Oxford Case Histories in Rheumatology Oxford Case Histories Series Editors Sarah Pendlebury and Peter Rothwell Published: Neurological Case Histories (Sarah Pendlebury, Philip Anslow, and Peter Rothwell ) Oxford Case Histories in Cardiology (Rajkumar Rajendram, Javed Ehtisham, and Colin Forfar) Oxford Case Histories in Gastroenterology and Hepatology (Alissa Walsh, Otto Buchel, Jane C ollier, and Simon Travis) Oxford Case Histories in Respiratory Medicine (John Stradling, Andrew Stanton, Anabell Nick ol, Helen Davies, and Najib Rahman) Oxford Case Histories in Rheumatology (Joel David, Anne Miller, Anushka Soni, and Lyn Willi amson) Upcoming: Oxford Case Histories in Neurosurgery (Harutomo Hasegawa, Matthew Crocker, and Pa wanjit Singh Minhas) Oxford Case Histories in TIA and Stroke (Sarah Pendlebury, Ursula Schulz, Aneil Malhotra, a nd Peter Rothwell) Oxford Case Histories in Rheumatology Joel David Consultant Rheumatologist and Lead Physician, Nuffield Orthopedic Center, Oxford , UK Anne Miller Associate Specialist in Rheumatology, Nuffield Orthopedic Center, Oxford, UK Anushka Soni Clinical Lecturer in Rheumatology, University of Oxford, Oxford, UK Lyn Williamson Consultant Rheumatologist, Great Western Hospital, Swindon, UK 1 1 Great Clarendon Street, Oxford ox2 6dp Oxford University Press is a department of the Unive rsity of Oxford. It furthers the University \200\231s objective of excellence in research, scholarship, and education by publishing worldwide in Oxford New York Auckland Cape Town Da r es Salaam Hong Kong Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi S hanghai Taipei Toronto With offices in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Tha iland Turkey Ukraine Vietnam Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries Published in the United States by Oxford University Press Inc., New York Oxford University Press, 2012 The moral rights of the author have been asserted Database right Oxford University Press (maker) First published 2012 All rights reserved. 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Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, a t the address above You must not circulate this book in any other binding or cover and you must impose the same condition on any acquirer British Library Cataloging in Publication Data Data available Library of Congress Cataloging in Publication Data Library of Congress Control Number: 2011 939859 Typeset in Minion by Cenveo, Bangalore, India Printed in Great Britain on acid-free paper b y CPI Group (UK) Ltd, Croydon, CR0 4YY ISBN 978 \200\2230 \200\22319 \200\223958750 \200\2236 10 9 8 7 6 5 4 3 2 1 Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and c linical procedures with the most up-to-date published product information and data sheets p rovided by the manufacturers and the most recent codes of conduct and safety regulations. T he authors and the publishers do not accept responsibility or legal liability for any error s in the text or for the misuse or misapplication of material in this work. Except where ot herwise stated, drug dosages and recommendations are for the non-pregnant adult who is not breastfeeding. A note from the series editors Case histories have always had an important role in medical education, but most published m aterial has been directed at undergraduates or residents. The Oxford Case Histories series aims to provide more complex case-based learning for clinicians in specialist training and consultants, with a view to aiding preparation for entry- and exit-level specialty examinat ions or revalidation. Each case book follows the same format with approximately 50 cases, each compris- ing a bri ef clinical history and investigations, followed by questions on differential diagnosis and management, and detailed answers with discussion. All cases are peer-reviewed by Oxford consultants in the relevant specialty. At the end of each book, cases are listed by mode of presentation, etiology, and diagnosis. We are gratef ul to our colleagues in the various medical specialties for their enthusiasm and hard work in making the series possible. Sarah Pendlebury and Peter Rothwell From reviews of other books in the series: Neurological Case Histories \200\230 \200 conta ins 51 cases that cover the spectrum of acute neurology and the neurology of general medici ne \200\224this breadth makes the volume unique and provides a formidable challenge \200 i t is a heavy-duty diagnostic series of cases, and readers have to work hard, to recognize t he diagnosis and answer the questions that are posed for each case \200 I recommend this e xcellent volume highly \200 \200\231 Lancet Neurology \200\230This short and well-written text is \200 designed to enhance the reader \200\231s diagnostic abil- ity and clinical understanding \200 A well-documented and practical book. \200\231 European Journal of Neurology Oxford Case Histories in Gastroenterology and Hepatology \200\230 \200 a fascinating insig ht in to clinical gastroenterology, an excellent and enjoyable read and an education for al l levels of gastroenterologist from ST1 to consultant. \200\231 Gut This page intentionally left blank Preface This book contains a series of case histories that the authors have encountered in the Oxfo rd region. The purpose of the cases is to provide trainees, and indeed all practi- tioners in rheumatology, with clinical scenarios and an evidenced approach to answering questions r aised by the cases. It is hoped that the book will be useful for training as well as in pre paration for exit examinations. The book may also be helpful for rheumatologists in their r e-validation. General medical trainees might find it useful in preparation for MRCP and PAC ES. Many of the cases require clinical judgment in the approach to the management decisions and questions. The authors have expressed their views and hope that you generally agree! The c ases cover inflammatory joint and connective tissue disease, pediatric rheumatology, sports and exercise medicine, and metabolic bone disease. Some of the cases include acute present ations and others are more chronic muscu- loskeletal and mechanical problems where there ar e dilemmas in clinical practice. The authors have used the format of case reports, with detailed discussions of dif- ferenti al diagnosis and management, for three reasons. First, one of the best ways to learn advanc ed clinical medicine is through the analysis of individual cases. In almost all areas of me dicine it is extremely difficult to illustrate the practical process of diag- nosis within the format of a traditional textbook. Secondly, it is simply more interesting to consider r eal cases than to read a text. This allows a clinician to reflect on their own differential diagnosis and treatment. Finally, there is a lack of case series that stretch the abilitie s of experienced clinicians and specialists: most are aimed at medical students or young do ctors doing early postgraduate exams. It is for this reason that the cases and questions ar e sometimes challenging, although many are simple since the aim is to educate. Wherever pos sible radiology and clinical pictures have been included. The authors would like to thank their colleagues, including those allied to medicine, for c ontributing cases and providing illustrations or administrative support. The clinicians who contributed cases are listed in the Acknowledgements. We hope you enjoy the book! Joel David Anne Miller Anushka Soni Lyn Williamson This page intentionally left blank Acknowledgements Dr Kuljeet Bhamra Miss Jane Flynn Dr Lawrence John Dr Maria Juarez Dr Sarah Keidel Ms Fiona Kinnear Dr Lucy Mackillop Dr Kulveer Mankia Dr Brendan McDonald Dr Ishita Patel Dr Elizabeth Price Dr Nick Ridley Dr Joanna Robson Dr Shilpa Selvan Dr Bill Smith Dr Anisha Sodha Dr Ravi Suppiah Dr Rosemary Waller Dr Thamindu Wedatilake Dr Luke Williamson This page intentionally left blank Contents Abbreviations xiii Table of normal ranges xv Cases 1 \200\22346 1 List of cases by diagnosis 270 List of cases by aetiological mechanisms 271 Index 273 This page intentionally left blank Abbreviations AAS ABPI ACCP atlanto-axial subluxation ankle \200\223brachial pressure index anticitrullinated C-peptide (also referred to as ACPA) angiotensin-converting enzyme anticardiolipin antibody alkaline phosphatase antinuclear antibody antineutrophil cytoplasmic antibody adverse neural dynami cs antiphospholipid syndrome activated partial thromboplastin time ankylosing spondylitis a ntistreptolysin-O titre aspartate transaminase Bath Ankylosing Spondylitis Disease Activity Index Beh et \200\231s disease bone mineral density body mass index British Society for R heumatology creatine kinase cytomegalovirus central nervous system vasculitic cyclo-oxgenas e-2 creatine phosphokinase calcinosis, Raynaud \200\231s, (o)esphageal involvement, sclerod actyly, telangiectasia chronic relapsing multifocal osteomyelitis C-reactive protein comple x regional pain syndrome cerebrospinal fluid Churg \200\223Strauss syndrome computed tomogr aphy CTX carboxy-terminal collagen crosslinks chest X-ray Disease Activity Score dual-energy X-ray a bsorptiometry diffuse infiltrative lymphocytosis syndrome diffuse idiopathic skeletal hyper ostosis disease-modifying anti-rheumatic drug Epstein \200\223Barr virus electrocardiogram eosinophilic fasciitis enzyme immunoassay enzyme-linked immunosorbent assay electromyograph y extractable nuclear antigen erythrocyte sedimentation rate European League Against Rheuma tism full blood count familial Mediterranean fever follicle-stimulating hormone granulomato us angiitis of the central nervous system giant cell arteritis glomerular filtration rate g amma glutamyl transferase growth hormone granulomatosis with polyangiitis (also known as We gener \200\231s granulomatosis (WG)) hemophiliac arthropathy hemoglobin human leucocyte ant igen high-power field CXR DAS DEXA ACE aCL ALP ANA ANCA DILS DISH DMARD AND APS APTT EBV ECG EF EIA ELISA AS ASOT AST BASDAI EMG ENA ESR EULAR BD BMD BMI BSR CK CMV CNSV FBC FMF FSH GACNS COX-2 CPK CREST GCA GFR GGT GH GPA CRMO CRP CRPS CSF CSS CT HA Hb HLA hpf xiv ABBREVIATIONS IBD IGF-1 INR IP IRIS inflammatory bowel disease insulin-like growth factor 1 international normalized ratio inte rphalangeal immune reconstitution inflammatory syndrome juvenile idiopathic arthritis lupus anticoagulant lactate dehydrogenase liver function test luteinizing hormone mouth and geni tal ulcers with inflamed cartilage macrophage activation syndrome metacarpophalangeal mean cell volume multiple endocrine neoplasia I major histocompatibility complex microscopic pol yangiitis magnetic resonance angiography magnetic resonance imaging PFJ PFPS PMR PT PTH PTT PUK PUO RA RBC RCVS patello-femoral joint patello-femoral pain syndrome polymyalgia rheumatica prothrombin time parathyroid hormone partial thromboplastin time peripheral ulcerative keratitis pyrexia of unknown origin rheumatoid arthritis red blood cell reversible cerebral vasoconstrictive sy ndrome rheumatoid factor relapsing polychondritis serum amyloid protein synovitis, acne, pu stulosis, hyperostosis, and osteitis standard deviation sex-hormone-binding globulin system ic lupus erythematosus systemic-onset juvenile idiopathic arthritis short T 1 inversion rec overy Takayasu \200\231s arteritis transcutaneous electrical nerve stimulation thyroid func tion test transforming growth factor- tumor necrosis factor Treponema pallidum haemagglu tination test thyroid-stimulating hormone urea and electrolytes Visual Analog Score Venerea l Disease Research Laboratory vastus medialis obliterans ventral subluxation venous thrombo embolism varicella zoster virus white blood cell white cell count Wegener \200\231s granulo matosis (also known as granulomatosis with polyangiitis (GPA)) JIA LA LDH LFT LH MAGIC RF RP SAP SAPHO MAS MCP MCV MEN-I MHC SD SHBG SLE SOJIA MPA MRA STIR TakA TENS MRI MSCRAMM microbial surface components recognizing adhesive matrix molecules medial tibial stress syndrome National Institute of C linical Excellence neck of the femur non-steroidal anti- inflammatory drug non-specific int erstitial pneumonia cross-linked N-telopeptides of type 1 collagen New York Heart Associati on osteoarthritis osteogenesis imperfecta primary angiitis of the central nervous system po lyarteritis nodosa periodic acid \200\223Schiff polymerase chain reaction positron emission tomography TFT TGF- TNF TPHA MTSS NICE NOF NSAID TSH U&E VAS VDRL NSIP NTX NYHA OA OI PACNS VMO VS VTE VZV WBC WCC WG PAN PAS PCR PET Normal ranges Hematology hemoglobin males g/L (130 \200\223180) females g/L (115 \200\223165) MCV fL (80 \200\22396) \227109/L (4.0 \200\22311.0) white cell count \227109/L (1.5 \200\2237.0) neutrophil count \227109/L (1.5 \200\2234.0) lymphocyte count \227109/L (<0.8) monocyte count \227109/L (0.04 \200\2230.40) eosinophil count \227109/L (150 \200\223400) platelet count \227106/L (430 \200\2231690) CD4 count erythrocyte sedimentation rate under 50 years: males mm/ h (<15) females mm/ h (<20) over 50 years: males mm/ h (<20) females mm/ h (<30) Haematinics serum iron mol/L (12 \200\22330) serum iron-binding capacity mol/L (45 \200\22375) serum ferritin g/L (15 \200\223300) serum transferrin g/L (2.0 \200\2234.0) Chemistry Blood serum sodium mmol/L (137 \200\223144) serum potassium mmol/L (3.5 \200\2234.9) serum creatinine mol/L (60 \200\223110) estimated glomerular filtration rate mL/min (>60) serum corrected calcium mmol/L (2.20 \200\2232.60) xvi NORMAL RANGES serum total protein g/L (61 \200\22376) serum albumin g/L (37 \200\22349) serum globulin g/L (24 \200\22327) serum alanine aminotransferase U/L (5 \200\22335) serum alkaline phosphatase U/L (45 \200\223105) serum gamma glutamyl transferase males U/L (<50) females U/L (4 \200\22335) serum lactate dehydrogenase U/L (10 \200\223250) serum creatine kinase (CPK) males U/L (24 \200\223195) females U/L (24 \200\223170) fasting plasma glucose mmol/L (3.0 \200\2236.0) serum urate males mmol/L (0.23 \200\2230.46) females mmol/L (0.19 \200\2230.36) serum angiotensin-converting enzyme U/L (25 \200\22382) Urine glomerular filtration rate mL/min (70 \200\223140) 24-h urinary total protein g (<0.2) Lipids and lipoproteins serum cholesterol mmol/L (<5.2) serum LDL cholesterol mmol/L (<3.36) serum HDL cholesterol mmol/L (>1.55) fasting serum triglycerides mmol/L (0.45 \200\2231.69) Thyroid hormones plasma thyroid-binding globulin mg/L (13 \200\22328) plasma T4 nmol/L (58 \200\223174) plasma parathyroid hormone pmol/L (0.9 \200\2235.4) serum cholecalciferol (vitamin D3) nmol/L (60 \200\223105) serum 25-OH-cholecalciferol nmol/L (45 \200\22390) serum 1,25-(OH)2-cholecalciferol pmol/L (43 \200\223149) Immunology serum complement C3 mg/dL (65 \200\223190) serum complement C4 mg/dL (15 \200\22350) xvii NORMAL RANGES C-reactive protein (CRP) mg/L (<8) serum immunoglobulin G g/L (6.0 \200\22313.0) serum immunoglobulin A g/L (0.8 \200\2233.0) serum immunoglobulin M g/L (0.4 \200\2232.5) Autoantibodies anticentromere antibodies (negative at 1:40 dilution) anticardiolipin antibodies: immunoglobulin G U/mL (<23) immunoglobulin M U/mL (<11) anti-cyclic citrullinated peptide antibodies (ACPA) anti-double-stranded DNA antibodies (ELISA) U/mL (<73) anti-neutrophil cytoplasmic antibodies: c-ANCA p-ANCA PR3-ANCA U/mL (<10) MPO-ANCA U/mL (<10) antinuclear antibodies (negative at 1:20 dilution) extractable nuclear antigen anti-Jo-1 antibodies anti-La antibodies antimitochondrial antibodies (negative at 1:20 dilution) anti-RNP antibodies anti-Scl-70 antibodies anti-Ro antibodies anti-Sm antibodies anti-smooth muscle antibodies (negative at 1:20 dilution) anti-thyroid colloid and microsomal antibodies (negative at 1:10 dilution) rheumatoid factor kIU/L (<30) This page intentionally left blank 1 CASE 1 Case 1 A 76-year-old widow presented to the Emergency Department with a mid-shaft right femoral fr acture after a low-impact fall outside a supermarket. She had a past history of ischaemic h eart disease, peripheral vascular disease, intermittent claudication, and mechanical right knee pain. She had been reviewed in rheumatology outpatients 3 months prior to admission fo r investigation of a painful swollen right elbow. She lived alone and had moved from County Durham where her husband had been a coal miner. Her usual medication included aspirin, ben droflumethiazide, and simvastatin. On examination, in addition to the fractured femur she had a warm swollen R distal upper ar m. She was haemodynamically stable, normotensive, and in sinus rhythm. Her distal pedal pul ses were all impalpable. Her initial blood results showed the following: \227\206 Hb 10.5 g/dL (MCV 88 fL); WCC 6.8 \227 109/L; platelets 468 \227 109/L \227\206 Creatinine 138 mol/L; asparatate transaminase (AST) 48 IU/L; gamma glutamyl transferase (GGT) 52 IU/L; ALP 785 IU/L \227\206 Corrected calcium 2.23 mmol/L; phosphate 1.2 mmol/L \227\206 C-reactive protein (CRP) 8 mg/L. Her femoral fracture was successfully pinned and plated, and she made a good post- operativ e recovery. Prior to discharge she was given an intravenous infusion. One week after discha rge she was re-admitted profoundly unwell with nausea, vomiting, and tingling in her hands and feet. Second admission bloods were as follows. \227\206 Hb 11.5 g/dL (MCV 88 fL); WCC 7.9 \227 10 9 /L; platelets 488 \227 10 9 /L \227\206 Creatinine 144 mol/L; asparatate transaminase (AST) 55 IU/L; gamma glutamyl transferase (GGT) 30 IU/L; ALP189 IU/L \227\206 CRP 10 mg/L \227\206 Corrected calcium 1.87 mmol/L; phosphate 0.8 mmol/L \227\206 Vitamin D level 7 nmol/L (threshold 20). Radiographic findings are shown in Figs 1.1 , 1.2 , 1.3 and 1.4 Questions 1. What is the underlying bony diagnosis? What is the differential diagnosis? Describe the radiographic features in Figs 1.1 \200\223 1.4 . 2. Describe the clinical features, natural history, and potential complications of this condition . 3. What is the likely infusion she was given? 4. What complication of treatment did she develop and why? 5. Her daughter accompanies her to appointments and asks if she is likely to have this condition? 2 CASE HISTORIES IN RHEUMATOLOGY Fig. 1.1 Right humerus. Fig. 1.2 Isotope bone scan. 3 CASE 1 Fig. 1.3 Right femoral mid-shaft fracture. Fig. 1.4 Repaired right femoral mid-shaft fracture. 4 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is the underlying bony diagnosis? What is the differential diagnosis? The diagnosis is Paget \200\231s disease of bone. The differential diagnosis of a low-impact fracture in an elderly woman includes osteoporos is, osteomalacia, pathological fracture through a malignant focus, and Paget \200\231s dise ase. This patient \200\231s calcium was low normal on admission. Her phos- phate was also l ow normal and her alkaline phosphate was very high. The rise in ALP could have been due to Paget \200\231s disease, osteomalacia, malignancy, or her recent fracture. The plain radiographic features in the humerus (Fig. 1.1 ), and below the femoral fracture site (Fig. 1.3 ) in this case are typical of Paget \200\231s disease (Fig. 1.5 ). The bones are expanded with coarse trabeculation, cortical thickening, a mixture of lytic and sclero tic areas with intra-cortical resorption, loss of cortico-medullary junction, and early sec ondary osteoarthritis changes in the knee. Radiographic features are pathognomonic in estab lished disease, but early or isolated lesions might be con- fused with malignancy and sever e osteomalacia. Fig. 1.5 Typical pagetic changes in a humerus with disorganized architecture, coarse trabec ulation, cortical thickening, bowing and fractures in the cortex (arrow), and osteoarthriti c changes in elbow (arrow) and shoulder. 5 CASE 1 Fig. 1.6 MRI spine with spinal cord compression (arrow) and multi-level degeneration. The technetium-99m isotope bone scan (Fig. 1.2 ) shows increased uptake in the right humerus right distal femur, right hemi-pelvis, and thoracic spine. Isotope bone scans are the current standard method of establishing the pattern of skeletal site involvement. Typical abnormalities are easily recognized. However, if abnormalities ar e detected, further clinical and radiographic assessment is neces- sary. There is a move to wards limited skeletal survey, imaging the clinically signifi- cant sites of skull, long bo nes, and spine as first-line investigation. In this patient s technetium scan the characteristic V-shaped advancing front of Paget \200 \231s disease is seen in the femur and humerus. This represents marked osteolysis without a ccompanying sclerosis. Other affected areas include the sacrum and the T9 vertebral body. CT imaging may be useful to delineate difficult fractures and MRI should be used to charact erize spinal Paget \200\231s disease which may cause nerve root compression and spinal cana l stenosis (Fig. 1.6 ). 2. Describe the clinical features, natural history, and potential complications of this condition Paget \200\231s disease of bone occurs in up to 10 % of the population aged over 80 years a nd can affect any bone. The most common bones affected are pelvis (75 % ), lumbar spine (50 % ), femur (35 % ), sacrum (35 % ), skull (35 % ), tibia (30 % ) radius (15 % ). Patients often present with pain or deformity. The pain is of a deep bony, boring 6 CASE HISTORIES IN RHEUMATOLOGY quality, and is present at rest. If the pagetic lesions involve subchondral bone they may r esult in secondary osteoarthritic changes and additional mechanical pain. Pagetic bone is often increased in size, bowed, and mechanically weak. The bones are hyperv ascular, warm, and prone to fracture. Bony enlargement in the spine may cause mechanical co mpression of the nerve roots or spinal canal, leading to radicular pain or spinal claudicat ion. Microfracture and vertebral collapse may lead to pain and kyphosis. The cause of pain may be difficult to determine and requires careful history and examination. This patient \200\231s fracture is just above her pagetic bone and a typical site for patho - logical fracture. Prior to the fracture, her most troublesome symptom was her knee pain, attributed to associated osteoarthritis. As with many elderly patients, she has a number of comorbidities, including vascular claudication, which may have complicated the clinical pi cture. Pagetic bone is hypervascular, and this has important consequences in relation to joint rep lacement surgery or surgery after fracture. The bleeding from hypervascu- lar pagetic bone needs to be anticipated and is often difficult to control. Pretreatment with bisphosphonate s may help prevent perioperative blood loss (see below). High- output cardiac failure, alth ough often cited, is rarely seen in practice. Deformity and associated symptoms are site-specific. Skull involvement can cause deafness f rom cranial nerve VIII compression, change in head shape, deep- seated headache, toothache (mandible involvement); blindness from optic nerve compression, and change in voice from na sal bone and airway narrowing. Long bones such as the tibia ( \200\230saber tibia \200\231) and femur may be bowed, warm, and painful. Associated leg-length inequalities can lead to mechanical low back pain. Spinal involvement may lead to pain, spinal claudication; radicul ar symptoms from nerve root entrapment, or vertebral collapse and kyphosis. Many patients are asymptomatic and Paget \200\231s disease is an incidental finding on X-ra y or from a raised alkaline phosphatase (ALP) as part of a routine blood screen for liver f unction. The natural history is unknown. Patients may be asymptomatic for many years, and i t is not yet known whether treatment of asymptomatic patients increases longevity or preven ts future problems. However, treatment is generally given for lower-limb long-bone, spinal, skull, and painful pagetic lesions. 3. What is the likely infusion she was given? This patient was treated with a potent intravenous bisphosphonate, either pamid- ronate or zoledronate. The treatment of symptomatic Paget \200\231s disease of bone has been improved by the intro duction of bisphosphonates which are potent inhibitors of bone turnover. The current regime s include 2 months oral risedronate 35 mg daily or 6 months oral alendronate 40 mg, quarter ly intravenous pamidronate 30 \200\22390 mg over 2 h, or annual zolendronate 5 mg over 30 m in. The aim of bisphosphonate therapy is to decrease pain, prevent further fracture, and no rmalize the alkaline phophatase. This is particularly effective prior to orthopedic operati ons. Although there is a theoretical 7 CASE 1 risk of impeding bone healing and remodeling by preventing osteoclast function, it is accep table practice to use bisphosphonate therapy to try to prevent disease complications such a s long-bone fracture. ALP is the most commonly used marker of bisphosphonate activity. Bone resorp- tion markers such as urinary cross-linked N-telopeptides of type 1 collagen (NTX) and serum carboxy-term inal collagen crosslinks (CTX) are raised, but are rarely helpful in clinical decision-maki ng. An ALP within the normal range may still be abnormally high for an individual patient, and comparison with premorbid ALP levels, if available, will help inform treat- ment decisions. In general, high ALP levels are associated with high disease activity. Oral bisphosphonate normalizes ALP in 60 % of patients at 18 months, IV pamidronate normali zes ALP in 50 % at 6 months, and IV zoledronate normalizes ALP in 80 % of patients at 6 mon ths. There is no benefit in terms of subsequent fracture rate or quality of life in treat- ing P aget \200\231s disease to maintain normal ALP levels. Treatments are repeated accord- ing t o patient symptoms. As yet there are no data about the safety and efficacy of long-term bis phosphonate use. Patients who are intolerant of bisphosphonates may respond to calcitonin given by subcutane ous injection \200\224 100 units daily for 3 \200\2236 months. This treatment should reduc e pain and ALP in up to 50 % of patients at 6 months. Side effects, including flushing, nau sea, and headache, are common and may limit therapy. 4. What complication of treatment did she develop and why? This patient developed profound hypocalcaemia in the presence of previously undiagnosed hyp ovitaminosis D. Hypovitaminosis D is very common and under- diagnosed in the elderly, parti cularly from northern latitudes. Low vitamin D levels can lead to myalgia, bone pain, weakn ess, and even falls. Borderline vitamin D levels in this woman prior to bisphosphonate infu sion exaggerated the hypocalcaemic effect and led to dangerously low serum calcium levels. All bisphosphonates can cause hypocalcaemia. The effect is greater with the more powerful l onger-acting preparations and in patients with low vitamin D lev- els. Ideally, all patient s should have their serum calcium and vitamin D levels checked before administration of par enteral bisphosphonate. As vitamin D levels are not always readily available, it is recomme nded that all patients receiving bisphos- phonate treatment should receive calcium and vita min D supplementation unless there are specific contraindications. Oral bisphosphonate preparations need to be taken on an empty stomach with a large glass of water, and the patient should remain upright for at least 30 minutes before eating. Gastri tis and indigestion are common. Many centers are moving towards using the more powerful lon ger-acting intra-venous preparations because of poor compliance and gastrointestinal side e ffects with the oral preparations. This general move is mirrored in the treatment of osteop orosis, where there is widespread use of bisphosphonates. Therefore this case serves to ill ustrate a potential problem that could occur with increasing use of powerful long-acting bi sphosphonates. 8 CASE HISTORIES IN RHEUMATOLOGY 5. Her daughter accompanies her to appointments and asks if she is likely to have this condition? Paget \200\231s disease of bone commonly occurs in families with an autosomal dominant but incompletely penetrant pattern of inheritance. As a first-degree relative, this woman \200 \231s daughter has a seven times increased risk of developing the condition. There is ethnic and geographic clustering around cooler latitudes, particularly Europe, Nor th America, and Australasia. The highest prevalence is in populations from northern Britain and where they have subsequently migrated into the former British colonies. Recent genetic studies from familial Paget \200\231s disease of bone have linked a number o f genetic loci and mutations have been identified in four genes, the most impor- tant of wh ich is sequestosome 1 (SQSTM1). This is a scaffold protein in the nuclear factor kappa B (N FkappaB) signaling pathway. Patients with SQSTM1 mutations have severe Paget \200\231s dise ase with a high degree of penetrance with increasing age. Environmental factors, such as de ficiency in dietary calcium, and repeated mechanical loading have recently been linked to P aget \200\231s disease of bone. Other possible envi- ronmental triggers include paramyxovir al infection, measles, canine distemper, and respiratory syncytial virus. Given the ubiquit ous nature of many of these viruses, interplay of genetic and environmental factors must oc cur to explain the geograph- ical distribution as well as the focal and heterogenous nature of the condition. Further reading Cooper MS , Gittoes NJ ( 2008 ). Diagnosis and management of hypocalcaemia . BMJ ; 336 : 1298 \200\223 1302 . Langston AL , Campbell MK , Fraser WD , et al . ( 2010 ). Randomized trial of intensive bisphosphonate treatment versus symptomatic management in Paget \200\231s disease of bone . J Bone Miner Res ; 25 : 20 \200\223 31. Mouyis M Ostor AJ , Crisp AJ , et al. ( 2008 ). Hypovitaminosis D among rheumatology outpatients in clinical practice . Rheumatology ; 47 : 1348 \200\223 51. Paget, J. (1877). On a form of chronic inflammation of bones (osteitis deformans). Trans Med-Chir Soc ; 60 : 235 \200\223 56. Peter R , Mishra V , Fraser WD ( 2007 ). Severe hypocalcaemia after being given intravenous bisphosphonate . BMJ ; 328 : 335 \200\223 6. Scarsbrook A , Brown M , Wilson D ( 2004 ). UK guidelines on management of Paget \200\231s disease of bone . Rheumatology ; 43 : 399 \200\223 400. Siris ES , Lyles KW , Singer FR , Meunier PJ ( 2006 ). Medical management of Paget \200\231 s disease of the bone: indications for treatment and review of current therapies . J Bone M iner Res ; 21 ( Suppl 2) : 94 \200\223 8 . Soni A , Williamson L ( 2008 ). Paget \200\231s disease \200\224 limited skeletal survey m ay be better than isotope bone scan; an inconvenient truth? Clin Radiol ; 63 : 108 \200\223 10. 9 CASE 2 Case 2 A 60-year-old woman was referred to the lymphoma clinic in view of a 2 month history of nig ht sweats, fatigue, and general malaise. There was no past medical or travel history of not e, but significant weight loss had been noted by her husband. She denied any gas- trointest inal symptoms but had been experiencing recurrent generalized headaches over the last 6 wee ks. She was a lifelong non-smoker and drank alcohol only occasionally. On examination she had a temperature of 38.2 C, but other vital signs were normal. She a ppeared thin with no lymphadenopathy. Full systemic examination, including urinalysis, was otherwise normal. Investigations revealed elevated inflammatory markers (erythrocyte sedimentation rate (ESR) 85 mm/h, CRP 44 mg/L) but no evidence of hematological abnormality, infection, or malignan cy. The results of diagnostic and staging investigations are shown in Figs 2.1 and 2.2 , re spectively. Fig. 2.1 (See also Plate 1) Diagnostic investigation. 10 CASE HISTORIES IN RHEUMATOLOGY Fig. 2.2 Staging investigation . 11 CASE 2 Questions 1. What is the diagnosis? What is the diagnostic investigation that was performed and what abnormalities are shown in Fig. 2.1? 2. Which investigation results are shown in Fig. 2.2 ? When should this investigation be considered? 3. What is the most worrying complication of this condition? 4. What features should be sought on examination? 5. What immediate action should be taken when this condition is suspected? 6. Which other imaging modality may be helpful in the investigation of this condition? 12 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is the diagnosis? What is the diagnostic investigation that was performed and what abnormalities are shown in Fig. 2.1? The diagnosis is giant cell arteritis (GCA), also known as temporal arteritis or Horton \200\231s headache. It is a primary large vessel vasculitis with a mean age at onset of 70 years. It is rare before the age of 50 years and is more common in Caucasian than African C aribbean people. It has a significant female preponderance. Headache is the most common com plaint; it occurs in 90 % of patients and is the presenting feature in 48 % of cases. Heada ches can be quite variable in quality and nature, and can mimic tension headache, migraine, and cluster headaches. Other common features include scalp tenderness and jaw or tongue cl audication. Systemic features including fever, weight loss, and malaise occur in 50 % of pa tients. Rarely, it can present with systemic features alone or limb claudication. The diagnostic investigation is a temporal artery biopsy (Figs 2.1 and 2.3). This investiga tion should be considered in all cases of suspected temporal arteritis. Ideally, a temporal artery biopsy should be obtained within a week of commencing steroids in order to maximize its diagnostic and prognostic value. However, there is evidence to suggest that temporal a rtery biopsy may remain positive up to 28 days after commencing steroid therapy. Contralate ral biopsy does not provide any additional information and is not routinely recommended. In order to maximize the diagnostic potential, a biopsy at least 1 cm long is suggested. This example (Fig. 2.3) demonstrates the classical histological features of GCA which include: \227\206 disruption of the internal elastic membrane (1) \227\206 multinucleate giant cells (2) \227\206 occlusion of the lumen (3) \227\206 intimal hyperplasia (4). 1 4 2 3 Fig. 2.3 (See also Plate 2) Temporal artery biopsy. 13 CASE 2 The severity of intimal hyperplasia on temporal artery biopsy is associated with increased risk of neuro-ophthalmic complications. 2. Which investigation results are shown in Fig. 2.2 ? When should this investigation be considered? Figure 2.2 shows the results of a whole-body FDG PET scan. The use of FDG, a glucose analog , enables the visualization of inflamed vessels, which are glucose- consuming, provided tha t they are greater than 4 mm in diameter. This size limita- tion and proximity to the high glucose consumption of the brain explains why the temporal arteries themselves are not visi ble using this imaging modality. Large- vessel vasculitis can be demonstrated and is partic ularly specific to large-vessel vasculitis when seen in the larger thoracic vessels, as is seen here with marked aortitis. This type of imaging should be considered in patients demonstrating systemic features, limb claudication, or persistent symptoms despite adequate steroid therapy. MRI can also be use d to assess for large-vessel involvement and does not expose the patient to radiation. 3. What is the most worrying complication of this condition? Visual loss is the most serious complication of GCA, and occurs in 15 % of patients. If one eye is affected, there is high risk (20 \200\22350 % ) of bilateral loss of vision if ther e is any delay or cessation of treatment. Blindness is most commonly the result of optic is chae- mic neuropathy and is associated with a positive temporal artery biopsy. Retinal and ophthalmic artery thromboses are rare causes of blindness in GCA. 4. What features should be sought on examination? Examination findings include the following: \227\206 Cranial : tender, thickened, or beaded superficial temporal artery with reduced or absent pulsation, scalp tenderness, and upper cranial nerve palsies. \227\206 Visual : transient or permanent reduction in acuity, relative afferent pupillary defect, and pale swollen optic disc. \227\206 Systemic : asymmetrical pulses and blood pressure, presence of bruits. The presence of temporal artery prominence, beading, and tenderness all increase the likeli hood of obtaining a positive temporal artery biopsy. 5. What immediate action should be taken when this condition is suspected? All patients with suspected GCA should be commenced on high-dose steroids imme- diately. Th e dose and administration of steroids depends on the clinical scenario. \227\206 Uncomplicated GCA with no claudication or visual symptoms: 40 \200\22360 mg daily . \227\206 Evolving visual loss or amaurosis fugax: intravenous methylprednisolone 500 mg for 3 days before commencing oral steroids. \227\206 Established visual loss: 60 mg prednisolone daily, to protect the contralateral e ye. 14 CASE HISTORIES IN RHEUMATOLOGY All patients should receive bone protection with calcium and vitamin D supple- ments and a bisphosphonate (see p. 7). Gastric protection with a proton pump inhibitor should also be c onsidered. Once the diagnosis has been confirmed, aspirin is recommended if no contraindica tion exists, and statin therapy can also be con- sidered. Steroid-sparing agents, such as m ethotrexate or azathioprine, may be indicated if there is evidence of recurrent relapse or difficulty weaning steroids. Essential investigations include full blood count, liver function tests, urea and electroly tes, ESR, CRP, and urgent temporal artery biopsy. These investigations should not delay ini tiation of appropriate treatment. 6. Which other imaging modality may be helpful in the investigation of this condition? The diagnostic use of ultrasound in GCA is currently under investigation. It is widely avai lable, relatively inexpensive, repeatable, non-invasive, and lacks radiation expo- sure. It can provide information regarding the vessel wall, lumen, pulsatility, and blood flow char acteristics. The main potential drawback of ultrasound is operator dependency, although rec ent studies of temporal artery ultrasound have shown inter-observer agreement of more than 90 % . The features shown on ultrasound include the following: \227\206 Oedema : a dark hypoechoic thickening or halo around the vessel wall. \227\206 Stenosis : manifests as disrupted turbulent blood flow on color Doppler. \227\206 Occlusion : color signals are absent.