Journal of Clinical Medicine

Editorial

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Open AccessEditorial

Rheumatoid Arthritis from Pathogenesis to Therapeutic Strategies

by Ruediger B. Mueller and Paul Hasler

J. Clin. Med. 2020, 9(8), 2562; https://doi.org/10.3390/jcm9082562 - 7 Aug 2020

Viewed by 2010

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joint destruction [...] Full article

(This article belongs to the Special Issue Rheumatoid Arthritis Therapy Reappraisal: Strategies, Opportunities and Challenges)

Research

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17 pages, 2499 KiB

Open AccessArticle

Pseudoerosions of Hands and Feet in Rheumatoid Arthritis: Anatomic Concepts and Redefinition

by Lena Hirtler, Claus Rath, Hannes Platzgummer, Daniel Aletaha and Franz Kainberger

J. Clin. Med. 2019, 8(12), 2174; https://doi.org/10.3390/jcm8122174 - 9 Dec 2019

Cited by 3 | Viewed by 12046

Abstract

Rheumatoid arthritis is a chronic inflammatory disease characterized by the development of osseous and cartilaginous damage. The correct differentiation between a true erosion and other entities—then often called “pseudoerosions”—is essential to avoid misdiagnosing rheumatoid arthritis and to correctly interpret the progress of the [...] Read more.

Rheumatoid arthritis is a chronic inflammatory disease characterized by the development of osseous and cartilaginous damage. The correct differentiation between a true erosion and other entities—then often called “pseudoerosions”—is essential to avoid misdiagnosing rheumatoid arthritis and to correctly interpret the progress of the disease. The aims of this systematic review were as follows: to create a definition and delineation of the term “pseudoerosion”, to point out morphological pitfalls in the interpretation of images, and to report on difficulties arising from choosing different imaging modalities. A systematic review on bone erosions in rheumatoid arthritis was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The following search terms were applied in PubMed and Scopus: “rheumatoid arthritis”, “bone erosion”, “ultrasonography”, “radiography”, “computed tomography” and “magnetic resonance imaging”. Appropriate exclusion criteria were defined. The systematic review registration number is 138826. The search resulted ultimately in a final number of 25 papers. All indications for morphological pitfalls and difficulties utilizing imaging modalities were recorded and summarized. A pseudoerosion is more than just a negative definition of an erosion; it can be anatomic (e.g., a normal osseous concavity) or artefact-related (i.e., an artificial interruption of the calcified zones). It can be classified according to their configuration, shape, content, and can be described specifically with an anatomical term. “Calcified zone” is a term to describe the deep components of the subchondral, subligamentous and subtendinous bone, and may be applied for all non-cancellous borders of a bone, thus representing a third type of the bone matrix beside the cortical and the trabecular bone. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis Therapy Reappraisal: Strategies, Opportunities and Challenges)

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16 pages, 2487 KiB

Open AccessArticle

Methotrexate Restores CD73 Expression on Th1.17 in Rheumatoid Arthritis and Psoriatic Arthritis Patients and May Contribute to Its Anti-Inflammatory Effect through Ado Production

by Marion Bossennec, Céline Rodriguez, Margaux Hubert, Anthony Di-Roio, Christelle Machon, Jérôme Guitton, Priscilla Battiston-Montagne, Mathilde Couturier, Hubert Marotte, Christophe Caux, Fabienne Coury and Christine Ménétrier-Caux

J. Clin. Med. 2019, 8(11), 1859; https://doi.org/10.3390/jcm8111859 - 3 Nov 2019

Cited by 5 | Viewed by 3184

Abstract

Objectives: Th1.17 are highly polyfunctional, potentially harmful CD4⁺ effector T cells (Teff) through IFN-γ and IL-17A coproduction. Th1.17 take part in the pathophysiology of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), in which their hyper activation results in part from defects in [...] Read more.

Objectives: Th1.17 are highly polyfunctional, potentially harmful CD4⁺ effector T cells (Teff) through IFN-γ and IL-17A coproduction. Th1.17 take part in the pathophysiology of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), in which their hyper activation results in part from defects in negative regulation mechanisms. We recently demonstrated that the ecto-nucleotidase CD73 delineates a Th1.17-enriched Teff population and acts as an endogenous regulatory mechanism. Because Methotrexate (MTX), used as first line treatment of RA and PsA, increases extracellular concentrations of AMP and immunosuppressive adenosine, we investigated the modulation of CD73 by MTX treatment on Teff in RA/PsA patients. Methods: In a prospective cohort of 26 RA and 15 PsA patients before or under MTX treatment, we evaluated CD73 expression on blood Teff subsets, their cytokine production and AMPase functions. Results: We showed a decreased CD73 expression on Th1.17 and Th1 in untreated patients compared to healthy donors that was partly restored under MTX. This decrease in untreated patients leads to a halved Ado production by Th1.17 cells. CD73⁺ Teff remained functional under MTX treatment, but their CD73 re-expression may contribute to control their activation. Conclusion: Our study unveils uncovered mode of action of MTX on Teff subsets modulation and in the adenosine-dependent termination of inflammation in RA and PsA. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis Therapy Reappraisal: Strategies, Opportunities and Challenges)

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14 pages, 1198 KiB

Open AccessArticle

Effectiveness, Tolerability, and Safety of Tofacitinib in Rheumatoid Arthritis: A Retrospective Analysis of Real-World Data from the St. Gallen and Aarau Cohorts

by Ruediger B. Mueller, Caroline Hasler, Florian Popp, Frederik Mattow, Mirsada Durmisi, Alexander Souza, Paul Hasler, Andrea Rubbert-Roth, Hendrik Schulze-Koops and Johannes von Kempis

J. Clin. Med. 2019, 8(10), 1548; https://doi.org/10.3390/jcm8101548 - 26 Sep 2019

Cited by 33 | Viewed by 6001

Abstract

Introduction: Tofacitinib is an oral JAK inhibitor indicated for the treatment of rheumatoid arthritis (RA). The efficacy and safety of tofacitinib have been shown in several randomized clinical trials. The study presented here aimed to assess the clinical tolerability and effectiveness of tofacitinib [...] Read more.

Introduction: Tofacitinib is an oral JAK inhibitor indicated for the treatment of rheumatoid arthritis (RA). The efficacy and safety of tofacitinib have been shown in several randomized clinical trials. The study presented here aimed to assess the clinical tolerability and effectiveness of tofacitinib among RA patients in real life. Methods: Consecutive patients between January 2015 and April 2017 with RA who fulfilled the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 criteria were included in a prospectively designed analysis of retrospective data. Patients were initiated on tofacitinib 5 mg bid. The primary objective was to analyze the safety of tofacitinib in a real-life cohort. Safety was assessed by the reasons to stop tofacitinib during follow up and changes of liver enzymes, hemoglobin, and creatinine. The secondary outcome was to analyze the frequency of and time to achieve low disease activity (LDA) and remission as defined by 28 joint count disease activity score (DAS28). Results: A total of 144 patients were treated with tofacitinib. A total of 84.9% of patients were pre-exposed to at least one biological agent. The average DAS28 at the initiation of tofacitinib was 4.43. A total of 50.0% of patients were positive for rheumatoid factor and 49.0% for ACPA. The mean follow up was 1.22 years (range 10d–3.7a) after initiation of tofacitinib treatment. A total of 94 (64.4%) patients remained on tofacitinib during follow-up. The average time to stop tofacitinib was 190.0 days. Reasons to stop tofacitinib were: insufficient response (n = 23), gastrointestinal symptoms (n = 18), infection (n = 5), myalgia (n = 2), remission (n = 2), headache (n = 2), cough, blue finger syndrome, intolerance, heartburn, psoriasis, and increased liver enzymes (all n = 1). Increased alanine amino transferase (ALAT) or aspartate amino transferase (ASAT) > 2× upper limit of normal (ULN) were detected in 3.3% and 4.4% of patients, respectively. Hemoglobin decrease of >10% was detected in 15.1% of the patients and decreased lymphocytes <500/μL in 3.4%. An increase of creatinine >20% was detected in 9.4% of patients. A total of 62.9% and 50.0% of the patients achieved low disease activity (LDA) or remission after a median of 319 and 645 days, respectively. These rates were significantly higher in patients naïve to biologic agents as compared to patients pre-exposed to biologics (LDA: naïve 100% 92 d, pre-exposed 57.0% 434 d, p ≤ 0.001; remission: naïve 86.7% 132 d, pre-exposed 44.1%, 692 d, p = 0.001). Conclusions: Tofacitinib is a safe and effective treatment option for patients with RA. Tofacitinib may induce high rates of LDA and remission in patients with active disease, even after the use of one or more biologics, though the rate appeared higher in patients naïve to biologics. Tofacitinib may be a valuable option in a treat-to-target approach. Our data demonstrate that Janus kinase (JAK) inhibitors are safe and efficacious in real life patients. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis Therapy Reappraisal: Strategies, Opportunities and Challenges)

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12 pages, 1068 KiB

Open AccessArticle

Effect of Baricitinib and Adalimumab in Reducing Pain and Improving Function in Patients with Rheumatoid Arthritis in Low Disease Activity: Exploratory Analyses from RA-BEAM

by Bruno Fautrel, Bruce Kirkham, Janet E. Pope, Tsutomu Takeuchi, Carol Gaich, Amanda Quebe, Baojin Zhu, Inmaculada de la Torre, Francesco De Leonardis and Peter C. Taylor

J. Clin. Med. 2019, 8(9), 1394; https://doi.org/10.3390/jcm8091394 - 5 Sep 2019

Cited by 40 | Viewed by 5820

Abstract

Patients with rheumatoid arthritis (RA) may experience residual pain and functional impairment despite good control of disease activity. This study compared improvements in pain and physical function in patients with well-controlled RA after 24 weeks’ treatment with baricitinib, adalimumab or placebo in the [...] Read more.

Patients with rheumatoid arthritis (RA) may experience residual pain and functional impairment despite good control of disease activity. This study compared improvements in pain and physical function in patients with well-controlled RA after 24 weeks’ treatment with baricitinib, adalimumab or placebo in the 52-week RA-BEAM phase III study. Adults with active RA and inadequate response to methotrexate received baricitinib 4 mg once daily, adalimumab 40 mg every two weeks or placebo, with background methotrexate. Patients (N = 1010) were categorised as in remission, in remission or low disease activity, or not in remission or low disease activity at week 24. For patients in remission or low disease activity (n = 310), improvements in mean pain and physical function scores at week 24 were significantly greater with baricitinib than placebo (p < 0.001 and p < 0.01, respectively) and adalimumab (p < 0.05 for both). For both outcomes, differences between adalimumab and placebo were not significant. The proportions of patients in remission or low disease activity with minimal or no pain and with normalised physical function were numerically greater with baricitinib than placebo. Baricitinib 4 mg once daily provided enhanced improvement in pain and physical function in patients with well-controlled RA, suggesting it may produce effects beyond immunomodulation. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis Therapy Reappraisal: Strategies, Opportunities and Challenges)

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17 pages, 3689 KiB

Open AccessArticle

Next-Generation Sequencing Profiles of the Methylome and Transcriptome in Peripheral Blood Mononuclear Cells of Rheumatoid Arthritis

by Chia-Chun Tseng, Yuan-Zhao Lin, Chia-Hui Lin, Ruei-Nian Li, Chang-Yi Yen, Hua-Chen Chan, Wen-Chan Tsai, Tsan-Teng Ou, Cheng-Chin Wu, Wan-Yu Sung and Jeng-Hsien Yen

J. Clin. Med. 2019, 8(9), 1284; https://doi.org/10.3390/jcm8091284 - 22 Aug 2019

Cited by 10 | Viewed by 3846

Abstract

Using next-generation sequencing to decipher methylome and transcriptome and underlying molecular mechanisms contributing to rheumatoid arthritis (RA) for improving future therapies, we performed methyl-seq and RNA-seq on peripheral blood mononuclear cells (PBMCs) from RA subjects and normal donors. Principal component analysis and hierarchical [...] Read more.

Using next-generation sequencing to decipher methylome and transcriptome and underlying molecular mechanisms contributing to rheumatoid arthritis (RA) for improving future therapies, we performed methyl-seq and RNA-seq on peripheral blood mononuclear cells (PBMCs) from RA subjects and normal donors. Principal component analysis and hierarchical clustering revealed distinct methylation signatures in RA with methylation aberrations noted across chromosomes. Methylation alterations varied with CpG features and genic characteristics. Typically, CpG islands and CpG shores were hypermethylated and displayed the greatest methylation variance. Promoters were hypermethylated and enhancers/gene bodies were hypomethylated, with methylation variance associated with expression variance. RA genetically associated genes preferentially displayed differential methylation and differential expression or interacted with differentially methylated and differentially expressed genes. These differentially methylated and differentially expressed genes were enriched with several signaling pathways and disease categories. 10 genes (CD86, RAB20, XAF1, FOLR3, LTBR, KCNH8, DOK7, PDGFA, PITPNM2, CELSR1) with concomitantly differential methylation in enhancers/promoters/gene bodies and differential expression in B cells were validated. This integrated analysis of methylome and transcriptome identified novel epigenetic signatures associated with RA and highlighted the interaction between genetics and epigenetics in RA. These findings help our understanding of the pathogenesis of RA and advance epigenetic studies in regards to the disease. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis Therapy Reappraisal: Strategies, Opportunities and Challenges)

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12 pages, 2802 KiB

Open AccessArticle

Regulation of Th17 Cytokine-Induced Osteoclastogenesis via SKI306X in Rheumatoid Arthritis

by Hae-Rim Kim, Kyoung-Woon Kim, Bo-Mi Kim, Ji-Yeon Won, Hong-Ki Min, Kyung-Ann Lee, Tae-Young Kim and Sang-Heon Lee

J. Clin. Med. 2019, 8(7), 1012; https://doi.org/10.3390/jcm8071012 - 10 Jul 2019

Cited by 13 | Viewed by 2825

Abstract

This study aimed to investigate the regulatory effect of SKI306X, a mixed extract of three herbs, in T helper (Th)17 cytokine-induced inflammation and joint destruction in rheumatoid arthritis (RA). Synovial fibroblasts were isolated from RA patients and cultured with Th17 cytokines including interleukin [...] Read more.

This study aimed to investigate the regulatory effect of SKI306X, a mixed extract of three herbs, in T helper (Th)17 cytokine-induced inflammation and joint destruction in rheumatoid arthritis (RA). Synovial fibroblasts were isolated from RA patients and cultured with Th17 cytokines including interleukin (IL)-17, IL-21, and IL-22 and SKI306X, and tumor necrosis factor (TNF)-α, IL-1β, and receptor activator of nuclear factor kappa-Β ligand (RANKL) expression and production were investigated using real-time PCR and ELISA of culture media. After peripheral blood (PB) cluster of differentiation (CD)14⁺ monocytes were cultured in media supplemented with Th17 cytokines and SKI306X, tartrate-resistant acid phosphatase positive (TRAP⁺) multinucleated giant cells (mature osteoclasts) were enumerated and gene expression associated with osteoclast maturation was assessed via real-time PCR analysis. After PB monocytes were co-cultured with IL-17-stimulated RA synovial fibroblasts in the presence of SKI306X, osteoclast differentiation was assessed. When RA synovial fibroblasts were cultured with IL-17, IL-21, and IL-22, TNF-α, IL-1β, and RANKL expression and production were increased; however, SKI306X reduced cytokine expression and production. When PB monocytes were cultured in media supplemented with Th17 cytokines, osteoclast differentiation was stimulated; however, SKI306X decreased osteoclast differentiation and osteoclast maker expression. When PB monocytes were co-cultured with IL-17-stimulated RA synovial fibroblasts, osteoclast differentiation was increased; however, SKI306X decreased osteoclast differentiation and osteoclast maker expression. SKI306X reduced Th17 cytokine-induced TNF-α, IL-1β, and RANKL expression and osteoclast differentiation, providing novel insights into adjuvant therapy for regulating inflammation and joint destruction in RA. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis Therapy Reappraisal: Strategies, Opportunities and Challenges)

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6 pages, 403 KiB

Open AccessArticle

Maintained Clinical Remission in Ankylosing Spondylitis Patients Switched from Reference Infliximab to Its Biosimilar: An 18-Month Comparative Open-Label Study

by Evripidis Kaltsonoudis, Eleftherios Pelechas, Paraskevi V. Voulgari and Alexandros A. Drosos

J. Clin. Med. 2019, 8(7), 956; https://doi.org/10.3390/jcm8070956 - 2 Jul 2019

Cited by 14 | Viewed by 3148

Abstract

Background: Switching from reference infliximab (RI) to biosimilar infliximab (BI) had no detrimental effects on efficacy and safety. However, long-term follow-up data is missing. Objective: To evaluate patients with Ankylosing Spondylitis (AS) in clinical remission who were switching from RI to BI, in [...] Read more.

Background: Switching from reference infliximab (RI) to biosimilar infliximab (BI) had no detrimental effects on efficacy and safety. However, long-term follow-up data is missing. Objective: To evaluate patients with Ankylosing Spondylitis (AS) in clinical remission who were switching from RI to BI, in terms of the safety and efficacy of this, in a long-term fashion. Methods: One hundred and nine consecutive unselected AS patients were investigated. All were naïve to other biologics and were followed-up at predefined times receiving RI. Patients in clinical remission were asked to switch from RI to BI. Those who switched to BI were compared with a matched control-group receiving continuous RI. During follow-up, several parameters were recorded for at least 18 months. Disease activity was measured using the Bath Ankylosing Spondylitis disease activity index (BASDAI), and the Ankylosing Spondylitis disease activity score (ASDAS), using the C-reactive protein. Remission was defined as BASDAI < 4 and ASDAS < 1.3. Results: Eighty-eight patients were evaluated (21 excluded for different reasons). From those, 45 switched to BI, while 43 continued receiving RI. No differences between groups regarding demographic, clinical and laboratory parameters were observed. All patients were in clinical remission. During follow-up, five patients from the BI-group and three from the maintenance-group discontinued the study (4 patients nocebo effect, 1 loss of efficacy). After 18 months of treatment, all patients in both groups remained in clinical remission. No significant adverse events were noted between groups. Conclusion: BI is equivalent to RI in maintaining AS in clinical remission for at least 18 months. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis Therapy Reappraisal: Strategies, Opportunities and Challenges)

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11 pages, 1498 KiB

Open AccessArticle

Achieving Pain Control in Rheumatoid Arthritis with Baricitinib or Adalimumab Plus Methotrexate: Results from the RA-BEAM Trial

by Peter C. Taylor, Yvonne C. Lee, Roy Fleischmann, Tsutomu Takeuchi, Elizabeth L. Perkins, Bruno Fautrel, Baojin Zhu, Amanda K. Quebe, Carol L. Gaich, Xiang Zhang, Christina L. Dickson, Douglas E. Schlichting, Himanshu Patel, Frederick Durand and Paul Emery

J. Clin. Med. 2019, 8(6), 831; https://doi.org/10.3390/jcm8060831 - 12 Jun 2019

Cited by 61 | Viewed by 9059

Abstract

The purpose of the study was to assess the proportion of patients who achieve pain relief thresholds, the time needed to reach the thresholds, and the relationship between pain and inflammation among patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate [...] Read more.

The purpose of the study was to assess the proportion of patients who achieve pain relief thresholds, the time needed to reach the thresholds, and the relationship between pain and inflammation among patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate in RA-BEAM (NCT0170358). A randomized, double-blind trial was conducted, comparing baricitinib (N = 487), adalimumab (N = 330), and placebo (N = 488) plus methotrexate. Pain was evaluated by patient’s assessment on a 0–100 mm visual analog scale (VAS). The following were assessed through a 24-week placebo-controlled period: the proportion of patients who achieved ≥30%, ≥50%, and ≥70% pain relief, the time to achieve these pain relief thresholds, remaining pain (VAS ≤ 10 mm, ≤20 mm, or ≤40 mm), and the relationship between inflammation markers and pain relief. Baricitinib-treated patients were more likely (p < 0.05) to achieve ≥30%, ≥50%, and ≥70% pain relief than placebo- and adalimumab-treated patients, as early as Week 1 vs. placebo and at Week 4 vs. adalimumab. A greater proportion of baricitinib-treated patients achieved ≤20 mm or ≤40 mm remaining pain vs. placebo- and adalimumab-treated patients. Baricitinib-treated patients tended to demonstrate consistent pain relief independent of levels of inflammation control. In RA patients with an inadequate response to methotrexate, baricitinib provided greater and more rapid pain relief than adalimumab and placebo. Analyses suggest the relationship between inflammation and pain may be different for baricitinib and adalimumab treatments. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis Therapy Reappraisal: Strategies, Opportunities and Challenges)

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14 pages, 1125 KiB

Open AccessArticle

Infliximab Induced a Dissociated Response of Severe Periodontal Biomarkers in Rheumatoid Arthritis Patients

by Mélanie Rinaudo-Gaujous, Vincent Blasco-Baque, Pierre Miossec, Philippe Gaudin, Pierre Farge, Xavier Roblin, Thierry Thomas, Stephane Paul and Hubert Marotte

J. Clin. Med. 2019, 8(5), 751; https://doi.org/10.3390/jcm8050751 - 26 May 2019

Cited by 20 | Viewed by 3750

Abstract

Objective: Rheumatoid arthritis and periodontal disease are associated together, but the effect of therapy provided for one disease to the second one remained under-investigated. This study investigated effect of infliximab therapy used to treat rheumatoid arthritis (RA) on various biomarkers of periodontal disease [...] Read more.

Objective: Rheumatoid arthritis and periodontal disease are associated together, but the effect of therapy provided for one disease to the second one remained under-investigated. This study investigated effect of infliximab therapy used to treat rheumatoid arthritis (RA) on various biomarkers of periodontal disease (PD) severity including serologies of Porphyromonas gingivalis and Prevotella intermedia and matrix metalloproteinase 3. Methods: Seventy nine RA patients were enrolled at the time to start infliximab therapy and the 28 joint disease activity score (DAS28), anti-cyclic citrullinated petides 2nd generation (anti-CCP2), anti-P. gingivalis antibody, and Matrix metalloproteinase 3 (MMP-3) were monitored before and at 6 months of infliximab therapy. Joint damage and severe periodontal disease were assessed at baseline. Anti-CCP2, anti-P. gingivalis antibody, and MMP-3 were determined by enzyme-linked immunosorbent assay (ELISA). Results: At baseline, anti-CCP2 titers were associated with anti-P. gingivalis lipopolysaccharide (LPS)-specific antibodies titers (p < 0.05). Anti-P. gingivalis antibodies were not significantly correlated with clinical, biological, or destruction parameters of RA disease. At 6 months of infliximab therapy, MMP-3 level decreased (from 119 ± 103 ng/mL to 62.44 ± 52 ng/mL; p < 0.0001), whereas P. gingivalis antibody levels remained at the same level. DAS28 and inflammation markers C-reactive protein (CRP) and Erythrocyte sedimentation rate (ESR) also decreased significantly during infliximab therapy (p < 0.05) as anti-CCP2 levels (p < 0.001). Only high MMP-3 level at baseline was associated with infliximab efficacy (p < 0.01). Conclusion: MMP-3 level can be a useful marker of the efficacy of infliximab in RA patients. The treatment did not affect anti-P. gingivalis antibodies. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis Therapy Reappraisal: Strategies, Opportunities and Challenges)

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18 pages, 864 KiB

Open AccessArticle

Periodontal Health and Oral Microbiota in Patients with Rheumatoid Arthritis

by Kaja Eriksson, Guozhong Fei, Anna Lundmark, Daniel Benchimol, Linkiat Lee, Yue O. O. Hu, Anna Kats, Saedis Saevarsdottir, Anca Irinel Catrina, Björn Klinge, Anders F. Andersson, Lars Klareskog, Karin Lundberg, Leif Jansson and Tülay Yucel-Lindberg

J. Clin. Med. 2019, 8(5), 630; https://doi.org/10.3390/jcm8050630 - 8 May 2019

Cited by 70 | Viewed by 7491

Abstract

This study aimed to investigate the periodontal health of patients with established rheumatoid arthritis (RA) in relation to oral microbiota, systemic and oral inflammatory mediators, and RA disease activity. Forty patients underwent full-mouth dental/periodontal and rheumatological examination, including collection of blood, saliva, gingival [...] Read more.

This study aimed to investigate the periodontal health of patients with established rheumatoid arthritis (RA) in relation to oral microbiota, systemic and oral inflammatory mediators, and RA disease activity. Forty patients underwent full-mouth dental/periodontal and rheumatological examination, including collection of blood, saliva, gingival crevicular fluid (GCF) and subgingival plaque. Composition of plaque and saliva microbiota were analysed using 16S rRNA sequencing and levels of inflammatory mediators by multiplex-immunoassay. The majority of the patients (75%) had moderate or severe periodontitis and the rest had no/mild periodontitis. Anti-citrullinated protein antibody (ACPA) positivity was significantly more frequent in the moderate/severe periodontitis (86%) compared to the no/mild group (50%). No significance between groups was observed for RA disease duration or activity, or type of medication. Levels of sCD30/TNFRSF8, IFN-α2, IL-19, IL-26, MMP-1, gp130/sIL-6Rß, and sTNF-R1 were significantly higher in serum or GCF, and April/TNFSF13 was significantly higher in serum and saliva samples in moderate/severe periodontitis. The microbial composition in plaque also differed significantly between the two groups. In conclusion, the majority of RA patients had moderate/severe periodontitis and that this severe form of the disease was significantly associated with ACPA positivity, an altered subgingival microbial profile, and increased levels of systemic and oral inflammatory mediators. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis Therapy Reappraisal: Strategies, Opportunities and Challenges)

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14 pages, 1284 KiB

Open AccessArticle

Superiority of a Treat-to-Target Strategy over Conventional Treatment with Fixed csDMARD and Corticosteroids: A Multi-Center Randomized Controlled Trial in RA Patients with an Inadequate Response to Conventional Synthetic DMARDs, and New Therapy with Certolizumab Pegol

by Ruediger B. Mueller, Michael Spaeth, Cord von Restorff, Christoph Ackermann, Hendrik Schulze-Koops and Johannes von Kempis

J. Clin. Med. 2019, 8(3), 302; https://doi.org/10.3390/jcm8030302 - 3 Mar 2019

Cited by 10 | Viewed by 4106

Abstract

Background: Treatment of rheumatoid arthritis (RA) includes the use of conventional (cs), biologic (b) disease-modifying anti-rheumatic drugs (DMARDs) and oral, intramuscularly, intravenous, or intraarticular (IA) glucocorticoids (GCs). In this paper, we analysed whether a treat-to-target (T2T) strategy optimizing csDMARD, oral, and IA-GC treatment [...] Read more.

Background: Treatment of rheumatoid arthritis (RA) includes the use of conventional (cs), biologic (b) disease-modifying anti-rheumatic drugs (DMARDs) and oral, intramuscularly, intravenous, or intraarticular (IA) glucocorticoids (GCs). In this paper, we analysed whether a treat-to-target (T2T) strategy optimizing csDMARD, oral, and IA-GC treatment as an adjunct new therapy to a new certolizumab pegol (CZP) therapy improves the effectivity in RA patients. Methods: 43 patients with active RA (≥6 tender, ≥6 swollen joints, ESR ≥ 20 mm/h or CRP ≥ 7mg/L) despite csDMARD treatment for ≥ 3 months and naïve to bDMARDs were randomized to CZP (200 mg/2 weeks after loading with 400 mg at weeks 0–2–4) plus a treat-to-target strategy (T2T, n = 21), or to CZP added to the established csDMARD therapy (fixed regimen, n = 22). The T2T strategy consisted of changing the baseline csDMARD therapy (1) SC-methotrexate (dose: 15 ≥ 20 ≥ 25 mg/week, depending on the initial dose) ≥ leflunomide (20 mg/d) ≥ sulphasalazine (2 × 1000 mg/d) plus (2) oral GCs (prednisolone 20–15–12.5–10–7.5–5–2.5–0 mg/d tapered every five days) and (3) injections of ≤5 affected joints with triamcinolone. DMARD modification and an addition of oral GCs were initiated, depending on the achievement of low disease activity (DAS 28 < 3.2). The primary objective was defined as the ACR 50 response at week 24. Results: ACR 50 was achieved in 76.2% of the T2T, as compared to 36.4% of the fixed regimen patients (p = 0.020). ACR 20 and 70 responses were achieved in 90.5% and 71.4% of the T2T patients and 59.1% and 27.3% of the fixed regimen patients, respectively (p = 0.045 and p = 0.010, respectively). The adverse event rate was similar for both groups (T2T n = 51; fixed regimen n = 55). Conclusion: Treat-to-target management with the optimization of csDMARDs, oral, and IA-GCs of RA patients in parallel to a newly established CZP treatment was safe and efficacious in comparison to a fixed regimen of csDMARDs background therapy. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis Therapy Reappraisal: Strategies, Opportunities and Challenges)

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14 pages, 249 KiB

Open AccessArticle

Prevalence and Fracture Risk of Osteoporosis in Patients with Rheumatoid Arthritis: A Multicenter Comparative Study of the FRAX and WHO Criteria

by Sang Tae Choi, Seong-Ryul Kwon, Ju-Yang Jung, Hyoun-Ah Kim, Sung-Soo Kim, Sang Hyon Kim, Ji-Min Kim, Ji-Ho Park and Chang-Hee Suh

J. Clin. Med. 2018, 7(12), 507; https://doi.org/10.3390/jcm7120507 - 2 Dec 2018

Cited by 37 | Viewed by 4695

Abstract

(1) Background: We evaluated the prevalence and fracture risk of osteoporosis in patients with rheumatoid arthritis (RA), and compared the fracture risk assessment tool (FRAX) criteria and bone mineral density (BMD) criteria established by the World Health Organization (WHO). (2) Methods: This retrospective [...] Read more.

(1) Background: We evaluated the prevalence and fracture risk of osteoporosis in patients with rheumatoid arthritis (RA), and compared the fracture risk assessment tool (FRAX) criteria and bone mineral density (BMD) criteria established by the World Health Organization (WHO). (2) Methods: This retrospective cross-sectional study, which included 479 RA patients in 5 hospitals, was conducted between January 2012 and December 2016. The FRAX criteria for high-risk osteoporotic fractures were calculated including and excluding the BMD values, respectively. The definition of high risk for fracture by FRAX criteria and BMD criteria by WHO was 10-year probability of ≥ 20% for major osteoporotic fracture or ≥ 3% for hip fracture, and T score ≤ −2.5 or Z score ≤ −2.0, respectively. (3) Results: The mean age was 61.7 ± 11.9 years. The study included 426 female patients (88.9%), 353 (82.9%) of whom were postmenopausal. Osteoporotic fractures were detected in 81 (16.9%) patients. The numbers of candidates for pharmacological intervention using the FRAX criteria with and without BMD and the WHO criteria were 226 (47.2%), 292 (61%), and 160 (33.4%), respectively. Only 69.2%–77% of the patients in the high-risk group using the FRAX criteria were receiving osteoporosis treatments. The following were significant using the WHO criteria: female (OR 3.55, 95% CI 1.46–8.63), age (OR 1.1, 95% CI 1.08–1.13), and BMI (OR 0.8, 95% CI 0.75–0.87). Glucocorticoid dose (OR 1.09, 95% CI 1.01–1.17), age (OR 1.09, 95% CI 1.06–1.12), and disease duration (OR 1.01, 95% CI 1–1.01) were independent risk factors for fracture. (4) Conclusions: The proportion of RA patients with a high risk of osteoporotic fractures was 33.4%–61%. Only 69.2%–77% of candidate patients were receiving osteoporotic treatments while applying FRAX criteria. Independent risk factors for osteoporotic fractures in RA patients were age, the dose of glucocorticoid, and disease duration. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis Therapy Reappraisal: Strategies, Opportunities and Challenges)

11 pages, 221 KiB

Open AccessFeature PaperArticle

Sleep Quality in Patients with Rheumatoid Arthritis and Associations with Pain, Disability, Disease Duration, and Activity

by Igor Grabovac, Sandra Haider, Carolin Berner, Thomas Lamprecht, Karl-Heinrich Fenzl, Ludwig Erlacher, Michael Quittan and Thomas E. Dorner

J. Clin. Med. 2018, 7(10), 336; https://doi.org/10.3390/jcm7100336 - 9 Oct 2018

Cited by 55 | Viewed by 10417

Abstract

We aimed to assess the subjective sleep quality in patients with rheumatoid arthritis (RA) and its correlation with disease activity, pain, inflammatory parameters, and functional disability. In a cross-sectional study, patients with confirmed RA diagnosis responded to a questionnaire (consisting of socio-demographic data, [...] Read more.

We aimed to assess the subjective sleep quality in patients with rheumatoid arthritis (RA) and its correlation with disease activity, pain, inflammatory parameters, and functional disability. In a cross-sectional study, patients with confirmed RA diagnosis responded to a questionnaire (consisting of socio-demographic data, the Health Assessment Questionnaire Disability Index, and the Medical Outcome Study Sleep Scale). Disease activity was assessed with the Clinical Disease Activity Index, and pain levels using the visual analogue scale. In addition, inflammatory markers (C-reactive protein, interleukin-6, and tumor necrosis factor alpha) were analyzed. Ninety-five patients were analyzed, predominantly female, with an average age of 50.59 (9.61) years. Fifty-seven percent reported non-optimal sleep duration, where functional disability (92.7% vs. 69.8%; p = 0.006) and higher median pain levels (3.75 (2.3–6.0) vs. 2.5 (2.0–3.5); p = 0.003) were also more prevalent. No differences in sociodemographic variables, disease duration or activity, inflammatory parameters, or use of biological and corticosteroid therapy were observed. The multivariate regression analysis showed that more intense pain was associated with a lower likelihood of optimal sleep (odds ratio (OR) = 0.68, 95% confidence interval (CI) 0.47–0.98, p = 0.038). Patients with RA report a high prevalence of non-optimal sleep, which is linked to pain level. Clinicians need to be aware of this issue and the potential effects on health and functional status. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis Therapy Reappraisal: Strategies, Opportunities and Challenges)

Review

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15 pages, 1453 KiB

Open AccessReview

Current Therapeutic Options in the Treatment of Rheumatoid Arthritis

by Birgit M. Köhler, Janine Günther, Dorothee Kaudewitz and Hanns-Martin Lorenz

J. Clin. Med. 2019, 8(7), 938; https://doi.org/10.3390/jcm8070938 - 28 Jun 2019

Cited by 151 | Viewed by 18021

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the joints. Untreated RA leads to a destruction of joints through the erosion of cartilage and bone. The loss of physical function is the consequence. Early treatment is important to [...] Read more.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the joints. Untreated RA leads to a destruction of joints through the erosion of cartilage and bone. The loss of physical function is the consequence. Early treatment is important to control disease activity and to prevent joint destruction. Nowadays, different classes of drugs with different modes of action are available to control the inflammation and to achieve remission. In this review, we want to discuss differences and similarities of these different drugs. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis Therapy Reappraisal: Strategies, Opportunities and Challenges)

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12 pages, 296 KiB

Open AccessReview

The Potential Role of Genomic Medicine in the Therapeutic Management of Rheumatoid Arthritis

by Marialbert Acosta-Herrera, David González-Serna and Javier Martín

J. Clin. Med. 2019, 8(6), 826; https://doi.org/10.3390/jcm8060826 - 10 Jun 2019

Cited by 11 | Viewed by 4245

Abstract

During the last decade, important advances have occurred regarding understanding of the pathogenesis and treatment of rheumatoid arthritis (RA). Nevertheless, response to treatment is not universal, and choosing among different therapies is currently based on a trial and error approach. The specific patient’s [...] Read more.

During the last decade, important advances have occurred regarding understanding of the pathogenesis and treatment of rheumatoid arthritis (RA). Nevertheless, response to treatment is not universal, and choosing among different therapies is currently based on a trial and error approach. The specific patient’s genetic background influences the response to therapy for many drugs: In this sense, genomic studies on RA have produced promising insights that could help us find an effective therapy for each patient. On the other hand, despite the great knowledge generated regarding the genetics of RA, most of the investigations performed to date have focused on identifying common variants associated with RA, which cannot explain the complete heritability of the disease. In this regard, rare variants could also contribute to this missing heritability as well as act as biomarkers that help in choosing the right therapy. In the present article, different aspects of genetics in the pathogenesis and treatment of RA are reviewed, from large-scale genomic studies to specific rare variant analyses. We also discuss the shared genetic architecture existing among autoimmune diseases and its implications for RA therapy, such as drug repositioning. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis Therapy Reappraisal: Strategies, Opportunities and Challenges)

7 pages, 207 KiB

Open AccessReview

Golimumab for Rheumatoid Arthritis

by Eleftherios Pelechas, Paraskevi V. Voulgari and Alexandros A. Drosos

J. Clin. Med. 2019, 8(3), 387; https://doi.org/10.3390/jcm8030387 - 20 Mar 2019

Cited by 34 | Viewed by 6173

Abstract

Since the advent of infliximab for the treatment of rheumatoid arthritis (RA), new genetically-engineered molecules have appeared. This review aims to present the current data and body of evidence for golimumab (GLM). Safety, efficacy, tolerability and immunogenicity are all being investigated, not only [...] Read more.

Since the advent of infliximab for the treatment of rheumatoid arthritis (RA), new genetically-engineered molecules have appeared. This review aims to present the current data and body of evidence for golimumab (GLM). Safety, efficacy, tolerability and immunogenicity are all being investigated, not only through phase III trials (GO-BEFORE, GO-FORWARD, GO-AFTER, GO-MORE, GO-FURTHER, GO-NICE), but also through studies of real-world data. It seems that GLM in the subcutaneous form is an efficacious molecule with a good safety profile at the standard dosage scheme, but a 100 mg subcutaneous dose is associated with a higher risk of opportunistic infections, lymphoma and demyelination. Furthermore, when compared to other tumor necrosis factor-α molecules, it is non-inferior, and, at some points, such as when it comes to immunogenicity and persistence of the drug, it has a better profile. In summary, GLM is an effective, well-tolerated option for the treatment of RA, for both the clinician and patients who are seeking a convenient dosage scheme. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis Therapy Reappraisal: Strategies, Opportunities and Challenges)

Other

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29 pages, 342 KiB

Open AccessPerspective

How to Get the Most from Methotrexate (MTX) Treatment for Your Rheumatoid Arthritis Patient?—MTX in the Treat-to-Target Strategy

by Peter. C. Taylor, Alejandro Balsa Criado, Anne-Barbara Mongey, Jerome Avouac, Hubert Marotte and Rudiger B. Mueller

J. Clin. Med. 2019, 8(4), 515; https://doi.org/10.3390/jcm8040515 - 15 Apr 2019

Cited by 57 | Viewed by 11341

Abstract

Methotrexate (MTX) is a remarkable drug with a key role in the management of rheumatoid arthritis (RA) at every stage of its evolution. Its attributes include good overall efficacy for signs and symptoms, inhibition of structural damage and preservation of function with acceptable [...] Read more.

Methotrexate (MTX) is a remarkable drug with a key role in the management of rheumatoid arthritis (RA) at every stage of its evolution. Its attributes include good overall efficacy for signs and symptoms, inhibition of structural damage and preservation of function with acceptable and manageable safety, a large dose-titratable range, options for either an oral or parenteral route of administration, and currently unrivalled cost-effectiveness. It has a place as a monotherapy and also as an anchor drug that can be safely used in combination with other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or used concomitantly with biological DMARDs or targeted synthetic DMARDs. MTX is not without potential issues regarding toxicity, notably hepatotoxicity and bone marrow toxicity, as well as tolerability problems for some, but not all, patients. But many of these issues can be mitigated or managed. In the face of a welcome expansion in available targeted therapies for the treatment of RA, MTX looks set to remain at the foundation of pharmacotherapy for the majority of people living with RA and other inflammatory rheumatic diseases. In this article, we provide an evidence-based discussion as to how to achieve the best outcomes with this versatile drug in the context of a treat-to-target strategy for the management of RA. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis Therapy Reappraisal: Strategies, Opportunities and Challenges)

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