Cost-effectiveness of adalimumab, etanercept, and tocilizumab as first-line treatments for moderate-to-severe rheumatoid arthritis

Figures & data

Figure 1.  Simplified model structure.

Table 1.  Adjusted ACR responses, constant withdrawal rates, HAQ drops, and HAQ progressions together with their probabilistic distributions.

Response	ACR20	ACR50	ACR70	Dirichlet D	Source20
ADAL, ETAN, INFL	0.63	0.39	0.16	One	First-line bDMARD
TOC	0.65	0.44	0.29	parameter	First-line bDMARD
RTX	0.60	0.35	0.18	Gamma	after bDMARD
ABAT	0.59	0.33	0.15	distribution	after bDMARD
tDMARDs	0.32	0.12	0.04		after tDMARD
Withdrawal	Rate (SE)	Probability (SE)		Beta D
ETAN	0.080 (0.0135)	NA			29
INFL	0.120 (0.0207)	NA		NA
bDMARDs	0.100 (0.0172)	0.095 (0.0156)		33.67, 320.15	29 average
tDMARDs	NA	0.270 (0.0442)		26.97, 72.92	30
HAQ drop	Mean	SE		D
No response	0.13572	0.01679		Normal	17–19
ACR 20	0.44266	0.01831
ACR 50	0.66795	0.02610
ACR 70	0.92257	0.03201
HAQ progression	Mean	SE		D
bDMARDs (not TOC)	0.00000	0.00162		Normal	27
TOC	−0.01622	0.00162			31
tDMARDs	0.02250	NA		Triangular, R:0.0150–0.0300	[NICE 2006: RTX appraisal data on file]
MTX (last resort)	0.03000	NA		Triangular, R:0.0225–0.0375
Mortality	Multiplier	Lowest 2.5%		Highest 97.5%
Per HAQ unit	1.330	1.099		1.610	33

D, distribution; MTX, methotrexate; ABAT, abatacept; ADAL, adalimumab; CSA, cyclosporine; LEFL, leflunomide; ETAN, etanercept; INFL, infliximab; RTX, rituximab; SE, standard error; TOC, tocilizumab; tDMARD, traditional drug; bDMARD, biologic drug; R, range.

Table 2.  Resource use and costs (healthcare unit costs at 2010 values; drug costs at 9/2011 values).

Resource	Cost (€)	Specification	Resource use
ADAL per 40 mg	597.89	Finnish	40 mg/fortnight
ETAN per 50 mg	285.28	Medicine	50 mg/week
TOC per 20 mg	36.25^a	Tariff	582.6 mg/month
(Retail without VAT)	(47.05)	9/2011
RTX per 1 mg	3.05^a		1000 mg twice every 9 months
Methylprednisolone per 1 mg	0.05^a		100 mg twice every 9 months
ABAT per 250 mg	372.00^a		750 mg days 1, 15, 29, every 4 weeks
INFL per 100 mg	622.20^a		218.5 mg 7 times/year
CSA per 1 mg	0.05		236.7 mg daily
LEFL per 20 mg	1.26		20 mg daily
MTX per 1 mg	0.09		15 mg/week
TOC administration (1.5 h inf.)	131.30^c	(incl. 2 clinician visits/cycle)	1/month
RTX administration (8 h inf.)	213.87^c	(incl. 1 clinician visit/cycle)	every 9 months
ABAT administration (30 min inf.)	98.77^c	(incl. 1 clinician visit/cycle)	days 1, 15, 29, then every 4 weeks
INFL administration (2 h inf.)	136.13^c	(incl. 1 clinician visit/cycle)	7 times/year
Administration guidance	76.89^c	ADAL, ETAN	Initiation
Outpatient visit (internal diseases)	196.39^c	All treatments	1/cycle
General practitioner visit^b	46.22^c	All treatments	1/cycle
Inpatient day (internal diseases)	648.37^c	0.0 <HAQ score <0.5	0.68/year^d
		0.6 <HAQ score <1.0	2.77/year^d
		1.1 <HAQ score <1.5	4.12/year^d
		1.6 <HAQ score <2.0	8.86/year^d
		2.1 <HAQ score <2.6	10.25/year^d
		2.6 <HAQ score <3.0	4.56/year^d
Phone consulting by patient^e	19.28^c	bDMARD, tDMARD	After tests
Chest X-ray, quantiferon, antibodies^g	50.39^c	First-line bDMARD	First bDMARD initiation
CBC, ALAT, creatine (twice year)^g	13.75^c	MTX^f	3/cycle
CBC, ALAT, ALP, RR^g	54.68^c	LEFL	3/cycle
Creatine, RR^g	54.45^c	CSA	3/cycle
Travelling to primary health care	6.62^c	Excl. VAT	*
Travelling to secondary health care	33.82^c	Excl. VAT	*

MTX, methotrexate; ABAT, abatacept; ADAL, adalimumab; CSA, cyclosporine; LEFL, leflunomide; ETAN, etanercept; CBC, complete blood count; ALAT, alanine aminotransferase; ALP, alkaline phosphatise; INFL, infliximab; RR, blood pressure; RTX, rituximab; TOC, tocilizumab; VAT, value-added tax; tDMARD, traditional drug; bDMARD, biologic drug.

^aWholesale/hospital price used in publicly funded hospitals. ^b The unit cost of an outpatient visit in primary healthcare for rheumatic diseases. ^c Hujanen et al.36. ^dKobelt et al.37. ^e The patient is informed of the laboratory results by phone. ^f Includes the tests for bDMARDs. ^g Includes the cost of test taking. * Number of visits varies according to treatment.

Table 3.  Base-case simulation results.

Outcome	Life-years		Death	QALYs	Costs (discounted)
Treatments	0%	3%	age	3%	Payer	Societal
MTX alone	25.575	17.205	78.061	5.833	96,753	111,927
Lower 2.5%	25.250	17.033	77.736	5.775	95,717	110,809
Higher 97.5%	25.900	17.377	78.386	5.892	97,789	113,044
ETAN + MTX^a	27.022	17.864	79.508	9.515	173,159	190,184
Lower 2.5%	26.691	17.694	79.177	9.415	170,937	187,865
Higher 97.5%	27.353	18.035	79.838	9.615	175,381	192,503
ICUR of ETAN + MTX^a vs MTX alone					20,754	21,257
ADAL + MTX^a	27.022	17.864	79.508	9.515	175,348	192,373
Lower 2.5%	26.691	17.694	79.177	9.415	173,060	189,990
Higher 97.5%	27.353	18.035	79.838	9.615	177,636	194,757
ICUR of ADAL + MTX^a vs MTX alone					21,349	21,852
TOC + MTX^a, wholesale	27.232	17.953	79.717	10.029	168,318	183,633
Lower 2.5%	26.899	17.782	79.385	9.916	166,275	181,541
Higher 97.5%	27.564	18.124	80.050	10.142	170,362	185,726
ICUR TOC (wholesale) + MTX^a vs MTX alone					17,057	17,091
TOC + MTX^a, retail	27.232	17.953	79.717	10.029	176,289	191,604
Lower 2.5%	26.899	17.782	79.385	9.916	174,023	189,297
Higher 97.5%	27.564	18.124	80.050	10.142	178,556	193,911
ICUR TOC (retail sale) + MTX^a vs MTX alone					18,957	18,991

QALY, quality-adjusted life-year; MTX, methotrexate; ADAL, adalimumab; ETAN, etanercept; TOC, tocilizumab; ICUR, incremental cost-utility ratio.

^a→ RTX + MTX → INFL + MTX → BSC.

Figure 2.  The cost-effectiveness efficiency frontier (CEEF) presents the cost-effective treatment options and their expected lifetime average costs and effectiveness.

Figure 3.  (a) Wholesale price for TOC, and (b) retail price for TOC. Probabilistic sensitivity analysis (PSA) results: cost-effectiveness acceptability frontier presenting the optimal treatments together with multinomial expected value of perfect information (mEVPI) for the comparison between ADAL, ETAN, and TOC before the fixed sequence of RTX followed by INFL followed by BSC, and MTX alone.

Table 4.  Deterministic sensitivity analyses.

Sensitivity analysis scenario	Lifetime outcomes		Treatments*				ICUR (€/QALY gained) vs MTX			ICUR (€/QALY gained) change
			TOC + MTX (wholesale)	TOC + MTX (retail sale)	ETAN + MTX	MTX alone	TOC + MTX (wholesale)	TOC + MTX (retail sale)	ETAN + MTX	TOC + MTX (wholesale)	TOC + MTX (retail sale)	ETAN + MTX
Base case^a	Costs	Payer	168,318	176,289	173,159	96,753	17,057	18,957	20,754
		Societal	183,633	191,604	190,184	111,927	17,091	18,991	21,257
	QALYs		10.029	10.029	10.029	9.515	5.833
ACR50 and ACR70 responses	Costs	Payer	143,630	149,200	144,804	98,331	14,235	15,985	16,963	−2822	−2972	−3791
		Societal	157,640	163,211	160,468	114,439	13,576	15,326	16,801	−3515	−3664	−4456
	QALYs		8.640	8.640	8.640	8.197	5.458
ACR70 responses only	Costs	Payer	127,917	131,799	123,962	99,466	12,574	14,290	13,589	−4483	−4667	−7165
		Societal	140,934	144,816	138,402	115,865	11,080	12,796	12,503	−6011	−6195	−8755
	QALYs		7.495	7.495	7.495	7.036	5.233
Fixed treatment times15	Costs	Payer	153,834	159,836	148,079	96,753	21,665	23,943	26,887	4608	4986	6133
		Societal	169,008	175,010	164,499	111,927	21,665	23,943	27,540	4574	4952	6283
	QALYs		8.468	8.468	8.468	7.742	5.833
No HAQ improvement for TOC	Costs	Payer	171,874	179,844	173,159	96,753	19,994	22,115	20,754	2937	3158	0
		Societal	188,949	196,919	190,184	111,927	20,500	22,621	21,257	3409	3631	0
	QALYs		9.591	9.591	9.591	9.515	0.833
50% rebound, one cycle	Costs	Payer	147,755	155,726	152,866	96,753	7373	8525	8643	−9684	−10,432	−12,112
		Societal	160,082	168,053	167,837	111,927	6961	8114	8611	−10,129	−10,877	−12,646
	QALYs		12.751	12.751	12.751	12.326	5.833
No excess mortality	Costs	Payer	177,635	185,609	183,084	108,043	15,879	17,698	19,430	−1178	−1259	−1325
		Societal	193,083	201,057	200,253	123,488	15,880	17,699	19,876	−1,211	−1291	−1381
	QALYs		10.375	10.375	10.375	9.855	5.993
Bansback et al.30 QoL	Costs	Payer	168,318	176,289	173,159	96,753	19,293	21,442	24,189	2236	2485	3435
		Societal	183,633	191,604	190,184	111,927	19,331	21,480	24,775	2240	2489	3518
	QALYs		8.233	8.233	8.233	7.683	4.524
Hawthorne et al.38 QoL	Costs	Payer	168,318	176,289	173,159	96,753	24,769	27,528	30,934	7712	8571	10,179
		Societal	183,633	191,604	190,184	111,927	24,818	27,576	31,683	7727	8586	10,426
	QALYs		11.045	11.045	11.045	10.626	8.156
Hurst et al.39 QoL	Costs	Payer	168,318	176,289	173,159	96,753	17,160	19,071	21,604	103	114	850
		Societal	183,633	191,604	190,184	111,927	17,194	19,105	22,127	103	115	870
	QALYs		8.314	8.314	8.314	7.680	4.143
QoL can be worse than death	Costs	Payer	16,8318	176,289	173,159	96,753	16,500	18,337	20,000	−558	−620	−754
		Societal	18,3633	191,604	190,184	111,927	16,532	18,370	20,485	−559	−621	−772
	QALYs		10.009	10.009	10.009	9.492	5.672
Constant hospitali- zations40	Costs	Payer	164,234	172,205	164,951	62,940	24,143	26,042	27,709	7085	7085	6955
		Societal	179,548	187,519	181,976	78,114	24,176	26,076	28,212	7085	7085	6955
	QALYs		10.029	10.029	10.029	9.515	5.833
ABAT instead of RTX	Costs	Payer	186,584	194,555	191,308	96,753	21,733	23,662	26,152	4676	4705	5398
		Societal	202,053	210,024	208,315	111,927	21,805	23,733	26,659	4714	4743	5402
	QALYs		9.967	9.967	9.967	9.449	5.833
Baseline age 40 years	Costs	Payer	190,740	198,730	196,006	116,083	15,418	17,069	18,914	−1639	−1888	−1841
		Societal	216,340	224,331	224,243	142,025	15,348	16,998	19,456	−1743	−1993	−1801
	QALYs		10.947	10.947	10.330	6.105
Baseline age 60 years	Costs	Payer	149,364	157,290	153,441	80,516	19,604	21,861	23,650	2547	2904	2896
		Societal	156,785	164,711	161,399	85,465	20,308	22,565	24,626	3218	3575	3369
	QALYs		8.963	8.963	8.535	5.451
Baseline HAQ 1.3	Costs	Payer	161,215	169,187	166,195	90,460	17,475	19,443	21,172	417	486	417
		Societal	173,312	181,283	179,809	103,161	17,325	19,294	21,427	235	303	170
	QALYs		11.081	11.081	10.609	7.032
Baseline HAQ 1.7	Costs	Payer	175,758	183,728	179,725	102,012	17,354	19,229	21,020	296	272	266
		Societal	190,196	198,166	193,704	118,600	16,848	18,723	20,314	−243	−267	−943
	QALYs		9.001	9.001	8.448	4.751
10-year analysis	Costs	Payer	99,178	106,331	101,701	40,512	42,578	47,770	50,048	25,521	28,813	29,294
		Societal	112,113	119,266	116,034	52,419	43,324	48,516	52,032	26,234	29,525	30,775
	QALYs		5.493	5.493	5.338	4.115
0% discounting	Costs	Payer	237,876	247,108	244,642	145,623	13,531	14,885	16,684	−3527	−4072	−4070
		Societal	256,145	265,377	265,034	164,348	13,464	14,818	16,965	−3627	−4173	−4292
	QALYs		14.256	14.256	14.256	13.373	7.438
6% discounting	Costs	Payer	128,104	135,139	131,738	68,468	21,386	23,908	25,727	4329	4951	4973
		Societal	141,149	148,184	146,178	80,962	21,583	24,106	26,518	4492	5115	5261
	QALYs		7.524	7.524	7.524	7.195	4.735

*→ RTX + MTX → INFL + MTX → BSC. Baseline: HAQ 1.51 and age 52.49 years. Please note that only the most cost-effective treatments are presented here (i.e., ADAL + MTX is excluded).

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