**7.1 TNF- inhibitors**

The TNF- inhibitors adalimumab, etanercept and infliximab have been approved by the FDA and EMEA for psoriasis and PsA treatment; they have been reviewed quite extensively in the past and the table 2 summarizes the clinical outcome for primary endpoints (e.g. PASI and ACR) in randomized controlled studies.

In this chapter, instead will focus on the new TNF- blockers such as golimumab and certolizumab (Mössner et al., 2008; Pathirana et al., 2009).


Infliximab SPIRIT

Infliximab EXPRESS I

Infliximab EXPRESS II

Infliximab IMPACT

Infliximab IMPACT II

Golimumab GO-REVEAL

Golimumab GO-REVEAL

The Role of Immune Response and the Impact of Biological Drugs in Psoriasis Patients 247

(301) Placebo (77)

(11)

(311) I 5 mg·kg-1 (314)

I 10 mg·kg-1

Placebo (11)

Placebo (208)

I 5 mg·kg-1 (52) Placebo (52)

I 5 mg·kg-1 (100)

Placebo (100)

G 50 mg q4 wks

G 50 mg q4wks

G 100 mg q4wks

Placebo (113)

(146) G 100 mg q4 wks (146) Placebo (113)

(146)

(146)

A= Adalimumab; E = Etanercept; I = Infliximab; G = Golimumab; OLE = Open Level Extension; q4 wks

I 5 mg·kg-1 (99) Placebo (51)

PASI 75 at week 10: 72 PASI 75 at week 10: 88 PASI 75 at week 10: 6

PASI 75 at week 10: 80 PASI 75 at week 10: 3

PASI 75 at week 10: 82 PASI 75 at week 10: 73 PASI 75 at week 10: 18

PASI 75 at week 10: 70 PASI 75 at week 10: 76 PASI 75 at week 10: 2

ACR 20 at week 16: 65 ACR 20 at week 16: 10

ACR 20 at week 24: 54 ACR 20 at week 24: 16

PASI 75 at week 14: 40 PASI 75 at week 14: 58 PASI 75 at week 14: 3

ACR 20 at week 14: 51 ACR 20 at week 14: 45 ACR 20 at week 14: 9

Gottlieb *et al*.,

Reich *et al*., 2005 *Lancet* 

366: 1367–1374.

Chaudhari *et al*., 2001 *Lancet* 357: 1842–1847.

Menter *et al*.,

Antoni *et al*.,

1227–1236.

Kavanaugh *et al*., 2007 *Ann Rheum Dis* 

Kavanaugh *et al*., 2009° *Arthritis Rheum* 

Kavanaugh *et al*., 2009° *Arthritis Rheum* 

*Arthritis Rheum* 

2007 *J Am Acad Dermatol* 56: 31.e1–31.e5.

2005

52:

66: 498–505.

60: 976–986.

60: 976–986.

2004 *J Am Acad Dermatol* 51: 534–542.

Psoriasis RDBPC I 3 mg·kg-1 (99)

Psoriasis RDBPC I 5 mg·kg-1

Psoriasis RDBPC I 3 mg·kg-1

16-week RDBPC OLE week

24-week RDBPC OLE 52 weeks

RDBPC

24-week RDBPC

= every 4 weeks; RDBPC = Randomized Double-Blind Placebo Controlled Trial

Table 2. Efficacy of anti-TNF- in the treatment of psoriasis and psoriasis arthritis

50

Psoriasis 24-week

Infliximab Psoriasis RDBPC I 5 mg·kg-1 (11)

Psoriasis arthritis

Psoriasis arthritis

Psoriasis arthritis


A 40 mg eow

Placebo (49)

E 25 mg twice weekly (57) Placebo (55)

weekly (196) E 50 mg twice weekly (194) Placebo (193)

E 25 mg twice weekly (162) E 50 mg twice weekly (164) Placebo (166)

E 50 mg twice weekly (311) Placebo (307)

E 25 mg twice weekly (30) Placebo (30)

E 25 mg twice weekly (101) Placebo (104)

(160)

(51)

OLE A (281) week 12: 14

ACR 20 at week 48: 58.7 ACR 20 at week 104: 57.3

ACR 20 at week 12: 39 ACR 20 at week 12: 16

PASI 75 at week 12: 30 PASI 75 at week 12: 2

PASI 75 at week 12: 34 PASI 75 at week 12: 49 PASI 75 at week 12: 3

PASI 75 at week 12: 14 PASI 75 at week 12: 34 PASI 75 at week 12: 49 PASI 75 at week 12: 4

PASI 75 at week 12: 47 PASI 75 at week 12: 5

ACR 20 at week 12: 73 ACR 20 at week 12: 13

ACR 20 at week 12: 59 ACR 20 at week 12: 15 52:

2007

56: 476–488. Mease *et al*., 2009

68: 702–709.

2007

2003

139: 1563–1570.

152: 1304–1312.

2003

349: 2014–2022.

2006

35.

50:

 3279–3289. Gladman *et al*.,

*Arthris Rheum* 

*Ann Rheum Dis* 

Genovese *et al*.,

*J Rheumatol* 34: 1040–1050.

Gottlieb *et al*.,

*Arch Dermatol* 

Papp *et al*., 2005

*Br J Dermatol* 

Leonardi *et al*.,

*N Engl J Med* 

Tyring *et al*.,

*Lancet* 367: 29–

Mease *et al*., 2000 *Lancet* 356: 385–390.

Mease *et al*., 2004

2264–2272.

*Arthritis Rheum* 

OLE week

OLE week 104

12-week RDBPC OLE until week 24

RDBPC

Etanercept Psoriasis RDBPC E 25 mg weekly

RDBPC

12-week RDBPC

24-week RDBPC OLE until week 48

Psoriasis RDBPC E 25 mg twice

48

Adalimumab Psoriasis

Etanercept CONSORT arthritis

Etanercept Psoriasis 12-week

Etanercept Psoriasis 12-week

arthritis

arthritis

Etanercept Psoriasis

Etanercept Psoriasis


A= Adalimumab; E = Etanercept; I = Infliximab; G = Golimumab; OLE = Open Level Extension; q4 wks = every 4 weeks; RDBPC = Randomized Double-Blind Placebo Controlled Trial

Table 2. Efficacy of anti-TNF- in the treatment of psoriasis and psoriasis arthritis

**Anti-TNF-a therapy** 

**Frequent side effects** 

tract infections Injection site reactions Headache

Adalimumab Upper respiratory

Etanercept Upper respiratory

Infliximab Upper respiratory

psoriasis

tract infections Acute infusion reaction: fever, chills, nausea Headache Pruritus Urticaria Elevated

transaminases

tract infections Injection site reactions Pruritus

The Role of Immune Response and the Impact of Biological Drugs in Psoriasis Patients 249

Severe/ Opportunistic

Reactivation/progression of

 Onset/exacerbation of CNS demyelinating disorders (e.g. Multiple Sclerosis) Increased risk of cancer (e.g. Lymphoma) Drug-induced lupus Exacerbation of congestive

infections

 heart failure Vasculitis

infections

heart failure Vasculitis

infections

heart failure Vasculitis Pancytopenia

Table 3. Overview of side effects of most prescribed anti-TNF-a treatments in patients with

TBC

Aplastic anaemia

Severe/ Opportunistic

Reactivation/progression of

 Onset/exacerbation of CNS demyelinating disorders (e.g. Multiple Sclerosis) Increased risk of cancer (e.g. Lymphoma) Drug-induced lupus Exacerbation of congestive

TBC

Severe/ Opportunistic

Reactivation/progression of

 Onset/exacerbation of CNS demyelinating disorders (e.g. Multiple Sclerosis) Increased risk of cancer (e.g. Lymphoma) Drug-induced lupus Exacerbation of congestive

TBC

**Rare severe side effects Reference** 

Pathirana *et al*., 2009 *J Eur Acad Dermatol Venerol 23* (Suppl. 2):

Smith *et al*., 2009 *Br J Dermatol*  161: 987–1019.

Pathirana *et al*., 2009 *J Eur Acad Dermatol Venerol 23* (Suppl. 2):

Smith *et al*., 2009 *Br J Dermatol*  161: 987–1019.

Pathirana *et al*., 2009 *J Eur Acad Dermatol Venerol 23* (Suppl. 2):

Smith *et al*., 2009 *Br J Dermatol*  161: 987–1019.

S5–70.

S5–70.

S5–70.

Up to now, treatment with MoaB anti-TNF-has proven to be effective and relatively safe in patients with psoriasis and PsA (Lima et al., 2009).

Since TNF- has showed an osteoclast stimulating effect, alongside being synergic with DKK-1 in reducing osteoblasts maturation, anti-TNF- drugs should improve PsA-related bone altering processes, as confirmed by significant inhibition of radiographic progression during treatment with etanercept or infliximab (Antoni et al., 2008; Mease et al., 2006b; van der Heijde et al., 2007).

Equally importantly, anti-TNF- therapy might have a preventive effect on PsA overlapping in psoriasis patients. In fact, in a case-control study, Gisondi group (Gisondi et al., 2008) has demonstrated that lower limb enthesopathy can be documented in asymptomatic psoriasis patients without any clinical sign of arthropathy. Similar findings were reported in the past concerning entheseal abnormalities (De Filippis et al., 2005) and increased Achilles tendon thickness (Ozcakar et al., 2005); all of which were detected in asymptomatic patients.

Different evidences have proved that anti-TNF- treatments infliximab and adalimumab are effective in controlling gut inflammation, whereas etanercept is not (Bosani et al., 2009).

There are reports of CD development in patients with ankylosing spondylitis or PsA (Song et al., 2008) and treated with etanercept. However, it is well-known that such patients are burdened with a high risk of chronic IBD development. It is therefore hard to assess whether these cases of CD were really a consequence of anti-TNF- therapy or rather a coincidental event in predisposed patients.

The reason for the discordant effect of anti-TNF- treatments on IBD probably lies in different pharmacodynamic features of these drugs, and a number of hypotheses have been expressed in this regard.

Firstly, it has been noted that etanercept, unlike anti-TNF- Moabs, doesn't induce apoptosis of activated lymphocytes in CD patients (Van den Brande et al., 2003). Given the existing results, it is reasonable to conclude that etanercept has no potential to control or to prevent gut inflammation and hence IBD appearance. A preventive role of anti-TNF- Moabs against the IBD development in susceptible psoriasis patients cannot be rule out considering the effectiveness of these drugs in both conditions.

About the effects of anti-TNF-a Moabs in MS and CVD, studies regarding the consequence on blood lipids have shown unclear results. A study of RA patients reported a significant decreased atherogenic index of low-density lipoprotein (LDL)/high-densitiy lipoprotein (HDL) ratio after 6 months of therapy with anti-TNF-a (Spanakis et al., 2006); another showed increased HDL levels and reduced C-reactive protein (CRP) and IL-6 levels after 2 weeks (Popa et al., 2005). In contrast, in some cases anti-TNF-a therapy has resulted in a proatherogenic effect in RA and PsA patients, with increase of LDL/ HDL ratio and triglycerides levels (Dahlqvist et al., 2004). Another study demonstrated a sudden reduction in HDL levels the day after infliximab infusion, but without any significant variation in the HDL profile (Irace et al., 2004).

No conclusions can be drawn from these inconsistent findings regarding long-term clinical outcomes. As a consequence, many authors seem to agree on the fact that despite the prominent role of TNF- on lipid regulation, the emerging efficacy of anti-TNF- therapy

Up to now, treatment with MoaB anti-TNF-has proven to be effective and relatively safe

Since TNF- has showed an osteoclast stimulating effect, alongside being synergic with DKK-1 in reducing osteoblasts maturation, anti-TNF- drugs should improve PsA-related bone altering processes, as confirmed by significant inhibition of radiographic progression during treatment with etanercept or infliximab (Antoni et al., 2008; Mease et al., 2006b; van

Equally importantly, anti-TNF- therapy might have a preventive effect on PsA overlapping in psoriasis patients. In fact, in a case-control study, Gisondi group (Gisondi et al., 2008) has demonstrated that lower limb enthesopathy can be documented in asymptomatic psoriasis patients without any clinical sign of arthropathy. Similar findings were reported in the past concerning entheseal abnormalities (De Filippis et al., 2005) and increased Achilles tendon

Different evidences have proved that anti-TNF- treatments infliximab and adalimumab are effective in controlling gut inflammation, whereas etanercept is not (Bosani et al., 2009).

There are reports of CD development in patients with ankylosing spondylitis or PsA (Song et al., 2008) and treated with etanercept. However, it is well-known that such patients are burdened with a high risk of chronic IBD development. It is therefore hard to assess whether these cases of CD were really a consequence of anti-TNF- therapy or rather a

The reason for the discordant effect of anti-TNF- treatments on IBD probably lies in different pharmacodynamic features of these drugs, and a number of hypotheses have been

Firstly, it has been noted that etanercept, unlike anti-TNF- Moabs, doesn't induce apoptosis of activated lymphocytes in CD patients (Van den Brande et al., 2003). Given the existing results, it is reasonable to conclude that etanercept has no potential to control or to prevent gut inflammation and hence IBD appearance. A preventive role of anti-TNF- Moabs against the IBD development in susceptible psoriasis patients cannot be rule out

About the effects of anti-TNF-a Moabs in MS and CVD, studies regarding the consequence on blood lipids have shown unclear results. A study of RA patients reported a significant decreased atherogenic index of low-density lipoprotein (LDL)/high-densitiy lipoprotein (HDL) ratio after 6 months of therapy with anti-TNF-a (Spanakis et al., 2006); another showed increased HDL levels and reduced C-reactive protein (CRP) and IL-6 levels after 2 weeks (Popa et al., 2005). In contrast, in some cases anti-TNF-a therapy has resulted in a proatherogenic effect in RA and PsA patients, with increase of LDL/ HDL ratio and triglycerides levels (Dahlqvist et al., 2004). Another study demonstrated a sudden reduction in HDL levels the day after infliximab infusion, but without any significant variation in the

No conclusions can be drawn from these inconsistent findings regarding long-term clinical outcomes. As a consequence, many authors seem to agree on the fact that despite the prominent role of TNF- on lipid regulation, the emerging efficacy of anti-TNF- therapy

thickness (Ozcakar et al., 2005); all of which were detected in asymptomatic patients.

in patients with psoriasis and PsA (Lima et al., 2009).

coincidental event in predisposed patients.

considering the effectiveness of these drugs in both conditions.

expressed in this regard.

HDL profile (Irace et al., 2004).

der Heijde et al., 2007).


Table 3. Overview of side effects of most prescribed anti-TNF-a treatments in patients with psoriasis

The Role of Immune Response and the Impact of Biological Drugs in Psoriasis Patients 251

could be achieved in 51% of patients treated with golimumab 50 mg and in 45% of patients receiving golimumab 100 mg versus only 9% in the placebo group. At week 24, an ACR 20 response was observed in 52% in the golimumab 50-mg group and in 61% in the golimumab 100-mg group versus 12% in the placebo group (*P* < 0.001). ACR 50 and 70 responses were also significantly higher in both golimumab groups than in the placebo group. At week 104, 91.4% of patients in the 50-mg group and 73.1% in the 100-mg group achieved an ACR 20 (Kavanaugh et al., 2009). A good or moderate DAS 28 response was significantly (*P* < 0.001) more often achieved in the golimumab 50 and 100-mg recipients than in the placebo group at week 14 (66 and 67% vs. 24%) and at week 24 (64 and 78% vs. 24%) (Kavanaugh et al., 2009). Assessment of physical function and health-related quality of life were measured by the Health Assessment Questionnaire (HAQ) and Short Form 36 Health Survey (SF-36) and significantly improved in both golimumab groups compared with the placebo group (*P* < 0.001 for HAQ and SF-36 at all comparisons at week 24).Thus, in this study golimumab improved significantly the clinical signs and symptoms of PsA as well as the physical

About the of safety of this treatment, Kavanaugh and coll. (Kavanaugh et al., 2009) reported that 8.6% of patients treated with golimumab shown a serious adverse event up to week 104: serious infectious adverse events comprised sepsis/cholecystitis and abscess formation. about the cancers registered: one basal cell carcinoma, one colon cancer and one small lung cell carcinoma in the golimumab 50-mg group. In the golimumab 100-mg group, three basal

As for adverse events, infections of the upper respiratory tract and nasopharyngitis were

Certolizumab pegol, a pegylated Fab-9 fragment of a humanized anti-TNF-a Moab, has been approved for the treatment of patients with CD (Bourne et al., 2008) and it has also been

It binding to TNF-, blocks the interaction with specific receptors. Whereas adalimumab, etanercept and infliximab contain an IgG1 Fc region, which can induce antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), certolizumab lacking this Fc region, isn't able of inducing ADCC and CDC (European

Pharmacokinetic analysis in the CDP870 trial showed a bioavailability of 85% (EMEA, 2008). Peak plasma concentrations were attained between 54 and 171 h after subcutaneous injection. The mean serum concentration (Cmax) after the subcutaneous administration of 400-mg certolizumab ranged from 46.3 ± 13.1 to 49.5 ± 8.2 mg· mL-1. An increase of Cmax and area under the curve (AUC) was observed with higher doses in a dose-proportional manner. The half-life of certolizumab was found to be approximately 14 days (EMEA, 2008) Certolizumab pegol has been investigated in patients with moderate to severe psoriasis. In a phase II trial, patients were randomized to receive certolizumab pegol 200 mg, 400 mg or placebo subcutaneously every 2 weeks up to week 12. At week 12, significantly more patients receiving certolizumab pegol 200 or 400 mg achieved PASI 75 than in the placebo

cell carcinomas, one prostate cancer and one small lung cancer occurred.

function and quality of life (Kavanaugh et al., 2009).

investigated in RA patients (Barnes & Moots, 2007).

most frequently reported.

**7.1.2 Certolizumab pegol (CDP870)** 

Medicines Agency [EMEA], 2008).

on CV morbidity and mortality is likely independent of the induced blood lipid variations (Soubrier et al., 2008).

Results derived from studies about the effects of anti-TNF- drugs on insulin resistance in psoriasis patients, appear to show an improvement in insulin sensitivity (Marra et al., 2007). This outcome seems to confirm the beneficial effects of anti-TNF- Moabs already documented in many RA studies (Huvers et al., 2007; Yazdani-Biuki et al., 2004). In particular, infliximab has proved capable of enhancing insulin sensitivity after the infusion to up to one year (Huvers et al., 2007). Lastly, there have been few isolated cases of psoriasis patients with diabetes developing unpredictable hypo- or hyperglycemia after commencing treatment with TNF inhibitors (Boulton & Bourne, 2007; Wu & Tsai 2008).

In the table 3 are reported the side effects of adalimumab, etanercept and infliximab treatment in psoriasis patients.
