Joint Involvement in Asymptomatic Egyptian Patients ...

The Egyptian Rheumatologist

ISSN 1110-1164

Joint Involvement in Asymptomatic Egyptian Patients with HCV Infection; Ultrasonographic Study Geilan A. Mahmoud1, Mohamed M. El-Wakd1, Hatem M. El-Azizi2 and Ghada A. El-Morsy3 Rheumatology and Rehabilitation Department, Cairo University; 2Radiodiagnosis Department, Cairo University; 3National Institute of Neuromotor Rehabilitation 1

Abstract Objectives: This case control diagnostic ultrasonographic study was undertaken to detect the presence of early articular and peri-articular involvement in Egyptian patients infected with hepatitis C virus (HCV) without any articular manifestation. Patients and Methods: The knee, hip and shoulder were evaluated clinically and by ultrasonography in a cohort of fifty patients with HCV without any current or previous articular manifestations in comparison with twenty healthy controls who were negative for HCV and HBV infections. Results: Ultrasonographic alterations were detected in 96% of the HCV patients with highly significant difference in comparison to controls (p < 0.000). Slight inflammatory changes were found in all the joints examined more than the moderate or severe changes. The knee and shoulder joints were involved in 74% of the HCV patients for each and the hip in 68%. There were higher prevalence and highly significant differences as regard the knee synovial thickening and effusion, hip effusion, trochanteric bursitis, supraspinatus tendon fluid collection and acromioclavicular joint effusion in comparison to the control group. Conclusions: Our study demonstrated the presence of joint changes in near all the asymptomatic patients with HCV with the prevalence of slight inflammatory alterations that can be explained by the presence of sub-clinical synovitis as well as the presence of significant changes in some of peri-articular structures. In countries like Egypt, the HCV is an endemic disease, so it is thus recommended that patients with rheumatic symptoms should be tested for the HCV infection and conversely that sign and symptoms of articular involvement should be evaluated in HCV patients. Key words: HCV, Joint ultrasonography. Egypt. Rheumatologist Vol. 30, No. 1, 2008: 1-6

Introduction The extrahepatic autoimmune rheumatic manifestations of the HCV infection were well documented in the literature that may appear during the course of the disease. Polyarthralgia or polyarthritis are the most commonly reported rheumatic manifestations1. A non-erosive and non-deforming polyarthritis resembles the rheumatoid arthritis (RA) is frequently associated with HCV infection. In acute onset it usually has a RA distribution but with frequent remissions2. HCV-RNA has been detected in both the serum and synovial fluid of patients with HCV infection. The high frequency of rheumatoid factor positivity in patients with HCV infection usually makes it very difficult to make the differential diagnosis between RA and HCV related polyarthritis.

Another possible confounding factor is the documented role of INF-α, which is used in the treatment of HCV infection, to precipitate or exacerbate some autoimmune diseases3. Fibromyalgia, myalgia, myositis4, mixed cryoglobulinemia5-7, vasculitis8 or sicca syndrome9 may also be present in HCV infected patients. At the same time, in a relatively large number of patients no rheumatic symptoms appear. Diagnostic ultrasonography is a highly sensitive noninvasive imaging method for the identification of articular and periarticular changes either in the presence or absence of symptoms10.

Personal non-commercial use only. The Journal of Rheumatology Copyright © 2008. All rights reserved.

1

The Egyptian Rheumatologist; Vol. 30, No. 1, 2008: 1-6

Aim of the work: This case control diagnostic ultrasonographic study was undertaken to detect the presence of early articular and periarticular involvement in Egyptian patients infected with HCV without any articular manifestation.

of the patella by both transverse and longitudinal scans. The normal thickness of the posterior wall of the synovial membrane is between 2-3 mm11. Synovial thickening was considered slight if the thickness between 4-5.9 mm and moderate if it was between 6-7.9 mm and severe if it was more than 8 mm12.

Patients and Methods

Effusion was considered when hypoechoic or anechoic fluid collection appeared within the joint12.

Patients: fifty patients with HCV infection without any current or previous articular manifestations were recruited from the out-patient clinic of the tropical medicine department-Faculty of Medicine-Cairo University Hospitals. They were examined rheumatologically in the out-patient clinic of the rheumatology and rehabilitation departmentFaculty of Medicine-Cairo University Hospitals for any signs for associated extra-hepatic rheumatic manifestations of the HCV.

Baker’s cyst was considered to be present when hypoechoic image appeared within the gastrocnemius-semimembranous bursa12. Ultrasonographic examination of the hip: included evaluation of the joint effusion, trochanteric bursitis and joint capsule thickness.

They were diagnosed previously as having HCV infection by positive anti-HCV antibodies by third generation enzymelinked immunosorbent assay (ELISA) and confirmed by detection of HCV-RNA by polymerase chain reaction (PCR).

Effusion was diagnosed if the longest distance between the bony surface of the femur and joint capsule was greater than 7 mm13. It is considered slight if it is between 7.1-8.9 mm and moderate if it was between 9-10.9 mm and severe if it was greater than 11 mm12.

Exclusion criteria: 1. HCV Patients with extrahepatic autoimmune rheumatic manifestations as palpable purpura, dry eye and or mouth. 2. Patients with previous treatment with INF-α, HBV surface antigen, hepatocellular carcinoma or other non related cancers, cholestatic liver disease, acute hepatitis or other acute infections were excluded.

The appearance of the hypoechoic image within the trochanteric bursa with a thickness of the bursa > 2 mm was considered to be a sign of bursitis14. The normal joint capsule thickness is about 1 mm and it was considered to be thick when it was at least double the normal12. Ultrasonographic examination of the shoulder: included evaluation of the long head of biceps tendon, 3 rotator cuff tendons (supraspinatus, infraspinatus and subscapularis), the subacromial and subscapularis bursae, and the acromioclavicular and gleno-humeral joints.

Complete blood count, erythrocyte sedimentation rate (ESR), liver function tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), gammaglutamil transpeptidase (GGT), bilirubin, albumin, prothrombin and alkaline phosphatase] and creatinine were performed to all patients.

Variation of tendon thickness was considered to be significant if it was at least 1/3 of the normal thickness. Tendon structure was evaluated by studying the homogeneity of their fibrillar pattern and irregularities of their margins. The presence of tendon tears was diagnosed when a hypoechoic discontinuity appeared within the tendon fibrillar pattern; a full thickness tear was considered to be present when the defect extended through the entire tendon, and a partial thickness tear when it was limited to only a part of the tendon thickness15.

Twenty healthy subjects with matched age and sex were included as a control group. They were negative for HCV and HBV infection. Ultrasonography: Siemens diagnostic ultrasound machine with a 7.5 MHz linear transducer was used to evaluate the shoulders and knees joints, and with a 5 MHz linear transducer was used to evaluate the hips joints. In every patient, knees, hips and shoulders were examined.

As regard the long head of biceps tendon, the presence of hypoechoic area surrounding the tendon and within its sheath was considered as a sign of tenosynovitis10.

Ultrasonographic examination of the knee: included evaluation of the supra-patellar synovial bursa to study the synovial membrane thickness and proliferation and to detect synovial effusion. The posterior aspect of the knee was examined for Baker’s cyst.

Subacromial and subscapularis bursitis were diagnosed when a hypoechoic image appeared within the bursae, indicating effusion; this finding was considered significant if the effusion caused a thickening of bursa > 2 mm16.

With the patient supine and the knees in the neutral position, the thickness of the posterior wall of the synovial membrane (lining the anterior surface of the femur) was measured in the supra-patellar synovial bursa 2 cm above the upper pole

Acromioclavicular joint effusion was considered if the capsule was convex to articular space with a simultaneous hypoechoic image within the joint. Gleno-humeral joint 2

Geilan A. Mahmoud et al. - Joint Involvement in Asymptomatic Egyptian Patients

effusion was considered slight when the longest distance between the bony surface of the humerus and the joint capsule was between 4-5.9 mm, moderate if it was between 6-7.9 mm and severe if it was > 8 mm17.

Baker’s cyst was detected in 9 (18%) HCV patients in contrast to 2 (10%) in the healthy controls and the difference was statistically non-significant (n.s.).

Statistical Analysis: It was performed using SPSS 11.0 (Statistical Package for Scientific Studies) for Windows. Quantitative (numerical) data were presented as minimum, maximum, mean and standard deviation (SD) values. Qualitative (categorical) data were presented as frequencies and percentages. Chi-square test was used to test the significant difference of different ultrasonographic features between the patient and control groups. The significance level was set at P ≤ 0.05.

The total involvement of the knee joint was seen in 37 patients (74%) versus 3 of the control group (p < 0.000). The detailed ultrasonographic findings of the knee joints were mentioned in tables (1). Table 1: The different ultrasonographic findings in the knee joints: Joint

Results Fifty patients suffering from HCV infection were included in the study. They were 26 males (52%) and 24 females (48%). Their age varied from 28-70 years with a mean of 46.6 ± 9.4 years and disease duration varied from 0.25-6 years with a mean of 1.7 ± 1.6 years. Twenty healthy subjects with matched age and sex were included as a control group.

Knee

Anatomic structure

Changes

HS

HCV

Synovial thickening

Absent Present Slight Moderate Severe

20 0 0 0 0

34 16 15 1 0

Synovial proliferation

Effusion

No significant difference was found between HCV patients and healthy control subjects regarding the ESR and creatinine. No differences were observed between patients who showed joint changes and patients who did not regarding serum liver function tests, such as ALT, AST, GGT, bilirubin, albumin, prothrombin and alkaline phosphatase

Baker’s cyst

P

0.003

Absent

20

49

Present Absent Present Slight Moderate Severe Absent

0 19 1 1 0 0 18

1 19 31 17 13 1 41

1.000

Present

2

9

0.494

0.000

Hip joint: A higher prevalence of hip effusion (p < 0.000) and trochanteric bursitis (p = 0.008) were found in HCV patients (23 patients; 46% and 18 patients; 36% respectively) compared to the healthy controls (none for effusion and 1 for trochanteric bursitis; 5%) (Figure 2).

Simultaneous involvement of more than one joint was found in 48 patients (96%) with HCV infection versus 4 (20%) among the control group with a very highly significant difference (p < 0.000). Knee joint: The knee synovial thickening and proliferation were not detected among the healthy controls while, both were detected in 16 (32%) and 1 (2%) in HCV patients respectively. The difference was statistically significant as regard the synovial thickening (p = 0.003). A statistically higher prevalence (p = 0.000) of knee joint effusion was found in HCV patients (31 patients; 62%) compared to healthy controls (1 healthy control; 5%) (Figure 1).

Figure 2: A: Moderate hip effusion with a distance between the bony surface of the hip and joint capsule = 9.5 mm. B: Trochanteric bursitis.

Hip joint capsule thickening was detected in 1 (2%) HCV patient in contrast to none among the healthy controls and the difference was statistically non-significant. The total involvement of the hip joint was detected in 34 (68%) HCV patients in contrast to one (5%) of the control group (p < 0.000). The detailed ultrasonographic findings in hip joints were mentioned in tables (2). Figure 1: Suprapatellar knee effusion; A: Mild knee effusion and B: Moderate knee effusion as indicated by white arrows. E: effusion.

3


Table 2: The different ultrasonographic finding in the hip joints: Joint

Anatomic structure

Effusion Hip Bursitis Joint capsule

Changes

HS

HCV

Absent Present Slight Moderate Severe Absent Present

20 0 0 0 0 19 1

27 23 18 5 0 32 18

Normal

20

49

Thickened

0

1

(p < 0.000). The detailed ultrasonographic findings in the shoulder joints were mentioned in tables (3).

P

Table 3: The different ultrasonographic findings in the shoulder joints: Joint

0.000

Anatomic structure

0.008 1.000 Long head of biceps tendon

Shoulder joint: None of the healthy control subjects showed any ultrasonographic changes in the shoulder joint or in the surrounding soft tissues. On the contrary, the most prevalent ultrasonographic finding was supraspinatus effusion that was detected in 27 (54%, p < 0.000), followed by the acromioclavicular joint effusion in 15 (30%, p = 0.004) HCV patients (Figure 3; A and B).

49

Present Slight Moderate Severe

0 0 0 0

1 1 0 0

Tendon’s changes: Absent

20

50


0 0 0 0

0 0 0 0 49

0 0 0 0

1 1 0 0

Absent

20

23

Supraspinatus tendon effusion


0 0 0 0

27 23 4 0

Absent

20

50


0 0 0 0

0 0 0 0

Absent

20

50


0 0 0 0

0 0 0 0 48

Subscapularis bursitis

Absent

20

Present

0

2

Absent

20

50

Present

0

0

Acromioclavicular joint effusion

Absent

20

35

Present

0

15

Acromioclavicular joint thickness

Absent

20

46

Present

0

4

Absent

20

50

Present

0

0

Gleno-humeral joint effusion

4

20

20

Subacromial bursitis

The total involvement of the shoulder was detected in 37 patients (74%) and in one (5%) of the control group

Peritetendinous fluid collection: Absent

Absent

Subscapularis tendon changes

No changes in the long head of bicepital tendon, infraspinatus tendon, subscapular tendon could be detected by ultrasongraphy in HCV patients as well as no detectable gleno-humeral joint effusion and subscapular bursitis.

HCV


Infraspinatus tendon changes

The acromioclavicular joint capsule thickening was detected in 4 (8%, n.s.), subacromial bursitis in 2 (4%, n.s.), changes in the supraspinatus tendon in 1 (2%, n.s.) and fluid collection in the long head of biceps tendon in 1 (2%, n.s.) HCV patients.

HS

Supraspinatus tendon changes

Shoulder

Figure 3: A: Supraspinatus effusion, B: Acromioclavicular joint effusion. E: effusion. A: acromion. C: clavicle.

Changes

P

1.000

-

1.000

0.000

-

-

1.000 -

0.003

0.319

-

Geilan A. Mahmoud et al. - Joint Involvement in Asymptomatic Egyptian Patients

The following figure (4) showed the only significant ultrasonographic findings in HCV patients in comparison with the healthy control subjects which were the knee synovial thickening, knee effusion, hip effusion, trochanteric bursitis, supraspinatus effusion and acromioclavicular joint effusion.

as with statistically high prevalence for the knee synovial thickening (32%, p = 0.003) and knee effusion(62%, p < 0.000). On the other hand, our results regarding the knee synovial proliferation and baker’s cyst were statistically nonsignificant compared to the control, in contrast to Iagnocco’s study12.

Figure 4: The significant ultrasonographic findings in HCV patient in comparison to the control group.

In our study, there was a statistically higher prevalence (p < 0.000) of hip involvement in HCV patients (68%) compared to controls (5%). Our patients’ hip involvement was more than that in Iagnocco’s study (27.6%). There was a statistically higher prevalence of hip joint effusion (46%, p < 0.000), which indicated the presence of inflammation, and this came in accordance with that of Iagnocco’s study. Also, there was a statistically higher prevalence of trochanteric bursitis (36%, p = 0.008) in HCV patient compared to the controls and this came in contrast to Iagnocco’s study. The rare finding of hip joint capsule thickening (2% of patients) that came in accordance with that of Iagnocco’s study (1.7%) confirmed the absence of a long lasting inflammatory process in most patients.

Discussion

In our study, the shoulder joint was frequently involved in HCV patients (74% of patients) as the knee joint but less than that reported in Iagnocco’s study (89.6%). The ultrasonographic features came mostly with slight inflammatory characteristics with statistically prevalence of supraspinatus effusion (54%, p < 0.000) and acromioclavicular joint effusion (30%, p = 0.004). The rarity of changes in the tendon structure confirmed the absence of a long lasting inflammatory process in most cases as reported in Iagnocco’s study. However, even involvement of the tendons but not the synovial sheath (such as the rotator cuff tendons) could possibly be explained as a sign of inflammatory process within them, similarly to the changes in RA18,19.

Many rheumatic manifestations may appear during the course of the HCV2. Polyarthralgia or polyarthritis are the most commonly reported rheumatic manifestations1. A nonerosive and non-deforming polyarthritis resembles the RA is frequently associated with HCV infection. Fibromyalgia, myalgia, myositis4, mixed cryoglobulinemia5-7, vasculitis8 or sicca syndrome9 may also be present in HCV infected patients. At the same time, in a relatively large number of patients no rheumatic symptoms appear. Consequently, the present ultrasonographic study was undertaken to detect the possible presence of early articular and peri-articular involvement in HCV patients without any articular manifestation.

The gleno-humeral joint effusion was not detected in our patients. It was found in only one patient (3.6%) in Iagnocco’s study. The rarity of gleno-humeral joint effusion could be explained by either two hypotheses: the low sensitivity of the ultrasound in detecting a very slight fluid collection in such a large joint; or the rarity of the gleno-humeral joint effusion involvement in HCV patients12.

Ultrasonography is an imaging method that accurately detects joint changes and has been recently successfully applied to the evaluation of articular alterations in many different rheumatic disorders10,11,15. To our knowledge, this study represents the first Egyptian and the second world wide ultrasonographic study, followed Iagnocco’s study in 2004, aimed at detecting the appearance of possible early articular and peri-articular involvement in HCV patients without any articular manifestation12.

In conclusion, our preliminary study demonstrated the presence of ultrasonographic joint changes in near all the asymptomatic patients with HCV with the prevalence of slight inflammatory alterations that can be explained by the presence of sub-clinical synovitis as detected in Iagnocco’s study12. HCV infection appears to be strongly associated with many rheumatic manifestations. It is recognized that the HCV can replicate outside the liver and this may account for the well known systemic involvement7. In countries like our country, the HCV infection is an endemic disease, so it is thus recommended that patients with rheumatic symptoms should be tested for the presence of HCV infection and conversely that sign and symptoms of articular involvement should be evaluated in HCV patients.

Our result showed the presence of ultrasonographic alterations in 96% of HCV patients with highly significant differences with respect to the controls (p < 0.000) and this result came in accordance with that of Iagnocco’s study12. This finding confirms the high sensitivity of ultrasound in the early detection of joint alterations. In our study, the knee joint was frequently involved (74%, p < 0.000) in HCV patients as in Iagnocco’s study (79.3%), mostly with slight inflammatory characteristics as well 5


9.

Corresponding author

10.

Date received: Date accepted:

11.

References

12.

1.

2. 3.

4. 5. 6.

7.

8.

Ueno Y, Kinoshita R, Kishimoto I, Okamoto S. Polyarthritis associated with hepatitis C virus infection. Br.J.Rheumatol. 1994 Mar;33(3):28991. Siegel LB, Cohn L, Nashel D. Rheumatic manifestations of hepatitis C infection. Semin.Arthritis Rheum. 1993 Dec;23(3):149-54. Maillefert JF, Muller G, Falgarone G, Bour JB, Ratovohery D, Dougados M, et al. Prevalence of hepatitis C virus infection in patients with rheumatoid arthritis. Ann.Rheum.Dis. 2002 Jul;61(7):635-7. Nishikai M, Miyairi M, Kosaka S. Dermatomyositis following infection with hepatitis C virus. J.Rheumatol. 1994 Aug;21(8):1584-5. Ferri C, Mascia MT. Cryoglobulinemic vasculitis. Curr.Opin. Rheumatol. 2006 Jan;18(1):54-63. Saadoun D, Delluc A, Piette JC, Cacoub P. Treatment of hepatitis C-associated mixed cryoglobulinemia vasculitis. Curr.Opin. Rheumatol. 2008 Jan;20(1):23-8. Nissen MJ, Fontanges E, Allam Y, Zoulim F, Trepo C, Miossec P. Rheumatological manifestations of hepatitis C: Incidence in a rheumatology and non-rheumatology setting and the effect of methotrexate and interferon. Rheumatology (Oxford) 2005 Aug;44(8):1016-20. Manna R, Todaro L, Latteri M, Gambassi G, Massi G, Grillo MR, et al. Leucocytoclastic vasculitis associated with hepatitis C virus antibodies. Br.J.Rheumatol. 1997 Jan;36(1):124-5.

13. 14. 15.

16.

17. 18.

19.

6

Haddad J, Deny P, Munz Gotheil C, Ambrosini JC, Trinchet JC, Pateron D, et al. Lymphocytic sialadenitis of Sjogren's syndrome associated with chronic hepatitis C virus liver disease. Lancet 1992 Feb 8;339(8789):321-3. Naredo E, Aguado P, De Miguel E, Uson J, Mayordomo L, Gijon Banos J, et al. Painful shoulder: Comparison of physical examination and ultrasonographic findings. Ann.Rheum.Dis. 2002 Feb;61(2):132-6. Iagnocco A, Coari G, Palombi G, Valesini G. Knee joint synovitis in Sjogren's syndrome. Sonographic study. Scand.J.Rheumatol. 2002;31(5):291-5. Iagnocco A, Coari G, Mammarella A, Basili S, Donnarumma L, Valesini G, et al. Joint sonography in asymptomatic patients with HCV correlated hepatitis. Clin.Exp.Rheumatol. 2004 Jan-Feb;22(1):43-8. Koski JM, Anttila PJ, Isomaki HA. Ultrasonography of the adult hip joint. Scand.J.Rheumatol. 1989;18(2):113-7. ERROR IN THIS REFERENCE. van Moppes FI, Veldkamp O, Roorda J. Role of shoulder ultrasonography in the evaluation of the painful shoulder. Eur.J.Radiol. 1995 Jan;19(2):142-6. Alasaarela E, Takalo R, Tervonen O, Hakala M, Suramo I. Sonography and MRI in the evaluation of painful arthritic shoulder. Br.J.Rheumatol. 1997 Sep;36(9):996-1000. Koski JM. Axillar ultrasound of the glenohumeral joint. J.Rheumatol. 1989 May;16(5):664-7. Frediani B, Falsetti P, Storri L, Allegri A, Bisogno S, Baldi F, et al. Ultrasound and clinical evaluation of quadricipital tendon enthesitis in patients with psoriatic arthritis and rheumatoid arthritis. Clin. Rheumatol. 2002 Aug;21(4):294-8. Naranjo A, Marrero Pulido T, Ojeda S, Francisco F, Erausquin C, Rua Figueroa I, et al. Abnormal sonographic findings in the asymptomatic arthritic shoulder. Scand.J.Rheumatol. 2002;31(1):17-21.