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Review paper / Pregledni rad

PSORIATIC IMAGING – AN OVERVIEW AND UPDATE SLIKOVNE METODE U PSORIJATIČNOM ARTRITISU – PREGLED I NOVOSTI

Gordana Ivanac, Eugen Divjak Clinical Department for Diagnostic and Interventional , University Hospital Dubrava, Zagreb, Croatia

Corresponding author address: Assistan Professor Gordana Ivanac, Md, PhD Clinical Department for Diagnostic and University Hospital Dubrava Av. Gojka Šuška 6, 10000 Zagreb Croatia tel. 01-2903255 Received/Primljeno: 4. 7. 2017. e-mail: [email protected] Accepted/Prihvaćeno: 18. 7. 2017.

Abstract (PsA) is a chronic infl ammatory joint disease that occurs in patients with psoriasis. Typically, involvement of the peripheral joints (with an asymmetric pattern) and the axial skeleton can be recognized. Th ere are no specifi c laboratory tests for PsA and the diagnosis relies on clinical and imaging fi ndings. Conventional radiology and magnetic resonance are the most valuable imaging modalities, with ultrasound becoming more and more used due to its feasibility and high sensitivity for peripheral disease manifestations. Th e authors off er a concise overview of PsA, common imaging fi ndings, and literature update. Keywords: Arthritis, psoriatic – diagnostic imaging, ; Diagnostic imaging – methods; Magnetic reso- nance imaging – methods; Ultrasonography; Tomography, x-ray computed; Joints – diagnostic imaging, pathology; Tenosynovtis – diagnostic imaging; Enthesopathy – diagnostic imaging

Sažetak Psorijatični artritis kronična je upalna bolest zglobova koja se javlja u pacijenata sa psorijazom. Tipično zahvaća periferne zglobove (s asimetričnim uzorkom) te aksijalni skelet. Ne postoje laboratorijski testovi specifi čni za psorija- tični artritis pa dijagnostički postupak počiva na kliničkom nalazu i slikovnim pretragama. Najčešće se rabe klasične radiološke pretrage i magnetska rezonancija, a sve više raste i upotreba ultrazvuka zbog njegove jednostavnosti i viso- ke osjetljivosti za periferne pokazatelje bolesti. Autori donose sažeti pregled psorijatičnog artritisa, tipičnih nalaza sli- kovnih metoda i novosti iz literature. Ključne riječi: Psorijatični arthritis – dijagnostički prikaz, patologija; Diagnostički prikaz – metode; Magnetska rezonancija – metode; Ultrazvuk; Kompjutorizirana tomografi ja; Zglobovi – dijagnostički prikaz, patologija; Tenosi- novitis – dijagnostički prikaz; Entezopatija – dijagnostički prikaz

Introduction tumor necrosis factor (TNF)-α, interleukin (IL)-1β, Psoriatic arthritis (PsA) is a chronic infl ammatory IL-6, IL-13, and nuclear factor-κ β ligand, which fi nally occurring in 6% to 48% of the patients leads to osteoclast-driven destruction of the joint (3, with skin psoriasis (1, 2, 3), typically presenting with 5). Although there are some similarities with rheuma- arthritis, , and/or , while the skin toid arthritis (RA), PsA is oft en seronegative for rheu- symptoms may be subtle (4). Evidence suggests that matoid factor, and, on closer inspection, diff erent clin- the underlying pathology includes both genetic and ical and imaging patterns are evident (4, 6). Th e disease environmental factors that cause profuse proinfl am- typically begins as enthesitis of articular capsules, fas- matory processes in the skin and synovium, involving ciae, tendons, and ligaments. Typically, involvement of

Reumatizam 2017;64(Suppl 1):43–50 43 Review paper / Pregledni rad Ivanac G. et al. Psoriatic arthritis imaging – an overview and update the peripheral joints (with an asymmetric pattern) and ble, and relatively inexpensive imaging of the bone the axial skeleton can be recognized (7). Based on the structure (4). It is not as sensitive in the detection of clinical presentation, fi ve patterns of PsA have been de- erosive lesions as CT, but it has a high specifi city (11). scribed by Moll and Wright (1): Th e main drawback is the 2-D visualization of a 3-D (a) asymmetric oligoarticular or monoarticular ar- structure, resulting in suboptimal delineation of bone, thritis primarily aff ecting the distal interphalangeal especially in complex joints (4). Imaging includes AP (DIP), proximal interphalangeal (PIP), and metatar- and lateral views of painful joints, as well as AP and sophalangeal joints; (b) DIP-predominant arthritis; (c) lateral views of hands and feet for evaluation of the arthritis mutilans; (d) symmetric, structural changes in DIP joints, which can oft en show (RF)-negative ; and (e) psoriatic spondy- typical radiographic signs, even if the joint is asympto- loarthropathy. As there are no specifi c laboratory tests matic (3, 10). Evaluation of the axial skeleton for atypi- for PsA, the diagnosis is mainly based on the clinical cal syndesmophytes is also recommended, but since presentation and imaging fi ndings (3). Based on a higher radiation doses are involved, MRI has recently study involving 588 patients with PsA and 536 control become the more favoured modality in spine assess- subjects, the Classifi cation of Psoriatic Arthritis (CAS- ment (4, 12). Th e characteristics of a bone lesion seen PAR) study group has formulated criteria for the diag- in PsA result from a combination of erosive and prolif- nosis of PsA: the presence of psoriasis or a family his- erative bone changes: a large, poorly demarcated ero- tory of psoriasis, dactylitis, juxta-articular new bone sion of the bony cortex in a para-articular site is oft en formation, negative RF, and nail dystrophy (8). If three seen, closely associated with new bone formation (3, of the above-mentioned criteria are met, there is a 6). Typical fi ndings include opera-glass deformity (tel- strong indication of PsA. escoping erosive joint destruction), fl uff y Methods due to periosteal ossifi cation; pencil-in-cup deformity consisting of destruction of the head of the middle and A computerized literature search, from January 1, expansion of the base of the distal phalanx, and ac- 2015 to May 31, 2017, was conducted by the authors to roosteolysis – resorption of the tuft of the distal pha- identify articles on imaging in patients with PsA. Arti- lanx (Figures 1 and 2). In patients with axial disease, cles were retrieved through PubMed search using the , syndesmophytes, paravertebral ossifi ca- US National Library Medical Subject Headings (MeSH) tion, and destructive discovertebral lesions can be term “Arthritis, Psoriatic/diagnostic imaging”. Publica- found (3, 10). Early diagnosis is of utmost importance, tions both in English and in German were considered. and Haroon et al. have shown that even a 6-month de- Reviews, editorials, case reports, letters, and commen- lay from symptom onset to the fi rst visit with a rheu- taries were excluded. Th e search yielded a total of 60 matologist contributes to the development of periph- articles and aft er an abstract review, 32 were found eli- eral joint erosions and worse long-term physical func- gible and retrieved as full-text articles. Some articles tion (13). Unfortunately, CR reveals infl ammatory were excluded due to having been electronically pub- changes in peripheral joints months or years aft er the lished on an earlier date. A total of 24 articles fulfi lling onset of clinical symptoms (10, 14). all inclusion criteria were included in the study. Semi-quantitative scoring methods originally devel- Results oped for , designed to measure the degree of radiographically detectable joint damage and Imaging methods changes over time, have been adopted for the use in Various imaging methods are used in patients with PsA and described by Wassenberg (15). A novel scor- suspected or established PsA, mainly conventional ra- ing method called Reductive X-ray Score for Psoriatic diography (CR), ultrasonography (US), and magnetic Arthritis has been proposed by Tillet et al (16). Th e resonance imaging (MRI) (4, 9). Computed tomogra- method is sensitive to change and includes three hall- phy (CT) is the gold standard for assessment of bone mark features of PsA: erosion, joint space narrowing structure, but is only used in exceptional cases of arth- (JSN), and osteoproliferation. Fewer joints need to be ritides due to ionizing radiation (4, 7, 10). Other imag- assessed than in using the most common and most fea- ing modalities, i.e., scintigraphy, positron emission to- sible score, PsA-modifi ed Steinbrocker, while the mography (PET), single photon emission CT, and du- method maintains a similar sensitivity to change as the al-emission x-ray absorptiometry, are seldom used in Sharp/van der Heijde (SvdH) score, which is currently PsA (4, 7). the most sensitive method developed. Geijer et al. (17) obtained hand and foot radiographs Conventional radiography for 72 of 197 PsA patients enrolled in the Swedish pso- CR remains the most widely used imaging tech- riatic arthritis registry and followed for 5 years. Radio- nique, off ering high spatial resolution, and fast, relia- graphic progression in early PsA was generally slow

44 Reumatizam 2017;64(Suppl 1):43–50 Ivanac G. et al. Psoriatic arthritis imaging – an overview and update Review paper / Pregledni rad

Figure 1 Conventional AP radiographs of the hands of an 85-year-old male patient with PsA. Note the narrowing of the interphalangeal joint spaces with osteophytosis and sclerosis – classic signs of osteoarthritic changes (white arrows). Fluff y bone appearance is seen at the site of active disease (asterisk). Erosion of the heads of the proximal phalanges results in the “pencil-in-cup” sign (black arrows). Subluxation of the fi rst MCP joint can also be seen (white arrowhead). Typically of PsA, changes are asymmetric and seen in the distal joints. Slika 1. Standardne rendgenske snimke obiju šaka 85-godišnjega muškog pacijenta sa PsA učinjene u AP projekciji. Vidljivo je suženje interfalangealnih zglobnih prostora s osteofi tozom i sklerozacijom zglobnih tijela – tipični znakovi Figure 2 Conventional AP radiographs of the feet of an osteoartritičkih promjena (bijele strjelice). Kost na mjestu 85-year-old male patient with PsA. Erosion of the head of the aktivne bolesti ima „čupav” izgled (zvjezdica). Erozija glava proximal phalanx resulting in the “pencil-in-cup” sign is seen proksimalnih falangi dovodi do pojave znaka „olovke u šalici” in the right big toe (black arrowhead). Some soft tissue (crne strjelice). Također je vidljiva subluksacija prvog MCP swelling is also present. zgloba (bijeli vrh strjelice). Uobičajeno za PsA, promjene su Slika 2. Standardne rendgenske snimke obaju stopala asimetrične i zahvaćaju distalne zglobove. 85-godišnjeg muškog pacijenta sa PsA učinjene u AP projekciji. Vidljiva je erozija glave proksimalne falange palca desnog stopala koja uzrokuje znak „olovke u šalici“ (crni vrh strjelice). but substantial. Male sex appeared to be a risk factor Prisutan je i edem mekih česti. for early radiographic damage while the presence of baseline radiographic damage and dactylitis develop- patients who achieved or did not achieve minimal dis- ing during follow-up could predict further destruc- ease activity (MDA) through 5 years of golimumab tion. treatment in the GO‐REVEAL trial. Golimumab treat- Jadon et al. reported on diff erences between clinical ment yielded signifi cantly higher MDA response rates characteristics of patients with PsA with PsA mutilans versus patients randomized to placebo, and achieve- (PAM) and without PAM (18). In a retrospective co- ment of MDA at ≥3 and ≥4 consecutive visits was as- hort study including 610 patients (36 of who had sociated with signifi cantly less radiographic progres- PAM), PAM cases were diagnosed with PsA at an ear- sion (measured by SvdH score). lier age, had poorer function, more prevalent nail dys- Jadon et al. also reported on prevalence as well as trophy, and more severe radiographic axial disease/ clinical and radiographic characteristics of psoriatic sacroiliitis. Th e rate of was higher in earlier spondyloarthritis (PsSpA) in PsA with ankylosing disease, and more severe in those with nail dystrophy. (AS) (21). In a combined cohort of 201 pa- Kavanaugh et al. (19) reported results from a rand- tients with PsA and 201 patients with AS from a single omized, placebo‐controlled phase III trial that evalu- centre, 24% fulfi lled the classifi cation criteria for both ated clinical effi cacy and radiographic benefi t through conditions. Th e pattern of axial disease was signifi cant- two years of ustekinumab in patients with ac- ly infl uenced by the presence of skin psoriasis and tive PsA. A total of 615 adult patients with PsA were HLA-B*27. enrolled and radiographic progression was scored us- In a recent study on 45 PsA patients (22) CR was ing the modifi ed SvdH score with modifi cations for used to establish an association between nail psoriasis PsA. Th e results showed that mean changes were nu- and DIP involvement. Th e results showed that a sig- merically lower in the ustekinumab groups than in the nifi cant proportion of PsA patients had nail involve- placebo crossover group. ment and DIP arthritis. Kavanaugh et al. recently published another paper Haroon et al. conducted a study on axial involve- (20) on evaluation of long‐term outcomes in 395 PsA ment (23), aiming to identify clinical and genetic as-

Reumatizam 2017;64(Suppl 1):43–50 45 Review paper / Pregledni rad Ivanac G. et al. Psoriatic arthritis imaging – an overview and update sociations of sacroiliitis (SI) in patients with PsA, and distribution, and Tonset (time of onset) that can be to describe the radiographic patterns of SI in PsA. Th e coded in color maps for further analysis (28). study showed that early onset of PsA, severe skin dis- For peripheral disease, T1-weighted sequences in 2 ease, peripheral joint erosions, and HLA-B*0801 are planes supplemented by a T2-weighted, fat-suppressed, signifi cantly associated with SI, whereas HLA-B*2705 or short tau inversion recovery sequences are generally only showed marginal signifi cance. In this study, HLA- performed to visualize synovitis, enthesitis, tenosyno- B*27 positive Axial-PsA patients resembled AS, while vitis, periarticular infl ammation, bone marrow , HLA-B*0801 positive Axial-PsA patients had asym- , and bone proliferation. Additional T1- metrical and/or unilateral SI, typical of PsA. weighted sequences aft er intravenous injection of a gadolinium contrast agent can aid identifi cation of in- Computed tomography fl amed tissue (4, 29, 30). MRI can aid in diff erential While CT off ers excellent imaging of bone structures diagnosis between PsA, RA, and OA. Bone marrow and is considered to be the “gold standard” in the eval- edema in PsA is frequently found close to the entheses, uation of bone, this modality is still not able to detect while in RA it is located near the capsular attachments, active infl ammation sites. Besides, there is the issue of and in OA closer to subchondral areas (4, 31). Bone the ionizing radiation exposure limit applicability of erosions are commonly located adjacent to collateral CT in routine diagnosis and management of PsA (4, 7, ligament insertions in PsA, and in OA they tend to 10). Findings of micro-CT scans of peripheral joints in have a central location (4, 32). Periostitis has been PsA patients include Ω-shaped erosions in the meta- shown to be more frequent in PsA, while bone erosions carpophalangeal joints (24), and new bone formation are more common in RA (4, 33). Bone marrow edema at entheses can be detected in both psoriasis patients and/or enthesitis in diaphyses are much more common without arthritis and PsA patients (25, 26). Regarding in PsA than in RA (4, 34). the assessment of the axial skeleton, although CT of Th ere are no specifi c defi nitions for MRI assessment the SI joints can give a satisfactory display of bone ero- of axial PsA, but defi nitions regarding SpA are available sion, sclerosis, and joint space alterations including an- (35, 36). Th e main lesions assessed are bone marrow kylosis, MRI is the preferred technique. In the assess- edema/osteitis, enthesitis, fat infi ltration, bone erosion, ment of the spine, CT is mainly used when vertebral bone proliferation, and ankylosis. Regarding the spine, fracture is suspected in PsA patients (4, 12). bone marrow edema or soft tissue edema/enthesitis, are A study by Kocijan et al. (27) evaluated bone micro- commonly seen at the anterior and posterior corners of structure and volumetric bone mineral density (BMD) the vertebral bodies, and at the costovertebral, facet, in patients with PsA and psoriasis using high-resolu- and costotransverse joints, while erosive discovertebral tion peripheral quantitative CT (HR-pQCT) scans at lesions (Andersson lesions) are less frequent but can be the ultradistal and periarticular radius. Th e study en- the fi rst sign of the disease (4, 37). rolled 50 PsA patients, 30 psoriasis patients, and 70 Yanaba et al. (38) used the PsA MRI scoring system healthy, age- and sex-related controls. Th e results sug- (PsAMRIS) (30) to evaluate the eff ects of adalimumab gest that PsA is associated with signifi cantly decreased treatment in fi ve adult Japanese male patients with ac- trabecular volumetric BMD and deterioration of tra- tive PsA. Th e study indicated that adalimumab treat- becular bone microstructure. Th e cortical BMD and ment is associated with a dramatic improvement of microstructure in PsA patients didn’t diff er from the enthesitis, whereas bone erosions may be resistant to control group, in contrast with current fi ndings in RA. such treatment. Also, the duration of skin disease was associated with Zubler et al. (39) compared MRI fi ndings of the fore- trabecular bone loss in PsA patients, a fi nding support- feet in 31 healthy volunteers, 30 patients with sympto- ing the concept of subclinical musculoskeletal disease matic RA, and 30 patients with symptomatic PsA, to in psoriasis patients. identify MRI patterns of RA or PsA. Mild bone mar- row edema was a common fi nding, and tenosynovitis Magnetic resonance and joint eff usion were occasional fi ndings in healthy MRI allows high-resolution imaging of all structures volunteers. Tenosynovitis and soft -tissue edema were involved in arthritis, and is sensitive for peripheral and more frequently observed in patients with PsA, while axial disease manifestations (4). Today, all joints can be other arthritis-like fi ndings on MRI were similar in pa- evaluated with similar effi cacy, and the technique is tients with RA and PsA. suffi ciently standardized (7). Dynamic contrast-en- hanced MRI in combination with current soft ware of- Ultrasound fers acquisition of quantitative data about infl amma- Ultrasound (US) provides feasible, high-resolution tory processes, such as: ME (maximum enhancement), visualization of all structures involved in peripheral ar- IRE (initial rate of enhancement), GD (gadolinium) thritis, and is sensitive for peripheral disease manifes-

46 Reumatizam 2017;64(Suppl 1):43–50 Ivanac G. et al. Psoriatic arthritis imaging – an overview and update Review paper / Pregledni rad

Figure 3 US imaging of the interphalangeal joints in the hand of an 85-year-old male patient with PsA. Longitudinal scan (a) and transversal scan (b) show periarticular calcifi cations, some (asterisks), and soft tissue swelling. Power-Doppler scan verifi es increased vascularization in the extensor tendon (white arrow) and synovial membrane (black arrow). Slika 3. UZ pregled interfalangealnih zglobova šake stopala 85-godišnjega muškog pacijenta sa PsA. Uzdužni (a) i poprečni (b) prikaz pokazuju periartikularne kalcifi kacije i nekoliko osteofi ta (zvjezdice) te edem mekih česti. Prikaz Power Dopplerom potvrđuje pojačanu vaskularizaciju u području tetive ekstenzora (bijela strjelica) i u sinovijskoj membrani (crna strjelica). tations, but is not recommended for the assessment of tients with or without musculoskeletal symptoms (44). axial involvement (4). Th e current European League Data were obtained from 340 entheses in 34 patients. Against Rheumatism (EULAR) recommendations on At baseline, US abnormalities were found in 97.1% of the use of imaging techniques encourage the use of US the total population and in 86.4% of the asymptomatic in chronic arthridides (12, 40), and over recent years patients. At 6 months under systemic treatment, US research has proved US to be valid, sensitive, and reli- morphological abnormalities were likely to improve. able in the assessment of synovitis, tenosynovitis, and Lin et al. (45) aimed to compare high-frequency ul- enthesitis, including anatomical damage (bone and/or trasound (HFU) fi ndings in the fi ngers with PsA and tendon erosions) in patients with RA or PsA (Figure RA and to explore the potential use of HFU in the ear- 3). Moreover, there are also promising results regard- ly diagnosis of PsA. Th e study enrolled 44 PsA and 39 ing its prognostic value (41, 42). Because an US wave RA patients, and 20 healthy individuals. Th e results cannot penetrate bones, the technique is less sensitive suggested that HFU is valuable in the detection of soft than MRI and CT for diagnosing bone erosions and tissue infl ammation and enthesitis in the fi ngers of PsA unable to diagnose osteitis (4). US fi ndings in clinical or subclinical synovitis are nonspecifi c and the diag- patients, and that it may be an easy, safe, and eff ective nostic value lies in recognizing the joint infl ammation examination method in the early diagnosis of PsA as (4, 12). US diagnosis of enthesitis has received a lot of well as in the observation of related pathological scientifi c attention lately. Th e hallmark lesions of en- changes. thesitis are (a) chronic changes: presence of entheso- Michelsen et al. conducted a cross-sectional study phytes, calcifi cations, and erosions at the insertion site involving 141 PsA outpatients to investigate the asso- and (b) infl ammatory changes: increased thickness, ciation between clinical and ultrasonographic (US) hypoechogenicity, and Doppler activity in the enthesis evidence of infl ammation in psoriatic arthritis (PsA), (4, 43). An example of US imaging in PsA is shown in as well as to compare clinical and US remission criteria Figure 3. (46). Th e Disease Activity Index for PSoriatic Arthritis Acquacalda et al. conducted a study on the preva- (DAPSA) and 28-joint Disease Activity Score (DAS28) lence of ultrasonographic enthesitis in psoriasis pa- refl ected US fi ndings better than the Composite Psori-

Reumatizam 2017;64(Suppl 1):43–50 47 Review paper / Pregledni rad Ivanac G. et al. Psoriatic arthritis imaging – an overview and update atic Disease Activity Index (CPDAI) and Psoriatic Ar- outcomes in PsA patients on intensifi ed antirheumatic thritiS Disease Activity Score (PASDAS). MDA was treatment. fulfi lled in 22.7% and the clinical remission criteria in 5.7%–9.9% of the patients. US remission (no Power Other modalities Doppler activity in all examined joints, enthuses, and Other modalities, such as PET-CT and scintigraphy, tendons) was found in 49.6% of the patients. Minimal are rarely used in clinical practice, but are an impor- disease activity (MDA), DAPSA, and Boolean’s remis- tant focus of clinical research. Th e authors have found sion criteria predicted US remission. articles on use of PET-CT in the detection of asympto- Fiocco et al. have recently investigated contrast-en- matic enthesitis in psoriasis patients, which could be a hanced US (CEUS) imaging with histopathological prognostic factor of the onset of psoriatic arthritis (54). and immunohistochemical quantitative estimation of Another group investigated the role of PET-CT in the microvascular proliferation on synovial samples of pa- assessment of disease activity in PsA and RA (55). A tients aff ected by PsA (47) and investigated a possible group of authors from Italy off ered a novel approach to association with the frequencies of pathogenic T help- the assessment of peripheral PsA, using functional in- er (Th )-17 cells in PsA joints in eight patients (48). Th e frared imaging (fIRI) with promising results (56). results indicate that CEUS can truly measure synovial infl ammation, and could be a useful tool to develop a Conclusion quantitative imaging biomarker for monitoring target PsA is an infl ammatory joint disease that is similar therapeutics in PsA. to RA but can be easily distinguished from it upon a Cozzi et al. (49) used CEUS to to assess synovial in- closer inspection. It usually shows a specifi c pattern of fl ammation in hand joints and evaluate the eff ects of joint involvement: peripheral joints with an asymmet- mud-bath therapy on the clinical picture of PsA pa- ric pattern and the axial skeleton are most commonly tients treated with TNF inhibitors. Th eir results sug- aff ected. Th e clinical diagnosis relies heavily on imag- gest a decrease of residual synovial infl ammation and a ing fi ndings. Typical fi ndings result from a combina- benefi cial clinical eff ect of spa therapy in PsA patients tion of erosive and proliferative bone changes and in- treated with TNF inhibitors. fl ammatory changes in the synovia, tendons, and en- A study by Bandinelli et al. (50) has shown that US theses. Various imaging methods have a role in PsA abnormalities of the hand and wrist were independent diagnosis, but CR and US are mostly used due to their of early clinical PsA indices (except erosions), while feasibility and relatively low cost. Th ere is an increasing they correlated to dermatological (except PASI), sero- interest among researchers in the investigation of new logical, and genetic parameters of disease. possibilities in PsA diagnosis and follow-up of patients Janta et al. (51) compared clinical and musculoskel- using both conventional US and CEUS. etal (MS) US features between PsA patients treated with full and tapered dosages of biologic (b) disease- Conflict of interest statement: Th e authors have no modifying antirheumatic drugs (DMARDs). Th e sec- confl ict of interest. ondary objective was to compare clinical and MSUS Izjava o sukobu interesa: Autori izjavljuju da nisu u features between PsA patients treated with bDMARDs sukobu interesa. with and without concomitant synthetic (s) DMARDs. Th e presence of B-mode and Doppler synovitis, teno- synovitis, enthesopathy, and paratenonitis was investi- LITERATURE gated. No signifi cant diff erences were found between 1. Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum. clinical, laboratory, and US variables, both for BM and 1973;3(1):55–78. CD, between patients with full and tapered dosages 2. Gladman DD. 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