Different Clinical Relevance of Anti-Citrullinated Protein Antibodies in RA Patients.

The objective of the study was to find a potential relationship between ACPAs and disease activity, bone destruction, and ACPA responses to various therapeutic regimens. The study included 232 patients with rheumatoid arthritis (RA); 90 patients had early RA, and 142 patients had an advanced stage of the disease. 77 (85.6%) patients with early RA were highly positive for anti-CCP, and 29 (70.7%) patients were highly positive for anti-MCV. A positive correlation was found between anti-MCV and DAS28 (r = 0.4; p = 0.04). As for advanced RA, 78 (80.4%) patients were high-positive for anti-CCP, and 70 (79.5%) were high-positive for anti-MCV. There was a positive correlation between anti-MCV concentration and SDAI (r = 0.4; p = 0.02), as well as CDAI (r = 0.4; p = 0.02). No significant correlations were found between the anti-CCP levels and activity indices, anti-CCP and acute-phase parameters in both early and advanced RA groups. Higher total Sharp scores (96.5 (65.0-122.0)) were found in pts highl-positive for anti-MCV (n = 79), compared to low-positive/negative (n = 27) patients (57.0 (31.0-88.0); p < 0.05). Anti-MCV levels dropped significantly in pts on rituximab and tocilizumab therapy at weeks 12 and 24 after initiation of treatment, while high anti-CCP concentration persisted throughout the treatment. Anti-MCV levels correlated with inflammatory activity and development of bone destruction and decreased in pts on treatment. Anti-CCP was less responsive and showed minor changes during treatment; therefore, its thorough monitoring was not feasible.

Using Treg, Tr1, and Breg Expression Levels to Predict Clinical Responses to csDMARD Treatment in Drug-naive Patients With Rheumatoid Arthritis.

BACKGROUND/AIM: Regulatory T cells (Treg) play a crucial role in maintaining immune tolerance and preventing autoimmune diseases. Recent data also indicate that type 1 regulatory T (Tr1) and regulatory B (Breg) cells play an inhibitory (i.e., protective) role in autoimmune diseases. Conventional synthetic disease-modifying antirheumatic drugs (csDMARD) are a first-line therapy for rheumatoid arthritis (RA), and our aim was to predict clinical responses of this treatment using immunophenotyping. MATERIALS AND METHODS: We first detected the presence of immune cells in fresh blood from 16 healthy controls (HC) and 26 patients with RA (14 drug-naive and 12 csDMARD-experienced). Then, we recorded immunophenotypic changes in 14 drug-naive RA (naive RA) patients prior to csDMARD treatment (i.e., day 0) and after receiving treatment for 6 months. The observed changes were also compared with other clinical indicators, including the presence of anti-citrullinated peptide antibodies (anti-CCP), rheumatoid factor (RF) levels, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels. RESULTS: Naive RA patients had significantly lower Tregs than HC and csDMARD-experienced patients (both p<0.0001) and the number of Tregs correlated with the diagnosis of RA and therapeutic efficacy of csDMARD treatment. Furthermore, lower baseline levels of Treg, memory Treg, Tr1, and higher PD-1+ Marginal B, Breg cells were significantly associated with decreased development of the 28-joint Disease Activity Score (DAS28) (all p<0.05), revealing better medical response. Multiple regression and principal component analysis identified Treg, Tr1, and Breg as potential predictors of csDMARD responses (Area under curve: 0.9; Accuracy: 92.86%). Furthermore, elevated Treg, Tr1, and Breg cells were associated with decreased DAS28, ESR, and CRP (all p<0.05); changes in Treg and Breg cell expression were also more pronounced among double negative anti-CCP and RF in RA patients with better outcomes (p<0.05). CONCLUSION: Immunophenotyping can be an adjunct clinical tool to identify patients who are poor candidates for csDMARD therapy. Alternative therapeutic interventions in the early stages of disease should be formulated for these patients.

Anti-citrullinated protein antibodies as biomarkers in rheumatoid arthritis.

INTRODUCTION: The serological biomarker anti-citrullinated protein antibodies (ACPAs) may have several functions but is especially important for the diagnosis of rheumatoid arthritis (RA) along with clinical symptoms. AREAS COVERED: This review provides an overview of ACPAs, which are useful in RA diagnostics and may improve our understanding of disease etiology. PubMed was searched with combinations of words related to antibodies recognizing epitopes containing the post-translationally modified amino acid citrulline in combination with rheumatoid arthritis; cyclic citrullinated peptide, CCP, anti-CCP, anti-citrullinated protein antibodies, ACPA, citrullination, peptide/protein arginine deiminase, PAD, filaggrin, vimentin, keratin, collagen, perinuclear factor, EBNA1, EBNA2, and others. From this search, we made a qualitative extract of publications relevant to the discovery, characterization, and clinical use of these antibodies in relation to RA. We highlight significant findings and identify areas for improvement. EXPERT OPINION: ACPAs have high diagnostic sensitivity and specificity for RA and recognize citrullinated epitopes from several proteins. The best-performing single epitope originates from Epstein-Barr Virus nuclear antigen 2 and contains a central Cit-Gly motif, which is recognized by ACPAS when located in a flexible peptide structure. In addition, ACPAs may also have prognostic value, especially in relation to early treatment, although ACPAs' main function is to aid in the diagnosis of RA.

Clinical characteristics of multicentric reticulohistiocytosis and distinguished features from rheumatoid arthritis: a single-center experience in China.

OBJECTIVE: To investigate the clinical features of multicentric reticulohistiocytosis (MRH). METHODS: The clinical manifestations, laboratory examination results and histologic characteristics of eleven patients with MRH were collected and compared with those of 33 patients with rheumatoid arthritis. RESULTS: In total, 72.7% of the MRH patients were women. The median age was 46 years (range 33-84 years). Diagnosed by specific pathologic features, all MRH patients exhibited cutaneous involvement. The dorsa of the hands, arms, face and auricle were the most commonly affected areas. Nodules were also located on the legs, scalp, trunk, neck, and even the hypoglossis and buccal mucosa. Ten MRH patients (90.9%) had symmetric polyarthritis. Compared with rheumatoid arthritis (RA) patients, MRH patients were more likely to have distal interphalangeal joint (DIP) involvement (63.6% vs 24.2%, P = 0.017) and less likely to have elbow (36.4% vs 72.7%, P = 0.003), ankle (45.5% vs 93.9%, P < 0.001) and metacarpophalangeal joint (MCP) (36.4% vs 78.8%, P = 0.009) involvement. Positivity for rheumatoid factor (RF) (36.4% vs 84.6%, P = 0.001) and anti-CCP antibody (9.1% vs 81.8%, P = 0.000), as well as the median RF titer [43.8 (31.7-61.0) vs 175.4 (21.3-940.3), P = 0.021], in MRH patients was lower than in RA patients. Elevation of the erythrocyte sedimentation rate (ESR) was also less common in MRH patients than in RA patients (36.4% vs 72.7%, P = 0.030). After treatment with median- to large-dose corticosteroids and disease-modifying antirheumatic drugs, 8 patients achieved complete remission and 2 patients partial remission (skin lesions ameliorated, joint lesions not ameliorated). CONCLUSION: Always pathologically diagnosed, MRH is a systemic disease involving RA-like erosive polyarthritis and a specific distribution of skin nodules characterized by "coral beads". More DIP involvement and less elbow, ankle and MCP involvement are seen in MRH than in RA. In addition, less positivity and lower-titer RF, uncommon presence of anti-CCP antibodies and ESR elevation may be helpful to distinguish MRH from RA.

Pathogenesis, clinical features, and treatment strategy for rheumatoid arthritis-associated interstitial lung disease.

Rheumatoid arthritis is an autoimmune disease that primarily affects the joints. The emergence of highly effective anti-rheumatic drugs such as biologic agents and janus kinase inhibitors has dramatically improved the management of the disease by preventing irreversible joint destruction and disability. This disease can manifest the serious extra-articular involvements including interstitial lung disease, which has the significant impact on the patients' morbidity and mortality. However, treatment strategy specific for rheumatoid arthritis-associated interstitial lung disease (RA-ILD) has not been yet established. Therefore, understanding the pathogenesis and clinical features of RA-ILD is critical to provide the better management and improve the prognosis of the patients. Accumulation of evidence suggest that it is essentially important to achieve remission or at least low disease activity of arthritis to prevent new emergence, progression, or acute exacerbation of RA-ILD. RA-ILD patients frequently show high titers of autoantibodies including rheumatoid factor and anti-CCP antibody, and the excessive formation of tertiary lymphoid organs is found in the local affected lungs, indicating the adaptive immune response as a key pathogenic inducer. In this regard, non-TNF inhibitors targeting adaptive immune responses such as abatacept and rituximab were reported to be promising for the stabilization and improvement of RA-ILD. Nintedanib, an anti-fibrotic agent, was shown to be effective for reducing the decline of forced vital capacity in RA-ILD. In this review, we summarized the current evidence in the pathogenesis, clinical features, and treatments for RA-ILD and provide future prospects.

Effects of nonsurgical periodontal therapy in patients with rheumatoid arthritis: a prospective before and after study.

Background: periodontal therapy has been suggested to have systemic effects. However, studies of periodontal therapy in rheumatoid arthritis patients have produced controversial results. Aim: To compare the effects of nonsurgical periodontal therapy on biochemical markers of rheumatoid arthritis and periodontal parameters in patients with and without rheumatoid arthritis. Methods: a prospective before-and-after study was conducted that included 21 participants without and 29 participants with rheumatoid arthritis. Periodontal parameters, Porphyromonas gingivalis detection, C-reactive protein, rheumatoid factor and anti-citrullinated protein antibodies were measured at baseline and three months after nonsurgical periodontal therapy and the changes were statistically assessed. Results: In general, both groups presented statistically significant improvement in periodontal parameters (p<0.05). There was an increase in the counts of P. gingivalis in both groups at three months. In addition, there was a reduction in levels of anti-citrullinated protein antibodies and rheumatoid factor in participants with rheumatoid arthritis. In contrast, C-reactive protein levels increased in both groups but were higher in the rheumatoid arthritis group. Periodontal parameters in rheumatoid arthritis participants under disease-modifying antirheumatic drugs presented a slightly higher improvement (p <0.05). Conclusions: Nonsurgical periodontal therapy has similar improvements in periodontal parameters in patients with and without rheumatoid arthritis. In addition, nonsurgical periodontal therapy may benefit serum levels of anti-citrullinated protein antibodies and rheumatoid factors in patients with rheumatoid arthritis. NCT04658615.

Antecedentes: se ha sugerido que la terapia periodontal tiene efectos sistémicos. Sin embargo, los estudios de la terapia periodontal en pacientes con artritis reumatoide han producido resultados controvertidos. Objetivo: comparar los efectos de la terapia periodontal no quirúrgica sobre los marcadores bioquímicos de la artritis reumatoide y los parámetros periodontales en pacientes con y sin artritis reumatoide. Métodos: se realizó un estudio prospectivo de antes y después que incluyó a 21 participantes sin artritis reumatoide y 29 participantes con artritis reumatoide. Se midieron los parámetros periodontales, detección de Porphyromonas gingivalis, proteína C reactiva, factor reumatoide y anticuerpos anti-proteína citrulinada al inicio del estudio y tres meses después de la terapia periodontal no quirúrgica y los cambios se evaluaron estadísticamente. Resultados: En general, ambos grupos presentaron mejoría estadísticamente significativa en los parámetros periodontales (p <0.05). Hubo un aumento en los recuentos de P. gingivalis en ambos grupos a los tres meses. Además, hubo una reducción en los niveles de anticuerpos anti-proteína citrulinada y factor reumatoide en participantes con artritis reumatoide. Por el contrario, los niveles de proteína C reactiva aumentaron en ambos grupos, pero fueron más altos en el grupo de artritis reumatoide. Los parámetros periodontales en los participantes con artritis reumatoide bajo fármacos antirreumáticos modificadores de la enfermedad presentaron una mejoría ligeramente mayor (p <0.05). Conclusiones: La terapia periodontal no quirúrgica tiene mejoras similares en los parámetros periodontales en pacientes con y sin artritis reumatoide. Además, la terapia periodontal no quirúrgica puede beneficiar los niveles séricos de anticuerpos anti-proteína citrulinada y factor reumatoide en pacientes con artritis reumatoide. NCT04658615.

Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases.

Excessive release of neutrophil extracellular traps (NETs) is associated with disease severity and contributes to tissue injury, followed by severe organ damage. Pharmacological or genetic inhibition of NET release reduces pathology in multiple inflammatory disease models, indicating that NETs are potential therapeutic targets. Here, we demonstrate using a preclinical basket approach that our therapeutic anti-citrullinated protein antibody (tACPA) has broad therapeutic potential. Treatment with tACPA prevents disease symptoms in various mouse models with plausible NET-mediated pathology, including inflammatory arthritis (IA), pulmonary fibrosis, inflammatory bowel disease and sepsis. We show that citrulline residues in the N-termini of histones 2A and 4 are specific targets for therapeutic intervention, whereas antibodies against other N-terminal post-translational histone modifications have no therapeutic effects. Because citrullinated histones are generated during NET release, we investigated the ability of tACPA to inhibit NET formation. tACPA suppressed NET release from human neutrophils triggered with physiologically relevant human disease-related stimuli. Moreover, tACPA diminished NET release and potentially initiated NET uptake by macrophages in vivo, which was associated with reduced tissue damage in the joints of a chronic arthritis mouse model of IA. To our knowledge, we are the first to describe an antibody with NET-inhibiting properties and thereby propose tACPA as a drug candidate for NET-mediated inflammatory diseases, as it eliminates the noxious triggers that lead to continued inflammation and tissue damage in a multidimensional manner.

Eficacia diagnóstica de anticuerpos antipéptidos citrulinados de segunda y tercera generaciones para la artritis reumatoide / Diagnostic effectiveness of anti-citrullinated peptides antibodies of second and third generations for rheumatoid arthritis

Introducción: La artritis reumatoide es una enfermedad autoinmune caracterizada por la presencia de anticuerpos contra péptidos citrulinados, que constituyen indicadores para el diagnóstico de la enfermedad. Es necesario determinar la utilidad de diferentes métodos de determinación de estos anticuerpos para el diagnóstico de pacientes cubanos con artritis reumatoide. Objetivo: Determinar la eficacia de los ensayos de determinación de anticuerpos anti-CCP2 y anti-CCP3 para el diagnóstico de pacientes cubanos con artritis reumatoide. Material y método: Participaron 101 pacientes con artritis reumatoide, 58 pacientes con otras enfermedades reumáticas e inflamatorias y 43 individuos sanos. Se determinó la eficacia diagnóstica de los anticuerpos factor reumatoideo (FR), anti-CCP2 y anti-CCP3 medidos mediante ELISA, con el cálculo de la sensibilidad, especificidad, valores predictivos positivos y negativos. Resultados: El ensayo anti-CCP2 mostró un mejor balance sensibilidad (48,5 por ciento) y especificidad (98,0 por ciento). Cuando se fijó la especificidad a 98 por ciento, se observó la menor sensibilidad para el FR (40,3 por ciento). Utilizar los ensayos anti-CCP2 y FR aumentó la especificidad a 100 por ciento. Todos los autoanticuerpos mostraron asociación con la proteína C reactiva y correlación con la velocidad de sedimentación globular. Solamente los anticuerpos anti-CCP2 no mostraron correlación con el indicador clínico de actividad DAS 28. Conclusiones: Los anticuerpos anti-CCP2 son los de mayor eficacia para el diagnóstico de pacientes cubanos con artritis reumatoide. La determinación de FR permite identificar pacientes con artritis reumatoide seronegativos de anticuerpos anti-CCP2, por lo que la combinación de ambos inmunoensayos produce una mejoría en la eficacia diagnóstica(AU)

Introduction: Rheumatoid arthritis is an autoimmune disease characterized by the presence of antibodies against citrullinated peptides, which are one of the indicators for the diagnosis of a disease. The usefulness of different methods for the determination of these antibodies in the diagnosis of Cuban patients with rheumatoid arthritis is necessary to be established. Objective: To establish the diagnostic effectiveness of the second (anti-CCP2) and third (anti-CCP3) generation assays for the determination these antibodies against citrullinated peptides in Cuban patients with rheumatoid arthritis. Material and method: 101 patients with rheumatoid arthritis, 58 patients with other rheumatic and inflammatory diseases, and 43 healthy persons participated in the study. The diagnostic efficiency of rheumatoid factor (RF), anti-CCP2 and anti-CCP3 antibodies were determined using ELISA test, by calculating sensitivity, specificity, and positive and negative predictive values. Results: The anti-CCP2 assay showed a better balance of sensitivity (48.5 percent) and specificity (98.0 percent). The lower sensibility was observed for RF (40.3 percent) when the specificity was set at 98 percent. Specificity increased to 100 percent when anti-CCP2 and RF assays were used. All autoantibodies showed association with C-reactive protein and correlation with erythrocyte sedimentation rate. Only anti-CCP2 antibodies showed no correlation with the DAS28 clinical indicator. Conclusions: Anti-CCP2 antibodies are the ones of greater effectiveness in the diagnosis of Cuban patients with rheumatoid arthritis. RF identification allows to identify seronegative anti-CCP2 patients; therefore, the combination of both immunoassays leads to an improvement in the diagnostic effectiveness(AU)

ACPA mediates the interplay between innate and adaptive immunity in rheumatoid arthritis.

The production of anti-citrullinated peptide antibodies (ACPAs) requires the participation of both innate immunity and adaptive immunity. On the one hand, activated innate immunity is able to produce citrullinated auto-antigens that fuel autoimmunity and provide an inflammatory environment that facilitates the breach of self-tolerance, proliferation of self-reactive T/B cells and the production of ACPAs. On the other hand, after their production by plasma B cells, ACPAs are also able to interact with innate immunity to exacerbate the manifestation and chronicity of rheumatoid arthritis (RA). This article discusses the roles of citrullinated peptides and ACPA played in innate immunity and autoimmunity. In addition, we emphasise the relationships between environmental factors and innate immunity, as well as the pathogenic function of ACPAs per se. In doing so, we hope to provide fundamental knowledge of RA pathogenesis and reveal potential therapeutic targets in RA treatment.

The Role of Autoantibodies in Bone Metabolism and Bone Loss.

Many autoimmune diseases are associated with deranged bone metabolism. The resulting localized or systemic bone loss can compromise the quality of life of patients by causing local bone deformities or fragility fractures. There is emerging evidence that antibodies have a direct impact on key players of bone homeostasis, in particular osteoclasts. Clinical and pre-clinical studies provide insight into the function of autoantibodies related to Rheumatoid Arthritis (rheumatoid factor, anti-citrullinated protein antibodies, and anti-carbamylated protein antibodies) and their inflammation-independent interaction with bone cells. Furthermore, we summarize the current knowledge about neutralizing antibodies to the antiresorptive protein osteoprotegerin, which have been described in patients with Coeliac Disease, Rheumatoid Arthritis, and Spondyloarthritis.