Digital vasculopathy in systemic sclerosis (SSc) consists of a spectrum of Raynaud's phenomenon (RP), digital ulcers (DUs), critical digital ischaemia and escalation to gangrene. The complications of severe digital vasculopathy often require hospital-based management with intravenous therapies and surgery.1–3 Although gangrene is not infrequent in the clinic, data on the prevalence and implications of gangrene in patients with SSc are scarce.3–7 The DU Outcomes (DUO) Registry is a European, prospective, multicentre, observational cohort of patients with SSc and past and/or current DUs at enrolment.8–10 The aims of the current study were (i) to describe the characteristics of an SSc–DU population according to the presence/history of gangrene and (ii) to identify the risk factors for the development of incident gangrene.
All patients in the participating centres with SSc and a history or presence of DUs are eligible for inclusion in the DUO Registry, irrespective of their treatment regimen. At enrolment, data were collected on demographic and clinical variables. Patients were categorised into three groups according to their past history of gangrene and current gangrene status at enrolment: ‘never gangrene’: no past and no current gangrene; ‘ever gangrene’: past and/or current gangrene; and ‘current gangrene’: gangrene reported at enrolment, irrespective of gangrene history (a subset of the ‘ever gangrene’ group).
Categorical variables were analysed using descriptive statistics. Potential risk factors for the development of incident gangrene in patients with ≥1 follow-up visit and no current gangrene at enrolment were analysed using univariable logistic regression (ULR) conducted on demographics, clinical variables and autoantibody measurements collected at enrolment. Multivariable logistic regression (MLR) using forward selection was conducted on patients with complete covariate information using those variables with a p value <0.15 and sample size >3000 from the ULR models, considering interdependency among similar factors.
Among the 4944 patients enrolled in the DUO Registry from April 2008 to November 2014, 4642 had information recorded on their gangrene status: 81.6% (n=3787) were categorised as ‘never gangrene’, 18.4% (n=855) as ‘ever gangrene’ and 5.6% (n=258) as ‘current gangrene’. The three groups were generally similar regarding demographics and SSc characteristics, although more current smokers at enrolment were in the ‘ever gangrene’ and ‘current gangrene’ groups than in the ‘never gangrene’ group, and the ‘current gangrene’ group had the shortest time between first RP and enrolment (table 1). The proportion of patients with a history of DU-associated complications, interventions and hospitalisations was greater in the ‘ever gangrene’ group compared with the ‘never gangrene’ group.
Table 1.
Enrolment characteristics and patient demographics according to gangrene status*
| Never† gangrene (n=3787) |
Ever‡ gangrene (n=855) |
Current gangrene (n=258)§ |
|
|---|---|---|---|
| Gender | |||
| Female, % | 82.1 | 77.7 | 77.5 |
| Age at enrolment | |||
| Mean (95% CI), years | 54.4 (53.9 to 54.8) | 54.8 (53.9 to 55.8) | 52.8 (50.9 to 54.7) |
| Smoking status | |||
| n | 3386 | 757 | 233 |
| Current, % | 14.4 | 17.6 | 24.0 |
| Former, % | 23.3 | 25.6 | 17.6 |
| Never, % | 62.3 | 56.8 | 58.4 |
| Pack-years of smoking | |||
| n | 868 | 206 | 73 |
| Mean (95% CI) | 37.8 (31.3 to 44.3) | 37.9 (27.5 to 48.4) | 44.9 (24.9 to 64.9) |
| Age at first RP | |||
| n | 3409 | 752 | 229 |
| Mean (95% CI), years | 41.3 (40.8 to 41.8) | 40.7 (39.6 to 41.8) | 41.2 (39.0 to 43.3) |
| Age at first DU | |||
| n | 3000 | 700 | 218 |
| Mean (95% CI), years | 47.6 (47.1 to 48.2) | 47.1 (45.9 to 48.2) | 48.3 (46.1 to 50.5) |
| SSc cutaneous subset | |||
| n | 3774 | 850 | 256 |
| Diffuse SSc, % | 37.7 | 32.0 | 33.6 |
| Limited SSc, % | 52.3 | 58.2 | 54.3 |
| Overlap, % | 6.5 | 6.0 | 7.8 |
| Other, % | 3.6 | 3.8 | 4.3 |
| Organ manifestations | |||
| n | 3787 | 855 | 258 |
| GI tract, % | 54.0 | 56.8 | 46.5 |
| Lung fibrosis, % | 40.4 | 40.1 | 38.0 |
| PAH, % | 12.1 | 15.2 | 13.2 |
| Heart, % | 9.9 | 10.9 | 12.4 |
| Kidney, % | 4.1 | 6.0 | 5.8 |
| Time from first RP to enrolment visit | |||
| n | 3409 | 752 | 229 |
| Mean (95% CI), years | 13.1 (12.8 to 13.5) | 14.4 (13.6 to 15.3) | 11.9 (10.4 to 13.5) |
| Time from first DU to enrolment visit | |||
| n | 3000 | 700 | 218 |
| Mean (95% CI), years | 5.9 (5.7 to 6.2) | 7.4 (6.8 to 8.0) | 4.6 (3.8 to 5.5) |
| Antibodies, n1/n2 (%) | |||
| ACA | 1184/2942 (40.2) | 303/668 (45.4) | 88/216 (40.7) |
| ANA | 3307/3511 (94.2) | 750/785 (95.5) | 226/238 (95.0) |
| Anti-Scl 70 | 1397/3145 (44.4) | 282/690 (40.9) | 87/218 (39.9) |
| Anti-U1 RNP | 170/2158 (7.9) | 52/470 (11.1) | 17/151 (11.3) |
| Anti-U3 RNP | 59/1534 (3.8) | 19/300 (6.3) | 4/104 (3.8) |
| RNA polymerase III | 127/1584 (8.0) | 25/323 (7.7) | 6/103 (5.8) |
| Employed/self-employed, n (%) | 983/2674 (36.8) | 167/564 (29.6) | 75/207 (36.2) |
| History of complications/interventions, % (95% CI)¶ | |||
| Critical digital ischaemia | 30.1 (28.5 to 31.8) | 82.2 (78.6 to 85.4) | 69.4 (61.6 to 76.4) |
| Gangrene | – | 91.7 (89.7 to 93.5) | 71.9 (65.9 to 77.4) |
| Autoamputation | 3.1 (2.6 to 3.7) | 24.1 (21.2 to 27.2) | 15.9 (11.6 to 21.1) |
| Soft-tissue infection requiring systemic antibiotics | 23.9 (22.5 to 25.3) | 53.5 (49.9 to 57.0) | 44.5 (38.1 to 51.1) |
| Osteomyelitis | 1.3 (0.9 to 1.7) | 11.9 (9.7 to 14.3) | 7.4 (4.4 to 11.4) |
| Hospitalisations for DUs | 32.7 (31.2 to 34.2) | 70.1 (66.9 to 73.2) | 58.9 (52.5 to 65.2) |
| Upper limb sympathectomy | 2.2 (1.8 to 2.7) | 8.8 (6.9 to 10.9) | 7.2 (4.2 to 11.2) |
| Digital sympathectomy | 1.4 (1.0 to 1.8) | 4.8 (3.4 to 6.5) | 3.4 (1.5 to 6.6) |
| Arterial reconstruction | 0.7 (0.5 to 1.0) | 2.1 (1.3 to 3.4) | 4.3 (2.1 to 7.7) |
| Arthrodesis | 1.4 (1.0 to 1.9) | 5.7 (4.1 to 7.6) | 2.0 (0.5 to 4.9) |
| Debridement | 7.5 (6.6 to 8.4) | 25.7 (22.5 to 29.1) | 21.0 (15.6 to 27.2) |
| Surgical amputation | 2.4 (1.9 to 3.0) | 34.0 (30.5 to 37.5) | 18.9 (13.8 to 24.8) |
| Use of parenteral prostanoids | 51.6 (49.9 to 53.2) | 74.4 (71.2 to 77.4) | 74.4 (68.3 to 79.8) |
| Prior DUs, n1/n2 (%) | 3759/3787 (99.3) | 852/855 (99.6) | 255/258 (98.8) |
| Ongoing medications, % | |||
| n | 3787 | 855 | 258 |
| Analgesics and anti-inflammatories | 52.4 | 60.6 | 65.1 |
| Immunosuppressants | 33.5 | 28.2 | 29.5 |
| Systemic antibiotics | 13.3 | 19.6 | 36.0 |
| ERAs | 39.9 | 52.0 | 50.4 |
| CCBs | 46.0 | 52.5 | 53.1 |
| Prostacyclins | 35.0 | 36.5 | 51.9 |
| PDE-5i | 5.9 | 7.6 | 5.8 |
| Topical DU treatments | 19.1 | 24.4 | 36.8 |
| Other medications | 64.8 | 74.2 | 67.1 |
| ERA+PDE-5i | 2.2 | 3.3 | 2.7 |
| ERA+prostacyclin | 14.3 | 18.5 | 24.4 |
| PDE-5i+prostacyclin | 1.7 | 2.8 | 3.1 |
| ERA+PDE-5i+prostacyclin | 0.8 | 1.5 | 1.6 |
| ERA only** | 24.1 | 31.8 | 24.8 |
*Only patients who provided information on gangrene status (n=4642/4944) were categorised.
†Patients with no past and no current gangrene.
‡Patients with past and/or current gangrene.
§Patients with current gangrene at enrolment. The current gangrene group is a subset of the ‘ever gangrene’ group.
¶Data include only patients who provided information on the given item.
**Out of ERA, PDE-5i and prostacyclins, only ERA is ticked.
ACA, anticentromere antibody; ANA, antinuclear antibody; CCB, calcium channel blocker; DU, digital ulcer; ERA, endothelin receptor antagonist; GI, gastrointestinal; n1/n2, n patients tested positive/n patients who had the test done; PAH, pulmonary arterial hypertension; PDE-5i, phosphodiesterase-type 5 inhibitor; RNP, ribonucleic protein; RP, Raynaud's phenomenon; SSc, systemic sclerosis.
Overall, 3809 patients were eligible for inclusion in the ULR analysis; the final number of patients included in each ULR model varied depending on missing data (table 2A). On MLR analysis, being a current/former smoker, having ≥3 finger DUs, previous gangrene and previous upper limb sympathectomy were independent risk factors at enrolment for development of incident gangrene (table 2B).
Table 2.
Risk factors associated with the development of incident gangrene during the observation period
| Risk factor | Incident gangrene n/N (%) | No incident gangrene, n/N (%) | OR (95% CI) | p Value* |
|---|---|---|---|---|
| (A) ULR (N=3809)† | N=243 | N=3566 | ||
| Female gender | 189/243 (77.8) | 2938/3566 (82.4) | 0.73 (0.53 to 1.01) | 0.055 |
| Smoking status | ||||
| Current | 45/205 (22.0) | 438/3102 (14.1) | 1.91 (1.32 to 2.76) | <0.001 |
| Former | 58/205 (28.3) | 728/3102 (23.5) | 1.46 (1.04 to 2.04) | 0.028 |
| Number of finger DUs at enrolment | ||||
| 1–2 | 89/236 (37.7) | 1315/3546 (37.1) | 1.27 (0.93 to 1.72) | 0.132 |
| 3+ | 58/236 (24.6) | 666/3546 (18.8) | 1.54 (1.09 to 2.17) | 0.015 |
| Anti-Scl 70 | 103/196 (52.6) | 1279/2872 (44.5) | 1.39 (1.04 to 1.87) | 0.027 |
| Previous gangrene | 96/229 (41.9) | 404/3378 (12.0) | 4.75 (3.57 to 6.34) | <0.0001 |
| Previous autoamputation | 32/231 (13.9) | 188/3386 (5.6) | 2.69 (1.78 to 4.04) | <0.0001 |
| Previous soft-tissue infection requiring systemic antibiotics | 94/222 (42.3) | 933/3253 (28.7) | 1.76 (1.33 to 2.32) | <0.0001 |
| Previous osteomyelitis | 19/232 (8.2) | 84/3367 (2.5) | 3.24 (1.19 to 5.47) | <0.0001 |
| Ongoing autoamputation | 6/242 (2.5) | 46/3552 (1.3) | 2.32 (0.97 to 5.57) | 0.059 |
| Ongoing osteomyelitis | 4/243 (1.6) | 24/3558 (0.7) | 2.36 (0.80 to 6.99) | 0.121 |
| Previous hospitalisation(s) for DUs (at least 1 day) | 144/231 (62.3) | 1290/3385 (38.1) | 2.49 (1.89 to 3.29) | <0.0001 |
| Previous upper limb sympathectomy | 20/228 (8.8) | 100/3345 (3.0) | 3.24 (1.94 to 5.40) | <0.0001 |
| Previous digital sympathectomy | 11/228 (4.8) | 58/3341 (1.7) | 2.70 (1.38 to 5.31) | 0.004 |
| Previous arterial reconstruction | 5/227 (2.2) | 21/3336 (0.6) | 3.43 (1.25 to 9.44) | 0.017 |
| Not employed/self-employed | 205/243 (84.4) | 2687/3566 (75.4) | 1.78 (1.22 to 2.61) | 0.003 |
| (B) MLR‡(N=2479) | N=157 | N=2322 | ||
| Observation time, mean (SD), weeks | 174.7 (78.7) | 126.2 (78.9) | 1.03 (1.02 to 1.04) | <0.0001 |
| Smoking status | ||||
| Current | 27/157 (17.2) | 311/2322 (13.4) | 1.72 (1.07 to 2.77) | 0.025 |
| Former | 47/157 (29.9) | 509/2322 (21.9) | 1.69 (1.14 to 2.51) | 0.009 |
| Number of finger DUs at enrolment | ||||
| 1–2 | 60/157 (38.2) | 951/2322 (41.0) | 1.35 (0.90 to 2.03) | 0.144 |
| 3+ | 46/157 (29.3) | 491/2322 (21.1) | 1.69 (1.09 to 2.62) | 0.020 |
| Anti-Scl 70 | 79/157 (50.3) | 1031/2322 (44.4) | 1.39 (0.99 to 1.96) | 0.058 |
| Previous gangrene | 63/157 (40.1) | 244/2322 (10.5) | 4.67 (3.24 to 6.73) | <0.0001 |
| Previous upper limb sympathectomy | 15/157 (9.6) | 67/2322 (2.9) | 2.21 (1.15 to 4.27) | 0.018 |
*Wald χ2 test.
†For the ULR analysis, observation time was a fixed covariate in the model. Data are shown for variables having p<0.15 and n>3000 for the patients for whom information is available).
‡For the MLR analysis, observation time was forced into the model as a fixed covariate and not included by the forward selection procedure; variables were selected with a selection criterion of p=0.15. Data are shown for the subset of patients making up the final models (n=2479) to allow comparison with the full cohort.
ACA, anticentromere antibody; ANA, antinuclear antibody; DU, digital ulcer; MLR, multivariable logistic regression; PAH, pulmonary arterial hypertension; RNP, ribonucleic protein; ULR, univariable logistic regression.
This analysis was the largest to date describing an SSc–DU population according to the presence/history of gangrene at enrolment and risk factors for incident gangrene during follow-up. It has demonstrated that, in current practice, gangrene is still a common event occurring in 18% of patients with SSc–DUs. Participating centres involved in the DUO Registry are specialist centres for the management of SSc–DUs; this may be selective for patients with more severe vascular disease, and therefore more prevalent gangrene. Multivariate analyses indicated that, in patients with no current gangrene, along with previous gangrene, being a current/former smoker, having ≥3 DUs and previous upper limb sympathectomy were independent risk factors at enrolment for developing incident gangrene. These results will help to risk-stratify patients with SSc–DUs and to evaluate preventive gangrene management strategies.
annrheumdis-2016-209481supp.pdf (235.3KB, pdf)
Acknowledgments
Medical writing support was provided by Lynda McEvoy, PhD (ApotheCom, London, UK) and was funded by Actelion Pharmaceuticals.
Footnotes
Collaborators: List of DUO investigators in online supplementary appendix.
Funding: This DUO Registry is sponsored by Actelion Pharmaceuticals. The registry sponsor was involved in the registry design, and in the collection, analysis and interpretation of data.
Competing interests: YA has had consultancy relationships and/or has received research funding in relation to the treatment of systemic sclerosis from Actelion Pharmaceuticals, Bayer, Biogen Idec, Bristol-Myers Squibb, Genentech/Roche, Inventiva, Medac, Pfizer, Sanofi/Genzyme, Servier and UCB. CPD has received consultant and speaker fees from Actelion Pharmaceuticals, GlaxoSmithKline, Bayer, Inventiva and Takeda, and has received grant support from Actelion Pharmaceuticals, CSL Behring, and Novartis. TK has received grant and speaker fees from Actelion Pharmaceuticals. PC is an employee of SDE Services, based 100% at Actelion Pharmaceuticals. DR and BS are employees of and own shares in Actelion Pharmaceuticals. MM-C has received grant/research support and/or speaker fees from Actelion Pharmaceuticals.
Ethics approval: Ethical approval was obtained as required from the institutional ethics committees of the participating centres.
Provenance and peer review: Not commissioned; externally peer reviewed.
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annrheumdis-2016-209481supp.pdf (235.3KB, pdf)