Developments in systemic immunomodulatory therapy for psoriasis

Developments in systemic immunomodulatory therapy for psoriasis Emily M Berger and Alice B Gottlieb Psoriasis is an inflammatory skin condition that can be accompanied by joint disease. Pre-biological and biological systemic therapies are effective. Dermatologists have used systemic immunomodulators including methotrexate to treat moderate-to-severe disease for over 30 years. Pre-biological agents have toxicities and side effects that can be difficult to tolerate and require frequent monitoring. Beginning with alefacept in 2003, several biologics including cell-adhesionmolecule antagonists and cytokine antagonists such as tumor necrosis factor-blockers gained approval for psoriasis. They greatly advanced our understanding of psoriasis pathogenesis. Because they are so new, their safety is not established. Tumor necrosis factor-blockers have controversial associations with certain cancers and infections. Biologics require clinical monitoring and have specific contraindications. Scientists are exploring several new therapeutic targets. Addresses Department of Dermatology, Tufts-New England Medical Center, Tufts University School of Medicine, Tufts-NEMC Box #114, 750 Washington Street, Boston, MA 02111, United States Corresponding author: Berger, Emily M ([email protected])

Current Opinion in Pharmacology 2007, 7:434–444 This review comes from a themed issue on Immunomodulation Edited by Gordon Duff and Anthony G Wilson Available online 12th July 2007 1471-4892/$ – see front matter # 2007 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2007.06.002

Introduction Psoriasis is a common dermatologic indication for immunomodulatory therapy. It is a chronic immune-mediated disease often characterized by pruritic, well-demarcated erythematous, and scaling plaques. Over one third of patients have psoriatic arthritis (PsA). Moderate-to-severe psoriasis (determined by the extent and severity of skin disease and/or ‘quality of life considerations’) requires phototherapy or systemic therapy [1]. This review summarizes the past 2–5 years of developments regarding mechanism, efficacy, and safety of selected pre-biological and biological systemic immunomodulatory therapies currently approved or used off-label for psoriasis treatment. The highest level of evidence is discussed, emphasizing randomized, double-blind, placebo-controlled Current Opinion in Pharmacology 2007, 7:434–444

trials (RDBPCTs) where available, including phase III trials of the biological therapies, for which psoriasis is the only approved dermatologic indication (Tables 1 and 2).

Pre-biological systemic therapies FDA/EMEA-approved therapies

Methotrexate Methotrexate (MTX) is an antimetabolite agent that inhibits dihydrofolate reductase to disrupt folate metabolism for the synthesis and repair of DNA [2]. It is indicated for solid tumor and hematologic cancer chemotherapy, rheumatoid arthritis (RA) or polyarticular juvenile RA, and severe psoriasis. In psoriasis, oral MTX is increased slowly per clinical effect and patient-tolerance by 2.5–5.0 mg [3] up to 25–30 mg total weekly dose [2]. The mechanism by which MTX improves psoriasis may be separate from effects on folate metabolism [4,5]. No RDBPCTs have evaluated the efficacy and safety of MTX for psoriasis. How MTX compares with placebo can be extrapolated from a phase III study of the TNFblocking antibody adalimumab [J Saurat et al., poster, 15th Congress of EADV, Rhodes, Greece, October 2006]. The study’s three treatment arms included the following: oral (PO) placebo with subcutaneous (SC) adalimumab; PO MTX with SC placebo; and PO placebo with SC placebo. Methotrexate doses ranged from 7.5 mg/week at weeks 0–1 to 25 mg/week at weeks 12–15. At week 16, 18.9% of placebo-treated patients as compared with 35.5% of MTX-treated patients achieved at least a 75% improvement in psoriasis area and severity index (PASI) score (i.e. a PASI-75 response) (Table 1). Infections occurred in 41.8 and 43.4% of patients in the MTX and placebo groups, respectively. Adverse events (AEs) in the MTX group leading to treatment withdrawal included optic neuritis and liver function test (LFT) elevations with symptomatic hepatitis. Previously reported side effects in patients with inflammatory diseases include cirrhosis, bone marrow suppression, nausea, and pneumonitis [2]. Methotrexate is a category X drug, meaning that it is contraindicated in pregnant females with inflammatory diseases because it causes fetal death and teratogenic effects [2]. The risks in a pregnant woman exceed any potential therapeutic benefits. Folic acid (FA) supplementation of 1–5 mg PO daily may abate potential side effects (i.e. nausea and anemia) from MTX [3]. In an RDBPCT specific for psoriasis patients, FA supplementation of 5 mg PO daily reduced the efficacy of MTX therapy over 12 weeks in 22 adult patients www.sciencedirect.com

Developments in systemic immunomodulatory therapy for psoriasis Berger and Gottlieb 435

Table 1 Efficacy data for selected FDA/EMEA-approved immunomodulatory therapies for moderate-to-severe psoriasis Drug

FDA/EMEA approval of the agent

Trial design

Methotrexate (MTX)

1970s

Randomized, double-blind, placebocontrolled comparison of adalimumab vs. MTX or placebo

Three treatment arms were compared: (1) adalimumab: PO placebo + adalimumab 40 mg SC every other week; (2) MTX: MTX 7.5–25 mg PO weekly + SC placebo; (3) placebo: PO placebo + SC placebo for 16 wks

PASI-75 = 35.5% (MTX), 79.6% (adalimumab), 18.9% (placebo) at wk 16 (P < 0.001 for adalimumab vs. placebo, adalimumab vs. MTX)

J Saurat, 2006; N = 271 (N = 108 in adalimumab, N = 110 in MTX, N = 53 in placebo)

Cyclosporine (CsA)

1997

Randomized, multidose, double-blind, placebocontrolled trial

CsA 3.0, 5, or 7.5 mg/kg PO divided BID vs. placebo for 16 wks (dose adjustment per safety/efficacy at wk 8)

‘Clear’ or ‘almost clear’ = 36% (3 mg/kg)a, 65% (5 mg/kg)a, 80% (7.5 mg/kg)a, 0% (placebo) at wk 8

C Ellis, 1991; N = 85

CsA vs. MTX

N/A

Randomized, uncontrolled comparison of MTX and CsA

Cyclosporine 3.0–5.0 mg/ kg/day vs. methotrexate 15–22.5 mg/week for 16 wks

‘Partial remission’ (PASI-75) = 60% (MTX), 71% (CsA) at wk 16 (P = 0.55) ‘Complete remission’ (PASI-90) = 40% (MTX), 33% (CsA) at wk 16 (P = 0.29)

V Heydendael, 2003; N = 88

Acitretin

1980s

Randomized, multidose, double-blind, placebocontrolled trial (1st 8 wks)

Acitretin 10, 25, 50, or 75 mg PO daily vs. placebo for 1st 8 wks

Change in % BSA affected = 3% more BSA (10 mg), 3.2% more BSA (25 mg), 5.5% less BSA (50 mg), 17.4% less BSA (75 mg)b, 0.8% more BSA (placebo) at wk 8

M Goldfarb, 1988; N = 38

Alefacept

2003

Randomized, double-blind, placebocontrolled phase III trial

Alefacept 15 mg IM weekly, alefacept 10 mg IM weekly, or placebo weekly for 12 wks ! 12-wk follow-up

PASI-75 = 33% (15 mg)c, 28% (10 mg)c, 13% (placebo). Note: reported PASI-75 is over 24 weeks (12 wks treatment and 12 wks follow-up)

M Lebwohl, 2003; N = 507

Efalizumab

2003

Randomized, double-blind, placebocontrolled phase III trial Randomized, double-blind, placebocontrolled phase III trial

Efalizumab 0.7 mg/kg SC ‘conditioning dose’  1 wk ! 1 mg/kg SC weekly  11 wks vs. placebo weekly for 12 wks First treatment (wk 0–wk 12): placebo vs. efalizumab (2 mg/kg SC or 1 mg/kg SC) weekly ! extended treatment (wk 13–wk 24): placebo vs. efalizumab 2 mg/kg SC weekly, 2 mg/kg SC every other week, or 4 mg/kg SC weekly depending on first treatment response ! observation (wk 25–wk 36) Efalizumab 0.7 mg/kg SC ‘conditioning dose’  1 wk ! 1 mg/kg SC or 2 mg/kg SC weekly for 11 wks vs. placebo weekly for 12 wks

PASI-75 = 27% (efalizumab), 4% (placebo) at wk 12 (P < 0.001 vs. placebo)

K Gordon, 2003; N = 556

PASI-75 = 22% (1 mg/kg)c, 28% (2 mg/kg)c, 5% (placebo) at wk 12. Note: PASI-75 at wk 24 = 77% (2 mg/kg weekly), 78% (2 mg/kg every other week), 20% (placebo)

M Lebwohl, 2003; N = 597

PASI-75 = 39% (1 mg/kg)c, 27% (2 mg/kg)c, 2% (placebo) at wk 12

C Leonardi, 2005; N = 498

PASI-75 = 31.4% (efalizumab), 4.2% (placebo) at wk 12 (P < 0.0001 vs. placebo)

L Dubertret, 2006; N = 793 (includes 526 ‘high need’ patients who could not be on an alternate systemic therapy)

Randomized, double-blind, placebocontrolled phase III trial (1st 12 wks) Randomized, double-blind, placebocontrolled phase III trial

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Dose

Efalizumab 0.7 mg/kg SC ‘conditioning dose’  1 wk ! 1 mg/kg SC weekly  11 wks vs. placebo weekly for 12 wks

Efficacy (at primary endpoint)

Reference

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436 Immunomodulation

Table 1 (Continued ) Drug

FDA/EMEA approval of the agent

Etanercept

2004

Trial design

Randomized, double-blind, placebocontrolled phase III trial

Randomized, double-blind, placebocontrolled phase III trial

Randomized, double-blind, placebocontrolled phase III trial

Infliximab

2006

Randomized, double-blind, placebocontrolled phase III trial

Randomized, double-blind, placebocontrolled phase III trial

Dose

Efficacy (at primary endpoint)

Reference

Induction: placebo vs. etanercept 25 mg or 50 mg SC BIW x 12 wks ! Maintenance: etanercept 25 mg SC BIW  12 wks Induction: placebo vs. etanercept 25 mg SC weekly, 25 mg SC BIW, or 50 mg SC BIW  12 wks ! Maintenance: original dose etanercept  12 wks (placebo group received etanercept 25 mg SC BIW) Placebo vs. etanercept 50 mg SC BIW  12 wks

PASI-75 = 49% (50 mg BIW)a, 34% (25 mg BIW)a, 3% (placebo) at wk 12. Note: PASI-75 at wk 24: 54% (original 50 mg cohort), 45% (original 25 mg cohort), 28% (original placebo cohort) PASI-75 = 49% (50 mg BIW)c, 34% (25 mg BIW)c, 14% (25 mg weekly)c, 4% (placebo) at wk 12. Note: PASI-75 at wk 24: 59% (50 mg BIW), 44% (25 mg BIW), 25% (25 mg weekly)

PASI-75 = 47% (etanercept), 5% (placebo) at wk 12 (P < 0.0001 vs. placebo). Significant improvement in depression measures at wk 12 (P = 0.0012 vs. placebo) and mean improvement in fatigue measures at wk 12 (P < 0.0001 vs. placebo)

S Tyring, 2006; N = 618

Induction: placebo vs. infliximab 5 mg/kg IV at wks 0, 2, 6 ! Maintenance: placebo vs. infliximab 5 mg/kg IV every 8 wks to wk 46 (placebo group received infliximab 5 mg/kg induction and maintenance starting at wk 24) Induction: placebo vs. infliximab 3 mg/kg or 5 mg/kg IV at wks 0, 2, 6 ! Maintenance: infliximab 3 mg/kg or 5 mg/kg IV every 8 wks or PRN to wk 50 (placebo group received infliximab 5 mg/kg induction and maintenance starting at wk 16)

PASI-75 = 80%a ! 82%a ! 61% (infliximab), 3% ! 4% ! N/A (placebo) at wk 10 ! wk 24 ! wk 50. Note: decreased efficacy in infliximab group over time was associated with antibody production and decreased drug levels PASI-75 = 70.3% (3 mg/kg)c, 75.5% (5 mg/kg)c, 1.9% (placebo) at wk 10. Note: PASI-75 = 43.8% (3 mg/kg continuous), 25.4% (3 mg/kg PRN), 54.5% (5 mg/kg continuous), 38.1% (5 mg/kg PRN) at wk 50

K Reich, 2005; N = 378

K Papp, 2005; N = 583

C Leonardi, 2003; N = 652

A Menter, 2006; N = 835

BID, twice a day; BIW, twice a week; IM, intramuscular injection; IV, intravenous infusion; Mo(s), month(s); PO, oral administration; PRN, administered as needed; SC, subcutaneous injection; Wk(s), week(s). P < 0.0001 vs. placebo. b P = 0.03 vs. placebo. c P < 0.001 vs. placebo. a

[6]. Such supplementation may thus require higher MTX doses. Influence on side effects was inconclusive, but FA appeared to reduce the risk of myelosuppression [6]. Cyclosporine

Cyclosporine (CsA) is a calcineurin inhibitor indicated to prevent rejection of solid organ transplants, to treat severe RA with or without MTX, and to treat adults with severe psoriasis [7]. In psoriasis, CsA inhibits keratinocyte hyperproliferation and dampens T cells’ transcription of cytokines including IL-2, which is essential for activation and Current Opinion in Pharmacology 2007, 7:434–444

proliferation of helper T cells [8]. Oral doses of 2.5– 5.0 mg/kg are divided twice daily to treat psoriasis [9]. There are dose-dependent risks of nephrotoxicity and hypertension that warrant frequent monitoring (Table 3) [9]. Psoriasis patients have experienced increased incidences of lymphoma and skin cancer, hyperlipidemia, gum hypertrophy, and paresthesia or hyperesthesia [7]. One of the larger RDBPCTs investigating the efficacy and safety of CsA for moderate-to-severe psoriasis was published in 1991 [10]. At 8 weeks, 36, 65, and 80% of www.sciencedirect.com

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Table 2 Efficacy data for selected immunomodulatory therapies used off-label or in development for moderate-to-severe psoriasis Drug

Trial design

Dose

Efficacy at primary endpoint

Reference

Mycophenolate mofetil (MMF)

Open-label, prospective study

MMF 1 g PO BID up to 3 g PO daily  12 weeks

PASI-75 = 22% (4 patients) PASI-50 = 61% (11 patients) at wk 12 Reduction in mean PASI score from baseline = 24% (wk 6), 47% (wk 12) (P < 0.001 from baseline)

Y Zhou, 2003; N = 23 (18 patients completed the study)

Adalimumab

Randomized, double-blind, placebo-controlled phase III trial (see also Table 1 for phase III trial results)

Three treatment periods, 1st treatment period (1) wk 0–wk 16 (initial response): adalimumab 40 mg SC every other week vs. placebo

PASI-75 = 71% (adalimumab), 6.5% (placebo) at wk 16 (P < 0.001 vs. placebo)

A Menter, 2007; N = 1212

patients receiving daily CsA 3, 5, and 7.5 mg/kg, respectively, were ‘clear’ or ‘almost clear’ of skin lesions compared with no placebo patients (P < 0.0001) (Table 1) [10]. Improvements were evident by 2 weeks of therapy [10]. Adverse events including decreases in glomerular filtration rate and elevations in blood pressure, serum uric acid, bilirubin, and cholesterol levels increased with higher CsA doses [10]. Acitretin

Psoriasis is the only approved indication for acitretin, a systemic retinoid [11]. Retinoids attach to specific receptors in the skin to influence keratinocyte differentiation and inflammation [12]. For example, retinoic acid can block production of vascular endothelial growth factor (VEGF) by keratinocytes to decrease angiogenesis and inflammation [13]. Genetic polymorphisms in VEGF may influence one’s response to acitretin [13]. As monotherapy, acitretin 25–50 mg PO daily is administered with food [11]. In the largest RDBPCT (conducted in 1988), only patients receiving 75 mg acitretin daily over 8 weeks improved significantly compared with placebo (Table 1) [14]. Adverse events including mucocutaneous effects and alopecia increased with dose, and some patients experienced elevated serum lipids and LFTs [14]. Acitretin is a category X drug that causes major birth defects and is thus contraindicated during pregnancy [11]. It should be used with caution in women of childbearing potential, who must have two negative pregnancy tests before initiating therapy and must agree to use two methods of birth control while taking acitretin and for 3 years after discontinuing its use (Table 3) [11]. Psoriasis patients have experienced mucocutaneous side effects (i.e. cheilitis, hair loss), hyperlipidemia, and musculoskeletal AEs [11]. Dermatologists administer lower acitretin doses in combination with alternate systemic therapy or photo(chemo)therapy. For example, acitretin and ultraviolet B (UVB) phototherapy or psoralen plus ultraviolet www.sciencedirect.com

A (PUVA) photochemotherapy act synergistically to treat moderate-to-severe psoriasis while allowing smaller doses and fewer side effects, including less photodamage from UV light [15]. Off-label use of mycophenolate mofetil

Mycophenolate mofetil (MMF) is approved to prevent rejection of solid organ transplants. The liver converts MMF to mycophenolic acid, which inhibits inosine monophosphate dehydrogenase, an enzyme for de novo purine synthesis [16]. Thus, MMF halts nucleic acid production by cells including T lymphocytes and B lymphocytes [16]. Although MMF is used off-label to treat psoriasis, no RDBPCTs have evaluated it for psoriasis. Eighteen patients completed one of the larger prospective, open-label trials [17]. A PASI-75 response was achieved in 22% (four patients) at 12 weeks of up to 3 g MMF daily (Table 2) [17]. Side effects included nausea (five patients), periorbital edema and pruritis (one patient), and transient leucopenia (one patient) [17]. Three patients discontinued treatment for lack of effect, one patient for angioedema, and one for an unrelated cause [17].

Biologics In psoriasis, biologics are recombinant proteins, either monoclonal antibodies or fusion proteins, produced in living cell systems to target and block particular pathogenic cells or immune mediators [18]. Two classes of biologics used to treat psoriasis or PsA are ‘cell-adhesionmolecule antagonists’ and ‘cytokine antagonists’ [8]. Cell-adhesion-molecule antagonists: targeting the pathogenic T cell Alefacept

Alefacept (Amevive1, Biogen Idec, Inc., Cambridge, MA) was the first biologic to be FDA/EMEA-approved for moderate-to-severe psoriasis. This dimeric fusion protein joins the Fc fragment of human IgG1 with the Current Opinion in Pharmacology 2007, 7:434–444

438 Immunomodulation

extracellular region of LFA-3 to bind CD2 on T cells [19]. T lymphocyte counts, specifically CD4+ T cell counts can be reversibly decreased during therapy [20]. In phase III trials, there was no correlation between decreases in

CD4+ T cell counts and the incidence of infections [20,21]. In a randomized trial, patients mounted a proper immune response to vaccination with a bacteriophage and a tetanus booster [22].

Table 3 Clinical monitoring and contraindications for selected non-biological systemic therapies (based on prescribing information and clinical experience) Drug

Baseline assessments

Follow-up labs

Follow-up procedures

Contraindicated or precautionary conditions

Selected concomitant medication precautions/ contraindications a

Methotrexate (MTX)

CBC with differential, LFTs, renal function, hepatitis virus serology, pregnancy test, PPD, liver biopsy (selected patients) b

CBC, weekly until MTX dose is stable, then monthly; LFTs, every 4–12 wks; renal function, every 3–4 mos [3]; pregnancy test, monthly

Liver biopsy every 1.5 g cumulative dose c

-Pregnancy category X: contraindicated in women who are pregnant or nursing; men planning to father a child -Liver disease -Cytopenia(s) -Serious infections -Renal disease [2]

-TMP/SMX (bone marrow toxicity) -Sulfonamides, phenytoin, salicylates (toxicity by displacing MTX from albumin) -Tetracycline, chloramphenicol, broad spectrum antibiotics (decrease intestinal absorption of MTX) -Penicillins (MTX toxicity) -Nonsteroidal antiinflammatories, probenecid (reduced tubular secretion of MTX) -Hepatotoxins: ethanol, azathioprine, retinoids, sulfasalazine -Decreased clearance of theophylline [2]

Cyclosporine (CsA)

Renal function (x2), blood pressure (x2), ageappropriate and skin cancer screening, LFTs, serum potassium, lipids, uric acid, bilirubin, magnesium [9]

Renal functiond, every Blood pressure, every 2 wks  6 2 wks  2 mos ! wks ! monthly [9] monthly; lipids, magnesium, every 6 mos [9]

-Malignancy -Kidney disease/abnormal kidney function -Hypertension, especially if uncontrolled -Immunodeficiency -Serious infection -Diabetes -Obesity -Elderly -Pregnancy category C [9] -No live vaccinations during therapy [7]

-MTX (MTX toxicity) -Photo(chemo)therapy (skin cancer risk) -Grapefruit juice, calcium channel blockers, systemic antifungals, macrolide antibiotics, methylprednisolone, metoclopramide, amiodarone, oral contraceptive pills, allopurinol (inhibit cytochrome P450 metabolism) -Antiepileptics, barbiturates, octreotide, rifampicin, St. John’s wort (induce P450 metabolism) -Nonsteroidals, aminoglycosides, ciprofloxacin, amphotericin-B, H2 antagonists, trimethoprim, melphalan (nephrotoxicity) -Potassium-sparing drugs (hyperkalemia) [7] -Increases the toxicity of digoxin, prednisolone, colchicine [9], statins [7]

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Developments in systemic immunomodulatory therapy for psoriasis Berger and Gottlieb 439

Table 3 (Continued ) Drug

Acitretin

Baseline assessments

Follow-up labs

LFTs, fasting lipids, blood LFTs, every month sugar, 2 pregnancy tests until dose is stable, (must be negative) [11] then every 3 mos; fasting lipids, every month until clinically stable, then every 3 mos; pregnancy test, monthly [11]

Mycophenolate CBC, pregnancy test mofetil (MMF) (must be negative) [16], renal function

Follow-up procedures

History and clinical exam for hyperostosis with follow-up X-ray if an abnormality is detected on longterm therapy [11]

CBC, weekly  1 mo ! every 2 wks  2 mos ! monthly  1 year [16]; Pregnancy test, monthly

Contraindicated or precautionary conditions

Selected concomitant medication precautions/ contraindications a

-Hypersensitivity -Pregnancy category X: females should not become pregnant for 3 years after discontinuing therapy (see text) -Caution against initial worsening of psoriasis, depressive symptoms, decreased night vision -Blood donation is contraindicated during therapy and for 3 years after [11]

-Ethanol (influences metabolism to etretinate that is stored in fat) -MTX (hepatotoxicity) -Tetracyclines (increased intracranial pressure) -Vitamin A (hypervitaminosis A) -Decreases protein binding of phenytoin -Decreases efficacy of ‘minipill’ contraceptive [11]

-Hypersensitivity to agent or components -Pregnancy category C: females should not become pregnant during therapy or for 6 weeks after discontinuing therapy -HGPRT deficiency (Lesch– Nyhan or Kelley–Seegmiller syndromes) -Serious, active digestive system disease (GI bleeding risk) -Caution in renal insufficiency -Caution against sun exposure (skin cancer risk) -Live vaccinations are contraindicated during therapy [16]

-Immunosuppressants (caution against cancer and infection) -Azathioprine (bone marrow suppression) -Acyclovir, ganciclovir (mutually increased concentrations) -Cholestyramine (decreases enterohepatic recirculation) -Antacids (decrease MMF absorption) -Efficacy of oral contraceptives may be decreased [16]

CBC, complete blood count; PPD, purified protein derivative (tuberculosis (TB) skin test). Please see an updated reference before prescribing concomitant medications [9]. b Patients requiring a baseline liver biopsy have risk factors for liver disease, including excessive ethanol consumption, persistently abnormal LFTs, history of liver disease (including hepatitis B or C virus), family history of liver disease, diabetes, obesity, history of hepatotoxic drug/chemical exposure [3]. c In Europe, measurement of procollagen III aminopeptide in the serum is emerging as a tool to monitor for liver toxicity in patients with psoriasis receiving long-term MTX therapy [56]. d If a patient is on CsA for more than 1 year, check yearly renal function. In general, rises in serum creatinine or blood pressure may require dose adjustments or discontinuation of CsA [7]. a

In clinical practice, alefacept is administered as weekly intramuscular injections of 15 mg for 12 weeks [19]. With this administration of alefacept in a phase III trial, 21% of patients experienced a PASI-75 response after 12 weeks of treatment and 2 weeks of follow-up [21]. As demonstrated in phase III trials, psoriasis improves slowly, and improvement continues after a full course of alefacept [20,21]. Alefacept enacts disease remission, allowing periods of clearance without continuing therapy [21]. Among approximately 2000 patients in 13 clinical trials, less than 1% of patients acquired a serious infection [23]. With up to nine courses of alefacept over an average of 5 www.sciencedirect.com

years, headache, upper respiratory tract infection (URI), and pruritus were the most common AEs [23]. Alefacept demonstrated efficacy and safety in elderly, obese, and diabetic patients [24]. Efalizumab

Efalizumab (Raptiva1, Genentech, Inc., San Francisco, CA) is a humanized monoclonal antibody that recognizes the CD11a subunit of the LFA-1 adhesion molecule on T cells [25]. It prevents communication between LFA-1 and ICAM-1 during co-stimulation as well as T cell travel in the blood and skin [26]. Efalizumab prevents memory CD8+ T cells from entering the skin, thus peripheral lymphocytosis can occur [27]. Current Opinion in Pharmacology 2007, 7:434–444

440 Immunomodulation

Efalizumab is administered as a 0.7 mg/kg SC ‘conditioning dose’ with continued weekly self-injections of 1 mg/kg SC up to 200 mg [25]. An open-label trial demonstrated that efalizumab maintained efficacy without an increase in AEs over 36 months of continuous therapy [28]. In phase III clinical trials [29,30,31], including ‘high need’ patients who could not receive an alternate systemic therapy [32], 22–39% of patients achieved a PASI-75 response in 12 weeks (Table 1). Transient flu-like symptoms were the most common AEs [29,30,31,32]. Monitoring should be performed for possible AEs including thrombocytopenia [31], initiation or flare of PsA [30,32], and worsening psoriasis (local breakouts or generalized flares of inflammatory lesions) (Table 4) [30,31,32]. One should not abruptly discontinue efalizumab because psoriasis can rebound; ‘tapering’ or ‘transition’ to another antipsoriatic agent is recommended [30]. A clinical trial demonstrated that efalizumab is not an effective PsA treatment [KA Papp et al., poster, 10th International Psoriasis Symposium, Toronto Canada, 2004]. Cytokine antagonists: TNF blockade

Tumor necrosis factor alpha (TNFa) is a type 1 cytokine important in psoriasis, PsA, RA, ankylosing spondylitis (AS), Crohn’s disease (CD), and ulcerative colitis (UC) [33]. By activating nuclear factor kappa beta (NF-kb, a nuclear transcription factor), TNFa orchestrates inflammatory mediators including cytokines (i.e. IL-1, IL-8, and IL-6), chemokines, iNOS, and adhesion molecules [8,33,34]. Psoriasis plaques demonstrate elevated levels of TNFa and NF-kb [35]. TNF-blocking agents cleared psoriasis lesions in clinical trials, establishing that TNFa is central to psoriasis pathogenesis [36,37,38,39–42]. Approved agents: etanercept and infliximab Etanercept

The extracellular domains of a human TNF receptor and the Fc fragment of human IgG1 combine to form the soluble TNF receptor etanercept (Enbrel1, Amgen and

Wyeth Pharmaceuticals, Immunex Corporation, Thousand Oaks, CA) [43]. This dimeric fusion protein neutralizes two molecules of TNFa or TNFb/lymphotoxin [43]. Etanercept is indicated to treat psoriasis, juvenile RA and AS and to decrease symptoms, physical limitations, and radiographic progression of PsA and RA [43]. Moderateto-severe psoriasis patients receive 50 mg SC self-injections twice weekly for 3 months, then 50 mg SC selfinjections weekly as continuous therapy [43]. In clinical studies, patients receiving continuous therapy were more responsive than patients receiving intermittent therapy [44]. In phase III trials, a PASI-75 response was achieved in approximately 50% of patients who received 50 mg etanercept twice a week for 3 months (Table 1) [36,37,38]. Etanercept relieved concomitant fatigue and depression, symptoms often experienced by psoriasis patients [38]. Mild-to-moderate injection site reactions were the most commonly reported AE [36,37,38]. Some AEs occurring in at least 5% of patients (in at least one clinical trial) included headache, injection site bruising, URI, flu-like symptoms, and accidental injury [36,37,38]. Infliximab

Infliximab (Remicade1, Centocor, Inc., Malvern, PA) is a chimeric monoclonal antibody specific to TNFa that is indicated for AS, CD, and UC treatment and to treat and prevent progression of PsA and RA [45]. It was recently approved to treat severe forms of psoriasis [45]. In phase III trials, 75.5–80% of psoriasis patients experienced a PASI-75 response after induction therapy (5 mg/kg intravenous infusions at weeks 0, 2, and 6) [42,46]. After several subsequent months of receiving 5 mg/kg ‘maintenance’ infusions every 8 weeks, these response rates decreased even though most patients maintained or achieved a PASI-75 response for the duration of each study (up to 50 weeks) (Table 1) [42,46]. Of note, as compared with 5 mg/kg ‘as needed’ infusions, 5 mg/kg ‘maintenance’ infusions every 8 weeks were associated

Table 4 Clinical monitoring and contraindications of biologics (based on prescribing information and clinical experience) Drug

Alefacept

Baseline assessments CBC, CD4+ cell count

Follow-up labs

CD4+ cell count every 2 wks or weekly if an abnormality is detected [19]

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Follow-up procedures

Contraindicated or precautionary conditions -Hypersensitivity -CD4+ cell count below normal -HIV or AIDS -Serious infection -Exercise caution: high risk/history of malignancy, pregnancy (category B) -Live vaccines are contraindicated during therapy [19]

Concomitant medication precautions/ contraindications Immunosuppressive therapy or phototherapy [19]

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Developments in systemic immunomodulatory therapy for psoriasis Berger and Gottlieb 441

Table 4 (Continued ) Drug

Baseline assessments

Follow-up labs

Efalizumab

CBC (platelet count); joint examination

CBC (platelet count) monthly  3 mos ! every 3 mos [25]

Etanercept

PPD (positive test requires TB treatment before starting therapy)a, CBC, LFTs, hepatitis panel, ANA titers b

Infliximab

Adalimumab

a b c

Follow-up procedures Joint examination (to assess for PsA) every 3 mos

Contraindicated or precautionary conditions

Concomitant medication precautions/ contraindications

-Hypersensitivity -Serious infection -Exercise caution: PsA, high risk/history of malignancy, pregnancy (category C) -Live vaccines are contraindicated during therapy [25]

Immunosuppressive therapy [25]

CBC, LFTs every 3 mos; PPD yearly

-Hypersensitivity -Serious infection -Lupus -Exercise caution: CHF, CNS demyelinating disorders (i.e. MS), malignancy, pregnancy (category B) c -Live vaccines are contraindicated during therapy [43]

-Cyclophosphamide -Immunosuppressive therapy including Anakinra [43]

PPD/CXR (positive test requires TB treatment before starting therapy) [45], CBC, LFTs, hepatitis panel, ANA titers b

CBC, LFTs every 3 mos; PPD yearly

-Hypersensitivity -Serious infection -Jaundice/LFTs>5x the upper limit of normal -Lupus -Exercise caution: CHF, HBV carrier status, CNS demyelinating disorders, malignancy, pregnancy (category B)c, COPD -Live vaccines are contraindicated during therapy [45]

-Anakinra -Immunosuppressive therapy including azathioprine and 6-MP (hepatosplenic T cell lymphoma in young patients) [45]

PPD (positive test requires TB treatment before starting therapy) [47], CBC, LFTs, hepatitis panel, ANA titers b

CBC, LFTs every 3 mos; PPD yearly

-Hypersensitivity -Serious infection -Lupus -Exercise caution: CHF, HBV carrier status, CNS demyelinating disorders, malignancy, pregnancy (category B) c -Live vaccines are contraindicated during therapy [47]

Anakinra [47]

This is a standard of care, although not indicated in prescribing information. ANA titers may become positive during therapy with or without signs of a lupus-like syndrome [43,45,47]. There are no prospective clinical trials investigating therapy for pregnant patients or patients with cancer [8].

with better clinical response, less anti-chimeric antibody formation, and fewer infusion reactions (IRs) [46]. Anti-chimeric antibodies are raised to portions of infliximab derived from mouse proteins. In phase III trials, from 27 to 35.8% of subjects receiving 5 mg/kg therapy at www.sciencedirect.com

regular intervals raised antibodies to infliximab [42,46]. In general, antibody-positive patients were less likely to achieve or sustain clinical responses versus antibodynegative patients [42,46]. The high incidence of antibody formation in these trials may be because MTX was not administered [42,46]. Infliximab can induce immediate Current Opinion in Pharmacology 2007, 7:434–444

442 Immunomodulation

IRs or delayed serum sickness-like reactions [42,46]. The incidence of IRs may be highest in patients who raise antibodies to infliximab [46]. Infliximab can be associated with LFT elevations and may elevate the risk for certain cancers [42,45,46]. In advanced study: adalimumab

Adalimumab (Humira1, Abbott Laboratories, North Chicago, IL) is a human monoclonal antibody specific to TNFa that prevents receptor binding, causes lysis of cells with surface TNFa, and decreases expression of cellular adhesion molecules [47]. Current indications include inhibition of progression and treatment for PsA and RA, and treatment of AS and CD (in the US) [47]. It is not yet approved to treat psoriasis. Two phase III studies demonstrated PASI-75 responses in 71 and 79.6% of psoriasis patients receiving adalimumab 40 mg SC every other week for 16 weeks (P < 0.001 versus placebo) (Tables 1 and 2) [A Menter et al., abstract in J Am Acad Dermatol 2007, 56:AB5; J Saurat et al., poster, 2006]. The most common AEs in adalimumab groups were URI, nasopharyngitis, arthralgia, and headache. Overall, infections (non-severe/non-serious) were more common in adalimumab groups. TNF blockade controversies

TNF-blockers have warnings for infection and malignancy in their prescribing information. A 2006 meta-analysis of nine total infliximab and adalimumab trials including 3500 RA patients reported an increased risk for serious infection (odds ratio = 2.0) and cancer (odds ratio = 3.3) with active therapy versus placebo [48]. Serious infections include any infection that requires hospitalization and/or the administration of intravenous antimicrobial therapy. In this meta-analysis, only 12 out of 126 serious infections were ‘granulomatous infections’ such as tuberculosis, histoplasmosis, or coccidiomycosis [48]. Notably, data were not adjusted to account for the duration of exposure to each anti-TNF antibody, disease severity, or prior exposure to immunosuppressive medications, and data do not include etanercept trials [48]. In clinical trials, etanercept and placebo both incurred a 1% risk for serious infections [43]. A meta-analysis demonstrated a relative risk for malignancy of 0.86 (95% CI, 0.56–1.31) associated with etanercept versus placebo [49]. Infections and cancer rates did not increase over 8.2 years of clinical experience with etanercept in RA patients [50]. Of note, psoriasis patients, similar to RA patients, have an increased risk at baseline for developing lymphoma as compared with the general population [51]. Similarly, patients with inflammatory diseases like RA have an increased risk for non-melanoma skin cancer, which is enhanced by TNFa inhibition and combination therapy with MTX [52].

with therapy, in part because of inconvenience and side effects [53]. Methotrexate is a widely used, inexpensive monotherapy, and combination therapy with newer agents is increasing in popularity. Cyclosporine is known to provide patients with quick relief from painful, widespread lesions. Investigators compared 16 weeks of oral CsA versus MTX in psoriasis patients and found no significant differences between the therapies in responding patients regarding efficacy, quality of life, and time to disease remission (Table 1) [54]. CsA was commonly associated with muscle aches, headache, and paresthesias, whereas MTX was commonly associated with nausea and LFT elevations [54]. Of note, there are no RDBPCTs evaluating off-label systemic therapies. As scientists develop increasingly targeted therapies that clear disease with minimal collateral immune system damage, they acquire new knowledge about disease pathogenesis. Biologics are developing niches among systemic therapies—infliximab for ‘rapid’ relief of very severe psoriasis, unstable psoriasis, erythrodermic psoriasis, and pustular psoriasis; etanercept in patients with stable disease who are beginning TNF blockade and in patients with PsA; and efalizumab and alefacept in patients with contraindication(s) to TNF blockade [55]. The safety of biological agents has not been solidified. Both pre-biological and biological systemic immune modulators require close monitoring and have specific contraindications (Tables 3 and 4). Precise mechanisms of efficacy and AEs of systemic therapies remain elusive [8]. Likewise, predominant mechanisms of disease pathogenesis are incompletely understood [8]. There remains a void to be filled in the data for existing systemic and topical therapies, and there is room for drug development.

Acknowledgements Dr. Gottlieb has research/educational grants from Centocor, Amgen, Wyeth, Immune Control, Genentech, Abbott, and Pharmacare. She has consultant/ advisory board agreements with Amgen, Inc., BiogenIdec, Inc., Centocor, Inc., Wyeth Pharmaceuticals, Schering-Plough Corporation, Eisai, Celgene, Corp., Bristol Myers Squibb Co., Beiersdorf, Inc., Warner Chilcott, Abbott Labs., Roche, Sankyo, Medarex, Kemia, Celera, TEVA, Actelion, UCB, Novo Nordisk, Almirall, Immune Control, RxClinical, Dermipsor Ltd., Medacorp, DermiPsor, Can-Fite, and Incyte. All income from these activities goes to Dr. Gottlieb’s employer.

References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:  of special interest  of outstanding interest 1.

Callen JP, Krueger GG, Lebwohl M, McBurney EI, Mease P, Menter A, Paller AS, Pariser DM, Weinblatt M, Zimmerman G: AAD consensus statement on psoriasis therapies. J Am Acad Dermatol 2003, 49:897-899.

2.

Rheumatrex1 (methotrexate) [full prescribing information]. Cranbury, NJ: STADA Pharmaceuticals, Inc.; 2005.

Conclusion Many patients who use pre-biological systemic agents (i.e. MTX, PUVA, CsA, acitretin) are not very satisfied Current Opinion in Pharmacology 2007, 7:434–444

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Roenigk HH Jr, Auerbach R, Maibach H, Weinstein G, Lebwohl M: Methotrexate in psoriasis: consensus conference. J Am Acad Dermatol 1998, 38:478-485.

4.

Sigmundsdottir H, Johnston A, Gudjonsson JE, Bjarnason B, Valdimarsson H: Methotrexate markedly reduces the expression of vascular E-selectin, cutaneous lymphocyte-associated antigen and the numbers of mononuclear leucocytes in psoriatic skin. Exp Dermatol 2004, 13:426-434.

5.

6.

Johnston A, Gudjonsson JE, Sigmundsdottir H, Ludviksson BR, Valdimarsson H: The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules. Clin Immunol 2005, 114:154-163. Salim A, Tan E, Ilchyshyn A, Berth-Jones J: Folic acid supplementation during treatment of psoriasis with methotrexate: a randomized, double-blind, placebocontrolled trial. Br J Dermatol 2006, 154:1169-1174.

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8.

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9.

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36. Papp KA et al.: A global phase III randomized controlled trial of  etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol 2005, 152:1304-1312. This is one of the phase III clinical trials of etanercept that included dose reduction from 50 mg SC twice a week to 50 mg SC weekly. Of note, this is the indicated dosing regimen for psoriasis. 37. Leonardi CL et al.: Etanercept as monotherapy in patients with psoriasis. N Engl J Med 2003, 349:2014-2022. 38. Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A,  Lalla D, Woolley M, Jahreis A, Zitnik R et al.: Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet 2006, 367:29-35. In this phase III study, etanercept significantly reduced symptoms of fatigue and depression in psoriasis patients. There seems to be an association between TNF, fatigue, and depression, although more research is needed to demonstrate a direct relationship between TNF and psychiatric symptoms in psoriasis patients. 39. Gottlieb AB, Masud S, Ramamurthi R, Abdulghani A, Romano P, Chaudhari U, Dooley LT, Fasanmade AA, Wagner CL: Pharmacodynamic and pharmacokinetic response to antitumor necrosis factor-a monoclonal antibody (infliximab) treatment of moderate to severe Psoriasis vulgaris. J Am Acad Dermatol 2003, 48:68-75. 40. Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB: Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 2001, 357:1842-1847. 41. Gottlieb AB, Evans R, Li S, Dooley LT, Guzzo CA, Baker D, Bala M, Marano CW, Menter A: Infliximab induction therapy for patients with severe plaque-type psoriasis: a randomized, doubleblind, placebo-controlled trial. J Am Acad Dermatol 2004, 51:534-542. 42. Reich K et al.: Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet 2005, 366:1367-1374. This pivotal phase III trial demonstrated significant improvements in moderate to severe psoriasis with the administration of induction and maintenance regimens of infliximab. Improvements in nail psoriasis were also demonstrated. 43. Enbrel1 (etanercept) [full prescribing information]. Thousand Oaks, CA: Amgen and Wyeth Pharmaceuticals, Immunex Corporation; 2005. 44. Moore A, Gordon KB, Kang S, Gottlieb A, Freundlich B, Xia HA, Stevens SR: A randomized, open-label trial of continuous versus interrupted etanercept therapy in the treatment of psoriasis. J Am Acad Dermatol 2007, 56:598-603. 45. Remicade1 (infliximab) [full prescribing information]. Malvern, PA: Centocor, Inc.; 2006. 46. Menter A, Feldman SR, Weinstein GD, Papp K, Evans R, Guzzo C, Li S, Dooley LT, Arnold C, Gottlieb AB: A randomized

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