One- and 2-year Flare Rates After Treat-to-Target and Tight-Control Therapy of Gout

Results From the NOR-Gout Study

Till Uhlig; Lars F. Karoliussen; Joe Sexton; Tore K. Kvien; Espen A. Haavardsholm; Fernando Perez-Ruiz; Hilde Berner Hammer

Disclosures

Arthritis Res Ther. 2022;24(88)

Abstract and Introduction

Abstract

Objectives: To explore the frequency and predictors of flares over 2 years during a treat-to-target strategy with urate-lowering therapy (ULT) in patients with gout.

Methods: In the treat-to-target, tight control NOR-Gout study patients started ULT with escalating doses of allopurinol. Flares were recorded over 2 years. Baseline predictors of flares during months 9–12 in year 1 and during year 2 were analyzed by multivariable logistic regression.

Results: Of 211 patients included (mean age 56.4 years, disease duration 7.8 years, 95% males), 81% (150/186) of patients experienced at least one gout flare during the first year and 26% (45/173) during the second year. The highest frequency of flares in the first year was seen during months 3–6 (46.8% of patients).

Baseline crystal depositions detected by ultrasound and by dual-energy computed tomography (DECT) were the only variables which predicted flares both during the first period of interest at months 9–12 (OR 1.033; 95% CI 1.010–1.057, and OR 1.056; 95% CI 1.007–1.108) and also in year 2. Baseline subcutaneous tophi (OR 2.42, 95% CI 1.50–5.59) and prior use of colchicine at baseline (OR 2.48, 95% CI 1.28–4.79) were independent predictors of flares during months 9–12, whereas self-efficacy for pain was a protective predictor (OR 0.98 per unit, 95% CI 0.964–0.996).

Conclusions: In patients with gout, flares remain frequent during the first year of a treat-to-target ULT strategy, especially during months 3–6, but are much less frequent during year 2. Baseline crystal depositions predict flares over 2 years, supporting ULT early during disease course.

Trial registration: ACTRN12618001372279

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Arthritis Res Ther. 2022;24(88) © 2022 BioMed Central, Ltd.
Copyright to this article is held by the author(s), licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original citation.

Abstract and Introduction
Background
Methods
Results
Discussion
Conclusions
References

Table 2. Baseline characteristics for all patients, and patients with and without a flare (percentage or mean with standard deviation (SD)
	Baseline		1 year follow-up (N = 186)			2 year follow-up (N = 173)
	Baseline		No flare Months 9–12	Flare Months 9–12	p-value	No flare Year 2	Flare Year 2	p-value
	N = 211		N = 116	N = 70	p-value	N = 128	N = 45	p-value
Age (years)	211	56.4 (13.7)	56.3 (13.8)	57.6 (13.2)	0.52	56.8 (13.9)	57.1 (12.9)	0.88
Male	201/211	95.3%	96.6%	92.9%	0.30	93.8%	97.8%	0.45
Caucasian	183/202	90.6%	89.5%	92.4%	0.51	92.0%	86.0%	0.25
Disease duration (years)	204	7.8 (7.6)	7.4 (6.8)	9.6 (9.3)	0.10	8.1 (8.2)	8.8 (6.3)	0.62
College education	118/206	57.3%	61.7%	58.2%	0.64	58.3%	66.7%	0.34
Married/cohabiting	155/208	74.5%	76.7%	77.6%	0.89	76.4%	76.7%	0.96
Working	133/208	63.9%	69.8%	61.2%	0.23	64.1%	73.8%	0.25
Body mass index (kg/m²)	211	28.8 (4.5)	28.5 (4.6)	29.7 (4.6)	0.09	29.2 (4.5)	28.1 (4.7)	0.18
Co-morbidities (SCQ sum)	210	3.7 (3.2)	3.3 (1.1)	4.5 (3.4)	0.013	3.7 (3.3)	3.8 (3.4)	0.91
Physical activity ≥ 3 times weekly	163/207	30.4%	36.8%	26.5%	0.15	29.1%	41.9%	0.12
Smoking, daily	23/208	11.1%	10.3%	4.5%	0.16	10.9%	2.4%	0.12
Alcohol consumption at least weekly	128/207	61.8%	61.2%	62.1%	0.90	63.0	57.1%	0.61
Sugar sweetened drinks daily	80/207	38.6%	40.5%	33.3%	0.34	38.6%	38.1%	0.96
≥ 1 subcutaneous tophus present	35/211	16.6%	12.1%	24.3%	0.017	14.1%	22.2%	0.20
Allopurinol use ever	31/211	14.7%	13.8%	14.3%	0.92	14.8%	6.7%	0.16
NSAID use ever	160/205	78.0%	74.3%	88.1%	0.028	77.6%	86.0%	0.23
Colchicine use ever	107/201	53.2%	43.8%	67.7%	0.002	50.4%	56.1%	0.53
Prednisolone use ever	91/199	45.7%	47.3%	53.1%	0.46	45.1%	52.4%	0.41
Baseline SUA (μmol/L)	211	500 (77)	491 (81)	510 (78)	0.12	496 (81)	504 (81)	0.58
ESR (mm/h)	199	14 (14)	14 (13)	15 (15)	0.46	14 (14)	17 (15)	0.21
Creatinine (μmol/L)	211	96 (18)	96 (17)	96 (19)	0.90	95 (17)	99 (20)	0.11
eGFR (ml/min. per 1.73 m²)	210	78 (19)	78 (18)	77 (18)	0.71	78 (18)	75 (18)	0.27
Previous flares					0.042			0.10
0	16	7.7%	6.0%	9.0%		7.8%	7.1%
1	25	12.0%	16.4%	3.0%		12.5%	2.4%
2–5	65	31.3%	29.3%	28.4%		32.0%	23.8%
> 5	102	49.0%	48.3%	49.7%		47.7%	66.7%
Previous flares during last 12 months	151/206	73.4%	73.7%	77.6%	0.38	69.3%	90.5%	0.053
Strongest joint pain ever (0–10)	208	8.4 (1.6)	8.1 (1.6)	8.7 (1.4)	0.013	8.2 (1.6)	8.7 (1.1)	0.051
Joint pain last flare (0–10)	207	7.5 (5.5)	7.1 (2.0)	7.1 (2.1)	0.96	7.1 (2.1)	7.3 (1.9)	0.51
Swollen joint present	72/209	34.4%	33.8%	37.7%	0.60	31.0%	44.4%	0.10
Tender joint present	110/210	52.4%	47.8%	62.3%	0.06	50.0%	57.0%	0.37
Health assessment questionnaire (0–3)	209	0.38 (0.57)	0.33 (0.58)	0.41 (0.44)	0.35	0.34 (0.54)	0.43 (0.69)	0.35
SF-36 physical component summary (0–100)	204	39 (11)	40 (11)	36 (10)	0.006	40 (10)	37 (12)	0.21
SF-36 mental component summary (0–100)	204	50 (10)	50 (10)	50 (10)	0.91	51 (10)	49 (10)	0.31
Self-efficacy pain (10–100)	209	65 (19)	68 (19)	61 (20)	0.015	65 (19)	64 (21)	0.69
Self-efficacy symptoms (10–100)	205	72 (15)	73 (17)	72 (18)	0.51	73 (17)	72 (15)	0.84
Beliefs about Medicines Questionnaire
Necessity subscale (5–25)	198	17.9 (4.4)	16.8 (4.2)	17.2 (4.5)	0.54	16.8 (4.3)	17.0 (4.6)	0.99
Concerns subscale (5–25)	197	13.4 (4.9)	12.8 (4.5)	14.2 (4.1)	0.053	13.3 (4.5)	14.0 (4.1)	0.30
Overuse subscale (4–16)	203	10.6 (2.8)	10.5 (2.9)	10.7 (2.5)	0.57	10.6 (2.8)	10.8 (2.7)	0.57
Harm subscale (4–16)	203	9.4 (2.4)	9.3 (2.5)	9.5 (2.3)	0.68	9.4 (2.5)	9.5 (2.1)	0.66
Ultrasound sum score	209	20.0 (13.9)	17.4 (12.0)	23.7 (15.6)	0.004	18.8 (13.0)	23.5 (14.0)	0.036
Dual energy computed tomography sum score	187	4.6 (6.4)	3.8 (6.0)	6.2 (7.0)	0.019	4.0 (5.9)	6.7 (7.5)	0.037

SCQ Self-Administered Comorbidity Questionnaire, NSAID non-steroidal anti-inflammatory drug, ESR erythrocyte sedimentation rate, eGFR electronic glomerular filtration rate, SF-36 Short-form 36

Table 2. Flares in 1-year completers ( n = 186) per month and in intervals
	Flare last month or since last examination		Cumulative flares
	N	%	N	%
Month 1	34/183	18.6	34/186	18.3
Month 2	26/176	14.8	48/186	25.8
Month 3	32/178	18.0	60/186	32.3
Month 4	39/164	23.8	87/186	46.8
Month 5	17/70	24.3	93/186	50.0
Month 6	60/182	33.0	118/186	63.4
Month 7	14/55	25.5	120/186	64.5
Month 8	10/42	23.8	123/186	66.1
Month 9	34/166	20.5	134/186	72.0
Month 10	16/59	27.1	135/186	72.6
Month 11	4/27	14.8	135/186	72.6
Month 12	57/186	30.6	150/186	80.6
Months 0–3	59/186	31.7
Months 3–6	87/186	46.8
Months 6–9	56/186	30.1
Months 9–12	70/186	37.6
Months 0–12	150/186	80.6

Table 3. Characteristics of patients with at least one flare during 3-month periods and during year 2
	Year 1				Year 2
	0–3 months	3–6 months	6–9 months	9–12 months	Year 2
N with flare	59/189	90/187	52/167	70/186	45/173
Age (years)	56.0 (13.9)	56.9 (13.0)	59.5 (14.7)	57.6 (13.2)	57.1 (12.9)
Disease duration (years)	8.4 (8.6)	8.4 (7.3)	10.2 (9.8) *	9.6 (9.3)	8.8 (6.3)
Baseline > 1 tophus	16.9%	14.4%	19.2%	24.3% *	22.2%
Co-morbidities (SCQ) sum	4.6 (3.9) *	4.0 (3.4)	4.5 (3.4)	4.5 (3.4)*	3.8 (3.4)
Baseline SUA	502 (76)	504 (76)	498 (81)	510 (38)	504 (81)
3 months SUA	361 (76) *	343 (62)	339 (61)	345 (60)	351 (68)
6 months SUA	325 (65)	328 (61)	335 (63)*	331 (63)	331 (66)
9 months SUA	312 (54)	317 (61)	318 (69)	328 (60)	311 (58)
12 months SUA	304 (47)	309 (46)	299 (47)	308 (48)	313 (51)
24 months SUA	330 (80)	331 (79)	323 (68)	337 (85)	328 (67)
Baseline allopurinol user (%)	15.3%	17.8%	13.5%	14.3%	6.7%
Month 3 allopurinol (mg)	238 (86)	239 (98)	224 (105)	253 (97)*	228 (105)
Month 6 allopurinol (mg)	287 (98)	275 (120)	272 (134)	308 (124)**	275 (124)
Month 9 allopurinol (mg)	292 (128)	281 (133)	293 (145)	307 (137)*	291 (146)
Month 12 allopurinol (mg)	303 (126)	295 (135)	301 (146)	333 (142)**	292 (138)
Ever use
- NSAID	87.5%	79.3%	80.4%	88.1%*	86.0%
- Colchicine	52.7%	60.0%	57.7%	67.7%*	56.1%
- Prednisolone	51.8%	53.6%	56.9%	53.1%	52.4%
≥ 1 flare last 12 months	82.5%	82.4%	88.5%	77.6%	90.5%
> 5 previous flares	59.6%	56.8%	63.5%*	59.7%	52.4%*
Strongest pain ever	8.7 (1.3)*	8.5 (1.5)	8.6 (1.2)	8.7 (1.4)	8.7 (1.1)
Strongest pain last flare	7.1 (2.0)	7.2 (2.0)	7.4 (2.0)	7.1 (2.1)	7.3 (1.9)

*p-value < 0.01 and with higher value compared to non-flare group
**p-value < 0.01 and with higher value compared to non-flare group
SUA serum urate, NSAID non-steroidal anti-inflammatory drug

Table 4. Prediction of flares during time periods by baseline variables using logistic regression
	Flare year 1 (months 9–12)		Flare year 2
	Unadjusted OR (95% CI), p-value	Adjusted OR (95% CI)^a, p-value	Unadjusted OR (95% CI), p-value	Adjusted OR (95% CI)^a, p-value
Ultrasound sum score	1.034 (1.011–1.058) p = 0.004	1.033 (1.010–1.057) p = 0.005	1.025 (1.001–1.050) p = 0.040	1.027 (1.00–1.55) p = 0.049
DECT sum score	1.059 (1.010–1.111) p = 0.017	1.056 (1.007–1.108) p = 0.026	1.062 (1.009–1.117) p = 0.021	1.064 (1.003–1.029) p = 0.035
Subcutaneous tophus	2.34 (1.07–5.10) p = 0.033	2.42 (1.50–5.59) p = 0.038	1.75 (0.74–4.13) p = 0.20	–
Self-efficacy for pain (10–100)	0.981 (0.965–0.997) p = 0.017	0.980 (0.964–0.996) p = 0.017	0.998 (0.981–1.016) p = 0.83	–
Colchicine ever used at baseline	2.69 (1.42–5.11) p = 0.002	2.48 (1.28–4.79) p = 0.007	1.26 (0.62–2.56) p = 0.53	–

^aAdjusted for age, gender, and disease duration
DECT dual-energy computed tomography

Authors and Disclosures

Till Uhlig^1,2*, Lars F. Karoliussen¹, Joe Sexton¹, Tore K. Kvien^1,2, Espen A. Haavardsholm^1,2, Fernando Perez-Ruiz^3–5 and Hilde Berner Hammer^1,2

¹Division of Rheumatology and Research, Diakonhjemmet Hospital, Box 23, Vinderen, N-0319 Oslo, Norway. ²Faculty of Medicine, University of Oslo, Oslo, Norway. ³Osakidetza, OSI EE-Cruces, Division of Rheumatology, Cruces University Hospital, Baracaldo, Spain. ⁴Biocruces-Bizkaia Health Research Institute, Baracaldo, Spain. ⁵Medicine Department, Medicine School, University of the Basque Country, Leioa, Spain.

*Correspondence
tillmann.uhlig@medisin.uio.no

Authors' contributions
TU has made a substantial contributions to the conception and design of the work, the acquisition of data, some of the analysis, interpretation of data for the work, drafted the manuscript as well as revising it critically for important intellectual content, given a final approval of the version to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. LK has given substantial contributions to the design of the study as well as the interpretation of data for the work; revised the manuscript critically for important intellectual content; given a final approval of the version to be published; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. KF has given substantial contributions to the design of the study as well as the interpretation of data for the work as a statistician, revised the manuscript critically for important intellectual content, given a final approval of the version to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. EH has given substantial contributions to the design of the study as well as the interpretation of data for the work; and revised the manuscript critically for important intellectual content, given a final approval of the version to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. TKK has given substantial contributions to the design of the study as well as the interpretation of data for the work, revised the manuscript critically for important intellectual content, given a final approval of the version to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. FPR has given substantial contributions to the design of the study as well as the interpretation of data for the work and revised the manuscript critically for important intellectual content, given a final approval of the version to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. HBH has given substantial contributions to the design of the study as well as the interpretation of data for the work and revised the manuscript critically for important intellectual content, given a final approval of the version to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The authors read and approved the final manuscript.

Competing interests
Dr. Uhlig reports personal fees from Grunenthal and Novartis, outside the submitted work.
Dres. Karoliussen, Sexton, and Borgen have nothing to disclose. Dr. Kvien reports grants and personal fees from AbbVie, MSD, UCB, Hospira/Pfizer, Eli-Lilly, grants from BMS, personal fees from Roche, Hikma, Orion, Sanofi, Celltrion, Sandoz, Biogen, Amgen, Egis, Ewopharma, and Mylan, outside the submitted work. Dr. Haavardsholm reports personal fees from Pfizer, UCB, Eli Lilly, Celgene, Janssen-Cilag, AbbVie, and Gilead outside the submitted work. Dr. Perez-Ruiz reports personal fees from Amgen, Biogen, and Galapagos, outside the submitted work, and personal fees from Algorithm, Alnylam, Astellas, Arthriti, Menarini, NMD, and Parexel, related to the topic of gout.
Dr. Hammer reports personal fees from AbbVie, Lilly, and Novartis, outside the submitted work.