Allopurinol Hypersensitivity Reactions - Ingenta Connect

Send Orders of Reprints at [email protected] Inflammation & Allergy - Drug Targets, 2013, 12, 19-28

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Allopurinol Hypersensitivity Reactions: Desensitization Strategies and New Therapeutic Alternative Molecules Gianfranco Calogiuri1,2, Eustachio Nettis2, Elisabetta Di Leo2, Caterina Foti3, Antonio Ferrannini2 and Lavjay Butani4 1

Pneumology Department - Hospital Ninetto Melli-S. Pietro Vernotico, Brindisi, Italy

2

Section of Allergology and Clinical Immunology, Department of Internal Medicine and Infectious Diseases, University of Bari Medical School, Italy 3

Department of Biomedical Science and Human Oncology, Unit of Dermatology, University of Bari Medical School, Italy

4

Department of Pediatrics Section of Transplant Nephrology, Department of Internal Medicine, University of California, Davis Medical Center, Sacramento, CA, USA Abstract: Allopurinol, an analog of hypoxanthine has been worldwide used for the treatment of hyperuricemia and gout for over 40 years. Unfortunately some patients assuming this medication have developed hypersensitivity reactions ranging from mild cutaneous eruption to more severe clinical manifestations such as allopurinol hypersensitivity syndrome or Steven-Johnson syndrome and lethal toxic epidermal necrolysis. Various strategies of slow desensitization have been elaborated to reintroduce allopurinol in a part of these patients, mainly patients affected by mild skin reactions as fixed drug eruption or exanthema. However, several new uricosuric therapies have been recently introduced. Actually drugs as recombinant urate oxidase and febuxostat are under post-marketing surveillance to control potential adverse effects related to their immunogenicity even.

Keywords: Allopurinol, anakinra, desensitization, febuxostat, hypersensitivity, rasburicase. INTRODUCTION

(1)

a clear history of exposure to allopurinol;

The xanthine oxidase inhibitor allopurinol is the urate lowering pharmaceutical molecule most frequently used in patients with gout. It blocks uric acid formation by inhibiting the enzyme responsible for the formation of uric acid from hypoxanthine and xanthine.

(2)

lack of exposure to another drug that may have caused a similar clinical picture; plus

(3)

A clinical picture including at least two of the following major criteria:

Uric acid-lowering therapy is recommended for patients with gout who are experiencing frequent attacks of acute gouty arthritis, chronic gouty joint disease, tophaceous gout, impaired renal function, uric acid nephropathy, and nephrolithiasis [1]. It has been estimated that approximately 2% of patients treated with allopurinol will develop minor adverse reactions such as fixed drug eruption, pruritic maculopapular exanthema or minor vasculitis which often disappear on suspension of treatment, but which preclude further administration [2]. In contrast, Allopurinol Hypersensitivity Syndrome (AHS) represents a more fearful life threatening clinical condition with a delayed onset, which needs to be promptly recognized and treated because it could have a fatal outcome [3, 4]. Singer and Wallace identified the main criteria for recognizing AHS [5]; i.e.: *Address correspondence to this author at the Pneumology Department Hospital Ninetto Melli-S. Pietro Vernotico, Brindisi, Italy; Tel: 00-39-831-675353; Fax: 00-39-831-675452; E-mail: [email protected] 2212-4055/13 $58.00+.00

(a) deteriorating renal function, (b) acute hepatocellular injury, (c) a cutaneous rash including ranging from erythema multiforme, generalised maculopapular exanthem or generalised exfoliative dermatitis (GED) to Steven Johnson Syndrome/ toxic epidermal necrolysis (SJS/TEN), or one of the above major clinical criteria and at least one of the following minor criteria: (a) fever, (b) eosinophilia, (c) leukocytosis. The exact pathogenesis of AHS remains unclear, but is likely to involve a complex interaction of many factors including drug metabolism with accumulation of the allopurinol active metabolite, oxypurinol, which is able to trigger a drug specific T cell response [6], probably facilitated by genetic HLA-restricted molecules. Indeed, in 2005, an Asian study linked HLA B*58:01 to allopurinolinduced hypersensitivity reactions [7]. In that study, 51 patients with allopurinol hypersensitivity and 228 control individuals (135 allopurinol-tolerant © 2013 Bentham Science Publishers

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Inflammation & Allergy - Drug Targets, 2013, Vol. 12, No. 1

patients and 93 healthy volunteers) were typed for HLA-A, B, C and DRB1. All 51 patients with allopurinol hypersensitivity had the B*58:01 allele whereas only 20 (15%) were positive in the allopurinol-tolerant group and 19 (20%) of the healthy volunteers were positive for B*58:01 [7]. Little work has been done with Caucasians or AfricanAmericans to see if a similar association could be documented, although allopurinol represents the most frequent causative agent of SJS and TEN in Europe and Israel [8]. Although a T-cell mediated immune response seems responsible for the pathogenesis and clinical picture of AHS [9], a humoral IgM component has also been suggested, based on heavy granular IgM deposition at the dermoepidermal junction noted on a skin biopsy in a single patient with AHS, in the absence of T-cell activation on in vitro exposure to allopurinol [10]. DRUG DESENSITIZATION Drug desensitization (DD) is a medical procedure to induce a temporary unresponsiveness towards drug antigens responsible for a hypersensitivity reaction. It is based on the gradual re-introduction of incremental amounts of the drug antigens gradually increasing up to a full therapeutic dose. DD was first used in patients allergic to penicillin and is now often used in IgE mediated drug allergies, and even in non IgE mediated hypersensitivity reactions. While the oral route is generally considered to be safer, DD may be carried out through the intravenous pathway. DD can be performed through rapid protocols to allow use of medications in patients with IgE-mediated sensitivity to the drug [11]. Different mechanisms have been proposed to explain the temporary immunological tolerance induced by a desensitization protocol to a drug including hapten inhibition, mast cell and basophil mediator depletion, IgE Table 1.

Calogiuri et al.

consumption and mast cell desensitization [11]. As far as slow desensitization protocols for drug allergy are concerned, they are safer than the rapid ones and are used for the management of patients with drug allergy involving a delayed pathogenesis not related to antigen-specific IgE. The mechanism of desensitization in these instances is more obscure. It has been suggested, for instance, that gradually increasing antigen doses allows metabolic adaptation resulting in increased clearance of reactive drug metabolites. This efficient metabolism of the drug minimizes the formation of the haptenated carrier molecules that induce immune responses and elicit allergic reactions [12]. In contrast, a recently performed study with allopurinol in a 37 year old man affected by allopurinol fixed drug eruption (FDE) showed that T cells could also be involved in the induction of immune tolerance following a desensitization protocol. The patient was desensitized with increasing doses (10, 50,100 200, 500 mcg then 1 5, 10, 25, 50, and 100 mg) of allopurinol, starting with 10 mcg of allopurinol twice a day for two days, after which the dose was increased every second day. During the desensitization procedure skin biopsies were performed on the skin FDE lesions prior to desensitization and following desensitization. Biopsy specimens obtained from pigmented FDE lesions showed the presence of a significant number of CD3+ T cells; 91% of the CD3+ T cells were CD8+ T cells and 3,4 % were CD4+ T cells in the lesional epidermis of FDE. After desensitization the percentage of CD8+ T cells was seen to be decreased to 35%, while the percentage of CD4+ T cells was increased up to 55%. Nearly half of the intradermal CD4+ T cells expressed CD25, identified as T cells with regulatory functions, for their ability to produce Interleukin (IL)-10 [13], although such percentages of different T cells subset could have also been influenced by the daily 10 mg of oral prednisone that was administered during the entire desensitization protocol period [13]. Previously, two other detailed reports described allopurinol desensitization schedules in FDE. The first was performed by

Scheme for Allopurinol Desensitization up to 300 mg Dose in FDE Day

Solution Dose

Day

Solution Dose

Day

Dose

1

0.1 ml =10 μg

4

1 ml = 100 μg

8

50 mg

0.2 ml =20 μg

2 ml = 200 μg

9

75 mg

0.3 ml =30 μg

4 ml = 400 μg

10

100 mg

11

125 mg

12

150 mg

13

175 mg

14

200 mg

5

6 ml = 600 μg 8 ml = 800 μg

2

0.4 ml =40 μg

10 ml = 1 mg

0.5 ml =50 μg 0.6 ml =60 μg

6

20 ml = 2 mg 40 ml = 4 mg 80 ml = 8 mg

3

0.7 ml =70 μg

7

160 ml = 16 mg

0.8 ml =80 μg

250 ml = 25 mg

15

250 mg

0.9 ml =90 μg

350 ml = 35 mg

16

300 mg

Allopurinol Hypersensitivity Reactions

Kelso and Keating in a 71 year old man with tophaceous gout and multiple medical problems, including diabetes, hypertension, chronic renal insufficiency and atrial fibrillation, who had developed FDE on the glans penis. The patient received allopurinol at a dose of 50 mcg/day for 3 days, after which the dose was increased to 100 mcg, 200 mcg, 500 mcg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg at 3 day intervals, up to 100 mg. The patient continued to receive 10 mg of oral prednisone daily during the desensitization [14]. The second schedule for FDE lesions, reported by a Spanish group, reached a maximum dose of 300 mg, as shown in Table 1 [15]. Allopurinol 50 mg was dissolved in 500 ml of distilled water with 14% sodium bicarbonate. The patient began receiving allopurinol at a very low dose of 10 μg, increasing to 300 mg/day over a period of 16 consecutive days. During the first 7 days, he received three daily doses at half hour intervals [15]. The protocol was a modified regimen from the original one, first proposed by Meyrier in 1976, as illustrated in Table 2. In that 40 mg of allopurinol was dissolved in 500 ml of 14% sodium bicarbonate aqueous solution and given to a 51 year old man affected by a generic severe rash that appeared 48 hours after he started a second course of allopurinol [16]. Webster and Panush used Meyrier’s protocol in a patient with severe gouty arthritis who had developed a pruritic erythematous maculopapular rash on the face, trunk and extremities, which faded after suspension [17]. Although the patient showed no hypersensitivity symptoms during the desensitization process, the long term clinical outcome of allopurinol treatment was not reported [17].


Table 2.

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Meyrier Protocol

Day

Solution

Dosage of Allopurinol (mg)

1

0.1 ml

0.008

2

0.2 ml

0.016

3

0.3 ml

0.024

4

0.4 ml

0.032

5

0.5 ml

0.040

6

0.6 ml

0.048

7

0.7 ml

0.056

8

0.8 ml

0.064

9

0.9 ml

0.072

10

1 ml

0.080

11

2 ml

0.160

12

4 ml

0.320

13

6 ml

0.480

14

8 ml

0.640

15

10 ml

0.800

16

12 ml

0.960

17

14 ml

1.120

18

16 ml

1.280

Fam et al. confirmed the efficacy and safety of oral allopurinol desensitization in a group of nine patients who had a well documented recent history of a pruritic erythematous maculopapular or morbilliform eruption shortly after their initial allopurinol intake. All nine patients had chronic renal failure, tophaceous gout and a documented history of a cutaneous reaction to allopurinol, which resolved following drug discontinuation. The authors excluded from the study patients with a history of severe adverse reactions to allopurinol such as interstitial nephritis, hepatitis and SJS/TEN [18].

19

20 ml

1,600

20

25 ml

2.000

21

32 ml

2.560

22

64 ml

5.120

23

128 ml

10.240

24

250 ml

20.00

25

1/2 tablet

50.00

26

1/2 + 1/4 tablet

75.00

The solution for the desensitization protocol, shown in Table 3, was prepared by crushing 100 mg tablets of allopurinol in a mortar and slowly adding 33 mL of 1% methylcellulose to make a slurry. It was then made up to a volume of 100 mL sterile water. Ten ml of this suspension was further diluted to 100 mL to yeld a final concentration of 1 mg/5 mL. The desensitization process varied from 21 to 81 days. Three patients had clinical improvement with cessation of gouty attacks and normalization of serum uric acid levels. One patient did not improve after desensitization because of poor compliance, while two patients developed a late cutaneous rash, one after 2 months and the second after 20 months. The rest of the patients were lost to follow-up [18]. Some years later, the same author replicated the safety of the desensitization procedure in a larger group of 32 patients, enrolled with the aforementioned criteria [19]. The desensitization protocol was similar to the previous one, but it was tailored to the personal immune reactivity of each patient in a second modified protocol with initial daily doses of allopurinol of 10 to 25 mcg and a dosage change every

27

1 tablet

100.00

28

1 + 1/2 tablet

150.00

29

2 tablets

200.00

30

3 tablets

300.00

5-10 days or longer used in elderly patients with multiple comorbidities and in patients with generalized confluent skin rashes, especially if associated with facial swelling, fever, stomatitis and eosinophilia [19]. Mild reactions developed in 30% of the patients during desensitization, mainly after the transition to pharmacologically active dosage; the drug was suspended until resolution of the reaction and then resumed the next lowest dosage level. In that way, 78% of the 32 allopurinol allergic patients were able to resume allopurinol therapy, although in the short-term, four patients were unable to complete the desensitization procedure because of recurrent rashes (one patient developed an unmanageable rash despite dosage adjustments). On long term follow-up, up to 32 months after the beginning of the desensitization protocol, 7 of the 28 patients showed late post-

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desensitization recurrent cutaneous eruptions, which occurred at a mean of 6 months following desensitization. Four of the 7 patients responded to dosage adjustment, but 3 discontinued allopurinol treatment [19]. Table 3.

Fam Standard Allopurinol Desensitization Protocol*

Daily Dose

Preparation†

Days (Approximate)

50 μg

0.25-ml suspension (1 mg/5 ml)

1-3

100 μg


4-6

200 μg

1-ml suspension (1 mg/5 ml)

7-9

500 μg


10-12

1 mg


13-15

5 mg


16-18

10 mg


19-21

25 mg


22-24

50 mg

One-half a 100-mg tablet

25-27

100 mg

One 100-mg tablet

28 up

*For high-risk patients, a modified desensitization protocol, with initial allopurinol doses of 10 μg and 25 μg (0.05 ml and 0.12 ml of 1 mg/5 ml suspension, respectively), and a dosage escalation every 5-10 days or longer, is recommended. †Two concentrations of allopurinol suspension were used: 1 mg/5 ml and 10 mg/5 ml, depending on the dosage required.

Fam’s protocol was successfully modified by Gillott et al. and used with two different concentrations of allopurinol suspensions (0.5 and 5 mg/ml), prepared by mixing powdered allopurinol with equal parts of distilled water, on two patients with a mild cutaneous rash, flu like symptoms, vomiting and oral ulcerations that appeared a few weeks after beginning allourinol [20]. Gillott’s scheme has been successfully used in a patient affected by hyperuricemia and familial predisposition to allopurinol hypersensitivity [21]. After desensitization, the patient was able to resume allopurinol 200 mg daily and took it for eight years. Other groups, however, have reported serious adverse reactions, that highlight the risks inherent in allopurinol desensitization. Unsworth et al. described the failure of allopurinol desensitization. A 54 year old woman with normal renal function and a history of urticarial rash, swelling of the head and neck and stridor after treatment with allopurinol was desensitized using Fam protocol. Two weeks after being desensitized, the patient developed sudden stridor, neck swelling and a diffuse systemic itchy lumpy rash. The reaction subsided within one week after stopping allopurinol and allopurinol was not re-administered [22]. Tannan et al. subsequently described failure of a desensitization protocol in a 64 year old male patient with renal impairment and an erythema multiforme like rash with eosinophilia on initial administration of allopurinol. On initial desensitization, the patient received allopurinol 0.05 mg/day for two days, followed by increasing doses until a dose of 5mg was reached; the patient developed rash and eosinophilia. Allopurinol was promptly stopped and the rash subsided within a month. A second attempt to desensitize the patient was performed successfully, by starting from the same dose of 0,05 mg daily but with a more gradual increase in three day intervals to a final dose of 100 mg [23].

Calogiuri et al.

However, there are two case reports where allopurinol has been reinstituted in therapy following oral rush desensitization protocols in patients with urticaria/angioedema a few days after their first course of allopurinol [24, 25]. The desensitization protocol was also derived from the Fam scheme, but was different from the original schedule because doses were administered from 50 mcg up to 1 mg in the first day with one hour intervals, with 5 and 10 mg administered on the second day, 25 mg and 50 mg on the third day and 100 mg on the fourth day. In that way, instead of one month, the therapeutic dose was reached in 4 days [24]. In the patient affected by gout and systemic lupus, the therapeutic dose was reached in a week [25]. Alternatively, allopurinol has been administered through an intravenous desensitization regimen in a patient with generalized urticarial rash, fever, chills and edema shortly after having started allopurinol treatment. Oral desensitization failed because of poor compliance, so the authors experimented with an innovative desensitization protocol (Table 5) wherein the small doses used in stage 1 were preloaded in a 3 ml syringe and injected into the intravenous tubing and in stage 2 intravenous drug was administered by adjusting a prepared infusion pump [26]. The entire procedure was performed under strict medical and nursing supervision, by monitoring vital signs hourly. The patient tolerated intravenous desensitization without complication [26]. Recently the same intravenous protocol was used in a 57 year old patient with a heart transplant for severe idiopathic cardiomyopathy, renal insufficiency and gout, with the exception of a slower progression from the starting dose of 0.1μg to the 500 μg dose. The 30-minute intervals between the higher doses in the protocol were chosen because of the longer infusion times required for those doses [27]. Sometimes, the IV route for drug desensitization may be safer than oral desensitization, because IV drug administration can be stopped promptly in the event of a reaction, whereas discontinuance of oral administration is followed by continued gastrointestinal absorption for a variable period of time. However, the safety and efficacy of allopurinol intravenous desensitization for routine use has not been fully established. Table 4.

Gillot’s Desensitization Schedule

Days

Dose of Allopurinol (mg)

Amount of Suspension 1 (0.5 mg/ml) Given (ml)

1-3

0.05

0.1

4-6

0.1

0.2

7-9

0.2

0.4

10-12

0.5

1

13-15

1

2

16-18

5

10

Amount of suspension 2 (5 mg/ml) given (ml) 19-21

10

2

22-24

25

5

25-27

50

10

28-up

tablet 100 mg


Table 5.

Intravenous Allopurinol Desensitization Procedure

Stage 1: (All Doses Given at 15 Minutes Intervals) 0.1 μg 1 μg 10 μg


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longer available in many countries. Benzbromarone, for instance, has been withdrawn from the European market since 2003, due to the risk of fulminant hepatitis [38]. Some of these therapeutic alternatives which have been used in the setting of allopurinol hypersensitivity are discussed below. Table 6.

Allopurinol Desensitization Scheme in Allopurinol Hypersensitivity Syndrome

50 μg 100 μg

Days

Daily Dose

500 μg

1-3

6.5 μg

Stage 2: 200 mg in 500 ml 5% Dextrose, (All Doses, Except the Last Given at 30 Minute Intervals)

4-6

12.5 μg

7-9

25 μg

10-12

50 μg

13-15

100 μg

16-18

200 μg

19-21

400 μg

22-24

800 μg

25-27

1.6 mg

28-30

3.2 mg

31-33

6.4 mg

34-36

12.5 mg

37-39

25 mg

40-42

50 mg

43-45

100 mg

46-

150 mg

Up to 270

300 mg

1 mg (2.5 ml) 2 mg (5 ml) 5 mg (12.5 ml) 10 mg (25 ml) 20 mg (50 ml) 50 mg (125 ml) 100 mg (250 ml given 1 hour later), then switched to oral allopurinol 200 mg the following day

Most authors agree that desensitization procedures usually should be avoided in severe cutaneous reactions such as SJS/TEN or acute generalized exanthematous pustulosis (AGEP) [11, 12, 19], but, exceptionally DD has been performed in patients with SJS related to trimethoprim/sulphamethoxazole [28] and in patients with AGEP induced by epoetin-alpha [29] or clopidogrel [30]. For those reasons perhaps Vaquez-Mellado et al. performed an allopurinol desensitization procedure in a 36 year old male patient with allopurinol hypersensitivity syndrome as shown in Table 6 [31]. The patient presented with most of the criteria for an allopurinol hypersensitivity syndrome and a daily dose of 6.5 μg was started and doubled every 3 days until a 150 mg per day was reached. That dose was maintained from day 47 to day 270 and then increased to a maximum of 300 mg/day. The lowest doses of allopurinol (25 mg/day) were obtained by dissolving allopurinol powder in distilled water and preparing three solutions at concentrations of 500 μg/mL, 25 μg/mL and 0.5 mg/mL. Doses of 25 mg were provided in fractionated and whole tablets and the patient was hospitalized during the first two weeks of the desensitization treatment [31]. Although desensitization schedules have been demonstrated to be a valid method to reintroduce drugs, in the case of particular hypersensitivity reactions such as eosinophilic folliculitis [32, 33], drug induced aseptic meningitis [34, 35] or hypersensitivity syndromes associated with pure red cell aplasia [36], alternative therapeutic agents are required because no desensitization protocols have been developed in such situations. In the case of allopurinol, some alternative drugs are available, although several such as probenecid, sulphinpyrazone, benzbromarone and colchicine [37] have sometimes been demonstrated to be insufficient in lowering serum urate [16, 17, 20, 23, 26]. It has therefore been necessary to produce new uricosuric agents, especially becuase some of the other ‘older’ alternative drugs are no

The lowest dose of allopurinol (25 mg/ml) was obtained by dissolving allopurinol powder in distilled water and preparing three solutions at concentrations of 500 μg/ml, 25 μg/ml and 0.5 μg/ml. Patient was hospitalized during the first 2 weeks of desensitization.

BIOLOGICAL AGENTS The introduction of recombinant protein technology and hybrid antibody technology has permitted extensive production of protein-based products derived from living sources such as bacteria, yeast or mammalian cells genetically engineered as recombinant proteins, monoclonal chimeric antibodies and fusion proteins. They represent the “magic bullets” conveniently designed to interact selectively with a single specific receptor or serum factor. RASBURICASE Rasburicase, a recombinant urate oxidase, is a urolytic enzyme developed for the prevention and treatment of acute renal failure induced by hyperuricemia produced by tumor lysis following chemotherapy (tumor lysis syndrome) [39]. Urate oxidase converts uric acid to allantoin, which is 5 to 10 time more soluble in urine than uric acid and is rapidly excreted by the kidneys. Because humans do not produce uricase, it has been necessary to develop a recombinant DNA-engineered version of that enzyme [40]. Rasburicase is originated from a cDNA code derived from a modified Aspergillus flavus strain expressed and obtained in a

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genetically engineered strain of the yeast Saccharomyces cerevisiae. Although rasburicase has been approved only for the management of tumor lysis syndrome, it has been proposed as therapeutic alternative molecule to treat gout in allopurinol sensitive patients, based on a few isolated case reports [41-44]. The recommended dose of rasburicase in patients with tumor lysis syndrome is 0.20 mg/kg/day diluted in 50 ml of sodium chloride solution 0.9%, administered intravenously over 30 minutes, daily or twice daily for 5-7 days. The same dose (0.15 -0.20 mg/kg) has been used in the treatment of gout [41-44]. Usually patients’ serum uric acid levels decrease quickly in the days after rasburicase infusion, but increase again in the following weeks [41]. Rasburicase is a tetrameric protein made up of 4 identical subunits of 301 aminoacids each with a molecular weight of 34 kDa, it is considered a complete antigen and consequently can be highly immunogenic, inducing the production of binding and neutralizing antibodies in healthy volunteers [45]. For that reason, serious adverse reactions attributed to raburicase have been reported and include anaphylaxis, rash, and hemolysis, each of which has been reported to occur in 1% of patients. Even respiratory distress with fatal outcome has been reported following the first infusion of rasburicase in two patients [46]. The authors in this report suggested that the origin of the respiratory arrest may have been from severe bronchospasm, secondary to a rasburicase-induced anaphylactic reaction [46]. Interestingly, Aspergillus species are prevalent indoor airborne fungi, able to induce IgE mediated respiratory disorders such as asthma and allergic bronchopulmonary aspergillosis. Because Aspergillus flavuus has been shown to be the predominant airborne Aspergillus species in the Taipei area and its major allergen, identified, purified and characterized as Asp fl 13, was determined to be an enzymatic protein with a molecular weight of 34 kDa, having, and having a high IgE-binding (63%) frequency for sera from asthmatic patients in SDSPAGE immunoblotting assays [47]. Furthermore, results from immunoblot inhibition studies indicate that IgE crossreactivity occurs among the 34 kDa major allergens of A. flavus and A. fumigatus [47] Therefore, before administering intravenous rasburicase, a clinical history of previous asthma to molds or allergic bronchopulmonary aspergillosis should be investigated and excluded in patients. In the largest pilot study published [48] Richette, et al. retrospectively studied 10 subjects with chronic tophaceous gouty arthropathy and mild to severe renal insufficiency. Allopurinol had been previously discontinued in these patients because of severe cutaneous hypersensitivity in 5 patients or allopurinol-refractory hyperuricemia in the other 5. All subjects, with appropriate informed consent, received infusions of Rasburicase 0.2 mg/kg intravenously over 30 minutes, with intravenous methylprednisolone (60 mg) as premedication. The short term safety and efficacy of rasburicase 0.2 mg/kg in monthly vs daily dosing schedules was compared in these patients. In 5 subjects, a single, short, intensive management regimen of 5 daily infusions (adapted from regimens used for tumor lysis syndrome) led to a rapid reduction in serum urate concentrations but was not sustained at 1 month, nor was there a reduction in tophi in any of the subjects. The other 5 subjects received monthly infusions for 6 months with more effective and sustained mean serum urate-lowering (from ~10 mg/dl to ~5.6 mg/dl

Calogiuri et al.

after the sixth of the monthly infusions) and had a clear reduction in tophi size (in two of the patients). Serum urate was dramatically decreased with a maximal decline at 7 days. The short serum half-life of uricase theoretically renders a relatively small fraction of total free urate stores accessible to rasburicase in the serum in patients with typical chronic tophaceous gout. Therefore, one suspects that the monthly regimen induced substantial serum urate-lowering by 6 months since rasburicase was entering, dwelling, and acting at sites of peripheral tissue urate accumulation. The study by Richette, et al. confirms late problems due to immunogenicity when receiving monthly rasburicase infusions in patients with gout. Two patients developed hypersensitivity reactions to the medication and one patient each had bronchospasm and urticaria at the sixth infusion [48]. Furthermore some patients have been shown to be refractory to rasburicase [49]. Unfortunately, data regarding optimal dosing and intervals between infusions are lacking due to the absence of large clinical studies of rasburicase in patients with gout, the routine use of rasburicase is likely to be limited, especially considering its immunogenicity, high cost, poor manageability due to the route of administration, off-label use and possibility of resistance. Moreover the need for allergic tests to recombinant Aspergillus allergens remains undervalued by oncologists even when an allergic evaluation is required to develop a useful desensitization regimen to rasburicase (personal experience, unpublished). Recently, a new formulation of rasburicase associated with polyethylene glycol, i.e. pegylated mammalian uricase or pegloticase, has been produced to decrease the immunogenic properties of that drug, making its use safer in humans [50]. CHIMERIC ANTIBODIES AND FUSION PROTEINS Monosodium urate (MSU) crystal accumulation promotes a strong local inflammatory response mediated by the so-called “inflammasome”, which is a protein complex formed within monocytes and macrophages after phagocytosis of the crystals [51]. This complex activates the caspase-1 pro-enzyme and leads to the release of mature interleukin 1(IL1-) and Tumor Necrosis Factor-alpha (TNF-alpha) by mononuclear cells [51]; for this reason the use biological drugs has been proposed to reduce intraarticular inflammatory damage induced by urates. Anecdotal reports have described the effectiveness of TNF-alpha blockers such as the fusion protein etanercept at a dose of 25 mg twice weekly [52] and the chimeric antibody infliximab at a dose of 400 mg intravenously in weeks 0, 2, 6 and then every 8 weeks [53] in the management of severe tophaceous gouty arthritis. The authors have reported successful reduction and good de-bulking of tophaceous lesions with both anti-TNF-alpha agents [52, 53]. Even anakinra, a recombinant IL-1 receptor antagonist has been shown to be effective in the treatment of exacerbations of chronic tophaceous gout in a few case reports [54, 55], although in two somewhat larger studies involving patients with difficult-to-treat acute gout, anakinra produced controversial results. In the first study anakinra was rapidly effective in suppressing flares, pain and inflammation [56]. All patients responded within 48 hours, and in four of the 10 patients, symptoms improved within 24 hours. However, in two


patients, both of whom had tophaceous gout, the response was not so satisfactory [56]. In the second study, among the 10 patients who received anakinra at a daily subcutaneous dose of 100 mg, for urate crystal-induced arthritis, only six subjects showed a good response. Three patients had a partial response and one patient was unresponsive [57]. Nine patients had documented recurrent flares after discontinuing therapy. The last study dampened enthusiasm for the use of anakinra, although inhibition of IL-1 seemed to be a more effective strategy for treating acute gout than inhibition of TNF- in patients with severe gouty flares who cannot or should not receive NSAIDs, colchicine or high-dose corticosteroids, or who are refractory to such treatments [57]. Although the use of biologic agents may be an alternative treatment for patients with allopurinol hypersensitivity, they are currently not approved for the management of gout by the Food Drug Admnistration (FDA) or the European Medicines Agency (EMEA). They are also limited by their high cost [58]. Furthermore while anti TNF- agents and anakinra may be effective in ameliorating the consequences of acid uric accumulation (i.e. gouty arthritis) their pharmacologic action does not affect any of the metabolic abnormalities leading to urate overproduction [57, 58]. FEBUXOSTAT Febuxostat is an orally administered thiazolecarboxylic acid derivative that is a novel non-purine selective inhibitor of xanthine oxidase. It has been developed for the management of hyperuricaemia and gout almost 40 years after the appearance of allopurinol on the market. Febuxostat selectively inhibits xanthine oxidase and unlike allopurinol, does not inhibit any other enzymes in the purine and pyrimidine metabolic pathways [59]. It has several potential advantages over allopurinol including tolerability in those who are allopurinol-hypersensitive, better efficacy, especially in renal impaired patients and possibly more rapid dissolution of tophi. It is mainly metabolized by the liver, and so, unlike allopurinol may not require dosage modification in renal failure. However potential problems with its use include liver enzyme elevations, more gastrointestinal symptoms than with allopurinol and a small increase in the risk of vascular events compared with allopurinol. For this reason caution is advised with the use of febuxostat in patients with severe hepatic impairment [59]. Becker et al. randomly assigned more than 760 patients with gout and serum urate concentrations of at least 8.0 mg/dL (480 mol/L) to receive either febuxostat or allopurinol. Patients were given febuxostat (80 mg or 120 mg) or allopurinol at a dose of 300 mg once daily for 52 weeks. The investigators initiated prophylaxis against gout flares with naproxen or colchicine during weeks 1 through 8. The primary end point was a serum urate concentration of less than 6.0 mg/dL (360 mol/L) in the last three monthly measurements [60]. The secondary end points included reduction in the incidence of gout flares and in the tophus area. The investigators found that febuxostat at a daily dose of either 80 mg or 120 mg was more effective than allopurinol in lowering serum urate. They reported similar


25

reductions in gout flares and tophus area in all three treatment groups. There were four deaths in the febuxostat groups and none in the allopurinol group. No serious rashes or hypersensitivity reactions occurred in this study, although more patients in the high-dose febuxostat group discontinued the study compared to the other 2 groups. Febuxostat appeared to be more effective than allopurinol in lowering serum urate levels in this study, although a large percentage of patients taking that drug did not achieve the primary end point of serum urate levels less than 6.0 mg/dL. One of the advantages of febuxostat is that it seems to be less allergenic than allopurinol. Because febuxostat has a chemical structure unrelated to that of allopurinol, the probability of developing cross-related intolerance to febuxostat is low, theoretically. Interestingly, however, in clinical trials, adverse effects associated with febuxostat have included rash (2% incidence) without reported severe cutaneous reactions; indeed the incidence of rash with febuxostat 80 mg/day was similar to that with allopurinol 300 mg/day [61]. The first study to evaluate immunological tolerability of febuxostat in allopurinol hypersensitive patients has been performed by Chohan [62]. Febuxostat was administered to 13 patients (8 males, 5 females) 10 of whom had severe cutaneous allopurinol reactions with the remaining 3 patients having multisystem involvement including skin, acute or acute on chronic renal insufficiency, hepatitis and/or hematologic abnormalities following allopurinol administration. All patients except one, tolerated febuxostat at the starting dose of 40 mg. The exception was an 85-yearold woman, previously hospitalized with documented exfoliative erythroderma during allopurinol treatment, who developed biopsy-confirmed cutaneous leukocytoclastic vasculitis after 4 days of exposure to febuxostat [62]. Although the Food and Drug Administration had received 11 reports of hypersensitivity reactions to febuxostat as of May 2010 with 2 anaphylactic reactions, 1 case of angioedema, 2 of Stevens-Johnson syndrome, and 6 of rashes/allergies [63], in the literature, the first case of febuxostat hypersensitivity was described recently in a 69-year-old woman with multiple medical problems including gout and moderate renal insufficiency [64]. This patient developed a hypersensitivity syndrome similar to allopurinol hypersensitivity syndrome shortly after initiating febuxostat. Febuxostat had been initiated at 40 mg daily and then titrated to 80 mg daily after 1 week. Within days of starting the higher dose, she developed fatigue, diffuse itching associated with an urticarial lesion in the left axilla, facial swelling, erythema and a markedly erythematous tongue, without other mucosal involvement [64]. Laboratory tests revealed a creatine level of 2.8 mg/dl (247.5 μmol/l), as well as a peripheral eosinophilia of 16%, although the uric acid had normalized from 10.7 mg/dl to 5.8 [64]. Interestingly, in 2009, Sullivan had already elaborated the first febuxostat desensitization protocol [65] as illustrated in Table 7; however it is not clear how many patients have undergone treatment with such a protocol and in what kind or degree of hypersensitivity reactions it was successful. Because febuxostat has been commercially authorized by the FDA in USA since 2008, that experience suggests that febuxostat hypersensitivity reactions are more common and widespread than previously suspected.

26


Table 7.

Febuxostat Desensitization Schedule

Day

Concentration

Amount

1

0.1 mg/ml

0.1 ml

2

0.1/mg/ml

0.2 ml

3

0.1 mg/ml

0.4 ml

4

0.1 mg/ml

0.8 ml

5

0.1 mg/ml

1.6 ml

6

0.1 mg/ml

3 ml

7

0.1 mg/ml

6 ml

8

0.1 mg/ml

12 ml

9

0.1 mg/ml

24 ml

10

10/mgml

0.5 ml

11

10 mg/ml

1 ml

12

10 mg/ml

2 ml

13

10 mg/ml

3 ml

14

10 mg/ml

4 ml

Prepare 0.1 mg/mL suspension followed by 10 mg/mL 1.Take one dose once a day, then advance to the next dose 2.Weekend doses are prepared and marked for the patient to add to water and take at home. Other doses should be given in the office to assure correct doses and absence of reactions 5. Then start one 40 mg Febuxostat tablet once a day 7. If the patient misses more than one dose, the desensitization should be repeated.

Calogiuri et al.

Because adverse reactions to febuxostat have been reported, intense post-marketing surveillance will be necessary to monitor for their incidence, given the limitations of clinical trials in reporting this face of febuxostat use. CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS Declared none. REFERENCES [1] [2] [3]

[4] [5] [6]

Febuxostat is also sold as a suspension in the USA, but not in Europe. Hence to prepare useful dilutions of febuxostat solution for desensitization it is necessary to follow the European Network for Drug Allergy (ENDA) position paper on drug desensitization [66]. ALKALIZERS Drugs such as piperazine citrate and kalnacitrate increase uric acid excretion by increasing urinary pH. Despite their widespread use in Europe, there are only a few reports describing their use in allopurinol hypersensitive patients as alternative drugs [67]. Calogiuri et al. described a case report of a 70 year old obese man with allopurinol hypersensitivity syndrome in whom kalnacitrate 200 mg twice daily lowered uric acid within a few weeks [67]. Unfortunately prolonged and extensive use seems to be limited by the possibility of increasing serum potassium in patients with chronic kidney disease. Nevertheless short courses of kalnacitrate or piperazine citrate intake represent a possible alternative in patients with gout and allopurinol hypersensitivity with close monitoring of serum potassium levels (personal experience, unpublished). CONCLUSIONS Although new drugs have been developed to treat hyperuricemia and gout, practical therapeutic choices remain limited. Allopurinol remains the drug of first choice, although in allopurinol sensitive subjects, febuxostat is the best option because it avoids the use of desensitization protocols which may be longer, requiring a close monitoring in experienced hands and present some risk to the patient.

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Received: May 17, 2012

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Revised: October 13, 2012

Accepted: October 14, 2012