indonesian journal of rheumatology 2018 vol10 no1 rev ok.pdforiginal article 4 indonesian journal of...

January - June, 2018 Vol 10 No.1ISSN: 2086–1435

The official journal of Indonesian Rheumatology Association

INDONESIAN JOURNAL OF

RHEUMATOLOGY

IJRIndonesian Journal of RheumatologyThe Official Journal of the Indonesian Rheumatology Association (IRA)

Cover image: Ultrasound of the left shoulder, prior aspiration (left) and on aspiration (right)

AIMS AND SCOPEIndonesian Journal of Rheumatology is self-focused on rheumatic diseases and connective tissue disorders in forms of original article (extended or concise reports), review articles, editorial, letters, leaders, lesson from memorable cases, book review, and matters arising. Both clinical and laboratory including animal studies are welcome.

Editor-in-ChiefYoga I Kasjmir

Associate EditorsAnna ArianeSandra S. LangowLinda Kurniaty Wijaya

Editorial Board / Peer ReviewerBambang Setiyohadi (Indonesia)Joewono Soeroso (Indonesia)Nyoman Kertia (Indonesia)Laniyati Hamijoyo (Indonesia)Rachmat Gunadi Wachjudi (Indonesia)C Singgih Wahono (Indonesia)RM Suryo Anggoro (Indonesia)Kusworini Handono (Indonesia)Rudy Hidayat (Indonesia)Bagus Putu Putra (Indonesia)I Nyoman Suarjana(Indonesia)Joko Rilo Pambudi (Indonesia)Rohini Handa (India)Chak Sing Lau, (Hongkong)Sandra Navarra (Philippines)Chng Hiok Hee(Singapore)Attiqul Haq,(Bangladesh)Kazuhiko Yamamoto(Japan)Zuljasri Albar (Jakarta, Indonesia)Sandra Sinthya Langow (Jakarta, Indonesia)Jeffrey Arthur Ongkowijaya (Manado, Indonesia)

Advisory CommitteeHarry Isbagio Handono KalimZulasri AlbarJoewono SoerosoNyoman KertiaZaenal Arifin Adnan

Editorial TeamRatna Dwi Puji Astuti

INSTRUCTION FOR AUTHORSFull instruction is available online athttp://www.reumatologi.or.id. If you do not have any access please contact editorial office.

Copyright© 2016 Indonesian Rheumatology Association. All rights reserved.No part of this publication may be produced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise without the prior permission.

Contents Volume 10 Number 1 | IJR January - June, 2018

Editorial3 Editorial Note Yoga I Kasjmir

Original article4 The Use of Tocilizumab in Combination with Methotrexate in Indonesian

Rheumatoid Arthritis Patients (PICTURE INA Study) Bambang Setyohadi, Harry Isbagio, Rachmat Gunadi Wachjudi, Joewono Soeroso,

Handono Kalim, Deddy Nur Wachid Achadiono

11 Proportion and Factors that Associate with Incidence of Hepatotoxicity in Rheumatoid Arthritis Patients Treated with Methotrexate in RSCM Year 2013−2015

Rahma Anindya Prathitasari, Harry Isbagio

15 Clinical Manifestation and Laboratory Finding of Sclerosis Systemic Patient in Dr. Hasan Sadikin General Hospital Bandung : A Descriptive Quantitative Study

Annisa Meivira Budiman, Sumartini Dewi, Marietta Shanti Prananta

20 Correlation of sCD40L Level with Force Vital Capacity Value in Restrictive Lung Disease of Systemic Sclerosis Patients SusantoSalim, Rachmat Gunadi Wachjudi, Sumartini Dewi

24 Validation of Modified COPCORD Questionnaire Indonesian Version as Screening Tool for Joint Pain and Musculoskeletal Diseases

Muhammad Anshory, C.Singgih Wahono, Handono Kalim, Harun Al Rasyid

31 Prevalence of Albuminuria and Associated Factors among Gout Arthritis Patients in Cipto Mangunkusumo Hospital

Jeffrey Christian Mahardhika, R.M. Suryo Anggoro

CASE REPORT37 Management of Salmonella Septic Bursitis in Renal Transplant Recipient Albert Prasetya, Anna Ariane, Bambang Setyohadi

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January - June, 2018 Vol 10 No.1ISSN: 2086–1435

The official journal of Indonesian Rheumatology Association

INDONESIAN JOURNAL OF

RHEUMATOLOGY

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Editorial

Editorial NoteYoga I Kasjmir

3Indonesian Journal of Rheumatology 2018; Vol 10 No.1

Last but not least, we provide article about prevalence of albuminuria and associated factors among gout arthritis patients in Cipto Mangunkusumo General Hospital.6 This article explained whether albuminuria in gout patients have significant correlation with some factors. What an interesting found from this article is although the researchers not found significant correlation between some factors with albuminuria, but their found that prevalence of albuminuria among the patient in Cipto Mangunkusumo General Hospital was high, especially in patients who have stage-2 hypertension.6

Last article we have case report about management of Salmonella septic bursitis in immunocompromised host post renal transplant.7 Salmonella as causative agent in septic bursitis and septic arthritis is rare. Some report salmonella as etiologic agent in bone and joint infection about <1% cases.7 This case report gives a very useful recommendation in making diagnosis and managing septic bursitis caused Salmonella.

Finally, we hope all readers get some knowledge regarding rheumatic disease which could be implemented in your clinical practice. We honourly invite all the clinicians and researchers to give contribution for the next edition of our magazine with your articles, cases, or studies by sending your manuscript to [email protected] or www.journalrheumatology.or.id with subjects “manuscript for IJR”. More information regarding the script collection is available on our website www.journalrheumatology.or.id.

Reference1 Setyohadi B, Isbagio H, Wachjudi RG, Soeroso J, Kalim H,

Achdiono DNW. The use of tocilizumab in combination with methotrexate in Indonesian Rheumatoid Arthritis Patients (PICTURE INA Study)

2 Prathitasari RA, Isbagio H. Proportion and factors that associate with incidence of hepatotoxicity in Rheumatoid Arthritis patients treated with methotrexate in RSCM year 2013 – 2015.

3 Budiman AM, Dewi S, Prananta MS. Clinical manifestation and laboratory finding of sclerosis systemic patient in Dr Hasan Sadikin General Hospital Bandung: a descriptive quantitative study.

4 Salim S, Wachjudi RG, Dewi S. Correlation of sCD40L level with force vital capacity value in restrictive lung disease of systemic sclerosis patients.

5 Anshory M, Wahono CS, Kalim H, Al Rasyid H. Validation of Modified COPCORD Questionnaire Indonesian Version as Screening Tool for Joint Pain and Musculoskeletal Disease.

6 Mahardika JC, Anggoro RMS. Prevalence of albuminuria and associated factors among gout arthritis patients in Cipto Mangunkusumo hospital.

7 Prasetya A, Ariane A, Setiyohadi B. Management of Salmonella Septic Bursitis in Immunocompromised host post renal transplant.

Rheumatoid Arthritis (RA) is a common, chronic, inflammatory condition causing systemic illness and pain, swelling and destruction of the joints. Treatment aims to control pain and inflammation, reduce joint damage and disability, and maintain or improve physical function and quality of life. Conventional treatment of RA followed by Disease Modifying Anti-Rheumatic Drugs (DMARDs) such as methotrexate, hydroxychloroquine, and sulfasalazine in short-term is proved efficacy but in long-term effectiveness is less optimal and also has toxic effect. Therefore studies about effectiveness and efficacy of other RA treatments are needed. Our first article written by Setyohadi B, et al, issues about the use of tocilizumab in combination with methotrexate in Indonesia Rheumatoid Arthritis patients (PICTURE INA study).

1 Tocilizumab (TCZ) represents a novel approach to the treatment of RA which may offer an alternative for patients who have an inadequate clinical response to non-biologic DMARDs. 1 The finding of this study is tocilizumab seems to be efficacious and safe treatment to RA patient. This study provide the basis for clinical practice recommendations to Indonesian physicians on the management of patients treated with TCZ.1

In this edition, we also have one article which describe about proportion and factors that associate with incidence of hepatotoxicity in Rheumatoid Arthritis patients treated with methotrexate in Cipto Mangunkusumo general hospital.2 Although the study is not find correlation between some factors which suspect with incidence hepatotoxicity, this study find that proportion of hepatotoxicity in Cipto Mangunkusumo Hospital is higher than previous study conducted by Sotoudenamesh et al.2 The other articles are showing about clinical manifestation and laboratory findings of sclerosis systemic patient in Hasan Sadikin General Hospital Bandung, and correlation of sCD40L Level with force vital capacity value in restrictive lung disease of systemic sclerosis patients.3,4

The need of epidemiological data on joint and musculoskeletal diseases, especially in Indonesia is very important. Because based on data we can see the impact of the disease to the population and provide recommendation for intervention plan both in terms of detection and therapy.5 This edition provide article written by Anshory et al which adopt COPCORD questionnaire Indonesian version from WHO-ILAR as good tool in the screening of joint pain and musculoskeletal diseases.5 What makes this article interesting is the author reveal that all question on the COPCORD questionnaire has significant correlation and some of the question has good sensitivity and specificity.7 So the modified COPCORD questionnaire Indonesian version can adopt to screen joint pain and musculoskeletal disease in Indonesia.5

Original Article

4 Indonesian Journal of Rheumatology 2018; Vol 10 No.1

Introduction Rheumatoid arthritis (RA) is a progressive, systemic autoimmune disease characterized by inflammation of the synovial membrane lining the joints. This inflammation causes cartilage and bone erosion leading to deformity and loss of function, resulting in pain, stiffness and swelling, ultimately leading to irreversible joint destruction and disability. RA is the most common chronic inflammatory disease in the western world with a prevalence of 0.5% to 1.0%1.

Current treatment in RA such as NSAID, DMARD and biological compounds that target TNF-α, B-cells or T-cells had some limitation of effectiveness in many patients2,3,4,5, hence there is a medical need for more effective treatments for RA based on an understanding of the underlying pathophysiology of the course of the disease.

IL-6 is a multifunctional pro inflammatory cytokine produced by a variety of cell types. IL-6 has been implicated in the pathogenesis of a variety of diseases including inflammatory rheumatic diseases, osteoporosis, neoplasia, and aging.6,7 IL-6 exerts its effects through a ligand-specific receptor (IL-6R), present both in soluble and membrane-expressed forms. Elevated serum and synovial IL-6 levels have been reported in RA patients compared with controls reflecting local production of IL-6 by the synovium.6 Preclinical studies suggest that IL-6 is associated with demargination of neutrophils and egress from the bone marrow so that the opposite effect may occur with IL-6R signaling inhibition. IL-6 levels correlate with disease activity in RA,8 and improvements associated with DMARD use are accompanied by a reduction in serum IL-6 levels.7

Tocilizumab (TCZ) is a recombinant humanized anti-human monoclonal antibody of the immunoglobulin IgG1 subclass directed against the IL-6 receptors and produced by recombinant DNA technology. Administration of TCZ is expected to inhibit all IL-6 related negative effects in RA patients. The present study is intended to assess the efficacy, safety and tolerability of TCZ in combination with methotrexate (MTX) in patients with moderate to severe active RA in a routine clinical practice setting in Indonesian patients.

AbstractBackground Aim of this research is to assess the efficacy and safety of tocilizumab (TCZ) in combination with methotrexate (MTX) in Indonesian patients with moderate to severe active rheumatoid arthritis (RA) who have an inadequate response to non-biologic DMARDs.Methods This was a interventional, prospective, single arm, multicenter, study in Indonesian male or female patients aged ≥ 18 years old, with a diagnosis of RA for > 6 months based on ACR 1987 revised criteria with moderate to severe disease activity (DAS28 score > 3.2) after ≥ 12 weeks of non-biologic DMARDs treatment. The treatment consisted of tocilizumab, 8 mg/kg, intravenous (IV), every 4 weeks for a total of 6 infusion in combination with oral MTX (10−25 mg) every week. Efficacy was assessed based on the percentage of patients achieving low disease activity state (DAS28 < 3.2), percentage of patients achieving reduction > 1.2 point of DAS28, percentage of patients achieving remission (DAS28 < 2.6), and percentage of patients with ACR20, ACR50, and ACR70 responses. Descriptive statistics will be used for presentation of results.Results 100% patients reached low disease activity (DAS28 ≤ 3.2) at last study visit (week 24) and clinically significant improvement (reduction at least 1.2 units) at every visit in DAS28, both for ITT or PP patients. Remission (DAS28 < 2.6) was observed in 82.1% (ITT patients) and 93.1 % (PP patients) on last study visit. ACR20, ACR50, and ACR70 were achieved in 20%, 34%, and 34% (ITT patients), and 7%, 24%, and 62% (PP patients) on week 24. There were 3 out of 39 patients (7.69%) with adverse events (AE) and serious adverse events (SAE) that resulted in discontinuation of TCZ treatment, consisting of 1 patient with SAE of sepsis ec acquired community pneumonia, 1 patient with SAE of pneumonia tuberculosis, and 1 patient with AE of candidiasis. Most common adverse events were hepatic dysfunction (30.7%), hypercholesterolemia (23.1%), followed by arthralgia (20.5%) Twelve percent of patients needed dose modification due to elevated liver enzyme (elevated ALT/SGPT level). Conclusion Tocilizumab seems to be efficacious and likely to have good safety profile in non- biologic DMARD nonresponsive RA patients of PICTURE INA study. Keywords: Rheumatoid Arthritis, Tocilizumab, DMARD, DAS28

1 Cipto Mangunkusomo Hospital, Jakarta, 2 Hasan Sadikin Hospital, Bandung, 3 Soetomo Hospital, Surabaya, 4 Dr. Saiful Anwar Hospital, Malang, 5 Sardjito Hospital, Yogyakarta

Corresponding author: Bambang Setyohadi MD, [email protected]

The Use of Tocilizumab in Combination with Methotrexate in Indonesian Rheumatoid Arthritis Patients (PICTURE INA Study)

Bambang Setyohadi1, Harry Isbagio1, Rachmat Gunadi Wachjudi2,Joewono Soeroso3, Handono Kalim4, Deddy Nur Wachid Achadiono5

Original Article


MethodsThis study was using an interventional, single-arm, multicenter clinical study conducted from March 2011 to July 2012 in Indonesian patients, aged > 18 years, suffering from rheumatoid arthritis for more than 6 months duration based on ACR 1987 revised criteria. The patients have moderate to severe disease activity (DAS28 > 3.2) at screening and still have active RA after ≥ 12 weeks of non-biologic DMARDs (methotrexate, chloroquine, hydroxychloroquine, parenteral gold, sulfasalazine, azathioprine, and leflunomide). DMARD dose should have been stable for a period of 8 weeks or longer; but have inadequate clinical response.

Excluded from the study were patients with the following criteria: major surgery (including joint surgery) within 8 weeks prior to screening or planned to have major surgery within 6 months following enrollment; autoimmune disease other than RA including systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), scleroderma, polymyositis, or significant systemic involvement secondary to RA (e.g. vasculitis, pulmonary fibrosis or Felty’s syndrome); prior history of or current inflammatory joint disease other than RA (e.g. gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, lyme disease). Those receiving the following drugs were also excluded: any investigational agent or calcineurin inhibitors (e.g. tacrolimus or cyclosporine), mycophenolate mofetil or mycophenolic acid sodium within 4 weeks (or 5 half-lives of drug, whichever is longer); previous treatment with any biologic drug that is used in the treatment of RA, treatment with IV gamma globulin, plasmapheresis within 6 months before the study; intra articular or parenteral corticosteroids within previous 6 weeks; immunization with a live/attenuated vaccine within 4 weeks prior to baseline; previous treatment with TCZ; any previous treatment with alkylating agents, such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation. Renal dysfunction (serum creatinine > 1.6 mg/dL for female or 1.9 mg/dL for male), liver dysfunction (serum transaminases > 1.5 ULN), anemia with hemoglobin < 8 g/dL, leucopenia (WBC <300/mm3), thrombocytopenia (platelet count < 100.000/mm3), and positive HBsAg, anti HCV, HIV, tuberculosis within 3 years prior to the study, were also excluded.

The protocol for this study was reviewed and approved by Ethical Committee of Faculty of Medicine of University of Indonesia, Jakarta. All participating subjects in this study signed the informed consent for participation in the study.

Study treatmentPatients receive an intravenous infusion of 8 mg/kg of tocilizumab every 4 weeks on an outpatient basis for a total of 6 infusions (week 0, week 4, week 8, week 12, week 16 and week 20). For patients weighing more than 100 kg, the maximum dose of TCZ will be 800 mg. Oral methothrexate (MTX) is continued with the range dose of 10−25 mg every week, according to previous stable dose of the patient. The dose and route of MTX is to be continued without change unless an adjustment is necessary for safety reasons. Schematic representation of treatment and follow up can be seen in figure 1.

Forty patients were planned to be enrolled in this study. There was no sample size calculation due to exploratory nature of the study. The number of subjects enrolled in the study was determined based on practical considerations in study site according to their potential for enrollment.

Figure 1. Schematic representation of treatment with TCZ and MTX.

Efficacy evaluationEfficacy of treatment was measured in intent to treat (ITT) patients, i.e all patients, who take at least one dose of study drug and return at least once after receiving one dose. Per protocol (PP) patients who completed TCZ treatment of six doses, without eligibility violation will also be evaluated.

The following parameters will be evaluated are: 1) number and percentage of patients achieving low disease state (DAS28 < 3.2), 2) number and percentage of patients achieving significant improvement (reduction of at least 1.2 units of DAS28) and time to clinically significant improvement in DAS28, 3) number and percentage of patients achieving remission (DAS28 < 2.6) at every visit, 4) disease activity as measured by American College of Rheumatology 20%, 50%, and 70% improvement (ACR 20/50/70) were measured at week 24, 5) Laboratory improvement in term of CRP and ESR was also evaluated.

The DAS28 is a combined index for measuring disease activity in RA. The index includes swollen and tender joint counts, acute phase response (ESR or CRP), and general health status. The DAS28, which uses a 28 joint count, is derived from the original DAS, which includes a 44 swollen joint count. The index is calculated using the following formula:,

DAS28 = 0.56 × √(TJC) + 0.28 × √(SJC) + 0.70 × ln(ESR) + 0.014 × GH which TJC = tender joint count on 28 joints, SJC = swollen joint count on 28 joints, ln = natural log, ESR = erythrocyte sedimentation rate (mm/hr), and GH = general health, i.e. patient’s global assessment of disease activity (100 mmVAS). The DAS28 scale ranges from 0 to 10 which higher scores represent higher disease activity.

Safety evaluationAll patients who receive at least one dose of the study drug and return at least once after receiving study drug will be subject to safety evaluation. Parameters of safety will include incidence of adverse events, serious adverse events, and adverse event of special interest (e.g. ALT (SGPT) or AST (SGOT) elevations, serum lipids elevations).

Original Article


Data analysisThis is an interventional, single arm, multicenter study. Primary endpoint and other end points are reported as descriptive statistics. Thirty nine patients were enrolled from March 20, 2011 –July 4, 2012.

ResultsDisposition of patientsFifty eight patients were screened and 39 patients were enrolled to this study and included for evaluation of safety. Four patients were withdrawn during the study due to SAE (3 patients) and treatment failure (1 patient). There were 7 patients who had protocol violations related with the entry criteria (eligibility criteria), in which 6 patients completed the study until week 24 due to delay in identifying the protocol deviation related to the eligibility criteria while the other patient was one of the four patients withdrawn during the study. Thus, only 29 patients included as per protocol (PP) evaluation. Patient disposition is presented in figure 2.

Figure 2. Patient disposition of study subjectsFigure 2. Patient disposition of study subjects

Characteristics data of the study subjects can be seen in table 1. Most of patients were female, and more than half were less than 50 years old. Ethnicity was dominated by those from Java island (Javanese and Sundanese).

Patients consented and screened (n=58)

Patients enrolled (n=39 patients)

Patients performed baseline/week 0 (n=39 (100%))

Patients performed Week 4 (n=39 (100%))

Patients performed Week 8 (n=38 (97.5%))

Patients performed Week 12 (n=38 (97.5%))




Patients screened failure (n=19) patients

Patients withdrawn (SAE) (n=1 (2.5%)) patients

Patients withdrawn (treatment failure) (n=1 (2.5%))

Patients withdrawn (SAEs) (n=2 (5%))

Patients excluded from PP population due to protocol deviation of eligibility

criteria (n=6 (16%)) Per protocol (PP) Population (n=29 (74%))

Characteristics data of the study subjects can be seen in table 1. Most of patients were female, and more than half were less than 50 years old. Ethnicity was dominated by those from Java island (Javanese and Sundanese).

Table 1. Demographic Characteristic and baseline data of study subjects

Variable n (%) Mean + SD Median (min-max)

Gender Male Female

3 (7.7)36 (92.3)

Age >50 yrs< 50 yrs

17 (43.6)22 (56.4)

53 ( 19 – 75 )

Ethnic Javanese SundaneseChinese BataknesePadangneseJavanese-Sundanese

23 (59.0)8 (20.5)3 (7.7)2 (5.1)2 (5.1)1(2.6)

Length of disease >5 yrs< 5 yrs

11 (28.2)28 (71.8)

3 ( 1 – 31 )

SBP (mmHg)DBP (mmHg)

119.6 + 11.278.6 + 6.5

Previous RA related treatmentsMethotrexate Folic acidChloroquineCalciumCelecoxib

36.6%30.8%4.8%1.9%1.9%

Lab parameters Mean + SD Min - Max

ESR (mm) 48.1 +26.10) 9 - 105CRP (mg/L) 17.6 +21.58) 0.25 - 77Hemogloblin (g/dL) 12.2 +1.29) 8.3 - 14Platelet (x103) 351.3 +116.6) 41.1 - 594ANC 6.26 +2.4) 2.58 - 11.51Total Cholesterol 179.8 +37.5) 94 - 275Triglyceride 102.3 +43.9) 45 - 211HDL Chol. (mg/dL) 56.8 +11.5) 37 - 82LDL Chol. (mg/dL) 105.9 +28.7) 47 - 178SGOT (mg/dL) 18.3 +7.5) 7 - 46SGPT (mg/dL) 17.7 +8.8) 4 - 50

Note: SBP: Systolic Blood Pressure; DBP: Diastolic Blood Pressure; ESR: Erithrocyte Sedimentation Rate, CRP: C-Reactive Protein, ANC: Absolute Neutrophyl Count, HDL: High Density Lipoprotein; LDL: Low Density Lipoprotein; SGOT: Serum Glutamic-Oxaloasetic Transaminase, SGPT: Serum Glutamic Pyruvic Transaminase.

Efficacy Evaluation1. Proportions of patients achieving low disease activity

(DAS28 ≤3.2)The efficacy of tocilizumab (TCZ) in combination with MTX was observed based on achievement of low disease activity DAS28 (DAS28 ≤ 3.2). The patients in this study showed good efficacy result as measured by DAS28 that decreased over time. For ITT populations at week 24, mean of DAS28 value was 1.75, (ranging 0.3 to 2.9), while for PP patients, mean of DAS28 value was 1.8 (ranging 0.49 to 2.9). In some patients, this low disease state has been attained since week 4 (after one dose of tocilizumab injection).

Original Article


Table 2. Percentage of patients achieving low disease activity (DAS28 < 3.2) on each time visit based on ITT and PP patients.

% of DAS28 <3.2n ITT PP

Baseline 39 0 0W-4 39 30.8 27.6W-8 38 48.7 48.3W-12 38 69.2 72.4W-16 37 82.1 86.2W-20 37 89.7 96.6W-24 35 100 100

2. Achievement of clinically significant improvement (Reduction of DAS28 at least 1.2 unit):

Figure 3. Percentage of patients achieving clinically significant improvement (DAS28 reduction of more than 1.2) during each visit in ITT patients (open bar) and PP patients (solid bar).

In ITT patients, a clinically significant improvement (reduction at least 1.2 units at every visit) in DAS28 was observed in 87.2% patient at week-4, 91.2% at week-8, 94.7% at week-12, 97.3% at week-16 and week-20. At week-24, all patients (100%) have significant improvement. A clinically significant improvement was observed in the PP population, 93.1% of patients at week-4, 96.4% at week-8, and all patients achieved 100% improvement at week-12, 16, 20 and 24 (Figure 3). Overall, large majority of patients only required a single infusion in order to achieve a clinically significant improvement (reduction at least 1.2 units) in DAS28.

3. Number and percentage of patients achieving remission (DAS28 < 2.6) at every visit and time to DAS28 remission. In ITT population there were 20.5% of patients achieving remission (DAS28<2.6) by week four, which increased at subsequent visits as shown in Figure 4. 36.8% patients were achieving remission by week 8, 44.7% by week 12, 59.0% by week 16, 74.4% and 82.1% by week 20 and 24. However in PP patients, there were 13.8% patients achieved remission by week 4; 34.5 % by week 8; 37.9% by week 12; 55.2 % by week 16; 86.2% by week 20 and 93.1% by week 24.

Figure 4. Percentage of patients achieving remission (DAS28 <2.6) in each visit.

4. Percentage of patients with ACR20, ACR50, and ACR70 response at week 24For ACR response on ITT patient population, ACR20 has been achieved in 20% patients, while on ACR50 and ACR70 have been achieved in 34% patients on week 24. PP population showed that ACR20, ACR50, and ACR70 have been achieved in 7%, 24% and 62% patients, respectively. However, there are 12% patients as per ITT and 7% as per PP did not response by week 24 (figure 5). The classification of patient’s response was made based on non-overlapping ACR response rate categories, instead of cumulative categories. The patients with ACR50 were not included in calculation of percentage of patients with ACR20 and patients with ACR 70 were not included in calculation of patients with ACR50 and ACR20.

Figure 5. Percentage of patients with ACR20, ACR50, and ACR70 response at week 24 (ITT and PP)

5. ESR and CRP at every visitESR and CRP are important markers used for diagnosis and monitoring of disease activity and response to anti-inflammatory therapy. Mean of hs-CRP and ESR were normalized (0−20 mm & hs CRP ≤10 mg/L) after first infusion and stable until last follow up at week-24 both for ITT and PP patient population (Figure 6)

Original Article


Figure 6. ESR and CRP at every visit during the treatment with tocilizumab and metothrexate.

Safety EvaluationCommon adverse events can be seen in table 3. The most frequent adverse events are increased hepatic enzyme (30.7%), followed by hypercholesterolemia (23.1%) and arthralgia (20.5%).

Table 3. Adverse events during administration of TCZ in combination with MTX.3

No Adverse Events N %

1 Increased hepatic enzyme 12 30.72 Hypercholesterolemia 9 23.13 Arthralgia 8 20.54 Extremity Pain 6 15.45 Ankle pain 5 12.86 Stomatitis 5 12.87 Cough 3 7.78 Dyspepsia 3 7.79 Headache 3 7.710 Influenza 3 7.7

There were 3 out of 39 patients (7.69%) with adverse events (AE) and serious adverse events (SAE) that resulted in discontinuation of TCZ treatment, consisting of 1 patient with SAE of sepsis ec acquired community pneumonia, 1 patient with SAE of pneumonia tuberculosis, and 1 patient with AE of candidiasis.

Most common adverse event special interest (AESI) was hepatic events (13 events), followed by infection which was treated with anti-infection (2 events) and bleeding event (1 event). There were 2 patients indicated as withdrawn patients however all cases have been resolved at the time of study closed.

Figure 7 shows lipid profiles of patients treated with TCZ and MTX in every visit. There were increases of total and LDL cholesterol, while triglyceride and HDL were relatively unchanged.

Figure 7. Number of patients with elevations in lipid.

DiscussionThis was an interventional study with single arm to assess the efficacy of tocilizumab (TCZ) in combination with methotrexate (MTX) in Indonesian patients with active rheumatoid arthritis who have an inadequate response to non-biologic DMARDs. The limitations of this study included a non-comparative study design and small number of subjects. Fifty eight patients were screened but only 39 patients were enrolled to this study and included as ITT population. Four patients were withdrawn during the study due to SAE/AE (3 patients) and treatment failure (1 patient). There were 7 patients had protocol violations related with the entry criteria (eligibility criteria). Six patients out of those 7 ineligible patients had completed the study until week 24 due to delay in identifying the this protocol deviation related to the eligibility criteria while the other 1 patient was one of the four patients withdrawn during the study. Thus, only 29 patients were included in the per protocol (PP) population (refer to figure 2). However, the overall results of this study show that treatment with TCZ, alone or in combination with MTX, is associated with significant improvements of RA symptoms compared to non-biologic DMARDS that have been received by the subjects. In addition, results of this treatment showed a favorable safety profile.

Rheumatoid arthritis is a chronic autoimmune inflammatory disease with a tendency of progression. Control of this disease is often problematic due to progressive nature of the disease. Spontaneous remission is rare, although still possible. TCZ represents a novel approach to the treatment of RA and, therefore, may offer an alternative for patients who have had an inadequate clinical response to non-biologic DMARDs. Overall the benefit/risk ratio for tocilizumab treatment in patients with moderate to severe RA is considered positive. These data provide the basis for clinical practice recommendations to Indonesian physicians on the management of patients treated with TCZ.

As based on efficacy result in this study, 100% patients reached low disease activity (DAS28 ≤ 3.2) and a clinically significant improvement (reduction at least 1.2 units at every visit) in DAS28 on last study visit (week 24) both for ITT or PP patient populations. Although this was a non-comparative study, this significant improvement is unlikely attributable to either carry over effect of MTX or spontaneous

Original Article


improvement. This statement is supported by the fact that all patients have been inadequately responsive to DMARDs after 8 weeks of stable dose. The rapid improvement after TCZ administration indicates that TCZ does have significant contribution to this improvement.

Clinical remissionIn addition, on last study visit, most of patients reached clinical remission (DAS28 < 2.6), 82.1% in ITT population and 93.1 % in PP population.

The study by Jones et al compared the effect of MTX with TCZ and placebo in 673 RA patients. It was reported that after 24 weeks, TCZ gave significantly better outcome in term of ACR20 and DAS28 < 2.6. A study with similar methodology has been conducted by Genovese et al. Proportion of patients achieving ACR20 response at week 24 was significantly greater in the TCZ plus DMARD group compared to control group, and combination of TCZ with other DMARD was shown to be better than DMARD alone. A double blind randomized control trial comparing TCZ alone or in combination with MTX or MTX alone in European RA patients with inadequate response to DMARDs has been reported by Maini et al.5 Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of TCZ plus MTX. SURPRISE study by the group of Kaneko et al reported that tocilizumab treatment added to methotrexate more rapidly suppressed inflammation than switching from methotrexate to tocilizumab.13 Regarding to other biologic non-TNF drugs, tocilizumab shows highest performance compared to rituximab, abatacept and tofacitinib in patients with RA.14

In our study, ACR20, ACR50 and ACR70 have been achieved in 20%, 34% and 34% by ITT patients, respectively, while on PP patients, the results were 7%, 24%, and 62%. It means that the longer the administration of TCZ, the better the outcome is.

ESR and CRP at every visitAfter one dose of TCZ, the ESR and CRP were rapidly normalized in this study, signifying the efficacy of TCZ in controlling inflammation of the patients. Again in these cases, the effects on ESR and CRP are unlikely to be due to MTX, since this non-biologic DMARD had previously been administered for at least eight weeks, yet the ESR and CRP remained elevated. Only after addition of TCZ those parameters normalized. This statement is supported by the study of Smolen et al,12 which reported a rapid decrease of CRP level after administration of 8 mg/kg TCZ, while in a lower dose (4 mg/kg), the CRP re-increased after further observation, and it never decrease in placebo group.

Safety profileSerious adverse eventsRegarding that immunosuppressive agents including MTX and TCZ modify immune response of patients, the risk of infection in patients receiving these agents should be taken into account. Administration of MTX for at least 8 weeks followed by addition of TCZ for further 20 weeks has been

associated with several incidences of serious infection. There were 3 out of 39 patients (7.69%) had adverse events (AE) and serious adverse events (SAE) which caused discontinuation of TCZ treatment. SAE occurred in 2 patients (<5%), 1 patient experienced sepsis ec acquired community pneumonia and 1 patient experienced pneumonia tuberculosis. Other study by Jones et al11 reported an incidence of serious infection was comparable in group receiving TCZ 8 mg/kg or MTX (1.4% vs 0.7%).

Other adverse eventsIt can be seen in table 4 that increased liver enzyme represents the most frequent adverse event (30.7%) followed by hypercholesterolemia (23.1%). Increased total cholesterol, LDL-cholesterol has been observed, suggesting a precaution for increased risk for cardiovascular disease. Thus, lipid profile of patients, especially those with cardiovascular risk factors, should be taken into account before giving tocilizumab.

Twelve percent of patients needed dose modification due to elevated liver enzymes. Liver enzyme levels had reached normal value in all patients since week 20. This incidence of increased liver enzyme is consistent with other TCZ phase III, randomized, double blind trials, OPTION study,15 AMBITION study,11and TOWARD study.12

For overall monitoring of vital sign it was observed that there was no significant difference in vital sign parameter (blood pressure, body temperature, pulse rate) from time to time.

ConclusionTocilizumab in combination with methotrexate seems to be efficacious and likely to have good safety profile in RA patients of PICTURE INA Study in Indonesia. Patient screening and effective monitoring for efficacy and safety is essential in order to get optimal results.

AcknowledgementThis study is funded by PT. Roche Indonesia. The authors gratefully acknowledge the assistance of Dr. Nafrialdi in preparing the manuscript and Dr. Joedo Prihartono, MPH for providing statistical analysis.

References1. Silman AJ. Epidemiology and the rheumatic diseases. In: Maddison PJ,

Isenberg DA, Woo P, Glass DN, eds. Oxford Textbook of Rheumatology: Oxford University Press:1993;499-513.

2. Brooks PM. Clinical management of rheumatoid arthritis. Lancet. 1993;341:286-290.

3. Edmonds JP, Scott DL, Furst DE, Brooks P, Paulus HE. Antirheumatic drugs: a proposed new classification. Arthritis Rheum 1993; 36:336-339.

4. Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000; 343:1586-1592.

5. Maini RN, Taylor PC, Szechinski J, Pavelka K, Broll J, Balint G, et al. CHARISMA Study Group. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with Rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum 2006; 54:2817-2829.

Original Article


6. Hirano T, Matsuda T, Turner M, Miyasaka N, Buchan G, Tang B, et al. Excessive production of IL-6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol 1988; 18:1797-801.

7. Keller TK, Wanagat J, Erschler WB. Molecular and cellular biology of interleukin-6 and its receptor. Frontiers Biosci 1996; 1:340-57.

8. Tamura T, Udagawa N, Takahashi N, Miyaura C, Tanaka S, Yamada Y, et al. Soluble interleukin-6 receptor triggers osteoclast formation by interleukin-6. Proc Natl Acad Sci USA 1993; 90:11924-11928.

9. The American Rheumatism Association 1987 revised criteria for the classificationof rheumatoid arthritis.Arthritis Rheum 1988;31:315–24

10. Van der Heijde DM, van‘t Hof MA, van Riel PL, Theunisse LA, Lubberts EW,van Leeuwen MA, et al. Judging disease activity in clinical practice in rheumatoidarthritis. First step in the development of a ‘disease activity score’. Ann RheumDis 1990; 49:916-920

11. Jones G, Sebba A, Gu J, Lowenstein M B, Calvo A, Gomez-Reino J J et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis 2010;69:88–96. doi:10.1136/ard.2008.105197

12. Genovese MC, McKay JD, Nasonov EL, Mysler E F, da Silva N A, Alecock E, et al. Interleukin-6 Receptor Inhibition WithTocilizumab Reduces Disease Activity in Rheumatoid Arthritis With Inadequate Response to Disease-Modifying Antirheumatic Drugs. ARTHRITIS & RHEUMATISM. 2008; 58(10):2968–80. DOI 10.1002/art.23940

13. Kaneko Y, Atsumi T, Tanaka Y et al. Comparison of adding tocilizumab to methotrexate with switching to tocilizumab in patients with rheumatoid arthritis with inadequate response to methotrexate: 52-week results from a prospective, randomised, controlled study (SURPRISE study). Ann Rheum Dis 2016;0:1–7. doi:10.1136/annrheumdis-2015-208426

14. Lee YH and Bae SC. Comparative efficacy and safety of tocilizumab, rituximab, abatacept and tofacitinib in patients with active rheumatoid arthritis that inadequately responds to tumor necrosis factor inhibitors: a Bayesian network meta-analysis of randomized controlled trials. Int J Rheumatic Dis.2015;1-9

15. Smolen J S, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, et al. forthe OPTION Investigators. Effect of interleukin-6 receptor inhibition with tocilizumabin patients with rheumatoid arthritis (OPTION study):a double-blind, placebo-controlled, randomised trial. Lancet 2008; 371: 987–97

Original Article


Proportion and Factors that Associate with Incidence of Hepatotoxicity in Rheumatoid Arthritis Patients Treated with Methotrexate in RSCM Year 2013−2015

Rahma Anindya Prathitasari1, Harry Isbagio2

1 General Medicine, Faculty of Medicine, University of Indonesia2 Rheumatology Division, Department of Internal Medicine, Faculty of Medicine University of Indonesia

Corresponding author: Rahma Anindya Prathitasari, [email protected]

proliferation that contributes to the progressivity of RA.1-7

Methotrexate is known to trigger liver dysfunction as side effect. Liver function is evaluated based on alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) serum titer. Elevation of liver enzyme above the upper limit indicates liver dysfunction. Based on study in India on 30 patients who were treated with MTX for 3 months, there was 25% elevation of AST above normal range.8 Study in Israel on 119 patients who were treated with MTX showed 43% of RA patients have abnormal liver enzyme titer.9 Study in Iran on 286 patients who were treated with MTX found that 23.7% of patients have experienced liver dysfunction.10 Based on the previous studies, factors that suspected association with liver dysfuction are gender, age, MTX cumulative dose, and MTX duration therapy.8-11

There is not any study about proportion of liver dysfuction on RA patients who are treated with MTX in Indonesia. The purpose of this study is to know the proportion of liver dysfunction in patients who are treated with MTX, and to analyze the association between age, gender, MTX cumulative dose, MTX therapy duration with liver dysfunction incidence, so that clinicians will be more aware with MTX use in patients.

MethodsThis study is a descriptive-analytic study with cross-sectional method. From the sample population, AST and ALT lab results, age, gender, MTX cumulative dose, and MTX duration therapy were obtained. The study was conducted in RSUPN Dr Cipto Mangunkusumo (RSCM) and RSCM Kencana, Jakarta for 11 months, from January to November 2016.

Data were obtained from patients’ medical records unit RSCM and RSCM Kencana, which meet inclusion criteria and opposite of exclusion criteria. The inclusion criterias are patients who fulfill diagnosis criteria of based on ACR/EULAR 2010, received MTX therapy for minimum period of one month, and patients of RSCM and RSCM Kencana. The exclusion criterias are patients who have other comorbidities that can cause liver dysfunction.

AbstractBackground Rheumatoid arhtirtis (RA) is a chronic autoimmune disease that mainly attacks joints. It may causes joint deformities which leads to lower quality of life of RA patients. RA is treated with metothrexate (MTX) which inhibiting disease progression. MTX is known for its hepatotoxicity side effect, which is described by an elevation of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) beyond the upper normal limit. Factors that may enhance hepatotoxicity are gender, age, cummulative dose of MTX, and duration therapy of MTX. Prevalence of hepatotoxicity caused by MTX therapy in RA patients in Indonesia is still unknown. The objective of this research is to know the proportion of hepatotoxicity and its associations with the factors that may enhance hepatotoxicity caused by MTX therapy in RA patients in RSCM. Method Data about gender, age, cummulative dose and duration therapy of MTX are obtained from 115 RA patients’ medical records. Result Proportion of hepatotoxicity in RA patients treated with MTX in RSCM is 42.60%. Gender, age, cummulative dose and duration therapy of MTX do not significantly enhance hepatotoxicity (p>0.05).Conclusion In conclusion gender, age, cummulative dose and duration therapy of MTX do not have association with hepatotoxicity in RA patients treated with MTX.Keywords: Rheumatoid Arthritis, Methotrexate, Hepatotoxicity

IntroductionRheumatoid arthritis (RA) is an inflammatory disease which has large impacts on daily activities of its sufferers. Inflammation manifests as pain that causes joint immobility. American College of Rheumatology and European Leauge Against Rheumatism (ACR-EULAR) created a tool to help diagnose RA in 2010. After the diagnosis is set, patient would be treated with Disease Modifying Anti Rheumatic Drugs (DMRADs). The target of DMARDs therapy is inhibiting joint erosion and causing remission. Based on ACR guideline on management of RA in year 2015, the first line therapy for is methotrexate (MTX). MTX works by supressing cytokine release and lymphocyte

Original Article


Data were processed by SPSS software and analyzed with inferential statistic. Gender and liver function variables were analyzed with Fisher test. Age, MTX cumulative dose, and MTX therapy duration variables undergone sample normality test with Kolmogorov Smirnov test. If the data distribution were normal, unpaired T- test between age, MTX cumulative dose, and MTX duration therapy and liver function would be conducted. If not normal, the Mann-Whitney test would be done. From the Mann-Whitney test, p value showed data significance.

ResultFrom 115 samples who were obtained, all the samples were given MTX with minimum dosage of 7.5 mg each week for minimum duration of one month. Samples do not have any comorbidities that could result in liver dysfunction. Samples demographic datas are shown in Table 1.

Table 1. Samples Demographic Data

Variable ResultGender, frequency (%)

MenWomen

9 (7.83%)106 (92.17%)

Age (year) 53.55 (19.98−84.53)*MTX cumulative dose (mg) 480.00 (25.00−3967.50)*MTX duration therapy (week) 44.00 (4−226)*AST titer, frequency (%)

Normal1−2 times above normal>2 times above normal

73 (63.48%)36 (31.30%)6 (5.22%)

ALT titer, frequency (%)Normal

1−2 times above normal >2 times above normal

75 (65.22%)34 (29.56%)6 (5.22%)

Liver dysfunction, frequency (%) 49 (42.60%)

*:not normally distributed data, data presented in median (range)

Association between gender and liver dysfunctionThere is no significant difference between proportion of men and women (p>0.05) in group with liver dysfunction and without.

Table 2. Association between gender and liver dysfunction

Variables Normal LFT Disturbed LFT P value

Women 63 (95.5)

3 (4.5)

43 (87.8)

6 (12.2)0.167

Men

LFT: Liver Function Test

Association between age and liver dysfunctionThere is no significant association between age and liver dysfunction incidences (p>0.05).

Table 3. Association between age and liver dysfunction

Liver function Result P score

AgeNormal 52.85 (19.98−84.53)*

0.46−0.23Disturbed 54.78 (23.56−72.75)*


Association between MTX cumulative dose and liver dysfunctionThere is no significant association between MTX cumulative dose and liver dysfunction incidences (p>0.05).

Table 4. Association between MTX cumulative dose and liver dysfunction

Liver function Result P scoreMTX

cumulative dose

NormalDisturbed

378.75 (25.00−3337.50)*

0.23−0.115495.00 (50.00−3967.50)*


Association between MTX duration therapy and liver dysfunctionThere is no significant association between MTX duration therapy and liver dysfunction incidences (p>0.05).

Table 5. Association between MTX duration and liver dysfunction Liver function Result P score

MTX duration therapy

Normal 43 (4−226) *

0.519−0.259Disturbed 44 (5−207) *


DiscussionProportion of liver dysfuction in patients who are treated with MTX in RSCM and RSCM Kencana is 42.60%. The proportion of liver dysfunction in this study is higher than study conducted by Sotoudenamesh et al which has proportion of liver dysfunction 23.7%.11 However, proportion of liver dysfunction in this study is suitable with other studies which conducted by Ede et al which stated that proportion of liver dysfunction is 53% and Bath et al which stated proportion of liver dysfunction is 15−50%. RA patients who are treated with chronic MTX experienced elevations in ALT and/or AST above the normal upper limit. About 5% of which experienced elevation until 2 times the normal range.12 This study result has 5.22% samples who experienced AST and/or ALT 2 times normal range. In the literature review by Conway et al liver dysfunction incidence is higher than liver dysfunction incidence in this study, AST and/or ALT elevations above normal upper limit and those who elevated above two times normal range is 48.9% and 16.8% respectively.13

Variations of liver dysfunction proportion in other studies might be caused different definitions of liver dysfunction. In this study, liver dysfunction is described as ALT and or AST abnormal result while treated with MTX. Sotoudenamesh et al described liver dysfunction as two abnormal ALT and AST results in interval of 2 weeks.10 Kremer et al described liver dysfunction based on liver hystology. The proportion differences also can be caused by different sample characteristics (ethnic and genetic variation).10

The time of laboratory test from last administration of MTX can also affect the liver enzyme titer. If the lab test were conducted after MTX administration, liver enzyme titer would be higher.14

Original Article


Folic acid supplementation is known to decrease the frequency of liver enzyme elevation.15 MTX hepatotoxicity mechanism is still unknown but allegedly result from the same mechanism of this drug mechanism of action. MTX causes inhibition of DNA and RNA synthesis in liver which result in damage and degeneration of liver cell. If the patients were given folic acid, DNA and RNA synthesis are not disturbed.14,

16 Epidemiologically, RA incidence is two to three times

higher in women than in men. The reason behind it is still unknown but thought to be genetic factor that X linked and estrogen factor.14 Studies by Amital et al and Parvin et al found women are more fragile to liver enzyme elevations.8,9 Hoekstra et al study shown women are more prone to MTX treatment discontinuation.15 However, in this study, gender and liver dysfunctions do not have any significant association. This study result is suitable to Sotoudenamesh et al study.10

Age median in this study is 52.8 years (19.98, 84.53) in group without liver dysfunction and 54.78 years (23.56, 72.75) in group with liver dysfuncton. There is no significant association between age and liver dysfunction incidence. This result is suitable to study by Sotoudenamesh et al, Hoekstra, and McKendry which also did not find any association between age and liver dysfunction in RA patients who are treated with MTX.10,15

Most of MTX would be eleminated from the body through kidney, meanwhile kidney function would degenerate as the age increased. If MTX titer in body high, the risk of hepatotoxicity is even higher. Therefore age is considered as risk factor for MTX hepatotoxicity. However, some studies showed different result from the theory. Study by Felson in 496 RA patients and Bologna in 469 RA patients did not find association between age, kidney function, and elevation of liver enzymes.15 In this study, the researchers do not know about patients’ kidney function.

In this study, there is no significant comparison between MTX cumulative dose in group with liver dysfunction and without liver dysfunction. MTX cumulative dose median in group with liver dysfunction is 495 mg, meanwhile in group without liver dysfunction is 378.75 mg. Even though there is no significant difference, MTX cumulative dose median in group with liver dysfunction is higher than cumulative dose median in group without liver dysfunction. In this study, MTX cumulative dose is lower than in other previous studies.

The result of this study is not suitable with studies which conducted by Sakthiswary et al and Sotoudenamesh et al which were acquired significant difference of MTX cumulative dose in group with liver dysfunction and without liver dysfunction.10,17 According to the theory, incidences of hepatotoxicity are associated with increasing MTX dose. However, in various studies by West et al and Lanse et al also did not find any increasing risk of hepatotoxicity with increasing of MTX dose.18

Study by Bath et al showed significant association between MTX cumulative dose and liver dysfunction in RA patients treated with MTX once a day or every two days. However, in RA patients treated with MTX once a week, there is a weak association between MTX cumulative dose and hepatotoxicity.

Liver dysfunction incidence is more associated with time interval between two MTX administrations than MTX cumulative dose. When the drug is administrated in one week interval, MTX titer in the body is not high enough to cause hepatotoxicity.18 In this study, RA patients are treated with MTX weekly. No significant difference in MTX cumulative dose and liver dysfunction could be caused by time interval between two administrations. Studies by Parvin et al and Rau et al stated that liver enzymes elevations were transient and will normalized after decreasing of MTX dose, giving of folic acid, or even without changes in MTX dose. 8,19

No significant difference between MTX cumulative dose and liver dysfunction incidence could be caused by MTX cumulative dose which are lower in this study than other previous studies. In this study, MTX cumulative dose median in group without liver dysfunction is 378.75 mg and group with liver dysfunction is 495 mg. Meanwhile in Sotoudenamesh et al, MTX cumulative dose mean in group without liver dysfuncton is 1707.3 mg with 45.2% of them were given MTX more than 1.5 g.10 In the literature review by Kremer, hepatotoxicity incidence in RA patients who are treated with MTX is low. Hepatotoxicity incidence is higher in cancer patients who are treated with higher MTX dose.8

The median MTX duration therapy in group with liver dysfunction is 43 weeks and without liver dysfunction is 44 weeks. In this study, there is no significant association between MTX duration therapy and liver dysfunction. This result could be caused by short MTX duration therapy. Sotoudenamesh et al studies found significant association between MTX duration therapy and liver dysfunction. In Sotoudenamesh et al study, MTX duration therapy in group with liver dysfunction reached 59.6±42.3 months.10

MTX duration therapy is associated with MTX cumulative dose. However, hepatotoxicity is more associated with time interval between two drug administrations than the MTX duration therapy. In study by Rau et al, hepatotoxicity is not a significant side effect in weekly low dose MTX therapy. Patients are more tolerant with weekly MTX therapy than daily MTX therapy.

ConclusionBased on this study, it could be concluded proportion of RA patients who have liver dysfunction caused by MTX therapy in RSCM is 42.70%. Gender, age, MTX cumulative dose, and MTX duration therapy do not have any statistically significant association with liver dysfunction.

References1. O’dell JR. Rheumatoid arthritis, In: Goldman-Cecil Medicine. Ed 25.

Philadelphia: Elsevier Saunders; 2016. p1754-622. Ferri FF. Ferri’s Clinical Advisor 2016. Philadelphia: Elsevier; 2016. p1084-

63. Singh JA, Saag KG, Bridges Jr. SL, Vaysbrot E, Bannuru RR, Sullivan MC,

et al. 2015 American college guideline for the treatment of rheumatoid arthritis. Arthritis Res Ther. 2016 Jan; 68: 4-8

4. IRA. Rekomendasi Diagnosis dan Pengelolaan Artritis Reumatoid. Perhimpunan Reumatologi Indonesia. 2014:4-22

Original Article


5. O’Dell JR. Treatment of rheumatoid arthritis, In: Firestein FS, Budd RC, Gabriel SE, McInnes IB, O’Dell JR. Kelly’s Textbook of Rheumatology. Ed 9. Philadelphia: Elsevier Saunders; 2013. p1137-60

6. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, et al. 2010 Rheumatoid arthritis classification criteria. Arthritis & Rheumatism. 2010 Sept 9; 62(9); 2572-4.

7. Cronstein BN. Low-dose methotrexate: A mainstay in treatment of rheumatoid arthritis. Pharmacol Rev. 2005;57(2): 163-70

8. Parvin MS, Rashid MU, Ekram ARMS, Begum HA. Early hepatotoxicity of methotrexate in rheumatoid arthritis. TAJ. 2008 Dec; 21(2): 147-51

9. Amital H, Arnson Y, Chodick G, Shalev V. Hepatotoxicity rates do not differ in patients with rheumatoid arthritis and psoriasis treated with methotrexate. Rheumatology Advance Access. 2009 July;48: 1107-10

10. Sotoudehmanesh R, Anvari B, Akhlaghi M, Shahraeeni S, Kolahdoozan S. Methotrexate hepatotoxicity in patients with rheumatoid arthritis. Middle East Journal of Digestive Diseases. 2010 Sept; 2(2): 104-8

11. Neogi T, Felson D, McMahon S, Koltzenburg M, MA T, Turk DC. Osteoarthritis and rheumatoid arthritis, In: Wall & Melzack’s Textbook of Pain. Ed 6. Philadelphia: Elsevier Saunders; 2013. p653-7

12. Bath RK, Brar NK, Forouhar FA, Wu GY. A review of methotrexate-associated hepatotoxicity. 2014; 15(10): 517 – 524. doi: 10.1111/1751-2980.12184

13. Conway R, Low C, Coughlan RJ, O’Donnell MJ, Carey JJ. Risk of liver injury among methotrexate users – a meta-analysis of randomized controlled trials. Seminars in Arthritis and Rheumatism. 2015;05(003): 2-16

14. Hoekstra M, A E van Ede, C J Haagsma, M A F J van de Laar, T W J Huizinga, M W M Kruijsen, R F J M Laan. Factors associated with toxicity, final dose, and efficacy of methotrexate in patients with rheumatoid arthritis. Ann Rheum Dis. 2003;62:423-6

15. Dehestani V, Shariati-Sarabi Z, Mohitt S, Akhlaghi S. Liver Toxicity in Rheumatoid Arthritis Patients Treated with Methotrexate. Asia Pac J Med Toxicol. 2015;4:102-5

16. Sakhtiswary R, Chan GYL, Koh ET, Leong KP, Thong BYH. Methotrexate-associated nonalcoholic fatty liver disease with transaminitis in rheumatoid arthritis. TSWJ. 2014(823763): 1-4

17. Bath RK, Brar NK, Forouhar FA, Wu GY. A review of methotrexate-associated hepatotoxicity. 2014; 15(10): 517 – 524. doi: 10.1111/1751-2980.12184

18. Rau R, Herborn G. Benefit and risk of methotrexate treatment in rheumatoid arthritis. Clin Exp Rheumatol. 2004;22(35):83-94

Original Article


Clinical Manifestation and Laboratory Finding of Sclerosis Systemic Patient in Dr. Hasan Sadikin General Hospital Bandung : A Descriptive Quantitative Study

Annisa Meivira Budiman1, Sumartini Dewi2, Marietta Shanti Prananta3

1 Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia2 Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia3 Departement of Physical Medicine and Rehabilitation, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia

Corresponding Author: Annisa Meivira Budiman, [email protected]

extracellular matrix and autoimmunity.1 Based on cutaneous involvement patterns, clinical manifestations and laboratory findings, systemic sclerosis is classified into 2 types: diffuse and limited systemic sclerosis. Cutaneous involvement in diffuse systemic sclerosis extend up to proximal knees and elbows, face and trunk. Raynaud’s phenomenon usually follows cutaneous manifestations. Organ involvement such as musculoskeletal, kidneys, heart and lungs often appear. Signs of limited systemic sclerosis are known from the mnemonic CREST syndrome, consisting of calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia.2

Ten years survival rate of systemic sclerosis patient has increased significantly from 53% in 1970s to 67% in 1990s.3 However, this rate is lower than SLE patients, which is 93%.4 A previous study stated that most frequent cause of death in systemic sclerosis patients is related to heart and lungs involvement.5 Irreversible organ involvement following disease progression may further complicates the disease, hence the long-term prognosis of systemic sclerosis depends on organ involvement and disease manifestation.

Systemic sclerosis is the third most common patients in rheumatology clinic Dr. Hasan Sadikin General Hospital, after systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).6 Most of them often delayed referral, diagnosis, and management of systemic sclerosis from primary health care and district hospital take place. As a consequences, patients come to rheumatology clinic Dr. Hasan Sadikin General Hospital Bandung in severe condition with multiple organ involvement. Delayed referral corresponds with the low education profile of health care provider regarding clinical manifestation and laboratory findings of systemic sclerosis. As a result, a study about clinical manifestations and laboratory findings of systemic sclerosis patient is needed as an important information to help health care providers establish early diagnosis as a way to prevent irreversible organ involvement.

AbstractBackground Systemic sclerosis is a chronic progressive multisystem autoimmune disease in connective tissue, characterized by its heterogeneous clinical manifestation. The purpose of this study is to give information regarding clinical manifestations and laboratory findings of systemic sclerosis patients to establish diagnosis of disease.Methods This study was conducted using descriptive quantitative design in September−October 2016. Data was collected from medical records of patients visiting Rheumatology Clinic Dr. Hasan Sadikin General Hospital from 1 July 2015−30 June 2016 using total sampling method. The collected data were expected to comprise patient’s clinical manifestation and laboratory finding.Results Most of patients had cutaneous 57 (100.0%) and musculoskeletal 40 (70.2%) involvement. Some of the disease manifestations were Raynaud’s phenomenon 38 (66.7%), fingertip lesion 33 (57.9%), stiffness in skin 34 (59.6%), and arthalgia 29 (50.9%). Gastrointestinal involvements were present in 29 (50.9%) patients. Renal involvement were determined from urinalysis result showed proteinuria 10 (17.5%) and hematuria 8 (14.0%), found in 24 (42.1%) patients, while pulmonary and cardiac involvements were found in 30 (52.6%) patients, acknowledged from clinical symptoms such as dyspnea 12 (21.1%). Identification of autoantibodies was found in 12 (21.1%) patients, with 10 (17.5%) patients had reactive ANA and 3 (3.5%) had positive anti-Scl70.Conclusion Most of systemic sclerosis patients had cutaneous involvement. Renal, pulmonary, and cardiac involvement were concluded based on laboratory findings.Keywords: Systemic sclerosis, clinical manifestation, laboratory finding

IntroductionSystemic sclerosis (SSc) is a chronic progressive multisystem autoimmune disease in connective tissue, characterized by its heterogeneous clinical manifestation. Pathophysiologic processes that occur on this disease are vascular abnormality, fibrosis due to collagen deposits and excessive

Original Article


MethodsThis study conducted during September−October 2016 at rheumatology clinic Dr. Hasan Sadikin General Hospital Bandung. Medical records of patients was analyzed and presented descriptively using a retrospective method. Sample was selected using total sampling method. Subjects of this study were patients diagnosed with systemic sclerosis who were treated at rheumatology clinic Dr. Hasan Sadikin General Hospital Bandung during July 1, 2015 to June 20, 2016. After ethical clearance letter had been issued, clinical manifestations and results of supportive examination that the patient took were recorded from their medical records. Afterwards, data were grouped based on cutaneous, gastrointestinal, renal, cardiac and pulmonary involvement. The exclusion criteria of the study was patients who have not been completed data on their medical records and patients with overlap syndrome or mixed connective tissue disease (MCTD).

ResultsTotal participants who fulfilled inclusion were 57 patients. Table 1 showed characteristic of systemic sclerosis patients in rheumatology clinic Dr. Hasan Sadikin General Hospital. The table showed that most of systemic sclerosis patients was female 56 (98.2%) with age range from 31−40 years 19 (33,3%).

Table 1. Characteristics of SSc patients at rheumatology clinic Dr. Hasan Sadikin Bandung General Hospital in July 2015−June 2016

Characteristics Frequency (n=57) Percentage (%)Sex

FemaleMale

561

98.2%1.8%

Age<20 years20-30 years31-40 years41-50 years51-60 years>60 years

19191756

1.8%15.8%33.3%29.8%8.8%10.5%

Table 2 showed the distribution of clinical manifestation in involved organ on patients with systemic sclerosis at rheumatology clinic Dr. Hasan Sadikin General Hospital Bandung. The table showed that all 57 subjects are patient with cutaneous involvement (100.0%). Raynaud’s phenomenon was found in 38 (67.9%) patients.

Table 2. Distribution of clinical manifestations on organs involved in SSc patients at rheumatology clinic Dr. Hasan Sadikin General Hospital Bandung in July 2015−June 2016

Clinical Manifestation Frequency (n=57) Percentage (%)Skin

Raynaud’s PhenomenonFingertip lesionTelangiectasiaCalsinosis cutisSclerodactylyHardened skin

n = 5738339212525

100.0%66.7%57.9%15.8%36.8%43.9%43.9%

Clinical Manifestation Frequency (n=57) Percentage (%)Skin stiffnessPainful skinItchy skinMask-faceFish mouthSalt and pepper appearance

34261682219

59.6%45.6%28.1%14.0%38.6%33.3%

GastrointestinalNauseaDifficulty in swallowingEpigastric painDiarrhea

n = 29141364

50.9%24.6%22.8%10.5%7.0%

MusculoskeletalSwelling fingersArthalgiaMyalgiaJoint stiffnessMuscle contractureKnee painBack pain

n = 4014291310264

70.2%24.6%50.9%22.8%17.5%3.5%10.5%7.0%

Renal n=24 42.1%Pulmonary and cardiac n=30 52.6%

Table 3 showed multiple of organ involvements in systemic

sclerosis patient. Most patients (40.4%) had combination of skin, musculoskeletal, and gastrointestinal organ

Table 3. Distribution of multiple organ involvements in SSc patients at rheumatology clinic Dr. Hasan Sadikin General Hospital Bandung in July 2015−June 2016

Multiple Organ Involvements Frequency (n=57) Percentage (%)

Skin only 13 22.8%Skin and musculoskeletal 16 28.1%Skin and gastrointestinal 5 8.8%Skin, musculoskeletal, and gastrointestinal

23 40.4%

Table 4 showed the distribution of constitutional symptoms

which appeared on systemic sclerosis patients at rheumatology clinic Dr. Hasan Sadikin General Hospital. The table showed that the most frequent constitutional symptoms experienced by patients were easy fatigability 12 (21.1%) and weakness 11 (19.3%).

Table 4. Distribution of constitutional symptoms in SSc patients at rheumatology clinic Dr. Hasan Sadikin General Hospital Bandung in July 2015−June 2016

Constitutional Symptom Frequency (n=57) Percentage (%)Easily fatigue 12 21.1%Weakness 11 19.3%Hair fall 6 10.5%Epistaxis 4 7.0%Weight loss 8 14.0%

Renal, cardiac and pulmonary involvement in patients with

systemic sclerosis can be assessed from clinical manifestations and/or supporting examination. Examinations which usually carried out were routine urinalysis, serum creatinine, plain

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chest x-ray, chest CT scan, spirometry and echocardiography. Table 5 showed the distribution of clinical manifestations and laboratory findings of systemic sclerosis patients with renal, cardiac and pulmonary involvement at Dr. Hasan Sadikin General Hospital.

Tabel 5. Distribution of clinical manifestations and laboratory findings on renal, cardiac, and pulmonary involvement in SSc patients at rheumatology clinic Dr. Hasan Sadikin General Hospital Bandung in July 2015−June 2016

Organ Involvement Frequency (n=57) Percentage (%)Renal Involvement

Clinical manifestationDysuriaOligouria

Laboratory findingsUrinalysis

ProteinuriaHematuriaBakteriuria

Increased creatinine serum

n=24

62

10834

42.1%

10,5%3,5%

17,5%14,0%5,3%7,0%

Pulmonary and Cardiac Involvement Clinical manifestation

DyspneaDyspnea with edema in lower extremitiesDyspnea with coughCoughPalpitation

Laboratory findingsPlain chest x-ray

CardiomegalyCardiomegaly without pulmonary edemaSuspected ILDIdiopathic pulmonary fibrosis

CT ScanILD appearance

SpirometryMild restrictiveModerate restrictive

EchocardiographyPulmonary hypertension Diastolic dysfunction

n=30

122752

2521

3

24

21

52,6%

21,1%3,5%12,3%8,8%3,5%

3,5%8,8%3,5%1,8%

5,3%

3,5%7,0%

3,5%1,8%

Table 6 showed the distribution of autoantibody test result

on systemic sclerosis patients at Dr. Hasan Sadikin General Hospital Bandung. The tests included antinuclear antibody (ANA) and anti-Scl70.

Table 6. Distribution of autoantibody test in SSc patients at rheumatology clinic Dr. Hasan Sadikin General Hospital Bandung in July 2015−June 2016

Autoantibody Frequency (n=57) Percentage (%)Autoantibody test

ANAReactive

Speckled patternNuclear patternHomogenous typeNot-specified

Non-reactiveAnti-Scl70

Positive

n=12

1023322

3

21.1%

17.5%3.5%5.3%5.3%3.5%3.5%

5.3%N/A 45 78.9%

DiscussionsIt was obtained from this study that most patients with systemic sclerosis were female 56 (98.2%) with age range from 31-40 years 19 (33.3%). This result corresponded with previous study conducted by Pagalavan dan Ong in Malaysia, where most systemic sclerosis patients were 31−40 years old female.7

All systemic sclerosis patients showed cutaneous involvement as disease manifestation. This result suited to previous study which stated that even though clinical manifestations in systemic sclerosis were heterogeneous, most patients had cutaneous involvement.8 Systemic sclerosis patients which showed clinical manifestation and positive laboratory findings on organs without any cutaneous involvement were called systemic sclerosis sine scleroderma (ssSSc). On a study conducted by Marangoni, et al., in Brazil, it was found that among 947 systemic sclerosis patients, there were only 79 (8.3%) patients with ssSSc.9

Based on Le Roy vascular hypothesis, dysfunctional blood vessel was an initial pathophysiologic process in systemic sclerosis marked by Raynaud’s phenomenon.10 The result of this study revealed that the most frequent clinical manifestation found on skin was Raynaud’s phenomenon (66.7%). This result corresponded with a previous study conducted by Pagalavan and Ong in Malaysia, where 38 (83.6%) patients with systemic sclerosis experienced Raynaud’s phenomenon.7 Hanitsch in Germany published a higher rate; 1160 (96.7%) patients experienced Raynaud’s phenomenon.11

This study revealed that 9 (15.8%) patients experienced telangiectasia and 21 (36.8%) patients experienced cutaneous calcinosis. This result was different with the study by Pagalavan and Ong in Malaysia, where 28 (45.9%) patients experienced telangiectasia and 7 (11.5%) patients experienced calcinosis cutis.7 The result might be affected by the type of systemic sclerosis experienced by patients, calcinosis cutis was more frequently found in limited systemic sclerosis.12

Musculoskeletal involvement as the main cause of disability was frequently found on systemic sclerosis.13 From the study result, it was revealed that 40 (70.2%) systemic sclerosis patients had a musculoskeletal involvement. The most frequently found manifestation was arthalgia 29 (50.9 %). This result was suitable with the previous literature which stated that the most common clinical manifestation on musculoskeletal involvement was arthalgia.14 This result corresponded with the study by Pagalavan and Ong in Malaysia which reported that arthalgia/arthritis were frequently found (49.2%).7

There were 29 (50.9%) systemic sclerosis patients in this study with gastrointestinal involvement. The most manifestation which frequently found was difficulty in swallowing 13 (22.8%). This result corresponded with previous study which stated that gastroesophageal reflux and dysphagia were the frequent manifestations of systemic sclerosis on patients.15 The other common complaint were nausea 14 (22.8%). These gastrointestinal manifestations were one factor which might cause malnutrition on systemic sclerosis patients. Baron, et al reported 18% patients were at risk for malnutrition.16

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On this study, the most frequent constitutional symptoms reported by systemic sclerosis patients were fatigue (21.1%) and weakness (19.3%). This result suited to previous study by Sandusky, et al., in USA which stated that 76% subjects experienced fatigue, while 61% of those patients stated that this was one of the most physically and socially disturbing symptoms.17

Renal involvement on systemic sclerosis patients can be assessed from clinical features or from supporting examination. On this study, there were 24 (42.1%) patients with renal involvement; 8 (14.0%) patients with clinical symptoms such as dysuria (10.5%) and oliguria (3.5%), while the rest of them had abnormal supporting examination test result. The supporting examinations conducted were routine urinalysis and serum creatinine level. Abnormalities found on patients from those test were proteinuria (17.5%), hematuria (14.0%) and bacteriuria (5.3%). Albuminuria could be used as vasculopathy marker, which was one of the pathophysiologic processes on systemic sclerosis.18 On this study, increasing creatinine serum level was found on 4 (7.0%) patients. The increasing creatinine serum level did not completely describe a renal dysfunction, since renal dysfunction could also occur on patients with normal creatinine serum level.18

There were 30 (52.6%) patients on this study showed cardiac and pulmonary involvement marked by clinical manifestations and supporting examination. On this study, there were 12 (21.1%) patients with dyspnea, 2 (3.5%) patients with dyspnea and edema on extremities and 7 (12.3%) patients with dyspnea and cough. Meanwhile, a study by Hanitsch in Germany reported 390 (32.5%) patients had dyspnea.11 Patients with dyspnea needed further observation and screening for pulmonary hypertension. The most frequent pulmonary manifestations and the main cause of death on 60% systemic sclerosis patients were interstitial lung disease (ILD) and pulmonary hypertension.19 From plain chest x-ray and chest CT scan, respectively there were 2 (3.5%) and 3 (5.3%) patients with interstitial lung disease, while from echocardiography there were 2 (3.5%) patients with pulmonary hypertension. Systolic and diastolic dysfunction are early signs of heart problems on patients with systemic sclerosis.20 On this study, there were 1 (1.8%) patients presented with diastolic dysfunction from echocardiography.

One of the pathophysiologic process occur on systemic sclerosis is the synthesis of autoantibody. The number and level of this autoantibody fluctuates depending on the disease activity, hence it could be used as diagnostic markers and determine prognosis of systemic sclerosis.2 There were 10 (17.5%) patients on this study had positive ANA (antinuclear antibody) test result while 3 (5.3%) patients with positive anti-Scl70. This result was different from Pagalavan and Ong in Malaysia who stated that there were 51 (83.6%) patients with positive ANA and 21 (34.4%) patients with positive anti-Scl70 test result. This difference because not all patients who were treated at rheumatology clinic Dr. Hasan Sadikin General Hospital had autoantibody tests.7

ConclusionFrom 57 sample, it could be concluded that most systemic sclerosis patients had cutaneous involvement, renal, pulmonary, and cardiac involvement based on laboratory findings.

This study was a retrospective study that evaluated history taking and supporting examination test result on medical records. Most of the medical records had not been on computerized system, hence there could still be a possibility that there were mistakes in interpreting the writings on the medical records. On the other hand, not all patients took autoantibody test hence their records were not reported.

Recommendation from this study is demographic data on medical records could be completed. The medical records should also comprise the recordings of all examination the patient took to help clinician establish the diagnosis of the patient.

Reference1. Khanna D. Diagnosis and Treatment of Systemic and Localized

Scleroderma. Expert Rev Dermatol [Internet]. 2011;6(33):287–302. Available from: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed10&NEWS=N&AN=2011317109

2. Longo D, Fauci A, Kasper D, Hauser S, Jameson JL, Loscalzo J. Harrison’s Principles of Internal Medicine. 18th ed. McGraw-Hill; 2012. p. 2757-2769

3. Steen VD, Medsger TA. Changes in Causes of Death in Systemic Sclerosis, 1972-2002. Ann Rheum Dis [Internet]. BMJ Publishing Group Ltd and European League Against Rheumatism; 2007 Jul [cited 2016 Jul 14];66(7):940–4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17329309

4. Doria A, Iaccarino L, Ghirardello A, Zampieri S, Arienti S, Sarzi-Puttini P, et al. Long-Term Prognosis and Causes of Death in Systemic Lupus Erythematosus. Am J Med. 2006;119(8):700–6.

5. Elhai M, Meune C, Avouac J, Kahan A, Allanore Y. Trends in Mortality in Patients with Systemic Sclerosis Over 40 Years: A Systematic Review and Meta-Analysis of Cohort Studies. Rheumatology (Oxford) [Internet]. 2012;51(6):1017–26. Available from: http://rheumatology.oxfordjournals.org/content/51/6/1017.abstract

6. Mulasimadhi K, Wachjudi R, Rahmadi A, Hamijoyo L, Dewi S, Pramudiyo R. Perubahan Pola Penyakit Pasien di Poliklinik Reumatologi Rumah Sakit Dr. Hasan Sadikin Sebelum dan Sesudah Diberlakukannya JKN. 2014;2014.

7. Pagalavan L, Ong SG. Demography, Clinical and Laboratory Features of Systemic Sclerosis in A Malaysian Rheumatology Centre. Med J Malaysia. 2007;62(2):117–21.

8. Krieg T, Takehara K. Skin disease: a cardinal feature of systemic sclero-sis. Rheumatology [Internet]. 2009 [cited 2016 Nov 10]; Available from: http://search.ebscohost.com/login.aspx?direct=true&profile=ehost&scope=site&authtype=crawler&jrnl=14620324&AN=79307975&h=Xp4vDtTDbYJdGbqy6xiP4GfSP2FcW82feJi66uWMvGHMilLSGsJoHbXH-PYhyJrwjdG5ccW5esJIrIBAbr3jJpA%3D%3D&crl=c

9. Marangoni RG, Rocha LF, Del Rio APT, Yoshinari NH, Marques-Neto JF, Sampaio-Barros PD. Systemic sclerosis sine scleroderma: Distinct features in a large Brazilian cohort. Rheumatol (United Kingdom). 2013;52(8):1520–4.

10. Riemekasten G, Sunderko C. Pathophysiology and clinical consequences of Raynaud ’ s phenomenon related to systemic sclerosis. 2006;33–5.

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11. Hanitsch LG, Burmester GR, Witt C, Hunzelmann N, Genth E, Krieg T, et al. Skin sclerosis is only of limited value to identify SSc patients with severe manifestations - An analysis of a distinct patient subgroup of the German Systemic Sclerosis Network (DNSS) Register. Rheumatology. 2009;48(1):70–3.

12. Nitsche A. Raynaud, Digital Ulcers and Calcinosis in Scleroderma. Reumatol Clínica (English Ed [Internet]. 2012;8(5):270–7. Available from: http://dx.doi.org/10.1016/j.reumae.2012.08.001

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20. Desai C, Lee D, Shah S. Systemic Sclerosis and The Heart: Current Diagnosis and Management. Curr Opin Rheumatol. 2011;23(3):1–2.

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Correlation of sCD40L Level with Force VitalCapacity Value in Restrictive Lung Disease of Systemic Sclerosis Patients

Susanto Salim,1 Rachmat Gunadi Wachjudi,1 Sumartini Dewi1

1 Internal Medicine Department, Faculty of Medicine, Universitas Padjadjaran,dr. Hasan Sadikin General Hospital

Corresponding author: Susanto Salim MD, [email protected]

autoimmune connective tissue disease that involving many organs. The etiology of this disease is still not well known.1-3 Lung is common organ involved in systemic sclerosis patients, such as Interstitial Lung Disease (ILD) and pulmonary arterial hypertension.4 Systemic Sclerosis patients suffered with ILD tend to has lower quality of life compared to healthy person.5 European Scleroderma Trials and Research (EUSTAR) group reported ILD was a major cause of death in systemic sclerosis. Data of 5800 systemic sclerosis patients showed as much as 35% deaths caused by pulmonary fibrosis, 26% by pulmonary arterial hypertension and 4% by kidney disorder.6

ILD is difficult to diagnose, especially in developing country, due to unavailability of High Resolution Computed Tomography (HRCT) scanning which is the gold standard for diagnosing ILD.4,7,8 Moreover, it is not affordable for the most patients. Other pulmonary function tests are more commonly used as initial screening of ILD in systemic sclerosis patients in our center.4,7 Those PFT instruments consist of test for diffusing capacity of the lung for carbon monoxide (DLCO), spirometry to define forced vital capacity (FVC), etc. The pulmonary function tests (PFT) play as key role to determine the severity of pulmonary complication in SSc patients. FVC is one of the common test which use to determine the severity of restrictive abnormality in ILD.8

T-cells trigger fibroblasts activation which causing fibrosis process in systemic sclerosis patients. Activated CD4 T-cells will express CD40 ligand (CD40L/CD154) that binds to CD40 on the surface of the B-cells. T cells will produce cytokines and stimulate fibroblast to start fibrosis cascade as the main pathogenesis of systemic sclerosis.9 CD40L is suggested playing role in fibrosis cascade. CD40L can be cleaved from the cell surface, releasing a soluble CD40L (sCD40L) which is biologically active.10,11 Allanore, et al reported an increase of plasma sCDL40 associated with vascular complication in systemic sclerosis patients. Instead, other studies reported controversially role of CD40-CD40L bond in pulmonary fibrosis.11,12

Aim of this study is to analyze the correlation of sCD40L level with FVC value in restrictive lung

AbstractBackground: Interstitial Lung Disease (ILD) is one of the major cause of morbidity and mortality in Systemic Sclerosis (SSc). The gold standard to diagnose ILD is using High Resolution Computed Tomography (HRCT) scan. HRCT scan need a lot of cost and not always available, so another diagnosing test is needed as an alternative modality to diagnose ILD. ILD is a restrictive lung disease caused by lung fibrosis which is proved by the decrease of Forced Vital Capacity (FVC) in spirometry, and followed by the increase of soluble CD40L (sCD40L) level in plasma. This sCD40L may become a potential biomarker to evaluate lung fibrosis in SSc patients. The aim of this study is to analyze the correlation of sCD40L levels with FVC score in SSc patients with restrictive lung disease.Method: This cross sectional study was enrolled by the SSc patient who has restrictive lung disease based on spirometry test, at Rheumatology outpatient clinic dr. Hasan Sadikin Hospital from May 2015 to May 2016. All subject took underwent history, physical examination, spirometry and blood test for sCD40L. Data were analyzed using Pearson correlation.Result: There were 38 subjects involved in this study, dominated bywoman (92.1%) with mean age 41(±11) years. Subjects consist of 22(57,9%) with limited SSc, 16(42,1%) with diffuse SSc patients and 33 subjects treated with DMARD. Mean sCD40L serum in this study was 6.690,3(±2.377,3) pg/mL, with no statistical difference between limited and diffuse type (p=0.154). Mean FVC score in this study was 58.2(±10,8). There was no significant correlation between sCD40L serum with FVC (r=0.058; p=0.366). There was weak correlation on DMARD naïve subject between sCD40L serum and FVC (r=0.058; p=0.366) but statistically insignificant. There was no significant correlation between sCD40L serum with mRSS (r=0,066; p=0,346).Conclusion: This study founds no correlation between sCD40L with FVC in SSc at dr. Hasan Sadikin Hospital.Keyword: sCD40L, Forced Vital Capacity, Restrictive Lung Disease, Systemic Sclerosis

IntroductionSystemic Sclerosis (SSc) is a chronic progressive

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disease of systemic sclerosis patients.

MethodThis cohort retrospective study enrolled the systemic sclerosis patients who had restrictive lung disease based on spirometry test. Data were collected from outpatient subjects at clinic rheumatology, Hasan Sadikin General Hospital from May 2015 to May 2016. The inclusion criteria were patients who diagnosed with systemic sclerosis based on ACR/EULAR 2013 criteria with restrictive lung disorders and willing to participate in this study, includes carried out blood test and spirometry examination. Exclusion criteria were patients who diagnosed with other autoimmune diseases and/or diagnosed with restrictive lung disease other than ILD through history, physical examination and history from previous medical records.

This study used two step of data collection. Initial step was screening to get subjects who meet the inclusion and exclusion criteria. The next step was venous blood sampling to determine the sCD40L level followed by spirometri test to evaluate FVC value. Then data was analyzed with Pearson correlation test.

ResultWe included 38 patients in this study. Characteristics of the subject are shown at table 1.

Table 1. Characteristics of Subjects

CharacteristicsAll Subjects

n=38Limited Type

n=22 (57.9%)Diffuse Type

n=16 (42.1%)

Age (mean ± SD) years 41 ± 11Sex

Male (n%) 3 (7.9)Female (n%) 35 (92.1)

Treatment HistoryMethotrexate (n%) 33 (86.8)Steroid (n%) 33 (86.8)Cyclophosphamide (n%) 2 (5.3)DMARD-naïve (n%) 5 (13.2)

mRSS (median, range) 17 (4 – 36) 12 (4 – 23) 27 (10 – 36)FVC (mean ± SD) 58.2 ± 10.8 57,1 ± 12,7 59,6 ± 7,5sCD40L (mean ± SD) (pg/mL) 6690.3±2377.3 6218,0 ± 2170,7 7339,8 ± 2562,5

The median of modified Rodnan Skin Score (mRSS) is 17 and has range 4 to 36. Mean of FVC by spirometry examination was 58.2 + 10.8. The most were 15 (40%) moderate restrictive lung patients, 10 (26%) severe restrictive lung patients, 8 (21%) moderate to severe restrictive lung patients, and 5 (13%) mild restrictive lung patients. Mean of sCD40L was 6690.3±2377.3 pg/mL. There were no statistically different of sCD40L level and FVC value between diffuse type and limited type systemic sclerosis subjects.

There was five (13.2%) subjects who were for the first time diagnosed as systemic sclerosis and had never taken DMARD treatment before this study. mRSS score was higher in DMARD-naïve patients (p = 0.036, Mann-Whitney) sCD40L and FVC had no different between DMARD patients and

DMARD-naïve patients shown in table 2.

Tabel 2. Difference between DMARD and DMARD-naïve patients

Variabel DMARD-naïven=5

DMARDn=33 p-value

mRSS (median, range) 32 (15 – 36) 14 (4 – 34) 0.036sCD40L (mean ± SD) 5909.8 ± 783.8 6808.6 ± 2519.5 0.438FVC (mean ± SD) 58.4 ± 9.1 58.1 ± 11.1 0.958

Bivariate test was used to analyze correlation between sCD40L level and FVC value revealed that sCD40L was not correlated with FVC (r=0.058, R2 = 0.0034, p=0.366, Pearson correlation). Figure 1 show scatter diagram of this study.

Figure 1. Scatter diagram between sCD40L and FVC

There was weak correlation on DMARD naïve subject between sCD40L serum and FVC (r=-0.225; p=0.358, Pearson correlation) but not significant as shown in table 3.

Tabel 4. Bivariate Analysis between sCD40L and FVC in DMARD and DMARD-naïve Patients

Variable PatientsFVC

r p-value

sCD40LDMARD-naïve -0.225 0.358

DMARD 0.069 0.351

DiscussionAverage age of the subjects was 41±11 years, it is in accordance with the onset of systemic sclerosis disease which the highest in the fourth and fifth decade.13,14 Mean age was smaller compared to the research conducted by Allanore et al (50 subjects) 57±11 years and Komura et al (49 subjects) 51.4±15.6 years but in accordance with study on Asian population in Singapore by Low et al (200 subjects), namely 46±14.9 years.11,15,16 This difference maybe due to race differences in both populations. So, age of systemic sclerosis patient in Caucasian population is older than in Asian populations.

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Most of the subjects were women (92.1%). These results were differed by the proportion of women and men incidence in US that reached 3−5:1.1,14,17 But, similar to the result obtained by Komura, et al. study in Asia (92%) and Low research in Singapore (86%).15,16

Mean FVC value by spirometry was 58.2±10.8%. All subject as restrictive lung disorder that may be a pulmonary fibrosis. There was no difference in FVC value between limited type and diffuse type subjects (p=0.482). Abnormalities of pulmonary fibrosis is more common in diffuse type since it is a rapidly progressing disorder that affects a large area of the skin and compromises one or more internal organs including lung. Expression of antinuclear antibody is more dominant in diffuse type SSc compared to the limited type.1 FVC examination can be used as an initial screening test but the incidence of pulmonary fibrosis may not be used as the gold standard to diagnosis pulmonary fibrosis.

Mean of sCD40L levels in our study were 6690.3±2377.3 pg/mL. This is higher when compared with control values in Allanore, et al study (median sCD40L 79 (50−118) pg/mL) and Salibi, et al. study (mean sCD40L 717 pg/mL). sCD40L levels in our study is also higher than sCD40L level in systemic sclerosis patients in Allanore, et al. study with a median sCD40L 495 (10−2690) pg/mL and Salibi, et al study with a mean sCD40L 1564 pg/mL.11,18 This difference happened due to the difference subjects involved in Allanore, et al study used all systemic sclerosis patients with or without pulmonary complication, while in the Salibi, et al study, the subjects were included the lung fibrosis subjects with any underlying disease. Whereas the subjects in our study were the systemic sclerosis patients with restrictive lung disorders. CD40L is believed to play role in the fibrosis cascade of systemic sclerosis patients. CD40-CD40L bond between T-cells and B-cells trigger proliferation and differentiation of B-cells into plasma cells and forms a bond autoantibody.19,20 CD40-CD40L activates the proliferation of fibroblasts, produces pro-inflammatory cytokines, and begins fibrosis process.21,22 Komura and Fukasawa reported the increase of plasma CD40 protein due to CD40 expression on fibroblasts surface in systemic sclerosis patients.15,21 CD40L can be cleaved from cell surface and dissolved as a soluble CD40L on plasma that biologically active.10,23

From our study, we found no statistically correlation between sCD40L level and FVC (r=0.058, R2=0.0034, p=0.366). This is consistent with Allanore, et al study that reported lack correlation between sCD40L levels with pulmonary fibrosis and carbon monoxide diffusing capacity (DLCO).11 Other study by Salibi, et al reported a significantly increasing of sCD40L levels in pulmonary fibrosis patients when compared to the healthy population (p < 0.05).18 Salibi, et al also reported a correlation sCD40L level with FVC (R2=0.16, r=0.4) but not significantly related (p=0.16).12

There are some differences between our study and the study conducted by Allanore, et al or Salibi, et al. This study included 38 subjects while Allanore, et al study followed by 50 subjects and Salibi et al study followed by 13 subjects. This study uses retrospective cohort while the two other studies using cross sectional method. This research together with

Salibi, et al analyzed the correlation of sCD40L levels with the value of FVC, while Allanore, et al analyzed the association of sCD40L levels with the incidence of pulmonary fibrosis and DLCO.

Other difference is our study and Allanore, et al study used systemic sclerosis patients, while Salibi, et al. research used all subjects with pulmonary fibrosis. Study conducted by Allanore, et al only involve systemic sclerosis patients who have not received immunosuppressive therapy, while in our study, only five subjects who have not received immunosuppressive therapy and the remaining subjects have been treated with methotrexate.

Different level of sCD40L may be affected by several conditions in our subject settings. First, 83.8% subject has been treated with DMARD (methotrexate, cyclophosphamide). Methotrexate could interfere activation of T-cell that might affect the level of sCD40L.24 Second, we measured sCD40L to represent the activity of CD40L, because sCD40L has the CD40L biologic activity. However, there were not any data about the equivalent of sCD40L level on serum and CD40L level on T-cell. Third, many factors could interfere the result of FVC measurement such as age, sex, weight, height, chest abnormality. Fourth, disease activity shown by sCD40L level might fluctuate rapidly while lung damage shown by FVC level might be change in a slow progression.

ConclusionOur study showed increased plasma soluble CD40 ligand concentrations in restrictive lung disease of systemic sclerosis patients. Our result found no significant correlation between sCD40L with FVC in SSc at dr. Hasan Sadikin General Hospital.

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17. Rami S, Robert MK, Everett P, Richard P, Patricia JS. CD40 Ligand (CD154) Is Elevated In Fibrotic Lung Diseases. B28 Emerging Biomarkers of Complex Lung Diseases. Am J Respir Crit Care Med 185;2012:A2658.

18. Vogel LA, Noelle RJ. CD40 and its crucial role as a member of the TNFR family. Semin Immunol. 1998;10(6):435-42.

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20. Fukasawa C, Kawaguchi Y, Harigai M, Sugiura T, Takagi K, Kawamoto M, et al. Increased CD40 expression in skin fibroblasts from patients with systemic sclerosis (SSc): Role of CD40-CD154 in the phenotype of SSc fibroblasts. Eur J Immunol. 2003;33(10):2792-800.

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24. Manno R, Boin F. Immunotherapy of systemic sclerosis. Immunotherapy. 2010;2(6):863-78.

Original Article


Validation of Modified COPCORD Questionnaire Indonesian Version as Screening Tool for Joint Pain and Musculoskeletal DiseasesMuhammad Anshory1, C.Singgih Wahono1, Handono Kalim1, Harun Al Rasyid2

1 Rheumatology and Allergy Immunology Division, Internal Medicine Department, Faculty of Medicine, Universitas Brawijaya, Saiful Anwar General Hospital, Malang 2 Public Health and Preventive Medicine Department, Universitas Brawijaya, Malang

Corresponding author: Muhammad Anshory MD, [email protected]

AbstractBackground: WHO-ILAR COPCORD Program is a program that aimed to obtain data on joints pain and musculoskeletal diseases in developing countries, one aspect which has not been studied is the ability of COPCORD questionnaire as a screening tool which standardized for screening joint pain and musculoskeletal diseases. Objective of this study is to assess the validity of modified COPCORD questionnaire Indonesian version in screening joint pain and musculoskeletal disease compared to examination by rheumatologists.Methods: The initial phase of the research is determining essential points, translation to Indonesian, and back translation. The second stage is testing questionnaires in communities which 100 respondents involved. Dependent variable is the diagnosis of rheumatic diseases and independent variables are pain in less and more than 7 days, high degree pain in less and more than 7 days, history of NSAIDs/Steroids/DMARDs use, and disabilities. Validation test was assessed by calculating the sensitivity, specificity, PPV, NPV, LR+, and ROC curve. Bivariate analysis using Chi Square analysis, and multivariate analysis using logistic regression.Results: The sensitivity test results is best obtained on the question history of NSAIDs/steroids/DMARDs use (100%) and specificity is best obtained on the question about disability (98%). ROC curve analysis which the results >85% obtained on the question of pain >7 days (90%), high degree pain >7 days (93%), and history of NSAIDs/steroids/DMARDs use (92%). LR+ to diagnose rheumatic diseases found in all questions. Chi square analysis showed that all questions were significant with p <0.05 and odds ratio (OR) obtained most on high degree pain more than 7 days (OR: 180.167; 95% CI: 38.196-849.834). Conclusion: The modified COPCORD questionnaire Indonesian version has been adapted and can be a good tool in the screening of joint pain and musculoskeletal diseases compared to examination by rheumatologists.Keyword: Validation, Questionnaire, COPCORD

IntroductionJoint pain and musculoskeletal disease is the most common cause of morbidity in general population. Even rheumatic diseases not increase mortality

but it can lead to disabilities and low quality of life and productivity.1 On the other hand the need of data on the magnitude of the problem and the effects of joint and musculoskeletal diseases is very important, especially in developing countries such as Indonesia. Based on these data we can see the effect of the disease and provide recommendation and intervention plan both in terms of detection and therapy.2

In the 1981 the International League against Rheumatism (ILAR) and the World Health Organization (WHO) jointly launched the WHO-ILAR Community Oriented Program for the Control of Rheumatic Diseases (COPCORD) to obtain data on the joints and musculoskeletal diseases in developing countries. COPCORD is a low cost program which requires minimal infrastructure by relying on existing resources. Using the same and validated method, COPCORD Phase 1 ( out of 3 phase) has been succeeded to collect data from Australia,3 Bangladesh,4 Brazil,5 Chile,5 China,6 Cuba,7 Egypt,8 Guatemala,9 India,10 Indonesia,11 Iran,12 Kuwait,13 Malaysia,14 Mexico,5, 15 Pakistan,16 Philippines,17 Thailand,18 Taiwan,19 Tunisia20 and Vietnam.10, 21-23

One aspect of COPCORD which has not been studied is the ability COPCORD questionnaire as a screening tool that is standardized in rheumatic diseases. For population who has limited health facility level or limited time and resources, this questionnaire would be more suited to be applied in a broad population. The consideration of COPCORD as a standardized tool, requires validation of certain aspects like diagnostic tests, especially when compared to complete examination conducted by rheumatologist.24, 25 In the other hand, the adaptation and translation into Indonesian questionnaire also have consequences in language and cultural adaptation that may be different from the original.26 Based on this fact, it is necessary to validate a modified COPCORD questionnaire Indonesian version for screening of joint pain and musculoskeletal diseases in Malang.

The aim of this study is to assess the validity of modified COPCORD questionnaire Indonesian version, for screening joint pain and musculoskeletal disease in the population compare to examination done by rheumatologist.

Original Article


MethodThis research was an analytic study using cross sectional approach, involving 100 respondents consist of Malang’s residents. Inclusion criteria for this study are all people aged over 15 years and exclusion criteria are respondents who are unwilling or unable to be interviewed and examined.The dependent variable in this study was the diagnosis of rheumatic disease, while independent variables were based on the core of the questions in the COPCORD questionnaire which are, the pain are less than 7 days and more than 7 days, high degree pain of less than 7 days and more than 7 days, history of NSAIDs/Steroids/DMARD use, and disabilities. Descriptive statistics in this study were sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio and the ROC curve of each question to the diagnosis of rheumatic disease. This questionnaire is valid if sensitivity and specificity >80%, LR+ >1 and ROC curve are more than 0.8.27 Chi square analysis method was used to analyze association between two categorical variables. Furthermore, multivariate analysis of the significant variables was done by logistic regression. The analysis was performed with SPSS software version 22.The workflow in this study displayed on picture 1:

Picture 1. Workflow of Validating COPCORD Questionnaire

This study conducted in two stage, are stage 1 is an adaptation of COPCORD questionnaire, including:a. Determine important points in COPCORD questionnaire In this step, agreement was made on some important

points such as pain, degree of pain, therapies which have been obtained and the impact of rheumatic diseases on disability. Questions about ethnicity and religion were

eliminated because the population is homogeneous and researchers believe that religion is not associated with joint pain and musculoskeletal disease. In addition, the question about the activity index is adapted from questionnaires GPPAQ28.

b. Translating COPCORD quesionnaire into Bahasa Indonesia

The next step was the translation of modified COPCORD questionnaire into Bahasa Indonesia. The translation process was carried out by researchers in join discussions with rheumatologist. Addition of question about physical activity which adapted from GPPAQ in to questionnaire was agreed by researchers. 28 Then, questionnaire was translated back into English by using a third party service from English Language Laboratory, Faculty of Medicine, Brawijaya University.

c. Questionnaire trial and researchers agreement After obtaining a good translation of the COPCORD

questionnaire into Bahasa Indonesia and evaluation on the back translation, trials conducted on questionnaires with fellow researchers and research agreements. From the test results of this questionnaire show that the words of the questionnaire can be well-received and found interview duration about 30 minutes so researchers can estimate time on the field.

On the stage-2, the community validation study was performed to evaluate the usefulness of modified COPCORD questionnaire Indonesia version to detect joint pain and musculoskeletal diseases compared to physical examination performed by rheumatologists. In this way the sensitivity and specificity of the questionnaire COPCORD compared with clinical diagnosis can be seen and whether the instrument is a good screening tool for joint pain and musculoskeletal diseases in the community.

In this research there was also reliability study to assess internal concistency with cronbach alpha and test retest method analyzed with intraclass correlation coefficient (ICC). Test retest method in this study was done by asking the same questionnaire to 15 random participants twice within 4 weeks interval. ICC value ranged from 0 until 1 and interpreted as follow: 0−0.2 indicate poor agreement: 0.3−0.4 indicate fair agreement; 0.5−0.6 indicate moderate agreement; 0.7−0.8 indicate strong agreement; and >0.8 indicate almost perfect agreement.29

Result Sample Baseline Characteristics In this research we include 100 respondents in our study. Sample baseline characteristics in this study can be seen in table 1.

Original Article


Table 1. Sample Baseline Characteristics

CharacteristicsPercentage

N = 100Rheumatic Disease

Yes 50 No 50

Pain < 7 hariYes 39 No 61

Pain >7 hariYes 52 No 48

High degree pain <7 hari (VAS >4/10)Yes 15 No 85

High degree pain >7 hari (VAS >4/10)Yes 49 No 51

History of NSAID/Steroid/DMARD useYes 58 No 42

DisabilityYes 16 No 84

Validation of COPCORD Questionnaire for the screening of Joint Pain and Musculoskeletal Disease

Validation study in the community, the aim is to see questions’ sensitivity and specificity, are: the presence of pain, degree of pain, medication history, and disability. By doing this way we can see the sensitivity and specificity of the modified COPCORD questionnaire Indonesian version compared to clinical diagnosis and investigate whether the instrument is can be used as a good screening tool for joint pain and musculoskeletal diseases in the community.

We present the results of our analysis in the form of sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratio positive (LR +), and the ROC curve (area under the receiver operating characteristic curve) on how the questions in the COPCORD questionnaire can predict clinical evaluation of rheumatic diseases can be seen in table 2. The highest results of the sensitivity among others are on the question about history of pain over 7 days (92%), high degree pain (pain with VAS> 4/10) at pain over 7 days (92%), and history of NSAIDs/steroids/DMARDs use (100%). While the highest specificity obtained on question about high degree pain on pain of less than 7 days (96%), a high degree of pain on pain of more than 7 days (94%) and the disability (98%).

Table 2. Diagnostic Test of COPCORD Questionnaire Points against Rheumatic Disease Diagnosis

COPCORDQuestions

Rheumatic Disease Diagnosis (n = 100)Sensitivity

(%)Specificity

(%)PPV (%)

NPV (%)

LR (+) ROC

Pain < 7 days 64 86 82 70 6.25 0.75Pain >7 days 92 88 88 92 4.57 0.90High degree pain <7 days

26 96 87 56 7.67 0.61

High degree pain >7 days

92 94 94 92 6.5 0.93

History of NSAID/Steroid/DMARD use

100 84 86 100 15.3 0.92

Disability 30 98 94 58 15 0.64

High degree pain: pain with visual analog scale >4/10, NSAID: Non Steroidal Anti Inflammatory Drug, DMARD: Disease Modifying Anti Rheumatoid Drug, LR (+): Positive Likelihood Ratio, ROC: area under the receiver operating characteristic curve

Picture 1. ROC Curve of COPCORD Questionnaire Points against Rheumatic Disease Diagnosis

ROC curve analysis with the results >85% obtained on the question of pain >7 days (90%), high degree pain >7 days (93%), history of NSAIDs/Steroids/DMARDs use (92%) showed a strong predictive value against rheumatic diseases diagnosis.

Additionally, LR+ >1 to the diagnosis of rheumatic disease was found in all the questions, pain in less than 7 days, history of pain more than 7 days, high degree pain of less than 7 days, history of high degree pain of more than 7 days, history of NSAIDs/steroids/DMARDs use and disability according to MHAQ. These variables were analyzed using chi square analysis showed that all the questions were significance with p <0.05 with odds ratio (OR) obtained at the most from history of high degree pain (VAS >4) more than 7 days, OR = 180.167 (95% CI 38.196−849.834). The results of bivariate analysis can be seen on table 3.

Original Article


Multivariate analysis on the questions carried out simultaneously by logistic regression do not show significant results.

Table 3. Analysis of Each COPCORD Questionnaire Points against Rheumatic Disease Diagnosis

COPCORD Questions p OR 95% CI

Pain < 7 days <0.001 10.921 4.075−29.263

Pain >7 days <0.001 84.333 22.283−319.171

High degree pain <7 days 0.002 8.432 1.791−39.698

High degree pain >7 days <0.001 180.167 38.196−849.834

History of NSAID/Steroid/ DMARD use

<0.001 - -

Disability <0.001 21.000 2.649−166.454

High degree pain: pain with visual analog scale >4/10, NSAID: Non Steroidal Anti Inflammatory Drug, DMARD: Disease Modifying Anti Rheumatoid Drug, OR: Odd Ratio, CI: Confidence Interval

The reliability study showed that cronbach alpha analysis is good in all question with coefficient ranged from 0.737 until 1.000. While analysis with ICC the result ranged from 0.754 until 1.000. The results of reliability study can be seen on table 4.

Tabel 4. Reliability Study of Each COPCORD Questionnaire Points

COPCORD QuestionsCronbach

AlphaICC p

Pain < 7 days 0.756 0.767 0.004

Pain >7 days 0.737 0.754 0.005

High degree pain <7 days 0.772 0.754 0.005

High degree pain >7 days 0.822 0.808 0.001

History of NSAID/Steroid/ DMARD use 1.000 1.000 <0.001

Disability 0.737 0.754 0.005

ICC: Intraclass Correlation Coefficient

DiscussionQuestionnaire as a tool is already frequently used in medical research. By the increasing number of multinational and multicultural research, the need of adaptation to the questionnaire which has been used in languages other than English also growing rapidly because most of the questionnaire are in English.30 The need of adaptation to the language and culture become important in Asia-Pacific because of the need of data on rheumatic diseases. Hopefully the questionnaire will produce a study about the identification of risk factors and at the same time it will ensure the uniformity of data, and if collected, could be identification of risk factors with high quality and precision. Generally, most of questionnaires were made in English but only a few population who uses English as daily language. Therefore, there was a necessary to adapt questionnaires into local language and culture.31

This study was conducted to determine the ability of modified COPCORD questionnaire Indonesian version as a screening tool for rheumatic diseases. The questionnaire was validated and applied as a screening tool to detect musculoskeletal disorders in the community, especially in developing countries like Indonesia.Until now its ability to identify patients with joint pain and musculoskeletal disease still need further investigation, especially in Indonesia. However, a similar study has been done in other COPCORD research6, 32, 33

In this study, the adaptation is done by selecting the important points which are already covered in the questionnaire COPCORD that has been validated in multiple languages before. Selection of these points affect to the removal of questions on ethnicity and religion, it because religion does not affect the joints pain and musculoskeletal diseases.34 Although ethnicity play an important role in the incidence of some joints and muskuloskeletal diseases ,34 there is no ethnic differences in people of Malang.

Besides, the modifications were made by addition question about physical activity which adapted from questionnaires GPPAQ used by the health department in the UK,34 The additional questioncan also be used to measure the level of daily activity, so we can see if there a relationship between the activities of a person with the incidence of joint pain and musculoskeletal diseases. In the UK, the questionnaire is used to assess person’s activity level, so it can give some advice to person to act an active lifestyle to avoid the various chronic and metabolic diseases caused by inactive lifestyle35.

The key points are selected in this analysis include pain in less than 7 days and more than 7 days, high degree pain in less than 7 days and more than 7 days, history of NSAIDs/Steroids/DMARDs use, and disabilities. It based on the definition of joint pain and musculoskeletal diseases are collection of symptoms include joint pain, swelling and/or limitation of motion. Therefore by asking if any joint pain in the form of signs of joint pain, and/or soft tissue/musculoskeletal pain, and/or joint swelling, and/or stiffness of the joints and/or stiffness in the spine, and/or reduced movement on any joint and/or reduced movement in spine or neck are expected to see their joint pain and musculoskeletal diseases then it would be confirmed by physical examination.

Adding a category about high degree of pain is based on the results of a previous study by Bennett, et al which was cross-cultural adaptation and validation of the questionnaire COPCORD in Mexico, originally the sensitivity and specificity of the questionnaire COPCORD was 84% and 61.3%, but by adding a category based on VAS pain score >4, the sensitivity decreased to 42.7% and the specificity increased to 80%, 36 so the researchers decided to use both components of the pain question. In this study, variable about duration of pain and high degree of pain have high sensitivity and specificity (Pain <7 days: sensitivity 64%, specificity 86%; Pain >7 days: sensitivity 92%, specificity 88%; High degree of pain <7 days: sensitivity 26 %, specificity 96%; High degree of pain > 7 days: sensitivity 92%, specificity 94%). It indicates that the questionnaire can be a good screening tool for joint pain and musculoskeletal diseases.

Original Article


Questions about the use of medicines such as NSAIDs, DMARDs and steroids also affect the diagnosis of joint and musculoskeletal disease which in patients with joint pain and musculoskeletal disease pain are the main complaint so that patients will seek treatment to relief the pain either by self treatment or by going to the doctor, and the treatment carried out in the short term or long term, depending on the patient’s perceived pain. Usually patients who have been diagnosed with joints and musculoskeletal diseases will get treatment from doctors such as pain killer or other drugs to slow or halt the disease process such as steroids or DMARD.37 The variable about history of drug use whether NSAIDs, steroids and DMARD has sensitivity 100% and specificity of 84%. It indicates that all respondents who have diagnosed joint disease and musculoskeletal disease, not all of them take drugs in accordance with indication.

Questions about disability in this study was adapted from MHAQ questionnaires, which has relationship between disability and joint pain and musculoskeletal disease.38 In this study, obtained with a sensitivity 30% and specificity 98%, illustrating that the question is specific but not sensitive to patients with a diagnosis of joint pain and musculoskeletal disease.

After determining the important points, translation and back translation was done by linguists to ensure that no significant changes during the translation process that will change the meaning or intent of the questions.

COPCORD modified questionnaire in this study can serve as a tool to measure magnitude of the epidemiology of joint pain and musculoskeletal disease and also to assess the risk factors that influences to the diseases. This questionnaireis expected not only can be used by clinicians as a screening tool for joint pain and musculoskeletal disease, but also applicable for other health professionals such as paramedics.

In a population study at Mexico by Robles, et al there are four variables which have good performance in diagnostic tests are: pain in the past 7 days, the high degree of pain, history of treatment with NSAIDs, and earlier diagnosis. However, these results vary in certain diseases, such as in Osteoarthritis (OA).. Most of significant question of OA is a pain in the last 7 days, HAQ score, and earlier diagnosis; for Rheumatic Regional Pain Syndrome (RRPS), just a pain in the last 7 days; and for Rheumatoid Arthritis (RA) (in addition to the 4 questions) are history of pain without trauma, use of NSAIDs, HAQ score, and physical limitations are reported all correlated with the diagnosis. In addition, it is estimated that the questions that have LR + ≥ 2, showed a clear correlation with the diagnosis of arthritis which can be applied at population. 25 Another study in the Philippines by Dans, et al found that the sensitivity of the COPCORD questionnaire was 91% (95% CI, 85−95) while the specificity was 51% (95% CI, 43−59).39 This association indicates that the questionnaire could be implemented as part of the referral process, start from primary care to specialist care. It is because important considerations should be noted in the screening test addition is the questions not only having adequate sensitivity but also it has high specificity.

The questionnaire in this study meet these requirements, which some variables have good sensitivity such as the

history of pain over 7 days (92%), high degree of pain (pain with VAS> 4/10) at pains over 7 days (92%), and history of drug use (NSAIDs/dsteroid/DMARD) (100%) and specificity of the question : high degree of pain which less than 7 days (96%), high degree of pain which more than 7 days (94%) and the presence of disability ( 98%), makes the questionnaire is more specific than sensitive.The result of reliability study with cronbach alpha dan ICC in this study showed good result with coefficient of Cronbach alpha ranged from 0.737 until 1.000. While ICC analysis results ranged from 0.754 until 1.000. Landis and Koch29 stated that value 0.7−0.8 indicates strong agreement; and value >0.8 indicates almost perfect agreement this result showed that the questionnaire is reliable in diagnosis of joint pain and musculoskeletal diseases.

The benefits of COPCORD questionnaire can detect a common rheumatic disease which can help patients to promptly diagnosed and treated by rheumatologists. It is becoming an alternative in developing countries where health systems are still not well organized like in Indonesia. Moreover in the first-level health facilities, efficient guides for detecting rare cases and health facilities are still inadequate. This questionnaire method in the first-level health facility is needed to be introduced for screening rheumatic disease. Woolf, et al wrote a persuasive article about prevention of musculoskeletal diseases , especially in developing countries40, and give a number of recommendations, such as: (1) effective prevention and control against musculoskeletal diseases as a priority, (2) increasing public and individual awareness about issues which relate to musculoskeletal disease such as spreading a good quality information, (3) and the need of early diagnosis the musculoskeletal disease.

The advantages of this questionnaire is easy to carry out the screening process because it requires minimal resources, so that it can reach all health professionals, especially in developing countries like in Indonesia. Therefore we can obtain epidemiological data that would support health planning system and as an initial screening for diagnosis of joint pain and musculoskeletal diseases in the wider community.

But the obstacles that may be encountered is the question-naire consist of many questions which could be make the respondent and interviewer feel bored or uncooperative during the interview process. It can be repaired with practice regularly, so the interviewer can ask nicely without makes respondents feel bored and cooperative during the interview process.

ConclusionModified COPCORD Questionnaire to Indonesian Version has been adapted and can be asa good tool in screening and detection of joint pain and musculoskeletal diseases, especially in Indonesia. This questionnaire has good sensitivity and specificity, so it can be a valid and effective tool for screening joint pain and musculoskeletal diseases compared to examination by rheumatologists

The authors suggest for the application of a modified version of the questionnaire COPCORD Indonesian in epidemiological studies especially on basic health facilities as a first step in screening for joint pain and musculoskeletal diseases in Indonesian society.

Original Article


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Prevalence of Albuminuria and Associated Factors among Gout Arthritis Patients in Cipto Mangunkusumo HospitalJeffrey Christian Mahardhika1, R.M. Suryo Anggoro2

1 Faculty of Medicine, Universitas Indonesia, 2 Rheumatology Division, Department of Internal Medicine, Fakultas Kedokteran, Universitas Indonesia.

Corresponding author: Jeffrey Christian Mahardika, [email protected]

AbstractBackground Gout arthritis associates with many comorbodities such as hyperuricemia, hypertension, hyperglycemia, obesity, and dyslipidemia, which are also factors for the development of/or predisposition factors of chronic kidney diseases (CKD). Albuminuria is a predictor factors for CKD. Screening for albuminuria is needed to be done in patients with high risk of CKD. This research was conducted to examine the prevalence of albuminuria and the associated factors in gout arthritis patients. Methods This research was a cross-sectional study from gout arthritis patients’ medical records in Cipto Mangunkusumo Hospital. We included all gout patients who treated within 2011−2015. Subjects with chronic kidney disease, in kidney replacement therapy, hypertension ≥ 10 years, and diabetes ≥ 5 years were excluded. Albuminuria was determined by urine dipstick result of protein ≥ 1+. Factors associated were age, sex, hyperuricemia, hypertension, stage of hypertension, hyperglycemia, obesity, dyslipidemia, uric acid level, and body mass index (BMI). Data associated with the factors were recorded and the associations were tested with chi square, fisher’s exact, or independent t-test.Results from 54 subjects included in this research, the prevalence of albuminuria was 20.4%. There were no significant associations between all factors and albuminuria tested by chi square and fisher’s exact test. Independent t-test’s results also showed no significant associations between all the factors and albuminuriaConclusion The prevalence of albuminuria in gout arthritis patient was 20.4%. There were no significant associatons between age, sex, hyperuricemia, hypertension, hyperglycemia, obesity, dyslipidemia, uric acid level, and body mass index (BMI) tested with albuminuria in gout arthritis patients in Cipto Mangunkusumo Hospital from 2011−2015.Keywords: Prevalence, Albuminuria, Gout Arthritis, Risk Factors

IntroductionGout arthritis is a common disease in Indonesia, 1.7% male population suffer from this disease.1 Gout arthritis is caused by the precipitation of uric acid in joints occured in hyperuricemic patients. Hyperuricemia is defined when plasma uric acid level reaches ≥ 6.8 mg/dL in normal

body temperature.2 The precipitation will lead inflammation involving complement system activation and phagocytosis. Activation of complement system makes neutrophils attracted to get out to synovial fluid compartment, while phagocytosis leads production of IL-1β through the activation of NLRP3 inflammasome. IL-1β will increase the proliferation, differentiation, and apoptosis of cells, and the influx of neutrofil to synovial fluid compartement. These processes will induce continuous inflammation, and lead the release of matrix metalloproteinase (MMP), an enzyme that can erode the bones.2,3

There are 4 phases of gout arthritis: asymptomatic, acute gout, intercritical phase, and chronic gout. Acute phase or gout attacks happens several hours with clinical symptoms, includes swollen joint and sharp pain in metatarsophalangeal I, ankle, achilles, knee, wrist, fingers, or elbow. The attack will be followed by resolution phase. Intercritical phase is an asymptomatic phase between two attacks. In several cases, intercritical phase are not found between the attacks, thus the phase is classified as chronic phase. In chronic phase, tophi can be developed in fingers, hands, knees, ankles, elbows, and antihelix.4

Gout arthritis decreases the patients’ life quality, 21.1% of the patients suffer from moderate disability.5 Gout arthritis and hyperuricemia could also induce kidney injury that will lead to a chronic kidney disease. Gout nephrolitiasis and urate nephropathy are the etiology of kidney injury in gout arthritis and hyperuricemic patients.6 Moreover, chronic kidney disease (CKD) is the most prevalent comorbidities of gout patients in Indonesia (53.08%).7 The previous statement were supported by the studies conducted by Roughley MJ, et al. 8 and Krishnan, et al. 9 The incidence of kidney injury was increasing three times in the group with serum uric acid ≥ 9.0 mg/dL and twice in the 7.0−8.9 mg/dL group.10

Gout patients often have comorbidities such as hypertension, dyslipidemia, diabetes, and obesity, which could increase the risk of developing kidney disease.9 Hypertension may induce arteriolopathy, glomerulosclerosis, and tubulointerstitial fibrosis, whereas hyperglycemia in diabetic patients could lead to diffuse mesangial sclerosis,

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hypertrophy of mesangium cells, and membrane thickening glomerulopathy.11–13 Dyslipidemia and obesity can increase the release of free radicals that could damage glomeruli capilers and mesangium cells, thus leading kidney injury.14,15 These conditions show us that gout patients are vulnerable to develop kidney injury and chronic kidney disease. Therefore, screening for chronic kidney disease is needed to be performed in all gout patients. Albuminuria is known as a screening tool for CKD and end-stage renal disease.16–18 The usage of urine dipstick with albuminuria category ≥ +1 is reported as good as albumin-creatinin ratio with category ≥ 30 mg/g.19,20 Therefore, we decided to conduct this research to find out the prevalence of albuminuria and risk factors associated in gout arthritis patients in RSUPN Cipto Mangunkusumo.

MethodsThis is a cross sectional study, done using secondary data from medical records of all patients who have diagnosed gout and treated in RSUPN Cipto Mangunkusumo between January 2011 and December 2015. Gout diagnosis is made by the rheumatologists and given code as ICD 10 (International Classification of Disease 10) of M10.0. Gout was diagnosis using diagnostic criteria in RSUPN Cipto Mangunkusumo which is also adapted from American College of Rheumatology Guideline in 1987. Patients who have history of chronic kidney disease consistent with KDIGO criteria (the presence of kidney injury and/or GFR < 60 ml/min/1.73 m2) prior or at the time when gout arthritis diagnosis made, history of diabetes mellitus ≥5 years, history of hypertension ≥10 years, and no data of dipstick urinalysis were excluded from this study.

Data collected were included age when diagnosus was made, sex, weight, height, body mass index (BMI), serum uric acid (sUA), blood glucose test (HbA1C, random blood glucose, fasting blood glucose, or 2-hours-post-prandial blood glucose), blood lipid test (HDL, LDL, total cholesterol, or triglyceride), blood pressure test, dipstick urinalysis test, history of hypertension, diabetes, dyslipidemia or other illnesses, and previous treatment related to gout arthritis and its risk factors.

Independent variables in this study were risk factors in 2 types of data: categorical and numerical. Risk factors in categorical data were defined as: sex (men/women), age (>60 years old / ≤ 60 years old), hyperuricemia (severe = sUA ≥9.0 mg/dL, mild = sUA 7.0−8.9 mg/dL, and normal = <7.0 mg/dL), obesity (BMI ≥ 25 kg/m2), hypertension (history of hypertension or consumption of hypotension agent), stage of hypertension (Stage I = systolic pressure < 160 mmHg or diastolic pressure <100 mmHg, Stage II = systolic pressure ≥ 160 mmHg atau diastolic pressure ≥ 100 mmHg), dyslipidemia (total cholesterol ≥ 240 mg/dL or LDL ≥ 160 mg/dL or HDL < 40 mg/dL or trigliserida ≥150 mg/dL or history of dyslipidemia or consumption of hypolipidemic agents), and hyperglycemia (2-hr PP ≥ 140 mg/dL or FBG ≥ 100 mg/dL or RBG ≥200 mg/dL or HbA1C >5.6% or history of diabetes mellitus or consumption of hypoglycemic agents).10,22–28 Risk factors in numerical data were serum uric acid, body mass index, and age. The dependent variabel was albuminuria, defined as urine dipstick ≥ +1 with categorical data (yes/no).18–20

All data were recorded in secondary data form made by researcher and then inserted in statistical packages for social sc i e n c e s ( S P S S ) for windows version 20.0. Independent t-test was used to analyze numerical-categorical data. Chi square test was used to analyze categorical-categorical data. Fisher’s exact test was used if the data did not meet the criteria to be analyzed by chi square test.

ResultThere were 191 patients who were diagnosed with gout or ICD 10 M10.0 during period January 2011 – December 2015, 137 samples were excluded consistent to exclusion criteria. Excluded samples were mainly due to the lack of urine dipstick data and had developed chronic kidney disease prior to the study. Other 54 patients was accounted as subjects. From these subjects, 40.4% suffered from gout arthritis less than 1 month, while 25.0% had chronic gout (more than 5 years). Tophi were developed in 38.9% subjects. Major subjects were male (88.9%) and aged below 60 years old (79.6%), with mean age was 50.80 ± 13.05 years old. Severe hyperuricemia was found in 30 subjects (58.8%) with mean serum uric acid level was 9.27 ± 2.82 mg/dL. Most subjects also suffered from dyslipidemia (72.2%). Hypertension found in 50% of subjects, 44% of them were stage-2 hypertension. As many as 40.7% of subjects suffered from hyperglycemia, while obesity happened in 44.4% of subjects, with the mean BMI was 26.69 ± 5.17 kg/m2. The prevalence of albuminuria in gout arthritis patients was 20.4% (table 1).

Table 1. Characteristics of Gout Arthritis Patients in RSUPN Cipto Mangunkusumo in 2011−2015

Characteristics N (%)Age > 60 year-old 11 (20.4%)≤ 60 year-old 43 (79.6%)Sex

Men 48 (88.9%)Hyperuricemia

Severe (≥ 9.0 mg/dL)Mild (7.0-8.9 mg/dL)Normal (< 7.0 mg/dL)No data

30 (58.8%)10 (19.6%)11 (21.6%)

3Hypertension 27 (50.0%)

Stage 1Stage 2No data

8 (40.0%)12 (60.0%)

7Hyperglycemia 22 (40.7%)ObesityDyslipidemia

24 (44.4%)39 (72.2%)

Albuminuria 11 (20.4%)Duration of Illness

< 1 month1-6 months6-12 months1-3 years3-5 years> 5 years

Missing data

21 (40.4%)1 (1.9%)7 (13.5%)4 (7.7%)6 (11.5%)13 (25.0%)

2Tophus 21 (38.9%)

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Allopurinol was the most prescribed medicine for subjects (33 patients). Metyhlprednisolone and colchicine were two other agents that were prescribed less frequent then NSAID in order to reduce the inflammation occurred in acute attack (figure 1). For hypertension treatment given to 27 subjects, angiotensin-converting enzyme inhibitor was the most anti-hypertensive agent used. Most patients (56.4%) with dyslipidemia frequently got statins rather than other agents.

Figure 1. Treatment Characteristics for Gout Arthritis Patients in RSUPN Cipto Mangunkusumo in 2011-2015

Tabel 2. Associations between Age, BMI, and Serum Uric Acid with Albuminuria

Risk factors

Albuminuria

p valueMean difference (95% CI)

Yes

(N,%)

No

(N,%)Age 56.00 ± 12.47

(11, 20.4%)49.47 ± 13.00(43, 79.6%)

0.140 6.53(-2.21 – 15.28)

UA 9.98 ± 2.94 (9, 17.7%)

9.12 ± 2.80 (42, 82.3% )

0.411 0.86(-1.23 – 2.94)

BMI 23.81 ± 2.89 (8,18.6%)

27.35 ± 5.37 (35,81.4%)

0.071 - 3.54( -7.52 – 0.45)

UA: Serum Uric Acid; BMI: Body Mass Index

Table 3. Associations between Risk Factors and Albuminuria and the Statistical Test Used

Risk FactorsAlbuminuria

Yes N (%)

NoN (%)

p OR (95% CI)

Age > 60 years old 4 (36.%) 7 (63%) 0.206 2.939

(0.675−12.798)≤ 60 years old 7 (16.3%) 36 (83.7%)Sex

MenWomen

10 (20.8%)1 (16.7%)

38 (79.2%)5 (83.3%)

1.000 1.316 (0.38−12.574)

HyperuricemiaSevere Mild and normalMissing data

6 (20.0%)3 (14.3%)

3

24 (80.0%)18 (85.7%)

0.720 1.500 (0.330−6.822)

Risk FactorsAlbuminuria

Yes N (%)

NoN (%)

p OR (95% CI)

Stage of Hypertension

Controlled and Stage 1Stage 2

0 (0.0%)

4 (33.3%)

8 (100.0%)

8 (66.7%)

0.118 Could not be computed*

HyperglycemiaYesNo

5 (22.7%)6 (18.8%)

17 (77.3%)26 (81.2%)

0.721 1.275 (0.335−4.843)

ObesityYesNoMissing data

DyslipidemiaYesNo

2 (8.3%)6 (31.6%)

11

9 (23.1%)2 (13.3%)

22 (91.7%)13 (68.4%)

30 (76.9%)13 (86.7%)

0.111

0.708

0.197 (0.035−1.123)

1.950 (0.369−10.304)

Severe hyperuricemia (≥9.0 mg/dL), mild and normal hyperuricemia (<9.0 mg/dL)* The risk of stage of hypertension couldn’t be computed as there was one cell that had 0 value

Independent T-test was used to analyze the association between age, BMI, and serum uric acid with albuminuria. It showed that there were no significant associations between all the risk factors with albuminuria (p value >0.05). However, there was quite a difference in mean age between the two groups (6.53 years; 95% CI -2.21–15.28). Moreover, the mean BMI of albuminuria group was lower than the non-albuminuria group (23.81 ± 2.89 vs 27.35 ± 5.37 kg/m2, respectively), making it more interesting because this result was contradictive to others (table 2). When other factors were analyzed by chi square and fisher’s exact test, there were no significant associations between all risk factors and albuminuria (table 3).

DiscussionThis study showed us that 88.9% subjects were men, which is similar to the study conducted by Limanjaya, et al (81.96%).7 Fewer women suffered from gout arthritis because of the estradiol effect which decrease uric acid serum level and prevent gout arthritis.29 Most of gout patients were younger than 60 years old, with mean age at 50.80 ± 13.05. It is consistent with the previous study which stated the mean gout patients at 50.5 ± 13.0 years old,30 and also consistent with theory which said that gout arthritis occurred frequently in the age of 50s.31

The mean of serum uric acid level found in this study (9.27 ± 2.82 mg/dL) was higher than in the study by Chen J, et al.32 However, this result correlates with gout pathogenesis. Patients with uric acid serum more than 8 mg/dL are more likely to suffer from monosodium urate crystallization rather than patients with lower level of uric acid serum.33 The prevalence of hyperuricemia in this study was also higher than the previous study conducted in Indonesia by Darmawan, et al. which was found only 24.3% patients. The difference might be occured because of the different subject population,

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as we conducted a hospital-based study while this previous study conducted a population-based study.1

Hypertension prevalence in this study was lower than Krishnan, et al. (93%) and Choi, et al. (69.1%). It is proved that the different of races, lifestyles, and ages of subjects are affected the prevalence of hypertension..9,34 However, the prevalence we found was higher than general Indonesian population (9.5%). This fact showed us that hypertension is more likely to happen in gout patients than in general population. It is in accordance with the result of study conducted by Yu, et al. (OR 7.21; 95% CI 7.00−7.44).35,36 The less prevalence showed by this study also happened in hyperglycemia (40.7% in this study, vs 70.8%, 48.4%, and 53.7% in Chen J, et al, Choi, et al, and Fraile, et al, respectively).32,34,37 The difference was caused by the different inclusion criteria and targeted population, which made the different races, lifestyles and characteristics of other illness between these studies.21,38–40 However, the prevalence we found was higher than general Indonesian population (10.0%).41 It indicates that hyperglycemia is also more likely to happen in gout patients than in general population.

Prevalence of dyslipidemia in subjects (72.2%) was higher than Choi, et al study (53.7% for hypertriglyceridemia and 47.4% for low HDL level) and than general Indonesia population prevalence (48.9% of low HDL level, 33.9% of high LDL level, and 24.8% of high total cholesterol level).34,42 This might be happened due to the different inclusion criteria of dyslipidemia used in this study, which include all aspects of blood lipid test, thus the findings was bigger. The other findings with higher prevalence were also occured in obesity (44.4%), with mean BMI is also higher than Chen J, et al study (23,5% and mean BMI 25.0 ± 3.2 kg/m2). The difference is happened due to the different criteria of obesity used in Chen J, et al study which defined obsesity with BMI > 27 kg/m2.32

The prevalence of albuminuria in this study (20.4%) was higher than other studies, such as Yu and Berger (14.9%)43 and Kuo, et al (9.8%).44 The difference of population, leads to the different races and lifestyles, could explain this difference. Asian race is a predisposing factor of albuminuria compared to Caucasian (OR 1.42; IK 1.26−1.61).21 Both race and lifestyle were risk factors of albuminuria which was not included in this study.21,38–40

There were no significant associations between all the risk factors with albuminuria. No significat association of albuminuria with age, sex, and other hyperuricemia factors might be happened due to the characteristic of gout patients. Gout patients are tend to be occured at the population with age 50s (in ≤ 60 years old group), men, and had severe hyperuricemia, with or without albuminuria, thus making it difficult to differentiate between the groups. The medications given to gout patients, such as allopurinol and colchicine, could also disturb the result of this study due to their protective effect to the kidney. 45–47 However, the prevalence of albuminuria was increasing from 16.3% in ≤ 60 years old group to 36.4% in the older group, which is consistent with Ramirez, et al. (adjusted OR 2.7; IK 95% 2.2−3.3).48

We found hyperglycemia had no association with albuminuria. This result was different from other studies49,50 Hyperglycemia in diabetes patients could alter the basal

membrane of glomerulus after 3−5 years.13,51 The method to determine hyperglycemia in this study could not detect a long-term hyperglycemia condition, so this could be the reason why we found no association in this study. Meanwhile, for dyslipidemia, since our study used fewer sample size than other studies, the different rate of dyslipidemia observed in this study (9.8%) can not used to detect a significant difference.26,52 Moreover, the majority of dyslipidemia patients in this study had used statin (56.4%), which could decrease the rate of albuminuria or proteinuria.53

Obesity also did not have any significant association with albuminuria. This result is also different from the others.50,52 However, the prevalence of albuminuria in obese group was lower than in non-obese group (8.3% and 31.6%, respectively). The mean BMI of albuminuria group was lower than non-albuminuria group. All patients in non-obese group which developed albuminuria had other illnesses which were associated with albuminuria, such as tuberculosis, chronic heart failure, gout nephropathy, pneumonia, and stroke.54–58

Hypertension did not have any significant assosciation with albuminuria either. This result was inconsistent with the other studies due to the different characteristics of population, sample size, and method to determine albuminuria.11,24,50,52 Moreover, most hypertension patients used angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) which can decrease the incidence of proteinuria and prevent end-stage renal disease (ESRD).59,60 All albuminuria happened in stage-2 hypertension patients. This fact was consistent with the other studies which showed that high systolic or/and high diastolic pressure were the risk factors of proteinuria.48,61 No significant association observed in this study was due to the fewer sample size and the missing data. Therefore, we recommend perform a bigger study to prove the association between hypertension (high systolic and diastolic pressures) and albuminuria in gout arthritis patients.

In spite of the fact that there were no significant association between the observed factors and albuminuria, this study showed us that there is a lot number of albuminuria occurring in gout patients. Since albuminuria has a predictive value on chronic kidney disease, the future study should seek the association between albuminuria and the incidence of chronic kidney disease in gout patients. Moreover, the fact that all gout patients who had stage-2 hypertension suffered from albuminuria were an indication that systolic and diastolic pressures were risk factors of albuminuria in gout patients. Therefore, precaution actions should be taken when dealing with gout patients who had stage-2 hypertension to prevent the progression of albuminuria. Future studies should also address the exact limit of blood pressure needed in gout patients in order to prevent the occurance of albuminuria and chronic kidney disease.

Lack of significant correlation found in this study was due to minimal sample size and data limitation, we do not assess the data of lifestyle which potentially confound the result. Thus, future studies should have a bigger sample size and measure the population’ lifestyle, as well as the other confounders like other comorbidities, and medicine taken by subjects. The use of other albuminuria test methods (albumin-creatinine ratio or

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24-hour urine collection) is suggested to get numerical data, so that it is possible for future studies to seek the correlation between the risk factors and albuminuria more accurately.

ConclusionThe prevalence of albuminuria in gout patients in RSUPN Cipto Mangunkusumo in 2011−2015 was 20.4%. There were no significant correlation between age, sex, hyperuricemia, obesity, hypertension and stage of hypertension, hyperglycemia, and dyslipidemia with albuminuria. However, the prevalence of albuminuria was considerably high, especially in patients who had stage-2 hypertension. Therefore, preventive actions to those patients and future studies related to albuminuria’s association with chronic kidney disease incidence in gout patients are needed.

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Case Report


Management of Salmonella Septic Bursitis in Renal Transplant Recipient

Albert Prasetya1, Anna Ariane2, Bambang Setyohadi2

1 Internal Medicine Residency Program, Department of Internal Medicine, Faculty of Medicine University of Indonesia, Cipto Mangunkusumo Hospital2 Rheumatology Division, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Cipto Mangunkusumo Hospital

Corresponding author: Albert Prasetya, MD, [email protected]

AbstractSalmonella as a causative agent in septic bursitis is considered rare. We report a case of 56 years old male with history of renal transplantation and using mycophenolate mofetil, cyclosporine and methylprednisolone as maintenance, admitted due to 3-week-fever associated with tenderness and swelling on left shoulder. Upon investigation, a diagnosis of septic bursitis was established. Salmonella enteritidis as the definitive causative agent was revealed. He was treated with meropenem 1g IV three times daily and levofloxacin 500 mg IV once a day for 3 weeks, followed by oral ciprofloxacin 500 mg twice a day for 2 weeks and oral metronidazole 500 mg three times a day for 1 week with a total duration of 5 weeks of antibiotics. On the subsequent follow up there was no recurrence episode of fever and the swelling of the left shoulder subsided, no tenderness noted and the patient has no limitation of range of movement. Since immunocompromised state complicates the management, the duration of therapy may twice longer than the typical management of septic bursitis. Salmonella as etiologic agent should be considered as differential in immunocompromised patient with septic bursitis.Keywords: Immunocompromised state, septic bursitis, deep bursae, Salmonella, duration of therapy.

IntroductionBursae is an enclosed sac which contains a small amount of synovial fluid, lined with a cellular membrane similar to synovium.1-3,7 Bursae may be divided based on its location into superficial and deep. Septic bursitis on deep bursae may occurred in patients with bacteremia and more common in the immunocompromised state.2-8,16,20 The patient is in immunosuppressive therapy on mycophenolate mofetil and cyclosporine secondary to post renal transplantation.

Septic bursitis refers to inflammation of the bursae which is due to infection, typically resulting from bacterial inoculation either direct (e.g puncture wound), spread from nearby soft tissues (e.g, cellulitis), or hematogenous (e.g, bacterial endocarditis). Mycobacteria, fungi, or algae are less common as the causative agents.

The most common cause of septic bursitis both in immunocompetent or immunocompromised population mentioned in some references is Staphylococcus aureus (>80%) followed by Streptococcus.2,6,12,16 Salmonella as an etiologic agent in septic bursitis is rare and reported in less than 1% as an infectious cause in bone and joint infection.20 In this case report, we present a case of septic bursitis in immunocompromised patient with Salmonella enteritidis as the causative agent.

Case ReportA 56 years old male with a history of renal transplantation and using mycophenolate mofetil (2x250 mg), cyclosporine (2x25 mg), and methylprednisolone (2 mg, q48h) as maintenance, presented with a chief complaint of fever associated with left shoulder tenderness for 3 weeks prior to admission. Initially, he got recurrent fever for 1 week and more frequent at night. He was medicated himself with over the counter medicine, no consult to physician was done. Three weeks prior to admission, he began complaining of left shoulder stiffness and swelling. He was consult to a physician, upon ultrasound examination revealed fluid accumulation on his left shoulder. Fluid aspiration culture result shown Salmonella spp. Then, He was referred to Cipto Mangunkusumo General Hospital for further evaluation and management.

On physical examination, temperature of his body was 38.5 0C and other vital signs were normal. The patient was able to walk, but he had an obvious pain and fatigue. His left shoulder was swollen and fluctuation, limited of range of movement, no wound puncture or sign of skin infections either on the left shoulder or other parts of the body.

Upon admission, accumulation of fluid on subacromion subdeltoid bursa was found by ultrasound, fluid aspiration was yellow and cloudy fluid (Figure 1). Fluid analysis shown 208440 cells/µl with 94% neutrophils (Table 1 and Table 2). A culture of the bursa aspirate revealed Salmonella enteritidis. Then the patient was given meropenem 1g IV q8h and levofloxacin 500 mg IV once a day for three weeks. Mycophenolate mofetil and cyclosporine was continued.

Case Report


Table 1. Laboratory examination result

Parameters Result ReferenceHb 9.1 g/dL 13−16 g/dLHt 26.5% 40−48%MCV 71 fL 82−92 fLMCH 24.4 pg 27−31 pgWBC 4.85x103 /µL 5−10 x 103 /µLPlatelets 129000 150000−400000Diff countEosinophil 1.4% 1−3%Neutrophil 48.3% 52−76%Lymphocyte 37.9% 20−40%Monocyte 12.2% 2−8%

Ureum 47 mg/dL <50 mg/dLCreatinine 1.00 mg/dL 0.8−1.3 mg/dLeGFR 83.8 mL/min/1.73 m2 79−117 mL/min/1,73 m2

Na 148 mEq/L 132−147 mEq/LK 3.8 mEq/L 3.3−5.4 mEq/LProcalcitonin 1.07 ng/mL <0.05 ng/mL

Hb: Hemoglobin; Ht: Hematocrite; MCV: Mean Corpuscular Volume; MCH: Mean Corpuscular Hemoglobin; WBC: White Blood Cells; eGFR: Estimated Glomerular Filtration Rate; Na: Sodium; K: Potassium

Table 2. Bursal fluid analysis

Test Reference ResultMacroscopicColor Colorless BrownClarity Clear CloudyViscosity <4 cmMucin clot test Negative PoorMicroscopicCell count 208440/µLDiff. countPMN (segment) 196680 (94%)/µLMN (lymphocyte) 11760.0 (0.05%)/µLCrystals No uric crystals foundFluid Protein 8.0Fluid Glucose 80Fluid uric acid 6Serum uric acid 3.5−7.2 4.0Rheumatoid Factor <11

PMN: Polymorphonuclear cells; MN: Mononuclear cells

During hospitalization, there was no recurrence episode of fever and swelling on the left shoulder. MRI (Magnetic Resonance Imaging) on left shoulder shown abscess formation with M. supraspinatus, tendon of M. biceps brachii and left subacromial bursa involvement. After 3 weeks of hospitalization, ultrasound examination revealed no fluid accumulation in subacromial subdeltoid bursae (Figure 2). Antibiotics shifted to oral ciprofloxacin 500 mg twice a day for 2 weeks and metronidazole 500 mg thrice a day for 1 week, hence discharged. Three weeks after discharged, there was no recurrence episode of fever and the swelling on the left shoulder subsided, no tenderness noted and the patient has no limitation of range of movement.

Figure 1. Ultrasound of the left shoulder, prior aspiration (left) and on aspiration (right)

Figure 2. MRI of the left shoulder

Figure 3. Photos taken after 3 weeks of antibiotic course.The left shoulder swelling subsided.

DiscussionBursitis is an inflammation or degeneration of the sac-like structures which form in utero to protect the soft tissues from underlying bony prominences.9 Septic bursitis refers to inflammation of the bursae which is cause infection. Septic bursitis on deep bursae may have been occurred in patients with bacteremia which is more common in the immunocompromised state.2-8,16,20 Direct inoculation to deep bursae (e.g, subacromial, iliopsoas, trochanter bursae) is rare although iatrogenic infections may occur through injection procedure to the bursa, intra articular injection, acupuncture.16,17 If no direct inoculation or iatrogenic course found, hematogenous seeding and impaired response to infection as one of the predisposing factor must be considered.16 In our report, the patient is taking immunosuppressive agent (i.e mycophenolate mofetil, cyclosporine and methylprednisolone).

The definitive pathogen in this case is Salmonella enteritidis inoculated from the infected bursa. Salmonella is

Case Report


considered rare as a causative agent in both septic bursitis and septic arthritis.4,5,18,20 Sky et al, in his report mentioned the Salmonella as etiologic agent in bone and joint infection in <1% of cases.20 The peak incidence of nontyphoidal salmonella (NTS) is on rainy season in tropical climates, and during the warmer months in temperate climates, coinciding with the peak in foodborne outbreaks.18 The mortality and morbidity is significant in immunocompromised populations. Transmission is most commonly associated with animal food products, especially egg, poultry, undercooked ground meat, dairy products, and fresh produce contaminated with animal waste.18 More than 8% of this infection causes bacteremia.13

Diagnostic approach in septic bursitis includes history and physical examination. Ultrasound, CT scan, MRI, are tools which help in defining bursal effusion within deep bursae. Bursal fluid aspiration is indicated if effusions and septic bursitis are present or suspected. Laboratory analysis of bursal fluid consists determination of the nucleated cell count (white cell count), gram stain, and culture for bacteria.7,16 Immunocompromised hosts may have more limited inflammatory response. A threshold for bursal leukocytosis of >2000/mm3 [>2.0 x 109/L] was noted to have a sensitivity and specificity for septic bursitis of 94 % and 79 %, respectively, in a study of 36 patients with olecranon or prepatellar bursitis. The sensitivity of gram stain ranges from 15 − 100 %. Bursal fluid glucose utility is uncertain, the majority of patients with septic bursitis have a low glucose level defined as serum glucose ratio <50%.16

Overall, management of septic bursitis includes antibiotic therapy, drainage, and surgical intervention.14 In our case, we administered antibiotic therapy and drainage. The differentiation of management in immunocompetent and immunocompromised host is the duration of antibiotic therapy. The immunosuppressive agents taken by the patient complicates the treatment. Duration of antibiotic therapy in septic bursitis is determined by the clinical response, microbiologic findings, and patient’s general conditions. In general, antibiotic therapy is given in 2−3 weeks duration and more prolonged between 4 and 6 weeks in more serious infection in compromised host or even three times longer.2,14-16,19 Hirsansuthikul et al, 2016 reported antibiotic duration for 5 weeks in management of septic bursitis in HIV patients.3 Olut et al, 2012 in his case report giving antibiotics for 8 weeks in managing septic arthritis of hip caused S.Typhi in a multiple sclerosis patient who was under steroid therapy.5 Both of the reports give an excellent follow up with no significant residual lesion.3,5 In our report, we administered meropenem 3x1g IV, levofloxacin 1x500 mg IV as guided by the culture results for 3 weeks, followed by oral ciprofloxacin 2x500 mg for 2 weeks and oral metronidazol 3x500 mg for 1 week with a total duration of 5 weeks. On subsequent follow up, the patient reported no recurrence of fever, improvement on the left shoulder tenderness and range of movement, the swelling is subsided.

ConclusionSeptic bursitis is referred as a condition of infection in bursa which may occur from direct inoculation, iatrogenic cause from joint aspiration, or hematogenic seeding from bacteremia. Septic bursitis on deep bursae may have been occurred in patients with bacteremia which is more common in the immunocompromised state. Salmonella is considered rare as a causative agent in both septic bursitis and septic arthritis, more than 8% of this infection causes bacteremia. Bursal fluid analysis and culture may confirm the diagnosis. Immunocompromised state complicates the management of septic bursitis, hence the duration of therapy may twice longer than the typical duration in the immunocompetent host.

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