Introduction
In chronic, destructive arthritis, interleukin-1 (IL-1) and tumor necrosis factor (TNF) are regarded as the master cytokines. TNF, a significant inflammatory mediator in rheumatoid arthritis (RA) and a strong inducer of IL-1; anti-TNF medication exhibits great efficacy in RA patients, has been the main target of therapeutic methods in RA patients up to this point. The arthritic process in the affected joints of good responders is not completely controlled by it, nor is it beneficial in all patients. With IL-1 receptor antagonist, directed therapy for IL-1 primarily lowers erosions and has only weak anti-inflammatory effects.
Tumor necrosis factor (TNF) is clearly engaged in the early joint swelling in studies using precise animal models of arthritis. Interleukin-1 (IL-1) is induced by TNF, which has the ability to cause arthritis but is neither arthritogenic nor damaging on its own. It's intriguing that TNF-independent IL-1 production may be observed in numerous model scenarios, including immune complexes, macrophages, and T cells. Its applicability is demonstrated by the high effectiveness of anti-IL-1 therapy and the complete absence of chronic, erosive arthritis in IL-1-deficient mice. IL-1 and the mixture of TNF and T-cell-derived IL-17 both promote osteoclast-mediated bone degradation. Immune complexes significantly increase cartilage degradation, which is IL-1 dependent.
What Is the Arthritogenic Potency of TNF and IL-1?
Numerous cytokines, chemokines, and growth factors are present in abundance during the synovial reaction in RA patients. TNF and IL-1 are now widely acknowledged as master cytokines in the process of chronic joint inflammation and the accompanying erosive alterations in bone and cartilage. Rodent arthritis induction supported the arthritogenic potential of TNF and IL-1, which had previously been shown to have proinflammatory and destructive effects in culture studies in vitro.
Recombinant cytokines can be locally injected into the knee joint to cause arthritis. This observation was supported by the discovery of persistent, erosive arthritis in transgenic mice with global TNF overexpression. It's interesting that there is still a lot of mystery around the dominating expression of TNF-mediated disease in joint tissues in these transgenic mice. More recently, the production of arthritis via local cytokine overexpression in joint tissues utilising viral vectors provided more evidence of arthritogenicity.
It's interesting to note that IL-1 is far more effective than TNF at causing cartilage to break down in vivo. Tiny doses of IL-1 are sufficient to block proteoglycan synthesis in chondrocytes, but TNF requires a dose that is 100–1000 times larger to have the same effect. It's significant that the interaction between IL-1 and TNF has been proven.
In addition to potency variations, it is evident that it is challenging to detect substantial TNF levels in inflamed synovial tissue or synovial fluid from RA patients, and those levels are unquestionably not larger than those of IL-1. The majority of impacts might be connected to membrane-bound cytokines, which are challenging to quantify. In contrast, trafficking of soluble forms is likely required for the action of synovium-derived mediators on articular cartilage. Sites of pannus expansion, where close contact between synovial cells and chondrocytes does occur, may present a different set of circumstances.
Elegant investigations using TNF transgenic mice have provided a compelling case for the limited, direct function of TNF in arthritic disease. When these mice were given anti-IL-1 receptor antibodies, joint inflammation was entirely stopped. According to this, the disease is caused by the induction of IL-1, the actual arthritogenic trigger, either on its own or in combination with TNF. After receiving treatment with antibodies against the IL-1 receptor, TNF levels remained high, suggesting that TNF alone is unlikely to be an arthritogen.
Which Are the Clinical Trials With Anti-TNF/Anti-IL-1?
TNF and IL-1 cytokines were found in higher concentrations in RA synovial tissue, and these cytokines were also found to have cell-associated receptors. The remarkable anti-inflammatory effects of a first neutralising monoclonal anti-TNF antibody in RA patients demonstrated the potential of anti-cytokine therapy and sparked the creation of improved anti-TNF reagents, such as fully humanised antibodies and engineered fusion proteins of TNF soluble receptors and Fc fragments, with decreased immunogenicity and a prolonged half-life.
TNF blockers unquestionably offer remarkable defence against discomfort and swollen joints in the majority of RA sufferers. It is also clear that not all RA patients respond well to anti-TNF medication, and not even good responders experience arthritic control in all affected joints.
The soluble IL-1 type I receptor was used in the earliest IL-1 research trials. It was disheartening at the time and raised concerns regarding the utility of IL-1 as a therapeutic target in human RA when clinically relevant effects were not observed. The selection of the type I receptor, however, is now recognised to have been unlucky because this soluble receptor has a high affinity for the IL-1 receptor antagonist, scavenging the endogenous IL-1 inhibitor in the process. The decoy type II receptor might be a stronger inhibitor in that regard, but it has the drawback of having a lesser affinity for IL-1. Studies using the best designed IL-1 receptor fragments or strong anti-IL-1 antibodies that neutralise them are awaited.
Is Anti-TNF Treatment Anti-erosive?
Interestingly, joint erosions after anti-TNF therapy for RA patients offered the first proof of a joint protective effect, as reported at the 1999 ACR meeting. This was demonstrated for both a single treatment using anti-TNF antibodies and TNF soluble receptor, as well as for the combination of anti-TNF antibodies and Methotrexate. Unfortunately, the actual statistics have not yet been released, which prevents this evaluation from giving it full consideration. The results might support the theory that excessive TNF synthesis in RA synovial tissue is primarily brought on by synoviocytes' dysfunctional conduct, which results in excessive TNF production.
If this is the case, TNF will promote the synthesis of IL-1, and TNF blockage will be sufficient to inhibit the TNF-IL-1 pathway. It is interesting to note that it supports the initial signature finding in RA synovial cell cultures: neutralising anti-TNF antibodies significantly lowered IL-1 production. Unfortunately, this finding was isolated to isolated cell cultures, has not been verified by others, and is still awaiting confirmation in whole synovial tissue.
The aforementioned findings are not yet sufficient to establish a dominating TNF-IL-1 cascade in RA synovial tissue as a fact. Clinically utilized anti-TNF antibodies exhibit cytotoxic effects. This suggests that binding to TNF-bearing cells and subsequent killing of these cells, possibly including TNF/IL-1-producing cells or nearby cells, could be one mechanism of the anti-TNF impact.
Additionally, in some anti-TNF trials, the TNF soluble receptor is employed, and in addition to binding to TNF, it also scavenges lymphotoxin. The latter could affect pathways that are governed by T cells. Notably, TNF appears to be the main cytokine expressed in RA synovial tissue rather than lymphotoxin.
Conclusion
Early synovial biopsies taken from RA patients show a substantial heterogeneity in cytokine patterns, with varying staining of TNF and IL-1, suggesting that at least some patients produce IL-1 independently of TNF. Experimental arthritis in rodents provided evidence for this mechanism, which is enumerated in this review. It is required to inhibit IL-1 in addition to TNF if components of the models are applicable to the arthritic process in RA patients.
