|Year : 2017 | Volume
| Issue : 1 | Page : 17-22
Open-label use of Anakinra (Kineret) in the treatment of patients with osteoarthritis
Craig Davis Scoville, John Partridge Dickson
Institute of Arthritis Research, Idaho Falls, Idaho, USA
|Date of Web Publication||23-Feb-2017|
Craig Davis Scoville
Institute of Arthritis Research, 2220 East 25th Street, Idaho Falls, Idaho, 83404
Source of Support: None, Conflict of Interest: None
Background: Novel treatments for osteoarthritis (OA) are needed for patients not responding to and/or not tolerating conventional treatments. In this prospective study the usefulness of Anakinra (Kineret) in the treatment of OA was evaluated.
Methods: Eleven patients with symptomatic OA were treated with Anakinra (Kineret) over a 2–3 month period. Efficacy of response was determined if patients showed >30% improvement in the Western Ontario and McMaster Universities Osteoarthritis Index and/or Australian/Canadian Osteoarthritis Hand Index scoring with treatment. Nine of the 11 patients received Kineret intra-articular (IA) injections and 2/11 patients with erosive polyosteoarthritis received Kineret 100 mg subcutaneous injections daily for 30 days.
Results: One of the two patients receiving systemic administration of Kineret showed mild efficacy. A total of 21 IA Kineret injections were performed on nine patients. Only 2/5 patients receiving IA Kineret injections into small/medium-sized joints showed efficacy and only 2/5 patients receiving IA Kineret injections into large joints (knees, shoulders) showed efficacy – but those patients showing efficacy with large joints injections had >50% improvement.
Conclusion: In this study it was found that patients receiving large joint injections were more likely to show greater efficacy than those receiving small joint injections. Therefore, there seems to be a possible benefit of using Kineret (150–200 mg) in the treatment of OA in large joints and may represent an alternative to IA steroid in those patients in whom steroids may be contraindicated.
Keywords: Anakinra, kineret, treatment of osteoarthritis
|How to cite this article:|
Scoville CD, Dickson JP. Open-label use of Anakinra (Kineret) in the treatment of patients with osteoarthritis. Indian J Rheumatol 2017;12:17-22
| Introduction|| |
Osteoarthritis (OA) is the most common rheumatic condition occurring in 10.6% of men and 18% of women over age 60 worldwide. OA is associated with progressive cartilage degeneration and contributes to pain and disability. Conventional treatments include nonsteroidal anti-inflammatory drugs (NSAIDs), narcotics, corticosteroids, viscosupplementation, physical therapy, occupational therapy, and surgical replacement of joints. Attempts to find disease-modifying therapies for OA have not been successful. For example, Anakinra (Kineret), an interleukin-1 receptor antagonist, has been tested in three clinical research trials of which two double-blinded, placebo controlled studies showed no significant benefit.,,, Despite these findings, there may be a subpopulation of OA patients who might benefit from this treatment. In this prospective study the usefulness of Anakinra (Kineret) in the treatment of OA was evaluated. We also sought to determine if there is a subset of OA patients in whom Kineret may be a good alternative treatment compared to conventional treatments.
| Methods|| |
Patients age 18 or older were eligible for enrollment in this study if they had moderate to severe OA of hands, wrists, knees, ankles, and/or shoulders and were on a stable dose of treatment(s) (inclusive of NSAIDs, narcotics, and glucosamine) within 30 days of baseline visit and also had to show a pain intensity score of ≥3 on a 10 point visual analog scale at baseline. All patients recruited for this study met criteria for OA of hands, knees, and other joints as defined by the American College of Rheumatology (ACR) Criteria for OA., All 11 patients met ACR criteria for OA of the hands, six Patients (#1, #2, #3, #6, #10, and #11) also met ACR criteria for OA of the knees, and five Patients (#3, #4, #5, #7, and #8) had symptomatic OA of other joints inclusive of wrists, ankles, and shoulders. All patients had radiographic evidence of OA. One patient (#1) had erosive polyosteoarthritis with chondrocalcinosis confirmed by synovial fluid crystal analysis. Patients were excluded if they had had an intra-articular (IA) steroid injection within 30 days of the baseline visit, or IA hyaluronic acid injection within 3 months of baseline visit or history of allergic reaction to Kineret or pregnant or nursing, or any confounding medical condition that would complicate a pain assessment.
The study design consisted of recruiting appropriate patients and the screen and baseline visits were combined into one visit (visit 1). Patients meeting inclusion criteria were then administered Kineret at baseline visit and then assessed at month 1 (visit 2) and also offered Kineret injection at that time, and then assessed at month 2 (visit 3) and offered Kineret injection at that time, and then seen for end of study visit on month 3 (visit 4). Nine patients received IA Kineret injections during this study consisting of 30 mg IA for each small joint(s) of hands, or 50–100 mg IA for each medium joint(s) of wrists or ankles, or 150–200 mg IA for each large joint(s) of knees or shoulders. All IA injections were performed by rheumatologist(CS); however, without ultrasound guidance since this was not available at the time of this study. Two patients with erosive polyosteoarthritis were given Kineret 100 mg subcutaneous injection daily for 30 days with a 60 days post treatment observation period. Patients were allowed to continue taking OA medications (NSAID, narcotics, and glucosamine) during this study as long as the patient was on a stable dose of these medications 30 days before baseline visit and remained on a stable dose during the study. Patients were required to stop their narcotics 24 h before a study visit.
WOMAC in this study used the visual analog format for which pain had five items (0–100 mm/item) and therefore could score from 0 to 500, stiffness had two items and therefore could score from 0 to 200, and physical function had 17 items and therefore could score from 0 to 1700. The total WOMAC Index represents the total of all these scores (0–2400). AUSCAN Index used five-point Likert-type format which numerically scores 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = extreme and therefore for which pain can score 0–20, stiffness 0–4, and physical function 0–36, and the composite or index score 0–60. WOMAC and AUSCAN validation has already been shown.,,
The study was approved by the Investigational Review Board of the institute. Informed written consent was obtained from all patients prior to their enrollment in this study.
| Results|| |
The main features of the 11 patients recruited into this study are shown in [Table 1]. The age range was 59–82 years old (mean 71 years old) and nine women and two men. Two patients (Patient #1 and Patient #2) had erosive polyosteoarthritis, but Patient #2 had mostly symptomatic erosive OA of the hands. These two patients were treated with subcutaneous injections of Kineret at 100 mg daily for 30 days and then observed for 2 months. Nine patients with symptomatic OA were treated with IA Kineret injections inclusive of injections into PIPs (Patients #6, #9), wrists (Patients #3, #4), shoulders (Patients #5, #6, and #8), knees (Patients #10, #11), and ankle (Patient #7). A total of 21 IA Kineret injections were performed on nine patients. AUSCAN Index scoring was done in place of WOMAC index scoring for those patients with primarily symptomatic OA of the hands/wrists (Patients #2, #3, #4, #7, and #9). However, Patient #6 had both symptomatic OA of hands and large joints – and therefore both WOMAC and AUSCAN scoring were performed. The results of these assessments are shown in [Table 2]. These assessments include global, pain, function, stiffness, and index scoring for WOMAC and AUSCAN scoring.
|Table 1: Demographics and characteristics of 11 patients with osteoarthritis receiving Kineret injections|
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|Table 2: The Western Ontario and McMaster Universities Osteoarthritis Index and Australian/Canadian Osteoarthritis Hand Index scoring for the 11 osteoarthritis patients treated with Kineret|
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The percentage change in WOMAC Index and AUSCAN Index scoring is shown in [Figure 1]a, [Figure 1]b, and [Figure 2]a, [Figure 2]b, respectively. These results show that patients showing > 30% improvement in either WOMAC or AUSCAN scoring were Patients #2, #5, #6, #7, and #9, of whom Patient #6 showed efficacy with large joints injections but not with small joint injections. In addition, Patient #7 showed efficacy initially, but subsequent injections were ineffective. Patient #2 showed efficacy with systemic administration of Kineret whereas Patient #1 did not. When examining all the five patients who had OA of the hands/wrists who received IA Kineret injections, only Patient #9 showed efficacy at 33% improvement in AUSCAN index scoring. Five patients received a total of nine IA Kineret injections into knees/shoulders with two patients showing moderate efficacy (>50% improvement). Patient #5 received a single injection into shoulder with 56% improvement. Patient #6 received single injection into knee at visit 1 with 71% improvement and this benefit fell to 32% at visit 3 and stayed at this level of benefit at visit 4. Patient #6 also received a single injection into shoulder at visit 2 with 54% improvement. Therefore, of the total of 11 patients receiving Kineret, five patients did show efficacy with treatment and patients receiving large joint injections were more likely to show efficacy than those receiving small joint injections. Patient #10 received injection into a knee with 14% improvement with the first injection and 28% improvement with the second injection suggesting some improvement with repeat injections when dealing with large joints. No site reactions were ever reported with IA Kineret injections.
|Figure 1: (a) The Western Ontario and McMaster Universities Osteoarthritis Index scoring (0–2400) used the visual analog format representing the composite of pain (0–500), stiffness (0–200), and physical function (0–1700) and is shown for Patients #1, 5, 6, 7, 8, 10, and 11 and each bar represents the composite scoring for that patient at visit 1, 2, 3, and 4. The Western Ontario and McMaster Universities Osteoarthritis Index scoring at visit 1 represent baseline score before treatment. Patient #1 received Kineret by subcutaneous injection daily ×30 days and then observed at visit 2 and visit 3. Patients #5, 6, 7, 8, 10, and 11 received Kineret by intra-articular injections inclusive of shoulders (#5, #6, #8), knees (#6, #10, #11), and ankle (#7). Patient #5 received only a single injection at visit 1, and Patient #6 received single injection into knee at visit 1, single injection into shoulder at visit 2, and all subsequent visits were observations post injection. Patient #7 received injection into same ankle at visit 1, again at visit 2, and again at visit 3. Patient #8 received injection into shoulder at visit 1 and again at visit 2. Patients #10 and #11 both received Kineret 150 mg into respective knees at visit 1 and then 200 mg into same joints at visit 2. (b) Analysis of data from Figure 1a showing % improvement in the Western Ontario and McMaster Universities Osteoarthritis Index scoring compared to visit 1 (except for Patient #6S which represents injection into shoulder at visit 2). Improvement in this study is defined as having the Western Ontario and McMaster Universities Osteoarthritis Index score that has improved > 30%. Results showed improvement at visit 2 for Patients #1, 5, 6K, 7, 10, and 11, respectively 4%, 56%, 71%, 32%, 14%, and 7%. Patient #6 received an injection into the shoulder (6S) at visit 2 and showed 54% improvement at visit 3. Patient #7 showed no benefit after the initial injection. Patient #8 showed progressive worsening with injections|
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|Figure 2: (a) Australian/Canadian Osteoarthritis Hand Index scoring (0–60) used the five-point Likert-like format representing the composite score of pain (0–20), stiffness (0–4), and physical function (0–36) and is shown for Patients #2, #3, #4, #6, #7, and #9 and each bar represents the composite scoring for that patient at visit 1, 2, 3, and 4. The Australian/Canadian Osteoarthritis Hand Index scoring at visit 1 represents baseline score before treatment. Patient #2 received Kineret by subcutaneous injection daily ×30 days and then observed at visit 2 and visit 3. Patients #3, #4, #6, and #9 received Kineret by intra-articular injections into finger/wrist joints. Patients #3, #4 received single injections into wrists at visit 1 and then observed thereafter. Patient #6 received single injections into finger joints at visit 3 and then observed at visit 4. Patient #7 received intra-articular injections into an ankle, and both the Australian/Canadian Osteoarthritis Hand Index and Western Ontario and McMaster Universities Osteoarthritis Index scoring were performed. Patient #9 received Kineret injections at visit 1 and visit 2. (b) Analysis of data from Figure 2a showing % improvement in Australian/Canadian Osteoarthritis Hand Index scoring compared to visit 1 (except for patient #6 who had injections into finger joints at visit 3 and then observed at visit 4). Improvement in this study is defined by having an Australian/Canadian Osteoarthritis Hand Index score that has improved by >30%. Results showed improvement at visit 2 for Patients #2, 3, and 9, respectively 36%, 6%, 33%. Patient #6 received an injection into finger joints at visit 3 and showed 4% improvement at visit 4. Patients #4 and #7 (after initial injection) showed no improvement with injections|
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| Discussion|| |
This is a small study involving a total of 11 OA patients, but there were some important observations made. Six of the 11 patients did not experience any significant improvement with this treatment. The most unsuccessful treatments involved IA injections into hand/wrist joints – for which 4/6 patients did not show any significant improvement with small- or medium-sized joint injections. Patient #7 showed a 32% improvement with the initial ankle injection, but subsequent injections had no benefit – suggesting that repeat injections into small or medium joints did not show increased efficacy. Patient #9 did show about a 33% improvement with IA injections into finger joints. Patient #2 had erosive OA of the hands and did experience about a 36% improvement with Kineret 100 mg SC daily suggesting that this treatment strategy may be of benefit to other patients with erosive OA of the hands not responding to usual treatments. This favorable response was also reported in another study using subcutaneous injections of Kineret 100 mg daily for erosive OA. Interestingly, Patient #1 received daily injectable Kineret but did not show efficacy but this patient also had chondrocalcinosis in addition to erosive polyosteoarthritis. Of the five patients receiving large joint Kineret injections, two Patients #5 and #6 showed at least a 50% improvement in WOMAC Index scoring. Interestingly, Patient #10 showed 14% improvement after the first Kineret IA injection of 150 mg into the knee but then showed 28% improvement with the next injection of 200 mg suggesting that 200 mg injection may be a better dosing when a patient does not respond to the lower dose. Although Patient #10 did not meet improvement criteria, the patient did show improvement with this treatment.
Based on these findings, it would appear that Kineret may be a reasonable alternative to steroid injections when contemplating large joint injections such as knees, shoulders, hips whereas Kineret injections into smaller joints such as ankles, wrists, and fingers, appears to be less responsive. Perhaps, this is a reflection of using smaller dosing for small joints; nonetheless, this study suggests that larger joint injections responded better to treatment. This study also showed that 200 mg Kineret IA was safe and effective in those patients who received this dose for large joint injections. This finding suggests that lack of efficacy in the previous trials may be due to using Kineret at 150 mg when a higher dose would have been effective. Hopefully, further work will be done assessing the efficacy and safety of Kineret 200 mg or higher in palliative treatment of OA of large joints such as knees, shoulders, hips, and also in a subset of OA patients who may need an alternative to steroid injections to provide relief.
Intra-articular corticosteroid injections have been shown to be effective in the treatment of OA., However, there are patients who do not tolerate corticosteroids due to mood swings, irritability, and behavioral changes and/or symptomatic palpitations. There are also patients who either do not respond to corticosteroid treatments or for whom this treatment may exacerbate an underlying disease such as diabetes or congestive heart failure. This study suggests that Kineret (anakinra) may be a worthwhile alternative treatment in those patients. Although the number of patients assessed in this study was small, the results do suggest that a large clinical trial should be conducted in osteoarthritic patients for whom steroid injections may be contraindicated– such as diabetics and/or congestive heart failure and/or patients hypersensitive to corticosteroids. Such a clinical trial should assess the efficacy and safety of Kineret 200 mg IA injections into large joints as well.
In conclusion, this study did show a possible benefit in using higher doses of Kineret (150-200 mg) in the treatment of osteoarthritis of large joints and may represent a viable alternative to IA steroid.
Financial support and sponsorship
The study was funded by the Institute of Arthritis Research.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bull World Health Organ 2003;81:646-56.
Krasnokutsky S, Samuels J, Abramson SB. Osteoarthritis in 2007. Bull NYU Hosp Jt Dis 2007;65:222-8.
Malemud CJ. Anticytokine therapy for osteoarthritis: Evidence to date. Drugs Aging 2010;27:95-115.
Chevalier X, Goupille P, Beaulieu AD, Burch FX, Bensen WG, Conrozier T, et al.
Intraarticular injection of anakinra in osteoarthritis of the knee: A multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum 2009;61:344-52.
Chevalier X, Giraudeau B, Conrozier T, Marliere J, Kiefer P, Goupille P. Safety study of intraarticular injection of interleukin 1 receptor antagonist in patients with painful knee osteoarthritis: A multicenter study. J Rheumatol 2005;32:1317-23.
Auw Yang KG, Raijmakers NJ, van Arkel ER, Caron JJ, Rijk PC, Willems WJ, et al.
Autologous interleukin-1 receptor antagonist improves function and symptoms in osteoarthritis when compared to placebo in a prospective randomized controlled trial. Osteoarthritis Cartilage 2008;16:498-505.
Iqbal I, Fleischmann R. Treatment of osteoarthritis with anakinra. Curr Rheumatol Rep 2007;9:31-5.
Altman R, Alarcón G, Appelrouth D, Bloch D, Borenstein D, Brandt K, et al.
The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hand. Arthritis Rheum 1990;33:1601-10.
Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, et al.
Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and therapeutic criteria committee of the American Rheumatism Association. Arthritis Rheum 1986;29:1039-49.
Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: A health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol 1988;15:1833-40.
Bellamy N, Campbell J, Haraoui B, Buchbinder R, Hobby K, Roth JH, et al.
Dimensionality and clinical importance of pain and disability in hand osteoarthritis: Development of the Australian/Canadian (AUSCAN) Osteoarthritis Hand Index. Osteoarthritis Cartilage 2002;10:855-62.
Bellamy N, Campbell J, Haraoui B, Gerecz-Simon E, Buchbinder R, Hobby K, et al.
Clinimetric properties of the AUSCAN osteoarthritis hand index: An evaluation of reliability, validity and responsiveness. Osteoarthritis Cartilage 2002;10:863-9.
Bacconnier L, Jorgensen C, Fabre S. Erosive osteoarthritis of the hand: Clinical experience with anakinra. Ann Rheum Dis 2009;68:1078-9.
Raynauld JP, Buckland-Wright C, Ward R, Choquette D, Haraoui B, Martel-Pelletier J, et al.
Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: A randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2003;48:370-7.
Meenagh GK, Patton J, Kynes C, Wright GD. A randomised controlled trial of intra-articular corticosteroid injection of the carpometacarpal joint of the thumb in osteoarthritis. Ann Rheum Dis 2004;63:1260-3.
[Figure 1], [Figure 2]
[Table 1], [Table 2]
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