ABSTRACT
Sirolimus, also known as rapamycin (SRL, Rapamune®), was approved in 1999 by the US Food and Drug Administration to prevent graft rejection in renal transplantation. As a member of the mammalian target of rapamycin (mTOR) inhibitor class, its potent immunosuppressant, anti-angiogenic and anti-proliferative properties are well recognized. When compared to other immunosuppressants, SRL has a lower risk of renal, neurologic and lymphoproliferative complications. It has become a promising treatment modality for angiofibromas, Kaposi’s sarcoma and other inflammatory and malignant disorders of the skin. With the recent discovery that mTOR inhibitors extend the lifespan of mice, sirolimus and other rapamycin analogs (rapalogs) are emerging as therapeutic targets for the treatment and prevention of age-related diseases.

Key Words:
immunosuppressant, Rapamune, rapamycin, sirolimus, skin disease

Mechanism of Action

Sirolimus (SRL) is a fermentation product of Streptomyces hygroscopicus and belongs to the mammalian target of rapamycin (mTOR) inhibitor class. Discovered on a Canadian expedition to Easter Island “Rapa Nui,” it was first utilized for its potent antifungal properties.¹ In cells, SRL binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. Unlike cyclosporine and tacrolimus, the sirolimus-FKBP-12 complex has no effect on calcineurin activity. Rather, this complex inhibits the activation of mTOR, a key regulatory kinase. The inhibition of mTOR by sirolimus suppresses T-lymphocyte activation and proliferation, antibody production and prevents cell cycle progression from the G1 to the S phase (Figure 1).

The bound SRL-FKBP-12 complex down-regulates the translation of hypoxia-inducible factor (HIF) 1 and 2 which, in turn, regulates vascular endothelial growth factor (VEGF). Through these, and other mechanisms, SRL plays an important anti-angiogenic role.^2,3 More recently, SRL has shown promise as a treatment option for aging and cancer.^4,5 New rapamycin analogues [temsirolimus, everolimus and deforolimus (ridaforolimus)] have been developed to improve the pharmacokinetic and pharmacodynamic profile.

Pharmokinetics and Metabolism

Sirolimus is currently available as an oral solution (1 mg/ml) and as tablets (1 mg, 2 mg, 5 mg). Though costly, SRL has been compounded topically in emollient base (i.e., Aquaphor® Healing Ointment), typically in a dose ranging from 0.05% to 2%. As immunosuppressive therapy, SRL blood levels are recommended to fall between 3 and 5 ng/ml. SRL is rapidly absorbed orally, with peak serum concentrations (t_max) of 1 hour in healthy individuals and 2-3 hours in renal transplant recipients.⁶ It has poor oral bioavailability of approximately 15% and a long halflife of 57-62 hours.^7,8 Of the absorbed drug, 95% is bound to blood elements.⁸ SRL is metabolized by the hepatic cytochrome P450 (CYP) 3A4 enzyme and p-glycoprotein intestinal countertransport pump.⁹ The seven metabolites of SRL contribute little to its pharmacological action, two of which show ≤30% of its in vitro immunosuppressive activity.⁸ Fecal excretion of the parent compound accounts for 90% of drug elimination with the remainder by urinary excretion.

Adverse Effects

As compared to calcineurin inhibitors, SRL shows lower rates of hypertension, nephrotoxicity, neurotoxicity and lymphoproliferative complications.¹⁰ In most patients, it is well tolerated. In clinical studies, common adverse reactions of SRL include (>30%): hypertriglyceridemia, hypercholesterolemia, hypertension, arthralgia, anemia, thrombocytopenia, headache, fever, peripheral edema, urinary tract and latent viral infections, as well as gastrointestinal effects such as anorexia, abdominal pain, diarrhea, and constipation. Potentially serious adverse events include upper respiratory infections and non-infective pneumonitis.¹⁰

Possible dermatologic complications include: acne, folliculitis, exanthema, mouth ulcers and onychopathy.¹¹ Impaired wound healing and wound dehiscence have been reported in patients receiving SRL following solid organ transplantation.^12-14 Lymphocele and lymphedema were also described in a case series of eight transplant patients receiving SRL.¹⁵

Upon entering the cell, sirolimus binds the intracellular receptor, FKBP-12, in turn preventing the interaction between mTOR and Raptor within the mTORC1 complex. Downstream effector molecules of mTORC1, including eIF4E and p70S6K1, are inhibited, preventing cell proliferation, cell survival, tumor growth, angiogenesis and protein synthesis. In the presence of sirolimus, upstream regulatory molecules, including the tuberous sclerosis complex (TSC) are no longer able to regulate the activation of mTORC1. (Abbreviations: GF, growth factor; SRL, sirolimus; AKT, also known as protein kinase B; Rheb: Ras homolog enriched in brain; mTORC2, mTOR complex 2; Rictor, rapamycin-insensitive companion of mTOR; 4E-BP1, 4E binding protein 1; mLST8, mammalian lethal with SEC13 protein 8; mSIN1, mammalian stress activated protein kinase interacting protein 1; GbL, G protein beta subunit-like.

Figure 1: Mechanism of action of sirolimus

Clinical Uses

Skin Cancer in Solid Organ Transplantation

The risk of developing skin cancer, most notably squamous cell carcinoma (SCC), is 65-fold greater in organ transplant recipients (OTRs) as compared to the general population. The role of SRL in preventing SCCs in OTRs has recently been reviewed.^16,17 In renal transplant recipients, SRL therapy after cyclosporine withdrawal was shown to reduce the risk of SCC and basal cell carcinoma (BCC).¹⁸ Further, results from five multi-center studies demonstrated that the incidence of skin and non-skin malignancies was significantly lower in patients receiving SRL monotherapy versus combination SRL and cyclosporine.¹⁹ A prospective, randomized, controlled trial reported that SRL monotherapy induced regression of pre-existing keratotic dysplasia and reduced the incidence of non-melanoma skin cancer.¹⁹ Another trial confirmed that switching from calcineurin inhibitors to sirolimus had an anti-tumoral effect among kidneytransplant recipients with previous SCCs.²⁰ Finally, a multi-center, randomized-controlled trial found that there was a statistically significant reduction in the rate of melanoma development in patients treated with SRL.²¹

Kaposi’s Sarcoma

Sirolimus decreases the production of VEGF in vivo and inhibits the stimulation of vascular endothelial cells. The anti-angiogenic properties of SRL make it an attractive therapeutic option for Kaposi’s sarcoma (KS) and other malignancies. In a case series of 15 renal transplant recipients with KS, Stallone et al. reported complete clinical remission of cutaneous KS 3 months following the initiation of SRL.²² Histological remission was confirmed after 6 months of therapy. In a patient with pemphigus vulgaris and iatrogenic KS, remission of both was maintained at 24 months with low dose prednisone, dapsone and SRL, 2 mg daily.²³ Extensive cutaneous KS with pulmonary, gastric and hepatic lesions, resolved with cessation of cyclosporine and initiation of SRL at a target serum level of 4-7 ng/ml.²⁴ In addition to the effects of SRL on VEGF, Nichols et al. demonstrated that SRL can repress the expression of the Kaposi’s sarcoma-associated herpes virus lytic master switch protein, thereby impairing virion production.²⁵ Though the use of an immunosuppressant to control a malignancy seems paradoxical, the anti-angiogenic, anti-proliferative and anti-viral effects of SRL make it an important treatment option for KS.

Cutaneous T-Cell Lymphomas

Cutaneous T-cell lymphomas (CTCL) incorporate a group of heterogenous lymphoproliferative disorders characterized by the localization of neoplastic T lymphocytes to the skin. The mTORC1 pathway has been identified as a possible therapeutic target for CTCL, although its cytostatic action may limit its efficacy as monotherapy.²⁶ SRL has little effect on apoptosis despite inhibiting cell growth of primary cell lines in patients with CTCL and Sézary syndrome both in vitro and in vivo.²⁷ A prospective clinical trial is currently underway to determine the efficacy and safety of topical 1% SRL in the treatment of early stage CTCL.

Tuberous Sclerosis

Tuberous sclerosis (TS) is an autosomal dominant condition characterized by the formation of multisystem hamartomatous tumors. Mutations in the TSC1 or TSC2 genes, which encode tuberin and hamartin, result in dysregulation of mTOR signalling.²⁸ As mTOR is downstream of the tuberous sclerosis complex (TSC), the main cellular function of the TSC1/2 proteins is to inhibit the mTOR pathway. Immunosuppressive treatment with SRL in a TS patient who underwent renal transplantation was reported to reduce facial angiofibromas.²⁹ Topical SRL 1% ointment was also shown to reduce and, in some instances, induce complete regression of angiofibromas.^30,31 In a left-right comparison, SRL 2% showed a greater reduction in angiofibroma elevation, size and erythema as compared to tacrolimus 0.03%.³² Furthermore, a pilot study found that topical 0.1% sirolimus was rapidly effective for clearing angiofibromas in four children with the TS complex.³³ The authors suggest that the lower dose of topical SRL is as effective as the higher dose and less invasive than standard pulse dye laser therapy. Systemic treatment with SRL also reduced the volume of renal angiomyolipomas in TS, thereby preserving renal function.^34-36 As topical SRL has the potential to become a first-line treatment for facial angiofibromas, a multicenter, randomized, prospective, double-blind, placebo-controlled trial is currently underway.

Muir-Torre Syndrome

Muir-Torre syndrome (MTS) is an autosomal dominant cancer syndrome considered to be a variant of hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome.³⁷ It is characterized by the presence of visceral malignancy, sebaceous neoplasms and keratoacanthomas.³⁸ Levi et al. reported a case of unrecognized MTS in a kidney transplant recipient who experienced an eruption of multiple sebaceous tumors following immunosuppression with tacrolimus.³⁹ Switching to SRL prevented the development of new sebaceous tumors. Griffard et al. also reported a patient with MTS who developed 18 sebaceous adenomas and 9 sebaceous carcinomas while on cyclosporine for renal transplantation.⁴⁰ Switching to SRL resulted in the patient developing only 5 sebaceous adenomas in the following 18 months, suggesting that SRL may prevent the development of new lesions and the malignant transformation of pre-existing adenomas.

Pachyonychia Congenita

Pachyonychia congenita (PC) is a rare autosomal dominant disorder characterized by focal palmoplantar hyperkeratosis, hypertrophic nail dystrophy, follicular hyperkeratosis and oral leukokeratosis.⁴¹ It is divided into two main variants, PC-1 (Jadassohn-Lewandowsky type) and PC-2 (Jackson-Lawler type), with mutations in the genes encoding keratin K6A or K16 and K6B or K17, respectively.⁴² Interestingly, it has been demonstrated that SRL inhibits keratinocyte proliferation by selectively blocking expression of keratin K6A.⁴³ Treatment with 2 mg SRL daily resulted in clinical improvement in three patients with PC, as measured by a subjective pain rating and the Dermatology Life Quality Index. As SRL was shown to down-regulate expression of K6A in human keratinocytes, it is not surprising that response to treatment was reported to be greatest in a patient known to have a K6A mutation.⁴³

Psoriasis

In a randomized, controlled trial comparing SRL to a subtherapeutic dose of cyclosporine for the treatment of severe plaque psoriasis, SLR 3 mg/m² + cyclosporine 1.25 mg/kg demonstrated significantly better results than cyclosporine 1.25 mg/kg alone, as measured by a mean percentage decrease in PASI score.⁴⁴ The addition of SRL improved clinical scores, however monotherapy with SRL 3 mg/m² was shown to be ineffective in the treatment of psoriasis. Ormerod et al. conducted a randomized, controlled trial to determine the efficacy of topically applied SRL, 2.2% and 8% in plaque psoriasis.⁴⁵ Topical SRL was shown to penetrate normal skin and reduce the number of CD4+ T-cells in the epidermis. The improvement in clinical score was significant with topical SRL, however secondary outcome measures, which included plaque thickness and plaque erythema, did not demonstrate significant improvement. The concomitant administration of SRL to a subtherapeutic dose of cyclosporine may limit their respective toxicities, most notably cyclosporine-induced nephrotoxicity.⁴⁶ Topical SRL has also shown limited benefit in the treatment of psoriasis.⁴⁵

Graft Versus Host Disease (GVHD)

Preliminary evidence for the use of SRL as first-line therapy in acute GVHD demonstrates response rates of 50%, similar to the rates observed with glucocorticoids.⁴⁷ In 32 patients who underwent allogeneic hematopoietic cell transplantation, 16 achieved complete response of acute GVHD following primary therapy with SRL without the addition of systemic glucocorticoids or any other immunosuppressive agents.⁴⁸ The 16 patients who achieved complete resolution of acute GVHD did so within a median of 14 days. An additional 38% achieved complete resolution of acute GVHD when a glucocorticoid dose of less than 1 mg/kg was added to their treatment regime. In an early Phase I trial, 10 of 21 patients discontinued SRL therapy due to toxicity or lack of improvement.⁴⁹ The use of SRL in steroid refractory acute GVHD showed a complete resolution rate of 44% for a minimum of 1 month following initiation of SRL without additional immunosuppressants.⁴⁹ In a retrospective singlecenter study of 22 patients with steroid refractory acute GVHD, the rate of sustained remission was 72%.⁵⁰ This data suggests that SRL may be an effective alternative to high-dose glucocorticoid therapy, which can lead to early and late complications.

Anti-Aging

The discovery that SRL extended the lifespan of genetically heterogenous mice was considered in 2009 by Science as a top 10 scientific breakthrough.⁵¹ The mTOR-dependent and mTORindependent mechanisms of life span extension have been thoroughly reviewed elsewhere.⁵ Newer analogs of rapamycin (or rapalogs), such as temsirolimus, everolimus and deforolimus, are currently under clinical investigation as potential anti-aging therapeutics.

Other Uses

SRL has successfully treated blue rubber bleb nevus syndrome, microcystic lymphatic malformations and kaposiform hemangioendothelioma with Kasabach-Merritt syndrome.⁵² It has served as a useful adjunct to pulse dye laser therapy in the treatment of port-wine stains.⁵³ Experimental evidence suggests that it may also be of benefit for the treatment of keloids and hypertrophic scars.⁵⁴ Further, clinical trials are currently underway to study the efficacy of SRL in patients with complex venous malformations, chronic urticaria, erosive oral lichen planus, scleroderma, systemic lupus erythematosus, pemphigus vulgaris, melanoma, basal cell nevus syndrome, neurofibromatosis and Birt-Hogg-Dubé syndrome.

Conclusion

Sirolimus has been successfully used to treat a variety of vascular, inflammatory and neoplastic skin disorders. With established anti-cancer and anti-aging properties, SRL and the new rapalogs are emerging as targeted therapy for the treatment and prevention of age-related diseases. As compared to other immunosuppressants, these therapies have a lower risk of renal, neurologic and lymphoproliferative complications. Given their potential for use in dermatology, randomized clinical trials are warranted to validate their safety and efficacy.

References

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30. Haemel AK, O’Brian AL, Teng JM. Topical rapamycin: a novel approach to facial angiofibromas in tuberous sclerosis. Arch Dermatol. 2010 Jul;146(7):715-8.
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33. Foster RS, Bint LJ, Halbert AR. Topical 0.1% rapamycin for angiofibromas in paediatric patients with tuberous sclerosis: a pilot study of four patients. Australas J Dermatol. 2012 Feb;53(1):52-6.
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36. Peces R, Peces C, Cuesta-Lopez E, et al. Low-dose rapamycin reduces kidney volume angiomyolipomas and prevents the loss of renal function in a patient with tuberous sclerosis complex. Nephrol Dial Transplant. 2010 Nov;25(11):3787-91.
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39. Levi Z, Hazazi R, Kedar-Barnes I, Hodak E, Gal E, Mor E, et al. Switching from tacrolimus to sirolimus halts the appearance of new sebaceous neoplasms in Muir-Torre syndrome. Am J Transplant. 2007 Feb;7(2):476-9.
40. Griffard EA, McCoppin HH, Wieberg J, et al. The cutaneous effects of posttransplant immunosuppression with cyclosporine in Muir-Torre syndrome. J Am Acad Dermatol. 2011 May;64(5):e86-7.
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Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

ABSTRACT

Solid organ transplant recipients (OTRs) have an increased incidence of skin cancer, resulting in significant morbidity and mortality post-transplantation. Chemoprevention strategies are focused on reducing and delaying the development of skin cancer in these patients. Although systemic retinoids are widely used in OTRs, few randomized controlled trials have been performed. Limited data suggest that acitretin may have a beneficial role in high-risk OTRs. Since rebound flares occur upon discontinuation of retinoids, chemoprevention should be viewed as a lifelong therapy. Further studies are required to establish the efficacy and long-term safety of systemic retinoids as chemopreventive agents for high-risk transplant recipients.

Key Words:
basal cell carcinoma, BCC, chemoprevention, organ transplantation, SCC, squamous cell carcinoma, skin cancer, systemic retinoids

Non-melanoma skin cancers (NMSC) are the most common human cancers worldwide. In Canada, the estimated incidence of NMSC is approximately 75,000 cases annually.¹ Though basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) represent the two major types of NMSC, the term also encompasses Merkel cell carcinomas, cutaneous lymphomas, adnexal tumors, and other primary cutaneous neoplasms. Risk factors for the development of NMSC include ultraviolet radiation, immunosuppression, and chronic inflammation, thus supporting the interplay of the immune system in cancer development.^2,3 Chemical carcinogens, other forms of radiation, infection with oncogenic strains of the human papilloma virus, and certain genodermatoses are additional known risk factors.^2,3 Several complex genotypic, phenotypic, and environmental factors contribute to the pathogenesis of NMSC. Although cumulative sun exposure is the main risk factor for skin cancer development, further studies are required to fully understand the process of cutaneous oncogenesis.^4,5

The high incidence of skin cancer after solid organ transplantation is well recognized. In organ transplant recipients (OTRs), the risk of SCC development is 64 to 250 times greater than in the general population.^6-8 While the overall metastatic rates for SCCs range from 2% to 10%, rates of up to 47% have been reported.⁹ Further, the incidence of SCCs to BCCs is inverted in OTRs at a ratio of 4:1.¹⁰ Skin cancers occur at a younger age of onset, often three to five years after transplantation.¹⁰

Surgical excision with predetermined margins remains the mainstay of therapy for most NMSCs. Of the non-invasive treatment options, only imiquimod and photodynamic therapy have established efficacy in the treatment of select NMSC subtypes. Given the high incidence of NMSC in OTRs, chemopreventive therapies have been used to reduce and delay the development of skin cancer.^10-12 Herein, we review the literature on retinoid chemoprevention in organ transplant recipients.

Mechanisms of Action

Retinoids, natural and synthetic derivatives of vitamin A, are protective against a variety of cancers.¹³ They exert their physiologic effects by binding specific nuclear receptors.¹⁴ These receptors belong to a superfamily of glucocorticosteroid, thyroid hormone, vitamin D and peroxisome proliferator-activated receptors.¹⁵ There are two classes of retinoid nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs).¹⁵ Each receptor family has three isoforms (α, β, and γ) which are encoded by separate genes.¹⁵ While RARs form heterodimers with RXRs, RXRs may form homodimers with RXRs or heterodimers with RARs, vitamin D3receptors or thyroid hormone receptors.¹⁵ In turn, these dimers act as ligand-dependent transcription factors for genes containing a retinoic acid response element (RARE).¹⁶ To date, over 500 genes have been reported to be regulatory targets of retinoids.¹⁷

The mechanism by which retinoids have a chemopreventive effect for skin cancer remains largely unknown. Several different mechanisms may be involved, including: immunomodulation, induction of apoptosis, effects on cell cycle control, inhibition of ornithine decarboxylase, inhibition of cellular proliferation and keratinization, and promotion of cellular differentiation.¹⁸ Experimental data suggest that retinoids exert their effects during the promotion and progression stages of carcinogenesis.¹⁹ The pharmacology of specific retinoids is reviewed in Table 1.²⁰

Efficacy

The role of systemic retinoids in skin cancer chemoprevention was first established in patients with xeroderma pigmentosum.^21,22 By the late 1980s, Shuttleworth et al. studied the efficacy of etretinate in preventing skin cancer in renal transplant recipients.23 Although systemic retinoids are widely used in OTRs, few randomized controlled trials have been performed. Each trial has varying limitations, including small sample sizes. To date, the majority of studies on retinoid chemoprevention consist of case series.

While several case series support the efficacy of etretinate in the chemoprevention of NMSCs in OTRs, there are no clinical trials to validate these findings.^23-26 Similarly, only a single case report supports the use of isotretinoin.²⁷ The best available evidence suggests that acitretin may be beneficial for high-risk OTRs.

In a prospective, open, randomized, cross-over trial, George et al. evaluated the efficacy of acitretin, a second generation retinoid, on NMSC development in renal transplant recipients.²⁸ Acitretin (25 mg per day) was administered to 14 patients, while nine patients received no therapy. Cross-over occurred at one year, and only 47.8% of patients completed the two-year trial. The number of SCCs observed in patients on acitretin was significantly lower than that in the drug-free period (p = 0.002). A similar, yet not significant, trend was observed for BCCs. In one patient, a severe rebound in SCC development occurred upon discontinuation of acitretin. Poor drug tolerability resulted in a high withdrawal rate.

Bouwes Bavinck et al. carried out a randomized, double- blind, placebo-controlled trial to study the effect of acitretin (30 mg per day) on NMSC development in renal transplant recipients.29 All patients had ten or more keratotic skin lesions on the hands and forearms. During the six-month treatment period, two of 19 patients (11%) in the acitretin group reported a total of two new SCCs. In the placebo group, nine of 19 patients (47%) developed a total of 18 new SCCs (p = 0.01). The relative decrease in the number of keratotic skin lesions in the acitretin group was 13.4%, as compared to a relative increase of 28.2% (p < 0.01) in the placebo group. A relapse in keratotic skin lesions and skin cancers was noted upon discontinuation of therapy.

In a randomized, controlled, open-label trial, 26 renal transplant recipients were assigned randomly to two different one-year treatment protocols with acitretin.³⁰ Thirteen patients were treated with acitretin 0.4 mg/kg/day and 13 patients received acitretin 0.4 mg/kg/day during the first three months followed by 0.2 mg/kg/day for the remaining nine months. At nine different time points, the number of actinic keratoses and tumors were counted. The erythema and thickness of the lesions, as well as the severity of side-effects, were scored. In both groups, the number of actinic keratoses decreased by nearly 50%, but the number of new malignant tumors during the study year was similar to the pre-treatment period. Thickness of the keratoses decreased significantly in both groups. The frequency of mucocutaneous side-effects, such as cheilitis, excessive peeling of the skin, and hair disorders, resulted in significant dose reductions (only three of the 14 patients maintained acitretin at a dose of 0.4 mg/kg/day).

In a retrospective before-after study, Harwood et al. evaluated the efficacy of acitretin in the chemoprevention of SCCs.31 A total of 32 OTRs received acitretin (0.2 mg to 0.4 mg/kg/day) for one to 16 years. The number of SCCs developing annually during retinoid therapy was compared to the number of SCCs during the 12-month pre-treatment period. A statistically significant reduction in SCCs was noted in the first (p = 0.006), second (p < 0.001), and third (p = 0.02) years post-treatment.

Adverse Effects

The major limitation to the use of retinoids is poor tolerability.¹¹ In OTRs, mucocutaneous side-effects (i.e., cheilitis, xerosis, skin peeling, photosensitivity, and alopecia), headaches, and dyslipidemia frequently result in dose reductions.^10,11,18 As dyslipidemia has been associated with accelerated cardiovascular disease post-transplantation, cholesterol and triglyceride levels warrant close monitoring.

Other known adverse effects include: ocular (i.e., reduced night vision, dry eyes), skeletal (i.e., diffuse skeletal hyperostosis, osteophyte formation, premature epiphyseal closure), gastrointestinal (i.e., nausea, diarrhea, pancreatitis), hepatic (i.e., transaminitis, toxic hepatitis), hematologic (i.e., leukopenia, agranulocytosis), neurologic (i.e., pseudotumor cerebri, depression, suicidal ideation) and muscle (i.e., myalgias, myopathy) involvement.^10,11,18 Because of the risk of teratogenicity, retinoids are classified as US FDA Pregnancy Category X.

While it has been postulated that retinoids induce immunostimulation, thereby potentiating graft rejection, these concerns have not been validated.10 In all studies to date, there have been no significant liver or renal alterations during the treatment or follow-up periods.^23-31 The potential drug interactions with systemic retinoids and monitoring guidelines are reviewed in Tables 2 and 3.²⁰

Conclusion

Over the years, it has been well recognized that solid organ transplant recipients are at an increased risk of developing skin cancers. Data from a small number of randomized, controlled trials suggest that acitretin may have a beneficial role in high-risk OTRs. While appropriate patient selection (i.e., patients with multiple SCCs) may improve the risk-benefit ratio, indications for use and optimal dosing regimens have yet to be established.

Given the theoretical risk of allograft rejection with systemic retinoids, low starting doses of acitretin (i.e., 10 mg per day) have been recommended. The dose of acitretin may be increased to 30 mg per day, depending on clinical response and drug tolerability. Since rebound flares occur upon discontinuation of retinoids, chemoprevention should be viewed as a lifelong therapy in OTRs. Further studies are ultimately required to establish the efficacy and long-term safety of systemic retinoids as chemopreventive agents for high-risk transplant recipients.

References

1. Canadian Cancer Statistics. 2009. Available at: http://www.cancer.ca/Canada-wide/About%20cancer/Cancer%20statistics/Canadian%20Cancer%20Statistics.aspx?sc_lang=en. Accessed May 25, 2010.
2. Foote JA, Harris RB, Giuliano AR, et al. Predictors for cutaneous basal- and squamous-cell carcinoma among actinically damaged adults. Int J Cancer 95(1):7-11 (2001 Jan 20).
3. Marks R. An overview of skin cancers. Incidence and causation. Cancer 75(2 Suppl):607-12 (1995 Jan 15).
4. Christenson LJ, Borrowman TA, Vachon CM, et al. Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years. JAMA 294(6):681-90 (2005 Aug 10).
5. Demers AA, Nugent Z, Mihalcioiu C, et al. Trends of nonmelanoma skin cancer from 1960 through 2000 in a Canadian population. J Am Acad Dermatol 53(2):320-8 (2005 Aug).
6. Hartevelt MM, Bavinck JN, Kootte AM, et al. Incidence of skin cancer after renal transplantation in The Netherlands. Transplantation 49(3):506-9 (1990 Mar).
7. Harwood CA, Surentheran T, McGregor JM, et al. Human papillomavirus infection and non-melanoma skin cancer in immunosuppressed and immunocompetent individuals. J Med Virol 61(3):289-97 (2000 Jul).
8. Jensen P, Hansen S, Moller B, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol 40(2 Pt 1):177-86 (1999 Feb).
9. Rowe DE, Carroll RJ, Day CL, Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol 26(6):976-90 (1992 Jun).
10. Kovach BT, Sams HH, Stasko T. Systemic strategies for chemoprevention of skin cancers in transplant recipients. Clin Transplant 19(6):726-34 (2005 Dec).
11. Chen K, Craig JC, Shumack S. Oral retinoids for the prevention of skin cancers in solid organ transplant recipients: a systematic review of randomized controlled trials. Br J Dermatol 152(3):518-23 (2005 Mar).
12. Lansbury L, Leonardi-Bee J, Perkins W, et al. Interventions for non-metastatic squamous cell carcinoma of the skin. Cochrane Database Syst Rev 4:CD007869.
13. Niles RM. Recent advances in the use of vitamin A (retinoids) in the prevention and treatment of cancer. Nutrition 16(11-12):1084-9 (2000 Nov-Dec).
14. Chambon P. The nuclear receptor superfamily: a personal retrospect on the first two decades. Mol Endocrinol 19(6):1418-28 (2005 Jun).
15. Germain P, Chambon P, Eichele G, et al. International Union of Pharmacology. LX. Retinoic acid receptors. Pharmacol Rev 58(4):712-25 (2006 Dec).
16. Xiao JH, Durand B, Chambon P, et al. Endogenous retinoic acid receptor (RAR)-retinoid X receptor (RXR) heterodimers are the major functional forms regulating retinoid-responsive elements in adult human keratinocytes. Binding of ligands to RAR only is sufficient for RAR-RXR heterodimers to confer ligand-dependent activation of hRAR beta 2/RARE (DR5). J Biol Chem 270(7):3001-11 (1995 Feb 17).
17. Balmer JE, Blomhoff R. Gene expression regulation by retinoic acid. J Lipid Res 43(11):1773-808 (2002 Nov).
18. Lens M, Medenica L. Systemic retinoids in chemoprevention of non-melanoma skin cancer. Expert Opin Pharmacother 9(8):1363-74 (2008 Jun).
19. Cheepala SB, Syed Z, Trutschl M, et al. Retinoids and skin: microarrays shed new light on chemopreventive action of all-trans retinoic acid. Mol Carcinog 46(8):634-9 (2007 Aug).
20. Patton TJ, Zirwas MJ, Wolverton SE. Systemic retinoids. In: Wolverton SE (ed.). Comprehensive dermatologic drug therapy. 2nd ed. Philadelphia: Saunders-Elsevier, p275-300 (2007).
21. DiGiovanna JJ. Retinoid chemoprevention in patients at high risk for skin cancer. Med Pediatr Oncol 36(5):564-7 (2001 May).
22. Kraemer KH, DiGiovanna JJ, Moshell AN, et al. Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med 318(25):1633-7 (1988 Jun 23).
23. Shuttleworth D, Marks R, Griffin PJ, et al. Treatment of cutaneous neoplasia with etretinate in renal transplant recipients. Q J Med 68(257):717-25 (1988 Sep).
24. Gibson GE, OÂ’Grady A, Kay EW, et al. Low-dose retinoid therapy for chemoprophylaxis of skin cancer in renal transplant recipients. J Eur Acad Dermatol Venereol 10(1):42-7 (1998 Jan).
25. Kelly JW, Sabto J, Gurr FW, et al. Retinoids to prevent skin cancer in organ transplant recipients. Lancet 338(8779):1407 (1991 Nov 30).
26. Rook AH, Jaworsky C, Nguyen T, et al. Beneficial effect of low-dose systemic retinoid in combination with topical tretinoin for the treatment and prophylaxis of premalignant and malignant skin lesions in renal transplant recipients. Transplantation 59(5):714-9 (1995 Mar 15).
27. Bellman BA, Eaglstein WH, Miller J. Low dose isotretinoin in the prophylaxis of skin cancer in renal transplant patients. Transplantation 61(1):173 (1996 Jan 15).
28. George R, Weightman W, Russ GR, et al. Acitretin for chemoprevention of non-melanoma skin cancers in renal transplant recipients. Australas J Dermatol 43(4):269-73 (2002 Nov).
29. Bouwes Bavinck JN, Hardie DR, Green A, et al. The risk of skin cancer in renal transplant recipients in Queensland, Australia. A follow-up study. Transplantation 61(5):715-21 (1996 Mar 15).
30. de Sevaux RG, Smit JV, de Jong EM, et al. Acitretin treatment of premalignant and malignant skin disorders in renal transplant recipients: clinical effects of a randomized trial comparing two doses of acitretin. J Am Acad Dermatol 49(3):407-12 (2003 Sep).
31. Harwood CA, Leedham-Green M, Leigh IM, et al. Low-dose retinoids in the prevention of cutaneous squamous cell carcinomas in organ transplant recipients: a 16-year retrospective study. Arch Dermatol 141(4):456-64 (2005 Apr).

Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

ABSTRACT

The pemphigus variants represent a group of potentially life-threatening autoimmune mucocutaneous blistering diseases. Though systemic corticosteroids have dramatically reduced the rate of disease mortality, current therapeutic options are limited by their toxicity profiles. Advancements in our understanding of the molecular mechanisms involved in the pathogenesis of pemphigus have translated into the development of novel therapies. However, few treatments have been subject to randomized controlled trials to firmly establish therapeutic efficacy. Herein, we focus on the new and emerging therapies in the management of pemphigus.

Key Words:
pemphigus, autoimmune skin disease

Pemphigus represents a group of rare autoimmune mucocutaneous blistering disorders. The 2 main subtypes are pemphigus vulgaris (PV) and pemphigus foliaceus (PF), each with its own clinical variants. Less common forms include paraneoplastic pemphigus, IgA pemphigus, and pemphigus herpetiformis. Since PV is the most common subtype of pemphigus worldwide, it will be the focus of this article.

PV affects both genders equally and has a mean age of onset of 50-60 years. A higher prevalence has been noted in individuals of Ashkenazi Jewish, Mediterranean, Northern Indian and Persian descents.1 Patients often present with multiple, painful erosions or flaccid bullae on the skin and/or mucous membranes. Mucosal disease precedes cutaneous involvement in the majority of the cases.²

The disease is mediated by circulating immunoglobulin G (IgG) autoantibodies against the desmosomal cadherins, desmogleins 1 and 3.³ Histopathology reveals a loss of cell-cell adhesion (acantholysis) in the suprabasilar layer of the epithelium and direct immunofluorescence (DIF) of perilesional skin reveals intercellular deposition of IgG +/– C3. As antibodies often correlate with disease activity, indirect immunofluorescence (IIF), immunoblots, and enzyme-linked immunosorbent assays (ELISA) are commonly used to quantify circulating antibody levels.⁴

If left untreated, PV is frequently fatal with a mortality rate ranging from 60% to 90%.5-8 While systemic corticosteroid use and other therapeutic advances have reduced this mortality rate to approximately 10%, complications from treatment are now the primary cause of morbidity and mortality in this population.^6,7 The goal of managing pemphigus patients is, therefore, to induce and maintain remission with the lowest possible doses of medication, so as to minimize the risk of serious and potentially fatal adverse effects.²

Conventional Therapies

Systemic corticosteroids remain the treatment of choice for pemphigus as they are both effective and capable of inducing a rapid remission. However, adverse effects of corticosteroids are both time- and dose-dependent.⁹ They include weight gain, diabetes, hypertension, glaucoma, cataracts, osteoporosis, avascular necrosis, peptic ulcer disease, adrenal insufficiency, electrolyte and lipid abnormalities, psychosis, immunosuppression, and increased susceptibility to infections.⁹ Adjuvant therapies are, therefore, used to provide a steroid-sparing effect. As these treatments typically have a slower onset of action (i.e., 4-6 weeks), they are most beneficial as maintenance therapies. Conventional adjuvants include various immunosuppressive agents such as azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide, chlorambucil and cyclopsorine, as well as anti-inflammatory agents such as gold, dapsone, colchicine and a variety of tetracycline antibiotics (Table 1).^2,4,10 Unfortunately, these medications are often associated with significant toxicities and must be used with caution. Though the majority of patients will ultimately respond to conventional therapies, few patients develop recalcitrant disease.

Emerging Therapies

Over the years, advances have been made to expand our therapeutic armamentarium for pemphigus. Emerging therapies include intravenous immunoglobulin (IVIg), plasmapheresis, immunoadsorption (IA), extracorporeal photochemotherapy (ECP), rituximab, tumor necrosis factor-alpha (TNF-á) antagonists (infliximab and etanercept), cholinergic agonists, and other experimental therapies such as desmoglein 3 peptides and KC706.

Intravenous Immunoglobulin (IVIg)

IVIg is a fractionated and purified blood product derived from the plasma of between 1,000 and 15,000 healthy donors per batch.4 It contains a high concentration of IgG and has a broad range of antibodies directed against pathogens, foreign antigens, and self-antigens.11 Although its exact mechanism of action remains unclear, IVIg is associated with a rapid and selective decline in the serum levels of pathogenic PV autoantibodies.¹²

Three case series and 1 retrospective analysis document the efficacy of IVIg in PV.13-16 The dosage and frequency of IVIg infusions were comparable between the studies. In all 4 studies, treatment with IVIg resulted in a rapid clinical response and a corticosteroid-sparing effect.^13-16 In 2 retrospective analyses, however, IVIg demonstrated a less favorable response.17,18 As the published studies are limited by their methodologies and small sample sizes, a Canadian multi-centre randomized controlled trial is underway to establish the role of IVIg in the management of PV patients.

Plasmapheresis

Plasmapheresis is the process by which plasma is removed from blood using a cell separator. The blood cells and an appropriate plasma substitute are then returned to the patient undergoing treatment. As antibodies are contained within plasma, plasmapheresis results in the removal of the pathogenic PV autoantibodies. In a multicenter study, PV patients (n=40) were randomized to receive prednisolone alone or prednisolone plus large-volume plasma exchange.¹⁹ While plasmapheresis failed to demonstrate a therapeutic benefit in this study, it has been suggested that an additional immunosuppressive (i.e., cyclophosphamide) or immunomodulatory (i.e., IVIg) therapy may be required to prevent the rebound production of pathogenic autoantibodies associated with disease flares. Multiple case series have evaluated the efficacy of plasmapheresis in treating PV.20-23 Of the 28 patients evaluated in these studies, 18 (64%) experienced complete remission, 6 (33%) experienced partial remission and 4 (22%) had no clinical improvement. Adverse effects encountered included systemic infections, acute hepatitis, thrombocytopenia, anemia, hypocalcemia, nausea, dizziness, urticaria, fever, and hypotension.^20-24

Immunoadsorption (IA)

IA consists of collecting patient plasma, passing it through an adsorber column (i.e., Protein A) to remove circulating immune complexes and IgG and then returning the filtered plasma to the patient.²⁵ Four case series and 2 case reports document the efficacy of IA for the treatment of recalcitrant PV.^26-31 Though patients were allowed to remain on concomitant immunosuppressive therapies, IA resulted in a dramatic clinical response and a rapid decline in desmoglein-specific IgG autoantibodies.^26-31 In the study by Schmidt, et al., a corticosteroid-sparing effect was observed.²⁷ More recently, a small case series demonstrated that IA, administered in combination with rituximab, may result in long-term remission.³² In all studies, IA was safe and well tolerated.

Extracorporeal Photochemotherapy (ECP)

In ECP, also known as photopheresis, a patient’s white blood cells are collected (leukapheresis), exposed to 8-methoxypsoralen, irradiated with ultraviolet-A light and reinfused into the patient. The proposed mechanism of action may involve inhibition of pathogenic autoantibody production by B lymphocytes.¹⁰ There are only 2 small case series and 2 case reports in the literature that document the use of ECP for refractory PV.^33-36 Of the 9 PV patients treated with ECP in these studies, all experienced significant clinical improvement, and no adverse effects from ECP were noted.

Rituximab

Rituximab is a chimeric murine/human IgG1 anti-CD20 monoclonal antibody that targets pre-B and mature B lymphocytes, resulting in complement and antibody-dependent cytotoxicity and apoptosis. Rituximab reduces circulating B cells, thereby preventing their maturation into antibody-producing plasma cells. Multiple case reports suggest that rituximab is an effective treatment option for PV.³⁷ Of the 18 patients with refractory PV reviewed, 3 (17%) experienced complete remission, 4 (22%) experienced clinical remission with further therapy required and 11 (61%) experienced partial remission. Systemic infections occurred in 4 of the 18 patients, resulting in 1 fatal outcome.

The largest clinical study evaluating the use of rituximab in PV has been a case series of 14 patients with refractory PV in which 12 (86%) experienced a complete remission at 3 months after a single cycle of rituximab.³⁸ This agent was also shown to be effective when used in combination with IVIg. In a series of 11 patients with extensive, recalcitrant PV, 9 (82%) experienced a clinical remission lasting between 22-27 months with combination therapy.³⁹

Tumor Necrosis Factor-alpha (TNF-á) Antagonists

TNF-á antagonists may be beneficial for the treatment of PV as experimental studies have demonstrated that TNF-á plays a role in the acantholytic process.^40,41 Two case reports document the successful use of infliximab for refractory PV.^42,43 Two additional case reports have shown clinical improvement of PV with the use of etanercept.^44,45 Clinical trials for both infliximab and etanercept are currently underway.

Cholinergic Agonists

Research suggests that acetylcholine and its receptors are involved in the acantholytic process of pemphigus.² To date, only 2 clinical studies have been performed.^46,47 In a case series of 6 patients with active PV, 3 (50%) experienced clinical improvement with the cholinergic agonist pyridostigmine bromide (Mestinon®, Valeant Pharmaceuticals).⁴⁶ Two of the 3 responders were able to control their disease with pyridostigmine bromide alone and 1 patient was able to remain in remission without any medications. In a recent double-blind, placebo-controlled trial of 3 PV patients with a total of 64 lesions, those lesions treated with 4% pilocarpine gel were found to have a significantly higher epithelialization index compared with placebo.⁴⁷

Other Experimental Therapies

Selective therapy using intravenous desmoglein 3 peptides was developed to suppress the production of anti-desmoglein 3 antibodies through inactivation and/or deletion of disease-associated CD4+ T lymphocytes.⁴⁸ However, an open-label phase I clinical trial of PI-0824 failed to demonstrate significant changes in anti-desmoglein 3 antibody titres following treatment with 2 IV infusions of desmoglein 3 peptides.⁴⁸

A novel therapy, KC706 (Kémia, Inc.) is an oral allosteric p38 mitogen-activated protein kinase (p38MAPK) inhibitor. In a murine model of pemphigus, p38MAPK inhibition prevented blister formation.⁴⁹ A clinical trial is underway to determine the safety and efficacy of KC706 in the management of PV.

Conclusion

While corticosteroid therapy remains the mainstay of treatment for PV, the morbidity associated with its use is significant. Conventional immunosuppressive and anti-inflammatory therapies are further associated with serious and potentially life-threatening adverse events. With an improved understanding of PV pathogenesis, a number of novel therapies have been developed. Though many of these therapies appear promising, case reports and case series dominate the dermatologic literature. Randomized controlled trials are urgently required to establish their efficacy and safety in the management of pemphigus patients.

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45. Lin MH, Hsu CK, Lee JY. Successful treatment of the recalcitrant 45. pemphigus vulgaris and pemphigus vegetans with etanercept and carbon dioxide laser. Arch Dermatol 141(6):680-2 (2005 Jun).
46. Grando SA, Dahl MV. Activation of keratinocyte muscarinic 46. acetylcholine receptors reverses pemphigus acantholysis. J Eur Acad Dermatol Venereol 2(2):72-86 (1993 May).
47. Iraji F, Yoosefi A. Healing effect of pilocarpine gel 4% on skin 47. lesions of pemphigus vulgaris. Int J Dermatol 45(6):743-6 (2006 Jun).
48. Anhalt G, Werth V, Strober B, et al. An open-label phase I clinical 48. study to assess the safety of PI-0824 in patients with pemphigus vulgaris. J Invest Dermatol 125(5):1088 (2005 Nov).
49. Berkowitz P, Hu P, Warren S, et al. p38MAPK inhibition prevents 49. disease in pemphigus vulgaris mice. Proc Natl Acad Sci USA 103(34):12855-60 (2006 Aug).

Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

ABSTRACT

Rituximab (Rituxan^®, Genentech/ Biogen Idec) is a genetically engineered chimeric murine/human monoclonal antibody directed against CD20, a B lymphocyte-specific antigen. Initially approved for the treatment of relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma (NHL), rituximab has been increasingly used to treat a variety of immune-mediated and autoimmune diseases. While anecdotal case reports recommend its “off-label” use in dermatology, randomized clinical trials are required to firmly establish the safety and efficacy of this emerging biologic therapy.

Key Words:
Rituximab, Rituxan^®, immune skin disease, monoclonal antibody

In 1994, Reff and colleagues developed a chimeric murine/ human anti-CD20 monoclonal antibody which induced the rapid depletion of CD20+ B lymphocytes in vivo.1 By 1997, rituximab (Rituxan^®) was approved by the US FDA for the treatment of relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma (NHL). Originally developed for the treatment of B cell malignancies, rituximab has since been used to treat a variety of immune-mediated and autoimmune diseases (i.e., rheumatoid arthritis, systemic lupus erythematosus, and idiopathic thrombocytopenic purpura). Herein, we review the potential applications and limitations of rituximab use in dermatology.

Mechanism of Action/ Pharmacology

Rituximab is an immunoglobulin G1 (IgG1) kappa monoclonal antibody composed of a murine variable region (Fab portion) that is fused onto a human constant region (Fc portion). The Fab portion binds specifically to the CD20 antigen, located exclusively on the surface of pre-B and mature B lymphocytes. Once bound, the Fc portion of rituximab recruits immune effector cells to help mediate cell lysis of the CD20+ B lymphocytes via 3 possible mechanisms:

• complement-dependent cytotoxicity (CDC)
• antibody-dependent cell-mediated cytotoxicity (ADCC)
• apoptosis.¹

The exact contribution of each mechanism remains unclear, and different mechanisms may prevail in different diseases.²
The use of rituximab results in the rapid depletion of both normal and malignant CD20+ B lymphocytes in the peripheral blood and, to a lesser extent, the lymph nodes.1 The CD20 antigen is not expressed on the surface of hematopoietic stem cells or pro-B cells; thus, the capacity of these precursor cells to regenerate the B lymphocyte population remains intact.1 As the majority of plasma cells fail to express the CD20 antigen, plasma cells are generally spared and serum immunoglobulin levels tend not to fall dramatically.³ Here lies the selective advantage of rituximab.

Pharmacokinetics

In patients receiving rituximab intravenously, serum levels are dose-proportional, correlate with patient response to therapy, and increase with each successive infusion.3-5 The half-life of rituximab is also proportional to the dose, increases with each subsequent infusion, and varies greatly from patient to patient. The wide variability in elimination half-lives may reflect differences in tumor burden and changing CD20+ B cell populations with repeated administrations. Though the mechanisms involved in the metabolism and elimination of rituximab are not fully understood, it is postulated that rituximab is degraded nonspecifically in the liver and excreted in the urine.⁶

Dosage

In adults, the standard dosing schedule for rituximab is 375mg/m2 given intravenously once per week for 4 consecutive weeks. Premedication with an antipyretic (i.e., acetaminophen) and an antihistamine (i.e., diphenhydramine) should be administered prior to and throughout each infusion to reduce the likelihood of infusion-related reactions.7
In order to minimize the risk of tumor lysis syndrome, bulky tumors require higher doses of rituximab to be staggered over several weeks. As there is a limited number of CD20+ B cells in the normal immune system, an alternate dosing regimen was developed for patients with rheumatoid arthritis (RA). In RA patients, rituximab may be given as two-1000mg intravenous infusions separated by 2 weeks.⁸

Recently, a few cases of primary cutaneous B-cell lymphoma have been treated successfully with intralesional injections of rituximab. The dose ranged from 1-3mL of a 10mg/mL solution and variable numbers of injections were administered.^9-12

Rituximab is currently supplied at a concentration of 10mg/mL in either 100mg (10mL) or 500mg (50mL) single-use vials.⁷

Adverse Effects/ Drug Interactions

Rituximab is generally well tolerated, though most patients experience mild-to-moderate infusion-related reactions with their first treatment. The most common symptoms include fever (48%), chills (32%), weakness (18%), nausea (17%), headache (13%), pruritus (12%), and rash (11%).7 The symptoms are usually reversible by temporarily discontinuing the infusion and providing symptomatic relief. Infusion-related side-effects tend to diminish or disappear with subsequent infusions.

Severe and potentially fatal adverse events, though rare, have been associated with rituximab therapy. These include severe infusion-related reactions, tumor lysis syndrome, mucocutaneous reactions such as Stevens-Johnson Syndrome (SJS), anaphylaxis, serious pulmonary events, cardiac arrythmias, renal failure, hematological abnormalities, bowel obstruction/perforation, and significant infections, such as bacterial sepsis, reactivation of hepatitis B with fulminant hepatitis, and progressive multifocal leukoencephalopathy (PML).⁷ With regard to PML, a recent safety warning was issued by the US FDA regarding the development of this potentially fatal viral infection in the central nervous system (CNS) in 2 patients with systemic lupus erythematosus (SLE) who were being treated with rituximab.¹³ Patients should be urged to seek prompt medical attention if they develop any new neurological symptoms (i.e., changes in vision, balance, or cognition).

The use of rituximab in children and in patients with renal or hepatic failure has not been studied extensively. Rituximab should be avoided during pregnancy unless the potential benefit justifies the potential risk to the fetus (Pregnancy Risk Category C). As human IgG is excreted in breast milk, lactating mothers should be advised to discontinue nursing until circulating blood levels are no longer detectable. Though there have been no formal drug interaction studies performed with rituximab, the concomitant use of rituximab and cisplatin should be avoided as this combination has been associated with renal failure.⁷

Clinical Uses

Although approved for the treatment of relapsed or refractory low-grade or follicular NHL, the list of “off-label” indications for rituximab continues to grow. Case reports and small case series document its use in the dermatologic literature. Potential indications are listed in Table 1, and select dermatologic diseases are reviewed.

Primary Cutaneous B-Cell Lymphoma (PCBCL)

In a recent review, more than 40 individual cases of PCBCL were treated with rituximab intravenously.2 In the two largest case series, 10 patients were enrolled in each study. The overall response rate was 70% (20% complete response, 50% partial response) in the first study and 90% (70% complete response, 20% partial response) in the second study.14,15

Nineteen cases of PCBCL treated with intralesional rituximab were found in the literature.9-12,16 A complete response was seen in 84% of patients, while a variable response was seen in the remaining 16%. Relapse rates were found to be higher with intralesional therapy when compared with standard systemic therapy.

Dermatologic Disease

• Primary cutaneous B-cell lymphoma
• Immunobullous disease
• Pemphigus vulgaris
• Pemphigus foliaceus
• Paraneoplastic pemphigus
• Bullous pemphigoid
• Mucous membrane pemphigoid
• Epidermolysis bullosa acquisita
• Chronic graft versus host disease
• Dermatomyositis
• Systemic lupus erythematosus
• Vasculitis
• Small vessel vasculitis
• Hypocomplementemic urticarial vasculitis Antineutrophil cytoplasmic antibody-vasculitis
• Cryoglobulinemia
• Schnitzler syndrome
• Waldenstrom’s macroglobulinemia
• Angioedema
• Vitiligo

Table 1: Potential dermatological uses of rituximab

Pemphigus Vulgaris (PV)

Multiple case reports suggest that rituximab is an effective treatment option for PV. In a recent review of 18 patients with refractory PV, 3 patients (17%) experienced complete remission (no further therapy required), 4 patients (22%) experienced clinical remission (healing of all lesions but further therapy required), and 11 patients (61%) experienced partial remission.17 The standard course of rituximab was administered in all but 2 patients who received additional infusions. Serious infections occurred in 4 of the 18 patients, of which 1 was fatal. Notably, patients were allowed to remain on concomitant immunosuppressive therapy.

In 11 patients with extensive, recalcitrant PV, efficacy was noted using a combination of rituximab and intravenous immunoglobulin (IVIG).¹⁸ Rituximab (375mg/m2) was administered once weekly for 3 weeks and followed by an infusion of IVIG (2g/kg) in the fourth week. The cycle was repeated once and, upon completion of the induction therapy, monthly rituximab and IVIG infusions were given for 4 consecutive months. Of the 11 patients, 9 patients had a clinical remission lasting between 22–27 months; no serious adverse events were noted. Taken together, the data suggest that rituximab may be effective for patients with severe, refractory PV.

Other Immunobullous Diseases

Case reports document the successful use of rituximab in other immunobullous diseases, including: pemphigus foliaceus, paraneoplastic pemphigus, bullous pemphigoid, mucous membrane pemphigoid and epidermolysis bullosa acquisita.19-24 In most cases, complete remission was achieved with the standard therapeutic regimen. However, several cases of PNP have shown resistance to rituximab therapy.

Chronic Graft Versus Host Disease (CGVHD)

The use of rituximab in the treatment of refractory CGVHD has been documented in multiple case series with mixed results. In one case series, 8 patients with extensive CGVHD were treated with the standard course of rituximab.²⁵ Four of these patients (50%) responded to rituximab therapy whereas the other 4 patients (50%) were nonresponders. In the largest series of 21 patients with steroid-refractory CGHVD, the overall response was 70% and included 2 patients who experienced a complete remission.²⁶ In these patients, rituximab facilitated a statistically significant reduction in the median dose of steroid use from 40mg/day to 10mg/day (p<0.001). A steroid-sparing effect was therefore demonstrated in patients with CGVHD.

Dermatomyositis (DM)

In an open-label pilot study of 6 patients with longstanding refractory DM, patients received four weekly intravenous infusions of rituximab at a dose of 100mg/m2 (three patients) or 375mg/m2 (three patients).²⁷ All patients experienced marked clinical improvement in both cutaneous and muscle disease. Overall, rituximab was well tolerated in this patient group and no major adverse events were reported.

In another study, three patients with refractory DM experienced marked clinical improvement of their cutaneous disease.²⁸ In this small cohort, the heliotrope rash and the violaceous poikiloderma were most responsive to therapy.

Other Dermatologic Disease

Rituximab has been shown to benefit other dermatologic conditions including systemic lupus erythematosus (SLE), cryoglobulinemia, Waldenstrom’s macroglobulinemia, Schnitzler syndrome, vitiligo, angioedema as well as cutaneous vasculitides such as small vessel vasculitis, hypocomplementemic urticarial vasculitis and antineutrophil cytoplasmic antibody-associated vasculitis.^21,29-31

Conclusion

Though approved for the treatment of low-grade or follicular NHL, rituximab has demonstrated therapeutic efficacy in a variety of recalcitrant immune-mediated and autoimmune skin disorders. Few therapeutic failures have been described, possibly resulting from long-lived CD20- plasma cells capable of producing pathogenic autoantibodies. In most patients, rituximab is safe and tolerable with infusion-related reactions and infectious complications dominating the adverse-event profile. Clinical trials with long-term follow-ups are warranted to firmly establish the efficacy, tolerability and dosing of rituximab in the treatment of dermatologic disease.
References

1. Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83(2):435-45 (1994 Jan).
2. Graves JE, Nunley K, Heffernan MP. Off-label uses of biologics in dermatology: rituximab, omalizumab, infliximab, etanercept, adalimumab, efalizumab, and alefacept (part 2 of 2). J Am Acad Dermatol 56(1):e55-79 (2007 Jan).
3. Maloney DG, Liles TM, Czerwinski DK, et al. Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 84(8):2457-66 (1994 Oct).
4. McLaughlin P, Grillo-López AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 16(8): 2825-33 (1998 Aug).
5. Berinstein NL, Grillo-López AJ, White CA, et al. Association of serum rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol 9(9):995-1001 (1998 Sep).
6. Cartron G, Blasco H, Paintaud G, Watier H, Le Guellec C. Pharmacokinetics of rituximab and its clinical use: thought for the best use? Crit Rev Oncol Hematol 62(1):43-52 (2007 Apr).
7. Canadian Pharmacists Association. Compendium of pharmaceuticals and specialties: the Canadian drug reference for health professionals. Toronto: Canadian Pharmacists Association (2006).
8. Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at 24 weeks. Arthritis Rheum 54(9):2793-806 (2006 Sep).
9. Heinzerling L, Dummer R, Kempf W, Schmid MH, Burg G. Intralesional therapy with anti-CD20 monoclonal antibody rituximab in primary cutaneous B-cell lymphoma. Arch Dermatol 136(3):374-78 (2000 Mar).
10. Paul T, Radny P, Krober SM, Paul A, Blaheta HJ, Garbe C. Intralesional rituximab for cutaneous B-cell lymphoma. Br J Dermatol 144(6):1239-43 (2001 Jun).
11. Roguedas AM, Watier H, Paintaud G, de Muret A, Vaillant L, Machet L. Intralesional therapy with anti-CD20 monoclonal antibody rituximab: local and systemic efficacy in primary cutaneous B-cell lymphoma. Br J Dermatol 152(3):541–4 (2005 Mar).
12. Kerl K, Prins C, Saurat JH, French LE. Intralesional and intravenous treatment of cutaneous B-cell lymphomas with the monoclonal anti-CD20 antibody rituximab: report and follow-up of eight cases. Br J Dermatol 155(6):1197-200 (2006 Dec).
13. FDA warns of safety concern regarding rituxan in new patient
14. population. Retrieved January 30, 2007, from http://www.fda.gov/bbs/topics/NEWS/2006/NEW01532.html.
15. Heinzerling LM, Urbanek M, Funk JO, et al. Reduction of tumor burden and stabilization of disease by systemic therapy with anti-CD20 monoclonal antibody (rituximab) in patients with primary cutaneous B-cell lymphoma. Cancer 89(8):1835-44 (2000 Oct).
16. Gellrich S, Muche JM, Wilks A, et al. Systemic eight-cycle anti-CD20 monoclonal antibody (rituximab) therapy in primary cutaneous B-cell lymphomas–an applicational observation. Br J Dermatol 153(1):167-73 (2005 Jul).
17. Fink-Puches R, Wolf IH, Zalaudek I, Kerl H, Cerroni L. Treatment of primary cutaneous B-cell lymphoma with rituximab. J Am Acad Dermatol 52(5):847-53 (2005 May).
18. Schmidt E, Hunzelmann N, Zillikens D, Brocker EB, Goebeler M. Rituximab in refractory autoimmune bullous diseases. Clin Exp Dermatol 31(4):503-8 (2006 Jul).
19. Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med 355(17):1772-9 (2006 Oct).
20. Goebeler M, Herzog S, Bröcker EB, Zillikens D. Rapid response of treatment-resistant pemphigus foliaceus to the anti-CD20 antibody rituximab. Br J Dermatol 149(4):899–901 (2003 Oct).
21. Arin MJ, Engert A, Krieg T, Hunzelmann N. Anti-CD20 monoclonal antibody (rituximab) in the treatment of pemphigus. Br J Dermatol 153(3):620-5 (2005 Sep).
22. Fatourechi MM, el-Azhary RA, Gibson LE. Rituximab: applications in dermatology. Int J Dermatol 45(10):1143-55 (2006 Oct).
23. Schmidt E, Benoit S, Bröcker EB, Zillikens D, Goebeler M. Successful adjuvant treatment of recalcitrant epidermolysis bullosa acquisita with anti-CD20 antibody rituximab. Arch Dermatol 142(2):147–50 (2006 Feb).
24. Crichlow SM, Mortimer NJ, Harman KE. A successful therapeutic trial of rituximab in the treatment of a patient with recalcitrant, high-titre epidermolysis bullosa acquisita. Br J Dermatol 156(1):194-6 (2007 Jan).
25. Schmidt E, Seitz CS, Benoit S, Bröcker EB, Goebeler M. Rituximab in autoimmune bullous diseases: mixed responses and adverse effects. Br J Dermatol 156(2):352-6 (2007 Feb).
26. Ratanatharathorn V, Ayash L, Reynolds C, et al. Treatment of chronic graft-versus-host disease with anti-CD20 chimeric monoclonal antibody. Biol Blood Marrow Transplant 9(8):505-11 (2003 Aug).
27. Cutler C, Miklos D, Kim HT, et al. Rituximab for steroid-refractory chronic graft-versus-host disease. Blood 108(2):756-62 (2006 Jul).
28. Levine TD. Rituximab in the treatment of dermatomyositis: an open-label pilot study. Arthritis Rheum 52(2):601-7 (2005 Feb).
29. Dinh HV, McCormack C, Hall S, Prince HM. Rituximab for the treatment of the skin manifestations of dermatomyositis: a report of 3 cases. J Am Acad Dermatol 56(1):148-53 (2007 Jan).
30. Risselada AP, Kallenberg CGM. Therapy-resistant lupus skin disease successfully treated with rituximab. Rheumatology 45(7):915-16 (2006 Jul).
31. Chung L, Funke AA, Chakravarty EF, Callen JP, Fiorentino DF. Successful use of rituximab for cutaneous vasculitis. Arch Dermatol 142(11):1407-10 (2006 Nov).
32. Saigal K, Valencia IC, Cohen J, Kerdel FA. Hypocomplementemic urticarial vasculitis with angioedema, a rare presentation of systemic lupus erythematosus: rapid response to rituximab. J Am Acad Dermatol 49(5 Suppl):S283-5 (2003 Nov).

Introduced in the 1970s as a treatment for psoriasis, mycophenolic acid has since been reformulated as mycophenolate mofetil (MMF). With an improved side-effect profile and enhanced bioavailability, MMF is a promising drug for immune-mediated skin disease. Currently approved for the prevention of organ rejection, its list of “off-label” dermatologic indications continues to grow. As a noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH), MMF inhibits de novo purine synthesis. Its relative lack of hepatonephrotoxicity and seemingly low risk of carcinogenicity offer important therapeutic advantages. While case reports and case series dominate the dermatologic literature, preliminary results are sufficiently promising to warrant larger, randomized clinical trials with this emerging therapy.

Key Words:
mycophenolate mofetil, CellCept®, inflammatory skin disease, dermatology

In the past two decades, an increasing number of immunosuppressive agents have been developed to prevent allograft rejection in organ transplantation. A number of these medications have shown therapeutic efficacy in inflammatory skin disease; however, patients and physicians must be mindful of their toxicities. Originally isolated from cultures of Penicillium stoloniferum, mycophenolic acid (MPA) was first recognized as a lipid-soluble, weak organic acid.¹ It was later shown to have antibacterial, antiviral, antifungal, antitumoral and immunosuppressive properties.^2-6 In 1975, MPA demonstrated therapeutic efficacy in psoriasis.⁷ However, it soon fell into disrepute with growing concerns about its long-term risk of carcinogenicity. Moreover, tolerability of MPA was limited by gastrointestinal upset. Subsequent investigations led to the development of mycophenolate mofetil (MMF) (CellCept®, Roche Pharmaceuticals), the semi-synthetic 2-morpholinoethyl ester of MPA.⁸ This new formulation showed enhanced bioavailability, tolerability and efficacy.⁸ By 1995, MMF received US FDA approval for the prevention of acute renal allograft rejection and soon became recognized as an effective treatment option for immune-mediated skin disease.

Mechanism of Action

Mycophenolate mofetil selectively and noncompetitively inhibits inosine monophosphate dehydrogenase (IMPDH) in the de novo purine synthesis pathway. This enzyme facilitates the conversion of inosine monophosphate to xanthine monophosphate, an intermediate metabolite in the production of guanosine triphosphate. As MMF results in the depletion of guanosine nucleotides, it impairs RNA, DNA and protein synthesis.⁹

The purine bases, adenosine and guanosine, may be synthesized through two pathways: the de novo purine synthesis pathway, and the hypoxanthine-guanine phosphoribosyl transferase salvage pathway. As lymphocytes lack the salvage pathway, MMF selectively inhibits lymphocyte proliferation and antibody formation. Moreover, MMF preferentially blocks the type II isoform of IMPDH, predominantly located on lymphocytes; thus, it also holds potent cytostatic effects on T and B cells.⁹ Herein lies the selective advantage of this immunosuppressive agent.

Mycophenolate also prevents the glycosylation of lymphocyte and monocyte glycoproteins that are involved in adhesion to endothelial cells. It may further inhibit the recruitment of leukocytes to sites of inflammation and impair antigen presentation.10 While it does not inhibit early events in the activation of human peripheral blood mononuclear cells (i.e., IL-1 and IL-2 production), MMF blocks the coupling of these events to DNA synthesis and proliferation.⁹

Pharmacokinetics

After ingestion, MMF is hydrolyzed to its parent compound, MPA, by plasma esterases. Predominantly bound to albumin, MPA has a bioavailability that approaches 94%.¹¹ The peak concentration of the active metabolite is obtained within 60-90 minutes after oral administration. Upon systemic absorption, MPA undergoes hepatic conjugation to its inactive glucuronide form (MPAG).

Approximately 87% of the drug is excreted through the kidneys, 6% in the feces and the remainder undergoes enterohepatic recirculation. Beta-glucuronidase, found within the epidermis and gastrointestinal tract, can convert MPAG to the active MPA form.¹¹

Safety

At usual doses, MMF is generally well tolerated. Compared to other immunosuppressants, such as methotrexate, azathioprine and cyclosporine, the lack of hepatonephrotoxicity with MMF offers an important therapeutic advantage. The most common side-effects are gastrointestinal (i.e., nausea, diarrhea, abdominal cramps, constipation, vomiting and anorexia) and genitourinary (i.e., urgency, frequency, dysuria, hematuria and, occasionally, sterile pyuria). These occur in up to 36% and 40% of patients, respectively. Other reported adverse events include neurologic (i.e., headache, tinnitus and insomnia), cutaneous (i.e., exanthematous eruptions, acne and pedal edema), cardiorespiratory (i.e., dyspnea, cough, chest pain, palpitations and hypertension) and metabolic (i.e., hypercholesterolemia, hyperglycemia, hypophosphatemia and hypo/hyperkalemia) reactions. Severe leukopenia has been reported to occur in less than 3% of MMF-treated patients. However, unlike treatment with azathioprine, use of MMF does not put patients with an inherited deficiency of thiopurine methyltransferase at risk.¹²

Infection rates with MMF therapy are difficult to quantify in the dermatologic literature. Opportunistic infections occur in up to 40% of transplant patients treated with MMF; however, the majority of these patients are also treated with other immunosuppressive agents.¹³ In addition to standard bacterial and viral infections, patients are at increased risk for herpes simplex, herpes zoster, cytomegalovirus, candidiasis, cryptococcosis, aspergillosis, mucormycosis and Pneumocystis carinii pneumonia.¹³ When compared to renal transplant patients treated with azathiprine, those treated with MMF have a higher incidence of herpes simplex and tissue invasive CMV infections.¹³

The long-term risk of carcinogenicity with MMF remains controversial. In the dermatologic literature, few malignancies have been reported in patients receiving MMF or its pro-drug, MPA. Lymphoproliferative disease or lymphoma developed in 0.4%-1% of patients receiving MMF with other immunosuppressive agents for renal, cardiac and hepatic transplantation.¹³ As part of controlled clinical trials, these patients were followed for >1 year. Non-melanoma skin cancer occurred in 1.6%-4.2% of patients, while other types of malignancy appeared in 0.7%-2.1% of patients.¹³ Three-year safety data in renal and cardiac transplant patients failed to reveal any changes in the incidence of malignancy.¹³

The risk of malignancy may be related to the intensity and duration of immunosuppression rather than the use of any specific agent. However, certain immunosuppressants are known to be mutagenic and carcinogenic. For instance, urinary, myeloproliferative, lymphoproliferative and cutaneous malignancies occur in a significant number of patients treated with cyclophosphamide.¹³ Moreover, the active metabolite of azathioprine, 6-thioguanine, is a purine analogue that becomes incorporated into DNA. This process may cause chromosomal breakage with resultant mutagenesis.¹⁴ As a noncompetitive inhibitor of purine synthesis, MMF fails to initiate chromosomal breaks. Potentially less mutagenic than azathioprine, MMF may have a lower risk of carcinogenicity; however, it will take several years for this advantage to be substantiated.
While there are no adequate studies on MMF in pregnant women, the drug has been shown to be teratogenic in animals. Therefore, MMF should be avoided during pregnancy unless the potential benefit justifies the potential risk to the fetus (pregnancy risk C).

Possible drug interactions with MMF are listed in Table 1.

Dosage

In adults, the usual dose of MMF ranges from 2-3g/day.15 In the pediatric population, MMF should be administered as 600mg/m2 per dose every 12 hours.15 While renal insufficiency has no consistent effect on the pharmacokinetics of MPA, dose reductions should be considered in patients with severe renal impairment.15 In order to prevent a disease flare, many clinicians would consider tapering MMF slowly.

Mycophenolate mofetil is currently available as 250mg capsules, 500mg tablets, a powder for oral suspension (200mg/ml), and a lyophilized, sterile powder for intravenous administration. In many countries, an enteric-coated formulation may also be accessible. While a topical formulation may yield promising results, one has yet to be made commercially available.
The average cost for a 1-month course of MMF in Canada, administered at a dose of 1g twice daily, amounts to $560 CDN.

Clinical Uses

Approved for the prevention of organ rejection, the list of “off-label” indications for MMF continues to grow. Case reports and open-label clinical trials document its use in the dermatologic literature. Potential indications are listed in Table 2, and select dermatoses are reviewed below.

Psoriasis

Multiple case reports suggest that MMF is an effective treatment option for psoriasis.16-20 In a study of 11 patients with stable plaque-type psoriasis, the efficacy of MMF was measured using the Psoriasis Area and Severity Index (PASI) score.21 Patients initially received MMF 1g twice daily for 3 weeks followed by 0.5g twice daily. Within 3 weeks of therapy, there was a reduction in PASI of between 40% and 70% in seven of the 11 patients. Only one patient achieved a reduction in PASI of <25% from baseline. After 6 weeks, there was further improvement in six patients. However, PASI worsened in four patients when MMF was tapered to the lower dosage.

In a two-center, prospective, open-label clinical trial, 23 patients with moderate to severe psoriasis were treated with MMF 2-3g/day for 12 weeks.22 In the 18 patients who completed the study, the PASI was reduced by 24% (p < 0.001) at 6 weeks and by 47% (p < 0.001) at 12 weeks. Moreover, MMF appeared to have a beneficial effect on patients suffering from psoriatic arthritis. The treatment was well tolerated: five patients developed nausea, one patient experienced periorbital edema and pruritus, and one patient had a transient leukopenia. Thus, MMF monotherapy appears to be an effective treatment for patients with moderate-to-severe, plaque-type psoriasis.

Dermatitis

In a pilot study of 10 patients with severe refractory atopic dermatitis, MMF was increased to a dose of
2g/day.23 After 12 weeks of therapy, the median scores for disease severity (SCORAD index) improved by 68%. These findings were associated with a significant decrease in serum IgE and a shift in the T-helper (Th)-1 to Th2 cytokine ratio.

In another study of 10 patients with moderate-to-severe atopic dermatitis, MMF was administered at 2g/day for a month and tapered to 1g/day.24 In a 20 week follow-up period, there was a 74% reduction in the SCORAD index as compared with baseline (p < 0.01). Dyshidrotic eczema and chronic actinic dermatitis have also responded to MMF therapy.

Immunobullous Disease

Multiple case series have documented the efficacy of MMF as a steroid-sparing agent in the autoimmune mucocutaneous blistering diseases. In a historical, prospective study, Mimouni, et al. studied 42 consecutive patients with pemphigus who were recalcitrant to standard therapies.25 Of these patients, 31 were diagnosed with pemphigus vulgaris (PV) and 11 with pemphigus foliaceus (PF). A complete remission was obtained in 22 (71%) and 5 (45%) of PV and PF patients, respectively. The treatment was administered for an average of 22 months, and the median time to achieve remission was 9 months. In two patients, MMF was discontinued for nausea and symptomatic, reversible neutropenia. Others have demonstrated similar success with MMF in treating patients with PV, PF, paraneoplastic pemphigus, bullous pemphigoid, mucous membrane pemphigoid, linear IgA disease and epidermolysis bullosa acquisita.^26-32

Connective Tissue Disease

The efficacy of MMF in systemic lupus erythematosus has been clearly validated. Moreover, the cutaneous lesions of subacute cutaneous lupus, chronic discoid lupus and lupus perniosis have shown response to MMF therapy. Clinical improvement has also been demonstrated in other connective tissue diseases such as dermatomyositis, scleroderma, urticarial vasculitis, Takayasu’s arteritis, microscopic polyangiitis, Wegener’s granulomatosis, polyarteritis nodosa and Behçet’s disease.^6,15

Other Dermatologic Disease

Mycophenolate mofetil has been shown to benefit other dermatologic conditions including lichen planus, pyoderma gangrenosum, graft-versus-host disease, recurrent erythema multiforme, Steven-Johnson syndrome, sarcoidosis, and cutaneous Crohn’s disease.^6,15

Conclusion

In a variety of inflammatory skin disorders, MMF has been successfully used both in combination with systemic steroids and as monotherapy. Early reports on efficacy and tolerability suggest that MMF offers hope to patients with immune-mediated skin disease. As gleaned from transplant data, its safety profile appears reassuring. However, randomized clinical trials with long surveillance periods are warranted to validate the efficacy and safety of MMF in the treatment of dermatologic disease.

References

1. Alsberg CL, Black OF. Contribution to the study of maize deterioration; biochemical and toxicological investigations of Penicillium puberulum and Penicillium stoloniferum. Bull Burl Anim Ind. US Dept Agr 270:1-47 (1913).
2. Abraham EP. The effect of mycophenolic acid on the growth of Staphylococcus aureus in heart broth. Biochem J 39:398-404 (1945).
3. Abrams R, Bentley M. Biosynthesis of nucleic acid purines. I. Formation of guanine from adenine compounds in bone marrow extracts. Arch Biochem 56(1):184-95 (1955 May).
4. Cline JC, Nelson JD, Gerzon K, Williams RH, Delong DC. In vitro antiviral activity of mycophenolic acid and its reversal by guanine-type compounds. Appl Microbiol 18(1):14-20 (1969 Jul).
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7. Jones EL, Epinette WW, Hackney VC, Menendez L, Frost P. Treatment of psoriasis with oral mycophenolic acid. J Invest Dermatol 65(6):537-42 (1975 Dec).
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11. Bullingham RE, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 34(6):429-55 (1998 Jun).
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15. Assmann T, Ruzicka T. New immunosuppressive drugs in dermatology (mycophenolate mofetil, tacrolimus): unapproved uses, dosages, or indications. Clin Dermatol 20(5):505-14 (2002 Sep-Oct).
16. Nousari HC, Sragovich A, Kimyai-Asadi A, Orlinsky D, Anhalt GJ. Mycophenolate mofetil in autoimmune and inflammatory skin disorders. J Am Acad Dermatol 40(2 Pt 1):265-8 (1999 Feb).
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Division of Dermatology¹, Department of Medicine² & Department of Pharmacology³,
University of Toronto, Toronto, ON, Canada

ABSTRACT

A manufactured blood product derived from fractionated human plasma, intravenous immunoglobulin (IVIg) contains supra-physiologic levels of IgG. IVIg is currently used in the treatment of immunodeficiency syndromes, inflammatory disorders and infectious diseases. Uncontrolled clinical studies and anecdotal case reports recommend its use in dermatology, but randomized clinical trials are lacking. In selecting the most appropriate IVIg for the patient, convenience, efficacy, safety and tolerability of the different products should be considered. With several measures in place to ensure its safety, IVIg offers new hope for the treatment of many severe dermatologic conditions.

Key Words:
Intravenous immunoglobulin, IVIg, immunodeficiency syndromes, inflammatory disorders, autoimmune disease, infectious disease

Intravenous immunoglobulin (IVIg) is currently used in the treatment of primary and secondary immunodeficiency diseases, autoimmune disorders and certain infectious states. Off-label (non-approved) uses for high-dose IVIg are becoming increasingly common in dermatology.^1,2 As a blood product derivative, IVIg is manufactured from the sterilized, purified human plasma of between 10,000 to 20,000 donors per batch.³ The final IVIg preparation is primarily composed of IgG, with trace amounts of IgA, IgM and albumin.³ For the treatment of autoimmune diseases such as dermatomyositis and pemphigus, the precise mechanism of action is unknown. The immunomodulatory effects may be exerted through one or more of the following: 1) functional blockade of the Fc receptors; 2) inhibition of complement-mediated damage; 3) alteration of cytokine and cytokine antagonist profiles; 4) reduction of circulating antibodies via anti-idiotype antibodies; and 5) neutralization of toxins which trigger autoantibody production.⁴ In toxic epidermal necrolysis, IVIg blocks Fas (CD95) mediated keratinocyte death by inhibiting Fas – Fas ligand interactions.⁵

Use in Dermatology

The efficacy of IVIg is best documented in patients with graft-versus-host disease, Kawasaki’s disease and dermatomyositis; however, its utility in dermatology continues to grow.^6-8 A number of case series have found IVIg effective in the treatment of patients with pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane pemphigoid, herpes gestationis and epidermolysis bullosa acquisita (EBA).^9-16 A consensus statement was recently published on the use of IVIg in patients with autoimmune mucocutaneous blistering diseases.¹⁷ For autoimmune bullous disease the recommended guidelines for IVIg are as follows: 1) failure of conventional therapy; 2) significant adverse effects from conventional therapy; 3) contraindications, relative or absolute, to the use of high-dose long-term systemic therapy; 4) progressive disease despite conventional therapy; 5) uncontrolled, rapid debilitating disease; and 6) rapidly progressive EBA with generalized cutaneous involvement.¹⁷

The evidence for the use of IVIg in toxic epidermal necrolysis has been recently the subject of debate.^5,18-20 No consensus has been reached due to the lack of randomized clinical trials. The anecdotal results differ from one center to another. Yet, IVIg remains commonly used as initial therapy for toxic epidermal necrolysis. Current data are insufficient to recommend the routine administration of IVIg in patients with pyoderma gangrenosum, atopic dermatitis, chronic urticaria and Steven-Johnson syndrome.^21-25 For a review of the major clinical trials and larger case series, refer to Tables 1 and 2.

Table 1. A review of the major clinical trials and case series of IVIg in dermatology.

Table 2. Guidelines for use of IVIg in dermatology. Adapted from Bloody Easy.

Prior to starting IVIg therapy, complete blood cell counts, liver function and renal function studies are preformed. Immunoglobulin levels are measured to exclude IgA deficiency. In the absence IgA, or in the presence of low IgA, anti-IgA titers are ordered to minimize the risk of anaphylaxis. Screening for rheumatoid factor and cryoglobulins is recommended as these patients are at an increased risk of acute renal failure. In patients with compromised cardiac or renal function, IVIg must be carefully administered in order to prevent fluid overload. For medicolegal reasons, baseline testing for hepatitis B, C and the human immunodeficiency virus is advisable. Lastly, a small sample of serum should be stored for future analysis in the event of infectious disease transmission.^17,26

Premedications may be administered to minimize the risk of infusion-related side effects, such as headaches, myalgias and rigors. Analgesics (i.e., acetaminophen), nonsteroidal antiinflammatory agents (i.e., celecoxib), antihistamines (i.e., diphenhydramine) and even low-dose intravenous corticosteroids may be of benefit to a subset of individuals.¹⁷

In Kawasaki’s disease, IVIg is administered as a single 2g/kg infusion over 6-12 hours.⁷ For toxic epidermal necrolysis, a dose of 1g/kg for 3 consecutive days (i.e., total dose 3g/kg) appears most effective.¹⁹ In autoimmune disease, the published experience would suggest that the dose of 2g/kg per cycle is most valuable; however, clinical improvement has been noted with lower doses.¹⁷ A typical cycle consists of the total dose divided equally over 2-5 consecutive days (i.e., 1g/kg daily for 2 days, or 0.4g/kg daily for 5 days). As the half-life of IVIg ranges from 3-5 weeks, the infusions are given monthly until there is effective disease control. While the maintenance schedule for its use has not been adequately established, tapering the frequency of IVIg infusions may be useful in maintaining a disease-free state. Ahmed and Dahl have suggested that the intervals between infusions be increased from 4 to 6, 8, 10, 12, 14 and 16 weeks before discontinuing the IVIg therapy.¹⁷ The rate of IVIg infusion is dependent upon the product recommendations (Table 3).

Table 3. Comparison of the various IVIg preparations available in Canada.

Product Differences

IVIg is distributed by the Canadian Blood Services with the exception of Québec, where Hema Québec is the main distributor. There are four licensed IVIg preparations available in Canada (Table 3). While there are no studies which compare the safety and efficacy of the four products, there are some differences that may be clinically important.

Variability of the manufacturing processes may lead to differences in the marketed IVIg products. The use of additional production steps (i.e., stabilization, purification and/or pathogen safety) has the potential to impact negatively the biological activity and integrity of the IgG molecule, tolerability and yield. As shown in Table 3, IVIg preparations are available in both liquid and lyophilized formulations. While the lyophilized formulations require reconstitution, the liquid formulations are ready-to-use. If the lyophilized form is reconstituted to a higher than recommended concentration, the final osmolarity will be significantly increased above physiologic  levels. Moreover, the higher the concentration of the IVIg product, the less volume required for infusion. For example, a 70-kg individual receiving 1g/kg would require either 700ml of a 10% solution, or 1400ml of a 5% solution. In high-risk patients, such as those with cardiac or renal failure, these factors must be taken into consideration. In selecting the most appropriate IVIg for the patient, convenience, efficacy, safety and tolerability of the different products must be considered.

Safety

Adverse effects with IVIg are usually rare and self-limiting. Infusion-related side effects include: headache, flushing, chills, myalgias, low back pain, nausea, wheezing, chest pain, tachycardia and blood pressure changes.^1,26 These symptoms are generally mild and begin within 30-60 minutes of the infusion. If encountered, the symptoms are easily managed by slowing or temporarily discontinuing the infusion. If symptoms are anticipated, the patient may be premedicated with antihistamines or intravenous steroids.

Anaphylaxis has been reported in IgA-deficient patients with anti-IgA antibodies. As most IVIg preparations contain trace amounts of IgA, administration of IVIg may result in antigen-antibody complex formation.¹⁷ Aseptic meningitis, often presenting with headache and photophobia, occurs in up to 11% of patients treated with IVIg.^29,30 More common in patients with a history of migraines, aseptic meningitis may last several days. Both hematological and dermatological reactions (i.e., eczema, erythema multiforme, urticaria) have also been described.²⁶

Patients with cardiac or kidney disease must be closely followed to prevent fluid overload. Those receiving lyophilized formulations or sucrose containing products (US and Europe only) are at increased risk of renal failure as a result of osmotic injury to the proximal renal tubules.^17,26

An association between IVIg and thromboembolic events has been reported in the literature. Sugar-stabilized and hyperosmolar products may increase serum viscosity.³¹ The risk appears to be greater in the patients receiving high doses or rapid infusion rates. By lowering the dose and slowing the rate of infusion, the risk of thrombotic events may be minimized.³¹

While donors are carefully selected and screened to ensure pathogen safety, a number of viral inactivation methods are used as part of the IVIg manufacturing process. These include: physical inactivation steps (i.e., heat and pasteurization) and chemical inactivation steps (i.e., solvent/detergent, low pH, trypsin, pepsin and caprylate). Pathogens are removed by precipitation, chromatography and filtration techniques. In the Gamunex process, the combination of caprylate precipitation, cloth filtration and chromatography has further been shown to significantly reduce prion transmission.^3,32,33

Pharmacoeconomics

Over the years, there has been an increase in both the cost and utilization of IVIg in Canada. At an average cost of $70 CDN per gram, the pharmacoeconomic impact of IVIg is significant.²⁸ For a 70-kg pemphigus patient receiving IVIg at a dose of 2g/kg, the cost for one cycle amounts to $9,800 CDN. As the average number of cycles required is 18, the total drug bill approaches $176,400 CDN.¹⁵ With an incidence of 1 per 100,000 population, the overall cost for the Canadian health care system exceeds $52 million CDN.

In toxic epidermal necrolysis, a 70-kg patient would receive 1g/kg for three consecutive days, amounting to an overall drug cost of $14,700 CDN. At an estimated annual incidence of 1 per million population, an aggregate cost for Canada is projected at over $400,000 CDN. Laboratory expenses, nursing costs and hospital expenditures must also be considered when determining the economic impact of IVIg. These costs must be balanced against improvement of symptoms and quality of life, reduced costs of conventional therapy, decreased complications, fewer hospital admissions and time off work.

Conclusion

IVIg has become increasingly recognized as a safe, effective therapy for a number of dermatological conditions. The cost impact of this medication is potentially large if the list of indications continues to expand. Formal pharmacoeconomic, burden of illness studies and collaborative clinical trials are required to further explore the role of IVIg in dermatology.

References

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