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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. REFERENCES

Objective

To investigate whether patients with idiopathic recurrent acute anterior uveitis (AAU) have enthesis alterations comparable with those in patients with spondylarthritis (SpA).

Methods

A blinded, controlled study of enthesis evident on ultrasound (US) examination was performed in 100 patients and controls classified into 5 groups, as follows: patients with confirmed SpA (group 1), patients with recurrent AAU who were positive for HLA–B27 and did not have SpA (group 2), patients with recurrent AAU who were negative for HLA–B27 and did not have SpA (group 3), patients with forms of uveitis other than those related to SpA (group 4), and healthy controls (group 5). In total, 12 enthesis locations were explored in each patient and control subject by 2 ultrasonographers who were blinded with regard to the diagnosis. A newly developed US method, the Madrid Sonography Enthesitis Index (MASEI), in which the diagnosis of SpA is determined as a cutoff score of 18 points, was used.

Results

A total of 1,200 entheses were explored by US in 100 patients and controls. The MASEI cutoff limit was met or exceeded by 81%, 55.6%, 40%, 10%, and 19% of the subjects in the 5 groups, respectively. The MASEI score was significantly higher in groups 1 and 2 than in groups 4 and 5. The differences between groups 1 and 3 were also found to be significant.

Conclusion

Our findings indicate that a high percentage of HLA–B27–positive patients with idiopathic recurrent AAU without features of SpA have enthesis lesions comparable with those seen in patients with SpA. These data suggest that patients with recurrent AAU, especially those who are HLA–B27 positive, have an abortive or incomplete form of SpA.

Eye inflammation can be a prominent feature of several autoimmune diseases; in fact, it may be the key manifestation of a previously undiagnosed disease. Recurrent acute anterior uveitis (AAU) is present in up to 40% of patients with spondylarthritis (SpA). Conversely, ∼50% of AAU cases are idiopathic, regardless of their association with HLA–B27 (1). Some authors have suggested that recurrent AAU in patients who are positive for HLA–B27 should be included as a part of the spectrum of SpA (2); however, many of these patients never develop the clinical symptoms of SpA.

Inflammatory involvement of the enthesis, a characteristic feature of SpA, is regarded as the primary lesion in the disease (3, 4). Ultrasound (US) detection of enthesitis is more sensitive and more specific than clinical examination, and furthermore, it is reproducible (5–7). Recently, we developed a US enthesis score known as the Madrid Sonography Enthesitis Index (MASEI) (8). This score has a sensitivity, specificity, positive predictive value, and negative predictive value of 84%, 80.77%, 82.76%, and 85.71%, respectively, for the diagnosis of SpA independent of the presence of other clinical manifestations (8). This index bilaterally assesses 6 enthesis locations in each patient. Enthesis thickness, structure, calcifications/cortical bone proliferation, erosions, bursa inflammation, and power Doppler signal are scored in the cortical bone profile, tendon, and bursa.

In the present study, we used the MASEI score to investigate whether patients with idiopathic AAU had enthesis alterations evident on US that were comparable with those seen in SpA despite the absence of clinical manifestations of enthesis.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. REFERENCES

Patients.

This blinded, controlled, cross-sectional, transverse study was conducted in 5 groups of subjects. The study was approved by the Ethics Committee of the La Paz Hospital. Informed consent was obtained from all subjects.

Group 1 (n = 21) patients were the disease control group. It was composed of patients who fulfilled the European Spondylarthropathy Study Group (ESSG) criteria for the classification of SpA (9), including those who fulfilled the modified New York criteria for ankylosing spondylitis (AS) (10). This group included 13 patients with AS, 5 with undifferentiated SpA, 2 with psoriatic arthritis, and 1 with reactive arthritis. These patients were from our outpatient rheumatology clinic and were previously known SpA patients who experienced recurrent episodes of AAU.

Group 2 (n = 18) and group 3 (n = 20) patients were the study cases. These patients were classified as having idiopathic recurrent AAU using the International Uveitis Study Group classification system (11). All patients had had ≥2 flares of uveitis, with no clinical manifestation of SpA. The diagnosis of uveitis was determined at our uveitis clinic by a team of ophthalmologists and rheumatologists. For the purposes of this study, all patients who fulfilled the ESSG criteria for SpA were excluded from groups 2 and 3. Therefore, any candidate to be included in these groups had a complete ophthalmologic examination, a complete physical examination, including examination of the sacroiliac joints and use of the Maastricht AS Enthesitis Score (MASES) (12) to evaluate painful enthesis, a radiograph of the chest, and laboratory tests (including hematologic studies, biochemistry, erythrocyte sedimentation rate, fluorescent treponemal antibody absorption test, urinalysis, and test for HLA–B27). In addition, a pelvic radiograph was obtained in all patients from these groups to exclude the possibility of sacroiliitis. Patients in group 2 were positive for HLA–B27, and patients in group 3 were negative for HLA–B27.

Group 4 (n = 20) was a control group composed of patients with ophthalmic syndromes, such as posterior idiopathic or infectious uveitis, that are usually not related to SpA. Group 5 (n = 21) consisted of healthy control subjects in whom SpA was excluded.

US protocol.

In all groups, real-time US was performed by 2 experienced rheumatologists (EdM and TC-I) trained in musculoskeletal US using a GE Logiq 5 Pro US system (GE Healthcare, Piscataway, NJ) with a linear probe at 5–12 MHz. The sonographers were blinded with regard to the clinical data, and the subjects were asked not to communicate with the US examiners. Abnormalities were quantified using the MASEI score (8). This recently developed and validated index systematically explores 6 enthesis locations bilaterally (i.e., proximal plantar fascia, distal Achilles tendon, distal and proximal patellar ligament, distal quadriceps, and brachial triceps tendons) in each patient. Enthesis thickness, structure, calcifications, erosions, bursa inflammation, and power Doppler signal are scored in the cortical bone profile, tendon, and bursa. Predictive capacity of the index MASEI score was determined using logistic regression and receiver operating characteristic curves, and a value of 18 points was established as the best cutoff point to differentiate SpA cases from controls (8). This cutoff value was used in the present study in all patients from all groups. Reproducibility data for intraobserver measurements (intraclass correlation coefficients [ICCs]) were obtained for both ultrasonographers.

Statistical analysis.

Quantitative data are expressed as the mean ± SD and range, and qualitative data are expressed as percentages. One-way analysis of variance was performed to study the differences in the mean MASEI score between groups, using the Bonferroni method for post hoc pairwise comparisons. Odds ratios (ORs) were calculated in all cases in comparison with the healthy control group. The chi-square test was used to compare the percentages of cases within each group with a MASEI score greater than or equal to the cutoff value of 18 points. P values less than 0.05 (2-tailed) were considered significant.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. REFERENCES

The demographic characteristics and mean ± SD MASEI score for each group of patients and controls are shown in Table 1. The MASEI score cutoff value of 18 points, which discriminates between SpA patients and controls, was met or exceeded by 81% of the patients with SpA in group 1, 55.6% of the HLA–B27–positive patients with AAU in group 2, 40% of the HLA–B27–negative patients with AAU in group 3, and only 10% and 19% of the subjects in control groups 4 and 5, respectively.

Table 1. Characteristics of the study subjects*
 % maleAge, mean ± SD (range)MASEI score, mean ± SD (range)
  • *

    MASEI = Madrid Sonography Enthesitis Index; AAU = acute anterior uveitis.

  • Group 1 included 13 patients with ankylosing spondylitis, 2 patients with psoriatic arthritis, 5 patients with undifferentiated spondylarthritis (SpA), and 1 patient with reactive arthritis. Of these 21 patients, 76.2% were positive for HLA–B27.

  • Group 4 included 7 patients with idiopathic posterior uveitis, 7 patients with infectious uveitis, 3 patients with pars planitis, and 3 patients with other types of uveitis.

Group 1, patients with SpA (n = 21)8544.6 ± 15.7 (17–69)24.05 ± 7.13 (11–36)
Group 2, HLA–B27–positive patients with recurrent AAU (n = 18)23.549.9 ± 13.17 (24–73)18.44 ± 4.51 (10–25)
Group 3, HLA–B27–negative patients with recurrent AAU (n = 20)5052.28 ± 12.98 (27–75)16.65 ± 6.6 (4–27)
Group 4, patients with uveitis not related to SpA (n = 20)4046.47 ± 13.7 (22–66)12 ± 8.31 (4–41)
Group 5, healthy controls (n = 21)4343.33 ± 12.8 (22–61)11.52 ± 6.31 (3–24)

The overall differences between groups in the mean MASEI score were found to be statistically significant (P < 0.0001). Patients with SpA (group 1) did not have a significantly different score from patients in group 2. However, the scores in both groups 1 and 2 were significantly different from scores in the uveitis control and healthy control groups (groups 4 and 5) (Table 2). Group 3 was found to have a significantly lower mean ± SD score than group 1 (16.65 ± 6.6 versus 24.05 ± 7.13; P = 0.007), but we did not find any differences when group 3 was compared with the other groups (groups 2, 4, and 5). Table 3 shows the MASEI score in each enthesis affected and each elementary lesion detected. Figure 1 shows an example of a US image of a normal Achilles tendon and examples of enthesis lesions.

Table 2. Group-by-group comparison of Madrid Sonography Enthesitis Index scores*
 Group 1Group 2Group 3Group 4Group 5
  • *

    Values are the mean difference between groups (P). P values less than 0.05 were considered significant.

Group 15.6 (0.11)7.4 (0.007)12.05 (<0.0001)12.52 (<0.0001)
Group 25.6 (0.11)1.79 (1)6.44 (0.04)6.92 (0.018)
Group 37.4 (0.007)1.79 (1)4.65 (0.31)5.13 (0.17)
Group 412.05 (<0.0001)6.44 (0.04)4.65 (0.31)0.48 (1)
Group 512.52 (<0.0001)6.92 (0.018)5.13 (0.17)0.48 (1)
Table 3. Madrid Sonography Enthesitis Index scores by enthesis affected and type of elementary lesions detected*
 Group 1Group 2Group 3Group 4Group 5
  • *

    Values are the mean ± SD.

Enthesis affected     
 Plantar fascia2.35 ± 2.263.67 ± 2.473.17 ± 2.792.65 ± 2.231.32 ± 1.80
 Achilles tendon7.94 ± 4.106.27 ± 2.494.67 ± 2.723.95 ± 3.793.79 ± 3.49
 Distal patellar tendon3.12 ± 2.551.60 ± 1.591.83 ± 1.340.95 ± 1.101.58 ± 3.06
 Proximal patellar tendon5.29 ± 3.693.00 ± 2.831.94 ± 1.471.15 ± 2.373.16 ± 2.11
 Quadriceps3.18 ± 2.042.33 ± 2.063.28 ± 1.991.40 ± 1.411.26 ± 1.48
 Triceps2.41 ± 2.961.60 ± 1.241.61 ± 1.911.90 ± 1.600.63 ± 0.83
Elementary lesions     
 Calcifications/bone proliferation12.59 ± 4.3314.67 ± 4.6712.50 ± 5.578.05 ± 4.705.89 ± 3.75
 Structure/thickness1.47 ± 1.330.87 ± 0.990.78 ± 1.400.85 ± 1.090.93 ± 0.70
 Erosion6.35 ± 4.610.60 ± 1.241.44 ± 1.720.55 ± 0.721.46 ± 2.08
 Bursa2.12 ± 1.111.53 ± 1.131.72 ± 1.181.7 ± 1.262.25 ± 1.39
 Doppler1.94 ± 2.791.27 ± 1.870.33 ± 0.970.90 ± 2.090.66 ± 0.69
thumbnail image

Figure 1. Ultrasound images of a normal Achilles tendon and of enthesis lesions in the Achilles tendon. A, Longitudinal view of a normal Achilles tendon insertion, showing a normal fibrillar pattern and normal cortical bone profile. B, Longitudinal view showing bone erosion with Doppler signal. C, Longitudinal view showing enthesophytes (arrows) and lineal calcification parallel to the tendon fibers. D, Transverse view of the image in C, showing an enthesophyte (arrow). E, Longitudinal view showing a calcaneal bone erosion (asterisk). F, Transverse view of the image in E, showing a calcaneal bone erosion (asterisk). G, Longitudinal view showing a retrocalcaneal bursa (arrows) with synovial fluid and hypertrophy. H, Transverse view showing retrocalcaneal synovial hypertrophy with Doppler signal (arrow).

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These results were reproducible when we compared only the percentages of patients who met or exceeded the MASEI score cutoff value of 18 points in each group. Given that group 1 was composed primarily of men (which is typical of the SpA patient population), the analysis was adjusted for sex. The same results were obtained (data not shown).

When we considered a MASEI score of ≥18 to be a unique variable for the detection of SpA, the OR for detecting this disease in patients with recurrent AAU who were positive for HLA–B27 but had no other radiologic or clinical findings of SpA was 5.3 (95% confidence interval [95% CI] 1.3–22.2); this value was 5.8 after correction for sex. In group 3 patients with recurrent AAU who were negative for HLA–B27, the OR was 2.83 (95% CI 0.69–11.6).

Neither patients nor controls had painful enthesis on physical examination. The MASES index was very low in all groups, with mean values of 1.01, 0.53, 1.1, 0.05, and 0 in groups 1, 2, 3, 4, and 5, respectively. The MASEI and MASES indices did not show any correlation. Clinically evident enthesitis was present in only 4 patients, all in the SpA group. Intraobserver measurements of the MASEI score resulted in ICCs of 0.89 (95% CI 0.64–0.97) and 0.94 (95% CI 0.82–0.98) for the 2 ultrasonographers.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. REFERENCES

To our knowledge, this is the first report to describe the relevance of underlying enthesis involvement in patients with AAU exclusively. Using US, we explored a total of 1,200 entheses in 12 different locations in each of 100 patients and controls. The aim of our study was to investigate whether patients with idiopathic AAU who were positive or negative for HLA–B27 had a frequency of enthesis lesions similar to that seen in patients with SpA and could be considered to have an abortive, limited, or moderate form of SpA. Our US results showed that patients with recurrent AAU who were positive for HLA–B27 had underlying enthesis abnormalities comparable with those of patients with known SpA. Both groups showed significantly more enthesopathy on US than did patients with uveitis unrelated to SpA or healthy controls (groups 4 and 5, respectively).

These results suggest that patients in group 2 (i.e., HLA–B27–positive patients with AAU without musculoskeletal or radiologic manifestations of SpA) might have an abortive or incomplete form of SpA. In fact, if we had considered the enthesopathy evident on US to be enthesitis, the disease in these patients would have reached the 6 points necessary to meet the criteria of Amor et al for the classification of SpA (13). However, we do not know what histologic changes are represented by the changes evident on US images.

Uveitis that occurs in association with the cell surface antigen HLA–B27 is one of the most common forms of immune-mediated uveal inflammation. The relationship between SpA, AAU, and HLA–B27 is well established. In a previous study, patients with recurrent AAU constituted 34.2% of a large series of 407 patients with uveitis (14). Of these, 48.2% were found to have SpA, 24.5% were found to have idiopathic AAU not related to HLA–B27, and 11.5% were classified as having idiopathic AAU related to HLA–B27. This group of patients had a typical form of uveitis related to SpA but lacked the musculoskeletal manifestations of these diseases.

In another study, Rosenbaum found that 84% of patients with AAU had SpA, most of them previously undiagnosed (15). In our series, >50% and 40% of asymptomatic patients with AAU who were positive or negative for HLA–B27, respectively, exhibited enthesopathy on US.

Despite the presence of HLA–B27, patients with recurrent AAU without further SpA-related symptoms do not fulfill either the ESSG criteria (9) or the Amor et al criteria (13) for the classification of SpA. As a result, patients with recurrent AAU without any other clinical symptoms or familial history of SpA could not be classified as having SpA. However, it has been suggested that uveitis may be the first manifestation and key symptom of SpA (16, 17). Nevertheless, the patients in those previous studies usually had other clinical manifestations (e.g., underlying inflammatory back pain or oligosymptomatic radiologic sacroiliitis) that led to the diagnosis. SpA was diagnosed using a specific clinical protocol in which a pelvic radiograph was obtained in every patient with AAU, regardless of the presence or absence of symptoms (1, 16, 17). In the present study, SpA was excluded in patients in groups 2 and 3.

A search of the medical literature suggests that the majority of available information regarding AAU and HLA–B27 is related to SpA. Information about ocular symptoms in the absence of rheumatologic symptoms is scarce. HLA–B27–positive AAU is more likely to be of shorter duration, but more severe and more likely to recur, than HLA–B27–negative AAU (2).

US techniques are becoming useful tools for the diagnosis of early arthritis. In recent years, US has been proven to be a highly sensitive and noninvasive tool, especially in the assessment of tendon and joint involvement (4–8). These techniques can be helpful for the early diagnosis of SpA (18). We recently developed the MASEI score as a useful index to discriminate between established SpA patients and healthy people (8). This and other studies (4–7) have demonstrated a high frequency of abnormal peripheral enthesis in patients compared with controls. The MASEI score can be used for diagnostic purposes and classifies patients as having SpA using unique, quantitative, and objective criteria. Furthermore, it shows discriminant validity and reliability (8) and unveils the relevance of studying enthesis in these diseases.

It is well known that the spondylarthritides are quite heterogeneous diseases with a variety of clinical expressions. Genetics and sex may explain at least part of this clinical variability. Patients with longstanding SpA (i.e., those in group 1 in this study) are usually men, whereas 23.5% and 50% of the patients in groups 2 and 3 in the present study, respectively, were men. However, we repeated the statistical analysis adjusting for sex and obtained similar results.

In conclusion, this is the first study to demonstrate significant enthesopathy in patients with recurrent AAU who were positive for HLA–B27 and had no other features of SpA. Enthesis lesions were comparable with those in SpA patients in a high percentage of cases. Patients negative for HLA–B27 had fewer enthesis abnormalities. These data suggest that patients with recurrent AAU, especially those positive for HLA–B27, have an abortive or incomplete form of SpA. We suggest that these patients should be classified as SpA patients. The US technique used for detection of enthesopathy should be incorporated into the clinical protocol for studying recurrent AAU in daily clinical practice.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Muñoz-Fernández had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Muñoz-Fernández, de Miguel, Cobo-Ibáñez, Madero, Ferreira, Ventura Hidalgo, Schlincker, Martín-Mola.

Acquisition of data. Muñoz-Fernández, de Miguel, Cobo-Ibáñez, Madero, Ferreira, Ventura Hidalgo, Schlincker, Martín-Mola.

Analysis and interpretation of data. Muñoz-Fernández, de Miguel, Cobo-Ibáñez, Madero, Ferreira, Ventura Hidalgo, Schlincker, Martín-Mola.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. REFERENCES
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