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Injection-site reactions upon Kineret (anakinra) administration: experiences and explanationsLocal corticosteroid oral steroids vs injection for inflammation in can have serious septic and aseptic complications. From tomedical expert committees and mediation boards reviewed cases of alleged treatment errors relating to injections. The injections were intra-articular, paravertebral, intramuscular, and at other sites. Repeated injections with too little time between them ij the risk of infection. Physicians should pay more attention testosteron ampullen bestellen this fact, particularly when deciding on the indication for paravertebral injections. Aseptic technique should be strictly maintained.
Septic and Aseptic Complications of Corticosteroid Injections
Anakinra Kineret , a recombinant form of human interleukin-1 IL-1 receptor antagonist, is approved for the treatment of rheumatoid arthritis RA in combination with methotrexate. Kineret is self-administered by daily subcutaneous injections in patients with active RA. The mechanism of action of anakinra is to competitively inhibit the local inflammatory effects of IL Kineret is generally safe and well tolerated and the only major treatment-related side effects that appear are skin reactions at the injection site.
Due to the relatively short half-life of anakinra, daily injection of the drug is required. This, in combination with the comparably high rates of injection-site reactions ISRs associated with the drug, can become a problem for the patient. The present review summarises published data concerning ISRs associated with Kineret and provides some explanations as to their cause.
The objective is also to present some clinical experiences of how the ISRs can be managed. Anakinra is identical to native human IL-1Ra, except for the addition of a single methionine residue at its amino terminus [ 1 ]. The maintenance of balance between IL-1 and IL-1Ra is thought to be important in preventing the development of inflammatory arthritis.
Kineret is indicated for the treatment of rheumatoid arthritis in adult patients, in the European Union in combination with methotrexate in patients with inadequate response to methotrexate alone, in the United States also as monotherapy in patients failing at least one disease-modifying anti-rheumatic drug DMARD. Injection-site reactions ISR , often defined as a constellation of symptoms including swelling, erythema, pruritus and pain around the site of injection, is a common adverse event associated with different kinds of biologic therapies [ 3 ], and can present a challenge to patients.
ISRs are the most common and consistently reported treatment-related adverse events associated with Kineret. These are typically characterised by one or more of erythema, ecchymosis, inflammation and pain. The development of ISRs in patients who had not previously experienced ISRs was uncommon after the first month of therapy.
Early observations, in clinical trials with Kineret, indicated that a substantial amount of patients had skin reactions varying in intensity from mild to severe. Intradermal testing after 28 injections demonstrated that the response erythema and oedema for both vehicle alone and rhuIL-1Ra in vehicle generally followed the same pattern as that observed in histamine-injected positive control sites.
All test solutions, which consisted of the various components of the Kineret vehicle, induced permeability changes that were significantly greater than those occurring with PBS alone. Changing the vehicle to PBS significantly reduced the reactivity from that occurring with rhuIL-1Ra in citrate buffer.
However, the permeability increase was still higher over that occurring with PBS alone. Clearly, the results of the study show that the components of the vehicle have the potential to induce mast cell degranulation. Thus, the combination of vehicle constituents and a high protein concentration in the syringe give rise to mast cell degranulation upon subcutaneous injection [ 5 ].
In one of the dose-finding studies with Kineret [ 6 ], it was also noted that the injection-site reactions were dose related. The placebo used in all clinical trials performed with Kineret has consisted of the vehicle, i. A considerable amount of patients receiving placebo have also reported ISRs see above. Potential reasons for pain upon injection can be related to buffer citrate , non-physiological pH 6.
The formulation strategy is primarily to achieve stability of the protein, and the use of citrate in the Kineret formulation has indeed structural biologic reasons. This protein aggregation can be suppressed by the presence of citrate in the solution.
Phosphate, for instance, is an approximately fourfold weaker suppressant than citrate [ 7 ]. Sodium citrate is a common buffering agent for parenteral drugs formulated around pH 6 [ 8 ]. It turned out that pain scores with the vehicle or its citrate component were significantly higher than saline.
In a study on subcutaneous delivery of typical buffers for human growth hormone preparations in humans, 0. Another component of the Kineret formulation is polysorbate This substance is commonly used in many pharmaceuticals for its solubilising and stabilising effects. There are some case reports of patients who developed hypersensitivity reactions to erythropoietin.
The subsequent skin testing and clinical course suggested that the reactions were due to the excipient polysorbate 80 [ 12 ]. Hence, in patients who develop hypersensitivity reactions after subcutaneous injections of biological drugs, a control of the presence of polysorbate 80 is valid.
The clinical experience indicates that there are two different types of ISRs in relation to injections of Kineret. One immediate, with a stinging and burning feeling, and one delayed, which presents with rash, swelling and pain. The incidence rate of ISRs tends to diminish when patients are on concomitant oral steroids [ 13 — 15 ]. The delayed type can present with a more severe reaction involving erythema, pruritus, swelling and pain, i.
Five patients were reported with cutaneous drug reactions due to anakinra in [ 16 ]. A histopathological study was performed on punch biopsy specimens of skin lesions.
Within the dermis, the most striking feature was a prominent eosinophilic infiltrate with a tendency to concentrate around vessels and surrounding nerve fibres. The drug was discontinued in two patients systemic reaction in one while the other three completed the period of study but had occasional reappearances of drug eruptions. The immediate ISRs with acute pain, experienced by many patients, cannot to the same extent be relieved by the remedies mentioned above.
This reaction may, however, be alleviated by placing a cool pack on the injection site for a few minutes before and after the injection, thereby mildly anaesthetising the subcutaneous nerves. Many physicians assert that the immediate reaction is the one which is hardest to endure and is the cause of many drop outs from treatment with Kineret. During this study, patients were asked to apply a cool pack before and after the injection and to warm the syringe in their hand before injecting.
Only one patient experienced an intermediate ISR that subsided during follow-up, and no patient withdrew from the study because of ISRs. The clinical experiences put together can aid in the recommendation of remedies for the different kinds of ISRs. The delayed reactions can be mitigated by application of topical hydrocortisone or anti-histamine cream, and it is recommended to alternate the injection sites to avoid recall reactions. The clinical understanding is also that they will disappear over time.
In our opinion, the single most important measure to make patients manage both the acute and delayed ISRs is to inform in advance about the potential for such reactions. Convincing patients to remain motivated to push beyond the weariness of injections and injection-site reactions can be challenging, and these challenges have a major impact on adherence.
This has been particularly true for patients suffering from multiple sclerosis, where disease-modifying therapies are often burdened with ISRs [ 17 ]. Among patients receiving e.
Reactions to both therapies are considered to be of the delayed type. The ISRs present the first month of treatment and usually decrease in frequency with the continuation of therapy [ 18 ]. In one case report for Enbrel, the histologic findings differed considerably from the well-characterised Enbrel ISRs reported in the literature.
The dermal changes were those of eosinophilic cellulitis, unlike the lymphocyte-rich infiltrates seen in typical ISRs. The predominance of eosinophils would point towards a role for IL-5 and a mechanism more akin to a TH2 reaction. It was suggested that the ISRs in this patient could be explained by the rheumatoid factor autoantibody binding to the IgG Fc component found in both Enbrel and Humira, since the patient two weeks earlier had experienced the same type of reaction against Humira [ 19 ].
The inference made was that the PEG-moiety inhibited non-immune stimulated degranulation of mast cells which may explain the low level of ISRs seen with this therapy [ 20 ].
In vitro studies have shown that H1-blocking antihistamines reduce the release of proinflammatory mediators from mast cells and basophils and also reduce the chemotaxis and activation of inflammatory cells especially eosinophils and the expression of adhesion molecules induced by immunological and non-immunological stimuli in epithelial cell lines [ 21 ].
It is noteworthy that citric acid has been found to activate mast cells and cause airway constriction in guinea pigs, and the subsequent analysis of BAL bronchoalveolar lavage fluid showed increased levels of histamine [ 23 ]. This is in accordance with the findings by Bendele et al. The clinical observations that both the immediate and, principally, the delayed type of injection-site reactions can be alleviated by topical antihistamines, and corticosteroids can thus be explained along this route.
This reaction can be mitigated by some simple remedies and it is thus very important that the practitioners inform the patients about ISRs and how to manage them.
The delayed-type injection-site reactions tend to be transient and can be tolerated by most patients after adequate information. It is crucial to minimise the impact of adverse effects in order to help patients adhere to their treatment regimens. The authors declare that they have no conflict of interest. Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author s and source are credited.
National Center for Biotechnology Information , U. Published online Sep 1. Received Mar 18; Accepted Aug This article has been cited by other articles in PMC. Abstract Anakinra Kineret , a recombinant form of human interleukin-1 IL-1 receptor antagonist, is approved for the treatment of rheumatoid arthritis RA in combination with methotrexate.
Anakinra, Kineret, Injection-site reactions. Open in a separate window. Contribution of vehicle constituents to ISRs Early observations, in clinical trials with Kineret, indicated that a substantial amount of patients had skin reactions varying in intensity from mild to severe.
Clinical experiences The clinical experience indicates that there are two different types of ISRs in relation to injections of Kineret. Remedies to relieve ISRs The clinical experiences put together can aid in the recommendation of remedies for the different kinds of ISRs. Immunological clues In vitro studies have shown that H1-blocking antihistamines reduce the release of proinflammatory mediators from mast cells and basophils and also reduce the chemotaxis and activation of inflammatory cells especially eosinophils and the expression of adhesion molecules induced by immunological and non-immunological stimuli in epithelial cell lines [ 21 ].
Conflict of interest The authors declare that they have no conflict of interest. Zanette D, et al. Human IL-1 receptor antagonist from Escherichia coli: Arend WP, Gabay C. Physiologic role of interleukin-1 receptor antagonist. Clarke JB Mechanisms of adverse drug reactions to biologics.
Handb Exp Pharmacol Mertens M, Singh JA. Anakinra for rheumatoid arthritis: Bendele A, et al. J Lab Clin Med. Cohen S, et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: Raibekas AA, et al. Anion binding and controlled aggregation of human interleukin-1 receptor antagonist.
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Henny, F. A. Intra‐articular injection of hydrocortisone into the temporomandibular joint. J. Oral. Surg., – Oct. 2. Fisher, B. T. Effects of cortisone in the Rapoport, L., and Abrahamson, C. I. Application of steroid hormones in. van Riel PL: Oral steroids as bridge therapy in rheumatoid arthritis patients in patients with rheumatoid arthritis receiving prednisone compared to matched Attuil G: Frequency of sepsis after local corticosteroid injection (an inquiry on. Parenterally administered corticosteroids are used both for systemic route) and for local treatment (by infiltration or intra-articular injection). Treating Scoliosis in Early Childhood · Video Versus Direct Laryngoscopy for Osteonecrosis of the femoral head in men following short-course corticosteroid therapy: a report of .