Review of Anti TNF Therapy on Inflammation

This review explores the effectiveness of anti TNF therapy in treating inflammation, specifically in rheumatoid arthritis. It discusses the role of TNF alpha in inflammation and highlights a seminal paper on the subject. The emergence of anti TNF therapy as a treatment option for autoimmune disorders is also discussed.

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REVEW OF ANTI TNF THERAPY ON INFLAMMATION
STUDENT NAME
UNIVERSITY NAME
AURHOR NOTE

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Introduction:
Tumour necrosis factor alpha is a cytokine and it is associated with the inflammation
(Brenner, Blaser and Mak, 2015). Cell signalling is an important part of immune system and
TNF alpha is greatly responsible for maintaining tissue repairing system and immunity
(Maxwell et al., 2015). The malfunction or error in signalling could result in diseases such as
rheumatoid arthritis (Burmester, Feist and Dörner, 2013). Rheumatoid arthritis is an auto
immune disease which there is inflammation that leads to swelling in certain joints (Hua et
al., 2014). Rheumatoid arthritis affects a person’s overall immunity and health, and the
inflammation specifically targets certain parts of the tissues and organs (Smolen and Aletaha,
2015). According to Burmester, Feist and Dörner (2014), rheumatoid arthritis is initiated by
the interplay between the T cells, macrophages, B cells, and hence these are the imperative
target for the therapy. Hence, the cellular surface receptor and the intracellular signalling
process is associated with the other cellular functions that regulates cytokines production
(Hermanns, 2015).
Review of seminal paper:
The given paper by Williams, Feldmann and Maini (1992), has highlighted the
involvement of tumour necrosis factor in the pathogenesis of collagen induced rheumatoid
arthritis. The paper claimed about the universal presence of tumour necrosis factor in the
arthritic joints which cause inflammation and can lead to significant pathology in rheumatoid
arthritis. In addition to this the given paper shows that TNF alpha can control other cytokines
such as IL-1 and IL-6. Therefore, significance of this paper is important in arthritis and
controlling disease.
The involvement of major histocompatibility please be specific and mention which
MHC gene that associated with autoimmune disease for arthritis complex type II, in case of

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collagen induced arthritis and the objective of the paper is to find the relation of type II
collagen and rheumatoid arthritis. There is a universal TNF alpha presence in the arthritic
joints which is accompanied by up- regulation of receptors related to TNF alpha but it has
shown to neutralize TNF-a present in the joint cell cultures. This TNF-a neutralization in
vitro study has shown to inhibit Interleukin 1 production. TNF-a have been thought to be
leading to inflammation in joints and joint erosion. The type II collagen was purified from the
bovine cartilage. The cartilage was treated with 4 M guanidine hydrochloride in order to
remove the type II collagen
In this paper the authors tried to induce arthritis inter dermally at the base of the tail
with type II collagen in mice. This paper tried to assess the anti-TNF treatment on the mice.
The mice was also given the injections of TN3-19.12,a hamster IgG1 monoclonal antibody
which is antibody to TNF, for four weeks. This was followed by the anti TNF treatment. In
this paper the authors tried to established the relationship of anti-TNF treatment in the
development of arthritis. The severity and extension of arthritis was monitored and the
mechanism of anti-TNF in vivo study was established.
The measurement of the ant-collagen anti body level was demonstrated by ELISA and
the histopathology assay was performed, that was graded by the severity of the arthritis in
each joint which was accompanied with bone erosion and cartilage loss. The entire
experiment was conducted against the control (that is L2, a non- neutralizing hamster IgG1
mAb which is raised against the interleukin 2). However, the administration of TN3-19.12
dose of 300 or 500, ug resulted in reduced clinical score as well as reduced paw selling.
However, administration of 50 ug was less effective than the previous doses. By this
experiment the authors tried to achieve the understanding of the potency of the anti-TNF drug
in the case of RA.

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In this research the authors exclusively demonstrated the contribution of the cytokine
specific immunotherapy which can be a potent alternative immune suppressive agent like
anti-CD4 mAb which has already established immunosuppressive affects in the in vivo model
(according to Hom et al 1988) as previously it was only observed in in vitro. This is the
reason this paper is the foundation stone in the field of anti-TNF therapy, and this study has
put forward the role of TNF is an important part collagen induced arthritis. Nowadays,
medicines like antitumor necrosis factor drugs are used extensively as vital agents for the
pharmacological management of various inflammatory pathophysiology, especially of the
chronic type and also in severe cases which are refractory to traditional treatment modalities.
Opportunistic infections though are associated with anti-TNF therapy and risk protection
should include infection control.
Answer B
Emergence of anti- TNF therapy over the last decades
The article has opened a new field in terms treatment in the field of autoimmune disorders
especially in rheumatoid arthritis. The establishment of Tumour necrosis factor which is a master
regulator for cytokines production and anti-tumour necrosis factor in case of the rheumatoid arthritis
have pave the way for many potential outcomes in this field (Fischer et al., 2014). The treatment of
the rheumatoid arthritis has changed over the years, and previously the research had only given few
drugs that were effective (Ramiro et al., 2014). Non-steroidal anti-inflammatory drugs (NSAIDs) are
vastly used as anti-inflammatory drugs over the decades such as aspirin. But it has many side effects
like stomach pain, heart burn, leads to development of gastrointestinal ulcers, tinnitus, dizziness,
wheezing and liver related disorders. Hence, new age pharmacotherapy has emerged to address the
drawback.

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This paper proved to be an effective solution by the administration of 500 μg. In recent report it has
been suggested that there are rising recommended drugs that have evolved over the period of years ,
which are disease modifying anti rheumatic drugs which involve methotrexate, sulfasalazine,
glucocorticoids, however, anti-rheumatic drugs (DMARDS) also include TNF inhibitors which is
used to inhibit the TNF on the circulation and not the TNF production such as infliximab,
cetrolizumab and many more such drugs. Generally anti-inflammatory drugs, in addition to
minimizing inflammatory reactions and swelling development also has an analgesic effect as it
modifies the pain modulation pathway by inhibiting COX 2. In this research it has also highlighted
the fact that TNF inhibitors are more preferable than the other available biologics due to the long term
registry data (Ramiro et al., 2014). The study by Smolen and Aletaha (2015), reflected that there are
evidences where the anti-TNF antibody have failed to show the desired effect on the patients who
have early rheumatoid arthritis.
In another article the by Mitroulis, Skendros, and Ritis (2010), NLRP3 (Nucleotide-
binding oligomerization domain, leucine rich repeat and pyrin domain containing 3) causes
inflammatory activation and I-1β secretion that plays a profoundly significant role in central
mechanism of inflammatory pathogenesis. The nucleotide binding oligomerisation domain
had been associated pathogen associated molecular patterns. In this paper the initiation of
inflammation has been linked with NLRP3 inflammasome activation, which is important.
This paper has pointed out as the DMARDS as the corner stone in case of rheumatoid
arthritis. Anakinra is such drug which is used in the treatment of the rheumatoid arthritis
ranging from mild to severe, in comparison to the anti TNF alpha inhibitors (Vivar and Van
Vollenhoven, 2014). Monoclonal antibody are produced from B cells as form of a clone, and
these antibody specifically bind to the targets and has been appreciated form of
immunotherapy like cancer immunotherapy (Ecker, Jones and Levine, 2014).
Tumour necrosis factor is a key factor inflammation and recently there has been
associated with the subsequent targets for rheumatoid arthritis (Burmester, Feist and Dörner

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2014). Tumour necrosis factor is one of the first cytokine produced during injury and stress,
and it has been already evident that TNF as a target has been shown to reduce the collagen
induced rheumatoid arthritis (Williams, Feldmann and Maini, 1992). The anti-TNF therapy
has majorly progressed its utilisation not in rheumatoid arthritis but also in other chronic and
inflammatory diseases like osteoarthritis who are treated along with Methotrexates which can
be used as disease-modifying treatment in various autoimmune cases (Hermanns, 2015).
Furthermore, there is an evident molecular effect of drugs like Tocilizumab (TCZ) which is a
humanized anti-IL 6 receptor that can either be used as a monotherapy or in combination. In
comparison with the methotrexate or MTX alone in case of RA synovium, has been observed
strong correlation with the molecular MTX and rituximab on the synovial tissue (Ducreux et
al., 2013). Rituximab is generally used to treat certain types of cancer where it acts by
slowing down or blocking the tumour division and progression. It is also used in rheumatoid
arthritis as it decreases joint pain and swelling.
Combination drug therapy has been shown to be superior to the single drug therapy
(Sharma and Allison, 2015). According to Lee et al (2014), there has been observable
reduction in signs and symptoms of rheumatoid arthritis when the patients were given doses
of methotrexate, tofacitinib (which decreases tenderness, swelling and pain in joints) in
comparison with the methotrexate. However, there is a risk of adverse effects with the
administration of tofacitinib (Lee et al., 2014). However, according to Feagan et al., 2014, as
he recent interest has grown towards the combination of the immunosuppressive agents in
case of immune mediated diseases, there has been advanced progress made on the rheumatoid
arthritis, in which there is combination of methotrexate with TNF antagonist, but infliximab
have been shown to have no difference when administered in combination with methotrexate.
Rheumatoid arthritis has been linked with the degradation of the cartilage and tumour
necrosis factor-a (TNFa) levels were in correlation with cartilage destruction (Chen et al.,

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2014). The TNF alpha which has the potent induction capability of proinflammatory cytokine
that in return induces a proinflammatory cascade including IL1, and IL6 (Siebert et al., 2015).
Therefore, the focus has been given immensely on cytokines as therapeutic targets (Neurath,
2013). According to targeting the cytokines using anti-inflammatory cytokines as well as
recombinant soluble receptors could give preferable clinical outcomes (Rider, Carmi and
Cohen, 2016). However, it could lead to lack of danger signals that could lead to immune cell
activation (Amarasekara, Yu and Rho 2015). According to Lee et al (2014), it was observed
during a clinical trial that tofacitinib monotherapy showed better results than methotrexate,
however, the risks of adverse effects have to assess. Another clinical trial showed that
combination of DMARDs with methotrexate could be more cost effective (Scott 2017). The
steroids and NSAIDS or non-steroidal anti-inflammatory drugs were introduced to combat
the rheumatic diseases (Roubille et al. 2015). The biologic therapy can modulate extracellular
as well intracellular processes like production (synthesis), transport, secretion and neural
signalling of pain and inflammatory substances which has proven better efficacy as well as
safety (Mócsai, Kovács and Gergely 2014). In preclinical studies suggest that antibody
targeted delivery of IL 4, has been effective in autoimmune disease, and has also indicated
good tolerability towards the immunocytokine treatment (Hemmerle and Neri 2013). The
research has opened the gates from the immunogenetics to biotherapeutics that has enhanced
the role of anti-drug immune complexes and can be potent outcome to many clinical
conditions (Krishna and Nadler 2016). The Tumour necrosis factor treatment has not only
enabled the drug therapy for the rheumatoid arthritis but as also enhanced its efficacy on
diseases like diabetes as Donath (2014) determines to understand the role of autoimmunity in
diabetes type 1. The rheumatoid arthritis, the vagal response is reduced which stimulates the
inflammation reflex modulates in which it enhances TNF production, which in return reduces
the inflammation in human (Koopman et al. 2016). Therefore, there has been progressive

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advancement towards understanding the action tumour necrosis factor not only in rheumatoid
arthritis but also in other chronic conditions like diabetes, cancer and other inflammatory
diseases as according to a study by Van Laar et al. (2014), high-dose of immune suppressive
therapy along with autologous hematopoietic stem cell transplantation has shown to be
efficient.
Answer C
Importance of Janus Kinase
Though the current research has targeted the use of anti-tumour necrosis factor,
however here has been a recent reports on the increased risks of herpes during the anti-TNF
therapy (Che et al., 2014). Apart from TNF alpha inhibitors the rheumatoid arthritis treatment
has been progressing therapeutic approach selective Janus Kinase inhibition, that could lead
to potential drug therapy in future (Cheung and McInnes, 2017).
Janus family kinases is one of the most important subgroup of non-receptor protein
type tyrosine kinases. The Janus kinases are involved in survival, cell growth, cell
development and also immune cell differentiation and also in multiplication of hematopoietic
cells. They extend an adaptive immunity to the body. Deficiency of Tyk2 of JAK3 or
inactivating Jak3 mutations leads to severe forms of immunodeficiency syndrome.
There is another biopharmaceutical agent known as Anakinra, which has been used as
a remedial to rheumatoid arthritis which can be used as well (Vivar and Van Vollenhoven,
2014). However, in a study it was seen that there was no clinical benefit on the administration
of anakinra along MXT (Scott et al., 2016). Current research is going on the IL -17 A
proinflammatory cytokine, which proved that the subcutaneous treatment of secukinumab
effective could be another potential treatment (McInnes et al., 2015).

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Research has shown that treatment with anti TNF, has proven to give limited loss in bone
mineral density, therefore, the treatment could benefit people who have osteoporosis along
with the rheumatoid arthritis (Hoes, Bultink and Lems, 2015). The long term of effect of anti-
tumour necrosis factor, when patients were treated with adalimumab which acts by altering
immunological signalling. This could lead to better treatment response in patients treated
with rheumatoid arthritis (Jani et al., 2015). Though there is an advanced MXT treatment in
rheumatoid arthritis, the incorporation with a better understanding of genetics could lead to
the better understanding of the RA pathology and the treatment approach would be more
personalized (Zhu et al., 2014). The major concern still remains about treatment of
rheumatoid arthritis by the disease modifying anti-rheumatic drugs and risk of serious skin
infection that could affect the overall treatment of the person (Singh et al., 2016). Therefore,
the current practice in terms of treatment in which evidence based practice could be followed
which could make them better decisions in terms of understanding the advantages and
disadvantages of the use of the drug (Straus et al., al 2018).
There is an impressive and rapid response shown by anti-granulocyte macrophage
colony stimulating factor (GM-CSF) which enhances and modifies the immunological
mechanism that could be effective with no significant adverse effects (Hamilton et al., 2015).
The knowledge of cytokine inhibition in rheumatoid arthritis pathogenesis could lead to
better clinical outcomes and better stratification of future therapeutic drugs (McInnes,
Buckleyn and Isaacs 2016).
Recent observation shows that there is an observable cardiovascular disorder in case
of Rheumatoid arthritis patient, that could affect the treatment in patients, therefore, the
future treatment has to be associated keeping in mind all other health considerations (Choy et
al., 2014;Agca et al., 2016). When cost effectiveness of infliximab methotrexate along with
sulfasalazine + hydroxychloroquine was measured with the in early RA, it was found that it

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was not as cost effective as it should (Eriksson et al., 2014). For those cases individualized
therapy can be more effective (Steenholdt et al., 2013).
Evolution of the drugs like abatacept which is T cell co-stimulation blocker which
acts on the prophylactic and immune tolerant mechanisms, the management of methotrexate
has also improved in reamuthrid arthritis (Corominas and Shmerling, 2017). Apart from
diagnosis and early treatment, perhaps early aggressive therapy against T cells could prevent
damage that could have effect on the immune system (Pisetsky 2017; Emery 2018).
The new treatment options should be focused on inducing tolerance to potential
disease targets such as collagen. Some reports suggest there is loss of self-tolerance due to
autoimmune disease, therefore a future drug treatment can focused on reducing tolerance
(Corsiero and Marrelli, 2018). Hence, it could be concluded though anti-TNF drugs have
paved the way for better therapeutic effect, however, more research needs to be done to
eliminate the adverse effects and provide faster relief to the patients worldwide.

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REVEW OF ANTI TNF THERAPY ON INFLAMMATION