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Drug Update

Anakinra - an overview
Sujatha MB1

www.kjoonline.org

Govt. Medical Introduction receptor antagonist that is currently FDA


College Thrissur
Anakinra is an Interleukin - 1 approved for moderate to severe
Kerala, India
receptor antagonist for the management Rheumatoid arthritis that has been
of joint disease in Rheumatoid arthritis unresponsive to initial disease modifying
1
Assoc. Professor (RA). anti rheumatic drug therapy.
of Pharmacology
Rheumatoid arthritis is a Structure
mulltifactorial disease in which there are The Anakinra molecule is a non
Correspondence
should be sent to: a number of genetic and environmental glycosylated version of human IL-1
mbsuja@gmail.com influences. There are significant receptor antagonist (IL-1RA) prepared
evidences that activation of T cells and from cultures of genetically modified
macrophages with the consequent E.Coli, using recombinant DNA
release of a number of inflammatory technology. It consists of 153 amino
cytokines play a role in the initiation and acids and has a molecular weight of 17.3
maintenance of both systemic and local Kilodaltons. It differs from native human
synovial inflammation in Rheumatoid IL-1 RA in that it has the addition of a
arthritis. In particular, tumor necrosis single methionine residue on its amino
factor, interleukin-1 and interleukin-6 are terminus (Figure 1).
considered the pivotal inflammatory Figure 1. Molecular structure of
mediators, contributing to its Anakinra
pathogenesis. IL-1 has been
demonstrated in a number of in vitro and
animal models to play a role in the
inflammation and joint destruction seen
in Rheumatoid arthritis. This includes
direct stimulation of cartilage degradation
process and inhibition of cartilage matrix
synthesis. IL-1 has also been
Available online at demonstrated to be a stimulatory
www.kjoonline.org
cytokine for both osteoclast precursor
differentiation and osteoclast activity,
Quick response code
likely indicating a further role in
osteopenia and joint destruction seen
with Rheumatoid arthritis.

In the last decade, a novel class of Mechanism of action


therapies directed against specific Anakinra is the Biologic agent
cytokines implicated in the disease designed specifically to modify the
Kerala Journal of
Orthopaedics process of Rheumatoid arthritis called biological immune response of IL-1.
2012;25:51-54 the Biologics have greatly improved and Anakinra blocks the biologic activity of
expanded the scope of treatment for naturally occurring IL-1 by competitively
Kerala Journal of
Rheumatoid arthritis. Anakinra is an IL-1 inhibiting the binding of IL-1 to the IL-1
Orthopaedics

Kerala Journal Of Orthopaedics Volume 25 | Issue 1 | January 2011 51


Drug Update
Sujatha MB.: Anakinra - an overview

Figure 2. Mechanism of action

receptor (Figure 2). Thus it is able to selectively clinical response was measured according to
target the pathologic element of the disease. In American College of Rheumatology (ACR ) criteria
patients with RA, the natural IL-1 is not found in (ACR 20, 50 &70).
effective concentration in synovium and synovial
fluid to counteract the elevated IL-1 concentration After 24 weeks of treatment, the number of
in these patients. participants achieving ACR 20 were significantly
higher with Anakinra 50 to 150 mg daily vs. placebo
Kinetics (38% vs. 23%). Although this 15 % increase in
Anakinra has an absolute bioavailability of patients achieving ACR 20 with Anakinra versus
95% for healthy adults after subcutaneous placebo was thought to be modest, it was also
injection. Peak plasma concentration of Anakinra thought to be clinically meaningful. Other efficacy
generally occurred 3 to 7 hours after subcutaneous parameters - including ACR 50 (18% versus 7%),
administration of clinically relevant doses for ACR 70 (7% versus 2%), Health Assessment
patients with Rheumatoid arthritis. The terminal t Questionnaire, Visual analog scale for pain (VAS),
1/2 ranged from 4 to 6 hours. Larsen radiographic scores, and change in
Erythrocyte sedimentation rate (ESR) - all
Clinical trials demonstrated significant improvement with
To evaluate the efficacy and safety, Anakinra Anakinra 50 to 150 mg daily versus placebo as well.
have been assessed in five clinical trials involving
2846 patients. There were no statistically significant
differences noted in most safety outcomes with
Trials were conducted comparing Anakinra treatment with Anakinra versus placebo, including
alone or in combination with DMARDs or biologics number of withdrawals, deaths, adverse events
to placebo or other DMARDs or biologics in patients (total and serious) and infections (total and
above 18 years old with Rheumatoid arthritis. The serious). An increase in incidence of serious

52 Kerala Journal of Orthopaedics Volume 25 | Issue 1 | January 2012


Drug Update
Sujatha MB.: Anakinra - an overview

infections in Anakinra versus placebo group (1.8%) References


vs. (0.6%) was noted, that may be clinically 1. Marty Mertens and Jasvinder A.Singh.
Anakinra for Rheumatoid Arthritis: A
significant. Injection site reactions were
Systematic Review. The Journal of
significantly increased, occurring in 71% Anakinra
Rheumatology June 1, 2009 vol. 36 no. 6 1118-
vs. 25% of placebo group. 1125

There are no direct studies comparing 2.Fleischmann RM, Tesser J, Schiff MH, et al.
Anakinra with TNF alpha inhibitors, but indirect data (August 2006). Safety of extended treatment
with Anakinra in patients with rheumatoid
suggests that Anakinra may be inferior to TNF alpha
arthritis. Annals of the rheumatic diseases 65
inhibitors. (8): 100612.

Therapeutic use & adverse effects 3.Appraisal Consultation Document: Anakinra


Anakinra was approved by the US Food and for rheumatoid arthritis. From National Institute
for Clinical Excellence dated 30 March 2010
Drug Administration and the European Commission
for the treatment of patients with Rheumatoid
4. Kylie Thaler, Divya V Chandiramani, Richard
arthritis in 2001. It is used to slow the progression A Hansen, et al. Efficacy and safety of
of moderate to severe active Rheumatoid arthritis Anakinra for the treatment of rheumatoid
in patients over age 18 who has not responded to arthritis: an update of the Oregon Drug
one or more of the DMARDs. It can be combined Effectiveness Review Project. Biologics: Targets
and Therapy, Dovepress journal, November
with other DMARDs. Since there is an increased risk
2009 Volume 2009:3 Pages 485 498.
of serious infections in combination with Etanercept,
combination therapy with TNF alpha inhibitors is not 5. Edsel Maurice T. Salvana and Robert A.
recommended. Salata,Infectious Complications Associated with
Monoclonal Antibodies and Related Small
Molecules, Clinical Microbiology Reviews, April
Adverse effects primarily include injection site
2009, p. 274-290, Vol. 22, No.20893-8512/09/
reactions, recurrent infections, possibly pulmonary
$08.00+0, doi:10.1128/ CMR.00040-08
infections with history of asthma / COPD and
possible risk of malignancy. In patients receiving 6. Cohen, S. B., L. W. Moreland, J. J. Cush, M.
Anakinra, a decrease in neutrophil count may be W. Greenwald, S. Block, W. J. Shergy, P. S.
found. Neutrophil count should be assessed prior Hanrahan, M. M. Kraishi, A. Patel, G. Sun, M. B.
Bear, et al. 2004. A multicenter, double blind,
to initiating Anakinra treatment and while receiving
randomised, placebo controlled trial of Anakinra
Anakinra. (Kineret), a recombinant interleukin 1 receptor
antagonist, in patients with rheumatoid arthritis
Preparation & Dosage treated with background methotrexate. Ann.
Anakinra - 100 mg, pre-filled syringes for Rheum. Dis. 63:1062-1068.
subcutaneous administration. The usual dosage is
7. Fleischmann, R. M., J. Schechtman, R.
100 mg subcutaneously once a day. Duration of
Bennett, M. L. Handel, G. R. Burmester, J. Tesser,
therapy is usually 24 weeks. D. Modafferi, J. Poulakos, and G. Sun. 2003.
Anakinra, a recombinant human interleukin-1
Conclusion receptor antagonist (r-metHuIL-1ra), in patients
Anakinra, the first and only recombinant IL-1 with rheumatoid arthritis: a large, international,
multicenter, placebo-controlled trial. Arthritis
receptor antagonist, is a relatively safe and
Rheum. 48:927-934.
modestly efficacious biologic therapy for
Rheumatoid arthritis. More studies are needed to 8. James B. Galloway1, Kimme L. Hyrich1,
evaluate safety and efficacy, especially in Louise K. Mercer, William G. Dixon, The risk of
comparison to other therapies. Adverse event data serious infections in patients receiving Anakinra
for the long term use of Anakinra have yet to be for rheumatoid arthritis: results from the British
Society for Rheumatology Biologics Register,
assessed.
Rheumatology (2011) doi: 101093/
rheumatology/ker146 first published online: April
12, 2011.

Kerala Journal Of Orthopaedics Volume 25 | Issue 1 | January 2012 53


Drug Update
Sujatha MB.: Anakinra - an overview

9. Laurie Barclay, MD. Anakinra Is Relatively 10. R. M. Fleischmann Addressing the safety of
Safe, Modestly Effective in Rheumatoid Arthritis. Anakinra in patients with rheumatoid arthritis
Medscape Medical News Oxford Journals Medicine Rheumatology
,Volume 42, Issue suppl. Pp. ii29-ii35.

Source of funding: Nil; Conflict of interest: Nil

Cite this article as:


Sujatha MB. Anakinra - an overview. Kerala Journal of Orthopaedics. 2012;25:51-54.

54 Kerala Journal of Orthopaedics Volume 25 | Issue 1 | January 2012