the efficacy and tolerability of leflunomide 20 mg, leflunomide 10 mg, tacrolimus 3 mg, tacrolimus 1.5-2 mg, and placebo, based on the number of withdrawals of RA patients, were included. We performed a Bayesian random-effects network meta-analysis to combine direct and indirect evidence from the RCTs. Six RCTs including 1510 patients met the inclusion criteria. The proportion of patient withdrawals owing to lack of efficacy was significantly lower in the leflunomide 20 mg (OR 0.17, 95% credible interval (CrI) 0.08-0.34); leflunomide 10 mg (OR 0.16, 95% CrI 0.02-0.75); and tacrolimus 3 mg (OR 0.41, 95% CrI 0.21-0.74) groups than in the placebo group. Rank probability based on the surface under the cumulative ranking curve (SUCRA) values indicated that leflunomide 20 mg had the highest probability of being the best treatment based on the number of withdrawals owing to lack of efficacy (SUCRA = 0.8530), followed by leflunomide 10 mg (SUCRA = 0.8321), tacrolimus 3 mg (SUCRA = 0.4965), tacrolimus 1.5-2 mg (SUCRA = 0.3035), and placebo (SUCRA = 0.0150). Patient withdrawals owing to adverse events did not differ significantly among the groups; however, withdrawals in the placebo group were fewer than those in the leflunomide 20 mg group (OR 0.22, 95% CrI 0.07-0.74). Placebo had the highest probability of being the most tolerable treatment (SUCRA = 0.8161) followed by tacrolimus 3 mg (SUCRA = 0.6490), tacrolimus 1.5-2 mg (SUCRA = 0.4857), leflunomide 10 mg (SUCRA = 0.4651), and leflunomide 20 mg (SUCRA = 0.0841). Leflunomide 20 mg, leflunomide 10 mg, and tacrolimus 3 mg were more efficacious than placebo, while leflunomide 20 mg was less tolerable than placebo. Leflunomide is likely to be more efficacious but less tolerable than tacrolimus for RA treatment.
29052381 [Pharmacodynamic mechanism of modified Ganlu Yaoyu San intreatment of rheumatoid arthritis 2017 Apr According to the findings, modified Ganlu Yaoyu San has a good anti-inflammatory activity, and can significantly alleviate the degree of arthritis. Its therapeutic effect for rheumatoid arthritis may be related to the regulation of MAPK pathway of synovial cells. In the study, the rat adjuvant arthritis(AA) model was established to further investigate the pharmacodynamic mechanism for regulating MAPK pathway of synovial cells. Enzyme-linked immune assay was used to determine the serum TNF-α level of AA rats administered with drug for two weeks, synovial tissue protein kinases ERK1/2 and p38 content were determined by immunohistochemistry, synovial tissue JNK1, ERK1, p38 gene(mRNA) expression were detected with fluorescence quantitative PCR(RT-PCR) method. According to the results, after administration for two weeks, the levels of serum TNF-α of AA rat was significantly decreased(P<0.05). After administration for four weeks, the protein expressions of p38 and ERK1/2 in synovial tissue were reduced(P<0.05 or P<0.01), the gene expressions of JNK1, p38 and ERK1 in knee joint synovial tissue were reduced(P<0.05 or P<0.01). In conclusion, modified Ganlu Yaoyu San can effectively treat rheumatoid arthritis. Its mechanism might be related to the reduction of TNF-α levels in serum, protein expression of p38 and ERK1/2 in synovial tissue, and JNK1, p38 and ERK1 gene expressions, and regulation of MAPK pathway.
28029752 Effects of Baricitinib on Lipid, Apolipoprotein, and Lipoprotein Particle Profiles in a Ph 2017 May OBJECTIVE: To assess the effects of baricitinib on lipid profiles in patients with moderate-to-severe rheumatoid arthritis. METHODS: Treatment with once-daily doses of baricitinib (1, 2, 4, or 8 mg) or placebo was studied in 301 randomized patients. Changes in lipid profile and lipoprotein particle size and particle number were assessed at weeks 12 and 24, and associations with clinical efficacy were evaluated. Apolipoproteins were assessed at weeks 4 and 12 in the placebo group and the 4-mg and 8-mg baricitinib groups. RESULTS: Treatment with baricitinib resulted in dose-dependent increases in serum lipid levels from baseline to week 12 (low-density lipoprotein [LDL] cholesterol increases of 3.4 mg/dl and 11.8 mg/dl in the 1 mg and 8 mg treatment groups, respectively; high-density lipoprotein [HDL] cholesterol increases of 3.3 mg/dl and 8.1 mg/dl, respectively; triglycerides increases of 6.4 mg/dl and 15.4 mg/dl, respectively). Group-wise mean increases in LDL cholesterol were coincident with mean increases in large LDL particles and mean reductions in small dense LDL particles. Increases from baseline to week 12 in apolipoprotein A-I, apolipoprotein B, and apolipoprotein CIII were observed with 4-mg doses of baricitinib (9.5%, 6.8%, and 23.0%, respectively) and with 8-mg doses (12.2%, 7.1%, and 19.7%, respectively), with no increase in LDL-associated apolipoprotein CIII (-4.5% with 4-mg baricitinib; -9.0% with 8-mg baricitinib). Baricitinib reduced HDL-associated serum amyloid A when administered at 4 mg (-36.0%) and 8 mg (-32.0%); a significant reduction in lipoprotein (a) was observed only with 8-mg doses (-16.6%). Increased HDL cholesterol at week 12 correlated with improved Disease Activity Scores and Simplified Disease Activity Index; changes in total cholesterol, LDL cholesterol, and triglycerides did not reveal a similar relationship. CONCLUSION: Baricitinib-associated increases in serum lipid levels were observed in this study. Increases in levels of HDL cholesterol correlated with improved clinical outcomes.
28849709 Efficacy and tolerability of six-week extended dosing interval with tocilizumab therapy in 2018 May OBJECTIVES: To prospectively evaluate the efficacy and tolerability of a six-week extended dosing interval with tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) in sustained remission. METHODS: Patients who received over six doses of intravenous TCZ in clinical remission (disease activity score [DAS] 28 - erythrocyte sedimentation rate [ESR] ≤ 2.6) maintained over 3 months between December 2013 and December 2015 were included. Flare was defined as DAS28-ESR >3.2 at two consecutive visits. RESULTS: Twenty-five patients were enrolled; 87.5% achieved clinical remission at week 54 after six-week extension and 95.5% achieved a van der Heijde modified total Sharp score (ΔmTSS) ≤0.5. The Health Assessment Questionnaire Disability Index (HAQ-DI) did not increase during 54 weeks. HAQ-DI at baseline and ΔDAS28-ESR at week six positively correlated with increase in DAS28-ESR at week 54. ΔSwollen joint count at week six positively correlated with ΔmTSS at week 54. A total of 12 adverse events occurring in 10 patients did not lead to cessation of TCZ except for one case of recurrent lymphoproliferative disorder at week five. CONCLUSION: A six-week extended dosing interval of TCZ for patients with RA in sustained remission is proposed as an acceptable treatment option for maintaining efficacy and tolerability.
28064209 Efficacy and effectiveness of tumour necrosis factor inhibitors in the treatment of rheuma 2017 May 1 OBJECTIVE: Efficacy of TNF inhibitors in the treatment of RA assessed in randomized controlled trials (RCTs) may not be fully comparable to routine care owing to the stringent inclusion criteria. The objective of this study was to observe the effectiveness of TNF inhibitors in real-world patients and assess the patients' potential eligibility for the RCTs. METHODS: RA patients starting a TNF-inhibitor treatment between 2004 and 2014 were identified from the National Register for Biologic Treatment in Finland, which is a longitudinal observational cohort study. Effectiveness was measured using the ACR and EULAR response criteria and by studying the proportion of patients reaching DAS28 remission. The patients' baseline characteristics were compared against the inclusion criteria of 27 RCTs. RESULTS: EULAR moderate and good treatment responses at 6 months were achieved by 69 and 40% of the users of the first TNF inhibitor, respectively. ACR20, ACR50 and ACR70 responses were reached by 48, 27 and 13%, respectively. DAS28 remission was reached by 47%. Only 7.6-44% of the patients would have been potentially eligible for the RCTs. The eligible patients had better treatment responses compared with the non-eligible patients. Different TNF inhibitors were mostly equipotent, but the usage of MTX co-therapy had a major influence on treatment response. CONCLUSION: Only a small proportion of patients would have been eligible for RCTs, and the efficacy of TNF inhibitors assessed in them cannot be generalized directly into Finnish routine health care.
27482854 Validation of Standardized Questionnaires Evaluating Symptoms of Depression in Rheumatoid 2017 Jan OBJECTIVE: To validate standard self-report questionnaires for depression screening in patients with rheumatoid arthritis (RA) and compare these measures to one another and to the Montgomery-Åsberg Depression Rating Scale (MADRS), a standardized structured interview. METHODS: In 9 clinical centers across Germany, depressive symptomatology was assessed in 262 adult RA patients at baseline (T0) and at 12 ± 2 weeks followup (T1) using the World Health Organization 5-Item Well-Being Index (WHO-5), the Patient Health Questionnaire (PHQ-9), and the Beck Depression Inventory II (BDI-II). The construct validity of these depression questionnaires (using convergent and discriminant validity) was evaluated using Spearman's correlations at both time points. The test-retest reliability of the questionnaires was evaluated in RA patients who had not undergone a psychotherapeutic intervention or received antidepressants between T0 and T1. The sensitivity and the specificity of the questionnaires were calculated using the results of the MADRS, a structured interview, as the gold standard. RESULTS: According to Spearman's correlation coefficients, all questionnaires met convergent validity criteria (ρ > |0.50|), with the BDI-II performing best, while correlations with age and disease activity for all questionnaires met the criteria for discriminant validity (ρ < |0.50|). The only questionnaire to meet the predefined retest reliability criterion (ρ ≥ 0.70) was the BDI-II (r(s)  = 0.77), which also achieved the best results for both sensitivity and specificity (>80%) when using the MADRS as the gold standard. CONCLUSION: The BDI-II best met the predefined criteria, and the PHQ-9 met most of the validity criteria, with lower sensitivity and specificity.
28506920 Regulatory B cells in rheumatoid arthritis: Alterations in patients receiving anti-TNF the 2017 Nov Cytokines, including tumor necrosis factor alpha (TNFα) are involved in Rheumatoid arthritis (RA) pathogenesis by augmenting autoimmunity, sustaining long term inflammation in the synovium, and promoting joint damage. Anti-TNF therapy is one of the most efficient and widely used therapies for RA, although its mechanism is not clarified yet. Earlier we demonstrated that RA patients have a reduced number of IL-10 producing regulatory B cells (B10 cells) as compared to healthy individuals and they are functionally impaired. Our aim was to study the influence of anti-TNF therapy on B10 cells in RA, to follow the alteration of B cell activation markers (CD25, CD69) and to monitor the level of citrullinated peptid-specific antibodies and the secreted IL-10 in patients' sera during the therapy. We have observed that at six month after starting the therapy the frequency of B10 cells remarkably increased, while the expression of the activation marker, CD69 decreased on B cells. In contrast, serum levels of IL-10 and anti-citrullinated peptide antibodies did not change post-treatment. CONCLUSION: The reduced activation state of B cells and the increasing number of regulatory B10. cells might contribute to the therapeutic efficacy of anti-TNF agents in RA.
29120746 Segmented Filamentous Bacteria Provoke Lung Autoimmunity by Inducing Gut-Lung Axis Th17 Ce 2017 Nov 8 Lung complications are a major cause of rheumatoid arthritis-related mortality. Involvement of gut microbiota in lung diseases by the gut-lung axis has been widely observed, but the underlying mechanism remains mostly unknown. Using an autoimmune arthritis model, we show that a constituent of the gut microbiota, segmented filamentous bacteria (SFB), distantly provoke lung pathology. SFB induce autoantibodies in lung during the pre-arthritic phase, and SFB-dependent lung pathology requires the T helper 17 (Th17) responses. SFB-induced gut Th17 cells are preferentially recruited to lung over spleen due to robust expression in the lung of the Th17 chemoattractant, CCL20. Additionally, we found that in peripheral tissues, SFB selectively expand dual T cell receptor (TCR)-expressing Th17 cells recognizing both an SFB epitope and self-antigen, thus augmenting autoimmunity. This study reveals mechanisms for commensal-mediated gut-lung crosstalk and dual TCR-based autoimmunity.
28914367 No association of single nucleotide polymorphisms within H19 and HOX transcript antisense 2017 Nov The H19 (rs2839698, rs3741219) and HOTAIR (rs920778) polymorphisms were related to many kinds of cancers. However, these polymorphisms have been scarcely explored in different autoimmune diseases. Here, we aimed to examine the association of the polymorphisms with susceptibility to or protection against systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjögren's syndrome (pSS) among Chinese Han patients. We conducted a case-control study including 800 patients (300 with SLE, 350 with RA, and 150 with pSS) and 350 healthy control individuals. The polymorphisms were specified from genomic DNA using TaqMan genotyping assay on a 7300 real-time reverse transcription polymerase chain reaction system. H19 rs2839698 was not associated with SLE susceptibility and was not associated with RA and pSS, respectively (P > 0.05). Similarly, we did not find significant differences of allele or genotype frequencies between SLE, RA, and pSS patients and healthy controls for H19 gene rs3741219 polymorphism (P > 0.05). In addition, no significant evidence was detected for the relationship of HOTAIR rs920778 polymorphism with risk of these diseases. Our results suggested that H19 rs2839698, rs3741219, and HOTAIR rs920778 polymorphisms may not be involved in the genetic background of SLE, RA, and pSS in Chinese.
28118534 Persistence of Disease-Associated Anti-Citrullinated Protein Antibody-Expressing Memory B 2017 Jun OBJECTIVE: In rheumatoid arthritis (RA), autoreactive B cells are pathogenic drivers and sources of anti-citrullinated protein antibodies (ACPAs) that are a diagnostic biomarker and predictor of worse long-term prognosis. Yet, the immunobiologic significance of persistent ACPA production at the cellular level is poorly understood. This study was undertaken to investigate the representation of ACPA-expressing switched-memory B cells in RA. METHODS: In a cross-sectional study of RA patients, we investigated the presence of continued defects in immune homeostasis as a function of disease activity. Using an enzyme-linked immunosorbent assay (ELISA) and a sensitive multiplex bead-based immunoassay, we characterized fine binding antibody specificities in sera, synovial fluid (SF), and B cell culture supernatants. In this manner, we determined the frequency and epitope reactivity patterns of ACPAs produced by SF B cells and switched-memory blood B cells and compared the latter to serum ACPA levels and disease activity scores. RESULTS: Cultured B cells from SF were shown to spontaneously secrete ACPAs, while constitutive IgG autoantibody production by peripheral blood mononuclear cells (PBMCs) was substantially less frequent. After in vitro stimulation, PBMCs secreted IgG ACPA that was overwhelmingly from switched-memory B cells, across all patient groups treated with methotrexate and/or a tumor necrosis factor inhibitor. Intriguingly, the frequencies of ACPA-expressing switched-memory B cells significantly correlated with serum IgG anti-cyclic citrullinated peptide 3 (r = 0.57, P = 0.003). Moreover, treatment-induced clinical remission had little or no effect on the circulating burden of switched-memory ACPA-expressing B cells, in part explaining the continued dysregulation of humoral immunity. CONCLUSION: Our findings rationalize why therapeutic cessation most often results in disease reactivation and clinical flare. Hence, a clinical disease activity score is not a reliable indicator of the resolution of pathologic recirculating B cell autoimmunity.
28289873 Patient-reported outcomes as predictors of remission in early rheumatoid arthritis patient 2017 May Identifying prognostic factors for remission in early rheumatoid arthritis (ERA) patients is of key clinical importance. We studied patient-reported outcomes (PROs) as predictors of remission in a clinical trial. We randomized 99 untreated ERA patients to receive remission-targeted treatment with three disease-modifying antirheumatic drugs and prednisolone for 24 months, and infliximab or placebo for the initial 6 months. At baseline, we measured following PROs: eight Short Form 36 questionnaire (SF-36) dimensions, patient's global assessment [PGA, visual analogue scale (VAS)], Health Assessment Questionnaire (HAQ), and pain VAS. We used multivariable-adjusted regression models to identify PROs that independently predicted modified American College of Rheumatology remission at 2 years. Follow-up data at 2 years were available for 93 patients (92%), and 58 patients (62%) were in remission. At baseline, patients who achieved remission had higher radiological score (p = 0.04), lower tender joint count (p = 0.001), lower PGA (p = 0.005) and physician's global assessment (p = 0.019), lower HAQ (p = 0.016), less morning stiffness (p = 0.009), and significantly higher scores in seven out of eight SF-36 dimensions compared with patients who did not. In multivariable models that included all PROs, remission was associated with SF-36 dimensions higher vitality (odds ratio 2.01; 95% confidence interval 1.19-3.39) and better emotional role functioning (odds ratio 1.64; 95% confidence interval 1.01-2.68). PGA, pain VAS, HAQ, and other SF-36 dimensions were not associated with remission. We conclude that self-reported vitality and better emotional role functioning are among the most important PROs for the prediction of remission in ERA.
29104376 Anti-TNF-Alpha-Adalimumab Therapy Had Time Lag of Improvement in Synovial Hypertrophy Comp 2017 OBJECTIVES: The quantification of synovitis is of great significance for follow-up in patients with rheumatoid arthritis (RA). This study aimed to validate the use of power Doppler ultrasonography (PDUS) for evaluating synovial vascularity and synovial hypertrophy for synovitis in patients with rheumatoid arthritis treated with adalimumab. MATERIALS AND METHODS: The synovial disease activity and vascularity of RA on both wrists (radio-carpal joint) were assessed using GS and PDUS to derive the composite US scores based on abnormal counts and severity. The relationship between each measure was determined. RESULTS: The 71 patients who received adalimumab therapy had significantly decreased DAS28, ESR, and CRP. After one month, PD score decreased and then remained low for 12 months. Synovial hypertrophy did not change until 3-6 months after, when it started to improve (p = 0.017). By multivariate analysis, sex, age, BMI, and DAS28 did not lead to any difference between synovial hypertrophy and PDUS changes (p = 0.498). DISCUSSION: Composite US markers of synovial hypertrophy correlate significantly to the DAS28 score and ESR/CRP in adult RA. The time needed for synovial hypertrophy to decrease may be up to 3-6 months after adalimumab therapy. Switching to biological therapy before 3-6 months is inappropriate and ineffective.
28751821 Immunomodulation of RA Patients' PBMC with a Multiepitope Peptide Derived from Citrullinat 2017 Citrullinated peptides are used for measuring anticitrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA). Accumulation of citrullinated proteins in the inflamed synovium suggests that they may be good targets for inducing peripheral tolerance. In view of the multiplicity of citrullinated autoantigens described as ACPA targets, we generated a multiepitope citrullinated peptide (Cit-ME) from the sequences of major citrullinated autoantigens: filaggrin, β-fibrinogen, vimentin, and collagen type II. We assessed the ability of Cit-ME or the citrullinated β60-74 fibrinogen peptide (β60-74-Fib-Cit) which bears immunodominant citrullinated epitopes (i) to modify cytokine gene expression and (ii) to modulate Treg and Th17 subsets in PBMC derived from newly diagnosed untreated RA patients. RA patient's PBMC incubated with Cit-ME or β60-74-Fib-Cit, showed upregulation of TGF-β expression (16% and 8%, resp.), and increased CD4(+)Foxp3(+) Treg (22% and 19%, resp.). Both peptides were shown to downregulate the TNF-α and IL-1β expression; in addition, Cit-ME reduced CD3(+)IL17(+) T cells. We showed that citrullinated peptides can modulate the expression of anti- and proinflammatory cytokines in PBMC from RA patients as well as the proportions of Treg and Th17 cells. These results indicate that citrullinated peptides could be active in vivo and therefore might be used as immunoregulatory agents in RA patients.