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1.
MAbs ; 13(1): 1868078, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33557682

RESUMO

The biosimilar concept is now well established. Clinical data accumulated pre- and post-approval have supported biosimilar uptake, in turn stimulating competition in the biologics market and increasing patient access to biologics. Following technological advances, other innovative biologics, such as "biobetters" or "value-added medicines," are now reaching the market. These innovative biologics differ from the reference product by offering additional clinical or non-clinical benefits. We discuss these innovative biologics with reference to CT-P13, initially available as an intravenous (IV) biosimilar of reference infliximab. A subcutaneous (SC) formulation, CT-P13 SC, has now been developed. Relative to CT-P13 IV, CT-P13 SC offers clinical benefits in terms of pharmacokinetics, with comparable efficacy, safety, and immunogenicity, as well as increased convenience for patients and reduced demands on healthcare system resources. As was once the case for biosimilars, nomenclature and regulatory pathways for innovative biologics require clarification to support their uptake and ultimately benefit patients.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33432358

RESUMO

OBJECTIVE: To evaluate the impact of non-medical switch from rituximab originator (RTX-O) to biosimilar (RTX-B) in patients with RA. METHODS: Between October 2017 and October 2019, all patients on RTX-O in our centre requiring re-treatment were switched to RTX-B unless declined by the patient or specified by the treating clinician. Switch strategy effectiveness was assessed retrospectively using DAS28-CRP(3) and RTX retention, with patients remaining on RTX-O as a comparator group. RESULTS: The number of patients switching to RTX-B was 255/337 (75.7%) while 82 (24.3%) remained on RTX-O. There was no difference in DAS28-CRP(3) 4 months post-RTX-B switch vs the same time point post-RTX-O previous cycle (paired data available in 60%). Eighteen-month retention estimates were 75.6% (95% CI: 69.4, 80.7%) for RTX-B group and 82.3% (95% CI: 70.4, 89.8%) for RTX-O [adjusted hazard ratio 1.52 (95% CI: 0.85, 2.73)]. The number of patients who discontinued RTX-B for loss of effectiveness (LOE) was 42/255 (16.5%), five (2.0%) for adverse effects (AEs). Risk of RTX-B discontinuation was associated with comorbidities and ≥2 previous biologic DMARDs. Risk of adverse outcome RTX cessation was associated with comorbidities, and reduced risk with number of previous RTX-O cycles and pre-switch cycle B cell depletion. The number of patients who switched back to RTX-O was 34/255 (13.3%) (LOE: 30, AEs: 4), while 13/255 (5.1%) started other biologic/targeted synthetic DMARDs. Of patients who switched back for LOE, 28/30 remained on RTX-O at a mean 7.7 months follow-up. CONCLUSION: Non-medical switch to RTX-B was largely effective. Factors associated with RTX-B discontinuation, including comorbidities, previous biologic DMARDs, and RTX-O treatment history, may inform switch decisions. Most patients who switched back to RTX-O for LOE remained on treatment at short-term follow-up.

3.
Arthritis Res Ther ; 23(1): 3, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397481

RESUMO

Baricitinib is an oral selective inhibitor of Janus kinase (JAK)1 and JAK2 that has proved effective and well tolerated in the treatment of rheumatoid arthritis (RA) in an extensive programme of clinical studies of patients with moderate-to-severe disease. In a phase 2b dose-ranging study of baricitinib in combination with traditional disease-modifying antirheumatic drugs (DMARDs) in RA patients, magnetic resonance imaging showed that baricitinib 2 mg or 4 mg once daily provided dose-dependent suppression of synovitis, osteitis, erosion and cartilage loss at weeks 12 and 24 versus placebo. These findings correlated with clinical outcomes and were confirmed in three phase 3 studies (RA-BEGIN, RA-BEAM and RA-BUILD) using X-rays to assess structural joint damage. In patients naïve to DMARDs (RA-BEGIN study), baricitinib 4 mg once daily as monotherapy or combined with methotrexate produced smaller mean changes in structural joint damage than methotrexate monotherapy at week 24. Differences versus methotrexate were statistically significant for combined therapy. In patients responding inadequately to methotrexate (RA-BEAM study), baricitinib 4 mg plus background methotrexate significantly inhibited structural joint damage at week 24 versus placebo, and the results were comparable to those observed with adalimumab plus background methotrexate. In patients responding inadequately to conventional synthetic DMARDs (csDMARDs; RA-BUILD study), baricitinib 4 mg again significantly inhibited radiographic progression compared with placebo at week 24. Benefits were also observed with baricitinib 2 mg once daily, but the effects of baricitinib 4 mg were more robust. The positive effects of baricitinib 4 mg on radiographic progression continued over 1 and 2 years in the long-term extension study RA-BEYOND, with similar effects to adalimumab and significantly greater effects than placebo. Findings from the phase 3 studies of patients with RA were supported by preclinical studies, which showed that baricitinib has an osteoprotective effect, increasing mineralisation in bone-forming cells. In conclusion, baricitinib 4 mg once daily inhibits radiographic joint damage progression in patients with moderate-to-severe RA who are naïve to DMARDs or respond inadequately to csDMARDs, including methotrexate, and the beneficial effects are similar to those observed with adalimumab.

4.
Semin Arthritis Rheum ; 51(1): 266-277, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33401055

RESUMO

OBJECTIVES: To perform a systematic literature review (SLR) analysing all studies that reported on the efficacy and safety of pharmacological treatments for palindromic rheumatism (PR). METHODS: We performed a SLR using PubMed, Embase and Cochrane databases. Three main aspects of PR were considered: treating flares, preventing recurrence of flares (i.e. achieving remission), and preventing progression to RA or to other persistent arthritis. Quality assessment of the studies was performed using the Newcastle-Ottawa Scale (NOS). RESULTS: Twenty-seven articles met the inclusion criteria: 6 (22.2%) retrospective studies, 8 (29.6%) longitudinal studies, and 13 (48.1%) case series/case reports. No randomized controlled trials (RCTs) were found. Most of the studies (21/27, 77.7%) had a high risk of bias according to NOS. Non-steroidal anti-inflammatory drugs were the most commonly reported treatments for flares of PR, with variable results. Anti-malarials, such as hydroxychloroquine and chloroquine phosphate, showed efficacy in reducing the frequency of the flares and, to a lesser extent, in preventing progression to RA. There was minimal evidence in support of other conventional/biological disease modifying anti-rheumatic treatments, or corticosteroids. CONCLUSION: Although a frequent clinical dilemma for rheumatologists, the pharmacological management of PR has not been thoroughly evaluated, with no RCTs reported. Of all therapies, antimalarials have been the best studied and may be capable of reducing the recurrence of flares. The optimum treatment strategy for PR remains largely undefined and should be evaluated by robust RCTs in well-defined PR cohorts.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33393636

RESUMO

OBJECTIVE: Ankylosing spondylitis (AS) is a chronic inflammatory arthritis primarily affecting the spine and sacroiliac joints. TNF inhibitor (TNFi) drugs are recommended for patients not responding to NSAIDs; however, there is a significant need for biomarkers of response. IFN-regulated genes (IRGs) and other cytokines/chemokines are linked to autoimmune diseases and have been associated with treatment response. Our objective was to explore whether IRGs and cytokines/chemokines can be associated with response to TNFiagents in AS. METHODS: Peripheral blood mononuclear cells were obtained from 26 AS patients who were to receive a TNFi (I, n = 15) or placebo (P, n = 11) at week 0 and week 22. Response (R)/non-response (NR) was defined as reduction in ASDAS ≥ 1.2 points or reduction in sacroiliac/vertebral MRI lesions. The expression of 96 genes was quantified using TaqMan assays. Finally, ELISA was used to measure IL-6 in serum samples from another 38 AS patients. RESULTS: Analysis of gene expression in 26 baseline samples segregated patients into four groups defined by a signature of 15 genes (mainly IRGs). ASDAS response was associated with one group independently of treatment received. We then analysed response to the TNFi (n = 15) and identified a 12-gene signature associated with MRI response. A third IRG signature was also associated with a reduction in IRGs expression post-TNFi samples (n = 10 pairs). Finally, decreased circulating IL-6 was associated with BASDAI-R. CONCLUSION: This pilot study suggests an association between IRG expression and response to TNFi in AS. These findings require validation in a larger cohort in order to construct predictive algorithms for patient stratification.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33416954

RESUMO

PURPOSE: Synaptic abnormalities are associated with many brain disorders. Recently, we developed a novel synaptic vesicle glycoprotein 2A (SV2A) radiotracer [18F]SynVesT-1 and demonstrated its excellent imaging and binding properties in nonhuman primates. The aim of this study was to perform dosimetry calculations in nonhuman primates and to evaluate this tracer in humans and assess its test-retest reliability in comparison with [11C]UCB-J. METHODS: Three rhesus monkeys underwent whole body dynamic PET scanning to estimate the absorbed dose. PET scans in six healthy human subjects were acquired. Time-activity curves (TACs) were generated with defined regions of interest (ROI). Reproducibility of distribution volume (VT) values and its sensitivity to scan duration were assessed with the one-tissue compartment (1TC) model. Non-displaceable binding potential (BPND) was calculated using centrum semiovale as the reference region. RESULTS: The dosimetry study showed high uptake in the urinary bladder and brain. In humans, [18F]SynVesT-1 displayed high uptake with maximum SUV of ~10 and appropriate kinetics with a quick rise in tracer uptake followed by a gradual clearance. Mean 1TC VT values (mL/cm3) ranged from 3.4 (centrum semiovale) to 19.6 (putamen) and were similar to those of [11C]UCB-J. Regional BPND values were 2.7-4.7 in gray matter areas, and mean BPND values across all ROIs were ~ 21% higher than those of [11C]UCB-J. The absolute test-retest variability of VT and BPND was excellent (< 9%) across all brain regions. CONCLUSIONS: [18F]SynVesT-1 demonstrates outstanding characteristics in humans: fast and high brain uptake, appropriate tissue kinetics, high levels of specific binding, and excellent test-retest reproducibility of binding parameters. As such, [18F]SynVesT-1 is proved to be a favorable radiotracer for SV2A imaging and quantification in humans.

7.
J Immunol ; 206(4): 785-796, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33441439

RESUMO

Human plasmacytoid dendritic cells (pDCs) play a vital role in modulating immune responses. They can produce massive amounts of type I IFNs in response to nucleic acids via TLRs, but they are also known to possess weak Ag-presenting properties inducing CD4+ T cell activation. Previous studies showed a cross-regulation between TNF-α and IFN-α, but many questions remain about the effect of TNF-α in regulating human pDCs. In this study, we showed that TNF-α significantly inhibited the secretion of IFN-α and TNF-α of TLR-stimulated pDCs. Instead, exogenous TNF-α promoted pDC maturation by upregulating costimulatory molecules and chemokine receptors such as CD80, CD86, HLA-DR, and CCR7. Additionally, RNA sequencing analysis showed that TNF-α inhibited IFN-α and TNF-α production by downregulating IRF7 and NF-κB pathways, while it promoted Ag processing and presentation pathways as well as T cell activation and differentiation. Indeed, TNF-α-treated pDCs induced in vitro higher CD4+ T cell proliferation and activation, enhancing the production of Th1 and Th17 cytokines. In conclusion, TNF-α favors pDC maturation by switching their main role as IFN-α-producing cells to a more conventional dendritic cell phenotype. The functional status of pDCs might therefore be strongly influenced by their overall inflammatory environment, and TNF-α might regulate IFN-α-mediated aspects of a range of autoimmune and inflammatory diseases.

8.
Nat Commun ; 11(1): 6149, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33262343

RESUMO

Autoimmune connective tissue diseases arise in a stepwise fashion from asymptomatic preclinical autoimmunity. Type I interferons have a crucial role in the progression to established autoimmune diseases. The cellular source and regulation in disease initiation of these cytokines is not clear, but plasmacytoid dendritic cells have been thought to contribute to excessive type I interferon production. Here, we show that in preclinical autoimmunity and established systemic lupus erythematosus, plasmacytoid dendritic cells are not effector cells, have lost capacity for Toll-like-receptor-mediated cytokine production and do not induce T cell activation, independent of disease activity and the blood interferon signature. In addition, plasmacytoid dendritic cells have a transcriptional signature indicative of cellular stress and senescence accompanied by increased telomere erosion. In preclinical autoimmunity, we show a marked enrichment of an interferon signature in the skin without infiltrating immune cells, but with interferon-κ production by keratinocytes. In conclusion, non-hematopoietic cellular sources, rather than plasmacytoid dendritic cells, are responsible for interferon production prior to clinical autoimmunity.

9.
J Clin Pharmacol ; 2020 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-33314148

RESUMO

We evaluated interleukin-6 (IL-6) receptor-α subunit (IL-6Rα) signaling inhibition with sarilumab and tocilizumab, the association between IL-6Rα receptor occupancy (RO) and C-reactive protein (CRP), and the potential clinical relevance of any differences. For this, we measured IL-6Rα binding and signaling inhibition with sarilumab and tocilizumab in vitro, simulated soluble IL-6Rα RO over time for approved sarilumab subcutaneous (SC) and tocilizumab intravenous (IV) and SC doses, and assessed associations between calculated RO and CRP reduction, 28-joint Disease Activity Score based on CRP, and 20%/50%/70% improvement in American College of Rheumatology responses from clinical data. Sarilumab binds IL-6Rα in vitro with 15- to 22-fold higher affinity than tocilizumab, and inhibits IL-6-mediated classical and trans signaling via membrane-bound and soluble IL-6Rα. Sarilumab 200 and 150 mg SC every 2 weeks achieved >90% RO after first and second doses, respectively, maintained throughout the treatment period. At steady-state trough, RO was greater with sarilumab 200 mg (98%) and 150 mg SC every 2 weeks (94%), and tocilizumab 162 mg SC weekly (>99%) and 8 mg/kg IV every 4 weeks (99%), vs tocilizumab 162 mg SC every 2 weeks (84%) and 4 mg/kg IV every 4 weeks (60%). Higher RO was associated with greater CRP reduction and 28-joint Disease Activity Score based on CRP reduction, and more sarilumab patients achieving 20%/50%/70% improvement in American College of Rheumatology responses. The greatest reduction in CRP levels was observed with sarilumab (both doses) and tocilizumab 8 mg/kg IV every 4 weeks (reductions proportionally smaller with 4 mg/kg IV every 4 weeks). Higher IL-6Rα binding affinity translated into higher RO with sarilumab vs tocilizumab 4 mg/kg every 4 weeks or 162 mg every 2 weeks; tocilizumab required the higher dose or increased frequency to maintain the same degree of RO and CRP reduction. Higher RO was associated with clinical parameter improvements.

10.
Artigo em Inglês | MEDLINE | ID: mdl-33331938

RESUMO

OBJECTIVES: To evaluate real world efficacy of approved JAK inhibitors (JAKi) tofacitinib and baricitinib in a large, single-centre cohort of RA patients across the treatment pathway, including those refractory to multiple biologic drugs. METHODS: All RA patients, treated with tofacitinib (from time of compassionate access scheme) or baricitinib since approval in 2017 had DAS28-CRP scores and components recorded at baseline, 3 and 6 months (with retrospective data for compassionate access scheme). Efficacy was evaluated in the total cohort, each treatment group, and subgroups of number of prior biologic classes failed. RESULTS: One hundred and fifteen patients were treated with a JAKi (tofacitinib 54, baricitinib 69, 8 both); 76.4% female; mean (SD) age 57.3 (14.3) years. On average patients had received 3 previous bDMARDs; 11 (9.6%) were bDMARD naïve. Combined group baseline DAS28-CRP (SD) 5.62(1.14) improved by 1.49(1.44) and 1.67(1.61) at 3 and 6 months respectively, comparable in individual JAKi groups; with 24% in at least low disease activity at 3 months. The biggest improvement was observed in the biologic-naïve group (mean DAS28-CRP improved from 5.16-2.14 after 6 months); whilst those with prior exposure to minimum 3 bDMARD classes had DAS28-CRP improvement of > 1.2. 5/8 patients treated with both JAKi sequentially responded. Twelve patients previously unresponsive to IL-6 blockade responded to JAKi. No unexpected safety events were recorded. Two cases of venous thrombo-embolism were observed. CONCLUSION: JAK inhibition is effective in a real world population of RA patients, including in a subset of patients refractory to multiple previous bDMARDs.

11.
Artigo em Inglês | MEDLINE | ID: mdl-33313854

RESUMO

OBJECTIVE: Individuals with newly diagnosed RA have a distinct microbiome when compared with healthy controls. However, little is known as to when these microbiome perturbations begin. Using a prospective at-risk cohort of individuals positive for anti-citrullinated protein (anti-CCP) antibody with new onset musculoskeletal symptoms, but without clinical arthritis, we investigated for the presence of a gut dysbiosis before the onset of RA. METHODS: The gut microbiota of 25 anti-CCP positive individuals without clinical synovitis were sequenced targeting the V4 region of the 16S rRNA gene. Using a publicly available database, a control population of 44 individuals, approximately matched in age, gender, diet and ethnicity was selected for comparison, using the same sequencing methodology. Median interval between sample collection and progression to RA was 188 days. Taxonomic analysis was performed using QIIME and MEGAN, and statistical analysis using R software. RESULTS: There were significant differences (P =0.01) at family level in gut microbiomes of anti-CCP positive individuals vs controls. The anti-CCP positive population had an overabundance of Lachnospiraceae, Helicobacteraceae, Ruminococcaceae, Erysipelotrichaceae and Bifidobacteriaceae, among others. Five individuals progressed to RA between sample collection and analysis. Clustering of the progressor population was observed on a phylogenetic network created using a probabilistic similarity index (Goodall's index). CONCLUSIONS: Anti-CCP positive at-risk individuals without clinical synovitis appear to have a distinct gut microbiome compared with healthy controls. Phylogenetic clustering was observed in individuals who progressed to RA, suggesting that distinct taxa are associated with the development of RA many months before its onset.

12.
Ann Rheum Dis ; 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33158881

RESUMO

OBJECTIVES: Janus kinase inhibitors (JAKi) have been approved for use in various immune-mediated inflammatory diseases. With five agents licensed, it was timely to summarise the current understanding of JAKi use based on a systematic literature review (SLR) on efficacy and safety. METHODS: Existing data were evaluated by a steering committee and subsequently reviewed by a 29 person expert committee leading to the formulation of a consensus statement that may assist the clinicians, patients and other stakeholders once the decision is made to commence a JAKi. The committee included patients, rheumatologists, a gastroenterologist, a haematologist, a dermatologist, an infectious disease specialist and a health professional. The SLR informed the Task Force on controlled and open clinical trials, registry data, phase 4 trials and meta-analyses. In addition, approval of new compounds by, and warnings from regulators that were issued after the end of the SLR search date were taken into consideration. RESULTS: The Task Force agreed on and developed four general principles and a total of 26 points for consideration which were grouped into six areas addressing indications, treatment dose and comedication, contraindications, pretreatment screening and risks, laboratory and clinical follow-up examinations, and adverse events. Levels of evidence and strengths of recommendations were determined based on the SLR and levels of agreement were voted on for every point, reaching a range between 8.8 and 9.9 on a 10-point scale. CONCLUSION: The consensus provides an assessment of evidence for efficacy and safety of an important therapeutic class with guidance on issues of practical management.

13.
ACR Open Rheumatol ; 2(11): 672-680, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33164349

RESUMO

OBJECTIVE: This post hoc analysis evaluated the safety and efficacy of open-label sarilumab in patients with rheumatoid arthritis (RA) who completed the phase III double-blind ASCERTAIN study (NCT01768572) and switched from intravenous (IV) tocilizumab to subcutaneous (SC) sarilumab, or who continued SC sarilumab in the open-label extension (OLE) study EXTEND (NCT01146652). METHODS: Patients who completed ASCERTAIN were eligible to enroll in EXTEND to receive sarilumab 200 mg SC every 2 weeks (Q2W). Safety and efficacy were reported through 96 weeks in the OLE in patients who switched from tocilizumab IV to sarilumab 200 mg SC Q2W, who switched from sarilumab 150 mg SC Q2W to sarilumab 200 mg SC Q2W, or who continued sarilumab 200 mg SC Q2W. RESULTS: Of 175 patients who completed ASCERTAIN, 168 (96%) enrolled in EXTEND, and 38 of these patients (23%) discontinued the OLE. Cumulative sarilumab exposure during follow-up was 273.7 patient-years. No new safety signals were identified, infections occurred at a rate of 59.9/100 patient-years, and there were no cases of grade 4 neutropenia. Efficacy-as assessed by Disease Activity Score (28 joints) based on C-reactive protein, Clinical Disease Activity Index, and Health Assessment Questionnaire-Disability Index scores-was sustained over 96 weeks of follow-up when switching to, or continuing, sarilumab 200 mg SC Q2W. CONCLUSION: Switching from IV to SC interleukin-6 receptor inhibitor therapy produced no new safety concerns, and clinical efficacy was sustained over 96 weeks of follow-up. These findings alleviate potential concerns over switching route of administration with interleukin-6 receptor inhibitor therapy for RA.

14.
Front Med (Lausanne) ; 7: 587827, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33195348

RESUMO

In individuals at-risk of developing inflammatory arthritis, the value of an ultrasound (US) scan assessment to predict progression has been demonstrated repeatedly. However, depending on recruitment criteria, these individuals may be at different stages in the arthritis development continuum, therefore representing a heterogeneous population. As a consequence, the predictive value of ultrasound results may differ between cohorts. As other reviews have focused on the challenges in population recruitment or have combined biomarkers predicting value according to one recruitment pathway, we wanted to focus on the sole use of ultrasound assessment and its variation according to population recruitment criteria. In this review, we discuss the use of ultrasound in the different at-risk populations across the inflammatory arthritis disease continuum. This review demonstrates that although some sub-population data is scarce, ultrasound is best predictive in three at-risk populations: those with a positive ACPA test in the context of non-specific MSK symptoms, those with clinically suspect arthralgia and those with palindromic rheumatism. We consider that ultrasound assessment will be a cornerstone in prediction risk modeling and prevention studies of the preclinical phases of IA in the future.

16.
Arthritis Rheumatol ; 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33205906

RESUMO

OBJECTIVE: Patients with rheumatoid arthritis (RA) achieving remission on methotrexate plus etanercept therapy (Combo) face ongoing medication burden. Whether those in sustained remission on Combo can maintain remission with monotherapy (mono) after discontinuing either methotrexate or etanercept has not been adequately tested. METHODS: Adult RA patients on Combo (N=371) maintaining Simplified Disease Activity Index (SDAI) remission through a 24-week open-label period (N=253) entered a 48-week, double-blind period and were randomized to: (1) methotrexate-mono (N=101); (2) etanercept-mono (N=101); or (3) Combo (N=51). Patients with disease-worsening received Combo rescue therapy at prior dosages. The primary endpoint was the proportion of patients in SDAI remission without disease-worsening at week 48 in the etanercept-mono vs methotrexate-mono arms. Secondary endpoints included time to disease-worsening and proportion of patients recapturing SDAI remission after rescue therapy. RESULTS: Baseline characteristics were similar across treatment arms. At week 48, SDAI remission was maintained by significantly more patients on etanercept-mono vs methotrexate-mono (49.5% vs 28.7%; P=0.004) and by more patients on Combo vs methotrexate-mono (52.9% vs 28.7%; P=0.006; secondary endpoint). Time to disease-worsening was shorter with methotrexate-mono compared with etanercept-mono and Combo (P<0.001 for both comparisons). Among patients receiving rescue therapy, 70-80% in each arm recaptured SDAI remission. No new safety signals were reported. CONCLUSIONS: Etanercept-mono was superior to methotrexate-mono and similar to Combo in maintaining remission during the double-blind phase. Most patients on rescue therapy recaptured remission. These data inform decision-making around withdrawing therapy to reduce treatment burden in well-controlled RA.

17.
Front Cell Dev Biol ; 8: 538130, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33134291

RESUMO

Once referred to as "normal commensal flora" the human microbiome plays an integral role between health and disease. The host mucosal surface replete with a multitude of immune cells is a vast arena constantly sensing and responding to antigen presentation and microbial by-products. It is this key role that may allow the microbiome to prime or protect the host from autoimmune disease. Rheumatoid arthritis (RA) is a chronic, disabling inflammatory condition characterized by a complex multifactorial etiology. The presence of certain genetic markers has been proven to increase susceptibility to RA however it does not guarantee disease development. Given low concordance rates demonstrated in monozygotic twin studies there is a clear implication for the involvement of external players in RA pathogenesis. Since the historical description of rheumatoid factor, numerous additional autoantibodies have been described in the sera of RA patients. The presence of anti-cyclic citrullinated protein antibody is now a standard test, and is associated with a more severe disease course. Interestingly these antibodies are detectable in patient's sera long before the clinical signs of RA occur. The production of autoantibodies is driven by the lack of tolerance of the immune system, and how tolerance is broken is a crucial question for understanding RA development. Here we review current literature on the role of the microbiome in RA development including periodontal, gut and lung mucosa, with particular focus on proposed mechanisms of host microbiome interactions. We discuss the use of Mendelian randomization to assign causality to the microbiome and present considerations for future studies.

18.
Ann Rheum Dis ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004333

RESUMO

OBJECTIVES: An increased prevalence of periodontitis and perturbation of the oral microbiome has been identified in patients with rheumatoid arthritis (RA). The periodontal pathogen Porphyromonas gingivalis may cause local citrullination of proteins, potentially triggering anti-citrullinated protein antibody production. However, it is not known if oral dysbiosis precedes the onset of clinical arthritis. This study comprehensively characterised the oral microbiome in anti-cyclic citrullinated peptide (anti-CCP) positive at-risk individuals without clinical synovitis (CCP+at risk). METHODS: Subgingival plaque was collected from periodontally healthy and diseased sites in 48 CCP+at risk, 26 early RA and 32 asymptomatic healthy control (HC) individuals. DNA libraries were sequenced on the Illumina HiSeq 3000 platform. Taxonomic profile and functional capability of the subgingival microbiome were compared between groups. RESULTS: At periodontally healthy sites, CCP+at risk individuals had significantly lower microbial richness compared with HC and early RA groups (p=0.004 and 0.021). Microbial community alterations were found at phylum, genus and species levels. A large proportion of the community differed significantly in membership (523 species; 35.6%) and structure (575 species; 39.1%) comparing CCP+at risk and HC groups. Certain core species, including P. gingivalis, had higher relative abundance in the CCP+at risk group. Seventeen clusters of orthologous gene functional units were significantly over-represented in the CCP+at risk group compared with HC (adjusted p value <0.05). CONCLUSION: Anti-CCP positive at-risk individuals have dysbiotic subgingival microbiomes and increased abundance of P. gingivalis compared with controls. This supports the hypothesis that the oral microbiome and specifically P. gingivalis are important in RA initiation.

19.
Front Med (Lausanne) ; 7: 498, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32984378

RESUMO

Background: Rituximab is commonly used for systemic lupus erythematosus (SLE) but secondary non-depletion and non-response (2NDNR) associated with anti-drug antibodies is a notable problem with repeat rituximab cycles. Other B cell-targeted therapies include other anti-CD20 monoclonal antibodies or belimumab. Objective: To compare efficacy of switching to alternative anti-CD20 agents vs. belimumab in SLE patients with 2NDNR to rituximab. Methods: One hundred and twenty five patients received rituximab and had evaluable data. 77/125 received repeat rituximab cycles. Of these, 14/77 (18%) had 2NDNR. 8/14 patients were switched to belimumab (CD20-to-belimumab group) and 6/14 patients were switched to an alternative humanised anti-CD20 agent (CD20-to-CD20 group, ocrelizumab n = 3, ofatumumab n = 2, obinutuzumab n = 1). Efficacy was assessed using the BILAG-2004, SLEDAI-2K, SRI-4, and daily prednisolone requirement at baseline and 6 months. Results: In the CD20-to-belimumab group, only one patient achieved an SRI-4 and 2/8 patients had new/worsening BILAG-2004 grade A for lupus nephritis. There was no improvement in SLEDAI-2K; median (IQR) was 11.0 (9.5-14.8) at baseline and 10 (9.5-15.5) at 6 months. Median (IQR) prednisolone dose increased from 7.5 mg (4.4-12.5) to 10 mg (6.3-10). In the CD20-to-CD20 group, all 6 patients achieved an SRI-4. Median (IQR) SLEDAI-2K improved from 16.0 (10.3-24.0) at baseline to 5.0 (2.5-6.0) at 6 months. Median (IQR) prednisolone dose decreased from 15 mg (15-15) to 10.5 mg (5.3-15.0). Conclusion: This is the first assessment of belimumab's efficacy in a post-rituximab population. Our data suggests that patients with 2NDNR to rituximab, which constituted 11% of all patients initiated on this drug, should be switched within the same biologic class to another anti-CD20 agent.

20.
Artigo em Inglês | MEDLINE | ID: mdl-32910153

RESUMO

OBJECTIVES: RA patients often present with low muscle mass and decreased strength. Quantitative MRI offers a non-invasive measurement of muscle status. This study assessed whether MRI-based measurements of T2, fat fraction, diffusion tensor imaging and muscle volume can detect differences between the thigh muscles of RA patients and healthy controls, and assessed the muscle phenotype of different disease stages. METHODS: Thirty-nine RA patients (13 'new RA'-newly diagnosed, treatment naïve, 13 'active RA'-persistent DAS28 >3.2 for >1 year, 13 'remission RA'-persistent DAS28 <2.6 for >1 year) and 13 age and gender directly matched healthy controls had an MRI scan of their dominant thigh. All participants had knee extension and flexion torque and grip strength measured. RESULTS: MRI T2 and fat fraction were higher in the three groups of RA patients compared with healthy controls in the thigh muscles. There were no clinically meaningful differences in the mean diffusivity. The muscle volume, handgrip strength, knee extension and flexion were lower in all three groups of RA patients compared with healthy controls. CONCLUSION: Quantitative MRI and muscle strength measurements can potentially detect differences within the muscles between RA patients and healthy controls. These differences may be seen in RA patients who are yet to start treatment, those with persistent active disease, and those who were in clinical remission. This suggests that the muscles in RA patients are affected in the early stages of the disease and that signs of muscle pathology and muscle weakness are still observed in clinical remission.

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