A 4-year non-randomized comparative phase-IV study of early rheumatoid arthritis: integrative anthroposophic medicine for patients with preference against DMARDs versus conventional therapy including DMARDs for patients without preference

Figures & data

Figure 1 Patient enrollment, follow-up, and analysis.

Abbreviations: DMARD, disease-modifying antirheumatic drug; RA, rheumatoid arthritis.

Table 1 Demographics and baseline characteristics

Item	Anthroposophic group	Conventional group	p-value
Female gender, n (%)	122/129 (94.6%)	85/122 (69.7%)	<0.0001
Age (years)	47.58±11.25	50.65±12.15	0.0205
Duration of rheumatoid arthritis (months)	15.10±9.21	10.84±9.17	<0.0001
<12, n (%)	54/125 (43.2%)	78/122 (63.9%)	0.0014
12–23, n (%)	45/125 (36.0%)	27/122 (22.1%)
24–35, n (%)	26/125 (20.8%)	17/122 (13.9%)
Rheumatoid factor (IU/mL)	137.37±222.44	194.82±266.22	0.4634
Rheumatoid factor positive (≥20 IU/mL), n (%)	87 (74.4%)	80 (65.6%)	0.1593
C-reactive protein (mg/dL)	2.59±3.49	2.66±4.64	0.2584
Erythrocyte sedimentation rate (mm/hour)	32.72±26.73	35.44±25.42	0.2221
Rheumatoid Arthritis VAS (patient ratings, 0–400)	193.87±87.16	238.30±93.36	<0.0001
Joint inflammation in past 3 months (VAS, 0–100)	57.83±26.55	77.73±19.78	<0.0001
Joint swelling today (VAS, 0–100)	46.58±25.33	52.91±29.72	0.0916
Joint pain today (VAS, 0–100)	46.24±25.90	55.10±30.85	0.0116
Joint stiffness today (VAS, 0–100)	42.36±24.98	52.56±29.84	0.0067
Joint tenderness (Ritchie Index, 0–78)	13.87±7.60	12.56±9.97	0.0268
Number of swollen joints	15.22±8.37	14.00±7.11	0.4242
Hanover Functional Ability Questionnaire	18.02±4.26	16.70±5.10	0.0683
Radiological signs of joint destruction (Ratingen Score)	2.40±3.90	2.17±4.66	0.1059
Patient self-rating of current health status (0–100)	54.72±23.40	56.20±26.15	0.6408
Patient satisfaction with current health status (0–100)	59.23±24.74	54.43±29.18	0.1647
Erosive arthritis with Ratingen Score ≥1, n (%)	67/123 (54.5%)	51/119 (42.3%)	0.0737
Corticosteroid use, n (%)	33/129 (25.6%)	59/122 (48.4%)	0.0003

Note: Data are presented as mean ± SD, unless otherwise stated.

Abbreviation: VAS, visual analog scales.

Table 2 Secondary categorical outcomes at months 0 and 48

Outcome	Month 0				Month 48
	A-group		C-group		A-group		C-group
	n	Percent	n	Percent	n	Percent	n	Percent
Steinbrocker staging system
0. No radiological abnormalities	14	11.2	40	33.1	15	21.1	16	29.6
1. Periarticular osteoporosis	41	32.8	23	19.0	13	18.3	7	13.0
2. As 1, with initial cartilage or bone erosion	65	52.0	50	41.3	34	47.9	22	40.7
3. Marked cartilage and bone erosion, joint deformation	5	4.0	8	6.6	9	12.7	8	14.8
4. As 3, with joint ankylosis	0	0.0	0	0.0	0	0.0	1	1.9
Total	125	100.0	121	100.0	71	100.0	54	100.0
	p=0.0289				p=0.7779
Steinbrocker functional classification
I. Complete ability to carry out all the usual duties without handicaps	7	5.4	2	1.6	37	51.4	26	40.0
II. Adequate for normal activities despite handicap of discomfort or limited motion of one of the joints	102	79.1	85	69.7	32	44.4	37	56.9
III. Limited to little or none of the duties of usual occupation or self-care	19	14.7	32	26.2	3	4.2	2	3.1
IV. Incapacitated, largely or wholly bed-ridden or confined to a wheelchair with little or no self-care	1	0.8	3	2.5	0	0.0	0	0.0
Total	129	100.0	122	100.0	72	100.0	65	100.0
	p=0.0043				p=0.2536
Disease Activity Score
1. Low (≤2.4)	3	2.3	11	10.1	52	73.2	43	68.3
2. Moderate (2.4 to ≤3.7)	51	39.5	42	38.5	18	25.4	17	27.0
3. High (>3.7)	75	58.1	56	51.4	1	1.4	3	4.8
Total	129	100.0	109	100.0	71	100.0	63	100.0
	p=0.1431				p=0.4848
Patient rating of therapy tolerability
1. Poor	4	4.0	8	9.3	0	0.0	1	1.8
2. Average	27	27.3	18	20.9	2	2.9	14	24.6
3. Good	68	68.7	60	69.8	66	97.1	42	73.7
Total	99	100.0	86	100.0	68	100.0	57	100.0
	p=0.9616				p=0.0001

Note: p-values: between-group differences, Mann–Whitney U test.

Abbreviations: A-group, Anthroposophic group; C-group, Conventional group.

Table 3 Use of corticosteroids and NSAIDs in years 1–4

Year	Patients using medication				Odds ratio for use (A-group vs C-group)			Daily dose* (mg) in medication users
	A-group		C-group					A-group	C-group
	n	Percent	n	Percent	OR	95% CI	p-value	Mean ± SD	Mean ± SD
Corticosteroids (oral or intravenous)
1	58/127	45.7	90/111	81.1	0.20	0.11–0.35	<0.0001	13.56±18.09	7.00±2.85
2	59/118	50.0	70/101	69.3	0.44	0.25–0.77	0.0040	7.46±5.94	5.36±2.40
3	45/99	45.5	55/91	60.4	0.55	0.31–0.97	0.0428	6.18±7.32	5.18±2.77
4	30/84	35.7	43/68	63.2	0.32	0.17–0.63	0.0010	4.74±2.84	5.28±2.32
NSAIDs
1	67/127	52.8	76/111	68.5	0.51	0.29–0.90	0.0191	75.23±37.98	95.96±31.70
2	33/118	28.0	48/101	47.5	0.43	0.24–0.78	0.0043	57.18±27.59	86.64±40.27
3	28/99	28.3	38/91	41.8	0.55	0.29–1.05	0.0723	60.14±26.99	85.55±30.17
4	20/84	23.8	32/68	47.1	0.35	0.17–0.74	0.0046	46.54±26.44	81.43±39.28

Note:

* Daily dose of prednisolone equivalents (corticosteroids) and diclofenac equivalents (NSAID), respectively.

Abbreviations: A-group, Anthroposophic group; C-group, Conventional group; NSAID, nonsteroidal anti-inflammatory drug.

Table 4 Primary clinical outcome analyses

Outcome	Anthroposophic group			Conventional group
	n	Mean ± SD	Median	n	Mean ± SD	Median
RA-VAS (0–400)
Months 0–9	117	1,104.7±542.0	1,071.0	94	1,233.6±674.5	1,128.8
Months 39–48	70	773.4±655.7	606.8	50	861.8±661.5	884.3
Change: months 0–9 to 39–48	69	−308.1±637.7	−333.0	45	−381.3±566.9	−315.0
	p<0.001			p<0.001
Change in A- vs C-groups*	p=0.9261
C-reactive protein (mg/dL)
Months 0–9	117	15.07±16.13	7.80	89	9.83±8.14	7.47
Months 39–48	70	8.94±11.03	4.95	54	6.84±5.85	4.66
Change: months 0–9 to 39–48	68	−5.14±13.76	−1.16	45	−3.81±9.20	−2.55
	p=0.0014			p=0.0024
Change in A- vs C-groups*	p=0.8626
Ratingen Score (0–190)
Rating by Prof R Rau
Month 0	123	2.40±3.90	1.00	118	2.17±4.66	0.00
Month 48	71	5.98±7.68	3.00	61	4.66±7.22	1.00
Change: months 0–48	71	4.16±6.10	1.00	61	2.04±3.98	1.00
	p<0.001			p<0.001
Change in A- vs C-groups*	p=0.1205
Rating by Prof PL van Riel
Month 0	123	2.93±4.40	1.00	118	2.63±5.01	1.00
Month 48	71	7.16±8.91	4.00	61	5.44±8.85	3.00
Change: months 0–48	71	4.28±6.08	2.00	61	2.69±4.87	1.08
	p<0.001			p<0.001
Change in A- vs C-groups*	p=0.1788

Notes: RA-VAS and C-reactive protein in months 0–9 and 39–48: area under the curve for score values at months 0, 3, 6, 9 and 39, 42, 45, 48, respectively.

* Mann–Whitney U test. All other p-values refer to Wilcoxon test.

Abbreviations: A- vs C-groups, Anthroposophic group versus Conventional group; RA-VAS, Rheumatoid Arthritis Visual Analog Scale.

Figure 2 RA-VAS total score.

Note: Total score (0–400) in months 0 (Anthroposophic group: n=127, Conventional group: n=119), 3 (127+110), 6 (123+109), 9 (119+99), 12 (113+89), 15 (107+89), 18 (101+81), 21 (94+84), 24 (94+79), 27 (85+63), 30 (85+59), 33 (83+59), 36 (79+58), 39 (76+61), 42 (74+60), 45 (73+57), and 48 (71+60).
Abbreviation: RA-VAS, Rheumatoid Arthritis Visual Analog Scale.

Figure 3 C-reactive protein.

Note: CRP in months 0 (Anthroposophic group: n=129, Conventional group: n=109), 3 (126+107), 6 (123+106), 9 (118+103), 12 (118+99), 15 (116+96), 18 (112+94), 21 (105+97), 24 (102+91), 27 (93+70), 30 (90+70), 33 (85+70), 36 (86+66), 39 (76+60), 42 (73+60), 45 (73+60), and 48 (72+64).
Abbreviation: CRP, C-reactive protein.

Figure 4 Ratingen Score.

Note: Ratingen Score of radiological joint destruction (0–190) in months 0 (Anthroposophic group: n=123, Conventional group: n=118), 36 (88+63), and 48 (71+61).

Table 5 Safety outcomes in months 0 and 48

Primary safety outcomes	Anthroposophic group		Conventional group		A-group vs C-group
	Number of patients	Percent	Number of patients	Percent	p-value
Patients withdrawn from the study	46/129	35.7	38/122	31.1	0.5040
Patients with SAE	31/129	24.0	30/122	24.6	1.0000
Patients with ADR	65/129	50.4	85/122	69.7	0.0020
Secondary safety outcomes
Patients with ADR, study medication stopped	17/129	13.2	36/122	29.5	0.0019
Patients with ADR of severe intensity	6/129	4.7	13/122	10.7	0.0946
	Number of events	Percent	Number of events	Percent	p-value
Causes of ADR by medication classes					0.0005*
Nonsteroidal anti-inflammatory drugs	18/105	17.1	25/170	14.7	0.6110
Corticosteroids	36/105	34.3	26/170	15.3	0.0003
AM medications (in A-group) vs DMARD (in C-group)	51/105	48.6	119/170	70.0	0.0005
Total	105/105	100.0	170/170	100.0
Intensity of SAE					0.0567**
Mild	18/41	43.9	12/42	28.6
Moderate	21/41	51.2	22/42	52.4
Severe	2/41	4.9	8/42	19.0
Total	41/41	100.0	42/42	100.0
Causes of SAE					0.1034*
Concomitant disorder with probable or possible relation to study medication	0/41	0.0	4/42	9.5
Joint surgery or complications of rheumatoid arthritis	5/41	12.2	7/42	16.7
Concomitant disorder unrelated to study medication or rheumatoid arthritis	36/41	87.8	31/42	73.8
Total	41/41	100.0	42/42	100.0
SAE resolved or improved at last follow-up	37/41	90.2	32/42	76.2	0.1415

Notes: p-values refer to Fisher’s exact test, unless otherwise stated.

* Fisher–Freeman–Halton test.

** Mann–Whitney U test.

Abbreviations: A-group, Anthroposophic group; ADR, adverse drug reaction; AM, anthroposophic medicine; C-group, Conventional group; DMARDs, disease-modifying antirheumatic drugs; SAE, serious adverse events.

Figure S1 Patient ratings of therapy tolerability (“poor”–“average”–“good”).

Note: Percentage of patients with the rating “good tolerability” are as follows: in months 0 (Anthroposophic group: n=99, Conventional group: n=86), 3 (122+107), 6 (115+105), 9 (114+95), 12 (109+95), 15 (107+92), 18 (105+87), 21 (98+88), 24 (95+86), 27 (87+61), 30 (84+61), 33 (84+60), 36 (82+56), 39 (70+53), 42 (73+56), 45 (69+53), and 48 (68+57).

Figure S2 Physician ratings of therapy tolerability.

Note: Physician ratings of therapy tolerability on a VAS (0= no adverse reactions, 100= most severe adverse reactions) in months 0 (Anthroposophic group: n=99, Conventional group: n=86), 3 (126+111), 6 (122+110), 9 (118+107), 12 (117+102), 15 (115+99), 18 (112+94), 21 (103+94), 24 (100+92), 27 (92+69), 30 (89+68), 33 (85+68), 36 (83+65), 39 (75+60), 42 (72+61), 45 (71+59), and 48 (71+64).

Abbreviation: VAS, visual analog scale.

Figure S3 Use of corticosteroids in months 0–48.

Note: Use is calculated as average dose in prednisolone equivalents among steroid users in each 3-month period (“3” indicating “months 1–3” and so on).

Figure S4 Use of NSAIDs in months 0–48.

Note: Use is calculated as average dose in diclofenac equivalents among NSAID users in each 3-month period (“3” indicating “months 1–3” and so on).

Abbreviation: NSAID, nonsteroidal anti-inflammatory drug.

Figure S5 Disease Activity Score (0–10).

Note: Disease Activity Score (0–10) in months 0 (Anthroposophic group: n=129, Conventional group: n=108), 3 (176+104), 6 (123+103), 9 (118+99), 12 (118+99), 15 (115+94), 18 (111+90), 21 (105+90), 24 (101+89), 27 (93+66), 30 (89+64), 33 (85+64), 36 (86+63), 39 (74+56), 42 (73+59), 45 (72+55), and 48 (71+63).

Table S1 Patient numbers at each follow-up

Month	Anthroposophic group						Conventional group
	Scheduled		Follow-up		No follow-up		Scheduled		Follow-up		No follow-up
	n	Percent	n	Percent	n	Percent	n	Percent	n	Percent	n	Percent
3	129	100.0	127	98.4	2	1.6	122	100.0	115	94.3	7	5.7
6	129	100.0	123	95.3	6	4.7	122	100.0	110	90.2	12	9.8
9	129	100.0	119	92.2	10	7.8	122	100.0	106	86.9	16	13.1
12	129	100.0	118	91.5	11	8.5	122	100.0	104	85.2	18	14.8
15	129	100.0	116	89.9	13	10.1	122	100.0	102	83.6	20	16.4
18	129	100.0	113	87.6	16	12.4	122	100.0	101	82.8	21	17.2
21	129	100.0	106	82.2	23	17.8	122	100.0	100	82.0	22	18.0
24	129	100.0	96	74.4	33	25.6	122	100.0	80	65.6	42	34.4
27	123	100.0	93	75.6	30	24.4	106	100.0	75	70.8	31	29.2
30	123	100.0	90	73.2	33	26.8	106	100.0	74	69.8	32	30.2
33	123	100.0	86	69.9	37	30.1	106	100.0	73	68.9	33	31.1
36	123	100.0	81	65.9	42	34.1	106	100.0	66	62.3	40	37.7
39	118	100.0	77	65.3	41	34.7	103	100.0	66	64.1	37	35.9
42	118	100.0	74	62.7	44	37.3	103	100.0	65	63.1	38	36.9
45	118	100.0	73	61.9	45	38.1	103	100.0	65	63.1	38	36.9
48	118	100.0	72	61.0	46	39.0	103	100.0	65	63.1	38	36.9

Table S2 Dropout analyses

Baseline characteristics	48-month follow-up data available?
	Yes (n=137)	No (n=114)	p-value
Female gender, n (%)	109/137 (79.6%)	99/114 (86.8%)	0.1275
Age (years)	50.96±11.28	48.02±12.01	0.0413
Duration of rheumatoid arthritis (months)	14.44±9.76	12.23±8.93	0.0813
Rheumatoid factor (IU/mL)	148.22±217.62	188.35±276.85	0.6467
Rheumatoid factor positive (≥20 IU/mL), n (%)	112/129 (86.8%)	92/109 (83.6%)	0.4875
C-reactive protein (mg/dL)	2.77±4.74	2.45±3.03	0.6224
Joint tenderness (Ritchie Index, 0–78)	13.14±8.02	13.34±9.77	0.7506
Number of swollen joints	14.11±7.90	15.25±7.64	0.2469
Hanover Functional Ability Questionnaire	17.75±4.44	16.92±5.04	0.2597
Radiological signs of joint destruction (Ratingen Score)	2.12±4.05	2.52±4.58	0.5744
Erosive arthritis with Ratingen Score ≥1, n (%)	45/137 (32.8%)	35/104 (33.7%)	0.8954
Corticosteroid use, n (%)	54/137 (39.4%)	38/114 (33.3%)	0.3194

Note: Data are presented as mean ± SD, unless otherwise stated.

Table S3 RA-VAS and C-reactive protein, alternative analyses

	Anthroposophic group			Conventional group
	n	Mean ± SD	Median	n	Mean ± SD	Median
RA-VAS (0–400)
Month 0	127	193.9±87.2	191.0	119	238.3±93.4	240.0
Month 48	71	79.4±75.5	44.0	60	97.4±82.1	86.0
Change: months 0–48	70	−116.6±109.2	−110.5	58	−122.7±99.2	−117.5
Wilcoxon test	p<0.0001			p<0.0001
Change in A- vs C-groups*	p=0.4961
C-reactive protein (mg/dL)
Month 0	129	2.59±3.49	1.00	109	2.66±4.64	1.40
Month 48	72	1.06±1.63	0.50	64	0.92±1.17	0.35
Change: months 0–48	72	−1.64±3.59	−0.21	57	−2.03±6.00	−0.63
Wilcoxon test	p<0.0001			p<0.0001
Change in A- vs C-groups*	p=0.6428

Note:

* Mann–Whitney U test.

Abbreviatios: A- vs C-groups, Anthroposophic group versus Conventional group; RA-VAS, Rheumatoid Arthritis Visual Analog Scale.