SEARCH

SEARCH BY CITATION

Abstract

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

Objective

To investigate the response of tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) by ultrasonographic evaluation of changes in the wrist and hand, and to determine whether such assessments during early TCZ treatment predict later clinical outcome.

Methods

Thirty-two RA patients about to receive TCZ treatment were examined by ultrasound at baseline and after 2 weeks using the Outcome Measures in Rheumatology Clinical Trials semiquantitative scoring of 22 joints (both wrists, proximal interphalangeal joints 1–5, and metacarpophalangeal joints 1–5) as well as clinical and laboratory variables, leading to a calculation of composite indexes. The aim was to determine whether methotrexate treatment and clinical, laboratory, and ultrasonographic evaluation after 2 weeks of TCZ treatment predict treatment outcome at 24 weeks, as assessed by the Disease Activity Score in 28 joints (DAS28).

Results

Changes of ultrasound scores after 2 weeks were found to be correlated with changes in DAS28 at 24 weeks (r = 0.545–0.622, P < 0.05). The change of sum power Doppler scores after 2 weeks of treatment was identified as the variable most closely correlated with the change in DAS28 at 24 weeks (r = 0.622, P < 0.05).

Conclusion

The best predictors after 2 weeks of favorable treatment outcome at 24 weeks were improved power Doppler scores. Methotrexate treatment and composite indexes did not predict favorable treatment outcome in this study.


INTRODUCTION

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

Ultrasonography (US) has been shown to be sensitive and reliable for evaluating joint inflammation (1). In patients with rheumatoid arthritis (RA), B-mode US (BMUS) and power Doppler US (PDUS) have often been used in clinical studies (2). PDUS is especially considered to be useful for monitoring responses to anti–tumor necrosis factor (anti-TNF) therapy in patients with RA (3).

Tocilizumab (TCZ) is a humanized monoclonal antibody that binds to both soluble and membrane-bound forms of the interleukin-6 receptor, and has shown clinical efficacy (4, 5) in patients with RA.

Although TCZ has proven to be clinically effective in patients with RA, sometimes its effects are more delayed than TNF inhibitors (6). It is therefore important to determine early treatment predictors of future outcome in order to target patients most likely to benefit from continued treatment. Furthermore, identifying the predictors in the early phase of TCZ therapy will be useful to reduce the cost for TCZ nonresponders. The purpose of the present study was to determine whether US assessments, as well as clinical and laboratory findings, can predict later responses, and whether these could be sufficiently reliable to adequately monitor trials of treatment with TCZ.

Significance & Innovations

  • Tocilizumab (TCZ) has proven to be clinically effective in patients with rheumatoid arthritis (RA), although sometimes its effects are more delayed than tumor necrosis factor (TNF) inhibitors. It is therefore important to determine early treatment predictors of future outcome in order to target patients most likely to benefit from continued treatment. Furthermore, to identify the predictors in the early phase of TCZ therapy will be useful to reduce the cost for TCZ nonresponders.

  • This study showed that ultrasonography (US; especially power Doppler US [PDUS]) in the early period is a sensitive imaging tool for assessing the later response to treatment of TCZ.

  • Improved PDUS scans at 2 weeks predict later good responses to treatment with TCZ in RA. Surprisingly, methotrexate treatment and composite indexes (global activity, pain, erythrocyte sedimentation rate, and Disease Activity Score in 28 joints) did not predict favorable treatment outcome in this study.

PATIENTS AND METHODS

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

Study design.

This was a prospective study, blinded to the US technician and the physician assessing the patient. It was approved by the appropriate ethical committees (Hiroshima Clinic ethical committees).

Patients.

Candidates were recruited from patients diagnosed with RA according to the American College of Rheumatology (ACR) criteria (7). They were seen at Hiroshima Clinic between December 2006 and December 2009. RA patients were eligible if they had active disease (Disease Activity Score in 28 joints [DAS28] >3.2) (8) despite prior treatment with disease-modifying antirheumatic drugs (DMARDs), including methotrexate (MTX), during the previous 8 weeks. All patients received MTX as a basic DMARD, if possible. All DMARD regimens remained stable for at least 8 weeks. None of the patients had been treated previously with biologics (TNF inhibitors, TCZ, etc.). Patients were excluded if they were age <18 years, pregnant, or had ever received intraarticular steroid injections at the wrist and the proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints of the hand. The subjects were recruited consecutively.

Study protocol.

TCZ 8 mg/kg was administered by intravenous infusion every 4 weeks for a total of 24 weeks. Clinical, laboratory, and US assessments were performed at 0 (baseline), 2, and 24 weeks. After 2 weeks of TCZ treatment, potential predictors (MTX treatment [dose] and clinical, laboratory, and US evaluations) were correlated with the outcome at 24 weeks by the DAS28 as a primary end point. An experienced rheumatologist (KK) carried out all of the physical examinations. The clinical, laboratory, and US examinations were performed at the Rheumatology Department of Hiroshima Clinic, Japan. Permitted concomitant drugs included stable doses of nonsteroidal antiinflammatory drugs and steroids (maximum daily dose of 10 mg of prednisone or equivalent orally). No intraarticular injections were permitted in any joints. No changes in the dose of DMARDs were permitted during the study.

US evaluation.

US examinations were performed by an experienced sonographer (KA) blinded to both clinical and laboratory findings. The same investigator carried out followup examinations using the same US equipment, the same values for the setting parameters, and the same scanning technique as those used for baseline assessment.

A Toshiba EU 7000 with a 5–12-MHz linear probe was used. PDUS settings were standardized with a pulse repetition frequency of 1,200 Hz and a color mode frequency of 7 MHz. The wall filters and the color gain of the PDUS equipment were identical to those proposed by Rubin et al (9). The following joints were assessed bilaterally using standard projections (10): PIP 1–5 (dorsal), MCP 1–5 (dorsal), and wrist (radiocarpal, intercarpal, and radioulnar joints; dorsal), equaling a total of 22 joints. All joints were scored according to Outcome Measures in Rheumatology Clinical Trials (11) criteria for BMUS (presence of synovitis and joint fluid) and PDUS (presence of vascularization): 0 = none, 1 = minor, 2 = moderate, or 3 = major presence (giving a total separate range for the sum scores of 0–66 for BMUS and PDUS). All US assessments were conducted in a temperature-controlled room at 22°C between 3:00 PM and 6:00 PM, and the pressure of the probe was as low as possible to have optimal PDUS signals. Patients were asked to refrain from smoking and drinking alcohol and beverages containing caffeine for at least 24 hours prior to the examination. The hands were assessed while resting on a small table with the patients lying on a bench after a 30-minute resting period. Images were stored from all of the examinations, and the US scoring reliability was examined by having the BMUS and PDUS scores on 22 joints assessed at the end of the study by the same and a different experienced sonographer (SY).

Clinical and laboratory evaluation.

A rheumatologist with more than 10 years of experience with joint counts in clinical studies assessed 28 joints for tenderness and swelling (PIP 1–5, MCP 1–5, wrist, elbow, shoulder, and knee). He was blinded to the results of the US examinations.

The patients as well as the study rheumatologist (assessor) evaluated the global disease activity on a visual analog scale. Patients evaluated the global assessment of pain on a visual analog scale. The laboratory tests included erythrocyte sedimentation rate (ESR) and C-reactive protein level (in-house standard methodology). The DAS28 based on ESR (8) was computed.

Statistical analysis.

Sample size calculation.

The sample size was estimated using unpublished assessments, the correlation of US evaluations after 2 weeks with improved DAS28 at 24 weeks after TCZ, and reliability (intraclass correlation coefficient [ICC] 0.88). The smallest detectable difference was calculated as 3.23 (12), giving a required sample of 20 patients per group (α = 0.05, power 80%). Assuming a 30% dropout rate, we aimed to recruit 30 patients for each treatment.

Data were statistically analyzed using the SPSS (IBM) software package (version 15 for Windows). Correlation between changes of predictors after 2 weeks of TCZ treatment was analyzed by Spearman's rank correlation test. The mean changes of US (BMUS and PDUS) scores and clinical and laboratory data after 2 weeks of TCZ treatment were correlated with the change in DAS28 after 24 weeks of TCZ treatment using Pearson's correlation. The level of significance set was P values less than 0.05.

US intraobserver and interobserver reliability.

Intraobserver and interobserver reliability of the US assessment was evaluated by recording representative images. The stored images from each patient were scored for BMUS and PDUS signal under blinded conditions by the same investigator, who performed real-time US examination a minimum of 3 months later. Intraobserver reliability for US was evaluated by calculating the ICC (2-way mixed effects) and single measurements (13, 14). Interobserver reliability between US investigators was evaluated using Kendall's W test. A Kendall's W value of <0.40 was considered poor, 0.40–0.50 was considered moderate, 0.50–0.70 was considered good, and 0.70–1 was considered excellent.

RESULTS

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

Patient characteristics.

This study enrolled 34 patients. Two patients were withdrawn before treatment due either to ineligibility or at the patient's request, leaving a total of 32 patients. Characteristics (age, sex, RA disease activity, disease duration, and US data) at baseline are shown in Table 1. Eleven patients received TCZ as monotherapy and 21 also received a stable dose of MTX in addition to TCZ. A total of 29 patients completed the study at 24 weeks.

Table 1. Characteristics at baseline*
 Enrolled patients
  • *

    Values are the mean ± SD unless otherwise indicated. RF = rheumatoid factor; ACPA = anti–citrullinated protein antibody; VAS = visual analog scale (range 0–100 mm, where 0 = worst score); ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; DAS28 = Disease Activity Score in 28 joints; HAQ = Health Assessment Questionnaire; DI = disability index; MTX = methotrexate; BMUS = B-mode ultrasonography; PDUS = power Doppler ultrasonography.

No. of patients32
Age, years58 ± 14
Sex, female/male26/6
Disease duration, years6 ± 4
RF positive, %78.2
ACPA positive, %72.2
Patient's global assessment of health (VAS, mm)41 ± 22
Patient's global assessment of pain (VAS, mm)35 ± 31
Assessor's global assessment of health (VAS, mm)38 ± 21
Swollen joints (n = 28)7 ± 4
Tender joints (n = 28)9 ± 5
ESR, mm/hour29 ± 7
CRP level, mg/liter10.1 ± 5.2
DAS285.35 ± 1.33
HAQ DI score1.1 ± 0.5
MTX dosage, mg/week12.2 ± 3.5
Prednisolone, mg/day4.5 ± 2.4
Sum BMUS score32 ± 12
Sum PDUS score19 ± 6

Relationship between predictors.

Increasing correlation coefficients between predictors from baseline to after 2 weeks of TCZ treatment were found during the study (Table 2).

Table 2. Spearman's rank correlations between predictors after 2 weeks of tocilizumab*
 MTX treatmentSum BMUS score (22 joints)Sum PDUS score (22 joints)Patient's global assessment of health (VAS)Patient's global assessment of pain (VAS)Assessor's global assessment of health (VAS)Swollen joints (28 joints)Tender joints (28 joints)ESR, mm/hourCRP level, mg/liter
  • *

    MTX = methotrexate; BMUS = B-mode ultrasonography; PDUS = power Doppler ultrasonography; VAS = visual analog scale; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; DAS28 = Disease Activity Score in 28 joints.

  • P < 0.05.

MTX treatment1         
Sum BMUS score (22 joints)0.121        
Sum PDUS score (22 joints)0.130.551       
Patient's global assessment of health (VAS)0.150.110.111      
Patient's global assessment of pain (VAS)0.110.190.090.611     
Assessor's global assessment of health (VAS)0.110.090.120.590.661    
Swollen joints (28 joints)0.090.410.420.330.310.311   
Tender joints (28 joints)0.080.250.210.130.280.320.351  
ESR, mm/hour0.110.250.230.210.290.210.170.161 
CRP level, mg/liter0.080.250.260.220.210.190.170.190.31
DAS28 (ESR)0.080.110.120.160.220.180.160.140.20.19

Primary end point.

Table 3 shows how the mean change of each parameter after 2 weeks of treatment correlated with the change in DAS28 at 24 weeks. The changes of sum PDUS scores and sum BMUS scores after 2 weeks were well correlated with the change in DAS28 at 24 weeks. The change of sum PDUS scores after 2 weeks of treatment was the variable most closely correlated with the change in DAS28 at 24 weeks (Table 3).

Table 3. Mean change of each parameter after 2 weeks of treatment correlated with the change in DAS28 at 24 weeks*
 Mean change after 2 weeks of TCZ treatmentCorrelation, rP
  • *

    The mean changes of US (BMUS and PDUS) scores, patient's global assessment of health (VAS), patient's global assessment of pain (VAS), assessor's global assessment of health (VAS), number of swollen and tender joints, ESR, CRP level, and DAS28 after 2 weeks of TCZ treatment were correlated to the change in DAS28 after 24 weeks of TCZ treatment using Pearson's correlation. DAS28 = Disease Activity Score in 28 joints; TCZ = tocilizumab; MTX = methotrexate; BMUS = B-mode ultrasonography; PDUS = power Doppler ultrasonography; VAS = visual analog scale; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein.

  • P < 0.05.

MTX treatment0.0560.326
Sum BMUS score (22 joints)−40.5450.025
Sum PDUS score (22 joints)−70.6220.019
Patient's global assessment of health (VAS)−20.2920.144
Patient's global assessment of pain (VAS)−20.2720.144
Assessor's global assessment of health (VAS)40.0220.622
Swollen joints (28 joints)00.0310.412
Tender joints (28 joints)00.0310.412
ESR, mm/hour−60.1440.232
CRP level, mg/liter−2.60.3010.058
DAS28 (ESR)−1.960.1210.192

All 16 patients with improved sum PDUS scores at 2 weeks (>20% from baseline; PDUS positive) showed good responses (change in DAS28 >1.2; good response DAS28) (8) from baseline to 24 weeks after TCZ (Figure 1).

thumbnail image

Figure 1. One typical patient had improved power Doppler images at the wrist from baseline to 24 weeks after tocilizumab (TCZ).

Download figure to PowerPoint

All 4 patients with no sum PDUS score improvement (<5% from baseline; PDUS negative) and 5 patients with no sum BMUS score improvement (<5% from baseline) at 2 weeks failed to respond (change in DAS28 <0.6) (8) from baseline to 24 weeks after TCZ. The relative risk of good response DAS28 from baseline to 24 weeks after TCZ of PDUS positive/PDUS negative at 2 weeks is 9.56; this value is quite high.

Intraobserver and interobserver reliability of US assessment.

All intraobserver ICCs for BMUS and PDUS variables were significant at the level of P < 0.001, reflecting a high degree of intraobserver reliability.

Interobserver agreement in assessments of BMUS and PDUS was significant (P < 0.05). Kendall's W coefficient was 0.88 for assessment of BMUS and 0.87 for PDUS.

DISCUSSION

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

In recent years, US (especially PDUS) has proven itself to be a sensitive tool for assessing disease activity in patients with RA. There are several studies indicating that PDUS is an effective tool to evaluate changes to wrist, hand, and small joints following treatment with TNF blockers (3, 15). Naredo et al reported that cumulative counts of joints with BMUS or PDUS scores improve very quickly within 1 month after receiving anti-TNF biologics in patients with RA (3). There is a report that cumulative counts of joints with BMUS or PDUS signals change more remarkably in early stages rather than in late stages in patients receiving anti-TNF biologics (3). We have observed this same phenomenon in patients receiving TCZ. Data on day-to-day US image changes (BMUS and PDUS) over the course of disease in patients treated with TCZ will be published as part of a different study. The early stage is more informative. Because TCZ is very expensive, it is important to determine whether RA patients continue to use TCZ in the early stage or not. We then chose to look at 2 weeks to predict outcome, rather than other time points.

In the present study, the best predictors at 2 weeks of favorable TCZ treatment outcome after 24 weeks were improvements in sum PDUS scores. Surprisingly, global disease activity, pain, ESR, and DAS28 did not predict a favorable treatment outcome in this study.

According to ACR and European League Against Rheumatism recommendations (16), in patients responding insufficiently to MTX, a TNF inhibitor should be started. Also, patients with RA for whom a first TNF inhibitor has failed should receive another biologic (include TCZ). But in this study, we used TCZ as a first biologic in MTX-resistant active RA. We need further research in patients responding insufficiently to TNF inhibitors.

We chose DAS28-ESR as a measure of disease activity. According to a sensitivity analysis using different definitions of disease activity, the response of DAS28 may be influenced by TCZ rather than a true clinical response (17). We need further research of other composite measures as disease activity as well.

In US reliability, the comparisons were made using static images. Although this approach has been previously applied, it is clearly not informative in practice (as prospective assessment is made on live images). We need US reliability check on live images.

We also only evaluated the dorsal scan in the hand and wrist without evaluating the flexor tendons and the presence of synovitis or PDUS signal inside the tendon sheath, and the use of a linear probe with a maximum frequency of 12 MHz was probably not enough to properly evaluate the small joints of the hand (18). Recently, 3-dimensional US also has been developed and it is more informative than our method (19, 20). We need to evaluate further studies of the abovementioned method.

Therefore, when using TCZ in patients with RA, if the US images (especially sum PDUS scores) show marked improvement despite a lack of improvement in conventional disease activity measures in the early treatment period (global activity, pain, ESR, and DAS28), we suggest that TCZ should be continued.

AUTHOR CONTRIBUTIONS

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

Acquisition of data. Kume, Amano, Yamada, Hatta.

Analysis and interpretation of data. Kume, Kuwaba, Ohta.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  • 1
    Kane D, Balint PV, Sturrock RD. Ultrasonography is superior to clinical examination in the detection and localization of knee joint effusion in rheumatoid arthritis. J Rheumatol 2003; 30: 96671.
  • 2
    Naredo E, Bonilla G, Gamero F, Uson J, Carmona L, Laffon A. Assessment of inflammatory activity in rheumatoid arthritis: a comparative study of clinical evaluation with grey scale and power Doppler ultrasonography. Ann Rheum Dis 2005; 64: 37581.
  • 3
    Naredo E, Moller I, Cruz A, Carmona L, Garrido J. Power Doppler ultrasonographic monitoring of response to anti–tumor necrosis factor therapy in patients with rheumatoid arthritis. Arthritis Rheum 2008; 58: 224856.
  • 4
    Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Ramus C, Rovensky J, Alecock E, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomized trial. Lancet 2008; 371: 98797.
  • 5
    Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumor necrosis factor biologicals: results from a 24-week multicentre randomized placebo-controlled trial. Ann Rheum Dis 2008; 67: 151623.
  • 6
    Bergman GJ, Hochberg MC, Boers M, Wintfeld N, Kielhorn A, Jansen JP. Indirect comparison of tocilizumab and other biologic agents in patients with rheumatoid arthritis and inadequate response to disease-modifying antirheumatic drugs. Semin Arthritis Rheum 2010; 39: 42541.
  • 7
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 31524.
  • 8
    Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight–joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995; 38: 448.
  • 9
    Rubin JM, Adler RS, Fowlkes JB, Spratt S, Pallister JE, Chen JF, et al. Fractional moving blood volume: estimation with power Doppler US. Radiology 1995; 197: 18390.
  • 10
    Backhaus M, Burmester GR, Gerber T, Grassi W, Machold KP, Swen WA, et al. Guidelines for musculoskeletal ultrasound in rheumatology. Ann Rheum Dis 2001; 60: 6419.
  • 11
    D'Agostino MA, Conaghan PG, Naredo E, Aegerter P, Iagnocco A, Freeston JE, et al. The OMERACT Ultrasound Task Force: advances and priorities. J Rheumatol 2009; 36: 182932.
  • 12
    Lassere M, Boers M, van der Heijde D, Boonen A, Edmonds J, Sauden A, et al. Smallest detectable difference in radiological progression. J Rheumatol 1999; 26: 7319.
  • 13
    Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 1: 30710.
  • 14
    Wells G, Beaton D, Shea B, Boers M, Simon L, Strand V, et al. Minimal clinically important differences: review of methods. J Rheumatol 2001; 28: 40612.
  • 15
    Hammer HB, Sveinsson M, Kongtorp AK, Kvien TK. A 78-joints ultrasonographic assessment is associated with clinical assessments and is highly responsive to improvement in a longitudinal study of patients with rheumatoid arthritis starting adalimumab treatment. Ann Rheum Dis 2010; 69: 134951.
  • 16
    Smolen JS, Landewe R, Breedveld FC, Dougados M, Emery P, Gaujoux-Viala C, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010; 69: 96475.
  • 17
    Smolen JS, Aletaha D. Interleukin-6 receptor inhibition with tocilizumab and attainment of disease remission in rheumatoid arthritis: the role of acute-phase reactants. Arthritis Rheum 2011; 63: 4352.
  • 18
    Scire CA, Meenagh G, Filippucci E, Riente L, Delle Sedie A, Salaffi F, et al. Ultrasound imaging for the rheumatologist. XXI. Role of ultrasound imaging in early arthritis. Clin Exp Rheumatol 2009; 27: 3914.
  • 19
    Naredo E, Moller I, Acebes C, Batlle-Gualda E, Brito E, de Aqustin JJ, et al. Three-dimensional volumetric ultrasonography: does it improve reliability of musculoskeletal ultrasound? Clin Exp Rheumatol 2010; 28: 7982.
  • 20
    Filippucci E, Meenagh G, Delle Sedie A, Salaffi F, Riente L, Lagnocco A, et al. Ultrasound imaging for the rheumatologist. XX. Sonographic assessment of hand and wrist joint involvement in rheumatoid arthritis: comparison between two- and three-dimensional ultrasonography. Clin Exp Rheumatol 2009; 27: 197200.