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IntroductionIn recent years, there has been considerablebreakthrough in understanding the pathogenesis ofpsoriasis as a T cell mediated autoimmune disease. Ingenetically predisposed individuals, a triggering antigen,the nature of which is still not clear, is captured byLangerhans' cells in the epidermis. The Langerhans' cellmigrates into the regional lymph node and presents theantigen to the T lymphocyte. When the antigen-Langerhans' cell complex interacts with the T cell in thelymph node, the T lymphocyte is activated by two co-stimulatory signals 1 and 2. In predisposed individuals,these activated T cells undergo TH1 differentiation intoeffector memory T cells and selectively traffics back tothe skin and releases inflammatory cytokines such astumour necrosis factor (TNF) alpha. These cytokines acton the epidermal keratinocytes, dermal blood vessels andother inflammatory cells, producing inflammatoryresponses that result in clinical lesion of psoriasis.

Biologic agents are synthetic proteins designed to blockone or more of these specific steps in the pathogeneticpathway. Four targets are aimed:

Four of these new biologic agents, namely alefacept,efalizumab, infliximab and etanercept are discussedbelow. Comparison of their modes of actions, clinicaluses, efficacy, side effects and precautions aresummarized in Table 1.

AlefaceptIn psoriasis, the lymphocyte function-associated antigen(LFA)-3 presents on the Langerhans' cell binds to the

Target 1: Inhibiting T cell activation by blocking theco-stimulatory signal 2 (e.g. by efalizumab,alefacept);

Target 2: Inducing immune deviation from TH1differentiation to TH2 differentiation inthe activated T cell;

Target 3:Eliminating activated T cells selectively(e.g. by alefacept);

Target 4: Inhibiting the action of cytokines,especially tumour necrosis factor (TNF)alpha (e.g. by infliximab, etanercept)

CD2 expressed on activated T cell, producing co-stimulating interaction (signal 2) and leads to T cellactivation and a cascade of inflammatory responseresulting in psoriasis. Alefacept is a recombinant humanLFA-3/IgG1 dimeric fusion protein that binds to CD2receptor expressed on these activated T cells, thusinhibiting T cell activation (Target 1) and proliferation.In addition, it also causes apoptosis and selectiveelimination of these pathogenic T cells (Target 3) whilepreserving the naive T cells. In January 2003, Alefaceptwas approved by FDA of USA for the treatment ofmoderate to severe plaque psoriasis in adult patientswho are candidates for systemic therapy orphototherapy. It is administered weekly either byintramuscular injection of 15mg or by intravenous bolusinjection of 7.5mg. A course of 12 weeks is usuallyrecommended.

In most clinical trials on efficacy of treatment forpsoriasis, the widely adopted parameter is the PASI 75which measures the percentage of patients achieving atleast 75% reduction of their Psoriasis Area and SeverityIndex (PASI) score from the pretreatment baseline. Inalefacept, PASI 75 was achieved in 33% of patients afterweekly intramuscular injection for 12-week.1 Similarly,28% of patients achieved PASI 75 after a 12 week courseof once weekly intravenous alefacept injection while asecond course further enhanced clinical efficacy up to40%.2 Significant clinical response occurred at aroundeight weeks after starting treatment.3 The best clinicalefficacy occurred approximately six weeks after the lastdose.1 Comparing with other biologics, remission in theresponders was long-lasting and at week 24, 24% ofpatients still remained clear or almost clear withoutadditional therapy and 71% maintained at least PASI 50( i.e. 50% reduction of PASI as compared with baseline). 1For those who needed retreatment, a median interval of10 months (range: 6 to 18) between the last dose tosubsequent retreatment was noted.4

The most common side effects were pharyngitis,headache, rhinitis and dizziness.1,2,3,4 Mild injection sitereaction occurred more often in the intramuscularadministration1,2 while transient chill during the first dayof treatment occurred more often in the intravenousroute. One of the important side effects is the reductionof circulating T cell counts. Weekly CD4 T lymphocyte

Comparison of Various Biological Agentsin the Treatment of Psoriasis

Dr. KH Lau

MBBS(HK), FRCP, FHKCP, FHKAM(Med)

Yaumatei Dermatology Clinic, Social Hygiene Service.

Dr. KH Lau

This article has been selected by the Editorial Board of the Hong Kong Medical Diary for participants in the CME programme ofthe Medical Council of Hong Kong (MCHK) to complete the following self-assessment questions in order to be awarded one CMEcredit under the programme upon returning the completed answer sheet to the Federation Secretariat on or before 30 September2006.

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count monitoring is recommended during treatment.Alefacept should be withheld if the CD4 T lymphocytecount is below 250 cells/mL and discontinued if itremains below 250 cells/mL for four weeks. Ten percentand 2% of patients discontinued intravenous alefacepttemporarily and permanently because of low CD4 Tlymphocyte count2 while 4% and none when alefaceptwas given intramuscularly.1 The rate of infectionrequiring hospitalization was 0.9%. Up to date, alefacepthas a satisfactory safety profile.

EfalizumabEfalizumab is a recombinant humanized monoclonalantibody against the alpha subunit of LFA-1(i.e. theCD11a) expressed on T lymphocytes. It inhibits theinteraction between CD11a and the intercellularadhesion molecule (ICAM)-1 expressed on antigenpresenting cells hence stopping the co-stimulatorysignal 2 (Target 1) that activates the T cells which leadto a sequence of inflammatory events. Efalizumab wasapproved by FDA in October 2003 to treat moderate tosevere plaque psoriasis in adult patients who arecandidates for systemic therapy or phototherapy. It isusually given by subcutaneous injection of single firstconditioning dose at 0.7mg/kg followed by weekly doseat 1mg/kg for a course of 12 weeks.

Twenty-two to 29.2% versus 28 to 41% of patientsachieved PASI 75 after 12 week treatment with dose of1mg/kg versus 2mg/kg respectively.5,6 Seventy-sevenpercent of these good responders maintained theirimprovement when additional 12 week treatment weregiven.6 The improvement occurred as early as fourweeks.6 Study showed that additional clinicalimprovement could be achieved by prolongedtreatment beyond 12 weeks.5 Treatment up to 24 and 60weeks, which were well tolerated, increased thepercentage of patients achieving PASI 75 to 51% and64% respectively.5 However, when stopping treatment,significant clinical relapse is one of the majordisadvantages and 0.7% of patients experiencedrebound after discontinuation, suggesting long termmaintenance therapy with efalizumab is necessary.7

Common minor side effects such as flu-like symptomsoccurred in 37% of patients during the first fewinjections.8 It can be minimized by the use of reducedconditioning dose in the first injection. More seriousside effect of thrombocytopenia was rarely reported.7Monitoring of platelet count is recommended everymonth initially and then three-monthly during thetreatment period and treatment should be stopped ifsignificant thrombocytopenia occurs.

InfliximabInfliximab is a chimeric monoclonal antibody whichbinds to transmembrane and soluble TNF alpha. Itbinds to TNF specifically and blocks its interaction withcell surface receptors (Target 4). Thus, TNF alpha,which is an important mediator secreted by theactivated pathogenic T cells, cannot bind with itsnatural receptors in various sites and the inflammatoryresponse leading to psoriasis ceases. Infliximab isapproved for the treatment of Crohn's disease andrheumatoid arthritis by FDA and is currently underreview by the authority for other indications includingpsoriasis. The drug is usually given 3mg/kg to 5mg/kg

by intravenous infusion over two hours at week 0, 2, 6then every 8 week if maintenance is necessary.

Infliximab is highly efficacious and 72% versus 88% ofpatients achieved PASI 75 at week 10 after infusion at3mg/kg versus 5mg/kg respectively.9 Almost half of theresponders achieved PASI 75 at 4 weeks. 9 Other studiesshowed that 40% and 73% of patients receiving 5mg/kgand 10mg/kg infliximab respectively were able tomaintain at PASI 50 at week 26.10 Hence, infliximabcould produce a rapid, effective and sustainable effectin the treatment of psoriasis.

Common side effects are mild including headache,pruritus, fatigue and myalgia. Five percent of patientsmay develop infusion reactions ranging from mildhypotension and allergic reactions to severeanaphylaxis and seizures which usually occur during orwithin two hours of infusion.11 Serious opportunisticinfections such as disseminated or extrapulmonarytuberculosis were reported.11,12 Reactivation of latenttuberculosis may develop within the first three to sixmonths after starting treatment. Pretreatmenttuberculin test, chest x ray and anti-tuberculosisprophylaxis are recommended before thecommencement of infliximab.11,12 Infliximab is alsocontraindicated in patients with moderate to severeheart failure.

EtanerceptEtanercept is a dimeric fusion protein consisting of twoTNF receptor components linked to the Fc portion ofhuman IgG. Similar to infliximab, etanercept binds toTNF specifically and blocks its interaction with cellsurface receptors (Target 4). In April, 2004, FDA hasapproved the use of etanercept for the treatment ofmoderate to severe chronic plaque psoriasis who arecandidates for systemic therapy or phototherapy. It isalso approved for treating psoriatic arthritis,rheumatoid arthritis and ankylosing spondylitis. It isgiven subcutaneously 50mg twice per week usually fora course of 12 weeks, then 50mg once per week formaintenance if necessary.

PASI 75 was achieved in 49% of patients at week 12 andincreased to 59% when twice weekly treatment wasextended to 24 weeks.13 Clinical improvement wasevident as early as 2 weeks. The main side effects wereupper respiratory infection (57%), injection sitereactions (20%), and headache (13%). Eleven percentand 15% reported induction of antinuclear antibodiesand anti-double-stranded DNA but full cases of lupuserythematosus are rare.14

ConclusionThese new biologic agents are exciting additions ofarmamentarium for the treatment of psoriasis. Ascompared with the conventional immunosuppressivetherapy (e.g. cyclosporin), they seem to have animproved risk-efficacy ratio. Among them, infliximabseems to be highly efficacious while alefaceptapparently offers longer remission to responders.Furthermore, some of them (e.g. efalizumab andetanercept) can conveniently be administered by thepatients themselves at home. The downside of thesenew treatments are the need of laboratory monitoring insome agents (e.g. platelet count in efalizumab and CD4count in alefacept) as well as the potential serious side

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effects such as infusion reaction and opportunisticinfections (e.g. tuberculosis in infliximab). The cost of allthese new therapeutic agents are very high. Furtherstudies are needed to compare the cost-effectiveness ofthese new agents with the current systemic anti- psoriatictherapies.

Lebwohl M, Christophers E, Langley R, Ortonne JP, Roberts J, GriffithsCE; Alefacept Clinical Study Group. An international, randomized,double-blind, placebo controlled phase 3 trial of intramuscular alefaceptin patients with chronic plaque psoriasis.Arch Dermatol 2003;139:719-27.Krueger GG, Papp KA, Stough DB, Loven KH, Gulliver WP, Ellis CN;Alefacept Clinical Study Group. A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2courses of alefacept in patients with chronic plaque psoriasis. J Am AcadDermatol 2002;47:821-33.Ellis CN, Krueger GG; Alefacept Clinical Study Group. Treatment ofchronic plaque psoriasis by selective targeting of memory effector Tlymphocytes.N Engl J Med 2001;345:248-55.Krueger GG, Ellis CN. Alefacept therapy produces remission forpatients with chronic plaque psoriasis. Br J Dermatol 2003;148:784-8.Gottlieb AB, Blacker K, Duvic M, Leonardi CL. Efficacy and safety ofefalizumab long term treatment: preliminary findings from an openlabel trial. Program of the 61st Annual Meeting of the AmericanAcademy of Dermatology; March 21-26, 2003; San Francisco, California.Poster 11.

1.

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4.

5.

Lebwohl M, Tyring SK, Hamilton TK, Toth D, Glazer S, Tawfik NH, etal. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis.N Engl J Med 2003; 349:2004-13.Genentech. Full prescribing information. www.gene.com/gene/products/information/immunological/ raptiva/insert.jspGottlieb A, Miller B, Chaudhari U, Oh C, Sherr A, Solodkina G, et al.Clinical and histologic effects of subcutaneously administered anti-CD11a (hu1124) in patients with psoriasis. J Invest Dermatol2000;114:840.Gottlieb AB, Li S, Evans R, Menter A. Infliximab in the treatment ofpsoriasis: results from the first 10 weeks of the phase II trial. Program ofthe 61st Annual Meeting of the American Academy of Dermatology;March 21-26, 2003; San Francisco, California. Poster 596.Gottlieb AB, Chaudhari U, Mulcahy LD, Li S, Dooley LT, Baker DG.Infliximab monotherapy provides rapid and sustained benefit forplaque-type psoriasis. J Am Acad Dermatol 2003;48:829-35.Centocor. Full prescribing information. www.remicade.com/PI/interactive_PI.jsp.12. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J,Schwieterman WD, et al. Tuberculosis associated with infliximab, atumor necrosis factor alpha-neutralizing agent. N Engl J Med2001;345:1098-104.13. Leonardi CL, Powers JL, Matheson RT, Goffe BS, Zitnik R, Wang A,et al. Etanercept as monotherapy in patients with psoriasis. N Engl JMed 2003;349:2014-22.Shakoor N, Michalska M, Harris CA, Block JA. Drug induced systemiclupus erythematosus associated with etanercept therapy. Lancet2002;359:579-80.

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References

Table 1 summary of four biological agents for the treatment of psoriasisBiological agent

Description

Mechanism

Target of action

FDA indication

Route ofadministration

Dosing for one course

Time of onset ofimprovement

Relative efficacy: % ofpatients achievingPASI 75 after a courseof 12 week Px

FDA baseline &monitoring

Side effect

Contraindication

Advantage

Disadvantage

Estimated drug cost(US$)

Alefacept(AmeviveTM)

Fusion protein of human LFA-3and Fc portion of Ig G1

Block LFA-3/CD2 interactionand selective eliminateactivated T cells

Target 1 & 3

Mod to severe plaque psoriasisin adults who are candidatesfor systemic therapy orphototherapy (approved Jan2003)

Intramuscular or intravenousbolus

15mg imi or 7.5mg ivi weeklyfor 12 weeks

~8weeks

~28-40%

CD4 count (baseline andweekly)

Flu-like symptoms, injectionsite reaction , transient chill

Hypersensitivity to alefacept;discontinue if CD4<250cells/uLfor 4 weeks

Long lasting remission

Need for CD4 countmonitoring, withhold ifCD4<250cells/uL, discontinue ifpersists for 4 weeks

~$10,000 per course dependingon dosing

Efalizumab(RaptivaTM)

Humanized form of murineantibody against CD11a

Block LFA-1/ICAM-1interaction and inhibit T cellactivation and inflammatoryevents

Target 1

Mod to severe plaque psoriasisin adults who are candidatesfor systemic therapy orphototherapy (approved Oct2003)

Subcutaneous (by patients athome after training)

Begin with single dose of0.7mg/kg sc, then 1mg/kg scweekly for 12 weeks

~4 weeks

~22 -41%(Increase to 64% if prolongedtreatment)

Platelet count monthly, thenevery 3 months

Flu-like symptoms

Hypersensitivity to efalizumabor any murine or humanizedmonoclonal antibody

Self administered by patientspossible

Significant relapse aftertreatment; long termmaintenance necessary

~$15,000 per year formaintenance treatment

Infliximab(RemicadeTM)

Chimeric antibody against TNFalpha with a human IgG1constant domain and murinevariable regions

Binds soluble and bound TNFalpha and blocks its activities

Target 4

Crohn's disease and RA

Slow intravenous infusion over2 hours

3 to 5 mg/kg iv infusion at week0,2,6.

~4weeks

~72-88%

Screening for latent TB(tuberculintest, CXR) at baseline

Headache, myalgia, infusionreaction, opportunistic infections

Hypersensitivity to infliximabor murine products; congestiveheart failure

Highly efficacious

Manpower for iv infusion;risk of anaphylactic infusionreaction; risk of seriousopportunistic infection

~12,000 per year depending ondosage

Etanercept (EnbrelTM)

Fusion protein of the Fc ofhuman IgG1 and theextracellular TNF receptor

Binds soluble and boundTNF alpha and blocks itsactivities

Target 4

Mod to severe plaquepsoriasis in adults (approvedApr 2004); psoriatic,rheumatoid and juvenilerheumatoid arthritis,ankylosing spondylitis

Subcutaneous (by patients athome after training)

50mg sc twice a week for 12week (50mg sc weekly ifmaintenance)

~2 weeks

~49%(Increase to 59% if prolongedtreatment)

None

Upper respiratory infection,injection site reaction, headache

Hypersensitivity to etanercept;active infections or sepsis;congestive heart failure; poorlycontrolled diabetes

Also effective against psoriaticarthritis; self administered bypatient possible

Serious opportunisticinfection reported, priortuberculin test and CXRadvisable in TB endemic area

~12,000 per year

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MCHK CME Programme Self-assessment QuestionsPlease read the article entitled "Comparison of Various Biological Agents in the Treatment of Psoriasis" by Dr.KH Lauand complete the following self-assessment questions. Participants in the MCHK CME Programme will be awarded 1CME credit under the Programme for returning completed answer sheet via fax (2865 0345) or by mail to the FederationSecretariat on or before 30 September 2006. Answers to questions will be provided in the next issue of The Hong KongMedical Diary.

Questions 1-10: Please choose the best answer.

1. The following statements concerning treatment of psoriasis by etanercept are correct except:a. Comparing with other biological agents, the onset of clinical improvement is slow.b Etanercept has a similar mode of action as infliximab.c. It is approved by FDA for the treatment of moderate to severe chronic plaque psoriasis patients who are candidates for systemic therapy orphototherapy.d. The main side effects are upper respiratory tract infection and injection site reactions.e. Induction of antinuclear antibodies and anti-double stranded DNA were reported after treatment with etanercept.

2. The following are relevant side effects of alefacept except:a. Pharyngitisb. Headachec. Rhinitisd. Lymphoctyosise. Injection site reaction and transient chill during the first day of treatment

3. FDA recommends monitoring of the following parameter(s) during treatment with efalizumab:a. Chest X rayb. White cell countc. Tuberculin testd. Platelet counte. All of the above

4.. The following are correct modes of action of the biological agents designed to block the specific steps in the pathogenetic pathway ofpsoriasis except:a. Alefacept inhibits T cell activation by blocking the co-stimulatory signal 2.b. Etanercept binds soluble and bound tumour necrosis factor (TNF) alpha and blocks its action.c . Alefacept eliminates activated T cells selectively.d. Efalizumab induces immune deviation from TH1 to TH2 differentiation in the activated T cell.e. Infliximab inhibits the action of cytokines, especially tumour necrosis factor (TNF) alpha.

5 The following is/are disadvantage of treatment with infliximab in psoriasis:a. High treatment cost.b. Reactivation of latent tuberculosis.c. Potential serious anaphylaxis during drug administration.d. a and c.e. All of the above

6. The following statements concerning the use of alefacept in the treatment of psoriasis are correct except:a. Comparing with other biologics, the remission induced by alefacept is transient and significant clinical relapse is one of the major disadvantages.b. It was already approved by FDA of USA for the treatment of moderate to severe plaque psoriasis in adult patients.c Alefacept is a recombinant human LFA-3/IgG1 dimeric fusion protein.d. Alefacept is administered weekly either by intramuscular or by intravenous bolus injection.e. The best clinical efficacy usually occurs few weeks after completing the course of treatment.

7. The following biological agent(s) can be administered at home by trained patients themselves:a. Efalizumabb. Infliximabc. Etanerceptd. a and ce. all of the above

8. The following statements concerning the use of efalizumab in the treatment of psoriasis are correct except:a. The usual dosage is 1mg/kg weekly for a course of 12 week.b Long term treatment of efalizumab up to 60 weeks was proven to be safe and well tolerated.c. Comparing with other biologics, remission in the responders was long-lasting and a significant number of patients still remained clear even afterstopping treatment.d. It is usually given by subcutaneous injection.e. Additional clinical improvement could be achieved by prolonged treatment beyond 12 weeks with enhanced clinical efficacy.

9. In treating patients with psoriatic arthropathy complicating extensive stable plaque psoriasis, the following biological agent is an FDAapproved treatment option:

a. Alefaceptb. Efalizumabc. Infliximabd. Etanercepte. None of the above

10. Which of the following statement(s) concerning the use of infliximab in the treatment of psoriasis is/are correct:a. It is administered subcutaneously.b. It is given in 50mg twice a week for a course of 12 week.c. It is approved by FDA for the treatment of Crohn's disease and rheumatoid arthritis.d. No laboratory monitoring is required by FDAe. All of the above.

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Comparison of Various Biological Agents in the Treatment of Psoriasis

Dr. KH LauYaumatei Dermatology Clinic, Social Hygiene Service.

MBBS(HK), FRCP, FHKCP, FHKAM(Med)