Remission in Early Rheumatoid Arthritis

MARGARET H.Y. MA; IAN C. SCOTT; GABRIELLE H. KINGSLEY; DAVID L. SCOTT

doi:10.3899/jrheum.091131

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Figure 1.
The process of the search strategy.
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Figure 2.
Metaanalyses of RCT using (A) DAS remission criteria; (B) ACR remission criteria.

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Table 1.

Remissions in observational studies * remission over 6 months at any point. Results are mean values unless denoted “i” indicating median data; “ii”, DAS.

Study	Year	Remission	Disease Duration, mo	Age, yrs	Female, %	RF+, %	ESR	DAS28	Followup, mo	DMARD	Number at Entry	Number at Followup	Remission, at Study End (%)
Prevoo⁹	1996	ACR	< 12	55ⁱ	63	78	—	—	72	Monotherapy	227	49	15 (31)
Eberhardt³⁸	1998	ACR	< 24	—	63	75	29	—	60	Monotherapy	183	176	37 (20)**
Young³⁹	2000	ACR	8	—	66	63	—	—	60	Monotherapy	941	732	94 (13)
Makinen⁴⁰	2005	ACR	5	56	61	54	—	—	60	Monotherapy	127	111	19 (17)
Möttönen⁴¹	1996	ACR	< 24	46	75	63	30ⁱ	—	72	Combination included	142	142	45 (32)
Lindqvist⁴²	2002	ACR	< 24	—	63	75	—	—	120	Combination included	183	163	30 (18)
Sanmarti⁴³	2003	ACR	< 24	52	78	—	45	5.8	12	Combination included	65	60	12 (20)
Fransen³⁰	2004	ACR	< 12	55	66	76	—	—	72	Combination included	424	77	9 (12)
Cantagrel¹⁷	1999	DAS	< 12	—	—	71	—	—	24	Not stated	108	108	15 (14)
Tengstrand⁴⁴	2004	DAS	< 12	57	64	58	—	5.1	24	Monotherapy	844	844	279 (33)
Vázquez⁴⁵	2007	DAS	< 24	55	81	74	40	5.7	24	Monotherapy	115	105	34 (32)
Khanna⁴⁶	2007	DAS	< 14	51	—	100	43	5.5	24	Monotherapy	200	101	33 (33)
Gossec⁴⁷	2004	DAS	< 12	51	73	81	40	4.1ⁱⁱ	60	Combination included	191	165	38 (23)
Forslind⁴⁸	2007	DAS	≤ 12	58	64	60	—	5.3	60	Combination included	698	608	234 (39)
Proudman²³	2007	DAS	< 24	56	76	61	42	5.3	36	Combination included	61	52	28 (54)
Sanmarti⁴⁹	2007	DAS	< 24	55	81	74	40	5.7	24	Combination included	115	105	34 (32)
Machold²¹	2007	DAS	≤ 3	51	75	—	—	—	36	Combination included	138	55	16 (29)

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Table 2A.

Summary of inclusion criteria of clinical trials. Results are mean values.

Study	Control						Treatment
Study	Year	Age, yrs	Female, %	RF+, %	ESR	DAS28	Age, yrs	Female, %	RF+, %	ESR	DAS28
Monotherapy
Eberhardt⁵⁰	1996	53	63	80	36	—	50	52	67	32	—
Rau⁵¹	1997	54	60	68	41	—	57	72	54	41	—
Van Jaarsveld⁵²	2000	56	69	67	42	—	57	64	65	41	—
Choy¹⁸	2002	58	74	54	—	5.3	57	76	58		5
Monotherapy vs combination therapy
Boers¹	1997	49	52	72	—	—	50	66	78	—	—
Möttönen⁷	1999	48	66	66	39	—	47	58	70	37	—
Proudman⁵³	2000	50	55	79	31.4	5.1	51	65	80	39.1	5.4
Ferraccioli⁵⁴	2002	59	86	55	43	—	59	86	73	52	—
Gerards⁵⁵	2003	51	70	97	46	—	53	62	93	53	—
Wassenberg⁵⁶	2005	50	65	47	40	—	53	75	43	44.5	—
St. Clair⁵⁷	2004	50	75	71	43	6.7	50	68	73	44	6.7
Svensson²⁴	2005	59	63	66	—	5.4	51	65	66	—	5.28
Allaart³	2006	54	68	67	DAS 44	4.5	54	66	64	DAS 44	4.3
Breedveld⁶	2006	52	74	—	—	6.3	52	72		—	6.3
Choy²	2008	54	67	66	—	5.8	55	67	72	—	5.6
Emery⁴	2008	52	73	—	49	6.5	51	74	—	47.8	6.5
Hetland¹⁹	2006	51	70	59	27	5.5	53	64	70	28	5.3
Combination vs combination therapy
Verstappen⁵⁸	2007	53	66	62	39	—	54	69	66	36	—
Saunders⁵⁹	2008	55	79	72	45	6.9	55	76	69	36	6.8
Verschueren²⁰**	2008	55	65	52	DAS28	CRP 4.76	45	63	79	DAS28	CRP 5.28

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Table 2B.

Remission in clinical trials (cases at end of followup).

Study	Year	Disease Duration, mo	Followup, mo	Remission	Control			Treatment
Study	Year	Disease Duration, mo	Followup, mo	Remission	Cases	Treatment	Remission (%)	Cases	Treatment	Remission (%)
Monotherapy
Eberhardt⁵⁰	1996	24	24	ACR derivative	22	Placebo	5 (12)	21	D-Penicillamine	4 (12)
Rau⁵¹	1997	16	12	ACR derivative	87	MTX	10 (12)	87	GSTM	21 (24)
Van Jaarsveld⁵²	2000	< 12	24	ACR derivative	107	HCQ	29 (27)	105	MTX (short lag)	25 (24)
Choy¹⁸	2002	< 12	12	DAS28	55	Diclofenac	0	62	SSZ	0
Monotherapy vs combination therapy
Boers¹	1997	< 24	12	ACR	76	SSZ	19 (24)^*	79	SSZ/MTX/Pred	24 (32)^*
Möttönen⁷	1999	< 24	24	ACR	98	SSZ or MTX	18 (18)	97	MTX/SSZ/HCQ/Pred	36 (37)
Proudman⁵³	2000	< 12	12	ACR	42	SSZ	4 (10)	40	Methylpred	MTX/CSA/1A 5 (13)
Ferraccioli⁵⁴	2002	16	36	ACR	42	SSZ	3 (7)	42	MTX/CsA	4 (9)
Gerards⁵⁵	2003	< 36	12	ACR	60	CsA	4 (7)	60	CsA/MTX	6 (10)
Wassenberg⁵⁶	2005	< 24	24	ACR	86	DMARD	8 (9)	80	DMARD/Pred	13 (16)
St. Clair⁵⁷	2004	< 36	12	DAS28	245	MTX	37 (15)	325	MTX/Infliximab	101 (31)
Svensson²⁴	2005	< 12	24	DAS28	126	DMARD	42 (33)	116	DMARD/Pred	65 (56)
Allaart³	2006	< 12	24	DAS44	126	DMARD	58 (46)	128	MTX/Infliximab	54 (42)
Breedveld⁶	2006	< 36	24	DAS28	257	MTX	64 (25)	268	MTX/Adalimumab	131 (49)
Choy²	2008	< 24	24	DAS28	117	MTX	21 (18)	116	MTX/CsA/Pred	32 (28)
Emery⁴	2008	< 24	12	DAS28	263	MTX	73 (28)	265	MTX/Etanercept	132 (50)
Hetland¹⁹	2006	< 6	12	1. DAS28	68	MTX/IA	1. 23 (34)	69	MTX/CsA/IA/steroids	1.30 (43)
Hetland¹⁹	2006	< 6	12	2. ACR		Steroids	2. 19 (28)			2.24 (35)
Combination vs combination therapy
Verstappen⁵⁸	2007	< 12	24	ACR derivative	148	Conventional MTX +/– CsA	55 (37)	151	Intensive MTX +/– CsA	76 (50)
Saunders⁵⁹	2008	Mean 11.5^†	12	DAS28	44	Step up	21 (45)	47	Parallel	16 (33)
Verschueren²⁰^**	2008	< 12	12	DAS28	17	Step up	No values	46	Step down	No values

↵* Achieving remission at some point during followup (probable and definite remissions included).
↵** Not randomized. Inclusion criteria of symptoms < 5 years but mean disease duration < 12 months (SD < 12 mo). GSTM: Gold sodium thiomalate; MTX: methotrexate; HCQ: hydroxychloroquine; SSZ: sulfasalazine; Methylpred: methylprednisolone; Pred: prednisolone; CsA: cyclosporin A.

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Table 3.

Metaanalysis of remission rates in randomized controlled trials of monotherapy versus combination therapy.

Subgroups	No. Studies	Monotherapy		Combination Therapy		Random OR (95% CI)	Chi-square (p)
Subgroups	No. Studies	Cases	Remission	Cases	Remission	Random OR (95% CI)	Chi-square (p)
DAS remission	7	1202	318	1287	545	2.01 (1.46, 2.78)	19.1 (0.004)
ACR remission	7	472	75	467	112	1.69 (1.21, 2.36)	2.8 (0.84)
Steroids	3	328	91	315	132	1.95 (1.39, 2.73)	1.99 (> 0.05)
Anti-TNF	4	928	226	1383	390	2.05 (1.26, 3.34)	17.18 (0.0006)
Combination DMARD	10	841	200	953	294	1.51 (0.99, 2.31)	28.33 (0.0008)
Tight control regimes	2	246	95	248	142	2.23 (1.26, 3.97)	2.39 (> 0.05)

DAS: Disease Activity Score; ACR: American College of Rheumatology; TNF: tumor necrosis factor; DMARD: disease-modifying antirheumatic drug.

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Table 4.

Summary of radiographic outcomes in observational trials of patients in remission.

Study	Year	Remission	Numbers at Followup	Radiographic Outcome
Makinen⁴⁰	2005	ACR	111	Radiological remission (no new or increased erosions) at 5 years in 66 patients (55%)
Vázquez⁴⁵	2007	DAS	105	Increase in Larsen score > 4 at 2 years: Remission 9/34 (27%); no remission 23/71 (34%)
Proudman²³	2007	DAS	52	Increase in erosion score at 3 years: Remission 15/28 (54%); no remission 14/24 (58%)
Machold²¹	2007	DAS	55	New erosions over 3 years: Lasting remission^* 3/16 (19%) no lasting remission 28/39 (72%)

↵* Lasting remission = DAS28 < 2.6 for > 1 year.

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Table 5.

Summary of radiographic outcomes in randomized controlled trials of patients in DAS remission.

Study	Year	Monotherapy	Combination Therapy
Svensson²⁴	2005	Median change in Larsen Score at 2 years, Remission 2.5 (IQR 0.5–8.0)	Median change in Larsen Score at 2 years, Remission 1.0 (IQR 0–3.5)
Allaart³	2006	Continuous remission, 25% damage progression	Continuous remission, 3% damage progression