Biomarkers for rheumatoid and psoriatic arthritis
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).
References (80)
- et al.
Rheumatoid arthritis
Lancet
(2010) - et al.
Anti-citrullinated protein/peptide antibodies (ACPA) in rheumatoid arthritis: specificity and relation with rheumatoid factor
Autoimmun. Rev.
(2005) - et al.
Novel autoantibody markers for early and seronegative rheumatoid arthritis
J. Autoimmun.
(2011) - et al.
Characterization of a multiplex, 12-biomarker test for rheumatoid arthritis
J. Pharm. Biomed. Anal.
(2012) - et al.
Evaluating relationships between symptom duration and persistence of rheumatoid arthritis: does a window of opportunity exist? Results on the Leiden Early Arthritis Clinic and ESPOIR cohorts
Ann. Rheum. Dis.
(2015) - et al.
Early treatment of psoriatic arthritis is associated with improved patient-reported outcomes: findings from the etanercept PRESTA trial
Clin. Exp. Rheumatol.
(2015) - et al.
Psoriasis
N. Engl. J. Med.
(2009) Psoriatic arthritis: recent progress in pathophysiology and drug development
Arthritis Res. Ther.
(2013)- et al.
Cardiovascular disease and risk factors in patients with psoriasis and psoriatic arthritis
J. Rheumatol.
(2010) - et al.
R. European League Against, European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies
Ann. Rheum. Dis.
(2012)
EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update
Ann. Rheum. Dis.
2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative
Ann. Rheum. Dis.
Classification criteria for psoriatic arthritis: development of new criteria from a large international study
Arthritis Rheum.
Anti-CCP antibodies in rheumatoid arthritis and psoriatic arthritis
Clin. Rheumatol.
Anticyclic citrullinated peptide antibodies in rheumatoid and nonrheumatoid rheumatic disorders: experience with 1162 patients
J. Rheumatol.
Crossreactive autoantibodies directed against cutaneous and joint antigens are present in psoriatic arthritis
PLoS ONE
On the occurrence of a factor in human serum activating the specific agglutintion of sheep blood corpuscles. 1939
Acta Pathol. Microbiol. Immunol. Scand.
Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis
Ann. Intern. Med.
Anti-CCP antibodies: the past, the present and the future
Nat. Rev. Rheumatol.
The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis
Arthritis Rheum.
Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis
Arthritis Res. Ther.
Pretreatment serum levels of anti-cyclic citrullinated peptide antibodies are associated with the response to methotrexate in recent-onset arthritis
Ann. Rheum. Dis.
Fine specificity of the anti-citrullinated protein antibody response is influenced by the shared epitope alleles
Arthritis Rheum.
The ACPA recognition profile and subgrouping of ACPA-positive RA patients
Ann. Rheum. Dis.
Distinct ACPA fine specificities, formed under the influence of HLA shared epitope alleles, have no effect on radiographic joint damage in rheumatoid arthritis
Ann. Rheum. Dis.
ACPA fine-specificity profiles in early rheumatoid arthritis patients do not correlate with clinical features at baseline or with disease progression
Arthritis Res. Ther.
Validation of a multiplex chip-based assay for the detection of autoantibodies against citrullinated peptides
Arthritis Res. Ther.
Marked differences in fine specificity and isotype usage of the anti-citrullinated protein antibody in health and disease
Arthritis Rheum.
Epitope spreading of the anti-citrullinated protein antibody response occurs before disease onset and is associated with the disease course of early arthritis
Ann. Rheum. Dis.
Disease factors in early rheumatoid arthritis are associated with differential risks for cardiovascular events and mortality depending on age at onset: a 10-year observational cohort study
J. Rheumatol.
Rheumatoid factor and anti-citrullinated protein antibody positivity, but not level, are associated with increased mortality in patients with rheumatoid arthritis: results from two large independent cohorts
Arthritis Res. Ther.
Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage
Proc. Natl. Acad. Sci. U. S. A.
Anti-CarP antibodies in two large cohorts of patients with rheumatoid arthritis and their relationship to genetic risk factors, cigarette smoking and other autoantibodies
Ann. Rheum. Dis.
Anti-carbamylated protein (anti-CarP) antibodies precede the onset of rheumatoid arthritis
Ann. Rheum. Dis.
Anti-carbamylated protein antibodies are present prior to rheumatoid arthritis and are associated with its future diagnosis
J. Rheumatol.
Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage
Arthritis Res. Ther.
Anti-carbamylated protein antibodies are present in arthralgia patients and predict the development of rheumatoid arthritis
Arthritis Rheum.
Anti-CarP antibodies as promising marker to measure joint damage and disease activity in patients with rheumatoid arthritis
Immunol. Res.
Increased levels of autoantibodies against copper-oxidized low density lipoprotein, malondialdehyde-modified low density lipoprotein and cardiolipin in patients with rheumatoid arthritis
Rheumatology
Malondialdehyde–acetaldehyde adducts and anti-malondialdehyde–acetaldehyde antibodies in rheumatoid arthritis
Arthritis Rheumatol.
Cited by (46)
Highlighting the versatility of the citrullination process
2022, ImmunobiologyCitation Excerpt :Rheumatoid Arthritis is a chronic inflammatory joint disease characterized by inflammation of the joint frequently leads to joint destruction and disability (Moeez et al., 2013). The etiology of this disease is still not fully elucidated, although genetic and environmental factors like also serological elements play a role in initiation and progression of this disease (Verheul et al., 2015). Citrullination is linked to its pathogenesis as anticitrullinated peptide autoantibodies are the most important biomarker of the disease related to its severity and even extraarticular manifestations (cardiovascular disease) (DeMizio and Geraldino-Pardilla, 2020).
Essential oil-based nanostructures for inflammation and rheumatoid arthritis
2020, Journal of Drug Delivery Science and TechnologyEmerging molecular biomarkers for predicting therapy response in psoriatic arthritis: A review of literature
2020, Clinical ImmunologyCitation Excerpt :Biomarkers are an important clinical need to improve personalized medicine in care for patients with PsA [7,16–19]. Currently there is much progress in biomarkers discovery on this topic, which we will summarize here [16–18,20,21]. Moreover, we will highlight their practical clinical use, review ongoing research, discuss future perspectives, and suggest recommendations for future research.
Anti-inflammatory effects of infliximab and methotrexate on peripheral blood and synovial fluid mononuclear cells: ex vivo study
2024, Scandinavian Journal of Rheumatology