Periodontal Infection May Determine Best Treatment for Patients with RA

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July 4, 2016 • By

The Rheumatologist

The pathology of rheumatoid arthritis (RA) includes a breach in self-tolerance, chronic synovial inflammation and joint destruction. As the disease progresses, patients are increasingly likely to have high serum levels of anti-cyclic citrullinated peptide (CCP) antibody. A search for the source of anti-CCP antibodies has led researchers to suggest that infection with a common periodontal pathogen, Porphyromonas gingivalis, may play an important role in the generation of the anti-CCP antibodies. Porphyromonas gingivalis produces an enzyme known as peptidularginine deiminase (PPAD), which modifies peptidylarginine residues to citrulline, thereby creating the antigen that is the target of the anti-CCP antibody. This connection between RA and Porphyromonas gingivalis infection has also led investigators to question whether the relationship can be leveraged to improve the treatment of RA.

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Anti‑citrullinated peptide antibodies and their value for predicting responses to biologic agents: a review

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Rheumatol Int DOI 10.1007/s00296-016-3506-3

Emilio Martin‑Mola1,7 · Alejandro Balsa1 · Rosario García‑Vicuna2 · Juan Gómez‑Reino3 · Miguel Angel González‑Gay4 · Raimon Sanmartí5 · Estíbaliz Loza

Abstract Anti-citrullinated peptide antibodies (ACPAs) play an important pathogenic role both at the onset and during the disease course. These antibodies precede the clinical appearance of rheumatoid arthritis (RA) and are associated with a less favorable prognosis, both clinically and radiologically. The objective of this work was to conduct a comprehensive review of studies published through September 2015 of ACPAs’ role as a predictor of the therapeutic response to the biological agents in RA patients. The review also includes summary of the biology and detection of ACPAs as well as ACPAs in relation to joint disease and CV disease and the possible role of seroconversion. The reviews of studies examining TNF inhibitors and tocilizumab yielded negative results. In the case of rituximab, the data indicated a greater probability of clinical benefit in ACPA+ patients versus ACPA− patients, as has been previously described for rheumatoid factor. Nonetheless, the effect is discreet and heterogeneous. Another drug that may have greater effectiveness in ACPA+ patients is abatacept. Some studies have suggested that the drug is more efficient in ACPA+ patients and that those patients show greater drug retention. In a subanalysis of the AMPLE trial, patients with very high ACPA titers who were treated with abatacept had a statistically significant response compared to patients with lower titers. In summary, the available studies suggest that the presence of or high titers of ACPA may predict a better response to rituximab and/or abatacept. Evidence regarding TNFi and tocilizumab is lacking. However, there is a lack of studies with appropriate designs to demonstrate that some drugs are superior to others for ACPA+ patients.

Review: Preclinical Rheumatoid Arthritis: Progress Toward Prevention

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  1. Kulveer Mankia and
  2. Paul Emery†,*
Arthritis & Rheumatology

Volume 68, Issue 4, pages 779–788, April 2016

Introduction

Starting therapy early leads to better outcomes for rheumatoid arthritis (RA) patients. Early initiation of disease-modifying treatments is associated with less joint damage and increased chances of achieving remission. But what is early disease? Conventionally, this is taken to mean the initial phase after arthritis becomes clinically detectable. However, recent studies have challenged this presumption and have suggested that disease processes become established in the preclinical period, a phase often described as pre-RA. The corollary of this represents a paradigm shift; clinical arthritis is not the beginning of the disease but is, instead, the culmination of a whole series of well-established pathologic events.

In this review, we provide an overview of the preclinical phases of RA, with special focus on recent advances in the field. Specifically, we will review evidence suggesting that localized autoimmunity may be an important trigger in preclinical disease, an area attracting growing research interest. Newly characterized immunologic and imaging biomarkers and their significance in prospective cohorts will also be discussed. Finally, the clinical features and management of individuals at-risk of developing RA are also described.

Defining pre-RA: classification of at-risk individuals

Many important pathologic events occur before RA becomes clinically manifest. In order to standardize the terminology for the phases leading up to and including RA, the European League Against Rheumatism Standing Committee on Investigative Rheumatology devised a recommendation for nomenclature [1]. Six phases of RA development were agreed upon (Figure 1). The categories are genetic and environmental risk factors for RA (phases A and B, respectively), systemic autoimmunity associated with RA (phase C), symptoms without clinical arthritis (phase D), and both undifferentiated arthritis and RA (phases E and F, respectively). The proposed categories are intended as a broad framework based on the current understanding of the etiology of RA. It is clear that individuals may not necessarily progress through all phases, and that individual phases are not mutually exclusive. Importantly, although individuals are at risk of RA, the terms preclinical RA and pre-RA should only be used retrospectively, as many at-risk individuals will never develop clinical arthritis or RA. This is especially true for individuals in phases A and B who are healthy individuals with risk factors that may never translate into pathologic processes.

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ACPA-Positive & ACPA-Negative Patients with RA: The Difference Begins in the Lungs

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January 4, 2016 • By Lara C. Pullen, PhD
The Rheumatologist

Rheumatoid arthritis (RA) is characterized by chronic inflammation in the joints. Approximately two-thirds of patients with RA have anti-citrullinated protein antibodies (ACPA), and these individuals are more likely to have an aggressive disease phenotype. Results from recent studies have suggested that citrullinated proteins may emerge in extra-articular sites and contribute to RA pathogenesis. Some investigators have suggested that the emergence of these citrullinated proteins may precede RA because ACPA can be found in the peripheral blood several years before the onset of RA. Researchers have also noted that patients with seropositive, active RA are also more likely to have inflammation in the lungs.
A new study from Stockholm, Sweden, further strengthens the link between the lungs and ACPA-positive RA. Gudrun Reynisdottir, a graduate student at the Karolinska University Hospital and Institutet, and colleagues published the results of their analysis of 24 patients online on Nov. 3 in the Annals of the Rheumatic Diseases.1 They analyzed the bronchial tissue and bronchoalveolar lavage (BAL) of untreated patients with early RA who did not have concomitant lung disease. Although these patients were within a year of diagnosis, their lungs had signs of immune cell accumulation and activation. The results suggest that early inflammatory events in the lungs are a critical initiating factor for the development of ACPA-positive RA.

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Me han detectado (anticuerpos) ACPA (+) ¿Tengo Artritis Reumatoide?

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Desde hace unos años sabemos que los pacientes que en un futuro desarrollarán una artritis reumatoide (AR) poseen en su sangre desde bastantes años antes de padecer la enfermedad, unos anticuerpos que jugarán un factor decisivo en la aparición de una AR. Fundamentalmente estamos hablando de los ACPA, también conocidos en su terminología antigua como anti-CCP. Los ACPA están ligados al tabaquismo, aunque hay otros muchos factores que influyen en su desarrollo, y por tanto el tabaco se ha convertido en uno de los factores de riesgo extrínsecos más relevantes, para poder desarrollar una AR. No obstante, el tabaco no es el único factor y no es infrecuente ver a personas que tienen ACPA que nunca fumaron.

En primer lugar una advertencia muy importante: muchas personas que tienen ACPA en su sangre, nunca tendrán una AR. Por tanto hay que ser extremadamente cauto a la hora de establecer un juicio clínico. Sin embargo, a veces nos encontramos personas sanas, que por cualquier motivo se le ha hecho una analítica para detectar ACPA y ésta ha sido positiva. Esto motiva consultas médicas de gente que quiere saber qué posibilidades tendrá de desarrollar una AR.

Como hemos dicho antes, el tabaco y la obesidad (no mencionada hasta ahora) son dos factores muy relevantes en las personas que tienen ACPA, para que en un futuro desarrollen una AR. Por tanto, nuestro consejo siempre irá orientado a suspender el tabaco y a perder peso. ¿Hasta qué punto estas medidas van a ser efectivas?, en este momento son desconocidas. Como también lo es el número de personas obesas y fumadoras con ACPA positivos, que desarrollarán una AR.

En resumen, aunque la detección de ACPA, no es habitual en un análisis de rutina, si un día se los determinan y son positivos, consulte con su reumatólogo, aunque no tenga ningún dolor. Él sabrá explicarle qué significado tienen estos anticuerpos y sobre todo ante qué síntomas debe consultar. Pero no lo olvide: la positividad de los ACPA se da en muchas personas que nunca tendrán una AR.

 

Abatacept more effective in RA patients with high levels ACPA

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Impact of baseline anti-cyclic citrullinated peptide-2 antibody concentration on efficacy outcomes following treatment with subcutaneous abatacept or adalimumab: 2-year results from the AMPLE trial

Sokolove J, et al. Ann Rheum Dis 2015;0:1–6. doi:10.1136

ABSTRACT Objectives To examine whether baseline anti-cyclic citrullinated peptide-2 (CCP2) antibody status and concentration correlated with clinical outcomes in patients treated with abatacept or adalimumab on background methotrexate (MTX) in the 2-year AMPLE (Abatacept versus adaliMumab comParison in bioLogicnaïvE rheumatoid arthritis subjects with background MTX) study. Methods In this exploratory analysis, anti-CCP2 antibody concentration was measured at baseline, and antibody-positive patients were divided into equal quartiles, Q1–Q4, representing increasing antibody concentrations. Clinical outcomes analysed by baseline anti-CCP2 status and quartile included change from baseline in disease activity and disability and remission rates. Results Baseline characteristics were generally comparable across quartiles and treatment groups. In both treatment groups, anti-CCP2 antibody-negative patients responded less well than antibody-positive patients. At year 2, improvements in disease activity and disability and remission rates were similar across Q1–Q3, but were numerically higher in Q4 in the abatacept group; in contrast, treatment effects were similar across all quartiles in the adalimumab group. Conclusions In AMPLE, baseline anti-CCP2 positivity was associated with a better response for abatacept and adalimumab. Patients with the highest baseline antiCCP2 antibody concentrations had better clinical response with abatacept than patients with lower concentrations, an association that was not observed with adalimumab.

Doc, in my blood test they found the Cyclic Citrullinated Peptide Antibody (anti-CCP or ACPA) positive. Do I have Rheumatoid Arthritis?

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Sometimes, your doctor may ask for this blood test. Usually, the test is performed for people with pain/swelling joint. But on other occasions it can be done, for complaints that nothing has to do with arthritis in your joints.
We know that ACPA test has specificity for rheumatoid arthritis (RA) close to 97%. That means that people with arthritis and a positivity of this test, the probability of having RA is very high. But, what happens with people who have a positive test and they are asymptomatic?
They always ask, Doc, what are the chances to get RA? We have no answer to this question. We know that many patients with RA they have this positive test in his/her blood for many years before the disease developed. But also we know that many people with this antibody never will develop the disease. So, in case of being asymptomatic, the first question should be, why doctor you asked for this test? Did you have pain/swelling joint when the test was done? Any first-grade relative has RA? If you answer is yes to any of these questions, you need a close follow up by your rheumatologist. If this is not the case, you should ask your doctor, what was the point to inquire for this test that at this moment means nothing.