JEADV
DOI: 10.1111/jdv.12997
SHORT REPORT
The risk of post-operative complications in psoriasis and psoriatic arthritis patients on biologic therapy undergoing surgical procedures W. Bakkour,1 H. Purssell,1 H. Chinoy,2 C.E.M. Griffiths,1 R.B. Warren1,* 1
The Dermatology Centre, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, University of Manchester, UK 2 Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK *Correspondence: R. Warren. E-mail: [email protected]
Abstract Background There is limited evidence as to whether biologic therapy should be stopped or continued in patients with psoriasis and/or psoriatic arthritis (PsA) who are undergoing surgical procedures. Current guidelines of care recommend a planned break from biologic therapy in those undergoing major surgical procedures. Objective To audit current practice of managing biologic therapy peri-operatively in a tertiary referral psoriasis clinic against guidelines of care and to investigate the effects of continuing/stopping biologic therapy in psoriasis and PsA patients. Methods A retrospective audit of psoriasis and PsA patients who had a surgical procedure whilst on biologic therapy. A proforma was used to collect information on the biologics used, whether they were stopped peri-operatively and whether patients developed post-operative complications and/or disease flare. Results A total of 42 patients who had 77 procedures were identified. Procedures ranged from skin surgery to orthopaedic and cardiothoracic surgery. Biologic therapy was continued in the majority of procedures (76%). There was no significant difference in post-operative risk of infection and delayed wound healing between those patients who continued and those who stopped biologic therapy, including those undergoing major surgery. Interrupting biologic therapy peri-operatively was associated with a significant (P = 0.003) risk of flare of psoriasis or PsA. Conclusion Continuing biologic therapy in psoriasis and PsA patients peri-operatively did not increase the risk of post-operative complications. Interrupting biologic therapy peri-operatively significantly increased the risk of disease flare. This study is limited by cohort size and requires replication, ideally in a prospective randomized controlled manner. Received: 17 November 2014; Accepted: 7 January 2015
Conflicts of interest RBW has acted as a consultant and/or speaker and/or received research grants for Abbvie, Amgen, Celgene, Eli Lilly, Pfizer, Novartis and Janssen all of whom manufacture biologic therapies. CEMG has received honoraria and/or research grants from Abbvie, Actelion, Celgene, Eli Lilly, GSK-Stiefel, Janssen, MSD, Novartis, Pfizer and Sandoz. HC has acted as a consultant and/or speaker and/or received research grants for Abbvie, Celgene, Pfizer, Janssen, MSD, UCB, Roche, Servier all of whom manufacture biologic therapies.
Funding sources None.
Introduction Biologic agents are well-established therapies for patients with severe psoriasis and/or psoriatic arthritis (PsA). They include two classes of biologics: tumour necrosis factor (TNF) inhibitors (adalimumab, etanercept and infliximab; in addition to golimumab and certolizumab for PsA alone) and; the interleukin (IL) 12/23 inhibitor ustekinumab. Psoriasis and PsA patients may undergo surgical intervention whilst on biologic therapy. The current British Association of
JEADV 2016, 30, 86–91
Dermatologists (BAD) and British Society for Rheumatology (BSR) guidelines for use of biologic therapy both recommend stopping biologic therapy for at least four half-lives prior to major surgical procedures (2 weeks for etanercept; 6–8 weeks for adalimumab; 4–6 weeks for infliximab and; 12 weeks for ustekinumab) and restarting post-operatively if there is no evidence of infection and if wound healing is satisfactory.1,2 However, the evidence on which these recommendations are based comes mainly from small retrospective studies in rheumatoid
© 2015 European Academy of Dermatology and Venereology
Post-operative complications risk in patients on biologics
87
Table 1 Continuation of biologic therapy peri-operatively by procedure type Frequency (%)
Number continued biologic (%)
Number stopped biologic (%)
Skin surgery
40 (52)
33 (82.5)
7 (17.5)
Orthopaedic surgery
15 (19.5)
Cardiovascular surgery
6 (7.8)
9 (60)
6 (40)
2 (33.4)
4 (66.6)
Gastrointestinal and urologic surgery
12 (15.6)
9 (75)
3 (25)
ENT, Maxillofacial and dental surgery
4 (5.2)
4 (100)
0
arthritis (RA) and inflammatory bowel disease (IBD). We have therefore performed an audit to assess adherence to these guidelines in addition to investigating the risk of post-operative complications, namely, infection and delayed wound healing in psoriasis and PsA patients on biologic therapy.
Methods Patients with either psoriasis or PsA, on biologic therapy at the time of surgical intervention, were identified from electronic patient records held at Salford Royal NHS Foundation Trust, UK. Information on demographics, indication for biologic therapy and agent used were collected. Types of surgical procedures, whether biologic therapy was stopped peri-operatively, and if so for how long were also recorded, in addition to data on post-operative complications, namely infection and delayed wound healing. Microbiology reports for infections were identified. Data on concomitant immunosuppressive therapy, smoking, diabetes status and the use of prophylactic antibiotics as potential confounding factors were recorded, in addition to details on disease flare. Data analysis was performed using SPSS Inc. Version 20 (Chicago, IL, USA). Each procedure was considered an independent event. Fisher’s exact test was used to calculate significance and logistic regression to adjust for confounding factors.
The median number of days that each biologic therapy was stopped before a procedure compared to the recommended four half-lives in the BAD guidelines is shown in Fig. 1. Ustekinumab and golimumab were not stopped in any of the five cases where they were used. The median numbers of stopping days prior to the procedure for adalimumab, etanercept and infliximab were 14, 17.5 and 17.5 days respectively. The median number of days for restarting biologic therapy post-procedure was 28, 15.5 and 35 for adalimumab, etanercept and infliximab respectively. There were 8 (10.39%) post-operative complications (Table 2). Microbiology information was available for one case which showed infection with staphylococcus aureus. There were significantly more complications (Fishers Exact; P = 0.014) in the group who had their biologic therapy stopped peri-operatively (25%) compared to those who continued (5.2%). Age and gender had no effect on the rate of complications. Patients were on concomitant immunosuppressive therapies, had a diagnosis of diabetes or were smokers in 25 (32%), 11 (14%) and 17 procedures (22%) respectively. Prophylactic antibiotics were prescribed in four procedures (5%). Logistic regression to adjust for these potential confounding factors demonstrated that none of them appeared to influence outcome.
Results Over a 6-year period from 2005 to 2011, a total of 300 psoriasis and PsA patients on biologic therapy were identified. Of these, 42 patients had undergone at least one surgical procedure, whilst some had multiple procedures (2–7); the total number of procedures was 77. Fifty-four procedures (70%) were performed on 28 psoriasis patients and 23 procedures (30%) on 14 PsA patients. The overall male to female split was 67.5% and 32.5% respectively. A total of 40 procedures (52%) were considered minor (mainly skin surgery) and 37 (48%) were major. Etanercept was the most commonly used biologic therapy in 30 (39%) procedures, followed by adalimumab in 28 (36%) and infliximab in 11(14%). Biologic therapy was stopped prior to the procedure in 20 cases (26%), and continued in 57 (74%) procedures. Patients were more likely to have biologic therapy stopped if undergoing cardiothoracic surgery (66.6%) or orthopaedic surgery (40%) as compared to only 17.5% for skin surgery (Table 1).
JEADV 2016, 30, 86–91
45 40 35 30 25 20 15 10 5 0
Median number of stopping days
4 Half-lives
Figure 1 Median number of days for stopping biologic therapy pre-operatively vs. the recommended four half-lives.
© 2015 European Academy of Dermatology and Venereology
Bakkour et al.
No
No
No
No
No
Yes (MTX)
Yes (MTX)
No No
No
No No
No
No No
No
Prophylactic antibiotics
No No Wound infection Stopped. Time not recorded Toenail removal Adalimumab Psoriatic Arthritis 34 8
Female
No Yes Wound infection Stopped 2 weeks before Double coronary bypass Etanercept Psoriatic Arthritis 77 7
Male
No Delayed wound healing 64 6
Male
Psoriasis
Adalimumab
Excision of SCC and skin graft
Stopped 1 week
No
No No Both Stopped 1 month before procedure Excision of SCC Adalimumab Psoriasis 51 5
Male
No
No No
No Wound infection
Wound infection Continued
Continued Incisional skin biopsy
Right knee replacement Etanercept
Adalimumab Psoriasis
Psoriasis
51 4
Male
47 3
Male
48 2
Male
Psoriasis
Infliximab
Incisional skin biopsy
Continued
Delayed wound healing
Yes
No No Both Stopped 4 weeks prior to procedure Excision of SCC Adalimumab Psoriasis 65 1
Male
Procedure Biologic Indication Age
Gender
When combining psoriasis and PsA patients, significantly more patients suffered disease flare when treatment was stopped peri-operatively compared to when treatment continued (40%, and 8.7% respectively, P = 0.003). The case was similar for psoriasis with 55% flaring when treatment was stopped vs. 11% when continued (P = 0.006). More PsA patients flared when treatment was interrupted (30%) compared to when treatment was continued (0%), however, the difference was not statistically significant (P = 0.09). Half of those who had disease flare when biologic therapy was interrupted were on etanercept and half were on adalimumab.
Discussion
Case
Table 2 Summary of cases that developed post-operative complications
Stopped biologic/ continued biologic/ timed procedure
Complication
Diabetic
Smoker
On concomitant immunosuppression
88
JEADV 2016, 30, 86–91
To our knowledge, this is the first analysis of post-operative complications in dermatology patients on biologic therapy for psoriasis or PsA. We found that the risk of post-operative complications was higher in those who had their biologic therapy stopped peri-operatively compared to those who continued, even after adjusting for potential confounders. As anticipated, stopping biologic therapy peri-operatively was associated with a significant risk of disease flare (P = 0.003). The BAD guidelines recommend stopping biologic therapy at least four half-lives before major surgery.1 However, the guidelines do not define what is meant by ‘major’ surgery. When analysing all types of surgical procedure we found that stopping biologic therapy peri-operatively was infrequent (26%) vs. continuing (74%). If general anaesthesia is used to define major surgery then biologic therapy was stopped in 12 of 37 ‘major’ procedures (32%). A sub-analysis of major procedures showed no difference in risk of complications in those who continued or stopped treatment (Fisher’s exact; P = 0.253) but the numbers are too small to draw firm conclusions. There was significant variation in practice and when we excluded those patients who stopped therapy for less than the recommended four half-lives1,2 (65%) we found no significant difference in the risk of post-operative complication between those who stopped and those who continued biologic therapy (Fishers Exact; P = 0.37). Although, etanercept was the most commonly used biologic, adalimumab seemed to be associated with more complications (five cases), however, the difference between the two was not statistically significant (P = 0.13). Neither ustekinumab nor golimumab were stopped in any patients, none of whom had any complications. The current literature on the risk of post-operative complications in patients on biologic therapy is conflicting (Table 3) with no prospective randomized controlled trials to our knowledge. Three studies compared the risk of surgical complications following abdominal surgery between IBD patients who were on infliximab peri-operatively vs. a control group who were infliximab na€ıve.3–5 They all found no increased risk of complications associated with peri-operative infliximab use.3–5
© 2015 European Academy of Dermatology and Venereology
JEADV 2016, 30, 86–91
Rheumatoid arthritis
Rheumatoid arthritis
Crohn’s disease
Giles et al.11
Kubota et al.10
Marchal et al.4
1 Psoriatic arthritis
10 Rheumatoid arthritis
Talwalkar et al.8
36 procedures
55 procedures
Group 1: discontinued >5 half-lives Group 2: discontinued 2–4 half-lives
Abdominal
Orthopaedic
Orthopaedic
Orthopaedic
40 procedures 39 procedures
Group 2: Control
278 procedures
Group 1: had infusions prior to surgery
Group 2: Joints in patients not on biologics
276 procedures
81 patients
Group 2: No post-operative infection Group 1: Joints in patients on Biologics
10 patients
12 procedures
Group B: Anti-TNF therapy discontinued
Group 1: Had post-operative infection
4 procedures
32 procedures
18 procedures
Group A: anti-TNF therapy continued
Group 2: surgery timed between injections
Abdominal (6) Head and Neck (5)
Group 1: anti-TNF stopped
10 procedures
92 procedures
Group 2b: continued anti-TNF
Group 3: discontinued
DOI: 10.1111/jdv.12997
SHORT REPORT
The risk of post-operative complications in psoriasis and psoriatic arthritis patients on biologic therapy undergoing surgical procedures W. Bakkour,1 H. Purssell,1 H. Chinoy,2 C.E.M. Griffiths,1 R.B. Warren1,* 1
The Dermatology Centre, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, University of Manchester, UK 2 Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK *Correspondence: R. Warren. E-mail: [email protected]
Abstract Background There is limited evidence as to whether biologic therapy should be stopped or continued in patients with psoriasis and/or psoriatic arthritis (PsA) who are undergoing surgical procedures. Current guidelines of care recommend a planned break from biologic therapy in those undergoing major surgical procedures. Objective To audit current practice of managing biologic therapy peri-operatively in a tertiary referral psoriasis clinic against guidelines of care and to investigate the effects of continuing/stopping biologic therapy in psoriasis and PsA patients. Methods A retrospective audit of psoriasis and PsA patients who had a surgical procedure whilst on biologic therapy. A proforma was used to collect information on the biologics used, whether they were stopped peri-operatively and whether patients developed post-operative complications and/or disease flare. Results A total of 42 patients who had 77 procedures were identified. Procedures ranged from skin surgery to orthopaedic and cardiothoracic surgery. Biologic therapy was continued in the majority of procedures (76%). There was no significant difference in post-operative risk of infection and delayed wound healing between those patients who continued and those who stopped biologic therapy, including those undergoing major surgery. Interrupting biologic therapy peri-operatively was associated with a significant (P = 0.003) risk of flare of psoriasis or PsA. Conclusion Continuing biologic therapy in psoriasis and PsA patients peri-operatively did not increase the risk of post-operative complications. Interrupting biologic therapy peri-operatively significantly increased the risk of disease flare. This study is limited by cohort size and requires replication, ideally in a prospective randomized controlled manner. Received: 17 November 2014; Accepted: 7 January 2015
Conflicts of interest RBW has acted as a consultant and/or speaker and/or received research grants for Abbvie, Amgen, Celgene, Eli Lilly, Pfizer, Novartis and Janssen all of whom manufacture biologic therapies. CEMG has received honoraria and/or research grants from Abbvie, Actelion, Celgene, Eli Lilly, GSK-Stiefel, Janssen, MSD, Novartis, Pfizer and Sandoz. HC has acted as a consultant and/or speaker and/or received research grants for Abbvie, Celgene, Pfizer, Janssen, MSD, UCB, Roche, Servier all of whom manufacture biologic therapies.
Funding sources None.
Introduction Biologic agents are well-established therapies for patients with severe psoriasis and/or psoriatic arthritis (PsA). They include two classes of biologics: tumour necrosis factor (TNF) inhibitors (adalimumab, etanercept and infliximab; in addition to golimumab and certolizumab for PsA alone) and; the interleukin (IL) 12/23 inhibitor ustekinumab. Psoriasis and PsA patients may undergo surgical intervention whilst on biologic therapy. The current British Association of
JEADV 2016, 30, 86–91
Dermatologists (BAD) and British Society for Rheumatology (BSR) guidelines for use of biologic therapy both recommend stopping biologic therapy for at least four half-lives prior to major surgical procedures (2 weeks for etanercept; 6–8 weeks for adalimumab; 4–6 weeks for infliximab and; 12 weeks for ustekinumab) and restarting post-operatively if there is no evidence of infection and if wound healing is satisfactory.1,2 However, the evidence on which these recommendations are based comes mainly from small retrospective studies in rheumatoid
© 2015 European Academy of Dermatology and Venereology
Post-operative complications risk in patients on biologics
87
Table 1 Continuation of biologic therapy peri-operatively by procedure type Frequency (%)
Number continued biologic (%)
Number stopped biologic (%)
Skin surgery
40 (52)
33 (82.5)
7 (17.5)
Orthopaedic surgery
15 (19.5)
Cardiovascular surgery
6 (7.8)
9 (60)
6 (40)
2 (33.4)
4 (66.6)
Gastrointestinal and urologic surgery
12 (15.6)
9 (75)
3 (25)
ENT, Maxillofacial and dental surgery
4 (5.2)
4 (100)
0
arthritis (RA) and inflammatory bowel disease (IBD). We have therefore performed an audit to assess adherence to these guidelines in addition to investigating the risk of post-operative complications, namely, infection and delayed wound healing in psoriasis and PsA patients on biologic therapy.
Methods Patients with either psoriasis or PsA, on biologic therapy at the time of surgical intervention, were identified from electronic patient records held at Salford Royal NHS Foundation Trust, UK. Information on demographics, indication for biologic therapy and agent used were collected. Types of surgical procedures, whether biologic therapy was stopped peri-operatively, and if so for how long were also recorded, in addition to data on post-operative complications, namely infection and delayed wound healing. Microbiology reports for infections were identified. Data on concomitant immunosuppressive therapy, smoking, diabetes status and the use of prophylactic antibiotics as potential confounding factors were recorded, in addition to details on disease flare. Data analysis was performed using SPSS Inc. Version 20 (Chicago, IL, USA). Each procedure was considered an independent event. Fisher’s exact test was used to calculate significance and logistic regression to adjust for confounding factors.
The median number of days that each biologic therapy was stopped before a procedure compared to the recommended four half-lives in the BAD guidelines is shown in Fig. 1. Ustekinumab and golimumab were not stopped in any of the five cases where they were used. The median numbers of stopping days prior to the procedure for adalimumab, etanercept and infliximab were 14, 17.5 and 17.5 days respectively. The median number of days for restarting biologic therapy post-procedure was 28, 15.5 and 35 for adalimumab, etanercept and infliximab respectively. There were 8 (10.39%) post-operative complications (Table 2). Microbiology information was available for one case which showed infection with staphylococcus aureus. There were significantly more complications (Fishers Exact; P = 0.014) in the group who had their biologic therapy stopped peri-operatively (25%) compared to those who continued (5.2%). Age and gender had no effect on the rate of complications. Patients were on concomitant immunosuppressive therapies, had a diagnosis of diabetes or were smokers in 25 (32%), 11 (14%) and 17 procedures (22%) respectively. Prophylactic antibiotics were prescribed in four procedures (5%). Logistic regression to adjust for these potential confounding factors demonstrated that none of them appeared to influence outcome.
Results Over a 6-year period from 2005 to 2011, a total of 300 psoriasis and PsA patients on biologic therapy were identified. Of these, 42 patients had undergone at least one surgical procedure, whilst some had multiple procedures (2–7); the total number of procedures was 77. Fifty-four procedures (70%) were performed on 28 psoriasis patients and 23 procedures (30%) on 14 PsA patients. The overall male to female split was 67.5% and 32.5% respectively. A total of 40 procedures (52%) were considered minor (mainly skin surgery) and 37 (48%) were major. Etanercept was the most commonly used biologic therapy in 30 (39%) procedures, followed by adalimumab in 28 (36%) and infliximab in 11(14%). Biologic therapy was stopped prior to the procedure in 20 cases (26%), and continued in 57 (74%) procedures. Patients were more likely to have biologic therapy stopped if undergoing cardiothoracic surgery (66.6%) or orthopaedic surgery (40%) as compared to only 17.5% for skin surgery (Table 1).
JEADV 2016, 30, 86–91
45 40 35 30 25 20 15 10 5 0
Median number of stopping days
4 Half-lives
Figure 1 Median number of days for stopping biologic therapy pre-operatively vs. the recommended four half-lives.
© 2015 European Academy of Dermatology and Venereology
Bakkour et al.
No
No
No
No
No
Yes (MTX)
Yes (MTX)
No No
No
No No
No
No No
No
Prophylactic antibiotics
No No Wound infection Stopped. Time not recorded Toenail removal Adalimumab Psoriatic Arthritis 34 8
Female
No Yes Wound infection Stopped 2 weeks before Double coronary bypass Etanercept Psoriatic Arthritis 77 7
Male
No Delayed wound healing 64 6
Male
Psoriasis
Adalimumab
Excision of SCC and skin graft
Stopped 1 week
No
No No Both Stopped 1 month before procedure Excision of SCC Adalimumab Psoriasis 51 5
Male
No
No No
No Wound infection
Wound infection Continued
Continued Incisional skin biopsy
Right knee replacement Etanercept
Adalimumab Psoriasis
Psoriasis
51 4
Male
47 3
Male
48 2
Male
Psoriasis
Infliximab
Incisional skin biopsy
Continued
Delayed wound healing
Yes
No No Both Stopped 4 weeks prior to procedure Excision of SCC Adalimumab Psoriasis 65 1
Male
Procedure Biologic Indication Age
Gender
When combining psoriasis and PsA patients, significantly more patients suffered disease flare when treatment was stopped peri-operatively compared to when treatment continued (40%, and 8.7% respectively, P = 0.003). The case was similar for psoriasis with 55% flaring when treatment was stopped vs. 11% when continued (P = 0.006). More PsA patients flared when treatment was interrupted (30%) compared to when treatment was continued (0%), however, the difference was not statistically significant (P = 0.09). Half of those who had disease flare when biologic therapy was interrupted were on etanercept and half were on adalimumab.
Discussion
Case
Table 2 Summary of cases that developed post-operative complications
Stopped biologic/ continued biologic/ timed procedure
Complication
Diabetic
Smoker
On concomitant immunosuppression
88
JEADV 2016, 30, 86–91
To our knowledge, this is the first analysis of post-operative complications in dermatology patients on biologic therapy for psoriasis or PsA. We found that the risk of post-operative complications was higher in those who had their biologic therapy stopped peri-operatively compared to those who continued, even after adjusting for potential confounders. As anticipated, stopping biologic therapy peri-operatively was associated with a significant risk of disease flare (P = 0.003). The BAD guidelines recommend stopping biologic therapy at least four half-lives before major surgery.1 However, the guidelines do not define what is meant by ‘major’ surgery. When analysing all types of surgical procedure we found that stopping biologic therapy peri-operatively was infrequent (26%) vs. continuing (74%). If general anaesthesia is used to define major surgery then biologic therapy was stopped in 12 of 37 ‘major’ procedures (32%). A sub-analysis of major procedures showed no difference in risk of complications in those who continued or stopped treatment (Fisher’s exact; P = 0.253) but the numbers are too small to draw firm conclusions. There was significant variation in practice and when we excluded those patients who stopped therapy for less than the recommended four half-lives1,2 (65%) we found no significant difference in the risk of post-operative complication between those who stopped and those who continued biologic therapy (Fishers Exact; P = 0.37). Although, etanercept was the most commonly used biologic, adalimumab seemed to be associated with more complications (five cases), however, the difference between the two was not statistically significant (P = 0.13). Neither ustekinumab nor golimumab were stopped in any patients, none of whom had any complications. The current literature on the risk of post-operative complications in patients on biologic therapy is conflicting (Table 3) with no prospective randomized controlled trials to our knowledge. Three studies compared the risk of surgical complications following abdominal surgery between IBD patients who were on infliximab peri-operatively vs. a control group who were infliximab na€ıve.3–5 They all found no increased risk of complications associated with peri-operative infliximab use.3–5
© 2015 European Academy of Dermatology and Venereology
JEADV 2016, 30, 86–91
Rheumatoid arthritis
Rheumatoid arthritis
Crohn’s disease
Giles et al.11
Kubota et al.10
Marchal et al.4
1 Psoriatic arthritis
10 Rheumatoid arthritis
Talwalkar et al.8
36 procedures
55 procedures
Group 1: discontinued >5 half-lives Group 2: discontinued 2–4 half-lives
Abdominal
Orthopaedic
Orthopaedic
Orthopaedic
40 procedures 39 procedures
Group 2: Control
278 procedures
Group 1: had infusions prior to surgery
Group 2: Joints in patients not on biologics
276 procedures
81 patients
Group 2: No post-operative infection Group 1: Joints in patients on Biologics
10 patients
12 procedures
Group B: Anti-TNF therapy discontinued
Group 1: Had post-operative infection
4 procedures
32 procedures
18 procedures
Group A: anti-TNF therapy continued
Group 2: surgery timed between injections
Abdominal (6) Head and Neck (5)
Group 1: anti-TNF stopped
10 procedures
92 procedures
Group 2b: continued anti-TNF
Group 3: discontinued
