Seminars in Arthritis and Rheumatism 43 (2014) 648–653
Contents lists available at ScienceDirect
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ACTH as a treatment for acute crystal-induced arthritis: Update on clinical evidence and mechanisms of action Dimitrios Daoussis, MDn, Ioannis Antonopoulos, MD, Andrew P. Andonopoulos, MD, FACP Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, 26504 Rion, Patras, Greece
a r t i c l e in f o
Keywords: ACTH Gout Crystal-induced arthritis Treatment Pseudogout
abstract Background: ACTH, a member of the melanocortin group of proteins, has long been used in the treatment of gout and is considered as an alternative therapeutic option, especially in difficult-to-treat patients. Methods: We performed a systematic electronic search (Medline and ScienceDirect) using the keywords gout, treatment, ACTH, adrenocorticotropic hormone, and pseudogout. We identified 5 studies assessing the efficacy of ACTH in acute crystal-induced arthritis. Results: In the studies for acute gout, a total of 266 patients have been treated with ACTH; treatment was highly efficacious with a response rate of 77.9–100%. Only few side effects, such as hyperglycemia, hypokalemia, and edema, were reported, all of which were mild. The available evidence for acute CPP crystal arthritis is limited. A total of 19 patients have been assessed in retrospective studies; the response rate was 90–100%, whereas no significant side effects were recorded. The mechanism of action of ACTH in acute crystal-induced arthritis is not entirely known but seems to extend beyond stimulation of steroid release from the adrenal glands; ACTH is able to stimulate melanocortin receptors on macrophages and downregulate gouty inflammation. Conclusions: Data suggests that ACTH is effective in acute crystal-induced arthritis and may be a first-line therapy in patients with multiple medical problems. We propose that further evaluation of ACTH should be performed, with a large-scale, randomized controlled study focusing on safety issues in patients with multiple comorbidities. & 2014 Elsevier Inc. All rights reserved.
Introduction The prevalence of hyperuricemia and gout is constantly rising during the last decades. Nowadays, gout constitutes a significant public health issue, affecting 1% of the male population in Western countries [1]. Nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine are the most widely used agents for the treatment of acute gout. However, patients with gout usually suffer from multiple comorbidities, and therefore the use of these agents may be problematic. A recent study reported that the prevalence of hypertension and chronic kidney disease (CKD) in patients with gout was 90% and 50%, respectively, indicating that treatment of gout can be challenging in many cases [2]. Acute calcium pyrophosphate (CPP) crystal arthritis is the second-most frequent form of crystal-induced arthritis and is also commonly encountered in clinical practice. Patients suffering from acute CPP crystal arthritis are usually of advanced age and therefore frequently have cardiovascular disease (CVD), hypertension, CKD, or diabetes mellitus (DM). These comorbidities represent contraindications to most of the available therapeutic tools. n
Corresponding author. E-mail address: [email protected] (D. Daoussis).
0049-0172/$ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semarthrit.2013.09.006
There are only limited therapeutic options for the treatment of acute crystal-induced arthritis in patients with multiple comorbidities including steroids, IL-1 antagonists [3,4], and adrenocorticotropic hormone (ACTH). ACTH was first used as treatment for acute gout more than half a century ago [5]. Ever since, several studies have shown that this therapy is equally effective than NSAIDs and steroids and may be an attractive therapeutic option for patients with multiple medical problems or hospitalized patients; moreover, it exhibits an excellent safety profile [6–9]. It is not entirely known how ACTH dampens crystal-induced inflammatory responses; the prevailing hypothesis in the past was that ACTH acts solely by triggering release of endogenous steroids from the adrenal glands. However, experimental evidence, accumulated over the last decade, strongly indicates that this is not the case. ACTH is a member of a group of proteins called melanocortins; these molecules possess a variety of anti-inflammatory and immunomodulatory properties and seem to serve as natural inhibitors of inflammatory responses [10,11]. ACTH is able to stimulate melanocortin receptors on macrophages and downregulate crystal-induced inflammation in experimental models [12]. Herein, we review all the available clinical data related to the therapeutic use of ACTH in acute crystal-induced arthritis. Moreover, we provide the experimental evidence indicating the crucial
D. Daoussis et al. / Seminars in Arthritis and Rheumatism 43 (2014) 648–653
role of ACTH in downregulating gouty inflammation beyond the release of steroids.
Methods We performed a systematic electronic search (Medline and ScienceDirect) using the keywords gout, treatment, ACTH, adrenocorticotropic hormone, and pseudogout, in the following combinations: gout and treatment and ACTH (or adrenocorticotropic hormone) and pseudogout and treatment and ACTH (or adrenocorticotropic hormone). The limits used were (a) English language, (b) published from 1970 and onwards, and (c) articles in scientific journals. Abstracts from conference proceedings and textbooks were excluded. The search identified 90 articles from Medline and 180 articles from ScienceDirect (a total of 270 articles); following removal of duplicates, 147 articles remained. The abstracts of these articles were assessed in order to identify case reports, case series, or clinical studies where ACTH has been administered in human subjects as treatment for either acute gout or pseudogout. Of the articles, 62 were irrelevant to study subject and were excluded from further review. The full text of the remaining 85 articles was assessed. Moreover, we manually searched the reference lists of these articles; however, no additional relevant articles were found. Finally, only 5 articles fulfilled the search criteria and were included in the analysis. These are diagrammatically depicted in Figure 1. Results ACTH in acute gout The first systematic assessment of the efficacy of ACTH in acute gout was performed by Axelrod and Preston [7]. The authors conducted a prospective, randomized controlled study comparing ACTH vs indometacin in acute gout in an outpatient setting. This study enrolled 76 patients with crystal-proven acute gout; patients with tophi or renal failure were excluded. Treatment was administered within 24 h from attack onset in the form of either 40 IU of ACTH intramuscularly (n ¼ 36) or 50 mg of indometacin 4 times daily (n ¼ 40); colchicine was not administered concurrently. A dramatic response was seen in ACTH-treated patients with a mean time for pain relief of only 3 h compared to indometacin-treated patients who had a mean time for pain relief of 24 h (p o 0.0001). More importantly, no side effects were recorded in the ACTH group
270 arcles idenfied in search (Medline and ScienceDirect)
147 arcles remained following duplicate removal and their abstract was assessed for eligibility
62 arcles were irrelevant to study subject and were excluded
85 arcles remained and the full text was assessed
5 arcles fulfilled the search criteria and were included in the analysis Fig. 1. Flowchart of the search.
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in sharp contrast to the indometacin group where 22 patients had abdominal discomfort or dyspepsia, 15 had headaches, and 12 had difficulty with mentation. This study clearly showed that ACTH is highly effective for the treatment of acute gout, especially when administered shortly after attack onset. Moreover, this study provided evidence that ACTH is faster acting than NSAIDs and associates with fewer side effects. Potential limitations of this study are the quasi-randomization method used and the fact that it was not blinded. Siegel et al. [8] performed a prospective, controlled study in order to explore the best therapeutic strategy in patients with acute gout when NSAIDs and colchicine are contraindicated in an outpatient setting. The authors assessed the efficacy of ACTH compared to long-acting steroids in 31 patients with acute gout of less than 5 days duration. Patients received an intramuscular injection of either 40-IU ACTH (n ¼ 16) or 60 mg of triamcinolone acetonide (n ¼ 15) and were followed up for 30 days following treatment administration. No differences were recorded in the time for complete resolution of the attack, which was on average 8 days for both groups. No side effects were recorded in either group. However, triamcinolone-treated patients required fewer reinjections (n ¼ 5) compared to ACTH-treated patients (n ¼ 11), and eventually, 2 patients from the ACTH arm were transferred to the triamcinolone arm due to rebound arthritis. This study has several potential limitations including the relatively low number of participants and its design (non-randomized and non-blinded) and therefore solid conclusions cannot be reached. However, in this study, ACTH certainly had a less pronounced effect on acute gout compared to that in the study by Axelrod and Preston. Even though the efficacy in terms of time needed for complete resolution of arthritis was similar between ACTH and triamcinolone, ACTH-treated patients experienced more episodes of rebound arthritis. There may be several explanations for this. Firstly, ACTH may not be so effective when administered later in disease course, i.e., more than 24 h from attack onset. Moreover, the dose of 60 mg of triamcinolone used (equivalent to 75 mg prednisone) was relatively high compared to the 40 IU of ACTH. Ritter et al. [6] retrospectively assessed the efficacy of ACTH in 33 patients with acute gout and multiple comorbidities that precluded the use of NSAIDs and colchicine; mainly renal insufficiency, congestive heart failure, and history of gastrointestinal hemorrhage. A total of 38 attacks were treated with ACTH (intravenous, intramuscular, or subcutaneous). Study subjects had a mean age of 66 years; most of them were hospitalized. The majority of episodes (84% polyarticular) were treated with 40 IU of ACTH every 8 h with gradual tapering according to clinical improvement. Prophylactic, low-dose colchicine treatment was concurrently given in the majority of patients. Treatment with ACTH was highly effective with a response rate of 97%. Complete resolution of arthritis was seen at an average of 5.5 days. Side effects recorded were mild and easily controlled such as hypokaleamia, hyperglycemia, and edema (12.1% each), while there were 4 episodes of rebound arthritis. This study provided evidence in favor of the use of ACTH as first-line treatment of acute gout in patients with multiple comorbidities. Potential limitations of this study are the relatively low number of patients recruited, the retrospective chart review design, the lack of a control arm, and the concomitant use of colchicine. In our department, we have been using ACTH as first-line treatment for acute gout in hospitalized patients since 1995 and we have recently reported our experience [9]. We identified 181 cases of acute gout where ACTH was used as first-line treatment, in a retrospective manner. Patients were treated with 1 mg (100 IU) of synthetic depot ACTH intramuscularly. The vast majority of patients had multiple comorbidities; the most frequent one was hypertension (80%) followed by CVD (54%). ACTH was highly
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effective with a response rate of 77.90%; the clinical benefit was evident the day following ACTH injection. Most patients who did not respond were treated once more with ACTH the day following the first injection. The majority of these patients (82.85%) responded. Rebound arthritis was not a major issue; only 11.34% of responders suffered a second gouty attack that occurred at a median of 4 days from the initial attack. Treatment with ACTH was safe and no significant side effects were recorded. In order to investigate potential “steroid-related” side effects, we specifically study the effect of ACTH on blood pressure, glucose, and potassium levels. Blood pressure and potassium levels remained stable the first and second day following ACTH administration. This study included 42 diabetic patients, in 32 patients, blood glucose levels were available at baseline and at the first and second day following ACTH administration. Diabetic patients showed an increase in fasting blood glucose levels the first day following the injection compared to baseline but this increase was not evident the second day following ACTH administration. Of note, in the vast majority of patients (41/42) no change in the antidiabetic treatment following ACTH treatment was recorded, indirectly indicating that the effect of ACTH on glucose levels was mild and transient. Similarly with the study of Ritter et al., our study underlines the efficacy and safety of ACTH in the patients who are most difficult to treat, such as hospitalized patients with multiple comorbidities. Potential limitations of the study are the retrospective design and the lack of a control arm; however, the significant number of patients assessed counterbalances these limitations at least to some extent. In the 4 available studies for acute gout, a total of 266 patients have been treated with ACTH. This treatment modality was highly efficacious with a response rate of 77.9–100%. However, we should acknowledge that the majority of patients were assessed in the context of retrospective studies, and therefore the evidence supporting the use of ACTH in acute gout cannot be considered powerful. ACTH seems to be fast acting, especially when administered early; the only study that assessed time to pain relief found that patients substantially improved within 3 h in sharp contrast to indometacin-treated patients who required 24 h for pain relief. This is in accordance with our clinical experience regarding hospitalized patients with acute gout treated with ACTH; the vast majority exhibited alleviation from pain within a few hours following the injection. Time for complete resolution of arthritis was 5–8 days, which is comparable to other treatment options. These data indicate that ACTH is indeed effective in the treatment of acute gout and is at least as effective as the classic therapeutic tools. However, the most important question to be answered is if ACTH is safer than other therapies for acute gout. Based on the available evidence, a definite answer cannot be given. However, it is noteworthy that the use of ACTH in acute gout is associated with relatively few side effects such as hyperglycemia and hypokalemia; all of which were mild. How about the dose of ACTH required to treat acute gout? In 3 of the 4 studies, the dosage of 40 IU was mainly used, in most cases as single intramuscular injection. However, in our department we have been using a higher dose (100 IU) of depot ACTH in a single IM injection; with this scheme, we had an excellent response rate in the patients who are most difficult to treat, with only few episodes of rebound arthritis. This is why we recommend this scheme as the most appropriate for acute gout. ACTH in acute CPP crystal arthritis (pseudogout) There is extremely limited evidence regarding treatment options in acute CPP crystal arthritis despite the fact that it is not uncommon. The latest EULAR recommendations for the treatment of acute CPP crystal arthritis mention ACTH as an alternative therapeutic option that is based mainly on the data from gout [13].
The study by Ritter et al. [6], mentioned previously, also enrolled 5 patients with acute CPP crystal arthritis. All patients had a good response with complete resolution within 4.2 days. Recently, we have published our experience with ACTH in acute CPP crystal arthritis in hospitalized patients [14]. We retrospectively identified 14 cases of acute CPP crystal arthritis where ACTH was used as first-line treatment. In all the cases, diagnosis was crystal proven, whereas synovial fluid cultures were negative. Patients were treated with 1 mg (100 IU) of depot ACTH intramuscularly. Patients were of advanced age (mean 80 years) and had at least 1 comorbidity that represents a contraindication to NSAIDs, steroids, or colchicine use. The vast majority of patients (n ¼ 13) improved dramatically with attenuation of signs of inflammation within 24 h without the use of NSAIDs, colchicine, or steroids. There were no episodes of rebound arthritis during hospitalization. Treatment was safe since no adverse events were recorded. Patients treated with ACTH showed a nonstatistically significant increase in fasting glucose the day following the injection compared to baseline. Systolic blood pressure and potassium levels at 24 h following ACTH treatment did not change compared to baseline. In accordance with the experience in gout, this study provides evidence indicating that ACTH is effective and safe in acute CPP crystal arthritis and supports its use as first-line treatment in hospitalized patients. This patient population may be extremely challenging to treat because they are usually of advanced age and suffer from multiple comorbidities and are therefore poor candidates for NSAIDs, colchicine, or steroid administration. The small number of patients assessed and the retrospective design of the study do not allow definite conclusions to be drawn. However, we should note that treatment of acute CPP crystal arthritis is mainly empirical due to the lack of properly performed, large-scale clinical studies. The available evidence supporting the use of ACTH in acute CPP crystal arthritis is limited, but this is the case for every treatment option in this disease. A total of 19 patients have been assessed in retrospective studies; the response rate was 90–100%. Despite the fact that all patients had multiple comorbidities, no significant side effects were recorded. All clinical data related to the use of ACTH in acute crystalinduced arthritis are summarized in the Table.
Discussion The mechanism of action of ACTH in acute crystal-induced arthritis is not entirely known but seems to extend beyond stimulation of steroid release from the adrenal glands. ACTH alongside with α, β, and γ melanocyte-stimulating hormone (MSH) belongs to a group of proteins called melanocortins. Evidence indicates that melanocortins act in peripheral tissues as natural inhibitors of inflammatory responses [15]. There are 5 types of melanocortin receptors (MC-R) named from 1 to 5. ACTH is the only melanocortin that is able to stimulate steroid release by binding MC-2 R in the adrenal glands. However, ACTH is able to bind and stimulate all types of MC-R and this is why it seems to have a broader, steroid-independent, anti-inflammatory action. This action is mainly linked to stimulation of MC-1 R and MC-3 R. There is relatively limited information on how ACTH exerts its steroid-independent, anti-inflammatory effects. However, there is a great amount of experimental evidence on the anti-inflammatory role of α-MSH, a peptide strongly related to ACTH. α-MSH downregulates the transcription factor NF-κB [16] and inhibits the expression of proinflammatory [11,17] and adhesion molecules [18,19], something that may lead to reduced influx of inflammatory cells and attenuation of inflammatory responses.
– 92.85
4.2 days
40 or 80 IU tid, gradual tapering 100 IU single dose
100
No
Patients with multiple comorbidities Hospitalized patients
Hospitalized patients 77.90 100 IU single dose
14 Daoussis et al. [14] Pseudogout
Ritter et al. [6]
5
Retrospective chart review Retrospective chart review Retrospective chart review 181 Daoussis et al. [9]
Retrospective chart review 33 Ritter et al. [6] Gout
–
Hypokalemia, hyperglycemia, and edema (in 12.1% each, all mild) Transient hyperglycemia – 5.5 days 97 40 or 80 IU tid, gradual tapering
No – 16 Siegel et al. [8]
Controlled (ACTH vs triamcinolone)
40 IU single dose
Time to pain relief 3 h 7.9 days
Early administration of treatment ( o24 h) ACTH was faster acting than indometacin ACTH-treated patients had episodes of rebound arthritis and required more reinjections Patients with multiple comorbidities No Not reported 100 40 IU single dose Randomized controlled (ACTH vs indometacin) 36 Axelrod and Preston [7]
Study type Number of ACTH-treated participants References
Table Studies assessing the efficacy of ACTH in acute crystal-induced arthritis
Treatment
Response rate (%)
Time to complete resolution
Side effects
Comments
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The first piece of experimental evidence that ACTH can dampen gouty inflammation, in a steroid-independent manner, came from a mouse model of monosodium urate (MSU) crystal-induced peritonitis [20]. Administration of ACTH4-10, a fragment of ACTH that does not stimulate endogenous steroid release, strongly inhibited the accumulation of inflammatory cells in the peritoneal cavity without altering systemic corticosterone levels. Administration of SHU9119, an MC-3/4 R antagonist, inhibited the effect of ACTH4-10 on crystal-induced inflammation in a dose-dependent manner, indicating that ACTH4-10 exhibits its anti-inflammatory action via MC-3 R or MC-4 R. The authors focused their attention on peritoneal macrophages that are responsible for the initiation of the crystal-induced inflammatory process and found that these cells express solely MC-3 R. The investigators suggested that ACTH4-10 acts by stimulating MC-3 R on peritoneal macrophages. Stimulation of melanocortin signaling in macrophages leads to reduced release of chemokines responsible for neutrophil recruitment; therefore, less neutrophils are attracted to the peritoneal cavity and the whole inflammatory process is dampened. The same research team further explored the role of melanocortin signaling in gouty inflammation in an experimental model of MSU crystal-induced arthritis [12]. This model is based on direct injection of MSU crystals in rat knee joints; this produces an acute inflammatory arthritis, characterized by neutrophil infiltration, closely resembling human gout. The authors reported that ACTH administered locally was effective in attenuating the crystal-induced inflammatory response without altering circulating corticosterone levels. Intra-articular ACTH treatment was highly efficacious; cell influx, joint swelling, and arthritis score were reduced by 82%, 88%, and 75%, respectively. Most importantly, local ACTH treatment retained its efficacy in rats subjected to adrenalectomy, providing solid evidence that ACTH exhibits a strong anti-inflammatory effect in a steroid-independent manner. In an effort to gain further insight into the molecular background of ACTH's anti-inflammatory properties, the authors showed that macrophages derived from rat knee joints express functional MC-3 R. Administration of SHU9119, an MC-3 R antagonist, inhibited the anti-inflammatory action of ACTH; on the other hand, treatment with γ2-MSH, an MC-3 R agonist, showed similar efficacy with ACTH. These data strongly suggest that ACTH mainly acts by stimulating MC-3 R located on macrophages. The significant role of MC-3 R on macrophages in the pathophysiology of gouty inflammation was underscored in another study as well [21]. The authors reported that treatment of macrophages derived from wild-type (WT) mice with D [Trp8]-γ-MSH, a specific MC-3 R agonist, resulted in inhibition of IL-1 release by 50%. However, this effect was not reproduced in macrophages derived from MC-3 R / mice. When D [Trp8]-γ-MSH was administered in vivo in an animal model of crystal-induced peritonitis, in WT mice, a robust downregulation of the inflammatory response was seen. In sharp contrast, no treatment effect could be seen in the same experimental model in MC-3 R / mice. Moreover, this agonist, administered either systemically or locally, was found to be highly effective in an experimental model of crystal-induced arthritis. These data underline the important role of MC-3 R signaling in controlling gouty inflammation. Apart from MC-3 R, MC-1 R has also been implicated in mediating the anti-inflammatory effect of melanocortins. However, it has been shown that MC-1 R is not involved in the downregulation of gouty inflammation. Stimulation of MC-3 R was effective in attenuating crystal-induced inflammation not only in WT mice but also in recessive yellow mice, a defective MC-1 R mouse strain, whereas administration of MS05, a selective MC-1 R agonist, was ineffective in WT mice [22]. The role of melanocortins in crystal-induced inflammation was further explored in a recent study. The authors performed a series
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Fig. 2. Mechanisms of action of ACTH in acute crystal-induced arthritis. ACTH binds MC-2 R and stimulates the release of steroids from the adrenal glands; steroids have a nonspecific suppressive effect on gouty inflammation. Moreover, ACTH binds MC-3 R on macrophages. Stimulation of melanocortin signaling in macrophages leads to reduced release of chemokines responsible for neutrophil recruitment; therefore, less neutrophils are attracted and the whole inflammatory process is dampened.
of in vitro experiments in order to explore how α-MSH downregulates crystal-induced inflammatory responses [23]. It was found that α-MSH affects monocytes in a way that they are less able to prime and attract neutrophils; moreover, α-MSH directly downregulated neutrophil activation. These data indicate that α-MSH affects both monocytes and neutrophils, which are the key cells in gout pathophysiology. These data indicate that ACTH, apart from the release of steroids, also mediates its effects on crystal-induced inflammation by stimulation of melanocortin receptors on macrophages. The mechanisms of action of ACTH in crystal-induced inflammation are diagrammatically shown in Figure 2. On clinical grounds, treatment of acute crystal-induced arthritis is not always easy and straightforward since many patients have multiple comorbidities. Clinical data suggests that ACTH is effective in acute crystal-induced arthritis and that this efficacy is similar to that seen with the classic therapeutic tools such as NSAIDs, steroids, and colchicine. However, due to its excellent safety profile, ACTH may be a first-line therapy in patients with multiple medical problems that preclude the use of other therapies. It is noteworthy that ACTH is an FDA-approved treatment for 19 indications, including exacerbations of several systemic rheumatic diseases (such as rheumatoid arthritis and systemic lupus erythematosus), nephrotic syndrome [24], or infantile spasms [25]. In cases of long-term use, ACTH associates with several “steroidrelated” side effects such as hypertension, edema, mood changes. However, its short-term use, as is the case for the treatment of acute crystal-induced arthritis, does not appear to associate with this kind of side effects, at least as depicted from the few available clinical studies. Current guidelines for gout, either do not mention ACTH at all [26,27] or recommend it solely for patients who cannot receive oral medications [28]. We feel that the role of ACTH as a treatment for acute crystal-induced arthritis should be reappraised, especially in light of experimental evidence, indicating that ACTH is more than a steroid-releasing hormone. We propose that further evaluation of ACTH should be performed, with a large-scale,
randomized controlled study, focusing on safety issues, in patients with multiple comorbidities.
Conclusions ACTH is effective in the treatment of acute crystal-induced arthritis and can be used as first-line therapy in patients with multiple comorbidities due to its excellent safety profile. ACTH should not be regarded solely as a steroid-releasing hormone; it has a wide range of immunomodulatory/anti-inflammatory actions by stimulating melanocortin receptors. References [1] Neogi T. Clinical practice. Gout. N Engl J Med 2011;364:443–52. [2] Keenan RT, O'Brien WR, Lee KH, Crittenden DB, Fisher MC, Goldfarb DS, et al. Prevalence of contraindications and prescription of pharmacologic therapies for gout. Am J Med 2011;124:155–63. [3] Ghosh P, Cho M, Rawat G, Simkin PA, Gardner GC. Treatment of acute gouty arthritis in complex hospitalized patients with anakinra. Arthritis Care Res (Hoboken) 2013;65:1381–4. [4] McGonagle D, Tan AL, Madden J, Emery P, McDermott MF. Successful treatment of resistant pseudogout with anakinra. Arthritis Rheum 2008;58:631–3. [5] Gutman AB, Yu TF. Effects of adrenocorticotropic hormone (ACTH) in gout. Am J Med 1950;9:24–30. [6] Ritter J, Kerr LD, Valeriano-Marcet J, Spiera H. ACTH revisited: effective treatment for acute crystal induced synovitis in patients with multiple medical problems. J Rheumatol 1994;21:696–9. [7] Axelrod D, Preston S. Comparison of parenteral adrenocorticotropic hormone with oral indomethacin in the treatment of acute gout. Arthritis Rheum 1988;31:803–5. [8] Siegel LB, Alloway JA, Nashel DJ. Comparison of adrenocorticotropic hormone and triamcinolone acetonide in the treatment of acute gouty arthritis. J Rheumatol 1994;21:1325–7. [9] Daoussis D, Antonopoulos I, Yiannopoulos G, Andonopoulos AP. ACTH as first line treatment for acute gout in 181 hospitalized patients. Joint Bone Spine 2013;80:291–4. [10] Getting SJ, Kaneva M, Bhadresa Y, Renshaw D, Leoni G, Patel HB, et al. Melanocortin peptide therapy for the treatment of arthritic pathologies. ScientificWorldJournal 2009;9:1394–414. [11] Brzoska T, Luger TA, Maaser C, Abels C, Bohm M. Alpha-melanocytestimulating hormone and related tripeptides: biochemistry, antiinflammatory
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ACTH as a treatment for acute crystal-induced arthritis: Update on clinical evidence and mechanisms of action Dimitrios Daoussis, MDn, Ioannis Antonopoulos, MD, Andrew P. Andonopoulos, MD, FACP Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, 26504 Rion, Patras, Greece
a r t i c l e in f o
Keywords: ACTH Gout Crystal-induced arthritis Treatment Pseudogout
abstract Background: ACTH, a member of the melanocortin group of proteins, has long been used in the treatment of gout and is considered as an alternative therapeutic option, especially in difficult-to-treat patients. Methods: We performed a systematic electronic search (Medline and ScienceDirect) using the keywords gout, treatment, ACTH, adrenocorticotropic hormone, and pseudogout. We identified 5 studies assessing the efficacy of ACTH in acute crystal-induced arthritis. Results: In the studies for acute gout, a total of 266 patients have been treated with ACTH; treatment was highly efficacious with a response rate of 77.9–100%. Only few side effects, such as hyperglycemia, hypokalemia, and edema, were reported, all of which were mild. The available evidence for acute CPP crystal arthritis is limited. A total of 19 patients have been assessed in retrospective studies; the response rate was 90–100%, whereas no significant side effects were recorded. The mechanism of action of ACTH in acute crystal-induced arthritis is not entirely known but seems to extend beyond stimulation of steroid release from the adrenal glands; ACTH is able to stimulate melanocortin receptors on macrophages and downregulate gouty inflammation. Conclusions: Data suggests that ACTH is effective in acute crystal-induced arthritis and may be a first-line therapy in patients with multiple medical problems. We propose that further evaluation of ACTH should be performed, with a large-scale, randomized controlled study focusing on safety issues in patients with multiple comorbidities. & 2014 Elsevier Inc. All rights reserved.
Introduction The prevalence of hyperuricemia and gout is constantly rising during the last decades. Nowadays, gout constitutes a significant public health issue, affecting 1% of the male population in Western countries [1]. Nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine are the most widely used agents for the treatment of acute gout. However, patients with gout usually suffer from multiple comorbidities, and therefore the use of these agents may be problematic. A recent study reported that the prevalence of hypertension and chronic kidney disease (CKD) in patients with gout was 90% and 50%, respectively, indicating that treatment of gout can be challenging in many cases [2]. Acute calcium pyrophosphate (CPP) crystal arthritis is the second-most frequent form of crystal-induced arthritis and is also commonly encountered in clinical practice. Patients suffering from acute CPP crystal arthritis are usually of advanced age and therefore frequently have cardiovascular disease (CVD), hypertension, CKD, or diabetes mellitus (DM). These comorbidities represent contraindications to most of the available therapeutic tools. n
Corresponding author. E-mail address: [email protected] (D. Daoussis).
0049-0172/$ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semarthrit.2013.09.006
There are only limited therapeutic options for the treatment of acute crystal-induced arthritis in patients with multiple comorbidities including steroids, IL-1 antagonists [3,4], and adrenocorticotropic hormone (ACTH). ACTH was first used as treatment for acute gout more than half a century ago [5]. Ever since, several studies have shown that this therapy is equally effective than NSAIDs and steroids and may be an attractive therapeutic option for patients with multiple medical problems or hospitalized patients; moreover, it exhibits an excellent safety profile [6–9]. It is not entirely known how ACTH dampens crystal-induced inflammatory responses; the prevailing hypothesis in the past was that ACTH acts solely by triggering release of endogenous steroids from the adrenal glands. However, experimental evidence, accumulated over the last decade, strongly indicates that this is not the case. ACTH is a member of a group of proteins called melanocortins; these molecules possess a variety of anti-inflammatory and immunomodulatory properties and seem to serve as natural inhibitors of inflammatory responses [10,11]. ACTH is able to stimulate melanocortin receptors on macrophages and downregulate crystal-induced inflammation in experimental models [12]. Herein, we review all the available clinical data related to the therapeutic use of ACTH in acute crystal-induced arthritis. Moreover, we provide the experimental evidence indicating the crucial
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role of ACTH in downregulating gouty inflammation beyond the release of steroids.
Methods We performed a systematic electronic search (Medline and ScienceDirect) using the keywords gout, treatment, ACTH, adrenocorticotropic hormone, and pseudogout, in the following combinations: gout and treatment and ACTH (or adrenocorticotropic hormone) and pseudogout and treatment and ACTH (or adrenocorticotropic hormone). The limits used were (a) English language, (b) published from 1970 and onwards, and (c) articles in scientific journals. Abstracts from conference proceedings and textbooks were excluded. The search identified 90 articles from Medline and 180 articles from ScienceDirect (a total of 270 articles); following removal of duplicates, 147 articles remained. The abstracts of these articles were assessed in order to identify case reports, case series, or clinical studies where ACTH has been administered in human subjects as treatment for either acute gout or pseudogout. Of the articles, 62 were irrelevant to study subject and were excluded from further review. The full text of the remaining 85 articles was assessed. Moreover, we manually searched the reference lists of these articles; however, no additional relevant articles were found. Finally, only 5 articles fulfilled the search criteria and were included in the analysis. These are diagrammatically depicted in Figure 1. Results ACTH in acute gout The first systematic assessment of the efficacy of ACTH in acute gout was performed by Axelrod and Preston [7]. The authors conducted a prospective, randomized controlled study comparing ACTH vs indometacin in acute gout in an outpatient setting. This study enrolled 76 patients with crystal-proven acute gout; patients with tophi or renal failure were excluded. Treatment was administered within 24 h from attack onset in the form of either 40 IU of ACTH intramuscularly (n ¼ 36) or 50 mg of indometacin 4 times daily (n ¼ 40); colchicine was not administered concurrently. A dramatic response was seen in ACTH-treated patients with a mean time for pain relief of only 3 h compared to indometacin-treated patients who had a mean time for pain relief of 24 h (p o 0.0001). More importantly, no side effects were recorded in the ACTH group
270 arcles idenfied in search (Medline and ScienceDirect)
147 arcles remained following duplicate removal and their abstract was assessed for eligibility
62 arcles were irrelevant to study subject and were excluded
85 arcles remained and the full text was assessed
5 arcles fulfilled the search criteria and were included in the analysis Fig. 1. Flowchart of the search.
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in sharp contrast to the indometacin group where 22 patients had abdominal discomfort or dyspepsia, 15 had headaches, and 12 had difficulty with mentation. This study clearly showed that ACTH is highly effective for the treatment of acute gout, especially when administered shortly after attack onset. Moreover, this study provided evidence that ACTH is faster acting than NSAIDs and associates with fewer side effects. Potential limitations of this study are the quasi-randomization method used and the fact that it was not blinded. Siegel et al. [8] performed a prospective, controlled study in order to explore the best therapeutic strategy in patients with acute gout when NSAIDs and colchicine are contraindicated in an outpatient setting. The authors assessed the efficacy of ACTH compared to long-acting steroids in 31 patients with acute gout of less than 5 days duration. Patients received an intramuscular injection of either 40-IU ACTH (n ¼ 16) or 60 mg of triamcinolone acetonide (n ¼ 15) and were followed up for 30 days following treatment administration. No differences were recorded in the time for complete resolution of the attack, which was on average 8 days for both groups. No side effects were recorded in either group. However, triamcinolone-treated patients required fewer reinjections (n ¼ 5) compared to ACTH-treated patients (n ¼ 11), and eventually, 2 patients from the ACTH arm were transferred to the triamcinolone arm due to rebound arthritis. This study has several potential limitations including the relatively low number of participants and its design (non-randomized and non-blinded) and therefore solid conclusions cannot be reached. However, in this study, ACTH certainly had a less pronounced effect on acute gout compared to that in the study by Axelrod and Preston. Even though the efficacy in terms of time needed for complete resolution of arthritis was similar between ACTH and triamcinolone, ACTH-treated patients experienced more episodes of rebound arthritis. There may be several explanations for this. Firstly, ACTH may not be so effective when administered later in disease course, i.e., more than 24 h from attack onset. Moreover, the dose of 60 mg of triamcinolone used (equivalent to 75 mg prednisone) was relatively high compared to the 40 IU of ACTH. Ritter et al. [6] retrospectively assessed the efficacy of ACTH in 33 patients with acute gout and multiple comorbidities that precluded the use of NSAIDs and colchicine; mainly renal insufficiency, congestive heart failure, and history of gastrointestinal hemorrhage. A total of 38 attacks were treated with ACTH (intravenous, intramuscular, or subcutaneous). Study subjects had a mean age of 66 years; most of them were hospitalized. The majority of episodes (84% polyarticular) were treated with 40 IU of ACTH every 8 h with gradual tapering according to clinical improvement. Prophylactic, low-dose colchicine treatment was concurrently given in the majority of patients. Treatment with ACTH was highly effective with a response rate of 97%. Complete resolution of arthritis was seen at an average of 5.5 days. Side effects recorded were mild and easily controlled such as hypokaleamia, hyperglycemia, and edema (12.1% each), while there were 4 episodes of rebound arthritis. This study provided evidence in favor of the use of ACTH as first-line treatment of acute gout in patients with multiple comorbidities. Potential limitations of this study are the relatively low number of patients recruited, the retrospective chart review design, the lack of a control arm, and the concomitant use of colchicine. In our department, we have been using ACTH as first-line treatment for acute gout in hospitalized patients since 1995 and we have recently reported our experience [9]. We identified 181 cases of acute gout where ACTH was used as first-line treatment, in a retrospective manner. Patients were treated with 1 mg (100 IU) of synthetic depot ACTH intramuscularly. The vast majority of patients had multiple comorbidities; the most frequent one was hypertension (80%) followed by CVD (54%). ACTH was highly
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effective with a response rate of 77.90%; the clinical benefit was evident the day following ACTH injection. Most patients who did not respond were treated once more with ACTH the day following the first injection. The majority of these patients (82.85%) responded. Rebound arthritis was not a major issue; only 11.34% of responders suffered a second gouty attack that occurred at a median of 4 days from the initial attack. Treatment with ACTH was safe and no significant side effects were recorded. In order to investigate potential “steroid-related” side effects, we specifically study the effect of ACTH on blood pressure, glucose, and potassium levels. Blood pressure and potassium levels remained stable the first and second day following ACTH administration. This study included 42 diabetic patients, in 32 patients, blood glucose levels were available at baseline and at the first and second day following ACTH administration. Diabetic patients showed an increase in fasting blood glucose levels the first day following the injection compared to baseline but this increase was not evident the second day following ACTH administration. Of note, in the vast majority of patients (41/42) no change in the antidiabetic treatment following ACTH treatment was recorded, indirectly indicating that the effect of ACTH on glucose levels was mild and transient. Similarly with the study of Ritter et al., our study underlines the efficacy and safety of ACTH in the patients who are most difficult to treat, such as hospitalized patients with multiple comorbidities. Potential limitations of the study are the retrospective design and the lack of a control arm; however, the significant number of patients assessed counterbalances these limitations at least to some extent. In the 4 available studies for acute gout, a total of 266 patients have been treated with ACTH. This treatment modality was highly efficacious with a response rate of 77.9–100%. However, we should acknowledge that the majority of patients were assessed in the context of retrospective studies, and therefore the evidence supporting the use of ACTH in acute gout cannot be considered powerful. ACTH seems to be fast acting, especially when administered early; the only study that assessed time to pain relief found that patients substantially improved within 3 h in sharp contrast to indometacin-treated patients who required 24 h for pain relief. This is in accordance with our clinical experience regarding hospitalized patients with acute gout treated with ACTH; the vast majority exhibited alleviation from pain within a few hours following the injection. Time for complete resolution of arthritis was 5–8 days, which is comparable to other treatment options. These data indicate that ACTH is indeed effective in the treatment of acute gout and is at least as effective as the classic therapeutic tools. However, the most important question to be answered is if ACTH is safer than other therapies for acute gout. Based on the available evidence, a definite answer cannot be given. However, it is noteworthy that the use of ACTH in acute gout is associated with relatively few side effects such as hyperglycemia and hypokalemia; all of which were mild. How about the dose of ACTH required to treat acute gout? In 3 of the 4 studies, the dosage of 40 IU was mainly used, in most cases as single intramuscular injection. However, in our department we have been using a higher dose (100 IU) of depot ACTH in a single IM injection; with this scheme, we had an excellent response rate in the patients who are most difficult to treat, with only few episodes of rebound arthritis. This is why we recommend this scheme as the most appropriate for acute gout. ACTH in acute CPP crystal arthritis (pseudogout) There is extremely limited evidence regarding treatment options in acute CPP crystal arthritis despite the fact that it is not uncommon. The latest EULAR recommendations for the treatment of acute CPP crystal arthritis mention ACTH as an alternative therapeutic option that is based mainly on the data from gout [13].
The study by Ritter et al. [6], mentioned previously, also enrolled 5 patients with acute CPP crystal arthritis. All patients had a good response with complete resolution within 4.2 days. Recently, we have published our experience with ACTH in acute CPP crystal arthritis in hospitalized patients [14]. We retrospectively identified 14 cases of acute CPP crystal arthritis where ACTH was used as first-line treatment. In all the cases, diagnosis was crystal proven, whereas synovial fluid cultures were negative. Patients were treated with 1 mg (100 IU) of depot ACTH intramuscularly. Patients were of advanced age (mean 80 years) and had at least 1 comorbidity that represents a contraindication to NSAIDs, steroids, or colchicine use. The vast majority of patients (n ¼ 13) improved dramatically with attenuation of signs of inflammation within 24 h without the use of NSAIDs, colchicine, or steroids. There were no episodes of rebound arthritis during hospitalization. Treatment was safe since no adverse events were recorded. Patients treated with ACTH showed a nonstatistically significant increase in fasting glucose the day following the injection compared to baseline. Systolic blood pressure and potassium levels at 24 h following ACTH treatment did not change compared to baseline. In accordance with the experience in gout, this study provides evidence indicating that ACTH is effective and safe in acute CPP crystal arthritis and supports its use as first-line treatment in hospitalized patients. This patient population may be extremely challenging to treat because they are usually of advanced age and suffer from multiple comorbidities and are therefore poor candidates for NSAIDs, colchicine, or steroid administration. The small number of patients assessed and the retrospective design of the study do not allow definite conclusions to be drawn. However, we should note that treatment of acute CPP crystal arthritis is mainly empirical due to the lack of properly performed, large-scale clinical studies. The available evidence supporting the use of ACTH in acute CPP crystal arthritis is limited, but this is the case for every treatment option in this disease. A total of 19 patients have been assessed in retrospective studies; the response rate was 90–100%. Despite the fact that all patients had multiple comorbidities, no significant side effects were recorded. All clinical data related to the use of ACTH in acute crystalinduced arthritis are summarized in the Table.
Discussion The mechanism of action of ACTH in acute crystal-induced arthritis is not entirely known but seems to extend beyond stimulation of steroid release from the adrenal glands. ACTH alongside with α, β, and γ melanocyte-stimulating hormone (MSH) belongs to a group of proteins called melanocortins. Evidence indicates that melanocortins act in peripheral tissues as natural inhibitors of inflammatory responses [15]. There are 5 types of melanocortin receptors (MC-R) named from 1 to 5. ACTH is the only melanocortin that is able to stimulate steroid release by binding MC-2 R in the adrenal glands. However, ACTH is able to bind and stimulate all types of MC-R and this is why it seems to have a broader, steroid-independent, anti-inflammatory action. This action is mainly linked to stimulation of MC-1 R and MC-3 R. There is relatively limited information on how ACTH exerts its steroid-independent, anti-inflammatory effects. However, there is a great amount of experimental evidence on the anti-inflammatory role of α-MSH, a peptide strongly related to ACTH. α-MSH downregulates the transcription factor NF-κB [16] and inhibits the expression of proinflammatory [11,17] and adhesion molecules [18,19], something that may lead to reduced influx of inflammatory cells and attenuation of inflammatory responses.
– 92.85
4.2 days
40 or 80 IU tid, gradual tapering 100 IU single dose
100
No
Patients with multiple comorbidities Hospitalized patients
Hospitalized patients 77.90 100 IU single dose
14 Daoussis et al. [14] Pseudogout
Ritter et al. [6]
5
Retrospective chart review Retrospective chart review Retrospective chart review 181 Daoussis et al. [9]
Retrospective chart review 33 Ritter et al. [6] Gout
–
Hypokalemia, hyperglycemia, and edema (in 12.1% each, all mild) Transient hyperglycemia – 5.5 days 97 40 or 80 IU tid, gradual tapering
No – 16 Siegel et al. [8]
Controlled (ACTH vs triamcinolone)
40 IU single dose
Time to pain relief 3 h 7.9 days
Early administration of treatment ( o24 h) ACTH was faster acting than indometacin ACTH-treated patients had episodes of rebound arthritis and required more reinjections Patients with multiple comorbidities No Not reported 100 40 IU single dose Randomized controlled (ACTH vs indometacin) 36 Axelrod and Preston [7]
Study type Number of ACTH-treated participants References
Table Studies assessing the efficacy of ACTH in acute crystal-induced arthritis
Treatment
Response rate (%)
Time to complete resolution
Side effects
Comments
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The first piece of experimental evidence that ACTH can dampen gouty inflammation, in a steroid-independent manner, came from a mouse model of monosodium urate (MSU) crystal-induced peritonitis [20]. Administration of ACTH4-10, a fragment of ACTH that does not stimulate endogenous steroid release, strongly inhibited the accumulation of inflammatory cells in the peritoneal cavity without altering systemic corticosterone levels. Administration of SHU9119, an MC-3/4 R antagonist, inhibited the effect of ACTH4-10 on crystal-induced inflammation in a dose-dependent manner, indicating that ACTH4-10 exhibits its anti-inflammatory action via MC-3 R or MC-4 R. The authors focused their attention on peritoneal macrophages that are responsible for the initiation of the crystal-induced inflammatory process and found that these cells express solely MC-3 R. The investigators suggested that ACTH4-10 acts by stimulating MC-3 R on peritoneal macrophages. Stimulation of melanocortin signaling in macrophages leads to reduced release of chemokines responsible for neutrophil recruitment; therefore, less neutrophils are attracted to the peritoneal cavity and the whole inflammatory process is dampened. The same research team further explored the role of melanocortin signaling in gouty inflammation in an experimental model of MSU crystal-induced arthritis [12]. This model is based on direct injection of MSU crystals in rat knee joints; this produces an acute inflammatory arthritis, characterized by neutrophil infiltration, closely resembling human gout. The authors reported that ACTH administered locally was effective in attenuating the crystal-induced inflammatory response without altering circulating corticosterone levels. Intra-articular ACTH treatment was highly efficacious; cell influx, joint swelling, and arthritis score were reduced by 82%, 88%, and 75%, respectively. Most importantly, local ACTH treatment retained its efficacy in rats subjected to adrenalectomy, providing solid evidence that ACTH exhibits a strong anti-inflammatory effect in a steroid-independent manner. In an effort to gain further insight into the molecular background of ACTH's anti-inflammatory properties, the authors showed that macrophages derived from rat knee joints express functional MC-3 R. Administration of SHU9119, an MC-3 R antagonist, inhibited the anti-inflammatory action of ACTH; on the other hand, treatment with γ2-MSH, an MC-3 R agonist, showed similar efficacy with ACTH. These data strongly suggest that ACTH mainly acts by stimulating MC-3 R located on macrophages. The significant role of MC-3 R on macrophages in the pathophysiology of gouty inflammation was underscored in another study as well [21]. The authors reported that treatment of macrophages derived from wild-type (WT) mice with D [Trp8]-γ-MSH, a specific MC-3 R agonist, resulted in inhibition of IL-1 release by 50%. However, this effect was not reproduced in macrophages derived from MC-3 R / mice. When D [Trp8]-γ-MSH was administered in vivo in an animal model of crystal-induced peritonitis, in WT mice, a robust downregulation of the inflammatory response was seen. In sharp contrast, no treatment effect could be seen in the same experimental model in MC-3 R / mice. Moreover, this agonist, administered either systemically or locally, was found to be highly effective in an experimental model of crystal-induced arthritis. These data underline the important role of MC-3 R signaling in controlling gouty inflammation. Apart from MC-3 R, MC-1 R has also been implicated in mediating the anti-inflammatory effect of melanocortins. However, it has been shown that MC-1 R is not involved in the downregulation of gouty inflammation. Stimulation of MC-3 R was effective in attenuating crystal-induced inflammation not only in WT mice but also in recessive yellow mice, a defective MC-1 R mouse strain, whereas administration of MS05, a selective MC-1 R agonist, was ineffective in WT mice [22]. The role of melanocortins in crystal-induced inflammation was further explored in a recent study. The authors performed a series
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Fig. 2. Mechanisms of action of ACTH in acute crystal-induced arthritis. ACTH binds MC-2 R and stimulates the release of steroids from the adrenal glands; steroids have a nonspecific suppressive effect on gouty inflammation. Moreover, ACTH binds MC-3 R on macrophages. Stimulation of melanocortin signaling in macrophages leads to reduced release of chemokines responsible for neutrophil recruitment; therefore, less neutrophils are attracted and the whole inflammatory process is dampened.
of in vitro experiments in order to explore how α-MSH downregulates crystal-induced inflammatory responses [23]. It was found that α-MSH affects monocytes in a way that they are less able to prime and attract neutrophils; moreover, α-MSH directly downregulated neutrophil activation. These data indicate that α-MSH affects both monocytes and neutrophils, which are the key cells in gout pathophysiology. These data indicate that ACTH, apart from the release of steroids, also mediates its effects on crystal-induced inflammation by stimulation of melanocortin receptors on macrophages. The mechanisms of action of ACTH in crystal-induced inflammation are diagrammatically shown in Figure 2. On clinical grounds, treatment of acute crystal-induced arthritis is not always easy and straightforward since many patients have multiple comorbidities. Clinical data suggests that ACTH is effective in acute crystal-induced arthritis and that this efficacy is similar to that seen with the classic therapeutic tools such as NSAIDs, steroids, and colchicine. However, due to its excellent safety profile, ACTH may be a first-line therapy in patients with multiple medical problems that preclude the use of other therapies. It is noteworthy that ACTH is an FDA-approved treatment for 19 indications, including exacerbations of several systemic rheumatic diseases (such as rheumatoid arthritis and systemic lupus erythematosus), nephrotic syndrome [24], or infantile spasms [25]. In cases of long-term use, ACTH associates with several “steroidrelated” side effects such as hypertension, edema, mood changes. However, its short-term use, as is the case for the treatment of acute crystal-induced arthritis, does not appear to associate with this kind of side effects, at least as depicted from the few available clinical studies. Current guidelines for gout, either do not mention ACTH at all [26,27] or recommend it solely for patients who cannot receive oral medications [28]. We feel that the role of ACTH as a treatment for acute crystal-induced arthritis should be reappraised, especially in light of experimental evidence, indicating that ACTH is more than a steroid-releasing hormone. We propose that further evaluation of ACTH should be performed, with a large-scale,
randomized controlled study, focusing on safety issues, in patients with multiple comorbidities.
Conclusions ACTH is effective in the treatment of acute crystal-induced arthritis and can be used as first-line therapy in patients with multiple comorbidities due to its excellent safety profile. ACTH should not be regarded solely as a steroid-releasing hormone; it has a wide range of immunomodulatory/anti-inflammatory actions by stimulating melanocortin receptors. References [1] Neogi T. Clinical practice. Gout. N Engl J Med 2011;364:443–52. [2] Keenan RT, O'Brien WR, Lee KH, Crittenden DB, Fisher MC, Goldfarb DS, et al. Prevalence of contraindications and prescription of pharmacologic therapies for gout. Am J Med 2011;124:155–63. [3] Ghosh P, Cho M, Rawat G, Simkin PA, Gardner GC. Treatment of acute gouty arthritis in complex hospitalized patients with anakinra. Arthritis Care Res (Hoboken) 2013;65:1381–4. [4] McGonagle D, Tan AL, Madden J, Emery P, McDermott MF. Successful treatment of resistant pseudogout with anakinra. Arthritis Rheum 2008;58:631–3. [5] Gutman AB, Yu TF. Effects of adrenocorticotropic hormone (ACTH) in gout. Am J Med 1950;9:24–30. [6] Ritter J, Kerr LD, Valeriano-Marcet J, Spiera H. ACTH revisited: effective treatment for acute crystal induced synovitis in patients with multiple medical problems. J Rheumatol 1994;21:696–9. [7] Axelrod D, Preston S. Comparison of parenteral adrenocorticotropic hormone with oral indomethacin in the treatment of acute gout. Arthritis Rheum 1988;31:803–5. [8] Siegel LB, Alloway JA, Nashel DJ. Comparison of adrenocorticotropic hormone and triamcinolone acetonide in the treatment of acute gouty arthritis. J Rheumatol 1994;21:1325–7. [9] Daoussis D, Antonopoulos I, Yiannopoulos G, Andonopoulos AP. ACTH as first line treatment for acute gout in 181 hospitalized patients. Joint Bone Spine 2013;80:291–4. [10] Getting SJ, Kaneva M, Bhadresa Y, Renshaw D, Leoni G, Patel HB, et al. Melanocortin peptide therapy for the treatment of arthritic pathologies. ScientificWorldJournal 2009;9:1394–414. [11] Brzoska T, Luger TA, Maaser C, Abels C, Bohm M. Alpha-melanocytestimulating hormone and related tripeptides: biochemistry, antiinflammatory
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