Am J Clin Dermatol DOI 10.1007/s40257-014-0064-x

EVIDENCE-BASED REVIEW

Systemic Therapies for Psoriasis: An Evidence-Based Update Laura F. Sandoval • Allison Pierce Steven R. Feldman

•

Ó Springer International Publishing Switzerland 2014

Abstract Background The treatment of psoriasis has evolved over the years, with the focus now largely on the use of biologic agents. With treatment options expanding, evidence-based studies to guide physicians’ treatment decisions become increasingly important. Objective Our objective was to review current literature to provide an evidence-based update on systemic therapies for psoriasis. Methods A systematic review of the literature was conducted from 1 January 2012 through 1 July 2013 to identify all randomized clinical trials and systematic reviews of systemic psoriasis treatments. Results A total of 46 publications were identified and reviewed. Randomized clinical trials for the treatment of psoriasis focused heavily on biologic agents, both currently approved agents and anti-interleukin (IL)-17 agents in development. The anti-IL-17 agents appear effective according to phase II clinical trials. Several new oral agents are being studied, and, although they do not appear as

L. F. Sandoval
A. Pierce
S. R. Feldman (&) Department of Dermatology, Center for Dermatology Research, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1071, USA e-mail: [email protected] L. F. Sandoval e-mail: [email protected] S. R. Feldman Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA S. R. Feldman Department of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA

effective as the biologic agents, they may be an option as an alternative to traditional oral agents, with more favorable safety profiles. Several systematic reviews focused on efficacy among the biologics, with infliximab consistently superior to the others, and etanercept the least effective of the tumor necrosis factor-alpha inhibitors. Longer-term safety data on biologics is now available and encouraging. Limitations Current studies of traditional oral therapies are lacking. Conclusions Current studies continue to support the use of biologic agents in the treatment of moderate to severe psoriasis, with better efficacy and safety profiles than traditional systemic agents. Newer anti-IL-17 agents and several new oral agents are in development and have shown promise in clinical trials.

1 Introduction Psoriasis is a chronic inflammatory skin disease that requires long-term treatment. Systemic treatments, including oral and biologic agents and phototherapy, are used to treat moderate to severe disease. According to current guidelines on the management of psoriasis, these therapies should be considered in patients when adequate control of the disease cannot be accomplished with topical agents. Guidelines state that the definition of adequate control should be determined according to the patient’s own perception of disease burden and not by severity of disease based on measures that are often used to define moderate to severe disease (i.e. the use of body surface area affected) [1]. Individualized treatment based on needs of the patient is emphasized; to accomplish this, physicians must have up-to-date knowledge of treatment options in order to make appropriate recommendations.

L. F. Sandoval et al.

Systemic treatment of psoriasis has evolved over the years, and the focus is now largely on biologic agents. Traditional oral therapy, primarily methotrexate, cyclosporine, and acitretin, has remained relatively unchanged for many years, and the use of these drugs continues to be limited due to their end-organ toxicity and/or teratogenicity [1]. However, while research continues to focus heavily on biologics, with newer agents targeting interleukin (IL)-17, there are also several oral agents currently in development. As the treatment options for psoriasis expand, with new oral and biologic agents in development, and with longterm efficacy and safety data on existing approved therapies now available, evidence-based studies to guide physicians’ treatment decisions become increasingly important. The objective of this study was to review current literature to provide an evidence-based update on systemic therapies for psoriasis.

2 Methods We conducted a systematic review of the literature from 1 January 2012 through 1 July 2013 to identify all randomized clinical trials (RCTs) and systematic reviews of systemic psoriasis treatments. We searched PubMed for the term ‘psoriasis treatment,’ limiting the results to RCTs and systematic reviews. The publications were reviewed for content, and duplicates and publications in languages other than English were excluded (Fig. 1). The RCTs were grouped by oral therapy and biologic therapy. Biologic agents were further sub-grouped according to mechanisms of action: anti-IL-12/23, tumor necrosis factor (TNF)-alpha inhibitors, and anti-IL-17.

3 Results A total of 46 relevant publications met inclusion criteria, with 28 RCTs (21 on biologic therapy and seven concerning oral therapy) and 18 systematic reviews (Fig. 1). 3.1 Oral Therapies Four studies (six publications) reported on three new oral drugs currently in clinical trials: tofacitinib, apremilast, and CF101 (Table 1). A new therapy targeting Janus kinase has been studied in psoriasis, showing promising results. Tofacitinib is an oral Janus kinase inhibitor approved for the treatment of rheumatoid arthritis and is currently in phase III trials for the treatment of psoriasis. In a phase II trial, significantly more patients treated with 2 mg (25 %), 5 mg (41 %), or 15 mg (67 %) twice daily reached a 75 % reduction in

Psoriasis Area and Severity Index (PASI) score (PASI-75) compared with placebo (2 %) at week 12 [2]. Other efficacy and health-related quality of life (HRQoL) measures, including PASI-50, PASI-90, Physician’s Global Assessment (PGA) response rates, and change in Dermatology Life Quality Index (DLQI) score were also higher in all treatment groups compared with placebo [2, 3]. The incidence of adverse effects was comparable across all groups, with five serious adverse events reported. The 15-mg group was more likely to have a decline in hemoglobin and absolute neutrophil count. There was also a dose-dependent increase in total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol, which returned to baseline after treatment. Apremilast is an oral phosphodiesterase inhibitor currently in phase III clinical trials for the treatment of psoriasis. At week 16 of a phase II trial, in patients treated with apremilast 10 mg, 20 mg, 30 mg, or placebo twice daily, significantly more patients in the 20- (29 %) and 30-mg (41 %) groups achieved a PASI-75 compared with placebo (6 %) [4]. There were also significantly more patients reaching a PGA of ‘clear/minimal’ and a greater reduction in DLQI in the 20- and 30-mg groups compared with placebo [4, 5]. Most adverse effects were mild or moderate and included headache, nausea, diarrhea, and vomiting, with half occurring in the first 2 weeks and resolving in 1 week; headache and diarrhea were more common in the 30-mg group. There were no significant laboratory abnormalities. In a separate phase II trial, 20 mg twice daily was significantly more effective (24 % achieving PASI-75) than either 20 mg daily or placebo (10 % achieving PASI-75) [6]. Common adverse effects were again headache, diarrhea, and nausea. The third new oral drug currently being studied for the treatment of psoriasis is CF101, an anti-inflammatory agent that binds and inhibits A3 adenosine receptors. Psoriasis patients in a phase II trial were treated with 1 mg, 2 mg, 4 mg, or placebo twice daily for 12 weeks, with a significant change in PASI in patients in the 2-mg group compared with placebo [7]. The 4-mg dose was less effective than the 2-mg dose, and the 1-mg dose was not therapeutic. Of patients in the 2-mg group, 35 % reached a PASI-50 and 24 % reached a PGA score of 0 or 1. Incidences of adverse affects were comparable between all groups, with one serious adverse event reported in the placebo group. One additional study assessed the efficacy of low-dose cyclosporine (2.5 mg/kg/day) in combination with live attenuated varicella vaccine or placebo [8]. Significantly more patients receiving cyclosporine in addition to four doses of varicella vaccine every 3 weeks achieved PASI-50 at 12 weeks (83 and 47 %, respectively). The combination group was also more likely to reach a PGA of ‘clear’ or ‘almost clear’.

Psoriasis Systemic Therapies: Evidence-Based Update Fig. 1 Flowchart of literature search. RCT randomized clinical trial

3.2 Biologic Agents A total of 21 of the identified RCTs studied a biologic agent (six studies of anti-IL-12/23 agents, nine studies of TNF-alpha inhibitors, five studies of anti-IL-17 agents, and one study of an anti-T-cell agent) (Table 2). 3.2.1 Anti-Interleukin (IL)-12/23 Six publications reported on anti-IL-12/23 agents, four evaluating ustekinumab in Asian populations and two efficacy studies covering briakinumab. In Japanese patients, ustekinumab 45 mg and 90 mg significantly improved HRQoL at week 12 compared with placebo, and was maintained through week 64 [9]. In this same population, 59 % of patients treated with ustekinumab 45 mg and 68 % treated with 90 mg achieved a PASI-75, compared with 7 % of the placebo group, with responses maintained through week 64 in 65 and 79 % of treated patients, respectively [10]. Patients also showed improvement in Nail Psoriasis Severity Index (NAPSI) scores and joint pain at week 64. Results in terms of efficacy and safety in this population were consistent with the findings of the larger PHOENIX 1 and 2 trials, in which the majority of patients were White. In Chinese patients, ustekinumab 45 mg was significantly more effective than placebo, with 83 versus 11 % reaching PASI-75 at week 12 [11]. Placebo patients crossed-over at week 12 and had a

response comparable to that of the treatment group at week 28. Using the same study design in Korean and Taiwanese patients, a significant improvement in HRQoL was achieved in the treatment group compared with placebo, with a decrease in DLQI of 11.2 points versus 0.5, respectively [12]. The placebo crossover group achieved similar improvement at week 28. Improvement in DLQI was significantly correlated with improvement in PASI and PGA. Briakinumab, an anti-IL-12/23, was studied in psoriasis patients but has since been withdrawn from further development [13, 14]. In a 52-week study that included an induction phase and a maintenance phase, at the end of 12 weeks (induction), 76 % of briakinumab-treated patients reached a PGA of ‘clear/minimal’ and 81 % achieved PASI-75 compared with 4 and 5 %, respectively, in the placebo group [13]. At 52 weeks, more patients receiving briakinumab every 4 weeks reached a PGA of ‘clear/minimal’ (79 %) than those receiving the drug every 12 weeks (42 %) or placebo (6 %). There were more adverse events, including serious infections, non-melanoma skin cancers (NMSCs), and major cardiovascular events in treated patients compared with placebo. Briakinumab also had an effect on HRQoL, work productivity, and activity impairment, with 76 % of treated patients reaching minimum clinically important difference (MCID) for DLQI, 65 % for psoriasis-related pain scores and 54 % for psoriatic arthritis-related pain scores at week 12 [14].

CF101 [7] (n = 75)

Apremilast [6] (n = 259)

Apremilast [4, 5] (n = 352)

52

48

45

51

15

19

44

87

17

48

85

24

46

87

74

67

88

79

61

58

70

60

PL

30 mg bid

PL

4 mg bid

2 mg bid

1 mg bid

PL

20 mg bid

20 mg daily

PL, then 20 mg bid

44

88

57

20 mg bid

PL, then 30 mg bid

44

88

63

10 mg bid

PL

15 mg bid

5 mg bid

2 mg bid

Dose

34

45

87

71

72

63

59

59

% males

36

44

44

50

89

44

44

49

49

46

49

Tofacitinib [2, 3] (n = 197)

Ave age

No. pts

Oral therapy (total no. pts)

Table 1 Randomized clinical trials of oral therapies for the treatment of psoriasis

12

12

8, active tx

16, pc

12

Duration (wks)

17

22

23

17

19

21

19

18

19

19

18

22

23

21

22

BL PASI

35 (PASI-50)

10

10

24

33 at wk 24

24 at wk 24

6 at wk 16

41 at wk 16; 40 at wk 24

29 at wk 16; 26 at wk 24

11 at wk 16; 18 at wk 24

2

67

41

25

% achieving PASI-75

-3.5 wk 24

0 PGA of 0 or 1

24 % PGA of 0 or 1

-0.7 change in sPGA

-0.8 change in sPGA -1.3 change in sPGA

50 % PGA of 0 or 1

41 % PGA of 0 or 1

13 % PGA of 0 or 1; pruritus VAS -6.1

-1.9 wk 16 -4 wk 24

33 % PGA of 0 or 1 at wk 16/34 % wk 24; pruritus VAS -43.7

24 % PGA of 0 or 1 at wk 16/24 % wk 24; pruritus VAS -35.5

10 % PGA of 0 or 1 at wk 16/13 % wk 24; pruritus VAS -10.2

Other outcomes

-4.4 wk 16; -4.9 wk 24

-5.9 wk 16; -6.2 wk 24

-3.2 wk 16; -3.4 wk 24

-2

-9.4

-7.3

-7.7

Change in DLQI

AEs were 58 % in 1 mg, 18 % in 2 mg, 13 % in 4 mg. Two SAEs in 1 mg: pruritus and skin rash/psoriasis exacerbation

Most common AEs headache, nasopharyngitis, diarrhea, and nausea. 2 pts with SAEs, neither thought to be related to drug

Most AEs were mild/moderate and included nausea, upper respiratory infection, diarrhea, nasopharyngitis, headache, arthralgia (PL), gastroenteritis, dyspepsia. 8 SAEs: 3 in PL, 3 in 20 mg, 2 in 30 mg

Most frequently reported AEs: infections and infestations (2 mg = 22 %, 5 mg = 20 %, 15 mg = 37 %, PL = 6 %). Five SAEs: angina pectoris, pyelonephritis, urosepsis, and AF in 2 mg; and angina pectoris in 5 mg. 15-mg more likely to have decrease in hemoglobin and absolute neutrophil count. Dosedependent increase in lipids

AEs

L. F. Sandoval et al.

Cyclosporine 2.5 mg/kg/day plus PL

17

34

12 31

BL PASI

Duration (wks)

47 (PASI-50)

83 (PASI-50)

% achieving PASI-75

Change in DLQI

18 % PGA of 0 or 1

33 % PGA of 0 or 1

Other outcomes

Minimal AEs with no discontinuation

AEs

Ustekinumab [9, 10] (n = 158)

Approved drugs

Anti IL-12/23

Biologic therapy (total no. pts)

45

44

32

62

32

Ave age

64

No. pts

84

76

83

% males

PL 9 12 wks, then ustekinumab 90 mg at wk 12, 16, and then q12w

PL 9 12 wks, then ustekinumab 45 mg at wk 12, 16, and then q12w

90 mg SC at wks 0, 4, then q12w

45 mg SC at wks 0, 4, then q12w

Dose

64 wks

Duration

68 at wk 12; 79 at wk 64 7 at wk 12

30

59 at wk 12; 65 at wk 64

% achieving PASI-75

29

30

BL PASI

Table 2 Randomized clinical trials of biologic therapy for the treatment of psoriasis

-0.3 at wk 12

-7.4 at wk 12; -7.9 at wk 64

-8 at wk 12; -7.4 at wk 64

Change in DLQI

10 % PGA 0 or 1 at wk 12

-0.1 change in PDI;

-1 change in SF-36 PCS;

69 % PGA 0 or 1 at wk 12

12 change in PDI;

5.1 change in SF-36 PCS;

58 % PGA 0 or 1 at wk 12

8.6 change in PDI;

7.5 change in SF-36 PCS;

Other outcomes

Most common reported AE was exacerbation of psoriasis. Low proportion of SAEs through wk 12. Pneumonia in PL, eosinophilia, one case of prostate cancer. No CV deaths. AEs comparable in 45 mg and 90 mg through wk 72. SAEs 7.6 % in 45 mg and 9.3 % in 90 mg. No cases of TB. One cerebral hemorrhage. No CV events/deaths

AEs

AE adverse event, AF atrial fibrillation, bid twice daily, BL baseline, DLQI Dermatology Life Quality Index, PASI Psoriasis Area and Severity Index, pc placebo controlled, PGA Physician’s Global Assessment, PL placebo, pt(s) patient(s), q3w every 3 wks, SAE serious adverse events, sPGA Static Physician’s Global Assessment, tx treatment, VAS visual analog scale, wk(s) week(s)

Cyclosporine 2.5 mg/kg/d plus 4 doses of VarilrixÒ once q3w

Dose

18

% males

Cyclosporine plus varicella vaccine [8] (n = 35)

Ave age

No. pts

Oral therapy (total no. pts)

Table 1 continued

Psoriasis Systemic Therapies: Evidence-Based Update

Etanercept [15, 16] (n = 124)

Approved drugs

Anti TNF-alpha

Briakinumab [13, 14] (n = 1465)

In development

45

149

42

46

298

62

45

298

39

45

484

62

46

40

60

981

41

61

39

162

Ustekinumab [12] (n = 121)

40

160

Ustekinumab [11] (n = 322)

Ave age

No. pts

Biologic therapy (total no. pts)

Table 2 continued

58

53

67

67

70

71

68

88

82

76

78

% males

SC PL twice wkly 9 12 wks, then etanercept 50 mg SC twice wkly 9 12 wks

50 mg SC twice wkly 9 12 wks, then 50 mg SC once wkly 9 12 wks

PL

100 mg SC q12w

100 mg SC q4w

PL

200 mg SC wks 0 and 4, then 100 mg wk 8

PL, then ustekinumab 45 mg SC wk 12, 16

45 mg SC wk 0, 4, 16

PL, then ustekinumab 45 mg SC wk 12, 16

45 mg SC wk 0, 4, 16

Dose

24 wks

Wks 13–52, maintenance phase

12 wks, induction phase

16 wks

16 wks

Duration

15 (BL PSSI = 30)

16 (BL PSSI = 35)

19

18

18

19

19

23

25

23

23

BL PASI

59 at wk 24

5 at wk 12;

69 at wk 24

59 at wk 12;

5

81

-9.9 at wk 28

20 % improvement DLQI at wk 12; 67 % at wk 24

71 % improvement DLQI at wk 12

-5.9 from BL; 12 % MCID

-8.8 from BL; 43 % MCID

-11.3 from BL; 72 % MCID

-0.52; 19 % MCID

-10.1; 76 % achieved MCID DLQI

-10 at wk 28

-0.5 at wk 12;

-12.3 for pts with a PASI-75 at wk 12

-10.8 at wk 28;

-11.2 at wk 12;

-1.9 at wk 12;

92 at wk 28

-10.7 at wk 28

11 at wk 12;

-9.3 at wk 12;

83 at wk 12;

Change in DLQI

92 at wk 28

% achieving PASI-75

79 % PSSI improvement, 72 % achieving PSSI-75 at 24 wks

20 % PSSI improvement, 11 % reaching PSSI-75 at wk 12; scalp pruritus score 2.9 and pain score 3.4 at wk 12

91 % PSSI improvement, 86 % achieving PSSI-75 at wk 24

87 % PSSI improvement, 86 % achieving PSSI-75 at wk 12; scalp pruritus score 1 and pain score 0.7 at wk 12

6 % PGA 0 or 1

42 % PGA 0 or 1

79 % PGA 0 or 1

4 % PGA 0 or 1

72 % PGA 0 or 1

15 % PGA 0 or 1 at wk 12; 86 % at wk 28

79 % PGA 0 or 1 at wk 12; 86 % at wk 28

Other outcomes

Similar rates of AEs in both groups at wk 12 and 24. At wk 24, 3 pts (3 %) reported 5 SAEs: cholecystitis/ cholelithiasis, fall/rib fracture, metastatic malignant melanoma

Overall, 3 % of briakinumab pts had SAEs: 5 MACE in tx group vs. 0 in control; 4 SCC of the skin in tx group vs. 0 in control; 5 serious infections in tx group vs. 1 control

Not reported

Proportion of pts with AEs and SAEs were comparable between the groups, with most common AEs nasopharyngitis and upper respiratory infections. 5 pts with markedly abnormal ALT (3 PL, 3 tx group), all with concomitant isoniazid

AEs

L. F. Sandoval et al.

Certolizumab pegol [21] (n = 176)

In development

Adalimumab [20] (n = 72)

Adalimumab [19] (n = 827)

PL

400 mg SC eow 9 10 wks

400 mg SC eow 9 10 wks

63

72

37

43

59

400 mg SC at wk 0, then 200 mg eow 9 10 wks

PL

80 mg SC wk 0, then 40 mg eow

PL

40 mg SC eow

PL, then infliximab wks 10, 12, 16

5 mg/kg IV wks 0, 2, and 6, 14, 22

50 mg SC twice wkly 9 12 wks, then once wkly 9 12 wks, plus PL

50 mg SC twice wkly 9 12 wks, then once wkly 9 12 wks, plus MTX 9 24 wks

Dose

400 mg SC at wk 0, then 200 mg eow 9 10 wks

44

58

75

35

43

73

70

78

71

70

64

% males

34

43

55

23

59

49

44

270

49

42

40

45

557

39

45

239

84

43

239

Etanercept plus MTX [17] (n = 478)

Infliximab [18] (n = 129)

Ave age

No. pts

Biologic therapy (total no. pts)

Table 2 continued

12 wks re-tx phase

12 wks

16 wks

16 wks

10 wks induction phase/12 wks maintenance

18

24 wks

23

22

21

6

9

19

19

25

24

18

BL PASI

Duration

87

68

7

83

-7.9 from BL (-7.9 from re-tx BL)

-8.3 from BL (-3.5 from re-tx BL)

-0.8

-9.9

-8.3

-7.6 at wk 26

75

-1.5 at wk 10;

2 at wk 10;

-10.1 at wk 26

80 at wk 26

-8 at wk 10;

81 at wk 10;

57 % PGA 0 or 1

53 % PGA 0 or 1

2 % PGA 0 or 1

72 % PGA 0 or 1

53 % PGA 0 or 1

4 % hfPGA clear or almost clear; 12.5 % NAPSI

31 % hfPGA clear or almost clear; 57 % NAPSI-50

-2.3 change in TWPI; -3.3 change in TAI; -1.5 change in work impairment when present

-13.4 change in TWPI; -18.8 change in TAI; -12.9 change in work impairment when present

7 % PGA of 0 or 1; 71 % at wk 26

87 % at wk 26

88 % PGA of 0 or 1 at wk 10;

54 % at wk 24

93 at wk 26

47 % PGA of 0 or 1 at wk 12;

54 at wk 12;

72 % at wk 24

60 at wk 24

66 % PGA of 0 or 1 at wk 12;

Other outcomes

70 at wk 12;

Change in DLQI

77 at wk 24

% achieving PASI-75

Positive antibodies in 5 % after first tx and 18 % after re-tx with 200 mg and 4 and 25 %, respectively, with 400 mg. The majority showed no changes from BL for ANA, dsDNA, anticardiolipin IgG and IgM

6 pts with SAEs, all in first tx phase. One disseminated TB in 400-mg group

Not reported

Not reported

3 cases of TB in infliximab groups through 26 wks. One case of drug-induced hepatitis and pancreatic cancer with liver and spleen metastasis resulting in death. Ten subjects with newly developed ANA and 4 with new dsDNA antibodies, vs 3 and 1 in PL respectively. 12 % infusion reactions

AEs in 75 % combination and 60 % monotherapy with 3 SAEs in each arm

AEs

Psoriasis Systemic Therapies: Evidence-Based Update

No. pts

Ave age

Secukinumab [24] (n = 125)

Secukinumab [22] (n = 404)

In development

Anti IL-17

Alefacept plus nbUVB [44] (n = 98)

46

46

46

45

46

25

26

21

27

22

64

78

67

85

69

66

75 PL

150 mg SC wks 0, 4, 8

PL

150 mg SC wks 0, 4, 8

75 mg SC wks 0, 4, 8

25 mg SC wks 0, 4, 8

25 mg SC once, wk 0

PL, then 150 mg SC wks 12, 24 at start of relapse

44

67

150 mg SC wks 0,1,2,4

150 mg SC once, wk 0

150 mg SC wks 12, 24

44

138

79

80

15 mg IM every wk 9 12 wks

15 mg IM every wk plus nbUVB 9 12 wks

Dose

67

45

76

65

% males

65

43

66

48

49

133

47

49

Approved- no longer available

Anti T-cell

Biologic therapy (total no. pts)

Table 2 continued

12 wks tx

20 wks maintenance phase

12 wks induction phase

12 wks

Duration

22

21

20

21

22

21

21

20

20

18

18

BL PASI

4 at wk 36

9 at wk 12;

26 at wk 36

82 at wk 12;

19 at wk 36

57 at wk 12;

67

85

2

42

55

11

22 at wk 16

45 at wk 16

% achieving PASI-75

-4 at wk 16

-5.3 at wk 16

Change in DLQI

9 % IGA 0 or 1 at wk 12

48 % IGA 0 or 1 at wk 12

33 % IGA 0 or 1 at wk 12

23 % PGA of 0 or 1 at wk 16

43 % PGA of 0 or 1 at wk 16

Other outcomes

Higher incidence of AEs in 150 mg group compared to other dose regimens, which were comparable to PL. 4 % SAEs (2 in PL, 2 in 25 mg 9 3 doses group, 1 in 75 mg group) none of which were thought to be related to drug. 2 cases of neutropenia in the 150 mg group

No ISRs. No immunogenicity. Infections in 35 % of pts in induction phase, with all active groups similar to or lower than PL. Infections in 32 % of pts in maintenance phase, with slightly higher rate in fixed interval and openlabel groups vs. start of relapse group. Grade 1 or 2 neutropenia in 4.7 % active induction phase tx vs. 0.2 % PL and 7.9 % active maintenance. Serious AEs in 3.2 % of pts in induction and 4.7 % in maintenance periods

Combination group had more AEs vs. monotherapy, with erythema and pruritus most common. 3 SAEs in combination group with 1 (leg edema) possibly tx related

AEs

L. F. Sandoval et al.

42

38

700 mg IV PL

8

5

140 mg SC

PL

280 mg SC at day 1 and wk 4, 8

210 mg SC at day 1 and wks 1, 2, 4, 6, 8, 10

350 mg SC

76

58

71

62

140 mg SC at day 1 and wks 1, 2, 4, 6, 8, 10

70 mg SC at day 1 and wks 1, 2, 4, 6, 8, 10

PL

150 mg SC wks 0, 2, 4, 8, 12, 16

75 mg SC wks 0, 2, 4, 8, 12, 16

25 mg SC wks 0, 2, 4, 8, 12, 16

10 mg SC wks 0, 2, 4, 8, 12, 16

Dose

8

43

42

42

4

42

40

72

56

52

50

66

60

57

% males

85 days

12 wks

16 wks

Duration

14

19

18

21

19

18

17

18

17

19

19

BL PASI

0

88 at day 43

38 at day 43

0

0

67

82

77

33

8 at wk 12

82 at wk 12

83 at wk 12

77 at wk 12

29 at wk 12

% achieving PASI-75

DLQI score 10.3

DLQI score 3.9

DLQI score 2

DLQI score 2

DLQI score 6.5

-2.4 at wk 12

-7.8 at wk 12

-8.5 at wk 12

-7.1 at wk 12

Change in DLQI

3 % PGA 0 or 1

69% PGA 0 or 1

80 % PGA 0 or 1

85 % PGA 0 or 1

26 % PGA 0 or 1

-31 % PSSI change; 8 % PGA 0 or 1 at wk 12

-85 % PSSI change; 71 % PGA 0 or 1 at wk 12

-95 % PSSI change; 72 % PGA 0 or 1 at wk 12

-87 % PSSI change; 70 % PGA 0 or 1 at wk 12

-43 % PSSI change; 25 % PGA 0 or 1 at wk 12

Other outcomes

No SAEs. AEs were mild to moderate, and similar between active tx and PL groups. 2 pts (one each from 350 mg and 700 mg) developed antiAMG 827 antibodies at day 85

AEs: 70 mg = 68 %, 140 mg = 69 %, 210 mg = 82 %, 280 mg = 73 %, PL = 62 %. One discontinuation in 280 mg for urticaria. 3 serious AEs: renal colic in 70-mg pt (resolved with no change in drug), ectopic pregnancy in PL, 2 pts with asymptomatic grade 3 neutropenia in 210 mg. Incidence of brodalumab binding antibodies was similar across all tx groups. No neutralizing antibodies on bioassay

No serious AEs in any group; frequency of AEs similar across all groups. Four pts discontinued study due to AEs: 1 pt each for hypertriglyceridemia (PL), peripheral edema (10 mg), hypersensitivity (10 mg), and urticaria (25 mg). 6 pts with ISRs. 2 pts with grade 2 neutropenia (75- and 150-mg groups)

AEs

AE adverse events, ALT alanine aminotransferase, ANA antinuclear antibodies, BL baseline, CV cardiovascular, DLQI Dermatology Life Quality Index, dsDNA double-stranded DNA, eow every other week, hfPGA Physician’s Global Assessment of hands and/or feet, IGA Investigator’s Global Assessment, IgG/M immunoglobulin G/M, IL interleukin, IM intramuscular, ISR injection site reaction, IV intravenous, MACE major adverse cardiovascular event, MCID minimal clinically important difference, MTX methotrexate, NAPSI Nail Psoriasis Severity Index, nbUVB narrowband ultraviolet B, PASI Psoriasis Area and Severity Index, PCS Physical Component Scale, PDI Psoriasis Disability Index, PGA Physician’s Global Assessment, PL placebo, PSSI Psoriasis Scalp Severity Index, pt(s) patient(s), qxw every x weeks, SAE serious adverse events, SC subcutaneous, SCC squamous cell carcinoma, TAI total activity impairment, TB tuberculosis, TNF tumor necrosis factor, TWPI total work productivity impairment, tx treatment, wk(s) week(s)

Brodalumab (AMG 827) [28] (n = 25)

44

45

27

39

46

28

42

46

29

39

46

30

Brodalumab [27] (n = 198)

48

28

Ixekizumab [25] (n = 142)

Ave age

No. pts

Biologic therapy (total no. pts)

Table 2 continued

Psoriasis Systemic Therapies: Evidence-Based Update

L. F. Sandoval et al.

At 52 weeks, these measures were better in patients receiving the drug every 4 weeks than in those receiving the drug every 12 weeks. 3.2.2 Tumor Necrosis Factor (TNF)-Alpha Inhibitors Bagel et al. [15] reported that etanercept was effective in treating both overall psoriasis and scalp psoriasis. At week 12, 86 % of patients receiving etanercept 50 mg subcutaneously twice weekly achieved a Psoriasis Scalp Severity Index (PSSI)-75 and 59 % a PASI-75 versus 11 and 5 %, respectively, of patients receiving placebo. Patients also had significantly less scalp pruritus and pain and an improvement in DLQI compared with placebo at week 12 [16]. Rates of side effects were similar between both groups. In patients treated with a combination of etanercept and methotrexate for 24 weeks, significantly more patients reached a PASI-75 in the combination group compared with etanercept monotherapy (77 vs. 60 %, respectively) [17]. More adverse effects were reported in the combination group; however, most were mild to moderate. The efficacy and safety of infliximab was studied in Chinese patients with moderate to severe psoriasis [18]; 81 % of treated patients achieved a PASI-75 at week 10 compared with 2 % in the placebo group during the induction phase and 88 % of treated patients reached a PGA of ‘clear’ or ‘minimal’ (0 or 1) compared with 7 % of placebo patients. The treatment group also achieved a significant reduction in the DLQI score (-8), while the placebo groups remained almost unchanged (-1.5). The improvements in PASI, PGA, and DLQI scores were maintained through the maintenance phase to the end of the study (week 26). More adverse effects were reported in the infliximab group than in the placebo group, though this was not significant. Most adverse effects were mild to moderate; however, three patients receiving active treatment developed tuberculosis over the study period, highlighting the need to screen for this disease. Kimball et al. [19] reported on improvement in selfreported work productivity in psoriasis patients treated with adalimumab, with these patients achieving greater improvement in total work productivity impairment (TWPI) and total activity impairment (TAI) scores than those receiving placebo (16 and 11 % greater, respectively). Patients who achieved a PASI-75 had significantly greater improvements in work productivity and activity impairment (WPAI) outcomes, except employment rate, at 16 weeks. Adalimumab was also studied in patients with moderate to severe psoriasis of the hands and feet [20]. Significantly more patients treated with adalimumab (57 %) achieved a PGA of hands and/or feet (hfPGA) of ‘clear’ or ‘almost clear’ compared with placebo. More patients also reached a NAPSI-50 compared with placebo

(57 and 4 %, respectively), and those patients who achieved a NAPSI-50 were more likely to reach hfPGA of ‘clear’ or ‘almost clear’ compared with non-responders. Certizumab pegol (CZP), a PEGylated Fab’ monoclonal antibody against TNF-alpha that is currently US FDA approved for the treatment of Crohn’s disease and rheumatoid arthritis, was studied in psoriasis [21]. Of patients treated with 400 mg subcutaneous CZP followed by 200 mg every 2 weeks for 10 weeks, 75 % reached a PASI-75 at week 12, compared with 83 % of patients who received 400 mg every other week, and 7 % of the placebo group. Patients in treatment groups also had significant improvements in DLQI and in PGA scores compared with placebo. In patients who at least achieved a PASI-75 who subsequently relapsed and were retreated with their same initial treatment, 68 % in the 200-mg group and 87 % in the 400-mg group reached PASI-75 at week 12. Efficacy of first treatment and retreatment in both groups was similar. There were no significant differences between patients previously treated with TNF-alpha inhibitors and naı¨ve patients in terms of PASI-75 and PGA 0 or 1. 3.2.3 Anti-IL-17 Several anti-IL-17 biologic agents are currently in development. Secukinumab, a fully human immunoglobulin G (IgG)-1j monoclonal anti-IL-17A antibody, is currently in phase III clinical trials. In phase II clinical trials, significantly more patients who received early or monthly induction regimens reached PASI-75 compared with placebo (55, 42, and 2 %, respectively) [22]. During the maintenance phase, 85 % of patients in the fixed-interval regimen reached PASI-75 compared with the group of patients who restarted treatment at relapse (67 %). No injection site reactions or development of antibodies against the drug occurred. Neutropenia, a concern with the IL-17 inhibitors since IL-17 plays a role in neutrophil recruitment, was reported in 5 % of patients during the induction phase and 8 % during the maintenance phase [23]. In a separate study, significantly more patients receiving either 75 or 150 mg secukinumab at weeks 0, 4, and 8 reached PASI-75 at week 12 compared with placebo (57 and 82 vs. 9 %, respectively) [24]. Two patients developed transient neutropenia in the higher dose (150mg) group. Ixekizumab, a humanized IgG4 monoclonal anti-IL17A, was effective in phase II trials at treating psoriasis at three doses (25, 75, 150 mg) compared with placebo at 16 weeks of treatment, with 77, 83, and 82 % of patients, respectively, reaching PASI-75 compared with 8 % of placebo patients [25]. A total 39 % of the 150-mg group and 38 % of the 75-mg group reached PASI-100 compared with none in the placebo group. Adverse effects were similar

Psoriasis Systemic Therapies: Evidence-Based Update

studied the effects of adalimumab in vascular inflammation through positron emission tomography (PET) in psoriasis patients with risk factors or history of coronary atherosclerosis. At 15 weeks, there was a significant change in inflammation in the vessel with the greatest baseline target : background ratio in the adalimumab group (-0.23) but not in the control group (-0.1), though the difference between the groups was not significant. There was a significant improvement in the target : background ratio in both the ascending aorta and carotid artery for the treatment group compared with the control group. Adalimumab patients also had a 51 % reduction in C-reactive protein compared with 5 % in the control group. In patients with both psoriasis and sleep apnea, treatment with adalimumab did not result in a significant improvement in apnea/ hypopnea index (AHI) compared with placebo group as assessed by polysomnography [30].

between treatment groups and placebo, and no serious adverse reactions were reported. Two patients (150-mg and 75-mg groups) developed asymptomatic grade 2 neutropenia. The phase I and II trials of ixekizumab show promise, with efficacy comparable to that of currently approved biologics; however, these clinical studies have been small and have not assessed treatment past 16 weeks [26]. Brodalumab, an anti-IL-17-receptor monoclonal antibody, is another biologic currently in development for the treatment of psoriasis. In a phase II trial, four doses (70 mg, 140 mg, 210 mg subcutaneously at day 1, week 1, 2, 4, 6, 8, 10; or 280 mg subcutaneously at day 1, week 4 and 8) were significantly more effective at achieving a PASI-75 compared with placebo (33, 77, 82, and 67 % of patients, respectively, compared with 0 % for placebo) [27]. DLQI scores were also significantly lower in all treatment groups compared with placebo. Two cases of asymptomatic grade 3 neutropenia occurred in the 210-mg group. In the earlier phase I trial, patients were treated with a single dose of either 140 mg subcutaneously, 350 mg subcutaneously, or 700 mg intravenously, with 38 and 88 % of patients in the 350- and 700-mg groups reaching PASI-75 by day 43 compared with no patients in the 140-mg and placebo groups [28]. The 350-mg and 700-mg doses also led to significant reductions in epidermal thickness on skin biopsy and rapid improvement in several skin biomarkers. There were no serious adverse effects. Two patients (350-mg and 700-mg groups) developed drug antibodies.

4 Discussion With numerous systemic agents now available for the treatment of moderate to severe psoriasis, practitioners often rely on treatment guidelines to direct their therapeutic recommendations. Current consensus guidelines for the management of psoriasis do not provide a specific treatment algorithm, but instead provide options for first-line therapies. In terms of oral therapies, methotrexate is considered a first-line therapy for moderate to severe psoriasis, and acitretin is a first-line systemic treatment for chronic palmoplantar or pustular psoriasis. Several biologic agents also may be used as first-line therapy, including adalimumab, etanercept, and ustekinumab. Infliximab is recommended as a second- or third-line biologic agent [1].

3.2.4 Non-Psoriasis Outcomes In addition to the studies of biologic agents that focused on psoriasis outcomes, two studies of adalimumab reported on non-psoriasis outcomes (Table 3). Bissonnette et al. [29] Table 3 Adalimumab non-psoriasis outcomes Biologic therapy (total no. pts)

No. pts

Ave age

% males

Dose

Duration

BL PASI

Adalimumab [29] (n = 30)

20

56

85

80 mg SC wk 0, then 40 mg wk 1 and eow

4 months

12

10

57

60

Topicals, phototherapy, or no tx

10

56

90

10

49

90

80 mg SC wk 0, then 40 mg eow PL

Adalimumab [30] (n = 20)

% achieving PASI-75

13

56 days

Other outcomes

AEs

Change in target:background ratio of adalimumab vs. control ascending aorta -0.23/carotid artery -0.26; 51 % decrease in CRP with adalimumab vs. 5 % in control

Not reported

Proportion of pts with AEs was similar between groups, with no SAEs and no discontinuations

12

30

9.6 change in AHI

10

10

-1.23 change in AHI

AE adverse events, AHI Apnea/Hypopnea Index, BL baseline, CRP C-reaction protein, eow every other wk, PASI Psoriasis Area and Severity Index, PL placebo, pt(s) patient(s), SAE serious adverse events, SC subcutaneous, tx treatment

L. F. Sandoval et al. Table 4 Systematic reviews of systemic treatment for psoriasis Systematic review

Drugs reviewed

No. of publications reviewed

Results

Lucka et al. [31]

Ustekinumab, adalimumab, infliximab, etanercept, cyclosporine, methotrexate, fumaric acid

33 (27 trials)

Galvan-Banqueri et al. [32]

Ustekinumab, adalimumab, infliximab, etanercept

14

Infliximab and ustekinumab (90 mg every 12 wks) were the most efficacious tx in regards to proportion of pts achieving PASI-75 and reduction in DLQI at 24 wks. A decrease in efficacy for infliximab, adalimumab and etanercept was observed after 24 wks. Insufficient and unreliable data on long-term efficacy of non-biologic agents Indirect comparison showed ustekinumab, adalimumab, and infliximab were significantly superior to etanercept with an absolute risk difference for PASI-75 of 12, 11, and 24 %, respectively, although the 95 % CI does not achieve clinical relevance. These biologics can be considered clinically equivalent

Brezinski and Armstrong [36]

Etanercept, adalimumab, infliximab, ustekinumab, alefacept

23

Off-label dose escalation in non-responders generally resulted in increased efficacy. Continuous tx with anti-TNF agents and anti-IL-12/23 agent results in better efficacy than interrupted therapy

Nast et al. [45]

Adalimumab, alefacept, etanercept, infliximab, ustekinumab, cyclosporine, fumaric acid, methotrexate, retinoids

49

Time to onset of action (time for 25 % of pts to reach a PASI75) of the biologics: infliximab has shortest (3.5 wks), followed by ustekinumab (4.6 wks for 90 mg; 5.1 wks for 45 mg) and adalimumab (4.6 wks), then etanercept (6.6 wks for 50 mg twice wkly; 9.5 wks for 50 mg wkly). For orals, cyclosporine is the fastest (6 wks), and methotrexate 3.2 wks if pts are started on 7.5 mg then increased the next wk to 15 mg and 9.9 wks for a slower taper

Kim et al. [33]

Adalimumab, infliximab, ustekinumab, alefacept

Reich et al. [34]

Adalimumab, efalizumab, infliximab, ustekinumab, etanercept

20

Meta-analysis showed infliximab was most effective at reaching PASI-50, 75, and 90, followed by ustekinumab (90 mg, then 45 mg), adalimumab, etanercept, and then finally efalizumab from indirect comparison in short-term studies (10–30 wks)

Lin et al. [35]

Ustekinumab, adalimumab, alefacept, etanercept, infliximab

17

Bayesian network meta-analysis showed ustekinumab has significantly higher odds of achieving PASI-75 vs. adalimumab, alefacept, and etanercept, but not infliximab

Mattei et al. [38]

Adalimumab, efalizumab, infliximab, ustekinumab, etanercept, alefacept

23

The correlation coefficient for mean percent reduction in PASI vs. mean reduction DLQI was 0.898 in psoriasis pts treated with biologics. Pts reaching a PASI-75 had a significant reduction in DLQI vs. pts reaching a PASI 50-75 or \50

Baker et al. [46]

Alefacept, efalizumab, infliximab, etanercept, adalimumab, ustekinumab, briakinumab

38

Using Bayesian MTC, all biologics had significant improvement in PGA vs. PL, with anti-ILs showing greater response vs. anti-T-cells. Anti-TNFs and anti-ILs showed significant improvement in DLQI vs. PL. Anti-TNFs, but not anti-T cells showed significant improvement in SF-36 and physical component scores

Strohal et al. [37]

Etanercept

12

Short term, more than half of pts reach a PASI-75. Etanercept 50 mg twice wkly more effective at wk 24 than lower doses. After 24 wk, etanercept is effective as continuous or intermittent therapy, although continuous is better. Approved and effective in children as young as 6 years. Most common AEs were cutaneous skin reactions. Less risk of serious infections and malignancies such as skin cancer and lymphoma than adalimumab and infliximab. No additional safety risk with long-term vs. short-term use

Efficacy

Adalimumab, infliximab, ustekinumab, and alefacept were effective in treating moderate-to-severe psoriasis. Weighted average PASI-75 scores for infliximab, ustekinumab, adalimumab, etanercept, and alefacept were 78.6, 72.1, 70.5, 48.1, and 21 %, respectively over 12 wks

Psoriasis Systemic Therapies: Evidence-Based Update Table 4 continued Systematic review

Drugs reviewed

No. of publications reviewed

Results

Wu et al. [47]

Ustekinumab

7

Most relative risk showed significant differences for both high (90 mg) and low dose (45 mg) in terms of efficacy vs. PL. Studies comparing high vs. low dose show both are effective, with only one study in four showing high dose to be significantly more effective. Types, severity, and frequency of AEs were similar between tx and PL groups

Kwatra et al. [48]

Tasocitinib and ruxolitinib

3

JAK inhibitors, oral tasocitinib, and topical ruxolitinib were effective in psoriasis clinical trials. Tasocitinib 2, 5, and 15 mg bid resulted in a PASI-75 in 25, 40.8, and 66.7 % of pts, respectively, for moderate to severe psoriasis

Ren and Dao [26]

Ixekizumab

39 (2 trials)

Phase I and II trials of ixekizumab show promise, with efficacy in terms of reduction in PASI comparable to currently approved biologics; however, these clinical studies have been small and have not assessed tx past 16 wks. Evidence of histopathologic improvement of psoriasis

Malhotra et al. [49]

Thiazolidinediones

4

Pioglitazone alone or with concomitant acetretin use had greater reduction in PASI scores vs. control groups in two studies. No significant improvement in PASI was reached with rosiglitazone tx in 3 studies

Safety Rustin [39]

Etanercept, infliximab, adalimumab, efalizumab, alefacept, ustekinumab

Long-term ([1 year) safety data on biologics. Except for efalizumab which is no longer available due to risk for progressive multifocal leukoencephalopathy, the biologics are well tolerated in long-term studies. 4-year data for etanercept in psoriasis show few serious infections, malignancies, or CV events. Well tolerated in children. Infliximab studied up to 78 wks showed hepatotoxicity with elevated ALT and AST, and increased infection, as well as infusion reactions. AEs stable for adalimumab over 3 years, with no association to serious infections. May be increased risk for NMSC, but no lymphomas reported. 4-year safety data on ustekinumab, with overall infections and malignancy comparable between all groups and did not increase over time. No increase in MACE vs. general population

Tzellos et al. [41]

Ustekinumab, briakinumab

9

A possible higher risk of MACEs in pts treated with anti-IL-12/ 23 vs. PL from studies of 20 wks or less

Armstrong et al. [42]

Methotrexate, cyclosporine, TNF-alpha inhibitors, ustekinumab

20

Methotrexate’s cardioprotective effects in psoriasis are inconclusive. Long-term use of cyclosporine associated with hypertension and discontinuation of drug. TNF-alpha inhibitors may reduce risk for cardiovascular events but larger RCTs are needed. IL-12/23 inhibitors are not associated with increased CV events vs. general population from short-term studies

Kamangar et al. [40]

Etanercept, infliximab, adalimumab, efalizumab, alefacept, ustekinumab

9

8 trials showed increased risk of NMSC while on tx. Data suggest a possible increased risk in pts with history of prior tx with drugs known to increase risk of skin cancer

AE adverse events, ALT alanine aminotransferase, AST aspartate aminotransferase, bid twice daily, CI confidence interval, CV cardiovascular, DLQI Dermatology Life Quality Index, IL interleukin, JAK Janus kinase, MACE major adverse CV event, MTC mixed treatment comparison, NMSC non-melanoma skin cancer, PASI Psoriasis Area and Severity Index, PGA Physician’s Global Assessment, PL placebo, pt(s) patient(s), RCT randomized clinical trial, TNF tumor necrosis factor, tx treatment, wk(s) week(s)

Systematic reviews and meta-analyses on efficacy, safety, and cost can also provide some guidance on treatment options. Our review of the literature resulted in 14 systematic reviews reporting on the efficacy of systemic treatments for psoriasis (Table 4). Lucka et al. [31]

reviewed 33 publications (27 trials) of both oral and biologic agents, and through meta-analysis concluded that infliximab and ustekinumab (90 mg every 12 weeks) were the most efficacious treatments in regards to the proportion of patients achieving PASI-75 and reduction in DLQI at

L. F. Sandoval et al. Table 5 Approved systemic therapies for psoriasis and grade of recommendations based on published clinical trials from 1 January 2012 through 1 July 2013 Approved systemic agents recommended for tx of moderate to severe psoriasis

Grade of recommendation

Comments

Etanercept

Strong recommendation; high-quality evidence [16, 17, 32, 37, 39, 46]

May also be considered first-line therapy for children [37]

Adalimumab

Strong recommendation; high-quality evidence [32–34, 39, 46]

Infliximab

Strong recommendation; high-quality evidence [18, 31, 32, 34, 35, 39, 46]

Ustekinumab

Strong recommendation; high-quality evidence [9–11, 31–35, 39, 46, 47]

There were no published clinical trials reporting on methotrexate, cyclosporine, or acitretin during the review period available to provide evidence for a level of recommendation for the therapies

24 weeks. A review using an indirect comparison of biologics alone had similar findings, with infliximab and ustekinumab, as well as adalimumab, superior to etanercept in terms of absolute risk difference for PASI-75 [32]. Three additional reviews provided further support for these three agents, with infliximab most effective in terms of patients achieving PASI-75, followed by ustekinumab, then adalimumab [33–35]. For patients who are non-responders to a biologic agent, off-label dose escalation generally leads to improvement in efficacy [36]. This review also concluded that continuous treatment with biologics is more effective than interrupted therapy. However, a review of etanercept found that, after 24 weeks, it was effective as continuous or interrupted treatment [37]. Mean improvement in PASI correlated with DLQI changes (correlation coefficient 0.898) in patients treated with biologics, and patients who reached a PASI-75 had a significant reduction in DLQI compared with patients reaching a PASI 50–75 or PASI \50 [38]. With longer-term safety data now available for the TNFalpha inhibitors (which have long been studied in rheumatologic diseases), and 5-year safety data now available for ustekinumab, support for their use as first-line therapy is strengthened. In a review of long-term safety data in psoriasis, all biologics were well tolerated (except efalizumab, which has been removed from the market) [39]. In general, the rate of infections is comparable between treatment groups and placebo. The risk for serious infections is a concern for biologics; however, data show that they are not common. There does appear to be an increased risk of NMSC while receiving biologic therapy [40]. Data suggest a possible increase risk in patients who have had prior treatment with drugs known to increase the risk of skin cancer. Data are conflicting as to whether or not ustekinumab is associated with greater risk of major acute cardiovascular events; any uncertainty suggests that if there is an association, it is not of large magnitude [39, 41, 42] (Table 4).

Cost is an important factor in treatment decisions. Our review of the literature did not identify any articles comparing the cost of the current systemic psoriasis therapies. In a previous study, the annual cost of methotrexate was the lowest and it was the most cost effective in terms of cost per person to achieve a PASI-75 [43]. Phototherapy was the most cost effective in terms of cost per person to achieve a DLQI MID. Alefacept was the least cost effective for both. Data on long-term psoriasis treatment are lacking from the current literature and may provide better insight into the cost of treatment. Potential long-term sequelae, including organ toxicity from some of the oral drugs like methotrexate and cyclosporine, may make what seems like a less costly treatment more expensive in the long term.

5 Conclusion The appropriate treatment regime should be individualized to meet the needs of each patient, taking into consideration efficacy, safety, and cost, and patients’ personal preferences. Several first-line systemic treatment options can be considered. Current literature focuses heavily on biologic agents, providing more support for their use first-line over oral therapy in terms of efficacy and safety (Table 5). Studies of the newer anti-IL-17 agents support their efficacy and they have the potential to become a valuable option in the treatment of psoriasis. New oral agents, though their efficacy does not appear to match that of the biologic agents (head-to-head trials are lacking), may also play a role in the treatment of psoriasis, providing an alternative to current oral therapies with more favorable safety profiles. Acknowledgments The Center for Dermatology Research is supported by an unrestricted educational grant from Galderma Laboratories, L.P. Dr. Feldman is a consultant and speaker for Galderma,

Psoriasis Systemic Therapies: Evidence-Based Update Stiefel/GlaxoSmithKline, Abbott Labs, Warner Chilcott, Janssen, Amgen, Photomedex, Genentech, BiogenIdec, and Bristol Myers Squibb. Dr. Feldman has received grants from Galderma, Astellas, Abbott Labs, Warner Chilcott, Janssen, Amgen, Photomedex, Genentech, BiogenIdec, Coria/Valeant, Pharmaderm, Ortho Pharmaceuticals, Aventis Pharmaceuticals, Roche Dermatology, 3 M, Bristol Myers Squibb, Stiefel/GlaxoSmithKline, Novartis, Medicis, Leo, HanAll Pharmaceuticals, Celgene, Basilea, and Anacor and has received stock options from Photomedex. Dr. Feldman is the founder and holds stock in Causa Research. Dr. Sandoval and Ms. Pierce have no conflicts to disclose.

12.

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