Download New molecules for the treatment of rheumatoid

New molecules for the treatment of rheumatoid
arthritis
Back to the future: oral small molecule kinases
Small molecule kinase inhibitors, what are they and how are they effective?
The treatment of RA has changed dramatically over the
past century from medications addressing symptom control to DMARDs. The first recorded medication for use in
rheumatism was in the late 17th century when a Peruvian
bark that contains the antimalarial quinine was used in
therapy. Willow bark, which contains salicylate, was introduced in 1763. In 1897 the Bayer Company introduced
acetylsalicylic acid for the treatment of rheumatic disorders. Intramuscular gold was introduced in 1929, initially
as a treatment for tuberculosis, but it was quickly recognized as a treatment for RA [1]. In 1948 Hench and Kendall
[2, 3] discovered the anti-inflammatory effects of steroids.
In the last half of the 20th century, a number of NSAIDs
were introduced as well as synthetic oral small molecule
immune-mediating medications including MTX, SSZ,
penicillamine, AZA and finally LEF in 1999. All of these
medications were significant advances in treating the clinical symptoms of RA and several, including gold, MTX,
SSZ and LEF, have been shown to be disease modifying
by inhibiting radiographic progression [4]. What do all
these medications have in common? All, with the exception of injectable gold salts, are oral small molecules.
In 1998, etanercept, a complex protein produced in
mammalian cells that specifically targets TNF, was introduced for the treatment of RA, quickly followed by a
number of other targeted biologic medications; these
medications target TNF (infliximab, adalimumab, certolizumab and golimumab), IL-1 (anakinra), IL-6 (tocilizumab),
the co-stimulatory molecule (abatacept) or B cells (rituximab). These biologic medications interrupt two key
mechanisms for immunologic communication, cytokines
and cognate cell–cell interaction, by targeting extracellular
communication by blocking various receptors or ligands.
These targeted biologics have been as significant an
advance in the treatment of these diseases in the 21st century as was the introduction of aspirin (and other NSAIDs),
steroids, gold and the disease-modifying oral small
molecules, especially MTX, in the 20th century.
Despite these significant advances in the treatment of
RA, PsA and AS, there is still a significant unmet need
in the treatment of these patients; many patients do not
achieve adequate control of their disease with the use of
these medications, even if used aggressively, and there
are many who cannot tolerate or will not take these
medications for one reason or another.
In the past 20 years, interest has grown in taking a different approach by attempting to interrupt intracellular
signalling through inhibition of kinases. It was postulated
that by doing so the function of cellular structures including surface receptors, signalling proteins and transcription
of nuclear proteins would be modulated [5–7].
In this issue of Rheumatology, three key articles discuss
where we are in the development of kinase inhibitors in
2013. As the clinical use of oral small molecule inhibitors
of kinases is a relatively new development in the field of
rheumatology, it was felt that an overview of the intracellular mechanisms being targeted, and how several of
these new molecules interfere with intracellular mechanisms, would be most appropriate. The erudite review by
Kelly and Genovese [8] addresses this area in a comprehensive manner. It is clear from their review that these
molecules differ substantially in how they inhibit intracellular mechanisms and, because of their differences, may
well have different clinical effects, but, more importantly,
they may have a different safety profile. The review [8]
discusses the JAK-STAT pathway and how interfering
with phosphorylation of STAT is important in understanding how these molecules work and why interference by
different kinase inhibitors affects cell growth, mutagenesis
and cell–cell interactions differently. They then discuss the
specific mechanisms and consequences of several kinase
inhibitors in development, including inhibition of JAK,
SYK, BTK, PI3K and PDE4. After one reads this review,
one should have a much clearer understanding of
why developing inhibitors of kinases may be important
in changing the treatment paradigm of RA and possibly
PsA and AS.
Feist and Burmester [9] comprehensively review the
rationale for the development of tofacitinib, a JAK3/1/2
inhibitor of the JAK-STAT pathway, and the results of
the phase 2 and 3 clinical development programmes
with emphasis on clinical, functional and radiographic efficacy as well as the safety profile observed in the phase 3
programme and long-term extension studies. The phase 3
programme reported to date includes four studies conducted on DMARD incomplete responders, with tofacitinib as monotherapy in one, in combination with MTX in
two and in combination with DMARDS (including MTX) in
one, as well as one study on TNF inhibitor failures. This
excellent review of the clinical, functional, radiographic
! The Author 2013. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
EDITORIAL
RHEUMATOLOGY
Rheumatology 2013;52:1153–1154
doi:10.1093/rheumatology/ket155
Advance Access publication 25 April 2013
Editorial
and safety outcomes [9] should allow the practicing
rheumatologist to understand the benefits and risks of
the use of tofacitinib in clinical situations.
Nijjar et al. [10] complete this series with a comprehensive review of fostamatinib, an inhibitor of the Syk pathway.
This review discusses not only the results of the clinical
trials of fostamatinib in phase 2 (the phase 3 programme
is ongoing but has not been reported as yet), but also the
rationale behind the inhibition of kinases and the inhibition
of kinases in other diseases. Their review [10] ends with a
very interesting discussion of where oral small molecules
may fit into our treatment paradigm, considering the advantages and disadvantages of using an oral medication as
well as the patient perspective and compliance.
We have come a long way in the treatment of immunemediated diseases, but have not reached our goal of being
able to use a medication that is fully effective in every patient with no adverse events. We have progressed from the
use of oral small molecules for symptom control, such as
aspirin and steroids, to oral small molecule DMARDs such
as MTX, LEF and SSZ, to targeted biologics that affect a
single cytokine. We are back to the future with the use of
oral small molecules once again with inhibitors of kinases.
Hopefully these medications will be an important advancement in our ability to treat RA effectively as well as other
immune-mediated diseases. The answer is in the future.
Disclosure statement: The author has declared no
conflicts of interest.
Roy Fleischmann
1
1,2
Department of Medicine, Division of Rheumatology,
University of Texas Southwestern Medical Center and
2
Metroplex Clinical Research Center, Dallas, TX, USA.
Accepted 13 March 2013
Correspondence to: Roy Fleischmann, Department of
Medicine, Division of Rheumatology, University of Texas
Southwestern Medical Center, 8144 Walnut Hill Lane,
Suite 800, Dallas, TX 75231, USA.
E-mail: [email protected]
1154
References
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gold salts—results of six years experience. J Lab Clin Med
1935;20:827–840.
2 Hench PS, Kendall EC. The effect of a hormone of the
adrenal cortex (17-hydroxy-11-dehydrocorticosterone;
compound E) and of pituitary adrenocorticotropic
hormone on rheumatoid arthritis. Proc Staff Meet Mayo
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3 Hench PS, Kendall EC, Slocumb CH et al. Effects of
cortisone acetate and pituitary ACTH on rheumatoid
arthritis, rheumatic fever and certain other conditions.
Arch Intern Med 1950;85:545–666.
4 Strand V, Cohen S, Schiff M et al. Treatment of active
rheumatoid arthritis with leflunomide compared with
placebo and methotrexate. Leflunomide Rheumatoid
Arthritis Investigators Group. Arch Intern Med 1999;159:
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in immunoregulation and immune-mediated disease.
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DMARD therapy. Expert Opin Investig Drugs 2012;21:
961–73.
8 Kelly V, Genovese M. Novel small molecule
therapeutics in rheumatoid arthritis. Rheumatology 2013;
52:1155–62.
9 Feist E, Burmester GR. Small molecules targeting
JAKs—a new approach in the treatment of rheumatoid
arthritis. Rheumatology 2013;52:doi:10.1093/rheumatology/kes417.
10 Nijjar JS, Tindell A, McInnes IB et al. Inhibition of spleen
tyrosine kinase in the treatment of rheumatoid arthritis.
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ket225.
www.rheumatology.oxfordjournals.org