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Revisiting Cyclosporine in the Age of Biologics: Update on Efficacy and Mechanism of Action Increased understanding of the immunologic basis of supports the role of cyclosporine in patient management. By Tina Bhutani, MD; Kristine Busse, BS; and John Koo, MD

ur understanding of the immunological basis of cyclosporine in animal models.3,4 Three years later, psoriasis and the ability to treat this disease cyclosporine A was used experimentally in transplant with immunosuppressants has greatly expand- patients to prevent graft rejection, and it was in these Oed in the past few decades. With respect to the trials that Muller reported improvement of lesions in pathogenesis of psoriasis, the entire refocusing from transplant patients who happened to have psoriasis.2 hyperproliferation to immunology start- Following this discovery, further research led to a pre- ed with the serendipitous discovery that immune liminary understanding of the mechanism of action of modulating agents, namely cyclosporine, led to unde- cyclosporine. niable and often dramatic psoriasis improvement with Cyclosporine permeates into target cells and no effect on keratinocyte reproduction.1,2 Eventually, binds to molecules known as the . This understanding the role of immunology in psoriasis combined with new knowledge of protein engineering techniques has given us the capability to manufacture Take-Home Tips. The use of older systemic agents, such as specific proteins that selectively alter the immunologi- cyclosporine, has fallen out of the limelight. Unlike newer agents, cal processes in psoriasis, leading to the advent of bio- cyclosporine produces a broad “upstream” anti-inflammatory effect on the logics. However, of the immunosuppressive agents, immune pathogenesis of psoriasis by blocking the activation of Th1 cells, cyclosporine remains one of the most efficacious Th17 cells, and TIP-dendritic cells. This leads to very good efficacy and agents available for the treatment of psoriasis. wider applicability in not only dermatology but also many other medical Cyclosporine was first extracted in 1969 from the specialties. Therefore, the merits of cyclosporine should be re-evaluated fungus Tolyplocadium inflatum Gams and in 1976 Borel in the age of biologics. ● reported immunosuppressive properties of

28 | Practical Dermatology | July 2010 Revisiting Cyclosporine

Fig. 1. Fig. 2.

cyclosporine- complex binds Studies to Date (a calcium-dependent serine/threonine phos- We performed a literature search for in vitro studies, phatase), preventing nuclear factor of activated T in vivo studies, clinical trials, randomized control tri- cell (NFAT) dephosphorylation and thereby inacti- als, and review articles between 1984 and 2010. The vating the transcription factor NFAT.5-7 Because key word cyclosporine was combined with mecha- NFAT dephosphorylation is essential for transcrip- nism of action, immunology, cytokines, and molecular tion of a number of cytokine genes, including IL-2, biology. We then searched for other off-label uses of IL-4, IFN-γ, and TNF-α, the “upstream” prevention cyclosporine. The search yielded over 65 articles, of of NFAT dephosphorylation suppresses the tran- which 51 were chosen for this review. The pertinent scription of these cytokines and inhibits activation data are reviewed here. of various T cells, B cells, and macrophages.8 Originally, psoriasis was thought to be mediated (Figure 1) mainly by the activation of Th1 cells. However, new Because of the central role of IL-2 in the process discoveries have revealed the importance of a new T- of naïve T-cell clonal expansion and mature T-cell cell subtype, Th17, in the development of autoim- activation, many earlier studies with cyclosporine mune diseases including psoriasis. Th17 cells are acti- focused on its suppression of this specific vated by the dendritic cell cytokine IL-23. They pro- cytokine5 (Figure 2). Impairment of IL-2 production duce IL-17, IL-22, and TNF, and have many other by cyclosporine has been clearly demonstrated in downstream pro-inflammatory effects (Figure 2). human, murine, feline, and guinea pig models.5, 9-11 Haider et al. profiled affected genes in skin biopsies of In addition, earlier studies have also shown that psoriasis patients receiving cyclosporine 4mg/kg/day.13 treatment with cyclosporine at low doses Greater than 95 percent of CSA- down regulated genes (2.5mg/kg or 5mg/kg) markedly reduced the num- were associated with pro-inflammatory cells and skin ber of cells expressing IL-2 receptor, thereby resident cells such as and fibroblasts. revealing another method by which it may down- Within two weeks of commencing treatment with regulate T-cell activation.12 However, newer find- cyclosporine, there was a strong inhibition of two ings have demonstrated an even broader effect on pathways. First, Th1-type activation was sup- the inflammatory immune pathogenesis. This pressed by decreased STAT1, IFN-γ, and several review article provides an update on cyclosporine’s downstream genes regulated by IFN-γ such as genes effect on the immune system and reviews its role for IL-12 and IL-4. Second, there was suppression of in the treatment of an entire spectrum of immune Th17 activation with decreased IL-17, IL-22, and mediated skin diseases. down regulated downstream genes including DEFB-

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Fig. 3. Comparing Approximate 12 Week Efficacy Data Fig. 4. Effects of Cyclosporine on the Immune System

2, LCN-2, CXCL1, and CCL20. Hence, this study sug- Discussion gests that the effects of cyclosporine on the immune With the advent of new, targeted agents for the treat- system go well beyond the suppression of IL-2 and ment of psoriasis, the focus on older immunosuppres- the Th1 mediated pathway, but also suppress the sant agents such as cyclosporine has diminished. Th17 pathway.13 However, clinical study results suggest cyclosporine to Interestingly, the authors of this same study also be higher in efficacy than many of the biologic detected a significant suppression of dendritic cell agents. In a randomized, double blind study by Koo genes during cyclosporine treatment.14 Dendritic in 1998, 309 patients with severe, chronic plaque-type cells were strongly reduced, with decreased CD83 psoriasis were randomized to receive either Neoral cell surface protein expression as well as multiple (Novartis) or Sandimmune (Novartis) starting at a gene products associated with dendritic cell matura- mean dose of 2.5mg/kg/day for 24 weeks with dose tion. More specifically, cyclosporine suppressed key escalation as needed after four weeks of treatment. inflammatory products of TNF/iNOS producing den- By week 12, 80.3 percent of patients in the Neoral dritic cells (TIP-DC), a newly recognized population group (n=152) and 78.2 percent in the Sandimmune of inflammatory dendritic cells in psoriasis. These group (n=157) achieved PASI-75. No average dose CD11c+ myeloid-derived dendritic cells produce was reported, but 90 percent of patients attaining pro-inflammatory cytokines including IL-20, IL-23, PASI 75 were able to do so at a dose of less than TNF, and iNOS (inducible nitric oxide synthase) and 3.5mg/kg/day.16 activate epidermal keratinocytes.15 In psoriasis, The results from most clinical trials with the bio- cyclosporine decreased genomic expression of IL-23, logics reveal lower efficacy results than cyclosporine. TNF, and iNOS. In fact, the genes of the TIP-DC In a study with alefacept (Amevive, Astellas), 21 per- pathway correlated best with disease remission cent of patients achieved PASI 75 at week 14 with a when the entire treatment period was considered.13 dose of 15mg/week for 12 weeks.17 Lastly, the authors note no effects of (Enbrel, Amgen/Pfizer) in a phase III trial for 12 cyclosporine on gene expression in the blood in weeks showed PASI-75 in 49 percent of patients when contrast to the above findings from skin biopsies. used 50mg twice weekly and 34 percent when used Hence, although there was a strong inhibition of 25mg twice weekly.18 In another pivotal phase III pro-inflammatory cytokines in the skin, this was study, 67.7 percent of patients at week 12 treated not correlated with suppression of these cytokines with the currently approved dosing for in peripheral circulation. (Humira, Abbott) achieved PASI-75.19 In a phase III,

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randomized, double blind study, 80 percent of Table 1. Uses of Cyclosporine patients receiving (Remicade, Centocor Ortho Biotech, Inc.) 5mg/kg at weeks 0, 2, and 6 Dermatology achieved PASI 75 at week 10.20 The newest biologic Psoriasis Atopic Dermatitis agent, (Stelara, Centocor Ortho Biotech, Lichen Planus Lichen Nitidus Inc.), in one phase III trial showed PASI 75 response Contact Dermatitis Actinic reticuloid at week 12 in 67.1 percent of patients receiving the Photosensitive Dermatitis Solar Urticaria 45mg dose and in 66.4 percent of patients receiving Pyoderma Gangrenosum Sweet’s Disease the 90mg dose.21 Another larger phase III trial with Chronic Idiopathic Urticaria Autoimmune Pemphigus the same agent showed PASI-75 in 66.7 percent of Bullous Pemphigoid Erythema Multiforme patients receiving 45mg and 75.5 percent of patients Toxic Epidermal Necrolysis Herpes Gestationis receiving 90mg.22 Hence, among newer biologic Dermatitis Herpetiformis Epidermolysis Bullosa Acquisita agents, only infliximab (80 percent) has reached the Darier’s Disease Hailey-Hailey Disease reported efficacy of moderate dose cyclosporine (80.3 Systemic Lupus Erythematosus Discoid Lupus Erythematosus percent) (Figure 3). Dermatomyositis Cutaneous Necrotizing Vasculitis Cyclosporine’s effective immunosuppressive action Behcet’s Disease Generalized Granuloma Annulare is also evidenced by its treatment of a wide range of Dystrophic Epidermolysis Bullosa Pityriasis Lichenoides Chronica immune mediated diseases. An extensive literature Lichen Myxedematosus Eosinophillic Fasciitis search revealed effective treatment with cyclosporine Alopecia Areata Prurigo Nodularis 23-44 in over 50 different disease processes. (Table 1) Of Other note, in addition to psoriasis, there are 32 other der- Psoriatic Arthritis Wegener’s Granulomatosis matologic uses of cyclosporine including severe atopic Myocarditis Primary Biliary dermatitis,30 pyoderma gangrenosum,26 refractory Asthma Amyotrophic Lateral Sclerosis lichen planus,27 and many bullous skin disorders.28,29 Grave’s Ophthalmopathy Crohn’s Disease On the other hand, the use of biologic agents is cur- Uveitis Rheumatoid Arthritis rently limited to only a few diseases, including Nephrotic Syndrome Aplastic Anemia rheumatoid arthritis, Crohn’s disease, ankylosing Ulcerative Colitis Multiple Sclerosis spondylitis, and juvenile idiopathic arthritis in addi- Myasthenia Gravis Diabetes Mellitus Type 1 tion to psoriasis and psoriatic arthritis. Successful der- Chronic Demyelinating Retinal Vasculitis matologic off-label uses for biologics have been simi- Polyneuropathy Organ Transplant Rejection larly limited to hidradinitis suppurativa, Hailey-Hailey Scleritis disease, pyoderma gangrenosum, systemic lupus ery- thematosus, and Behcet’s diseas.45,46 From the new immunological findings presented appears to affect the activation of the three major above, this superior efficacy and wider clinical appli- players in the immunology of psoriasis—Th1 cells, cability may be explained by the broader effect of Th17 cells, and TIP dendritic cells—in contrast to bio- cyclosporine on the immune pathogenesis. Unlike the logic agents that block only the products of these targeted biologic agents that inhibit only one or, at cells. This, for cyclosporine, produces a broader effect most, two specific cytokines, cyclosporine leads to the on the immune system and a subsequent superior down-regulation of multiple immune mediators clinical response compared to the relatively focused (Figure 4). In addition, its strong inhibition of IL-2 action of the biologic agents. and down-regulation of IL-2 receptor gene transcrip- tion leads to an “upstream” blockade of the immune Conclusion cascade in contrast to TNF inhibitors that produce a The biologics have taken the center stage for psoriasis more “downstream” blockade. Lastly, cyclosporine treatment in the past few years. With this, the use of

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older systemic agents such as cyclosporine has fallen 19. Gordon K, Langley, RG, Leonardi, C, et al. Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: double-blind randomized trial and open-label out of the limelight. However, unlike newer agents, extension study. J Am Acad Dermatol. 2006;55:598-606. cyclosporine produces a broad “upstream” anti- 20. Reich K, Nestle, F, Papp, K, et al. Infliximab induction and maintenance therapy for mod- erate to severe psoriasis: a phase III, multicentre, double blind trial. Lancet. 2005;366:1367- inflammatory effect on the immune pathogenesis of 1374. psoriasis by blocking the activation of Th1 cells, Th17 21. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human /23 monoclonal , in patients with psoriasis: 76-week results from a cells, and TIP-dendritic cells. This leads to very good randomised, double blind, placebo controlled trial (PHOENIX 1). Lancet. efficacy and wider applicability in not only dermatol- 2008;371(9625):1665-1674. 22. Papp K, Langley, RG, Lebwohl, M, et al. Efficacy and safety of ustekinumab, a human ogy but also many other medical specialties. interleukin 12/23 , in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. Therefore, we suggest that the merits of cyclosporine 2008;371(9625):1675-1684. ✔ be re-evaluated in the age of biologics. ■ ❑ 23. Powles A, Baker, BS, Valdimarsson, H, et al. Four years experience with cyclosporine A for psoriasis. Br J Dermatol. 1990;122(suppl 36):13-19. 24. Capella GL, Casa-Alberighi OD, Finzi AF. Therapeutic concepts in clinical dermatology: Dr. Bhutani and Ms. Busse have no financial conflicts of inter- cyclosporine A in immunomediated and other dermatoses. International Journal of est to report. 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Off-label uses of biologics in dermatology: , cept in psoriasis: safety, efficacy, and effect of dose reduction Br J Dermatol. 2005;152:1304- , infliximab, etanercept, adalimumab, , and alefcept (Part 2 of 2). J Am 1312. Acad Dermatol. 2007;56:55-79.

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