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Interpretation of Diagnostic Tests

Pathways to Arriving at a Clinical Diagnosis

TENTH EDITION

Interpretation of Diagnostic Tests

Pathways to Arriving at a Clinical Diagnosis

TENTH EDITION

Edited by

Mary A Williamson, MT (ASCP), PhD

Vice President, Scientific Affairs & Laboratory Operations

ACM Medical Laboratory

Rochester, New York

Former Assistant Professor

Department of Medicine and Pathology

University of Massachusetts Medical School

UMass Memorial Medical Center

Worcester, Massachusetts

Chief Medical Officer

Quest Diagnostics MA, LLC

Marlborough, Massachusetts

Executive Editor: Rebecca Gaertner

Senior Product Development Editor: Kristina Oberle

Production Project Manager: Alicia Jackson

Design Coordinator: Joan Wendt

Senior Manufacturing Coordinator: Beth Welsh

Marketing Manager: Stephanie Manzo

Prepress Vendor: SPi Global

Printed in China

Copyright © 2015 Wolters Kluwer

© 2011, 2007 by LIPPINCOTT WILLIAMS & WILKINS, a Wolters Kluwer Business, © 2000 by Lippincott Williams & Wilkins, ©

1996, 1992 and 1986 by Jacques Wallach, MD, © 1978, 1974 and 1970 by Little, Brown and Company

Two Commerce Square

Library of Congress Cataloging-in-Publication Data Wallach's interpretation of diagnostic tests — Tenth edition / edited by Mary

A Williamson, L Michael Snyder.

p ; cm.

Includes bibliographical references and index.

ISBN 978-1-4511-9176-9 (paperback : alk paper)

I Williamson, Mary A., editor II Snyder, L Michael, editor.

[DNLM: 1 Clinical Laboratory Techniques 2 Diagnostic Techniques and Procedures QY 25]

The authors, editors, and publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accordance with the current recommendations and practice at the time of publication However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions This is particularly important when the recommended agent is a new or infrequently employed drug.

Some drugs and medical devices presented in this publication have Food and Drug Administration (FDA) clearance for limited use in restricted research settings It is the responsibility of the health care provider to ascertain the FDA status of each drug or device planned for use in his or her clinical practice.

9 8 7 6 5 4 3 2 1

I am deeply grateful to my parents Priscilla and Thomas Williamson for their unconditional love Sincere thanks to Joanne Saksa for her gracious hospitality and warmest gratitude to Brenda DeMay, for her unconditional love and continually

encouraging me to challenge myself.

I am most indebted to Dr L Michael Snyder, a true mentor throughout the years who has taught me that anything is possible— even the Boston Red Sox can win the World

Series! Special thanks to all of the authors for their hard work and commitment,

especially Liberto Pechet, a true gentleman.

Mary A Williamson, MT(ASCP), PhD

To my wife Barbara, and children Cathe, Lizzy, and John for their tireless

understanding and support throughout the years.

To my assistant Suzanne O’Brien for her dedication and help with the textbook.

I would also like to acknowledge Dr Mary Williamson, for without her commitment, dedication and hard work, we would not have met the target date for completion of

the tenth edition.

L Michael Snyder, MD

M Rabie Al-Turkmani, BPharm, PhD

Assistant Professor

Department of Pathology

University of Massachusetts Medical School

Associate Director, Immunology, Immunoassay & Hematology Laboratories

UMass Memorial Medical Center

Medical Director, Transfusion Medicine

North Shore University Hospital

Hofstra North Shore-LIJ School of Medicine North Shore-LIJ Health System

Manhasset, New York

Marzena M Galdzicka, PhD, MP(ASCP)CM, DABCC

Clinical Assistant Professor

Edward I Ginns, MD, PhD, DABCC

Professor of Neurology, Pathology, Pediatrics and Psychiatry

Director, Lysosomal Disorders Treatment and Research Program

University of Massachusetts Medical School

University of Massachusetts Medical School

Director, Andrology Laboratory

Director, Clinical Assay Research

UMass Memorial Medical Center

Worcester, Massachusetts

Patricia Minehart Miron, PhD

Clinical Associate Professor of Pathology and PediatricsUniversity of Massachusetts Medical School

Departments of Pathology and Medicine

University of Massachusetts Medical School

Worcester, Massachusetts

Lokinendi V Rao, PhD

Clinical Associate Professor

Department of Pathology

University of Massachusetts Medical School

Laboratory Director, UMass Memorial Clinical LaboratoriesUMass Memorial Medical Center

University of Massachusetts Medical School

Director, Cardiac Intensive Care

Department of Medicine and Pathology

University of Massachusetts Medical School

UMass Memorial Medical Center

Worcester, Massachusetts

Chief Medical Officer,

Quest Diagnostics MA, LLC

Marlborough, Massachusetts

Juliana G Szakacs, MD, MSW

Director of Pathology and Laboratory Medicine

Harvard Vanguard Medical Associates

Boston, Massachusetts

Mary A Williamson, MT (ASCP), PhD

Vice President, Scientific Affairs & Laboratory OperationsACM Medical Laboratory

Rochester, New York

Former Assistant Professor

University of Massachusetts Medical School

Director, Hematopathology and Hematopathology Fellowship ProgramDirector, Flow Cytometry Laboratory

UMass Memorial Medical Center

Worcester, Massachusetts

Tribute to Jacques Wallach

Jacques Wallach, pathologist, educator, and author of this book left us on August 10, 2010 He was

84 Forty years before that, he wrote the first edition, widely recognized as a necessary resource forboth busy house staff and seasoned clinicians alike It was the product of his vast experience as aclinical pathologist, his unquenchable thirst for medical knowledge, and his passion for teaching Hedevoted tireless hours of research toward updating this book seven times since then Severalhundreds of thousands of copies have been distributed in numerous translations throughout the world

As a resident in Internal Medicine in the mid-1980s, my first encounter with this book came in theearly hours before our daily morning report, as my fellow house officers scurried to review theovernight admissions prior to presenting these cases to the Department Chief The ensuing hour wasusually punctuated by moments when one or more of us incurred the Chief’s wrath for failure toaccurately appreciate the patient’s disorder or appropriately intervene In an effort to avoid a similarfate, each of us would keep a copy of the book in an overfilled pocket of our lab coat to reviewquickly prior to this daily inquisition Years later, I witnessed many students and house officers under

my supervision do same, often secretly racing each other to the passage contained therein that wouldearn them the sought after recognition of their peers

In the years that followed, I saw the third edition of the book become the fourth, fifth, and so on,never really appreciating the work that Jacques put into each update Like many of us, however, I didappreciate the place that each update had among my collection of those clinical books, which werealways kept within easy reach and never seemed to collect any dust in my personal medical library

When I first met Jacques, I was impressed by his dedication and commitment to medicaleducation He taught pathology at Albert Einstein, Rutgers, and SUNY Downstate and consulted forChildren’s Specialized Hospital in Mountainside, South Amboy Memorial Hospital, Kings County

Hospital in Brooklyn, and for the Bronx Zoo He also wrote Rheumatic Heart Disease (1962) and

Interpretation of Pediatric Tests (1983) as well as over 40 articles for peer review medical

journals He was a Fellow of the American College of Physicians, the American Society of ClinicalPathologists, the College of American Pathologists, and the New York Academy of Medicine From

1975 to 1985, he donated his time and expertise in pathology to laboratories around the world Hisoffice was crammed with countless notes he made while researching, scrolled on small pieces ofpaper, and filed between the pages of dozens of medical books and journals, waiting their turn toadorn the pages of his next book It was like he realized that clinicians and patients around the worlddepended on him to unlock the keys to their own medical mysteries, and he did not take thatresponsibility lightly More recently, Jacques asked me to join his small list of distinguishedcontributors and lend some assistance in my own area of expertise To contribute in some small way

to his labor of love was truly an honor

As the devoted teacher, nothing was more rewarding to Jacques than being able to impart thewisdom he had worked hard to accumulate to the pupil looking for guidance This ninth edition and

all subsequent editions, now entitled Wallach’s Interpretation of Diagnostic Tests, represent his

legacy and his ongoing gift to physicians around the world who continue to use his guidance everyday

to care for their patients I have no doubt that nothing would have made him happier

ANTHONY G AUTERI, MD

In the 10th edition of Wallach’s, the authors continue to modify the content and organization based onfeedback from readers as well as attempting to keep pace with a rapidly changing health careenvironment Since the main focus of the textbook is to stress the most efficient use of clinical labtesting, we have changed the format so that the first section will now be devoted to disease states.Moreover, we have extended the presentation of the patient’s chief complaints and physical findingsformat to additional chapters such as pulmonary, cardiac, and neurologic disease states We haveadded chapters on HLA, Transfusion Medicine, and OBGYN and updated the chapters on MolecularDiagnostics and Cardiology

The second section will now list the individual lab tests in alphabetical order stressing theintegration of the clinical laboratory results in the clinical decision-making process Whenappropriate, tests will include the sensitivity, specificity, and positive and negative probability.Infectious disease assays as before are listed separately

We have enhanced the index to make it easier for the reader to locate the subjects of interest Inaddition, we have created a robust electronic version, which will include “hypertexting” of testsmentioned in the disease section referring back to the individual test section This textbook does notinclude references to pathophysiology or therapy However, common pitfalls and limitations of testing

as well as identifying appropriate tests for specific clinical presentations are addressed

As in previous editions, this textbook is geared to the primary care physician, subspecialists,physician’s assistant, nurse practitioner, as well as medical and nursing students The 10th edition isnot an exhaustive catalogue of disease states but a practical guide We would appreciate continuedfeedback about changes we have instituted and further comments

L MICHAEL SNYDER, MD

GARY LAPIDAS

MARY A WILLIAMSON, MT (ASCP), PHD

Preface to the First Edition

Results of laboratory tests may aid in

Discovering occult disease

Preventing irreparable damage (e.g., phenylketonuria)

Early diagnosis after onset of signs or symptoms

Differential diagnosis of various possible diseases

Determining the stage of the disease

Estimating the activity of the disease

Detecting the recurrence of disease

Monitoring the effect of therapy

Genetic counseling in familial conditions

Medicolegal problems, such as paternity suits

This book is written to help the physician achieve these purposes the least amount of

Duplication of texts

Waste of patient’s money

Overtaxing of laboratory facilities and personnel

Loss of physician’s time Confusion caused by the increasing number, variety, and complexity oftests currently available Some of these tests may be unrequested but performed as part ofroutine surveys or hospital admission multitest screening

In order to provide quick reference and maximum availability and usefulness, this handy-sized book

features

Tabular and graphic style of concise presentation

Emphasis on serial time changes in laboratory findings in various stages of disease

Omission of rarely performed, irrelevant, esoteric, and outmoded laboratory tests

Exclusion of discussion of physiologic mechanisms, metabolic pathways, clinical features, andnonlaboratory aspects of disease

Discussion of only the more important diseases that the physician encounters and should be able

to diagnose

This book is not

An encyclopedic compendium of clinical pathology

A technical manual

A substitute for good clinical judgment and basic knowledge of medicine

Deliberately omitted are

Technical procedures and directions

Photographs and illustrations of anatomic changes (e.g., blood cells, karyotypes, isotope scans)Discussions of quality control

Selection of a referral laboratory

Performance of laboratory tests in the clinician’s own office

Bibliographic references, except for the most general reference texts in medicine, hematology, andclinical pathology and for some recent references to specific conditions

The usefulness and need for a book of this style, organization, and contents have been increased by

such current trends as

The frequent lack of personal assistance, advice, and consultation in large commercial

laboratories and hospital departments of clinical pathology, which are often specialized andfragmented as well as impersonal

Greater demand for the physician’s time

The development of many new tests

Faculty and administrators still assume that this essential area of medicine can be learned

“intuitively” as it was 20 years ago and that it therefore requires little formal training Thisattitude ignores changes in the number and variety of tests now available as well as theirincreased sophistication and basic value in establishing a diagnosis

The contents of this book are organized to answer the questions most often posed by physicianswhen they require assistance from the pathologist There is no other single adequate source ofinformation presented in this fashion It appears from numerous comments I have received that thisbook has succeeded in meeting the needs not only of practicing physicians and medical students butalso of pathologists, technologists, and other medical personnel It has been adopted by many schools

of nursing and of medical technology, physician’s assistant training programs, and medical schools.Such widespread acceptance confirms my original premise in writing this book and is most gratifying

A perusal of the table of contents and index will quickly show the general organization of thematerial by type of laboratory test or organ system or certain other categories In order to maintain aconcise format, separate chapters have not been organized for such categories as newborn, pediatric,and geriatric periods or for primary psychiatric or dermatologic diseases A complete index providesmaximum access to this information

Obviously, these data are not original but have been adapted from many sources over the years.Only the selection, organization, manner of presentation, and emphasis are original I have formulatedthis point of view during 40 years as a clinician and pathologist, viewing with pride the important andgrowing role of the laboratory but deeply regretting its inappropriate utilization

This book was written to improve laboratory utilization by making it simpler for the physician toselect and interpret the most useful laboratory tests for his clinical problems

J.W

Contributors Tribute to Jacques Wallach Preface

Preface to the First Edition

Introduction

CHAPTER 1 FALTs: Factors Affecting Laboratory Tests

Lokinendi V Rao

SECTION 1 DISEASE STATES

CHAPTER 2 Autoimmune Diseases

CHAPTER 5 Digestive Diseases

L Michael Snyder and Michael J Mitchell

CHAPTER 6 Endocrine Diseases

CHAPTER 10 Hereditary and Genetic Diseases

Marzena M Galdzicka, Patricia Minehart Miron, and Edward I Ginns

CHAPTER 11 Infectious Diseases

Michael J Mitchell

CHAPTER 12 Renal Disorders

M Rabie Al-Turkmani

CHAPTER 13 Respiratory, Metabolic, and Acid–Base Disorders

Lokinendi V Rao and Michael J Mitchell

CHAPTER 14 Toxicology and Therapeutic Drug Monitoring

Amanda J Jenkins

CHAPTER 15 Transfusion Medicine

Vishesh Chhibber

SECTION 2 LAB TESTS

CHAPTER 16 Laboratory Tests

Lokinendi V Rao and Liberto Pechet

CHAPTER 17 Infectious Disease Assays

Michael J Mitchell and Lokinendi V Rao

APPENDIX Abbreviations and Acronyms

Index

Introduction Chapter 1

FALTs: Factors Affecting Laboratory Tests

Diagnostic Test Values

Accuracy and Precision

Receiver Operating Characteristic (ROC) Curves

Postanalytic Errors

Reference Intervals

Performing the Right Test at the Right Time for the Right Reason

Laboratory testing is an integral part of modern medical practice Although clinical laboratory testingaccounts for only 2.3% of annual health care costs in the United States, it plays a major role in theclinical decisions made by physicians, nurses, and other health care providers for the overallmanagement of disease More than 4,000 laboratory tests are available for clinical use, and about 500

of them are performed regularly The number of Clinical Laboratory Improvement Amendments(CLIA)-certified laboratories has grown to exceed more than 200,000 The laboratory medicineworkforce comprises pathologists, doctorallevel laboratory scientists, technologists, and technicians,who play a vital role in the health care system

The health care system is increasingly dependent on reliable clinical laboratory services;however, as part of the overall health care system, these laboratory evaluations are prone to errors.Laboratory medicine comprises more than just the use of chemicals and reagents for the measurement

of various analytes for clinical diagnosis purposes Interference by both endogenous and exogenoussubstances is a common problem for the test analysis These substances play a significant role in theproper interpretation of results, and such interference is adverse to patient care and adds to the cost ofhealth care It would be an oversimplification to conclude that each variable will always produce a

specific effect; it depends on the person, the duration of exposure to that variable, and the timebetween initial stress, the sample collection, and the degree of exposure Awareness that many factorsoccurring outside the laboratory in and around the patient may affect the test result before the samplereaches the laboratory or even before the sample is collected is very important These factors can beminimized when the clinician takes a good history and when there is a good communication of suchinformation between the laboratory and the physician.

WHAT CAUSES ABNORMAL TEST RESULTS (BESIDES

DISEASE)?

The total testing process defines the preanalytic, analytic, and postanalytic phases of laboratorytesting and serves as the basis for designing and implementing interventions, restrictions, or limitsthat can reduce or remove the likelihood of errors Over the last several years, there has been aremarkable decrease in error rates, especially analytic errors Evidence from recent studiesdemonstrates that a large percentage of laboratory errors occur in preanalytic and postanalytic steps.Errors in the preanalytic (61.9%) and postanalytic (23.1%) processes occurred much more frequentlythan occurrences of analytic errors (15%) About one fourth of these can have consequences to thepatient either in delay of the test result or life threatening

PREANALYTIC ERRORS

Preanalytic factors act on both the patient and the specimen before analyses These factors may bedivided further into those acting in vivo (biologic or physiologic) and those acting in vitro (specimenhandling and interference factors)

PHYSIOLOGIC FACTORS

Some physiologic factors are beyond our control They include age, sex, and race, and so on, and can

be managed by placing appropriate reference limits Others factors such as diet, starvation, exercise,posture, diurnal and seasonal variations, menstrual cycle, and pregnancy must be considered in theinterpretation of the test results Age has noticeable effect on some test results and the need forestablishing appropriate reference intervals In newborns, the composition of blood is affected by thematurity of the infant at birth At birth, RBC and hemoglobin values are higher than adults due to lowlevels of oxygen in the uterus They continue to decrease and level out to adult values about the age of

15 Adult values are usually taken as the reference for comparison with those of the young and theelderly The concentration of most test constituents remains constant between puberty and menopause

in women and between puberty and middle age in men The plasma concentrations of manyconstituents increase in women after menopause Hormone levels are affected by aging However,changes in concentrations are much less pronounced than an endocrine organ’s response to stimuli.Until puberty, there are few differences in laboratory data between boys and girls After puberty, thecharacteristic changes in the levels of sex hormones become apparent

In addition to the commonly known hormonal changes during the menstrual cycle, there is apreovulatory increase in the concentrations of aldosterone and renin Coincident with the ovulation,

serum cholesterol levels are lower than at any other phase of the menstrual cycle In pregnancy, adilutional effect is observed due to the increase in mean plasma volume, which in turn causeshemodilution Normal pregnancy is characterized by major physiologic adaptations that alter maternalblood chemistry and hematology laboratory values In addition, there are time-related fluctuations inthe levels of certain analytes Many analytes—such as cortisol, thyrotropin (TSH), growth hormone,potassium, glucose, iron, and proinflammatory cytokines—exhibit diurnal variation Hormones such

as luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone released in shortbursts lasting barely 2 minutes make accurate measurements problematic Seasonal changes alsoaffect certain analytes like vitamin D (higher during summer), cholesterol, and thyroid hormones(higher during winter) Changes in the levels of some of the constituents in blood occur whenmeasured at sea level as opposed to measurement at a higher altitude Hematocrit, hemoglobin, andC-reactive protein (CRP) can be higher at high altitude Levels of plasma renin, transferrin, urinarycreatinine, creatinine clearance, and estriol decrease with increasing altitude

The dietary effect of laboratory test results is complex and simply cannot be separated into thecategories of “fasting” and “nonfasting” status of the patient A significant variation in some routinetests after a regular meal showing that fasting time needs to be carefully considered when performingtests to prevent spurious results Clinically significant differences are observed within 1–4 hours fortriglycerides, albumin, ALT, calcium, iron, LDH, phosphorus, magnesium, lymphocytes, RBC,hemoglobin, hematocrit, etc The type of diet (high fat, low fat, vegetarian, malnutrition), length oftime since last meal, and test-specific dietary concerns can affect some tests Consumption ofcaffeine, bran, serotonin (consumption of fruits and vegetables such as bananas, avocados, andonions), herbal preparations (e.g., aloe vera, Chinese rhubarb, senna, quinine, and quinidine),recreational drug use, ethanol, and smoking can induce both short- and long-term effects that alter theresults of several analytes Differentiations of the effects of race from those of socioeconomicconditions are difficult Carbohydrate and lipid metabolism differ in blacks and whites Glucosetolerance is less in blacks, Polynesians, and Native Americans in comparison to whites

Physical stress and mental stress influence the concentrations of many plasma constituents,including cortisol, aldosterone, prolactin, TSH, aldosterone, cholesterol, glucose, insulin, and lactate.With blindness, the normal stimulation of the hypothalamic–pituitary axis is reduced Consequently,certain features of hypopituitarism and hypoadrenalism may be observed In some blind individuals,the normal diurnal variations of cortisol may persist; in others, it does not Fever provokes manyhormonal responses as does shock and trauma The stress of surgery has been shown to reduce theserum triiodothyronine (T3) levels by 50% in patients without thyroid disease

Transfusions and infusions can also significantly affect the concentration of certain laboratoryvalues For persons receiving an infusion, blood should not be obtained proximal to the infusion site.Blood should be obtained from the opposite arm A minimum of 8 hours must elapse before blood isobtained from a subject who has received fat emulsion For patients receiving blood transfusions, theextent of hemolysis and with it increased levels of potassium, lactate dehydrogenase (LDH), and freehemoglobin are released progressively to the age of the transfused blood

Exercise such as running up and down several flights of stairs or strenuous activity such asworking out in a gymnasium or marathon running the night before the specimen collection can affectthe results obtained for several analytes To minimize preanalytic variables introduced by exercise,subjects should be instructed to refrain from strenuous activity on the night before testing and not toexert themselves by walking a long distance, running, or climbing stairs before blood specimencollection In addition, the muscle damage associated with trauma of surgery will increase the serum

activity of enzymes originating in skeletal muscles, and this activity may persist for several days.The plasma and extracellular volumes decrease within a few days of the start of bed rest Withprolonged bed rest, fluid retention occurs and plasma protein and albumin levels may be decreased

by an average of 0.5 and 0.3 g/dL, respectively As a result, concentrations of bound protein are alsoreduced Changes in posture during blood sampling can affect the concentrations of several analytesmeasured in serum or plasma Change in posture from a supine to an erect or sitting position canresult in a shift in body water from intravascular to interstitial compartments As a result, theconcentrations of larger molecules that are not filterable are increased These effects are accentuated

in patients with a tendency for edema, such as in cardiovascular insufficiency and cirrhosis of theliver

SPECIMEN HANDLING FACTORS

Among controllable preanalytic variables, specimen collection is most critical Unacceptablespecimen collection due to misidentification, insufficient volume to perform test, incorrect wholeblood-to-anticoagulant ratio, and specimen quality (hemolysis, clots, contaminated, collected inwrong container) accounts for the majority of preanalytic errors Hemolysis, lipemia, and ictericsamples have variable effects on assays and depend upon testing method and analyte The time andtemperature for storage of the specimen and the processing steps in the preparation of serum orplasma or cell separation can introduce preanalytic variables

Pneumatic tube systems of various lengths are routinely used in many hospitals to transport bloodcollection tubes to the testing laboratory Significant differences between plasma but not serum levels

of LDH are observed when blood collection tubes are transported through pneumatic tube systems.The application of a tourniquet, by reducing the pressure below the systolic pressure, maintains theeffective filtration pressure within the capillaries As a result, small molecules and fluid aretransferred from the intravasal space to the interstitium Application of tourniquet for longer than 1minute can result in hemoconcentration of large molecules that are unable to penetrate the capillarywall To minimize the preanalytic effects of tourniquet application time, the tourniquet should bereleased as soon as the needle enters the vein Avoidance of excessive fist clenching duringphlebotomy and maintaining tourniquet application time to no more than 1 minute can minimizepreanalytic errors

Various salts of heparin, ethylenediaminetetraacetic acid (EDTA), and sodium citrate are usedwidely in the clinical laboratory Heparin is the preferred anticoagulant for blood specimens forelectrolyte levels and other routine chemistry tests Obvious differences in the results of certainanalytes between serum and heparinized plasma are related to the consumption of fibrinogen and thelysis of cellular elements during the process of clotting EDTA is the commonly used anticoagulant forroutine hematologic determinations It functions as anticoagulant by chelating calcium ions, which arerequired for the clotting process Citrate has been used as an anticoagulant for collection of bloodspecimens intended for global coagulation tests such as prothrombin time (PT) and partialthromboplastin time (PTT) A laboratory that has been using one of the concentrations (3.2% or3.8%) to perform PT determination for patients receiving oral anticoagulant therapy should notinterchange the formulations Doing so will affect the international normalized ratios (INRs) that areused to report the results of PT Sodium fluoride and lithium iodoacetate have been used alone or incombination with anticoagulants such as potassium oxalate, EDTA, citrate, or lithium heparin forblood collection In the absence of glycolytic inhibitors, a decrease in the glucose level of as much as

24% can occur in 1 hour after blood collection in neonates, in contrast to a 5% decrease in healthyindividuals when specimen is stored at room temperature The anticoagulant-to-blood ratio is criticalfor some laboratory tests In general, collecting of blood specimens to less than nominal volumeincreases the effective molarity of the anticoagulant and induces osmotic changes affecting cellmorphologic features Furthermore, the binding of analytes such as ionic calcium or magnesium toheparin can be enhanced when the effective concentration of unfractionated heparin increased beyondthe normal 14.3 U/mL of blood In addition, stability of various analytes are significantly reduced inplasma (Lithium Heparin) compared to serum tubes when plasma is stored, but not separated from thegel after centrifugation.

Virtually, all drugs may affect the results of clinical laboratory tests that includes both in vivo(pharmacologic) and in vitro (interferences and methodologic) effects The problem of druginterference is complex, and physicians are generally aware of main therapeutic effects of drug, butmany secondary effects are ignored Some of the examples are increase in liver enzymes withDilantin and barbiturates, increase in fibrinogen, transferrin, amylase, etc following oralcontraceptives and contrast agents (gadolinium) decreasing total calcium levels

In coagulation, testing knowledge or access to the patient history may be necessary, as manymedications such as anticoagulant therapies (warfarin, heparin, and direct thrombin inhibitors), bloodproduct, and component transfusion and coagulation factor replacement therapies all impactcoagulation test results Over-the-counter drugs (aspirin) have prolonged effect on platelet functionstudies In addition, the patient’s physiologic state plays a role

The quality of the specimens submitted to the microbiology laboratory is critical for optimalspecimen evaluation The general techniques of specimen collection and handling that have beenestablished both to maximize the yield of organisms and isolate relevant pathogens from specimensobtained from different body sites should be reviewed with clinical laboratory prior to obtaining thespecimen In addition, valid interpretation of the results of culture can be achieved only if thespecimen obtained is appropriate for processing As a result, care must be taken to collect only thosespecimens that may yield pathogens, rather than colonizing flora or contaminants Specific rules forthe collection of material vary, depending on the source of the specimen, but several generalprinciples apply Prompt transport of specimens to the microbiology laboratory is essential tooptimize the yield of cultures and the interpretation of results Delays in processing may result in theovergrowth of some microorganisms or the death of more fastidious ones Samples for bacterialculture should ideally arrive in the microbiology laboratory within 1 to 2 hours of collection If adelay is unavoidable, most specimens (with the exception of blood, cerebrospinal fluid, joint fluid,

and cultures for Neisseria gonorrhoeae) should be refrigerated until transported.

ANALYTIC ERRORS

Clinical laboratories have long focused their attention on quality control methods and qualityassessment programs dealing with analytic aspects of testing Total analytic error (or measurementerror) refers to assay errors from all sources arising from the data collection experiment Some error

is expected, because not all components of measuring are the same There are four major types ofexperimental error: random (not predictable), systematic (one direction), total (random andsystematic), and idiosyncratic (nonmethodologic)

Errors due to analytic problems have been significantly reduced over time, but there is evidence

that, particularly for immunoassays, interference may have a serious impact on patients Paraproteinscan interfere in chemical measurements when they form precipitates during the testing procedure.Heterophilic antibodies are human antibodies that can bind animal antibodies They can causeproblems in immunoassays, particularly immunometric assays, where they can form a bridge betweenthe capture and detection antibodies, leading to false-positive results in the absence of analyte or ifanalyte is also present, a false increase in measured concentrations Very rarely, heterophilicantibodies can also lead to false-negative or falsely low results.

Very high hormone levels can interfere with immunoassay systems, resulting in falsely low analytedeterminations This is attributable to the “hook effect,” which describes the inhibition of immunecomplex formation by excess antigen concentration There are proteins that are well known to formaggregates with immunoglobulins or high molecular weight proteins Clinically relevant proteins thatcan have “macro” forms—including amylase, creatinine kinase, LDH, and prolactin—can elevate theresults when using certain laboratory tests, yet the patient lacks clinical disease related to elevatedanalyte concentration

Immunoassay interference is not analyte specific and is variable with respect to time In some

patients, this interference can lost for a long time and in some for only a short time This interferenceaffects lots of assays but not all of them In addition, a different manufacturer’s test kits have differentcross-reactions with interference compounds, and the test results vary from lab to lab

Incorrect results can also occur as a result of a large number of biologically common phenomenacausing analytic variation These include cold agglutinins, rouleaux, osmotic matrix effects, plateletagglutination, giant platelets, unlysed erythrocytes, nucleated erythrocytes, megakaryocytes, red cellinclusions, cryoproteins, circulating mucin, leukocytosis, in vitro hemolysis, extreme microcytosis,bilirubinemia, lipemia, and so on

DIAGNOSTIC TEST VALUES

Before a method is used routinely, method evaluation protocols must ensure that the measurementprocedure meets defined criteria, for example, the accuracy, precision, and stability required inmeeting the laboratory’s patient population needs Four indicators are most commonly used todetermine the reliability of a clinical laboratory test Two of these, accuracy and precision, reflecthow well the test method performs day to day in a laboratory The other two, sensitivity andspecificity, deal with how well the test is able to distinguish disease from the absence of disease

The accuracy and precision of each test method are established and are frequently monitored bythe clinical laboratory Sensitivity and specificity data are determined by research studies andclinical trials Although each test has its own performance measures and appropriate uses, laboratorytests are designed to be as precise, accurate, specific, and sensitive as possible

ACCURACY AND PRECISION

“Accuracy” (trueness) refers to the ability of the test to actually measure what it claims to measure

and is defined as the proportion of all test results (both positive and negative) that are correct

Precision (repeatability) refers to the ability of the test to reproduce the same result when repeated

on the same patient or sample The two concepts are related, but different For example, a test could

be precise but not accurate if on three occasions it produced roughly the same result but that result

differed greatly from the actual value determined by a reference standard.

Sensitivity is defined as the ability of the test to identify correctly those who have the disease It

is the number of subjects with a positive test who have the disease divided by all subjects who have

the disease A test with high sensitivity has few false-negative results Specificity is defined as the

ability of the test to identify correctly those who do not have the disease It is the number of subjectswho have a negative test and do not have the disease divided by all subjects who do not have thedisease A test with high specificity has few false-positive results Sensitivity and specificity aremost useful when assessing a test used to screen a free-living population These test characteristicsare also interdependent (Figure 1-1): an increase in sensitivity is accompanied by a decrease inspecificity and vice versa

Figure 1–1 Sensitivity, specificity, and predictive values in laboratory testing NPV, negative predictive value; PPV, positive

predictive value.

Predictive values are important for assessing how useful a test will be in the clinical setting at the

individual patient level The positive predictive value (PPV) is the probability of disease in a patient with a positive test Conversely, the negative predictive value (NPV) is the probability that the

patient does not have disease if he has a negative test result

PPV and sensitivity of tests are complementary in their examination of true positives Given thatthe test is positive, PPV is the probability that the disease is present, in contrast to sensitivity, which

is given that the disease is present, the probability that test is positive Likewise, NPV and specificityare complementary in their examination of true negatives Given that the test is negative, NPV is theprobability that the disease is absent This is in contrast to specificity, which is given that the disease

is absent, the probability that test is negative (see Figure 1-1 for more information) Predictive valuesdepend on the prevalence of a disease in a population A test with a given sensitivity and specificitycan have different predictive values in different patient populations If the test is used in a populationwith high disease prevalence, it will have a high PPV; the same test will have a low PPV when used

in a population with low disease prevalence

Likelihood ratios (LRs) are another way of assessing the accuracy of a test in the clinical setting.

They are also independent of disease prevalence LR indicates how much a given diagnostic testresult will raise or lower the odds of having a disease relative to the probability of the disease Eachtest is characterized by two LRs: positive LR (PLR) and negative LR (NLR) PLR tells us the odds of

the disease if the test result is positive, and NLR tells the odds of disease if the test result is negative.

An LR >1 increases the odds that the person has the target disease, and the higher the LR, the greaterthis increase in odds Conversely, an LR ratio <1 diminishes the odds that the patient has the targetdisease

RECEIVER OPERATING CHARACTERISTIC (ROC) CURVES

ROC curves allow one to identify the cutoff value that minimizes both false positives and falsenegatives An ROC curve plots sensitivity on the y axis and 1 − specificity on the x axis Applying avariety of cutoff values to the same reference population allows one to generate the curve The perfecttest would have a cutoff value that allowed an exact split of diseased and nondiseased populations(i.e., a cutoff that gave both 100% sensitivity and 100% specificity) It would plot as a right anglewith the fulcrum in the far upper left corner (x = 0, y = 1) This case, however, is very rare For mostcases, as one moves from the left to right on the ROC curve, the sensitivity increases and thespecificity decreases

Calculation of the area under the ROC curve allows comparison of different tests A perfect testhas an area under the curve (AUC) equal to 1 Therefore, the closer the AUC is to 1, the better thetest Similarly, if one wants to know the cutoff value for a test that minimizes both false positives andfalse negatives (and hence maximizes both sensitivity and specificity), one would select the point onthe ROC curve closest to the far upper left corner (x = 0, y = 1)

However, finding the right balance between optimal sensitivity and specificity may not involvesimultaneously minimizing false positives and false negatives in all situations For example, whenscreening for a deadly disease that is curable, it may be desirable to accept more false positives(lower specificity) in return for fewer false negatives (higher sensitivity) ROC curves allow a morethorough evaluation of a test and potential cutoff values but are not the ultimate arbiters of how to setsensitivity and specificity

POSTANALYTIC ERRORS

Approximately 70–80% of the patient chart or medical record is composed of laboratory test results.Postanalytic errors are dependent on the design and development of those processes and proceduresthat will ensure correct and timely notification of these test results to the patient’s medical recordwith right reference range and appropriate interpretation of the test result Manual and telephonereporting should be discouraged as this reporting is subject to transcription errors at the receiver end.The introduction of a hospitalized computer order entry system has eliminated some errors, but it hasnot eliminated the risk of mismatching the patients

REFERENCE INTERVALS

The term “reference values” has essentially replaced the obsolete term “normal values.” Laboratorytests are commonly compared to a reference interval before health care providers make physiologicassessments, medical diagnosis, or management decisions These comparisons may be cross-sectional or longitudinal A cross-sectional comparison is comparison of an analyte result for a singlepatient with the interval of results for that analyte obtained from a group of apparently healthyindividuals This is referred to as the “population-based” reference interval Another example of across-sectional comparison is when a single patient result is compared with a fixed value or cutoffvalue There are two types of population-based reference intervals The most common type is derivedfrom a reference sample of persons who are in good health (health associated) The other type ofreference interval has been termed “decision based” and defines specific medical decision limits thatclinicians use to diagnose or manage patients Longitudinal comparisons are when a patient’s mostrecent value is compared with previous values for the same analyte This may help detect a change inhealth status.

Comparison of patient results with a population-based reference interval or with the cutoff values

is used for diagnostic or screening purposes The reference value change over a period of time isused for monitoring patients Both healthy reference limits and disease-associated reference limits areimportant for the clinical interpretation of the laboratory test results and vary from laboratory tolaboratory These variations may be caused by preanalytic processing procedures, populations ofhealthy individuals, inherent random biologic variations, analytic platforms, or analytic imprecisionthat was present when reference intervals were determined

Decision limits for optimally classifying patients into “disease” versus “healthy” categories aredifficult to define Most diseases are not homogenous distributions but represent a continuum of mildand severe forms Various statistical tools and models have been developed to formalize the medicaldecision process, but most of the models do not include the methodologic differences in laboratorytest values The major utility of healthy reference intervals for clinicians is to provide a roughassessment of the possibility that a test value on a specific patient is difficult for the values normallyfound in similar healthy subjects The guidelines for medical decision making use a standard 95%reference interval By defining the healthy reference interval to include central 95% of matchedhealthy subjects, there is less than a 1 in 20 chance for a value outside the reference interval to befound in a matched healthy subject Conventionally, a common limit of acceptability is based on themean of population data ±2 standard deviation (SD), because this encompassed roughly 95% of theobservations expected to be “normal.” With this convention, it must be remembered that 5% (usually2.5% on the low side and 2.5% on the high side) of results can be expected to fall outside the ±2 SDlimit, even in a “normal” healthy population This is best illustrated in the use of multitest chemistryprofiles for screening of persons known to be free of disease The probability of any given test beingabnormal is about 2–5%, and the probability of disease if a screening test is abnormal is generallylow (0–15%) The frequency of abnormal single tests is 1.5% (albumin) to 5.9% (glucose) and up to16.6% for sodium Based on statistical expectations, when a panel of eight tests is performed in amultiphasic health program, 25% of the patients have one or more abnormal results; when the panelincludes 20 tests, 55% have one or more test abnormalities

In terms of qualitative test reports (e.g., positive, negative), optimal decision limits (cutoff) can

be determined with ROC curve analyses If false-positive labeling leads to a more harmful outcome,the decision limits should be moved away from the ROC optimum in a direction to minimize false-positive diagnoses Likewise, if false-negative labeling is more dangerous, the decision limits should

be moved to minimize the false-negative diagnoses Although decision limits are better tools than

reference values for deriving diagnostic value from laboratory tests, they have some drawbacks.First, decision limits will not address the degree of deviation of a test result above or below thedecision limit A test result slightly above the limit will be regarded as positive the same as a resultfar above the decision limit, and a test result slightly below the cutoff limit will be reported asnegative.

PERFORMING THE RIGHT TEST AT THE RIGHT TIME FOR THE RIGHT REASON

As with the absolute value of a result, a test result or change in sequential results must be interpreted

in the context of the clinical situation, recent changes in patient management, and historical results.Excessive repetition of tests is wasteful, and the excess burden increases the possibility of laboratoryerrors Appropriate intervals between tests should be dictated by the patient’s clinical condition.Negative laboratory values (or any other type of tests) do not necessarily rule out a clinical diagnosis.Tests should be performed only if they will alter the patient’s diagnosis, prognosis, treatment, ormanagement Incorrect test values or isolated individual variation in results may cause Ulyssessyndrome and result in loss of time, money, and peace of mind

SECTION 1

DISEASE STATES

Chapter 2

Autoimmune Diseases

M Rabie Al-Turkmani

Organ-Specific Autoimmune Diseases

Systemic Autoimmune Diseases

Systemic Lupus Erythematosus

Systemic Sclerosis (Scleroderma)

Autoimmune Vasculitis

Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome)

Giant Cell Arteritis

Granulomatosis with Polyangiitis (Wegener Granulomatosis)

Autoimmune disease is the pathologic result of autoimmunity, whereby the immune system attacksthe person’s healthy body tissues Autoimmunity is caused by the inappropriate activation of T cells

or B cells, or both, in the absence of a definite cause B lymphocytes can produce autoantibodies,which may interfere with a cellular function (e.g., Graves disease, myasthenia gravis) or cause tissuedamage, either directly or by forming immune complexes that are deposited in tissues or blood

vessels T lymphocytes may aggregate in tissues (or a tissue) with resultant destruction.

There are more than 80 different autoimmune disorders, and more than one autoimmune disordercan be manifested by one patient These disorders can be classified as systemic, affecting multipleorgans or tissues (e.g., connective tissue autoimmune diseases such as systemic lupus erythematosus,Sjögren syndrome, or scleroderma), or organ specific, targeting one particular organ

Multiple factors contribute to the development of autoimmune diseases:

Genetic susceptibility, mostly due to linkage to particular HLA molecules

Environmental triggers (e.g., drugs, chemicals)

Infectious agents (e.g., Mycoplasma pneumoniae, HIV)

Loss of regulatory T cells

Defects in cytokine production

ORGAN-SPECIFIC AUTOIMMUNE DISEASES

Organ-specific autoimmune diseases involve a particular organ or tissue of the body in which thetarget autoantigen is found Examples of these autoimmune diseases and their target organs:

Adrenal glands (e.g., autoimmune adrenal insufficiency) See Chapter 6, Endocrine DiseasesBile ducts (e.g., primary biliary cirrhosis) See Chapter 5, Digestive Diseases

Blood cells: RBC (e.g., autoimmune hemolytic anemia), WBC (e.g., autoimmuneneutropenia), platelets (e.g., immune thrombocytopenic purpura) See Chapter 9,Hematologic Disorders

Blood vessels (e.g., autoimmune vasculitis) Discussed in this Chapter and in Chapter 3,Cardiovascular Disorders

Gastrointestinal tract (e.g., celiac disease, Crohn disease, ulcerative colitis) See Chapter 5,Digestive Diseases

Kidney (e.g., anti–glomerular basement membrane antibody disease) See Chapter 12, RenalDisorders

Liver (e.g., autoimmune hepatitis) See Chapter 5, Digestive Diseases

Nervous system (e.g., myasthenia gravis [a disorder of the neuromuscular junction], multiplesclerosis, Guillain-Barré Syndrome, autoimmune autonomic failure) See Chapter 4, CentralNervous System Disorders

Pancreas: type 1 diabetes mellitus (see Chapter 6, Endocrine Diseases), autoimmunepancreatitis (see Chapter 5, Digestive Diseases)

Thyroid gland (e.g., Hashimoto thyroiditis, Graves disease) See Chapter 6, EndocrineDiseases

SYSTEMIC AUTOIMMUNE DISEASES

FELTY SYNDROME

Definition

Felty syndrome is characterized by the triad of long-standing, aggressive rheumatoid

arthritis (RA), neutropenia, and splenomegaly.

It develops in a minority of patients with RA (<1%)

Who Should Be Suspected?

Patients typically present with general malaise, fatigue, loss of appetite, and unintentionalweight loss Some patients have recurrent infections, such as respiratory or skin infections,attributed to the neutropenia

The syndrome is more common in women >30 years of age and in patients with a familyhistory of RA

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are very elevated

Circulating immune complexes and immunoglobulin levels are higher than those found inRA

Peripheral blood smear review and bone marrow aspirate or biopsy may be indicated toexclude other causes of neutropenia

MIXED CONNECTIVE TISSUE DISEASE

Who Should Be Suspected?

Presenting symptoms are often nonspecific, such as fatigue, myalgia, arthralgia, and grade fever In the early stages of disease, 90% of MCTD patients have Raynaudphenomenon, arthralgia, swollen hands, fingers with “sausage-like” appearance, and muscleweakness Other common symptoms that may develop gradually include swollen joints,esophageal dysfunction, sclerodactyly, and calcinosis

low-MCTD usually develops in the second or third decade of life, and is more common inwomen than men.

anti-double-Antiphospholipid antibodies have been reported in patients with MCTD, with a lowerfrequency than that found in SLE Anticardiolipin antibodies (ACAs) are present inapproximately 15% of MCTD patients

Elevated ESR and CRP

Positive RF and anti-CCP antibodies in approximately 50% of the patients

Anemia, leukopenia, and hypergammaglobulinemia may present

Suggested Reading

Ortega-Hernandez OD, Shoenfeld Y Mixed connective tissue disease: an overview of clinical manifestations, diagnosis and treatment.

Best Pract Res Clin Rheumatol 2012;26(1):61–72.

by an alternative diagnosis) and elevated CRP/ESR The elements of this algorithm includethe following:

Morning stiffness for more than 45 minutes (2 points)Hip pain/ limited range of motion (1 point)

Absence of rheumatoid factor and/or anti–citrullinated protein antibody (2 points)Absence of peripheral joint pain (1 point)

A score of 4 or more has 68% sensitivity and 78% specificity for distinguishing PMRpatients Ultrasound findings of bilateral shoulder abnormalities or abnormalities in oneshoulder and hip were found to significantly improve both sensitivity and specificity of theclinical criteria

Who Should Be Suspected?

The disease is almost exclusively found in individuals >50 years of age Patients typicallypresent with general malaise, fatigue, as well as aches and morning stiffness in the shoulder,hip girdles, neck, lower back, and knees Loss of appetite, unintentional weight loss, anddepression are also common findings

PMR develops in nearly 50% of patients with giant cell arteritis (GCA), and 15–30% ofpatients with PMR eventually develop GCA

Laboratory Findings

Laboratory finding are nonspecific

ESR is markedly elevated (>40 mm/hour, but values >100 may be seen) However, somepatients with mild disease may have only slight elevations of ESR

CRP is elevated and considered a more sensitive marker than ESR

Serologic tests such as RF, ANA, and anti-CCP antibodies are typically negative

Suggested Reading

Dasgupta B, Cimmino MA, et al 2012 provisional classification criteria for polymyalgia rheumatica: a European League Against

Rheumatism/American College of Rheumatology collaborative initiative Ann Rheum Dis 2012;71(4):484–492.

POLYMYOSITIS, DERMATOMYOSITIS, AND INCLUSION BODY

MYOSITIS

Definition

Polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM) are relatedinflammatory myopathies that share common features, including muscle weakness andinflammatory infiltrates on a muscle biopsy

PM and DM are characterized by a subacute onset of symmetric proximal muscle weakness,common involvement of other organ systems such as lung and skin, a strong association withautoantibodies, and responsiveness to immunosuppression Both are widely accepted ashaving an autoimmune basis Cutaneous involvement is the primary clinical featuredistinguishing patients with DM from those with PM

In contrast to PM and DM, patients with IBM typically have slowly progressive weakness inboth proximal and distal muscles, rarely have other extra-muscular involvement orautoantibodies, and most often do not respond to immunosuppressive therapies A musclebiopsy showing the presence of typical inclusion bodies is diagnostic for IBM

Who Should Be Suspected?

Patients with PM and DM typically present with progressive proximal muscle weakness andevidence of muscle inflammation They may also have constitutional symptoms andevidence of involvement of other organs (e.g., interstitial pulmonary disease, polyarthritis)

DM patients can be differentiated by having specific cutaneous signs such as Gottronpapules or heliotrope eruption

Patients with IBM generally have a more insidious onset compared to PM and DM, andmore prominent distal muscle weakness.

PM and DM can occur at any age, with peak incidence between the ages of 40 and 50,whereas IBM mainly affects individuals >50 years of age

Laboratory Findings

Diagnosis of the three conditions is based on clinical manifestations, serum muscle enzymes,autoantibodies, EMG findings, and muscle biopsy The latter is the definitive test for establishing thediagnosis of IBM, and in PM or DM patients presenting with atypical clinical or laboratory findings

Muscle enzymes:

Levels of the muscle enzyme creatine kinase (CK) are greatly elevated in PM and DMpatients (typically >10 folds the upper limit of normal but may be >50 folds), and to alesser extent in patients with IBM

Other muscle enzymes including lactate dehydrogenase (LDH), aldolase, aspartateaminotransferase (AST) and alanine aminotransferase (ALT) are also elevated Similar

to CK, elevations are less profound in IBM than in PM or DM

ANA test is positive in up to 80% of patients with DM or PM

Myositis-specific antibodies are positive in 30% of patients with PM or DM The mostcommon antibodies are those against histidyl-tRNA synthetase (anti-Jo-1), and titers ofthese antibodies have been found to correlate with disease activity Other myositis-specificantibodies include anti-Mi-2 and anti–signal recognition particle (anti-SRP) antibodies.Presence of other connective disease conditions associated with myositis is suggested whenanother type of autoantibodies is positive (e.g., anti-SSA/Ro, anti-SSB/La, anti-Sm, or anti-RNP)

ESR is normal or mildly increased

Myoglobin is elevated in the serum and urine

Psoriatic arthritis (PsA) is a type of arthritic inflammation that occurs in approximately 15%

of patients with psoriasis It can affect any joint in the body causing pain, swelling, andstiffness CD8+ T cells and T-cell-derived cytokines play a central role in the pathogenesis

of PsA

The Classification Criteria for Psoriatic Arthritis (CASPAR) require the presence of joint,spine, or entheseal inflammatory disease plus a minimum score of 3 points from thefollowing five categories (98.7% specificity and 91.4% sensitivity):

Current psoriasis (2 points); personal or family history of psoriasis (1 point)

Typical psoriatic nail dystrophy (1 point)Negative rheumatoid factor (1 point)Current dactylitis or history of dactylitis (1 point)Hand or foot plain radiography demonstrating juxta-articular new bone formation (1point)

Who Should Be Suspected?

Most patients who develop PsA have skin symptoms of psoriasis first (erythematous papuleand plaques with a silver scale), followed later by arthritis symptoms characterized bypain, tenderness, and stiffness in the joints and back

Several HLA types have been identified to be associated with PsA, suggesting a geneticpredisposition This is also indicated by the presence of a family history of psoriasis andpsoriatic arthritis in up to 40% of patients

Laboratory Findings

Laboratory finding are not specific

ESR and CRP are elevated in approximately 50% of cases; levels correlate with the number

often, causing pathogens are urogenital (e.g., Chlamydia) or enteric (e.g., Campylobacter,

Salmonella, Shigella, or Yersinia).

Who Should Be Suspected?

A likely patient is a young adult (20– 40 years of age) who develops postinfectiousasymmetric oligoarthritis (affecting most often the knees, ankles, and heels), enthesitis,dactylitis, and lower back pain In addition, patients may have extra-articular signsincluding urinary (urethritis, balanitis, dysuria, prostatitis in men, cervicitis, salpingitis or

vulvovaginitis in women), ocular (conjunctivitis or anterior uveitis), and/or constitutional(malaise, fever, weight loss) symptoms.

Laboratory Findings

Diagnosis is primarily clinical

Culture and serology tests are helpful in identifying the infectious etiology of the disease inonly a fraction of cases since pathogens may no longer be retrievable by the time arthritisdevelops Nevertheless, a trial to identify the following pathogens by stool or urine cultures,

or in some cases by serology, should be attempted:

Chlamydia, especially Chlamydia trachomatis and Chlamydia pneumoniae PCR for

urinary Chlamydia DNA has high sensitivity.

Yersinia enterocolitica and Yersinia pseudotuberculosis.

Salmonella of various serovars.

Shigella, especially Shigella flexneri and Shigella dysenteriae.

Campylobacter, especially Campylobacter jejuni.

Clostridium difficile.

Possibly other organisms (e.g., HIV, Escherichia coli, Mycoplasma genitalium).

HLA-B27 is positive in approximately half of the patients and seems to be associated with amore sudden and severe onset of symptoms as well as increased likelihood to have chronic(long-lasting) disease

Elevated ESR and CRP during the acute phase of disease

It has also been suggested that idiopathic retroperitoneal fibrosis is a manifestation of either

a systemic autoimmune disorder or IgG4-related disease

Who Should Be Suspected?

Most patients present with abdominal, lower back, or flank pain In addition, up to one half

of patients complain of constitutional manifestations such as fever, weight loss, fatigue, and

night sweats Renal failure due to obstruction of the ureters develops in more than 40% ofpatients, and newonset hypertension has been reported in approximately one third ofpatients.

The idiopathic disease most commonly occurs in individuals 40–60 years of age Men areaffected two to three times more than women

Laboratory Findings

Diagnosis is established by imaging studies

ESR and CRP are elevated in approximately one half to two thirds of patients

Anemia of chronic inflammation (normochromic, normocytic) is a frequent finding and canalso be related to renal dysfunction

Leukocytosis, eosinophilia, hyperferritinemia, or hypergammaglobulinemia may be present

in some patients

ANA test is positive in up to 60% of cases

Serum IgG4 levels are frequently elevated in patients with IgG4-related disease

Blood urea nitrogen (BUN) and creatinine can be elevated; levels are variable depending onthe presence and size of urinary obstruction Urine sediment is often normal

Given the presence of autoantibodies, RA is considered an autoimmune disease, and it is themost common type of autoimmune arthritis Autoimmunity and the overall systemic andarticular inflammatory load drive the destructive progression of the disease

According to the 2010 ACR/EULAR criteria, classification of RA is based on the confirmedpresence of synovitis in at least one joint, absence of an alternative diagnosis that betterexplains the synovitis, and achievement of a total score of 6 or greater (of a possible 10)from the individual scores in four domains:

Number and site/size of involved joints (score range 0–5)Serologic abnormality, based on serum levels of RF and anti–citrullinated proteinantibody (score range 0–3)

Elevated acute-phase response, based on CRP and ESR (score range 0–1)Symptom duration (< or ≥6 weeks; range 0–1)

Who Should Be Suspected?

Candidates are individuals presenting with fatigue, weakness, anorexia, and slowlyprogressive pain and swelling of the joints Involvement of the small joints of the hands orfeet should raise suspicion of RA Early symptoms may also include fatigue, muscle pain,low-grade fever, weight loss, and numbness and tingling of the hands

Onset of RA most often occurs between the fourth and sixth decades of life but can also beseen in the pediatric population (juvenile rheumatoid arthritis) as well as the elderly.Women are three times more likely to develop RA than are men

Sixty to seventy percent of RA patients of European ancestry carry the HLA-DR4 gene

compared to 30% in the general population, indicating a genetic predisposition

Anti–citrullinated protein antibody, tested as anti-CCP or anti–mutated citrullinatedvimentin, is more specific for RA than RF Anti-CCP antibodies are found in 60–70% of RAcases and have approximately 95% specificity

ANA test is positive in 25–50% of patients

Synovial fluid analysis reveals an inflammatory pattern with increased WBC counts (2,000–50,000/μL in affected joints), with a predominance of neutrophils Total hemolyticcomplement, C3, and C4 are markedly reduced

ESR and CRP are elevated

Suggested Reading

Aletaha D, Neogi T, Silman AJ, et al 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European

League Against Rheumatism collaborative initiative Arthritis Rheum 2010;62(9):2569–2581.

SJÖGREN SYNDROME

Definition

Sjögren syndrome (SjS) is an inflammatory, autoimmune disease in which the exocrineglands, mainly the salivary and lacrimal glands, are attacked and destroyed by the immunecells

The syndrome is divided into primary SjS (not associated with other diseases), orsecondary SjS, which is associated with other autoimmune rheumatic conditions,principally rheumatoid arthritis (most common) or SLE In both primary and secondary SjS,decreased exocrine gland function leads to the “sicca complex,” characterized by dry mouth(xerostomia) and dry eyes (keratoconjunctivitis sicca)

The American-European Consensus Group criteria for classification of SjS were developed

in 2002 In 2012, new criteria were proposed by the American College of Rheumatologyand the Sjögren’s International Collaborative Clinical Alliance Using the later criteria,classification of SjS, which applies to individuals with signs/symptoms that may besuggestive of SjS, will be met in the presence of at least two of the following threeobjective features:

Positive serum anti-SSA/Ro and/or anti-SSB/La or positive rheumatoid factor and

ANA titer ≥1:320Labial salivary gland biopsy exhibiting focal lymphocytic sialadenitis with a focusscore ≥1 focus/4 mm2

Keratoconjunctivitis sicca with ocular staining score ≥3 (assuming that the individual isnot currently using daily eye drops for glaucoma and has not had corneal surgery orcosmetic eyelid surgery in the last 5 years)

Who Should Be Suspected?

SjS patients typically present with complaints of ocular symptoms, such as persistent dryeyes for more than 3 months and oral symptoms of dryness (e.g., the need to drink water to

be able to swallow food) This may be associated with vague symptoms such as fatigue andmyalgia

SjS can affect people of any age, but symptoms usually appear between the ages of 45 and

55 It affects 10 times as many women as men, and about half of SjS patients also haverheumatoid arthritis or other connective tissue diseases, such as lupus

Occasionally, other tissues or organs may be involved As a result, extraglandularmanifestations develop, and they may include pain and stiffness in the joints, even in theabsence of rheumatoid arthritis or lupus, rashes on the arms and legs related to vasculitis, orinflammation in the lungs, liver, and kidneys

RF is frequently positive because of the association of SjS with rheumatoid arthritis

CRP and ESR are typically elevated

Other laboratory tests are indicated to evaluate systemic and extraglandular involvement,and they include serum electrolytes, anticardiolipin antibodies, lupus anticoagulant,cryoglobulins, liver function tests, and urinalysis

Imaging studies and specific diagnostic tests of the glands can help with the diagnosis Testscommonly used include Schirmer test to measure tear production, rose bengal test to assessthe damage to epithelial cells in the cornea and conjunctivae, and tear breakup time test tomeasure overall lacrimal function

Suggested Reading

Shiboski SC, Shiboski CH, Criswell L, et al American College of Rheumatology classification criteria for Sjögren’s syndrome: a

data-driven, expert consensus approach in the Sjögren’s International Collaborative Clinical Alliance cohort Arthritis Care Res.

According to the ACR classification criteria for SLE, a person is said to have SLE if anyfour or more of the following 11 criteria are present, serially or simultaneously, during anyinterval of observation:

Malar rashDiscoid rashPhotosensitivityOral ulcersNonerosive arthritis, involving two or more peripheral jointsPleuritis or pericarditis

Renal disorder, manifested by persistent proteinuria or cellular castsNeurologic disorder: seizures or psychosis

Hematologic disorder: hemolytic anemia, leukopenia, lymphopenia, orthrombocytopenia

Immunologic disorder: anti-dsDNA antibody, anti-Sm antibody, or positive finding ofantiphospholipid antibodies

Positive antinuclear antibody at any point in time and in the absence of drugs

Who Should Be Suspected?

Likely patients are individuals presenting with constitutional symptoms (fatigue, fever,weight loss) associated with features of multisystem or, in some cases, a single organinvolvement These features may include rash, photosensitivity, arthralgia or arthritis,anemia, serositis, nephritis, mild peripheral edema, or neurologic symptoms such asseizures, psychosis, or peripheral nephropathy

SLE affects 10 times as many women as men Disease onset commonly occurs between 20and 40 years of age

A variant of lupus, called drug-induced lupus erythematosus, may be the result of treatmentwith procainamide, hydralazine, chlorpromazine, quinidine, or, more recently, anti-TNFalpha Patients typically present with skin and joint manifestations but rarely have renal orneurologic features It is a self-limited condition in most cases, and symptoms usuallyrecede after discontinuing the drug