Clinical Pathology of Rheumatoid Arthritis

Clinical Pathology of Rheumatoid Arthritis Clinical Pathology korr.indd 1 2013.03.05. 19:00:37

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Clinical Pathology of Rheumatoid Arthritis Cause of Death, Lethal Complications and Associated Diseases in Rheumatoid Arthritis Miklós Bély MD, PhD, DSc Acad Sci Hung and Ágnes Apáthy MD AKADÉMIAI KIADÓ, BUDAPEST Clinical Pathology korr.indd 3 2013.03.05. 19:00:37

This book is published with the financial assistance of the Hungarian Academy of Sciences ISBN 978 963 05 9339 7 First English edition: 2012 Published by Akadémiai Kiadó, Members of Wolters Kluwer Group P.O.Box 245. H-1519 Budapest, http://www.akkrt.hu M. Bély, Á. Apáthy, 2012 Akadémiai Kiadó, 2012 All rights reserved. No part of this book may be reproduced by any means or transmitted or translated into machine language without the written permission of the publisher. Printed in Hungary Clinical Pathology korr.indd 4 2013.03.05. 19:00:38

We wish to express our gratitude to Károly Balogh MD, Associate Professor of Pathology, Harvard Medical School, who has altruistically contributed over the years to our work with his critical advice and professional editing of the English text. Clinical Pathology korr.indd 5 2013.03.05. 19:00:38

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In his new work, Professor Miklós Bély and his colleague Ágnes Apáthy describe and analyse the pathological features of rheumatoid arthritis, an important challenge to rheumatologists in today s ageing populations. They describe the associated, concurrent conditions of vasculitis, atherosclerosis, amyloidosis, infection and cancer. This new and important contribution to the literature is strongly recommended for its originality and for the breadth and depth of the experience on which it has been written. Dugald Gardner, first Director of the Kennedy Institute of Rheumatology, London, UK; Professor of Histopathology, University of Manchester; Honorary Fellow, College of Medicine and Veterinary Medicine, University of Edinburgh. Dr. Miklós Bély is one of the best friends among all of my European acquaintances. He wrote this book based on clinico-pathological information obtained from numerous autopsy samples of Rheumatoid Arthritis (RA) patients collected over the past 30 years. There are very few similar books on this area of medical research worldwide. I highly recommend this book which provides a valuable summarization of the latest information on RA. Dr. Humio Tsunoda, Professor Emeritus at Iwate Medical University in Japan and China Medical University in China, served as a member of the Science Council of Japan from 1997 to 2007. This monograph is based on an expert pathologist s (Miklós Bély MD, PhD, DSc Acad Sci Hung) observations of a large autopsy population of RA patients and these are correlated with the clinical data obtained by an expert rheumatologist neurologist (Ágnes Apáthy MD). The studies of a wide spectrum of complications include the peripheral and central nervous system, as well as unusual sites such as the hypophysis, etc. Light and electron microscopic observations are supplemented with detailed special studies of biopsies and postmortem material. Immunohistochemical Clinical Pathology korr.indd 7 2013.03.05. 19:00:38

and polarization optical microscopy of amyloid deposits has been used to predict the age and reversibility of the process in some early cases. This book should be of great interest not only to pathologists, but also to rheumatologists and clinicians treating various complications of rheumatoid arthritis. Dr. Károly Balogh, Associate Professor of Pathology, Harvard Medical School Im Schatten der von Gelenkprozessen dominierten Symptomatik entwickeln sich bei der RA in vielen Fällen weitere assoziierte Erkrankungen, die das klinische Bild und den Gesamtverlauf der Krankheit beeinflussen. Diese Sekundärprozesse entziehen sich unter dem Mantel der Gelenkdestruktion oft der klinischen Beobachtung. Niemand außer Bély, der 161 verstorbene RA-Patienten obduziert hat, kann die tatsächliche Häufigkeit latenter Begleiterkrankungen besser aufdecken. Bély lenkt die Aufmerksamkeit des Arztes auf die tatsächliche Komplexität der RA-Krankheit, woraus der Arzt entsprechende diagnostische Schlüsse und therapeutische Strategien entwickeln muss, damit er dem ganzen nosologischen Gewicht der Erkrankung gerecht wird. So ist dieses Buch einzigartig und für Rheumatologen unverzichtbar. Prof. Dr. Med. Hans Georg Fassbender Zentrum für Rheuma-Pathologie GmbH WHO Referenzzentrum Der erfahrene Rheuma-Pathologe Prof. Dr. Miklós Bély, Budapest, legt, gestützt auf ein umfangreiches Autopsie-Material von 161 Fällen von Rheumatoid-Arthritis eine interessante Studie zur klinischen Pathologie der Rheumatoid-Arthritis, ihren letalen Komplikationen und ihren klinischen Begleiterkrankungen vor. Die Basis der Studie bildet eine sorgfältige Erfassung der morphologischen Befunde in Korrelation zu den klinischen Daten. Die Kenntnis dieser Beziehungen ist klinisch bedeutungsvoll für die Erfassung von Komplikationen, ihrer Bewertung und Therapie. Klar abgegrenzt werden Krankheitsbilder wie zum Beispiel die Arteriosklerose mit ihren Komplikationen ohne pathogenetische Beziehungen zur Rheumatoid-Arthritis. Das abschließende Kapitel ist ausführlich der Amyloidose und ihrem Nachweis gewidmet. Die Monografie ist in gleicher Weise für Kliniker und Pathologen ein Gewinn. Prof. Dr. Med. Gottfried Geiler Clinical Pathology korr.indd 8 2013.03.05. 19:00:38

CONTENTS Abbreviations...................................................... 17 Preface............................................................ 19 Brief history........................................................ 21 1 Cause of death in rheumatoid arthritis....................... 27 Summary of Chapter 1...................................... 39 2 Lethal complications of rheumatoid arthritis.................. 41 Summary.................................................. 48 2.1 Systemic vasculitis in rheumatoid arthritis................... 50 2.1.1 Prevalence of systemic vasculitis in RA (literary data)........... 50 2.1.2 Prevalence of systemic vasculitis in our autopsy material with RA................................................... 51 2.1.3 Severity of vasculitis in 36 RA patients at death................. 54 2.1.4 Histological characteristics of systemic vasculitis in rheumatoid arthritis: the types of vasculitis, the size of blood vessels involved, and the incidence, severity and stages of vasculitis............... 58 2.1.4.1 Types of vasculitis........................................... 59 2.1.4.2 Size of blood vessels involved by vasculitis...................... 66 2.1.4.3 Incidence (frequency) of vasculitis in blood vessels of different size............................................. 66 2.1.4.4 Severity (density) of vasculitis in blood vessels of different size.... 67 2.1.4.5 Stages of vasculitis in blood vessels of different size............. 68 2.1.4.6 Incidence, severity and stages of vasculitis in blood vessels of different size............................................. 71 2.1.5 The incidence and severity of vasculitis in various organs........ 72 2.1.6 Main complications and associated diseases in 36 RA patients with SV.................................................... 85 Clinical Pathology korr.indd 9 2013.03.05. 19:00:38

2.1.7 Possible role of coexistent major complications (AA amyloidosis and lethal septic infection) of RA in the prevalence of SV and mortality of SV (The influence of AA amyloidosis and lethal septic infection on the prevalence and mortality of SV).......... 123 2.1.8 Clinically missed diagnosis of systematic vasculitis The severity, mortality and clinically missed diagnosis of SV in RA (The relationship between severity of SV with or without lethal outcome and clinical recognition of SV)....................... 125 2.1.9 Demographics, onset and duration of disease complicated with or without SV (Influence of age, sex, onset of RA, and disease duration on SV)............................................. 128 2.1.10 Clinical-laboratory parameters associated with SV in RA........ 132 2.1.10.1 Clinical-laboratory parameters associated with SV in comparison to RA patients without complications (such as: SV, AAa, SI with or without PA)......................................... 133 2.1.10.2 Clinical-laboratory parameters associated with SV in comparison to RA patients without SV.................................... 133 2.1.10.3 Clinical-laboratory parameters associated with mild and severe SV.............................................. 134 Summary of Section 2.1.............................................. 135 2.2 Systemic and localized forms of amyloidosis.................. 143 2.2.1 Systemic secondary (reactive) AA amyloidosis in RA (literary data).............................................. 145 2.2.2 Prevalence of AA amyloidosis in our autopsy material........... 146 2.2.3 Quantitative differences of amyloid A deposits at death in 34 RA patients with AA amyloidosis (Severity of AAa in RA patients at death Development of AA amyloidosis).................... 148 2.2.4 Quantitative differences (incidence and extent) in amyloid A deposits of various tissue structures........................... 153 2.2.5 Quantitative differences (incidence and extent) in amyloid A deposits of various organs.................................. 154 2.2.6 Stage-dependent qualitative differences of amyloid A deposits in rheumatoid arthritis...................................... 155 2.2.6.1 Histochemical characteristics of early and late (fresh and old) amyloid A deposits.......................................... 156 2.2.6.2 Ultrastructural characteristics of early and late (fresh and old) amyloid A deposits.......................................... 160 Clinical Pathology.indd 10 2013.03.07. 11:52:23

2.2.7 Main complications and associated diseases in RA patients with AAa.................................................. 168 2.2.8 Possible role of coexistent major complications (systemic vasculitis, lethal septic infection) of RA in the prevalence and mortality of AAa (Influence of systemic vasculitis and lethal septic infection on the prevalence and mortality of AAa)......... 175 2.2.9 Mortality and clinically missed diagnosis of AAa (Relationship between AAa with or without lethal outcome and clinical recognition of AAa).............................. 176 2.2.10 Demographics, onset and duration of disease complicated with or without AAa........................................ 181 2.2.11 Clinical and laboratory parameters, demographics and duration of disease associated with systemic AA amyloidosis.............. 184 2.2.11.1 Clinical-laboratory parameters associated with AAa............. 185 2.2.11.2 Clinical-laboratory parameters associated with mild or severe AAa.............................................. 186 2.2.11.3 Clinical-laboratory parameters associated with massive renal amyloidosis................................................ 187 2.2.12 Systemic and localized forms of amyloidosis in RA in our autopsy material................................................... 188 2.2.12.1 Systemic AA amyloidosis (Figures 2.2.12.1.1 2.2.12.1.21)......... 189 2.2.12.2 Systemic primary (myeloma-associated or B-cell dyscrasia related) immunoglobulin AL: κ-chain amyloidosis in our autopsy material (Figures 2.2.12.2.1 2.2.12.2.4)................................. 203 2.2.12.3 Cerebral β protein-related amyloidosis (Cerebral amyloid angiopathy CAA)(Aβ protein precursor Aβ) in our autopsy material (Figures 2.2.12.3.1 2.2.12.3.6)................. 205 2.2.12.4 Dystrophic (aging related) linear or globular amyloidosis (Figures 2.2.12.4.1 2.2.12.4.6)................................. 210 2.2.12.5 Hormone-related amyloidosis localized to islets of Langerhans (Figures 2.2.12.5.1 2.2.12.5.9)................................. 213 2.2.12.6 Localized β2 microglobulin amyloid (Aβ2M) deposits in the kidney (Figures 2.2.12.6.1 2.2.12.6.8)................................. 216 2.2.12.7 Prostatic or pulmonary corpora amylacea (β2-microglobulin Aβ2M) (Figures 2.2.12.7.1 2.2.12.7.6).......................... 219 Summary of Section 2.2.............................................. 221 Clinical Pathology korr.indd 11 2013.03.05. 19:00:38

2.3 Lethal septic infection and purulent arthritis in rheumatoid arthritis................................................... 244 2.3.1 The prevalence of septic infection in RA (literary data)............................................... 244 2.3.2 The prevalence of lethal septic infection (SI) in our autopsy material with RA........................................... 245 2.3.3 Prevalence of purulent arthritis (PA) in RA with or without lethal SI.................................................... 247 2.3.4 The relationship between lethal SI and PA in RA................ 248 2.3.5 Main complications and associated diseases in RA patients with lethal SI............................................... 248 2.3.6 Pathogens in lethal SI........................................ 256 2.3.7 Possible role of coexistent major complications (systemic vasculitis, secondary AA amyloidosis) of RA in the mortality due to lethal SI (with or without PA) and the influence of associated diabetes mellitus, iatrogenic hazards (invasive procedures: intraarticular puncture, injection or surgery) or gastric or duodenal ulcer in the mortality due to lethal SI (with or without PA)........................................ 257 2.3.8 Clinically missed diagnosis of lethal SI and PA (the relationship between lethal SI with or without PA, and clinical recognition of lethal SI)................................................. 259 2.3.9 Demographics, onset and duration of disease complicated with SI or PA Influence of age, sex, onset of RA, and disease duration on generalized lethal SI with or without PA............ 261 2.3.10 Clinical laboratory parameters associated with SI in RA......... 264 2.3.10.1 Clinical-laboratory parameters associated with SI in comparison to RA patients without SI....................... 264 2.3.10.2 Clinical laboratory parameters associated with SI in comparison to RA patients without complications (such as: SV, AAa, SI with or without PA)......................................... 265 2.3.10.3 Clinical-laboratory parameters of septic RA patients with or without PA.............................................. 266 2.3.11 Histological characteristics of coincident systemic vasculitis in lethal SI (with or without PA).............................. 266 2.3.11.1 Prevalence and histological characteristics of systemic vasculitis (SV) in RA without lethal SI......................... 267 2.3.11.2 Prevalence and histological characteristics of systemic vasculitis (SV) in RA with lethal SI............................ 273 Clinical Pathology korr.indd 12 2013.03.05. 19:00:38

2.3.11.3 Differential diagnosis of systemic septic vasculitis (with or without PA) and systemic vasculitis of autoimmune origin in RA............................................... 279 2.3.12 Histology of PA and histologically diagnosed infective agents..... 284 Summary of Section 2.3.............................................. 288 3. Associated diseases in rheumatoid arthritis.................. 295 Comments and conclusion................................... 300 3.1 Atherosclerosis in rheumatoid arthritis...................... 300 3.1.1 Prevalence and mortality of atherosclerosis in our autopsy material with RA........................................... 301 3.1.2 Main complications and associated diseases in 74 RA patients with severe or lethal atherosclerosis.......................... 302 3.1.3 Possible role of coexistent associated diseases (Hy, DM, Tb, mtb and mtu) in the prevalence and mortality of atherosclerosis in RA (The influence of Hy, DM, Tb, mtb and mtu on the prevalence and mortality of Ath)........................ 321 3.1.4 Clinically missed diagnosis of atherosclerosis (The clinical recognition of Ath with or without lethal outcome).............. 324 3.2 Tuberculosis and miliary tuberculosis in rheumatoid arthritis.................................................. 326 3.2.1 Prevalence and mortality of tuberculosis in RA (literary data).... 326 3.2.2 Prevalence and mortality of tuberculosis and miliary disseminated tuberculosis in our autopsy material.............. 328 3.2.3 Relationship between Tb and mtb in RA...................... 338 3.2.4 Main complications and associated diseases in RA patients with Tb or mtb............................................. 339 3.2.5 Possible role of coexistent associated diseases (Ath, Hy, DM and mtu) in the prevalence and mortality of Tb or mtb in RA (Influence of Ath, Hy, DM and mtu on the prevalence and mortality of Tb or mtb with or without lethal outcome)............................................. 348 3.2.6 Clinically missed diagnosis of tuberculosis (with or without mtb)...................................... 350 3.2.7 Influence of age, sex, onset of RA, and disease duration on Tb and mtb............................................. 351 3.2.8 Clinical-laboratory parameters associated with Tb or mtb in RA................................................. 353 Clinical Pathology korr.indd 13 2013.03.05. 19:00:38

3.2.8.1 Clinical-laboratory parameters associated with Tb in comparison to RA patients without Tb or without complications (such as: SV, AAa, SI with or without PA)...................... 354 3.2.8.2 Clinical-laboratory parameters associated with mtb in comparison to RA patients without mtb or without complications (such as: SV, AAa, SI with or without PA).......... 354 3.2.8.3 Clinical-laboratory parameters of tuberculosis RA patients with or without mtb........................................ 356 Summary of Section 3.2.............................................. 357 3.3 Tumors in rheumatoid arthritis............................. 362 3.3.1 Prevalence and mortality of tumors in RA (data from the literature)..................................... 362 3.3.2 Prevalence and mortality of malignant and benign tumors (mtu and btu) in our autopsy material with RA................. 364 3.3.3 Main complications and associated diseases in our RA patients with mtu or btu............................................ 370 3.3.4 Possible role of coexistent associated diseases (Ath, Hy, DM and Tb or mtb) in the prevalence and mortality of mtu in RA (Influence of Ath, Hy, DM, Tb and mtb on the prevalence and mortality of mtu with or without lethal outcome)........... 377 3.3.5 Mortality and clinically missed diagnosis of mtu or btu in RA with or without lethal outcome............................... 379 3.3.6 Influence of age, sex, onset of RA, and disease duration on mtu or btu.............................................. 382 3.3.7 Clinical-laboratory parameters associated with mtu or btu in RA.................................................. 384 3.3.7.1 Clinical-laboratory parameters associated with malignant tumors in comparison to RA patients without tumors........... 385 3.3.7.2 Clinical-laboratory parameters associated with benign tumors in comparison to RA patients without tumors.................. 386 3.3.7.3 Clinical-laboratory parameters in rheumatoid arthritis associated with benign and malignant tumors.................. 386 Summary of Section 3.3.............................................. 387 4. Coexistent complications and associated diseases in RA........ 393 Summary of Chapter 4............................................... 401 Clinical Pathology korr.indd 14 2013.03.05. 19:00:38

5. Appendix Methods....................................... 409 5.1 Methods for the detection of vasculitis....................... 409 5.1.1 Light microscopic methods of vasculitis........................ 409 5.1.2 Immunohistochemical methods of vasculitis................... 409 5.2 Methods for the detection of amyloidosis..................... 410 5.2.1 Light microscopic methods................................... 410 5.2.2 Histochemical methods...................................... 410 5.2.3 Immunohistochemical methods.............................. 411 5.2.4 Electron microscopic methods................................ 412 5.3 Description of the original methods.......................... 412 5.3.1 Romhányi s Congo red staining (1971) (Original description)..... 412 5.3.2 Romhányi s Congo red staining (1971) Modified according to Bély and Apáthy (2000).................................... 413 5.3.3 Performate pretreatment Congo red staining according to Romhányi (1979) (Original description)..................... 414 5.3.4 Performate pretreatment Congo red staining according to Romhányi (1979) Modified according to Bély (2006)......... 414 5.3.5 Permanganate method according to Wright (1977) (Original description)....................................... 415 5.3.6 Permanganate method according to Wright (1977) Modified according to Bély (2006)............................. 416 5.3.7 Bennhold s Congo red method (1922).......................... 417 5.3.8 Alkaline Congo red method according to Puchtler et al. (1962).... 417 5.3.9 Toluidine blue staining according to Wolman (1971)............. 418 5.3.10 Crystal violet staining....................................... 419 5.3.11 Sirius red staining........................................... 420 5.4 Sensitivity and specificity of light microscopic staining methods of amyloidosis............................................. 420 5.4.1 Systemic amyloid A deposits (in rheumatoid arthritis) (Figures 5.4.1.1 5.4.1.16)..................................... 421 5.4.2 Systemic AL-kappa immunoglobulin light chain (B-cell lymphoma related) amyloid deposits (Figures 5.4.2.1 5.4.2.16).............. 430 5.4.3 β2 microglobulin amyloid (Aβ2M) deposits localized to the kidney and amyloid A deposits (in rheumatoid arthritis) (Figures 5.4.3.1 5.4.3.18)..................................... 436 Clinical Pathology korr.indd 15 2013.03.05. 19:00:38

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ABBREVIATIONS RA Rheumatoid Arthritis SV Systemic Vasculitis AAa Systemic AA amyloidosis SI Lethal Septic Infection PA Purulent Arthritis C Carditis (endo-, myo-, epior pancarditis) IPn Interstitial Pneumonitis ILyH Pulmonary Interstitial Lymphoid Hyperplasia mlypn migratory Lymphoid Pneumonitis IN Interstitial Nephritis Gln Glomerulonephritis gu, du or cu gastric, duodenal or colonic Ulcer (with massive internal bleeding, perforation and peritonitis or lethal septic infection) CI Cardiac Insufficiency AD Alzheimer s disease AP Amyloid plaques CAA Cerebral Amyloid Angiopathy Ath Atherosclerosis Hy Hypertension Tb Tuberculosis mtb miliary Tuberculosis Fc Fibrocaseous Tuberculosis F Fibrous tuberculotic scar mtu malignant Tumor btu benign Tumor DM Diabetes Mellitus Ca Carcinoma G Gout G-l tract GastroIntestinal tract AG Adrenal Gland CD Cause of Death ND No Data (not defined) NS Not Significant Cl+ Clinically diagnosed Cl- Clinically not recognized BrPn Bronchopneumonia Blood vessels and tissue structures a arteriole A Small artery AA medium size artery v venule V small vein VV medium size vein coll collagen fibers ret reticulin fibers (collagen IV) BM basal lamina n peripheral nerves HE Hematoxylin and Eosin Prn/y protocol number/year Clinical Pathology korr.indd 17 2013.03.05. 19:00:38

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PREFACE Interactions of coexisting complications in rheumatoid arthritis (RA) modify the basic disease as well as the typical clinical manifestations of the complications. These changes may lead to misdiagnosis or late recognition of the complications (1). Even the coexisting associated diseases may mask the characteristic clinical symptoms of RA or on the contrary may mimic the clinical symptoms of RA. The atypical symptoms may lead to an incorrect diagnosis or late recognition of complications or even the associated diseases as well (1). The interaction of major complications of RA, such as systemic vasculitis (SV), amyloidosis (AA), lethal septic infection (SI) with or without purulent arthritis (PA) and associated diseases: atherosclerosis (Ath), tuberculosis (Tb) with or without miliary tuberculosis (mtb), malignant tumors (mtu) is the subject of this book. The aim was to evaluate the exact prevalence of different complications of RA and coexisting associated diseases in RA and determine statistically the relationship between them. The authors wanted to assess (evidence based) the modifying effect of coexistent complications of RA, and to estimate the effect of associated diseases on complications of basic disease. Some of these relationships are well known, others reveal possible life-threatening combinations of coexisting complications or diseases (for example, the role of vasculitis, amyloidosis, septic infection, exacerbation of inactive tuberculosis in lethal outcome or the influence of coexisting atherosclerosis, diabetes mellitus on RA-complications, etc.). Knowledge of these relationships is important from the viewpoint of prevention of complications or their treatment. Some of the recognized correlations confirm the known relationships (such as atherosclerosis and hypertension* or diabetes mellitus and atherosclerosis*) and some of them are not known (see differential diagnosis of septic and autoimmune vasculitis, relationship between granulomatous type of vasculitis** and mtb, etc.). Clinical Pathology korr.indd 19 2013.03.05. 19:00:38

20 Preface The study is supported by extensive clinical data, and the accuracy of the postmortem data is based on a large, histologically evaluated, autopsy population of RA patients in one institution. The applied methods are easy to apply and are available worldwide in basic diagnostic laboratories. The results are well documented and illustrated with figures and microphotographs of RA. The clinicopathological relationships are demonstrated by diagrams and charts. The meticulous histological evaluation and presentation of the basic pathological processes that take place in RA are presented and discussed in a style easily understandable by rheumatologists as well as general practitioners. The book is recommended to all clinicians and pathologists, who are working with autoimmune diseases. 1. Bély M: Krankheitsmodifizierende Faktoren bei chronischer Polyarthritis: Über Zusammenhänge zwischen generalisierter Vaskulitis, sekundärer Amyloidose, septischen Infektionenen und Auftreten von miliaren epitheloidzelligen Granulomen. D.Sc. Thesis, Budapest 1993 2. Bély M, Apáthy Ágnes: Atherosclerosis, Hypertension and Diabetes Mellitus in Rheumatoid Arthritis - A Retrospective Clinicopathologic - Statistical Study of 234 Autopsy Patients (Abstract) Annals Rheum Dis 65, Suppl.11, 162-163 (2006) http://www.abstracts2view.com/eular/ ** There was no significant relationship between clinically controlled hypertension or diabetes mellitus and atheros clerosis (with or without lethal outcome) in 161 RA patients. The relationship between hypertension and atherosclerosis (with or without lethal outcome) was significant in 234 RA patients (2). ** Granulomatous vasculitis is a special type of autoimmune vasculitis not identical with tuberculous vasculitis, which is characterized by subendothelial, intimal epitheloid granulomas. Granulomatous systemic vasculitis is an important diagnostic histologic feature of disseminated miliary tuberculosis in RA patients. The presence of granulomatous type of vasculitis should alert the pathologist to communicate with the clinicians to rule out a possible coexistent tuberculosis. Clinical Pathology korr.indd 20 2013.03.05. 19:00:38