FormalPara Key Summary Points

Misclassification of spondyloarthritis (SpA) as rheumatoid arthritis (RA) can lead to delayed diagnosis and treatment and poor outcomes for patients with SpA.

This study evaluated the literature for clinical manifestations of SpA and RA to understand the potential overlap, distinction, and most reliable approaches for accurate diagnosis.

Clinical manifestations observed exclusively in SpA included psoriasis, nail psoriasis, and dactylitis.

Advanced imaging techniques, such as ultrasonography and magnetic resonance imaging, provided a more accurate distinction between SpA and RA.

While SpA manifestations were observed among patients with RA, improvement and standardization of imaging protocols can positively impact clinical outcomes and quality of life.

Introduction

Spondyloarthritis (SpA) refers to a group of chronic, inflammatory diseases that includes axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA), as well as other peripheral types of SpA including enteropathic arthritis, reactive arthritis, and undifferentiated SpA [1, 2]. AxSpA predominantly involves inflammation of the sacroiliac joints and spine; inflammation of the spinal vertebrae, connective tissue, and joints causes chronic back pain and may eventually lead to the fusion of vertebral units [1]. AxSpA with radiographic sacroiliitis is termed radiographic axSpA, also known as ankylosing spondylitis (AS), and fulfills the definition of AS based on the 1984 modified New York criteria and the 2009 Assessment of SpondyloArthritis international Society criteria for radiographic axSpA [3]. Conversely, axSpA without radiographic sacroiliitis, which does not meet the modified New York criteria for AS, can be subclassified as nonradiographic axSpA [3]. The prevalence of axSpA ranges from 0.9 to 1.4% in the US adult population [4]. However, the true disease prevalence is not known, partly due to the significant delays in diagnosis and recognition; recent reports indicate a mean diagnostic delay of 6.7 years [5]. Challenges in distinguishing inflammatory back pain (IBP), a key symptom of axSpA that affects the spine and sacroiliac joints, from other forms of low back pain in the general population are a primary contributor to delay or lack of diagnosis, especially among patients without definitive radiographic sacroiliitis [4]. AxSpA is associated with substantial physical, economic, and emotional liabilities [4].

PsA has a prevalence of approximately 100–200 per 100,000 in the general adult population and an incidence rate of 3.6–7.2 per 100,000 patient-years [6]. PsA manifests with axial disease, peripheral joint inflammation, enthesitis, dactylitis, and skin and nail psoriasis, either alone or in combination [7]. A PsA diagnosis delayed by as few as 6 months may be associated with worse peripheral joint erosions, progressive joint damage, and substantial physical limitations [7].

Rheumatoid arthritis (RA), with an estimated global age-standardized point prevalence and annual incidence rate of 246.6 and 14.9 per 100,000 population, respectively, is characterized by pain, swelling, and stiffness in multiple joints [8]. Disability is common and substantial; in a large US study, 35% of patients with RA had employment-related disability after 10 years [9]. Prompt diagnosis and treatment are associated with improved clinical and radiographic outcomes, as well as the probability of remission; diagnosis delays beyond 3 months may be detrimental [10].

Infiltration of the joint synovia with inflammatory cells and cellular mediators (cytokines) is the hallmark of arthritis in both RA and SpA [11]. Resultant lytic destruction of bone and cartilage follows in both RA and SpA; in SpA, there are also areas of bony proliferation and ankylosis [12]. Inflammation of ligament and tendon insertions into bone (enthesitis) and bone itself (osteitis) are also characteristic pathologies of SpA [1, 2]. However, several key factors distinguish SpA from other types of arthritis, including the distribution and type of musculoskeletal manifestations and particular extra-articular features, as well as genetic associations and structural outcome [12]. Joint damage in RA comprises widespread destruction with minimal or no indications of repair; in AS, damage to the spine or joint is usually accompanied by remodeling [12]. The pathophysiology of chronic inflammatory diseases is rooted in the interaction network of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1, IL-6, IL-17, and IL-23 [13]. For many patients with inflammatory conditions such as RA and SpA, their response to inhibitors of these inflammatory cytokines may differ, suggesting a disease-dependent, hierarchical cytokine effect [13]. Ongoing studies implicate TNF-α, IL-1, and IL-6 in RA pathology and TNF-α, IL-17, and IL-23 in SpA [13]. Thus, correct diagnosis is important when steering the patient toward appropriate therapies.

As many patients with axSpA, PsA, and RA initially seek medical care from primary care physicians or other nonrheumatology healthcare providers, correct and prompt diagnosis is variable and often delayed. Numerous recommendations and guidelines exist to promote early rheumatology referrals [14,15,16]. Early diagnosis and treatment before irreversible changes occur are crucial for optimal disease management and improved patient quality of life. Diagnostic algorithms for axSpA [1], PsA [17], and RA [18] are available as a guide for rheumatologists in their clinical assessments. Overall, diagnosis relies on clinical judgement of features that are characteristic of each disease spectrum, including the patient’s history of symptoms and manifestations, physical findings, laboratory workup, and imaging information. However, overlap in clinical manifestations of inflammatory rheumatic diseases, particularly early in the disease course, may lead to misdiagnosis. Thorough evaluation of disease presentations is crucial to guide decisions pertaining to treatment and patient care. This systematic review assesses the available evidence on overlapping clinical manifestations associated with axSpA, PsA, and RA to better understand whether disease misclassification, and therefore delayed diagnosis, may occur.

Methods

Data Sources

This systematic literature review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines [19]. We searched the MEDLINE Literature Analysis and Retrieval System Online (including MEDLINE In-Process), Excerpta Medica (Embase), BIOSIS Previews, and Evidence-Based Medicine Reviews databases for original research articles (up to July 23, 2020) reporting studies on clinical manifestations of SpA and RA. The list of search terms is provided in Table S1. Additionally, abstract archives of the American College of Rheumatology/Association of Rheumatology Health Professionals Annual Meeting and the European League Against Rheumatism Annual European Congress of Rheumatology were searched (January 1, 2018–July 31, 2020) to identify abstracts not yet indexed in the aforementioned biomedical databases at the time of the search. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Eligibility Criteria and Article Selection

Eligible records for inclusion were English-language, noninterventional, original research studies of adult patients that either included both RA and SpA or seropositive and/or seronegative RA as major populations and that also reported SpA-related clinical manifestations. The key inclusion and exclusion criteria are described in Table 1. Abstracts of all records retrieved from the literature search were screened for eligibility by two independent reviewers; discrepancies were reconciled by a third.

Table 1 Details of systematic literature review methodology
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Data Extraction and Quality Assessment

Data from the final list of included publications were extracted by one reviewer and validated by a second independent reviewer; any discrepancies were resolved by a third reviewer. For each record, the study title, year of publication, study design, total study population, objective, inclusion/exclusion criteria, baseline patient data, outcomes assessed, and authors’ conclusions were extracted. Baseline patient data collected included age, sex, geographic region, race/ethnicity, proportion of patients with rheumatoid factor (RF) and anticyclic citrullinated peptide (anti-CCP) expression, and disease and symptom duration. Outcomes extracted comprised current and historical SpA-related clinical manifestations, imaging, laboratory tests, and disease activity measures. Clinical manifestation outcomes included oligoarthritis, polyarthritis, IBP, peripheral arthritis, enthesitis, uveitis, dactylitis, psoriasis, nail disease (psoriatic nail psoriasis or nail psoriasis), inflammatory bowel disease (specifically Crohn’s disease and ulcerative colitis), and good response to nonsteroidal anti-inflammatory drugs. Imaging outcomes consisted of sacroiliitis on imaging, active (acute) inflammation on magnetic resonance imaging (MRI) suggestive of sacroiliitis, definitive radiographic sacroiliitis, structural damage, hip involvement, and spinal deformities. Laboratory tests comprised HLA-B27 expression and elevated C-reactive protein (CRP) levels. Subjective measures of disease activity included physician global assessment (PGA); patient-reported outcome (PRO) measures were pain and fatigue on a visual analog scale such as patient global assessment (PtGA) of disease activity.

The procedural quality of each publication was evaluated using the Downs and Black Quality Index for evaluating risk of bias [20]. Briefly, study methodology was assessed using 26 questions examining the characteristics of study reporting, external validity, and internal validity (bias and confounding) (Table S2). The total possible score on the Downs and Black scale was 27, with higher numbers indicating higher methodological quality or lower risk of bias.

Results

Study Selection, Characteristics, and Quality Assessment

The initial search yielded 4712 records, from which 79 unique studies were identified for inclusion after screening (Fig. 1) [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99]. Of these, 54 included study populations with RA and SpA [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74], and 25 included study populations with seropositive and/or seronegative RA [75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99]. SpA-related outcomes or manifestations reported in included studies assessed by clinical examination and/or imaging comprised peripheral arthritis [21,22,23,24,25,26,27,28, 30,31,32,33,34,35,36, 38,39,40,41,42, 45,46,47,48,49,50,51,52, 57,58,59,60,61,62,63, 66, 68, 71, 72, 74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99], polyarthritis [22, 33, 36, 78, 79], and oligoarthritis [22, 33], enthesitis or enthesopathy [22,23,24,25,26,27,28,29, 31,32,33, 36, 44, 45, 47,48,49, 54,55,56, 60, 63, 66, 67, 69, 71, 72, 75, 84], psoriasis [21,22,23, 25, 26, 30, 59, 70, 74], dactylitis [21, 27, 33, 36, 46, 55, 71,72,73], nail psoriasis [21, 23, 28, 54, 59, 72], axial disease (IBP [25, 26, 32, 33, 38, 48, 55, 61,62,63, 69], spinal deformities [33, 37, 38, 43, 51, 64, 90], hip involvement or damage [35, 47, 64, 90], and sacroiliitis [43, 55, 90]), extra-articular manifestations (uveitis [53, 55, 70] and inflammatory bowel disease [70, 74]), and laboratory measures (HLA-B27 positivity [24,25,26, 53, 55, 65, 69, 78] and elevated CRP levels [21, 34, 46, 47, 49, 65, 76, 89, 99]). Other data reported included PROs (pain [30, 34, 38, 40, 46, 57, 61, 76, 98], fatigue [30, 38, 98], and PtGA of disease activity [30, 34, 38, 61, 62, 77, 81, 98]), and PGA of disease [30, 38, 62, 77, 81]. Imaging methods used across included studies comprise ultrasonography [21,22,23, 25, 26, 28, 29, 31, 32, 34, 39, 44, 47, 48, 50, 54,55,56, 59, 66, 67, 69, 71, 72, 74, 75, 82, 84, 85], classic radiography (i.e., X-ray) [29, 33, 36, 40, 45, 46, 51, 56, 68, 75,76,77,78,79,80, 83, 86, 89, 93, 95, 99], computed tomography [43], and MRI [24, 27, 37, 41, 47, 49, 57, 60].

Fig. 1
figure 1

PRISMA diagram for article selection. PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses, SLR systematic literature review

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Study characteristics are described in Table 2. The 79 included analyses, published between 1997 and 2020, were conducted in Europe (n = 47), North America (n = 11), Asia (n = 8), Africa (n = 4), South America (n = 1), and combined populations across multiple geographical regions, including Europe, Asia, North America, North Africa, and Oceania (n = 8). Of those studies reporting information on study design and setting, most were prospective cohort (n = 41) or cross-sectional (n = 21) studies in single (n = 31) or multicenter (n = 19) settings, comprising a study population of 35–117,794 patients with SpA and RA. Across all studies, the proportion of men with SpA and RA (both seropositive and seronegative) ranged from 17.4 to 87.5% and from 6.7 to 68.2%, respectively. Included patients with SpA and RA (both seropositive and seronegative) had a mean age of 30.9–54.5 years and 41.6–67.3 years, respectively, and a mean disease duration of 8.0–1083.6 months and 2.5–192.0 months, respectively.

Table 2 Characteristics of articles reporting SpA manifestations among patients with SpA and RA
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The methodological quality of each study included in the analysis is described in Table S3; the overall scores on the quality index ranged from 9 to 15 (index range 0–27). For questions assessing study reporting, scores ranged from 5 to 8 (index range 0–11), with most studies (n = 59) having a score ≥ 7. For questions assessing external validity, scores ranged from 0 to 2 (index range 0–3); most records had a score of 0. For questions assessing internal validity (bias), scores ranged from 2 to 5 (index range 0–7), with 53 studies having a score of 4. Lastly, for questions assessing internal validity (confounding–selection bias), scores ranged from 1 to 3 (index range 0–6), with most studies (n = 73) having a score of 1. For questions relating to internal and external validity, “unable to determine” and “no” responses were both scored as 0, which lowered the overall validity scores of included studies. Notably, some of the questions in the Downs and Black checklist are relevant only to interventional studies, which were excluded from this review; therefore, this may have contributed to lower checklist scores for studies included in this review.

Clinical Manifestations and Outcomes in SpA vs. RA

Peripheral Arthritis

Overall, 65 studies reported data on peripheral arthritis (Fig. 2). Key outcomes included findings from both clinical examination (Clinical Disease Activity Index, Disease Activity Score in 28 joints [DAS28], swollen joint count, tender joint count, morning stiffness, grip strength, and synovial biopsy by needle arthroscopy) and imaging (synovitis by imaging, joint effusion, joint space narrowing, periostitis, erosion, periosteal inflammation on MRI, bursitis, joint osteolysis, juxta-articular new bone formation, and bone cyst formation). A total of 26 studies evaluated peripheral arthritis as a primary focus of their study, making comparisons among patients with SpA and RA; of these, only two concluded that there were no differences between SpA and RA based on MRI [41] and ultrasonographic and MRI [47] findings (Table 3). In general, the frequency of presence or absence of peripheral arthritis was relatively equal among patients with SpA and RA. However, several studies noted specific anatomical sites that were more prominently affected by SpA than RA. Ottaviani and colleagues reported ultrasound findings indicating that patients with SpA had a higher frequency of acromioclavicular joint synovitis than those with RA, as well as lower occurrence of subacromial and subdeltoid bursitis, glenohumeral effusion, and humeral bone erosion [25]. Office extremity MRI revealed that periosteal inflammation at the first interphalangeal joint was exclusively present among patients with PsA vs. RA, whereas synovitis in the metacarpophalangeal (MCP) joint was observed more frequently among patients with RA vs. PsA [27]. At baseline, tibiotalar joint synovitis was observed significantly more frequently in patients with SpA and gout by ultrasound vs. those with RA and reactive arthritis; after 1 year, tibiotalar joint synovitis was observed more frequently in the RA group than in the SpA, gout, and reactive arthritis groups [48]. Subtalar and talonavicular joint synovitis were observed more frequently in the early RA group than in the SpA, gout, and reactive arthritis groups [48]. Ultrasound findings of synovitis and erosions at the distal interphalangeal joints were exclusively observed in PsA vs. RA, and joint effusion was frequently seen at radiocarpal and midcarpal joints in RA vs. PsA [66]. Effusion at the third proximal interphalangeal (PIP) joint was detected more significantly in PsA than RA [66]. A registry analysis revealed similarities with regard to swollen joint count and tender joint count among patients with seronegative RA and SpA [30]. Of note, Figus and colleagues highlighted that although clinical examinations showed no differences between RA and PsA, ultrasound studies detected significant score differences in joint effusion, synovial hypertrophy, Doppler signal, II MCF, and wrist between oligoarticular PsA and RA, but no differences were observed between polyarticular PsA and RA [50].

Fig. 2
figure 2

Summary of the number of studies reporting SpA clinical manifestations and the authors’ conclusions regarding the feasibility of distinguishing between SpA and RA populations. IBP inflammatory back pain, PRO patient-reported outcome, RA rheumatoid arthritis, SpA spondyloarthritis

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Table 3 Summary of SpA manifestations among patients with SpA and RA, and authors’ conclusions regarding the feasibility of differentiating the two diseases
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Enthesitis

A total of 29 studies reported data on enthesitis or enthesophytes (Fig. 2). Suboutcomes included tenosynovitis, pulley inflammation, soft tissue or bone marrow edema, entheseal erosion, and inflammation of the tendon or peritendon. Overall, 23 studies focused their evaluation on enthesitis, comparing imaging findings among patients with SpA and RA. Of these, only three concluded that there were no differences in this manifestation among patients with SpA vs. RA based on ultrasonographic [26, 32] and both ultrasonographic and MRI [47] findings (Table 3). In general, enthesitis on imaging was found almost exclusively in patients with SpA (particularly PsA) vs. RA, with few exceptions. Batticciotto and colleagues reported that significantly more patients with early RA had erosions in ≥ 1 MCP joint as visualized by ultrasound than those with early SpA, and significantly more patients with early SpA showed paratenonitis of the extensor tendons in ≥ 1 finger than those with early RA [44]. Tibialis posterior tenosynovitis appeared to be more specific for RA, whereas Achilles’ tendonitis was more frequent in axSpA and reactive arthritis [48]. Ahmed and colleagues reported that tenosynovitis was observed more frequently at the extensor tendons among patients with RA than those with PsA and at the flexor tendons in patients with PsA than those with RA [66]. While examining extrasynovial changes indicative of enthesitis by ultrasound, Fournié and colleagues described pseudotenosynovitis, characterized by diffuse inflammation of the digital soft tissue, in the fingers of patients with PsA; they conclude that pseudotenosynovitis may play a role in the development of dactylitis [28]. Of 34 patients with SpA who underwent careful clinical (i.e., physical) examination by an independent examiner, 88 of 612 entheses (14%) were deemed clinically abnormal in 21 patients (62%); however, with ultrasound imaging, 220 entheses (36%) were considered abnormal in 32 patients (94%) [55].

Psoriasis and/or Nail Psoriasis

Overall, 15 studies reported data on psoriasis and/or nail psoriasis (Fig. 2). Three focused their analyses on this clinical manifestation, comparing them among patients with PsA and RA; all three studies concluded that psoriasis and/or nail psoriasis occurred exclusively in patients with PsA vs. RA (Table 3) [23, 54, 59]. Of patients initially diagnosed with early seronegative RA, 25% were reclassified as having early PsA after presenting with cutaneous or nail psoriasis upon further rheumatology–dermatology evaluation [23]. One patient initially presented with seronegative oligoarthritis, and a diagnosis of PsA was suspected because of a family history of psoriasis; this patient was then formally diagnosed with PsA with the subsequent development of skin lesions [24].

IBP

Overall, 11 studies reported data on IBP (Fig. 2). Key outcomes assessed included Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index. Only one study evaluated IBP as a primary focus of the investigation (Table 3)—patients with axSpA had significantly higher Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index scores than those with RA [38].

Dactylitis

A total of nine studies reported data on dactylitis (Fig. 2). Three studies focused their evaluation on dactylitis among patients with PsA and RA; of these studies, the authors reported that dactylitis occurred exclusively in patients with PsA vs. RA (Table 3) [21, 33, 73].

Spinal Deformities

A total of seven studies reported data on spinal deformities (Fig. 2) [33, 37, 38, 43, 51, 64, 90]. Sub-outcomes included vertebral fractures and spinal pain and stiffness (Table 3). Overall, of three publications that evaluated spinal deformities as a primary focus of study, comparing this manifestation among patients with SpA and RA, only one study used imaging (computed tomography) and concluded that there were no differences between patients with SpA vs. RA [43].

Hip Involvement or Damage

A total of four studies reported data on hip involvement or damage (Fig. 2) [35, 47, 64, 90], two of which focused their evaluation on erosions and risk of fractures as a primary endpoint (Table 3). Neither study was able to differentiate between patients with SpA and RA with regard to this manifestation [47, 64].

PROs and Other Clinical Manifestations

Other manifestations evaluated included various PROs (pain, fatigue, PtGA, and Health Assessment Questionnaire), PGA, hand and grip strength, uveitis, CRP levels, erythrocyte sedimentation rate, DAS28, oligoarthritis, and body composition (Fig. 2). There were no studies that solely focused on differences in PROs between patients with SpA and RA; however, of the ten studies that incorporated PROs and other outcomes in their analyses among patients with SpA and RA, one concluded that there was no difference in PGA and PtGA among those with RA and AS (Table 3) [62]. Patients with PsA had significantly increased body mass index, waist circumference, and hip circumference vs. those with seropositive RA but not seronegative RA [35]. Anterior uveitis was exclusively observed in patients with AS vs. RA [53]. Patients with RA presented with worse mean hand grip strength than those with PsA [42, 58].

Clinical Manifestations and Outcomes in Seropositive and/or Seronegative RA vs. SpA

Of 25 studies comparing patients with seropositive and/or seronegative RA vs. SpA, only two studies concluded that no significant differences in RA disease activity can be delineated based on serostatus or in relation to SpA as measured by ultrasound, DAS28 [82], and histology [96] scores (Table 3). In general, although seronegative RA appeared to be milder in disease severity, pain, and discomfort than seropositive RA, Cappelli and colleagues reported that CCP− was significantly associated with greater fatigue, which persisted after adjusting for age, sex, race, and swollen joints [98]. MCP, PIP [79], and ankle [89] joints were more frequently involved in seropositive than seronegative patients. In a cross-sectional study comparing patients with seronegative RA with those who had seropositive RA, patients with AS, or healthy controls, more patients with seronegative RA presented with enthesopathy findings than those with seropositive RA. However, patients with AS had significantly higher findings of enthesopathy (e.g., bone erosion at the common extensor tendon, calcification of the Achilles’ tendon, and erosion at the triceps tendon) than those with seronegative RA [31]. In another cross-sectional study by Zabotti and colleagues, prevalence of peritendon inflammation indicative of enthesitis was significantly more common in patients with early PsA compared with those with seronegative RA (36 vs. 8%; P = 0.006) [23].

Discussion

Various overlapping clinical characteristics, both temporary and persistent, occur in SpA and RA, including inflammation and destruction of joints, pain, diminished functional ability, and increased risk for comorbidities; these overlapping clinical manifestations are mainly related to peripheral—and not spinal—manifestations. While the ASAS axial and peripheral SpA classification criteria do attempt to make this distinction, classification is not limited to those purely with axial or peripheral manifestations, which may contribute to likely reasons for misclassification of disease. Among patients with milder symptoms, negative serology, or those lacking definitive clinical signs, especially early in the disease course, determining the type of inflammatory arthritis may be challenging. In our analysis, we noted differences in the occurrence of SpA manifestations, not only among patients with SpA vs. RA, but also among those with early vs. late RA and by RA serostatus. Timelier and more comprehensive evaluation, especially aided by use of imaging techniques to evaluate peripheral manifestations such as enthesitis and peripheral arthritis, may reduce disease misclassification and inappropriate treatment.

The majority of the 79 studies reported on peripheral arthritis and enthesitis. Of 54 studies comparing SpA and RA study populations, only seven studies concluded that no distinction can be made between SpA and RA based on the SpA manifestations and outcomes examined [26, 32, 41, 43, 47, 62, 64]. Of 25 studies comparing patients with seropositive and seronegative RA, only two concluded that no significant differences in RA disease activity can be delineated based on serostatus [82, 96]. Although peripheral arthritis reportedly occurred at a similar frequency among patients with SpA and RA, distinct anatomical sites were involved [25, 27, 48, 66]. Two studies concluded that no distinction can be made between SpA and RA with regard to peripheral arthritis based on MRI [41] and ultrasonographic and MRI findings [47]. In their study, Cimmino and colleagues focused exclusively on the comparison of the degree of synovitis in the wrists of patients with PsA and RA using a low-field extremity-dedicated MRI device after accounting for disease activity [41]. The authors postulated that more sophisticated quantification tools may expose greater details of synovitis, allowing for better distinction of inflammation in SpA vs. RA; accordingly, in a later MRI study, they reported that the volume of inflammation was significantly higher in RA than PsA for two of three extensor compartments and in the joint synovial membrane [57]. In our analysis, enthesitis occurred almost exclusively among patients with SpA vs. those with RA, although three studies concluded that no distinction can be made between these two conditions based on ultrasonographic [26, 32] and both ultrasonographic and MRI findings [47]. As similar Madrid Sonographic Enthesitis Index [26] and Glasgow Ultrasound Enthesitis Scoring System [32] scores were noted among patients with RA and those with SpA, it may be interesting to follow up and observe the RA cohorts for the development of SpA because enthesopathy is a key SpA feature [100]. Psoriasis or nail psoriasis, IBP, dactylitis, and uveitis occurred exclusively among patients with SpA vs. RA. Based on PRO measures, the burden of disease was relatively equal between SpA and RA. While some studies did examine HLA-B27 as a laboratory measure in their patient population [24,25,26, 53, 55, 65, 69, 78], no comparisons were made between SpA and RA. As genetic and other biomarker assays become more validated as diagnostic tools to differentiate between specific disease states, this will hopefully address and potentially resolve some of the challenges associated with diagnosis highlighted here.

Technological advances in the development of more sophisticated imaging modalities and novel therapeutic interventions have greatly enhanced clinical practice with regard to disease detection, diagnosis, and management. The inclusion of imaging as a part of early diagnosis and differentiation of inflammatory arthritis underscores its significance, especially because similarities in synovitis and joint involvement and inflammation may be observed in SpA and RA [1, 17, 18]. In our analysis, ultrasonography and MRI were instrumental in detecting subclinical synovitis, entheseal inflammation, bone erosions, and bone marrow edema; in addition, two studies reported significant ultrasound findings that differentiated RA and SpA when routine clinical examinations could not [50, 55]. These reports may compel clinicians to pursue further investigation using advanced imaging modalities when presented with patients early in their course of inflammatory arthritis. Indeed, the role of imaging is multifaceted; in various clinical studies, imaging techniques may play a key role in ascribing the proper treatment course to patients based on diagnostic or prognostic information and in tracking treatment effectiveness and complications. Accordingly, imaging features such as flexor tenosynovitis, bone erosion, and regional inflammation beyond the joint may be indicative of early SpA development and pathophysiology. Consequently, biologic interventions approved for SpA may be prescribed for these patients to address their symptoms. A delay in accurate diagnosis and initiation of appropriate treatment confers substantial burden on patients and may result in increased healthcare costs [4, 7, 10].

Limitations

Various diagnosis criteria and outcome measures were used to classify and assess patients with SpA and RA, which may contribute to the heterogeneity of study populations among the studies. As most of the studies included in this review were conducted across Europe and Asia, the results may not be representative of all patients or healthcare systems. Advanced imaging modalities may not be widely available for use in clinical practice, especially among rural practices or medically underserved populations. Along with the limited number of studies with higher methodological quality and small patient population, these limitations precluded meaningful meta-analysis for the outcome measures assessed; thus, the results of our systematic literature review are descriptive in nature.

Conclusions

Overall, SpA manifestations were observed among patients with RA, especially those with early or seronegative disease, suggesting that misclassification could occur. The use of imaging may allow for a timely and thorough assessment of subclinical manifestations in SpA and RA, thus reducing misdiagnosis and inappropriate treatment. As effective, but not always overlapping, therapies for SpA and RA are available, imaging tools can be critical for accurate diagnosis and subsequent appropriate disease management. As next steps, the improvement and standardization of imaging protocols and interpretation can be undertaken to positively impact clinical outcomes and quality of life.