Clinical and economic burden of extra-articular manifestations in ankylosing spondylitis patients treated with anti-tumor necrosis factor agents

Figures & data

Table 1.  Assumptions used in the uveitis costing.

Parameter	French assumptions	German assumptions	Reference(s)
Diagnosis
Laboratory	Directly from Literature and Expert Opinion	Directly from Literature and Expert Opinion	Expert opinion; Losch et al.27
Office visit	Cost is mean value (between societal and NHS costs of visit to ophthalmologist in France); frequency (1–2 visits/year) based on expert opinion	Cost is mean value (between societal and NHS costs of visit to ophthalmologist in Germany); frequency (1–2 visits/year) based on expert opinion	Expert opinion; Lafuma et al.26
Medication
Dexamethasone	Per expert opinion	–	Expert opinion
Prednisolone acetate	Treatment duration based on expert opinion: 2–3 weeks per flare	Treatment duration based on expert opinion: 2–3 weeks per flare	Expert opinion
Rheumatrex	Per expert opinion: 5% of patients with uveitis will receive 5-mg methotrexate injection once a week for 12 weeks	Treatment for >8 weeks, assuming it will be given through the flare (2.5 months = 10 weeks)	Expert opinion
Decortin H	Per expert opinion: 20% of patients with uveitis will receive 1 mg/kg per day as initial dose and then decrease for 90 days	Treatment duration based on expert opinion: 2–3 weeks per flare	Expert opinion
Cyclosporin A	–	Per expert opinion: treatment for >8 weeks, assuming it will be given through the flare (2.5 months = 10 weeks); 2–5 mg/kg per day	Expert opinion
Azathioprine	–	Per expert opinion: treatment for >8 weeks, assuming it will be given through the flare (2.5 months = 10 weeks): 100 mg/day	Expert opinion
Monitoring
Office visits	Per expert opinion: 2 ophthalmologic visits per flare for flare management	Per expert opinion: 2 ophthalmologic visits per flare	Expert opinion; Lafuma et al.26
Hospitalization	Per expert opinion: <10% of patients hospitalized and the average length of hospital stay is 7 days; average per day cost of hospital stay was literature based	Per expert: <10% of patients hospitalized and the average length of hospital stay is 7 days; average per day cost of hospital stay in a general ward was literature based	Expert opinion; Bonastre et al.26 Expert opinion; Martin et al.28
Office visits for AEs	Per expert opinion: 10% of AEs are due to systemic immunosuppressant, with three additional ophthalmologist visits per year (i.e., one visit per flare) for AEs; cost was literature based	Per expert opinion: 10% of AEs are due to systemic immunosuppressant, with three additional ophthalmologist visits per year (i.e., one visit per flare) for AEs; cost was literature based	Expert opinion; Lafuma et al.26
In between flares	Per expert opinion: includes office visits and laboratory tests, assuming four additional office visits/laboratory tests per year for in-between flare monitoring for ⅓ of patients (∼1.3 additional office visits/laboratory tests per flare assuming three flares per year)	Per expert opinion: includes office visits and laboratory tests, assuming four additional office visits/laboratory tests per year for in-between flare monitoring for ⅓ of patients (∼1.3 additional office visits/laboratory tests per flare assuming three flares per year)
Prophylactic treatment	Per EO expert opinion ⅓ of patients will additionally receive the same treatment listed under ‘Medication’	Per expert opinion: ⅓ of patients will additionally receive the same treatment listed under ‘Medication’	Expert opinion
Indirect costs
Missed work days	Per expert opinion: 50% of patients will miss 3 days per flare; 50% will miss 9 days; wages lost per day was literature based	Per expert opinion: 50% of patients will miss 3 days per flare; 50% will miss 9 days; wages lost per day was literature based	Expert opinion; Boonen et al.19 Expert opinion; Sohn et al.29

NHS, National Health Service.

Table 2.  Summary of the incidence of anterior uveitis in anti-TNF studies.

Agent	n	Exposure (PY)	AU flares (n)	Flares/100-PYs (95% CI)*	Absolute rate reduction vs placebo (95% CI)*
Braun et al.24 meta-analysis
Placebo	190	70.5	11	15.6 (7.8–27.9)
Infliximab	90	146.4	5	3.4 (1.1–8.0)	12.2 (4.5–19.9)
Etanercept	297	430	34	7.9 (5.5–11.1)	7.7 (0.1–15.2)
Anti-TNF total	387	576.4	39	6.8 (4.8–9.2)	8.8 (2.0–15.7)
ATLAS and RHAPSODY9,16†
Adalimumab	1561	917	34	3.7 (2.6–5.2)	–
Sieper et al.18 meta-analysis
Placebo	249	83.0	10	12.0 (5.8–22.2)
Etanercept	1074	1136.9	55	4.8 (3.6–6.3)	7.2 (2.1–12.4)
Summary of Braun et al.24, ATLAS & RHAPSODY9,16, and Sieper et al.17
Total placebo	439	153.5	21	13.7 (8.5–20.9)
Total infliximab	90	146.4	5	3.4 (1.1–8.0)	10.3 (3.6–16.9)
Total etanercept	1371	1566.9	89	5.7 (4.6–7.0)	8.0 (3.8–12.2)
Total adalimumab	1561	917	34	3.7 (2.6–5.2)	10.0 (6.1–13.8)
Total anti-TNF	3022	2630.3	128	4.9 (4.1–5.8)	8.8 (5.0–12.6)

*Updated statistical comparisons (p-values were calculated using chi-square tests) were infliximab vs total placebo: p = 0.0025; Total etanercept vs total placebo: p = 0.0002; Total adalimumab vs total placebo: p ≤ 0.001; Total infliximab vs total etanercept: p = 0.26; Total infliximab vs total adalimumab: p = 0.86; and total etanercept vs total adalimumab: p = 0.033. Adalimumab 95% CI was calculated based on the normal distribution.

† For adalimumab only, including the ATLAS study9 (1.9 flares/100-PYs with a cumulative exposure of 622-PYs) and RHAPSODY study16 (7.4 flares/100-PYs with a cumulative exposure of 295-PYs). Placebo uveitis data were not reported in these two studies.

Table 3.  Summary of the incidence of IBD in anti-TNF studies.

Agent	n	Exposure (PY)	IBD flares (n)	Flares/100-PYs (95% CI)	Absolute rate reduction vs. placebo (95% CI)*
Braun et al.6
Placebo	434	150.4	2	1.3 (0.2–4.8)
Infliximab	366	618	1	0.2 (0.0–0.9)	1.2 (0.1–2.3)
Etanercept	419	625.4	14	2.2 (1.2–3.8)	−2.0 (–5.1–1.1)
Adalimumab	295	132.3	3	2.3 (0.5–6.6)	−0.9 (−4.0–2.2)
Anti-TNF total	1080	1375.7	18	1.3 (0.8–2.1)	0.0 (−1.9–1.9)
Updated with ATLAS9†
Adalimumab	606	794.3	5	0.63 (0.2–1.5)‡	0.7 (−0.8–2.2)
Anti-TNF total	1391	2037.7	20	1.0 (0.6–1.5)	0.3 (−1.3–2.0)

*Updated statistical comparisons (p-values were calculated using chi-square tests) were infliximab vs placebo: p = 0.04; etanercept vs placebo: p = 0.49; adalimumab vs placebo: p = 0.68; infliximab vs etanercept: p < 0.001; infliximab vs adalimumab: p = 0.18; and etanercept vs adalimumab: p = 0.009.

†For adalimumab only. Placebo IBD data were not reported in the ATLAS study9.

‡95% CI was calculated based on the Poisson distribution.

Table 4.  Direct and indirect costs associated with an IBD event in AS patients (in 2010 Euros).

	France31 (n = 258)* Mean per-patient cost over 6 weeks	Germany32 (n = 483)† Mean per-patient cost over 4 weeks
Total direct medical cost	€6443	€483
Diagnosis	€3222	NR
Outpatient physician consults	€100	€42
General practitioner	€48	NR
Gastroenterologist	€52	NR
Non-physician consults	NR	€14
Hospitalization	€3095	€77‡
Planned	€747	NR
Unplanned	€2374	NR
Medications	NR	€314
Special diet	NR	€15
Other medical products	NR	€18
Other expenditures	NR	€3
Indirect costs	€176‡	€877
Short-term productivity losses	€176‡	€238
Long-term productivity losses	NR	€639
Direct non-medical costs	NR	€52
Household support	NR	€18
Patient activities	NR	€19
Transportation	NR	€18

NR, not reported.

*For France, 30% of respondents had been hospitalized and/or were inpatients.

†For Germany, costs were estimated based on an outpatient survey.

‡Measured retrospectively for the previous 3 months.

Table 5.  Resource use and cost for patients with AS treated for uveitis (per flare) in France and Germany.*

	% Utilization		Units/Flare		Cost/Unit (€)*		Cost (€)
	France	Germany	France	Germany	France	Germany	France	Germany
Diagnosis
Laboratory	100	100	1.0	1.0	734.34	762.75	734.34	762.75
Office visit	100	100	1.0	1.0	34.38	44.44	34.38	44.44
Subtotal	–	–	–	–	–	–	768.72	807.19
Medication
Dexamethasone	100	NA	3.0	NA	2.57	NA	7.71	NA
Prednisolone acetate	20	95	360.0	1.0	0.23	14.88	16.67	14.14
Rheumatrex	5	5	12.0	10.0	2.27	35.20	1.36	17.60
Decortin H	NA	5	NA	25.0	NA	0.50	NA	0.63
Cyclosporin A	NA	5	NA	686.0	NA	1.11	NA	37.92
Azathioprine	NA	5	NA	140.0	NA	0.53	NA	13.15
Subtotal	–	–	–	–	–	–	25.74	83.44
Non-drug medical services
Office visits	100	100	2.0	2.0	34.38	44.72	68.76	89.44
Hospitalization	5	5	7.0	7.0	554.63	1247.77	194.12	436.72
Office visits for AEs	10	10	1.0	3.0	34.38	44.44	3.44	13.33
In between flares	33	33	1.3	1.3	768.72	807.19	338.24	346.29
Prophylactic treatment	33	33	1.3	1.3	25.74	83.44	11.04	35.61
Subtotal	–	–	–	–	–	–	615.60	921.39
Indirect costs
Missed work days†	50	50	3	3	104.74	105.09	157.10	157.64
	50	50	9	9	104.74	105.09	471.31	472.92
Direct costs subtotal	–	–	–	–	–	–	1410.06	1812.02
Indirect costs subtotal	–	–	–	–	–	–	628.41	630.56
Direct and indirect costs total	–	–	–	–	–	–	2038.47	2442.58

NA, Not applicable; AE, adverse event.

Utilization refers to patients with AS diagnosed with concomitant uveitis. Totals may not sum owing to rounding.

*Details on costing assumptions are presented in Table 1.

†Assuming 50% of patients missed 3 days and 50% missed 9 days based on expert opinions.

Losch A, Scheuerle A, Rupp V, et al. Transpalpebral measurement of intraocular pressure using the TGDc-01 tonometer versus standard Goldmann applanation tonometry. Graefes Arch Clin Exp Ophthalmol 2005;243:313-6

 PubMed Web of Science ®Google Scholar

Lafuma A, Berdeaux G. Modelling lifetime cost consequences of ReSTOR in cataract surgery in four European countries. BMC Ophthalmol 2008;8:12

 PubMed Web of Science ®Google Scholar

Martin J, Neurohr C, Bauer M, et al. [Cost of intensive care in a German hospital: cost-unit accounting based on the InEK matrix]. Anaesthesist 2008;57:505-12

 PubMed Web of Science ®Google Scholar

Boonen A, van der HD, Landewe R, et al. Costs of ankylosing spondylitis in three European countries: the patient's perspective. Ann Rheum Dis 2003;62:741-7

 PubMed Web of Science ®Google Scholar

Sohn S, Schoeffski O, Prinz J, et al. Cost of moderate to severe plaque psoriasis in Germany: a multicenter cost-of-illness study. Dermatology 2006;212:137-44

 PubMed Web of Science ®Google Scholar

Braun J, Baraliakos X, Listing J, et al. Decreased incidence of anterior uveitis in patients with ankylosing spondylitis treated with the anti-tumor necrosis factor agents infliximab and etanercept. Arthritis Rheum 2005;52:2447-51

 PubMed Web of Science ®Google Scholar

van der HD, Kivitz A, Schiff MH, et al. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2006;54:2136-46

 PubMedGoogle Scholar

Rudwaleit M, Rodevand E, Holck P, et al. Adalimumab effectively reduces the rate of anterior uveitis flares in patients with active ankylosing spondylitis: results of a prospective open-label study. Ann Rheum Dis 2009;68:696-701

 PubMed Web of Science ®Google Scholar

Sieper J, Koenig A, Baumgartner S, et al. Analysis of uveitis rates across all etanercept ankylosing spondylitis clinical trials. Ann Rheum Dis 2010;69:226-9

 PubMed Web of Science ®Google Scholar

Braun J, Sieper J. What is the most important outcome parameter in ankylosing spondylitis? Rheumatology (Oxf) 2008;47:1738-40

 PubMedGoogle Scholar

Braun J, Baraliakos X, Listing J, et al. Differences in the incidence of flares or new onset of inflammatory bowel diseases in patients with ankylosing spondylitis exposed to therapy with anti-tumor necrosis factor alpha agents. Arthritis Rheum 2007;57:639-47

 PubMed Web of Science ®Google Scholar

Rolland N, Grandbastien B, Merle V, et al. [Cost of early management of chronic inflammatory intestinal disease]. Gastroenterol Clin Biol 1999;23:483-8

 PubMedGoogle Scholar

Stark R, Konig HH, Leidl R. Costs of inflammatory bowel disease in Germany. Pharmacoeconomics 2006;24:797-814

 PubMed Web of Science ®Google Scholar