Private practice, Niagara Falls, ON, Canada

ABSTRACT
Now that several formulations of botulinum toxin type-A (BoNT-A) are on the market in North America and throughout the world, it is of great practical importance for those who administer these medications to be familiar with the differences between the formulations. These differences pertain to the stability of the medications, in particular during the period of time between reconstitution and administration, which may affect the degree of diffusion through various tissues after injection. A variety of relatively new uses of BoNT-A for dermatological conditions will be discussed.

Key Words:
botulinum toxin type-A, BoNT-A, abobotulinumtoxinA, incobotulinumtoxinA, onabotulinumtoxinA, neuromodulator, BOTOX®, Dysport®, XEOMIN®

Medicines formulated from the highly purified, naturally occurring protein known as botulinum toxin type-A (BoNT-A) have been in use since 1980, when ophthalmologist Alan Scott used an injectable formulation of BoNT-A to treat strabismus and blepharospasm in humans. The first formulation of BoNT-A to become commercially available was onabotulinumtoxinA (BOTOX®), licensed in the United States in 1989 for treatment of three conditions: strabismus, blepharospasm, and hemifacial spasm. In recent years, two other formulations of BoNT-A have been licensed for use in the United States and a number of other countries: abobotulinumtoxinA (Dysport®) and incobotulinumtoxinA (XEOMIN®).

Those interested in BoNT-A should become familiar with the non-proprietary names for the various formulations of BoNT-A, because increasingly, presentations at meetings and in scientific publications are using the non-proprietary rather than the trade names for these products.¹ A different non-proprietary name was assigned to each formulation of BoNT-A to reflect the fact that while the active ingredient in all three formulations is BoNT-A, the biological activity, in particular the stability and diffusion kinetics,^2,3 of the active ingredient is modulated by the other components of the formulation, notably the protective proteins (hemagglutinins and non-hemagglutinins, which are associated with BoNT-A in onabotulinumtoxinA and abobotulinumtoxinA) and the amount and type of human serum albumin (added to the formulations to keep the BoNT-A in solution after reconstitution). Biological activity is also affected by the manufacturing process (as each BoNT-A formulation is manufactured differently), as well as other excipients in the vial (e.g., sodium chloride and sucrose). The effects (if any) on stability after reconstitution caused by the presence of trypsin-like proteolytic activity in incobotulinumtoxinA4 remain to be elucidated.

Non-interchangeability of Products

There is no consensus on how to switch patients between the three formulations. Each formulation is dosed using units specific to the product, which are determined in a manner that is proprietary to the manufacturer. It is important to note that because the dosing units are unique to each formulation, the products are considered to be non-interchangeable.⁵

While it is possible to construct test systems in which various dose ratios can be compared under standard conditions (e.g., hyperhidrosis on the forehead⁶ or frontalis muscle contractions⁷), there is no simple ratio that can be used to facilitate conversion of patients from one formulation of BoNT-A to another.^8,9

Widening Applications

Since Alan Scott’s pioneering use of BoNT-A for the treatment of blepharospasm and strabismus, various formulations of this versatile biological product have been reported to be useful in the management of over 140 medical, surgical, and aesthetic indications. Of interest to dermatologists, indications that regulatory authorities have approved for marketing and advertising in Canada include (for onabotulinumtoxinA) treatment of upper facial rhytides, including forehead, lateral canthus and glabellar lines,¹⁰ as well as for the treatment of hyperhidrosis of the axillae in patients 18 years of age and older.¹⁰ It is expected that other formulations of BoNT-A could receive similar regulatory approval for marketing and advertising in Canada in the future.

When they were first introduced, medicines incorporating BoNT-A were used to block the vesicle-mediated release of the neurotransmitter acetylcholine, and so produce for a period of several months very precise and localized relaxation of the striated muscles to which it was applied by injection.

The first suggestion that BoNT-A could be used for purposes other than muscle relaxation came from Bushara and Park in 1994, who observed reduced sweating in the treated area when BoNT-A was used for treatment of hemifacial spasm.¹¹ Based on observations that BoNT-A was useful for controlling excessive sweating, it was found to also be beneficial for the control of persistent facial flushing,¹² gustatory sweating (Frey’s syndrome),¹³ and for conditions made worse by excessive sweating and associated maceration (e.g., familial benign pemphigus (Hailey-Hailey disease),¹⁴ dishydrotic eczema,¹⁵ and inverse psoriasis¹⁶). Its use was even extended to the treatment of facial chromhidrosis¹⁷ where part of its mechanism of action was thought to come from inhibition of the release of substance-P.¹⁸ Excessive lacrimation,^19,20 chronic rhinitis,^21,22 sialorrhea,²³ and parotid fistulas resulting from skin cancer surgery^24,25 have also been reported to respond to treatment with BoNT-A.

Basic science research has shown that BoNT-A blocks the vesiclemediated release of neurotransmitters other than acetylcholine, including substance-P,²⁶ glutamate,²⁷ and calcitonin-gene related peptide.²⁸ These properties of BoNT-A may account for its neuromodulating effect on autonomic nerves,²⁹ which makes possible the use of BoNT-A as a therapeutic option for Raynaud’s phenomenon, where treatment with BoNT-A can be safer and simpler than sympathectomy. Onset of action occurs within days and lasts for months, controlling rest pain, shortening and reducing the severity and frequency of attacks, and speeding the healing of ischemic ulcerations.^30-33

The observation that BoNT-A inhibits the release of some painmediating neurotransmitters, such as substance-P, helps to explain why BoNT-A has proven useful in the management of a variety of painful conditions, including headache,^34-36 multiple cutaneous piloleiomyomas,³⁷ notalgia paresthetica,³⁸ and postherpetic neuralgia in the trigeminal distribution, but not on the trunk or extremities.³³

BoNT-A has even proven to be of value in athletes, for example as a treatment for an intention tremor known as “the yips,” afflicting up to 30% of golfers.³⁹ Similar dystonias and occupational cramps that can occasionally trouble dermatologic surgeons might also benefit from treatment with BoNT-A.

Systems for the topical administration of BoNT-A are in development,^40,41 and may turn out to be useful for certain medical and aesthetic indications.

The N-terminal light chain component of BoNT-A (known as LC) is the part that cleaves SNAP-25, resulting in the blockade of vesicle-mediated release of a variety of neurotransmitters. This component (or the corresponding LC element from other botulinum neurotoxins) can be attached to a variety of ligands, which are proteins that bind to various glycoproteins that are specific for certain cell types or can be produced by recombinant techniques.^42,43

It is likely that such derivatives of BoNT-A and other clostridial neurotoxins, which are now emerging from the labs and in some cases entering clinical trials, will become commercially available. These advances are poised to extend the utility of this class of medications to tissues that are currently unresponsive to BoNT-A, improve tissue specificity, modulate durations of action, and benefit our patients in ways that remain to be explored.

Conclusions

Medications formulated with BoNT-A as their active ingredient have a long record of safety and efficacy for a very wide and growing spectrum of medical and aesthetic indications. Future medications based on derivatives of BoNT-A are likely to further expand the range of utility and improve the risk/benefit ratio of this class of agents.

It is important for those interested in BoNT-A to become familiar with the non-proprietary names for the various formulations of BoNT-A, because non-proprietary nomenclature is being used exclusively in a growing number of academic and educational settings. Additionally, the use of non-proprietary names have been mandated by the US FDA to differentiate between the various formulations of BoNT-A.

It is important for those interested in BoNT-A to realize that each formulation of BoNT-A has unique pharmacologic and pharmacokinetic properties, and may behave differently in various clinical situations and indications, e.g., depending on the dosage, degree of dilution when the product is reconstituted, and the anatomic area being treated. For these reasons, there are no simple “universal” conversion ratios between the various formulations of BoNT-A.

References

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2. de Almeida AT, De Boulle K. Diffusion characteristics of botulinum neurotoxin products and their clinical significance in cosmetic applications. J Cosmet Laser Ther 9(Suppl 1):17-22 (2007).
3. de Boulle K, de Almeida AT. Addressing recent concerns in comparative studies of botulinum toxin type A. J Cosmet Laser Ther 12(5):246-8 (2010 Oct).
4. Hunt T, Rupp D, Shimizu G, et al. Characterization of SNARE cleavage products generated by formulated botulinum neurotoxin type-A drug products. Toxins 2:2198-212 (2010).
5. Albanese A. Discussion of unique properties of botulinum toxins. Toxicon 54(5):702-8 (2009 Oct).
6. Trindade de Almeida AR, Marques E, de Almeida J, et al. Pilot study comparing the diffusion of two formulations of botulinum toxin type A in patients with forehead hyperhidrosis. Dermatol Surg 33(1 Spec No.):S37-43 (2007 Jan).
7. de Boulle K, Smuts J, van Coller R, et al. An electrophysiological study to demonstrate in vivo differences between two formulations of botulinum toxin type A (BOTOX® and Dysport®). Poster presented at: Basic and Therapeutic Aspects of Botulinum and Tetanus Toxins International Conference 2005 (Toxins 2005). Denver, CO, 23-25 June 2005.
8. De Boulle K, Fagien S, Sommer B, et al. Treating glabellar lines with botulinum toxin type A-hemagglutinin complex: a review of the science, the clinical data, and patient satisfaction. Clin Interv Aging 5:101-18 (2010).
9. Marchetti A, Magar R, Findley L, et al. Retrospective evaluation of the dose of Dysport and BOTOX in the management of cervical dystonia and blepharospasm: the REAL DOSE study. Mov Disord 20(8):937-44 (2005 Aug).
10. BOTOX Cosmetic® product monograph. In: Compendium of Pharmaceuticals and Specialties (CPS) 2011: The Canadian Drug Reference for Health Professionals. Ottawa: Canadian Pharmacists Association, p426-31 (2011).
11. Bushara KO, Park DM. Botulinum toxin and sweating. J Neurol Neurosurg Psychiatry 57(11):1437-8 (1994 Nov).
12. Yuraitis M, Jacob CI. Botulinum toxin for the treatment of facial flushing. Dermatol Surg 30(1):102-4 (2004 Jan).
13. Martos Diaz P, Bances del Castillo R, Mancha de la Plata M, et al. Clinical results in the management of Frey’s syndrome with injections of Botulinum toxin. Med Oral Patol Oral Cir Bucal 13(4):E248-52 (2008 Apr).
14. Kang NG, Yoon TJ, Kim TH. Botulinum toxin type A as an effective adjuvant therapy for Hailey-Hailey disease. Dermatol Surg 28(6):543 (2002 Jun).
15. Swartling C, Naver H, Lindberg M, et al. Treatment of dyshidrotic hand dermatitis with intradermal botulinum toxin. J Am Acad Dermatol 47(5):667-71 (2002 Nov).
16. Zanchi M, Favot F, Bizzarini M, et al. Botulinum toxin type-A for the treatment of inverse psoriasis. J Eur Acad Dermatol Venereol 22(4):431-6 (2008 Apr).
17. Matarasso SL. Treatment of facial chromhidrosis with botulinum toxin type A. J Am Acad Dermatol 52(1):89-91 (2005 Jan).
18. Wu JM, Mamelak AJ, Nussbaum R, et al. Botulinum toxin a in the treatment of chromhidrosis. Dermatol Surg 31(8 Pt 1):963-5 (2005 Aug).
19. Owecki MK, Kapelusiak-Pielok M, Kowal P, et al. [Bilateral “crocodile tears syndrome” associated with Melkersson-Rosenthal syndrome–case report]. Neurol Neurochir Pol 40(5):450-545 (2006 Sep-Oct).
20. Laing TA, Laing ME, O’Sullivan ST. Botulinum toxin for treatment of glandular hypersecretory disorders. J Plast Reconstr Aesthet Surg 61(9):1024-8 (2008 Sep).
21. Braun T, Gurkov R, Kramer MF, et al. Septal injection of botulinum neurotoxin A for idiopathic rhinitis: a pilot study. Am J Otolaryngol. 2011 Mar 16. [Epub ahead of print]
22. Rohrbach S, Junghans K, Kohler S, et al. Minimally invasive application of botulinum toxin A in patients with idiopathic rhinitis. Head Face Med 5:18 (2009).
23. Reddihough D, Erasmus CE, Johnson H, et al. Botulinum toxin assessment, intervention and aftercare for paediatric and adult drooling: international consensus statement. Eur J Neurol 17(Suppl 2):109-21 (2010 Aug).
24. Hill SE, Mortimer NJ, Hitchcock B, et al. Parotid fistula complicating surgical excision of a basal cell carcinoma: successful treatment with botulinum toxin type A. Dermatol Surg 33(11):1365-7 (2007 Nov).
25. Hatzis GP, Finn R. Using botox to treat a mohs defect repair complicated by a parotid fistula. J Oral Maxillofac Surg 65(11):2357-60 (2007 Nov).
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27. Carlton SM, Hargett GL, Coggeshall RE. Localization and activation of glutamate receptors in unmyelinated axons of rat glabrous skin. Neurosci Lett 197(1):25-8 (1995 Sep 1).
28. Rapp DE, Turk KW, Bales GT, et al. Botulinum toxin type a inhibits calcitonin gene-related peptide release from isolated rat bladder. J Urol 175(3 Pt 1): 1138-42 (2006 Mar).
29. MacKenzie I, Burnstock G, Dolly JO. The effects of purified botulinum neurotoxin type A on cholinergic, adrenergic and non-adrenergic, atropineresistant autonomic neuromuscular transmission. Neuroscience 7(4):997- 1006 (1982 Apr).
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35. Diener HC, Dodick DW, Aurora SK, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebocontrolled phase of the PREEMPT 2 trial. Cephalalgia 30(7):804-14 (2010 Jul).
36. Aurora SK, Dodick DW, Turkel CC, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebocontrolled phase of the PREEMPT 1 trial. Cephalalgia 30(7):793-803 (2010 Jul).
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ABSTRACT
If methotrexate were introduced as a new drug today, it would be hailed as a major advance in the management of psoriasis, as well as for a number of other conditions. Because the patent on methotrexate expired decades ago, this medication has not recently received the attention it deserves. When patients are properly screened and educated about the correct use of methotrexate, and appropriately monitored during treatment, this drug is a safe, inexpensive, well-tolerated and effective medication for the control of psoriasis.

Key Words:
psoriasis, methotrexate, systemic therapy

Introduction

In 1951 Gubner¹ reported improvement in psoriatics treated with the folate antagonist aminopterin, but clinical use was limited by mucosal and GI side-effects. In 1958, Edmundson and Guy² reported good control of psoriasis with amethopterin, or methotrexate (MTX), an analog of aminopterin.

MTX can produce a number of side-effects, particularly GI and liver toxicities. However, administrator of folic acid has been shown to reduce or eliminate the GI distress sometimes associated with MTX, and does not interfere with its efficacy⁴. Several different dosage schedules have been reported to be effective. The author finds 10mg of folic acid (Leucovorin), by contrast, reduces the efficacy of MTX⁵, and should be administrated as an antidote in cases of MTX overdose.

Studies in animals demonstrated that MTX toxicity was more closely related to duration of contact with tissues than with total dose, and in 1963, Berlin³ suggested that an intermittent dosage schedule might improve the therapeutic index. The current practice in dermatology is to administer MTX as a single dose once a week, or in three divided doses 12 hours apart is safer, and there are occasional reports of serious or lethal toxicity when patients mistakenly take MTX every 12 hours, every day of the week.

Mechanism of Action

MTX is one of the most effective systemic therapies for psoriasis, but the mechanism of action is not completely understood. The proliferating lymphoid cells THP-1 (macrophages) and MOLT-4 (T-cells) are over 1000 times more sensitive to MTX than keratinocytes at the concentrations seen in vivo with once-weekly therapy⁶. Low-dose MTX also promotes the intracellular accumulation of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) by inhibiting AICAR transformylase. Under conditions of cell injury, AICAR increases the release of the autocoid adenosine, a potent anti-inflammatory agent⁷.

Patient Selection and Management

The best candidates for treatment with MTX are those patients who, in addition to lacking contraindications to methotrexate, are honest, reliable, and realistic. Patients must be willing to avoid alcohol consumption while taking methotrexate, and should be willing to continue topical medications to reduce the dose of methotrexate required to obtain an adequate degree of control of their psoriasis.

Patients should be instructed to obtain ALL of their medication from a SINGLE pharmacy, to reduce the chances of drug interaction. A letter should be sent to every physician who is caring for the patient, informing them that MTX is being started, and a copy of all bloodwork should be ordered for each treating physician. Patients who do not have a family doctor should not be offered methotrexate unless your office is set up to deal with bloodwork abnormalities, regardless of whether you are available. Patients who do not cooperate with the regular bloodwork necessary for the safe use of this drug should be waned firmly, and a letter about this warning should be sent to each of the patient’s doctors. If non-cooperation continues, MTX must be stopped. Documentation about the patient’s history with regard to MTX, whether MTX was well tolerated, and the cumulative dose of this drug is important.

It is also important to document the justification for offering to prescribe MTX (e.g., the extent and location of the psoriasis, and the impact the psoriasis is having on the patient’s life, employment and relations with others).

Patient Information

Prior to starting MTX, patients must be educated about the precautions necessary for the safe use. Discuss the need for contraception with women who are candidates for treatment with methotrexate. Women must avoid pregnancy while taking this drug and for 3 months after stopping it because it has been associated with teratogenicity. There is no evidence that MTX has any adverse effect on spermatogenesis or fertility in men at the doses used in dermatology, and men should be reassured about this.

Management

Prior to starting MTX, and from time to time during treatment, a list of the patient’s prescription and non-prescription medications (including “natural” or herbal remedies) should be reviewed, and the patient again cautioned to avoid alcohol consumption. Laboratory studies prior to starting MTX should include CBC, SGOT, alkaline phosphatase, bilirubin, creatinine, serum albumin, and hepatitis B and C serology. As well, HIV-1 should be checked in those at risk for HIV. However, MTX has been used successfully to treat psoriasis in HIV infected patients⁸. CBC and SGOT should be repeated twice a month for the first two months of treatment, then monthly while the patient is taking MTX. The SGPT should NOT be tested. It is frequently elevated when there is no clinical problem, leading to an unacceptable number of “false alarms.”

Hepatitis in low-dose therapy is not common seen, and may be more common in patients receiving combination therapy with etretinate, in those with heavy alcohol consumption, or in those with a higher total cumulative dose of methotrexate. Some drugs that can affect the toxicity of MTX are listed in Table 1. Liver biopsy is generally not performed prior to starting MTX in otherwise healthy patients. However, each prescription for this drug should be recorded in a flow chart, and when the total dose reaches 1.5gm, the patient should be referred to a gastroenterologist for consideration of a liver biopsy. As a general rule, a liver biopsy is not performed in healthy, young, non-obese, non-diabetic patients who have normal liver function studies. Patients should return to the gastroenterologist for reassessment each time the total dose of MTX increases by 1.5gm.

The Roenigk classification of liver biopsies (Grades 1-4)⁹ has been criticized because it was adapted from a classification system developed many years ago for use in primary biliary cirrhosis here portal inflammation is the major feature. For this reason, it is not an ideal classification tool for assessing MTX toxicity, which tends to produce entrilobular changes.

The starting dose of MTX in an adult is usually in the range of 10-15mg at bedtimes, once a week. Improvement in psoriasis is usually seen within 4-8 weeks. The dose may be increased to 25mg once a week if necessary. Topical medications and UVB or PUVA are usually continued in order to reduce the long-term need for MTX. Phototoxicity associated with MTX has been reported, but is very rare in clinical practice, and MTX is often used successfully with UVB or PUVA.

When a patient has improved to a satisfaction degree, the dose of MTX can be adjusted each week within a specified range (e.g., between 2.5-15mg once a week), as necessary. This is done in order to maintain adequate (but not necessarily perfect) control of the psoriasis, and often allows for a lower cumulative dose of MTX than would be the case if the patient was maintained on a fixed dose, e.g., 15mg once a week.

Rotational Therapy

The successful use of “rotational therapy” (e.g., switching every 3-6 months between several treatments including methotrexate, cyclosporine, acitretin and PUVA) depends on many variables, including the patient’s finances, ability to attend on a regular basis for UV light treatment, underlying medical conditions, and medications. The increased complexity and cost of rotational therapy is sometimes justified by the reduced long-term load on any one organ system:

• Methotrexate – liver damage
• Cyclosporine – altered kidney function
• PUVA – skin
• Acitretin – elevated lipids

Conclusion

Methotrexate is an effective medication for the control of psoriasis. When patients are properly screened and educated about the correct use of this drug, and appropriately monitored during treatment, MTX is often very safe, simple to use, inexpensive, and well-tolerated.

Table 1: Drugs that may effect the toxicity of methotrexate

References

1. Gubner R. Effect of “aminopterin” on epithelial tissues. Arch Dermatol Syphilol 64: 688-699 (1951).
2. Edmundson EF, Guy WB: Treatment of psoriasis with folic acid antagonists. Arch Dermatol 78: 200-203 (1958).
3. Berlin NI (Moderator). Folic acid antagonists: effects on the cell and the patient. Combined clinical staff conference at the National Institutes of Health. Ann Intern Med 59:931-956 (1963)
4. Morgan SL, Baggott JE, Vaughn WH, et al. The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 33:9-18 (1990).
5. Guzzo C. Folic acid supplementation with methotrexate therapy: what benefit if any? J Am Acad Dermatol 31 (4):689 (1994 Oct.)
6. Jeffes EWB III, McCullough JL, Pittelkow MR, et al. Methotrexate therapy of psoriasis: differential sensitivity of proliferating lymphoid and epithelial cells to cytotoxic and growth-inhibitory effects of methotrexate. J Invest Dermatol 104 (2): 183-8 (1995 Feb).
7. Cronstein BN, Naime D, Ostad E. The anti-inflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation. J Clin Invest 92(6):2675-82 (1993 Dec).
8. Maurer TA, Zackheim HS, Tuffanelli L, Berger TG. The use of methotrexate for treatment of psoriasis in patients with HIV infection. J Am Acad Dermatol 31 (2 Pt 2):372-5 (1994 Aug).
9. Roenigk HH Jr, Auerbach R, Maibach HI and Weinstein GD. Methotrexate in psoriasis: Revised guidelines. J Am Acad Dermatol 19 (1 Pt 1):145-56 (1988 Jul).