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Rheumatoid Arthritis: Clinical Updates on Diagnosis and Treatment

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Immunology".

Deadline for manuscript submissions: 31 July 2025 | Viewed by 11292

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Dr. Shunsuke Mori

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Department of Rheumatology, Clinical Research Center for Rheumatic Diseases, National Hospital Organization Kumamoto Saishun Medical Center, Kohshi, Kumamoto, Japan
Interests: rheumatoid arthritis; disease-modifying antirheumatic drugs; inflammatory rheumatic disease; interstitial lung disease; bronchietasis; infectious disease

Special Issue Information

Dear Colleagues,

Over the past two decades, significant advances have been made in the management of rheumatoid arthritis (RA). Early diagnosis, the prompt initiation of pharmaceutical therapies, and the application of a treat-to-target strategy with tight disease control have greatly improved the long-term outcomes of patients with RA. A growing array of conventional, biological, and nonbiological targeted disease-modifying antirheumatic drugs (DMARDs) are available in the current pharmaceutical approach.

Despite this remarkable therapeutic revolution, we are confronted by many difficulties in our daily practice of managing patients with RA. Many patients remain unresponsive to current DMARD therapies or experience disease flares after achieving a state of remission or low disease activity. Additionally, the presence of persistent subclinical inflammation may induce the progressive damage of joints, even after patients have achieved clinical remission. It is not clear when a drug can be discontinued or reduced once the remission state is achieved and sustained. We lack the reliable biomarkers by which we can predict patient responses to individual treatments. It is essential that we address these unmet clinical needs in the management of patients with RA.

The aim of this Special Issue is to provide new information concerning diagnosis and treatment strategies using targeted therapies with biological and nonbiological DMARDs. I welcome original research papers, reviews, meta-analyses, and communications that will contribute to optimizing the use of the existing DMARDs and developing new ideas and future research directions.

Dr. Shunsuke Mori
Guest Editor

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Keywords

rheumatoid arthritis
disease-modifying antirheumatic drugs (DMARDs)
biological therapies
Janus kinase inhibitors (JAK inhibitors)
treatment strategies
joint destruction
comorbidity
drug safety

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Published Papers (9 papers)

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Research

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12 pages, 1301 KiB

Open AccessArticle

Clinical Significance of Antinuclear Antibodies in Patients with Rheumatoid Arthritis: From SETOUCHI-RA Registry

by Kazuhisa Nakano, Shunichi Fujita, Sumie Hiramatsu-Asano, Akiko Nagasu, Shoko Tsuji, Yuka Koide, Masatomo Yamada, Yo Mizuta, Masakatsu Ikeda, Hiroyasu Hirano and Yoshitaka Morita

J. Clin. Med. 2025, 14(5), 1553; https://doi.org/10.3390/jcm14051553 - 26 Feb 2025

Viewed by 525

Abstract

Background/Objectives: Rheumatoid arthritis (RA) is a representative systemic autoimmune rheumatic disease (SARD) characterized by synovial inflammation. While antinuclear antibodies (ANAs) positivity in patients with RA varies widely, the relationship between ANA patterns and clinical features remains unclear. This study aimed to evaluate the clinical significance of ANA in patients with RA. Methods: This single-center RA registry study included 814 Japanese patients after excluding those with coexisting SARDs. ANA titers and staining patterns were assessed by indirect immunofluorescence assays on HEp-2 cells. Clinical and laboratory features were analyzed, and logistic regression was used to identify risk factors for pulmonary involvement. Hierarchical clustering and statistical analyses were performed to explore associations between ANA patterns and clinical features. Results: ANA positivity was observed in 41.5% of patients, with the speckled and homogeneous patterns being the most common. ANA-positive patients exhibited significantly higher rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) positivity rates and titers, along with elevated disease activity markers, including Evaluator’s Global Assessment and Swollen Joint Count. Nucleolar pattern positivity was independently associated with pulmonary complications, predominantly interstitial lung disease, and higher rates of JAK inhibitor use. Discrete-speckled pattern-positive patients exhibited high ANA titers but lower RF and ACPA levels, reflecting a distinct subset of RA. Conclusions: ANA staining patterns and titers are clinically relevant in RA, with nucleolar and discrete-speckled patterns indicating distinct clinical and pathophysiological profiles. ANA should be interpreted alongside other serological markers and clinical parameters rather than as a standalone tool. Further studies are needed to refine its clinical applicability and integration into RA management. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis: Clinical Updates on Diagnosis and Treatment)

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18 pages, 274 KiB

Open AccessArticle

Mortality and Predictive Factors for Death Following the Diagnosis of Interstitial Lung Disease in Patients with Rheumatoid Arthritis: A Retrospective, Long-Term Follow-Up Study

by Shunsuke Mori, Fumikazu Sakai, Mizue Hasegawa, Kazuyoshi Nakamura and Kazuaki Sugahara

J. Clin. Med. 2025, 14(4), 1380; https://doi.org/10.3390/jcm14041380 - 19 Feb 2025

Viewed by 946

Abstract

Objective: The aim of this study was to determine mortality and predictive factors for death in patients with rheumatoid arthritis (RA) diagnosed with and without interstitial lung disease (ILD). Methods: We retrospectively performed a long-term follow-up study of patients diagnosed with RA at our medical center between April 2001 and June 2023. The diagnosis and classification of ILD were made based on pulmonary high-resolution computed tomography (HRCT), taken at RA diagnosis and during follow-up. Results: Among 781 patients with RA, 78 were diagnosed with ILD; all cases except one were subclinical. The most common HRCT pattern was definite usual interstitial pneumonia (UIP) followed by nonspecific interstitial pneumonia (NSIP)/UIP, probable UIP, NSIP, and early UIP. During follow-up (mean of 10.0 years), the crude incidence rate of death (95% confidence interval [CI]) was 7.1 (5.2–10.0) and 1.5 (1.0–1.9) per 100 person-years in RA patients with and without ILD. Poor control of RA activity was associated with increased incidence rates of death. The standardized mortality ratio (95% CI) compared with the general population was 1.32 (1.11–1.53) for all RA patients, 2.09 (1.45–2.73) for RA-ILD patients, and 1.16 (0.95–1.38) for non-ILD RA patients. Lung cancer and respiratory failure were the most common causes of death in RA-ILD patients. The Multivariable Fine-Gray regression analysis revealed that ILD (adjusted hazard ratio [HR] 2.97 [95% CI 1.95–4.53]), advanced age (1.08 per additional year [1.05–1.10]), and low body mass index (3.07 [2.10–4.49]) were strong predictive factors for mortality in RA patients. HRCT patterns did not affect the risk of death in RA-ILD patients. Conclusions: Regardless of HRCT pattern, RA-ILD contributes to the increased mortality risk in patients with RA. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis: Clinical Updates on Diagnosis and Treatment)

14 pages, 1103 KiB

Open AccessFeature PaperArticle

Asymmetrical Damage of the Wrist Joint Induces Lateralized Cortical Bone Loss in the Metacarpal Diaphysis in Patients with Rheumatoid Arthritis

by Akikatsu Nakashima, Hiroshi Fujii, Masahiro Kuroda, Takeshi Zoshima, Ichiro Mizushima, Hideki Nomura and Mitsuhiro Kawano

J. Clin. Med. 2024, 13(24), 7652; https://doi.org/10.3390/jcm13247652 - 16 Dec 2024

Viewed by 1082

Abstract

Background/Objectives: Osteoporosis is common in rheumatoid arthritis (RA), occurring either systemically or locally around inflamed joints. Decreased metacarpal bone density is a known marker of RA progression and hand function impairment. Although RA is generally characterized by symmetrical arthritis, some patients exhibit asymmetrical joint involvement. This study investigates the frequency of unilateral metacarpal bone density reduction in RA patients and aims to identify associated factors. Methods: This study included 143 RA patients (107 females, mean age 62.4 yrs., mean disease duration 11.1 yrs.). Bilateral hand X-rays were used to measure the cortical thickness rate (CTR) of the 2nd to 4th metacarpals. Unilateral bone density reduction was defined as a thin-to-thick-side CTR ratio (CTRR) < 0.8. Associations between CTR reduction and unilateral wrist joint damage (WJD) were analyzed. Results: Unilateral CTR reduction (CTRR < 0.8) was observed in 16.8% of patients, significantly associated with unilateral WJD. Among patients with unilateral WJD, 50.0% showed CTRR lateral (+) compared to 10.1% without unilateral WJD (p < 0.01). ANCOVA revealed significant effects of WJD laterality on CTRR, with an interaction effect showing greater CTRR laterality when thin-side WJD was present without thick-side WJD. Post-biologic treatment, CTR values decreased in both hands, indicating no improvement in bone density reduction. Conclusions: Approximately 17% of RA patients exhibited unilateral relative metacarpal bone density reduction, closely associated with unilateral WJD. This first detailed report on bone density laterality in RA underscores the need for early intervention and rehabilitation strategies in RA patients with hand involvement. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis: Clinical Updates on Diagnosis and Treatment)

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12 pages, 647 KiB

Open AccessArticle

Real-World Clinical Effectiveness and Safety of Antifibrotics in Progressive Pulmonary Fibrosis Associated with Rheumatoid Arthritis

by Javier Narváez, Martí Aguilar-Coll, Vanesa Vicens-Zygmunt, Juan José Alegre, Guadalupe Bermudo and María Molina-Molina

J. Clin. Med. 2024, 13(23), 7074; https://doi.org/10.3390/jcm13237074 - 22 Nov 2024

Cited by 1 | Viewed by 961

Abstract

Background/Objectives: Interstitial lung disease (ILD) is one of the most severe complications of rheumatoid arthritis (RA). Real-world data on antifibrotic treatment are needed. Our objective was to evaluate the real-world effectiveness and tolerability of antifibrotic agents in patients with progressive fibrosing RA-ILD. Methods: A longitudinal, retrospective, observational study was conducted on a cohort of RA-ILD patients treated with either nintedanib or pirfenidone. The data collected included pulmonary function test (PFT) results, adverse events (AEs), tolerability, and drug retention. Results: Twenty-seven patients were included; 25 (92.5%) initiated nintedanib, while two initiated pirfenidone. The median follow-up duration was 25 months (IQR 7–27). The mean decline in %pFVC and %pDLCO from ILD diagnosis to the initiation of antifibrotic therapy were −8.9% and −14.8%, respectively. After 6 months of treatment, most patients achieved stabilization in PFT: a ∆%pFVC of +1.2% (p = 0.611 compared with baseline) and a ∆%pDLCO of +3.9% (p = 0.400). Eighteen patients completed one year of therapy, with a modest improvement in %pFVC (+4.7%; p = 0.023) and stabilization in %pDLCO (−3.8%; p = 0.175). This trend persisted among the nine patients who completed 2 years of treatment (%pFVC +7.7%; p = 0.037 and %pDLCO −2.2%; p = 0.621). During the follow-up period, 15% of patients died, and 4% underwent lung transplantation. Adverse events occurred in 81% of patients, leading to discontinuation in 18.5% of cases. The most frequent adverse events were gastrointestinal events and hepatitis, leading to a permanent dose reduction of 40% for nintedanib and 14% for pirfenidone. A second antifibrotic agent was prescribed for 18.5% of the patients. At the end of the follow-up period, 63% of the total cohort remained on antifibrotic therapy. Conclusions: According to our results, antifibrotic initiation was associated with a modest improvement in the trajectory of %pFVC and stabilization in %pDLCO. The discontinuation rate in our cohort (37%) was higher than that reported in clinical trials but similar to that reported in previously published real-world studies. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis: Clinical Updates on Diagnosis and Treatment)

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10 pages, 860 KiB

Open AccessArticle

Serum Anti-Aminoacyl-Transfer Ribonucleic Acid Synthetase Antibody Levels Are Involved in Rheumatoid Arthritis Complicated with Interstitial Lung Disease

by Shomi Oka, Takashi Higuchi, Hiroshi Furukawa, Kota Shimada, Akira Okamoto, Misuzu Fujimori, Atsushi Hashimoto, Akiko Komiya, Koichiro Saisho, Norie Yoshikawa, Masao Katayama, Toshihiro Matsui, Naoshi Fukui, Kiyoshi Migita and Shigeto Tohma

J. Clin. Med. 2024, 13(22), 6761; https://doi.org/10.3390/jcm13226761 - 10 Nov 2024

Viewed by 1025

Abstract

Objectives: A common complication in patients with rheumatoid arthritis (RA) is interstitial lung disease (ILD). Antibodies (Abs) to anti-aminoacyl-transfer ribonucleic acid synthetase (ARS) are linked to ILD in patients with idiopathic inflammatory myopathies (IIM). There have been limited studies of anti-ARS Abs in RA. In this study, we examined anti-ARS Abs in ILD in patients with RA. Methods: Anti-ARS Abs in serum from patients with RA were measured. Results: There were higher anti-ARS Ab levels in RA patients with ILD (mean ± SDM, 16.3 ± 32.3 vs. 7.4 ± 7.0 (Index), p = 5.58 × 10⁻¹²), usual interstitial pneumonia (14.4 ± 24.4 vs. 7.4 ± 7.0 [Index], p = 3.14 × 10⁻¹²), and nonspecific interstitial pneumonia (17.9 ± 37.7 vs. 7.4 ± 7.0 (Index), p = 5.07 × 10⁻⁵) compared with patients without chronic lung disease. The area under the curve (AUC) of the receiver operating characteristic curve for anti-ARS Ab was too low to allow for discrimination among RA patients with/without chronic lung disease (0.608, 95% confidence interval (CI) 0.560–0.655, p = 8.69 × 10⁻⁶). Multiple logistic regression analyses of age, smoking status, anti-ARS Abs, as well as Steinbrocker stage generated an ARS-index with a high AUC value (0.707, 95%CI 0.662–0.752, p = 2.20 × 10⁻¹⁹). Conclusions: Anti-ARS Abs are related to ILD pathogenesis in RA and may be a biomarker for ILD. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis: Clinical Updates on Diagnosis and Treatment)

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9 pages, 449 KiB

Open AccessArticle

Influence of Safety Warnings on the Prescribing Attitude of JAK Inhibitors for Rheumatoid Arthritis in Italy

by Marino Paroli, Andrea Becciolini, Alberto Lo Gullo, Simone Parisi, Elena Bravi, Romina Andracco, Valeria Nucera, Francesca Ometto, Federica Lumetti, Antonella Farina, Patrizia Del Medico, Matteo Colina, Viviana Ravagnani, Palma Scolieri, Maddalena Larosa, Marta Priora, Elisa Visalli, Olga Addimanda, Rosetta Vitetta, Alessandro Volpe, Alessandra Bezzi, Francesco Girelli, Aldo Biagio Molica Colella, Rosalba Caccavale, Eleonora Di Donato, Giuditta Adorni, Daniele Santilli, Gianluca Lucchini, Eugenio Arrigoni, Ilaria Platè, Natalia Mansueto, Aurora Ianniello, Enrico Fusaro, Maria Chiara Ditto, Vincenzo Bruzzese, Dario Camellino, Gerolamo Bianchi, Francesca Serale, Rosario Foti, Giorgio Amato, Francesco De Lucia, Ylenia Dal Bosco, Roberta Foti, Massimo Reta, Alessia Fiorenza, Guido Rovera, Antonio Marchetta, Maria Cristina Focherini, Fabio Mascella, Simone Bernardi, Gilda Sandri, Dilia Giuggioli, Carlo Salvarani, Maria Ilenia De Andres, Veronica Franchina, Francesco Molica Colella, Giulio Ferrero, Bernd Raffeiner and Alarico Ariani Show full author list Hide full author list

J. Clin. Med. 2024, 13(13), 3929; https://doi.org/10.3390/jcm13133929 - 4 Jul 2024

Cited by 2 | Viewed by 2180

Abstract

Background/Objectives: The Janus kinase inhibitors (JAKi) tofacitinib (TOFA), baricitinib (BARI), upadacitinib (UPA), and filgotinib (FILGO) are effective drugs for the treatment of rheumatoid arthritis. However, the US Food and Drug Administration (FDA) raised concerns about the safety of TOFA after its approval. This prompted the European Medicines Agency (EMA) to issue two safety warnings for limiting TOFA use, then extended a third warning to all JAKi in patients at high risk of developing serious adverse effects (SAE). These include thrombosis, major adverse cardiac events (MACE), and cancer. The purpose of this work was to analyze how the first two safety warnings from the EMA affected the prescribing of JAKi by rheumatologists in Italy. Methods: All patients with rheumatoid arthritis who had been prescribed JAKi for the first time in a 36-month period from 1 July 2019, to 30 June 2022 were considered. Data were obtained from the medical records of 29 Italian tertiary referral rheumatology centers. Patients were divided into three groups of 4 months each, depending on whether the JAKi prescription had occurred before the EMA’s first safety alert (1 July–31 October 2019, Group 1), between the first and second alerts (1 November 2019–29 February 2020, Group 2), or between the second and third alerts (1 March 2021–30 June 2021, Group 3). The percentages and absolute changes in the patients prescribed the individual JAKi were analyzed. Differences among the three groups of patients regarding demographic and clinical characteristics were also assessed. Results: A total of 864 patients were prescribed a JAKi during the entire period considered. Of these, 343 were identified in Group 1, 233 in Group 2, and 288 in Group 3. An absolute reduction of 32% was observed in the number of patients prescribed a JAKi between Group 1 and Group 2 and 16% between Group 1 and Group 3. In contrast, there was a 19% increase in the prescription of a JAKi in patients between Group 2 and Group 3. In the first group, BARI was the most prescribed drug (227 prescriptions, 66.2% of the total), followed by TOFA (115, 33.5%) and UPA (1, 0.3%). In the second group, the most prescribed JAKi was BARI (147, 63.1%), followed by TOFA (65, 27.9%) and UPA (33, 11.5%). In the third group, BARI was still the most prescribed JAKi (104 prescriptions, 36.1%), followed by UPA (89, 30.9%), FILGO (89, 21.5%), and TOFA (33, 11.5%). The number of patients prescribed TOFA decreased significantly between Group 1 and Group 2 and between Group 2 and Group 3 (p ˂ 0.01). The number of patients who were prescribed BARI decreased significantly between Group 1 and Group 2 and between Group 2 and Group 3 (p ˂ 0.01). In contrast, the number of patients prescribed UPA increased between Group 2 and Group 3 (p ˂ 0.01). Conclusions: These data suggest that the warnings issued for TOFA were followed by a reduction in total JAKi prescriptions. However, the more selective JAKi (UPA and FILGO) were perceived by prescribers as favorable in terms of the risk/benefit ratio, and their use gradually increased at the expense of the other molecules. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis: Clinical Updates on Diagnosis and Treatment)

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Review

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20 pages, 3280 KiB

Open AccessFeature PaperReview

Rheumatoid Factor: Diagnostic and Prognostic Performance and Therapeutic Implications in Rheumatoid Arthritis

by Tasuku Togashi, Ryuhei Ishihara, Ryu Watanabe, Mayu Shiomi, Yuya Yano, Yuhei Fujisawa, Masao Katsushima, Kazuo Fukumoto, Shinsuke Yamada and Motomu Hashimoto

J. Clin. Med. 2025, 14(5), 1529; https://doi.org/10.3390/jcm14051529 - 25 Feb 2025

Viewed by 919

Abstract

Rheumatoid factor (RF) is the first autoantibody identified in rheumatoid arthritis (RA) which targets the fragment crystallizable (Fc) region of immunoglobulin (Ig) G. Although IgM isotype is predominant, other Ig isotypes, including IgG and IgA, also exist. While RF is not specific to RA, it remains a valuable serological test for diagnosing the disease, as evidenced by its inclusion in the 2010 classification criteria for RA based on elevated serum RF levels. RF is also associated with RA severity, including joint damage and extra-articular manifestations, serving as a poor prognostic factor and aiding in the identification of difficult-to-treat RA. Recent studies have demonstrated that high serum RF levels are associated with a reduced response to tumor necrosis factor (TNF) inhibitors. In contrast, anti-TNF antibodies lacking the Fc portion have shown stable efficacy in RA patients regardless of baseline RF levels. These findings reaffirm the clinical significance of RF measurement, 80 years after its initial discovery. This review explores the diagnostic and prognostic significance of RF and its impact on treatment selection in RA management. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis: Clinical Updates on Diagnosis and Treatment)

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20 pages, 1124 KiB

Open AccessReview

Osteoporosis and Rheumatoid Arthritis: Mechanisms Underlying Osteoclast Differentiation and Activation or Factors Associated with Hip Fractures

by Takeshi Miyamoto

J. Clin. Med. 2025, 14(4), 1138; https://doi.org/10.3390/jcm14041138 - 10 Feb 2025

Viewed by 966

Abstract

Osteoporosis is defined as a condition of increased risk of fracture due to decreased bone strength. In developed countries, the number of patients with osteoporosis and fragility fractures has been increasing in recent years due to the growing elderly population, posing a social challenge not only to fracture patients and their families but also to the social healthcare economy. Osteoporosis can be divided into two categories: primary osteoporosis caused by aging or menopause and secondary osteoporosis caused by metabolic or inflammatory diseases or drugs such as glucocorticoids. The majority of patients have primary osteoporosis, and the pathogenesis of postmenopausal osteoporosis and factors associated with fragility fractures in the elderly have been elucidated. On the other hand, rheumatoid arthritis (RA) is one of the causes of secondary osteoporosis. RA is a chronic inflammatory disease characterized by joint swelling and destruction. Most often, treatment focuses on suppressing these symptoms. However, physicians should be aware of the risk of osteoporosis in RA patients, because (1) RA is a chronic inflammatory disease, which itself can be a risk factor for osteoporosis; (2) glucocorticoids, which are sometimes administered to treat RA, can be a risk factor for osteoporosis; and (3) patients with RA are becoming older, and aging is an osteoporosis risk factor. A comprehensive understanding of the pathogenesis of osteoporosis and its fragility fractures requires elucidating the mechanisms underlying osteoclast activation, which drives their development. Furthermore, identifying the factors associated with fragility fractures is essential. This review summarizes the pathogenesis of osteoporosis, the factors associated with fragility fractures, and the associations between RA and osteoporosis development. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis: Clinical Updates on Diagnosis and Treatment)

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16 pages, 1731 KiB

Open AccessReview

Unmet Needs and Current Challenges of Rheumatoid Arthritis: Difficult-to-Treat Rheumatoid Arthritis and Late-Onset Rheumatoid Arthritis

by Satoshi Takanashi and Yuko Kaneko

J. Clin. Med. 2024, 13(24), 7594; https://doi.org/10.3390/jcm13247594 - 13 Dec 2024

Cited by 1 | Viewed by 1978

Abstract

Despite remarkable advances in the management of RA, there are still unmet needs that rheumatologists need to address. In this review, we focused on difficult-to-treat RA (D2T RA) and late-onset RA (LORA), and summarized their characteristics and management. The prevalence of D2T RA is reported to be 6–28% and many factors have been identified as risk factors for D2T RA, including female sex, long disease duration, seropositivity for rheumatoid factor and anti-cyclic citrullinated peptide antibody and their high titer, baseline high disease activity, and comorbidities. D2T RA is broadly divided into inflammatory and non-inflammatory conditions, and clinical features differ according to background. A proportion of D2T RA can be managed with treatment modification, mainly with interleukin-6 receptor inhibitors or Janus kinase inhibitors, but some D2T RA patients have a poor prognosis; thus, the implementation of precision medicine by stratifying patients according to disease status is needed. In the aging society, the epidemiology of RA is changing and the prevalence of LORA is increasing worldwide. LORA has distinct clinical features compared with young-onset RA, such as acute onset, low seropositivity, and high inflammation. The pathogenesis of LORA remains to be elucidated, but proinflammatory cytokines, including interleukin-6, have been reported to be significantly elevated. LORA has several management concerns other than RA itself, such as geriatric syndrome and multimorbidity. The treat-to-target strategy is effective for LORA, but the evidence is still lacking; thus, it is important to accumulate clinical and related basic data to establish the optimal treatment strategy for LORA. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis: Clinical Updates on Diagnosis and Treatment)

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