- Email: [email protected]
MISSTATEMENTS ON CRYOPYRIN-ASSOCIATED PERIODIC FEVERS
of new therapeutic products. FDA policy (1992) includes the following statement: “When stereoisomers are biologically distinguishable, they might seem to be different drugs, yet it has been past practice to develop racemates (ie, compounds with 50:50 proportion of enantiomers). The properties of the individual enantiomers have not generally been well studied or characterized.” Whether separated enantiomers should be developed was largely an academic question because commercial separation of racemates was difficult. Now that technological advances permit production of many single enantiomers on a commercial scale, it is appropriate to consider what FDA’s policy with respect to stereoisomeric mixtures should be. Development of racemates raises issues of acceptable manufacturing control of synthesis and impurities, adequate pharmacologic and toxicologic evaluation, proper characterization of metabolism and distribution, and appropriate clinical evaluation.”1 The FDA’s assertion on the use of racemates when allowed because of few differences between the enantiomers is a point well taken. Indeed, because some racemic mixtures are substantially more economic than pure isomers, a physician should always take into consideration the real measure of benefit the pure isomer offers compared with a racemate. Some would argue that this should be done without the influence of cost, but cost has become more and more a part of the equation when considering the use of therapeutic agents. Acknowledging these points, one also should remember that evidence on this matter is constantly evolving. Appearance of conflicting data in the literature in regard to certain properties of racemic drugs and their isomers attests to such evolution. The inconclusive evidence often originates from small-scale studies or from extrapolation of data from experiments performed in vitro or with animal models. Studies set forth solely by pharmaceutical companies marketing a certain drug, however conclusive they may seem, should also be viewed cautiously because the possibility for inaccuracies increases with the increased market pressures. Expert panel reports and similar guidelines are probably the best tools the health care community has to base recommendations on. However, even these tools need constant updating as new data appear. In our review,2 we attempted to present the current information without introducing strong support for any particular clinical practice. However, the rate of accumulation of new knowledge about stereoactive medications lays a platform for the necessity of the development of regularly reviewed clinical guidelines for the use of stereoactive medications. LEONARD BIELORY, MD ANDREY LEONOV, MD UMDNJ–New Jersey Medical School Newark, New Jersey [email protected] 1. FDA’s policy statement for the development of new stereoisomeric drugs. 1992. http://www.fda.gov/cder/Guidance/stereo.htm. Accessed April 10, 2008. 2. Bielory L, Leonov A. Stereoconfiguration of antiallergic and immunologic drugs. Ann Allergy Asthma Immunol. 2008;100:1– 8.
COMBINATION THERAPY WITH AZELASTINE AND FLUTICASONE NASAL SPRAYS To the Editor: The article by Ratner et al1 regarding combination therapy with azelastine and fluticasone nasal sprays for allergic Disclosures: Authors have nothing to disclose.
VOLUME 101, JULY, 2008
rhinitis clearly demonstrates that by day 4 of therapy combination treatment is superior to either agent used alone in improving nasal symptoms. By day 12 of therapy, however, although combination therapy remained statistically significantly superior to azelastine alone, combination therapy was no longer statistically significantly superior to fluticasone alone. The authors rightly note “the lower cost associated with generic fluticasone” and suggest, therefore, that “the combination of azelastine nasal spray and fluticasone nasal spray may be cost-effective.” I suggest, since after 12 days there is no difference between combination therapy and fluticasone treatment, that the most cost-effective strategy is to use azelastine together with fluticasone only for the first 12 days of therapy or to simply wait 12 days to get the maximal effect of fluticasone alone. JOHN M. KELSO, MD Division of Allergy, Asthma, and Immunology Scripps Clinic San Diego, California [email protected] 1. Ratner PH, Hampel F, Van Bavel J, et al. Combination therapy with azelastine hydrochloride nasal spray and fluticasone propionate nasal spray in the treatment of patients with seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2008;100: 74 – 81.
MISSTATEMENTS ON CRYOPYRIN-ASSOCIATED PERIODIC FEVERS To the Editor: Having experience with cryopyrin autoinflammatory periodic syndromes,1–3 we feel obligated to respond to what we consider to be some misconceptions in the recent article entitled “Differential Diagnosis of Chronic Urticaria” by Brodell and Beck.4 The first issue relates to the statement that “no test currently exists that is both sensitive and specific enough to make the diagnosis.” The authors should be aware of the cloning DNA test for diagnosis established by one of the authors1 as a result of his discovery of the cryopyrin-encoding gene (C1AS1/NLRP3) on the chromosome 1q44 gene. This mutated gene causes all 3 autosomal dominant syndromes with dysregulated interleukin-1 production, that is, familial cold autoinflammatory syndrome (FCAS), MuckleWells syndrome (MWS), and chronic, infantile, neurologic, cutaneous, and articular syndrome (CINCA). Most patients exhibit mutations on this gene, although there are some that do not have mutations in CIAS1.5 The second issue relates to the statement that “cold provocation tests with ice cubes will initiate urticaria in persons with FCAS but may not in patients with MWS or CINCA.” In fact, topical application of a cold stimulus will not induce a dermatologic response in these syndromes. Only environmental cold exposure can precipitate symptoms, and, in some patients, the temperature range may even be in a temperate zone, but a change in temperature of a few degrees can trigger mild symptoms. The dermatosis of all 3 syndromes is not a typical urticaria because the rash is usually maculopapular and does not exhibit classic pruritic wheals. Furthermore, skin biopsy specimens reveal infiltration by polymorphonuclear neutrophils and monocytes. It has taken years to clarify that FCAS is not a form of typical urticaria, and, for that reason, the name was changed from familial cold urticaria to the current nomenclature used by investigators in the field. Disclosures: Author has nothing to disclose.
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Last, there is the statement that corticosteroids can be used for acute attacks. To our knowledge based upon our experience and a review of the literature no evidence has shown that this class of medication is useful in controlling patient symptoms. There is now ample evidence that drugs that target interleukin-1, such as anakinra and rilonacept, are effective in these disorders.3 We hope that these comments will clarify the subject material in this article. ALAN WANDERER, MD Allergy and Asthma Consultants of Montana Bozeman, Montana [email protected]
Disclosures: Authors have nothing to disclose.
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HAL HOFFMAN, MD Division of Rheumatology, Allergy, and Immunology University of California at San Diego La Jolla, California 1. Hoffman HM, Wright FA, Broide DH, Wanderer AA, Kolodner RD. Identification of a locus on chromosome 1q44 for familial cold urticaria. Am J Hum Genet. 2000;66:1693–1698. 2. Wanderer AA, Hoffman HM. The spectrum of acquired and familial cold-induced urticaria/urticaria-like syndromes. Immunol Allergy Clin North Am. 2004;24: 259 –286. 3. Hoffman HM, Rosengren S, Boyle DL, et al. Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet. 2004;364:1779 –1785. 4. Brodell LA, Beck LA. Differential diagnosis of chronic urticaria. Ann Allergy Asthma Immunol. 2008;100:181–188. 5. Aksentijevich I, Putnam C, Remmers EF, et al. The clinical continuum of cryopyrinopathies: novel CAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum. 2007;56:1273–1285.
ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
COMBINATION THERAPY WITH AZELASTINE AND FLUTICASONE NASAL SPRAYS To the Editor: The article by Ratner et al1 regarding combination therapy with azelastine and fluticasone nasal sprays for allergic Disclosures: Authors have nothing to disclose.
VOLUME 101, JULY, 2008
rhinitis clearly demonstrates that by day 4 of therapy combination treatment is superior to either agent used alone in improving nasal symptoms. By day 12 of therapy, however, although combination therapy remained statistically significantly superior to azelastine alone, combination therapy was no longer statistically significantly superior to fluticasone alone. The authors rightly note “the lower cost associated with generic fluticasone” and suggest, therefore, that “the combination of azelastine nasal spray and fluticasone nasal spray may be cost-effective.” I suggest, since after 12 days there is no difference between combination therapy and fluticasone treatment, that the most cost-effective strategy is to use azelastine together with fluticasone only for the first 12 days of therapy or to simply wait 12 days to get the maximal effect of fluticasone alone. JOHN M. KELSO, MD Division of Allergy, Asthma, and Immunology Scripps Clinic San Diego, California [email protected] 1. Ratner PH, Hampel F, Van Bavel J, et al. Combination therapy with azelastine hydrochloride nasal spray and fluticasone propionate nasal spray in the treatment of patients with seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2008;100: 74 – 81.
MISSTATEMENTS ON CRYOPYRIN-ASSOCIATED PERIODIC FEVERS To the Editor: Having experience with cryopyrin autoinflammatory periodic syndromes,1–3 we feel obligated to respond to what we consider to be some misconceptions in the recent article entitled “Differential Diagnosis of Chronic Urticaria” by Brodell and Beck.4 The first issue relates to the statement that “no test currently exists that is both sensitive and specific enough to make the diagnosis.” The authors should be aware of the cloning DNA test for diagnosis established by one of the authors1 as a result of his discovery of the cryopyrin-encoding gene (C1AS1/NLRP3) on the chromosome 1q44 gene. This mutated gene causes all 3 autosomal dominant syndromes with dysregulated interleukin-1 production, that is, familial cold autoinflammatory syndrome (FCAS), MuckleWells syndrome (MWS), and chronic, infantile, neurologic, cutaneous, and articular syndrome (CINCA). Most patients exhibit mutations on this gene, although there are some that do not have mutations in CIAS1.5 The second issue relates to the statement that “cold provocation tests with ice cubes will initiate urticaria in persons with FCAS but may not in patients with MWS or CINCA.” In fact, topical application of a cold stimulus will not induce a dermatologic response in these syndromes. Only environmental cold exposure can precipitate symptoms, and, in some patients, the temperature range may even be in a temperate zone, but a change in temperature of a few degrees can trigger mild symptoms. The dermatosis of all 3 syndromes is not a typical urticaria because the rash is usually maculopapular and does not exhibit classic pruritic wheals. Furthermore, skin biopsy specimens reveal infiltration by polymorphonuclear neutrophils and monocytes. It has taken years to clarify that FCAS is not a form of typical urticaria, and, for that reason, the name was changed from familial cold urticaria to the current nomenclature used by investigators in the field. Disclosures: Author has nothing to disclose.
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Last, there is the statement that corticosteroids can be used for acute attacks. To our knowledge based upon our experience and a review of the literature no evidence has shown that this class of medication is useful in controlling patient symptoms. There is now ample evidence that drugs that target interleukin-1, such as anakinra and rilonacept, are effective in these disorders.3 We hope that these comments will clarify the subject material in this article. ALAN WANDERER, MD Allergy and Asthma Consultants of Montana Bozeman, Montana [email protected]
Disclosures: Authors have nothing to disclose.
112
HAL HOFFMAN, MD Division of Rheumatology, Allergy, and Immunology University of California at San Diego La Jolla, California 1. Hoffman HM, Wright FA, Broide DH, Wanderer AA, Kolodner RD. Identification of a locus on chromosome 1q44 for familial cold urticaria. Am J Hum Genet. 2000;66:1693–1698. 2. Wanderer AA, Hoffman HM. The spectrum of acquired and familial cold-induced urticaria/urticaria-like syndromes. Immunol Allergy Clin North Am. 2004;24: 259 –286. 3. Hoffman HM, Rosengren S, Boyle DL, et al. Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet. 2004;364:1779 –1785. 4. Brodell LA, Beck LA. Differential diagnosis of chronic urticaria. Ann Allergy Asthma Immunol. 2008;100:181–188. 5. Aksentijevich I, Putnam C, Remmers EF, et al. The clinical continuum of cryopyrinopathies: novel CAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum. 2007;56:1273–1285.
ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY