VOLUME 5 NUMBER 3 2007 www.advancesinrheumatology.com
INTERNATIONAL JOURNAL OF ADVANCES IN RHEUMATOLOGY
Editors-in-Chief Michael E Weinblatt, Boston, MA, USA Ferdinand C Breedveld, Leiden, The Netherlands
Clinical Assessment of Spondyloarthropathies: The Role of Radiography in Identifying the Bath Ankylosing Spondylitis Instruments Osteoporotic Vertebral Compression Fractures Andrei Calin Martine De Vos Extra-Articular Manifestations in Case Study: A Rare Complication Rheumatoid Arthritis of Leflunomide Therapy Carl Turesson and Eric L Matteson Vinod Ravindran and Patrick DW Kiely
Jointly sponsored by the University of Kentucky Colleges of Pharmacy and Medicine and Remedica. This journal is supported by an The University of Kentucky is an equal opportunity university. educational grant from Abbott. Faculty Disclosures The following are relevant financial relationships declared by the journal’s Editors-in-Chief, Editors, and Editorial Board members. Ferdinand C Breedveld: Abbott, Schering- Plough, Wyeth. Michael E Weinblatt: Abbott, Alza, Amgen, AstraZeneca, BioAssets, Biogen Idec, Bristol-Myers Squibb, CanFite, Celgene, Centocor, CombinatoRx, Critical Therapeutics, Eisai, EntreMed, Genentech, Gilead, Lilly, Merrimack, Merck, Millennium, Novartis, Pfizer, Praecis, Proprius, Rigel, Roche, Sanofi-Aventis, Scios, Serono, Synta, TAP, Trubion, Wyeth, UCB, Vascular Biogenics. Tom Huizinga: None declared. Peter Nigrovic: None declared. Eric Ruderman: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Roche. Hendrik Schulze-Koops: Abbott, Aspreva, Essex, Roche, Wyeth. Mark Quinn: Abbott, Roche, Schering-Plough, Wyeth. Steven Abramson: Amgen, GlaxoSmithKline, Novartis, Pfizer. Carol Black: None declared. Gerd Burmester: Abbott, Essex, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, UCB, Wyeth. Maxime Dougados: Abbott, Bristol-Myers Squibb, Roche, Wyeth. Paul Emery: Abbott, Amgen, Bristol-Myers Squibb, Centocor, Roche, Schering-Plough, Wyeth. Daniel Furst: Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genentech, Merck, Novartis, Roche, UCB. Mark Genovese: Biogen Idec, Bristol-Myers Squibb, Genentech, Roche, Serono, Wyeth. Gabriel Herrero-Beaumont: None declared. Joachim Kalden: Abbott, Roche, Schering-Plough, Wyeth. Arthur Kavanaugh: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Centocor, Genentech. Edward Keystone: Abbott, Amgen, AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer, Roche, Schering-Plough, Wyeth. Lars Klareskog: Awaited. Vicente Rodriguez-Valverde: Abbott, Bristol-Myers Squibb, Schering-Plough. Josef Smolen: Abbott, Bristol-Myers Squibb, Centocor, Roche, Sanofi-Aventis, Schering-Plough, Wyeth. Désirée van der Heijde: Abbott, Amgen, Bristol-Myers Squibb, Centocor, Chugai, Dainippon Sumitomo, GlaxoSmithKline, Roche, Schering-Plough, UCB, Wyeth. Editorial Policy International Journal of Advances in Rheumatology is an independent journal published by Remedica Medical Education and Publishing. Editorial control is the sole responsibility of the Editors-in-Chief, Editorial Advisory Board, and the Editors. Before publication, all material submitted to the journal is subjected to rigorous review by the Editors-in-Chief, Editorial Advisory Board, Editors, and/or independent reviewers for suitability of scientific content, scientific accuracy, scientific quality, and conflict of interest.
Aims and Scope International Journal of Advances in Rheumatology is designed to bring a critical analysis of the world rheumatology literature, written by clinicians, for clinicians, to an international, multidisciplinary audience. Our mission is to promote better understanding of rheumatological medicine across the global healthcare system by providing an active forum for the discussion of clinical and healthcare policy issues. Leading Articles - These major review articles are chosen to reflect topical clinical and healthcare issues in rheumatology. All contributions undergo a strict editorial review process. Clinical Reviews - The most important papers from the best of the international literature on rheumatology are systematically selected by an internationally recognized panel of experts. The Editors then prepare concise and critical analyses of each paper, and, most importantly, place the findings into clinical context. Meeting Reports - International Journal of Advances in Rheumatology also provides incisive reportage from the most important international congresses.
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Editors-in-Chief Ferdinand C Breedveld, MD Contents Professor of Rheumatology, Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands Michael E Weinblatt, MD Leading Articles Professor of Medicine, Harvard Medical School, Division of Rheumatology, Clinical Assessment of Spondyloarthropathies: 66 Immunology and Allergy, Brigham and Women’s Hospital, Boston, MA, USA the Bath Ankylosing Spondylitis Instruments Andrei Calin Editors Tom WJ Huizinga, MD Professor, Department of Rheumatology, Leiden University Medical Center, Extra-Articular Manifestations 72 Leiden, The Netherlands in Rheumatoid Arthritis Peter Nigrovic, MD Carl Turesson and Eric L Matteson Fellow, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital Boston, MA, USA Eric M Ruderman, MD The Role of Radiography in Identifying 78 Associate Professor, Division of Rheumatology, Northwestern University Osteoporotic Vertebral Compression Fractures School of Medicine, Chicago, IL, USA Maurits HJ Voormolen Hendrik Schulze-Koops, MD Professor, Division of Rheumatology, University of Munich, Munich, Germany Case Study Pulmonary Cavitation: A Rare Complication 85 Case Study Editor of Leflunomide Therapy Mark A Quinn, MD Consultant Rheumatologist, Department of Rheumatology, York Hospital, Vinod Ravindran and Patrick DW Kiely York, UK Clinical Reviews Editorial Advisory Board Treatment Strategies 89 Steven B Abramson, MD Professor of Medicine and Pathology, New York University School of Medicine, New York, NY, USA Prognosis and Assesment 96 Carol M Black, MD Professor of Rheumatology, Department of Rheumatology, Royal Free Hospital, Epidemiology 98 London, UK Gerd R Burmester, MD Professor of Medicine, Department of Rheumatology and Clinical Immunology, Genetics 99 Charite University Hospital, Humboldt-University of Berlin, Berlin, Germany Maxime Dougados, MD Pathogenesis 100 Professor of Rheumatology, Department of Rheumatology, Hospital Cochin, Paris, France Paul Emery, MD Meeting Report ACR Professor of Rheumatology, Academic Department of Musculoskeletal European League Against Rheumatism 102 Disease, Department of Rheumatology, Leeds General Infirmary, Leeds, UK (EULAR) 8th Annual Congress Daniel E Furst, MD Carl M Pearson Professor of Rheumatology, UCLA Medical School, Barcelona, Spain, June 13–16, 2007 Los Angeles, CA, USA Mark C Genovese, MD Forthcoming International Events 104 Assistant Professor of Medicine, Division of Rheumatology, Stanford University Medical Center, Palo Alto, CA, USA Gabriel Herrero-Beaumont, MD Professor of Rheumatology, Inflammation Research Unit, Fundacion Jimenez Diaz, Universidad Autonoma, Madrid, Spain Joachim R Kalden, MD Professor of Internal Medicine, University of Erlangen-Nuremberg, Erlangen, Germany Arthur F Kavanaugh, MD Professor of Medicine, Division of Rheumatology, Allergy and Immunology, Center for Innovative Therapy, UCSD, La Jolla, CA, USA Edward Keystone, MD Professor of Medicine, University of Toronto, Director, Center for Advanced Therapeutics in Arthritis, Mount Sinai Hospital, Toronto, ON, Canada Lars Klareskog, MD Professor of Rheumatology, Department of Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden Vicente Rodriguez-Valverde, MD Professor of Medicine and Chief, Rheumatology Service, Hospital Universitario Marqués de Valdecilla, Facultad de Medicina, Universidad de Cantabria, Santander, Spain Josef S Smolen, MD Professor, 2nd Department of Medicine, Krankenhaus Lainz, Vienna, Austria Désirée van der Heijde, MD Professor of Rheumatology, Department of Rheumatic Diseases, University Hospital Maastricht, Maastricht, The Netherlands RT92_3_REM_Rheum_5-3_05.qxd 7/11/07 14:19 Page 66
Clinical Assessment of Spondyloarthropathies: the Bath Ankylosing Spondylitis Instruments
Andrei Calin, MD Department of Rheumatology, Royal National Hospital for Rheumatic Diseases, Bath, UK LEADING ARTICLE Ankylosing spondylitis (AS) is an inflammatory disease of the spine that can also involve both extraspinal and non-articular tissue. In contrast to many rheumatic diseases, there are no laboratory variables for AS that can be used as indicators of disease activity, disease severity, or disease damage. Even treatment response has been difficult to define in AS given the absence of disease markers, and research into the condition has been hampered by the inherent difficulty of defining its natural history. The author’s group in Bath, UK, has developed a series of “patient-friendly” instruments to define spinal mobility, disease activity, function, and global status. Subsequent to this work, the Assessment in Ankylosing Spondylitis International Working Group developed and validated response criteria and treatment guidelines for AS. These efforts have improved the evaluation and management of the disease. Int J Adv Rheumatol 2007;5(3):66–71.
Ankylosing spondylitis (AS) is an inflammatory disorder of of disease status of AS, and it is necessary to consider other the spine, predominantly affecting the sacroiliac joints. dimensions of this disease. As imaging technology becomes The condition may lead to extraspinal articular disease and more sophisticated (and more expensive), support has been extra-articular systemic involvement [1,2]. Worldwide, provided for a variety of new approaches. the occurrence of AS approximately follows the distribution of human leukocyte antigen B27 (HLA-B27) [1,2]. This Defining the impact of chronic disease genetic marker occurs in >95% of Caucasian patients with There are two complementary frameworks that aid in the primary disease. The figure falls to 50–80% among defining the impact of chronic disease [5]. The first, other ethnic groups [1,2]. Those with secondary spondylitis which was proposed by the World Health Organization, (associated with psoriasis, inflammatory bowel disease, relates to the status of health in terms of impairment, or reactive arthritis) carry HLA-B27 at the same reduced disability, and handicap. Rheumatologists frequently favor a frequency (50–80%) [1,2]. In healthy populations, HLA-B27 second paradigm, which pertains to disease process, occurs in 1–4% of black people, 5–15% of Caucasian outcome, and prognosis. people, and varying percentages of other ethnic groups Many people would consider impairment, disability, and [1,2]. Approximately 10% of people with HLA-B27 develop handicap to be more easily defined than disease process, AS [1,2]. outcome, and prognosis. Impairment refers to aberrant In clinical trials, researchers typically use the modified anatomical, physiological, or psychological status (e.g. a New York criteria for the diagnosis of AS, which requires tissue or organ defect). Disability implies a failure in terms the presence of radiographic sacroiliitis [3]. More recently, of performance at a personal level, and is a consequence of the European Spondyloarthropathy Study Group proposed impairment. Handicap may be suffered by an individual, criteria for spondyloarthropathy that place less emphasis on within society, owing to either impairment or disability. radiological change [4]. For decades, radiological evidence The sequence of events might be impairment followed of sacroiliac joint damage had been pivotal for the clinical by disability and therefore handicap. Alternatively, one and differential diagnoses of AS. However, reliance on might be impaired without being disabled and yet still be radiography and laboratory tests yields an inadequate picture handicapped; for example, a child with a facial blemish (i.e. an impairment) may not be disabled but still find Address for correspondence: Andrei Calin, Royal National Hospital for him- or herself socially handicapped. Handicap is linked Rheumatic Diseases, Bath, BA1 1RL, UK. Email: [email protected] to society’s expectations, but there may be a difference
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between the public’s perception of the degree of handicap Table 1. Addresses for pages covering the Bath Ankylosing and that of the individual. Spondylitis instruments on the UK National Ankylosing In terms of the rheumatological framework of disease Spondylitis Society website (all last accessed September 2007). process, outcome, and prognosis, there is now a well- recognized need to focus more on assessments of outcome BASMI www.nass.co.uk/08_tbi.htm and less on those of process. Examples of the latter include BASFI www.nass.co.uk/09_tbi.htm laboratory tests relating to inflammation, markers of bone BASDAI www.nass.co.uk/10_tbi.htm and cartilage destruction, and a variety of clinical measures BAS-G www.nass.co.uk/11_tbi.htm such as joint counts and grip strength. In contrast, outcome AS: ankylosing spondylitis; BASDAI: Bath Ankylosing Spondylitis Disease (which may be divided into a series of dimensions, Activity Index; BASFI: Bath Ankylosing Spondylitis Functional Index; BAS-G: Bath Ankylosing Spondylitis Patient Global Score; BASMI: Bath Ankylosing subdimensions, and components) is defined more in terms Spondylitis Metrology Index. of the patient’s point of view rather than the clinician’s or biologist’s. For instance, one outcome dimension is discomfort, and its subdimensions relate to the associated Figure 1. The Bath Ankylosing Spondylitis Disease Activity physical and psychological aspects. In turn, these Index page on the UK National Ankylosing Spondylitis subdimensions may be further divided into components such Society website (www.nass.co.uk/10_tbi.htm [last accessed as pain and fatigue for the former and depression and September 2007]). anxiety for the latter. Prognosis is a concept that links disease process to outcome and is often considered synonymous with the prediction of future events. It is important to include in the discussion of these two frameworks the concept of “utilities” [6], which relates to the priorities of individual patients (i.e. the value that a patient attaches to a certain degree of health status). The term “outcome” is often used interchangeably with “health status”, which can be either specifically orientated (i.e. focusing on one dimension) or broadly orientated (i.e. focusing on several dimensions). Utility measurements have been incorporated into the evaluation of treatment for patients with rheumatological diseases, including AS, in part to assess the willingness of patients to accept risk in drug treatment. It was through the use of such instruments that a research team consisting of rheumatologists (including the author), physiotherapists, and research associates with a specialist interest in AS based in Bath, UK, determined that patient-focused, self-administered instruments were needed for the assessment of spinal mobility, function, and disease activity in AS. The indices produced by the team involved • The Bath Ankylosing Spondylitis Metrology Index input from patients with AS, which increased the clinical (BASMI) [7]. relevance of the measures. • The Bath Ankylosing Spondylitis Functional Index With the recent licensing of anti-tumor necrosis factor-α (BASFI) [8]. (anti-TNF-α) medications for use in patients with AS, the • The Bath Ankylosing Spondylitis Disease Activity Index Bath instruments are beginning to be used as part of the (BASDAI) [9]. screening process for the allocation of anti-TNF-α agents • The Bath Ankylosing Spondylitis Patient Global Score and for monitoring outcomes with the drugs. (BAS-G) [10].
The Bath instruments All four indices generate a score out of 10, giving a clear Four instruments for assessing different aspects of AS numerical outcome each time that provides an easy developed by the Bath group are discussed in this article and comparator for reference, and all have been studied for can be found on the UK National Ankylosing Spondylitis reliability, speed, variability, reproducibility, and sensitivity to Society website (Fig.1 and Table 1): change [7–10]. The study sample sizes were adequate,
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ranging between 163 and 392 subjects. Comparisons were to investigate activities related to functional anatomy, made using: an older, 20-measurement metrology assess- with the final two assessing the patient’s ability to cope ment; the Dougados Functional Index; a previous Bath with everyday life. A 10-cm visual analogue scale (VAS) disease activity index; and the Newcastle Enthesis Index. was chosen as the method of answering the questions. The researchers felt that this would improve both the sensitivity BASMI of the index to change and its capacity to elicit a range of In considering metrology, the researchers aimed to responses across the entire scale of values. The BASFI score determine the minimum number of clinically appropriate was defined as the mean value from the 10 scales. measurements that could be used to accurately assess axial Using a sample of 47 inpatients and 116 outpatients, status and from these derive an index to define clinically BASFI was compared with the Dougados Functional Index significant changes in spinal movement [7]. Evaluation of [8]. The comparison revealed the following: axial involvement included the cervical, dorsal, and lumbar spine, the hips, and the pelvic soft tissue. Following a • BASFI and the Dougados Functional Index required literature review, five simple clinical measurements were an equivalent amount of time to complete (≤100 s). included in the index: • Subjects expressed no preference for either instrument. • Across a possible range of 0–10, the BASFI scores had a • Lumbar side flexion. normal distribution of 0–9.5, compared with the narrower • Tragus-to-wall distance. range of 0–6.5 for the Dougados Functional Index. • Modified Schober’s result. • The reproducibility of both scores was statistically • Intermalleolar distance. significant (p<0.001). • Cervical rotation. • Inter-observer reliability was statistically significant for both scores (p<0.001). A guide on how to obtain the measurements is provided • Over a 3-week treatment period, the BASFI scores in Table 2. demonstrated a significant 19.6% improvement An older, 20-measurement metrology index was used (p=0.004). In contrast, the 5.9% improvement in the by the Bath group for comparison with BASMI [7]. Dougados Functional Index scores was non-significant. A statistically significant correlation of results from BASMI and the 20-measurement index was found on two occasions The significant improvement in score following treatment (p<0.001). BASMI also proved to be accurate and and the fuller range of values obtained were both benefits reproducible in terms of both inter- and intra-observer of BASFI over the Dougados Functional Index. It is plausible variability (p<0.001). With a sample of 56 patients that the latter benefit can be explained by the difference in undergoing 3 weeks of inpatient treatment, the sensitivity of methods used to capture patient responses. BASFI includes a the index to change was found to be significant, regardless VAS, while the Dougados Functional Index provides patients of disease severity (p<0.01). with only three possible answers to questions on whether Overall, these data showed that BASMI results were they can perform 20 activities: comparable to those from the original 20 measurements, were accurate and reproducible, and were sensitive to • “Yes, with no difficulty.” change. Furthermore, BASMI was found to be quick and • “Yes, but with difficulty.” easy to apply, taking approximately 7 mins. • “No.”
BASFI The middle option (“Yes, but with difficulty”) is vague The researchers observed that while treatment was focused as it does not distinguish between minor and major degrees on pain control and the improvement of function, the of difficulty. A VAS enables a broader range of possible available methods for assessing function were not specific to answers with greater ease, and therefore leads to a better AS and were inadequately validated. The team also recognized representation of the assessed population. The use of a VAS that after pain and stiffness, one of the most important can also explain the greater degree of sensitivity to change complaints of patients with AS is disability. Accordingly, a set shown by BASFI. Such a scale allows for smaller changes to of 10 questions (BASFI) was designed to determine the be identified than with the three-choice answer system. degree of functional limitation in patients with AS [8]. Ruof et al. compared the responsiveness of BASFI, The 10 questions were chosen based on input from the Dougados Functional Index, and an AS-specific version patients with AS. The first eight questions were developed of the Health Assessment Questionnaire, using data from a
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Table 2. A guide to obtaining the five Bath Ankylosing Spondylitis Metrology Index measurements in a standardized fashion.*
Measure Starting position Method Notes Lumbar side flexion** Patients should be standing Before any movement occurs, Ensure that patients keep their arms, with bare feet, their back and keeping the arms, wrists, fingers, and knees straight and their to a wall, knees straight, and fingers straight, measure from heels on the floor. Ensure that any scapulae, buttocks, and the tip of the middle finger to the forward flexion or extension or heels against the wall, floor. With their palms placed on rotation of the trunk is avoided. shoulders level, outer edges the lateral aspect of their thighs, It is best to use a wall without a of feet 30 cm apart, and patients should reach toward the skirting board (baseboard). If it is feet parallel. floor by side flexing. Measure again necessary to accommodate a leg from the tip of the middle finger to length discrepancy, place a block the floor. The difference between under the foot. the two measurements represents the amount of side flexion.
Tragus-to-wall distance** With the same starting Patients should retract their chin Ensure that no cervical extension, position as above, ensure that as far as possible. With one side of rotation, or flexion, or side flexion the head is in as neutral a the face pressed against the wall occurs. It is best to use a wall position as possible, in terms and both eyes open, measure the without a skirting board (baseboard). of anatomical alignment. distance between the tragus of the Ensure that retraction is maintained ear and the wall, using a rigid ruler. while both sides are measured.
Modified Schober’s result Patients should be standing Patients should flex forward from At the end of the movement, it is with bare feet aligned parallel, the waist with their knees fully permissible to allow slight knee and the outer edges of their extended. Measure the distance flexion in order to decrease the feet should be 30 cm apart. between the upper and lower influence of the hamstrings. Mark a point midway along marks. Any increase beyond This should be documented. a line level with the iliac crests 15 cm represents the amount (at the junction between of movement achieved. the fourth and fifth lumbar vertebrae), a second point 10 cm above this, and a third one 5 cm below the first, to give a 15-cm line.
Intermalleolar distance Patients should lie supine on With their knees kept straight and Be ready to take measurements the floor or on a wide plinth, their legs in constant contact with before asking patients to perform with their knees in extension. the resting surface, ask patients the movement, and measure to take their legs as far apart as distances quickly, as such movement possible. Measure the distance can be painful. between the medial malleoli.
Cervical rotation** Patients should lie supine on Use a goniometer or an Ensure that no neck flexion or side a plinth, with their forehead inclinometer as per the flexion occurs. If there is a good horizontal and their head in manufacturer’s instructions. range of movement, it may be a neutral position. It may be Patients should rotate their head necessary for patients to lie near necessary to use a pillow, to one side as far as possible, the edge of the plinth to allow some books, or a foam block keeping their shoulders still. full movement to occur. to achieve this. Carefully document the starting position to ensure that the same set-up can be used for reassessments.
*This represents an ideal scenario that may need adapting depending on patients’ individual posture and circumstances. It is recommended that any changes be carefully documented to make measurements reproducible for each patient. With all measurements, patients should be comfortable and suitably undressed. **Use the mean of the left and right measurements. Based on a table originally adapted by AStretch members from [7], available at www.nass.co.uk/08_tbi.htm (last accessed September 2007).
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double-blind, placebo-controlled study of 174 patients In addition to the English-language versions of BASFI who received vitamin E, diclofenac, or placebo [11]. BASFI and BASDAI, the instruments have been translated for use was found to be more responsive than either of the other in Sweden. Cronstedt et al. and Waldner et al. assessed the two indices for both improvements and deterioration. The translated version of these two indices [13,14]. In agreement suggested reason for this was that BASFI demonstrates with the studies at Bath [9,12], the Swedish versions of BASFI a better baseline distribution pattern and the VAS allows for and BASDAI proved to be reliable, valid, and sensitive to greater sensitivity. change following a course of inpatient therapy. In summary, BASFI was found to be quick and easy to Overall, BASDAI was found to be user-friendly, highly use, reliable, and sensitive to change across the whole reliable, reflective of the entire spectrum of disease, disease spectrum. and sensitive.
BASDAI BAS-G Input from the researchers’ patient group led to the For BAS-G, the Bath group decided to ask patients to identification of fatigue as a major component of the indicate on a 10-cm VAS the effect of the disease on their symptomatology of AS with a large impact on well-being. well-being during the previous week and the preceding It was clear that fatigue should be incorporated into 6 months, with the mean of the two responses yielding measures of disease activity, and BASDAI was subsequently a BAS-G score of 0–10 [10]. developed to include a 10-cm VAS for six questions Using data from a sample of 177 inpatients and pertaining to the five major symptoms of AS [9]: 215 patients reached by a postal survey, the researchers found the following [10]: • Fatigue. • Spinal pain. • BAS-G scores covered the whole scale of 0–10 • Joint pain or swelling. for both timeframes (1 week and 6 months). • Areas of localized tenderness. • BAS-G scores correlated well with those of both • Morning stiffness. BASDAI and BASFI, suggesting that disease activity and functional ability were playing a major role in For morning stiffness, the Bath group chose to patients’ well-being, and more so than metrology. incorporate scores for both duration and severity and • Of the five BASDAI items, the values for spinal pain calculate the mean of the two scores (to give all symptoms and fatigue had the first- and second-strongest equal weighting). Dividing the total by 5 was opted for to correlation with BAS-G scores, highlighting the yield a final possible range of 0–10 for the BASDAI score. importance of pain and fatigue to the patient. When clinically tested, the results demonstrated the • BAS-G demonstrated statistically significant following [9]: sensitivity to change (p<0.001).
• BASDAI was a quick and simple index to use (taking The investigators acknowledged that BAS-G should not between 30 s and 2 min to complete). be used in isolation, and should instead form one element • BASDAI results demonstrated statistically significant of a complete assessment. Nevertheless, an index of this reliability (p<0.001). type attaches a numerical value to a patient’s sense of well- • The individual symptoms and the index as a whole being, which allows for comparison between consultations; had good score distribution, using 95% of the scale. this is particularly useful when a patient is seen by different • BASDAI was superior in all aspects to the Newcastle clinicians on different occasions. Enthesis Index [9]. In short, the BAS-G provides a formalized and validated means of gaining responses to a question that is Calin et al. further assessed the validity of BASDAI frequently asked. in a double-blind, placebo-controlled study of 6 weeks’ duration (n=473) [12]. Subjects were divided into two ASAS response criteria and anti-TNF-α therapy groups, with one receiving a nonsteroidal anti-inflammatory Soon after the development of the Bath instruments, drug (NSAID) and the other given placebo. Disease activity a predominantly European research team known as the was assessed using BASDAI and also by analyzing a wide Assessment in Ankylosing Spondylitis International Working range of individual symptom components. The investigators Group (ASAS) focused on AS and developed preliminary sets concluded that BASDAI had excellent content validity. of core endpoints for the disease [15]. Subsequent research
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Table 3. The ASAS response criteria. Disclosure ASAS20 [18] The author has no relevant financial interests to disclose. A relative improvement of ≥20% and an absolute improvement of ≥10 units on a scale of 0–100 in three References of four domains (inflammation, pain, patient global 1. Calin A, Taurog J, editors. The Spondylarthritides. Oxford, UK: Oxford University Press, assessment, and physical function), with no worsening 1998:1–353. 2. Calin A. Ankylosing spondylitis. In: Maddison PJ, Isenberg D, Woo P et al., editors. of ≥20% and ≥10 units in the fourth. Oxford Textbook of Rheumatology – Volume II (2nd edition). Oxford, UK: Oxford University Press, 1998:1058–60. ASAS40 [21] 3. Bennett PH, Burch TA. Population Studies of Rheumatic Diseases. Amsterdam, A relative improvement of ≥40% and an absolute The Netherlands: Excerpta Medica Foundation, 1968:456. improvement of ≥20 units on a scale of 0–100 in three 4. Dougados M, van der Linden S, Juhlin R et al. Preliminary criteria for the classification of spondylarthropathy. European Spondylarthropathy Study Group. Arthritis Rheum of four domains (inflammation, pain, patient global 1991;34:1218–27. assessment, and physical function), with no worsening 5. Lee KR. Strategies to improve activities of daily living (ADL) function and quality of life. of ≥40% and ≥20 units in the fourth. In: Kippel JH, Dieppe PA, editors. Rheumatology. London, UK: Mosby-Year Book Europe, 1994:24. ASAS 5/6 [21] 6. Bakker C, Rutten-van Molken M, Hidding A et al. Patient utilities in ankylosing spondylitis and the association with other outcome measures. J Rheumatol 1994;21:1298–304. A relative improvement of ≥20% in five of six domains 7. Jenkinson TR, Mallorie PA, Whitelock HC et al. Defining spinal mobility in ankylosing (C-reactive protein level, inflammation, pain, patient global spondylitis (AS). The Bath AS Metrology Index. J Rheumatol 1994;21:1694–8. assessment, physical function, and spinal mobility). 8. Calin A, Garrett S, Whitelock H et al. A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol 1994;21:2281–5. ASAS partial remission [18] 9. Garrett S, Jenkinson T, Whitelock H et al. A new approach to defining disease status in AS: the A value of <20 units on a scale of 0–100 in each of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). J Rheumatol 1994;21:2286–91. domains of inflammation, pain, patient global assessment, 10. Jones SD, Steiner A, Garrett SL et al. The Bath Ankylosing Spondylitis Patient Global Score and physical function (BAS-G). Br J Rheumatol 1996;34:66–71. 11. Ruof J, Sangha O, Stucki G. Comparative responsiveness of 3 functional indices in ankylosing spondylitis. J Rheumatol 1999;26:1959–63. ASAS: Assessment in Ankylosing Spondylitis International Working Group. 12. Calin A, Nakache JP, Gueguen A et al. Defining disease activity in ankylosing spondylitis: is a combination of variables (Bath Ankylosing Spondylitis Disease Activity Index) an appropriate instrument? Rheumatology (Oxford) 1999;38:878–82. efforts and publications from this group validated several 13. Cronstedt H, Waldner A, Stenstrom CH. The Swedish version of the Bath ankylosing response criteria (ASAS20, ASAS40, ASAS 5/6, and ASAS spondylitis functional index. Reliability and validity. Scand J Rheumatol Suppl 1999;111:1–9. 14. Waldner A, Cronstedt H, Stenstrom CH. The Swedish version of the Bath ankylosing spondylitis partial remission; Table 3) and presented guidelines for the disease activity index. Reliability and validity. Scand J Rheumatol Suppl 1999;111:10–6. management of AS [16–22]. 15. van der Heijde D, Bellamy N, Calin A et al. Preliminary core sets for endpoints in ankylosing spondylitis. Assessments in Ankylosing Spondylitis Working Group. The ASAS consensus statement for the use of anti-TNF-α J Rheumatol 1997;24:2225–9. therapy in AS stipulates that initiation of anti-TNF-α therapy 16. van der Heijde D, Calin A, Dougados M et al. Selection of instruments in the core set for DC-ART, SMARD, physical therapy, and clinical record keeping in ankylosing spondylitis. can be considered if patients have had active disease, based Progress report of the ASAS Working Group. Assessments in Ankylosing Spondylitis. J Rheumatol 1999;26:951–4. ≥ on expert opinion, for 4 weeks and a BASDAI score of 17. van der Heijde D, van der Linden S, Dougados M et al. Ankylosing spondylitis: plenary ≥4 [22]. Debate is ongoing on the extent to which the Bath discussion and results of voting on selection of domains and some specific instruments. α J Rheumatol 1999;26:1003–5. indices should respond to anti-TNF- therapy in terms of 18. Anderson JJ, Baron G, van der Heijde D et al. Ankylosing spondylitis assessment group preliminary definition of short-term improvement in ankylosing spondylitis. Arthritis “success or failure” and thus indicate the requirement for Rheum 2001;44:1876–86. additional treatment or a change to another NSAID. 19. Pham T, van der Heijde D, Calin A et al. Initiation of biological agents in patients with ankylosing spondylitis: results of a Delphi study by the ASAS Group. Ann Rheum Dis 2003;62:812–16. Conclusion 20. Braun J, Pham T, Sieper J et al.; ASAS Working Group. International ASAS consensus statement for the use of anti-tumour necrosis factor agents in patients with ankylosing The Bath instruments were developed to address the need spondylitis. Ann Rheum Dis 2003;62:817–24. for indices of spinal mobility, disease activity, function, and 21. Brandt J, Listing J, Sieper J et al. Development and preselection of criteria for short term improvement after anti-TNF alpha treatment in ankylosing spondylitis. Ann Rheum Dis global status in patients with AS. The subsequent work of 2004;63:1438–44. 22. Braun J, Davis J, Dougados M et al.; ASAS Working Group. First update of the ASAS has led to the development of treatment guidelines international ASAS consensus statement for the use of anti-TNF agents in patients and response criteria for use in the era of TNF-α antagonists. with ankylosing spondylitis. Ann Rheum Dis 2006;65:316–20.
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Extra-Articular Manifestations in Rheumatoid Arthritis
Carl Turesson, MD1,2 and Eric L Matteson, MD2 1Department of Rheumatology, Malmö University Hospital, Malmö, Sweden, and 2Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN, USA
Rheumatoid arthritis (RA) is a systemic disease, which primarily affects the joints but is also associated with extra-articular LEADING ARTICLE manifestations. In patients with RA, the presence of vasculitis and other severe organ manifestations is associated with an increased mortality rate, mainly owing to an elevated risk of cardiovascular disease. RA-associated lung disease is a major diagnostic and therapeutic challenge. Recent insights into the pathogenesis of extra-articular RA (ExRA) manifestations come from studies of local and circulating T cell abnormalities, autoantibodies, and genetic factors. These developments may contribute to improved treatment strategies and a better long-term prognosis in patients with ExRA. Int J Adv Rheumatol 2007;5(3):72–7.
Rheumatoid arthritis (RA) is a systemic, inflammatory Spectrum of extra-articular involvement in RA disease that is characterized by chronic polyarthritis Systemic features and has a substantial impact on function and quality of life Signs of systemic inflammation in patients with RA include of affected patients. RA is also associated with certain constitutional symptoms, such as fatigue, low grade fever, comorbidities and premature mortality. It is a complex, and weight loss, and elevated levels of inflammatory multifactorial disease with a heterogeneous prognosis. biomarkers including erythrocyte sedimentation rate and A subset of patients develops severe extra-articular organ C-reactive protein. Uncontrolled systemic inflammation in manifestations, which contribute substantially to the risk RA is associated with several long-term complications. of disease-related morbidity and mortality (Fig. 1). For instance, rheumatoid cachexia, with a loss of lean body Additionally, patients with severe extra-articular RA (ExRA) mass, is often a feature of longstanding, severe disease. A manifestations are at an increased risk of developing low body mass index has been associated with an increased cardiovascular disease (CVD) or severe infections [1,2]. mortality risk in patients with RA [6]. Systemic inflammation Severe ExRA manifestations (including vasculitis, with activation of inflammatory cytokines and stimulation vasculitis-related neuropathy, Felty’s syndrome, glomerulo- of osteoclast differentiation may also lead to juxta-articular nephritis, pericarditis, pleuritis, and scleritis) develop in and systemic osteoporosis [7]. High disease activity and approximately 15% of patients with RA during long- persistent elevation of inflammatory biomarker levels is term follow-up, and the incidence was estimated in a associated with tissue amyloidosis and organ damage [8]. community-based RA cohort to be one case per 100 person-years [3]. Shared disease mechanisms for different Rheumatoid nodules severe ExRA manifestations include high levels of Perhaps the most characteristic ExRA manifestation is the rheumatoid factor (RF; Fig. 2), systemic endothelial development of subcutaneous rheumatoid nodules, which activation [4], and T cell abnormalities with features occur in 7% of patients with RA at disease onset and in of immunosenescence [5]. These mechanisms are usually approximately 30% of all patients with RA at some point more prominent in patients with RA-associated vasculitis, during the disease course [9]. Subcutaneous nodules occur and vascular pathology is common to a number of ExRA mainly in patients with RA who are seropositive for RF, and manifestations [4]. rarely in seronegative patients [10]. Presence of the nodules may reflect the level of rheumatoid disease activity, but can Address for correspondence: Carl Turesson, Department of occur in cases of relatively quiescent joint disease. Patients Rheumatology, Malmö University Hospital, Södra Förstadsgatan 101, with rheumatoid nodules in early RA are at an increased risk S-205 02 Malmö, Sweden. Email: [email protected] of developing more severe ExRA manifestations [10].
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Figure 1. The increased mortality rate in patients with severe ExRA manifestations compared with controls who had RA but not extra-articular disease. The diamonds represent risk ratios (adjusted for age and sex) and the error bars 95% confidence intervals.
Severe ExRA overall
Pericarditis
Pleuritis
Felty’s syndrome
Major cutaneous vasculitis
Vasculitis-associated neuropathy
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
ExRA: extra-articular rheumatoid arthritis; RA: rheumatoid arthritis. Based on data from [3].
Figure 2. RF levels in patients with extra-articular RA result of small vessel vasculitis with fibrinoid necrosis, which manifestations compared with controls who had RA but not forms the center of the nodule, and surrounding fibroblastic extra-articular disease. The thick horizontal lines represent proliferation; histologically, there is focal central fibrinoid medians, the boxes interquartile ranges, the whiskers 95th necrosis with surrounding fibroblasts [13]. percentiles, the asterisks individual outliers, and the circles clusters of outliers. Hematological disease Hematological abnormalities observed in patients with RA include anemia of chronic disease and lymphadenopathy, and 6000 there is also an increased risk of non-Hodgkin lymphoma compared with the general population [14]. The most 5000 * frequent hematological disease subtype in patients with RA is large diffuse B cell lymphoma [15]. High disease activity is the 4000 main recognized risk factor for lymphoma in patients with RA [15]. Chronic neutropenia with splenomegaly in the absence 3000 of lymphoma occurs in patients with Felty’s syndrome.
RF level (IU/mL) * However, chronic RA-related neutropenia that is otherwise 2000 * clinically and immunologically similar to that seen in classic * 1000 Felty’s syndrome may occur in patients with RA in the absence * of significant enlargement of the spleen [16]. Felty’s syndrome *º 0 typically occurs in patients with longstanding, seropositive, nodular, deforming RA, although patients have occasionally Vasculitis Felty’s Pericarditis RA been reported to present with features of Felty’s syndrome at controls disease onset [17]. The condition affects approximately 1% of patients with RA [18]. RA: rheumatoid arthritis; RF: rheumatoid factor. Based on data from [16]. Vasculitis Rheumatoid nodules develop most commonly on Vasculitis in patients with RA has a variety of possible pressure areas, including the elbows, finger joints, ischial and presentations, depending on the site of involvement. Systemic sacral prominences, the occipital scalp, and the Achilles vasculitis in patients with RA may present with involvement of tendon, but they can also occur in internal organ tissue, such small and medium-sized vessels of the skin and a progressive as the myocardium, the meninges, and lung tissue [11]. The sensorimotor neuropathy. Without proper treatment, this etiology of rheumatoid nodules is uncertain, but they appear infrequent phenotype can be associated with a poor prognosis. to be T helper 1 granulomata [12]. They may develop as a Cutaneous manifestations include nailfold infarcts, leg ulcers,
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purpura, and digital gangrene. Isolated nailfold infarcts or leg in some patients implicates immune complex-mediated ulcers may occur without associated systemic involvement. mechanisms [30]. Rheumatoid pleuritis is associated with In some patients, the vasculitis may extend to involve exudative pericarditis, and also with interstitial lung disease. mesenteric, coronary, and cerebral arteries. Systemic vasculitis Other clinical lung manifestations associated with RA include is also associated with severe eye involvement and CVD [19]. parenchymal rheumatoid nodules, cryptogenic organizing Patients with rheumatoid vasculitis usually have high serum pneumonia, obliterative bronchiolitis, and pulmonary fibrosis. titers of RF, cryoglobulins, and circulating immune The prevalence of diffuse interstitial pulmonary fibrosis in complexes, and low levels of complement [20]. In addition, RA varies, depending on the epidemiological and diagnostic they usually have an increased erythrocyte sedimentation methods used to detect and evaluate the condition. In rate, anemia, thrombocytosis, and a diminished serum a community-based study, 6% of patients developed albumin concentration. Recent studies suggest that patients symptomatic interstitial lung disease within 10 years of with RA-associated vasculitis and Felty’s syndrome have RA onset [31]. The most common radiographic finding is particularly high levels of anti-cyclic citrullinated peptide bilateral, basilar, interstitial abnormalities, which are often (anti-CCP) antibodies [21]. Clonal expansion of T cell asymmetric. Initially, these may appear as patchy alveolar populations with markers of immunosenescence occurs infiltrates; with progressive disease, a more reticulonodular relatively frequently in this subset of patients [22]. pattern is seen [32]. High-resolution computed tomography Lower leg ulcers are an especially vexing clinical and open lung biopsy are considered the gold-standard manifestation of severe, generally longstanding RA with or methods for the diagnosis of interstitial lung disease [33]. without Felty’s syndrome. The prognosis of patients with The clinical presentation and course of pulmonary fibrosis in RA-associated leg ulcers is highly variable. It is likely that other RA has been reported to be similar to that of idiopathic factors, in addition to the vasculitis, influence the final vascular pulmonary fibrosis, but response to immunosuppression may outcome. The pathogenesis of leg ulcers is thought to be due actually be better if pulmonary fibrosis occurs in the context to an underlying vasculitis that initiates the lesions, but ulcer of RA or other collagen diseases [34]. Histological findings expansion and its chronicity may be influenced by other and results of bronchoalveolar lavage can be variable, features, including concomitant venous insufficiency, arterial ranging from lymphocytic alveolitis to neutrophilic insufficiency, dependent edema, trauma, superimposed inflammation. Histological features from tissue obtained at infection, and long-term use of glucocorticoids [23]. lung biopsy include an inflammatory infiltrate with Patients with vasculitis and other severe ExRA mani- lymphocytes, plasma cells, and histiocytes, with varying festations have an increased risk of peripheral atherosclerotic degrees of fibrosis, and may be classified as usual interstitial vascular disease [24], other cardiovascular events [1], and pneumonitis (IP) or non-specific IP [33]. Specific stainings cardiovascular death [25]. These associations are independent have suggested a role for CD4+ T cells in patients with RA- of smoking status. Strategies to prevent vascular disease associated IP, but not in patients with idiopathic IP (Fig. 3) in patients with RA should include optimal antirheumatic [35]. RA-specific dysregulation of T cells may be important treatment to control disease activity, and interventions aimed in the pathogenesis of RA-associated lung disease, with at traditional cardiovascular risk factors. potential implications for targeted therapies [35]. Many patients with RA-associated IP have extensive RA-associated lung disease peribronchial (Fig. 4) or diffuse infiltrates of CD20+ B cells. Pulmonary involvement in RA is frequent, although not Structures resembling lymphoid follicles with a dominance of always clinically recognized [26]. Rheumatoid pleural effusions CD20+ B cells may be detected. Quantification of the CD20+ are usually exudates with mixed cell counts, high lactate cell infiltrates has revealed them to be significantly more dehydrogenase concentrations, high protein concentrations abundant in patients with RA-associated IP than those with (>4 g/L), and low glucose levels (<25 mg/dL) [27]. The low idiopathic IP [36]. Additional tissue studies have indicated glucose level in rheumatoid pleural effusions is a result of that while citrullinated peptides can be found to a similar increased glucose consumption by inflammatory cells and extent in RA-associated IP and idiopathic IP, the greater impaired transport across an inflamed pleura. The presence of density of T cells and B cells observed in the former has been multinucleated giant cells is highly specific for rheumatoid noted only in lung tissue in the presence of citrullinated pleuritis, but such cells are seen in <50% of cases [28]. peptides [37]. Together with the reported high levels of The pathogenesis of rheumatoid pleuritis is multifactorial. circulating anti-citrullinated antibodies in patients with High levels of the soluble form of the interleukin-2 receptor RA-associated IP [37], this suggests a role for an immune suggest that lymphocyte activation plays an important role response against Citrullinated peptides in the pathogenesis [29], whereas the presence of RF and low complement levels of RA-associated IP.
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Figure 3. CD4+ cells in a patient with rheumatoid Figure 4. CD20+ cells in a patient with rheumatoid arthritis- arthritis-associated usual interstitial pneumonitis associated non-specific interstitial pneumonitis (immunohistochemistry; magnification ×100). (immunohistochemistry; magnification ×50).
Published with permission from [24]. Available in full color on Available in full color on www.advancesinrheumatology.com, with a red stain www.advancesinrheumatology.com, with a red stain of the CD4+ cells. of the CD20+ cells.
RA-associated IP must be distinguished from also develop milder eye manifestations such as episcleritis, methotrexate-induced toxicity, which usually has a subacute often in the setting of active disease, or keratoconjunctivitis onset with rapidly progressive respiratory symptoms, sicca in the setting of secondary Sjögren’s syndrome. less radiographic evidence of fibrosis, and a histological pattern dominated by eosinophilia and type II pneumocyte Environmental and genetic risk factors hyperplasia [38]. Possible toxic drug reactions have also Smoking is a risk factor for the development of RA [42]. It is been reported in patients treated with leflunomide and associated specifically with anti-CCP antibody-positive RA, tumor necrosis factor-α (TNF-α) inhibitors [33]. The and the related increase in the risk of developing RA appears possibility of a superimposed respiratory tract infection to be restricted to individuals carrying risk alleles of the must be considered in the setting of rapid progression of human leukocyte antigen DRB1*04 (HLA-DRB1*04) subset pulmonary symptoms in patients with suspected RA- [43]. People with a history of smoking who develop RA associated or treatment-related lung disease. are more likely to have rheumatoid nodules at presentation than those who have never smoked [9]. Patients with RA Other manifestations who are smokers at the time of diagnosis have an increased Pericarditis is the most frequent cardiac manifestation of RA risk of developing severe ExRA manifestations [31,44]. In a [39]. Pericarditis presents as acute chest pain and dyspnea community-based cohort of patients with RA, the association with exudative fluid, or as longstanding right-sided heart between smoking and future development of ExRA was failure due to chronic constrictive pericarditis. The 30-year found to be independent of RF positivity [31], indicating that incidence of symptomatic and clinically detected pericarditis smoking may be involved in the pathogenesis of systemic in RA has been estimated to be 11% [3], although features of RA through several different mechanisms. subclinical involvement may be considerably more common RA has been associated with HLA-DRB1 shared epitope and is frequently detected at autopsy [40]. alleles in a number of different populations [45]. These RA-associated glomerulonephritis is often of the RA-associated alleles are also predictors of disease severity. mesangioproliferative type and is less likely to progress to In particular, in populations of mainly northern European renal failure than the nephritis of systemic lupus descent, patients with a double dose of HLA-DRB1*04 shared erythematosus [41]. Scleritis and peripheral ulcerative epitope alleles have an increased risk of developing severe keratitis are associated with severe, longstanding joint ExRA [46,47]. The gene dose phenomenon may be explained disease, which may or may not be active, and with ExRA by an effect on the selection and activation of T cells through manifestations involving other organs. Patients with RA may an interaction between major histocompatibility complex
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(MHC) class II molecules and T cell receptors [48]. In addition, for biological treatment of RA, physician-reported RA- MHC class I molecules have been implicated in RA-associated associated lung disease was strongly associated with vasculitis. The HLA-C*03 allele has been associated with mortality rate both in patients treated with TNF-α blockers vasculitis, but not with other ExRA manifestations [44,47]. and in those receiving traditional DMARDs, and there was a In a multivariate analysis of a large sample of patients with trend toward a worse survival rate in the anti-TNF-α treated severe ExRA and controls who had RA but not extra-articular subset [59]. There is a need for more data on the effects disease, HLA-C*03 and smoking were found to be of TNF-α blockers on pulmonary disease. Furthermore, independent predictors of vasculitis risk [42]. additional studies of specific treatments for ExRA are Genetic HLA-C variation could be a marker for other required, particularly in patients with RA-associated IP. linked genes, or could determine MHC class I-associated Other treatments with biological response modifiers directed immune responses. The latter include interactions with at specific cells, such as anti-T cell and anti-B cell treatment killer-like immunoglobulin receptors on natural killer (NK) for RA-associated lung disease, may be of value. cells and clonally expanded CD4+, CD28null T cells [47]. High levels of CD4+, CD28null T cells with NK cell markers, Conclusion including CD56, have been associated with ExRA RA is associated with a wide spectrum of extra-articular manifestations [5]. Expansion of such cells is dependent on manifestations. Patients with severe organ involvement, repeated stimulation and a proinflammatory environment in such as vasculitis, have poor survival rates owing to an vitro [5], and has been shown to be reversible in patients increased risk of morbidity and CVD-related mortality. with RA treated with TNF-α inhibitors [49]. Predictors of extra-articular disease include smoking and genetic factors such as HLA-DRB1 and HLA-C alleles. Treatment of extra-articular manifestations The underlying mechanisms of ExRA are beginning to be Recommendations for treatment of systemic features of RA defined, but there is a need for additional studies of the are based mainly on experience from treatment of RA in immunopathogenesis of ExRA. Optimal antirheumatic general, anecdotal case reports, and expert opinion and treatment is likely to reduce the risk of complications in experience [50]. Appropriate management of patients with patients with ExRA. Specific treatment for extra-articular ExRA manifestations includes adequate, long-term manifestations is based on limited evidence, and there is a treatment with disease-modifying antirheumatic drugs need for further research. (DMARDs), with the addition of glucocorticoids for severe organ complications. Controlled studies show improved outcomes in patients with systemic vasculitis treated with Disclosures cyclophosphamide and high-dose glucocorticoids [19,51]. Drs Turesson and Matteson have no relevant financial interests to disclose. In patients with Felty’s syndrome, white blood cell counts may improve with conventional DMARD therapy, such as References methotrexate [52]. Consistent with the suggested role for 1. Turesson C, McClelland RL, Christianson TJ et al. Severe extra-articular disease manifestations are associated with an increased risk of first ever cardiovascular events T cells in RA-associated IP discussed earlier, the authors of in patients with rheumatoid arthritis. Ann Rheum Dis 2007;66:70–5. several case reports have described the beneficial response 2. Doran MF, Crowson CS, Pond GR et al. Predictors of infection in rheumatoid arthritis. Arthritis Rheum 2002;46:2294–300. to cyclosporine, and scleritis may improve with cyclo- 3. Turesson C, O’Fallon WM, Crowson CS et al. Occurrence of extra-articular disease manifestations is associated with excess mortality in a community based study of phosphamide therapy [50,53]. rheumatoid arthritis. J Rheumatol 2002;29:62–7. Although the effect of TNF-α inhibitors and other 4. Turesson C. Endothelial expression of MHC class II molecules in autoimmune disease. Curr Pharm Des 2004;10:129–43. biological response modifiers on ExRA manifestations has 5. Michel JJ, Turesson C, Lemster B et al. CD56-expressing T cells that have senescent not been systematically evaluated, a number of reports features are expanded in rheumatoid arthritis. Arthritis Rheum 2007;56:43–5. 6. Kremers HM, Nicola PJ, Crowson CS et al. Prognostic importance of low body mass of excellent responses have been published, including index in relation to cardiovascular mortality in rheumatoid arthritis. Arthritis Rheum manifestations such as vasculitis and scleritis [50,54]. On the 2004;50:3450–7. 7. Townheed TE, Brouillard DE, Yendt E et al. Osteoporosis in rheumatoid arthritis: findings other hand, an induction of vasculitis and a worsening of in metacarpal, spine and hip and a study of the determinants of both localized and generalized osteopenia. J Rheumatol 1995;22:440–3. interstitial lung disease have also been reported after 8. Schneider F. AA amyoloidosis in inflammatory rheumatic diseases. A report of clinical treatment with TNF-α inhibitors [55–57]. Observational experiences. Z Rheumatol 1992;51:177–82. 9. Nyhäll-Wåhlin B, Jacobsson LT, Petersson IF et al. Smoking is a strong risk factor for studies have yielded conflicting results. In a recent analysis rheumatoid nodules in early rheumatoid arthritis. Ann Rheum Dis 2006;65:601–6. of a large US sample of patients with RA, there was no 10. Turesson C, Jacobsson L, Bergström U et al. Predictors of extra-articular manifestations in rheumatoid arthritis. Scand J Rheumatol 2000;29:358–64. association between current treatment with TNF-α blockers 11. Raven RW, Weber FP, Price LW. The necrobiotic nodules of rheumatoid arthritis. and the rate of hospitalization for RA-associated IP [58]. In a Ann Rheum Dis 1948;7:63–75. 12. Hessian PA, Highton J, Kean A et al. Cytokine profile of the rheumatoid nodule suggests report from the British Society for Rheumatology database that it is a Th1 granuloma. Arthritis Rheum 2003;48:334–8.
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J Exp Med 2001;193:1159–67. rheumatoid arthritis and relationship to extra-articular disease manifestations. Arthritis 48. Turesson C, Weyand CM, Matteson EL. Genetics of rheumatoid arthritis – is there a Rheum 2006;54:642–8. pattern predicting extra-articular manifestations? Arthritis Care Res 2004;51:853–63. 25. Maradit-Kremers HM, Nicola PJ, Crowson CS et al. Cardiovascular death in rheumatoid 49. Bryl E, Vallejo AN, Matteson EL et al. Modulation of CD28 expression with anti-tumor arthritis: a population-based study. Arthritis Rheum 2005;52:722–32. necrosis factor alpha therapy in rheumatoid arthritis. Arthritis Rheum 2005;52:2996–3003. 26. Saag KG, Kolluri S, Koehnke RK et al. Rheumatoid arthritis lung disease. Determinants 50. Turesson C, Matteson EL. Management of extra-articular disease manifestations in of radiographic and physiologic abnormalities. Arthritis Rheum 1996;39:1711–9. rheumatoid arthritis. Curr Opin Rheumatol 2004;16:206–11. 27. Walker WC, Wright V. Pulmonary lesions in rheumatoid arthritis. Medicine 51. Scott DG, Bacon PA. Intravenous cyclophosphamide plus methylprednisolone in treatment 1968;47:501–20. of systemic rheumatoid vasculitis. Am J Med 1984;76:377–84. 28. Boddington MM, Spriggs AI, Morton JA et al. Cytodiagnosis of rheumatoid pleural 52. Fiechtner JJ, Miller RD, Starkebaum G. Reversal of neutropenia with methotrexate in effusions. J Clin Pathol 1971;24:95–106. patients with Felty’s syndrome: correlation of response with neutrophil-reactive IgG. 29. Pettersson T, Söderblom T, Nyberg P et al. Pleural fluid soluble interleukin-2 receptor in Arthritis Rheum 1989;32:194–201. rheumatoid arthritis and systemic lupus erythematosus. J Rheumatol 1994;21:1820–4. 53. Clewes AR, Dawson JK, Kaye S et al. Peripheral ulcerative keratitis in rheumatoid arthritis: 30. Halla JT, Schrohenlober RE, Koopman WJ. Local immune responses in certain extra- successful use of cyclophosphamide and comparison of clinical and serological articular manifestations of rheumatoid arthritis. Ann Rheum Dis 1992;51:698–701. characteristics. Ann Rheum Dis 2005;64:961–2. 31. Turesson C, O’Fallon WM, Crowson CS et al. Extra-articular disease manifestations in 54. Botsios C, Sfriso P, Ostuni PA et al. Efficacy of the IL-1 receptor antagonist, anakinra, rheumatoid arthritis; incidence trends and risk factors over 46 years. Ann Rheum Dis for the treatment of diffuse anterior scleritis in rheumatoid arthritis. Report of two cases. 2003;62:722–7. Rheumatology 2007;46:1042–3. 32. Tanoue LT. Pulmonary manifestations of rheumatoid arthritis. Clinic Chest Med 55. Jarrett SJ, Cunnane G, Conaghan PG et al. Anti-tumor necrosis factor-alpha induced 1998;19:667–85. vasculitis: case series. J Rheumatol 2003;30:2287–91. 33. Kim DS. Interstitial lung disease in rheumatoid arthritis: recent advances. Curr Opin Pulm 56. Chatterjee S. Severe interstitial pneumonitis associated with infliximab therapy. Med 2006;12:346–53. Scand J Rheumatol 2004;33:276–7. 34. Scott DG, Bacon PA. Response to methotrexate in fibrosing alveolitis associated with 57. Lindsay K, Melsom R, Jacob BK et al. Acute progression of interstitial lung disease: connective tissue disease. Thorax 1980;35:725–31. a complication of etanercept particularly in the presence of rheumatoid lung and methotrexate treatment. Rheumatology (Oxford) 2006;45:1048–9. 35. Turesson C, Matteson EL, Vuk-Pavlovic Z et al. Increased CD4+ T cell infiltrates in rheumatoid arthritis-associated interstitial pneumonitis compared with idiopathic 58. Wolfe F, Caplan L, Michaud K. Rheumatoid arthritis treatment and the risk of severe interstitial pneumonitis. Arthritis Rheum 2005;52:73–9. interstitial lung disease. Scand J Rheumatol 2007;36:172–8. 36. Atkins SR, Turesson C, Myers JL et al. Morphological and quantitative assessment 59. Dixon WD, Watson KD, Lunt M et al. Rheumatoid arthritis, interstitial lung disease, of CD20+ B-cell infiltrates in rheumatoid arthritis associated nonspecific interstitial mortality and anti-TNF therapy: results from the BSR biologics register (BSBR). pneumonia and usual interstitial pneumonia. Arthritis Rheum 2006;54:635–41. Ann Rheum Dis 2007;66(Suppl 2):55.
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The Role of Radiography in Identifying Osteoporotic Vertebral Compression Fractures
Maurits HJ Voormolen, MD, PhD Department of Radiology, University Hospital Antwerp, Antwerp, Belgium LEADING ARTICLE Osteoporosis is frequently diagnosed after the occurrence of vertebral compression fractures (VCFs), the majority of which occur at the thoracolumbar spinal junction. Most patients are unaware of fractures, and the clinical signs of symptomatic osteoporotic VCFs are varied. The detection of osteoporotic VCFs has a major impact on the individual patient as well as on public health, with the diagnosis of both asymptomatic and symptomatic VCFs being crucial in reducing the rate of complications from osteoporosis. Assessment of osteoporotic VCFs is preferentially made on optimal lateral X-rays of the thoracolumbar spine. Int J Adv Rheumatol 2007;5(3):78–84.
Osteoporosis is a common disease characterized by low Osteoporotic VCFs can present with symptoms bone mass and microarchitectural deterioration of bone (symptomatic) or without symptoms (asymptomatic). These tissue. These systemic changes lead to increased bone VCFs can be visible on a spine X-ray (radiographically fragility and result in increased fracture risk. It is estimated detectable) or not visible (radiographically undetectable). that osteoporosis affects >200 million individuals Radiographically undetectable symptomatic osteoporotic worldwide, making the consequences of this disease, such as VCFs are called “occult” VCFs. However, many VCFs are osteoporotic fractures, a major public health concern [1]. asymptomatic, which makes the diagnosis of VCF – and, Patients with osteoporosis commonly fracture their proximal consequently, osteoporosis – difficult. VCFs are frequently femur, distal radius, or proximal humerus, but the most either not detected by clinicians or diagnosed but not frequently occurring events are vertebral compression treated; in addition, underdiagnosis by radiologists has been fractures (VCFs) [2–5]. There are approximately 700 000 noted [6–9]. This is of concern, in part because VCFs are incidents of VCF in the US each year, and they typically associated with a decreased quality of life and increased occur earlier in life than hip fractures and are twice as morbidity and mortality rates [10–14]. The earlier that common [5]. osteoporosis is detected in a patient, the sooner that anti- In most patients, the diagnosis of osteoporosis is osteoporotic (pharmacological) therapy can be administered made only after the occurrence of a VCF. This makes the to prevent the occurrence of new fractures attributable to diagnosis of osteoporotic VCF very important, because only the disease. Detection is important even for asymptomatic after proper diagnosis can patients be selected for VCFs because of the increased risk of future fractures: for pharmacological treatment to prevent future fractures. Bone patients with one VCF, there is a 20% risk of developing mineral density (BMD) is helpful in assessing the severity of a second VCF in the following year, and this risk increases osteoporosis and can be used to monitor the effects of with the presence of more pre-existing fractures [15–17]. therapy. It is necessary to exclude non-osteoporotic causes In addition, the risk of a hip fracture is increased four-fold of VCF, such as malignancy and trauma; the techniques after the occurrence of a VCF [17]. that can be used are biochemical evaluation of blood and In patients with a VCF who are receiving treatment urine, computed tomography (CT), and magnetic resonance with analgesics but who still have debilitating back pain, imaging (MRI). further therapeutic options are becoming available. Recent developments in minimally invasive spine therapy, such as Address for correspondence: Maurits HJ Voormolen, Department of percutaneous vertebroplasty and kyphoplasty, can be Radiology, University Hospital Antwerp, Wilrijkstraat 10, 2650 Edegem, incorporated into the treatment of certain cases to relieve Antwerp, Belgium. Email: [email protected] back pain attributable to VCF.
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In summary, the detection of osteoporotic VCFs has a loss due to the VCF are difficult to measure in a clinical major impact on individual patients as well as on public setting without the use of radiography [22,23]. health, with the diagnosis of both asymptomatic and Osteoporotic VCFs usually consolidate over a period of symptomatic VCFs being crucial in reducing the rate of 2 weeks to several months, with accompanying pain relief complications from osteoporosis. [24,25]. In patients with VCFs, quality of life is generally diminished and the loss of physical function results in Clinical signs of osteoporotic VCFs difficulties with performing activities of daily living [20,26]. Osteoporotic VCFs occur at all levels of the thoracic and At a later stage, a combination of chronic back and limited lumbar spine but are most commonly seen at the spine mobility or even immobilization may lead to patients thoracolumbar junction (from the 11th thoracic vertebra to becoming socially isolated and depressed [20,26]. the second lumbar vertebra). Characteristically, only the In patients who have a first VCF diagnosed on a lumbar or vertebral body is fractured, while the posterior wall of the thoracic X-ray but for whom a radiograph has not previously vertebral body and the posterior complex surrounding the been obtained, it is recommended that X-rays of the entire spinal canal are left intact. The majority of osteoporotic VCFs thoracolumbar spine should also be performed. VCFs may be are associated with only minor local back pain symptoms, observed at other levels of the spine, and, as has already been or an absence of such symptoms, and these fractures discussed, the higher the number of VCFs, the higher the risk generally heal within 4–8 weeks, with an evident reduction of future vertebral or hip fractures. Moreover, it is important to in any back pain [17,18]. In approximately half of cases, determine the number of VCFs and the grade of osteoporosis VCFs develop spontaneously, while around one-third occur as accurately as possible, since these figures have implications as a result of a minimal trauma [19]. for medical treatment of the osteoporosis. Osteoporotic VCFs are often difficult to recognize clinically. In a cross-sectional survey carried out in a regional Radiological signs of osteoporotic VCFs hospital in New England, USA, Gehlbach et al. determined Upon suspicion of a VCF, a radiological confirmation is that a correct diagnosis at the first visit to a healthcare required. Plain radiographs show diffuse osteoporosis and provider was made in only 43% of cases [6]. This under- often reveal additional healed VCFs. The most important diagnosis is related to the frequent absence of symptoms radiographic examination is a lateral X-ray of the thora- and the difficulty in determining their cause. Unless back columbar spine: from this view, deformities of the vertebral pain is associated with a trauma, a VCF may not be body can be best assessed. The lateral X-ray also provides a suspected in patients complaining of the symptom, because global impression of the possible presence of osteopenia or most patients with back pain do not have VCFs. In a typical osteoporosis, with loss of trabecular bone. It is of great case of acute osteoporotic VCF, patients experience a deep, importance to have an optimal lateral radiograph of the sharp, focal pain located at or very near to the level of the vertebra involved (Fig. 1). Ideally, the superior and inferior fractured vertebral body. Characteristically, VCFs are endplates of the index vertebral body should be parallel to associated with pain during physical motion. In cases of the X-ray beam and the right and left pedicles should be thoracic VCF, patients may also feel pain during breathing, superimposed on one another. In cases where doubt especially deep inhalations and exhalations. Vertebral pain is remains, perhaps owing to spinal deformity such as scoliosis, located at the midline of the spine. additional radiographs are advisable. In addition to this central pain, patients may complain An anteroposterior view is less important than the lateral during the subacute stage of a more persistent paraspinal X-ray, but can contain useful information on the presence of pain or tenderness radiating uni- or bilaterally to the hip or scoliosis and the intactness of the pedicles and transverse leg region. At clinical examination, the patient may be able processes. The pedicles and transverse processes are usually to indicate the collapsed vertebra during the application of intact in osteoporotic VCFs. manual pressure on the spinous process of the involved Most osteoporotic VCFs consist of multiple microfractures vertebral body. with accompanying endplate deformity (typically of the In other cases of osteoporotic VCF, patients do not have superior endplate). A fracture line is almost never evident on back pain during the subacute or chronic stages, but do plain radiographs; however, an osteosclerotic band parallel to have pulmonary or digestive problems owing to the the fractured vertebral plateau may be seen as a result of the increased kyphosis caused by a wedge-shaped VCF, which impaction of trabeculae in a compressed vertebral body, increases pressure on the lungs and stomach [20,21]. With before intraosseous callus remodeling has occurred. increased kyphosis, the lower ribs may come into contact Osteoporotic VCFs range from minor deformities of with the anterior pelvis. Both increased kyphosis and height the endplate to vertebra plana (in which there is marked
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Figure 1. The importance of optimal lateral X-rays of the spine To diagnose VCFs and to differentiate the underlying in diagnosing osteoporotic VCFs is can be seen by comparing disease, qualitative “observation” of thoracolumbar spine the two images. A: This lateral radiograph is suboptimal owing radiographs is usually performed by radiologists in cases to lumbar scoliosis. The interpretation of the second through of trauma or in patients with acute back pain who have to the fourth lumbar vertebra is difficult; it is not clear if osteoporosis or malignancies. Complementary examinations an osteoporotic VCF is present. B: In this optimal lateral such as CT, MRI, and bone scintigraphy are commonly radiograph, there is superimposition of the endplates and performed. Usually, the vertebral body involved is compared pedicles. It is clear that no osteoporotic VCF is present. visually with adjacent levels. However, in these cases the degree of the VCF is not characterized. It is helpful A B to have previous radiographs to be able to compare vertebral deformities. VCFs should be diagnosed when a loss of height of ≥15% in the anterior, middle, or posterior part of the vertebral body is detected on lateral radiographs. Various approaches have been taken to quantitatively assessing VCFs in which morphometric vertebral dimensions are measured, but these methods are time-consuming and cumbersome [32–37]. In clinical practice, the exact degree to which a vertebral body has collapsed is not of great importance, and it is more practical to use a standardized method that categorizes VCFs into distinct grades according to their severity, without having to take exact measurements of the vertebral dimensions. Such a method should be reproducible and relatively simple to perform. A semiquantitative method to assess the severity of a
VCF: vertebral compression fracture. VCF by visual determination of the extent of the vertebral height reduction (vertebral grade) and morphological change (vertebral shape) has been described by Genant height loss). In some cases of osteoporotic VCF, there may et al. (Fig. 2) [38]. The grade of a VCF is approximately be retropulsion of a posterior bone fragment into the determined by the degree of height reduction on a lateral spinal canal, usually along the superior endplate [27]. X-ray of the spine and categorized as mild (grade 1; Radiculopathy is rare but has been reported [28]. Severe 15–25% reduction), moderate (grade 2; 26–40%), or severe neurological deficit or spinal cord compression is even more (grade 3; >40%). The type or shape of the vertebral unusual [29]. In Kümmel’s disease, which is thought to be deformity is classified on the basis of reduction in anterior a result of avascular necrosis, gas collects between the height (wedge), middle height (biconcave), or posterior collapsed endplates [30,31]. Posterior wall fractures are height (crush), of which the first occurs most frequently rare in osteoporosis, and CT provides the best modality for [39]. The shape and grade of the VCF determined by this their assessment. method are independent. The semiquantitative method of In the work-up of a patient with symptoms of back pain Genant et al. is more accurate than the qualitative visual that are possibly due to an osteoporotic VCF, it is important assessment. Moreover, the semiquantitative approach has to exclude other possible causes of VCF, such as metastases better sensitivity and specificity than the quantitative and osteomyelitis, and other origins of back pain. approach [40–42]. It is generally considered as the gold Frequently, the source of back pain is not an osteoporotic standard in both a clinical and a research-based setting. VCF, but another underlying condition, such as myalgia, degenerative disease, a herniated disc, or alterations in the Potential pitfalls in diagnosis spinal stature. It is necessary to exclude these conditions Differential diagnosis through clinical examination and additional diagnostic tests. In addition to the aforementioned changes in shape and A diagnosis of an osteoporotic VCF can be made through reduction of height used in diagnosing osteoporotic VCFs, qualitative, semiquantitative, or quantitative assessment. further qualitative evidence comes from the presence of Until recently, no globally accepted standard for both endplate deformities, the absence of endplate parallelism, qualitative and quantitative approaches existed. and a general altered appearance compared with adjacent
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Figure 2. Semiquantitative scoring method of osteoporotic vertebral compression fractures by Genant et al.
Normal (grade 0)
Wedge fracture Biconcave fracture Crush fracture
Mild fracture (grade 1, 20–25%)
Moderate fracture (grade 2, 26–40%)
Severe fracture (grade 3, >40%)
Redrawn with permission from [38].
vertebrae. A suboptimal lateral spine radiography technique immediate post-injury radiographs [44]. In patients with and the presence of scoliosis can lead to pitfalls in compromised BMD due to osteoporosis, a VCF may result osteoporotic VCF diagnosis. In addition, non-physiological from minor trauma or even activities of daily living. The vertebral deformities can be observed in conditions other patient may experience pain from the fracture, but the than osteoporosis. The shape of vertebrae can be altered radiographs of these occult VCFs obtained in the immediate with developmental variants (such as Cupid’s bow or limbus post-injury period may reveal only minor collapse of the vertebrae), Scheuermann’s disease (Schmorl’s nodes), vertebra involved, or no collapse at all [44,45]. However, spondylosis, and sickle cell disease (H-shaped vertebrae) such fractures often continue to collapse (Fig. 3) [44,45]. [37]. In addition, VCFs may occur in other non-osteoporotic Bone scintigraphy and MRI of the spine can reveal increased systemic diseases such as vertebral metastases and multiple uptake and bone marrow edema (BME), respectively. In the myeloma [43]. event of persistent pain, repeat radiographs after several Further exploration is generally warranted to investigate weeks may reveal vertebral collapse. Such occult VCFs occur the underlying nature of the VCF. Based on clinical most frequently in the lower lumbar spine, whereas non- information and additional examinations (e.g. bone occult VCFs, particularly the more severe ones, usually occur densitometry, CT, MRI, scintigraphy, and blood sampling) at the thoracolumbar junction [45]. The lumbar spine the diagnosis of an osteoporotic VCF can be confirmed. It is receives less biomechanical stress than the thoracolumbar common for older people to have skeletal degenerative spine as a whole [43], which could explain the temporary disease, which can lead to a difficult differential diagnosis preservation of vertebral bodies weakened by a fracture. in cases where there are minimal vertebral deformities suggestive of an osteoporotic VCF. In such patients, MRI additional MRI or repeat radiographs of the spine can be MRI can be used to narrow down the location of a valuable to diagnose or rule out an osteoporotic VCF. symptomatic VCF, which can be helpful in cases with multiple VCFs or in the event of a discrepancy between Occult VCFs clinical and radiographic signs. In healthy patients with a normal BMD, traumatic VCFs The presence of MRI abnormalities is common in new generally occur after a substantial force on the spine. Such osteoporotic vertebral collapses. Although non-specific, VCFs rarely collapse to a greater extent than that seen on various MRI features – such as posterior rim morphology,
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Figure 3. Evolution of a wedge superior endplate osteoporotic Figure 4. Assessment of the age of an osteoporotic vertebral VCF of L1 and an occult VCF of L2, as shown on lateral compression fracture on lateral X-rays of the lumbar spine with X-rays of the lumbar spine. A: A mild superior endplate magnetic resonance imaging confirmation. There is a subacute fracture of L1 and an intact aspect of L2 can be observed. fracture of L1, a healed or chronic fracture of L2, and an occult B: Six weeks later, further collapse of L1 can be seen, fracture of L3. A: A lateral X-ray of the lumbar spine reveals along with a severe wedge fracture of L2. a mild wedge superior endplate deformity of L1 with a dense osteosclerotic band of compressed trabeculae, a superior A B endplate deformity with mild fracture of L2 without a dense aspect, and a normal aspect of L3. B: A lateral T1-weighted image of the lumbar spine shows a hypointense signal of the vertebral body of L1 and the superior part of L3, and an aspect of L2 that is isointense to normal bone. C: A lateral T2-weighted Short Tau Inversion Recovery image of the lumbar spine reveals a hyperintense signal of the vertebral body of L1 and the superior part of L3, and a hypointense signal of L2.
A B C
L1: first lumbar vertebra; L2: second lumbar vertebra; L5: fifth lumbar vertebra; T12: 12th thoracic vertebra; VCF: vertebral compression fracture.
band-like images, diffuse or localized signal changes, and soft tissue involvement – when combined, are considered to discriminate well between benign and malignant L1: first lumbar vertebra; L2: second lumbar vertebra; L3: third lumbar vertebra. compression fractures [46–50]. In a non-collapsed vertebral body, these MRI features may be considered indicative of bone disease other than osteoporosis. Based on these observations, VCFs with BME are considered A major benefit of using MRI lies in its sensitivity to to be acute or subacute. On the other hand, VCFs without the presence, location, and extent of BME in collapsed BME are considered to be chronic or healed [51,54,55]. osteoporotic vertebral bodies [43,51–53]. Characteristic The extent of BME in VCFs can vary from a minimal changes in marrow signal are thought to be indicative of the high-intensity band at the fracture line to complete edema age and healing stage of VCFs (Fig. 4) [43,51–53]. BME is of a vertebral body. A band of hyperintense T2-weighted believed to result from microfractures within the medullar signals adjacent to the fractured endplate is described bone and the resultant hemorrhage. Little is known about in approximately half of benign VCFs. These fractures the natural history of BME on MRI in osteoporotic VCFs. In become isointense to normal vertebrae after administration general, fractures <30 days old are found to be hypointense of gadolinium [47]. on T1-weighted images and hyperintense on T2-weighted In VCFs with extensive MRI signal anomalies of the and Short Tau Inversion Recovery sequences [51,53]. entire vertebral body, it is important to also consider the Approximately 1 month after vertebral collapse, the majority possibility of metastatic collapse or multiple myeloma of osteoporotic VCFs become isointense to normal bone [48,50]. A bone biopsy may be performed to differentiate marrow on T1- and T2-weighted sequences [51,53]. between the possible causes. Disappearance of BME is considered a sign of fracture Like MRI, bone scintigraphy can be used to narrow healing. Fully healed VCFs either demonstrate a return to down the location of a symptomatic fracture and may aid the normal marrow signal or, in the presence of sclerosis, in differentiating acute from chronic fractures [56,57]. may appear hypointense on T1- and T2-weighted sequences. However, bone scans may show increased uptake for as long
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J Am Geriatr Soc 1997;45:682–7. osteoporotic VCFs go undiagnosed, and some that are 24. Institute of Quality of National Health Care CBO. Second Revised Guideline: Osteoporosis. Alphen aan den Rijn, The Netherlands: Van Zuiden Communications, 2002. diagnosed are not treated. A standardized radiographic 25. Levernieux J, Julien D, Caulin F. The effect of calcitonin on bone pain and acute resorption description of an osteoporotic VCF can be made using the related to recent osteoporotic crush fractures: results of a double blind and open study. In: Cecchetin M, Sergre G, editors. Calcitropic Hormones and Calcium Metabolism. method of Genant et al. In some cases, an occult VCF can Amsterdam, The Netherlands: Elsevier, 1986;171–8. occur, with no evidence of collapse of vertebra involved in 26. Gold DT. The nonskeletal consequences of osteoporotic fractures. Psychologic and social outcomes. Rheum Dis Clin North Am 2001;27:255–62. the acute phase and a gradual worsening on subsequent 27. Cuénod CA, Laredo JD, Chevret S et al. Acute vertebral collapse due to osteoporosis X-rays. In order to differentiate symptomatic VCFs or to or malignancy: appearance on unenhanced and gadolinium-enhanced MR images. Radiology 1996;199:541–9. assess the age of a fracture, an MRI assessment of the spine 28. Heggeness MH. Spine fracture with neurological deficit in osteoporosis. Osteoporos Int with T2-weighted images can be helpful. BME can be seen 1993;3:215–21. 29. Salomon C, Chopin D, Benoist M. Spinal cord compression: an exceptional complication up to 2 years after an initial fracture. of spinal osteoporosis. Spine 1988;13:222–4. 30. Kümmel H. Uber die traumatischen Erkrankungen der Wirbelsaule. Dtsch Med Wochenschr 1895;21:180–1. Disclosure 31. Dupuy DE, Palmer WE, Rosenthal DI. Vertebral fluid collection associated with vertebral The author has no relevant financial interests to disclose. collapse. AJR Am J Roentgenol 1996;167:1535–8. 32. Hurxthal LM. Measurement of anterior vertebral compressions and biconcave vertebrae. Am J Roentgenol Radium Ther Nucl Med 1968;103:635–44. References 33. Minne HW, Leidig G, Wüster C et al. A newly developed spine deformity index (SDI) to 1. Cooper C. Epidemiology of osteoporosis. Osteoporosis Int 1999;9(Suppl 2):S2–8. quantitate vertebral crush fractures in patients with osteoporosis. Bone Miner 1988;3:335–49. 2. Melton LJ 3rd, Lane AW, Cooper C et al. Prevalence and incidence of vertebral 34. Eastell R, Cedel SL, Wahner HW et al. Classification of vertebral fractures. J Bone Miner deformities. Osteoporosis Int 1993;3:113–9. Res 1991;6:207–15. 3. Kado DM, Browner WS, Palermo L et al. Vertebral fractures and mortality in older women. 35. Black DM, Cummings SR, Stone K et al. A new approach to defining normal vertebral Study of Osteoporotic Fractures Research Group. Arch Intern Med 1999;159:1215–20. dimensions. J Bone Miner Res 1991;6:883–92. 4. O’Neill TW, Felsenberg D, Varlow J et al. The prevalence of vertebral deformity in European men 36. McCloskey EV, Spector TD, Eyres KS et al. The assessment of vertebral deformity: a and women: the European Vertebral Osteoporosis Study. J Bone Miner Res 1996;11:1010–8. method for use in population studies and clinical trials. Osteoporosis Int 1993;3:138–47. 5. Cummings SR, Melton LJ 3rd. Epidemiology and outcomes of osteoporotic fractures. 37. Ferrar L, Jiang G, Adams J et al. Identification of vertebral fractures: an update. Lancet 2002;359:1761–7. Osteoporosis Int 2005;16:717–28. 6. Gehlbach SH, Bigelow C, Heimisdottir M et al. Recognition of vertebral fracture in a 38. Genant HK, Wu CY, van Kuijk C et al. Vertebral fracture assessment using a clinical setting. Osteoporosis Int 2000;11:577–82. semiquantitative technique. J Bone Miner Res 1993;8:1137–48. 7. Gehlbach SH, Fournier M, Bigelow C. Recognition of osteoporosis by primary care 39. Ismail AA, Cooper C, Felsenberg D et al. Number and type of vertebral deformities: physicians. Am J Public Health 2002;92:271–3. epidemiological characteristics and relation to back pain and height loss. European Vertebral Osteoporosis Study Group. Osteoporos Int 1999;9:206–13. 8. Kroth PJ, Murray MD, McDonald CJ. Undertreatment of osteoporosis in women, based on detection of vertebral compression fractures on chest radiography. 40. Genant HK. Assessment of vertebral fractures in osteoporosis research. Am J Geriatr Pharmacother 2004;2:112–8. J Rheumatol 1997;24:1212–4.
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41. O’Neill TW, Silman AJ. Definition and diagnosis of vertebral fracture. J Rheumatol 50. Lecouvet FE, Vande Berg BC, Maldague BE et al. Vertebral compression fractures in 1997;24:1208–11. multiple myeloma. Part 1. Distribution and appearance at MR imaging. Radiology 42. Grados F, Roux C, de Vernejoul MC et al. Comparison of four morphometric definitions 1997;204:195–9. and a semiquantitative consensus reading for assessing prevalent vertebral fractures. 51. Do HM. Magnetic resonance imaging in the evaluation of patients for percutaneous Osteoporos Int 2001;12:716–22. vertebroplasty. Top Magn Reson Imaging 2000;11:235–44. 43. Baker LL, Goodman SB, Perkash I et al. Benign versus pathologic compression fractures of 52. Modic MT, Steinberg PM, Ross JS et al. Degenerative disk disease: assessment of changes vertebral bodies: assessment with conventional spin-echo, chemical-shift, and STIR MR in vertebral body marrow with MR imaging. Radiology 1988;166:193–9. imaging. Radiology 1990;174:495–502. 53. Yamato M, Nishimura G, Kuramochi E et al. MR appearance at different ages of 44. Lyritis GP, Mayasis B, Tsakalakos N et al. The natural history of the osteoporotic vertebral osteoporotic compression fractures of the vertebrae. Radiat Med 1998;16:329–34. fracture. Clin Rheumatol 1989;8(Suppl 2):66–9. 54. Brown DB, Glaiberman CB, Gilula LA et al. Correlation between preprocedural MRI findings and clinical outcomes in the treatment of chronic symptomatic vertebral compression 45. Pham T, Azulay-Parrado J, Champsaur P et al. “Occult” osteoporotic vertebral fractures: fractures with percutaneous vertebroplasty. AJR Am J Roentgenol 2005;184:1951–5. vertebral body fractures without radiologic collapse. Spine 2005;30:2430–5. 55. Alvarez L, Pérez-Higueras A, Granizo JJ et al. Predictors of outcomes of percutaneous 46. Tan DY, Tsou IY, Chee TS. Differentiation of malignant vertebral collapse from osteoporotic vertebroplasty for osteoporotic vertebral fractures. Spine 2005;30:87–92. and other causes using magnetic resonance imaging. Ann Acad Med Singapore 2002;31:8–14. 56. Matin P. The appearance of bone scans following fractures, including immediate and long-term studies. J Nucl Med 1979;20:1227–31. 47. Cuénod CA, Laredo JD, Chevret S et al. Acute vertebral collapse due to osteoporosis or 57. Matin P. Bone scintigraphy in the diagnosis and management of traumatic injury. malignancy: appearance on unenhanced and gadolinium-enhanced MR images. Radiology Semin Nucl Med 1983;13:104–22. 1996;199:541–9. 58. Dansie DM, Luetmer PH, Lane JI et al. MRI findings after successful vertebroplasty. 48. Moulopulos LA, Yoshimitsu K, Johnston DA et al. MR prediction of benign and malignant Am J Neuroradiol 2005;26:1595–600. vertebral compression fractures. J Magn Reson Imaging 1996;6:667–74. 59. Voormolen MH, van Rooij WJ, van der Graaf Y et al. Bone marrow edema in osteoporotic 49. Yuh WT, Zachar CK, Barloon TJ et al. Vertebral compression fractures: distinction between vertebral fractures after percutaneous vertebroplasty and relation with clinical outcome. benign and malignant causes with MR imaging. Radiology 1989;172:215–8. Am J Neuroradiol 2006;27:983–8.
84 INTERNATIONAL JOURNAL OF ADVANCES IN RHEUMATOLOGY Vol 5 No 3 2007 CASE STUDY 85 Vol 5 No 3 2007 Vol HEUMATOLOGY R A diagnosis of rheumatoid arthritis (RA) was made on A diagnosis of rheumatoid arthritis (RA) Although the patient had continued to smoke, he did report symptoms consistent with Raynaud’s phenomenon. consistent with Raynaud’s symptoms report found to support were On examination, no further features X-rays of the Findings from a diagnosis of systemic sclerosis. demonstrated unchanged. Blood tests hands and chest were inflammatory markers elevated levels of RF (90 IU/mL) and were ANA test results (ESR 54 mm/h and CRP 31 mg/L). pattern. weakly positive, with a homogeneous–nucleolar extractable nuclear Anti-Scl-70 antibodies and other absent. antigens remained and the patient was started on prednisolone clinical grounds 7.5 400 mg/day and hydroxychloroquine mg/day. of ANA positivity Sulfasalazine was avoided because (MTX) was avoided owing to chronic and methotrexate disease. Leflunomide smoking history and pulmonary 3 months later because of 20 mg/day was introduced well tolerated, was persistent active disease. This treatment symptoms and signs. in with significant improvements dosage was halved 2 months later The hydroxychloroquine to dosage was gradually reduced and the prednisolone Between 2004 and 2006, the patient did not 5 mg/day. were and there joint pain or early morning stiffness report no clinical signs of synovitis or extra-articular manifestations he 2005 onward, December of RA on examination. From was noticed to have fluctuating but persistently elevated inflammatory marker levels (ESR range 29–105 mm/h and was no clear CRP range 13.7–92.3 mg/L), for which there clinical explanation. X-rays at this stage demonstrated several small PIP joint erosions. pleuritic chest pain, sputum production, coughing, not report night sweats, weight loss, or other localizing symptoms. fever, bacille Calmette–Guérin (or BCG) scar and He had a prominent (TB). In October 2006, no contact with tuberculosis reported DVANCES IN A OURNAL OF J (3):85–8. 5 NTERNATIONAL I 2007; The patient was next seen in January 2003. The A 54 year old Caucasian male first presented to the presented A 54 year old Caucasian male first Hospital St George’s Department of Rheumatology at a 6-month history (London, UK) in January 2002 with of some of the of small joint arthralgia, swelling interphalangeal metacarpophalangeal (MCP) and proximal There stiffness. (PIP) joints of the hands, and early morning bowel disease. was no history of psoriasis or inflammatory childhood and The patient had had asthma since in 1969 and experienced spontaneous pneumothoraces 30 pack- 1970. He was a smoker and had accumulated synovitis of the second and years. Examination revealed MCP joint the third fifth PIP joints on the right hand and was within normal limits on the left hand. Blood pressure Blood tests unremarkable. were and urinalysis results rheumatoid factor demonstrated elevated levels of (RF; 42 markers (erythrocyte IU/mL) and inflammatory protein C-reactive sedimentation rate [ESR] 31 mm/h and [CRP] 30 mg/L). Antinuclear antibody (ANA) test results positive, showing a homogeneous–nucleolar strongly were anti-Scl-70 antibodies and other pattern; however, X-rays of the not present. extractable nuclear antigens were and the chest X-ray hands did not show erosions demonstrated hyperinflated lung fields, bilateral upper zone and several small bullae at both apices. The three fibrosis, and at hydrocortisone, injected with inflamed joints were a 3-month follow-up no synovitis was noted. to a symmetrical small joint had progressed arthropathy distribution, and the patient had also developed some did not He tightening of skin on the face and forearms. Case Study Editor: Mark Quinn, MD Case Study Editor: UK Hospital, York, York Department of Rheumatology, Int J Adv Rheumatol Case Study presented by: Vinod Ravindran, MRCP and Patrick DW Kiely, FRCP and Patrick DW Kiely, Ravindran, MRCP by: Vinod Case Study presented Hospital, London, UK George’s St Department of Rheumatology, Pulmonary Cavitation: A Rare Cavitation: Pulmonary Therapy Leflunomide of Complication Address for correspondence: Patrick DW Kiely, Department of Patrick DW Kiely, for correspondence: Address Hospital, Blackshaw Road, London, St George’s Rheumatology, [email protected] UK. Email: SW17 0QT, RT92_3_REM_Rheum_5-3_05.qxd 7/11/07 14:19 Page 85 Page 14:19 7/11/07 RT92_3_REM_Rheum_5-3_05.qxd RT92_3_REM_Rheum_5-3_05.qxd 7/11/07 14:19 Page 86
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Figure 1. Chest X-ray At bronchoscopy, no abnormalities were noted in the from October 2006 upper respiratory tract, trachea, carina, or bronchial tree. showing left apical Bronchoalveolar lavage (BAL) microscopy revealed a highly cavitation (arrow) and cellular fluid consisting almost entirely of neutrophils with fibrotic changes at the scattered macrophages and epithelial cells. Malignant cells right apex, after a chest and viral cytopathic changes were not seen and bacteria examination had revealed (including mycobacteria), yeasts, and fungi were not no focal signs. identified using specific histochemical stains. BAL culture yielded Haemophilus influenzae and a scanty growth of diphtheroids and group B hemolytic streptococci. CT-guided biopsy of the medial wall of the left upper lobe cavity revealed a hypocellular fibrous tissue with no significant inflammation. Granulomas, necrosis, malignant cells, and infectious organisms were not present and prolonged Figure 2. High-resolution CT images of the thorax showing cultures yielded no growth. a left apical cavity (arrows). A: The first CT image, from The patient was treated with appropriate antibiotics for October 2006. B: A repeat CT image, from July 2007. H influenzae in the BAL fluid. A repeat high-resolution CT of the thorax in July 2007 showed persistence of the left A apical cavity with a reduction in the thickness of the wall and less nodularity (Fig. 2B). His RA remained extremely well controlled on leflunomide, hydroxychloroquine, and prednisolone therapy, and the inflammatory marker levels diminished (ESR 34 mm/h and CRP 7.1 mg/L).
Discussion Leflunomide is a relatively new disease-modifying drug for the treatment of RA and psoriatic arthritis (PsA) [1–3]. Although its recognized side effects include liver toxicity, B diarrhea, rash, alopecia, and hypertension [1–3], it has been considered to have a good pulmonary safety profile. Recently, fatal acute interstitial lung disease (ILD) [4,5], pulmonary abscess [6], and reactivation of TB [7,8] have been reported, and the summary of product characteristics for leflunomide has recently been updated to include pneumonia and ILD as rare adverse events [9]. Cavitating pulmonary lesions have wide differential diagnoses (Table 1). Owing to immunosuppressive therapy and chronic smoking, both malignancy and infections CT: computed tomography (including reactivation of TB) were major concerns in the current patient. A cavitating rheumatoid nodule seemed chest examination revealed no focal signs but a chest X-ray unlikely given the histological features and the absence of demonstrated left apical cavitation and fibrotic changes at the other nodules either in the lung or subcutaneously. right apex (Fig. 1). A high-resolution computed tomography Bronchiolar check-valves with air trapping are thought to (CT) scan of the thorax demonstrated a 6 × 5 × 7 cm cavity in be the main mechanism responsible for the formation of the the left apex with nodular thickening of the wall (Fig. 2A). bullae and larger pneumatocoeles found with generalized Longstanding pleural thickening and scarring was noted at the emphysema, and may be important in the evolution of other right apex. There was no mediastinal lymphadenopathy or cavitating lung disease [10]. The current patient was a features consistent with interstitial lung disease. The results chronic smoker and a previous chest X-ray had revealed of Mantoux and QuantiFERON tests for TB were negative. hyperexpanded lung fields and small apical bullae. One Smear results for induced sputum were negative for acid-fast explanation for the raised acute-phase response and bacilli, and prolonged culture yielded no growth. increasing apical cavitating disease might therefore be simple
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Table 1. Causes of cavitating lung lesions. pain, or expectoration. Additionally, in common with many of the cases presented by Bruyn et al., the patient described Bronchogenic carcinoma (often squamous) here was also a smoker and had asthma. Infection (tuberculosis, Staphylococcus aureus, Klebsiella It is unclear whether the outcome in the current patient pneumoniae, Pneumocystis carinii, anerobic organisms, or invasive aspergillosis) would have been better if antibiotics had been given at an earlier stage. He remained symptomatically well for over a Pulmonary infarct year, despite a high acute-phase response, but given the Granulomatous vasculitides persistence of this response, and the ultimate size of the Rheumatoid nodules pulmonary cavity, the present authors feel that antibiotic Traumatic lung contusion therapy should be used, which concurs with the findings of Metastasis Bruyn et al. [14]. Lymphoma It seems likely that leflunomide did lead in some way to the development of significant pulmonary cavitation with remarkably few systemic or other clinical signs, in the community-acquired bacterial infection in the context of context of pre-existing smoking-induced lung disease smoking-induced emphysema. However, H influenzae is not and an infectious organism not normally implicated in usually associated with cavitating pneumonia, and the pulmonary cavitation. clinical presentation was insidious and not accompanied by It has been suggested that the increased risk of ILD in systemic illness, as would be expected with usual cavitating patients treated with leflunomide appears to be due to a pneumonia. Thus, it is intriguing to speculate on whether channeling bias, where patients with a history of ILD may leflunomide had a role in the etiology of the cavitating have been preferentially prescribed leflunomide rather than change, either through an exacerbatory effect on MTX on the assumption that, in contrast to MTX, no background commensal (H influenzae) infection [11], or via pulmonary toxicity was associated with leflunomide [15]. a direct parenchymal effect leading to the formation of This case study highlights the possibility that leflunomide cavitation. The absence of mediastinal nodes may also point may be associated with significant pulmonary toxicity in away from a purely chronic infectious process, although certain patients. The need for a high index of suspicion for perturbation of normal host responses is not infrequent in pulmonary disease including cavitation and infection cannot immunosuppressed patients. be overemphasized, as many of these patients may not have Leflunomide has anti-inflammatory and immuno- typical symptoms and signs. modulatory properties. Its active metabolite, A771726, mediates the suppression of B and T cells, inhibiting the Case Study Editor’s comments de novo synthesis of pyrimidine nucleotides. Higher doses Drs Ravindran and Kiely report on an interesting clinical also inhibit tyrosine kinases, which are involved in T and scenario raising several points for discussion. The patient B cell signaling, with a subsequent reduction in the levels of initially presented with a seropositive oligoarthritis with proinflammatory cytokines including tumor necrosis factor raised acute-phase markers, which was treated successfully (TNF) [12]. Leflunomide inhibits TNF-α-induced nuclear initially with local corticosteroid injections. Interestingly, factor-κB activation, TNF-mediated cytotoxicity, and the ANA test results were strongly positive, with a nucleolar generation of TNF-induced reactive oxygen intermediates pattern. The management of patients presenting in this way and lipid peroxidation [13]. Optimal activity of TNF-α and is less clear-cut than for those who present with classic other cytokines (interferon-γ, interleukin-12 [IL-12], and disease phenotypes. A question to be asked at the outset IL-15) is crucial in host defense against bacteria. This in this case is “How will this patient’s disease evolve?” provides a mechanism whereby leflunomide may have led to (i.e. to RA or to a connective tissue disorder). The advent of an increased commensal bacterial load. anti-cyclic citrullinated peptide antibody testing may allow From 1998 to 2005, Bruyn et al. prospectively followed for the evolution of disease in such cases to be more 136 adult Caucasian patients with active RA or PsA who accurately predicted, and for appropriate treatment to be were treated with leflunomide 20 mg/day. They reported introduced at an earlier stage. five patients who developed cavitating pneumonia, which Furthermore, the case highlights the difficulties of responded well to antibiotics in all cases [14]. The case therapy selection where significant comorbidities exist. presented here shares features with the patients described in While there have been huge advances in therapeutics during the report of Bruyn et al., namely the insidious onset, and the past 10 years, our knowledge of the role of these and the presence of anemia with no fever, rigors, pleuritic chest existing agents where there is underlying coexistent
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pathology is uncertain. An area that frequently promotes 3. Kaltwasser JP, Nash P, Gladman D et al. Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis: a multinational, double-blind, randomized placebo- significant debate is that of pulmonary disease and MTX. controlled clinical trial. Arthritis Rheum 2004;50:1939–50. Fortunately, there are now a growing number of registries 4. Sakai F, Noma S, Kurihara Y et al. Leflunomide-related lung injury in patients with rheumatoid arthritis. Mod Rheumatol 2005;15:173–9. and also international and national initiatives that are 5. Takeishi M, Akiba H, Adachi D et al. Leflunomide induced acute interstitial pneumonia. exploring the causal link between disease-modifying anti- J Rheumatol 2005;32:1160–3. 6. Ulusoy H, Bilgici A, Kuru OC et al. Pulmonary abscess due to leflunomide use in rheumatic drugs or biological agents and varying pulmonary rheumatoid arthritis: a case report. Rheumatol Int 2005;25:139–42. pathologies including fibrosis, bronchiectasis, and pneumonitis. 7. Hocevar A, Rozman B, Praprotnik S et al. Leflunomide-associated tuberculosis? Finally, the case highlights the need for rheumatologists Rheumatology 2006;45:228–9. 8. Grover R, Dhir V, Aneja R et al. Severe infections following leflunomide therapy for to be aware of the systemic complications of the diseases rheumatoid arthritis. Rheumatology 2006;45:918–20. and treatments that we see and use, and also to consider 9. Summary of product characteristics for leflunomide. Sanofi-Aventis, 2006. alternative pathologies when musculoskeletal symptoms and 10. Teramoto S, Fukuchi Y. Bullous emphysema. Curr Opin Pulm Med 1996;2:90–6. signs are lacking in the clinic. 11. Brogden KA, Guthmiller JM, Taylor CE. Human polymicrobial infections. Lancet 2005;365:253–5. 12. Cannon GW, Kremer JM. Leflunomide. Rheum Dis Clin North Am 2004;30:295–309. References 13. Manna SK, Mukhopadhyay A, Aggarwal BB. Leflunomide suppresses TNF-induced cellular responses: effects on NF-κB, activator protein-1, c-Jun N-terminal protein kinase and 1. Smolen JS, Kalden JR, Scott DL et al. Efficacy and safety of leflunomide compared with apoptosis. J Immunol 2000;165:5962–9. placebo and sulphasalazine in active rheumatoid arthritis: a double-blind randomised, multicentre trial. European Leflunomide Study Group. Lancet 1999;353:259–66. 14. Bruyn GA, Jansen TL, Ten Brinke A et al. Cavitating pneumonia, a severe complication of leflunomide therapy in chronic polyarthritis. Rheumatology 2007;46:553–4. 2. Kalden JR, Schattenkirchner M, Sorensen H et al. The efficacy and safety of leflunomide in patients with active rheumatoid arthritis: a five-year follow-up study. Arthritis Rheum 15. Suissa S, Hudson M, Ernst P. Leflunomide use and the risk of interstitial lung disease 2003;48:1513–20. in rheumatoid arthritis. Arthritis Rheum 2006;54:1435–9.
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CLINICAL REVIEWS Commentary and Analysis on Recent Key Papers
Clinical reviews were prepared by Tom Huizinga, MD, Peter Nigrovic, MD, Eric Ruderman, MD, and Hendrik Schulze-Koops, MD
TREATMENT STRATEGIES Anti-tumor necrosis factor alpha therapy and the risk of serious bacterial infections in elderly patients with rheumatoid arthritis
Clinical trial of a leucotriene B4 receptor Schneeweiss S, Setoguchi S, Weinblatt ME et al. antagonist, BIIL 284, in patients with Arthritis Rheum 2007;56:1754–64. rheumatoid arthritis Díaz-González F, Alten RH, Bensen WG et al. In this large cohort study, no increase in the rate of Ann Rheum Dis 2007;66:628–32. serious bacterial infections (defined as those that required hospitalization) was found among patients taking tumor In a large clinical trial of a potent, long-lasting necrosis factor-α (TNF-α) antagonists compared with
leukotriene B4 (LTB4) receptor antagonist, no effect those receiving methotrexate (MTX) therapy. However, – or at most a very modest one – was observed on glucocorticoid use doubled the rate of serious bacterial inflammatory signs and symptoms. This suggests that infections relative to that seen with MTX use, with a clear
LTB 4 is unlikely to be a major inflammatory mediator dose–response relationship for dosages of >5 mg/day. of the rheumatoid inflammatory process in humans. This study provides reassuring data for the use of TNF-α antagonists and shows that the side effects of steroids
Leukotriene B4 (LTB4), a product of the arachidonic acid administered in dosages of >5 mg/day are significant. pathway, is an active chemotactic factor for neutrophils,
eosinophils, and monocytes. Moreover, LTB4 is a key factor This cohort study included 15 597 patients with rheumatoid in the induction of inflammation in animal models of arthritis receiving routine clinical care in whom disease- collagen-induced arthritis. modifying antirheumatic drugs (DMARDs) were initiated. In the double-blind, randomized trial described here, The patients were aged >65 years and were selected from a 342 patients with active rheumatoid arthritis (RA) received pharmaceutical assistance contract provided by the state of placebo or a 5-mg/day, 25-mg/day, or 75-mg/day dosage of Pennsylvania, USA.
BIIL 284 (an LTB4 receptor antagonist) for up to 3 months. In Patients who were initiated on a DMARD between 1995 terms of ACR20 treatment response, assessed at days 14, 28, and 2003 were identified. All data regarding DMARD 56, and 84, no statistically significant differences were observed prescriptions, physician services, and hospitalizations were between the three dosage groups. In addition, no significant analyzed. The initiation of anti-tumor necrosis factor-α differences were observed for any of the active treatment (anti-TNF-α) agents or glucocorticoids was compared with groups relative to placebo, with the exception of a slightly the initiation of methotrexate (MTX). The incidence of higher response rate in the 25-mg/day group at day 28. Plasma serious bacterial infections was 2.2 per 100 patient-years in levels of the drug were also similar between responders and the patients receiving MTX monotherapy. Compared with non-responders, suggesting that inadequate dosing was not the these patients, those receiving glucocorticoid dosages of cause of the negative results. In conclusion, it is unlikely that the ≤5 mg/day, 6–9 mg/day, 10–19 mg/day, and ≥20 mg/day
LTB 4 pathway is of great relevance for human RA. had a risk ratio for serious bacterial infections of 1.34, 1.53, 2.97, and 5.48, respectively (p for trend <0.0001). Address for reprints: S Polmar, Therapeutic Area Immunology, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Road, Intriguingly, no increase in the rate of serious infections was PO Box 368, Ridgefield, CT 06877-0368, USA. observed among patients initiated on anti-TNF-α therapy. Email: [email protected] These data seem to suggest that physicians may be able to
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manage anti-TNF-α therapy, with regard to the risk of were not followed, providing further evidence that adherence serious infections, or that an improvement in patient to guidelines helps to prevent new TB cases in patients treated functioning may counteract some of the immunosuppressive with TNF-α antagonists. effects of these agents. 1. Carmona L, Gomez-Reino JJ, Rodriguez-Valverde V et al. Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. Arthritis Rheum 2005;52:1766–72. Address for reprints: S Schneeweiss, Harvard Medical School, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Address for reprints: JJ Gómez-Reino, Rheumatology, Hospital Medicine, Brigham and Women’s Hospital, 1620 Tremont Street, Suite Clínico Universitario, A Choupana s/n, 15706 Santiago, Spain. 3030, Boston, MA 02120, USA. Email: [email protected] Email: [email protected]
Risk of tuberculosis in patients treated with tumor The effect of methotrexate and anti-tumor necrosis factor antagonists due to incomplete necrosis factor therapy on the risk of lymphoma prevention of reactivation of latent infection in rheumatoid arthritis in 19,562 patients Gómez-Reino JJ, Carmona L, Angel Descalzo M; during 89,710 person-years of observation Biobadaser Group. Wolfe F, Michaud K. Arthritis Rheum 2007;57:756–61. Arthritis Rheum 2007;56:1433–9.
In March 2002, recommendations were implemented in The nature of the relationship between tumor risk and Spain for preventing the reactivation of latent tuberculosis rheumatoid arthritis is currently being investigated. The (TB) in patients treated with tumor necrosis factor-α current article is an update on previously reported data (TNF-α) antagonists. Despite this guidance, 15 new TB from the same authors. cases were subsequently noted during 8717 patient- years of observation; however, in 13 of the 15 cases, the This article is an update of a previously published report recommendations had not been completely followed. The concerning malignant lymphoma in patients with rheumatoid data suggest that adherence to guidelines helps to prevent arthritis (RA) [1]. In the original report, the authors new TB cases in patients treated with TNF-α antagonists. described 29 lymphomas, which occurred in 29 314 person- years of follow-up. Based on these data, it was deemed that The Spanish Society of Rheumatology has an active the lymphoma incidence in RA was increased (standardized pharmacovigilance program for patients treated with tumor incidence ratio [SIR] 1.9), with the SIR being greatest necrosis factor-α (TNF-α) antagonists. This group has in patients treated with anti-tumor necrosis factor-α (anti- previously shown that screening can profoundly reduce the TNF-α) agents. However, the differences in risk between rate of new tuberculosis (TB) cases in patients treated with therapies were slight, as reflected by overlapping confidence TNF-α antagonists [1]. In March 2002, recommendations intervals (CIs) for the different treatment groups. To further for preventing the reactivation of latent TB were explore the relationship that anti-TNF-α therapy and implemented in Spain. methotrexate (MTX) might have with the risk of lymphoma From March 2002, 5198 patients receiving treatment in patients with RA, the authors extended the study, with with tumor necrosis factor-α (TNF-α) antagonists were the same patients being evaluated. registered, including 3088 who were initiated on treatment The population analyzed comprised patients registered in after September 2003, when all three TNF-α antagonists the US National Data Bank for Rheumatic Diseases (NDB) (adalimumab, etanercept, and infliximab) were fully available longitudinal study for the outcomes of RA, who completed for the first time to the study population. Fifteen new TB cases semi-annual questionnaires in the period from 1998 to were observed during 8717 patient-years, but in 13 of the 2005. The authors also searched the US National Death 15 cases the aforementioned recommendations had not been Index and received reports of deaths from the family and completely followed. Among patients who were treated for friends of the participants. the first time after September 2003, five cases were noted While enrolled in the NDB, 55.3% of the patients in 1303 patient-years of infliximab treatment, two cases in received biological agents and 68.0% received MTX. The 1740 patient-years of etanercept treatment, and one in 565 analysis included 19 562 patients with 89 710 person-years patient-years of adalimumab treatment. The differences were of follow-up; 43 lymphomas occurred in 10 815 anti- not statistically significant, but the power to detect differences TNF-α-treated patients and 50 lymphomas occurred in between these three treatment regimens was limited. 8747 non-anti-TNF-α-treated patients. The overall lymphoma The probability of developing TB was found to be incidence rate was 105.9 per 100 000 person-years of approximately seven times higher when the recommendations exposure (95% CI 86.6–129.5 per 100 000 person-years).
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Using values from the SEER (Surveillance, Epidemiology, strategies in patients with rheumatoid arthritis (RA) of and End Results) lymphoma database for comparison, ≤2 years’ duration: the SIR was calculated to be 1.8 (95% CI 1.5–2.2). The odds ratio (OR) for lymphoma in patients who received • Group 1: methotrexate (MTX), switched to other anti-TNF-α therapy compared with patients who did not single agents if inadequately effective. receive anti-TNF-α therapy was 1.0 (95% CI 0.6–1.8). The • Group 2: MTX, escalated to dual and triple disease- OR for lymphoma in patients who received an anti-TNF-α modifying antirheumatic drug (DMARD) therapy agent and MTX, compared with those who received MTX as needed. treatment alone, was 1.1 (95% CI 0.6–2.0). In short, • Group 3: MTX and sulfasalazine with a tapered the investigators found no increase in the incidence of regimen of steroids. lymphoma among patients who received anti-TNF-α • Group 4: MTX and infliximab. therapy, compared with those who were not given this therapy. Patients were evaluated every 3 months, at which time Anti-TNF-α agents were also analyzed individually. No the medication regimen could be changed in the event association with lymphoma was found for any etanercept of inadequate disease control. The primary endpoints treatment or any infliximab treatment, with respective ORs were changes in Health Assessment Questionnaire (HAQ) of 0.7 (95% CI 0.3–1.6) and 1.2 (95% CI 0.6–2.2). A and radiographic scores. Patients in groups 3 and 4 statistically significant association between adalimumab improved more quickly, and reached plateau HAQ levels by treatment and lymphoma was found, but this was based on 3–6 months, compared with 15 months for groups 1 and 2. 56 cases and only two lymphomas in the group receiving However, by 2 years, 38–46% of patients in each group this treatment. The small number of cases is a reflection of were in clinical remission, and nearly 80% had a Disease the fact that, for inclusion in the analysis, patients receiving Activity Score of ≤2.4. Medication changes were required specific anti-TNF-α agents were required to have not more frequently in groups 1 and 2. Patients in groups 3 and received a different anti-TNF-α agent previously. After 4 experienced slightly less radiographic progression as relaxation of this condition, the number of adalimumab measured by the Sharp–van der Heijde score (2.0 vs. 1.0 of cases increased to 1482, with an OR for adalimumab 448 possible points), but dramatic worsening (>20 points) compared with all other therapies of 1.2 (95% CI 0.3–5.10). was seen in far fewer patients treated aggressively: 1. Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis: the effect of methotrexate and 18, seven, one, and one of approximately 120 patients in anti-tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum 2004;50:1740–51. groups 1–4, respectively. Although side effect rates were not Address for reprints: F Wolfe, National Data Bank for Rheumatic Diseases, significantly different between groups, one case of septic Arthritis Research Center Foundation, 1035 North Emporia Street, Suite arthritis and one death from disseminated tuberculosis 230, Wichita, KS 67214, USA. Email: [email protected] occurred in group 4. Strikingly, 74% of patients in group 4 Comparison of treatment strategies in early who had favorable results with MTX and infliximab rheumatoid arthritis: a randomized trial combination therapy were able to discontinue anti-tumor Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF et al. necrosis factor-α (anti-TNF-α) therapy by 2 years. The Ann Intern Med 2007;146:406–15. authors concluded that aggressive early management improved the speed of recovery and limited accumulated This authors present 2-year outcome data from the BeSt joint injury. (Behandel Strategieën [Dutch for “treatment strategies”]) Other conclusions may also be drawn from this rich study, in which four treatment protocols for recent-onset dataset. The ability to “back off” from steroids or infliximab rheumatoid arthritis were compared. Although protocols therapy without losing disease control suggests an that incorporated disease-modifying antirheumatic drug induction–maintenance paradigm for RA therapy, which is therapy with infliximab or high-dose glucocorticoids already practiced by some clinicians because of the time produced more rapid clinical improvement, disease required for full DMARD activity. A question that remains α control and functional status were similar in all groups unanswered is whether high-dose steroids, anti-TNF- after 15 months. Patients treated less aggressively therapy, or both are required for “induction”, or whether demonstrated more accumulated joint injury; however, lower-dose steroids, proactive conventional DMARD the difference was small. therapy, or their combination would be sufficient (as per the TICORA [Tight Control for Rheumatoid Arthritis] protocol, The BeSt (Behandel Strategieën [Dutch for “treatment for instance). Long-term follow-up will be important to strategies”]) study investigators compared four treatment discern whether aggressive early therapy yields persistent
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benefit, as observed in the COBRA (Combinatietherapie Bij p<0.05), while allergic reactions occurred more often in the Reumatoide Artritis [Dutch for “combination therapy in younger patients (20.0% vs. 10.7%; not significant). DAS28, rheumatoid arthritis”]) trial [1]. In the meantime, as noted in which was used as a measure of clinical effectiveness, an accompanying editorial, rheumatologists can be decreased by nearly identical amounts in the two groups at encouraged by the finding that the large majority of patients 6 months, 1 year, and 2 years after initiation of anti-TNF-α derived benefit, regardless of the initial therapy, as long as therapy. However, functional disability, as determined by the physicians had the flexibility to alter the drug regimen [2]. HAQ score, improved by significantly less in older patients 1. Landewe RB, Boers M, Verhoeven AC et al. COBRA combination therapy in patients than in younger patients (0.02 vs. 0.1; p<0.001). Further with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Arthritis Rheum 2002;46:347–56. analysis revealed that the absence of effect was observed 2. O’Dell JR. The BeSt way to treat early rheumatoid arthritis? Ann Intern Med only in the patients aged >75 years. 2007;146:459–60. The authors conclude that anti-TNF-α agents can be Address for reprints: YP Goekoop-Ruiterman, Department of administered to older patients and younger patients with Rheumatology, Leiden University Medical Center, C1-R, PO Box 9600, 2300 RC Leiden, The Netherlands. Email: [email protected] similar levels of effectiveness and tolerability. Although age should not, by itself, be a basis for therapeutic decisions Tolerance and effectiveness of anti-tumor necrosis concerning the introduction of anti-TNF-α medication, it factor α therapies in elderly patients with rheumatoid would be incorrect to conclude from this study that these arthritis: a population-based cohort study agents can be used in older patients with RA without Genevay S, Finckh A, Ciurea A et al.; Physicians of the Swiss considering other factors. Clinical Quality Management Program for Rheumatoid Arthritis. Address for reprints: C Gabay, Division of Rheumatology, University Arthritis Rheum 2007;57:679–85. Hospital of Geneva, 26 Avenue Beau-Séjour, 1211 Geneva 14, Switzerland. Email: [email protected] The investigators evaluated the safety and efficacy of anti-tumor necrosis factor-α agents in older patients Histopathologic and clinical outcome of rituximab (≥65 years old) and younger patients (<65 years old) treatment in patients with cyclophosphamide- with rheumatoid arthritis and found similar levels of resistant proliferative lupus nephritis tolerability and effectiveness. Gunnarsson I, Sundelin B, Jónsdóttir T et al. Arthritis Rheum 2007;56:1263–72. Although 20–30% of patients with rheumatoid arthritis (RA) are aged >60 years, this subgroup seems to be under- In a study of seven patients with therapy-resistant represented in RA clinical trials. Accordingly, there is a need for proliferative lupus nephritis, the combination of rituximab more research into the tolerability and effectiveness of anti- and cyclophosphamide was found to be a safe and α α tumor necrosis factor- (anti-TNF- ) agents in older patients. effective treatment in terms of clinical variables and The data obtained in the present study were derived renal histopathology. from the Swiss Clinical Quality Management program for RA, which is a large, longitudinal, population-based cohort Systemic lupus erythematosus (SLE) is an autoimmune of patients with RA. A total of 1571 patients with RA who connective tissue disease characterized by B cell hyper- had taken at least one dose of an anti-TNF-α agent reactivity and autoantibody formation. Patients with severe between 1997 and 2005 were divided into 344 older people organ involvement, especially those with lupus nephritis, (≥65 years old) and 1227 younger people (<65 years old). are treated with cyclophosphamide (CYC) by default. Baseline characteristics were similar in the two groups, with However, there are some patients who respond poorly to the exception of significantly higher values in the older CYC and are thus at risk of organ damage and renal group for disease duration, rheumatoid factor positivity, function impairment. The monoclonal antibody rituximab 28-joint Disease Activity Score (DAS28), and Health (anti-CD20 antigen) is commonly used in patients with Assessment Questionnaire (HAQ) score. B cell lymphomas and has also been successfully used in Tolerance was assessed by analyzing discontinuation several rheumatological diseases. The present study was rates using the time until drug discontinuation; values were designed to evaluate the efficacy and safety of combined almost identical in the two populations, with a median treatment with rituximab and CYC in a group of therapy- half-life of anti-TNF-α therapy of approximately 3 years in resistant patients with lupus nephritis. both cohorts. Analysis of specific reasons leading to drug Seven female patients with severe SLE and renal discontinuation revealed that cancer was significantly more involvement who had failed to respond to conventional frequent in the older patient group (7.1% vs. 0.0%; immunosuppressive therapy received rituximab in
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combination with CYC. CYC, hydrocortisone, methyl- A clinical pharmacogenetic model to predict prednisolone, and rituximab were administered intra- the efficacy of methotrexate monotherapy venously at the following dosages: in recent-onset rheumatoid arthritis Wessels JA, van der Kooij SM, le Cessie S et al.; • Day 1: CYC 0.5 g/m2 of body surface and Pharmacogenetics Collaborative Research Group. methylprednisolone 250 mg. Arthritis Rheum 2007;56:1765–75. • Days 2, 9, and 16: hydrocortisone 100 mg and 2 rituximab 375 mg/m of body surface. The current approach to initial therapy in rheumatoid • Day 23: CYC, methylprednisolone, and rituximab arthritis (RA) is essentially based on trial and error, with, at the same dosages as before. as yet, no means of tailoring medication choice to the individual. In this study, the researchers combined clinical Patients’ oral prednisolone dosage was increased from and genetic data from a cohort of 186 patients into a pretreatment levels to 1 mg/kg of body weight during composite score that predicts response to methotrexate the first week of the treatment regimen, tapered to with substantial accuracy. The score awaits validation 0.75 mg/kg during the second week, tapered further to in an independent cohort. 0.5 mg/kg during the third week, and then reduced as clinically allowed. The follow-up examination included Pharmacogenomics, which remains a “holy grail” in regular evaluations of overall disease activity, measured by rheumatology, would offer the possibility of choosing the the SLE Disease Activity Index (SLEDAI), and of renal optimal therapy for a given patient based on findings from involvement, using the British Isles Lupus Assessment Group simple clinical and genetic tests. In this interesting study, (BILAG) index and renal biopsy to analyze the infiltration of a cohort of patients with rheumatoid arthritis (RA) from T cells, B cells, and plasma cells. Evaluation of renal the BeSt (Behandel Strategieën [Dutch for “treatment response and remission was based on serum creatinine and strategies”]) study who received methotrexate (MTX) serum albumin levels. Serological measures included levels monotherapy was used to examine predictors of therapeutic of complement, immunoglobulin G (IgG) anti-double- response, defined as a Disease Activity Score (DAS) of ≤2.4 stranded DNA (anti-dsDNA) antibodies, and anti-C1q at 6 months. Patients who were unable to tolerate MTX antibodies. At a 6-month follow-up, there was a significant owing to toxicity were excluded. Through univariate analysis reduction in the SLEDAI (from a mean of 15 to 3; uncorrected for multiple comparisons, the authors found p=0.0022), and an improvement on the BILAG index was that a good response to MTX was associated with: also noted (from A to B–D). The mean serum creatinine level decreased from 88 μmol/L to 73 μmol/L (p=0.035) • Lower disease activity at baseline, based on DAS, joint and the mean serum albumin level increased from 27 g/L count, physician and patient scores, Health Assessment to 34 g/L (p=0.024). A reappearance of CD19+ B cells Questionnaire score, and erythrocyte sedimentation rate. was detected after a mean of 5 months. At the 6-month • Male sex. evaluation, a significant decrease in anti-dsDNA antibody • Premenopausal status in females. levels (from a mean of 174 IU/mL to 56 IU/mL; p=0.035) • The use of hormone supplementation in females. was observed, as was a significant decrease in anti-C1q • The presence of four single nucleotide polymorphisms antibody levels (from a mean of 35 units/mL to (SNPs) in genes potentially involved in the mechanism 22 units/mL; p=0.016). A reduction in the numbers of of action of MTX. CD3+, CD4+, and CD20+ cells in the renal interstitium was noted in half of the patients, and a decline in hematuria Through multivariate analysis, the investigators identified could be seen in all patients. a slightly different set of baseline variables as the optimal In summary, rituximab therapy was effective and well independent predictors of response: tolerated in patients with treatment-resistant, proliferative lupus nephritis. For patients who failed to respond • Sex. to conventional immunosuppressive therapy, combined • Rheumatoid factor status. treatment with rituximab and CYC can be very effective and • DAS. prevent the development of irreversible organ damage. • Presence of the four SNPs.
Address for reprints: I Gunnarsson, Department of Rheumatology, D2:01, Karolinska University Hospital at Solna, S-171 76 Stockholm, Using these variables, they developed a clinical score Sweden. Email: [email protected] ranging between 0 and 11.5, where a lower score correlated
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with a higher likelihood of MTX response. They found that Patients had been symptomatic for >9 months on 95% of patients with a score of ≤3.5 responded well, whereas average at the start of the trial. Treatment was tapered after 86% of patients with a score of ≥6 failed to achieve the target 12 months and discontinued by 18 months, while both DAS (60% of all patients fell into these two extremes). groups received standard nonsteroidal anti-inflammatory For patients with scores between 3.5 and 6, a decrease in DAS drug therapy. The primary endpoint was progression to of >1.2 at 3 months of therapy predicted ultimate response in rheumatoid arthritis (RA) by American College of 78% of cases. A model generated without the genetic data Rheumatology criteria; secondary endpoints included was not as strongly predictive, and categorized only 32% of radiographic progression. Patients treated with MTX patients as responders or non-responders. progressed to RA more slowly than those in the placebo To test the scores, the authors identified a validation group, and experienced reduced radiographic injury. Post cohort of 38 patients with RA who were being treated with hoc subgroup analysis showed that these effects were MTX monotherapy. These patients generally had low disease restricted to the 20–27% of patients who were positive for activity, but application of the clinical pharmacogenetic anti-cyclic citrullinated peptide (anti-CCP) antibodies at model was still reasonably effective: patients predicted to diagnosis. In contrast, patients who were negative for the respond did so in 70% of cases, whereas predicted antibodies developed RA at a rate that was unaffected non-responders failed on MTX in 72% of cases. Further by MTX therapy and they experienced little radiographic validation will be essential before this score can be employed progression even while receiving placebo therapy. in clinical settings. Interestingly, remission had occurred by 30 months in approximately 25% of patients in each arm. Although Address for reprints: H Guchelaar, Leiden University Medical Center, Department of Clinical Pharmacy and Toxicology, PO Box 9600, long-term data are still being collected, most MTX-treated 2300 RC Leiden, The Netherlands. Email: [email protected] patients who were positive for anti-CCP antibodies progressed to frank RA once therapy was withdrawn, Efficacy of methotrexate treatment in patients suggesting that treatment did not fundamentally change the with probable rheumatoid arthritis: a double-blind, course of the underlying illness. randomized, placebo-controlled trial It remains to be determined whether earlier or more van Dongen H, van Aken J, Lard LR et al. intense therapy would have greater effectiveness in altering Arthritis Rheum 2007;56:1424–32. the natural history of RA.
Address for reprints: T Huizinga, Department of Rheumatology, The current investigators examined the hypothesis that Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, treatment of undifferentiated arthritis (UA) may limit the The Netherlands. Email: [email protected] ultimate development of frank rheumatoid arthritis (RA). Indeed, patients with UA treated with methotrexate Pneumocystis jiroveci (carinii) pneumonia (MTX) satisfied RA criteria at a later time-point and after infliximab therapy: a review of 84 cases showed less radiographic progression at 18 months, Kaur N, Mahl TC. compared with untreated patients with UA. However, Dig Dis Sci 2007;52:1481–4. many patients developed RA when MTX was tapered, suggesting that such therapy did not effectively change Cases of Pneumocystis jiroveci following infliximab the natural history of the disease. therapy are reviewed in the present article. Treating physicians need to be aware of this potential Early therapy for inflammatory arthritis reduces joint injury complication because of the increased mortality and improves patient functional status. In the “window of rate associated with the infection. opportunity” hypothesis, it is postulated that early therapy might also fundamentally change the course of arthritis, Treatment with tumor necrosis factor-α antagonists has been converting a potentially aggressive and lifelong illness associated with a variety of atypical infections, most notably into a milder or even self-limiting process. Invoking this tuberculosis (e.g. [1]). Published reports have also linked this hypothesis, the PROMPT (Probable Rheumatoid Arthritis: therapy to infection with Pneumocystis jiroveci (previously Methotrexate versus Placebo Treatment) trial investigators called Pneumocystis carinii) (e.g. [2]). In the current report, treated patients who had undifferentiated arthritis with the authors review cases of P jiroveci associated with methotrexate (MTX; 15–30 mg/week) or placebo to infliximab therapy that were reported to the US Food and determine whether early therapy might alter the course of Drug Administration’s Adverse Event Reporting System disease (n=55 for each arm). (AERS) between 1998 and 2003 inclusive.
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A total of 84 cases of P jiroveci infection were identified Psoriatic Arthritis Trial) [1]. In ADEPT, eligible subjects were in the database for this time period; the 74 cases for which required to have active psoriatic arthritis and to have demographical information was available included 27 men previously failed at least one treatment trial of a nonsteroidal and 47 women, with a mean age of 55 years. The majority anti-inflammatory drug. In the present article, the authors of these patients (n=49) were receiving infliximab treatment report on a second study of adalimumab in psoriatic arthritis, for rheumatoid arthritis. Thirty-eight patients were receiving in which eligible subjects were required to have failed an concomitant methotrexate and 37 were receiving concomitant adequate treatment trial of a disease-modifying anti- prednisone, while azathioprine, cyclosporine, leflunomide, rheumatic drug (DMARD). and 6-mercaptopurine were being administered to The investigators assessed 100 subjects with active approximately five patients each. The numbers of patients psoriatic arthritis who were randomized to receive either receiving specific combinations of these agents are not placebo (n=49) or adalimumab (n=51) for 12 weeks. In provided. In the 76 patients for whom data were available, accordance with the inclusion criteria for the trial, all of these the mean number of infusions before the onset of symptoms subjects had previously been treated with a DMARD. of P jiroveci infection was 2.1. The mortality rate was high Approximately 80% of patients in each treatment group had (27%), with 23 deaths reported for the 84 cases. been or were being treated with methotrexate. Although Given the likely under-reporting of events to the AERS, improvement from baseline was statistically significant at it is difficult to know the true incidence of P jiroveci 12 weeks for adalimumab compared with placebo, the effect infection associated with infliximab, but the review does appears to have been more modest than that reported suggest that this is an important infection for clinicians to be previously. During the double-blind portion of the trial, aware of when monitoring patients receiving infliximab response rates for patients on adalimumab and placebo, therapy. While the authors raise the possibility of respectively, were: prophylactic therapy for this population, it is not clear that there are adequate data available to support this practice. • Thirty-nine percent and 16% for ACR20 criteria (p=0.012). Finally, although the authors did not review P jiroveci • Twenty-five percent and 2% for ACR50 criteria (p=0.001). infections associated with adalimumab or etanercept in the • Fourteen percent and 0% for ACR70 criteria (p=0.013). AERS, it would seem prudent to watch for signs of this infection in patients receiving these agents as well. While statistical analysis was not performed on the 1. Keane J, Gershon S, Wise RP et al. Tuberculosis associated with infliximab, a tumor results after the 12-week time-point, it appears that there necrosis factor α-neutralizing agent. N Engl J Med 2001;345:1098–104. 2. Kaur N, Mahl TC. Pneumocystis carinii pneumonia with oral candidiasis after infliximab was further clinical improvement in both groups through therapy for Crohn’s disease. Dig Dis Sci 2004;49:1458–60. week 24. Address for reprints: TC Mahl, Division of Gastroenterology, Safety outcomes in this trial were similar to those seen in Department of Medicine, VA Upstate New York, State University of previous studies with adalimumab. In particular, there were New York at Buffalo School of Medicine, Buffalo, NY 14215, USA. no reports of demyelinating disease, worsening congestive Email: [email protected] heart failure, or serious opportunistic infection during either the double-blind or the extension phases of this trial [2–4]. Safety and efficacy of adalimumab in treatment No radiographic endpoints were included in this study. of patients with psoriatic arthritis who had failed While adalimumab has previously been shown to be disease modifying antirheumatic drug therapy effective for treating psoriatic arthritis, this is the first study to Genovese MC, Mease PJ, Thomson GT et al.; conclusively demonstrate this effect in patients who have M02-570 Study Group. previously responded inadequately to conventional DMARDs. J Rheumatol 2007;34:1040–50. 1. Mease PJ, Gladman DD, Ritchlin CT et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis. Arthritis Rheum 2005;52:3279–89. 2. Keystone EC, Kavanaugh AF, Sharp JT et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) In this Phase III trial of adalimumab for psoriatic arthritis, in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: the drug was found to be effective, even in a population a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 2004;50:1400–11. 3. van de Putte LB, Atkins C, Malaise M et al. Efficacy and safety of adalimumab as that had previously failed disease-modifying monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug therapy. antirheumatic drug treatment has failed. Ann Rheum Dis 2004;63:508–16. 4. Weinblatt ME, Keystone EC, Furst DE et al. Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, for the treatment of rheumatoid arthritis in patients Adalimumab, one of three currently available tumor necrosis taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003;48:35–45. factor-α antagonists, has been shown to reduce the signs Address for reprints: MC Genovese, Division of Rheumatology, and symptoms of psoriatic arthritis in a previously published Stanford University Medical Center, 1000 Welch Road, Suite 203, 24-week study, ADEPT (the Adalimumab Effectiveness in Palo Alto, CA 94304, USA. Email: [email protected]
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Therapy of patients with rheumatoid arthritis: remaining 22 completed 12 weeks of etanercept therapy outcome of infliximab failures switched to etanercept without toxicity. Buch MH, Bingham SJ, Bejarano V et al. Overall, the findings suggest that there is a reasonable Arthritis Rheum 2007;57:448–53. likelihood of response to etanercept in patients switched after a non-response to infliximab, and that those who In this first large, prospective series of patients switched never responded to infliximab may have a higher likelihood to etanercept after an inadequate response to infliximab, of response. Of note is the fact that the dose of infliximab there appears to be a reasonable likelihood of response was limited after 6 weeks to 3 mg/kg every 8 weeks. It is to the second tumor necrosis factor-α antagonist. not clear how the results of this prospective series would extrapolate to patients failing to respond to higher, or more As larger numbers of patients with rheumatoid arthritis (RA) frequent, doses of infliximab. are being treated with biological therapies, and as new 1. Genovese MC, Becker JC, Schiff M et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor α inhibition. N Engl J Med 2005;353:1114–23. biological agents are becoming available, clinicians are 2. Cohen SB, Emery P, Greenwald MW et al.; the REFLEX Trial Group. Rituximab for increasingly faced with the decision of how best to treat rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, Phase III trial evaluating patients who respond inadequately to initial tumor necrosis primary efficacy and safety at twenty-four weeks. Arthritis Rheum 2006;54:2793–806. α α factor- (TNF- ) antagonist therapy. A critical element in Address for reprints: P Emery, Academic Section of Musculoskeletal this decision is determining whether to switch patients to Disease, Chapel Allerton Hospital, Chapeltown Road, Leeds, LS7 4SA, another TNF-α antagonist, or to one of the other available UK. Email: [email protected] biological agents. Published clinical trial data provide an indication of the likelihood of response to abatacept or PROGNOSIS AND ASSESSMENT rituximab in this population [1,2]; however, the data on switching to another TNF-α antagonist have largely been limited to anecdotal reports and uncontrolled series. Clinical assessment and core outcome variables Although the current series did not constitute a are poor predictors of hip arthritis diagnosed controlled trial, it represents the first prospective follow-up by MRI in juvenile idiopathic arthritis of a cohort of patients who switched to etanercept, after Nistala K, Babar J, Johnson K et al. failing therapy with infliximab, for predefined reasons. Rheumatology (Oxford) 2007;46:699–702. A total of 95 patients were included, all of whom had met the 1987 American College of Rheumatology (ACR) criteria This retrospective analysis of hip magnetic resonance for RA. Within this group, 34 patients were switched for images from patients with juvenile arthritis shows that primary non-response to infliximab, 38 were switched after there is difficulty in distinguishing between active arthritis a transient response that had lapsed, and 23 were switched and chronic joint injury in a clinical setting. owing to toxicity. The dosage of infliximab was 3 mg/kg administered intravenously at weeks 0, 2, and 6, and then Coxitis resulting in damage to the hip is potentially one of every 8 weeks, according to UK guidelines. All patients were the most debilitating consequences of juvenile idiopathic taking methotrexate and continued to do so after switching arthritis (JIA). Accordingly, the hip is the most commonly to etanercept. replaced joint in this population; however, this procedure has For the 72 patients switching because of non-response become increasingly rare as therapy has improved. to infliximab, the likelihood of achieving an ACR20 response In the current study, the authors assessed whether after 12 weeks of treatment with etanercept 50 mg/week clinical examination could be used to detect ongoing was 38%, while the likelihoods of ACR50 and ACR70 synovitis in the hip joint. They identified 34 magnetic responses were 24% and 15%, respectively. Among this resonance imaging (MRI) scans (68 hips) that had been group, there was a decrease in the mean 28-joint Disease performed for clinical indications on patients with any Activity Score from 6.4 at baseline to 4.9 at 12 weeks, subtype of JIA with a mean disease duration of 6.3 years which was highly significant (p<0.0001). Criteria for a (range 0.8–13.6 years). Using a novel scoring system, the moderate European League Against Rheumatism (EULAR) investigators quantified inflammation and injury, and sought response were met by 61% of patients, and 12% met correlations with physical examination and laboratory data criteria for a good EULAR response. extracted from chart reviews. It was observed that clinical Among the 23 patients switching from infliximab because assessment of ongoing hip inflammation had only a modest of toxicity, one developed sepsis and died after hospitalization correlation with inflammation as judged using MRI (based for what was described as an unrelated problem. The on synovial enhancement with gadolinium >2 mm, effusion,
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and bone edema), and that beyond 4 years of disease the relative contributions of sociodemographical and duration clinicians were unable to identify synovitis against immunological variables to clinical, laboratory, and radio- a background of chronic joint injury. Overall, clinical graphic pulmonary abnormalities in a prospective, multi- examination had a sensitivity of 26% and a specificity of ethnic cohort of patients with SSc. Patients were enrolled in 91% for inflammation as determined by MRI. Even in the study if they: undamaged hips, a concordance of clinical and MRI findings was observed in only 11 of 18 cases; it is unclear from the • Satisfied the 1980 American College of Rheumatology. data how many completely normal hips (without injury or preliminary SSc criteria, with a disease duration of ≤5 years. inflammation) were included in this series or whether • Defined their ethnicity. clinicians were able to accurately identify these through • Received medical care within the catchment area clinical examination. Laboratory tests were found to be of of the participating center. little utility in identifying hip arthritis, with an erythrocyte sedimentation rate of >7 mm/h imparting some increased A total of 203 patients were enrolled (104 were white, risk of inflammation (C-reactive protein was not discussed in 39 African American, and 60 Hispanic). Sociodemographical, the article). behavioral, psychological, serological, and genetic data were The authors acknowledged that the study was limited collected, and a detailed clinical assessment of each patient by the difficulties inherent to retrospective chart review was performed. Pulmonary involvement was estimated and by the fact that MRI data were only available for using the pulmonary function test, through clinical findings patients for whom the test was ordered for clinical such as established pulmonary disease, or by radio- indications. A history and physical examination conducted graphically evident pulmonary fibrosis on chest X-ray. Within prospectively to answer the question “Is this hip actively 2.8 years of the diagnosis of SSc, significant pulmonary arthritic?” may yield somewhat more optimistic figures for involvement was observed in one-quarter of patients. sensitivity and specificity. Furthermore, the prognostic At the time of recruitment, pulmonary fibrosis was seen significance of active inflammation in an already-injured hip significantly more frequently in African American patients is uncertain. Nevertheless, the study findings highlight the than in white or Hispanic patients. African American patients difficulties intrinsic to assessing disease activity in the hip. had a significantly lower percent predicted forced vital capacity and forced expiratory volume in 1 s than white Address for reprints: K Nistala, Paediatric Rheumatology Department, Birmingham Children’s Hospital, Steelhouse Lane, Birmingham, patients, and a significantly lower percent predicted diffusing B4 6NH, UK. Email: [email protected] capacity for carbon monoxide than both white and Hispanic patients. Factors that had a significant, independent impact Pulmonary involvement in systemic sclerosis: on early pulmonary involvement included African American associations with genetic, serologic, socio- ethnicity, cardiac involvement, hypothyroidism, serum demographic, and behavioral factors creatinine and creatine phosphokinase levels, and skin score. McNearney TA, Reveille JD, Fischbach M et al. An independent protective factor for restrictive lung Arthritis Rheum 2007;57:318–26. disease was anticentromere antibody seropositivity. Anti- topoisomerase I, fibrillarin, and ribonucleoprotein auto- Pulmonary manifestations of systemic sclerosis often antibodies were present significantly more often in African lead to death. Identifying predicting factors for the American patients than in white patients. 1. Laing TJ, Gillespie BW, Toth MB et al. Racial differences in scleroderma among women development of pulmonary manifestations is therefore in Michigan. Arthritis Rheum 1997;40:734–42. of great importance. 2. Morgan C, Knight C, Lunt M et al. Predictors of end stage lung disease in a cohort of patients with scleroderma. Ann Rheum Dis 2003;62:146–50. 3. Steen VD, Medsger TA Jr. Severe organ involvement in systemic sclerosis with diffuse Pulmonary arterial hypertension (PAH) and pulmonary scleroderma. Arthritis Rheum 2000;43:2437–44. fibrosis are typical lung-related manifestations of systemic 4. Briggs DC, Vaughan RW, Welsh KI et al. Immunogenetic prediction of pulmonary fibrosis in systemic sclerosis. Lancet 1991;338:661–2. sclerosis (SSc). Retrospective reports of patients with SSc 5. Greidinger EL, Flaherty KT, White B et al. African-American race and antibodies to have detailed a 17–24% reduction in survival rate topoisomerase I are associated with increased severity of scleroderma lung disease. Chest 1998;114:801–7. attributable to pulmonary involvement [1–3], but the 6. Nishioka K, Katayama I, Kondo H et al.; the Scleroderma Research Committee Japan. Epidemiological analysis of prognosis of 496 Japanese patients with progressive systemic etiology of pulmonary involvement in SSc is not completely sclerosis (SSc). J Dermatol 1996;23:677–82. understood. Associations with human leukocyte antigen (HLA) class II and ethnicity have been demonstrated in some Address for reprints: TA McNearney, Division of Rheumatology, University of Texas Medical Branch, 301 University Boulevard, studies [1,4–6]. In the present report, the authors examined Galveston, TX 77555-1165, USA. Email: [email protected]
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EPIDEMIOLOGY corticoid therapy) served as the most powerful predictor of lumbar spine osteoporosis and decreased hip BMD. Nephritis was also observed to be associated with lumbar Prevalence and etiology of low bone mineral spine osteoporosis on multivariate analysis, whereas total density in juvenile systemic lupus erythematosus glucocorticoid dose was either weakly predictive or non- Compeyrot-Lacassagne S, Tyrrell PN, Atenafu E et al. predictive of BMD. Since the intake of calcium and vitamin Arthritis Rheum 2007;56:1966–73. D could not be reliably ascertained, the potential impact of supplementation could not be addressed. Decreased bone mineral density (BMD) is a recognized The authors concluded that patients with juvenile-onset complication of adult and pediatric rheumatic illnesses. SLE are at risk of having a decreased BMD, especially after The present investigators extended these findings to a prolonged duration of disease. It remains to be determined juvenile systemic lupus erythematosus, and found whether these reductions in BMD represent a simple delay in osteopenia in 19–38% of patients, depending on the acquisition of bone mass or whether they will persist to site examined. Decreased BMD was found to correlate compromise peak bone mass in adulthood. The implications more strongly with disease duration than cumulative for therapy are also not straightforward, given the ongoing glucocorticoid dose did. uncertainty concerning the use of bisphosphonates in young patients [1]. The adolescent growth spurt brings the most dramatic gains 1. Nigrovic PA, White PH. Care of the adult with juvenile rheumatoid arthritis. Arthritis Rheum 2006;55:208–16. in skeletal mineral content, and processes that limit the acquisition of bone mass during this period may have long- Address for reprints: E Silverman, Division of Rheumatology, Hospital term consequences for peak bone mass and fracture risk. for Sick Children, 555 University Avenue, Toronto, ON, Canada. Email: [email protected] The authors of the present article examined dual X-ray absorptiometry data collected from 49 patients who had systemic lupus erythematosus (SLE) with disease onset at Prevalence and complications of uveitis in age <18 years (77% females, mean age of onset 11.4 years, juvenile idiopathic arthritis in a population-based mean disease duration at testing 2.9 years). Almost all of nation-wide study in Germany: suggested these patients had received glucocorticoids. Lumbar spine modification of the current screening guidelines bone mineral density (BMD) was found to be indicative of Heiligenhaus A, Niewerth M, Ganser G et al.; osteopenia (determined by a z-score of between –2.5 and –1 German Uveitis in Childhood Study Group. against age- and sex-matched controls) in 37.5% of patients Rheumatology (Oxford) 2007;46:1015–9. and of osteoporosis (a z-score lower than –2.5) in 20.3%. Hip BMD was compared with age- and sex-matched mean values In this study of >3200 patients with juvenile idiopathic in the absence of a sufficiently large normal population from arthritis (JIA) from a German database, the researchers which to derive a z-score. A decreased hip BMD was defined identified the presence of uveitis in 1–25% of patients as <80% of the normal BMD value and was found in 18.8% depending on JIA subclass (overall prevalence 12%). of patients. Univariate analysis demonstrated an association A high risk for uveitis was associated with early age at onset, between decreased spine and hip BMD and: certain types of JIA, antinuclear antibody positivity, and a short duration of disease. Based on their dataset, the authors • Disease duration. propose revised screening guidelines for children with JIA. • Duration and cumulative dose of glucocorticoid therapy. • Disease severity, including the presence of lupus nephritis. Although the pathogenesis of the association remains • Requirement for therapy with advanced obscure, uveitis is a well-recognized complication of juvenile immunosuppressive drugs. idiopathic arthritis (JIA). Since uveitis is often asymptomatic, especially in younger children, regular screening is essential to However, no correlation was observed between disease avoid permanent visual impairment. The current authors activity scores, such as the SLE Disease Activity Index or the examined a database of 3271 German children with JIA and European Consensus Lupus Activity Measurement, and the obtained additional information from ophthalmologists, by likelihood of spinal osteopenia, spinal osteoporosis, or questionnaire, on approximately one-quarter of children with decreased hip BMD. uveitis. An overall uveitis prevalence of 12% was documented Multivariate analysis showed that disease duration in patients with JIA, with rates ranging from 1% in systemic (which is inseparably correlated with the duration of gluco- JIA to 25% in extended pauciarticular JIA. Interestingly,
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persistent pauciarticular disease was associated with a many people in a given population have ever been told by a somewhat lower prevalence (16%). Polyarticular arthritis physician that they have arthritis. was rarely accompanied by uveitis (2–4%). Alarmingly, In this health survey of a population from Victoria, uveitis preceded the onset of arthritis in 10% of patients. Australia, 7500 randomly selected inhabitants were In 73% of cases, uveitis was detected before the end of the interviewed. Twenty percent of men and 26% of women first year of arthritis, while uveitis began >5 years after the reported having arthritis (with an overall figure of 23%). A start of the illness in 5% of patients. Predictors of uveitis report of arthritis was associated with an increased chance of identified by multivariate analysis included: psychological distress (odds ratio [OR] 1.2, 95% confidence interval [CI] 1.1–1.4) and poor self-reported health (OR 1.9, • Early age at onset (p=0.03). 95% CI 1.7–2.1). Women were found to be at a higher risk • JIA subtype (p=0.04). of arthritis, even after adjusting for age, body mass index, • Antinuclear antibody (ANA) positivity (p<0.01). education, income, occupation, and residence. An increased • Short duration of disease (p<0.01). prevalence was found in older or overweight patients, and among those in lower education or income groups. Although females were over-represented among patients The discrepancy between the prevalence of self-reported with uveitis, sex was not found to be an independent risk arthritis in this survey and the known prevalence of factor. Other clinical parameters, including arthritis activity rheumatoid arthritis suggests that there is a need to develop and inflammatory markers, were not predictive of uveitis. referral programs that accurately account for the different Complications of uveitis occurred in 56% of cases, including forms of arthritis. vision of 20/50 or worse in at least one eye in 46%. Address for reprints: R Osborne, Centre for Rheumatic Diseases, Damage at initial exam and uveitis onset before arthritis Department of Medicine, University of Melbourne, Melbourne, were predictors of complications, whereas ANA positivity Vic, Australia. Email: [email protected] and JIA subtype were not found to have an effect on disease course. Based on their findings, the authors proposed a revised set of screening guidelines for JIA, which are the GENETICS first to incorporate a JIA categorization scheme. The data presented in this article are broadly similar to uveitis data from a large, single-center, JIA inception cohort Strong combined gene-environment effects in in another article, also published this year [1]. Together, anti-cyclic citrullinated peptide-positive rheumatoid these studies provide a high-resolution view of inflammatory arthritis: a nationwide case-control study in Denmark eye disease in JIA. Pedersen M, Jacobsen S, Garred P et al. 1. Saurenmann RK, Levin AV, Feldman BM et al. Prevalence, risk factors, and outcome of uveitis Arthritis Rheum 2007;56:1446–53. in juvenile idiopathic arthritis: a long-term followup study. Arthritis Rheum 2007;56:647–57.
Address for reprints: A Heiligenhaus, Department of Ophthalmology at There is evidence to suggest that anti-cyclic citrullinated St Franziskus Hospital, Hohenzollernring 74, 48145 Münster, Germany. Email: [email protected] peptide (anti-CCP) antibody-positive and anti-CCP antibody-negative RA are two different syndromes. In this Danish study, these findings were replicated. Role of age, sex, and obesity in the higher prevalence of arthritis among lower socio- In recent years, it has become clear that different factors economic groups: a population-based survey confer risk to patients with rheumatoid arthritis (RA) who Busija L, Hollingsworth B, Buchbinder R et al. have anti-cyclic citrullinated peptide (anti-CCP) antibodies, Arthritis Rheum 2007;57:553–61. compared with those who do not have these antibodies. This strongly suggests that different pathological processes In a health survey of people living in Victoria, Australia, are involved, indicating that anti-CCP antibody-positive and 23% of the respondents reported having arthritis, and anti-CCP antibody-negative RA are two different syndromes women were found to be at a greater risk, even after [1,2]. In this nationwide case–control study, 309 incident or multiple adjustments. recently diagnosed cases of anti-CCP antibody-positive RA and 136 cases of anti-CCP antibody-negative RA were In the last decade it has become increasingly clear that early compared with 533 age- and sex-matched controls. referral to a rheumatologist is crucial for optimal arthritis The analysis revealed that shared epitope (SE) homo- management. It is therefore interesting to determine how zygotes were at a high risk of anti-CCP antibody-positive
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disease (odds ratio [OR] 17.8, 95% confidence interval [CI] The incidence of CIA, the mean CIA score, and the 10.8–29.4). However, SE homozygosity was not associated morphological signs of arthritis were dramatically reduced with an increased risk of anti-CCP antibody-negative RA (OR in STAT4–/– arthritic mice in comparison with STAT4+/– and 1.07, 95% CI 0.53–2.18). Strong combined gene–environment STAT4+/+ mice, suggesting the importance of STAT4 for CIA associations were reported, with an increased risk of anti-CCP incidence. Expression of tumor necrosis factor-α, IL-6, antibody-positive RA in SE homozygotes observed among and IL-17 by the splenic T cells from arthritic STAT4–/– mice those who were heavy coffee drinkers (OR 53.3, 95% CI was significantly lower than that in arthritic wild-type 15.5–183), heavy smokers (OR 52.6, 95% CI 18.0–154), or T splenocytes at the late stages of CIA, but not at the early oral contraceptive users (OR 44.6, 95% CI 15.2–131), relative phases of the disease. In contrast, interferon-γ production to SE non-carriers who were not exposed to these risk factors. was controlled by STAT4 during the whole period of disease. The findings presented in this article further strengthen the The data suggest that STAT4 regulates the T cell production notion that risk factors are different for anti-CCP antibody- of inflammatory cytokines during CIA manifestations. The positive disease and anti-CCP antibody-negative disease. intravenous injection of STAT4 AS oligonucleotides – which 1. Huizinga TW, Amos CI, van der Helm-van Mil AH et al. Refining the complex rheumatoid interfere with the STAT4 translation start site, thereby arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins. Arthritis Rheum 2005;52:3433–8. inhibiting STAT4 mRNA and protein expression – into mice 2. Kallberg H, Padyukov L, Plenge RM et al.; Epidemiological Investigation of Rheumatoid Arthritis with CIA reduced clinical manifestations and joint damage. study group. Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am J Hum Genet 2007;80:867–75. Address for reprints: KM Hildner, Laboratory of Immunology, I Medical Address for reprints: M Pedersen, Artillerivej 5, DK-2300, Copenhagen, Clinic, University of Mainz, Langenbeckstrasse 1, Mainz, Germany. Denmark. Email: [email protected] Email: [email protected]
Bone erosions and bone marrow edema as defined PATHOGENESIS by magnetic resonance imaging reflect true bone marrow inflammation in rheumatoid arthritis Jimenez-Boj E, Nöbauer-Huhmann I, Hanslik-Schnabel B et al. Targeting of the transcription factor STAT4 by Arthritis Rheum 2007;56:1118–24. antisense phosphorothioate oligonucleotides suppresses collagen-induced arthritis In this detailed study of preoperation magnetic Hildner KM, Schirmacher P, Atreya I et al. resonance imaging and post-operation histopathological J Immunol 2007;178:3427–36. evaluation of small joints, it was demonstrated that the inflammatory process in rheumatoid arthritis extends The investigators demonstrated that the pathogenesis to the bone marrow cavity. of collagen-induced arthritis in mice is controlled to a great extend by the proinflammatory transcription factor Destruction of bone is the hallmark of rheumatoid arthritis STAT4, the targeting of which by antisense DNA results (RA). This detailed study involved preoperation magnetic in amelioration of arthritis manifestations. resonance (MR) imaging of metacarpophalangeal and proximal interphalangeal joints in patients with RA STAT4 is a central transcription factor in mediating signals of who were scheduled for joint replacement surgery, the proinflammatory cytokines interleukin-12 (IL-12), IL-15, in addition to post-operation histopathological evaluation and IL-23, which are implicated in the pathogenesis of of joint sections. rheumatoid arthritis (RA). The precise contribution of STAT4 The presence of bone erosions on MR images was to RA is not fully understood. Therefore, the current authors associated with localized replacement of bone marrow fat by investigated the role of STAT4 in arthritis appearance and accumulated inflammatory cells in the vicinity of a disrupted progression using a well-established RA model – collagen- cortical bone barrier. Infiltration of the bone marrow by induced arthritis (CIA) in mice. The consequences of inflammatory tissue was a histopathological correlate of functional abrogation of STAT4 on the clinical course and bone marrow edema detected on MR images. These outcome of CIA were assessed by monitoring disease observations indicate that, in addition to the synovial incidence and severity, through histopathology of arthritis membrane, parts of the bone marrow adjacent to joint are joints, and by splenocyte cytokine production. STAT4- inflamed in RA. deficient conditions were achieved by using arthritis- Address for reprints: G Schett, Department of Internal Medicine III and susceptible STAT4-deficient mice or antisense (AS) oligo- Institute for Clinical Immunology, University of Erlangen–Nuremberg, nucleotides against the translational start site of STAT4. Erlangen 91054, Germany. Email: [email protected]
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Interaction between smoking, the shared included amount smoked (in pack-years) for the Inception epitope, and anti-cyclic citrullinated peptide: cohort. American College of Rheumatology criteria for RA a mixed picture in three large North American were satisfied by all patients. Significant differences were rheumatoid arthritis cohorts noted in baseline characteristics for the three populations, Lee HS, Irigoyen P, Kern M et al. which led to the analysis of the interaction between smoking Arthritis Rheum 2007;56:1745–53. and anti-CCP antibody, rheumatoid factor (RF), and SE allele profiles being carried out separately in each cohort. In the Although it has been suggested that the development NARAC and Inception cohorts, a significant interaction of rheumatoid arthritis (RA) results from the combined was found between smoking and positivity for anti-CCP roles of genetic susceptibility factors and environmental antibodies and RF; however, no such relationship was found exposures, few studies have shown convincing in the SONORA cohort. The presence of the SE alleles was gene–environment interaction in RA. related to positivity for anti-CCP antibodies in all three cohorts. In multiple logistic regression analyses, SE alleles A recent case–control study among Swedish participants in were found to be the most significant risk factor for EIRA (the Epidemiological Investigation of Rheumatoid anti-CCP antibody positivity. Finally, evidence of a Arthritis) revealed a striking relationship between smoking gene–environment interaction between SE alleles and and shared epitope (SE) alleles in conferring risk for the smoking in the formation of anti-CCP antibodies was development of rheumatoid arthritis (RA) with anti-cyclic detected only among the NARAC cohort, and this relation- citrullinated peptide (anti-CCP) antibody positivity [1]. With ship was weak. the aim of confirming this interaction between smoking and In conclusion, the authors of the current report, on three SE alleles, the authors of the present article performed North American RA cohorts, could not confirm the existence a case-only analysis of 2476 white patients from three RA of a strong gene–environment interaction between SE alleles cohorts based in North America (1105 from the NARAC and smoking in the formation of anti-CCP antibodies, which [North American Rheumatoid Arthritis Consortium] cohort, is in contrast with findings from EIRA. Their data suggest 753 from the National Inception Cohort of Rheumatoid that a need exists for further studies to address the full Arthritis Patients, and 618 from the SONORA [Study of range of environmental factors that may be associated with New Onset Rheumatoid Arthritis] cohort). the development of anti-CCP antibodies. Data on smoking history were derived from question- 1. Klareskog L, Stolt P, Lundberg K et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA–DR (shared epitope) – restricted immune reactions naire responses at enrolment for the NARAC and SONORA to autoantigens modified by citrullination. Arthritis Rheum 2006;54:38–46. cohorts, and at each visit for the Inception cohort. The data Address for reprints: P Gregersen, Robert S Boas Center for Genomics included smoking status (never smoked, ever smoked, and Human Genetics, 350 Community Drive, Manhasset, NY 11030, or currently smoke) for all three cohorts, and additionally USA. Email: [email protected]
INTERNATIONAL JOURNAL OF ADVANCES IN RHEUMATOLOGY Vol 5 No 3 2007 101 RT92_3_REM_Rheum_5-3_05.qxd 7/11/0714:19Page102 MEETING REPORT alcohol wassimilarinanti-cyclic citrullinatedpeptide-positive confidence interval[CI]0.4–0.7).Ofinterest, the effect of per weekbeingassociatedwithanoddsratioof0.5(95% developing RA,withtheconsumptionofmore thanthree week wasfoundtobeinverselycorrelated withtheriskof and drinkinghabits.Thenumberofalcoholicdrinks per authors classifiedthestudysubjectsbasedontheirsmoking included 1204patientswithRAand871controls. The data from apopulation-based,case–control studythat Institute, Stockholm,Sweden;abstractOP0129)described have long-termeffects thatprotect againstRA. investigators alsofoundthatbreastfeeding for>1yearmay an increased riskofdevelopingRA.Surprisingly, these an oralglucosechallengewasindependentlyassociatedwith development ofRA.Inaddition,alowerglucoselevelafter degree) were identifiedasindependentriskfactorsforthe formal education(elementaryschoolonlyversusuniversity Sweden; abstractOP0130),smokingandalowlevelof Bergström etal.(University HospitalofMalmö, rheumatoid arthritis(RA).Inastudypresented byUlf environmental factorscontributingtotheriskofdeveloping Two studiesfrom Swedenprovided more insightsinto New thoughtsontheepidemiologyofRA in thismeetingreport. of EULARinrecent years,wasclinicalresearch, asreflected spirit inthefield.Themainfocusofthiscongress, andalso EULAR meetingwasaperfectdemonstrationofthenew as dramaticallyinrecent yearsasrheumatology, andthe Arguably, there isnodisciplineinmedicinethathaschanged proved tobeavital,progressive, anddynamicspecialty. (EULAR) 8thAnnualCongress, asrheumatologyonceagain host cityfortheEuropean LeagueAgainstRheumatism stimulating atmosphere. There couldhavebeennobetter life, world-classentertainment,andlongnightsina The cityofBarcelona, Spain,iswellknownforitsvibrant Division ofRheumatology, UniversityofMunich,Germany Hendrik Schulze-Koops,MD,PhD Barcelona, Spain,June13–16,2007 (EULAR) 8thAnnualCongress European LeagueAgainstRheumatism 102 In asecondstudy, HenrikKällberg etal.(Karolinska I NTERNATIONAL J UNLOF OURNAL A VNE IN DVANCES levels, ortheuseofanalgesics. Health AssessmentQuestionnaire scores, C-reactive protein as diseaseactivityscores, physician’s globalassessmentscores, were notseeninotherclinicalorserological parameters,such no suchdecrease wasobservedintheIRgroup. Differences decrease of>30%inIL-6levelstheMRgroup (p<0.0001); Associated withthereduction inmorningstiffness wasa those receiving IRprednisone (22.7%vs.0.4%;p=0.0226). was significantlyhigherinpatientstakingMRprednisone than of morningstiffness from baselinetotheendoftreatment to prestudy doses.Themeanrelative reduction intheduration for 3monthsindailydosesof3–10mgthatwere equivalent After thepretreatment period,prednisone wasadministered morning andmodified-release prednisone intheevening. morning andplacebointheevening,or patients were randomizedtoreceive IRprednisone inthe prednisone anddisease-modifyingantirheumaticdrugs.The all ofwhomwere pretreated withimmediate-release (IR) reported ondatafrom 288patientswithlong-standingRA, University Hospital,Berlin,Germany;abstractOP0007) substantially reduced. FrankButtgereit etal.(Charité released duringthenight.Asaresult, morningstiffness is prednisone aftera4-hdelay, sothatthemedicationis diseases. Taken atbedtime,thenewformulationreleases this majorobstacleinthedailylifeofpatientswithrheumatic tablet formofprednisone mightprove beneficialincombating regulators, theglucocorticoids.Anewmodified-release (MR) as interleukin-6(IL-6),andtheirpotentialendogenous of thecircadian rhythmsofinflammatorycytokines,such diseases ismorningstiffness, whichislargely aconsequence A clinicalhallmarkofactiveinflammationinrheumatic Novel insightsintoestablishedagents antigen-DRB1 (HLA-DRB1)shared epitopealleles. modified bysmokingandthepresence ofhumanleukocyte the associationbetweenalcoholconsumptionandRAwas (anti-CCP-positive) andanti-CCP-negativeRA.Incontrast, R HEUMATOLOGY Vol 5No32007 RT92_3_REM_Rheum_5-3_05.qxd 7/11/07 14:19 Page 103
EULAR 2007
In further coverage of corticosteroids at the meeting, 4 mg/kg, and two patients administered placebo. There Eva Baecklund et al. (Uppsala University Hospital, Uppsala, were no cases of tuberculosis. Sweden; abstract OP0047) reported that long-term Another strategy in the treatment of rheumatic diseases steroid treatment reduces the risk of the development of currently under investigation is the targeting of receptor lymphoma in patients with RA. The investigators compared activator of nuclear factor-κB ligand (RANKL) – a major factor 378 patients who had RA and lymphoma with 378 age- in osteoclast development – in an attempt to inhibit or reduce matched controls who had RA but not lymphoma. A total bone resorption. Two presentations reported results from a steroid treatment duration of >2 years, but not one of Phase II trial of denosumab, which is a fully humanized <2 years, was associated with a markedly reduced monoclonal antibody to RANKL. In a study by Désirée van der lymphoma risk (relative risk 0.4, 95% CI 0.2–0.7). Of Heijde et al. (University Hospital Maastricht, Maastricht, interest for daily clinical practice was that steroids were The Netherlands; abstract OP0120), 227 patients with RA found to be protective, even if started late in the RA disease who were receiving background treatment with MTX were process. In summary, long-term steroid treatment may randomized to receive subcutaneous injections of placebo decrease lymphoma risk in RA. or denosumab (60 mg or 180 mg) every 6 months. Conventional X-ray and magnetic resonance images were Promising treatments on the horizon: obtained at 6 and 12 months and scored according to the new biological agents van der Heijde-modified total Sharp score (TSS) and its At the conference, early and advanced clinical data components (erosion score and joint space narrowing score) from research into several novel biological agents were to evaluate changes from baseline. A single dose of presented. Josef Smolen et al. (Krankenhaus Lainz, Vienna, denosumab 60 mg was found to significantly lessen the Austria; abstract OP0117) described results from OPTION increase in mean TSS from baseline within the 12-month (the Tocilizumab Pivotal Trial in Methotrexate Inadequate observation period, compared with placebo. On magnetic Responders), the first Phase III trial of tocilizumab, which resonance imaging, the bone-protective effects of denosumab is a humanized monoclonal antibody to the IL-6 receptor. were even more clearly observed, with patients in the group A total of 623 patients with active moderate-to-severe RA administered denosumab 180 mg showing significantly less despite treatment with methotrexate (MTX) were included progression of bone erosions at 6 months than patients in this double-blind, randomized, placebo-controlled study. receiving placebo (p<0.019). However, in accordance with the The patients continued to take MTX at their prestudy dose observation that denosumab does not affect inflammation, and were randomized into one of three groups: placebo, no changes were observed in the swollen joint count. Stanley tocilizumab 4 mg/kg body weight, or tocilizumab 8 mg/kg Cohen et al. (Radiant Research, Dallas, TX, USA; abstract body weight. Treatment was given every 4 weeks for six OP0226) presented further findings from this study, showing cycles by intravenous application. At week 24, ACR20 that RA flares were the most common adverse event (AE) and responses were noted in 27% of the patients administered that the AE profiles were similar across the three groups. placebo, 48% of those receiving tocilizumab 4 mg/kg patients, and 59% of those given tocilizumab 8 mg/kg. Conclusion ACR50 responses were observed in 11%, 32%, and 44% Overall, >3000 oral presentations and posters were of the respective patient groups, while ACR70 responses presented to a crowd of attendees who were both highly were seen in 2%, 12%, and 22%. Onset of the therapeutic interested and willing to be critical. The highlight of the effect was rapid, becoming prominent as early as 2 weeks entire meeting, as noted Tore Kvien, the Past President after the first application of the drug. The frequency of of EULAR, was the breadth of topics related to rheumatic adverse events was similar in all three groups, with serious diseases that was covered. Paris, France, will play host to the infections (those requiring hospitalization or treatment with conference next June, and the rheumatology research intravenous antibiotics) reported in six patients receiving community is confident that the range of topics will be tocilizumab 8 mg/kg, three patients given tocilizumab maintained, or even expanded further.
INTERNATIONAL JOURNAL OF ADVANCES IN RHEUMATOLOGY Vol 5 No 3 2007 103 RT92_3_REM_Rheum_5-3_05.qxd 7/11/07 14:19 Page 104
Forthcoming International Events 2008
JANUARY 8–10 APRIL 12th International Conference 29–30 on Lymphocyte Activation and 9–12 Royal College of Nursing Immune Regulation, T-Cell 8th European Congress on Rheumatology Nursing Regulation and Autoimmunity Clinical and Economic Aspects of Forum Annual Conference Newport Beach, CA, USA Osteoporosis and Osteoarthritis & Exhibition 2008 Contact: Conference Secretariat Istanbul, Turkey Cardiff, UK T +1 949 824 5818 Contact: Meeting Secretariat T +44 207 647 3591 E [email protected] T +32 4254 1225 F +44 207 647 3411 F +32 4254 1290 E [email protected] 14–18 W www.ecceo8.org W www.rcn.org.uk New Trends in Immuno- suppression & Immunotherapy, 22–25 Jan 26–Feb 1 8th International Conference British Society for Rheumatology Winter Rheumatology Symposium Berlin, Germany Annual Meeting & The British Snowmass Conference Center Contact: Secretariat Health Professionals in Snowmass Village, CO, USA T +41 22 908 0488 Rheumatology Spring Meeting W www.rheumatology.org/meetings F +41 22 732 2850 Liverpool, UK E [email protected] Contact: Hannah Gardner Jan 31–Feb 3 W www.kenes.com/immuno E [email protected] 32nd Scandinavian Congress T +44 020 7842 0917 of Rheumatology W www.bsrconference.org.uk Levi, Lapland, Finland MARCH Contact: Marja-Leena Porsanger 24–28 T +358 16 341 2799 1–5 35th European Symposium F +358 16 317 843 American College of on Calcified Tissues E [email protected] Rheumatology Keystone Pediatric Barcelona, Spain W www.congrex.fi/scr2008 Rheumatology Symposium Contact: Meeting Secretariat Keystone, CO, USA T +41 2233 99595 T +1 404 633 3777 F +41 2233 99601 FEBRUARY F +1 404 633 1870 E [email protected] W www.rheumatology.org W www.ectsoc.org/barcelona2008 3–6 1st International conference 6–8 on Drug Design and Discovery Infections, Rheumatism Dubai, United Arab Emirates and Autoimmunity Contact: Zakia Kazmi Milan, Italy T +97 142 237 651 Contact: Elena Guerriero F +97 142 237 687 T +39 02 6571200 E [email protected] E [email protected] W www.icddd.com W www.oic.it/ira2008
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104 INTERNATIONAL JOURNAL OF ADVANCES IN RHEUMATOLOGY Vol 5 No 3 2007 Clinical Trials A Practical Guide to Design, Analysis, and Reporting
• A jargon-busting guide to appreciating clinical trials • Short, easy-to-read chapters with trial examples • An essential book for everyone involved in planning, conducting or analysing clinical research
READERSHIP Physicians, statisticians, pharmacists, medical students, clinical researchers, medical writers, data managers, pharmaceutical sales representatives, financial (medical) analysts
DESCRIPTION Clinical trials form the backbone of evidence based medicine and appreciating clinical trial methods allows readers to critique, design and report clinical trials. In this book, the authors take a back-to-basics approach to explaining the conceptual and methodological issues that occur at all Published November 2005 stages of clinical trials. Based on the successful “Practical ISBN: 978 1 901346 722 Issues in Clinical Trial Design, Analysis and Reporting” series Price: $49.95/£30/€45 published in Remedica’s flagship journal “Clinical Researcher”, Extent: 496 pages and supplemented by key contributions from other leading Format: Paperback 170x240mm international experts, each article provides essential background information in an engaging style, explores its meaning, and explains how and when it should be applied. AUTHORS Readers will gain not only an understanding of the basics Duolao Wang PhD of clinical trials, but also critical insight into how to review, Statistician, Medical Statistics Unit, publish and evaluate clinical trial evidence. London School of Hygiene & Tropical Medicine, London, UK CONTENTS The book has five sections: Ameet Bakhai MBBS, MRCP • Part I: Fundamentals of Trial Design Cardiologist, Barnet General & Royal • Part II: Alternative Trial Design Free Hospitals, London, UK • Part III: Basics of Statistical Analysis • Part IV: Special Trial Issues in Data Analysis • Part V: Trial Reporting and Publishing
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