REVIEWS

Perioperative care for patients with rheumatic

diseases
Bharath M. Akkara Veetil and Tim Bongartz
Abstract | The perioperative care of patients with rheumatic diseases is hampered by a lack of evidence-
based recommendations. Rheumatologists are called upon to ‘clear’ their patients for surgery, yet the
evidence upon which to base decisions is fractionated and inconsistent. We have systematically reviewed
the current literature and developed suggestions for three key areas that require particular deliberations
in patients with rheumatic diseases scheduled for surgery: the management of cardiovascular risk, use
of immunosuppressive drugs, and states of altered coagulation. For patients with rheumatic diseases
associated with increased cardiovascular risk, such as rheumatoid arthritis and systemic lupus
erythematosus, we suggest following the American College of Cardiology–American Heart Association
guidelines using the underlying disease as a risk modifier. Most evidence suggests a neutral effect of
conventional DMARDs in the perioperative period, with no need to discontinue them prior to surgery.
Conversely, we suggest minimizing perioperative steroid use and unnecessary ‘steroid preps’. The potential
benefits of discontinuing biologic drugs in the perioperative setting needs to be carefully balanced with the
risks associated with a disease flare. We discuss the American College of Chest Physicians guidelines,
which classify individuals with antiphospholipid antibody syndrome as high-risk patients for perioperative
thrombosis who are likely to require bridging therapy in most perioperative settings.
Akkara Veetil, B. M. & Bongartz, T. Nat. Rev. Rheumatol. 8, 32–41 (2012); published online 15 November 2011;
doi:10.1038/nrrheum.2011.171

Introduction Perioperative cardiac assessment

Perioperative care in patients with rheumatic dis-
eases requires deliberations that go beyond what has
to be considered in otherwise healthy indivi­duals: the
increased cardiovascular risk associated with many
rheumatic conditions, the possible association between
immunosuppressive medications and surgical site infec-
tions, and states of altered coagulation in patients with
anti­phospholipid antibodies pose particular challenges
when preparing a rheumatologic patient for surgery.
In this article, we review the available evidence in an
attempt to generate a decision-support system that can
help pro­viders with the perioperative care of patients
with rheumatic diseases. Importantly, the purpose of
any preoperative evaluation is never to ‘clear a patient
for surgery’, but rather to provide a risk assessment that
the patient, the surgeon and the anesthesiologist can
use to make manage­ment decisions. In addition, recom-
mendations can be provided as to how the patient’s peri-
operative risk can be minimized. Where there are no
specific pointers in the literature, we have highlighted
Mayo Clinic, 200 1st
Street SW, Rochester,
guidelines by professional bodies that could serve as a
MN 55905, USA general framework for clinical decision making.
(B. M. Akkara Veetil,
T. Bongartz).
Competing interests
Correspondence to:
T. Bongartz T. Bongartz declares an association with the following company:
bongartz.tim@ Wyeth. See the article online for full details of the relationship.
mayo.edu B. M. Akkara Veetil declares no competing interests.
The risk of cardiovascular disease is increased in several
systemic autoimmune disorders, such as rheumatoid
arthritis (RA) and systemic lupus erythematosus (SLE).1–3
For example, a meta-analysis of patients with RA demon-
strated a 60% increase in the risk of cardio­vascular death
compared to the general population, with a combined
cardiovascular-disease-specific standardized mortality
ratio (ratio of observed to expected deaths) of 1.61 (95%
CI 1.48–1.75; P <0.0001).4 Moreover, patients with RA
and coronary heart disease are less likely to report typical
symptoms of angina, and are, therefore, at a particularly
increased risk of unrecognized myocardial infarction and
sudden cardiac death.3
When patients with rheumatic diseases require surgical
procedures, rheumatologists are frequently called upon
to evaluate and manage perioperative risks. In the fol-
lowing section, we suggest an algorithmic approach to
the preoperative cardiac risk assessment of patients with
systemic rheumatic diseases. Our suggestions are based
on the American College of Cardiology–American
Heart Association (ACC/AHA) 2007 Guidelines on
Perioperative Cardiovascular Evaluation and Care for
Noncardiac Surgery,5 modified to accommodate RA,
SLE and psoriatic arthritis as important cardiovascu-
lar risk factors independent of traditional risk factors.
We will illustrate our approach through a hypothetical
clinical scenario (Figure 1), which is only one of many

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 REVIEWS

scena­rios rheumatologists will encounter in their prac- Key points

tice. However, we hope that it offers a rather typical
example that can be easily modified according to the algo-
rithm described below. Our modification of the ACC/
AHA 2007 guidelines is based on indirect evidence, and
should be seen as a suggestion that tries to incorporate
this imperfect evidence into current clinical practice.
Scenario
Mrs Doe is a 65-year-old woman with longstanding
(>10 years) seropositive erosive RA who is currently
treated with methotrexate and etanercept. Her arthri-
tis has affected both knees and feet, resulting in limited
mobility. She has been maintained on methotrexate
and etanercept for the past 5 years, with stable disease
control and only very occasional flares. She has been
diagnosed with hypertension and hyperlipidemia,
which are both well controlled with pharmacotherapy.
She requires a total knee replacement owing to severe
degenerative disease of the left knee, and is presenting to
her rheumatologist for preoperative assessment.
■■ Patients with rheumatic diseases pose unique problems in the perioperative
setting owing to their increased cardiovascular risk, use of immunosuppressive
medications, and the possible need for anticoagulation in patients with
antiphospholipid syndrome (APS)
■■ We suggest the inclusion of rheumatoid arthritis, systemic lupus
erythematosus and psoriatic arthritis as additional cardiovascular risk factors
in the current American College of Cardiology–American Heart Association
(ACC/AHA) recommendations
■■ The lowest possible dose of steroids should be used in the perioperative
setting in order to minimize unnecessary exposure and reduce the risk of
surgical site infections and wound healing complications
■■ The majority of studies suggest that it is generally safe to continue conventional
DMARDs, such as methotrexate, perioperatively
■■ Biologic agents are best withheld before surgery, owing to the current lack
of data regarding their safety and evidence suggesting a general increase in
infection risk associated with their use
■■ In patients with APS, a careful risk:benefit assessment, which balances the
risk of a thromboembolic event with the risk of a major bleed, is required to
determine whether perioperative bridging therapy is required

Risk assessment Need for emergency Yes Proceed to surgery

noncardiac surgery Perioperative surveillance and postoperative
As the above scenario describes a patient who is due risk stratification and risk factor management
to undergo noncardiac surgery, the ACC/AHA 2007 No
guidelines provide a useful framework for the preopera- Yes Evaluate and treat per ACC/AHA guidelines
Active cardiac conditions
tive cardiovascular risk assessment.5 The quintessence Consider surgery
of the recommendations is that “intervention is rarely No
neces­sary to simply lower the risk of surgery, unless such Yes
Low-risk surgery Proceed with planned surgery
intervention is indicated irrespective of the perioperative
context,” and “no test should be performed unless it is No
likely to influence patient treatment.” The recommen­ Functional capacity >4 Yes
dations can be summarized in a simple algorithm that Proceed with planned surgery
METS without symptoms
contains six key decision points: the urgency of the No/unknown
planned surgery; the presence of active cardiac condi-
tions (such as unstable angina or decompensated heart Clinical risk factors
Ischemic heart disease, compensated or prior heart failure, diabetes mellitus,
failure); the risk of surgery; the functional capacity of the renal insufficiency, cerebrovascular disease, rheumatoid arthritis,
patient; the presence of cardiovascular risk factors; and ankylosing spondylitis or psoriatic arthritis1–3
the potential impact of cardiac testing on management.
≥3 1 or 2 None
Step 1: Urgency of the planned surgery Vascular surgery Intermediate-risk Vascular or Proceed with
Mrs Doe is scheduled for an elective total joint arthro- surgery intermediate-risk surgery
surgery
plasty, so we can proceed to step 2 in the algorithm. If
the surgery were to be an emergency procedure, detailed Test whether it
preoperative cardiovascular assessment would not will change
be recommended. management

Step 2: Presence of active cardiac conditions
While Mrs Doe does have medically controlled hyper­
tension, she is not affected by any active cardiac con-
ditions, defined as unstable coronary syndromes,
decompensated heart failure, significant arrhythmias,
and severe valvular heart disease (such as critical aortic
stenosis or severe mitral regurgitation). If present, it
would be desirable to treat and stabilize these conditions
before proceeding with an elective surgery.
Step 3: Risk of surgery
Surgical procedures are classified as low risk, inter­medi­
ate risk, or vascular. It is worth noting that, although
Proceed with planned surgery with heart rate control,
or consider noninvasive testing if it will change management
Figure 1 | Algorithm for cardiac risk assessment before surgery.5 Note the
addition of rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis as
clinical risk factors. Abbreviations: ACC/AHA, American College of Cardiology–
American Heart Association; METS, metabolic equivalents. Adapted from
Fleisher, L. A. et al. J. Am. Coll. Cardiol. 50, 1707–1732 (2007) with permission
from Elsevier Ltd ©.
coronary heart disease is the overwhelming risk factor
associated with perioperative morbidity, different
procedures are associated with differing morbidities.
Procedures associated with a low mortality rate (<1%),

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© 2011 Macmillan Publishers Limited. All rights reserved
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Table 1 | Guidelines for adrenal supplementation therapy19 is a key question in the preoperative cardiac assessment,
Medical or surgical stress Corticosteroid dosage as the level of exercise tolerance is a reliable predictor for
perioperative cardiac events.8 Climbing a flight of stairs,
Minor
walking at 4 mph on level ground, or performing light
Inguinal hernia repair 25 mg hydrocortisone or 5 mg methylprednisolone work around the house, such as dusting or doing the
Colonoscopy intravenous on day of procedure only
Mild febrile illness dishes, represent activities that require approximately
Mild–moderate nausea/vomiting four METs. As rheumatic diseases can markedly limit
Gastroenteritis a patient’s mobility, the assessment of their functional
Moderate capacity can be challenging. Some evidence suggests
Open cholecystectomy 50–75 mg hydrocortisone or 10–15 mg that limited activity due to noncardiac causes (such as
Hemicolectomy methylprednisolone intravenous on day of procedure; arthritis) is a marker for increased cardiovascular risk
Significant febrile illness taper quickly over 1–2 days to usual dose associated with noncardiac surgery (class IIa, level of
Pneumonia evidence [LOE] B). 9 This is the case for our sample
Severe gastroenteritis
patient Mrs Doe, who is functionally limited because
Severe
of severe osteoarthritis (OA) in both knees. She does
Major cardiothoracic surgery 100–150 mg hydrocortisone or 20–30 mg not climb stairs, uses an electric wheelchair and has
Whipple procedure methylprednisolone intravenous on day of procedure;
somebody else doing the housework for her. If she were
Liver resection taper quickly over 1–2 days to usual dose
Pancreatitis able to do these activities without problems or cardiac
symptoms, her cardiovascular risk assessment would
Critically ill
stop here. However, given her OA-related functional
Sepsis-induced hypotension 50–100 mg hydrocortisone intravenous every 6–8 h
impairment, we will have to proceed to step 5 for a
or shock or 0.18 mg/kg/h as a continuous infusion plus 50 μg
per day fludrocortisone until shock resolved; may detailed assessment of her cardiovascular risk factors.
take several days to a week or more, then gradually
taper, following vital signs and serum sodium Step 5: Presence of cardiovascular risk factors
Reproduced, with permission, from Coursin, D. B. & Wood, K. E. Corticosteroid supplementation for adrenal In patients with poor or unknown functional capac-
insufficiency. JAMA 287, 236–240 (2002). © (2002) American Medical Association. All rights reserved.
ity or cardiac symptoms, the presence of clinical risk
factors will determine the need for further cardiac
Table 2 | Studies of methotrexate use during the perioperative period testing. The following cardiovascular risk factors are
part of the ACC/AHA 2007 algorithm: history of ische­
Study Design Patients (on Recommendation:
methotrexate), withhold mic heart disease; history of compensated or previous
n methotrexate heart failure; history of cerebrovascular disease; dia­
before surgery? betes mellitus; and renal insufficiency (serum creati­
Murata et al. (2006)24 Retrospective 124 (60) No nine level ≥2 mg/dl). In the context of perioperative
Bibbo et al. (2003) 61
Retrospective 104 (104) No risk assessment for patients with chronic inflammatory
diseases, we suggest that this list is expanded to include
Jain et al. (2002)62 Retrospective 80 (46) No
a diagnosis of RA, psoriatic arthritis, ankylosing spon-
Grennan et al. (2001) 23
Prospective 388 (88) No dylitis or SLE as additional risk factors, 1,3 on the basis
Carpenter et al. (1996)63 Prospective 32 (13) Yes of the increased risk of cardiovascular events in these
Escalante et al. (1995)64 Retrospective/ 204 (?) No patients.1,10 A 2011 study demonstrated that RA is asso-
prospective ciated with the same risk of myocardial infarction as dia-
Kasdan et al. (1993)65 Retrospective 42 (15) No betes mellitus, and that the risk of myocardial infarction
Sany et al. (1993)66 Prospective 64 (32) No in patients with RA generally corresponds to the risk in
non-RA patients aged 10 years older.10 The European
Perhala et al. (1991) 67
Retrospective 121 (60) No
League Against Rheumatism (EULAR) has recom­
Bridges et al. (1991)68 Retrospective 38 (19) Yes
mended that risk score estimates for patients with RA be
multiplied by a factor of 1.5 to encompass this increased
such as ophthalmologic procedures, superficial derma- risk.11 However, it should be emphasized that there are
tologic procedures, cataract surgery, breast surgery and no published data demonstrating an increased risk of
endoscopy,6,7 will not need extensive pre­operative cardiac perioperative cardiovascular complications in patients
workup, even in high-risk patients. One of the objec- with RA. Two recent abstracts suggest that patients with
tives of preoperative cardiac assessment is to exclude the RA have an increased risk of cardiovascular events when
presence of coronary artery disease that is sufficiently undergoing surgery, but that this risk would be attribut-
serious to warrant some form of interven­tion, even if able to a higher prevalence of traditional cardio­vascular
no noncardiac operation was necessary. Our patient is risk factors and not RA as an independent predictor.12,13
due to undergo an orthopedic procedure classifi­ed as In our scenario, Mrs Doe is not affected by any of
in­termediate risk; therefore, we proceed to step 4. the traditional cardiovascular risk factors listed in the
ACC/AHA 2007 algorithm. However, she does have
Step 4: Assessment of functional capacity a diagnosis of RA, so would meet one criterion for an
Does Mrs Doe have a functional capacity of at least four increased cardio­vascular risk in our modified approach.
metabolic equivalents (METs) without symptoms? This For patients with an increased cardiovascular risk who

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© 2011 Macmillan Publishers Limited. All rights reserved

are planning to undergo surgery of at least intermediate
risk, the algorithm does offer two main options: peri­
operative administration of β-blockers or the use of non-
invasive cardiac stress testing if it might lead to a change
in management.
Step 6: Impact of cardiac testing on management
Would Mrs Doe benefit from noninvasive cardiac stress
testing? This is unlikely, given the evidence that sug-
gests no benefit of preoperative revascularization pro-
cedures for prevention of perioperative ischemic events
in patients with asymptomatic coronary ischemia.5,14 In
fact, the requirements of dual antiplatelet therapy after
stent placement might further complicate the situation
and pose additional risks to the patient if anti­platelet
agents have to be discontinued perioperatively. We
think that the most reasonable approach would be to
omit cardiac stress testing and provide our patient with
gradually titrated perioperative beta blockers.15
Management of disease modifying agents
Substantial controversy has evolved around the ques-
tion of whether immunosuppressive agents should be
discontinued perioperatively. This is owed to the widely
varying perceptions of the perioperative risk associated
with these medications, as well as the conflicting evi-
dence regarding the benefit of withholding them around
the time of surgery. As a result, there is no defined
standard of perioperative care for patients receiving
immunosuppressive therapies. We believe that a careful
risk:benefit analysis should be performed for every
individual patient, taking into account the full spec-
trum of predictors of surgical site infection and wound
healing complications. These include the type and site
of surgery, comorbidities, previous infections and the
type and dose of immuno­suppression. This risk has to
be balanced against the risk of a disease flare after dis-
continuing immunosuppressive drugs, which in itself is
likely to increase the risk of perioperative complications.
In the following section, we will briefly review the evi-
dence for some of the most commonly used immuno­
suppressive agents, and attempt to develop a strategy that
will hopefully help the reader make reasonable decisions
regarding a patient’s perioperative immunosuppressive
drug management.
Prednisone
When looking at studies that compare the immunosup-
pressive potency of anti-inflammatory medications used
in the treatment of rheumatic diseases, prednisone is
associated with one of the highest overall infection rates,
far exceeding the risks associated with most conven-
tional DMARDs and biologics.16 This observation sits
in sharp contrast to the common practice of discontinu-
ing DMARDs at the expense of ‘bridging’ patients with
corticosteroids, or giving ‘steroid preps’ at unnecessarily
high doses perioperatively. In patients who are receiv-
ing chronic corticosteroid therapy, high perioperative
doses are often given out of fear of adrenal gland insuf-
ficiency and the potentially devastating consequences of
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an inade­quate adrenal response in the setting of surgical
stress. Indeed, even moderate doses of glucocorticoids
(approxi­mately 5 mg prednisone daily or equivalent) can
result in depression of baseline and adreno­corticotropic
hormone (ACTH)-stimulated cortisol levels after just
12 weeks of therapy.17 Unfortunately, there are no reli-
able thresholds for corticosteroid doses and duration of
exposure that could help to better quantify the individual
patient risk for adrenal gland insufficiency. As a result,
high-dose steroid preps are given indiscriminately to
patients on long-term steroid therapy at the expense of
overtreating the majority of them.
We believe that steroids should be used more selec-
tively in the perioperative setting in order to minimize
unnecessary exposure and reduce the risk of surgical site
infections and wound healing complications. As there
is a close correlation between the preoperative adreno­
cortical response to ACTH and the hypothalamic–­
pituitary–adrenocortical response to surgery, a simple
ACTH stimulation test can help to clarify whether a
patient needs perioperative corticosteroid supplementa-
tion.18 This test measures serum cortisol concentrations
immediately before and 30 min and 60 min after intra­
venous injections of 250 μg of cosyntropin. A serum cor-
tisol level ≥20 μg at any of the three time points during
the test indicates a normal adrenal response. If test results
indicate adrenal gland insufficiency or if testing cannot
be obtained, we initiate perioperative steroid supplemen-
tation according to the regimen suggested by Coursin
and Wood (Table 1).19
Through this need-based approach to the use of peri-
operative corticosteroids at the lowest dose possible, we
hope to reduce the risk of perioperative infections, pro-
longed hospitalizations and delayed wound healing.20,21
In general, we try to minimize perioperative steroid use
with a target prednisone dose of <10 mg per day (or
equivalent),22 and use ‘stress dose’ steroid treatment only
for patients in whom cosyntropin testing indicates an
impaired adrenocortical stress response.
Methotrexate
Methotrexate is one of the most commonly used
immuno­suppressive drugs for treating a wide variety
of rheumatic diseases. The largest study evaluating the
effects of stopping methotrexate perioperatively was
presented by Grennan et al.23 This prospective cohort
study did not find an increased rate of infection or
wound healing complications in patients who continued
methotrexate therapy perioperatively; risk factors such as
concomitant diabetes or steroid treatment seemed to be
much more important. RA disease activity flares occurred
in 8% of patients who stopped metho­trexate 2 weeks
before surgery and in none of the patients in the control
group (those not on methotrexate). An increased rate of
RA flares in patients who discontinued metho­trexate in
the perioperative period was also noted by other investi-
gators (Table 2).24 These findings are consistent with the
vast majority of studies that have examined the impact
of perioperative methotrexate treatment on surgical
complications. Only two of the smallest studies—one
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Table 3 | Studies of TNF blockers in the perioperative period

Study Design Treatment groups Outcome studied Recommendation
Kawakami et al. Retrospective Anti-TNF vs DMARDs Surgical site infections, Anti-TNF agents more likely to cause
(2010)26 case–control DVT, disease flares SSI and DVT in patients with RA
study undergoing orthopedic surgery
Hirano et al. Retrospective Anti-TNF vs DMARDs Wound healing, febrile No specific adverse effects on
(2010)69 cohort study episodes, infections surgical wounds after orthopedic
operations; might improve
hemoglobin levels
den Broeder et al. Retrospective No anti-TNF vs anti-TNF Infection rates, Perioperative use of anti-TNF agents
(2007)25 parallel cohort withheld before surgery wound healing not an important risk factor for SSI
study vs continuous anti-TNF
Ruyssen-Witrand Retrospective Discontinuation of Complication rates No difference between patients who
et al. (2007)28 anti-TNF at various times discontinued anti-TNF treatment >5
before surgery half lives before surgery and those
who either discontinued nearer to
surgery or did not stop treatment at all
Giles et al. Retrospective Anti-TNF vs no anti-TNF Serious postoperative Significant association between use
(2006)27 infections of anti-TNF agents and postoperative
infections
Talwalkar et al. Retrospective Continuous anti-TNF vs Infections, No evidence that use or stoppage of
(2005)70 anti-TNF stopped before complications anti-TNF agents increases the risk
surgery of infection or complications
Wendling et al. Retrospective Continuous anti-TNF vs Infections, disease No increase in adverse events
(2005)71 anti-TNF stopped before flares associated with continuous anti-TNF
surgery treatment
Bibbo & Goldberg Prospective Anti-TNF vs DMARDs Infections, wound No difference in wound healing or risk
(2004)72 healing of infection
Abbreviations: DVT, deep venous thrombosis; RA, rheumatoid arthritis; SSI, surgical site infection; TNF, tumor necrosis factor.

of them including 13 patients and the other 19 patients
receiving ­methotrexate—came to the conclusion that
methotrexate should be dis­continued peri­operatively.
Furthermore, studies that examined the general infec-
tion risk in patients treated with methotrexate did not
find an increased risk of infections. In summary, there-
fore, we think that it is generally safe to continue metho­
trexate and other DMARDs such as hydroxychloroquine,
a­zathioprine, and sulfasalazine perioperatively.
Biologic agents
Over the past decade, the growing number of protein-
based pharmaceuticals (biologics) has greatly expanded
the armamentarium for the treatment of rheumatic dis-
eases. These agents also represent a new challenge in
the perioperative management of patients who require
surgery. Unfortunately, very little is known about the
possible effects of biologic agents on the risk of surgi-
cal site infections or wound healing complications. So
far, studies have exclusively focused on tumor necrosis
factor (TNF) inhibitors, and their findings have been
inconsistent (Table 3).
Den Broeder et al. 25 performed one of the larger
studies involving a non-TNF-inhibitor comparison
group, and concluded that perioperative continuation
of TNF inhibitors does not pose an important risk for
surgical site infections. This is in contrast to the find-
ings by Kawakami et al.26 and others,27,28 who demon-
strated higher complication rates in patients treated with
TNF blockers. The study by Ruyssen-Witrand et al.28 is
worth noting, as the investigators studied the effect of
discontinuing TNF inhibitors at least 5 half lives prior to
surgery, which is recommended by the British and Dutch
rheumatology practice guidelines.29,30 This study found
no difference in surgical complication rates between
patients who discontinued anti-TNF treatment >5 half
lives before surgery and those who either discontinued
nearer to surgery or did not stop treatment at all. In inter-
preting these results, it is important to keep in mind the
retrospective nature of the data, the varying definitions of
exposure and outcomes studied, the narrow purview
of the type of surgeries performed (mostly ortho­pedic),
the potentially differing effects of TNF blockers at
various stages of wound healing at different anatomical
sites, and so on. Notably, none of these studies examined
other important risks associ­ated with perioperative dis-
continuation of anti-TNF agents, such as disease flares,
delay in rehabilitation, problems with early mobilization
and accompanying costs and morbidity.
In summary, no definite conclusion can be drawn
regarding the effects of immunosuppressive biologic
agents on the risk of surgical site infections and wound
healing complications in patients with rheumatic dis-
eases. The available data for TNF inhibitors are con-
flicting, and no studies have explored perioperative
risks associated with other biologics such as rituximab,
abatacept, tocilizumab or anakinra. However, some
information arising from studies that explored the
general infection risk associated with anti-TNF inhibi-
tors might aid the clinical decision-making process:
randomized controlled trials,31 as well as large obser-
vational cohorts,32,33 suggest a generally increased risk

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of infection in patients treated with anti-TNF agents. In
patients with Crohn’s disease, use of infliximab within
the 3 months prior to surgery is associated with increased
risks of postoperative sepsis, abscess and readmission.34
In addition, a subgroup analy­sis based on data from the
British Biologics Register detected an increased risk of
soft-tissue infections in anti-TNF-treated patients. 32
Thus, it seems reasonable to err on the side of caution
and generally discontinue anti-TNF agents and other bio-
logics perioperatively. In this context, we find it impracti-
cal to withhold agents for 5 half lives prior to surgery 30
in order to achieve complete drug elimination around
the time of surgery: in our experience, this results in an
unacceptable rate of disease flares. Instead, we withhold
one dosing cycle before surgery. This will not result in
complete elimination, but at least a substantial reduction
in drug levels.
Summary
Risk estimates for surgical site infections and wound
healing complications differ widely between individual
patients. Several factors have to be taken into account,
including the type and site of surgery, comorbidities,
history of soft-tissue infections and the type of rheu-
matic disease involved. Thus, the answer to the ques-
tion of whether immunosuppressive therapy should be
discontinued perioperatively will vary according to the
individual clinical scenario: the baseline risk for surgical
site infection and the expected risk reduction achievable
through discontinuation of immunosuppressive agents
will have to be balanced with the likelihood of a disease
flare and its potential consequences.35 In general, we
think it is reasonable to continue therapy with conven-
tional DMARDs such as methotrexate, sulfasalazine,
hydroxychloroquine or leflunomide in the majority of
clinical settings. Most studies, especially those of higher
quality, point towards a neutral effect of these agents.
However, high-risk scenarios will exist in which the base-
line risk for surgical site infections is so high that even
very minor additional risks would result in a substantial
increase in the absolute risk. In these particular situ­
ations, it might be reasonable to stop immunosuppressive
treatments completely, as their possible contribution to
a small and usually negligible increase in risk cannot be
excluded with certainty.
As for the use of biologic agents, we tend to discon-
tinue them perioperatively in most situations. This is not
so much based on evidence linking anti-TNF agents or
other biologics to an increased risk of surgical site infec-
tions or wound healing complications, but rather the lack
of reassuring data. As several studies have suggested an
increased risk of infections associated with anti-TNF
agents in general (and soft-tissue infections in particu-
lar), a cautious approach to perioperative biologic use
seems reason­able. If a potential flare of a patient’s rheu-
matic disease would be unlikely to result in significant
morbidity, we stop therapy for one dosing cycle prior to
surgery and then resume therapy 1–2 weeks after the pro-
cedure. Importantly, in a patient for whom a flare of the
rheumatic disease would result in serious complications,
NATURE REVIEWS | RHEUMATOLOGY
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REVIEWS
the risk:benefit assessment might favor continuation of
biologic therapy. For example, we would continue bio-
logic therapy in a patient with rapidly destructive Still
disease who had just recently achieved improved disease
control with anti-TNF therapy and who required primary
hip replacement.
We believe that limiting perioperative steroid exposure
is one of the most important contributors to minimizing
the medication-related risk of surgical site infections and
wound healing complications. While daily doses <10 mg
prednisone equivalent were found to have a neutral effect
on the overall risk of infection in most studies, peri­
operative use of higher doses should be avoided. ACTH
stimulation testing offers a viable approach to avoiding
unnecessary exposure to high-dose ‘steroid preps’ in
patients who have been receiving chronic steroid therapy
before surgery.
Management of thrombophilia in APS
States of altered coagulation in patients with antiphos-
pholipid syndrome (APS) pose particular challenges in
the perioperative setting. APS can manifest as venous
or arterial thromboembolism, and is an independent
predictor of premature death.36–38 In a meta-analysis of
seven studies in patients with antiphospholipid anti­
bodies but without SLE, the risk of venous thrombo-
embolism (VTE) was increased 11.1-fold compared to
patients without antiphospholipid antibodies.39 Poor
post­operative outcomes and recovery have also been
documented in patients with APS.40,41 Although surgery
increases the risk of thrombosis, bleeding complications
can occur in patients with APS during the perioperative
period as a result of anticoagulation therapy, thrombo-
cytopenia or associated coagulation factor deficiencies,
such as the presence of antiprothrombin antibodies.42
Needless to say, the juxtaposition of the hypercoagulable
state and the need for chronic warfarin therapy poses
a dilemma in perioperative management. Furthermore,
sudden changes in anticoagulation, infection and surgi-
cal stress might trigger the dreaded catastrophic APS,
with widespread thrombosis and dismal outcomes.43
The questions we need to consider when preparing a
patient with APS for surgery are manifold: what is the
individual risk of perioperative thromboembolism with
discontinuation of anticoagulation therapy? Does the
patient require bridging therapy with heparin? Will
the risk of bleeding exceed the risk of thromboembolism
when using bridging therapy? In the absence of study
data that specifically address the issue of perioperative
anticoagulation management in patients with APS, we
highlight the utility of general consensus guidelines from
the American College of Chest Physicians (ACCP)44
and the UK National Institute for Health and Clinical
Excellence (NICE) guidelines for reducing the risk
of thromboembolism.45
Bridging therapy
Several studies have demonstrated that, after a first
episode of thrombosis, patients with persistent anti­
phospholipid antibodies have a higher risk of recurrent
VOLUME 8 | JANUARY 2012 | 37
REVIEWS

Risk stratification

High risk Moderate risk Low risk

■ VTE
■ Atrial fibrillation
■ Mechanical heart valve
■ Severe thrombophilia (APS)
■ Bileaflet aortic valve prosthesis plus at least
one of the following: Atrial fibrillation, prior
CVA/TIA, hypertension, diabetes mellitus,
CHF or age >75 years
■ Atrial fibrillation with CHADS2 score 3 or 4
■ VTE within previous 3–12 months,
recurrent VTE, non-severe thromphophilia
or active cancer
■ Bileaflet aortic valve without atrial
fibrillation or stroke risk factors
■ CHADS2 score 0–2
■ Single VTE >12 months ago and no
other risk factors

Recommended bridging anticoagulation therapy

■ Stop warfarin 5 days ahead of
surgery
■ Start therapeutic-dose subcutaneous
LMWH or intravenous UFH
■ Stop LMWH and UFH 24 h and 4 h
before surgery, respectively
■ Check INR on the morning of surgery
■ (Grade 1C)
■ Bridging anticoagulation with
therapeutic-dose or low-dose
subcutaneous LMWH or therapeutic-
dose intravenous UFH preferred over no
bridging during temporary interruption
of warfarin therapy
■ (Grade 2C)
■ Bridging anticoagulation with
low-dose subcutaneous LMWH or no
bridging preferred over bridging with
therapeutic-dose subcutaneous
LMWH or intravenous UFH
■ (Grade 2C)

Figure 2 | A practical approach to risk stratification in patients requiring anticoagulation in the perioperative period. 44 High-
risk VTE is defined as a deficiency of protein C or protein S, the presence of antithrombin or antiphospholipid antibodies, or
multiple abnormalities. High-risk atrial fibrillation is defined as VTE, stroke or transient ischemic attack within the last
3 months, or rheumatic valvular heart disease. Mechanical heart valve defined as a CHADS 2 score of 5 or 6, older aortic
valve prosthesis, stroke or transient ischemic attack within the last 6 months, and any mitral valve prosthesis.
Abbreviations: APS, antiphospholipid antibody syndrome; CHF, congestive heart failure; CVA, cerebrovascular accident; INR,
International Normalized Ratio; LMWH, low-molecular-weight heparin; TIA, transient ischemic attack; UFH, unfractionated
heparin; VTE, venous thromboembolism. Adapted from Douketis, J. D. et al. Chest 133 (6 Suppl.), 299S–339S (2008) with
permission from the American College of Chest Physicians ©.

thrombosis compared with patients without antiphos-
pholipid antibodies.36,40,41,43,46 This risk is appreciable
even when these patients are receiving long-term antico-
agulation therapy.47 Appropriately, the ACCP guidelines
classify indivi­duals with APS as high-risk patients for
peri­operative thrombosis, and likely to require bridg-
ing therapy (the administration of a short-acting anti-
coagulant, such as subcutaneous low-molecular-weight
heparin [LMWH] or intravenous unfrac­tionated heparin
[UFH] during the peri­operative period until resumption
of oral anticoagulants). Similarly, the NICE guidelines
state that if the risk of VTE outweighs the risk of bleed-
ing, such as in individuals with known thrombo­philias,
then the offer of LMWH or UFH can be cautiously con-
sidered.45 However, even in patients with a high risk of
thrombotic events, the risk of bleeding associated with
bridging therapy might exceed the risk of thrombosis.
Thus, a differen­tiated assessment that balances the risk
of thrombo­embolic events with the risks of a major bleed
is required. Factors that influence these risks include
patient-specific factors (such as age, smoking, the pres-
ence of thrombophilia, renal or hepatic disease, medica-
tions used and the presence of thrombo­cytopenia) and
surgical factors (such as the type and duration of surgery,
the associated risk of blood loss or thrombosis and
immobilization).45,48,49 Well-established risk factors for
thrombosis can coexist in patients with APS. 50 Several
models have been developed to assist in assessing bleed-
ing risk. The type of surgical procedure has a bearing
on the intensity of anticoagulation to be used and the
need for cautious anticoagulation in the post­operative
period. For example, bleeding risk is increased in coro-
nary artery bypass and heart valve replacement surgery,
intracranial or spinal surgery, aortic aneurysm repair,
peripheral artery bypass, and other major vascular sur-
geries, whereas major orthopedic surgery, such as hip
or knee replacements, and procedures involving the
prostate, bladder or other pelvic organs increase the risk
of thrombosis.44
In most patients, the pendulum is likely to swing in
favor of bridging therapy. Only in patients who undergo
procedures with a high risk of bleeding, and in whom
postoperative bleeds would have potentially devastat-
ing consequences (such as spinal surgery), we tend to
withhold anticoagulation completely. Once a decision to
utilize bridging therapy has been made, we suggest stop-
ping warfarin 5 days ahead of surgery and restarting it
24–48 h after surgery if hemostasis is achieved.44 ACCP
recommendations for bridging anticoagulation in high-
risk individuals suggest the use of therapeutic-dose sub-
cutaneous LMWH or intravenous UFH (grade 1C), with
a preference for LMWH over UFH (grade 2C) for con-
siderations of cost and ease of use. A practical approach
to risk stratification in patients requiring anticoagula-
tion during the perioperative period, adapted from the
ACCP guidelines, is shown in Figure 2.44,45 The adminis-
tration of a rapidly acting anticoagulant, such as LMWH
or UFH, after invasive procedures increases the risk of
bleeding, notably with the use of higher doses and rapid
resumption after surgery.51 UFH, if used, can be resumed
during the initial 24 h after surgery.52 A higher bleeding
risk was noted when heparin was administered closer to

38 | JANUARY 2012 | VOLUME 8  www.nature.com/nrrheum

© 2011 Macmillan Publishers Limited. All rights reserved
 REVIEWS

surgery, and was reduced by delaying the administration
by 48–72 h after surgery or avoiding its use altogether in
the postoperative period.53,54 Modalities such as intermit-
tent pneumatic compression have been shown to reduce
the risk of thromboembolism, but their utility in patients
with APS is unknown.55
Use of NSAIDs and antiplatelet agents
Patients with rheumatic diseases are often treated with
NSAIDs or antiplatelet agents, which confer increased
risks of perioperative bleeding. A 1.5-fold increase in
the risk of perioperative bleeding was associated with
aspirin continuation in patients undergoing noncardiac
surgery (with a 3.4-fold increase when administered in
combination with clopidogrel).56,57 Typically, in patients
at low risk of perioperative cardiovascular events and in
whom temporary interruption of these drugs would not
be expected to greatly increase this risk, they should be
withheld 7–10 days before surgery to avoid any effect
during the procedure.44 In high-risk patients, such as
those who have recently undergone stent placement,
discontinuation of antiplatelet therapy would result in
an unacceptable risk of cardiac events that would need
to be weighed against the risk of bleeding.44,58,59 We advo-
cate a multidisciplinary approach involving the cardiolo­
gist, anesthetist and hematologist in this regard.59 For
patients receiving NSAIDs and cyclo-oxygenase 2 inhibi-
tors, these drugs—being reversible inhibitors of cyclo-­
oxygenase activity—should be withheld 5 half-lives
before surgery to avoid all antiplatelet effects.60
Summary
Patients with APS who are predisposed to vascular
throm­b otic events are at an added risk in the peri­
operative period. By identifying all the potential risk fac­
tors, instituting a clear perioperative strategy to stop and
restart pharmacological antithrombotic interventions,
keeping periods without anticoagulation to a minimum
and maintaining close observation for thrombotic or
bleeding complications could help in managing this con-
dition. Though the above guidelines are not exhaustive
and can not possibly account for all the potential factors
that play into the decision-making process for the indivi­
dual patient, we feel that they form a decision-support
system for assessing the risk of develop­ing thrombo­
embolism weighed against the increased risk of bleeding
caused by pharmacologic prophylaxis.
Conclusions
With only sparse and often contradictory evidence avail-
able, the perioperative care for patients with rheumatic
diseases will always be a highly individualized process.
We have tried to emphasize the challenges and point
out factors that should influence this decision-making
process. Thus, our Review does not suggest a ‘one size fits
all’ approach, but offers a decision-support system that
we hope will aid rheumatologists when preparing their
patients for surgical procedures.
Review criteria
MEDLINE, EMBASE and SciVerse Scopus databases
were searched for English-language articles published
between 1980 and 2011 with the subject headings
“antiphospholipid antibody syndrome”, “antirheumatic”,
“methotrexate”, “disease modifying”, “adalimumab”,
“azathioprine”, “hydroxychloroquine”, “etanercept”,
“infliximab”, “leflunomide”, “rituximab”, “sulfasalazine”,
and “disease modifying agents, DMARD, antirheumatic,
rheumatic diseases”, and the text words “preoperative
care/period”, “intraoperative period”, “postoperative
complications related to healing, bleeding, infections”,
“adverse effects in surgical procedures”, “specific
complication of thrombosis”, and “complications caused
by anticoagulants in the perioperative period”. Case
reports and case series were excluded. Clinical trials,
cohort studies, randomized controlled trials, prospective
studies, retrospective studies, and international meeting
presentations were included.

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Acknowledgments
This article includes the schema presented by
Dr Howard Weitz and Dr Mark Crowther at the 2010
ACR/ARHP Annual Scientific Meeting (https://
acr.peachnewmedia.com/store/streaming/stream-
details.php?mode=stream&id=244925#topic20653).
Author contributions
Both authors contributed equally to researching data
for the article, discussing the content, writing and
review/editing of the manuscript before submission.
VOLUME 8 | JANUARY 2012 | 41