Elsevier

Clinical Immunology

Volume 161, Issue 1, November 2015, Pages 2-10
Clinical Immunology

Biomarkers for rheumatoid and psoriatic arthritis

https://doi.org/10.1016/j.clim.2015.04.005Get rights and content

Highlights

  • Many different types of biomarkers have been discovered in RA and PsA patients.

  • Even though RA and PsA have similar clinical characteristics, most biomarkers are different.

  • The major difference between RA and PsA is the presence of autoantibodies in RA and absence in PsA.

  • In the future, multiple biomarkers should be measured longitudinally within one cohort.

Abstract

Rheumatic diseases, such as rheumatoid and psoriatic arthritis are systemic inflammatory conditions characterized by a chronic form of arthritis, often leading to irreversible joint damage. Early treatment for patients with rheumatic diseases is required to reduce or prevent joint injury. However, early diagnosis can be difficult and currently it is not possible to predict which individual patient will develop progressive erosive disease or who may benefit from a specific treatment according to their clinical features at presentation. Biomarkers are therefore required to enable earlier diagnosis and predict prognosis in both rheumatoid arthritis and psoriatic arthritis. In this review we will examine the evidence and current status of established and experimental biomarkers in rheumatoid and psoriatic arthritis for three important purposes; disease diagnosis, prognosis and prediction of response to therapy.

Introduction

The term rheumatic musculoskeletal diseases (RMD) encompasses a large and varied group of diseases, that share a number of features such as the involvement of connective tissues, muscles and the joints. In addition to similarities, there is also significant variety across the RMD spectrum including inflammatory and non-inflammatory diseases. Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are two of the most prevalent inflammatory RMD while diseases such as osteoarthritis and fibromyalgia represent the main non-inflammatory conditions. RMD can also be classified according to duration of symptoms or impact on function. The duration may be acute, remitting or chronic persistent and the impact on the subject may vary from mild to severe, often depending on the level of inflammation or tissue damage. The level of inflammation is often quite different in patients with RA and PsA even though both may result in joint damage while fibromyalgia, which is painful, is not associated with inflammation or tissue damage. The signs and symptoms of RA and PsA may be quite similar especially at the earlier phases of disease, so it may be difficult to distinguish between them on clinical grounds, although early treatment may prevent the development of disability in both conditions if introduced appropriately [1], [2].

RA occurs in 0.5–1% of the adult population globally [3]. The main characteristics of RA are stiffness and swelling of the joints as a result of inflammation of the synovium, which normally is a thin translucent membrane lining the non-articular surfaces of the joint. The synovium may proliferate and invade surrounding structures leading to damage of the articular cartilage and erosions of the periarticular bone. The cause of RA is not clear, although both genetic and environmental factors have been identified to play a role in disease initiation and progression. RA patients exhibit an increased frequency of cardiovascular disease, a higher susceptibility to infections and have an increased risk for certain malignancies [3].

PsA occurs in 10–40% of psoriasis patients [4], [5]. Psoriasis is characterized by red, thickened and inflamed skin lesions and affects up to 3% of the general population. In addition to the skin lesions, patients may develop a chronic arthritis of the peripheral and/or axial joints, characterized by inflammation of the synovium and erosions similar to but distinct from RA. Classified as one of the spondyloarthropathies, due to axial joint involvement similar to ankylosing spondylitis, patients may also exhibit enthesitis, uveitis and nail disease [4], [5]. PsA patients, similar to RA, have an increased mortality due to cardiovascular disease, however there is no evidence of increased susceptibility to infections or lymphoma when compared to the general population [6].

The signs and symptoms of RA and PsA patients, including systemic features such as skin and eye manifestations, appear to respond well to anti-inflammatory drugs (corticosteroids and non-steroidal anti-inflammatories (NSAIDs)) and disease-modifying anti-rheumatic drugs (DMARDS) such as tumour necrosis factor inhibitors (TNFi). For some other biological agents there may be a differential response when comparing RA and PsA patients [7], [8].

Biomarkers may be defined in several ways. A simple definition proposed by the US Food and Drugs Administration (FDA) is; ‘Any measurable diagnostic indicator that is used to assess the risk or presence of disease’. However the US National Institutes of Health (NIH) has suggested a more comprehensive definition of a biomarker—‘A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to therapeutic intervention’. The NIH definition encompasses the concept of response to therapy, which is becoming more relevant and therefore more important in the context of RA and PsA.

Therapies for RA and PsA patients have developed rapidly in the past decade such that great improvements in signs and symptoms, but also in quality of life and function, have been realized. However, many patients do not respond to the first treatment that is offered, leaving room for substantial improvements [7], [8]. Also, in both RA and PsA, early treatment is important in order to prevent irreversible joint damage [1], [2]. In order to treat patients in an early stage of the disease, it is essential to determine which of the patients that visit the doctor with psoriasis or joint pain will eventually develop PsA or RA respectively. Only the patients that do acquire PsA or RA will benefit from the treatment, while people who do not develop severe disease might suffer from unnecessary side effects. Furthermore, not all treatments are effective in each patient and treatments are often given on basis of trial and error [7], [8]. It would therefore be useful to predict which RA and PsA patients will benefit from a specific treatment.

In this review, we describe the biomarkers that are generally accepted for PsA and RA, after which we will discuss a selection of interesting biomarkers that are still under investigation. This will include biomarkers that are used to improve diagnosis, to predict prognosis and to identify response to treatment.

Section snippets

Autoantibodies

For RA patients, one of the most important types of biomarkers at the moment is autoantibodies. The most recent criteria for the diagnosis of RA were described in 2010 [9]. Besides joint pain and inflammation, several serological biomarkers are used to classify RA patients. Serological biomarkers, described in the new criteria, include autoantibodies such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA).

Currently there is little evidence for a role of autoantibodies in

Other serum biomarkers

Besides autoantibodies, there are of course many other factors that have been investigated in RA patients. Cytokine levels for example were measured in order to investigate the pathogenesis of RA, although these levels appear to vary widely at different time points with little relationship to disease activity, but some may be useful as a possible biomarker. Also, many different proteins have been found increased or down regulated in RA patients, which might also make these interesting

Synovial tissue biomarkers

The antibodies and proteins measured above are mostly measurable by serological tests and do not require invasive methods for analysis. There are, however, other potential biomarkers, such as biomarkers that can be found in the synovial tissue at biopsy. Biomarkers that are derived from the inflamed tissue may be more reliable in predicting the local disease status and response to therapy, since the biomarkers are derived from the target tissue of the disease.

Conclusion

When comparing the biomarkers between RA and PsA, a clear difference is the presence of autoantibodies, which are observed in RA patients, but not in PsA patients. In RA patients, ACPA and RF are currently in use for clinical diagnosis. It seems that additional autoantibodies identified in RA patients, as yet, may not result in additional value as diagnostic biomarkers, however they may add prognostic information. As many patients are positive for several autoantibodies it is interesting to

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgements

The authors would like to acknowledge the financial support from the Dutch Arthritis Foundation (31308), The Netherlands Organization for Scientific Research, the IMI JU funded project BeTheCure, contract no 115142-2, and the Health Research Board, Ireland (R12983 and R13798). L.T. is supported by a ZON-MW Vidi (016.126.334) grant and by a fellowship from Janssen Biologics (QBS11031FELLUMC).

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