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Effects of biological response modifiers in psoriasis and psoriatic arthritis Goedkoop, A.Y.

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Citation for published version (APA): Goedkoop, A. Y. (2005). Effects of biological response modifiers in psoriasis and psoriatic arthritis

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General introduction and aims of the thesis

Introduction to psoriasis and psoriatic arthritis Psoriasis is a c h r o n i c inflammatory skin disease w i t h an estimated prevalence of 2 % w o r l d w i d e . The t e r m 'psoriasis' was first used by the Greek physician Galen, and is d e r i v e d f r o m the w o r d 'psora' meaning itch. Patients suffering f r o m psoriasis may e x p e r i e n c e p h y s i c a l d i s c o m f o r t as w e l l as a great psychological b u r d e n . The clinical manifestations of psoriasis are abundant and diverse, and the intensity of disease activity varies in t i m e . The most c o m m o n clinical presentation is plaque-type psoriasis or psoriasis vulgaris, w h i c h is characterized by sharply demarcated erythemateus plaques w i t h silvery scaling presenting symmetrically on the extensor side of the elbows a n d knees, a n d t h e l u m b o s a c r a l r e g i o n . This t y p e o f psoriasis is o f t e n accompanied by i n v o l v e m e n t of nails and scalp. O t h e r types of psoriasis are divided into those p r i m a r i l y describing the f o r m (guttate, pustular, annular) or t h e d i s t r i b u t i o n (flexural, palmoplantar, disseminated). Guttate psoriasis is characterized by n u m e r o u s small coin-sized papules d i s t r i b u t e d over the w h o l e body, and flexural psoriasis is characterized by erythemateus plaques in b o d y f o l d s such as t h e g r o i n s , axillae, a n d t h e s u b m a m m a r y r e g i o n . Erythrodermic psoriasis and generalized pustular psoriasis are potentially lifethreatening manifestations of psoriasis often r e q u i r i n g hospitalization. An arthritis associated w i t h psoriasis was first recognized in the m i d - n i n e t e e n t h century and in 1860 Paul Bazin c o i n e d the term 'psoriasis a r t h r o p a t h i q u e ' 1 2 . It was not until 1964 that the American Rheumatism Association recognised it as a separate entity. Approximately 25-34 percent of patients w i t h skin psoriasis develop psoriatic arthritis (PsA)3-4, a seronegative destructive joint disease w i t h 5 different subtypes: asymmetrical oligo-articular arthritis (70%), symmetrical poly-arthritis (15%), distal interphalangeal arthritis (5%), spinal/axial arthritis (5%), and arthritis mutulans (5%) 5 . W i t h o u t p r o p e r treatment PsA can lead to j o i n t degeneration and loss of f u n c t i o n . Usually the skin psoriasis precedes the arthritis, but in 19% of the cases arthritis is present before skin lesions develop 3 .

Immunopathology of psoriasis and psoriatic a r t h r i t i s 6 I n t r o d u c t i o n A l t h o u g h the exact origin of psoriasis and PsA has not been established yet, the i m m u n o p a t h o g e n e t i c pathways leading to the d e v e l o p m e n t of a psoriatic plaque have been subject t o extensive studies in the last decades. In a d d i t i o n , the i n t r o d u c t i o n of new biological therapies for psoriasis has p r o v e n t o be a powerful t o o l in the investigation of the psoriatic i m m u n e responses.

In general, the i n i t i a t i o n and e x a c e r b a t i o n of b o t h

p s o r i a s i s a n d PsA p r o b a b l y r e s u l t f r o m an i n t e r a c t i o n o f

genetic,

e n v i r o n m e n t a l , a n d i m m u n o l o g i c a l factors. The m o r p h o l o g y of lesional psoriatic skin is characterised by 3 major histological changes: 1) epidermal t h i c k e n i n g , p a r a k e r a t o s i s , and h y p e r k e r a t o s i s ; 2) a p r o n o u n c e d d e r m a l vascular plexus; and 3) the presence of inflammatory cells (e.g. T cells and n e u t r o p h i l i c granulocytes) in the superficial dermis and in the epidermis. Few studies have analyzed the i m m u n o h i s t o c h e m i c a l changes in synovial tissues in PsA. Histological features of synovial tissue i n c l u d e infiltration by m a c r o p h a g e s , T cells, a n d other i n f l a m m a t o r y cells 7 '', hyperplasia o f the synovial l i n i n g , a n d vascular changes, described as t o r t u o s i t y and higher intensity of villous vascularization 9 1 0 . In a d d i t i o n , high IL-8 levels were f o u n d in PsA synovial f l u i d , o u t l i n i n g t h e i m p o r t a n c e of this c h e m o k i n e in t h e r e c r u i t m e n t of i n f l a m m a t o r y cells in patients w i t h PsA". In a d d i t i o n t o cellm e d i a t e d i m m u n e responses, humoral i m m u n e responses are believed t o play a role in t h e pathogenesis of PsA as w e l l . For example, serum levels of IgA and IgC are higher in PsA patients", and synovial membranes f r o m patients w i t h PsA c o n t a i n h i g h e r numbers o f plasma cells positive for IgG or IgA than patients w i t h meniscal tears 12 .

T cells in psoriasis Increasing evidence suggests that T cells play a key role in the pathogenesis of psoriasis. In 1983, Bos e t a l . showed that the majority of the d e r m a l inflammatory infiltrate consists of partially activated CD4' and CD8 + T cells''. These cells express CD45RO on the surface, indicating their effector / m e m o r y status' 415 . M o s t of the infiltrating T cells also express markers such as t h e interleukin-2 receptor (CD25) a n d HLA-DR, indicating early and mid-tolate activation, respectively"'"'" 1 ". The infiltration of T cells into the skin precedes e p i d e r m a l p r o l i f e r a t i o n and endothelial cell activation 1 9 . The key role for T

l y m p h o c y t e s in the pathogenesis of psoriasis was s u p p o r t e d by r e p o r t e d beneficial effects of specific T-cell targeted therapies, such as cyclosporine A and DAB389IL-2 toxin, and more recently alefacept 20 2j . Because of this, psoriasis is n o w suggested t o be a T-cell mediated inflammatory disease. H o w d o T cells play a role in the d e v e l o p m e n t of a psoriatic plaque? To create a better u n d e r s t a n d i n g of this process, it can be b r o k e n d o w n in t h r e e separate steps: 1 t h e activation of T cells 2 the migration of T cells into the lesional skin 3 t h e release of cytokines by activated T cells in the skin.

Ad 1) Initial T-cell activation requires s t i m u l a t i o n of the T-cell receptor (TCR) by t h e m a j o r h i s t o c o m p a t i b i l i t y c o m p l e x ( M H C I o r II) o n t h e a n t i g e n p r e s e n t i n g cell (APC). A l t h o u g h this is believed t o be an antigen-specific process, the antigenic p e p t i d e responsible in psoriasis has as yet not been i d e n t i f i e d . The a d h e s i o n of the T cell w i t h t h e APC is facilitated by t h e interaction of surface molecules, such as CD2 o n t h e T cell w i t h leukocyte f u n c t i o n associated antigen (LFA)-3 o n t h e APC, or LFA-1 (CD11a) o n t h e T cells w i t h intercellular adhesion m o l e c u l e (ICAM)-1 o n the APC24. After the initial activation via the TCR, a second, non-antigen specific signal is needed t o c o m p l e t e the activation. T h i s ' c o s t i m u l a t o r y ' signal results f r o m interactions b e t w e e n molecules on the T cell and their ligands on APCs, for example CD2/ LFA-3, very-late antigen 4 (VLA-4)/vascular cell adhesion molecule 1 ( V C A M 1), LFA-1/ICAM-1, CD40/CD40L, and o t h e r s 2 " 0 . Simultaneous delivery of b o t h signals is essential f o r T cell activation, and if the c o s t i m u l a t o r y signal is i n h i b i t e d , T cells can become unresponsive or 'anergic'. A n u m b e r of new biological therapies for psoriasis have been d e v e l o p e d t o i n h i b i t T cell activation in one way or another, for example efalizumab, a h u m a n i z e d anti-CD11a m o n o c l o n a l a n t i b o d y , and alefacept, a LFA-3/lgG1 fusion p r o t e i n . These and o t h e r biologicals will be discussed f u r t h e r o n in this i n t r o d u c t i o n

Ad 2) O n c e activated, T cells obtain certain cell surface proteins, w h i c h are necessary for migration f r o m l y m p h nodes and b l o o d vessels into extranodal

tissue, such as the skin. T-cell trafficking t o the skin is a complicated process t h a t r e q u i r e s i n t e n s i v e i n t e r a c t i o n b e t w e e n the activated T cell a n d t h e e n d o t h e l i u m . First, T cells must be s l o w e d d o w n in the b l o o d stream in order t o be i m m o b i l i z e d and t o bind t o the e n d o t h e l i u m . This process, called ' t e t h e r i n g ' , is m e d i a t e d by the g l y c o p r o t e i n cutaneous l y m p h o c y t e antigen (CLA), w h i c h is expressed o n the surface of activated T cells in psoriasis 31 . CLA is an a d h e s i o n m o l e c u l e that interacts w i t h E-selectin and P-selectin, w h i c h are strongly upregulated o n e n d o t h e l i u m d u r i n g cutaneous i n f l a m mation 3 2 .

Both lesional a n d non-lesional skin of psoriasis patients shows

u p r e g u l a t i o n of t h e s e a d h e s i o n molecules 3 3 . T e m p o r a r y b i n d i n g o f t h e selectins w i t h the receptors on t h e T cell surface creates a r o l l i n g m o t i o n , w h i c h slows the T cell down 343 "'. This allows t h e T cell t o be e x p o s e d t o c h e m o k i n e s that activate T-cell surface proteins, such as LFA-1 and very-late a n t i g e n (VLA)-4. These integrin r e c e p t o r s f o r m h i g h - a f f i n i t y b o n d s w i t h respectively ICAM-1 and VCAM-1 o n endothelial cells, resulting in an arrest of t h e rolling process and subsequent flattening of the activated T cell, w h i c h facilitates the diapedesis of the T cell t h r o u g h the b l o o d vessel wall 36 . After extravasation t h r o u g h the bloodvessel wall, skin-homing Tcells migrate t o the d e r m i s and epidermis in response t o chemotactic gradients. The chemokines that enhance T-cell trafficking are p r o d u c e d by endothelial cells, keratinocytes, monocytes, and Langerhans cells, a n d their release is stimulated by interferon (IFN)-y and t u m o u r necrosis factor (TNF)-cc37.

Ad 3) Activated T cells p r o d u c e a certain c y t o k i n e profile and based on this T cells are g e n e r a l l y d i v i d e d in two types. Type 1 T cells p r o d u c e t h e p r o i n f l a m m a t o r y cytokines interleukin (IL)-2, IFN-y, and TNF-a, whereas type 2 T cells p r o d u c e cytokines such as IL-5, IL-4, and IL-10. Activated T cells isolated f r o m psoriasis lesions s h o w e d a p r e d o m i n a n t type 1 cytokine profile 38,39 . Both C D 4 * a n d C D 8 ' T cells can produce type 1 cytokines 4041 . There have been several reports describing a predominance of cytotoxic C D 8 l T cells in psoriatic lesional epidermis, whereas CD4 + cells are the predominant type in lesional dermis 1314 ' 42 . The secretion of cytokines by activated T cells influences n e i g h b o u r i n g cells, such as keratinocytes and dendritic cells, w h i c h in t u r n release additional cytokines, creating a chronic inflammatory cascade41. IFN-y has been s h o w n t o

induce epidermal hyperplasia w h e n injected into non-lesional skin of psoriasis patients 43 . Also, IFN-y stimulates the expression of ICAM-1 by e p i d e r m a l keratinocytes, facilitating the b i n d i n g of T cells t o keratinocytes. TNF-oc is a n o t h e r i m p o r t a n t p r o i n f l a m m a t o r y c y t o k i n e t h a t plays a r o l e in t h e pathogenesis and maintenance of psoriasis. The role o f TNF-a and TNF-a inhibitors w i l l be discussed f u r t h e r o n in the i n t r o d u c t i o n .

T cells in psoriatic arthritis cells predominate

744

In synovial tissue, activated m e m o r y CD4+ T

, w h i c h are focally distributed near small b l o o d vessels

and the intimal lining layer 8 , whereas in synovial PsA f l u i d activated CD8+ T cells predominate 4 5 . The d e m o n s t r a t i o n of oligoclonal expansions of T cells derived f r o m synovial f l u i d of patients w i t h PsA supports the hypothesis that T cells are involved in the pathogenesis of PsA4('. Findings of c o m m o n T cell receptor pV expansions in psoriatic skin and synovium suggest an i m p o r t a n t role for cognate T-cell responses and suggest that t h e i n c i t i n g antigens are identical or h o m o l o g o u s b e t w e e n afflicted skin and synovium 4 7 . N u m e r o u s c h e m o k i n e s and cytokines, such as TNF-a, IL-1[3, IL-2, IL-8, IL-10, IL-15, IL-18, and IFN-y are b e l i e v e d t o play a role in t r i g g e r i n g cell p r o l i f e r a t i o n and s u s t a i n i n g j o i n t i n f l a m m a t i o n in PsA 4852 . The e x p r e s s i o n of t h e cellular adhesion molecules I C A M - 1 , V C A M - 1 , and E-selectin facilitate m i g r a t i o n of activated T cells t h r o u g h the vascular e n d o t h e l i u m and f o r m a t i o n o f an infiltrate in synovial PsA tissue 51 . Further evidence that T cells play a role in the pathogenesis is p r o v i d e d by the observation that anti-T-cell targeted therapy has proven t o be beneficial in PsA54.

T N F - a in psoriasis

TNF-a is a p r o - i n f l a m m a t o r y c y t o k i n e p r o d u c e d by

activated T cells, keratinocytes, monocytes, and d e n d r i t i c cells in human skin 55 . It exists as a m e m b r a n e - b o u n d molecule on cells that p r o d u c e it, as a soluble protein in the circulation, and b o u n d t o cell surface receptors on target cells, such as keratinocytes, d e n d r i t i c cells, T cells, NK cells, and e n d o t h e l i a l cells 56 . TNF-a has n u m e r o u s effects on the i m m u n e response, correlating w i t h the clinical and histological pathology seen in psoriatic skin. TNF-a can induce t h e expression of a d h e s i o n molecules, such as I C A M - 1 , V C A M - 1 , a n d Eselectin 5758 , and vascular g r o w t h factors, such as vascular e n d o t h e l i a l g r o w t h

factor (VEGF)59 in the skin, p r o m o t i n g T cell trafficking. In a d d i t i o n , TNF-a has b e e n d e m o n s t r a t e d t o increase t h e expression of o t h e r p r o i n f l a m m a t o r y c y t o k i n e s , such as I L - 1 , IL-5, IL-6, and t r a n s f o r m i n g g r o w t h factor, a n d c h e m o k i n e s , such as IL-8, a member of the CXC c h e m o k i n e family, thereby e n h a n c i n g the i n f i l t r a t i o n of T cells into the epidermis'' 0 6 1 . Nuclear factor KB ( N F K B ) , a nuclear t r a n s c r i p t i o n factor that is crucial in i n f l a m m a t i o n , is also activated by TNF-a 6 2 . Finally, TNF-a stimulates mature Langerhans cells t o migrate f r o m the skin t o the lymph nodes, w h e r e antigen presentation and Tcell activation take place 65 . Substantial evidence suggests that TNF plays a f u n d a m e n t a l role in the pathogenesis o f psoriasis. Increased levels of TNF-a c o m p a r e d t o c o n t r o l s have been r e p o r t e d in psoriatic lesional skin 5864 . Levels of TNF-a in psoriatic lesional skin have been f o u n d t o correlate w i t h severity of psoriasis 65 . In a d d i t i o n , levels of TNF in skin and serum of psoriasis patients have been d e m o n s t r a t e d t o decrease after successful therapy 6660 . The most c o n v i n c i n g evidence, linkingTNF-a t o psoriasis, is the ability of TNF-a inhibitors such as etanercept, infliximab, and adalimumab to ameliorate clinical symptoms of psoriasis. Clinical trials w i t h infliximab and etanercept for psoriasis and PsA are discussed elsewhere in the introduction.

T N F - a in psoriatic arthritis In PsA, TNF-a activates N F - K B , leading to synovial cell p r o l i f e r a t i o n , l e u k o c y t e trafficking, f u r t h e r p r o i n f l a m m a t o r y c y t o k i n e p r o d u c t i o n , and u p - r e g u l a t i o n of RANKL-mediated osteoclastogenesis 50,53,69 . A significantly h i g h e r concentration of TNF-a and its receptors have been r e p o r t e d in PsA synovial f l u i d compared w i t h osteoarthritis 48 ' 49 "- 70 . Examination o f serial synovial biopsies in four PsA patients, w h o participated in an o p e n study o n the effects of the chimeric anti-TNF a n t i b o d y infliximab, has s h o w n that clinical i m p r o v e m e n t o f peripheral arthritis activity is associated w i t h decreased intimal l i n i n g layer hyperplasia, reduced vascularity, and reduced p o l y m o r p h o n u c l e a r cell and macrophage infiltration 7 1 .

Angiogenesis in psoriasis Neovacularization appears t o play an i m p o r t a n t role in t h e e v o l u t i o n of a psoriatic plaque. Epidermal p r o l i f e r a t i o n is closely associated w i t h vascular expansion in t h e superficial d e r m i s early in t h e d e v e l o p m e n t of a psoriatic plaque. Studies demonstrated that abnormal b l o o d

vessel g r o w t h c o u l d predict the area of skin to be involved in the inflammatory process 72 . Microvascular changes include exaggerated tortuosity, p r o n o u n c e d dilatation, increased permeability, and endothelial cell proliferation w i t h i n the capillaries in the dermal papillae 7 ^ 74 . Vascular proliferation is driven by the local expression of angiogenic molecules (mostly derived f r o m keratinocytes), such as transforming g r o w t h factor-a, TNF-a, plasminogen activator inhibitor (PAI)1, platelet-derived endothelial cell g r o w t h factor, endothelial cell stimulating angiogenesis factor (ESAF), and vascular endothelial g r o w t h factor (VEGF)75-76. VEGF induces microvascular hyperpermeability and acts as an endothelial cellspecific mitogen, and is recognized as a central regulator of angiogenesis 77,78 . Both ESAF and VEGF w e r e f o u n d t o be elevated in plaques of psoriasis as c o m p a r e d w i t h uninvolved skin and normal skin 79 . Tissue and serum levels of EASF, PAI-1, and VEGF correlated w i t h the clinical severity of psoriasis, suggesting a pathogenetic role in psoriasis80"02. Indeed, a randomized phase l/lI trial w i t h Neovastat, an inhibitor of angiogenesis, revealed a dose-dependent effect of this d r u g in the improvement in psoriasis 85 .

Angiogenesis in psoriatic arthritis

In previous studies of PsA t h e most

significant histological findings w e r e vascular changes, described as tortuosity and higher intensity of villous vascularization 9 ' 10 - 8485 , s u p p o r t i n g the t h e o r y that microvascular changes play an important role in the pathogenesis of PsA86. In a d d i t i o n , synovial fluid metalloproteinases such as matrix metalloproteinase (MMP)-9 correlate w i t h the pattern of neo-vascularization and synovial f l u i d VEGF levels 87 . Elevated VEGF concentrations, p r o d u c e d by macrophages and fibroblast-like synoviocytes, have been r e p o r t e d in serum and synovial f l u i d of patients w i t h PsA81'8889. O t h e r g r o w t h factors that c o n t r o l angiogenesis are the angiopoietins (Ang). Ang1 induces stable maturation of b l o o d vessels, whereas Ang2 plays a role in vessel r e m o d e l l i n g and maturation. Ang2 and VEGF mRNA expression and p r o t e i n levels w e r e significantly higher in early PsA c o m p a r e d w i t h rheumatoid arthritis synovium 81 - 86 . Angiogenesis also plays a role in b o n e f o r m a t i o n , since invasion of the cartilage by new b l o o d vessels precedes osteoblastic t r a n s f o r m a t i o n and ossification. H o w e v e r , data o n vascular changes in PsA synovial tissue are sparse and sometimes c o n f l i c t i n g , possible d u e t o differences in patient's selection.

Genetics in psoriasis and psoriatic arthritis 9 0 P o p u l a t i o n and t w i n studies support the concept that psoriasis and PsA have a g e n e t i c basis 9 1 9 2 . G e n e t i c l i n k a g e s t u d i e s have c o n f i r m e d a g e n e t i c predisposition. It has been estimated that the HLA-associated allele PSORS1 o n c h r o m o s o m e 6p accounts for 30 t o 50% of the genetic c o n t r i b u t i o n t o psoriasis 91 . This locus contains genes coding for HLA-C, corneodesmosin (Cdsn), a n d alpha-helix c o i l e d - c o i l rod h o m o l o g (HCR) w h i c h w e r e f o u n d t o be expressed at higher levels in psoriatic lesional skin than in normal skin 9 4 9 6 . Predisposing loci other than HLA include 17q24-q25 in a variety of Caucasian populations 9 7 9 9 , 4qter (PSORS3) in Irish families" 10 ,1q21 (PSORS4) in Italian and U.S. families101'102, 3q21 (PSORS5) in Swedish families 10 ' and some other loci. Strong evidence of familial aggregation in PsA has been f o u n d as well, the risk o f PsA was f o u n d t o be 50 times greater in first-degree relatives of PsA patients than in a c o n t r o l population 9 1 . However, association of the HLA locus w i t h PsA has been less clear-cut than with psoriasis 1 " 4 . HLA B27 has traditionally been associated w i t h spinal inflammation 1 "'', and associations of PsA w i t h other loci have been described as well1"'''107. Finally, p r o m o t e r polymorphisms of the genes e n c o d i n g TNF-a and IL-1[3 have been f o u n d to be associated w i t h different subtypes of psoriasis characterized by early and late disease onset108-109. It is clear that the genetic predisposition for psoriasis and PsA is c o m p l e x and c a n n o t be ascribed to a single gene. For n o w , the cause of psoriasis and PsA can be considered t o be multifactorial, resulting f r o m an interaction of genetic, e n v i r o n m e n t a l , and i m m u n o l o g i c a l factors.

Biological response modifiers in psoriasis and psoriatic a r t h r i t i s W h y d o w e n e e d n e w therapies for psoriasis and PsA? C u r r e n t therapies such as p h o t o ( c h e m o ) t h e r a p y , cyclosporine A, and methotrexate are effective for psoriasis, b u t are l i m i t e d in their use because of their potential side-effects. C y c l o s p o r i n e may cause hypertension and renal failure, and methotrexate c o m m o n l y causes malaise and h e p a t o t o x i c i t y . P h o t o ( c h e m o ) t h e r a p y , in particular PUVA, increases t h e risk of skin cancer, w h i c h limits its use in a c h r o n i c d i s e a s e such as psoriasis. In a d d i t i o n , a National Psoriasis Foundation Survey s h o w e d that o n l y 26% of patients w i t h psoriasis are satisfied w i t h their

c u r r e n t treatment" 0 . Therapeutic options for patients suffering f r o m PsA have been limited as well d u r i n g t h e last decades. In contrastto rheumatoid arthritis, n o disease-modifying anti-rheumatic therapy has been available for PsA except for methotrexate. Instead, s y m p t o m - m o d i f y i n g drugs such as non-steroidal a n t i - i n f l a m m a t o r y drugs (NSAIDs) are used t o ameliorate pain. For these reasons there is a clear need for effective and long-lasting anti-psoriatic and anti-PsA treatments w i t h limited side-effect profiles. I m p r o v e d u n d e r s t a n d i n g o f t h e i m m u n o p a t h o g e n e t i c m e c h a n i s m s in psoriasis and PsA has led t o the rapid d e v e l o p m e n t of the so-called biological response modifiers ("biologicals"), a versatile g r o u p of e n g i n e e r e d bioactive proteins. Biologicals can be d i v i d e d into three main groups a c c o r d i n g their molecular structure: m o n o c l o n a l antibodies, fusion proteins, and cytokines. The generic names of the biologicals comply to a strict nomenclature: chimeric monoclonals end w i t h - x i m a b , h u m a n i z e d monoclonals e n d w i t h - z u m a b , h u m a n monclonals end w i t h - u m a b , and receptor-antibody fusion proteins e n d w i t h -cept 6 . Table 1 shows the biological response modifiers currently a p p r o v e d or under d e v e l o p m e n t for psoriasis and/or PsA.

Monoclonal antibodies a n t i - a d h e s i o n Efalizumab Efalizumab is a recombinant, humanized monoclonal lgG1 antibody directed against the a subunit (CD11a) of leukocyte f u n c t i o n associated antigen (LFA)-1111. In psoriasis, b i n d i n g of LFA-1 on m e m o r y T-cells t o ICAM-1 on keratinocytes and vascular e n d o t h e l i a l cells leads t o T-cell activation as well as trafficking of T cells f r o m the circulation into the skin 112 . This provides the rationale f o r b l o c k i n g the LFA-1/ICAM-1 interaction w i t h e f a l i z u m a b in t h e t r e a t m e n t of psoriasis 1 1 3 . Data f r o m in v i t r o s t u d i e s d e m o n s t r a t e d that e f a l i z u m a b i n h i b i t s m u l t i p l e key p a t h o g e n i c steps in psoriasis: T-cell activation 114 , T-cell trafficking to the skin 115 , and T-cell adhesion t o keratinocytes" 4 . The biological effects of efalizumab and clinical activity were d e m o n s t r a t e d in clinical t r i a l s " 6 " 7 . Gottlieb et al (2000) d e m o n s t r a t e d in an o p e n label study that intravenous administered efalizumab resulted in i m p r o v e m e n t in psoriasis area and severity index (PASI), decreased n u m b e r s o f e p i d e r m a l a n d d e r m a l T cells, d e c r e a s e d e x p r e s s i o n o f I C A M - 1 on keratinocytes and b l o o d vessels, and epidermal t h i n n i n g . There was an inverse

relationship between sustained CD11a down-modulation and saturation and improvement of histological parameters'1". Another open-label study by the same author confirmed these observations, and demonstrated a doseresponse relationship both clinically and histological. The mean PASI decrease in the highest dosage group was 47 percent117. In the peripheral blood, administration of efalizumab to psoriasis patients resulted in an increase in circulating leukocytes, which was largely caused by an increase in T-cell numbers as opposed to other leukocytes. The largest increase was observed in memory CD8' T cells, suggesting that efalizumab blocks cutaneous entry of memory CD8' T cells11'1. Immunohistochemical changes induced by efalizumab were mirrored by reports on clinical improvement in psoriasis patients treated with efalizumab. In a randomized, double-blind, placebocontrolled multicentre phase II trial 144 psoriasis patients received either placebo or i.v. efalizumab 0.3 mg/kg for 8 weeks. The percentage of efalizumabtreated patients achieving more than 50% improvement in physician's global assessment at day 56 was 48%, compared to 15% of the placebo-treated patients. Epidermal thickness was reduced by 37% in efalizumab-treated patients and 19% in placebo-treated patients. Treatment was well tolerated; mild to moderate flu-like complaints were the most common adverse events. Depletion of circulating lymphocytes did not occur120. To provide a more c o n v e n i e n t mode of administration, a subcutaneous f o r m u l a t i o n of efalizumab was developed and used in phase III clinical trials. Five hundred ninety-seven patients with chronic plaque psoriasis were treated with either efalizumab (1 or 2 mg/kg s.c.) or placebo once weekly for 12 consecutive weeks in a phase III multicentre, randomized, placebo-controlled, double-blinded study. Depending on the response after 12 weeks, subjects received an additional 12 weeks of treatment with efalizumab or placebo. At week 12, PASI 75 (75% or more reduction in PASI) was achieved by 22% of the patients who had received 1 mg/kg of efalizumab and 28% of those who had received 2 mg/kg of efalizumab, as compared with 5% of the subjects in the placebo group. Efalizumab-treated subjects had greater improvement than those in the placebo group as early as week 4. After the discontinuation of efalizumab at week 24, an improvement of 50 percent or more in the PASI was maintained in approximately 30% percent of patients during the 12 weeks of follow-up.

Efalizumab was well tolerated, and adverse events were generally mild to moderate 1 - 1 . Finally, in a recently p e r f o r m e d phase III, multicentre, randomized, double-blinded, placebo-controlled study 556 patients with moderate to severe psoriasis were treated with efalizumab 1 mg/kg s.c. or placebo weekly for 12 weeks. At week 12, 27% of efalizumab-treated patients achieved PASI 75, and 59% of efalizumab-treated patients achieved PASI 50 (50% or more reduction in PASI). After the first 12-week treatment period, all patients were treated with 1 mg/kg efalizumab weekly for another 12 weeks. After 24 weeks of continuous efalizumab therapy, 44% of patients achieved PASI 75 and 67% achieved PASI 50, suggesting that extending efalizumab treatment from 12 to 24 weeks leads to improved efficacy. There was a decline in adverse events during the study without evidence of cumulative toxic effects122. In phase III studies, efalizumab has been anecdotally reported to improve PsA. This finding is in agreement with the notion that the interaction between LFA-1 and ICAM-1 represents a major adhesion pathway in lymphocytic homing in PsAl2\ Recently, efalizumab was tested in a phase II randomized trial in 107 patients with PsA. Preliminary results showed that after 12 weeks of treatment, 28 percent of the efalizumab-treated patients achieved a 20% or more reduction in American College of Rheumatology (ACR124) response criteria, compared to 19 percent of the placebo-treated patients125. Efalizumab is approved for the treatment of moderate to severe psoriasis in the U.S.A. and most countries in Europe.

anti-cytokine Infliximab

Infliximab is a monoclonal chimeric antibody composed of a

murine anti-TNF Fab fragment joined to the constant region of human lgG1. Each molecule of infliximab has two antigen-binding sites for TNF-a, allowing for increased binding avidity to both membrane-bound and soluble TNF-a56. Infliximab can neutralize both transmembrane-bound TNF-a on the cells that synthesize it (e.g. T cells, keratinocytes, and dendritic cells), and soluble circulating TNF-a, thereby inhibiting the pro-inflammatory effects of TNF-a. In addition, in vitro studies have suggested that binding of infliximab to membrane-bound TNF-a could lead to lysis of TNF-a producing cells via activation of complement-dependent or antibody-dependent cell-mediated

toxicity 126 . The clinical efficacy of infliximab in psoriasis was first demonstrated w h e n a patient treated w i t h infliximab for Crohn's disease s h o w e d a dramatic i m p r o v e m e n t of her psoriasis lesions as well' 2 7 . Next, the clinical efficacy of infliximab was c o n f i r m e d in a small investigator-initiated, randomized, d o u b l e b l i n d e d , p l a c e b o - c o n t r o l l e d trial of 33 patients w i t h plaque type psoriasis, w h o w e r e treated w i t h either infliximab i.v. 5 mg/kg, infliximab i.v. 10 mg/kg o r placebo at weeks 0,2, and 6. At w e e k 10, PASI 75 was achieved by 82 percent o f t h e patients in the 5 mg/kg i n f l i x i m a b and 73 percent in the 10 m g / k g i n f l i x i m a b g r o u p , c o m p a r e d with 18 percent of patients in the placebo g r o u p . The infliximab-treated g r o u p showed a safety p r o f i l e similar t o that of the placebo g r o u p , w i t h headache being the only adverse event recorded m o r e f r e q u e n t l y in the 10mg/kg group 128 . At the end of this study, ' n o n - r e s p o n d i n g ' patients in the p l a c e b o - g r o u p were r a n d o m i z e d t o receive either 5 mg/kg or 10 m g / k g infliximab at weeks 10, 12, and 16, and r e s p o n d i n g patients in the i n f l i x i m a b g r o u p s w e r e evaluated for relapse (loss of at least half o f t h e i m p r o v e m e n t in PASI at w e e k 10) and retreated w i t h open-label infliximab (5 or 10 mg/kg) as n e e d e d . In all, 29 patients received either 5 or 10 mg/kg of i n f l i x i m a b . At w e e k 26, 55 percent of patients maintained a PASI 50 or better, and 48 percent of patients maintained at least PASI 7512'1. Subsequently, the efficacy and safety of infliximab for the treatment of psoriasis were investigated in a phase II trial (SPIRIT trial) from w h i c h the results w e r e recently p u b l i s h e d . In this study, 249 patients w i t h severe plaque psoriasis were r a n d o m i z e d t o receive infliximab 5 mg/kg i.v., infliximab 3 mg/kg i.v., or placebo at weeks 0,2, and 6. At w e e k 10, 88 p e r c e n t of the patients in the 5 mg/kg infliximab g r o u p and 72 percent of t h e patients in the 3 mg/kg infliximab g r o u p achieved PASI 75, c o m p a r e d t o 6 percent in the placebo g r o u p . Furthermore, patients treated w i t h infliximab s h o w e d rapid onset of i m p r o v e m e n t f r o m baseline in psoriasis. M a x i m u m response t o infliximab therapy was observed 10 weeks after the first i n f u s i o n . The d u r a t i o n of response was variable for individual patients, but in general patients started to lose response after 10 weeks (3 mg/kg group) a n d 14 weeks (5 mg/kg), respectively. Four patients were c o n s i d e r e d t o have s e r i o u s a d v e r s e e v e n t s related t o i n f l i x i m a b t h e r a p y , w h i c h

included

squamous cell carcinoma, cholecystitis, diverticulitis, and pyelonephritis w i t h sepsis. Infusion reactions, such as chills, headache, nausea, and dyspnoea,

were reported in 18 and 22 percent of patients in the infliximab (3 and 5 mg/kg) groups, respectively, c o m p a r e d w i t h 2 percent in the placebo g r o u p . There were n o serious or life-threatening infusion reactions. A l t h o u g h the incidence o f infusion reactions at w e e k 26 was approximately 2 t o 3-fold higher for patients w i t h antibodies to infliximab relative to those w h o w e r e negative for antibodies, the majority of patients w i t h antibodies d i d not have any infusion reaction. The i n c i d e n c e of n e w l y positive anti-nuclear a n t i b o d i e s (ANAs) observed in this study was 22-25 percent, however, n o patients in this study d e v e l o p e d symptoms of d r u g - i n d u c e d lupus or lupus like s y n d r o m e . O t h e r safety c o n c e r n s such as t h e d e v e l o p m e n t of t u b e r c u l o s i s or m a l i g n a n t l y m p h o m a were not observed d u r i n g this study' 30 . In addition t o the beneficial e f f e c t o f i n f l i x i m a b o n s k i n l e s i o n s in p s o r i a s i s , i n f l i x i m a b has b e e n d e m o n s t r a t e d t o reduce clinical signs and s y m p t o m s o f PsA as w e l l . Ten patients w i t h severe polyarticular PsA w e r e treated w i t h infliximab 5 mg/kg i.v. in c o m b i n a t i o n w i t h their current therapy at weeks 0, 2, and 6 in a small open-label study. At w e e k 10,8 of 10 patients achieved an ACR 70 response 131 . In a n o t h e r open-label study, 9 patients w i t h active PsA w e r e treated w i t h infliximab 3 mg/kg i.v. at weeks 0, 2, 6,14, and 22. At week 22, ACR 20, ACR 50, a n d ACR 70 w e r e a c h i e v e d by 8, 5, a n d 2 p a t i e n t s , respectively 1 3 2 . The observations in these studies led t o a larger-scale, 16-week placebo-controlled trial f o l l o w e d by a 34-week o p e n label extension to test the efficacy and safety of infliximab 5 mg/kg in 102 patients w i t h PsA (IMPACT trial). At week 16, ACR 20, ACR 50, and ACR 70 w e r e achieved by 69,49, and 29 percent of patients in the infliximab g r o u p and 8,0, and 0 percent of patients in the placebo g r o u p . The i m p r o v e m e n t o b s e r v e d in this study was not clearly related t o the c o n t i n u e d use o f c o n c o m i t a n t disease-modifying a n t i - r h e u m a t i c drugs 133 . Recently, results w e r e p u b l i s h e d f r o m the IMPACT2 trial, a phase III study in w h i c h the efficacy and safety o f i n f l i x i m a b w e r e investigated in a larger p o p u l a t i o n of patients w i t h PsA. A total of 200 patients w i t h active PsA w e r e r a n d o m i z e d t o receive either placebo or infliximab 5 mg/kg i.v. at weeks 0,2, 6, 14, and 22, in c o m b i n a t i o n w i t h stable doses o f MTX. At w e e k 14, ACR 20, ACR 50, and ACR 70 was achieved by 58, 36, and 15 p e r c e n t of infliximabt r e a t e d p a t i e n t s , a n d 1 1 , 3, a n d 1 p e r c e n t o f p l a c e b o - t r e a t e d p a t i e n t s , respectively. The incidence of adverse events was comparable b e t w e e n the

i n f l i x i m a b g r o u p and t h e placebo g r o u p . No o p p o r t u n i s t i c infections, such as t u b e r c u l o s i s , or serious infusion reactions were observed. Five percent of infliximab-treated patients were positive for anti-infliximab antibodies at week 22. N e w l y positive ANAs w e r e detected in 10 percent of infliximab-treated patients. N o n e of the patients developed a lupus-like condition 1 5 4 .

A d a l i m u m a b A d a l i m u m a b is a fully human-derived recombinant monoclonal a n t i b o d y that binds TNF-a and blocks its interaction w i t h the p55 and p75 cell s u r f a c e TNF receptors 1 1 5 . Initially, a d a l i m u m a b was d e v e l o p e d t o treat r h e u m a t o i d arthritis, but recently t w o patients w i t h chronic severe recalcitrant psoriasis and PsA w e r e reported w h o experienced significant i m p r o v e m e n t in b o t h skin and j o i n t disease after treatment w i t h adalimumab 40 mg s.c. every o t h e r week 136 . The results of a phase II, d o u b l e - b l i n d e d , placebo-controlled, r a n d o m i z e d trial w e r e presented as a poster p u b l i c a t i o n at the American A c a d e m y of D e r m a t o l o g y meeting in February 2004. Patients w i t h moderate t o severe plaque psoriasis (n=148) were treated w i t h adalimumab 40 mg s.c. weekly, a d a l i m u m a b 40 mgs.c. every other w e e k (eow), or placebo. At week 12, PASI 50 was achieved by 88 percent of patients treated w i t h adalimumab weekly, by 76 percent of patients treated w i t h adalimumab eow, and by 17 percent of placebotreated patients. PASI 75 was achieved by 80 percent of patients treated w i t h a d a l i m u m a b weekly, 53 percent of patients treated w i t h adalimumab eow, and by 4 percent of placebo-treated patients. A d a l i m u m a b was well tolerated, and injection site reactions w e r e the primary side effect 135 . The effectiveness of adalimumab in PsA was evaluated in a placebo-controlled, d o u b l e - b l i n d study, called Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT). T h r e e - h u n d r e d a n d t h i r t e e n p a t i e n t s w i t h active PsA r e c e i v e d p l a c e b o or 40 m g of adalimumab s.c. every o t h e r w e e k . O f the 69 patients w i t h greater than three percent of body surface involvement w h o were treated w i t h a d a l i m u m a b , 42 p e r c e n t achieved a PASI 90 response at 24 weeks. Sixty p e r c e n t o f patients achieved an ACR 20 response at week 12, and sustained response t h r o u g h w e e k 24. O n e - f o u r t h o f these patients achieved an ACR 70 response at w e e k 24. The rates of adverse events and serious adverse events in t h e study w e r e c o m p a r a b l e for a d a l i m u m a b and placebo. Results f r o m the ADEPTtrial w e r e r e p o r t e d at the American College of Rheumatology congress in San A n t o n i o , Texas in October 2004.

Cases of tuberculosis have been r e p o r t e d in clinical trials w i t h adalimumab and o t h e r TNF blockers in r h e u m a t o i d arthritis

137

, and patients s h o u l d be

s c r e e n e d f o r l a t e n t t u b e r c u l o s i s p r i o r t o t r e a t m e n t . T h e i n c i d e n c e of l y m p h o m a was also increased d u r i n g a d a l i m u m a b therapy in RA patients c o m p a r e d t o the incidence in t h e general p o p u l a t i o n . H o w e v e r it is k n o w n that patients w i t h r h e u m a t o i d arthritis have an increased risk of l y m p h o m a c o m p a r e d t o the general p o p u l a t i o n " 8 . The assumption that a d a l i m u m a b is less i m m u n o g e n i c than other anti-TNF-a agents remains to be proven by longt e r m safety studies.

Fusion proteins Alefacept

Alefacept is a fully h u m a n fusion p r o t e i n consisting of the first

extracellular d o m a i n of LFA-3 fused t o the hinge, CH 2 , and C H , sequences of IgG,. The LFA-3 d o m a i n of alefacept binds CD2 on T cells and blocks the costimulatory LFA-3/CD2 interaction 139 " 141 , thereby inhibitingT-cell activation and p r o l i f e r a t i o n . In a d d i t i o n , w h e n alefacept binds CD2 o n m e m o r y T cells and engages w i t h FCyRIII IgG receptors o n natural killer cells, granzyme-mediated apoptosis ( p r o g r a m m e d cell death) of T cells is induced 1 4 2 1 4 3 . Because CD2 expression is higher on memory-effector (CD45RO + ) CD4 + and CD8 + T cells 26144 c o m p a r e d w i t h naïve (CD45RA + ) T cells, alefacept is t h o u g h t t o p r o d u c e a selective r e d u c t i o n in m e m o r y T cells. In a d d i t i o n , a small p o p u l a t i o n of circulating d e n d r i t i c cells is also CD2", suggesting that alefacept c o u l d have an additional effect o n this cell population 1 4 5 . In a phase II, m u l t i c e n t r e , r a n d o m i z e d , p l a c e b o - c o n t r o l l e d , d o u b l e - b l i n d e d study alefacept was evaluated as a t r e a t m e n t for psoriasis. T w o h u n d r e d t w e n t y - n i n e patients w i t h chronic plaque psoriasis received either alefacept i.v. or placebo w e e k l y for 12 weeks. T w e n t y - f o u r percent of patients w h o had received alefacept were clear or almost clear after 12 weeks of therapy, and the average d u r a t i o n of remission in those patients w h o w e r e clear was 8 m o n t h s . Alefacept reduced p e r i p h e r a l - b l o o d m e m o r y effector T-cell ( C D 4 5 R O ) counts, w h i c h was correlated w i t h the i m p r o v e m e n t in psoriasis. Alefacept was well tolerated and no serious adverse events related to alefacept w e r e observed 2 3 . The r e d u c t i o n in levels of circulating m e m o r y T-cell subsets after alefacept therapy was c o n f i r m e d in o t h e r studies 146 .

A phase I I I , r a n d o m i z e d , d o u b l e - b l i n d e d , p l a c e b o - c o n t r o l l e d study was c o n d u c t e d t o evaluate efficacy of t w o courses of alefacept in patients w i t h c h r o n i c plaque psoriasis. Five h u n d r e d fifty-three patients received t w o 12w e e k courses of once-weekly intravenous alefacept 7.5.mg or placebo. D u r i n g t r e a t m e n t and f o l l o w - u p , PASI 75 was achieved by 28% of alefacept-treated patients, and PASI 50 was achieved by 56% of alefacept-treated patients. After a single course of alefacept, patients achieving PASI 75 maintained PASI 50 for a m e d i a n d u r a t i o n of 7 months. In a d d i t i o n , 40% of patients w h o received 2 courses of alefacept achieved PASI 75 and 7 1 % of patients achieved PASI 50, i n d i c a t i n g that a second course of alefacept increases efficacy 147 . A m u l t i c e n t r e , r a n d o m i z e d , d o u b l e - b l i n d e d , placebo-controlled phase III trial investigated the efficacy of intramuscular alefacept. A total of 507 patients w i t h c h r o n i c plaque psoriasis were treated w i t h alefacept i.m. (10 mg or 15 mg) or placebo o n c e w e e k l y d u r i n g 12 consecutive weeks. M e a n reductions in PASI in t h e 15-mg alefacept, 10-mg alefacept, and placebo groups reached a m a x i m u m of 46%, 4 1 % , and 25%, respectively, at 6 weeks post dosing. Twentyo n e percent of the 15-mg dose group achieved PASI 75 at 2 weeks post dosing. I m p r o v e m e n t was long-lasting, and 12 weeks after c o m p l e t i o n of treatment, m e a n PASI in b o t h alefacept groups had not returned t o baseline values. There w e r e n o o p p o r t u n i s t i c i n f e c t i o n s a n d n o cases o f disease r e b o u n d 1 4 8 . P r e l i m i n a r y data suggest t h a t the efficacy of alefacept t h e r a p y m i g h t be e n h a n c e d by c o m b i n a t i o n w i t h n a r r o w b a n d or broadband UVB. In a d d i t i o n t o i m p r o v e m e n t of clinical parameters, alefacept therapy has been s h o w n t o be associated w i t h i m p r o v e m e n t of quality of life of patients w i t h psoriasis' 49,150 . Regarding the safety of alefacept therapy, no opportunistic infections or organ t o x i c i t y related to alefacept therapy have been reported as t o this date. The o n l y adverse events that had a >5% higher incidence in the alefacept g r o u p than t h e placebo g r o u p w e r e chills, pharyngitis, and accidental injuries 147 . H o w e v e r , s o m e c o n c e r n s have risen d u e t o t h e fact t h a t an a d e q u a t e s e c o n d a r y i m m u n e response to i n f e c t i o u s agents or antigens d e p e n d s on m e m o r y - e f f e c t o r (CD45RO + ) T cells, w h i c h are affected by alefacept therapy. For this reason a study was p e r f o r m e d to assess the effect of alefacept therapy o n b o t h p r i m a r y a n d secondary responses t o a newly e n c o u n t e r e d antigen and t h e a c q u i r e d i m m u n e response to a recall antigen (tetanus t o x i c o i d ) .

Results of this study showed that alefacept did not impair primary or secondary antibody responses to a neoantigen or memory responses t o a recall antigen 151 . Data available f r o m patients treated w i t h up t o nine cycles of alefacept indicate that there is no increase in toxicity over time. O t h e r safety issues c o n c e r n the p o s s i b l e d e v e l o p m e n t o f l y m p h o p r o l i f e r a t i v e d i s o r d e r s associated w i t h i m m u n o s u p p r e s s i v e t h e r a p y . I n d e e d , t h r e e cases o f l y m p h o m a s w e r e reported d u r i n g the trials. Future use of alefacept in the p o s t m a r k e t i n g period w i l l elucidate this i m p o r t a n t issue. Alefacept is a p p r o v e d for the treatment of moderate to severe psoriasis in the U.S.A., and to date more than 9000 patients w i t h psoriasis have been treated 152 .

Etanercept

Etanercept is a recombinant m o l e c u l e c o m p r i s i n g the h u m a n

TNF-a p75 receptor fused t o the Fc p o r t i o n of h u m a n lgG1 m o l e c u l e . By blocking the b i n d i n g of TNF-a t o cell surface receptors, etanercept neutralizes the biologic activity of TNF-a. In a d o u b l e - b l i n d e d , p l a c e b o - c o n t r o l l e d study 60 patients w i t h psoriasis and PsA were randomized t o receive either placebo or etanercept 25 mg s.c. twice weekly for 12 weeks. After 12 weeks, the median PASI i m p r o v e m e n t was 46 percent in etanercept-treated patients versus 9 percent in placebo-treated patients. PASI 75 was achieved by 26 percent of etanercept-treated patients, c o m p a r e d to none of the placebo-treated patients. ACR 20 was achieved by 73 percent of etanercept-treated patients versus 13 percent of placebo-treated patients. No serious adverse events were reported 1 5 3 . A n o t h e r r a n d o m i z e d , d o u b l e - b l i n d e d , p l a c e b o - c o n t r o l l e d study t o investigate the efficacy and safety of etanercept in 112 psoriasis patients showed similar data. After 12 weeks of treatment, 30 percent of the etanercepttreated patients achieved PASI 75, compared t o 2% of placebo-treated patients. The o b s e r v e d i m p r o v e m e n t was sustained in t i m e , a n d by 24 w e e k s of t r e a t m e n t 56 p e r c e n t o f e t a n e r c e p t - t r e a t e d patients versus 5 p e r c e n t of placebo-treated patients achieved PASI 75. Adverse events w e r e similar among etanercept and placebo g r o u p s , except for i n j e c t i o n site reactions w h i c h o c c u r r e d more f r e q u e n t l y in patients treated w i t h etanercept 154 . This phase II p r o o f - o f - c o n c e p t s t u d y d e m o n s t r a t e d t h a t e t a n e r c e p t in p a t i e n t s w i t h psoriasis was w e l l t o l e r a t e d a n d s i g n i f i c a n t l y i m p r o v e d t h e signs a n d symptoms of disease 155 . Based on these results, a larger trial f o l l o w e d . In a 24-

w e e k , d o u b l e - b l i n d e d , phase III study 652 psoriasis patients were treated w i t h either etanercept s.c. at a l o w dose (25 mg once weekly), a m e d i u m dose (25 mg t w i c e w e e k l y ) , a high dose (50 mg twice weekly), or w i t h placebo. After 12 weeks, patients in the placebo-group began treatment w i t h etanercept 25 mg t w i c e w e e k l y . At w e e k 12, PASI 75 was achieved by 14 percent of patients in the low-dose g r o u p , 34 percent of patients in the m e d i u m dose g r o u p , and 49 p e r c e n t in the h i g h dose group, c o m p a r e d t o 4 percent of patients in t h e p l a c e b o - g r o u p . The clinical responses c o n t i n u e d t o i m p r o v e w i t h longer t r e a t m e n t . At w e e k 24, PASI 75 was achieved by 25 percent of patients in the l o w - d o s e g r o u p , 44 p e r c e n t of the patients in the m e d i u m - d o s e g r o u p , and 59 percent of patients in the high-dose g r o u p . No occurrence of o p p o r t u n i s t i c i n f e c t i o n s o r t u b e r c u l o s i s was reported d u r i n g the course of the study. Eight e t a n e r c e p t - t r e a t e d patients had serum samples that tested positive for n o n n e u t r a l i z i n g a n t i - e t a n e r c e p t antibodies, but no differences in efficacy or adverse events w e r e observed in these patients c o m p a r e d t o patients w i t h o u t anti-etanercept antibodies 1 5 6 . The efficacy of etanercept in PsA was c o n f i r m e d in a p l a c e b o - c o n t r o l l e d , d o u b l e - b l i n d e d trial in w h i c h 205 patients w i t h active PsA received either placebo or 25 m g etanercept s.c. twice weekly plus a stable dose of m e t h o t r e x a t e for 24 weeks. Differences in clinical response b e t w e e n t h e g r o u p s w e r e e v i d e n t at week 4, a n d w e r e m a i n t a i n e d t h r o u g h o u t the t r e a t m e n t p e r i o d . At 12 weeks, ACR 20, ACR 50, and ACR 70 was achieved by 59, 38, and 11 p e r c e n t of patients in the etanercept g r o u p and 15, 4, and 0 p e r c e n t o f patients in t h e placebo g r o u p , respectively. After 24 weeks of t r e a t m e n t , ACR 20, ACR 50, and ACR 75 was achieved by 50, 37, and 9 percent o f etanercept-treated patients, whereas the c o r r e s p o n d i n g placebo responses w e r e 13, 4, and 1 percent, respectively. In general etanercept therapy was w e l l t o l e r a t e d , h o w e v e r o n e patient i n t h e e t a n e r c e p t g r o u p d e v e l o p e d m u l t i p l e sclerosis at t h e e n d of t h e study 1 " 7 . Regarding the safety profile o f etanercept, some p u b l i s h e d reports have r e p o r t e d d r u g - i n d u c e d systemic l u p u s e r y t h e m a t o s u s (SLE) in a s s o c i a t i o n w i t h e t a n e r c e p t therapy 158,159 . H o w e v e r , t h e l u p u s - l i k e symptoms in all r e p o r t e d cases resolved f o l l o w i n g d i s c o n t i n u a t i o n of therapy. Etanercept is a p p r o v e d for treatment of psoriasis and PsA in t h e U.S.A and Europe.

Cytokines and chemokines rhulL-4 Psoriasis is characterized by the presence of type-1 cytokine-producing T cells in lesional skin 39 . In experimental animal models of type-1 mediated a u t o i m m u n e diseases i m m u n e deviation of type-1 into anti-inflammatory type2 responses g e n e r a l l y i m p r o v e s t h e disease, w i t h o u t i n d u c i n g g e n e r a l i m m u n o s u p p r e s s i o n . Recombinant h u m a n IL-4 (rhulL-4), w h i c h induces a t y p e - 2 p h e n o t y p e , has b e e n d e v e l o p e d f o r t r e a t m e n t of psoriasis. In a prospective dose-escalating study, rhulL-4 s.c. was administered to 20 patients w i t h severe psoriasis 3 times daily, 5 days a week, for 6 weeks. PASI decreased in all patients treated w i t h rhu-IL-4; psoriasis i m p r o v e d more than 50% (PASI 50) in 19 patients. O n immunohistochemical evaluation of lesional skin, rhu-IL4 i n d u c e d a switch f r o m type-1 t o type-2 responses, w i t h close correlation between clinical i m p r o v e m e n t and reversal of the IFN-y/IL-4 ratio. Adverse events were mild and included fever, headache, and oedema"' 0 .

r h l L - 1 1 R e c o m b i n a n t h u m a n IL-11 ( r h l L - 1 1 ) has d e m o n s t r a t e d a n t i inflammatory effects in vitro and in vivo. In animal models, treatment w i t h rhlL-11 reduced p r o - i n f l a m m a t o r y c y t o k i n e levels p r o d u c e d by T cells and macrophages, such as IFN-y and TNF-a 161 , and polarized the T-cell response t o w a r d a type-2 response w i t h increased IL-4 production 1 6 2 . In an o p e n - l a b e l , dose-escalating, phase I clinical trial rhlL-11 s.c. was administered to 12 patients w i t h psoriasis every day for 8 w e e k s .

Eleven o f 12 patients e x p e r i e n c e d

r e d u c t i o n in PASI, ranging f r o m 20 to 80 percent. A m e l i o r a t i o n of disease by r h I L - 1 1 , as s h o w n by r e d u c e d k e r a t i n o c y t e p r o l i f e r a t i o n a n d c u t a n e o u s i n f l a m m a t i o n , was associated w i t h decreased expression of p r o d u c t s o f disease-related genes, including k16, i N O S , IFN-y, IL-8, IL-12, TNF-a, IL-1(3, and CD8, and w i t h increased expression of e n d o g e n o u s IL-11 163 .

Other Tadekinig-alpha (rh-IL-18 BP) Tadekinig-alpha is a recombinant u n m o d i f i e d f o r m of the naturally occurring human IL-18 b i n d i n g protein that is capable of neutralising the biological activity of IL-18. IL-18 was first identified as an IFN-yinducing factor164'165, and it has costimulatory functions on other type-1 cytokines such as TNF-a and IL-1 as well. It is believed that by reducing the levels of these

pro-inflammatory cytokines by rh-IL-18 BP, immunological balance in psoriasis and PsA will be restored. Phase I studies of r-hll_-18 binding protein are now completed, and a phase II clinical study is on-going in psoriasis and PsA.

A i m s of t h e studies In the last decade a whole range of new 'biological' response modifiers have emerged for the treatment of psoriasis and PsA. Although clinical efficacy has been monitored in multicentre, randomized, placebo-controlled, doubleblinded trials, less is known about the actual mechanism of action of these drugs in lesional skin and synovium of patients with psoriasis and PsA in situ. Because biological response modifiers act on very specific steps in the immunological cascade, investigation of changes in immunohistochemical markers in lesional skin and synovium might provide us with more insight into the immunopathogenesis in psoriasis and PsA. Traditionally, the evaluation of the cellular infiltrate and protein expression in skin tissue sections is done by manual quantification. However, for reliable evaluation of histology in the development of new anti-psoriatic treatments there is a need for a more time-efficient and reproducible method. To test the use of digital image analysis in this situation we compared the assessment of immunohistochemically stained skin sections with the more traditional manual quantification and semi-quantitative analysis (chapter 2). The digital image analysis was used in subsequent studies with biological response modifiers. In chapter 3, we investigated the immunohistochemical changes in lesional psoriatic skin after alefacept therapy, a LFA-3/lgC1 fusion protein that interferes with the activation and proliferation of T cells by binding to the CD2 receptor on their surfaces. We focussed on lesional memory-effector T cells in particular, since it is known that alefacept selectively reduces memory-effector T cells in peripheral blood 2 '. In a similar way, we investigated changes in the inflammatory infiltrate, in particular memory-effector T cells, in synovial tissue in patients with PsA after alefacept therapy. This was the first time alefacept was administered to patients with PsA, and the clinically efficacy of this drug in PsA was reported as well (chapter 4). Next to biological response modifiers interfering with T cell activation, such as alefacept, the use of TNF-a-inhibitory drugs has proven to induce rapid and profound

improvement in clinical signs and symptoms of psoriasis and PsA. The mechanism of action of infliximab, a chimeric anti-TNF-oc antibody, has not been fully elucidated yet. In vitro studies suggest that besides neutralization of TNF-a, infliximab might be able to induce apoptosis of TNF-a producing cells via activation of complement-dependent or antibody-dependent cellmediated toxicity. In chapter 5, we first investigated the early effects (after 48 hours) of infliximab on serial skin and synovial tissue biopsy samples of patients with PsA, focussing in particular on apoptosis of T cells. Next, we evaluated the influence of infliximab on T cell infiltration and expression of adhesion molecules after 4 weeks of infliximab therapy in the same group of PsA patients (chapter 6). Another TNF-cx-inhibitory drug that is known to improve clinical signs and symptoms of psoriasis and PsA is etanercept, a fusion protein consisting of two identical chains of a recombinant human TNF receptor (p75) monomer fused to the Fc portion of human lgG1. By competitive inhibition of the interaction of circulatingTNF-awith cell surfacebound TNF-receptors, etanercept is thought to prevent TNF-mediated cellular responses by rendering TNF biologically inactive. To compare the mechanism of action of etanercept with infliximab, we studied the effects of etanercept therapy on the T-cell infiltrate, expression of adhesion molecules, and expression of angiogenesis markers in lesional skin of patients with chronic plaque psoriasis in a double-blinded placebo-controlled study (chapter 7).

T a b l e 1. List o f b i o l o g i c a l r e s p o n s e m o d i f i e r s t h a t are a p p r o v e d o r u n d e r d e v e l o p m e n t f o r psoriasis and/or psoriatic arthritis. Binding characteristics

Generic name

Monoclonal antibodies Anti-CD11a Efalizumab

Brand name

Molecular structure

M o d e of action

Indication / Status

Raptiva

Humanized Mab

Binds to a s u b u n i t of LFA-1; blocks LFA-1 / ICAM-1 interaction

Psoriasis, FDA and EMEA approved

Anti-TNF-cc

Infliximab

Rcmicade Chimeric M a b

Neutralizes TNF-a; mediated lysis of TNF-a* cells

Psoriasis and PsA, phase III

Anti-TNF-a

Adalimumab

Humira

Humanized Mab

Neutralizes TNF-a

Psoriasis and PsA, phase II and III

Fusion proteins Anti-CD2

Alefacept

Amevive

Fusion protein of Inhibits LFA-3 / extracellular CD2 interaction, domain of human induces NK- cell LFA-3 and Fc part mediated T-cell of human lgG1 apoptosis

Psoriasis, FDA approved

Anti-TNF-a

Etanercept

Enbrel

Fusion protein of the extracellular domain of the human TNF-aR and Fc part of human lgG1

Neutralizes TNF-a

Psoriasis and PsA, FDA and EMEA approved

Recombinant human IL-4

Immune deviation from Th1 to Th2

Psoriasis, phase II

32

Recombinant cytokines and shemokines IL-4 Rhu-IL-4 >

IL-11

Other IL-18BP

Rh-IL-11

?

Recombinant IL-11 Immune deviation from Th1 to Th2; suppression of inflammation

Psoriasis, ?

Tadckinig -alpha

?

recombinant human IL-18 binding protein

Psoriasis and PsA, phase II

Neutralizes IL-18

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