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Update on Systemic Therapies for Atopic Dermatitis

Kristopher S. Denby, Lisa A. Beck


Disclosures

Curr

pin Aller!y Clin "mmunol. #$%#&%#'()*(#%+(#,.

Abstract and "ntroduction


Abstract
Purpose of review* Althou!h many atopic dermatitis patients can be treated satisfactorily -ith topical medications and systemic anti+itch approaches, a smaller subset re.uire more a!!ressi/e systemic therapies. 0amiliarity -ith the latest literature on the benefits and risks of these treatments -ill enable the clinician and patient to select the most appropriate therapy based on the patient1s lifestyle, assessments of risks and comorbidities. Recent findings* Additional data ha/e come to li!ht alterin! the risk and benefit ratio of certain systemic atopic dermatitis therapies. "n #$%%, -e sa- se/eral head+to+head, randomi2ed controlled trials of established systemic medications for the treatment of atopic dermatitis. A fe- ne- systemic atopic dermatitis treatments ha/e hi!hli!hted ho- tar!eted therapies may inform us about disease patho!enesis. Summary* "n li!ht of the risk of hepatosplenic T+cell lymphomas, a !reater de!ree of caution is -arranted in the use of a2athioprine. 3BU4B, mycophenolate, and methotre5ate remain the reasonable first+line systemic treatment options for atopic dermatitis. A brief run+in -ith hi!h+dose cyclosporine to clear atopic dermatitis follo-ed by maintenance -ith lo-+dose cyclosporine or cellcept 6 both of -hich ha/e better risk and benefit ratios is a reasonable approach. "nterferon !amma and intra/enous immuno!lobulin, althou!h e5pensi/e, are potential options, and possibly most ideal for atopic dermatitis patients pla!ued by si!nificant /iral skin infections such as ec2ema herpeticum. A better understandin! of the immunopatho!enesis of atopic dermatitis -ill come -ith the e5ploration of no/el tar!eted therapies.

Introduction
Atopic dermatitis is a chronic inflammatory skin disorder characteri2ed by intensely pruritic ec2ematous skin lesions that typically de/elop in a!e+specific

anatomical locations. There are numerous theories proposed to e5plain the de/elopment of this common disorder. 0or years, the ma7or theory -as that patients had an aberrant and robust Th# adapti/e immune response to lar!ely innocuous en/ironmental anti!ens. 8ecent research hi!hli!hts the importance of skin barrier abnormalities and an inade.uate host response to common cutaneous microbes as other hi!hly plausible mechanisms that mi!ht predispose indi/iduals to de/elop atopic dermatitis. Aller!en and irritant identification and a/oidance, moisturi2in! the skin, as -ell as topical prescription anti+inflammatory therapies ha/e been the mainstay of treatment for mild+to+moderate atopic dermatitis. Althou!h some mild cases of atopic dermatitis can be mana!ed -ith bland emollients alone, most patients re.uire treatment -ith either topical corticosteroids or calcineurin inhibitors. 9hen patients fail these inter/entions and measures to minimi2e en/ironmental influences, systemic options are often considered. "n this re/ie-, -e -ill comment on the studies published primarily in #$%% that may help direct a clinician1s choice of systemic therapies for atopic dermatitis.

Cyclosporine, :ycophenolate :ofetil, and :ycophenolic Acid


Cyclosporine 'CSA) and mycophenolate mofetil, the prodru! of mycophenolic acid, are immunosuppressants appro/ed to pre/ent transplant re7ection. ;%,#< "n li!ht of the potential for nephroto5icity and hypertension -ith chronic CSA therapy, it is challen!in! to determine -hen and in -hich atopic dermatitis patients this medication should be considered. 0ifty+fi/e adult atopic dermatitis patients -ho -ere unresponsi/e to topical therapies -ere treated for , -eeks -ith hi!h+dose CSA '= m!>k!>day di/ided into t-o doses) as an acute mana!ement strate!y. ;?< This -as follo-ed by randomi2ation to recei/e maintenance treatment -ith either CSA ? m!>k!>day or enteric+coated mycophenolate sodium '%(($ m!>day) for ?$ -eeks follo-ed by a %#+-eek follo-+up period. Durin! the run+in phase, all patients e5perienced a si!nificant impro/ement in SC 8AD 'SC 8in! Atopic Dermatitis) and serum thymus and acti/ation+re!ulated chemokine 'TA8C) le/els. Althou!h initially patients randomi2ed to CSA maintenance had better control of their atopic dermatitis, by %$ -eeks the a/era!e SC 8AD /alues -ere comparable. "n the follo-+up phase, the mycophenolate+treated arm maintained !reater disease control than those -ho had recei/ed CSA as a maintenance treatment. Althou!h the potential for nephroto5icity and hypertension rele!ates CSA to a third+line choice as an atopic dermatitis maintenance strate!y, this study demonstrated the /alue of usin! hi!h+dose CSA to achie/e rapid initial control of atopic dermatitis prior to s-itchin! to an ar!uably

safer lon!er+term medication 'i.e. mycophenolate). This is an interestin! study that su!!ests a treatment approach -hereby hi!h+dose CSA is used to achie/e rapid, short+term control of atopic dermatitis and maintenance of this benefit is achie/ed -ith safer immunosuppressants. This approach a/oids the ad/erse effects, -hich commonly arise -ith chronic CSA use.

Tocili2umab
Tocili2umab is an "L+, receptor anta!onist, 0DA+appro/ed in #$$@ for the treatment of rheumatoid arthritis. ;(< 8ecent publications ha/e reported on the off+ label use of tocili2umab to treat other systemic inflammatory disorders includin! systemic sclerosis, systemic lupus erythematosus, lar!e /essel /asculitides and polymyositis. ;(< 3a/arini et al. ;=< reported their e5perience treatin! three adult atopic dermatitis patients -hose disease -as refractory to topical corticosteroids, topical calcineurin inhibitors and phototherapy. T-o of these patients had also failed CSA. These patients -ere treated -ith "4 infusions of @ m!>k! tocili2umab e/ery ( -eeks. 9ithin , -eeks of initiatin! tocili2umab therapy, all three patients reported resolution of pruritus and -ithin ? months, their Ac2ema Area and Se/erity "nde5 'AAS") scores dropped by more than =$B. "n addition, all patients -ere able to taper their topical therapies. ;=< The only si!nificant side+effects -ere bacterial infections obser/ed in t-o of the three patients. ne patient e5perienced left heel bursitis secondary to streptococcus %$ months into therapy. The other patient de/eloped an uncomplicated bacterial con7uncti/itis = months after initiatin! tocili2umab. These infections resol/ed -ith discontinuation of tocili2umab and appropriate therapies. "n a lar!e trial of rheumatoid arthritis patients treated -ith identical dosin! of tocili2umab '@ m!>k!), the rate of serious infections tripled 'from % to ?B), ;,< su!!estin! that "L+, blockade may enhance infection risks. 0urther studies are -arranted to better characteri2e the efficacy and safety ACATD" E8"3A.

A2athioprine
Like many immunosuppressants, a2athioprine, -hich is a purine analo!, -as initially de/eloped in the %F,$s to pre/ent or!an re7ection. "t has also been used to treat a number of immunolo!ic diseases includin! pemphi!us /ul!aris, ;G<rheumatoid arthritis, ;@< inflammatory bo-el disease, ;F< as -ell as atopic dermatitis. ;%$< An increased risk of mali!nancy 'includin! non+Dod!kin1s lymphomas ;%%< and sarcomas ;%#,%?< ) is a reco!ni2ed risk of lon!+term a2athioprine treatment in patients recei/in! treatment to pre/ent transplant re7ection or to mana!e inflammatory

bo-el disease. ;%(< This past year a2athioprine recei/ed a black bo5 -arnin! about the potential for a rare but fre.uently lethal lymphoma called hepatosplenic T+cell lymphoma 'DSTCL). ;%=<DSTCL responds poorly to chemotherapy and bone marro- transplantation. ;%,< "nitially, it -as thou!ht to occur primarily in youn! men -ith Crohn1s disease -ho -ere also treated -ith tumor necrosis factor 'T30) anta!onists, but a recent re/ie- of #= DSTCL cases indicates the profile of susceptible patients is a bit broader. ;%,< /er a third of the cases described do not fit this hi!h+risk patient profile. Three of the cases -ere in patients -ith rheumatoid arthritis, -hich indicates that the underlyin! disease process may play less of a role than the a2athioprine. Additionally, ? of the #= patients -ith DSTCL -ere treated -ith methotre5ate in con7unction -ith a T30 anta!onist 'and not a2athioprine). "mportantly, none of the reported DSTCL cases -as in atopic dermatitis patients recei/in! these dru!s. 0urther studies are -arranted to determine -hether lon!+term treatment -ith a2athioprine poses a risk for the de/elopment of DSTCL in atopic dermatitis patients.

:ethotre5ate
:ethotre5ate -as ori!inally de/eloped as a safer chemotherapeutic alternati/e to the folate analo!, aminopterin, for the treatment of childhood acute lymphoblastic leukemia. :ethotre5ate is an antimetabolite that directly competes -ith dihydrofolic acid for the bindin! site of dihydrofolate reductase. The resultin! decrease in tetrahydrofolate inhibits cellular proliferation by limitin! the synthesis of D3A, 83A, and se/eral amino acids. "n autoimmune diseases, it appears that methotre5ate may also act by suppressin! intercellular adhesion molecule+% '"CA:+%) and cutaneous lymphocyte+associated anti!en on T+cells. ;%G< "t has been used to treat mali!nancy, autoimmune diseases and inflammatory disorders like psoriasis and atopic dermatitis. Erior to #$%%, there had been no randomi2ed controlled trials '8CTs) to demonstrate the efficacy of methotre5ate in the treatment of atopic dermatitis. Schram et al. ;%@< conducted a study of (# adult atopic dermatitis patients randomi2ed to either methotre5ate %$ m! -eekly or a2athioprine %.= m!>k!>day for %# -eeks. Eatient dosin! -as titrated up-ard until they either achie/ed #=B reduction in disease acti/ity or reached the ma5imum dose allo-ed in the study '##.= m!>-eek methotre5ate, #.= m!>k!>day a2athioprine). 0ollo-in! this, patients entered a %#+-eek follo-+up period in -hich patients and pro/iders -ere allo-ed to either continue -ith their current medication or alter the treatment plan as per normal clinical practice. The t-o medications performed similarly in a number of disease se/erity measures includin! SC 8AD, "!A 'immuno!lobulin

A), AAS", and serum TA8C both durin! the initial %# -eeks of treatment and in the %#+-eek follo-+up phase. ;%@< A si!nificant impro/ement in SC 8AD -as obser/ed in both methotre5ate '(#B) and a2athioprine '?FB) treated patients at %# -eeks. :ethotre5ate had a similar side+effect profile to a2athioprine -ith the e5ception of lymphopenia, -hich -as only obser/ed in a2athioprine+treated patients ' P H $.$#). ;%@< These same patients e5perienced a trend to-ard more infections ' P H $.%F). This study su!!ests that methotre5ate and a2athioprine ha/e similar efficacy at the doses tested, but methotre5ate may ha/e a sli!htly more fa/orable side+effect profile. "t -ould ha/e been nice to see the relati/e efficacy of these treatments -hen methotre5ate -as increased to #= m!>-eek 6 a dose used not uncommonly to achie/e clearance in patients -ith psoriasis.

"nterferon Iamma
"nterferon !amma '"03J) is an important part of the host immune response, particularly a!ainst /iruses. "t is 0DA+appro/ed as a subcutaneous in7ection to reduce the fre.uency and se/erity of infections in chronic !ranulomatous diseases;%F< and to treat mali!nant osteopetrosis. ;#$< "n a recently published case series of pediatric atopic dermatitis patients -ith ec2ema herpeticum, it -as su!!ested that "03J and intra/enous immuno!lobulin '"4"I) are less likely to enhance the cutaneous /iral susceptibility of these patients than other immunomodulators. ;#%< "n summary, althou!h "03J is more e5pensi/e than CSA or methotre5ate, it may be useful as a treatment for moderate+to+se/ere atopic dermatitis patients -ho ha/e a history of recurrent skin infections -ith herpes simple5, molluscum conta!iosum or human papilloma /iruses. This is a particularly tou!h population to treat and more studies are needed to determine ho- and if their treatment should differ from atopic dermatitis patients -ho do not ha/e problems -ith cutaneous /iral infections.

"ntra/enous "mmuno!lobulin
"4"I is 0DA appro/ed for the treatment of pediatric D"4 infections, chronic lymphocytic leukemia, idiopathic thrombocytopenic purpura, Ka-asaki1s disease, primary immunodeficiencies, chronic inflammatory demyelinatin! polyneuropathy, and kidney transplantation -hen there is a hi!h likelihood of re7ection 'AB incompatibility or a recipient -ith markedly ele/ated antibody titer). There are a number of theories proposed for "4"Is mechanism of action in these diseases. These include competin! for 0c receptors of macropha!es and other anti!en presentin! cells, alterin! production of /arious cytokines, neutrali2ation of patho!ens that e5acerbate or initiate the disease process, neutrali2ation of autoantibodies, increasin! the turno/er rate of antibodies, decreasin! B and T

cell proliferation, increasin! the bindin! affinity of !lucocorticoid receptors, inhibitin! complement+mediated dama!e, inhibition of 0as+mediated cell death, and bindin! of cellular adhesion molecules. ;##< Treatment of se/ere refractory atopic dermatitis -ith "4"I has yielded conflictin! results and therefore it is not -idely used. 3e/ertheless, "4"I has been sho-n to contain hi!h concentrations of staphylococcal to5in+specific neutrali2in! antibodies that can inhibit the in+/itro acti/ation of T cells by staphylococcal to5ins. ;#?< "n #$%%, a small case series of four hi!hly aller!ic atopic dermatitis patients 'three pediatric>one adult) demonstrated si!nificant impro/ement -ith monthly infusions of "4"I '$.=6%.$ !>k!>dose), based on SC 8AD assessments, but this benefit -as only obser/ed in pediatric cases. ;#(< This is consistent -ith the prior literature that su!!ests this treatment is most effecti/e in pediatric cases as either a stand+alone treatment or more commonly as add+on therapy. "n a 8CT of "4"I '#.$ !>k!>month for ? months) to treat moderate+to+se/ere pediatric atopic dermatitis patients ' n H ($), a statistically si!nificant reduction in SC 8AD -as obser/ed after three infusions -hich -as e/en more impressi/e by ? months after discontinuin! treatment. ;#=< Unfortunately, disease relapse -as obser/ed by , months after discontinuin! treatment. These impro/ements -ere accompanied by reductions in serum "L+=>"03J ratio, soluble "CA:+%, and eosinophil cationic protein le/els, but no chan!es -ere noted in total eosinophil counts or serum total "!A /alues. Additional 8CT are needed to determine the optimum dose of "4"I for clearance and maintenance and the patient population most likely to respond to this therapy. As "4"I is an e5pensi/e treatment, -ith an unclear mechanism of action, it should !enerally be rele!ated to a last resort treatment approach and probably only in pediatric atopic dermatitis patients.

EEA8+J Anta!onists 'Thia2olidinediones)


Thia2olidinediones -ere ori!inally appro/ed for the treatment of type # diabetes mellitus. These dru!s acti/ate the nuclear receptor, pero5isome proliferator+ acti/ated receptor !amma 'EEA8+J), -hich is e5pressed on adipocytes and most immune cells. Acti/ation of EEA8+J enhances the response to insulin and decreases the production of a number of proinflammatory cytokines includin! "L+, and T30+K. ;#,< EEA8+J a!onists ha/e been e5plored as treatments for a number of inflammatory diseases includin! psoriasis, asthma, and focal se!mental !lomerulosclerosis. The potential benefit of this class of dru!s -as first noted in a retrospecti/e case series of si5 patients -ith recalcitrant atopic dermatitis -ho impro/ed -ith the

addition of rosi!lita2one. ;#G< A recent publication utili2ed a mouse model of atopic dermatitis, referred to as the 3c>3!aTnd mice, to e/aluate -hether systemic administration of rosi!lita2one -as effecti/e. ;#@<8osi!lita2one suppressed the acti/ation of dendritic cells and delayed the de/elopment of atopic dermatitis but had no effect on established atopic dermatitis. This obser/ation su!!ests that EEA8+J a!onists may also inhibit dendritic cell functions by suppressin! the e5pression of costimulatory molecules and the release of inflammatory mediators. Both EEA8+J and EEA8+K a!onists ha/e been sho-n to normali2e epidermal differentiation, ;#F< su!!estin! that they also ha/e potential as barrier repair treatments. The topical application of a EEA8+K a!onist decreased the clinical se/erity of a murine aller!ic contact sensiti2ation model, -hich -as associated -ith impro/ement in skin barrier function and reduced tissue inflammation. ;?$< "n summary, EEA8+J and EEA8+K a!onists, -hich ha/e both anti+inflammatory and barrier restorati/e acti/ity, may be reasonable treatment options for established atopic dermatitis or may ha/e their !reatest effect as pre/enti/e strate!ies.

Ehototherapy
Ehototherapy has lon! been used to treat a -ide /ariety of dermatolo!ic conditions as -ell as seasonal affecti/e disorder and circadian rhythm disorders. The superiority of narro-+band U4B '3BU4B 6 ?%%6?%? nm) ;?%< and hi!h+dose U4A '?($6($$ nm) ;?#,??< in treatin! atopic dermatitis o/er pre/iously used approaches 'broadband U4B and EU4A) is no- .uite clear. Unfortunately, e/en 3BU4B, the most effecti/e phototherapy approach, achie/es only about =$B complete clearance rates in atopic dermatitis patients, -hereas the ma7ority of psoriasis patients !et almost complete clearance. ;?(<
%

A lar!e ' n H %@$ patients), multicenter 8CT demonstrated that %$B Dead Sea salt baths -ith simultaneous 3BU4B therapy -as superior to 3BU4B alone in treatin! atopic dermatitis. ;?=<The authors obser/ed a #,B difference in the t-o treatment !roups as assessed by SC 8AD measurements after , months of therapy. A 8CT crosso/er trial to test the relati/e effecti/eness of 3BU4B, bath+ EU4A, and ?B Dead Sea salt bath plus 3BU4B is currently enrollin! '3CT$%($#(%() and may help sort out the best phototherapy approach for atopic dermatitis patients. A recent, open+label, prospecti/e study ;?,< of %# moderate+to+se/ere atopic dermatitis patients treated -ith three times per -eek 3BU4B treatments identified se/eral biomarkers that correlated -ith disease impro/ement as

measured by SC 8AD. All patients had at least a =$B impro/ement in their disease after %# -eeks of treatment. This impro/ement -as accompanied by decreased e5pression of T # and T## cytokines, normali2ation of epidermal barrier and hyperplasia !enes, and reduction in the dermal infiltrate. This study su!!ests that reducin! the inflammation characteristic of atopic dermatitis skin lesions -ill also re/erse at least some of the epidermal defects 6 a /alidation of the inside+out theory of atopic dermatitis 'e.!. immune+!enerated epidermal dysfunction). "mportantly, this study sets a ne- bar that all inter/entional studies should aspire to, namely, comparin! ob7ecti/e measures of treatment efficacy -ith biomarkers of path-ays rele/ant for disease patho!enesis.
D

Lastly, heliotherapy, or hi!h+dose natural sunli!ht e5posure typically obtained in specific locations 'e.!. the Canary "slands and the Dead Sea), has been sho-n to be effecti/e in treatin! atopic dermatitis. ;?G,?@< Se/eral !roups are be!innin! to e/aluate -hether these benefits can be obtained in an office settin! usin! full+ spectrum li!ht therapy '0SL 6 ?#$ nm6=$$$ nm). ;?F< "n summary, phototherapy is a useful ad7unct treatment in atopic dermatitis patients but is unfortunately not as effecti/e in atopic dermatitis as it is in psoriasis. 9e ha/e little information about the lon!+term side effects of 3BU4B, especially in our pediatric patients -ho mi!ht under!o treatment for many years. Until this increased risk is assessed, -e think it is best to use phototherapy as an intermittent treatment approach especially in the pediatric atopic dermatitis population.

Conclusion
The clinicaltrials.!o/ -ebsite currently lists == acti/ely enrollin! inter/entional studies for atopic dermatitis 'http*>>clinicaltrials.!o/, accessed ?$ :arch #$%#). ur !reater understandin! of the immunopatho!enesis of atopic dermatitis is be!innin! to dri/e much needed clinical trials in this common but inade.uately mana!ed disorder. ur current approach to the treatment of atopic dermatitis has focused on identifyin! and minimi2in! aller!en e5posure and reducin! the Th# predominant tissue inflammation. 9ith the reco!nition that this is a disease mediated at least in part by epidermal barrier disruption as -ell as the release of potent tissue+deri/ed ad7u/ants and cutaneous innate immune defects, -e are likely to see therapies de/eloped that be!in to address these other defects. 9e hope this multipron!ed approach -ill pro/ide !reater relief for our patients than our current treatments ha/e been able to achie/e. "t is certainly possible that an anti+Th#>T## treatment strate!y may also help repair some of the barrier defects,

as the e5pression of a number of key epidermal proteins are inhibited by the cytokines released by these T cells 'e.!. "L+(, "L+%?, and "L+##). "n summary, -e ha/e re/ie-ed key publications from #$%% that ha/e reported on the safety and efficacy of both ne- and pre/iously used systemic treatments for patients -ith moderate+to+se/ere atopic dermatitis.

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