Tumor Necrosis Factor-Alpha Inhibitors And Autoantibodies In Rheumatoid Arthritis [Clinical Insights]
The introduction of tumor necrosis factor-alpha inhibitor treatment has improved the outcomes for many patients with rheumatoid arthritis. TNF-alpha is now included in rheumatoid factor discussions.
Author:Suleman ShahReviewer:Han JuDec 05, 202416.1K Shares253K Views
What role does tumor necrosis factor-alpha inhibitor treatmentplay when it comes to the autoimmune and inflammatory disease called rheumatoid arthritis or RA?
To date, clinical response and disease activity after the induction of anti-TNF agents has been considered to discuss rheumatoid factor (RF) and anti-cyclic citrullinated protein (CCP) antibodies as serum markers.
However, the mechanism of the reduction in autoantibody levels in response to anti-TNF agents remains unknown.
In addition, many rheumatologists are still attempting to evaluate various difficult problems and to predict whether the effect of TNF inhibitors can be sustained over the clinical course.
This critical review focuses on the serum autoantibodies of rheumatoid factor and anti-CCP as predictors of the effectiveness of tumor necrosis factor inhibitor in patients being treated for rheumatoid arthritis.
TNF-Alpha And Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease, which primarily causes symmetric polyarthritis, clinically manifesting as:
- joint pain
- stiffness
- swelling
Untreated, most patients have a progressive course resulting in short-term and long-term disability.
Fortunately, the number of effective medications for the treatment of RA has rapidly expanded and includes synthetic disease-modifying antirheumatic drugs (DMARDs) and biological agents such as tumor necrosis factor-alpha (TNF-alpha or TNFα) inhibitors.
The introduction of biological agents has dramatically improved the outcomes and expectations of RA for both patients and rheumatologists.
There are currently four licensed TNF-alpha-blocking therapies:
- infliximab (a chimeric monoclonal antibody)
- golimumab (a fully humanized monoclonal antibody)
- etanercept (a soluble fusion protein)
- adalimumab (a fully humanized monoclonal antibody)
All four bind to TNF-alpha, both soluble and membrane bound, and etanercept is also capable of binding to lymphotoxin alpha (LTα), a cytokine that is known to be involved in lymphoid organ development but also plays a proinflammatory role.
The latter aspect has not been described as being relevant to the pathogenesis of RA.
It is now clear that early diagnosis, referral, and treatment of patients with RA result in improvement in the clinical signs and the prevention of joint destruction.
Due to the increasing number of medications available for the treatment of RA, physicians and other healthcare providers involved in the care of RA patients must decide:
- which medications to use
- when to start them
- when to change the therapeutic regimen
In recent years, research into the pathogenic mechanisms driving synovial inflammationand tissue damage in RA established a key role for proinflammatory cytokines such as TNF-alpha and interleukin 1 (IL-1), leading to the development and clinical use of biological agents that bind to and inactivate these cytokines.
Biological agents are effective in:
- relieving the signs and symptoms of RA
- slowing the progression of radiological joint damage
- decreasing serum C-reactive protein (CRP) levels
- down-regulating inflammatory cytokines stimulated by TNF-alpha
However, despite the remarkable overall clinical effectiveness of TNF-alpha inhibitors, more than one-quarter of patients have a poor clinical and radiological response.
Despite the impressive overall clinical impact of this treatment, more than a quarter of patients still have a poor response to these biological agents on the basis of both clinical and radiological evaluation.
Thus, many rheumatologists are being encouraged to evaluate whether the effect of TNF-alpha inhibitors can be sustained over the clinical course.
This critical review focuses on the serum autoantibodies of rheumatoid factor and anti-cyclic citrullinated protein (CCP) as useful tools for judging the response of TNF-alpha inhibitors in patients being treated for rheumatoid arthritis.
Rheumatoid Factor
Rheumatoid factor, an antibody against the Fc (Fragment, crystallizable) portion of immunoglobulin G (IgG), was first described by Henrik Waaler and Ronald E. Rose in 1940.
An increased level of rheumatoid factor is found in approximately 80% of patients with rheumatoid arthritis (RA), and the suppression of rheumatoid factor production in RA has been variably attributed to the use of disease-modifying antirheumatic drugs (DMARDs).
The existence of rheumatoid factor, especially immunoglobulin M-rheumatoid factor (IgM-RF), antibodies directed against the conserved region of immunoglobulin G (IgG) class immunoglobulin is one of the diagnostic criteria for RA.
Classic IgM-RF is currently assessed in clinical practice; however, the combined detection of additional isotypes may improve this marker’s diagnostic and prognostic value.
While some studies have demonstrated a decrease in IgM-RF titers during successful treatment with methotrexate, parenteral gold, and TNF-alpha inhibitor, some reports have described a decrease in IgA (immunoglobulin A)-RF titer during the treatment with TNF-alpha inhibitor.
Furthermore, there have been conflicting reports with regard to the influence of TNF-alpha inhibitor and DMARDs on serum rheumatoid factor levels in rheumatoid arthritis.
Infliximab
Most studies coincided in finding that high levels of IgM-RF or the presence of IgM-RF were related to a decreased clinical response to TNF-alpha inhibitor, whereas a few studies found a correlation between IgA, IgM, and IgG-RF and response.
In addition, in a study published in 2011 by the journal Rheumatology, the authors, with Ruth Klaasen as lead author, also reported that a positive rheumatoid factor status does not correlate with clinical response, but that high IgA-RF levels may predict a poor response rate.
Patients with low-positive IgA-RF and those with negative IgA-RF had a good response rate, whereas patients with high-positive IgA-RF were poor responders.
IgA-RF has been reported to be more specific for RA than classic IgM-RF and to be more specifically associated with radiographic erosions in early disease.
Previously, we reported that the clinical response to infliximab can be predicted by rheumatoid factor levels.
In this study, our results show that the changes of rheumatoid factor levels were correlated with those of the C-reactive protein (CRP) levels.
At baseline and at 12 months after the initiation of treatment with infliximab, rheumatoid factor titers in the low-CRP and good-CRP response group were lower than those in the high-CRP and poor-CRP response group.
In addition, low titers of rheumatoid factor at baseline seemed to be useful for predicting a good response to infliximab.
The mechanism by which infliximab could lead to a decrease in the generation of autoantibody, such as rheumatoid factor, has not been well understood, and the explanation for this phenomenon remains speculative.
Infliximab therapyhas been proven to reduce the number of synovial infiltration cells, including plasma cells.
Rheumatoid factor-producing cells are present in the inflamed rheumatoid synovium.
And because the local environment may favor synovial rheumatoid factor production, we can therefore speculate that the reduction in inflammatory lymphoplasmacytic infiltration into the rheumatoid synovium will lead to a reduced production of rheumatoid factor, although it is not known whether TNF blockers directly inhibit the production of antibodies.
Etanercept
Etanercept, a soluble TNF-alpha receptor fusion protein, can bind and neutralize extracellular TNF-alpha.
There was a marked clinical efficacy with minimal toxicity in RA patients who have an inadequate response to conventional DMARD treatment.
First, in a study published in 2006 by the journal Annals of the Rheumatic Diseases, the authors, with Hung-An Chen as lead author, showed a significant decrease in the levels of RF in the sera of rheumatoid patients after three months of etanercept treatment.
After their study, most reports coincided in finding that high levels of IgM-RF and IgA-RF were related to a decreased clinical response to etanercept.
The pivotal role of TNF-alpha in the inflammatory and proliferative processes of RA has been established.
Except for the inhibition of TNF-alpha activity, etanercept significantly reduces the number of peripheral blood mononuclear cells secreting:
- IL1β (interleukin-1 beta)
- IL-6 (interleukin-6)
- IFN-γ (interferon‐gamma)
High levels of IL-13 in RA sera have also been modulated by etanercept.
Etanercept is able to induce cell-type-specific apoptosis in the synovial monocyte/macrophage population and to decrease the number of these inflammatory cells in rheumatoid joints.
These anti-inflammatory effects may account for the reduction in acute-phase reactants and autoantibody generation.
However, more studies are needed to confirm and elucidate the role of etanercept in reducing these autoantibodies.
Adalimumab
Adalimumab, a fully human anti-TNF-alpha monoclonal antibody, was recently approved for the treatment of both moderate and severe RA.
As with other TNF-alpha inhibitors, a few studies have reported that adalimumab induced a significant decrease in rheumatoid factor titer, and the reduction was correlated with rheumatoid factor and the clinical response to the therapy.
So far, there has been no conflicting report about rheumatoid factor titers.
Cyclic Citrullinated Protein (CCP)
The presence or absence of anti-CCP antibodies has been shown to be a useful diagnostic tool, particularly in the early stages of the disease, and to be predictive of disease progression and radiological damage.
In particular, anti-CCP antibodies seem to possess a strong specificity for RA, though this was accompanied by a relatively poor sensitivity according to the first-generation anti-CCP test (anti-CCP1).
However, the currently available so-called second-generation anti-CCP test (anti-CCP2) has been shown to retain a high specificity for RA accompanied by a reasonable sensitivity.
Anti-CCP antibodies have also been found in the early phases of RA, with a significantly greater prevalence in the sera of patients who subsequently develop more severe radiological damage.
Rheumatoid arthritis is currently thought to be a clinical syndrome comprising different pathogenic subsets. Growing evidence suggests that the presence of anti-CCP antibodies defines a specific RA subset.
Indeed, specific gene-environment interactions involving the human leukocyte antigen (HLA)-DR4 shared epitope are mainly found in anti-CCP antibodies+ RA, at least in northwestern Europe.
Also, clonal alterations of synovial T cells are elevated in anti-CCP antibodies+ vs. anti-CCP antibodies-patients.
The role of anti-CCP antibodies as an early predictor for identifying patients at risk of more aggressive and erosive disease might be of great importance, as it has been suggested that early and aggressive treatment, even with the use of biological agents, can prevent the progression of joint damage.
Some studies have demonstrated a decrease in anti-CCP antibodies during successful treatment with TNF-alpha inhibitor.
However, several reports demonstrated that there is no correlation between the clinical response to TNF-alpha inhibitor and CCP antibodies in RA.
See Also: Culture And Characterization Of Cancer Stem Cells Derived From Glioblastoma Multiforme Tumors
Second Round Of Discussion - Infliximab, Etanercept, Adalimumab
Below, we summarized the current findings as to whether anti-CCP antibodies could be useful tools in the treatment with TNF-alpha inhibitor:
Infliximab And Rheumatoid Arthritis
In a clinical trial published in 2004 by Annals of the Rheumatic Diseases, the authors, with Cristiano Alessandri as lead author, reported that the titers of anti-CCP and rheumatoid factor in the sera of patients were decreased significantly after 24 weeks of anti-TNF-alpha treatment with infliximab.
While a reduction in rheumatoid factor after infliximab treatment has already been described, although in a small subgroup of patients, this is the first evidence of down-regulation of anti-CCP antibodies following anti-TNF-alpha treatment.
The relatively high prevalence of patients who were positive for anti-CCP antibodies and rheumatoid factor at baseline reflects the probable selection of patients with more aggressive disease, who were resistant to previous DMARD treatment and were eligible for anti-TNF-alpha.
This provides indirect confirmation of the association between anti-CCP antibodies and a more severe disease course.
However, small studies have investigated the utility of anti-CCP antibodies for predicting response to treatment with biological agents, but results have been inconsistent after the first report.
In a study published in 2007 by Annals of the Rheumatic Diseases, the authors, with Francesca Bobbio-Pallavicini as lead author, reported that anti-CCP antibody levels were not correlated with the response to infliximab.
Thus, no established data are currently available on the prognostic importance of a quantitative evaluation of anti-CCP levels in patients with RA.
The mechanisms whereby the blocking of infliximab could lead to a decrease in the generation of anti-CCP antibodies are not understood, and the explanation of this phenomenon remains speculative.
However, it has been shown that infliximab can down-regulate the production of several inflammatory cytokines and mediators, and these anti-inflammatory effects may account for the reduction in autoantibody generation, particularly in the synovial compartment.
It has also been shown that citrullination represents a posttranslational modification of proteins in the apoptotic process and that citrullinated fibrin is one of the major CCPs in rheumatoid synovium, and so represents an important antigenic target of anti-filaggrin antibodies.
It has been found that anti-TNF-alpha treatment can modulate apoptotic processes, as recently shown in inflammatory bowel disease; so, it is possible that the regulation of apoptosis following TNF-alpha inhibitor administration could partially explain our observation.
However, further studies involving large populations are needed to determine whether changes in the serum levels of anti-CCP antibodies occur during infliximab treatment.
Many authors have found a drop in rheumatoid factor levels during treatment with infliximab, whereas the changes induced in anti-CCP levels remain a controversial issue.
Etanercept And Rheumatoid Arthritis
In a study published in 2004 by the journal Arthritis & Rheumatology, the authors, with Ted R. Mikuls as lead author, reported that anti-CCP antibodies have been reported to be reduced by treatment only early in the disease course.
Data regarding etanercept are also conflicting.
In a study published in 2012 by Rheumatology, the authors, with Helena Canhão as lead author, have reported the reduction of both anti-CCP and rheumatoid factor levels with either etanercept or adalimumab, whereas in a study published in 2005 by Annals of the Rheumatic Diseases, the authors, with Dr. Babak Yazdani-Biuki as lead author, reported that a small series of patients failed to show any such reduction.
The changes induced in anti-CCP levels by etanercept also remain a controversial issue.
Adalimumab And Rheumatoid Arthritis
Several conflicting studies have also been reported regarding adalimumab, as with other TNF-alpha inhibitors. Some studies confirmed an association between a decrease in rheumatoid factor titer and treatment response.
In contrast, a shorter disease duration but not a specific treatment was associated with a decline in anti-CCP levels.
Furthermore, in a study published in 2006 by the journal Arthritis Research & Therapy, the authors, with Fabiola Atzeni as lead author, did not find any variation in rheumatoid factor and anti-CCP antibody serum levels in the group of patients with RA who were treated with methotrexate alone.
However, it must be pointed out that these patients did not display the same clinical characteristics as the patients with RA who were selected for the adalimumab treatment.
Yazdani-Biuki et al. reported that there was no significant change in anti-CCP antibodies after treatment with adalimumab.
However, the study was performed in a small group and over a short period.
To estimate the correlation between the clinical response and anti-CCP antibodies, further studies are needed.
Conclusion
With the growing number of medications available for the treatment of rheumatoid arthritis, physicians and patients are faced with difficult decisions pertaining to the initiation and discontinuation of medications.
Multiple studies support early, aggressive treatment that is goal-directed.
Evaluation of anti-CCP antibodies and rheumatoid factor may be useful in clinical practice, not only as a diagnostic tool but also for predicting possible clinical improvement with anti-TNF-alpha therapy.
More research regarding tumor necrosis factor-alpha inhibitor treatment is recommended.
Suleman Shah
Author
Suleman Shah is a researcher and freelance writer. As a researcher, he has worked with MNS University of Agriculture, Multan (Pakistan) and Texas A & M University (USA). He regularly writes science articles and blogs for science news website immersse.com and open access publishers OA Publishing London and Scientific Times. He loves to keep himself updated on scientific developments and convert these developments into everyday language to update the readers about the developments in the scientific era. His primary research focus is Plant sciences, and he contributed to this field by publishing his research in scientific journals and presenting his work at many Conferences.
Shah graduated from the University of Agriculture Faisalabad (Pakistan) and started his professional carrier with Jaffer Agro Services and later with the Agriculture Department of the Government of Pakistan. His research interest compelled and attracted him to proceed with his carrier in Plant sciences research. So, he started his Ph.D. in Soil Science at MNS University of Agriculture Multan (Pakistan). Later, he started working as a visiting scholar with Texas A&M University (USA).
Shah’s experience with big Open Excess publishers like Springers, Frontiers, MDPI, etc., testified to his belief in Open Access as a barrier-removing mechanism between researchers and the readers of their research. Shah believes that Open Access is revolutionizing the publication process and benefitting research in all fields.
Han Ju
Reviewer
Hello! I'm Han Ju, the heart behind World Wide Journals. My life is a unique tapestry woven from the threads of news, spirituality, and science, enriched by melodies from my guitar. Raised amidst tales of the ancient and the arcane, I developed a keen eye for the stories that truly matter. Through my work, I seek to bridge the seen with the unseen, marrying the rigor of science with the depth of spirituality.
Each article at World Wide Journals is a piece of this ongoing quest, blending analysis with personal reflection. Whether exploring quantum frontiers or strumming chords under the stars, my aim is to inspire and provoke thought, inviting you into a world where every discovery is a note in the grand symphony of existence.
Welcome aboard this journey of insight and exploration, where curiosity leads and music guides.
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