Chapter 12 – Connective Tissue Disease

Chapter 12 Connective Tissue Disease

Enjarn Lin and Stuart Hastings

Key Points

  • Connective tissue disorders comprise a number of diseases sharing an autoimmune origin. Disease expression is varied, as is the clinical course.

  • Patients with connective tissue disorders are at risk for increased perioperative morbidity and mortality.

  • Treatment strategies aim to relieve symptomatology and slow disease progression while limiting treatment-related complications. Common therapeutic agents include glucocorticoids and biologic and non-biologic disease-modifying agents.

  • The wide-ranging clinical effects and multisystem involvement of connective tissue diseases and treatment-related complications present a significant challenge for the perioperative physician. The increased risk of cardiovascular and respiratory co-morbidity calls for collaborative specialised evaluation and care.

  • Detailed airway assessment, planning and appropriate investigations are necessary, particularly in patients with rheumatoid arthritis and ankylosing spondylitis.

  • The lack of consensus and paucity of guidelines regarding perioperative care mandates an individualised approach to patients with connective tissue disorders.

  • Immunosuppression is essential for successful organ transplantation, but the balance between under- and over-immunosuppression is difficult. Rejection and organ dysfunction are the hallmarks of under-immunosuppression, while the undesired consequences of immunodeficiency are infection in the short term and cancer in the long term.

  • Many patients with cancer will display little physiological derangement, while some may have widespread multisystem disease due to the disease process or its treatment with anti-neoplastic agents. The rapid pace of change in oncological treatments and the availability and use of novel agents have resulted in a lag in awareness in the anaesthetic literature.


The wide-ranging effects of connective tissue diseases create a significant challenge for the perioperative physician. Multisystem involvement, treatment-related organ dysfunction and a heightened risk of cardiovascular disease call for collaborative specialised evaluation and care. The complex challenge of managing such patients in the perioperative period is perhaps reflected by the lack of consensus and paucity of guidelines directing care in this phase.

Rheumatoid Arthritis


Rheumatoid arthritis (RA) is a chronic, inflammatory, multisystem disease characterised by an erosive, symmetrical polyarthropathy. Worldwide prevalence is estimated to be 1 per cent and is three times more common in women than men (Fombon and Thompson, 2006; Samant, Shoukrey and Griffiths, 2011). The pathogenesis of this autoimmune process is multifactorial. Environmental and genetic factors are implicated, the most significant being the human leukocyte antigen (HLA) major histocompatibility (MHC) genes. Inter-individual variability in the course of the disease and its extent is substantial (McInnes and Schett, 2011)

Synovial inflammation results in pain, swelling and destruction in peripheral joints, with axial and central joint involvement occurring in 20–50 per cent of patients. Presentation of extra-articular manifestations is variable, but may be extensive and involve ocular, dermatological, respiratory, cardiovascular, renal, neurological and haematological systems. Systemic disease risk is enhanced in rheumatoid factor (RF) and anti-citrullinated peptide antibody (ACPA) positive patients, as well as in those who smoke (McInnes and Schett, 2011). Diagnosis is based on fulfilment of criteria established by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) in 2010 ( Patients with at least one joint with definite clinical synovitis, and with synovitis that is not better explained by another disease, with a score of >6/10 are considered to have definitive RA (Table 12.1).

Table 12.1 American College of Rheumatology and the European League Against Rheumatism classification criteria for rheumatoid arthritis.

Criteria Score
A: Joint involvement
1 large joint 0
2–10 large joints 1
1–3 small joints (+/- large joint involvement) 2
4–10 small joints (+/- large joint involvement) 3
>10 small joints (at least 1 small joint) 5
B: Serology (at least 1 test result)
Negative RF and negative ACPA 0
Low-positive RF or low-positive ACPA 2
High-positive RF or high-positive ACPA 3
C: Acute-phase reactants
Normal CRP and normal ESR 0
Abnormal CRP or normal ESR 1
D: Duration of symptoms
<6 weeks 0
>6 weeks 1

Legend: RF=rheumatoid factor, ACPA= anti-citrullinated peptide antibody, CRP= C-reactive protein, ESR= erythrocyte sedimentation rate

Prompt diagnosis and early implementation of therapy designed to halt disease progression is the cornerstone of management. Disease-modifying anti-rheumatic drug (DMARD) therapy reduces joint erosion and flare frequency with proven mortality benefit (Samanta et al., 2011). These agents are described in further detail in what follows. Non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids are utilised for symptom relief and control of natural exacerbations (disease ‘flares’). Surgical management is employed as a pain management strategy or to improve joint function and integrity.

Perioperative Management

The potential for involvement of multiple systems to varying degrees of severity makes the preoperative evaluation of the patient with rheumatoid arthritis particularly challenging. The fundamental principles apply; delineation of the extent of the disease involvement, severity of systemic manifestations and implications and adverse effects of treatment. Targeted inquiry to the key systems most likely to impact preoperative care provide the starting point.


The Cervical Spine

Cervical spine disease may influence airway management and patient positioning during anaesthetic care. The cervical spine of the rheumatoid arthritis patient may be paradoxically hyper-mobile and unstable, or immobile with a concomitant spondylitic process. Difficulties in the process of securing the airway, the potential to produce catastrophic neurological injury or post-operative respiratory complications must be at the forefront of preoperative planning. Myelopathy, quadriplegia and sudden death are thankfully rarely encountered outcomes (Samanta et al., 2011).

Atlanto-axial subluxation and subaxial subluxation are the most commonly encountered forms of cervical spine involvement. Quoted incidence of atlanto-axial involvement is variable across the literature, but may be as high as 61 per cent, with subaxial disease thought to be in the range of 9–43.6 per cent (Krause and Matteson, 2014). A high index of suspicion should be held for seropositive patients of older age having a high disease burden and level of disability, those with long-standing or poorly controlled illness, corticosteroid therapy and rheumatoid nodules (Bissar et al., 2013).

Atlanto-axial subluxation is most commonly anterior (80%) or posterior (5%) (Samanta et al., 2011). The anterior movement of the C1 vertebrae on C2 is a consequence of transverse ligament attenuation and exacerbated by neck flexion. Direct laryngoscopy is usually permissible in this cohort. Posterior C1 displacement is secondary to odontoid peg erosion and precipitated by neck extension and exacerbated by direct laryngoscopy (Fombon and Thompson, 2006). Catastrophic neurological injury may result from direct spinal cord compression and/or impaired cerebral perfusion from compromised vertebral artery flow. Subaxial subluxation occurs below the C2 vertebrae and is less common than atlanto-axial instability.

Clinical detection of cervical spine pathology requires a high index of suspicion as symptoms correlate poorly with disease prevalence and severity, and may overlap with features attributable to the underlying condition. Myelopathy, occipital or neck pain and radicular symptoms should serve as a red flag; however, alarmingly up to 50 per cent of patients may be asymptomatic. Despite these statistics, anaesthetic management has been undertaken in an unmodified fashion regardless of the level of instability without adverse consequences (Samanta et al., 2011). The decision to implement radiological investigation must consider the potential delay these investigations will impart on further care, and the possibility of inadequate or non-diagnostic information, which will be of little use to altering management strategies.

Plain imaging of the cervical spine in neutral and in flexion and extension may be utilised for screening; however, MRI may be required to delineate the severity of pathology should plain films be abnormal or fail to detect an abnormality in the setting of clear clinical symptoms. Significant pathology requires management in conjunction with rheumatology and surgical units.

Vigilance and care are required to avoid making a dangerous but clinically silent condition potentially worse, or even fatal. Ascertaining the patient’s range of neck movement and avoidance of these extremes should be attempted, but may be challenging in the clinical setting. Alternative methods to facilitate intubation with minimal cervical spine displacement, including video or fibre-optic laryngoscopy, may be considered. Use of cues to alert staff to the potential of cervical spine disease such as soft collars may be useful. Positioning such that the cervical spine is supported without anterior cranial displacement is advocated (Samanta et al., 2011). Diligence in maintaining adequate spinal cord perfusion while under anaesthesia is obligatory; however, the use of specific spinal cord monitoring has not been shown to be of benefit.

The Temporomandibular Joint

Disease involvement of the temporomandibular joint may manifest as reduced mouth opening and compound difficulties encountered in the process of airway instrumentation in the setting of cervical spine disease. Impaired mouth opening impedes direct visualisation of laryngeal structures and increases the degree of intubation difficulty. Iatrogenic subluxation may result from aggressive jaw manipulation and care must be taken to avoid exceeding the natural range of movement during airway manoeuvres.

The Cricoarytenoid Joints

Cricoarytenoid joint rheumatoid arthritis is frequently encountered in up to 80 per cent of patients, but as with cervical spine disease, patients may be asymptomatic or intermittently so. Hoarseness, sore throat, stridor, dysphagia and the persistent sensation of a mass in the throat should alert the clinician to this pathology. Involvement of these structures creates a relative stenosis and predisposes the patient to iatrogenic injury from airway instrumentation in the form of dislocation, erosion and oedema (Samanta et al., 2011). These consequences most commonly manifest as respiratory distress or potentially fatal airway obstruction requiring surgical airway salvage in the post-operative period. Preoperative clinical evaluation in the form of naso-endoscopy by an ENT surgeon, together with radiological evaluation, should be considered to arm the clinician with detailed information and allow appropriate planning.

Identification of cricoaretynoid dysfunction should lead to potential modification of the airway plan in order to minimise the potential for worsening this condition. These may include utilising regional techniques, under sizing the endotracheal tube, selecting an atraumatic method of intubation or foregoing an infra-glottic airway entirely. However, cases of aggravation of laryngeal rheumatoid involvement have been reported with the use of supraglottic airway devices (Miyanohara et al., 2006). Vigilance at the time of extubation is particularly important. This should take place in an environment equipped to provide expertise and equipment capable of rapidly re-instituting a definitive airway. Close and prolonged observation is required to ensure catastrophic post-operative respiratory obstruction can be promptly identified and managed. Severe cases of the disease may warrant a prophylactic tracheostomy.

The Cardiovascular System

Rheumatoid arthritis predisposes individuals to a heightened risk of cardiovascular disease including ischaemic heart disease, cardiac failure and arrhythmias. Cardiovascular system involvement is responsible for the elevated mortality rate seen in this population. The theorised reasons behind the accelerated atherosclerosis include altered vascular elasticity, deranged lipid kinetics, chronic prothrombotic tendency and therapy-induced insulin resistance (Samanta et al., 2011). A thorough preoperative assessment is paramount in such patients, in order to both accurately stratify and reduce the risk of a major adverse cardiac event. It is a prime opportunity to implement appropriate behavioural modifications and pharmacotherapy which may have been overlooked.

Ischaemic heart disease does not produce classic symptoms of angina in patients with rheumatoid arthritis. Silent ischaemia and myocardial infarction are between 10–50 per cent more common (Dala, Ibrahim and Taha, 2012), and, alarmingly, sudden cardiac death may be the primary manifestation. Therefore a high index of suspicion is required when evaluating these patients. Assessment should take place in accordance with the AHA/ACC guidelines for the cardiac patient undergoing non-cardiac surgery, bearing in mind the patient’s higher pre-test probability and the limited utility of investigations requiring physical exertion in the patient with significant mobility restrictions (Fleisher et al., 2014).

Cardiac failure occurs on account of microvasculitis and manifests as myocarditis and/or pericarditis (Yancy et al., 2013). Both systolic dysfunction and heart failure with preserved ejection fraction are more common findings compared with the general population in patients with rheumatoid arthritis (Bhatia et al., 2006). The mitral valve is the most commonly affected valve, closely followed by the aortic. Lesions of valve incompetence are frequently encountered and may be contributory to cardiac failure.

Causes of arrhythmia relate to ischaemia, rheumatoid nodule-induced conduction abnormalities, amyloidosis or cardiac failure. Right bundle branch block is seen in up to 30 per cent of patients secondary to AV node infiltration (Seferovic 2006). Heightened sympathetic nervous system output predisposes to tachyarrhymias, and QT interval abnormalities are frequent (Voskuyl 2006).

The capacity of rheumatoid arthritis to comprehensively involve the cardiovascular system means these patients have a heightened preoperative risk for cardiac events. Vigilant assessment, risk reduction as appropriate and consideration for high level post-operative surveillance are warranted.

The Respiratory System

Both the underlying disease and the pharmacology employed in its management may impact the respiratory system, and like the cardiovascular system, comprehensive involvement is possible but fortunately rare. Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a spectrum of disease with variable presentation and aetiology, but is likened to the idiopathic interstitial pneumonias (IIP). Pulmonary side effects from disease treatment, in particular methotrexate, may be superimposed. A restrictive ventilatory defect is the most likely clinical manifestation, which may be compounded by disease involvement of the costochondral joints resulting in reduced chest wall compliance or impaired respiratory muscle function (Fombon and Thompson, 2006). Impaired gas exchange (reduced DLCO) may be seen on pulmonary function tests.

Preoperative evaluation includes ascertaining respiratory system limitation and quantifying this with investigations, particularly in the setting of deteriorating functional capacity or recurrent infection. Avoidance of general anaesthesia and opioid minimisation strategies are considerations in patients with borderline function and minimal reserve. Adequate analgesia to allow rapid return to baseline preoperative function and secretion clearance is paramount. Post-operative care should include avoidance of excessive intravenous fluid administration, chest physiotherapy, thromboembolic prophylaxis and utilisation of appropriate post-operative monitoring to allow early intervention should deterioration ensue.

The Renal System

Therapy-related renal impairment is more frequent than dysfunction on account of the disease itself. NSAIDs, gold, cyclosporine and methotrexate are contributory. Renal protection strategies in the preoperative period include maintaining adequate perfusion and intravascular volume and avoidance of additional nephrotoxins.

The Haematological System

Anaemia is frequently encountered and has multiple contributing causes. The normocytic, normochromic anaemia of chronic disease may be superimposed on iron deficiency anaemia attributable to chronic NSAID-induced gastritis. Malabsorption and malnutrition may produce a B12-deficient state. Consideration of preoperative iron supplementation and erythropoiesis-stimulating agents should be considered prior to surgery.

Rheumatoid arthritis induces a prothrombotic state. Elevated D-dimer and fibrinogen are frequently encountered (Samanta et al., 2011). The risk of thromboembolism is substantial in the perioperative period and heightened in the setting of impaired mobility. Chemical thromboprophylaxis should be a strong consideration, as should anaesthesia techniques that facilitate an early return to mobility and engagement in post-operative physiotherapy.

Pharmacological Therapy

Pharmacological therapy in rheumatoid arthritis is directed at reducing symptoms related to inflammation to maintain quality of life and function, and to prevent ongoing joint destruction. DMARDs form the mainstay of therapy together with non-steroidal anti-inflammatory drugs (NSAIDs) and conventional and biologic disease-modifying anti-rheumatic drugs. While glucocorticoids have a role in treatment, they are no longer primary agents and instead used where possible on an as-needed basis to control disease flares, in the lowest possible dose for the shortest amount of time.

Non-steroidal anti-inflammatory Drugs

NSAIDs prevent the conversion of arachidonic acid to prostaglandins, prostacyclines and thromboxanes by targeting the cyclooxygenase activity of the enzyme prostaglandin synthetase. Agents may be non-selective for the isoforms COX-1 and 2, or specifically target the inducible COX-2 isoforms. COX-1 products have protective effects on the GI tract, and are involved in normal haemostasis and renal homeostasis while COX-2 products arise at the site of inflammation. The half lives of these agents are listed in table 12.2.

Table 12.2 Half life of non-steroidal anti-inflammatory drugs.

NSAIDs Half-life (hours)
Ibuprofen 1.6–1.9
Naproxen 12–15
Diclofenac 2
Indomethacin 4.5
Celecoxib 11
Meloxicam 15–20

Legend: NSAID= non-steroidal anti-inflammatory drugs

Patients should be screened for potential side effects of these agents, including peptic ulceration, renal impairment, electrolyte derangement (hyperkalaemia and hyponatraemia), fluid retention and hepatic dysfunction. Potential end organs affected should be preoperatively biochemically assessed. Caution with co-administration of other nephrotoxins is required, as well as judicious fluid management in the intraoperative period. A gastro-protective agent should be co-prescribed on recommencement post-operatively, particularly in the setting of surgical stress and glucocorticoid use.


While no longer first-line therapy, glucocorticoids may be used in patients when commencing DMARD therapy, to gain control of flares or in severe disease. Increased doses in the preoperative period may be instituted to cover the cessation of DMARDs. The major concern in the preoperative period is suppression of the hypothalamic-pituitary-adrenal axis and subsequent endogenous cortisol deficit in the face of stress. Other side effects include impairment of the immune response, steroid-induced glucose intolerance, hypertension, fluid retention and dermal atrophy. Preoperative assessment should target control of hypertension and blood sugar levels with specialist input employed as required. Strict procedural asepsis must be maintained and antibiotic prophylaxis administered intraoperatively. Care with positioning, when using non-invasive blood pressure cuffs, as well as tape application and removal, is required to prevent skin tears.

Disease-Modifying anti-Rheumatic Drugs

Conventional DMARDs

Conventional or non-biologic DMARDs are the mainstay of therapy in patients with rheumatoid arthritis. Their mechanism of action differs from agent to agent, whether directed at cellular immune function or interference with cytokine action. They consist of anti-malarials and immunosuppressants.

Methotrexate is one of the fundamental agents in the management of rheumatoid arthritis. It is a competitive inhibits of dihydrofolate reductase and interferes with DNA synthesis by reducing purine and pyrimidine supply in rapidly dividing cells. It has a dose-dependent half-life of 3–15 hours. Side effects may include myelosuppression, renal impairment, hepatic impairment and cirrhosis and pulmonary toxicity. Biochemical evaluation in the form of a full blood count, urea, creatinine and electrolytes and liver function tests should be performed for screening of these manifestations. History and clinical examination should assess for pulmonary involvement.

Hydroxychloroquine, leflunomide and sulphasalazine are other DMARDs which may be utilised. Less commonly used agents in rheumatoid arthritis include cyclophosphamide, azathioprine, cyclosporin and mycophenolate mofetil. Their mechanism of action, half-life and side effects are described in Table 12.3. The presence of such side effects should be elicited and managed preoperatively.

Table 12.3 Conventional disease-modifying anti-rheumatic drug.

Drug Mechanism of action Half-life Side effects
Hydroxychloroquine dentritic cell toll-like receptor inhibitor 1–2 months cardiotoxicity (cardiomyopathy)
prolonged QT
skeletal myopathy
ophthalmologic toxicity
Leflunomide prevents DNA synthesis by inhibiting pyrimidine synthesis, reducing lymphocyte proliferation 14–18 days hepatic toxicity
Sulphasalazine immunomodulation by incompletely understood mechanisms 8 hours bone marrow suppression
Steven Johnson syndrome
Cyclophosphamide prevents DNA synthesis by forming inter-strand cross links 3–12 hours myelosuppression
fluid retention and hyponatraemia
pulmonary toxicity
pseudocholinesterase inhibition
haemorrhagic cystitis
Azathioprine prevents DNA synthesis via enzyme inhibition 3–5 hours myelosuppression
may decrease non-depolarising muscle relaxant efficacy
Cyclosporin calcineurin inhibitor interferes with T cell production 8 hours nephrotoxicity
hepatic dysfunction
Mycophenolate mofetil inhibits nucleoside synthesis and lymphocyte production 12–17 hours gastrointestinal disturbance

Legend: DNA=deoxyribonucleic acid

Some agents may have interactions with anaesthetic agents, particularly muscle relaxants. Altered dose strategies or alternatives should be considered.

Biologic DMARDS are classified as tumour necrosis factor (TNF) inhibitors or non-TNF inhibitors. The non-TNF inhibitors impact the action of interleukin (IL)-1, IL-6 to affect T and B cell activity. Descriptions of these are outlined in Table 12.4. The main side effects associated with these agents is an increased susceptibility to infection.

Table 12.4 Biologic disease-modifying anti-rheumatic drug.

Drug Mechanism of action Half Life
Infliximab monoclonal anti-TNF alpha antibody 10 days
Adalimumab monoclonal anti-TNF alpha antibody 10–20 days
Etanercept TNF alpha receptor antagonist 3.5–5.5 days
Certolzumab Fab fragment of monoclonal anti-TNF alpha antibody 14 days
Golimumab monoclonal TNF alpha antibody 7–20 days
Anakinra IL-1 receptor antagonist 4–6 hours
Abatacept T cell inhibitor 13 days
Tocilizumab IL-6 receptor antagonist 11–13 days
Rituximab B cell inhibitor 18–22 hours
B cell effects up to 6 months

Legend: TNF=tumour necrosis factor , IL=interleukin

Perioperative Management of Pharmacological Agents

The anti-platelet effects of NSAIDs means preoperative cessation for three half-lives prior to surgery is advisable, and longer in patients with impairment of organs involved in the drug metabolism and clearance. While COX-2 specific agents do not pose an increased bleeding risk, this isoform likely has a role in wound healing and renal function, and should therefore be continued with caution. The increased risk of myocardial events with these agents should be considered, however, balanced against the potential sympathetic nervous system activation and inflammatory stress of increased pain.

The major concern in the preoperative period in the patient exposed to long-term corticosteroid use is suppression of the hypothalamic-pituitary-adrenal axis and subsequent endogenous cortisol deficit in the face of stress. Common practice is to supplement patients undergoing more than minor surgical procedures who have been maintained on more than 5 mg of prednisolone per day. This practice is not particularly evidence based and may predispose factors to the consequences of excess glucocorticoid including wound infection and hyperglycaemia. Nonetheless, this is prudent in major surgery with rapid dose tapering to baseline requirements over the following 24–48 hours.

The potent immunosuppressant effect of the conventional and biologic DMARDs creates a significant challenge in the preoperative period. The decision to discontinue or maintain administration of these agents in the preoperative period is a balance between the risk of a perioperative disease flare versus a potential heightened risk of post-operative infection in an already high-risk population. Infection increases morbidity and even mortality, and almost certainly increases the length of hospital stay, while disease flares limit compliance with rehabilitation and impair return to premorbid function.

The paucity of evidence to guide clinicians in this scenario has led to disparate recommendations from international rheumatology bodies. A recent review of the literature by Goodman has provided some insight (Goodman, 2015). Methotrexate is the most well-researched agent in this situation, and the weight of evidence indicates continuation in the preoperative setting appears safe. Less robust data are available for agents such as hydroxychloroquine, azathioprine and sulfasalazine; however, small studies have not demonstrated an association with agent continuation and perioperative infection. Continuation of these agents is therefore advocated. The propensity of these agents to cause renal dysfunction and leukopenia warrants increased clinical and biochemical surveillance for these eventualities. Conflicting data pertaining to the preoperative use of leflunomide mean no clear recommendation can be drawn. Discontinuation preoperatively is therefore reasonable.

Patients receiving TNF alpha inhibitors in the preoperative period are at an increased risk of surgical site infection (Goodman, 2015). No firm data are available to make recommendations on the optimal time for cessation and reinstitution; however, Goodman advocates one and a half times the dosing interval. Tocilizumab may predispose to impaired wound healing and infection, as well as mask the clinical manifestations of infection. A high index of suspicion is required in these patients, and preoperative cessation of treatment is prudent (Momohara et al., 2013). Similarly, rituximab can be continued perioperatively, but with increased vigilance for infective symptoms. If elective, non-urgent surgery is planned, it may be advisable to wait until B cell levels have been replenished in the circulation (Goodman, 2015).

Anakinra and abatacept have little scientific information to recommend preoperative management and as such, cessation of treatment preoperatively is a reasonable cautionary approach.

It seems reasonable to reinstitute these therapies when there is established evidence of near complete wound healing. Many clinicians suggest once foreign material such as sutures is removed is an appropriate time. Like all management decisions pertaining to complex and conflicting choices, involvement of specialist expertise should be sought and a decision made in a multidisciplinary context.

Systemic Lupus Erythematosus


Systemic lupus erythematosus (SLE) is a chronic autoimmune connective tissue disorder that encompasses a broad spectrum of disease severity and organ involvement. The potential for significant derangement of multiple systems together with the inherent complexities of the management regimes of these patients poses a challenge in preoperative care. SLE has a significant female bias (9:1) (Ben-Menachem, 2010), and the 10-year survival is approximately 70 per cent (Pons-Estel et al., 2010), with disease prevalence between 20–50 per 100,000 population (Tsokos, 2011). Pathogenesis is multifactorial and both inflammatory and immune-mediated sequelae contribute to a heterogeneous pattern of presentation.

Pathogenesis and Diagnosis

The manifestation of the disease is determined by the complex interplay of a diverse range of factors and produces autoimmunity against particular cellular components. Complex factors interact in the pathogenesis of SLE to produce a state of immune dysregulation with loss of immune tolerance to self-antigens and production of a heterogeneous group of autoantibodies. Anti-nuclear antibodies (ANA) together with those directed at cell membrane and cytoplasmic constituents are most prevalent. The disease course consists of periods of exacerbation and remission.

Genetic predisposition is mostly related to multiple gene variants, with immune response–related genes strongly implicated and major histocompatibility complexes playing a role. Environmental factors such as smoking, UV light exposure and Epstein-Barr virus have been linked. Additionally, immune cells and cytokines demonstrate atypical behaviour in patients with SLE, and may be abnormal in both quantity and function. A dysfunctional method of antigen presentation, exaggerated amplification of the immune response and an enhanced lifespan of immune cells and constituents are just some of the potential factors at play (Ben-Menachem, 2010; Tsokos, 2011). Auto-reactive T and B cells generate autoantibodies, immune complexes and cytokines responsible for inflammation and immune-mediated organ damage (Cozzani et al., 2014).

Diagnosis of SLE is based on clinical symptoms, signs and immunological testing. The Systemic Lupus International Collaborating Clinics (SLICC) group has developed diagnostic criteria to aid in the diagnosis of SLE (Petri et al., 2012) (Table 12.5).

Table 12.5 Systemic Lupus International Collaborating Clinics criteria for the diagnosis of systemic lupus erythematosus.

SLICC criteria
4 of 17 criteria (at least 1 clinical and 1 immunological cumulatively present, OR biopsy-proven SLE)
Clinical criteria
Acute cutaneous lupus lupus malar rash, toxic epidermal necrolysis variant OR subacute cutaneous lupus
Chronic cutaneous lupus classic discoid rash OR discoid lupus/lichen planus overlap
Non scarring alopecia diffuse thinning or hair fragility
Oral or nasal ulcers
Joint disease synovitis of 2 or more joints OR
tenderness of 2 or more joints with morning stiffness
Renal disorder elevated urine protein-creatinine ratio OR
red cell casts
Neurologic disorder seizures, psychosis, mononeuritis multiplex OR
acute confusional state
Haemolytic anaemia
Leukopenia or lymphopenia
Immunological criteria
ANA level above reference range
Anti-dsDNA above reference range
Anti-Sm antibody to Sm nuclear antigen
Antiphospholipid positive lupus anticoagulant or false positive rapid plasma regain or high anticardiolipin titre
Low complement low C3, C4 or low CH50
Direct Coombs’ test positive test

Legend: SLICC = Systemic Lupus International Collaborating Clinics, SLE = Systemic Lupus Erythematosus, ANA = antinuclear antibodies, DNA = deoxyribonucleic acid

Simultaneous or sequential fulfilment of 4 of 11 diagnostic criteria is required in order to formalise the diagnosis. Serology plays a role in the diagnosis, but there is no single fundamental marker offering diagnostic, prognostic or therapeutic information. Anti-smooth muscle antibodies and anti-double-stranded DNA (anti-dsDNA) are highly specific for SLE. The latter also correlates with renal and central nervous system involvement and disease flares, especially when paired with low complement levels (Ben-Menachem, 2010; Cozzani et al., 2014).

Pharmacological management of the disease is directed at inflammation reduction and limiting disease progression and consequent end organ damage. Treatment is based on disease severity and the predominant organ/s affected. Anti-inflammatory agents, anti-malarials, glucocorticoids and immunosuppressive agents are all employed. Disease activity is monitored by the systemic lupus erythematosus disease activity index (SLEDAI). Biochemical assessment of complement and antibody levels can be used to monitor disease activity and may play a role during the perioperative period.

Perioperative Management

The diverse, heterogeneous nature of SLE together with a range of pharmacological therapies makes standardised management of patients with this condition impractical. Appreciation of extent and implications of organ involvement, together with a familiarity of potential treatment side effects and a thorough, systematic assessment, will allow for an individualised management plan.


Airway involvement is an uncommon but potentially serious complication of SLE. Vocal cord paralysis, subglottic stenosis and generalised oedema of airway structures pose the greatest problems in the preoperative period. These are generally observed in patients with established disease and are unlikely to represent a primary presentation. Airway instrumentation should be conducted in the knowledge that a smaller-than-anticipated conduit may be required, and that strict monitoring in the immediate post-operative period is paramount to early detection of exacerbation of the underlying swelling which may result in complete airway obstruction. Consideration should be given to use of a supraglottic airway if appropriate as a means of limiting the potential for exacerbation of airway narrowing in the post-operative period.

Like rheumatoid arthritis, atlantoaxial instability may be a feature of SLE; however, the incidence and severity is less well delineated. The presence of neck pain or upper limb paraesthesia should be taken seriously and investigated accordingly, particularly in patients with long-standing disease.

The Cardiovascular System

SLE has the capacity to indiscriminately affect all components of the cardiovascular system, and cardiac involvement in patients with SLE has a prevalence of upwards of 50 per cent (Tincani, 2006). Atherosclerotic disease is the most common cause of death in patients with SLE for longer than 5 years (Sinicato, da Silva Cardoso and Appenzeller, 2013) and a primary cause of morbidity. Despite this, structural involvement is often mild and asymptomatic.

SLE is an independent risk factor for atherosclerosis. Atherosclerosis is 4–8 times more likely in patients with SLE than controls, leading to a 9–50-fold increased risk of myocardial infarction (Sinicato et al., 2013; Tincani, 2006). Importantly, subclinical disease as demonstrated by perfusion abnormalities is evident in nearly 40 per cent of adult patients (Zeller and Appenzeller, 2008). An increased occurrence of some traditional risk factors in patients with SLE does not sufficiently explain the observed accelerated rate of disease. Non-traditional risk factors have been identified, in particular renal disease manifestations and corticosteroid use (Zeller and Appenzeller, 2008). The elevated risk of cardiovascular disease, its accelerated rate of development and the potential subclinical expression should heighten the suspicion of the preoperative physician. Given the propensity for preoperative morbidity related to acute cardiovascular events, targeted assessment to delineate the presence and extent of the disease, along with risk factor modification, should be implemented with a lower threshold. Lack of traditional risk factors is not sufficient to rule out coronary artery disease in patients with SLE. A lower threshold for invasive intraoperative monitoring should be considered, particularly if coronary disease and impaired ventricular function are thought to coexist.

Myocarditis is a frequent finding in patients with SLE and may not produce clinical symptoms in mild cases. The significance of this condition relates to the propensity for arrhythmias, ventricular dysfunction and ultimately cardiomyopathy and cardiac failure. Patients should therefore be directly interrogated for symptoms of pericarditis and cardiac failure. Symptoms of dyspnoea at both rest, at night or on exertion, orthopnoea, arrhythmias, ankle swelling and limited exercise tolerance should be sought. Echocardiographic quantification of ventricular dysfunction may reveal global or regional wall motion abnormalities. Detection of cardiac dysfunction is important in the long-term prognosis of patients with SLE. Global dysfunction in the absence of coronary disease aggressively managed with immunosuppressant therapy may improve cardiac function and reverse the disease process (Gottenberg et al., 2004).

Libman-Sacks endocarditis defines the non-infective valvular lesions seen in patients with SLE. Seen in 10 per cent of patients, they are associated with longer duration of disease, anti-cardiolipin antibodies and anti-phospholipid syndrome (Moyssakis et al., 2007). Regurgitation is the predominant functional distortion and left-sided valves are more frequently involved with the mitral most commonly affected (Moyssakis et al., 2007). History and examination directed at symptoms and signs of valvular dysfunction and associated cardiac failure and any murmur should be formally quantified with echocardiography. The level of dysfunction associated with these lesions is predominantly mild, and the need for surgical correction is rare (4–6%) (Tincani, 2006). Nonetheless, this population may be predisposed to superimposed bacterial endocarditis and antibiotic prophylaxis should be considered.

Inflammation of the pericardium can produce pericarditis with or without a pericardial effusion. One quarter of patients with SLE are thought to have a symptomatic episode of pericarditis at some point in the illness, most likely during the primary manifestation of the disease or during a disease flare (Tincani, 2006). Pericarditis results in postural retrosternal or substernal chest pain, dyspnoea, tachycardia and possibly fever. Associated pericardial effusions are usually not haemodynamically significant and are generally recognised only on imaging.

Arrhythmias resulting from SLE are rarely malignant. The most commonly identified arrhythmias are sinus tachycardia, atrial fibrillation and atrial ectopics (Seferovic, 2006). Conduction disturbances may be present; however, complete heart block is uncommon. Importantly, the presence of arrhythmias or conduction disturbances may be secondary to active myocarditis or coronary artery disease. As such, ECG screening should be utilised with a low threshold in the preoperative period to detect both primary rhythm disturbances and secondary myocardial pathology.

The suspicion or confirmed presence of cardiac disease in patients with SLE mandates consideration of invasive haemodynamic monitoring, in conjunction with surgical and anaesthetic factors. Post-operative monitoring in a high-dependency unit may be required in those at significant risk of myocardial dysfunction or ischaemia.

The Respiratory System

SLE has a diverse range of pulmonary manifestations that are capable of affecting all components of the respiratory system. These may be primary, and attributed to SLE itself or secondary, and related to associated conditions.

Involvement of the pleura is the most frequently encountered feature and up to half of the patients with SLE will have a pleural effusion during their illness. Fever, cough and shortness of breath along with pleuritic chest pain are the main presenting symptoms. Pleural effusions are predominantly small and clinically significant effusions are rare. The presence of a pleural effusion should lead to consideration of important secondary causes, including cardiac failure, infection, malignancy and pulmonary embolism.

Parenchymal involvement includes interstitial lung disease and lupus pneumonitis. Fortunately both manifestations are rare as prognosis is particularly poor. In their most severe forms, both produce hypoxia and impaired diffusing capacity associated with pulmonary infiltrates and loss of lung volume (Pego-Reigosa, Medeiros and Isenberg, 2009). Management of patients with such manifestations in the preoperative period is particularly challenging and requires multidisciplinary involvement. Avoidance of mechanical ventilation, judicious fluid management and chest physiotherapy may be useful strategies.

Vascular involvement includes thromboembolic disease, pulmonary arterial hypertension and diffuse alveolar haemorrhage. Anti-phospholipid antibodies substantially increase the risk of thromboembolic events, with deep venous thrombosis risk heightened by increased disease activity (Pego-Reigosa et al., 2009). Chronic embolic events may produce secondary pulmonary artery hypertension. Patients may be anticoagulated as part of a secondary prevention strategy and bridging anticoagulation in the preoperative period may be required. This must be kept in mind should the planned anaesthetic technique involve regional or neuraxial intervention. Diffuse alveolar haemorrhage (DAH) is a severe complication of SLE and characterised by new onset dyspnoea, infiltrate and potentially haemoptysis (Ben-Menachem, 2010). The mortality may be as high as 50 per cent (Pego-Reigosa et al., 2009).

Pulmonary artery hypertension (PAH) may produce non-specific symptoms of dyspnoea, fatigue, cough and peripheral oedema. A high index of clinical suspicion is therefore required, and the perioperative physician should actively examine for signs of cardiac failure. Patients with PAH carry an elevated perioperative risk. Management therefore must be directed to preoperative optimisation of right heart function and implementation of pulmonary vasodilator therapy as appropriate, intraoperative management that avoids right ventricular ischaemia and perturbations to the pulmonary vascular resistance and post-operative monitoring in a high-dependency environment.

Diaphragmatic involvement produces ‘shrinking lung syndrome’ with a restrictive ventilatory defect that manifests as dyspnoea at rest and on exertion. While the occurrence is rare, unlike the parenchymal conditions, prognosis of this syndrome is good with appropriate steroid and immunosuppressant therapy.

While the perioperative physician is unlikely to be directly involved in the primary management of these pulmonary manifestations, an awareness of their characteristics is required. Preoperative quantification of severity and optimisation with multidisciplinary involvement is called for. Delineation of severity is achieved through a combination of clinical assessment and investigations, of which the most valuable is likely to be radiographic evaluation and pulmonary function testing, as directed by the observed clinical signs and symptoms. Post-operative dyspnoea and hypoxia should prompt consideration of these conditions in the differential for post-operative in patients with SLE. The occurrence of haemoptysis must be considered extremely serious.

The Renal System

Lupus nephritis is a severe complication of SLE with implications for morbidity and mortality. Persistent proteinuria, chronic renal impairment and end-stage renal disease may result directly as a consequence of SLE or from treatment complications. More than half of patients with SLE develop lupus nephritis, and it is frequently encountered early in the disease course. The pathogenesis is multifactorial and thought to relate to immune complex deposition, vascular involvement and inflammatory mediators (Ben-Menachem, 2010). Diagnosis is made from renal biopsy and there is poor correlation between serum creatinine and biopsy-observed disease. It is prudent, therefore, to consider all patients with SLE at risk of renal impairment and direct perioperative management accordingly (Ben-Menachem, 2010). The discordant nature of damage and derangement of laboratory-observed renal function means this test may only be useful to mark a trend of deterioration in the setting where dysfunction has already been demonstrated. Urinalysis is more sensitive and should be used to assess for renal involvement in the setting of silent disease. Particular attention to nephrotoxin avoidance, judicious fluid management and maintenance of renal perfusion in the preoperative period are advocated.

The Neurological System

As with other systems, ubiquitous involvement of the neurological system is possible in SLE. Seizures, psychiatric disorders, cognitive disorders including delirium and cerebrovascular disease are some of the many components outlined in the neuropsychiatric syndromes associated with SLE (NPSLE) (Muscal and Brey 2010). Attributing manifestation of these conditions in the perioperative period to SLE risks missing potential secondary causative factors. SLE as the primary cause should be a diagnosis of exclusion.

The Haematological System

All blood cellular elements and coagulation pathway constituents may be affected by SLE, and haematological involvement as a direct consequence of the disease or attributable to pharmacological therapy are common. Manifestations of highest preoperative clinical significance include anaemia, leukopenia, thrombocytopenia and antiphospholipid syndrome (APS).

Fifty per cent of patients with SLE have a form of anaemia (Janoudi and Bardisi, 2012). The underlying cause is most frequently attributable to anaemia of chronic disease (ACD), with iron deficiency anaemia (IDA), anaemia secondary to chronic renal insufficiency and autoimmune haemolytic anaemia (AIHA) contributing. ACD occurs on account of chronic inflammatory state of SLE suppressing erythropoiesis, while renal disease leads to deficient erythropoietin synthesis. IDA is usually attributable to insidious loss from the GI tract secondary to anti-inflammatory medications (NSAIDs and steroids) or from heavy menses. AIHA is a rare cause of anaemia and more commonly seen in the setting of severe disease (Janoudi and Bardisi, 2012).

The preoperative management of the patient with anaemia in the setting of SLE is complex and may require specialist input. The underlying cause must be delineated in order to appropriately direct therapy. The primary objective should be to optimise the level of haemoglobin in anticipation of potential blood loss, optimisation of oxygen-carrying capacity and delivery to end organs, and to reduce the potential for autologous blood transfusion.

Leukopenia is a reflection of disease activity and is seen in the range of 20–80 per cent of patients (Janoudi and Bardisi, 2012). It manifests as neutropenia, lymphocytopenia or a combination of both. Humoral and cellular immune mechanisms, medications and marrow dysfunction are potential causative factors. Leukopenia may form part of the reason for heightened susceptibility to infection in patients with SLE. However, when seen in the preoperative period, it is likely a signpost to address the underlying disease activity and modify management accordingly. In the operative setting, strict asepsis should be maintained when conducting invasive procedures. Prophylactic antibiotic administration is paramount in this cohort, particularly in the setting of impaired immune function inherent to the underlying disease, and often compounded by pharmacological therapy.

Thrombocytopenia is a consequence of immune-mediated platelet destruction, enhanced consumption or impaired production, most readily attributed to pharmacological agents (Janoudi and Bardisi, 2012). Thrombocytopenia may precede the diagnosis of SLE. Thrombocytopenia and fever warrants consideration of thrombocytopenic purpura (TTP). Low platelets may also be seen in the setting of antiphospholipid syndrome (APS). Management of thrombocytopenia in the preoperative period will depend on the underlying mechanism, and time available prior to the requirement for surgery. Steroids form the main component of management, with other immunosuppressants utilised depending on the response achieved and tolerance of side effects (Janoudi and Bardisi, 2012); however, some patients may require a splenectomy. If immediate surgery is required, autologous platelet transfusion may be required, and specialty oversight from a haematology unit will assist in this decision. Neuraxial and regional anaesthesia should be embarked upon with caution in such patients, and a recent full blood film timed closely with the intervention is advisable.

Patients with SLE may suffer from anti-phospholipid syndrome (APS) as a secondary consequence of the underlying autoimmune process. Anti-phospholipid antibodies (aPL) result in the false prolongation of the APTT via the lupus anticoagulant, thrombocytopenia and adverse pregnancy outcomes. Despite the deranged coagulation studies, these patients are susceptible to venous and less commonly arterial thromboses. These manifest as deep vein thromboses, more often in the legs and potentially intracerebral or coronary occlusions (Ben-Menachem, 2010). Patients who have suffered a venous or arterial occlusive event will likely be managed with long-term anticoagulation. This pro-thrombotic state has significant implications for management in the preoperative setting. Bridging of anticoagulation may be required prior to surgery, and judicious attention to implementation of strategies to prevent venous stasis and subsequent DVT are required. This should include chemical prophylaxis, as well as anaesthetic techniques that allow for opioid minimisation and early mobilisation. Reintroduction of therapeutic anticoagulation should be instigated as soon as practicable, particularly in patients with a proven thrombotic event. The presence of a prolonged APTT in such patients is not a contraindication to neuraxial or regional anaesthetic techniques, provided the aetiology of this spurious result is related to inhibitors such as the lupus anticoagulant (LAC). The clinician should have a high index of suspicion for pulmonary embolism in the setting of acute onset of shortness of breath in the preoperative period.

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Sep 15, 2020 | Posted by in ANESTHESIA | Comments Off on Chapter 12 – Connective Tissue Disease
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