INFLIXIMAB (Page 10 of 13)

14.6 Ankylosing Spondylitis

The safety and efficacy of Infliximab were assessed in a randomized, multicenter, double-blind, placebo-controlled study in 279 adult patients with active AS. Patients were between 18 and 74 years of age, and had AS, as defined by the modified New York criteria for Ankylosing Spondylitis. Patients were to have had active disease as evidenced by both a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score >4 (possible range 0–10) and spinal pain >4 (on a Visual Analog Scale [VAS] of 0–10). Patients with complete ankylosis of the spine were excluded from study participation, and the use of Disease Modifying Anti-Rheumatic Drugs (DMARDs) and systemic corticosteroids were prohibited. Doses of Infliximab 5 mg/kg or placebo were administered intravenously at Weeks 0, 2, 6, 12 and 18.

At 24 weeks, improvement in the signs and symptoms of AS, as measured by the proportion of patients achieving a 20% improvement in ASAS response criteria (ASAS 20), was seen in 60% of patients in the Infliximab-treated group vs. 18% of patients in the placebo group (p<0.001). Improvement was observed at Week 2 and maintained through Week 24 (Figure 3 and Table 10).

Figure 3: Proportion of Adult AS Patients Who Achieved a ASAS 20 Response

At 24 weeks, the proportions of patients achieving a 50% and a 70% improvement in the signs and symptoms of AS, as measured by ASAS response criteria (ASAS 50 and ASAS 70, respectively), were 44% and 28%, respectively, for patients receiving Infliximab, compared to 9% and 4%, respectively, for patients receiving placebo (P <0.001, Infliximab vs. placebo). A low level of disease activity (defined as a value <20 [on a scale of 0–100 mm] in each of the 4 ASAS response parameters) was achieved in 22% of Infliximab-treated patients vs. 1% in placebo-treated patients (P <0.001).

Table 10: Components of AS Disease Activity

	Placebo (n=78)		Infliximab 5 mg/kg (n=201)
	Baseline	24 Weeks	Baseline	24 Weeks	P -value
* Measured on a VAS with 0=”none” and 10=”severe” † Bath Ankylosing Spondylitis Functional Index (BASFI), average of 10 questions ‡ Inflammation, average of last 2 questions on the 6-question BASDAI § CRP normal range 0–1.0 mg/dL ¶ Spinal mobility normal values: modified Schober’s test: >4 cm; chest expansion:>6 cm; tragus to wall: <15 cm; lateral spinal flexion: >10 cm
ASAS 20 response
Criteria (Mean)
Patient Global Assessment *	6.6	6.0	6.8	3.8	<0.001
Spinal pain *	7.3	6.5	7.6	4.0	<0.001
BASFI †	5.8	5.6	5.7	3.6	<0.001
Inflammation ‡	6.9	5.8	6.9	3.4	<0.001
Acute Phase Reactants
Median CRP § (mg/dL)	1.7	1.5	1.5	0.4	<0.001
Spinal Mobility (cm, Mean)
Modified Schober’s test ¶	4.0	5.0	4.3	4.4	0.75
Chest expansion ¶	3.6	3.7	3.3	3.9	0.04
Tragus to wall ¶	17.3	17.4	16.9	15.7	0.02
Lateral spinal flexion ¶	10.6	11.0	11.4	12.9	0.03

The median improvement from baseline in the general health-related quality-of-life questionnaire SF-36 physical component summary score at Week 24 was 10.2 for the Infliximab group vs. 0.8 for the placebo group (P <0.001). There was no change in the SF-36 mental component summary score in either the Infliximab group or the placebo group.

Results of this study were similar to those seen in a multicenter double-blind, placebo-controlled study of 70 patients with AS.

14.7 Psoriatic Arthritis

Safety and efficacy of Infliximab were assessed in a multicenter, double-blind, placebo-controlled study in 200 adult patients with active PsA despite DMARD or NSAID therapy (≥5 swollen joints and ≥5 tender joints) with 1 or more of the following subtypes: arthritis involving DIP joints (n=49), arthritis mutilans (n=3), asymmetric peripheral arthritis (n=40), polyarticular arthritis (n=100), and spondylitis with peripheral arthritis (n=8). Patients also had Ps with a qualifying target lesion ≥2 cm in diameter. Forty-six percent of patients continued on stable doses of methotrexate (≤25 mg/week). During the 24-week double-blind phase, patients received either 5 mg/kg Infliximab or placebo at Weeks 0, 2, 6, 14, and 22 (100 patients in each group). At Week 16, placebo patients with <10% improvement from baseline in both swollen and tender joint counts were switched to Infliximab induction (early escape). At Week 24, all placebo-treated patients crossed over to Infliximab induction. Dosing continued for all patients through Week 46.

Clinical Response

Treatment with Infliximab resulted in improvement in signs and symptoms, as assessed by the ACR criteria, with 58% of Infliximab-treated patients achieving ACR 20 at Week 14, compared with 11% of placebo-treated patients (P <0.001). The response was similar regardless of concomitant use of methotrexate. Improvement was observed as early as Week 2. At 6 months, the ACR 20/50/70 responses were achieved by 54%, 41%, and 27%, respectively, of patients receiving Infliximab compared to 16%, 4%, and 2%, respectively, of patients receiving placebo. Similar responses were seen in patients with each of the subtypes of PsA, although few patients were enrolled with the arthritis mutilans and spondylitis with peripheral arthritis subtypes.

Compared to placebo, treatment with Infliximab resulted in improvements in the components of the ACR response criteria, as well as in dactylitis and enthesopathy (Table 11). The clinical response was maintained through Week 54. Similar ACR responses were observed in an earlier randomized, placebo-controlled study of 104 PsA patients, and the responses were maintained through 98 weeks in an open-label extension phase.

Table 11: Components of ACR 20 and Percentage of Adult PsA Patients with 1 or More Joints with Dactylitis and Percentage of Adult PsA Patients with Enthesopathy at Baseline and Week 24

	Placebo		Infliximab 5 mg/kg *
Patients Randomized	(n=100)		(n=100)
	Baseline	Week 24	Baseline	Week 24
* P <0.001 for percent change from baseline in all components of ACR 20 at Week 24, P<0.05 for % of patients with dactylitis, and P =0.004 for % of patients with enthesopathy at Week 24 † Scale 0–68 ‡ Scale 0–66 § Visual Analog Scale (0=best, 10=worst) ¶ Health Assessment Questionnaire, measurement of 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities (0=best, 3=worst) # Normal range 0–0.6 mg/dL
Parameter (medians)
No. of Tender Joints †	24	20	20	6
No. of Swollen Joints ‡	12	9	12	3
Pain §	6.4	5.6	5.9	2.6
Physician’s Global Assessment §	6.0	4.5	5.6	1.5
Patient’s Global Assessment §	6.1	5.0	5.9	2.5
Disability Index (HAQ-DI)¶	1.1	1.1	1.1	0.5
CRP (mg/dL)#	1.2	0.9	1.0	0.4
% Patients with 1 or more digits with dactylitis	41	33	40	15
% Patients with enthesopathy	35	36	42	22

Improvement in Psoriasis Area and Severity Index (PASI) in PsA patients with baseline body surface area (BSA) ≥3% (n=87 placebo, n=83 Infliximab) was achieved at Week 14, regardless of concomitant methotrexate use, with 64% of Infliximab-treated patients achieving at least 75% improvement from baseline vs. 2% of placebo-treated patients; improvement was observed in some patients as early as Week 2. At 6 months, the PASI 75 and PASI 90 responses were achieved by 60% and 39%, respectively, of patients receiving Infliximab compared to 1% and 0%, respectively, of patients receiving placebo. The PASI response was generally maintained through Week 54. [see Clinical Studies (14.8)].

Radiographic Response

Structural damage in both hands and feet was assessed radiographically by the change from baseline in the van der Heijde-Sharp (vdH-S) score, modified by the addition of hand DIP joints. The total modified vdH-S score is a composite score of structural damage that measures the number and size of joint erosions and the degree of joint space narrowing (JSN) in the hands and feet. At Week 24, Infliximab-treated patients had less radiographic progression than placebo-treated patients (mean change of -0.70 vs. 0.82, P <0.001). Infliximab-treated patients also had less progression in their erosion scores (-0.56 vs 0.51) and JSN scores (-0.14 vs 0.31). The patients in the Infliximab group demonstrated continued inhibition of structural damage at Week 54. Most patients showed little or no change in the vdH-S score during this 12-month study (median change of 0 in both patients who initially received Infliximab or placebo). More patients in the placebo group (12%) had readily apparent radiographic progression compared with the Infliximab group (3%).

Physical Function

Physical function status was assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. Infliximab-treated patients demonstrated significant improvement in physical function as assessed by HAQ-DI (median percent improvement in HAQ-DI score from baseline to Week 14 and 24 of 43% for Infliximab-treated patients vs 0% for placebo-treated patients).

During the placebo-controlled portion of the trial (24 weeks), 54% of Infliximab-treated patients achieved a clinically meaningful improvement in HAQ-DI (≥0.3 unit decrease) compared to 22% of placebo-treated patients. Infliximab-treated patients also demonstrated greater improvement in the SF-36 physical and mental component summary scores than placebo-treated patients. The responses were maintained for up to 2 years in an open-label extension study.