Anesthetic Implications of Polyautoimmunity in Surgical Patients

Anesthetic Implications of Polyautoimmunity in Surgical Patients
Ella Obrosky, SRNA, University of Pittsburgh Nurse Anesthesia Program

Introduction to Autoimmune Disease
ADs are a heterogeneous group of diseases characterized loss of self-tolerance Significant burden on health care, economic costs, quality of life Approximately 5% of people worldwide develop one or more ADs, 80% are women. AD is the leading cause of disability in women. Problems affecting anesthesia care include diverse and complex disease presentation, polyautoimmunity and insidious development of complications

Objectives Learners will be able to:
Define Autoimmune Tautology and describe the three lines of evidence for this theory Identify key components of autoimmune pathophysiology/pathogenesis Identify common effects and symptoms of autoimmune pathology by body system Identify common autoimmune diseases frequently associated with poly-autoimmunity Identify significant perioperative complications in patients with autoimmune disease and polyautoimmunity Identify anesthetic implications and interventions to reduce the risk of perioperative complications in patients with autoimmune disease. Our primary goal is to discuss current knowledge about autoimmune disease and relevance to anesthesia care. We are going to talk about autoimmune tautology, which describes how autoimmune diseases are related to each other and where they come from. We are also going to review disease presentations, complications and co-occurrence, or polyautoimmunity, and relate these concepts to anesthesia care

Autoimmune Tautology ADs share: Autoimmune Tautology
Pathophysiologic mechanisms Signs and symptoms Complications Autoimmune Tautology Familial aggregation Polyautoimmunity Shared genetic factors Many factors contribute to variable clinical presentations of autoimmunity Described as a kaleidoscope of autoimmunity Target cell, affected organ, gender, ancestry, trigger factors and age of onset Despite different central disease targets in tissues and organs, ADs frequently share physiologic mechanisms, clinical signs and symptoms, and complications. Autoimmune Tautology explains this interconnection and is supported by

Familial Aggregation Defined as presence of diverse ADs in multiple members of a nuclear family First clue that ADs were related: More common in twins > siblings & parents > other relatives Familial clustering is demonstrated in a multitude of studies over decades of research Clustering/aggregation/recurrence is more common than specific disease recurrence, known as familial autoimmune disease Familial Aggregation is also called recurrence risk, a more familiar term in some fields of study Different than familial autoimmune disease, which is the recurrence of a specific AD within a family Twins concordance rate for example: RA 12-35%, SLE 20-40%

Polyautoimmunity Presence of more than one AD
Three or more: multiple autoimmune syndrome (MAS) Secondary autoimmune disease is no longer used to describe the phenomenon Instead, polyautoimmunity appears to be a reflection of diverse manifestations of both disease-specific and non-specific autoantibodies. One example study of 1083 patients – 34.4% had more than one AD

Polyautoimmunity Examples
Specific common clusters have names Type 1 MAS: MG, thymoma, PM, GCA with myocarditis Type 2 MAS : Sjogren’s, RA, PBC, AI cirrhosis, SSc, AI thyroid disease Type 3 MAS : AI thyroid disease, MG and/or thymoma, Sjogren’s, pernicious anemia, ITP, Addison’s, DM1, vitiligo, AI hemolytic anemia, SLE, dermatitis herpetiformis Schmidt syndrome: Hashimoto’s + AI adrenal insufficiency/Addison’s

Commonly Associated ADs
Diabetes: 15% have 2nd AD Thyroid disease, Addison's, Myasthenia Gravis AI Thyroid Disease Myasthenia Gravis RA, Lupus, Pernicious Anemia, Pemphigus, ITP, Hemolytic anemia, Multiple sclerosis, Ulcerative colitis, Sjogren's, Sclerosis, Polymyositis, Thyroid disease Eaton-Lambert Thyroid disease, Collagen-Vascular Disease Polymyalgia Rheumatica Lupus, Giant cell arteritis in 15% Polymyositis, Dermatomyositis RA, Lupus, Sclerosis Primary Biliary Cirrhosis RA, Pernicious anemia, Sjogren's, pyoderma gangrenosum, Antiphospholipid syndrome Primary Sclerosing Cholangitis IBD (UC>CD), DM, Psoriasis, APS Rheumatoid Arthritis Myasthenia Gravis, Pemphigus, Lupus, PM/DM Systemic Lupus Erythematosus Pemphigus Sclerosis PM/DM, Myasthenia Gravis This is my no means an inclusive list These examples are from our anesthesia textbooks published in the last few years. An ever growing and large body of research supports a significant prevalence of polyautoimmunity.

Shared Genetic Factors
Not all AD’s share the same genetic susceptibilities At least 18 common non-major HLA complex loci clusters implicated in AD Disease-specific Non-disease specific Individual genes are not sufficient to explain heritability Individual variants only add incremental risk fold Only 10-15% of inherited risk could be explained as of 2010 Research repeatedly demonstrates shared genetic factors, the source of autoimmunity as well as polyautoimmunity and familial aggregation. Combination, plus hormonal, environmental, pathogenic factors results in extraordinary variety of disease presentation

Pathogen Triggers Pathogens: viral, bacterial, fungal, vaccines
ADs are commonly preceded by URI, gastroenteritis Viruses: EBV, CMV, HSV, adenoviruses Even oral and intestinal microbiomes are implicated in RA, IBD, reactive arthritis, ankylosing spondylosis, psoriatic arthritis, etc. Vaccines: bi-directional Can prevent infections that can trigger AD Can trigger AD Example: flu vaccine and Guillain-Barré A genetically primed individual may not yet experience AD without the contribution of an environmental trigger. Pathogens can begin the cascade of auto-immunity through an array of complex mechanisms. Viruses in particular are associated with initiating multiple AD’s. EBV alone is associated with at least NINE autoimmune diseases. Stress or illness-related reactivation of latent viruses is also a common thread of autoimmune pathogenesis. EBV: Polymyositis, SLE, antiphospholipid syndrome, RA, MS, pemphigus vulgaris, giant cell arthritis, Wegener's granulomatosis, polyarteritis nodosa (PAN) CMV: SLE HSV: MS, SLE Adenoviruses: Celiac disease Mechanism: cellular mimicry, protein changes, cryptic antigens, super-antigens, bystander activation, apoptosis, necrosis, clearance deficiency

Environmental Triggers
Smoking associated with trigger or exacerbation of at least 10 different ADs. Organic solvents, Occupational dust Sunlight Gluten Stress & hormones Drugs: Over 80 medications are known to induce Lupus alone, many others can also induce autoimmune hemolytic anemia. This is posited to explain why twin concordance rates are not higher RA 12-35% SLE 20-40% Further supported by geo-epidemiological distribution of cases, resulting in uneven exposure to triggers Many triggers are identified in retrospective studies, precluding the ability to determine if the exposure is the initial trigger or a propagating factor Drug-induced lupus is a milder form of the disease and generally resolves weeks to months after removal of the offending agent Drug-induced autoimmune hemolytic anemia Smoking: promotes inflammation, causes immunomodulation, and exposure to chemicals

Autoimmune Pathogenesis
Presence of genetic susceptibility Exposure to triggering factors Abnormal immune response Self-tolerance is reduced or lost Auto-antibodies: systemic tissue-specific organ-specific Non-specific autoantibodies include antinuclear antibodies (ANA), rheumatoid factor (RF), Anti-Ro antibodies, many others Will not cover here autoantibodies in detail due to the number, overlap and complexity of autoantibodies involved in autoimmune disease

This is an example of a table describing the autoantibodies involved in polymyositis and dermatomyositis – demonstrating the large number and complexity of a single category of disease. Antibody testing only sometimes definitively rules particular diseases in or out

Tissue Damage Direct and indirect damage
Inflammation: cytokines, prostaglandins, reactive oxygen species Immune complex deposition Direct immune attack: Antibodies, B cells, T cells, macrophages, etc. Loss of regulation of autoreactive cells

Mosaic of Autoimmunity
Simple or stereotypical disease descriptions are no longer useful in AD Only 50% of patients with lupus will have a butterfly rash Many symptoms are common to multiple diseases Arthralgia, arthritis, alopecia, fatigue, photosensitivity, Raynaud’s phenomenon, vasculitis, coagulopathy, skin rashes Combination of genetics, triggers, specific autoantibodies involved result in diverse presentations of even single diseases Change to one component of the immune system can change the presentation of autoimmunity and induce a second disease Splenectomy, thymectomy, immunosuppressants Individual phenotypes (presentation) change over time Severity varies by gender and age of onset Few autoimmune diseases are limited to their primary defining features: remembering butterfly rash and rheumatoid knuckles do not define lupus or rheumatoid arthritis. Early onset of disease, even subclinical, is the worst prognostic indicator in AD, independent of the severity of early symptoms. With a few exceptions, women are significantly more affected by autoimmune disease, both in severity and prevalence.

Disease Classification by Body System
Primary System Diseases Vascular Vasculotides, Raynaud's phenomenon Collagen-Vascular Polymyositis/dermatomyositis, Systemic sclerosis (scleroderma), Rheumatoid Arthritis, Systematic Lupus Erythematosus, Sjögren's syndrome Pulmonary Goodpasture syndrome, Idiopathic pulmonary hemosiderosis, Pulmonary alveolar proteinosis, PNS, CNS Vitamin B12 deficiency, Guillain-Barré syndrome, Eaton Lambert Myasthenic syndrome, Multiple Sclerosis Neuromuscular Polymyositis/dermatomyositis, Myasthenia Gravis, Eaton Lambert Myasthenic syndrome Joints/Rheumatic Rheumatoid Arthritis, Ankylosing Spondylitis, Psoriatic arthritis, Reactive arthritis (Reiter's), Relapsing polychondritis, Polymyalgia rheumatica, Systemic Lupus Erythematosus Cutaneous Psoriasis, Sjögren’s syndrome, Bechet’s disease, Bullous pemphigoid, Pemphigus vulgaris, Henoch-Schönlein purpura Hepatobiliary Autoimmune hepatitis, Primary Biliary Sclerosis, Primary Sclerosing Cholangitis GI IBD (ulcerative colitis, Crohn's disease), celiac disease (gluten-sensitive enteropathy) Heme Pernicious anemia, B12 deficiency, AI hemolytic anemia, HIT type 2, Idiopathic thrombocytopenic purpura (ITP), Antiphospholipid syndrome Renal Goodpasture syndrome, IgA nephropathy, Systematic Lupus Erythematosus, rapidly progressive glomerulonephritis Endocrine Diabetes Type 1, Addison’s disease, Hashimoto’s thyroiditis, Graves' disease, Reidel’s thyroiditis Autoimmune disease can be due to antibodies that target specific tissues or organs, or can be systemic.

Vasculotides Type of Vasculitis Diseases Large vessels
Bechet's disease, Cogan's syndrome, Giant cell arteritis (Temporal), Polymyalgia Rheumatica, Takayasu's arteritis Mostly medium vessels Buerger's disease (thromboangiitis obliterans), Kawasaki's disease, polyarteritis nodosa, cutaneous vasculitis Mostly small vessels Churg-Strauss syndrome, cryoglobulinemia vasculitis, IgA vasculitis, Henoch–Schönlein purpura (HSP), Hypersensitivity vasculitis, microscopic polyangiitis, Wegener's granulomatosis (granulomatosis with polyangiitis) Variable Medication-induced Only one of these diseases is not caused by autoimmune pathology: hypersensitivity vasculitis. This is still an aberrant immune response however. There is some overlap, but they are listed by predominance

Vascular Complications
Diseases General vasculitis Amyloidosis, Ankylosing spondylitis Dermatomyositis, Diabetes type 1, Pyoderma gangrenosum, Rheumatoid arthritis, Lupus, Scleroderma, vasculotides Aortic dissection Ankylosing spondylitis Aortitis/dilation Ankylosing spondylitis, Rheumatoid Arthritis Pulmonary artery aneurysm Bechet's Disease Vasculitis of Vasa Vasorum Rheumatoid arthritis, Kawasaki disease GI vasculitis IBD, microscopic polyangiitis, Dermatomyositis, Rheumatoid arthritis Raynaud’s phenomenon vasculotides, PM/DM, Rheumatoid arthritis (uncommon), Sjogren’s (20-30%), Lupus (20-30%), Scleroderma (85-95%), Autoimmune hemolytic anemia. Renal vasculitis Goodpasture syndrome, Dermatomyositis CNS vasculitis Giant cell arteritis, Takayasu’s arteritis, Polyarteritis nodosa, Wegener's Vasculotides are generally categorized according to the size and location of vessels which they affect. Today we will not elaborate on that classification, but will discuss specific organs affected. Here are specific manifestations of those disease, and secondary to non-vasculotides RA – widespread, varying sized vessels, may include Takayasu’s disease, may be necrotizing SLE – Prominent SSc – can be severe, with obliteration of vessels and protein leakage. Raynaud’s can be presenting symptom and is frequently severe, may occur years before diagnosis….same with CREST syndrome. Kawasaki’s includes risk for coronary aneurysm and/or thrombosis

Anesthetic Considerations - Vascular
Remember vasculitis in one place most likely means vasculitis any place. Preoperative assessment should focus on end-organ complications, known and unknown May need renal, cardiac, neuro or pulmonary assessment/evaluation if severe disease Plan for careful maintenance of baseline MAP ART line – avoid when unnecessary. Assess hand involvement before placing radial or brachial lines Hypertension – treat with nicardipine, sodium nitroprusside or nitroglycerine rather than inhaled agents. Temperature – some vasculopaths are more prone to clotting and/or vasospasm when they get cold. Keep them WARM, especially in the presence of Raynaud’s. Pathergy – present especially in Bechet’s, pyoderma gangrenosum, SLE, psoriasis. Will result in new lesions at the puncture site. Consider whether punctures can be avoided. If invasive monitoring is needed consider limiting to single site for central access and monitoring and one large IV. Vision – ASK specifically about vision history. Vision – we will get to that shortly, but vasculotides are notorious for causing ophthalmic complications.

Cardiac Complications
Diseases Accelerated atherosclerosis/CAD DM1, PAN, Psoriasis, RA, SLE, SSc, Takayasu’s, Buerger’s, TTP Ischemia (other causes) AkS, Cogan's, Autoimmune thyroid disease, Kawasaki's, PAN PM/DM RA, SLE, Takayasu's Hypertension CSS, Goodpasture, Grave’s, PAN, SLE Myocardial fibrosis Amyloidosis, AkS, SSc, PM/DM, SSc Myocarditis/endocarditis AkS, BD, CSS, IBD, PM/DM, RA, SLE Valvular dysfunction Amyloidosis, AkS, BD, PM/DM, reactive arthritis, relapsing polychondritis, RA, SLE, Takayasu’s, WG Pericardial effusion, lesion, inflammation Amyloidosis, BD, Hashimoto’s, IBD, PAN(acute), reactive arthritis, RA, SLE, SSc, WG LV dysfunction SLE, MG, PAN, PM/DM, PBC/PSC, RA, SLE, SSc RV dysfunction SLE, SSc, PBC/PSC, RA, SSc Cardiomyopathy amyloidosis, Cogan’s, MG, PAN, RA, SLE, WG CHF amyloidosis, CSS, Hashimoto’s, PM/DM, SLE, SSc Conduction defects, arrhythmias amyloidosis, AkS, AI thyroid, Kawasaki’s, MG, PAN, PM/DM, RA, SLE, SSc, Takayasu’s, WG Coronary vasculitis CSS, Cogan’s, PAN, RA, SLE, SSc, Takayasu’s, WG Atherosclerosis: Traditional CV risk factors do not explain the increase, but are also more prevalent in rheumatic diseases SLE MI risk 52 times higher in women years old versus without SLE Absolute numbers remain low AkS – 40% CV involvement, can include cardiomegaly SLE – 60% have pericardial effusion, but tamponade is uncommon Psoriasis – high output failure RA – can have nodular invasion SSc – myocardial fibrosis in virtually all patients. CV findings are often occult, only 25% symptomatic. Can sclerose coronary arteries. Wegener’s – myocardial vasculitis frequently necrotizing and can be source of mortality

Cardiovascular Risk Factors
(Agca et al., 2016)

Atherosclerosis (Agca et al., 2016)
Traditional CV risk factors are more prevalent in many ADs, particularly in rheumatic diseases. However, these traditional risk factors do not explain the increased risks by themselves. Rheumatic diseases contribute independently to CV risks, some researchers equate the CV risk of an individual rheumatic diagnosis to the level of risk associated with diabetes.

(Castaneda et al., 2015) Peripheral arterial disease Heart failure Cerebrovascular disease Myocardial infarction Angina Total

ANS Dysfunction Disease Examples Amyloidosis Bechet’s Diabetes type 1
Guillain-Barre Myasthenia Gravis & ELMS Scleroderma Multiple sclerosis Sjogren’s Vasculotides ANS Complications Vasomotor instability Autonomic hyperreflexia Inability to sweat, dry mouth, constipation, urinary retention, gastroparesis Sphincter incompetence Erectile dysfunction Resting tachycardia Orthostatic intolerance Silent Ischemia Vasomotor instability with exaggerated responses to DL and other stimuli, up to and including autonomic hyperreflexia, particularly in the presence of C-spine involvement in disease processes or complications: Bechet’s notorious. Orthostatic hypotension can be so severe in cases such as Guillain-Barre as to cause syncope simply from lifting the head from a pillow.

Anesthetic Considerations - Cardiovascular
Anesthetic choices should be tailored to the degree of myocardial dysfunction present. Expect vasomotor instability in patients with ANS dysfunction. Consider assessing in preoperative area. Basic info: Thorough assessment of cardiovascular history in ALL AD patients. ECG for ALL AD patients. Listen to those valves! Muffled heart sounds, pericardial friction rub, pulsus paradoxus, unexplained hiccups, hepatojugular reflex – Potential pericardial effusion. When in doubt refer for cardiac clearance and/or testing Consider they all might have ischemic heart disease, atherosclerotic and/or non CAD. Women with rheumatic disease have been cited to have up to 52 times the rate of sudden cardiac death related to insidious heart disease compared with their counterparts. Thankfully this is a small number in the age group (35-44 yrs) either way, but this is highly statistically and clinically significant.

ANS Assessment Test Normal Results Poor Man's Version
Normal Results Poor Man's Version HR response to Valsalva maneuver (PNS) PNS Normal ratio of longest R-R interval to shortest is >1.21 Does the HR slow down appropriately? HR response to standing from supine (PNS) Normal ratio of longest R-R interval around 30th beat (nadir of brady rate) to R-R interval around 15th beat (peak of tachy rate) is >1.04 Does the HR speed up a bit, then slow down a bit? HR response to deep breathing (PNS) 6 deep breaths in one minute. Normal MEAN of difference between peak HR and low HR should be >15 bpm Does the HR speed up and slow down with slow deep breathing? BP response to standing (SNS) SNS Normal drop is <10 mmHg SBP. >20 drop SBP or >10 drop DBP or HR increase >20 is abnormal. Hey this one is easy! BP response to sustained handgrip (SNS) Maintain a 30% maximum squeeze for 5 minutes. BP every minute. Initial DBP (low) subtracted from just before release (high) should be >16 mmHg Production pressure versus safety – an abnormal ANS assessment can indicate that a significantly different plan of care is needed.

Pulmonary Complications
Diseases Pulmonary Hypertension Autoimmune hepatitis, APS, BD, RA, SLE, SSc (asymptomatic!), Takayasu’s (50%) Pulmonary Vasculitis/capillaritis, hemorrhage/hemoptysis APS, CSS (reactive airway) Goodpasture, SLE, WG, other vasculotides Diffuse interstitial disease/fibrosis AkS, IBD, PM/DM, RA (rare), SLE, SSc (80%) Diffuse alveolar disease, deposits, infiltrates, lesions, tumors Amyloidosis, AkS, CSS PG, RA, SLE, WG Pleural effusions AkS, CSS, RA, (very common), SLE Restrictive pattern AkS, CSS, PM/DM, RA, SLE, SSc, WG Obstructive airway/bronchospasm BD, CSS, WG Respiratory muscle weakness, +/- aspiration ELMS, Graves, MG, MS, PM/DM, SLE, SSc Chronic cough Sjogren’s, PM/DM, SLE Dyspnea DM/PM, SLE ↓DLCO CSS, Goodpasture, PM/DM, RA, SLE, SSc, vasculotides Other details: SLE – high incidence of PHT in patients with Raynaud’s AkS, RA – lesions can mimic TB on CXR Symptomatic Dyspnea…. Depends on severity… DM/PM Restrictive disease can be from interstitial fibrotic changes, muscle weakness, changes to rib cage/cartilage ↓DLCO: Many processes can result in impaired exchange Hypothyroid: decreased ventilator response to CO2, O2 PM/DM: 50% have respiratory symptoms, dry cough common, even BOOP (bronchiolitis obliterans organizing pneumonia) Sjogren’s: lymphoproliferative, chronic cough SLE: pulm directly relates to degree of vascular involvement, bronchiolitis, weakness can be from phrenic neuropathy, PHT esp in patients with Raynaud’s. Pleuritis Bechet’s: bronchiectasis Wegener’s – can be devastating destruction of tissue, obliteration of vasculature, infection, hemorrhage, PNA at time of presentation, pleuritic chest pain, diminished reserve SSc: interstitial disease and PHT in 10-50%. Often asymptomatic Vasculitis – can result in significant V/Q mismatch Goodpasture – complicated care, consult pulmonology for anesthetic care. High airway pressure can exacerbate pulmonary hemorrhage.

Airway Complications Diseases
Oral/laryngeal lesions, fragility, pathergy Amyloidosis, BD, PV/BP, psoriasis, PG, RA, Sjogren’s, SLE, SSc, Wegener’s Nasal/sinus changes CSS, SSc, WG Tongue Amyloidosis (large), Hashimoto’s (large), B12 deficiency (atrophic) Subglottic narrowing RA, SLE, WG (major source of M&M) Cricoarytenoid arthritis Reactive arthritis, RA, SLE Loss of TMJ mobility AkS, PM/DM, RA, SSc (skin related) Loss of c-spine mobility AkS, DM1, RA, SSc, Takayasu (may limit CBF on extension) Dysphagia or CN weakness Graves, GBS, MG, PM/DM, RA, Sjogren’s, SSc Esophageal dysmotility, GERD, delayed gastric emptying DM1, Hashimoto’s, PM/DM, SSc/CREST Pathergy: Bechet’s, Pyoderma gangrenosum, Koebner phenomenon in psoriasis, SLE. Minor trauma leads to development of lesion/ulcer at site. Hazard in case of airway. Sjogren’s: comes with extreme dryness Amyloidosis, PV/BP – carries risk of spontaneous hemorrhage even without manipulation PV = pemphigus vulgaris, BP = Bullous pemphigoid – extensive oral involvement in 50%. AW management can be life-threatening, new lesions can compromise aw after extubation. RA can involve severe laryngeal involvement: stridor, voice changes, pain on swallowing, tenderness over larynx, visible redness/swelling on DL (can be asymptomatic), can even have deviation of trachea. RA can be an extremely difficult airway if difficulty is encountered, even in the case of subglottic emergency airway. SLE up to 30% have SSc – skin may be so taut as to limit mouth opening or neck extension, may be a challenge to ventilate by any modality CREST syndrome is a severe variant of SSc: Calcinosis, Raynaud’s, esophageal dysmotility, sclerodactyly, telangiectasia Hashimoto’s: OSA, grave’s and hashimoto’s may have goiter AkS: Consider ALL a difficult airway SLE: Laryngeal inflammation, VC palsy/paralysis in up to 1/3. AFOI if voice changes. RA: Significant risk of AO instability and SC impingement Wegener’s: Major airway complications due to upper and lower airway lesions, destruction of bone and tissue, laryngeal and tracheal stenosis, epiglottis destruction

Airway Considerations
Dangerous airways in multiple diseases Oral lesions = fragility, risk of hemorrhage Pathergy = risk for postoperative obstruction Laryngeal involvement and narrowing – Glide or FOI Neck clearance – RA, AkS Specifically assess subjective tolerance with extension in Takayasu’s and other vasculitis, RA, AkS, SLE Specifically ask about voice changes in ALL rheumatic cases When in doubt bring the difficult airway cart and use FO scope Emergency subglottic airway can be difficult in rheumatic patients! Pulmonary assessment is likely sufficient with careful questioning of patient symptoms and auscultation of lung sounds Delay/cancel elective surgery if patient presents with respiratory symptoms that have not been evaluated RA SC involvement can be asymptomatic. Consider requesting clearance if patient has long standing and/or particularly severe disease and has never had their neck evaluated.

CNS Complications Disease Examples
CNS Vasculitis Headaches, confusion, infarct Seizures Decreased BF at carotid or vertebral arteries (especially Takayasu’s) Myelopathy, demyelination, SC lesions Psych disturbances, dementia, cognitive decline (Especially SLE) Hearing disorders (Especially WG) Cortical visual disturbances Disease Examples Diabetes type 1 Guillain-Barre Lupus Multiple sclerosis Myasthenia Gravis & ELMS Pernicious anemia, B12 deficiency Rheumatoid arthritis Scleroderma Sjogren’s Vasculotides CNS complications are even more likely in the presence of APL’s RA – SC involvement is disproportional to symptoms. In the case of AO subluxation extending neck can decrease BF to brain due to pressure from the odontoid process, unless it has eroded. (This can also happen with Takayasu’s) Can have intradural compression from pannus formation or rheumatoid nodules Bechet’s: Cauda equina, aseptic meningitis,, coma, intracranial aneurysms, thrombosis Churg-Strauss: SAH Vitamin B12 causes peripheral and SC demyelination Psych disturbances ranging from depression to euphoria and psychosis – esp in SLE Takayasu’s you may see patient’s holding head drooped due to loss of consciousness, or presyncope symptoms when extended CNS manifestations more likely in the presence of +APL’s

Neurologic Considerations
All patients with vasculitis or potential vasculitis have an increased risk for neurologic symptoms Anesthesia can unmask insidious development of complications Assess EYE history and hearing history, even in young patients Perform at minimum a mini mental status exam, consider more detailed exam to elicit subtle deficits. Carefully maintain MAP at baseline Be cognizant of increased prevalence of dementia and psych disturbances that can both present early, or after prolonged disease If unsure what to assess perform an NIHH stroke scale as it will cover CNS and PNS basic functions

Pathophysiology of Neuropathy
Neurodegenerative, metabolic/nutritional (B12, DM1, etc), Infections/toxins, Vasculitis/Rheumatologic, Hereditary, Autoimmune Dorsal root ganglion/nerve roots, Vasa nervorum, interstitium (endoneurium, perineurium, epineurium), Schwann cells/myelin, Axon

PNS Complications Disease Examples
Vasculitis of vasa nervorum Demyelination, inflammation Cranial nerve dysfunction Peripheral neuropathy (MOST ADs) Paresthesia Weakness, myopathy, myalgia Compression syndromes Disease Examples Graves' & Hashimoto's Diabetes type 1 Guillain-Barre, CIDP SLE, RA & connective tissue diseases Multiple sclerosis Myasthenia Gravis & ELMS Pernicious anemia, B12 deficiency Polymyositis, Dermatomyositis Polymyalgia Rheumatica Scleroderma Sjogren’s Vasculotides CIDP: chronic inflammatory demyelinating polyneuropathy – similar to GBS: acute inflammatory demyelinating polyneuropathy. Vitamin B12 deficiency results in loss of vibrioception/proprioception, paresthesias in LE’s in stocking distribution, loss of Achille’s DTR, symmetrical subacute sensorimotor paralysis, Myalgia, myopathy and weakness are also very common, but not as prominent as in the primary neuromuscular disease.

Neuropathy Considerations
Assess all patients with AD for history of symptoms of neuropathy and paresthesia Anesthesia, stress, surgery, infection, inflammation, temperature derangements can all unmask subclinical neuropathy. Double Crush Phenomenon - subclinical processes are potentiated or unmasked by a second attack on a nerve pathway from positioning, hypotension, inflammation or medications. AVOID nitrous oxide in all patients with demyelinating processes, neuropathy, B12 deficiency. Assess carefully in postoperative period. Direct injury or ischemia manifests almost immediately Inflammatory processes develop over days to weeks AD patients are already susceptible to neuropathy of nearly any kind. Evidence is accumulating suggesting that postoperative neuropathy that occurs days after surgery is due to inflammatory states and demonstrates preexisting nerve changes in research subjects. Patients with AD already exist in a pro-inflammatory state, albeit at varying levels during the course of their illness. Surgery itself can promote disease flares and/or inflammation…making this kind of postoperative neuropathy more likely. Research has not yet examined this connection to AD and postoperative neuropathy. Expect to see this in the future. Nitrous oxide – evidence is limited here. We know that some patients will experience neuropathy even with only a single exposure to nitrous oxide. Patients at risk for neuropathy may be at higher risk, but this has not yet been studied because it is UNETHICAL to provide this agent for the purpose of testing a hypothesis that it’s really bad for them. Expect retrospective research in the future.

Neuromuscular Considerations
Specifically assess for weakness or history of symptoms preoperatively Discuss possible postoperative ventilation needs AVOID neuromuscular blockade when possible. TOF monitoring in unaffected muscle groups may overdose affected groups. TOF monitoring affected groups may under-dose unaffected groups. Titrate carefully for surgical needs only. AVOID hyperthermia and hypothermia in patients with known conduction deficits because changes to temperature can produce weakness or even full conduction block. Be vigilant for neuromuscular weakness on emergence and postoperatively Residual weakness, sensitivity or disease flare Assess EOM strength when patient fully awake. Stressors that can contribute to disease flares: emotional stress, infection, temperature changes, medications, anesthesia One degree increase in temperature can cause full conduction blockade and paralysis in susceptible patients

Primarily Rheumatic Diseases
Joint Manifestations Primarily Rheumatic Diseases Ankylosing spondylitis Psoriatic arthritis Rheumatoid arthritis Reactive arthritis (Reiter's syndrome) Relapsing polychondritis Polymyalgia rheumatica Joint Involvement Systemic Lupus Erythematosus: most common symptom Crohn's 10-20% Ulcerative colitis 2-7% Polymyositis & Dermatomyositis Pyoderma Gangrenosum Sjogren's syndrome Scleroderma Arthritis and arthralgia are very common to AD. Presentation varies considerably and can involve large joints or small, symmetrical or asymmetrical, migratory or constant, single joint or multiple, erosive or non-erosive, deforming or non-deforming. Osteoarthritis can be present concurrent to autoimmune arthritis and is ubiquitous in RA. Skin disease such as scleroderma or CREST syndrome can cause taut and thickened areas over joints to prevent mobility AO instability and subluxation …. Entails separation of atlantoodontoid articulation, cranial settling, subaxial instability. Spine involvement is common and varies by disease. AkS and RA should always be a red flag for c-spine problems. Atlantoaxial instability and subluxation are present in up to 40% of patients with RA and can remain asymptomatic despite significant spinal cord compression.

Gut to Joint pathway (Yeoh, 2013)

Joint Considerations Preoperative assessment of major joint function imperative for safe positioning and airway maneuvers Joint involvement can herald more serious disease complications Prolonged steroid use may result in osteoporosis, osteomalacia, pathological fractures. Severe rheumatic disease may require continuation of NSAIDS or antiplatelet medications during the perioperative period Increased severity of joint manifestations may be related to increased duration, severity or activity level of disease. For example, degree of extra-intestinal manifestations in IBD parallels disease activity level, though not necessarily severity.

Primary Cutaneous Diseases Secondary Skin Involvement
Bechet's disease Bullous Pemphigoid & Pemphigus Vulgaris Dermatomyositis Henoch-Scholein Purpura Psoriasis & Psoriatic Arthritis Lupus: Only 50% will have butterfly rash Sclerosis & CREST syndrome Sjogren's syndrome Wegener's granulomatosis Secondary Skin Involvement Amyloidosis Autoimmune hepatitis Autoimmune thyroid disease Crohn's disease Primary biliary sclerosis Reactive arthritis Rheumatoid arthritis Ulcerative colitis Vasculotides Pathergy: Bechet’s, Pyoderma gangrenosum, Koebner phenomenon in psoriasis, SLE. Occurs in during high disease activity level, can signal an oncoming or active flare Minor trauma leads to development of lesion/ulcer at site. Hazard in case of airway. Rashes, plaques, texture, color changes, thickening Pyoderma gangrenosum, erythema nodosum, pathergy common

Skin Considerations Specifically assess preoperatively
History of skin involvement Oral lesions Check current rash for signs of untreated infection Joint limitation Cricothyroid accessibility Venous access Avoid punctures to affected sites and in the presence of pathergy/Koebner Consider CVL instead of multiple IV’s Consider TEE or other noninvasive monitoring versus ART line Long term steroids may make skin fragile

Renal Complications Disease Examples
Proteinuria Nephrotic syndrome Glomerulonephritis Renal tubular acidosis Renal failure Renal artery stenosis Renal calculi Ureteral obstruction Nephrotoxicity Disease Examples Autoimmune hepatitis Autoimmune thyroid disease Amyloidosis Crohn's disease & Ulcerative colitis Dermatomyositis Diabetes type 1 Primary biliary cirrhosis & Primary sclerosing cholangitis Psoriasis Rheumatoid arthritis Scleroderma Sjogren's Vasculotides RCM – radiocontrast media PSGN type III – Churg-Strauss, Microscopic polyangiitis, Wegener’s PSGN type I – Goodpasture PSGN type II - Henoch–Schönlein purpura, SLE DM: nephropathy is more common in DM1 than DM2, major source of morbidity. Extent of proteinuria predicts outcomes. Graves: during thyroid storm and myopathy can result in rhabdomyolysis and acute renal failure Sjogren’s: interstitial cystitis, interstitial nephritis Other causes: vasculitis, immune complex deposition, acute failure related to ITP/TTP Major primary renal involvement in Goodpasture and Wegener’s – 12-50% require dialysis or transplant. Rapidly Progressing Glomerulonephritis (RPGN), IgA nephropathy Major complication in Lupus – up to 60%, with 10-20% requiring dialysis or transplant

Renal and Hepatic Considerations
Preoperative labs should be assessed for all AD patients Correct hypovolemia, electrolyte imbalances as applicable Avoid decreasing renal and hepatic blood flow Advocate for your patient in RCM exposure Consider early and aggressive treatment with fluids, bicarb, n- acetylcysteine. Choose anesthetic agents accordingly if renal or hepatic disease is present We will not review which agents are appropriate for kidney and liver disease here

Ophthalmologic Complications
Conjunctivitis Iritis, episcleritis, scleritis Uveitis Lesions, ulcers Ocular vasculitis or inflammation Sicca syndrome, keratoconjunctivitis sicca Eye pain Optic neuritis Altered pupillary light response Diplopia, EOM weakness, gaze abnormality Photophobia, unilateral blindness, blurring, field cuts Diseases Ankylosing spondylitis - 40% unilateral uveitis Autoimmune thyroid disease Bullous pemphigoid & Pemphigus vulgaris IBD % with uveitis Lupus Multiple sclerosis Myasthenia gravis - 10% have only ocular symptoms Polymyositis Reactive arthritis, Rheumatoid arthritis, psoriatic arthritis Sjogren's Vasculotides, especially Bechet's & Giant cell arteritis Vitamin B12 deficiency Wegener's - lesions & 50-60% have ocular vasculitis AkS: commonly visual impairment with photophobia and eye pain. Graves: exophthalmos, opthamalopathy. EOM’s and orbital tissues are infiltrated with lymphocytes, plasma cells, and mucopolysaccharides. EOM’s swell to 5-10 times size. INO: internuclear opthalmoplegia – form of dysconjugate gaze, affected eye will not adduct. MG type I: ocular symptoms only. Sicca/keratoconjunctivitis – lack tear formation, predisposes to corneal injury/abrasion Wegener’s ocular involvement in 50-60%: eye ulcerations, vision loss, ulcerative keratitis, necrotizing scleritis, peripheral keratopathy, orbital pseudotumor, ocular myositis, uveitis, vitreous hemorrhage, CRAO (central retinal artery occlusion)

Eye Considerations Preoperative assessment for all AD patients
Current or previous visual deficits Lesions, dryness, inflammation or any other physical signs Coach susceptible patients with history of potential for postoperative flare or exacerbation Meticulous eye care Consider goggles in patients with history or potential eye involvement Thorough and deliberate postoperative evaluation Potential for treatment of visual changes, deficits, eye inflammation flares if promptly recognized Thrombosis origin: anticoagulation. Inflammatory origin: corticosteroids. Flares: plasmapheresis POVL is difficult to study due to the small rate of occurrences. Research frequently focuses on the kind of surgery (spine), the position (prone) and the presence of hypotension and/or anemia. However, upon limited review of case study literature it can be noted that vasculitis and other AD’s are represented among the cases. More research and review of these cases studies is needed here and may be under way as early as this year at Pitt. Despite a paucity of information on the role of AD in POVL specifically it is well established that eye complications occur throughout the disease course of many AD’s. It is not unreasonable to presume these patients are at higher risk from any and all kinds of eye complications. Sicca predisposes to corneal abrasions. Diseases with lesions can result in more fragile tissue or un-noticed pre-existing lesions. Neuropathy can result in double-crush syndrome injuries. Vasculitis and hypercoagulability can contribute to ischemic optic neuritis such as AION and CRAO.

Hematologic Complications
Diseases Anemia Graves (mild), Hashimoto’s (mild), RA (most), Sjogren’s, Lupus, Scleroderma Hemolytic anemia AI hemolytic anemia, Lupus, Drug-induced Leukopenia Rheumatoid arthritis, Sjogren’s, Lupus Megaloblastic anemia Vitamin B12 deficiency, Crohn's disease, Ulcerative colitis Thrombocytopenia Graves', ITP, TTP, Lupus, Vitamin B12 deficiency. Usually well tolerated >50k Hypercoagulability APS, Bechet's, Primary sclerosing cholangitis, Primary biliary sclerosis, Lupus, TTP, Vitamin B12 deficiency, HIT type 2, Crohn's, Ulcerative colitis, vasculotides Slowed primary hemostasis ITP, Primary sclerosing cholangitis, Primary biliary sclerosis Vasculitis examples: Buerger’s 40% superficial venous thromboses. Kawasaki’s – cardiac thromboses

Coagulopathy APS: recurrent arterial and venous thrombosis
APLs may be present in AI hepatitis, SLE Frequently subclinical until a critical ‘second hit’ such as surgery, pregnancy, trauma Crisis: CAPS – Catastrophic Antiphospholipid Syndrome Virchow’s Triad: Vascular injury (or inflammation) Venous stasis (or arterial) Hypercoagulability Standard coagulation tests will frequently not reveal hypercoagulability in the face of AD and even may be elevated.

Antiphospholipid syndrome
Beyond the scope of discussion today However, APS is a very interesting disease process and good example of patients with subclinical disease. Many patients will remain free from symptoms until a provocation event such as pregnancy, disease, infection or surgery. Others will have arterial or venous thrombotic events in the absence of these triggers. In addition to thrombotic events, these patients may experience miscarriages, IUGR/placental insufficiency and other negative pregnancy outcomes. It is suggested in the literature that a many as half of repeated miscarrying women have APS, which potentially opens an avenue of changing pregnancy outcome via anticoagulation in susceptible individuals. Expect future research.. (I did not review this content at this time as I did not cover pregnancy)

Coagulation Considerations
Aggressive VTE prophylaxis is frequently warranted in AD patients Anesthesia providers can advocate Potential for reduced protamine doses Early threshold to use TEG Keep patients WARM Avoid hemoconcentration Monitor for CAPS in APS especially undergoing CPB It’s not hard to see where patients with AD get their clots from… they experience chronic inflammation in various tissue and vascular beds both intermittently and/or continuously. Hypercoagulability comes with some diseases. Venous stasis can come from debilitating illness of any kind. When you add surgery to a patient already in a hypercoagulable or inflamed state the risks of thrombosis increase more than in a healthy patient. Numerous studies have addressed the prevalence of postoperative VTE in patients with AD. Most studies evaluate individual disease, and in particular the rheumatic diseases have been well studied due to their utilization of orthopedic surgery. The evidence demonstrates increased risks for VTE, but also demonstrates that this attention has resulted in quality care and VTE prophylaxis for rheumatic patients receiving orthopedic surgery. Other surgical specialties do not always provide the same level of VTE prophylaxis due to lower risks compared with orthopedic surgery. AD need aggressive VTE prophylaxis for most types of surgery. CAPS Trauma, cancer, diabetes, overweight/obese, infections, heart and respiratory disease, surgery, aging, pregnancy/pp, HRT, AI disease, superficial venous thrombosis. Common link: inflammatory conditions… venous thromboembolism. Graphic: (Saghazadeh & Rezaei, 2016)

Catastrophic Antiphospholipid Syndrome
CAPS is a rare syndrome of intravascular thrombosis and multi-organ failure Precipitating factor: surgery, infection, medication APL’s when triggered activate the clotting cascade Differential: CAPS, hemolytic-uremic syndrome, DIC, HIT Treatments Anticoagulation Anti-platelet medications Immunosuppression Plasmapheresis IVIG Primarily in microvasculature APL’s activate endothelial cells, platelets, immune cells, complement, promoting proinflammatory and prothrombotic cellular events APL’s inhibit anticoagulants and impair fibrinolysis SIRS may accompany the phenomenon. High rate of mortality

Common Outpatient Medications
Immunosuppressants, with few exceptions, should be continued during the perioperative period. Corticosteroids should not be interrupted Stress doses not usually needed, but may be useful in adrenal destruction Sometimes NSAIDS and antiplatelet medications need to be continued Anticholinesterase medications should be continued and may require dosing adjustments If meds were ordered to be continued make sure the patient took them. Disease activity itself is a risk for increased infection. This risk often outweighs risks associated with immunosuppression during the perioperative period. Disease flares can prove especially harmful in orthopedic cases where participation in rehabilitation is needed and inflammation around prosthesis can increase postoperative pain.

Preclinical Disease or Suspicion
Prodromal illness is common in autoimmune disease Abnormalities in laboratory markers of disease before the onset of clinical sign and symptoms Wide variability in diagnosis and treatment practices early in disease processes, in part due to vague or nonspecific presentations of disease Other risk factors: known other autoimmune disease, autoimmune disease in nuclear family, Native American ancestry Consider in the presence of ongoing fatigue and arthralgia. Be SUSPICIOUS Up to 50% of patients with apparent autoimmune rheumatic disease cannot be diagnosed for the first 12 months and are often described as having undifferentiated connective tissue disease. Avoidance of triggers if possible, vigilance and early treatment when triggers are unavoidable, such as surgery and pregnancy Clinical care as if autoimmune disease is present. Example: ½ of patients with palindromic rheumatism will go on to develop RA. These patients can benefit both from symptomatic treatment, but also DMARDS: hydroxychloroquine and may also reduce likelihood of progressing to RA AD may benefit from intervention in the absence of fully classifiable disease or symptoms. Expect the future to seek more changes here towards personalized medicine According to the WHO – case finding should be a continuous process, not a once and for all approach.

Preclinical Disease TIDM: 2+ autoantibodies 100% predictive
IBD: +autoantibodies present in 24-31% that later develop UC or CD WG: ANCA’s elevate prior to symptoms APS: antibodies are present prior to embolic events, sometimes present prior to SLE RA: RF and ANCA’s increase prior to development of symptoms SLE: ANAs present prior to symptoms, APL’s with + Coombs highly predictive Sjogren’s: commonly positive antibodies years prior to development of symptoms Celiac: antibodies increase prior to onset of symptoms Autoimmune thyroid disease: antibodies often present and highly predictive Autoimmune biliary disease: majority with Sjogren’s and antibodies develop symptoms Autoimmune adrenal disease: in DM1 patients antibodies precede adrenal destruction In the face of the knowledge that autoimmunity is fairly common and complex in presentation, healthcare providers should be aware of the possibility they encounter many undiagnosed, underdiagnosed and subclinical cases of autoimmune disease.

!WARNING SIGNS! Active flare activity
Vasculitis, vasculitis, vasculitis! Raynaud’s phenomenon, other abnormal hand circulation Rashes, Pathergy or Koebner phenomenon Vitamin B12 deficiency not otherwise explained Unexplained neuropathy, especially in adult females without diabetes Unexplained clotting history, especially in the face of normal or elevated coagulation times Nuclear family history of AD, especially if multiple family members and/or multiple diseases Multiple non-specific sequelae of autoimmune diseases Restless leg syndrome Narcolepsy Fibromyalgia What is that rash?! Oral or eye lesions Patients currently experiencing active disease flares should be thought of as similar to patients with active infection. They may not be suitable candidates for elective surgery and clearance should be obtained from their primary providers or consult considered from pulmonary, cardiac, rheumatology, neurology or other appropriate specialties. Active systemic inflammation for example is a contributor to VTE, but also may worsen with surgery and impact patient healing, risk for infection and ability to participate in rehabilitation.

Conclusions AD is more diverse, complex and prevalent than many providers are aware Complications are also often diverse and complex Proof of polyautoimmunity is not necessary in order to be suspicious and vigilant Insidious development of complications is a major source of risk factors for cardiovascular disease and other end-organ involvement Patients with more complications, more diseases are sicker, even if their symptoms are not severe. Disease activity level is often highly correlated with complications, not just severity of symptoms The future will undoubtedly provide more research to guide evidence- based practice Current evidence suggests more aggressive preoperative assessment and perioperative care is warranted to reduce the likelihood of complications related to the stresses of surgery, disease flares, end-organ involvement. Patients currently experiencing flares should be thought of as similar to patients with active infection. They may not be suitable candidates for elective surgery and clearance should be obtained from their primary providers or consult considered from pulmonary, cardiac, rheumatology, neurology or other appropriate specialties A good question to ask yourself, when in doubt if this was your mom or your sister… what would you do? It’s time to see these patients for how diverse, complex and potentially sick they may be. We can have a lasting impact on their well-being by modifying risk factors during the perioperative period.

Abbreviations AkS – Anklyosing spondylitis
APS – Antiphospholipid syndrome BD – Bechet’s disease CSS – Churg-Strauss syndrome CD – Crohn’s disease DM – dermatomyositis DM1 – Diabetes type 1 ELMS – Eaton Lambert myasthenic syndrome GCA – Giant cell arteritis GBS – Guillain-Barre syndrome HSP – Henoch–Schönlein purpura HIT2 – Heparin-induced thrombocytopenia type 2 MS – Multiple sclerosis MG – Myasthenia gravis PAN - Polyarteritis nodosa PMR – Polymyalgia rheumatica PM – Polymyositis PBC – Primary biliary cirrhosis PSC – Primary sclerosing cholangitis PG – Pyoderma gangrenosum RA – Rheumatoid arthritis SLE – Systemic Lupus Erythematosus SSc – Systemic sclerosis (scleroderma) UC – ulcerative colitis WG – Wegener’s (Granulomatosis with polyangiits)

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Anesthetic Implications of Polyautoimmunity in Surgical Patients

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Anesthetic Implications of Polyautoimmunity in Surgical Patients

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